Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:26])=[C:6]([C:8]([C:10]2[CH:15]=[CH:14][C:13]([NH:16][C:17]3[CH:22]=[CH:21][C:20]([F:23])=[CH:19][C:18]=3[F:24])=[CH:12][C:11]=2[Cl:25])=[O:9])[CH:7]=1.[CH2:27]([N:34]=[C:35]=[O:36])[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>N1C=CC=CC=1>[CH2:27]([NH:34][C:35]([NH:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:26])=[C:6]([C:8](=[O:9])[C:10]2[CH:15]=[CH:14][C:13]([NH:16][C:17]3[CH:22]=[CH:21][C:20]([F:23])=[CH:19][C:18]=3[F:24])=[CH:12][C:11]=2[Cl:25])[CH:7]=1)=[O:36])[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: Cc1ccc(N)cc1C(=O)c1ccc(Nc2ccc(F)cc2F)cc1Cl
Reactant: O=C=NCc1ccccc1
Solvent: c1ccncc1
Product: Cc1ccc(NC(=O)NCc2ccccc2)cc1C(=O)c1ccc(Nc2ccc(F)cc2F)cc1Cl
Temperature: 25 °C
Reaction time: 18 h

Procedure:
Compound 494 (0.07 g, 0.18 mmol) was dissolved in pyridine (0.5 mL) and benzyl isocyanate (0.035 mL, 0.28 mmol) was added. The solution was stirred at room temperature for 18 h. Work up as described in the preparation of compound 259. The crude product was purified by flash chromatography using a MeOH/CH2Cl2 1:100 as the eluent. This afforded the title compound as slightly coloured solid. 13C NMR (DMSO-d6) δ 195.3, 158.8 (dd), 155.8 (dd), 155.2, 149.1, 140.3, 139.1, 138.2, 133.4, 131.4, 129.0, 128.3, 127.1, 126.7, 126.4 (dd), 124.4 (dd), 120.1, 118.2, 114.9, 112.0 (dd), 111.9, 105.1 (dd), 42.7, 19.1
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:15]=[C:14]([O:16][CH3:17])[CH:13]=[CH:12][C:4]=1[CH2:5][NH:6][C:7]1[S:8][CH:9]=[CH:10][N:11]=1.C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[Cl:28][C:29]1[C:38]2[C:33](=[CH:34][C:35]([S:39](OC3C(F)=C(F)C(F)=C(F)C=3F)(=[O:41])=[O:40])=[CH:36][CH:37]=2)[C:32]([F:54])=[CH:31][N:30]=1>O1CCCC1>[Cl:28][C:29]1[C:38]2[C:33](=[CH:34][C:35]([S:39]([N:6]([CH2:5][C:4]3[CH:12]=[CH:13][C:14]([O:16][CH3:17])=[CH:15][C:3]=3[O:2][CH3:1])[C:7]3[S:8][CH:9]=[CH:10][N:11]=3)(=[O:41])=[O:40])=[CH:36][CH:37]=2)[C:32]([F:54])=[CH:31][N:30]=1
Reactant: COc1ccc(CNc2nccs2)c(OC)c1
Reactant: O=S(=O)(Oc1c(F)c(F)c(F)c(F)c1F)c1ccc2c(Cl)ncc(F)c2c1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: COc1ccc(CN(c2nccs2)S(=O)(=O)c2ccc3c(Cl)ncc(F)c3c2)c(OC)c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solution of N-(2,4-dimethoxybenzyl)thiazol-2-amine (0.031 g, 0.123 mmol) in tetrahydrofuran (0.450 ml) was cooled in a dry ice-acetone bath for 5 min. Lithium bis(trimethylsilyl)amide (1M in THF) (0.129 ml, 0.129 mmol) was added drop wise, then the flask was removed from the cooling bath for 5 min. The flask was again cooled into a dry ice-acetone bath for 20 min, resulting in the formation of a thick slurry. A solution of perfluorophenyl 1-chloro-4-fluoroisoquinoline-6-sulfonate (0.050 g, 0.117 mmol) in THF (0.25 mL) was added drop wise, and the reaction was stirred for 30 minutes. The reaction was warmed to room temperature and quenched with saturated ammonium chloride solution, diluted with ethyl acetate and washed with water. The aqueous layer was extracted with ethyl acetate, and the combined organic layers were dried with sodium sulfate, filtered, and concentrated. The filtrate was purified by chromatography on a 12-g column with 0 to 100% EtOAc/Heptane to afford 1-chloro-N-(2,4-dimethoxybenzyl)-4-fluoro-N-(thiazol-2-yl)isoquinoline-6-sulfonamide (INTERMEDIATE PPP) as an oily solid. (ESI) 516.2 (M+H)+.
Reaction SMILES: Br[C:2]1[C:7]2[CH2:8][CH2:9][N:10]([CH3:13])[CH2:11][CH2:12][C:6]=2[C:5]([S:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[C:4]([O:21][CH3:22])[C:3]=1[O:23][CH3:24].C1(C)C=CC=CC=1.C([Li])CCC.[OH-].[Na+].CN(C)[CH:41]=[O:42]>CCCCCC>[CH3:22][O:21][C:4]1[C:3]([O:23][CH3:24])=[C:2]([CH:41]=[O:42])[C:7]2[CH2:8][CH2:9][N:10]([CH3:13])[CH2:11][CH2:12][C:6]=2[C:5]=1[S:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: CN(C)C=O
Reactant: COc1c(Br)c2c(c(Sc3ccccc3)c1OC)CCN(C)CC2
Agent: [Li]CCCC
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1
Solvent: CCCCCC
Product: COc1c(C=O)c2c(c(Sc3ccccc3)c1OC)CCN(C)CC2
Reaction time: 0.33 h

Procedure:
To a solution of 18.21 g. (0.0446 mole) of 9-bromo-7,8-dimethoxy-3-methyl-6-phenylthio-2,3,4,5-tetrahydro-1H-3-benzazepine (prepared as in Example 20) in 200 ml. of toluene, cooled to -78° C., is slowly added 26.0 ml. of 2.1 M n-butyl lithium in hexane. After 20 minutes at this temperature 23.1 ml. of dimethylformamide is added and the mixture is stirred for 1/2 hour. The reaction mixture, at room temperature, is poured into 10% sodium hydroxide solution and extracted with ethyl acetate. The extract is washed with water, dried and concentrated to give 7,8-dimethoxy-3-methyl-6-phenylthio-2,3,4,5-tetrahydro-1H-3-benzazepine-9-carboxaldehyde.
Reaction SMILES: [CH2:1]([O:8][CH:9]([CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[CH3:20])[CH2:10][CH2:11]O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CCN(S(F)(F)[F:27])CC>C(Cl)Cl>[CH2:1]([O:8][CH:9]([CH2:10][CH2:11][F:27])[CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[CH3:20])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCN(CC)S(F)(F)F
Reactant: Cc1ccccc1CC(CCO)OCc1ccccc1
Solvent: ClCCl
Product: Cc1ccccc1CC(CCF)OCc1ccccc1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
To a solution of 3-(benzyloxy)-4-o-tolylbutan-1-ol (3.0 g, 11.11 mmol) in DCM (50 ml) was added DAST (2.9 ml, 22.22 mmol) at 0° C. and stirred at room temperature for 5 h. Then cooled to 0° C. and quenched with NH4Cl (10 ml). The title compound was purified by separation methods A and E. (Yield 1.5 g).
Reaction SMILES: [Cl:1][C:2]1[C:14](I)=[CH:13][C:5]2[NH:6][C:7]([C:9]([F:12])([F:11])[F:10])=[N:8][C:4]=2[CH:3]=1.[Cl:16][C:17]1[CH:22]=[CH:21][C:20](B(O)O)=[CH:19][CH:18]=1.C(=O)([O-])[O-].[Na+].[Na+].O1CCOCC1>O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Cl:1][C:2]1[C:14]([C:20]2[CH:21]=[CH:22][C:17]([Cl:16])=[CH:18][CH:19]=2)=[CH:13][C:5]2[NH:6][C:7]([C:9]([F:12])([F:11])[F:10])=[N:8][C:4]=2[CH:3]=1
Reactant: OB(O)c1ccc(Cl)cc1
Reactant: FC(F)(F)c1nc2cc(Cl)c(I)cc2[nH]1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: FC(F)(F)c1nc2cc(Cl)c(-c3ccc(Cl)cc3)cc2[nH]1
Temperature: 100 °C
Reaction time: 4 h

Procedure:
Compound number 130 (i.e., 6-chloro-5-(4-chlorophenyl)-2-trifluoromethylbenzimidazole was prepared as follows. A 250-mL round-bottom flask was purged and maintained with an inert atmosphere of nitrogen. 5-chloro-6-iodo-2-(trifluoromethyl)-1H-1,3-benzodiazole (400 mg, 1.15 mmol, 1.00 equiv), (4-chlorophenyl)boronic acid (359 mg, 2.30 mmol, 1.99 equiv), sodium carbonate (380 mg), dioxane (40 mL), Pd(PPh3)4 (67 mg), and water (10 mL) was placed in the flask. The resulting solution was stirred for 4 h at 100° C. in an oil bath. The mixture was cooled. The resulting solution was diluted with 100 mL of H2O. The resulting solution was extracted with 3×100 mL of ethyl acetate and the organic layers combined. The resulting mixture was washed with 1×100 mL of brine (sat.). The combined organic layer was dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (1:30). This resulted in 34.9 mg (9%) of 6-chloro-5-(4-chlorophenyl)-2-trifluoromethylbenzimidazole as a white solid.
Reaction SMILES: [CH:1]([Si:4]([CH:37]([CH3:39])[CH3:38])([CH:34]([CH3:36])[CH3:35])[O:5][CH2:6][CH:7]1[CH2:12][CH2:11][N:10]([C:13]2[N:17]3[CH:18]=[C:19]([O:22][C@H:23]4[C:32]5[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=5)[C@@H:26]([NH2:33])[CH2:25][CH2:24]4)[CH:20]=[CH:21][C:16]3=[N:15][N:14]=2)[CH2:9][CH2:8]1)([CH3:3])[CH3:2].ClC(Cl)(Cl)C[O:43][C:44](=O)[NH:45][C:46]1[N:47]([C:55]2[CH:60]=[CH:59][C:58]([CH3:61])=[CH:57][CH:56]=2)[N:48]=[C:49]([C:51]([CH3:54])([CH3:53])[CH3:52])[CH:50]=1.CCN(C(C)C)C(C)C>O1CCOCC1>[C:51]([C:49]1[CH:50]=[C:46]([NH:45][C:44]([NH:33][C@@H:26]2[C:27]3[C:32](=[CH:31][CH:30]=[CH:29][CH:28]=3)[C@H:23]([O:22][C:19]3[CH:20]=[CH:21][C:16]4[N:17]([C:13]([N:10]5[CH2:11][CH2:12][CH:7]([CH2:6][O:5][Si:4]([CH:1]([CH3:2])[CH3:3])([CH:34]([CH3:36])[CH3:35])[CH:37]([CH3:39])[CH3:38])[CH2:8][CH2:9]5)=[N:14][N:15]=4)[CH:18]=3)[CH2:24][CH2:25]2)=[O:43])[N:47]([C:55]2[CH:60]=[CH:59][C:58]([CH3:61])=[CH:57][CH:56]=2)[N:48]=1)([CH3:54])([CH3:52])[CH3:53]
Reactant: CC(C)[Si](OCC1CCN(c2nnc3ccc(O[C@@H]4CC[C@H](N)c5ccccc54)cn23)CC1)(C(C)C)C(C)C
Reactant: Cc1ccc(-n2nc(C(C)(C)C)cc2NC(=O)OCC(Cl)(Cl)Cl)cc1
Solvent: C1COCCO1
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccc(-n2nc(C(C)(C)C)cc2NC(=O)N[C@H]2CC[C@@H](Oc3ccc4nnc(N5CCC(CO[Si](C(C)C)(C(C)C)C(C)C)CC5)n4c3)c3ccccc32)cc1
Reaction time: 2.5 h
Yield: 86 %

Procedure:
A solution of Intermediate 54c (171 mg, 0.311 mmol) and (5-tert-butyl-2-p-tolyl-2H-pyrazol-3-yl)-carbamic acid 2,2,2-trichloro-ethyl ester (Synthetic Communications, 2009, 39, 3999-4009, which is incorporated herein by reference in its entirety; 132 mg, 0.327 mmol) in 1,4-dioxane (3 mL) and DIPEA (87 μL, 0.50 mmol) was stirred at 90° C. for 3 h, and then at 100° C. for 2.5 h. The cooled mixture was concentrated in vacuo. The residue was purified by FCC, using 0-8% MeOH in DCM, to give the title compound as a pale brown solid (215 mg, 86%). LCMS (Method 3): Rt 5.70 min, m/z 805.4 [MH+].
Reaction SMILES: [OH:1][CH2:2][CH2:3][C:4]1[CH:9]=[CH:8][N:7]=[CH:6][CH:5]=1.C(N(CC)CC)C.[Si:17](Cl)([C:20]([CH3:23])([CH3:22])[CH3:21])([CH3:19])[CH3:18]>C(Cl)Cl>[Si:17]([O:1][CH2:2][CH2:3][C:4]1[CH:9]=[CH:8][N:7]=[CH:6][CH:5]=1)([C:20]([CH3:23])([CH3:22])[CH3:21])([CH3:19])[CH3:18]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: OCCc1ccncc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)[Si](C)(C)OCCc1ccncc1
Temperature: -78 °C
Yield: 97.9 %

Procedure:
4-(2-Hydroxyethyl)pyridine (8.1 g, 65.8 mmol) and triethylamine (10.1 mL, 66 mmol) were dissolved in CH2Cl2 (100 mL) and cooled to −78° C. To this solution, tert-butyldimethylsilyl chloride (11.0 g, 66 mmol) was added. The mixture was allowed to warm to room temperature overnight. The mixture was placed directly on a bed of SiO2 and eluted with 100:0-10:1 CH2Cl2 methanol to provide 4-[2-(tert-Butyldimethylsilyloxy)ethyl]pyridine (15.3 g, 97%).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6](/[CH:12]=[CH:13]\[C:14]2[CH:19]=[C:18]([O:20][CH3:21])[C:17]([O:22][CH3:23])=[C:16]([O:24][CH3:25])[CH:15]=2)[CH:7]=[CH:8][C:9]=1[O:10][CH3:11])([O-])=O>C(O)(=O)C.[Zn]>[NH2:1][C:4]1[CH:5]=[C:6](/[CH:12]=[CH:13]\[C:14]2[CH:15]=[C:16]([O:24][CH3:25])[C:17]([O:22][CH3:23])=[C:18]([O:20][CH3:21])[CH:19]=2)[CH:7]=[CH:8][C:9]=1[O:10][CH3:11]
Reactant: COc1ccc(/C=C\c2cc(OC)c(OC)c(OC)c2)cc1[N+](=O)[O-]
Agent: [Zn]
Solvent: CC(=O)O
Product: COc1ccc(/C=C\c2cc(OC)c(OC)c(OC)c2)cc1N
Reaction time: 1 h
Yield: 49.1 %

Procedure:
700 mg of (Z)-1-(3-nitro-4-methoxyphenyl)-2-(3,4,5-trimethoxyphenyl) ethene were dissolved in 35 ml of acetic acid, and 7 g of zinc were added thereto and stirred for one hour. The reaction liquid was filtered, concentrated and purified by silica gel column chromatography (dichloromethane: hexane=2:1 by volume) to obtain 314 mg of the intended compound. The yield was 49.3%.
Reaction SMILES: [CH2:1]([Si:5]([CH3:11])([CH3:10])[CH2:6][CH2:7][CH2:8][OH:9])[CH2:2][CH2:3][CH3:4].N1C=CC=CC=1.[C:18]1([CH3:28])[CH:23]=[CH:22][C:21]([S:24](Cl)(=[O:26])=[O:25])=[CH:20][CH:19]=1.Cl>O>[C:18]1([CH3:28])[CH:23]=[CH:22][C:21]([S:24]([O:9][CH2:8][CH2:7][CH2:6][Si:5]([CH2:1][CH2:2][CH2:3][CH3:4])([CH3:10])[CH3:11])(=[O:26])=[O:25])=[CH:20][CH:19]=1
Reactant: CCCC[Si](C)(C)CCCO
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: Cl
Solvent: c1ccncc1
Solvent: O
Product: CCCC[Si](C)(C)CCCOS(=O)(=O)c1ccc(C)cc1
Yield: 81.7 %

Procedure:
5.0 g (28.68 mM) of butyldimethyl-3-hydroxypropylsilane was added 50 ml of pyridine, followed by stirring. To the mixture, 5.4 g (28.32 mM) of p-toluenesulfonyl chloride was added under cooling on an ice bath, followed by stirring for 0.5 hour and further stirring for 4 hours at room temperature. After the reaction, the reaction mixture was poured into water, acidified with hydrochloric acid (pH≈2) and extracted with ethyl acetate, followed by washing with water and drying with anhydrous magnesium sulfate. The magnesium sulfate in the resultant mixture was filtered off and the filtrate was condensed into a solid to obtain 3-(butyldimethylsilyl)propyl p-toluenesulfonate (Yield: 81.7 %).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([Br:14])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.C(=O)([O-])[O-].[Cs+].[Cs+].[NH:21]1[CH2:25][CH2:24][C@@H:23]2[CH2:26][N:27]([C:29]([O:31][CH2:32][CH3:33])=[O:30])[CH2:28][C@H:22]12>ClCCl>[Br:14][C:11]1[CH:12]=[CH:13][C:8]([C:5]2[CH:6]=[CH:7][C:2]([N:21]3[CH2:25][CH2:24][C@@H:23]4[CH2:26][N:27]([C:29]([O:31][CH2:32][CH3:33])=[O:30])[CH2:28][C@H:22]34)=[CH:3][CH:4]=2)=[CH:9][CH:10]=1
Reactant: CCOC(=O)N1C[C@H]2CCN[C@H]2C1
Reactant: Brc1ccc(-c2ccc(Br)cc2)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: ClCCl
Product: CCOC(=O)N1C[C@H]2CCN(c3ccc(-c4ccc(Br)cc4)cc3)[C@H]2C1
Temperature: 20 °C

Procedure:
The catalyst solution was added to the vessel containing the 4,4′-dibromobiphenyl, cesium carbonate, and the product of Example 41C and the mixture was heated to 98° C. for 12 hours. The mixture was cooled to 20° C. and 80 g of dichloromethane was added. The resulting mixture was stirred and then filtered to remove the catalyst. The resulting solution was concentrated under reduced pressure and the residue was purified by column chromatography to yield 5.65 g of the title compound.
Reaction SMILES: O1CCCC1.[F:6][C:7]1[CH:16]=[C:15](F)[C:14]([F:18])=[CH:13][C:8]=1[C:9]([O:11][CH3:12])=[O:10].[CH2:19]([N:26]1[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>C(OCC)(=O)C>[CH2:19]([N:26]1[CH2:31][CH2:30][N:29]([C:15]2[C:14]([F:18])=[CH:13][C:8]([C:9]([O:11][CH3:12])=[O:10])=[C:7]([F:6])[CH:16]=2)[CH2:28][CH2:27]1)[C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1
Reactant: COC(=O)c1cc(F)c(F)cc1F
Reactant: c1ccc(CN2CCNCC2)cc1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COC(=O)c1cc(F)c(N2CCN(Cc3ccccc3)CC2)cc1F
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 33.7 %

Procedure:
To a 30 ml tetrahydrofuran solution of 4.25 g (22.35 mmol) of methyl 2,4,5-trifluorobenzoate, 3.89 ml (22.35 mmol) of N-benzylpiperazine was added with ice cooling. The mixture was stirred at 0° C. for 0.5 hour, and at room temperature for 2.5 hours. Then, the reaction mixture was diluted with ethyl acetate, and the dilution was washed with water and a saturated aqueous solution of sodium chloride in this order. The washed system was dried over sodium sulfate, and then the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate=2/1) to obtain 2.61 g (34%) of the captioned compound.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][CH:14]=1)[C:11](=[O:15])[N:10]([C:16]1[C:17]([CH:49]=[O:50])=[C:18]([N:22]3[CH:26]=[C:25]([C:27]#[N:28])[C:24]([NH:29][C:30]([C:43]4[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=4)([C:37]4[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=4)[C:31]4[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=4)=[N:23]3)[CH:19]=[CH:20][CH:21]=1)[N:9]=[CH:8]2)([CH3:4])([CH3:3])[CH3:2].[BH4-].[Na+]>C(Cl)Cl.CO>[C:1]([C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][CH:14]=1)[C:11](=[O:15])[N:10]([C:16]1[C:17]([CH2:49][OH:50])=[C:18]([N:22]3[CH:26]=[C:25]([C:27]#[N:28])[C:24]([NH:29][C:30]([C:31]4[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=4)([C:37]4[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=4)[C:43]4[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=4)=[N:23]3)[CH:19]=[CH:20][CH:21]=1)[N:9]=[CH:8]2)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)c1ccc2c(=O)n(-c3cccc(-n4cc(C#N)c(NC(c5ccccc5)(c5ccccc5)c5ccccc5)n4)c3C=O)ncc2c1
Agent: [BH4-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CO
Product: CC(C)(C)c1ccc2c(=O)n(-c3cccc(-n4cc(C#N)c(NC(c5ccccc5)(c5ccccc5)c5ccccc5)n4)c3CO)ncc2c1
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 76.1 %

Procedure:
To a solution of 1-[3-(6-tert-Butyl-1-oxo-1H-phthalazin-2-yl)-2-formyl-phenyl]-3-(trityl-amino)-1H-pyrazole-4-carbonitril (632 mg, 0.965 mmol) in methylene chloride (20 mL) and methanol (10 mL), at 0° C. was added sodium borohydride (37 mg, 0.965 mmol). The resulting turbid reaction mixture was stirred at 0° C. for 5 minutes and then allowed to stir at room temperature for 10 minutes. The reaction was then judged to be complete by TLC. The volatiles removed in vacuo and the crude product was bound to silica gel and purified over a 40 g silica gel cartridge eluting the column with a 20-50% EtOAc/hexanes gradient to give 1-[3-(6-tert-Butyl-1-oxo-1H-phthalazin-2-yl)-2-hydroxymethyl-phenyl]-3-(trityl-amino)-1H-pyrazole-4-carbonitrile (482 mg, 76%).
Reaction SMILES: Cl[C:2]1[C:11]([C:12]#[N:13])=[C:10]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([Cl:20])[CH:8]=2)[N:3]=1.[CH2:21]([NH:23][CH3:24])[CH3:22]>>[Cl:20][C:7]1[CH:8]=[C:9]2[C:4](=[CH:5][CH:6]=1)[N:3]=[C:2]([N:23]([CH2:21][CH3:22])[CH3:24])[C:11]([C:12]#[N:13])=[C:10]2[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: CCNC
Reactant: N#Cc1c(Cl)nc2ccc(Cl)cc2c1-c1ccccc1
Product: CCN(C)c1nc2ccc(Cl)cc2c(-c2ccccc2)c1C#N

Procedure:
The title compound was prepared in analogy to example 27 step C from 2,6-dichloro-4-phenyl-quinoline-3-carbonitrile (prepared as described in example 27 step B) and ethyl-methyl-amine. Yellow solid. MS (ESI): 322.2 (M+H)+.
Reaction SMILES: [OH:1][CH:2]1[CH:7]([C:8]2[CH:13]=[CH:12][C:11]([CH2:14][CH2:15][O:16][C:17]([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[CH:10][CH:9]=2)[CH2:6][CH2:5][N:4]([C:36]([O:38][C:39]([CH3:42])([CH3:41])[CH3:40])=[O:37])[CH2:3]1.Cl[CH2:44][C:45]1[CH:46]=[C:47]([O:55][CH2:56][O:57][CH2:58][CH2:59][Si:60]([CH3:63])([CH3:62])[CH3:61])[C:48]2[C:53]([CH:54]=1)=[CH:52][CH:51]=[CH:50][CH:49]=2>>[CH3:61][Si:60]([CH3:62])([CH3:63])[CH2:59][CH2:58][O:57][CH2:56][O:55][C:47]1[C:48]2[C:53](=[CH:52][CH:51]=[CH:50][CH:49]=2)[CH:54]=[C:45]([CH2:44][O:1][CH:2]2[CH:7]([C:8]3[CH:13]=[CH:12][C:11]([CH2:14][CH2:15][O:16][C:17]([C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)([C:24]4[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=4)[C:30]4[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=4)=[CH:10][CH:9]=3)[CH2:6][CH2:5][N:4]([C:36]([O:38][C:39]([CH3:42])([CH3:41])[CH3:40])=[O:37])[CH2:3]2)[CH:46]=1
Reactant: C[Si](C)(C)CCOCOc1cc(CCl)cc2ccccc12
Reactant: CC(C)(C)OC(=O)N1CCC(c2ccc(CCOC(c3ccccc3)(c3ccccc3)c3ccccc3)cc2)C(O)C1
Product: CC(C)(C)OC(=O)N1CCC(c2ccc(CCOC(c3ccccc3)(c3ccccc3)c3ccccc3)cc2)C(OCc2cc(OCOCC[Si](C)(C)C)c3ccccc3c2)C1

Procedure:
(α) In an analogous manner to that described in Example 1(g), by alkylating tert-butyl (3RS,4RS)-3-hydroxy-4-[4-(2-trityloxy-ethyl)-phenyl]-piperidine-1-carboxylate [Example 29(t)] with 3-chloromethyl-1-(2-trimethylsilanyl-ethoxymethoxy)-naphthalene [Example 5(c)] there was obtained tert-butyl (3RS,4RS)-3-[4-(2-trimethylsilanyl-ethoxymethoxy)-naphthalen-2-ylmethoxy]-4-[4-(2-trityloxy-ethyl)-phenyl]-piperidine-1-carboxylate.
Reaction SMILES: [S:1]1[CH2:6][CH2:5][NH:4][C:3]2[CH:7]=[CH:8][CH:9]=[CH:10][C:2]1=2.[C:11]([N:18]1[CH2:22][CH2:21][C:20](=O)[CH2:19]1)([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12].C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[S:1]1[CH2:6][CH2:5][N:4]([CH:21]2[CH2:20][CH2:19][N:18]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:22]2)[C:3]2[CH:7]=[CH:8][CH:9]=[CH:10][C:2]1=2
Reactant: c1ccc2c(c1)NCCS2
Reactant: CC(C)(C)OC(=O)N1CCC(=O)C1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Solvent: CC(=O)O
Product: CC(C)(C)OC(=O)N1CCC(N2CCSc3ccccc32)C1
Temperature: 0 °C
Reaction time: 11 h
Yield: 19.4 %

Procedure:
A mixture of 3,4-dihydro-2H-benzo[b][1,4]thiazine (1.00 g, 6.61 mmol), N-boc-3-pyrrolidinone (1.34 g, 7.27 mmol), and acetic acid (0.94 mL, 16.52 mmol) in 1,2-dichloroethane (20 mL) was cooled to 0° C. and then treated with solid sodium triacetoxyborohydride (2.10 g, 9.92 mmol). The reaction was brought to room temperature and was stirred for 11 hours. Additional equivalents of each of sodium triacetoxyborohydride (1.40 g, 6.61 mmol) and N-boc-3-pyrrolidinone (1.22 g, 6.61 mmol) were added to the reaction mixture. The reaction was stirred for 2 more days and was then quenched with 3 N NaOH (50 mL). The mixture was transferred to a separatory funnel and extracted with EtOAc (2×50 mL). The organic phase was washed with brine (50 mL) and dried (Na2SO4). The crude material was subject to flash chromatography on silica gel (10% EtOAc/hexanes then 20% EtOAc/hexanes). The sample was subject to additional flash chromatography on silica gel (7.5-15% EtOAc/hexanes) to give viscous oil (0.41 g, 19%). 1H NMR (CDCl3) δ 7.08 (dd, J=0.9, 7.5 Hz, 1H), 7.04-6.99 (m, 1H), 6.77 (d, J=8.1 Hz, 1H), 6.67-6.72 (m, 1H), 4.39-4.36 (m, 1H), 3.73-3.72 (m, 6H), 3.10-3.06 (m, 2H), 2.20-2.00 (m, 2H), 1.47 (s, 9H); ESI-MS (m/z, %): 345, 343 (M+Na, 4), 322, 320 (MH+, 3), 267, 265 (100).
Reaction SMILES: [Cl:1][C:2]1[C:7]([F:8])=[CH:6][N:5]=[C:4]([CH3:9])[CH:3]=1.[Br:10]Br.S(=O)(=O)(O)O>>[Br:10][C:3]1[C:4]([CH3:9])=[N:5][CH:6]=[C:7]([F:8])[C:2]=1[Cl:1]
Reactant: BrBr
Reactant: Cc1cc(Cl)c(F)cn1
Agent: O=S(=O)(O)O
Product: Cc1ncc(F)c(Cl)c1Br

Procedure:
4-Chloro-5-fluoro-2-picoline, the product of Exmnple 66, is treated with bromine in fuming sulfuric acid containing 65% sulfur trioxide for 7 hours at 80° C. as described by L. van der Does and H. J. Hertog in Rec Tray Chim 81:864 (1965) to afford the title compound.
Reaction SMILES: [NH2:1][C:2]1[C:11]([CH3:12])=[CH:10][C:9]([F:13])=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].C(OC(=O)C)(=O)C.C([O-])(=O)C.[K+].[N:26](OCCC(C)C)=O>C(Cl)(Cl)Cl>[F:13][C:9]1[CH:10]=[C:11]2[C:2](=[C:3]([C:4]([O:6][CH3:7])=[O:5])[CH:8]=1)[NH:1][N:26]=[CH:12]2
Reactant: COC(=O)c1cc(F)cc(C)c1N
Reactant: CC(C)CCON=O
Agent: CC(=O)[O-]
Agent: [K+]
Solvent: CC(=O)OC(C)=O
Solvent: ClC(Cl)Cl
Product: COC(=O)c1cc(F)cc2cn[nH]c12
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 42.6 %

Procedure:
To a solution of methyl 2-amino-5-fluoro-3-methylbenzoate (1.0 g, 5.5 mmol) from Step C above in chloroform (15 mL) was added acetic anhydride (1.2 ml) while maintaining the temperature below 40° C. The reaction mixture was stirred at room temperature for 90 min then potassium acetate (157 mg, 1.6 mmol) and isoamyl nitrite (1.62 ml, 12 mmol) were added to it. The reaction mixture was heated to reflux for overnight. The reaction mixture was cooled to room temperature, extracted with dichlormethane, washed with water, saturated sodium bicarbonate and brine. The organic extract was dried (Na2SO4) and concentrated in vacuo to afford a red solid, which was purified by column chromatography (silica gel, 0-50% ethyl acetate/hexanes) to afford methyl 5-fluoro-1H-indazole-7-carboxylate (455 mg, 43%) as a yellow brown solid: 1H NMR (500 MHz, CDCl3) δ 8.25 (s, 1H), 7.96 (dd, J=9.0, 3.0 Hz, 1H), 7.81 (dd, J=9.0, 3.0 Hz, 1H), 3.98 (s, 3H); MS (ESI+) m/z 195.
Reaction SMILES: [H-].[Na+].Br[C:4]1[CH:5]=[C:6]([CH:27]=[CH:28][N:29]=1)[C:7]([NH:9][C:10]1[S:11][C:12]2[C:18]([CH:19]3[CH2:24][O:23][CH2:22][CH2:21][O:20]3)=[CH:17][CH:16]=[C:15]([O:25][CH3:26])[C:13]=2[N:14]=1)=[O:8].C(Cl)(Cl)Cl.CN([CH:37]=[O:38])C>O1CCOCC1>[O:20]1[CH2:21][CH2:22][O:23][CH2:24][CH:19]1[C:18]1[C:12]2[S:11][C:10]([NH:9][C:7](=[O:8])[C:6]3[CH:27]=[CH:28][N:29]=[C:4]([O:20][CH:19]4[CH2:24][CH2:37][O:38][CH2:17][CH2:18]4)[CH:5]=3)=[N:14][C:13]=2[C:15]([O:25][CH3:26])=[CH:16][CH:17]=1
Reactant: CN(C)C=O
Reactant: COc1ccc(C2COCCO2)c2sc(NC(=O)c3ccnc(Br)c3)nc12
Agent: [H-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: ClC(Cl)Cl
Product: COc1ccc(C2COCCO2)c2sc(NC(=O)c3ccnc(OC4CCOCC4)c3)nc12

Procedure:
From (+)-2-bromo-N-(7-[1,4]dioxan-2-yl-4-methoxy-benzothiazol-2-yl)-isonicotinamide sodium hydride and tetrahydro-2H-pyranol-4-ol in dioxane and DMF. [α]D20=+12.4° (c=0.11, CHCl3), ES-MS m/e (%): 472 (M+H+, 100).