Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][S:2]([NH:5][C:6]1[CH:7]=[C:8]([C:12]2[N:13]=[C:14]3[C:20]4[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=4[NH:18][C:17]4[N:25]=[CH:26][CH:27]=[CH:28][C:16]=4[N:15]3[C:29]=2[C:30]2[CH:35]=[CH:34][C:33]([C:36]3([NH:40]C(=O)OC(C)(C)C)[CH2:39][CH2:38][CH2:37]3)=[CH:32][CH:31]=2)[CH:9]=[CH:10][CH:11]=1)(=[O:4])=[O:3].[ClH:48].O1CCOCC1>C(Cl)Cl>[ClH:48].[ClH:48].[ClH:48].[NH2:40][C:36]1([C:33]2[CH:32]=[CH:31][C:30]([C:29]3[N:15]4[C:16]5[CH:28]=[CH:27][CH:26]=[N:25][C:17]=5[NH:18][C:19]5[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=5[C:14]4=[N:13][C:12]=3[C:8]3[CH:7]=[C:6]([NH:5][S:2]([CH3:1])(=[O:4])=[O:3])[CH:11]=[CH:10][CH:9]=3)=[CH:35][CH:34]=2)[CH2:39][CH2:38][CH2:37]1
Reactant: CC(C)(C)OC(=O)NC1(c2ccc(-c3c(-c4cccc(NS(C)(=O)=O)c4)nc4n3-c3cccnc3Nc3ccccc3-4)cc2)CCC1
Agent: Cl
Solvent: ClCCl
Solvent: C1COCCO1
Product: CS(=O)(=O)Nc1cccc(-c2nc3n(c2-c2ccc(C4(N)CCC4)cc2)-c2cccnc2Nc2ccccc2-3)c1
Temperature: 25 °C
Reaction time: 11.5 h
Yield: 89.7 %

Procedure:
tert-Butyl {1-[4-(2-{3-[(methylsulfonyl)amino]phenyl}-9H-imidazo[1,2-d]pyrido[2,3-b][1,4]benzodiazepin-3-yl)phenyl]cyclobutyl}carbamate (13.7 mg, 0.0211 mmol) was dissolved in DCM (1 mL). 4M HCl/dioxane (1 mL) was added to the mixture and stirred at room temperature for 11.5 hours. The mixture was concentrated and solidified with ether. The precipitated solids were collected by filtration and washed with ether to afford desired product (12.5 mg, 89.7%) as pale yellow solid. 1HNMR (DMSO-d6) 400 MHz δ: 9.76 (s, 1H), 8.67 (br s, 2H), 8.62 (s, 1H), 8.10 (dd, J=4.6, 1.4 Hz, 1H), 7.94 (dd, J=7.6, 1.6 Hz, 1H), 7.53 (d, J=8.7 Hz, 2H), 7.49-7.47 (m, 1H), 7.41-7.29 (m, 4H), 7.25 (t, J=7.8 Hz, 1H), 7.19-7.08 (m, 3H), 6.88 (dd, J=7.8, 1.4 Hz, 1H), 6.73 (dd, J=8.0, 4.6 Hz, 1H), 2.90 (s, 3H), 2.61-2.48 (m, 4H), 2.25-2.12 (m, 1H), 1.89-1.76 (m, 1H).
Reaction SMILES: C(NC1C=C(C=C(C)C=1)[C:13]([NH:15][C@@H:16]([CH2:42][C:43]1[CH:48]=[C:47]([F:49])[CH:46]=[C:45]([F:50])[CH:44]=1)[C@@H:17]([C@H:26]1[CH2:30][C@@H:29]([O:31][CH2:32][CH2:33][CH3:34])[CH2:28][N:27]1C(OC(C)(C)C)=O)[O:18][Si](C(C)(C)C)(C)C)=[O:14])(=O)C1C=CC=CC=1.C(OC(N1C[C@H](OCCC)C[C@@H]1[C@@H](O[Si](C(C)(C)C)(C)C)[C@@H:72]([NH:82][C:83]([C:85]1[CH:86]=[C:87]([CH:91]=[C:92]([CH3:94])[CH:93]=1)C(O)=O)=[O:84])[CH2:73][C:74]1C=C(F)C=C(F)C=1)=O)(C)(C)C.CCN(C(C)C)[CH:106]([CH3:108])[CH3:107].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(NCCC)CC>ClCCl>[F:50][C:45]1[CH:44]=[C:43]([CH2:42][C@H:16]([NH:15][C:13](=[O:14])[C:87]2[CH:91]=[C:92]([CH3:94])[CH:93]=[C:85]([C:83]([N:82]([CH2:72][CH2:73][CH3:74])[CH2:107][CH2:106][CH3:108])=[O:84])[CH:86]=2)[C@H:17]([OH:18])[C@H:26]2[CH2:30][C@@H:29]([O:31][CH2:32][CH2:33][CH3:34])[CH2:28][NH:27]2)[CH:48]=[C:47]([F:49])[CH:46]=1
Reactant: CCCO[C@@H]1C[C@H]([C@@H](O[Si](C)(C)C(C)(C)C)[C@H](Cc2cc(F)cc(F)c2)NC(=O)c2cc(C)cc(C(=O)O)c2)N(C(=O)OC(C)(C)C)C1
Reactant: CCCO[C@@H]1C[C@H]([C@@H](O[Si](C)(C)C(C)(C)C)[C@H](Cc2cc(F)cc(F)c2)NC(=O)c2cc(C)cc(NC(=O)c3ccccc3)c2)N(C(=O)OC(C)(C)C)C1
Reactant: CCN(C(C)C)C(C)C
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCCNCCC
Product: CCCO[C@H]1CN[C@@H]([C@@H](O)[C@H](Cc2cc(F)cc(F)c2)NC(=O)c2cc(C)cc(C(=O)N(CCC)CCC)c2)C1
Reaction time: 0.33 h
Yield: 90 %

Procedure:
Step 10 (A): Preparation of (2R,4R)-tert-butyl 2-((1S,2S)-2-(3-(benzamido)-5-methylbenzamido)-1-(tert-butyldimethylsilyloxy)-3-(3,5-difluorophenyl)propyl)-4-propoxypyrrolidine-1-carboxylate. To a solution of 3-(((1S,2S)-1-((2R,4R)-1-(tert-butoxycarbonyl)-4-propoxypyrrolidin-2-yl)-1-(tert-butyldimethylsilyloxy)-3-(3,5-difluorophenyl)propan-2-yl)carbamoyl)-5-methylbenzoic acid (Preparation G, 26 mg, 0.037 mmol) in dichloromethane (1 mL) was added Hunig's base (15 mg, 0.114 mmol) to make a clear solution and HATU (18 mg, 0.05 mmol) was then added. After stirring for 20 min, the reaction mixture was added dipropylamine (6 mg, 0.057 mmol) and the reaction mixture was stirred at rt for 6 h. The crude mixture was purified by silica gel Flash Chromatography (0% to 10% to 30% EtOAc/Hexane step gradient) to give 27 mg of the title compound (90% yield): 1H NMR (CDCl3, 500 MHz) δ ppm 0.02 (3H, s), 0.06 (3H, s), 0.71 (3H, m), 0.85 (9H, s), 0.88 (3H, m), 0.96 (3H, m), 1.48-1.54 (12H, m), 1.67 (2H, m), 1.74 (2H, m), 2.03-2.09 (1H, m), 2.19 (1H, m), 2.38 (3H, s), 2.62 (1H, m), 2.94 (1H, m), 3.13 (2H, brd s), 3.26-3.36 (3H, m), 3.43 (2H, brd s), 3.76 (1H, m), 3.97 (1H, m), 4.04-4.07 (1H, m), 4.10-4.12 (1H, m), 4.58 (1H, m), 6.59 (1H, m), 6.76 (2H, d, J=5 Hz), 7.25 (1H, s), 7.60 (1H, s), 7.70 (1H, s), 7.98 (1H, brd s). MS (ESI) (M+H)+ 774.63.
Reaction SMILES: [C:1]1([C:7]2[CH:16]=[C:15]3[C:10]([CH2:11][CH2:12][C:13]([C:17]([NH:19][C:20]4[CH:25]=[CH:24][CH:23]=[C:22]([CH2:26][N:27]5[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]5)[CH:21]=4)=[O:18])=[CH:14]3)=[CH:9][CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:33][I:34]>CN(C=O)C>[I-:34].[CH3:33][N+:27]1([CH2:26][C:22]2[CH:23]=[CH:24][CH:25]=[C:20]([NH:19][C:17]([C:13]3[CH2:12][CH2:11][C:10]4[C:15](=[CH:16][C:7]([C:1]5[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=5)=[CH:8][CH:9]=4)[CH:14]=3)=[O:18])[CH:21]=2)[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]1
Reactant: CI
Reactant: O=C(Nc1cccc(CN2CCCCC2)c1)C1=Cc2cc(-c3ccccc3)ccc2CC1
Solvent: CN(C)C=O
Product: C[N+]1(Cc2cccc(NC(=O)C3=Cc4cc(-c5ccccc5)ccc4CC3)c2)CCCCC1
Product: [I-]
Temperature: 25 °C
Reaction time: 15 h

Procedure:
In DMF (3 ml) was dissolved 7-phenyl-N-[3—(piperidinomethyl)phenyl]-3,4-dihydronaphthalene-2-carboxamide (200 mg), and to the mixture was added methyl iodide (88 μl). The mixture was stirred at room temperature for 15 hours and concentrated under reduced pressure. The residue was recrystallized from methanol-ethyl acetate to give 1-methyl-1-[3—(7-phenyl-3,4-dihydronaphthalene-2-carboxamido)benzyl]-piperidinium iodide (Compound 218) (211 mg) as colorless crystals.
Reaction SMILES: [OH:1][CH2:2]/[CH:3]=[C:4](/[CH2:6][CH2:7]/[CH:8]=[C:9](/[CH2:11][CH2:12][CH:13]=[C:14]([CH3:16])[CH3:15])\[CH3:10])\[CH3:5].[N+](=[CH:19][P:20](=[O:25])([O:23][CH3:24])[O:21][CH3:22])=[N-]>CCOCC>[CH3:5][C:4]([CH2:6][CH2:7][CH:8]=[C:9]([CH3:10])[CH2:11][CH2:12][CH:13]=[C:14]([CH3:16])[CH3:15])=[CH:3][CH2:2][O:1][CH2:19][P:20](=[O:25])([O:23][CH3:24])[O:21][CH3:22]
Reactant: CC(C)=CCC/C(C)=C/CC/C(C)=C/CO
Reactant: COP(=O)(C=[N+]=[N-])OC
Solvent: CCOCC
Product: COP(=O)(COCC=C(C)CCC=C(C)CCC=C(C)C)OC
Temperature: 25 °C

Procedure:
(E,E)-Farnesol, (5.0 mmol, 1.11 g, 1.26 ml) was stirred under argon in 10 ml of dry deoxygenated benzene (10 ml) and treated in one portion with ##STR88## (1.0 mmol, 0.442 g). The dark blue/green solution was stirred at room temperature and a solution of (1.5 g, 10.0 mmol) of dimethyl diazomethylphosphonate (prepared according to D. Seyferth et al, J. Org. Chem., 1971, vol. 36, No. 10, pages 1379 to 1386) in 20 ml of dry, deoxygenated benzene was added dropwise over 4 hours via syringe pump. After addition, the reaction mixture was stirred an additional 45 minutes. The reaction mixture was stripped of solvent and applied as a 75% ethyl acetate/Hexane solution to a flash chromatography column (50 mm diameter, 6" of silica gel) eluted with 75% ethyl acetate/hexane to afford 0.627 g, yield), of the ether as a dark blue/green oil.
Reaction SMILES: O=[C:2]1[CH2:7][CH2:6][CH2:5][CH2:4][CH:3]1[C:8](OC)=[O:9].[NH2:12][C:13]1[CH:14]=[C:15]([CH:20]=[CH:21][C:22]=1[CH3:23])[C:16]([O:18][CH3:19])=[O:17].O1CCOCC1>O>[CH3:23][C:22]1[C:13]2[NH:12][C:2]3[CH2:7][CH2:6][CH2:5][CH2:4][C:3]=3[C:8](=[O:9])[C:14]=2[C:15]([C:16]([O:18][CH3:19])=[O:17])=[CH:20][CH:21]=1
Reactant: COC(=O)c1ccc(C)c(N)c1
Reactant: COC(=O)C1CCCCC1=O
Solvent: O
Solvent: C1COCCO1
Product: COC(=O)c1ccc(C)c2[nH]c3c(c(=O)c12)CCCC3
Temperature: 130 °C
Yield: 31.7 %

Procedure:
A mixture of methyl 2-oxocyclohexanecarboxylate (1.0 g, 6.4 mmol), methyl 3-amino-4-methylbenzoate (1.06 g, 6.4 mmol), polyphosphoric acid (4 mL) and dioxane (6 mL) was heated at 130° C. for 2 hours. After cooling to room temperature, the mixture was diluted with water (100 mL) and the resulting precipitate was collected by filtration and dried. The solid was suspended in methanol (100 mL) and SOCl2 (10 mL) was added. The mixture was stirred at reflux for 5 hours, concentrated and treated with water (80 mL), extracted with ethyl acetate (3×80 mL). The organic layer was separated, concentrated to give the crude product. Then the mixture was purified by chromatography column on silica gel (eluted with CH2Cl2/MeOH) to afford crude product, and the final product (0.55 g) was obtained from recrystallization using MeOH as solvent. 1H NMR (DMSO-d6) δ 10.3 (s, 1H), 7.41 (d, 1H, J=7.8 Hz), 6.99 (d, 1H, J=7.8 Hz), 3.73 (s, 3H), 2.78-2.81 (m, 2H), 2.50 (s, 3H), 2.35-2.37 (m, 2H), and 1.64-1.73 (m, 4H). MS (ESI) m/e [M+1]+272.0.
Reaction SMILES: [C:1]([CH:4]1[O:9][CH2:8][CH2:7][N:6]([C:10]([O:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[O:11])[CH2:5]1)(=[O:3])[CH3:2].[BH4-].[Na+]>C1COCC1.CCO>[OH:3][CH:1]([CH:4]1[O:9][CH2:8][CH2:7][N:6]([C:10]([O:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[O:11])[CH2:5]1)[CH3:2]
Reactant: CC(=O)C1CN(C(=O)OCc2ccccc2)CCO1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: C1CCOC1
Product: CC(O)C1CN(C(=O)OCc2ccccc2)CCO1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 1.38 of 2-acetyl-4-benzyloxycarbonylmorpholine in 50 mL of 1:1 THF-EtOH was added 400 mg of sodium borohydride, in several portions. The mixture was stirred at room temperature for 2 h, then quenched by addition of 25 mL of saturated NaHCO3. The mixture was diluted with 75 mL of water and 25 mL of EtOAc. The phases were separated and the aqueous phase was extracted with 2×25 mL of EtOAc. The combined organics were washed with 25 mL of brine, dried over Na2SO4, and concentrated. The residue was purified by flash chromatography, eluting with 2:1 hexanes-EtOAc, to yield 383 mg of diastereomer 1, 341 mg of diastereomer 2, and 436 mg of a mixture of the two isomers. Data for diastereomer 1. Rf 0.35 (1:1 hexanes-EtOAc) 1H NMR (500 MHz, CDCl3): δ7.30-7.43 (m, 4H), 5.12-5.23 (m, 2H), 3.80-4.18 (m, 4H), 3.57 (br t, J=11.0Hz, 1H), 3.32 (br s, 1H), 2.84-3.11 (m, 2H), 2.05 (br s, 1H),1.22 (d, J=6.5 Hz, 3H). Data for diastereomer 2. Rf 0.28 (1:1 hexanes-EtOAc).
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:5]2[O:6][CH2:7][CH2:8][O:9][C:4]=2[CH:3]=1.C([Li])CCC.[CH3:17][O:18][C:19]1[CH:20]=[C:21]([CH:24]=[CH:25][CH:26]=1)[CH:22]=[O:23].C(O)(C)C>C1COCC1.O>[O:6]1[C:5]2[CH:10]=[CH:11][C:2]([CH:22]([C:21]3[CH:24]=[CH:25][CH:26]=[C:19]([O:18][CH3:17])[CH:20]=3)[OH:23])=[CH:3][C:4]=2[O:9][CH2:8][CH2:7]1
Reactant: Brc1ccc2c(c1)OCCO2
Reactant: COc1cccc(C=O)c1
Agent: [Li]CCCC
Solvent: CC(C)O
Solvent: C1CCOC1
Solvent: O
Product: COc1cccc(C(O)c2ccc3c(c2)OCCO3)c1
Temperature: -78 °C
Reaction time: 0.33 h

Procedure:
A stirred mixture of 6-bromo-2,3-dihydro-benzo[1,4]dioxine (1.59 g, 7.4 mmol) and dry TRF (10 mL) was cooled to −78° C., evacuated and refilled with nitrogen for 10 cycles. To this clear solution was slowly added n-butyllithium (3.0 mL, 7.4 mmol) and stirred for 20 min. Then a mixture of 3-methoxy-benzaldehyde (0.92 g, 6.7 mmol) in dry THF (10 mL) was added and stirred for 1 hour at −78° C. The mixture was quenched with isopropanol (3.1 mL, 40 mmol) and added water (10 mL). The mixture was extracted with EtOAc (3×30 mL). The combined organic phases were washed with water (2×30 mL), dried over MgSO4 and concentrated to give (2,3-dihydro-benzo[1,4]dioxin-6-yl)-(3-methoxy-phenyl)-methanol as an oil (2.09 g, 114% crude yield). The product was used in the next step without further purification.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH2:8][S:9]([NH:12][CH2:13][CH2:14][CH2:15][O:16][CH3:17])(=[O:11])=[O:10])[CH:5]=[CH:6][CH:7]=1.Cl[C:19]1[CH:24]=[C:23]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=2[O:31][CH3:32])[N:22]=[CH:21][N:20]=1>CN(C=O)C>[CH3:32][O:31][C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][C:25]=1[C:23]1[N:22]=[CH:21][N:20]=[C:19]([NH:1][C:2]2[CH:3]=[C:4]([CH2:8][S:9]([NH:12][CH2:13][CH2:14][CH2:15][O:16][CH3:17])(=[O:11])=[O:10])[CH:5]=[CH:6][CH:7]=2)[CH:24]=1
Reactant: COCCCNS(=O)(=O)Cc1cccc(N)c1
Reactant: COc1ccccc1-c1cc(Cl)ncn1
Solvent: CN(C)C=O
Product: COCCCNS(=O)(=O)Cc1cccc(Nc2cc(-c3ccccc3OC)ncn2)c1
Temperature: 80 °C

Procedure:
A mixture of C-(3-amino-phenyl)-N-(3-methoxy-propyl)-methanesulfonamide (0.129 g, 0.50 mmol) and 4-chloro-6-(2-methoxyphenyl)-pyrimidine (0.110 g, 0.10 mmol) in DMFA (3 mL) was stirred at 80° C. till the reaction completion (TLC control), then evaporated in vacuo. The resulting residue was purified by column chromatography on silica gel yielding C-{3-[6-(2-methoxy-phenyl)-pyrimidin-4-ylamino]-phenyl}-N-(3-methoxy-propyl)-methanesulfonamide
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([O:9][CH3:10])[C:4]=1[CH:11]1[NH:15][C:14](=[O:16])[CH:13]([CH3:17])[CH2:12]1.Br[CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([O:26][CH:27]([F:29])[F:28])[N:21]=1>>[F:29][CH:27]([F:28])[O:26][C:22]1[N:21]=[C:20]([CH2:19][N:15]2[CH:11]([C:4]3[C:5]([O:9][CH3:10])=[CH:6][CH:7]=[CH:8][C:3]=3[O:2][CH3:1])[CH2:12][CH:13]([CH3:17])[C:14]2=[O:16])[CH:25]=[CH:24][CH:23]=1
Reactant: FC(F)Oc1cccc(CBr)n1
Reactant: COc1cccc(OC)c1C1CC(C)C(=O)N1
Product: COc1cccc(OC)c1C1CC(C)C(=O)N1Cc1cccc(OC(F)F)n1

Procedure:
Prepared according to the described general procedure 4 (GP4) by reaction of 5-(2,6-dimethoxyphenyl)-3-methylpyrrolidin-2-one with 2-(bromomethyl)-6-(difluoromethoxy)pyridine. Subsequent purification by preparative HPLC afforded the target compound. LC-MS (conditions A): tR=0.84 min.; [M+H]+: 393.19 g/mol.
Reaction SMILES: [F-].[Cs+].[CH3:3]B(O)O.[NH2:7][C:8]1[CH:17]=[C:16]([C:18]([F:21])([F:20])[F:19])[C:15](I)=[CH:14][C:9]=1[C:10]([O:12][CH3:13])=[O:11]>O1CCOCC1>[NH2:7][C:8]1[CH:17]=[C:16]([C:18]([F:21])([F:20])[F:19])[C:15]([CH3:3])=[CH:14][C:9]=1[C:10]([O:12][CH3:13])=[O:11]
Reactant: COC(=O)c1cc(I)c(C(F)(F)F)cc1N
Reactant: CB(O)O
Agent: [Cs+]
Agent: [F-]
Solvent: C1COCCO1
Product: COC(=O)c1cc(C)c(C(F)(F)F)cc1N
Temperature: 80 °C
Yield: 91.9 %

Procedure:
Add cesium fluoride (184.3 g, 1.21 mol), methyl boronic acid (63.7 g, 1.05 mol, 3 mol equiv.) and bis(diphenylphosphinoferrocene)palladium(II) chloride (27.83 g, 35.1 mmol) to a solution of methyl 2-amino-5-iodo-4-trifluoromethylbenzoate (121 g, 351 mmol) in anhydrous 1,4-dioxane (2.5 L) at room temperature under an atmosphere of nitrogen and heat the mixture at 80° C. for 3 h. Allow the mixture to cool to room temperature then partition between ethyl acetate (2.5 L) and water (2.5 L) and filter through a pad of Celite® to remove the fine black suspension. Extract the aqueous phase with ethyl acetate (2×100 mL) and wash the combined organic extracts with brine (1 L). Dry over anhydrous magnesium sulfate, filter and remove the solvent under reduced pressure at 45° C. to give a red oil. Purify the residue by column chromatography on silica gel, eluting with isohexane/ethyl acetate (9:1), to give the title compound as a pale yellow crystalline solid (75.25 g, 92%). 1H NMR (300 MHz, CDCl3) δ 7.73 (s, 1H), 6.93 (s, 1H), 5.70 (s, 2H), 3.90 (s, 3H), 2.33 (s, 3H).
Reaction SMILES: C([O:8][C:9](=[O:49])[CH2:10][C@@H:11]([N:32]1[CH:36]=[CH:35][C:34]([C:37]2[CH:42]=[CH:41][C:40]([C:43]3[CH:48]=[CH:47][N:46]=[CH:45][CH:44]=3)=[CH:39][CH:38]=2)=[CH:33]1)[C:12]([NH:14][C@H:15]([C:28]([CH3:31])([CH3:30])[CH3:29])[CH2:16][O:17]C(OCC1C=CC=CC=1)=O)=[O:13])C1C=CC=CC=1>CO.CCOC(C)=O.[OH-].[OH-].[Pd+2]>[CH3:29][C:28]([CH3:31])([CH3:30])[C@H:15]([NH:14][C:12](=[O:13])[C@H:11]([N:32]1[CH:36]=[CH:35][C:34]([C:37]2[CH:42]=[CH:41][C:40]([C:43]3[CH:44]=[CH:45][N:46]=[CH:47][CH:48]=3)=[CH:39][CH:38]=2)=[CH:33]1)[CH2:10][C:9]([OH:49])=[O:8])[CH2:16][OH:17]
Reactant: CC(C)(C)[C@H](COC(=O)OCc1ccccc1)NC(=O)[C@@H](CC(=O)OCc1ccccc1)n1ccc(-c2ccc(-c3ccncc3)cc2)c1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: CO
Product: CC(C)(C)[C@@H](CO)NC(=O)[C@@H](CC(=O)O)n1ccc(-c2ccc(-c3ccncc3)cc2)c1
Reaction time: 3 h
Yield: 73.6 %

Procedure:
A mixture of N-(1-benzyloxycarbonyloxy-3,3-dimethylbut-2(R)-yl)-3(R)-[3-[4-(pyridin-4-yl)phenyl]-1H-pyrrol-1-yl]succinamic acid benzyl ester (140 mg, 0.212 mmol) and Pd(OH)2 (60 mg of 20% Pd by content) in MeOH (1mL) and EtOAc (9 mL) was stirred under H2 atmosphere for 3 hours. The catalyst was filtered onto Celite and rinsed with 10% MeOH/CHCl3 (75 mL). The filtrate was concentrated in vacuo to provide a yellow solid, which was precipitated from hot CHCl3 solution with hexane to furnish 68 mg (95%) of N-[2,2-dimethyl-1(S)-(hydroxymethyl)propyl]-3(R)-[3-[4-(pyridin-4-yl)phenyl]-1H-pyrrol-1-yl]succinamic acid as a yellow solid, mp 192-4° C.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([C:14]#[N:15])[CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)=[CH:4][CH:3]=1.Cl[CH2:17][CH2:18][CH2:19][N:20]1[CH2:24][CH2:23][CH2:22][CH2:21]1.CN(C=O)C.C([O-])([O-])=O.[K+].[K+]>Cl.CC(OC)(C)C>[N:20]1([CH2:19][CH2:18][CH2:17][O:1][C:2]2[CH:7]=[CH:6][C:5]([C:8]3([C:14]#[N:15])[CH2:13][CH2:12][O:11][CH2:10][CH2:9]3)=[CH:4][CH:3]=2)[CH2:24][CH2:23][CH2:22][CH2:21]1
Reactant: N#CC1(c2ccc(O)cc2)CCOCC1
Reactant: ClCCCN1CCCC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: COC(C)(C)C
Product: N#CC1(c2ccc(OCCCN3CCCC3)cc2)CCOCC1
Yield: 51.6 %

Procedure:
4-(4-Hydroxy-phenyl)-tetrahydro-pyran-4-carbonitrile (2 g, 9.86 mmol), 1-(3-chloro-propyl)-pyrrolidine (2.33 g, 15.78 mmol), DMF (40 ml) and K2CO3 (5.45 g, 39.44 mmol) were reacted together according to general procedure E. The crude reaction product was diluted with 2M HCl solution (200 ml) and washed with ethyl acetate (3×50 ml). The aqueous phase was basified to pH 14 with 2M NaOH (200 ml) and extracted with ethyl acetate (4×50 ml). The combined organic extracts were dried over MgSO4, filtered, washed with ethyl acetate and concentrated in vacuo to give a white solid. The solid was slurried in TBME (15 ml) and heptane (15 ml), filtered, washed with heptane (8 ml) and dried on the filter for 2 hours to give the title compound as a white solid (1.6 g, 53%). 1H NMR (400 MHz, DMSO-d6) δ7.43 (d, 2H), 6.99 (d, 2H), 4.08-3.94 (m, 4H), 3.64 (dt, 2H), 2.57-2.47 (m, 2H), 2.46-2.36 (m, 4H), 2.12-1.94 (m, 4H), 1.87 (p, 2H), 1.73-1.62 (m, 4H).
Reaction SMILES: Br[C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH:7]([CH3:26])[N:8]([C:12]3[CH:17]=[C:16]([N:18]4[CH2:23][CH2:22][N:21]([CH3:24])[CH2:20][CH2:19]4)[N:15]=[C:14]([NH2:25])[N:13]=3)[CH2:9]2)=[CH:4][CH:3]=1.[CH3:27][NH:28][C:29]([C:31]1[CH:36]=[CH:35][C:34](B2OC(C)(C)C(C)(C)O2)=[CH:33][N:32]=1)=[O:30]>>[NH2:25][C:14]1[N:13]=[C:12]([N:8]2[CH:7]([CH3:26])[CH2:6][C:5]3[C:10](=[CH:11][C:2]([C:34]4[CH:35]=[CH:36][C:31]([C:29]([NH:28][CH3:27])=[O:30])=[N:32][CH:33]=4)=[CH:3][CH:4]=3)[CH2:9]2)[CH:17]=[C:16]([N:18]2[CH2:19][CH2:20][N:21]([CH3:24])[CH2:22][CH2:23]2)[N:15]=1
Reactant: CNC(=O)c1ccc(B2OC(C)(C)C(C)(C)O2)cn1
Reactant: CC1Cc2ccc(Br)cc2CN1c1cc(N2CCN(C)CC2)nc(N)n1
Product: CNC(=O)c1ccc(-c2ccc3c(c2)CN(c2cc(N4CCN(C)CC4)nc(N)n2)C(C)C3)cn1

Procedure:
This compound was prepared by using procedures analogous to those described for the synthesis of Example 2 starting from 4-(7-bromo-3-methyl-3,4-dihydroisoquinolin-2(1H)-yl)-6-(4-methylpiperazin-1-yl)pyrimidin-2-amine (Peak 2, Example 49, Step 7) and N-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine-2-carboxamide (Frontier, Cat. No. M10074). LCMS (M+H)+: m/z=473.4.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]2[N:12]([C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([CH3:19])[CH:14]=3)[N:11]=[C:10]([CH3:20])[CH:9]=2)[CH:5]=[CH:4][N:3]=1.[CH2:21]([CH2:23][NH2:24])[OH:22].C(OCC)(=O)C>O>[OH:22][CH2:21][CH2:23][NH:24][C:2]1[CH:7]=[C:6]([C:8]2[N:12]([C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([CH3:19])[CH:14]=3)[N:11]=[C:10]([CH3:20])[CH:9]=2)[CH:5]=[CH:4][N:3]=1
Reactant: Cc1cccc(-n2nc(C)cc2-c2ccnc(Cl)c2)c1
Reactant: NCCO
Solvent: CCOC(C)=O
Solvent: O
Product: Cc1cccc(-n2nc(C)cc2-c2ccnc(NCCO)c2)c1
Temperature: 100 °C
Yield: 80 %

Procedure:
A mixture of 2-chloro-4-[1-(3-methylphenyl)-3-methyl-1H-pyrazol-5-yl]pyridine (Example 45; 0.5 g, 0.0018 mol) and ethanolamine (15 mL) was heated at 100° C. for 18 hours. The reaction mixture was cooled and treated with ethyl acetate and water. The organic layer was washed with brine, dried over magnesium sulfate and filtered. The filtrate was concentrated and the crude was purified by chromatography on silica gel (ethyl acetate) to give 0.44 g (80% yield) of product as a yellow oil: Anal. Calc'd. for C18H20N4O: C, 70.11; H, 6.54; N, 18.17. Found: C, 69.89; H, 6.65; N, 18.35.
Reaction SMILES: [Cl:1][C:2]1[C:11]([Cl:12])=[C:10]2[C:5]([C:6](=O)[NH:7][CH:8]=[N:9]2)=[CH:4][CH:3]=1.P(Cl)(Cl)([Cl:16])=O>>[Cl:16][C:6]1[C:5]2[C:10](=[C:11]([Cl:12])[C:2]([Cl:1])=[CH:3][CH:4]=2)[N:9]=[CH:8][N:7]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: O=c1[nH]cnc2c(Cl)c(Cl)ccc12
Product: Clc1ccc2c(Cl)ncnc2c1Cl
Temperature: 25 °C
Yield: 81.8 %

Procedure:
A mixture of 7,8-dichloro-3H-quinazolin-4-one (0.72 g, 3.35 mmol) in phosphorus oxychloride (6.6 g, 12.8 mmol) was heated at reflux for about 4 hours. The reaction mixture was cooled at ambient temperature then added dropwise to ice-cold water. The precipitate was collected by filtration and dried in vacuo to give 4,7,8-trichloroquinazoline as a brown solid (0.64 g, 2.74 mmol, 82%).
Reaction SMILES: C[O:2][C:3](=[O:32])[C:4]([C:7]1[CH:12]=[CH:11][C:10]([C:13]#[C:14][C:15]2[CH:24]=[CH:23][C:22]3[CH:21]([N:25]([CH:27]4[CH2:29][CH2:28]4)[CH3:26])[CH2:20][CH2:19][C:18]([CH3:31])([CH3:30])[C:17]=3[CH:16]=2)=[CH:9][CH:8]=1)([CH3:6])[CH3:5].[OH-].[Na+]>CO.O1CCCC1>[CH:27]1([N:25]([CH3:26])[CH:21]2[CH2:20][CH2:19][C:18]([CH3:30])([CH3:31])[C:17]3[CH:16]=[C:15]([C:14]#[C:13][C:10]4[CH:9]=[CH:8][C:7]([C:4]([CH3:6])([CH3:5])[C:3]([OH:32])=[O:2])=[CH:12][CH:11]=4)[CH:24]=[CH:23][C:22]2=3)[CH2:28][CH2:29]1
Reactant: COC(=O)C(C)(C)c1ccc(C#Cc2ccc3c(c2)C(C)(C)CCC3N(C)C2CC2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: CN(C1CC1)C1CCC(C)(C)c2cc(C#Cc3ccc(C(C)(C)C(=O)O)cc3)ccc21
Yield: 88.7 %

Procedure:
A solution of 2-{4-[5-(cyclopropyl-methyl-amino)-8,8-dimethyl-5,6,7,8-tetrahydro-naphthalen-2-ylethynyl]-phenyl}-2-methyl-propionic acid methyl ester (Intermediate 170, 0.08 g, 0.19 mmol) in methanol (3 mL) and tetrahydrofuran (3 mL) was treated with a 2M solution of sodium hydroxide (2 mL, 4 mmol) and the resulting reaction mixture was refluxed overnight. The volatiles were evaporated in vacuo and the residue was diluted with saturated aqueous ammonium chloride solution and extracted with ethyl acetate. The organic phase was dried over anhydrous magnesium sulfate, filtered and evaporated in vacuo to afford the title product (0.07 g, ˜100%).
Reaction SMILES: [NH2:1][C:2]([NH2:4])=[NH:3].[Cl:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([Cl:12])[C:7]=1[CH:13]([Br:17])[C:14](Br)=[O:15].[OH-].[Na+]>O.CC(C)=O>[Cl:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([Cl:12])[C:7]=1[CH:13]([Br:17])[C:14]([NH:3][C:2]([NH2:4])=[NH:1])=[O:15]
Reactant: O=C(Br)C(Br)c1c(Cl)cccc1Cl
Reactant: N=C(N)N
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)=O
Solvent: O
Product: N=C(N)NC(=O)C(Br)c1c(Cl)cccc1Cl
Reaction time: 1 h

Procedure:
To a solution of 0.072 mols guanidine (from 6.9 g guanidine hydrochloride and 3 g NaOH) in 100 ml water, 20 g (0.06 mols) 2-(2,6-dichlorophenyl)-2-bromo-acetyl-bromide in 50 ml acetone and 2.4 g (0.06 mols) NaOH in 50 ml water at 10 degrees C. are simultaneously added dropwise. After one hour, the organic phase is extracted with methylene chloride, filtered, and further extracted in a counter-current manner with 1 N hydrochloric acid. The acid phase is then adjusted to an alkaline pH and extracted with CH2Cl2. Subsequent to the evaporation of the methylene chloride, the guanidine base is obtained. It has decomposition point of 155 degrees C. The hydrochloride is prepared in the usual way using ethanolic hydrochloric acid, and is recrystalized from a mixture of acetic acid and ethanol. The decomposition point is 228-229 degrees C.