Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]=[C:2]1[CH2:7][CH2:6][CH2:5][CH2:4][C:3]1([CH2:14]CC#N)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.O.[C:19]([OH:22])(=[O:21])[CH3:20]>Cl>[O:1]=[C:2]1[CH2:7][CH2:6][CH2:5][CH2:4][C:3]1([CH2:14][CH2:20][C:19]([OH:22])=[O:21])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: N#CCCC1(c2ccccc2)CCCCC1=O
Reactant: CC(=O)O
Agent: Cl
Solvent: O
Product: O=C(O)CCC1(c2ccccc2)CCCCC1=O
Temperature: 25 °C
Yield: 85 %

Procedure:
A mixture of 3-(2-oxo-1-phenylcyclohexyl)propanenitrile (5.05 g, 22.22 mmol) in acetic acid (11.1 mL), conc. HCl (33.2 mL), and water (11.1 mL) was refluxed for 16 h under N2, cooled to room temperature, and poured into water (66 mL). The product separated out as an layer of oil. The suspension was cooled to 0° C. in an ice bath for 30 min. with occasional swirling and the crystallized product was collected by filtration and rinsed several times with water, and dried in vacuo to obtain 3-(2-oxo-1-phenylcyclohexyl)propanoic acid (1B, 4.77 g, 85% yield) as a white crystalline solid. HPLC: tR=2.47 min, YMC Combiscreen ODS-A 4.6×50 mm, 4 min gradient, Detection Wave length 220 nm, Starting solvent: 10% aq. MeOH—0.1% TFA; Final solvent: 90% aq. MeOH—0.1% TFA. LC/MS: m/e 247.2 (M+H)+, 229.2 (M+H−H2O)+.
Reaction SMILES: [CH2:1](Br)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:9][S:10](=[S:13])([O-:12])=[O:11].[Na+]>CCO>[CH3:9][S:10](=[S:13])([O:12][CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)=[O:11]
Reactant: BrCc1ccccc1
Reactant: CS(=O)([O-])=S
Agent: [Na+]
Solvent: CCO
Product: CS(=O)(=S)OCc1ccccc1

Procedure:
Benzyl bromide (9.07 g, 0.053 mol) was slowly added to a suspension of sodium methanethiosulfonate (7.10 g, 0.0530 mol) in absolute EtOH (100 mL) and the reaction mixture was heated at reflux overnight. The reaction mixture was cooled with an ice bath and the solid (sodium bromide and sodium methanethiosulfonate) was filtered off. The filtrate was concentrated to give a crude product which was mainly the desired product. Pure product was obtained by flash chromatography on silica gel with EtOAc-hexanes (1:6) (7.92 g, 74%). The product was further purified by recrystallization from absolute ethanol. mp 39.5-40.2° C. (lit. 40-42.5° C.) IR (KBr): 3089, 3068, 3017, 3000, 2981, 2936, 2918, 1602, 1582, 1496, 1305, 1131, 960, 771, 741, 702 cm−1. 1H NMR (200 MHz, CDCl3): δ 7.38 (m, 5H, phenyl), 4.38 (s, 2H, SCH2), 2.91 (s, 3H, CH3SO2). 13C NMR (50 MHz, CDCl3): δ 135.12, 129.14, 129.03, 128.26, 51.09, 40.79.
Reaction SMILES: C([NH:8][C@H:9]1[CH2:18][CH2:17][C:16]2[C:11](=[CH:12][CH:13]=[CH:14][C:15]=2[C:19]2[C:20]([CH3:26])=[N:21][N:22]([CH3:25])[C:23]=2[CH3:24])[CH2:10]1)C1C=CC=CC=1.CO>C1COCC1.[Pd]>[CH3:25][N:22]1[C:23]([CH3:24])=[C:19]([C:15]2[CH:14]=[CH:13][CH:12]=[C:11]3[C:16]=2[CH2:17][CH2:18][C@H:9]([NH2:8])[CH2:10]3)[C:20]([CH3:26])=[N:21]1
Reactant: Cc1nn(C)c(C)c1-c1cccc2c1CC[C@H](NCc1ccccc1)C2
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CO
Product: Cc1nn(C)c(C)c1-c1cccc2c1CC[C@H](N)C2
Reaction time: 21 h
Yield: 83.8 %

Procedure:
A solution of (2S)-benzyl-[5-(1,3,5-trimethyl-1H-pyrazol-4-yl)-1,2,3,4-tetrahydro-naphthalen-2-yl]-amine (0.287 g, 0.832 mmol) in THF (4 mL) was added to Pd/C (0.10 g, 10% weight of Pd on activated carbon), and MeOH (10 mL) was added to the suspension. The reaction mixture was stirred under H2 (g) atmosphere (balloon) for 21 h. It was filtered through Celite washing with AcOEt (2×10 mL), the solvent was concentrated off and the crude was purified by flash chromatography on silica gel (CH2Cl2/MeOH/NH4OH 95:5:1), to yield 0.178 g of the title product (Rf=0.2 (AcOEt/MeOH/Et3N 20:3:2), pale yellow colored oil, 84% yield).
Reaction SMILES: [OH:1][C:2]([CH3:12])([CH:6]([CH3:11])[CH2:7][CH2:8][CH2:9][CH3:10])[CH2:3][CH2:4][NH2:5].C(=O)([O-])[O-].[Na+].[Na+].Cl[C:20]([O:22][CH2:23][CH3:24])=[O:21].O>CCO>[OH:1][C:2]([CH3:12])([CH:6]([CH3:11])[CH2:7][CH2:8][CH2:9][CH3:10])[CH2:3][CH2:4][NH:5][C:20](=[O:21])[O:22][CH2:23][CH3:24]
Reactant: CCOC(=O)Cl
Reactant: CCCCC(C)C(C)(O)CCN
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: CCCCC(C)C(C)(O)CCNC(=O)OCC
Reaction time: 0.5 h
Yield: 89 %

Procedure:
To a stirred suspension of 3-hydroxy-3,4-dimethyoctylamine (4.91 g; 28.38 mmole) and anhydrous sodium carbonate (5 g) in dry etanol (40 ml) was added ethyl chloroformate (3.65 g; 33.6 mmole) in dry ethanol (25 ml), over 30 min. The mixture was heated under reflux for 1 hr and then poured into water (200 ml). The product was extracted into diethyl ether (3×100 ml), and the combined organic layers washed with dilute hydrochloric acid (1×100 ml) and brine (1×100 ml) and dried. (Na2SO4). Evaporation in vacuo gave ethyl N-[3-hydroxy-3,4-dimethyloctyl]-carbamate (6.2 g; 891).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[N:9]([CH2:11][CH:12]1[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1)[CH:8]=[C:7]2[C:18](C(F)(F)F)=[O:19].[OH-:24].[Na+]>C(O)C>[Cl:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[N:9]([CH2:11][CH:12]1[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17]1)[CH:8]=[C:7]2[C:18]([OH:19])=[O:24]
Reactant: [OH-]
Reactant: O=C(c1cn(CC2CCCCC2)c2c(Cl)cccc12)C(F)(F)F
Agent: [Na+]
Solvent: CCO
Product: O=C(O)c1cn(CC2CCCCC2)c2c(Cl)cccc12
Temperature: 85 °C
Reaction time: 18 h

Procedure:
The mixture of 7-chloro-1-(cyclohexyl)methyl-3-[(trifluoromethyl)carbonyl]-1H-indole (8.6 g, 25.0 mmol) and 4N NaOH (60 ml) in ethanol (40 ml) was stirred at 85° C. for 18 h. The mixture was concentrated in vacuo and the residue was acidified with 5N HCl, then partitioned between dichloromethane and water. The aqueous layer was extracted with dichloromethane and combined organic layers were washed with brine, dried over sodium sulfate and concentrated in vacuo. The obtained crystals were washed with n-heptane to afford 7-chloro-1-(cyclohexyl)methyl-1H-indole-3-carboxylic acid (6.4 g, 21.9 mmol).
Reaction SMILES: [CH3:1][O-:2].[Na+].Cl[C:5]1[C:14]([CH2:15][C:16]2[CH:24]=[CH:23][C:19]([N:20]([CH3:22])[CH3:21])=[CH:18][CH:17]=2)=[C:13]([Cl:25])[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([I:26])[CH:11]=2)[N:6]=1>C1(C)C=CC=CC=1>[Cl:25][C:13]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([I:26])[CH:11]=2)[N:6]=[C:5]([O:2][CH3:1])[C:14]=1[CH2:15][C:16]1[CH:24]=[CH:23][C:19]([N:20]([CH3:22])[CH3:21])=[CH:18][CH:17]=1
Reactant: C[O-]
Reactant: CN(C)c1ccc(Cc2c(Cl)nc3ccc(I)cc3c2Cl)cc1
Agent: [Na+]
Solvent: Cc1ccccc1
Product: COc1nc2ccc(I)cc2c(Cl)c1Cc1ccc(N(C)C)cc1
Temperature: 110 °C
Reaction time: 3 h

Procedure:
Sodium methoxide (2.9 g, 54 mmol) was added to a solution of 4-((2,4-dichloro-6-iodoquinolin-3-yl)methyl)-N,N-dimethylaniline (3.5 g, 7.7 mmol, Intermediate 24: step b) in toluene (38 mL) with stirring. The mixture was heated to 110° C. After 3 hours, additional sodium methoxide (2 g, 37.2 mmol) was added. After 18 hours, the flask was allowed to cool to 50° C. The warm mixture was filtered through Celite®, rinsing with tetrahydrofuran. Silica gel (5 g) was added to the filtrate and the solvent was removed by rotary evaporation to afford a free-flowing powder. The powder was loaded onto a column of silica gel for purification. Elution with dichloromethane initially, grading to 1% methanol-dichloromethane provided the title compound as a solid.
Reaction SMILES: [CH3:1][C:2]1[C:3]([C:7]([O:9][CH3:10])=[O:8])=[CH:4][NH:5][CH:6]=1.[F:11][C:12]([F:21])([F:20])[C:13]1[CH:14]=[C:15](I)[CH:16]=[CH:17][CH:18]=1.C(=O)([O-])[O-].[K+].[K+]>CN1CCCC1=O>[CH3:1][C:2]1[C:3]([C:7]([O:9][CH3:10])=[O:8])=[CH:4][N:5]([C:17]2[CH:16]=[CH:15][CH:14]=[C:13]([C:12]([F:21])([F:20])[F:11])[CH:18]=2)[CH:6]=1
Reactant: COC(=O)c1c[nH]cc1C
Reactant: FC(F)(F)c1cccc(I)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN1CCCC1=O
Product: COC(=O)c1cn(-c2cccc(C(F)(F)F)c2)cc1C
Temperature: 170 °C
Reaction time: 1 h
Yield: 43.3 %

Procedure:
To a solution of methyl 4-methyl-1H-pyrrole-3-carboxylate (3.4 g) synthesized above in N-methyl-2-pyrrolidone (30 mL) were added 3-trifluoromethyliodobenzene (6.7 g), cuprous bromide (0.53 g) and potassium carbonate (4.4 g) at room temperature, and stirred for 1 hr with heating to 170° C. After cooling to room temperature, the reaction mixture was filtered through celite. Water was added to the filtrate and the mixture was extracted with diethyl ether. The extract was washed with brine, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (ethyl acetate:hexane=1:4, volume ratio) to give the title compound (3.0 g, 42%) as a slightly yellow solid.
Reaction SMILES: Cl.[O:2]([NH2:4])[CH3:3].[C:5]([C:9]1[CH:10]=[CH:11][CH:12]=[C:13]2[C:18]=1[N:17]([CH3:19])[CH2:16][CH2:15][C:14]2=O)([CH3:8])([CH3:7])[CH3:6]>N1C=CC=CC=1>[CH3:3][O:2][N:4]=[C:14]1[C:13]2[C:18](=[C:9]([C:5]([CH3:7])([CH3:6])[CH3:8])[CH:10]=[CH:11][CH:12]=2)[N:17]([CH3:19])[CH2:16][CH2:15]1
Reactant: CN1CCC(=O)c2cccc(C(C)(C)C)c21
Reactant: CON
Agent: Cl
Solvent: c1ccncc1
Product: CON=C1CCN(C)c2c1cccc2C(C)(C)C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Methoxylamine hydrochloride (0.86 g, 10.3 mmol) was added to a solution of Example 14D (2.04 g, 9.39 mmol) in pyridine (20 mL) and the mixture stirred overnight at ambient temperature. The mixture was concentrated under reduced pressure and ethyl acetate (200 mL) was added. The solution was washed twice with water (200 mL), once with brine, dried over anhydrous sodium sulfate, filtered, and concentrate under reduced pressure. The residue was chromatographed on silica gel eluting with 0-to-25% ethyl acetate in hexane to afford the title compound. 1H NMR (300 MHz, DMSO-d6) δ ppm 1.41 (s, 9H), 2.46 (s, 3H), 2.80 (m, 2H), 3.07 (m, 2H), 3.93 (s, 3H), 7.11 (t, J=7.80 Hz, 1H), 7.35 (dd, J=7.97, 1.53 Hz, 1H), 7.62 (dd, J=7.63, 1.53 Hz, 1H). MS (DCI) m/z 247.14 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([N+:12]([O-:14])=[O:13])=[C:5]2O.O=P(Cl)(Cl)[Cl:18]>>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([N+:12]([O-:14])=[O:13])=[C:5]2[Cl:18]
Reactant: O=[N+]([O-])c1cnc2ccc(Br)cc2c1O
Reactant: O=P(Cl)(Cl)Cl
Product: O=[N+]([O-])c1cnc2ccc(Br)cc2c1Cl
Temperature: 120 °C
Reaction time: 17 h

Procedure:
6-Bromo-3-nitro-quinolin-4-ol (Fluorochem Ltd., Derbyshire, UK, 10 g, 37.2 mmol) was added to POCl3 (70 ml). The RM was stirred at 120° C. for 17 h. Then the RM was cooled with an ice-bath, before being slowly dropped onto ice-water. The precipitate was filtered and washed with cold water. The residue was dissolved in DCM, washed with brine, dried over Na2SO4, filtered and evaporated to give the title compound as a beige solid (HPLC tR 3.64 min (Method A))
Reaction SMILES: [CH:1]1([C:7]([C:9]2[O:10][C:11]3[CH:18]=[CH:17][C:16]([N:19]4[CH2:24][CH2:23][S:22][CH2:21][CH2:20]4)=[CH:15][C:12]=3[C:13]=2[CH3:14])=[O:8])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[BH4-].[Na+]>O1CCCC1.CO>[CH:1]1([CH:7]([C:9]2[O:10][C:11]3[CH:18]=[CH:17][C:16]([N:19]4[CH2:24][CH2:23][S:22][CH2:21][CH2:20]4)=[CH:15][C:12]=3[C:13]=2[CH3:14])[OH:8])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: Cc1c(C(=O)C2CCCCC2)oc2ccc(N3CCSCC3)cc12
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Product: Cc1c(C(O)C2CCCCC2)oc2ccc(N3CCSCC3)cc12
Temperature: 25 °C
Reaction time: 1 h
Yield: 21.6 %

Procedure:
Cyclohexyl[3-methyl-5-(thiomorpholin-4-yl)-1-benzofuran-2-yl]methanone (0.83 g) synthesized in the above-mentioned (1) was dissolved in tetrahydrofuran (10 mL) and methanol (1 mL), and sodium borohydride (90%, 0.2 g) was added to the solution under ice-cooling. The ice bath was removed, and the reaction mixture was stirred at room temperature for 1 hr then ice-cooled again, and water (1 mL) and 1N hydrochloric acid (5 mL) were carefully added, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate:hexane=1:4, volume ratio) to give the title object compound (0.18 g, 22%) as a yellow oil.
Reaction SMILES: Cl[C:2]1[C:3]2[S:20][C:19]([NH2:21])=[N:18][C:4]=2[N:5]=[C:6]([S:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([F:16])[C:11]=2[F:17])[N:7]=1.Cl.[NH2:23][C@H:24]([CH3:28])[C:25]([NH2:27])=[O:26]>>[NH2:21][C:19]1[S:20][C:3]2[C:2]([NH:23][C@H:24]([CH3:28])[C:25]([NH2:27])=[O:26])=[N:7][C:6]([S:8][CH2:9][C:10]3[CH:15]=[CH:14][CH:13]=[C:12]([F:16])[C:11]=3[F:17])=[N:5][C:4]=2[N:18]=1
Reactant: Nc1nc2nc(SCc3cccc(F)c3F)nc(Cl)c2s1
Reactant: C[C@@H](N)C(N)=O
Agent: Cl
Product: C[C@@H](Nc1nc(SCc2cccc(F)c2F)nc2nc(N)sc12)C(N)=O

Procedure:
Prepared by the method of example 2 step a), using the product of example 4, step b) and (2R)-2-amino-propanamide hydrochloride,
Reaction SMILES: C([O:3][C:4](=O)[CH2:5][N:6]1[CH2:10][C@@H:9]2[CH2:11][CH2:12][CH2:13][C@@H:8]2[C:7]1=[O:14])C.[NH3:16]>CO>[O:14]=[C:7]1[C@H:8]2[CH2:13][CH2:12][CH2:11][C@H:9]2[CH2:10][N:6]1[CH2:5][C:4]([NH2:16])=[O:3]
Reactant: CCOC(=O)CN1C[C@@H]2CCC[C@@H]2C1=O
Reactant: N
Solvent: CO
Product: NC(=O)CN1C[C@@H]2CCC[C@@H]2C1=O
Temperature: 25 °C
Reaction time: 24 h

Procedure:
A solution of cis-hexahydro-1-oxo-cyclopenta[c]pyrrole-2(1H)-acetic acid ethyl ester (25 g, 0.0154 mole) in methanol is saturated with anhydrous ammonia and the mixture is stirred at room temperature 24 hours. The solution is concentrated at reduced pressure to yield a solid with mp 138°-141° C. Recrystallization (acetonitrile) yields pure cis-hexahydro-1-oxo-cyclopenta[c]pyrrole-2(1H)-acetamide with mp 142.5°-143.5° C.
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:13]=[CH:12][C:8]([C:9]([OH:11])=[O:10])=[CH:7][CH:6]=1)=O.[N:14]1[CH:19]=[CH:18][CH:17]=[C:16]([NH:20][C:21]([NH2:23])=[S:22])[CH:15]=1>C(O)C>[N:14]1[CH:19]=[CH:18][CH:17]=[C:16]([NH:20][C:21]2[S:22][CH:2]=[C:3]([C:5]3[CH:13]=[CH:12][C:8]([C:9]([OH:11])=[O:10])=[CH:7][CH:6]=3)[N:23]=2)[CH:15]=1
Reactant: NC(=S)Nc1cccnc1
Reactant: O=C(O)c1ccc(C(=O)CBr)cc1
Solvent: CCO
Product: O=C(O)c1ccc(-c2csc(Nc3cccnc3)n2)cc1
Yield: 739.9 %

Procedure:
A solution of 4-bromoacetylbenzoic acid (2.2 g, 10 mmol) in ethanol (50 mL) was treated with pyrid-3-ylthiourea (1.53 g, 1 mmol) and the mixture was refluxed for 3 hr. Solids were collected by filteration, washed with ether and dried to provide 4-(2-pyrid-3-ylaminothiazol-4-yl)benzoic acid (2.2 g, 74% yield). LC-MS: FAB LC-MS. 298.2 (M+H+).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([N:8]([CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([O:23][C:24]([F:29])([F:28])[CH:25]([F:27])[F:26])[CH:18]=2)[CH2:9][CH:10]([OH:15])[C:11]([F:14])([F:13])[F:12])[CH:5]=[CH:6][CH:7]=1.C(O)(=O)C.[CH:34](=O)[CH:35]([CH3:37])[CH3:36].[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>ClC(Cl)C>[CH3:34][CH:35]([CH3:37])[CH2:36][NH:1][C:2]1[CH:3]=[C:4]([N:8]([CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([O:23][C:24]([F:28])([F:29])[CH:25]([F:26])[F:27])[CH:18]=2)[CH2:9][CH:10]([OH:15])[C:11]([F:14])([F:13])[F:12])[CH:5]=[CH:6][CH:7]=1
Reactant: Nc1cccc(N(Cc2cccc(OC(F)(F)C(F)F)c2)CC(O)C(F)(F)F)c1
Reactant: CC(C)C=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(Cl)Cl
Solvent: CC(=O)O
Product: CC(C)CNc1cccc(N(Cc2cccc(OC(F)(F)C(F)F)c2)CC(O)C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 27.8 %

Procedure:
The 3-[(3-aminophenyl)[[3-(1,1,2,2-tetrafluoroethoxy)phenyl]methyl]amino]-1,1,1-trifluoro-2-propanol (50 mg, 0.12 mmol) was dissolved in 1 mL of dichloroethane. Acetic acid (8 μL, 0.14 mmol) followed by isobutyraldehyde (11.7 μL, 0.13 mmol) and solid NaBH(OAc)3 (37.3 mg, 0.18 mmol) were added. The solution was stirred at room temperature for 18 hours. The reaction was filtered through pre-wetted celite eluting with ethyl acetate. The solvent was evaporated, and the residue was purified by reverse phase HPLC eluting with 10% to 90% acetonitrile in water to afford 16.1 mg (29%) of the desired 3-[[3-[(2-methylpropyl)amino]phenyl][[3-(1,1,2,2-tetrafluoroethoxy) phenyl]methyl]amino]-1,1,1-trifluoro-2-propanol product as a yellow oil, which was greater than 98% pure by reverse phase HPLC analysis. HRMS calcd. for C22H26F7N2O2: 483.1883 [M+H]+, found: 483.1932. 1H NMR (CDCl3) δ1.0 (m, 6H), 2.0 (m, 1H), 3.0 (m, 2H), 3.6 (dd, 1H), 3.8 (dd, 1H), 4.3 (m, 11H), 4.6 (m, 2H), 5.9 (tt, 1H), 6.6 (d, 1H), 6.7 (d, 1H), 6.9-7.4 (m, 6
Reaction SMILES: [H-].[Na+].[F:3][CH:4]([F:42])[C:5]1[N:9]([C:10]2[N:15]=[C:14]([N:16]3[CH2:21][CH2:20][O:19][CH2:18][CH2:17]3)[N:13]=[C:12]([C:22]3[CH:27]=[CH:26][C:25]([NH:28][C:29](=[O:35])[O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[CH:24][CH:23]=3)[N:11]=2)[C:8]2[CH:36]=[CH:37][CH:38]=[C:39]([O:40][CH3:41])[C:7]=2[N:6]=1.I[CH3:44]>CN(C=O)C.O>[F:42][CH:4]([F:3])[C:5]1[N:9]([C:10]2[N:15]=[C:14]([N:16]3[CH2:17][CH2:18][O:19][CH2:20][CH2:21]3)[N:13]=[C:12]([C:22]3[CH:23]=[CH:24][C:25]([N:28]([CH3:44])[C:29](=[O:35])[O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[CH:26][CH:27]=3)[N:11]=2)[C:8]2[CH:36]=[CH:37][CH:38]=[C:39]([O:40][CH3:41])[C:7]=2[N:6]=1
Reactant: CI
Reactant: COc1cccc2c1nc(C(F)F)n2-c1nc(-c2ccc(NC(=O)OC(C)(C)C)cc2)nc(N2CCOCC2)n1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1cccc2c1nc(C(F)F)n2-c1nc(-c2ccc(N(C)C(=O)OC(C)(C)C)cc2)nc(N2CCOCC2)n1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 84.4 %

Procedure:
NaH (95%, 11 mg, 0.435 mmol) was added to a suspension of tert-butyl 4-[4-[2-(difluoromethyl)-4-methoxy-1H-benzimidazol-1-yl]-6-(4-morpholinyl)-1,3,5-triazin-2-yl]phenylcarbamate (Example 74) (120 mg, 0.217 mmol) in DMF (3 mL) at 0° C. After stirring at 0° C. for 15 min, iodomethane (0.020 mL, 0.321 mmol) was added. The reaction mixture was warmed to room temperature, stirred for additional 17 hrs, and then diluted with H2O. The resulting precipitate was collected by filtration and dried to give tert-butyl 4-[4-[2-(difluoromethyl)-4-methoxy-1H-benzimidazol-1-yl]-6-(4-morpholinyl)-1,3,5-triazin-2-yl]phenyl(methyl)carbamate (104 mg, 85%): mp (CH2Cl2/MeOH) 205-208° C.; 1H NMR (CDCl3) δ 8.42 (d, J=8.8 Hz, 2H), 8.09 (dd, J=8.4, 0.6 Hz, 1H), 7.63 (t, JHF=53.5 Hz, 1H), 7.45-7.40 (m, 3H), 6.86 (d, J=7.8 Hz, 1H), 4.13 (m, 2H), 4.07 (s, 3H), 4.00 (m, 2H), 3.86 (m, 4H), 3.35 (s, 3H), 1.50 (s, 9H); Anal. Calcd. for C28H31F2N7O4: C, 59.25; H, 5.5; N, 17.3. Found: C, 59.0; H, 5.3; N, 17.2%.
Reaction SMILES: [Li+].C[Si]([N-][Si](C)(C)C)(C)C.[O:11]1[C:15]([C:16]2[N:17]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[C:18]3[C:23]([CH:24]=2)=[CH:22][CH:21]=[CH:20][CH:19]=3)=[CH:14][N:13]=[CH:12]1.[Cl:32]C(Cl)(Cl)C(Cl)(Cl)Cl>C1COCC1>[Cl:32][C:12]1[O:11][C:15]([C:16]2[N:17]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[C:18]3[C:23]([CH:24]=2)=[CH:22][CH:21]=[CH:20][CH:19]=3)=[CH:14][N:13]=1
Reactant: CC(C)(C)OC(=O)n1c(-c2cnco2)cc2ccccc21
Reactant: ClC(Cl)(Cl)C(Cl)(Cl)Cl
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)n1c(-c2cnc(Cl)o2)cc2ccccc21
Temperature: -78 °C
Reaction time: 1 h
Yield: 99.3 %

Procedure:
LiHMDS (1.06 M in THF, 9.54 mL, 10.00 mmol) was added to a solution of tert-butyl 2-(oxazol-5-yl)-1H-indole-1-carboxylate 20 (2.37 g, 8.34 mmol) in THF (20 mL) at −78° C., and the mixture was stirred at −78° C. for 1 h. A solution of hexachloroethane (2.96 g, 12.50 mmol) in THF (5 mL) was added at −78° C., and the mixture was stirred at −78° C. for 2 h and allowed to warm to room temperature and stirred for 14 h. The reaction was quenched by adding EtOAC:H2O (50 mL:15 mL), and then extracted with Ethyl acetate. The extracts were washed with brine, dried (Na2SO4) and concentrated. The product was purified by column chromatography (Acetone/hexane as an eluent) to provide tert-butyl 2-(2-chlorooxazol-5-yl)-1H-indole-1-carboxylate 21 (2.64 g, 99% yield) as white solid. MS (ES) m/z 319 (M+H+).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]1[N:12]=[CH:13][C:14]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[C:7]1[N:6]([CH3:20])[C:5]2=[O:21].[C:22]1([N:28]=[C:29]=[S:30])[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.N1C=CC=CC=1>O>[CH3:20][N:6]1[C:5](=[O:21])[C:4]2[C:9](=[CH:10][CH:11]=[C:2]([NH:1][C:29]([NH:28][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)=[S:30])[CH:3]=2)[N:8]2[N:12]=[CH:13][C:14]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[C:7]12
Reactant: CCOC(=O)c1cnn2c3ccc(N)cc3c(=O)n(C)c12
Reactant: S=C=Nc1ccccc1
Solvent: c1ccncc1
Solvent: O
Product: CCOC(=O)c1cnn2c3ccc(NC(=S)Nc4ccccc4)cc3c(=O)n(C)c12

Procedure:
A solution of 5 g. (0.018 mole) of ethyl 7-amino-4-methyl-4,5-dihydro-5-oxopyrazolo[1,5-a]quinazoline-3-carboxylate and 2.4 g. (0.018 mole) of phenyl isothiocyanate in 250 ml. of pyridine was stirred and heated on a steam bath for about 2 hours, then cooled and diluted with water. The solid which separated was collected to give crude ethyl 4-methyl-7-phenylthioureido-4,5-dihydro-5-oxopyrazolo[1,5-a]quinazoline-3-carboxylate which was not further purified but used as such in Example 7T.
Reaction SMILES: [CH3:1][NH:2][C:3]([C:5]1[C:6]2[CH:16]=[CH:15][C:14]([O:17]C)=[CH:13][C:7]=2[O:8][C:9]=1[CH:10]([CH3:12])[CH3:11])=[O:4].B(Br)(Br)Br>>[CH3:1][NH:2][C:3]([C:5]1[C:6]2[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][C:7]=2[O:8][C:9]=1[CH:10]([CH3:12])[CH3:11])=[O:4]
Reactant: CNC(=O)c1c(C(C)C)oc2cc(OC)ccc12
Agent: BrB(Br)Br
Product: CNC(=O)c1c(C(C)C)oc2cc(O)ccc12

Procedure:
This material was prepared from 6-methoxy-2-(1-methylethyl)benzo[b]furan-3-carboxylic acid methylamide 15b (173 mg, 0.84 mmole) by treatment with BBr3 in a manner as previously described for example 1d to give 157 mg (80%) of a crisp foam. 1H NMR (DMSO-d6) δ9.54 (1H, s), 7.76 (1H, d, J=4.6 Hz), 7.45 (1H, d, J=8.6 Hz), 6.88 (1H, d, J=2.0 Hz), 6.74 (1H, dd, J=2.0, 8.6 Hz), 3.68–3.61 (1H, m), 2.75 (3H, d, J=4.6 Hz), 1.24 (6H, d, J=7.1 Hz).
Reaction SMILES: [H-].[Na+].C[O:4][C:5](=[O:20])[C@:6]1([CH3:19])[CH2:10][C@@H:9]([OH:11])[CH2:8][N:7]1[C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13].[Br:21][C:22]1[CH:29]=[CH:28][C:25]([CH2:26]Br)=[CH:24][CH:23]=1>C1COCC1.O>[C:12]([N:7]1[CH2:8][C@H:9]([O:11][CH2:26][C:25]2[CH:28]=[CH:29][C:22]([Br:21])=[CH:23][CH:24]=2)[CH2:10][C@@:6]1([CH3:19])[C:5]([OH:4])=[O:20])([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13]
Reactant: BrCc1ccc(Br)cc1
Reactant: COC(=O)[C@]1(C)C[C@@H](O)CN1C(=O)OC(C)(C)C
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1C[C@H](OCc2ccc(Br)cc2)C[C@@]1(C)C(=O)O
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 28.4 %

Procedure:
To a suspension of sodium hydride (60% in oil) (0.12 g) (1.5 eq.) in 5 mL of dry THF was added (2S,4R)-N-Boc-4-hydroxy-2-methyl-proline methyl ester (0.55 g) in 5 mL of dry THF. The reaction mixture was stirred for 45 min., and a solution of 4-bromobenzyl bromide (0.75 g) (1.5 eq.) in 5 mL of dry THF was added. The reaction mixture was refluxed for 3 h. After cooling to RT, the reaction mixture was diluted with water and extracted with EtOAc. The aqueous layer was acidified and extracted with DCM. The combined organic extracts were washed with water, dried over MgSO4 and evaporated under reduced pressure to afford (2S,4R)-N-Boc-4-(4-bromo-benzyloxy)-2-methyl-proline (0.25 g).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[CH3:10])[C:5]#[N:6].[Br:11]N1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(Cl)(Cl)(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]([C:5]#[N:6])[CH:7]=[CH:8][C:9]=1[CH2:10][Br:11]
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1ccc(C#N)cc1Cl
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: N#Cc1ccc(CBr)c(Cl)c1
Reaction time: 24 h

Procedure:
A mixture of 3-chloro-4-methyl-benzonitrile (30.0 g, 0.2 mol), N-bromosuccinimide (36.0 g, 0.21 mol) and benzoyl peroxide (100 mg) in 600 mL of CCl4 was refluxed with illumination for 72 h. N-Bromosuccinimide (5.0 g) was added and the reaction was continued for an additional 24 h. The mixture was cooled, filtered and evaporated. Recrystallization from heptane gave pure 2-chloro-4-cyanobenzyl bromide: yield 24.5 g; mp 83°-85° C. Anal. calcd for C8H5BrClN; C, 41.69; H, 2.19; N, 6.07. Found: C, 41.48; H, 1.80; N, 5.76.