Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Na].[N+:2]([NH:5][C:6]([NH2:8])=[NH:7])([O-:4])=[O:3].CC[O:11][C:12]([CH:14]1[C:19](=O)[CH2:18][CH2:17][CH2:16][CH2:15]1)=O>CO>[N+:2]([NH:5][C:6]1[NH:8][C:12](=[O:11])[C:14]2[CH2:19][CH2:18][CH2:17][CH2:16][C:15]=2[N:7]=1)([O-:4])=[O:3]
Reactant: CCOC(=O)C1CCCCC1=O
Reactant: N=C(N)N[N+](=O)[O-]
Agent: [Na]
Solvent: CO
Product: O=c1[nH]c(N[N+](=O)[O-])nc2c1CCCC2
Reaction time: 0.75 h
Yield: 83.8 %

Procedure:
To 14 ml of methanol, 256 mg of sodium was added at room temperature under stirring, then 1.04 g of nitroguanidine was added, followed by 45 minutes' heating under reflux. Successively, 1.70 g of ethyl 2-cyclohexanonecarboxylate was added, followed by 9 hours' heating under reflux. After cooling the reaction mixture, the solvent was distilled off under reduced pressure. Water was added to the residue, and the system was acidified with acetic acid. The precipitate was recovered by filtration and dried to provide 1.76 g (84%) of 2-nitroamino-5,6,7,8-tetrahydro-3H-quinazolin-4-one.
Reaction SMILES: [OH:1][C@H:2]([C:38]1[C:46]2[S:45][C:44](=[O:47])[NH:43][C:42]=2[C:41]([OH:48])=[CH:40][CH:39]=1)[CH2:3][N:4]([CH2:12][CH2:13][S:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][N:21]1[CH2:37][CH2:36][C:24]2([O:29][CH2:28][CH2:27][N:26](C(=O)C(F)(F)F)[CH2:25]2)[CH2:23][CH2:22]1)[C:5](=[O:11])[O:6][C:7]([CH3:10])([CH3:9])[CH3:8].C(=O)([O-])[O-].[K+].[K+]>CO.O>[O:29]1[C:24]2([CH2:23][CH2:22][N:21]([CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][S:14][CH2:13][CH2:12][N:4]([CH2:3][C@H:2]([OH:1])[C:38]3[C:46]4[S:45][C:44](=[O:47])[NH:43][C:42]=4[C:41]([OH:48])=[CH:40][CH:39]=3)[C:5](=[O:11])[O:6][C:7]([CH3:10])([CH3:9])[CH3:8])[CH2:37][CH2:36]2)[CH2:25][NH:26][CH2:27][CH2:28]1
Reactant: CC(C)(C)OC(=O)N(CCSCCCCCCN1CCC2(CC1)CN(C(=O)C(F)(F)F)CCO2)C[C@H](O)c1ccc(O)c2[nH]c(=O)sc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CO
Product: CC(C)(C)OC(=O)N(CCSCCCCCCN1CCC2(CC1)CNCCO2)C[C@H](O)c1ccc(O)c2[nH]c(=O)sc12
Temperature: 25 °C
Reaction time: 17 h

Procedure:
To a stirring solution of (R)-tert-butyl 2-hydroxy-2-(4-hydroxy-2-oxo-2,3-dihydrobenzo[d]thiazol-7-yl)ethyl(2-(6-(4-(2,2,2-trifluoroacetyl)-1-oxa-4,9-diazaspiro[5.5]undecan-9-yl)hexylthio)ethyl)carbamate (example 101, step f) (0.18 g) in methanol (10 mL) was added a solution of potassium carbonate (0.06 g) in water (10 mL). The mixture was stirred at RT for 17 h then the methanol was removed under a stream of nitrogen. The solution was diluted with brine, extracted with ethyl acetate (×3) and dried over sodium sulfate, filtered and evaporated in vacuo. The residue was dissolved in methanol and evaporated in vacuo to give the subtitled compound as a brown glass. Yield 0.15 g.
Reaction SMILES: [O:1]1CCO[CH:2]1[C:6]1[C:11]([NH2:12])=[CH:10][C:9]([F:13])=[CH:8][N:7]=1.[Cl-].[Li+]>CS(C)=O.O>[NH2:12][C:11]1[C:6]([CH:2]=[O:1])=[N:7][CH:8]=[C:9]([F:13])[CH:10]=1
Reactant: Nc1cc(F)cnc1C1OCCO1
Agent: [Cl-]
Agent: [Li+]
Solvent: CS(C)=O
Solvent: O
Product: Nc1cc(F)cnc1C=O
Temperature: 90 °C

Procedure:
To a solution of 2-(1,3-dioxolan-2-yl)-5-fluoropyridin-3-amine (5 g, 27.14 mmol) in DMSO: H2O (1:1) (162 mL) was added lithium chloride (6.9 g, 162.89 mmol). The reaction mixture was heated to 90° C. for 16 h and water was removed using dean-stark apparatus. Water was added to the reaction mass and extracted with EtOAc. Organic layer was washed with brine and dried over Na2SO4. The organic layer was concentrated in vacuo and purified by column chromatography on silica gel using 0-40% EtOAc in hexane to give 3-amino-5-fluoropicolinaldehyde: 1H NMR (400 MHz, DMSO-d6): δ 7.003-7.037 (m, 1H), 7.387 (br s, 2H), 7.944 (d, 1H, J=2.4 Hz), 9.853 (s, 1H); LC-MS (ESI) m/z 141.0 [M+H]+.
Reaction SMILES: [C:1]([O:4][CH2:5][CH2:6][CH2:7][N:8]1[C:13](=[O:14])[C:12]2[NH:15][C:16]([C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([O:25][C:26]([F:29])([F:28])[F:27])[CH:20]=3)=[C:17]([CH3:18])[C:11]=2[N:10]([CH3:30])[C:9]1=[O:31])(=[O:3])[CH3:2].[Cl:32][C:33]1[CH:38]=[CH:37][C:36]([CH2:39]Cl)=[CH:35][CH:34]=1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.CC(=O)OCC.[Cl-].[Na+].O>[C:1]([O:4][CH2:5][CH2:6][CH2:7][N:8]1[C:13](=[O:14])[C:12]2[N:15]([CH2:39][C:36]3[CH:37]=[CH:38][C:33]([Cl:32])=[CH:34][CH:35]=3)[C:16]([C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([O:25][C:26]([F:27])([F:28])[F:29])[CH:20]=3)=[C:17]([CH3:18])[C:11]=2[N:10]([CH3:30])[C:9]1=[O:31])(=[O:3])[CH3:2]
Reactant: CC(=O)OCCCn1c(=O)c2[nH]c(-c3cccc(OC(F)(F)F)c3)c(C)c2n(C)c1=O
Reactant: ClCc1ccc(Cl)cc1
Agent: O=C([O-])[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(=O)OCCCn1c(=O)c2c(c(C)c(-c3cccc(OC(F)(F)F)c3)n2Cc2ccc(Cl)cc2)n(C)c1=O
Temperature: 85 °C
Yield: 66.7 %

Procedure:
To a solution of 3-(1,7-dimethyl-2,4-dioxo-6-(3-(trifluoromethoxy)phenyl)-1H-pyrrolo[3,2-d]pyrimidin-3(2H,4H,5H)-yl)propyl acetate (See Compound 36, Step 2, 140 mg, 0.319 mmol) in DMF (2 mL) was added 1-chloro-4-(chloromethyl)benzene (102.6 mg, 0.637 mmol) followed by K2CO3 (132.1 mg, 0.956 mmol). The reaction was heated at 85° C. for 2 h, cooled to RT then diluted with EA (10 mL) and brine (5 mL). The organic layer was washed with aqueous 1N LiCl (3×20 mL), dried over Na2SO4 and concentrated to give 3-(5-(4-chlorobenzyl)-1,7-dimethyl-2,4-dioxo-6-(3-(trifluoromethoxy)phenyl)-1H-pyrrolo[3,2-d]pyrimidin-3(2H,4H,5H)-yl)propyl acetate (120 mg, 66.7% yield) LCMS: MH+ 564 and TR=2.151 min. Used without further purification.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]([N:10]2[CH2:15][CH2:14][C@:13]([CH2:22][C:23]3([CH3:26])[CH2:25][O:24]3)([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[O:12][C:11]2=[O:27])[CH3:9])=[CH:4][CH:3]=1.O1CCCC1.C([BH-](CC)CC)C.[Li+].OO>O.C(OC)(C)(C)C>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]([N:10]2[CH2:15][CH2:14][C@:13]([CH2:22][C:23]([OH:24])([CH3:25])[CH3:26])([C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=3)[O:12][C:11]2=[O:27])[CH3:9])=[CH:4][CH:3]=1
Reactant: C[C@@H](c1ccc(Br)cc1)N1CC[C@](CC2(C)CO2)(c2ccccc2)OC1=O
Agent: CC[BH-](CC)CC
Agent: OO
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Solvent: COC(C)(C)C
Product: C[C@@H](c1ccc(Br)cc1)N1CC[C@](CC(C)(C)O)(c2ccccc2)OC1=O
Temperature: 2.5 °C

Procedure:
To a 2.0 L 3-neck oven-dried RBF was charged the crude (S)-3-[(S)-1-(4-bromo-phenyl)-ethyl]-6-(2-methyl-oxiranylmethyl)-6-phenyl-perhydro-1,3-oxazin-2-one (7) and 750 mL of anhydrous tetrahydrofuran. The resulting solution was agitated and cooled to Tint=2-3° C. To the agitated clear solution was charged 1.0 M lithium triethylborohydride in tetrahydrofuran (Super Hydride, 348 mL, 348 mmol, 1.8 equiv). The addition is exothermic and addition controlled to maintain Tint=<8° C. The resulting solution was agitated at Tint=2-3° C. for 1.5 h and then allowed to warm to Tint=10-13° C. over a 2.5 h, which HPLC analysis indicates ˜94 A % (220 nm) conversion. To the agitated solution was charged a solution of hydrogen peroxide (95.7 mL of a 35 wt % aqueous solution diluted with 400 mL of water, 1.08 mol, 5.60 equiv). The addition is highly exothermic and addition controlled to maintain Tint=<25° C. The resulting solution was diluted with 1.00 L of methyl tert-butyl ether (MTBE) and washed with 1.00 L of water followed by 500 mL of a ˜30 wt % solution of sodium thiosulfate. The organic solution was dried with anhydrous sodium sulfate, filtered, and then concentrated via reduced pressure. The resulting material was subjected to flash silica chromatography (10-60% ethyl acetate, 600 g of silica) to produce 68 g of material consisting of both diastereomers (1.98:1 dr) and 41 g of the desired diastereomer (>99:1 dr). The material consisting of the mixed fractions was recrystallized from 250 mL of isopropyl acetate (IPAC) and 200 mL of heptane (anti-solvent) to produce upon filtration 31.3 g of product (95.7 A % at 220 nm, 74:1 dr). The two samples were combined to produce 72.3 g of product (83.6% yield for the two step operation). Analytical data for 8: 1H-NMR spectroscopy (400 MHz, CDCl3) δ 7.37-7.29 (m, 5H), 7.25-7.21 (m, 2H), 6.82-6.79 (m, 2H), 5.61 (q, J=6.9 Hz, 1H), 2.83 (ddd, J=2.5, 5.4 and 11.6 Hz, 1H), 2.39 (ddd, J=5.7, 12.0 and 14.1 Hz, 1H), 2.27 (ddd, J=2.6, 4.8 and 14.0 Hz, 1H), 2.21-2.14 (m, 3H), 2.08 (s, 1H), 1.49 (d, J=7.0 Hz, 3H), 1.18 (s, 3H), 1.13 (s, 3H). 13C-NMR spectroscopy (100 MHz, CDCl3) δ 153.2, 142.6, 138.5, 131.6, 129.13, 129.10, 128.0, 125.3, 121.6, 84.2, 71.4, 54.1, 53.3, 36.4, 33.6, 32.1, 30.8, 15.6.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([S:14]([C:17]2[CH:22]=[CH:21][C:20]([C:23]([F:26])([F:25])[F:24])=[CH:19][CH:18]=2)(=[O:16])=[O:15])[C@@H:10]([C:27](=[O:42])[NH:28][CH2:29][C:30]2[CH:35]=[CH:34][C:33]([O:36][C:37]([F:40])([F:39])[F:38])=[C:32]([F:41])[CH:31]=2)[CH2:9]1)=O)(C)(C)C.[ClH:43].O1CCOCC1>O1CCOCC1>[ClH:43].[F:41][C:32]1[CH:31]=[C:30]([CH:35]=[CH:34][C:33]=1[O:36][C:37]([F:40])([F:38])[F:39])[CH2:29][NH:28][C:27]([C@H:10]1[CH2:9][NH:8][CH2:13][CH2:12][N:11]1[S:14]([C:17]1[CH:22]=[CH:21][C:20]([C:23]([F:26])([F:25])[F:24])=[CH:19][CH:18]=1)(=[O:15])=[O:16])=[O:42]
Reactant: CC(C)(C)OC(=O)N1CCN(S(=O)(=O)c2ccc(C(F)(F)F)cc2)[C@@H](C(=O)NCc2ccc(OC(F)(F)F)c(F)c2)C1
Agent: Cl
Solvent: C1COCCO1
Product: O=C(NCc1ccc(OC(F)(F)F)c(F)c1)[C@H]1CNCCN1S(=O)(=O)c1ccc(C(F)(F)F)cc1
Temperature: 25 °C

Procedure:
To a solution of the compound (60 mg) obtained in Step 4 in 1,4-dioxane (0.6 ml) was added 4N hydrogen chloride/1,4-dioxane solution (0.6 ml) with stirring at room temperature. After stirring at room temperature for 2 days, the reaction mixture was concentrated under reduced pressure. Toluene was added to the residue, and the mixture was concentrated again under reduced pressure to give a crude product (about 0.095 mmol) containing the title compound as a main component. The obtained crude product was directly used for the next reaction.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][CH:6]=[C:5]2[N:12]1[CH2:17][CH2:16][O:15][CH2:14][CH2:13]1.C([Li])CCC.CN(C)[CH:25]=[O:26]>C1COCC1.[Cl-].[NH4+]>[N:12]1([C:5]2[C:4]3[C:9](=[CH:10][CH:11]=[C:2]([CH:25]=[O:26])[CH:3]=3)[N:8]=[CH:7][CH:6]=2)[CH2:17][CH2:16][O:15][CH2:14][CH2:13]1
Reactant: Brc1ccc2nccc(N3CCOCC3)c2c1
Reactant: CN(C)C=O
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Product: O=Cc1ccc2nccc(N3CCOCC3)c2c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 44.5 %

Procedure:
To a solution of 6-bromo-4-morpholin-4-ylquinoline (1.06 g, 3.62 mmol) in THF (22 mL) was added dropwise a 2.5M solution of n-butyllithium in hexanes (1.74 mL, 4.34 mmol, 1.2 equiv.) at −70° C. During the addition, the color of the solution was turned into red and this solution was stirred for 1 h at this temperature. Then, a solution of dimethylformamide (0.558 mL, 7.23 mmol) in THF (2 mL) was added dropwise. After addition, the mixture was allowed to warm to room temperature and stirred for 2 h. Then, the mixture was diluted with saturated ammonium chloride solution and the two layers were separated. The aqueous layer was extracted with ethyl acetate (3×50 mL). The combined organic extracts were washed with brine solution and dried over anhydrous magnesium sulfate. Filtration of the drying agent and removal of the solvent under the vacuum gave the crude residue which was purified by using a Biotage silica gel column chromatography to afford 0.390 g (44.5% yield) of 4-morpholin-4-yl-quinoline-6-carbaldehyde as a white solid: EI-LRMS m/e calcd for C14H14N2O2 (M+) 243.1, found 243.1.
Reaction SMILES: Br[C:2]1[C:3]([NH:8][C:9](=[O:11])[CH3:10])=[N:4][CH:5]=[CH:6][CH:7]=1.[CH2:12]([Sn](CCCC)(CCCC)C=C)[CH2:13]CC>C1(C)C=CC=CC=1.C([O-])(O)=O.[Na+].Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH:12]([C:2]1[C:3]([NH:8][C:9](=[O:11])[CH3:10])=[N:4][CH:5]=[CH:6][CH:7]=1)=[CH2:13]
Reactant: CC(=O)Nc1ncccc1Br
Reactant: C=C[Sn](CCCC)(CCCC)CCCC
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: Cc1ccccc1
Product: C=Cc1cccnc1NC(C)=O
Temperature: 95 °C
Yield: 46.4 %

Procedure:
To a stirred mixture of N-(3-Bromo-pyridin-2-yl)-acetamide (1.20 g, 5.58 mmol) in anhydrous toluene (40 mL) under argon was added Tri-n-butyl(vinyl)tin (3.25 mL, 11.1 mmol) and Bis(triphenylphosphine)Palladium dichloride (0.40g, 0.57 mmol). This mixture was heated at 95° C. for 30 minutes and cooled to room temperature. This mixture was then diluted with saturated NaHCO3 solution (100 mL) and extracted with EtOAc (3×120 mL). The combined EtOAc extracts were dried (MgSO4), filtered and concentrated in vacuo. This was purified by a ISCO auto CombiFlash with a RediSep 35 g column, eluted with CH2Cl2-EtOAc, detected at 220 nM to give 420 mg of N-(3-Vinyl-pyridin-2-yl)-acetamide 78C in 46% yield.
Reaction SMILES: C(C1N=C(N2CCOCC2)C2N=NN(CC3C=CC=CC=3Cl)C=2N=1)(C)(C)C.[C:28]([C:32]1[N:33]=[C:34](Cl)[C:35]2[N:40]=[N:39][N:38]([CH2:41][C:42]3[CH:47]=[CH:46][CH:45]=[CH:44][C:43]=3[Cl:48])[C:36]=2[N:37]=1)([CH3:31])([CH3:30])[CH3:29].Cl.[F:51][C:52]1([F:59])[CH2:56][NH:55][C@@H:54]([CH2:57][OH:58])[CH2:53]1>>[C:28]([C:32]1[N:33]=[C:34]([N:55]2[CH2:56][C:52]([F:59])([F:51])[CH2:53][C@@H:54]2[CH2:57][OH:58])[C:35]2[N:40]=[N:39][N:38]([CH2:41][C:42]3[CH:47]=[CH:46][CH:45]=[CH:44][C:43]=3[Cl:48])[C:36]=2[N:37]=1)([CH3:31])([CH3:30])[CH3:29]
Reactant: CC(C)(C)c1nc(Cl)c2nnn(Cc3ccccc3Cl)c2n1
Reactant: OC[C@H]1CC(F)(F)CN1
Agent: CC(C)(C)c1nc(N2CCOCC2)c2nnn(Cc3ccccc3Cl)c2n1
Agent: Cl
Product: CC(C)(C)c1nc(N2CC(F)(F)C[C@@H]2CO)c2nnn(Cc3ccccc3Cl)c2n1

Procedure:
In analogy to the procedure described for the synthesis of 5-tert-butyl-3-(2-chlorobenzyl)-7-morpholin-4-yl-3H-[1,2,3]triazolo[4,5-d]pyrimidine (example 1, step c), the title compound was prepared from 5-tert-butyl-7-chloro-3-(2-chlorobenzyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine and (R)-(4,4-difluoropyrrolidin-2-yl)methanol hydrochloride and isolated as white solid. MS (m/e): 437.3 (MH+).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]([C@H:13]2[CH2:18][CH2:17][C@H:16]([OH:19])[CH2:15][CH2:14]2)[CH3:12])(=[O:10])=[O:9])=[CH:4][CH:3]=1.Cl.[CH2:21]([N:23]([CH2:27][CH3:28])[CH2:24][CH2:25]Cl)[CH3:22].[OH-].[Na+]>C1(C)C=CC=CC=1.[N+](CCCC)(CCCC)(CCCC)CCCC.[O-]S(O)(=O)=O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]([C@H:13]2[CH2:18][CH2:17][C@H:16]([O:19][CH2:22][CH2:21][N:23]([CH2:27][CH3:28])[CH2:24][CH3:25])[CH2:15][CH2:14]2)[CH3:12])(=[O:9])=[O:10])=[CH:4][CH:3]=1
Reactant: CCN(CC)CCCl
Reactant: CN([C@H]1CC[C@H](O)CC1)S(=O)(=O)c1ccc(Br)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: Cl
Agent: O=S(=O)([O-])O
Solvent: Cc1ccccc1
Product: CCN(CC)CCO[C@H]1CC[C@H](N(C)S(=O)(=O)c2ccc(Br)cc2)CC1
Temperature: 25 °C

Procedure:
To 350 mg (1 mmol) trans-4-Bromo-N-(4-hydroxy-cyclohexyl)-N-methyl-benzenesulfonamide in 6 ml toluene was added 344 mg (2.0 mmol) 2-diethylamino-ethylchlorid.hydrochloride and a catalytic amount of Bu4NHSO4 followed by 4 ml 50% NaOH. The mixture was stirred at RT over night, the phases were separated and the organic phase dried over Na2SO4. Column chromatography on silica gel with CH2Cl2/MeOH 15:1 yielded 380 mg (84%) trans-4-Bromo-N-[4-(2-diethylamino-ethoxy)-cyclohexyl]-N-methyl-benzenesulfonamide as light yellow oil, MS: 447 (MH+, 1Br).
Reaction SMILES: [C:1](Cl)(=[O:4])[CH:2]=[CH2:3].[CH3:6][N:7]([CH3:39])[CH2:8][CH2:9][N:10]([CH3:38])[C:11]1[C:12]([NH2:37])=[CH:13][C:14]([NH:19][C:20]2[N:25]=[C:24]([C:26]3[C:34]4[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=4)[N:28]([CH3:35])[CH:27]=3)[C:23]([CH3:36])=[CH:22][N:21]=2)=[C:15]([O:17][CH3:18])[CH:16]=1.CCN(C(C)C)C(C)C>C1COCC1.O>[CH3:39][N:7]([CH3:6])[CH2:8][CH2:9][N:10]([CH3:38])[C:11]1[CH:16]=[C:15]([O:17][CH3:18])[C:14]([NH:19][C:20]2[N:25]=[C:24]([C:26]3[C:34]4[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=4)[N:28]([CH3:35])[CH:27]=3)[C:23]([CH3:36])=[CH:22][N:21]=2)=[CH:13][C:12]=1[NH:37][C:1](=[O:4])[CH:2]=[CH2:3]
Reactant: COc1cc(N(C)CCN(C)C)c(N)cc1Nc1ncc(C)c(-c2cn(C)c3ccccc23)n1
Reactant: C=CC(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: C1CCOC1
Product: C=CC(=O)Nc1cc(Nc2ncc(C)c(-c3cn(C)c4ccccc34)n2)c(OC)cc1N(C)CCN(C)C
Temperature: 0 °C
Reaction time: 1 h
Yield: 56.6 %

Procedure:
Acryloyl chloride (0.026 mL, 1M in THF, 0.32 mmol) was added dropwise to a mixture of N1-(2-dimethylaminoethyl)-5-methoxy-N1-methyl-N4-[5-methyl-4-(1-methylindol-3-yl)pyrimidin-2-yl]benzene-1,2,4-triamine (Intermediate 81, 147 mg, 0.32 mmol) and DIPEA (0.061 mL, 0.35 mmol) in THF (15 mL) at 0° C. under N2. The resulting suspension was stirred at 0° C. for 1 h then allowed to warm to r.t. The mixture was then diluted with water (15 mL) and concentrated in vacuo. The resulting material was dissolved in a mixture of CH2Cl2 (20 mL) and CH3OH (5 mL). The resulting solution was washed with water and sat. brine, and was then dried (MgSO4) and concentrated in vacuo. Purification by FCC, eluting with 1-8% 7M methnaolic ammonia in CH2Cl2 gave a yellow dry film after concentrating the appropriate fractions in vacuo. This material was dissolved in CH2Cl2 and the resulting solution was diluted with diethyl ether. This was concentrated in vacuo and dried to give the title compound (93 mg, 57%) as a beige solid; 1H NMR: 2.21 (6H, s), 2.28-2.34 (2H, m), 2.37 (3H, s), 2.73 (3H, s), 2.89 (2H, t), 3.81 (3H, s), 3.89 (3H, s), 5.72 (1H, dd), 6.19 (1H, dd), 6.38 (1H, dd), 7.02 (1H, d), 7.06 (1H, d), 7.18-7.23 (1H, m), 7.48 (1H, d), 7.91 (1H, s), 8.06 (1H, s), 8.22 (1H, s), 8.36 (1H, d), 8.75 (1H, s), 10.11 (1H, s); m/z: ES+ MH+ 514.36.
Reaction SMILES: [NH:1]1[C:5]2=[CH:6][N:7]=[CH:8][CH:9]=[C:4]2[CH:3]=[CH:2]1.Br[C:11]1[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][CH:12]=1.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>O1CCOCC1.[Cu]I>[Cl:17][C:14]1[CH:15]=[CH:16][C:11]([N:1]2[C:5]3=[CH:6][N:7]=[CH:8][CH:9]=[C:4]3[CH:3]=[CH:2]2)=[CH:12][CH:13]=1
Reactant: c1cc2cc[nH]c2cn1
Reactant: Clc1ccc(Br)cc1
Agent: [Cu]I
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Product: Clc1ccc(-n2ccc3ccncc32)cc1
Yield: 91 %

Procedure:
A suspension of 1H-pyrrolo[2,3-c]pyridine (1.18 g, 10.0 mmol), 1-bromo-4-chlorobenzene (2.87 g, 15.0 mmol), copper(I) iodide (95.0 mg, 0.50 mmol), K3PO4 (4.46 g, 21.0 mmol) and trans-diaminocyclohexane (250 μL, 2.00 mmol) in 1,4-dioxane (15 mL) was heated to reflux for 5 days. The mixture was concentrated and the residue was purified by flash chromatography (EtOAc) to yield the title compound as a light brown solid (2.08 g, 90%). MS (ESI+) m/z=229, 231 (M+H)+.
Reaction SMILES: [BH4-].[Na+].[CH2:3]([O:10][C:11]1[CH:12]=[CH:13][C:14]([CH2:18][C:19](=[O:32])[C:20]([O:23][C:24]2[CH:29]=[CH:28][C:27]([C:30]#[N:31])=[CH:26][CH:25]=2)([CH3:22])[CH3:21])=[N+:15]([O-:17])[CH:16]=1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1>C(O)C.O>[CH2:3]([O:10][C:11]1[CH:12]=[CH:13][C:14]([CH2:18][CH:19]([OH:32])[C:20]([O:23][C:24]2[CH:29]=[CH:28][C:27]([C:30]#[N:31])=[CH:26][CH:25]=2)([CH3:22])[CH3:21])=[N+:15]([O-:17])[CH:16]=1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: CC(C)(Oc1ccc(C#N)cc1)C(=O)Cc1ccc(OCc2ccccc2)c[n+]1[O-]
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: CC(C)(Oc1ccc(C#N)cc1)C(O)Cc1ccc(OCc2ccccc2)c[n+]1[O-]
Yield: 80.6 %

Procedure:
0.46 g of sodium borohydride was added to a stirred solution of 4.53 g of 5-benzyloxy-2-[3-(4-cyanophenoxy)-3-methyl-2-oxobutyl]pyridine N-oxide in 60 ml of ethanol. After 2 hours the solution was diluted with 200 ml of water and extracted with diethyl ether. The organic phase was evaporated to give 3.67 g of 5-benzyloxy-2-[3-(4-cyanophenoxy)-2-hydroxy-3-methylbutyl]pyridine N-oxide of melting point 125° C. after recrystallization from ethanol
Reaction SMILES: Cl.[N:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([N:12]2[CH2:17][CH2:16][CH:15]([C:18](Cl)=[O:19])[CH2:14][CH2:13]2)=[N:4][CH:3]=1.[C:21]([O:25][C:26](=[O:39])[NH:27][CH2:28][CH2:29][NH:30][CH2:31][C:32]1[CH:37]=[CH:36][C:35]([Cl:38])=[CH:34][CH:33]=1)([CH3:24])([CH3:23])[CH3:22]>CN(C1C=CN=CC=1)C.C(Cl)Cl>[C:21]([O:25][C:26](=[O:39])[NH:27][CH2:28][CH2:29][N:30]([CH2:31][C:32]1[CH:37]=[CH:36][C:35]([Cl:38])=[CH:34][CH:33]=1)[C:18]([CH:15]1[CH2:16][CH2:17][N:12]([C:5]2[C:6]3[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=3)[N:2]=[CH:3][N:4]=2)[CH2:13][CH2:14]1)=[O:19])([CH3:24])([CH3:22])[CH3:23]
Reactant: CC(C)(C)OC(=O)NCCNCc1ccc(Cl)cc1
Reactant: O=C(Cl)C1CCN(c2ncnc3ccccc23)CC1
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NCCN(Cc1ccc(Cl)cc1)C(=O)C1CCN(c2ncnc3ccccc23)CC1
Reaction time: 12 h
Yield: 57.5 %

Procedure:
Step 1-Quinazolin-4-yl-piperidine-4-carbonyl chloride hydrochloride (197 mg, 0.63 mmol) was added to a solution of [2-(4-chlorobenzylamino)-ethyl]-carbamic acid tert-butyl ester (180 mg, 0.63 mmol) and DMAP (154 mg, 1.26 mmol) in DCM (6.5 mL) cooled in an ice bath. After being stirred for 12 hours, the mixture was partitioned between DCM (50 mL) and H2O (80 mL) containing 1 mL of 1.0 M HCl. The DCM layer was drained off and the acidic aqueous layer was extracted 3 more times with DCM. The combined DCM extracts were dried (Na2SO4), filtered, and concentrated in vacuo. The crude material was chromatographed (SiO2) using EtOAc as eluent to give {2-[(4-chlorobenzyl)-(1-quinazolin-4-yl-piperidine-4-carbonyl)-amino]-ethyl}-carbamic acid tert-butyl ester (190 mg).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:12])[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7](Br)[CH:6]=1.[C:13]1(B(O)O)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C(=O)([O-])[O-].[Na+].[Na+].[Cl-].[NH4+]>C1(C)C=CC=CC=1.CCCCCCC.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C(OCC)(=O)C.C(OCC)(=O)C.CCCCCCC>[CH3:1][O:2][C:3](=[O:12])[CH2:4][C:5]1[CH:6]=[C:7]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:8]=[CH:9][CH:10]=1
Reactant: OB(O)c1ccccc1
Reactant: COC(=O)Cc1cccc(Br)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Cl-]
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Solvent: CCCCCCC
Product: COC(=O)Cc1cccc(-c2ccccc2)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Concentrated sulphuric acid (588 μL) was added to a solution of 3-bromophenyl acetic acid (10 g, 46.5 mmol) in methanol (100 mL). The mixture was refluxed for 1.5 h and then cooled to ambient temperature and evaporated under reduced pressure to afford a residue. The residue was redissolved in diethyl ether (500 mL), washed with water (2×100 mL), brine (100 mL), dried (MgSO4) and then evaporated under reduced pressure to afford 3-bromophenyl acetic acid methyl ester (10.65 g). The 3-bromophenyl acetic acid methyl ester was dissolved in toluene (117 mL) then phenyl boronic acid (6.8 g, 55.69 mmol) added, followed by a aqueous solution of sodium carbonate (93 mL, 2M) and tetrakis(triphenylphosphine)palladium (1.6 g, 1.41 mmol). The mixture was stirred overnight then cooled to ambient temperature and an aqueous solution of saturated ammonium chloride (100 mL) added. The mixture was extracted with ethyl acetate (2×200 mL), died (Na2SO4) and evaporated under reduced pressure to afford a residue. Flash chromatography of the residue over silica (200 g) using ethyl acetate:heptane (3:48) as the eluent gave biphenyl-3-yl acetic acid methyl ester, yield 10.5 g, (99%), TLC (single UV spot, Rf=0.24, 10% ethyl acetate in heptane), analytical HPLC Rt=19.55 min, HPLC-MS (single main UV peak with Rt=9.35 min, 227.1 [M+H]+).
Reaction SMILES: [CH2:1]([C:15]1[CH:16]=[C:17]([OH:21])[CH:18]=[CH:19][CH:20]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14].[C:22]([O-])(=[O:24])[CH3:23].[Cl-].[Al+3].[Cl-].[Cl-].Cl>CCOCC>[OH:21][C:17]1[CH:16]=[C:15]([CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14])[CH:20]=[CH:19][C:18]=1[C:22](=[O:24])[CH3:23]
Reactant: CCCCCCCCCCCCCCc1cccc(O)c1
Reactant: CC(=O)[O-]
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: CCOCC
Product: CCCCCCCCCCCCCCc1ccc(C(C)=O)c(O)c1

Procedure:
A 20 g portion of 3-tetradecylphenol, acetate was heated at 110° C. and 8.4 g of aluminum chloride was added in portions over a 3 hour period. The mixture was allowed to cool, then diluted with ether, poured onto ice containing 10 ml of concentrated hydrochloric acid and extracted several times with ether. The ether extracts were combined, washed with water, brine and dried. The crude material was chromatographed on silica gel, eluting with hexane:ethyl acetate (50:1), giving 15.8 g of the desired compound, mp 45°-46° C.