Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC([N:8]1[CH2:17][CH2:16][C:15]2[C:10](=[CH:11][CH:12]=[C:13](B3OC(C)(C)C(C)(C)O3)[CH:14]=2)[CH2:9]1)=O)(C)(C)C.C([O-])([O-])=O.[Na+].[Na+].Br[C:34]1[CH:35]=[C:36]([C:40]2[CH:45]=[C:44]([NH:46][CH:47]3[CH2:49][CH2:48]3)[N:43]=[C:42]([C:50]3[CH:55]=[CH:54][CH:53]=[CH:52][N:51]=3)[CH:41]=2)[CH:37]=[N:38][CH:39]=1>COCCOC.C(Cl)Cl>[CH:47]1([NH:46][C:44]2[N:43]=[C:42]([C:50]3[CH:55]=[CH:54][CH:53]=[CH:52][N:51]=3)[CH:41]=[C:40]([C:36]3[CH:37]=[N:38][CH:39]=[C:34]([C:13]4[CH:14]=[C:15]5[C:10](=[CH:11][CH:12]=4)[CH2:9][NH:8][CH2:17][CH2:16]5)[CH:35]=3)[CH:45]=2)[CH2:49][CH2:48]1
Reactant: CC(C)(C)OC(=O)N1CCc2cc(B3OC(C)(C)C(C)(C)O3)ccc2C1
Reactant: Brc1cncc(-c2cc(NC3CC3)nc(-c3ccccn3)c2)c1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: COCCOC
Product: c1ccc(-c2cc(-c3cncc(-c4ccc5c(c4)CCNC5)c3)cc(NC3CC3)n2)nc1

Procedure:
To a solution of 6-(4,4,5,5-Tetramethyl-[1,3,2]dioxaborolan-2-yl)-3,4-dihydro-1H-isoquinoline-2-carboxylic acid tert-butylester (Intermediate B26) (3 eq, 0.960 mmol, 0.344 g) in dry DME (1 ml) under an inert atmosphere of argon is added 2M Na2CO3 (2 eq, 0.640 mmol, 0.32 ml) followed by (5″-Bromo-[2,2′;4′,3″]terpyridin-6′-yl)-cyclopropyl-amine (Example 1.26) (1 eq, 0.320 mmol, 100 mg) and PdCl2dppf (0.1 eq, 0.032 mmol, 23 mg). The reaction mixture is heated using microwave radiation at 90° C. for 2 hours. The reaction mixture is dissolved in DCM and washed with water. The organic solvent is reduced in vacuo and the residue is purified by reverse phase column chromatography (Isolute™ C18, 0-40% acetonitrile in water—0.1% TFA). The appropriate fractions by HPLC are combined and concentrated in vacuo. The resulting residue is dissolved in MeOH and loaded onto a SCX-2 cartridge eluting with MeOH followed by 2M NH3 in MeOH. The methanolic ammonia fractions are combined, concentrated in vacuo and dried under vacuum to afford the title compound; [M+H]+ 420.
Reaction SMILES: [CH3:1][C:2]1[C:7]2[S:8](=[O:15])(=[O:14])[CH2:9][CH2:10][S:11](=[O:13])(=[O:12])[C:6]=2[CH:5]=[CH:4][C:3]=1[C:16]([OH:18])=O.S(Cl)([Cl:21])=O>C1(C)C=CC=CC=1.CN(C)C=O>[CH3:1][C:2]1[C:7]2[S:8](=[O:15])(=[O:14])[CH2:9][CH2:10][S:11](=[O:13])(=[O:12])[C:6]=2[CH:5]=[CH:4][C:3]=1[C:16]([Cl:21])=[O:18]
Reactant: O=S(Cl)Cl
Reactant: Cc1c(C(=O)O)ccc2c1S(=O)(=O)CCS2(=O)=O
Solvent: CN(C)C=O
Solvent: Cc1ccccc1
Product: Cc1c(C(=O)Cl)ccc2c1S(=O)(=O)CCS2(=O)=O
Reaction time: 4 h

Procedure:
10.0 g (0.0345 mol) of 8-methyl-2,3-dihydro-1,1,4,4-tetraoxobenz-[1,4]dithiin-7-carboxylic acid were dissolved in 100 ml of toluene, and two drops of dimethylformamide and then 4.5 g (0.038 mol) of thionyl chloride were added. After four hours of stirring under reflux, the mixture was concentrated. The colorless oil that remained (yield 10.6 g) could be directly employed further.
Reaction SMILES: [C:1]([NH:4][CH:5]1[CH2:10][CH2:9][N:8]([CH2:11][C:12]([OH:14])=O)[CH2:7][CH2:6]1)(=[O:3])[CH3:2].[NH2:15][CH2:16][C:17]([N:19]([C:21]1[CH:26]=[CH:25][C:24]([Cl:27])=[C:23]([CH2:28][O:29][C:30]2[C:38]3[N:37]=[C:36]([O:39][CH3:40])[N:35]([CH2:41][C:42]4[CH:47]=[CH:46][CH:45]=[CH:44][N:43]=4)[C:34]=3[CH:33]=[CH:32][CH:31]=2)[C:22]=1[Cl:48])[CH3:20])=[O:18]>>[C:1]([NH:4][CH:5]1[CH2:6][CH2:7][N:8]([CH2:11][C:12]([NH:15][CH2:16][C:17]([N:19]([C:21]2[CH:26]=[CH:25][C:24]([Cl:27])=[C:23]([CH2:28][O:29][C:30]3[C:38]4[N:37]=[C:36]([O:39][CH3:40])[N:35]([CH2:41][C:42]5[CH:47]=[CH:46][CH:45]=[CH:44][N:43]=5)[C:34]=4[CH:33]=[CH:32][CH:31]=3)[C:22]=2[Cl:48])[CH3:20])=[O:18])=[O:14])[CH2:9][CH2:10]1)(=[O:3])[CH3:2]
Reactant: COc1nc2c(OCc3c(Cl)ccc(N(C)C(=O)CN)c3Cl)cccc2n1Cc1ccccn1
Reactant: CC(=O)NC1CCN(CC(=O)O)CC1
Product: COc1nc2c(OCc3c(Cl)ccc(N(C)C(=O)CNC(=O)CN4CCC(NC(C)=O)CC4)c3Cl)cccc2n1Cc1ccccn1

Procedure:
2-(4-acetamidopiperidin-1-yl)acetic acid and 2-amino-N-(2,4-dichloro-3-(((2-methoxy-1-(pyridin-2-ylmethyl)-1H-benzo[d]imidazol-4-yl)oxy)methyl)phenyl)-N-methylacetamide are combined as previously described to give 15. LCMS (+ESI) 682 (M+). 1H-NMR (CDCl3, δ): 8.58 (m, 1H), 7.97 (bt, 1H), 7.58 (t, 1H), 7.47 (d, J=8.4 Hz, 1H), 7.29 (d, J=8.4 Hz, 1H), 7.19 (m, 1H), 7.03 (t, J=8.0 Hz, 1H), 6.92 (d, J=7.6 Hz, 1H), 6.83 (d, J=8.0 Hz, 1H), 6.81 (d, J=7.6 Hz, 1H), 5.67 (s, 2H), 5.33 (bd, 1H), 5.28 (s, 2H), 4.21 (s, 3H), 3.82 (dd, 1H), 3.81 (m, 1H), 3.56 (dd, 1H), 3.25 (s, 3H), 2.99 (d, 2H), 2.80 (m, 2H), 2.32 (m, 2H), 1.96 (s, 3H), 1.92 (m, 2H), 1.52 (m, 2H).
Reaction SMILES: [Cl:1][C:2]1[C:7]([CH:8]=[O:9])=[C:6](Cl)[N:5]=[C:4]([S:11][CH3:12])[N:3]=1.C(N(C(C)C)C(C)C)C.[C:22]([O:26][CH3:27])(=[O:25])[CH2:23][SH:24]>C(Cl)Cl>[CH3:27][O:26][C:22](=[O:25])[CH2:23][S:24][C:6]1[C:7]([CH:8]=[O:9])=[C:2]([Cl:1])[N:3]=[C:4]([S:11][CH3:12])[N:5]=1
Reactant: CSc1nc(Cl)c(C=O)c(Cl)n1
Reactant: COC(=O)CS
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)CSc1nc(SC)nc(Cl)c1C=O
Temperature: 25 °C

Procedure:
To an ice-cooled solution (−10° C.) of 4,6-dichloro-2-methylsulfanyl-pyrimidine-5-carbaldehyde (2.0 g, 8.97 mmol) and iPr2EtN (0.82 mL, 8.97 mmol) in DCM (40 mL) was added methyl thioglycolate (1.56 mL, 8.97 mmol) in DCM (20 mL) over 15 min. The reaction mixture was let warm to RT, then washed with sat. NaHCO3, dried over MgSO4, filtered, and concentrated. The product was used without further purification. ESIMS calcd 293 (M++H), found 293 (M++H).
Reaction SMILES: [CH2:1]([OH:6])[CH:2]([OH:5])[CH2:3][CH3:4].CN(C)C=O.[Si:12](Cl)([C:15]([CH3:18])([CH3:17])[CH3:16])([CH3:14])[CH3:13].N1C=CN=C1>ClCCl>[Si:12]([O:6][CH2:1][CH:2]([OH:5])[CH2:3][CH3:4])([C:15]([CH3:18])([CH3:17])[CH3:16])([CH3:14])[CH3:13]
Reactant: CCC(O)CO
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CCC(O)CO[Si](C)(C)C(C)(C)C
Reaction time: 10 h
Yield: 44.1 %

Procedure:
A 50 mL round bottom flask was charged with (±)-1,2-butanediol (1 g, 11.09 mmol) and to it was added dimethylformamide (8 mL) followed by tert-butyldimethylsilyl chloride (2.5 g, 16.64 mmol) and imidazole (1.88 g, 27.7 mmol). The reaction mixture was stirred for 10 hours after which it was diluted with dichloromethane and poured into a separatory finnel and washed with water (80 mL) and brine and dried over magnesium sulfate. After filtration and concentration the crude oil was purified by silica gel flash chromatography (hexanes:ethylacetate) to obtain 1 gm of pure desired product in 45% yield. 1H (CDCl3) δ (ppm): 3.6 (m, 1H), 3.5 (m, 1H), 3.4 (m, 1H), 2.4 (s, 1H), 1.44 (m, 2H), 0.99 (t, 3H), 0.9 (s, 9H), 0.06 (s, 6H).
Reaction SMILES: [CH:1](=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:9]([O:11][CH:12]([O:15][CH2:16][CH3:17])[CH2:13][NH2:14])[CH3:10].C(O)(=O)C.C([BH3-])#N.[Na+]>CO>[CH2:1]([NH:14][CH2:13][CH:12]([O:15][CH2:16][CH3:17])[O:11][CH2:9][CH3:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=Cc1ccccc1
Reactant: CCOC(CN)OCC
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: CCOC(CNCc1ccccc1)OCC
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of Benzaldehyde (1.27 g, 12 mmol) in MeOH (50 mL) was added aminoacetaldehyde diethyl acetal (1.75 mL, 12 mmol) and acetic acid (1.03 mL, 18 mmol). The reaction mixture was stirred at room temperature for 1 h. The reaction mixture was added to a stirred solution of sodium cyanoborohydride (816 mg, 13 mmol). The reaction mixture was stirred at room temperature for 12 h. The reaction mixture was concentrated under reduced pressure. Then H2O and ethyl acetate were added to the reaction mixture. The organic layer was washed with H2O and brine, dried over Na2SO4, and concentrated under reduced pressure. The crude compound was used next step without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:10][C@H:11]([CH2:20][N:21]([CH3:34])S(C2C=CC=CC=2[N+]([O-])=O)(=O)=O)[CH2:12][C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH:5]=[CH:6][C:7]=1[C:8]#[N:9].C1(S)C=CC=CC=1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.O>[Cl:1][C:2]1[CH:3]=[C:4]([NH:10][C@H:11]([CH2:20][NH:21][CH3:34])[CH2:12][C:13]([O:15][C:16]([CH3:19])([CH3:17])[CH3:18])=[O:14])[CH:5]=[CH:6][C:7]=1[C:8]#[N:9]
Reactant: CN(C[C@H](CC(=O)OC(C)(C)C)Nc1ccc(C#N)c(Cl)c1)S(=O)(=O)c1ccccc1[N+](=O)[O-]
Agent: O=C([O-])[O-]
Agent: Sc1ccccc1
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CNC[C@H](CC(=O)OC(C)(C)C)Nc1ccc(C#N)c(Cl)c1

Procedure:
The crude 1,1-dimethylethyl (3S)-3-[(3-chloro-4-cyanophenyl)amino]-4-{methyl[(2-nitrophenyl)sulfonyl]amino}butanoate from the previous step (31.8 g), phenyl hydrosulfide (1.5 equiv., 10.32 g, 94 mmol), and K2CO3 (325 mesh, 3 equiv., 25.9 g, 188 mmol) in DMF (100 mL) were stirred at room temperature for 30 min. The reaction mixture was diluted with H2O (300 mL) and extracted with Et2O (4×). The organic extracts were washed with H2O, and 10% aq. Na2CO3, dried, and concentrated to give the titled product which contaminated with the 2-nitrophenyl phenyl sulfide by product (31.7 g). This contaminated product was used directly in the next step.
Reaction SMILES: Cl.Cl.[NH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:8]=[CH:9][C:10]2[C:11]3[N:20]([CH2:21][CH:22]4[CH2:27][CH2:26][O:25][CH2:24][CH2:23]4)[C:19]([CH2:28][CH3:29])=[N:18][C:12]=3[C:13]([NH2:17])=[N:14][C:15]=2[CH:16]=1.C(N(CC)CC)C.[CH:37]([N:40]=[C:41]=[O:42])([CH3:39])[CH3:38].C(=O)([O-])[O-].[Na+].[Na+]>ClCCl>[NH2:17][C:13]1[C:12]2[N:18]=[C:19]([CH2:28][CH3:29])[N:20]([CH2:21][CH:22]3[CH2:27][CH2:26][O:25][CH2:24][CH2:23]3)[C:11]=2[C:10]2[CH:9]=[CH:8][C:7]([O:6][CH2:5][CH2:4][NH:3][C:41]([NH:40][CH:37]([CH3:39])[CH3:38])=[O:42])=[CH:16][C:15]=2[N:14]=1
Reactant: CC(C)N=C=O
Reactant: CCc1nc2c(N)nc3cc(OCCN)ccc3c2n1CC1CCOCC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCc1nc2c(N)nc3cc(OCCNC(=O)NC(C)C)ccc3c2n1CC1CCOCC1
Reaction time: 0.17 h
Yield: 83.3 %

Procedure:
7-(2-Aminoethoxy)-2-ethyl-1-(tetrahydro-2H-pyran-4-ylmethyl)-1H-imidazo[4,5-c]quinolin-4-amine dihydrochloride (0.480 g, 1.03 mmol; prepared as in Example 552), dichloromethane (10 mL), and triethylamine (0.702 mL, 5.03 mmol) were combined and stirred for 10 minutes. Isopropyl isocyanate (0.101 mL, 1.03 mmol) was added dropwise and the reaction was stirred for 16 hours. Saturated aqueous sodium carbonate (˜5 mL) was added and the reaction was stirred for 10 minutes. The layers were separated. The organic fraction was washed with water and then concentrated under reduced pressure. The resulting crude product was purified by chromatography on a HORIZON HPFC system (silica gel, gradient elution of 2-20% CMA in chloroform) followed by recrystallization from acetonitrile to provide 0.390 g of N-(2-{[4-amino-2-ethyl-1-(tetrahydro-2H-pyran-4-ylmethyl)-1H-imidazo[4,5-c]quinolin-7-yl]oxy}ethyl)-N′-isopropylurea as a white solid, mp 223-225° C.
Reaction SMILES: S(O)(=O)(=O)C.[NH2:6][C:7]1[CH:12]=[C:11]([Cl:13])[N:10]=[C:9]([SH:14])[N:8]=1.[H-].[Na+].[CH3:17][O:18][C:19]1[CH:20]=[N:21][C:22]([CH:27](Cl)[CH3:28])=[CH:23][C:24]=1[CH2:25][CH3:26]>CN(C)C=O.C(OCC)(=O)C>[NH2:6][C:7]1[CH:12]=[C:11]([Cl:13])[N:10]=[C:9]([S:14][CH:27]([C:22]2[CH:23]=[C:24]([CH2:25][CH3:26])[C:19]([O:18][CH3:17])=[CH:20][N:21]=2)[CH3:28])[N:8]=1
Reactant: CCc1cc(C(C)Cl)ncc1OC
Reactant: Nc1cc(Cl)nc(S)n1
Agent: CS(=O)(=O)O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCc1cc(C(C)Sc2nc(N)cc(Cl)n2)ncc1OC
Temperature: 25 °C
Reaction time: 18 h
Yield: 71.6 %

Procedure:
A solution of 4-amino-6-chloro-2-mercapto-pyrimidine mesylate salt (290 mg, 1.1 mmol) in 2 mL of N,N-dimethylformamide at 0° C. is treated with 92 mg (60% in oil, 2.3 mmol) of sodium hydride and warmed to room temperature for 1 h. A solution of 3-methoxy-4-ethyl-6-(1-chloroethyl)-pyridine (225 mg, 1.1 mmol) in 2×1 mL of N,N-dimethylformamide is added dropwise to the mixture and the reaction was stirred for 18 h. The reaction is diluted with 50 mL of ethyl acetate, was washed with 4×25 mL of 50% saturated sodium chloride and dried over potassium carbonate. The organics are concentrated in vacuo and the crude material is chromatographed over 20 g of silica gel (230-400 mesh), eluting with 50% ethyl acetate/hexanes to afford 256 mg of an oil which upon crystallization from ether gave 188 mg (53%) of Cpd #245 (Melting Pt. 136-137° C.).
Reaction SMILES: [H-].[Na+].C(S)C.[CH3:6][CH:7]([S:10][C:11]1[CH:16]=[CH:15][C:14]([O:17]C)=[CH:13][CH:12]=1)[CH2:8][CH3:9].S(=O)(=O)(O)O>CN(C=O)C>[CH3:6][CH:7]([S:10][C:11]1[CH:12]=[CH:13][C:14]([OH:17])=[CH:15][CH:16]=1)[CH2:8][CH3:9]
Reactant: CCC(C)Sc1ccc(OC)cc1
Agent: O=S(=O)(O)O
Agent: [H-]
Agent: [Na+]
Solvent: CCS
Solvent: CN(C)C=O
Product: CCC(C)Sc1ccc(O)cc1
Reaction time: 1.5 h

Procedure:
To sodium hydride (6.6 g, 275 mmol; prewashed with pentane) in 100 ml of DMF, under N2 and at 5°, is slowly added ethyl mercaptan (41.0 ml, 550.0 mmol) in 50 ml of DMF. This mixture is stirred for 1.5 hours, after which is added 4-(1-methylpropylthio)anisole (46.0 g, 250.0 mmol) and DMF. The mixture is heated to 150° with stirring overnight. After cooling to 20°, 10% aqueous sulfuric acid is added and the mixture is extracted with ether. The combined organic layers are washed with water and extracted with 5% NaOH. The aqueous portion is reacidified with conc. sulfuric acid and extracted with ether. The combined ether extracts are washed with water and with brine, dried and the solvent removed to give 4-(1-methylpropylthio)phenol.
Reaction SMILES: Cl[C:2]1[C:3]2[N:11]=[C:10]([NH:12]C(=O)OCC)[S:9][C:4]=2[N:5]=[C:6]([CH3:8])[N:7]=1.[CH3:18][O-:19].[Na+].CO>O>[CH3:18][O:19][C:2]1[C:3]2[N:11]=[C:10]([NH2:12])[S:9][C:4]=2[N:5]=[C:6]([CH3:8])[N:7]=1
Reactant: C[O-]
Reactant: CCOC(=O)Nc1nc2c(Cl)nc(C)nc2s1
Agent: [Na+]
Solvent: O
Solvent: CO
Product: COc1nc(C)nc2sc(N)nc12
Temperature: 25 °C
Yield: 55.6 %

Procedure:
Ethyl 7-chloro-5-methylthiazolo[5,4-d]pyrimidin-2-ylcarbamate (300 mg, 1.100 mmol) was suspended in a 25% w/w solution of sodium methoxide in methanol (5 mL, 23.14 mmol) and the mixture was refluxed overnight. The mixture was cooled to ambient temperature, diluted with water and extracted with chloroform (4×). The combined organics were washed with brine, dried over sodium sulfate, filtered and concentrated in vacuo to afford 7-methoxy-5-methylthiazolo[5,4-d]pyrimidin-2-amine (120 mg, 0.612 mmol, 55.6% yield). 1H NMR (400 MHz, DMSO-d6) δ ppm 7.71 (s, 2 H) 3.98 (s, 3 H) 2.52 (s, 3 H).
Reaction SMILES: [ClH:1].Cl.O[NH:4][C:5]([C:7]1[CH:15]=[CH:14][CH:13]=[C:12]2[C:8]=1[CH2:9][CH2:10][C:11]2=[N:16][N:17]1[CH:21]=[CH:20][N:19]=[C:18]1[NH2:22])=[NH:6]>[Ni].CO.O>[ClH:1].[ClH:1].[C:5]([C:7]1[CH:15]=[CH:14][CH:13]=[C:12]2[C:8]=1[CH2:9][CH2:10][C:11]2=[N:16][N:17]1[CH:21]=[CH:20][N:19]=[C:18]1[NH2:22])(=[NH:4])[NH2:6]
Reactant: N=C(NO)c1cccc2c1CCC2=Nn1ccnc1N
Agent: [Ni]
Agent: Cl
Solvent: CO
Solvent: O
Product: N=C(N)c1cccc2c1CCC2=Nn1ccnc1N

Procedure:
0.3 g of Raney nickel is added to a solution of 0.8 g (2.33 mmol) of 1-[4-(N-hydroxy-amidino)-2,3-dihydro-1H-inden-1-ylideneamino]-2-amino-imidazole dihydrochloride in 60 ml of methanol/water (1:1), and hydrogenation is carried out at room temperature and under normal pressure until the absorption of hydrogen has ceased. The filtrate is adjusted to pH 3 with a small amount of 3N methanolic hydrochloric acid and is concentrated by evaporation in vacuo. Recrystallization of the residue from methanol/water yields the title compound, m.p. >260° C., 1H-NMR (D2O): δ=8.15 (d, 1H); 7.82 (d, 1H); 7.58 (t, 1H); 7.17 (d, 1H); 6.90 (d, 1H); 3.29-3.35 (m, 2H); 3.12-3.18 (m, 2H).
Reaction SMILES: [CH2:1]([O:8][C:9]([C:11]1[C:19]2[C:14](=[CH:15][CH:16]=[C:17]([CH2:20][CH2:21][OH:22])[CH:18]=2)[NH:13][C:12]=1[CH3:23])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH3:31][S:32](Cl)(=[O:34])=[O:33]>C1COCC1>[CH2:1]([O:8][C:9]([C:11]1[C:19]2[C:14](=[CH:15][CH:16]=[C:17]([CH2:20][CH2:21][O:22][S:32]([CH3:31])(=[O:34])=[O:33])[CH:18]=2)[NH:13][C:12]=1[CH3:23])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cc1[nH]c2ccc(CCO)cc2c1C(=O)OCc1ccccc1
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: Cc1[nH]c2ccc(CCOS(C)(=O)=O)cc2c1C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 99.3 %

Procedure:
To a mixture of 5-(2-hydroxy-ethyl)-2-methyl-1H-indole-3-carboxylic acid benzyl ester (1.02 g, 3.3 mmol) and triethylamine (0.92 mL, 6.6 mmol) in dry THF (10 mL) was added methanesulfonyl chloride (0.26 mL, 3.3 mmol) under nitrogen atmosphere at room temperature. The mixture was stirred at room temperature for 3 hours and then partitioned between ethyl acetate and water. The organic phase was washed with water and brine, dried over Na2SO4 and filtered. The filtrate was concentrated in vacuo to give 1.27 g (99%) of the desired product as a white solid: mp 122-124° C.; MS(APCI−): m/z 386.0 (M−H); Anal. Calcd for C20H21N1O5S1: C, 62.00; H, 5.46; N, 3.62; S, 8.28. Found: C, 61.95; H, 5.61; N, 3.54; S, 8.32.
Reaction SMILES: [F:1][C:2]1[CH:47]=[CH:46][C:5]([C:6]([NH:8][C@:9]([C:35]2[CH:40]=[CH:39][C:38]([F:41])=[C:37]([C:42]([F:45])([F:44])[F:43])[CH:36]=2)([C:21]2[CH:26]=[C:25]([O:27][C:28]([F:33])([F:32])[CH:29]([F:31])[F:30])[CH:24]=[C:23]([F:34])[CH:22]=2)[CH2:10][C:11]2[CH:20]=[CH:19][C:14]([C:15](OC)=[O:16])=[CH:13][CH:12]=2)=[O:7])=[CH:4][C:3]=1[C:48]([F:51])([F:50])[F:49].C([BH-](CC)CC)C.[Li+]>C1COCC1>[F:1][C:2]1[CH:47]=[CH:46][C:5]([C:6]([NH:8][C@:9]([C:35]2[CH:40]=[CH:39][C:38]([F:41])=[C:37]([C:42]([F:43])([F:44])[F:45])[CH:36]=2)([C:21]2[CH:26]=[C:25]([O:27][C:28]([F:33])([F:32])[CH:29]([F:30])[F:31])[CH:24]=[C:23]([F:34])[CH:22]=2)[CH2:10][C:11]2[CH:20]=[CH:19][C:14]([CH2:15][OH:16])=[CH:13][CH:12]=2)=[O:7])=[CH:4][C:3]=1[C:48]([F:51])([F:50])[F:49]
Reactant: COC(=O)c1ccc(C[C@](NC(=O)c2ccc(F)c(C(F)(F)F)c2)(c2cc(F)cc(OC(F)(F)C(F)F)c2)c2ccc(F)c(C(F)(F)F)c2)cc1
Agent: CC[BH-](CC)CC
Agent: [Li+]
Solvent: C1CCOC1
Product: O=C(N[C@@](Cc1ccc(CO)cc1)(c1cc(F)cc(OC(F)(F)C(F)F)c1)c1ccc(F)c(C(F)(F)F)c1)c1ccc(F)c(C(F)(F)F)c1
Temperature: -78 °C
Reaction time: 1.5 h
Yield: 79 %

Procedure:
To a solution of (R)-methyl 4-(2-(4-fluoro-3-(trifluoromethyl)benzamido)-2-(4-fluoro-3-(trifluoromethyl)phenyl)-2-(3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)phenyl)ethyl)benzoate prepared as described in Procedure 96, 97, 98, 56 and 57 (29 mg, 0.039 mmol) in THF at −78° C. was added a solution of lithium triethylborohydride (1.0 M in THF, 0.5 mL, 0.5 mmol). The resulting mixture was stirred at −78° C. for 1.5 h. The reaction was quenched by addition of 1 N NaOH (1 mL) and the aqueous layer was extracted with EtOAc (15 mL). The organic layer was dried over magnesium sulfate, filtered and concentrated under reduced pressure. The residue was purified by ISCO (12 g silica gel column, 0-50% EtOAc/hexane over 30 min) to yield (R)-4-fluoro-N-(1-(4-fluoro-3-(trifluoromethyl)phenyl)-1-(3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)phenyl)-2-(4-(hydroxymethyl)phenyl)ethyl)-3-(trifluoromethyl)benzamide (Example 299) as a colorless film (22 mg, 79% yield). LCMS: RT=2.10 min [M+H] 714.31 (Phenomenex Luna C18 4.6×30 mm column, eluting with 10-90% MeOH/H2O containing 0.1% TFA, 2 min gradient, flow rate 5 mL/min, wavelength 220 nm); HPLC: RT=4.0 min (Phenomenex Luna C18 4.6×50 mm column, eluting with 10-90% MeOH/H2O containing 0.2% PPA, flow rate 4 mL/min, wavelength 220 nm); 1H NMR (400 MHz, CDCl3) δ ppm 7.98-7.80 (1H, m), 7.85-7.89 (1H, m), 7.39-7.43 (3H, m), 7.31 (1H, t, J=9.23 Hz), 7.19-7.27 (1H, m), 6.99 (1H, d, J=8.79 Hz), 6.76-6.83 (5H, m), 5.89 (1H, t, J=53.0 Hz), 4.16 (1H, d, J=13.18 Hz), 4.02 (1H, d, J=13.18 Hz).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH2:8])=[C:4]([F:9])[CH:3]=1.C([Li])CCC.Cl[Si](C)(C)CC[Si](Cl)(C)C.Cl[C:26]([O:28][CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)=[O:27].Cl>O1CCCC1.O>[CH2:29]([O:28][C:26](=[O:27])[C:3]1[C:2]([Cl:1])=[CH:7][CH:6]=[C:5]([NH2:8])[C:4]=1[F:9])[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: Nc1ccc(Cl)cc1F
Agent: C[Si](C)(Cl)CC[Si](C)(C)Cl
Agent: Cl
Agent: [Li]CCCC
Solvent: O
Solvent: C1CCOC1
Product: Nc1ccc(Cl)c(C(=O)OCc2ccccc2)c1F
Temperature: -78 °C
Reaction time: 0.33 h

Procedure:
To 4-chloro-2-fluoro-phenylamine (47, 6.30 mL, 57.0 mmol) in tetrahydrofuran (300 mL), cooled with dry ice/acetone bath under an atmosphere of nitrogen, n-butyllithium (2.50 M in hexane, 24.4 mL) was added slowly. After 20 minutes, 1,2-Bis-(chloro-dimethyl-silanyl)-ethane (12.9 g, 60.0 mmol) dissolved in tetrahydrofuran (40.0 mL) was added slowly to the reaction. After 1 hour, n-butyllithium (2.50 M in hexane, 25.0 mL) was added slowly to the reaction. The reaction was stirred at −78° C. for 20 minutes and then allowed to warm to room temperature over 60 minutes. The reaction was cooled to −78° C., followed by addition of n-butyllithium (2.50 M in hexane, 26.0 mL) slowly. After 80 minutes, benzyl chloroformate (10.0 mL, 70.0 mmol) was added to the reaction. The reaction mixture was stirred at −78° C. overnight followed by addition of water (80 mL) and concentrated hydrochloric acid (25 mL). The reaction was allowed to warm to room temperature for 2 hours. The organic layer was separated. The aqueous layer was basified with potassium carbonate and extracted with ethyl acetate. The organic layers were combined and washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated. The desired compound was isolated by silica gel column chromatography (ethyl acetate/hexane 20%) to give a colorless oil (48, 12.5 g, 78.3%). MS (ESI) [M+H+]+=280.0.
Reaction SMILES: C1C(=O)N([Br:8])C(=O)C1.[F:9][C:10]1[CH:11]=[CH:12][C:13]([NH2:16])=[N:14][CH:15]=1>CC#N>[Br:8][C:12]1[C:13]([NH2:16])=[N:14][CH:15]=[C:10]([F:9])[CH:11]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: Nc1ccc(F)cn1
Solvent: CC#N
Product: Nc1ncc(F)cc1Br
Temperature: 25 °C
Reaction time: 8 h
Yield: 48.4 %

Procedure:
NBS (10 g, 56.2 mmol) was added slowly to a solution of 5-fluoro-pyridin-2-ylamine (55) (12.4 g, 56.2 mmol) in MeCN (200 mL). The reaction mixture was stirred at RT overnight. After completion, the solution was filtered and the filtrate was concentrated to obtain a residue, which was purified by silica gel chromatography (10% to 20% EtOAc in petroleum ether) to give 3-bromo-5-fluoro-pyridin-2-ylamine (56) (5.2 g, 27.2 mmol, 31% yield) as a yellow solid.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][C:7]3([CH2:16][CH2:15][CH:14]([OH:17])[CH2:13][CH2:12]3)[C:8]2=[O:11])=[CH:4][C:3]=1[CH3:18].CI.[CH3:21]C(C)([O-])C.[K+].O>[Cl-].[Na+].O>[Br:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][C:7]3([CH2:16][CH2:15][CH:14]([O:17][CH3:21])[CH2:13][CH2:12]3)[C:8]2=[O:11])=[CH:4][C:3]=1[CH3:18]
Reactant: Cc1cc2c(cc1Br)C(=O)C1(CCC(O)CC1)C2
Reactant: CC(C)(C)[O-]
Agent: [Cl-]
Agent: [K+]
Agent: [Na+]
Solvent: CI
Solvent: O
Product: COC1CCC2(CC1)Cc1cc(C)c(Br)cc1C2=O
Temperature: 0 °C
Reaction time: 1 h
Yield: 72.2 %

Procedure:
6′-Bromo-4-hydroxy-5′-methylspiro[cyclohexane-1,2′-inden]-1′(3′H)-one (Intermediate 3, 1.72 g, 5.57 mmol) was dissolved in 2-Me THF (13 mL) under an inert atmosphere and the solution was cooled to 0° C. Methyl iodide (0.453 mL, 7.24 mmol) was added followed by portionwise addition of potassium tert-butoxide (0.875 g, 7.80 mmol). The resulting mixture was stirred at r.t. for 1 h. Potassium tert-butoxide (0.250 g, 2.23 mmol) was added and stirring continued. After another 30 min, potassium tert-butoxide (0.094 g, 0.84 mmol) was added and stirring continued. After a total of 4 h, full conversion was obtained and water (6 mL) and brine (3 mL) were added. The phases were separated and the organic layer was treated with charcoal and diatomaceous earth and then filtered through a plug of diatomaceous earth. The plug was rinsed with EtOAc and the organics were concentrated to yield 1.3 g (77% yield) of the title compound as a mixture of isomers with the methoxy group in either equatorial position (major) or axial position (minor). This mixture was used in the next step without further purification: MS (ES+) m/z 323, 325 [M+H]+.