Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O-]P([O-])([O-])=O.[K+].[K+].[K+].O[CH:10](S([O-])(=O)=O)[CH2:11][CH2:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[C:15]([CH3:25])[CH:14]=1.[Na+].[C:31]([O:35][C:36](=[O:50])[CH2:37][CH:38](P(OCC)(OCC)=O)[C:39]([OH:41])=[O:40])([CH3:34])([CH3:33])[CH3:32].CC(C)([O-])C.[Na+].C(O)(=O)CC(CC(O)=O)(C(O)=O)O.[C:70]12([NH2:80])[CH2:79][CH:74]3[CH2:75][CH:76]([CH2:78][CH:72]([CH2:73]3)[CH2:71]1)[CH2:77]2>O.C1(C)C=CC=CC=1>[C:70]12([NH2:80])[CH2:77][CH:76]3[CH2:75][CH:74]([CH2:73][CH:72]([CH2:78]3)[CH2:71]1)[CH2:79]2.[C:31]([O:35][C:36](=[O:50])[CH2:37]/[C:38](=[CH:10]\[CH2:11][CH2:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[C:15]([CH3:25])[CH:14]=1)/[C:39]([OH:41])=[O:40])([CH3:34])([CH3:32])[CH3:33]
Reactant: CCOP(=O)(OCC)C(CC(=O)OC(C)(C)C)C(=O)O
Reactant: Cc1cc(CCC(O)S(=O)(=O)[O-])ccc1-c1ccccc1
Agent: CC(C)(C)[O-]
Agent: NC12CC3CC(CC(C3)C1)C2
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Solvent: O
Solvent: Cc1ccccc1
Product: Cc1cc(CC/C=C(\CC(=O)OC(C)(C)C)C(=O)O)ccc1-c1ccccc1
Temperature: 22.5 °C
Reaction time: 16 h
Yield: 82.2 %

Procedure:
A solution of potassium phosphate tribasic (160 g, 0.762 moles) in demineralised water (500 ml) was added over 15 minutes to a stirred slurry of sodium 1 -hydroxy-3-(2-methyl-1,1′-biphenyl-4-yl)-1-propanesulfonate (125 g, 0.381 moles) in toluene (1500 ml) and demineralised water (1000 ml). The mixture was stirred at 20-25° C. for 16 hours. The organic phase was separated and the aqueous phase was extracted with toluene (100 ml). The combined organic extracts were washed with demineralised water (1000 ml), and the solution was azeotropically dried by distillation of toluene at 40° C. under reduced pressure. The volume of solution was reduced to 250 ml, and allowed to cool to 20-25° C. Meanwhile, 3-(diethoxyphosphoryl)succinic acid 1-tert-butyl ester (112 g, 0.360 moles) was added portionwise over 10 minutes to a solution of sodium tert-butoxide (114 g, 1.175 moles) in toluene (1120 ml) at −10° C. under nitrogen. The mixture was stirred for 30 minutes at −10° C. The toluene solution prepared previously was added over 45 minutes between −10° C. and 0° C. The mixture was stirred at −10° C. for 1 hour and aqueous citric acid solution (10% w/v, 1000 ml) was added. The biphasic mixture was stirred at 20-25° C. for 16 hours. The organic phase was separated and washed with demineralised water (1000 ml) . The organic phase was azeotropically dried by distillation at 40° C. under reduced pressure at a constant volume of 1330 ml. The solution was maintained at 40-45° C., and a solution of adamantanamine (53 g, 0.350 moles) in toluene (665 ml) was added in one portion. The mixture was cooled to 20-25° C., and was stirred for 16 hours. The precipitate was collected by filtration, washed with toluene (150 ml) and dried in vacuo at 50° C. to leave the title compound as a colourless solid (153 g, 76% yield).
Reaction SMILES: C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.O[CH:21]([C:25]1[CH:34]=[CH:33][C:28]([C:29]([O:31][CH3:32])=[O:30])=[CH:27][CH:26]=1)[CH2:22][CH2:23][CH3:24].C(Br)(Br)(Br)[Br:36]>C(Cl)Cl>[Br:36][CH:21]([C:25]1[CH:34]=[CH:33][C:28]([C:29]([O:31][CH3:32])=[O:30])=[CH:27][CH:26]=1)[CH2:22][CH2:23][CH3:24]
Reactant: BrC(Br)(Br)Br
Reactant: CCCC(O)c1ccc(C(=O)OC)cc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: CCCC(Br)c1ccc(C(=O)OC)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of PPh3 (42.2 g. 320 mmol) in DCM (200 mL) was added dropwise to a solution of methyl 4-(1-hydroxybutyl)benzoate (33.5 g, 160 mmol) and CBr4 (53.1 g, 320 mmol) in DCM (1200 mL) at 0° C. Once the addition was complete, the mixture was allowed to warm to room temperature and was stirred overnight. The mixture was concentrated, then the resulting residue was purified by silica gel chromatography eluting with 5% EtOAc/petroleum ether to afford the title compound. 1H NMR (300 MHz, CDCl3) δ 8.00 (d, J=6 Hz, 2 H); 7.45 (d, J=6 Hz, 2 H); 4.95 (t, J=7 Hz, 1 H); 3.91 (s, 3 H); 2.19-2.32 (m, 1 H); 2.02-2.14 (m, 1 H); 1.43-1.55 (m, 1 H); 1.24-1.38 (m, 1 H); 0.93 (t, J=7 Hz, 3 H).
Reaction SMILES: [OH:1][CH:2]([CH2:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([CH:16]2[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]2)=[CH:12][CH:11]=1)[C:3]([O:5][CH2:6][CH3:7])=[O:4].[N+:22]([O-])([OH:24])=[O:23].O.[OH-].[Na+]>CCOCC>[OH:1][CH:2]([CH2:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([CH:16]2[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]2)=[C:12]([N+:22]([O-:24])=[O:23])[CH:11]=1)[C:3]([O:5][CH2:6][CH3:7])=[O:4]
Reactant: O=[N+]([O-])O
Reactant: CCOC(=O)C(O)CCc1ccc(C2CCCCC2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCOCC
Product: CCOC(=O)C(O)CCc1ccc(C2CCCCC2)c([N+](=O)[O-])c1
Temperature: 0 °C

Procedure:
Ethyl α -hydroxy-γ-(4-cyclohexylphenyl)butyrate 0.066 mole is added to ice-cold concentrated sulfuric acid (18 ml.) and stirred with cooling for 5 minutes. Concentrated nitric acid (Sp. G. 1.51) (2.5 ml.) is added dropwise, maintaining the temperature between 30° and 40° by water cooling if necessary. After addition of the nitric acid is complete, the mixture is stirred for 1/2 hour, then poured into water. The mixture is made alkaline with sodium hydroxide, then ex-racted with ether. The ether extract is washed, dried over sodium sulfate, evaporated and the residue is fractionally distilled to obtain ethyl α-hydroxy-γ-(3-nitro-4-cyclohexylphenyl)butyrate.
Reaction SMILES: [C:1]([NH:3][C:4]([C:6]1[C:11]([NH2:12])=[N:10][C:9]([N:13]([CH3:15])[CH3:14])=[C:8]([Cl:16])[N:7]=1)=N)#[N:2].Cl.[NH2:18][OH:19].C(N(CC)CC)C.[Cl-].[Ca+2].[Cl-]>O.CO.O1CCCC1>[NH2:2][C:1]1[N:3]=[C:4]([C:6]2[C:11]([NH2:12])=[N:10][C:9]([N:13]([CH3:15])[CH3:14])=[C:8]([Cl:16])[N:7]=2)[O:19][N:18]=1
Reactant: CN(C)c1nc(N)c(C(=N)NC#N)nc1Cl
Reactant: NO
Agent: Cl
Agent: [Ca+2]
Agent: [Cl-]
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Solvent: O
Product: CN(C)c1nc(N)c(-c2nc(N)no2)nc1Cl
Yield: 95.9 %

Procedure:
To a solution of tetrahydrofuran (250 ml) containing 50 ml of methanol and 12.36 g (51.57 mmole) of N-cyano-3-amino-5-dimethylamino-6-chloropyrazinecarboxamidine is added hydroxylamine hydrochloride (6.65 g, 103.13 mmole) and triethylamine (21.56 ml, 154.71 mmole). The resulting reaction mixture is protected from moisture (calcium chloride) and heated to reflux for 6 hours. The reaction mixture is cooled, poured into water (1 l) and the yellow solid which forms is collected by filtration. Concentration of the filtrate affords more solid which when combined with the first crop yields 12.64 g (96%) of the desired product. The reaction product is dried at 60° C. and directly affords analytically pure 3-amino-5-(3-amino-5-dimethylamino-6-chloropyrazin-2-yl)-1,2,4-oxadiazole, m.p. 210°-211° C.
Reaction SMILES: C([NH:9][C:10]([NH:12][C:13]1[CH:18]=[C:17]([Br:19])[C:16]([F:20])=[CH:15][C:14]=1[F:21])=[S:11])(=O)C1C=CC=CC=1.[OH-].[Na+]>C1COCC1.O>[Br:19][C:17]1[C:16]([F:20])=[CH:15][C:14]([F:21])=[C:13]([NH:12][C:10]([NH2:9])=[S:11])[CH:18]=1
Reactant: O=C(NC(=S)Nc1cc(Br)c(F)cc1F)c1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: NC(=S)Nc1cc(Br)c(F)cc1F
Temperature: 70 °C
Reaction time: 15 h
Yield: 81.4 %

Procedure:
To a solution of 1-benzoyl-3-(5-bromo-2,4-difluoro-phenyl)-thiourea II (1.70 g, 4.60 mmol) in THF (35.0 mL) was added a solution of NaOH (0.97 g, 24.25 mmol) in water (13.0 mL). The resulting reaction mixture was stirred at 70° C. for 15 h. After the completion of the reaction (TLC monitoring), THF was evaporated, added water and extracted with EtOAc (3×50 mL). The combined organics was washed with brine and concentrated to obtain the desired compound (1.0 g, 83%). MS: 267.03 (M+H)+.
Reaction SMILES: [CH2:1]1[CH:5]2[CH2:6][NH:7][CH2:8][CH:4]2[CH2:3][N:2]1[C:9]1[CH:14]=[C:13]([C:15]([F:18])([F:17])[F:16])[N:12]=[C:11]([N:19]([CH3:21])[CH3:20])[N:10]=1.[F:22][C:23]1[CH:31]=[CH:30][CH:29]=[C:28]([C:32]2[N:37]=[CH:36][CH:35]=[CH:34][N:33]=2)[C:24]=1[C:25](O)=[O:26]>>[F:22][C:23]1[CH:31]=[CH:30][CH:29]=[C:28]([C:32]2[N:33]=[CH:34][CH:35]=[CH:36][N:37]=2)[C:24]=1[C:25]([N:7]1[CH2:6][CH:5]2[CH2:1][N:2]([C:9]3[CH:14]=[C:13]([C:15]([F:18])([F:17])[F:16])[N:12]=[C:11]([N:19]([CH3:21])[CH3:20])[N:10]=3)[CH2:3][CH:4]2[CH2:8]1)=[O:26]
Reactant: O=C(O)c1c(F)cccc1-c1ncccn1
Reactant: CN(C)c1nc(N2CC3CNCC3C2)cc(C(F)(F)F)n1
Product: CN(C)c1nc(N2CC3CN(C(=O)c4c(F)cccc4-c4ncccn4)CC3C2)cc(C(F)(F)F)n1

Procedure:
The title compound was prepared in a manner analogous to Example 15 utilizing Intermediate 36 and Intermediate 14. MS (ESI): mass calculated for C24H23F4N7O, 501.49; m/z found 502.0 [M+H]+. 1H NMR (400 MHz, CDCl3): 8.86-8.63 (m, 2H), 8.22-8.05 (m, 1H), 7.56-7.40 (m, 1H), 7.29-7.18 (m, 1H), 7.12 (br s, 1H), 6.03-5.73 (m, 1H), 4.19-2.90 (m, 16H).
Reaction SMILES: [CH2:1]([SnH:5]([CH2:10][CH2:11][CH2:12][CH3:13])[CH2:6][CH2:7][CH2:8][CH3:9])[CH2:2][CH2:3][CH3:4].[CH2:14]([N:21]1[CH2:26][CH2:25][CH2:24][C:23]([C:28]#[C:29][CH2:30][OH:31])([OH:27])[CH2:22]1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.C(N1CCCC(C([Sn](CCCC)(CCCC)CCCC)=CCO)(O)C1)C1C=CC=CC=1>C1(C)C=CC=CC=1>[CH2:14]([N:21]1[CH2:26][CH2:25][CH2:24][C:23]([CH:28]=[C:29]([Sn:5]([CH2:6][CH2:7][CH2:8][CH3:9])([CH2:10][CH2:11][CH2:12][CH3:13])[CH2:1][CH2:2][CH2:3][CH3:4])[CH2:30][OH:31])([OH:27])[CH2:22]1)[C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: CCCC[SnH](CCCC)CCCC
Reactant: OCC#CC1(O)CCCN(Cc2ccccc2)C1
Agent: CCCC[Sn](CCCC)(CCCC)C(=CCO)C1(O)CCCN(Cc2ccccc2)C1
Solvent: Cc1ccccc1
Product: CCCC[Sn](CCCC)(CCCC)C(=CC1(O)CCCN(Cc2ccccc2)C1)CO
Temperature: -5 °C
Reaction time: 2 h

Procedure:
Tributyltin hydride (7.8 ml, 29 mmol) was added dropwise to a degassed solution of 1-benzyl-3-(3-hydroxy-1-propyn-1-yl)piperidin-3-ol (Desc. 1; 5.91 g, 24.1 mmol) and tetrakis(trisphenylphosphine)palladium(0) (0.52 g, 0.45 mmol) in toluene (100 ml) at -5° C. The reaction mixture was stirred at -5° C. for 2 hours, allowed to warm up and concentrated in vacuo to afford an approximately 2.5:1 mixture of the title compound and isomeric 1-benzyl-3-(3-hydroxy-1-tributylstannyl-1-propen-1-yl)piperidin-3-ol. The mixture was purified by flash chromatography, eluting with ethyl acetate/hexane (1:2), to give the title compound (8.82 g, 68%; δH (250 MHz, CDCl3) 0.88 (15 H, m), 1.24-1.53 (14H, m), 1.78 (2H, m), 1.98 (1H, m), 2.11 (1H, d, J 11.1Hz), 2.69-2.80 (2H, m), 3.51 (1H, d, J. 13.2Hz, NCHACHBPh), 3.57 (1H, d, J 13.2Hz, NCHACHBPh), 4.44 (2H, br s, CH2OH), 5.38 (1H, br s, CH=C), 7.26-7.34 (5H, m ArH).
Reaction SMILES: [BH4-].[Na+].[CH3:3][C:4]1[C:21]([CH3:22])=[CH:20][C:19]([CH3:23])=[C:18]([CH3:24])[C:5]=1[CH2:6][O:7][C:8]1[CH:13]=[CH:12][C:11]([C:14](=[O:17])[CH2:15][CH3:16])=[CH:10][CH:9]=1>C1COCC1.CCO>[CH3:3][C:4]1[C:21]([CH3:22])=[CH:20][C:19]([CH3:23])=[C:18]([CH3:24])[C:5]=1[CH2:6][O:7][C:8]1[CH:9]=[CH:10][C:11]([CH:14]([OH:17])[CH2:15][CH3:16])=[CH:12][CH:13]=1
Reactant: CCC(=O)c1ccc(OCc2c(C)c(C)cc(C)c2C)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCO
Product: CCC(O)c1ccc(OCc2c(C)c(C)cc(C)c2C)cc1
Reaction time: 2 h
Yield: 99.3 %

Procedure:
NaBH4 (616 mg, 16.2 mmol) is added to the solution of 1-[4-(2,3,5,6-Tetramethyl-benzyloxy)-phenyl]-propan-1-one (4.0 g, 13.5 mmol) in THF (30 mL) and EtOH (5 mL). After stirring for 2 h, the reaction is quenched by water and extracted with ethyl acetate. The solvent is removed to afford the titled compound as a white solid (4.0 g).
Reaction SMILES: [Br:1][C:2]1[C:3]([C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=2)=[CH:4][C:5]2[N:6]([C:9](=[O:12])[NH:10][N:11]=2)[C:7]=1[CH3:8].BrC1C2N(C(=O)N([CH2:38][C:39]3[CH:40]=[N:41][C:42]([C:45]([F:48])([F:47])[F:46])=[CH:43][CH:44]=3)N=2)C(C)=CC=1C1C=CC(Cl)=CC=1>>[Br:1][C:2]1[C:3]([C:13]2[CH:14]=[CH:15][C:16]([Cl:19])=[CH:17][CH:18]=2)=[CH:4][C:5]2[N:6]([C:9](=[O:12])[N:10]([CH2:38][C:39]3[CH:40]=[N:41][C:42]([C:45]([F:48])([F:46])[F:47])=[CH:43][CH:44]=3)[N:11]=2)[C:7]=1[CH3:8]
Reactant: Cc1c(Br)c(-c2ccc(Cl)cc2)cc2n[nH]c(=O)n12
Reactant: Cc1cc(-c2ccc(Cl)cc2)c(Br)c2nn(Cc3ccc(C(F)(F)F)nc3)c(=O)n12
Product: Cc1c(Br)c(-c2ccc(Cl)cc2)cc2nn(Cc3ccc(C(F)(F)F)nc3)c(=O)n12
Yield: 66 %

Procedure:
The title compound (120 mg, 66% yield) as an off-white solid was prepared from 6-bromo-7-(4-chlorophenyl)-5-methyl-[1,2,4]triazolo[4,3-a]pyridin-3(2H)-one (125 mg, 0.369 mmol) by procedures analogous to those used for the preparation of 8-bromo-7-(4-chlorophenyl)-5-methyl-2-((6-(trifluoromethyl)pyridin-3-yl)methyl)-[1,2,4]triazolo[4,3-a]pyridin-3(2H)-one. HPLC/MS: retention time=4.10 min, [M+H]+=497.2.
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:9]=[CH:8][C:7]([N:10]2[C:18]([NH:19][CH:20]3[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]3)=[C:17]3[C:12]([CH:13]=[CH:14][CH:15]=[CH:16]3)=[N:11]2)=[CH:6][CH:5]=1.Cl[C:27]([O:29][CH:30]1[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]1)=[O:28].C(OC(C)=O)(C)C.[Cl-].[Na+].O>CN(C=O)C>[CH:30]1([O:29][C:27](=[O:28])[N:19]([C:18]2[N:10]([C:7]3[CH:8]=[CH:9][C:4]([Cl:3])=[CH:5][CH:6]=3)[N:11]=[C:12]3[C:17]=2[CH:16]=[CH:15][CH:14]=[CH:13]3)[CH:20]2[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]2)[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]1
Reactant: Clc1ccc(-n2nc3ccccc3c2NC2CCCCC2)cc1
Reactant: O=C(Cl)OC1CCCCC1
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CC(=O)OC(C)C
Product: O=C(OC1CCCCC1)N(c1c2ccccc2nn1-c1ccc(Cl)cc1)C1CCCCC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 4.6 %

Procedure:
To an ice cold suspension of NaH (6 mg, 160 umol) in DMF (3 ml) under an argon atmosphere was added a solution of [2-(4-chloro-phenyl)-2H-indazol-3-yl]-cyclohexyl-amine (50 mg, 153 μmol; example 11.1) in DMF (1 ml) within 10 min. The suspension was stirred for 1 h at ambient temperature. A solution of cyclohexyl chloroformate (33 mg, 203 μmol; [13248-54-9]) in DMF (1 ml) was added within 5 min. The reaction mixture was stirred for 14 h at ambient temperature, poured onto ice water/brine 1/1 and extracted two times with iPrOAc. The combined extracts were washed with brine and dried over Na2SO4. The solvent was removed under reduced pressure and the residue was purified by preparative thin layer chromatography (silica gel, iPrOAc/heptane) to give the title compound (3 mg, 7 μmol; 3%) as brown solid. MS: m/e=452.4 [M+H+].
Reaction SMILES: [OH:1][CH2:2][CH2:3][N:4]([CH3:32])[C:5]1[CH:10]=[C:9]([CH:11]2[CH2:16][CH2:15][N:14](C(OC(C)(C)C)=O)[CH2:13][CH2:12]2)[CH:8]=[C:7]([NH:24][C:25]2[CH:30]=[C:29]([CH3:31])[CH:28]=[CH:27][N:26]=2)[N:6]=1.Cl.O1CCOCC1>C(Cl)Cl>[CH3:32][N:4]([C:5]1[CH:10]=[C:9]([CH:11]2[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]2)[CH:8]=[C:7]([NH:24][C:25]2[CH:30]=[C:29]([CH3:31])[CH:28]=[CH:27][N:26]=2)[N:6]=1)[CH2:3][CH2:2][OH:1]
Reactant: Cc1ccnc(Nc2cc(C3CCN(C(=O)OC(C)(C)C)CC3)cc(N(C)CCO)n2)c1
Agent: Cl
Solvent: C1COCCO1
Solvent: ClCCl
Product: Cc1ccnc(Nc2cc(C3CCNCC3)cc(N(C)CCO)n2)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 49.3 %

Procedure:
To a solution of tert-butyl 4-(2-((2-hydroxyethyl)(methyl)amino)-6-(4-methylpyridin-2-ylamino)pyridin-4-yl)piperidine-1-carboxylate (100 mg, 0.22 mmol) in DCM (1.0 mL) was added hydrogen chloride (4 mol/L) in 1,4-dioxane (3.0 mL, 12 mmol). The resultant was stirred at room temperature for 3 h. It was purified by HPLC to give 37 mg (48%) of the title compound as a light yellow solid. 1H NMR (400 MHz, DMSO) δ 9.00 (s, 1H), 8.02 (d, J=5.1 Hz, 1H), 7.95 (s, 1H), 6.64 (d, J=5.1 Hz, 1H), 6.42 (s, 1H), 5.90 (s, 1H), 4.64 (s, 1H), 3.64-3.53 (m, 4H), 3.05-2.95 (m, 5H), 2.58-2.52 (m, 1H), 2.50-2.31 (m, 3H), 2.25 (s, 3H), 1.69-1.58 (m, 2H), 1.55-1.40 (m, 2H). LC-MS: m/z=342 (M+H+).
Reaction SMILES: [C:1]([O:5][C:6]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[C:14]1[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][CH:15]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Br:21]N1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(Cl)(Cl)(Cl)Cl>[Br:21][CH2:20][C:17]1[CH:18]=[CH:19][C:14]([C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=2[C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])=[CH:15][CH:16]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1ccc(-c2ccccc2C(=O)OC(C)(C)C)cc1
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: CC(C)(C)OC(=O)c1ccccc1-c1ccc(CBr)cc1
Temperature: 25 °C
Yield: 81.8 %

Procedure:
To a solution of 2-t-butoxycarbonyl-4'-methylbiphenyl (25.3 g, 95 mmol) in CCl4 (200 ml) were added freshly opened N-bromosuccinimide (17.6 g, 0.099 mole) and dibenzoyl peroxide (2.28 g, 0.0094 moles). The mixture was refluxed for 4 hours, cooled to room temperature and filtered. The filtrate was washed with sat. NaHSO3 (1×50 ml), sat. NaHCO3 (1×50 ml), water (1×50 ml), sat. NaCl (1×50 ml) and dried over MgSO4. The solution was filtered and concentrated in vacuo. The residue was dissolved in 100 ml of hot hexane. Crystallization gradually took place as the solution cooled. The flask was finally cooled to -20° C. and the precipitate recovered by filtration. The solid was washed with ice cold hexanes and dried in vacuo to give 27 g (88%) of a white solid. 1H-NMR (CDCl3): 1.23 (s, 9H), 4.53 (s, 2H), 7.2-7.5 (m, 7H), 7.68 (d, 1H).
Reaction SMILES: [CH3:1][N:2]1[CH2:27][CH2:26][C:5]2[N:6]([CH2:14][C:15]([C:18]3[CH:19]=[N:20][C:21]([O:24]C)=[CH:22][CH:23]=3)([OH:17])[CH3:16])[C:7]3[CH:8]=[CH:9][C:10]([CH3:13])=[CH:11][C:12]=3[C:4]=2[CH2:3]1>Cl>[CH3:1][N:2]1[CH2:27][CH2:26][C:5]2[N:6]([CH2:14][C:15]([C:18]3[CH:23]=[CH:22][C:21]([OH:24])=[N:20][CH:19]=3)([OH:17])[CH3:16])[C:7]3[CH:8]=[CH:9][C:10]([CH3:13])=[CH:11][C:12]=3[C:4]=2[CH2:3]1
Reactant: COc1ccc(C(C)(O)Cn2c3c(c4cc(C)ccc42)CN(C)CC3)cn1
Agent: Cl
Product: Cc1ccc2c(c1)c1c(n2CC(C)(O)c2ccc(O)nc2)CCN(C)C1

Procedure:
A solution of 1-(2,8-dimethyl-1,2,3,4-tetrahydro-pyrido[4,3-b]indol-5-yl)-2-(6-methoxy-pyridin-3-yl)-propan-2-ol (100 mg, 0.27 mmol) in 3N HCl (4 mL) was stirred at 100° C. for 4 h. The reaction mixture was concentrated under reduced pressure and the residue was purified by reverse phase HPLC to yield 5-[2-(2,8-dimethyl-1,2,3,4-tetrahydro-pyrido[4,3-b]indol-5-yl)-1-hydroxy-1-methyl-ethyl]-pyridin-2-ol. 1H NMR (CD3OD, freebase) δ (ppm): 7.58 (d, 1H), 7.2 (s, 1H), 7.1 (s, 1H), 7.0 (d, 1H), 6.8 (d, 1H), 6.4 (d, 1H), 4.6 (bs, 1H), 4.17 (m, 2H), 4.0 (m, 2H), 3.1-3.25 (m, 2H), 2.97 (m, 1H), 2.8 (s, 3H), 2.4 (s, 3H), 1.6 (s, 3H). Separation by chiral HPLC provides enantiomers II-80a-b.
Reaction SMILES: [NH:1]([C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[CH:7][CH:6]=1)[C:2]([CH3:4])=[O:3].C(=O)([O-])[O-].[K+].[K+].Br[CH2:19][C:20]([O:22][CH3:23])=[O:21]>CC(C)=O>[NH:1]([C:5]1[CH:10]=[CH:9][C:8]([O:11][CH2:19][C:20]([O:22][CH3:23])=[O:21])=[CH:7][CH:6]=1)[C:2]([CH3:4])=[O:3]
Reactant: CC(=O)Nc1ccc(O)cc1
Reactant: COC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: COC(=O)COc1ccc(NC(C)=O)cc1
Temperature: 25 °C

Procedure:
4-Acetaminophenol (1.51 g), potassium carbonate (1.38 g) and methyl bromoacetate (1.0 ml) were combined in acetone (40 ml) and heated to reflux for 5 hours. The mixture was allowed to cool to room temperature, filtered and evaporated. The residue was dissolved in ethyl acetate, washed with water and then with brine then dried, filtered and evaporated to give the subtitle compound (2.32 g).
Reaction SMILES: C([O:5][C:6]([C:8]1[CH:13]=[CH:12][C:11]([N:14]2[C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[CH:16]=[C:15]2[C:23]#[N:24])=[CH:10][CH:9]=1)=[O:7])(C)(C)C.Br>C(O)(=O)C>[C:6]([C:8]1[CH:13]=[CH:12][C:11]([N:14]2[C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[CH:16]=[C:15]2[C:23]#[N:24])=[CH:10][CH:9]=1)([OH:7])=[O:5]
Reactant: CC(C)(C)OC(=O)c1ccc(-n2c(C#N)cc3ccccc32)cc1
Agent: Br
Solvent: CC(=O)O
Product: N#Cc1cc2ccccc2n1-c1ccc(C(=O)O)cc1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 97.3 %

Procedure:
3.6 g (0.011 mol) of 1-[4-(tert-butoxycarbonyl)phenyl]-2-cyanoindole was dissolved in 40 ml of acetic acid and 10 ml of 30% hydrogen bromide in acetic acid was added dropwise. After stirring for 10 minutes, the slurry was poured onto 200 g of ice-water, and the resulting precipitate was filtered, washed with water and air-dried, to give 2.8 g (0.0107 mol) of 1-(4-carboxyphenyl)-2-cyanoindole, m.p., 128°-131° C.
Reaction SMILES: Cl[CH2:2][C:3]([N:5]1[CH2:10][CH2:9][N:8]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:7][CH:6]1[C:18]([OH:31])([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[O:4].[H-].[Na+].C(OCC)(=O)C>O1CCCC1>[O:4]=[C:3]1[CH2:2][O:31][C:18]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH:6]2[CH2:7][N:8]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:9][CH2:10][N:5]12
Reactant: CC(C)(C)OC(=O)N1CCN(C(=O)CCl)C(C(O)(c2ccccc2)c2ccccc2)C1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CCN2C(=O)COC(c3ccccc3)(c3ccccc3)C2C1
Temperature: 25 °C
Reaction time: 3 h
Yield: 93.3 %

Procedure:
To a solution of 1,1-dimethylethyl 4-(chloroacetyl)-3-[hydroxy(diphenyl)methyl]piperazine-1-carboxylate (0.28 g, 0.63 mmol) in tetrahydrofuran (5 mL) was added 60% sodium hydride (40 mg, 1.0 mmol), and the mixture was stirred at room temperature for 3 hours. To the reaction solution was added ethyl acetate, and the resulting mixture was washed with water, dried over anhydrous magnesium sulfate and concentrated under reduced pressure to obtain the title compound (0.24 g, yield 93%).
Reaction SMILES: CCC(C)[BH-](C(C)CC)C(C)CC.[Li+].[CH3:15][C:16]([S@:19](/[N:21]=[C:22]1/[CH2:23][CH2:24][CH2:25][C:26]2[C:31]/1=[CH:30][CH:29]=[CH:28][C:27]=2[O:32][CH2:33][C:34]([F:37])([F:36])[F:35])=[O:20])([CH3:18])[CH3:17].CO>C1COCC1.[Cl-].[Na+].O>[CH3:18][C:16]([S@:19]([NH:21][C@@H:22]1[C:31]2[C:26](=[C:27]([O:32][CH2:33][C:34]([F:35])([F:36])[F:37])[CH:28]=[CH:29][CH:30]=2)[CH2:25][CH2:24][CH2:23]1)=[O:20])([CH3:15])[CH3:17]
Reactant: CC(C)(C)[S@@](=O)/N=C1/CCCc2c(OCC(F)(F)F)cccc21
Agent: CCC(C)[BH-](C(C)CC)C(C)CC
Agent: [Cl-]
Agent: [Li+]
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)[S@@](=O)N[C@H]1CCCc2c(OCC(F)(F)F)cccc21
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 43.2 %

Procedure:
To a suspension of L-Selectride (3.90 mL, 3.90 mmol) in THF (1 mL) was added Intermediate 13A (0.45 g, 1.3 mmol) in THF (1 mL) at −50° C. The reaction mixture was warmed up to rt until the reduction was complete. To the reaction mixture was added MeOH (2 mL) and brine (2 mL). The resulting reaction mixture was stirred for 5 minutes, filtered, and the filtrate was concentrated in vacuo. The crude product was dissolved in a small amount of DCM and loaded on a 4 g silica gel cartridge eluting from 0 to 100% EtOAc in hexanes over 15 minutes to give Intermediate 13B (196 mg, 0.561 mmol, 43.1% yield). LCMS=2.09 min [M+1]=350 (Method B).
Reaction SMILES: [F:1][C:2]1[C:10]2[NH:9][CH:8]=[N:7][C:6]=2[C:5]([CH3:11])=[CH:4][CH:3]=1.[N+:12]([O-])([OH:14])=[O:13].[OH-].[NH4+]>S(=O)(=O)(O)O>[F:1][C:2]1[C:10]2[N:9]=[CH:8][NH:7][C:6]=2[C:5]([CH3:11])=[C:4]([N+:12]([O-:14])=[O:13])[CH:3]=1
Reactant: O=[N+]([O-])O
Reactant: Cc1ccc(F)c2[nH]cnc12
Agent: O=S(=O)(O)O
Agent: [NH4+]
Agent: [OH-]
Product: Cc1c([N+](=O)[O-])cc(F)c2nc[nH]c12
Temperature: 0 °C

Procedure:
To a cold (ice bath) solution of 4-fluoro-7-methylbenzimidazole (734 mg) in concentrated sulfuric acid (10 mL) is added dropwise concentrated nitric acid (0.22 mL) over 1 hour. The mixture is stirred an additional 15 minutes in the ice bath, then poured in a mixture of crushed ice (20 mL) and ammonium hydroxide (20 mL). The resulting mixture is extracted with ethyl acetate. The extract is dried over magnesium sulfate, filtered and rotary evaporated to afford 7-fluoro-4-methyl-5-nitrobenzimidazole as a pale yellow solid.