Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O:2][C:3](=[O:18])[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH3:11])=[C:6]([O:12][CH2:13][CH2:14][CH2:15][O:16][CH3:17])[CH:5]=1.[OH-].[Na+]>CO>[CH3:11][O:10][C:7]1[CH:8]=[CH:9][C:4]([C:3]([OH:18])=[O:2])=[CH:5][C:6]=1[O:12][CH2:13][CH2:14][CH2:15][O:16][CH3:17]
Reactant: COCCCOc1cc(C(=O)OC)ccc1OC
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: COCCCOc1cc(C(=O)O)ccc1OC

Procedure:
A solution of 4-methoxy-3-(3-methoxy-propoxy)-benzoic acid methyl ester (140 g, 0.55 mol) and NaOH (1N, 825 mL, 0.825 mol) in MeOH (840 mL) is stirred at RT for 18 h. After completion, the solvent is removed under reduced pressure, and the residue is diluted with water (200 mL) and extracted twice with AcOEt (250 mL). The aqueous layer is acidified by addition of aqueous HCl (2N, 470 mL) and extracted 3 times with AcOEt (1 L). The combined organic extracts are washed with brine, dried over Na2SO4, filtered and concentrated. The crude material is purified by crystallization in AcOEt to give the title compound. MS (LC-MS): 239.1 [M−H]−; tR (HPLC, CC 70/4 Nucleosil 3 C18HD column, 20 to 100% CH3CN in H2O in 2, then 4 min with 100% CH3CN, CH3CN and H2O with 0.1% TFA, flow: 1.5 mL/min): 2.43 min.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([NH:7][C:8]([C:10]2[C:14]3[N:15]=[CH:16][N:17]=[C:18]([C:19]4[C:27]5[O:26][CH2:25][O:24][C:23]=5[CH:22]=[CH:21][C:20]=4[O:28][CH2:29][CH3:30])[C:13]=3[NH:12][CH:11]=2)=[O:9])[CH2:3][CH2:2]1.[C:31](Cl)(=[O:34])[CH2:32][CH3:33]>>[C:31]([N:1]1[CH2:6][CH2:5][CH:4]([NH:7][C:8]([C:10]2[C:14]3[N:15]=[CH:16][N:17]=[C:18]([C:19]4[C:27]5[O:26][CH2:25][O:24][C:23]=5[CH:22]=[CH:21][C:20]=4[O:28][CH2:29][CH3:30])[C:13]=3[NH:12][CH:11]=2)=[O:9])[CH2:3][CH2:2]1)(=[O:34])[CH2:32][CH3:33]
Reactant: CCOc1ccc2c(c1-c1ncnc3c(C(=O)NC4CCNCC4)c[nH]c13)OCO2
Reactant: CCC(=O)Cl
Product: CCOc1ccc2c(c1-c1ncnc3c(C(=O)NC4CCN(C(=O)CC)CC4)c[nH]c13)OCO2

Procedure:
Starting from 4-(5-ethoxy-benzo[1,3]dioxol-4-yl)-5H-pyrrolo[3,2-d]pyrimidine-7-carboxylic acid piperidin-4-ylamide (example A175) and propionyl chloride the title compound was obtained as colorless solid.
Reaction SMILES: ClCCl.[CH3:4][C:5]1([CH3:38])[C:17]2[NH:16][C:15]3[C:10](=[CH:11][CH:12]=[C:13]([C:18]#[N:19])[CH:14]=3)[C:9]=2[C:8](=[O:20])[C:7]2[CH:21]=[CH:22][C:23]([O:25][CH:26]3[CH2:31][O:30]C(C4C=CC=CC=4)[O:28][CH2:27]3)=[CH:24][C:6]1=2>O>[OH:30][CH2:31][CH:26]([CH2:27][OH:28])[O:25][C:23]1[CH:22]=[CH:21][C:7]2[C:8](=[O:20])[C:9]3[C:10]4[C:15](=[CH:14][C:13]([C:18]#[N:19])=[CH:12][CH:11]=4)[NH:16][C:17]=3[C:5]([CH3:4])([CH3:38])[C:6]=2[CH:24]=1
Reactant: CC1(C)c2cc(OC3COC(c4ccccc4)OC3)ccc2C(=O)c2c1[nH]c1cc(C#N)ccc21
Solvent: O
Solvent: ClCCl
Product: CC1(C)c2cc(OC(CO)CO)ccc2C(=O)c2c1[nH]c1cc(C#N)ccc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 66.4 %

Procedure:
Anhydrous ferric trichloride (56 mg, 5 eq.) was added to the dichloromethane (2 mL) suspension of 6,6-dimethyl-11-oxo-8-(2-phenyl-[1,3]dioxan-5-yloxy)-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile (Compound A7-13-1, 13 mg, 0.028 mmol), and stirred at room temperature for 1 hr. The reaction solution was added to water, and then extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over sodium sulfate. The drying agent was removed by filtration and the residues obtained after concentration under reduced pressure were purified by high performance liquid chromatography to obtain the title compound (7 mg, 46%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[NH:6][C:7]3[C:12]([C:13]=2[CH:14]=1)=[CH:11][CH:10]=[CH:9][CH:8]=3.I[C:16]1[CH:28]=[CH:27][C:19]2[O:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=3[C:18]=2[CH:17]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].[C@@H]1(N)CCCC[C@H]1N>[Cu]I.O1CCOCC1>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:24]3[CH:25]=[CH:26][C:21]4[O:20][C:19]5[CH:27]=[CH:28][CH:16]=[CH:17][C:18]=5[C:22]=4[CH:23]=3)[C:7]3[C:12]([C:13]=2[CH:14]=1)=[CH:11][CH:10]=[CH:9][CH:8]=3
Reactant: Brc1ccc2[nH]c3ccccc3c2c1
Reactant: Ic1ccc2oc3ccccc3c2c1
Agent: [Cu]I
Agent: N[C@@H]1CCCC[C@H]1N
Agent: O=P([O-])([O-])[O-]
Solvent: C1COCCO1
Product: Brc1ccc2c(c1)c1ccccc1n2-c1ccc2oc3ccccc3c2c1
Yield: 56.3 %

Procedure:
A mixture of 8.9 g (36.2 mmole) 3-bromo-9H-carbazole, 10.6 g (36.2 mmole) of 2-iododibenzo[b,d]furan, 17.1 g (90 mmole) of copper(I) iodide, 19.1 g (90 mmole) of potassium phosphate, 10.3 g (90 mmole) of trans-1,2-cyclohexanediamine and 1,4-dioxane 700 ml were refluxed under nitrogen for about overnight. Then, the solution was filtered at 110° C. To receive the filtrate, And the 1,4-dioxane was removed under reduced pressure from the filtrate. The filtrate was extracted with 500 ml dichloromethane and 2000 ml water, the organic layer was dried with anhydrous magnesium sulfate, the solvent was removed and the residue was purified by column chromatography on silica (hexane-ethyl acetate) to give product 8.4 g (56%).
Reaction SMILES: [C:1]([NH:4][CH2:5][CH2:6][C:7]1[C:15]2[O:14][C:13]([C:16](OC)=[O:17])=[CH:12][C:11]=2[CH:10]=[CH:9][CH:8]=1)(=[O:3])[CH3:2].[BH4-].[Li+].Cl>O1CCCC1>[OH:17][CH2:16][C:13]1[O:14][C:15]2[C:7]([CH2:6][CH2:5][NH:4][C:1](=[O:3])[CH3:2])=[CH:8][CH:9]=[CH:10][C:11]=2[CH:12]=1
Reactant: COC(=O)c1cc2cccc(CCNC(C)=O)c2o1
Agent: Cl
Agent: [BH4-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CC(=O)NCCc1cccc2cc(CO)oc12
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A solution of 1.41 g of methyl 7-(2-acetylaminoethyl)benzofuran-2-carboxylate in 40 ml of tetrahydrofuran is admixed at 0° C. with 0.30 g of lithium borohydride. The reaction mixture is stirred at room temperature over 4 hours and then admixed slowly with 20 ml of 2N HCl. The mixture is concentrated by evaporation. The residue is taken up in methanol (2×) and once more concentrated by evaporation. The title compound is obtained as an orange oil from the residue by means of flash chromatography (SiO2 60F). Rf=0.47 (9:1 dichloromethane-methanol); Rt=2.67.
Reaction SMILES: [N:1]([C:4]1[CH:5]=[CH:6][C:7]([O:10][CH2:11][C:12]2[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=2)=[N:8][CH:9]=1)=[N+:2]=[N-:3].[C:20](OC=C)(=O)[CH3:21]>>[N:1]1([C:4]2[CH:5]=[CH:6][C:7]([O:10][CH2:11][C:12]3[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=3)=[N:8][CH:9]=2)[CH:21]=[CH:20][N:3]=[N:2]1
Reactant: C=COC(C)=O
Reactant: COc1ccc(COc2ccc(N=[N+]=[N-])cn2)cc1
Product: COc1ccc(COc2ccc(-n3ccnn3)cn2)cc1
Temperature: 100 °C

Procedure:
5-Azido-2-(4′-methoxybenzyloxy)pyridine from step 2 of this example (55 mg, 0.215 mmol) and vinyl acetate (692 μl, 7.51 mmol) were mixed in a flame dried high pressure sealable vessel. The reaction vessel was evacuated and charged with nitrogen, sealed, and heated to 100° C. for 15 hours. The reaction was cooled to room temperature and TLC indicated that the reaction was complete. Minimal dichloromethane was added to the reaction (just enough to dissolve solids that formed upon cooling) and the solution added to a Biotage 25 g SiO2 column, eluting with 20-50% ethyl acetate/heptane to give the title compound as a white solid.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([N+:8]([O-])=O)[CH:5]=[C:4]([CH3:11])[C:3]=1[C:12]1[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][CH:13]=1>C(O)C.[Pd]>[CH3:1][C:2]1[CH:7]=[C:6]([NH2:8])[CH:5]=[C:4]([CH3:11])[C:3]=1[C:12]1[CH:17]=[CH:16][C:15]([C:18]([F:19])([F:21])[F:20])=[CH:14][CH:13]=1
Reactant: Cc1cc([N+](=O)[O-])cc(C)c1-c1ccc(C(F)(F)F)cc1
Agent: [Pd]
Solvent: CCO
Product: Cc1cc(N)cc(C)c1-c1ccc(C(F)(F)F)cc1
Reaction time: 4 h
Yield: 103.1 %

Procedure:
To a solution of 2,6-dimethyl-4-nitro-4′-trifluoromethyl-biphenyl (0.68 g) in ethanol (20 mL) is added 10% palladium on carbon (0.02 g). The reaction is charged to 30 psi under a hydrogen atmosphere and allowed to stir for 4 h. The mixture is then filtered through a pad of Celite®. The solution is concentrated and purified by reverse phase HPLC using 0.1% TFA in water and acetonitrile to afford 0.63 g of the titled compound. 1H-NMR.
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[C:15]3[S:22][C:21]([CH3:23])=[CH:20][C:16]=3[N:17]=[CH:18][N:19]=2)[CH2:10][CH2:9]1)C1C=CC=CC=1.[NH:24]([C:37]([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38])[C@@H:25]([C:34]([OH:36])=O)[CH2:26][C:27]1[CH:32]=[CH:31][C:30]([Cl:33])=[CH:29][CH:28]=1.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C>CO.C(O)(C(F)(F)F)=O.[Pd]>[C:40]([O:39][C:37](=[O:38])[NH:24][CH:25]([CH2:26][C:27]1[CH:28]=[CH:29][C:30]([Cl:33])=[CH:31][CH:32]=1)[C:34]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[C:15]3[S:22][C:21]([CH3:23])=[CH:20][C:16]=3[N:17]=[CH:18][N:19]=2)[CH2:10][CH2:9]1)=[O:36])([CH3:43])([CH3:42])[CH3:41]
Reactant: Cc1cc2ncnc(N3CCN(Cc4ccccc4)CC3)c2s1
Reactant: CC(C)(C)OC(=O)N[C@H](Cc1ccc(Cl)cc1)C(=O)O
Agent: [Pd]
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: O=C(O)C(F)(F)F
Solvent: CO
Product: Cc1cc2ncnc(N3CCN(C(=O)C(Cc4ccc(Cl)cc4)NC(=O)OC(C)(C)C)CC3)c2s1
Reaction time: 4 h
Yield: 58.1 %

Procedure:
To a solution of 4-(4-Benzyl-piperazin-1-yl)-6-methylthieno[3,2-d]pyrimidine (65 mg, 0.20 mmol) in MeOH (10 mL) was added Pd/C (10%, 20 mg) and two drop of TFA. The mixture was stirred under H2 balloon for 4 hours. The catalyst was filtered off and the filtrate was concentrated. The residue was dissolved in DCM (6 mL) and TEA (2 mL), then Boc-D-Phe(4-Cl)—OH (59 mg, 0.20 mmol) was added, followed by HOBT (50 mg, 0.37 mmol) and EDCI (74 mg, 0.39 mmol). The mixture was stirred at room temperature for 12 hours. The solvent was removed and the residue was subject to chromatography on silica gel to give the product {1-(4-chlorobenzyl)-2-[4-(6-methylthieno[3,2-d]pyrimidin-4-yl)-piperazin-1-yl]-2-oxo-ethyl}-carbamic acid tert-butyl ester (60 mg, 59%). 1H NMR (CDCl3, 400 Hz) δ 8.54 (s, 1H), 7.28-7.26 (d, J=7.2 Hz, 2H), 7.17-7.15 (d, J=8.4 Hz, 2H), 7.08 (s, 1H), 5.37-5.35 9d, J=8.8 Hz, 1H), 4.86-4.84 (m, 1H), 3.87-3.57 (m, 7H), 3.24-3.22 (m, 1H), 3.00-2.98 (d, J=7.2 Hz, 2H), 2.63 (s, 3H), 1.43 (s, 9H). MS (ESI+) [M+H]+ 516.
Reaction SMILES: [Si]([O:8][C@H:9]([C:54]1[CH:63]=[CH:62][C:61]([OH:64])=[C:60]2[C:55]=1[CH:56]=[CH:57][C:58](=[O:65])[NH:59]2)[CH2:10][NH:11][CH2:12][C:13]1[CH:18]=[CH:17][C:16]([NH:19][C:20]([CH2:22][CH2:23][CH2:24][CH2:25][N:26]([CH3:53])[C:27]([CH2:29][CH2:30][N:31]2[CH2:36][CH2:35][CH:34]([O:37][C:38](=[O:52])[NH:39][C:40]3[CH:45]=[CH:44][CH:43]=[CH:42][C:41]=3[C:46]3[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=3)[CH2:33][CH2:32]2)=[O:28])=[O:21])=[CH:15][CH:14]=1)(C(C)(C)C)(C)C.[FH:66].F.F.C(N(CC)CC)C.CCOC(C)=O>C(Cl)Cl.CN(C=O)C>[FH:66].[FH:66].[OH:8][C@H:9]([C:54]1[CH:63]=[CH:62][C:61]([OH:64])=[C:60]2[C:55]=1[CH:56]=[CH:57][C:58](=[O:65])[NH:59]2)[CH2:10][NH:11][CH2:12][C:13]1[CH:14]=[CH:15][C:16]([NH:19][C:20]([CH2:22][CH2:23][CH2:24][CH2:25][N:26]([CH3:53])[C:27]([CH2:29][CH2:30][N:31]2[CH2:36][CH2:35][CH:34]([O:37][C:38](=[O:52])[NH:39][C:40]3[CH:45]=[CH:44][CH:43]=[CH:42][C:41]=3[C:46]3[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=3)[CH2:33][CH2:32]2)=[O:28])=[O:21])=[CH:17][CH:18]=1
Reactant: CN(CCCCC(=O)Nc1ccc(CNC[C@H](O[Si](C)(C)C(C)(C)C)c2ccc(O)c3[nH]c(=O)ccc23)cc1)C(=O)CCN1CCC(OC(=O)Nc2ccccc2-c2ccccc2)CC1
Agent: F
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CN(CCCCC(=O)Nc1ccc(CNC[C@H](O)c2ccc(O)c3[nH]c(=O)ccc23)cc1)C(=O)CCN1CCC(OC(=O)Nc2ccccc2-c2ccccc2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 105.1 %

Procedure:
To a stirred solution of biphenyl-2-ylcarbamic acid 1-(2-{[4-(4-{[(R)-2-(tert-butyldimethylsilanyloxy)-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethylamino]-methyl}phenylcarbamoyl)butyl]methylcarbamoyl}ethyl)piperidin-4-yl ester (3.87 g, 4.28 mmol) in a mixture of DCM (20 mL) and DMF (2.5 mL) was added triethylamine trihydrofluoride (2.1 mL, 13 mmol). The resulting mixture was stirred at room temperature overnight. DCM (68 mL) was added to the reaction mixture and then, with stirring, EtOAc (68 mL) was added dropwise. A light colored precipitate formed resulting in a slurry. The slurry mixture was filtered through a medium porosity fritted glass filter and the filter cake was rinsed with EtOAc (2×10 mL) and then pressed dry on a nitrogen press to give the title compound (3.73 g, 99% yield).
Reaction SMILES: C[O:2][C:3](=[O:24])[CH2:4][C@H:5]([NH:16][C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:6][C:7]1[CH:12]=[C:11]([F:13])[C:10]([F:14])=[CH:9][C:8]=1[F:15].O[Li].O.C([O-])(O)=O.[Na+]>C1COCC1.O>[C:20]([O:19][C:17]([NH:16][C@H:5]([CH2:6][C:7]1[CH:12]=[C:11]([F:13])[C:10]([F:14])=[CH:9][C:8]=1[F:15])[CH2:4][C:3]([OH:24])=[O:2])=[O:18])([CH3:23])([CH3:21])[CH3:22]
Reactant: COC(=O)C[C@@H](Cc1cc(F)c(F)cc1F)NC(=O)OC(C)(C)C
Agent: O=C([O-])O
Agent: [Li]O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)OC(=O)N[C@@H](CC(=O)O)Cc1cc(F)c(F)cc1F
Reaction time: 16 h
Yield: 95.1 %

Procedure:
To a solution of (R)-Methyl-3-[N-(tert-butoxycarbonyl)amino]-4-(2,4,5-tri-fluorophenyl)butanoate of Example 4 (1.28 g, 3.69 mmol) in 15 mL THF and 15 mL water was added 3 equiv. LiOH.H2O. The reaction mixture was stirred for 16 h. 10 ml saturated NaHCO3 was added. THF was evaporated and the aq solution was acidified to pH 2-3 with NaHSO4, then extracted by ethyl acetate (3×15 mL). The combined organic phase was washed with brine and dried over Na2SO4. Concentration in vacuo afforded 1.17 g of white solid (95.1%). 1H NMR (300 MHz, CD3OD) 7.13-7.03 (m, 2H), 4.20-4.10 (m, 1H), 3.00-2.90 (m, 1H), 2.75-2.60 (m, 1H), 2.45-2.55 (m, 2H), 1.35 (s, 9H)
Reaction SMILES: [CH2:1]([N:8]([CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[CH:9]([CH3:20])[CH:10]([C:12]1([C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH2:14][CH2:13]1)[OH:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.FC(F)(F)S(O[Si:34]([C:37]([CH3:40])([CH3:39])[CH3:38])([CH3:36])[CH3:35])(=O)=O.CC1C=CC=C(C)N=1.O>C1COCC1>[Si:34]([O:11][CH:10]([C:12]1([C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH2:13][CH2:14]1)[CH:9]([N:8]([CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[CH2:21][C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1)[CH3:20])([C:37]([CH3:40])([CH3:39])[CH3:38])([CH3:36])[CH3:35]
Reactant: CC(C)(C)[Si](C)(C)OS(=O)(=O)C(F)(F)F
Reactant: CCOC(=O)C1(C(O)C(C)N(Cc2ccccc2)Cc2ccccc2)CC1
Solvent: Cc1cccc(C)n1
Solvent: C1CCOC1
Solvent: O
Product: CCOC(=O)C1(C(O[Si](C)(C)C(C)(C)C)C(C)N(Cc2ccccc2)Cc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 17 h
Yield: 76 %

Procedure:
A solution of ethyl 1-[(1RS,2RS)-2-(dibenzylamino)-1-hydroxypropyl]cyclopropanecarboxylate (1.30 g) in THF (15 mL) was cooled to 0° C., tert-butyl(dimethyl)silyl trifluoromethanesulfonate (0.98 mL) and 2,6-dimethylpyridine (0.621 mL) were added, and the mixture was stirred at room temperature for 17 hr. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane/ethyl acetate=1/0→4/1) to give the title compound as a colorless oil (yield: 1.30 g, 76%).
Reaction SMILES: [CH2:1]([C:4]1[NH:5][C:6]([C:12](OCC)=O)=[C:7]([CH3:11])[C:8]=1[CH2:9][CH3:10])[CH2:2][CH3:3].[CH:17](=O)[CH2:18]C>>[CH2:1]([C:4]1[NH:5][C:6]([CH2:12][CH2:17][CH3:18])=[C:7]([CH3:11])[C:8]=1[CH2:9][CH3:10])[CH2:2][CH3:3]
Reactant: CCC=O
Reactant: CCCc1[nH]c(C(=O)OCC)c(C)c1CC
Product: CCCc1[nH]c(CCC)c(CC)c1C

Procedure:
2-n-propyl-3-ethyl-4-methyl-5-carbethoxy-pyrrole was reductively alkylated with propionaldehyde to yield 2,5-di(n-propyl)-3-ethyl-4-methylpyrrole. ##STR103##
Reaction SMILES: CN(C)[C:3]1[CH:4]=[C:5]([CH2:9][OH:10])[CH:6]=[CH:7][CH:8]=1.[Br:12][C:13]1[C:14]([CH3:20])=[C:15](O)[CH:16]=[CH:17][CH:18]=1.CC1(C)C(C)(C)OB(C2C=NNC=2)O1>>[Br:12][C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([O:10][CH2:9][CH:5]2[CH2:6][CH2:7][CH2:8][CH2:3][CH2:4]2)[C:14]=1[CH3:20]
Reactant: CN(C)c1cccc(CO)c1
Reactant: Cc1c(O)cccc1Br
Agent: CC1(C)OB(c2cn[nH]c2)OC1(C)C
Product: Cc1c(Br)cccc1OCC1CCCCC1

Procedure:
The title compound was prepared by substituting cyclohexylmethanol for (3-(dimethylamino)phenyl)methanol and 3-bromo-2-methylphenol for 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole in EXAMPLE 34A.
Reaction SMILES: C([Mg]Cl)(C)C.[CH2:6]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH2:9][CH2:8][NH:7]1.[F:16][C:17]([F:28])([F:27])[CH2:18][CH2:19][Si:20](OC)([O:23][CH3:24])[O:21][CH3:22]>C1COCC1>[F:28][C:17]([F:16])([F:27])[CH2:18][CH2:19][Si:20]([CH:6]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH2:9][CH2:8][NH:7]1)([O:21][CH3:22])[O:23][CH3:24]
Reactant: c1ccc2c(c1)CCNC2
Reactant: CO[Si](CCC(F)(F)F)(OC)OC
Agent: CC(C)[Mg]Cl
Solvent: C1CCOC1
Product: CO[Si](CCC(F)(F)F)(OC)C1NCCc2ccccc21
Temperature: 15 °C
Reaction time: 2 h
Yield: 99.1 %

Procedure:
3,3,3-Tritluoropropyl(1,2,3,4-tetrahydroisoquinolinyl)dimethoxysilane--A 500 mL round bottomed flask was charged with tetrahydrofuran (300 mL) and isopropyl-magnesium chloride (30 mL of a 2.0 M solution in THF, 60 mmol). The contents were cooled to 15° C. 1,2,3,4-Tetrahydroisoquinoline (60 mmol) was added over fifteen minutes via pressure equalizing addition funnel. The cold bath was removed and the contents stirred for two hours. 3,3,3-Trifluoropropyltrimethoxysilane (54.5 mmol) was added via pressure equalizing addition funnel. The contents were brought to reflux (65-70° C.) for two hours and reaction progress was monitored by GC. Isolation was accomplished by removing the THF via rotary evaporation, taking the residue up in ether (250 mL), filtration and ether removal via rotary evaporation. Purification was accomplished by distillation to provide 3,3,3-trifluoropropyl(1,2,3,4-tetrahydroisoquinolinyl)dimethoxysilane (54 mmol; 99% yield). C14H20NO2SiF3 (mw=319.39) bp=98° C. at 0.3 mmHg; 1H NMR: (CDCl3) δ 7.2-6.9 (m, 4H), 4.2-4.0 (d, 2H), 3.6-3.4 (s, 6H), 3.3-3.1 (dt, 2H), 2.8-2.6 (m, 2H), 2.2-1.9 (m, 2H), 0.9-0.8 (m, 2H); 13C NMR: (CDCl3) δ 135.9, 135.1, 129.4, 128 (quartet J=275 Hz), 126.0, 125.9, 125.8, 50.4, 46.5, 42.1, 29.9, 28 (quartet, J=30 Hz), 2.8; MS: m/z (relative abundance) 319 (38.3), 318 (100), 222 (7.9), 132 (21.0), 104 (21.4), 79 (9.8), 59 (13.4).
Reaction SMILES: [C:1]12([C:11]3[N:15]([CH3:16])[C:14]([C:17]4[CH:22]=[CH:21][C:20]([S:23][CH3:24])=[CH:19][CH:18]=4)=[N:13][N:12]=3)[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.ClC1C=CC=C(C(OO)=[O:33])C=1>C(Cl)Cl>[C:1]12([C:11]3[N:15]([CH3:16])[C:14]([C:17]4[CH:22]=[CH:21][C:20]([S:23]([CH3:24])=[O:33])=[CH:19][CH:18]=4)=[N:13][N:12]=3)[CH2:8][CH:7]3[CH2:6][CH:5]([CH2:4][CH:3]([CH2:9]3)[CH2:2]1)[CH2:10]2
Reactant: CSc1ccc(-c2nnc(C34CC5CC(CC(C5)C3)C4)n2C)cc1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: Cn1c(-c2ccc(S(C)=O)cc2)nnc1C12CC3CC(CC(C3)C1)C2
Temperature: 25 °C
Reaction time: 0.42 h

Procedure:
A mixture of 3-(1-adamantyl)-4-methyl-5-[4-(methylthio)phenyl]-4H-1,2,4-triazole (4-23) (50 mg, 0.15 mmol) and m-chloroperbenzoic acid (85%, MCPBA) (45 mg, 0.22 mmol) in methylene chloride (0.75 mL) was stirred at room temperature for 25 min. The mixture was diluted with methylene chloride, washed with 10% aqueous K2CO3, water, and saturated brine and dried (MgSO4). The residue after evaporation in vacuo was purified by reverse-phase chromatography on a C-18 silica gel column with an acetonitrile-0.1% trifluoroacetic acid gradient to give 3-(1-adamantyl)-4-methyl-5-[4-(methylsulfinyl)phenyl]-4H-1,2,4-triazole (4-24).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:18]=[C:17]2[C:12]([CH:13]=[C:14]([C:24]#[N:25])[C:15]([N:19]=[CH:20][N:21](C)C)=[CH:16]2)=[CH:11][C:10]=1[O:26][CH3:27])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:28][C:29]1[CH:35]=[C:34]([Cl:36])[C:33]([O:37][CH3:38])=[CH:32][C:30]=1N>C(O)(=O)C>[CH2:1]([O:8][C:9]1[C:10]([O:26][CH3:27])=[CH:11][C:12]2[CH:13]=[C:14]3[C:15](=[CH:16][C:17]=2[CH:18]=1)[N:19]=[CH:20][N:21]=[C:24]3[NH:25][C:30]1[CH:32]=[C:33]([O:37][CH3:38])[C:34]([Cl:36])=[CH:35][C:29]=1[Cl:28])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COc1cc(N)c(Cl)cc1Cl
Reactant: COc1cc2cc(C#N)c(N=CN(C)C)cc2cc1OCc1ccccc1
Solvent: CC(=O)O
Product: COc1cc(Nc2ncnc3cc4cc(OCc5ccccc5)c(OC)cc4cc23)c(Cl)cc1Cl
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of N′-(7-benzyloxy-3-cyano-6-methoxynaphthalen-2-yl)-N,N-dimethylformamidine and 0.092 g (0.48 mmol) of 2,4-dichloro-5-methoxyaniline in 4 mL of glacial acetic acid is heated under reflux for 7 hours, then cooled to room temperature and stirred overnight. The resulting solid is collected by filtration, washed with ether and dried to yield 0.05 g of (8-benzyloxy-7-methoxybenzo[g]quinazolin-4-yl)-(2,4-dichloro-5-methoxyphenyl)amine as a yellow solid, mp 275-280° C.
Reaction SMILES: [NH2:1][C:2]1[C:11]([NH2:12])=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=1.[H-].[Na+].[CH3:15]I>CN(C)C=O.C(OCC)(=O)C>[NH2:1][C:2]1[C:11]([NH:12][CH3:15])=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=1
Reactant: CI
Reactant: Nc1cc2ccccc2cc1N
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CNc1cc2ccccc2cc1N
Temperature: 2.5 °C
Reaction time: 0.12 h
Yield: 30.9 %

Procedure:
A solution of 2,3-diaminonaphthalene (500 mg, 3.16 mmol) in anhydrous dimethylformamide (3 mL) was cooled in an ice bath and treated with sodium hydride (130 mg of a 61% dispersion in mineral oil, 3.31 mmol). The mixture was stirred at 0-5° C. for 7 minutes, then treated with methyl iodide (0.206 mL, 3.31 mmol) and stirred in the cold for an additional 15 minutes. After warming to room temperature, the mixture was diluted with ethyl acetate (30 mL), washed with water (5×30 mL) and brine (20 mL), dried over magnesium sulfate, filtered, and evaporated under vacuum to a dark solid (0.5 g). The crude product was purified by silica gel chromatography (2.75×24 cm column) using 5% ethyl acetate in dichloromethane as eluting solvent. The product fractions were combined and evaporated to afford 2-amino-3-methylamino-naphthalene (168 mg) as a solid.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([S:14]([C:17]2[CH:18]=[CH:19][C:20]3[O:29][CH2:28][CH2:27][N:26]4[C:22](=[N:23][C:24]([C:30]5[N:31]([CH:35]([CH3:37])[CH3:36])[N:32]=[CH:33][N:34]=5)=[CH:25]4)[C:21]=3[CH:38]=2)(=[O:16])=[O:15])[CH2:10][CH2:9]1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH:35]([N:31]1[C:30]([C:24]2[N:23]=[C:22]3[N:26]([CH2:27][CH2:28][O:29][C:20]4[CH:19]=[CH:18][C:17]([S:14]([N:11]5[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]5)(=[O:15])=[O:16])=[CH:38][C:21]=43)[CH:25]=2)=[N:34][CH:33]=[N:32]1)([CH3:37])[CH3:36]
Reactant: CC(C)n1ncnc1-c1cn2c(n1)-c1cc(S(=O)(=O)N3CCN(C(=O)OC(C)(C)C)CC3)ccc1OCC2
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(C)n1ncnc1-c1cn2c(n1)-c1cc(S(=O)(=O)N3CCNCC3)ccc1OCC2
Temperature: 25 °C
Reaction time: 1 h
Yield: 88.8 %

Procedure:
A solution of 4-[2-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-1,3a-diazabenzo[e]azulene-9-sulfonyl]piperazine-1-carboxylic acid tert-butyl ester (175 mg, 0.32 mmol) in DCM (3 mL) was treated with TFA (3 mL) and the resulting mixture stirred at RT for 1 h then concentrated in vacuo. The resulting residues was loaded onto an Isolute® SCX-2 cartridge which was washed with MeOH and eluted with 2M NH3/MeOH affording 2-(2-Isopropyl-2H-[1,2,4]triazol-3-yl)-9-(piperazine-1-sulfonyl)-4,5-dihydro-6-oxa-1,3a-diazabenzo[e]azulene (126 mg, 88%). LCMS: RT 2.20 and 0.32 min [M+H]+ 444.3
Reaction SMILES: N[C:2]1[N:11]=[CH:10][C:9]2[C:8](=[O:12])[NH:7][CH:6]=[N:5][C:4]=2[CH:3]=1.N([O-])=O.[Na+].C([O-])([O-])=O.[Na+].[Na+].[H+].[B-](F)(F)(F)[F:25]>>[F:25][C:2]1[N:11]=[CH:10][C:9]2[C:8](=[O:12])[NH:7][CH:6]=[N:5][C:4]=2[CH:3]=1
Reactant: Nc1cc2nc[nH]c(=O)c2cn1
Reactant: F[B-](F)(F)F
Agent: O=C([O-])[O-]
Agent: O=N[O-]
Agent: [H+]
Product: O=c1[nH]cnc2cc(F)ncc12
Temperature: 20 °C
Reaction time: 0.5 h
Yield: 47 %

Procedure:
A solution of 7-amino-4-oxo-3H-pyrido[4,3-d]pyrimidine (1.00 g, 6.17 mmol) in 60% HBF4 (25 mL) at 0° C. is treated with solid NaNO2 (0.85 g, 12.3 mmol, added in portions over 2 h), and is then stirred at 0° C. for a further 1 h and at 20° C. for 30 min. The resulting mixture is ice-cooled, neutralized with saturated aqueous Na2CO3, and extracted with EtOAc (4×100 mL) The extract is washed with water, then filtered through silica gel (EtOAc) to give 7-fluoro-4-oxo-3H-pyrido[4,3-d]pyrimidine (0.48 g, 47%) as a cream solid. 1H NMR (DMSO) δ 12.69 (1H, brs), 9.01 (1H, s), 8.31 (1H, s), 7.34 (1H, s).