Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:7]=[C:6]([O:8][CH2:9][O:10][CH3:11])[CH:5]=[CH:4][C:3]=1[C:12]1[C:13]([CH2:25][OH:26])=[C:14]2[C:19](=[CH:20][CH:21]=1)[NH:18][C:17]([CH3:23])([CH3:22])[CH:16]=[C:15]2[CH3:24].CI.[C:29](=O)([O-])[O-].[K+].[K+]>CN(C)C=O.C(OCC)(=O)C.C(OCC)C>[OH:26][CH2:25][C:13]1[C:12]([C:3]2[CH:4]=[CH:5][C:6]([O:8][CH2:9][O:10][CH3:11])=[CH:7][C:2]=2[O:1][CH3:29])=[CH:21][CH:20]=[C:19]2[C:14]=1[C:15]([CH3:24])=[CH:16][C:17]([CH3:23])([CH3:22])[NH:18]2
Reactant: O=C([O-])[O-]
Reactant: COCOc1ccc(-c2ccc3c(c2CO)C(C)=CC(C)(C)N3)c(O)c1
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CCOCC
Solvent: CI
Product: COCOc1ccc(-c2ccc3c(c2CO)C(C)=CC(C)(C)N3)c(OC)c1
Temperature: 50 °C
Reaction time: 1 h
Yield: 66 %

Procedure:
A mixture of 6-(2-hydroxy-4-methoxymethoxyphenyl)-5-hydroxymethyl-2,2,4-trimethyl-1,2-dihydroquinoline (Reference Compound No. 1-(6), 746.1 mg, 2.10 mmol), methyl iodide (131 μL, 2.10 mmol) and potassium carbonate (582 mg, 4.21 mmol) was suspended in anhydrous N,N-dimethylformamide (10 mL) and the suspension was stirred at 50° C. for 1 hour. After cooling down, the mixture was diluted with ethyl acetate (50 mL) and diethylether (50 mL). The mixture was washed with water (100 mL, twice) and saturated brine (50 mL) successively, dried over anhydrous magnesium sulfate, and then the solvent was removed under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane-ethyl acetate) to give the titled reference compound (513.2 mg) as a colorless solid. (Yield 66%)
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([N+:19]([O-:21])=[O:20])=[C:13]([CH2:15][C:16]([OH:18])=[O:17])[CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:22][CH:23](O)[CH3:24].Cl.C(N=C=NCCCN(C)C)C>C(Cl)Cl.CN(C)C1C=CN=CC=1>[CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([N+:19]([O-:21])=[O:20])=[C:13]([CH2:15][C:16]([O:18][CH:23]([CH3:24])[CH3:22])=[O:17])[CH:14]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)Cc1cc(OCc2ccccc2)ccc1[N+](=O)[O-]
Reactant: CC(C)O
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Product: CC(C)OC(=O)Cc1cc(OCc2ccccc2)ccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 5-benzyloxy-2-nitrophenylacetic acid (25.1 g) in methylene chloride (250 ml) were added in turn 2-propanol (27 ml), 4-dimethylaminopyridine (1.07 and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (18.4 g) and the resulting mixture was stirred at room temperature for one hour and then allowed to stand overnight. After the solvent was distilled off under reduced pressure, the resulting residue was diluted with ethyl acetate, washed subsequently with 1N hydrochloric acid and saturated saline. The organic layer was dried over magnesium sulfate and distilled off under reduced pressure. The dark yellow oily substance thus obtained (29.7 g) was purified by a silica gel column chromatography (hexane:ethyl acetate=4:1) to give the title compound (22.5 g).
Reaction SMILES: [C:1]([N:8]1[CH2:15][CH2:14][CH2:13][C@H:9]1[C:10]([OH:12])=O)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[NH2:16][C:17]1[C:25]([C:26]([F:29])([F:28])[F:27])=[CH:24][CH:23]=[CH:22][C:18]=1[C:19](O)=[O:20]>C(Cl)Cl.CN1CCOCC1.ClC(OCC(C)C)=O>[O:20]=[C:19]1[C:18]2[CH:22]=[CH:23][CH:24]=[C:25]([C:26]([F:27])([F:28])[F:29])[C:17]=2[N:16]=[C:10]([C@@H:9]2[CH2:13][CH2:14][CH2:15][N:8]2[C:1]([O:3][C:4]([CH3:5])([CH3:6])[CH3:7])=[O:2])[O:12]1
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1C(=O)O
Reactant: Nc1c(C(=O)O)cccc1C(F)(F)F
Agent: CC(C)COC(=O)Cl
Solvent: ClCCl
Solvent: CN1CCOCC1
Product: CC(C)(C)OC(=O)N1CCC[C@H]1c1nc2c(C(F)(F)F)cccc2c(=O)o1

Procedure:
Using the procedure of Step A of Example 7, a solution of 16.14 ml of BOC-L-proline in 150 ml of methylene chloride, 20.6 ml of N-methyl-morpholine, 19.5 ml of isobutyl chloroformate in 75 ml of methylene chloride and 15.4 g of 2-amino-3-trifluoromethylbenzoic acid in 150 ml of methylene chloride and 8.3 ml of N-methyl-morpholine were reacted for 20 hours. The mixture was extracted with methylene chloride and the residue was chromatographed on silica gel and was eluted with methylene chloride to obtain 16.4 g of 1,1-dimethylethyl (2S) 2-[4-oxo-8-(trifluoromethyl)-4H-3,1-benzoxazin-2-yl]-1-pyrrolidine carboxylate having a specific rotation of [α]D =-75°±2.5° (c=0.6% in CH3COOH).
Reaction SMILES: [CH2:1]([CH:4]1[CH2:8][N:7]([CH2:9][C:10]2[C:18]3[C:13](=[N:14][CH:15]=[CH:16][CH:17]=3)[NH:12][CH:11]=2)[C:6](=[O:19])[CH2:5]1)[CH2:2][CH3:3].ClC1C=C(C=CC=1)C(OO)=[O:25].CCCCCC>COCCOC>[O-:25][N+:14]1[CH:15]=[CH:16][CH:17]=[C:18]2[C:10]([CH2:9][N:7]3[CH2:8][CH:4]([CH2:1][CH2:2][CH3:3])[CH2:5][C:6]3=[O:19])=[CH:11][NH:12][C:13]=12
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CCCC1CC(=O)N(Cc2c[nH]c3ncccc23)C1
Solvent: CCCCCC
Solvent: COCCOC
Product: CCCC1CC(=O)N(Cc2c[nH]c3c2ccc[n+]3[O-])C1
Temperature: 25 °C
Reaction time: 20 h
Yield: 46.9 %

Procedure:
To 4-propyl-1-(1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)pyrrolidin-2-one 231 (100 mg, 1 eq, 0.39 mmol) dissolved in 1,2-dimethoxyethane (3 ml) is added m-chloroperoxybenzoic acid (111 mg, 1.6 eq, 0.64 mmol). The resulting solution is stirred at room temperature for 20 hours. Hexane (10 ml) is added to the reaction mixture, and the decanted syrup is washed twice with hexane by decantation and dried under vacuum. To the residual solid are added 3 ml of water and a saturated solution of K2CO3 until pH 9. The resulting mixture is extracted with CH2Cl2 and the organic phase is dried over MgSO4. Volatiles are removed under reduced pressure and the residue is purified twice by chromatography on silicagel (CH2Cl2/MeOH/NH4OH 95/5/05) to give 50 mg of 1-[(7-oxido-1H-pyrrolo[2,3-b]pyridin-3-yl)methyl]-4-propylpyrrolidin-2-one 239.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1([C:12]2[CH:17]=[CH:16][C:15]([C:18]3[N:19]=[C:20]4[CH:25]=[CH:24][C:23]([O:26][CH2:27][CH3:28])=[CH:22][N:21]4[C:29]=3[C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)=[CH:14][CH:13]=2)[CH2:11][CH2:10][CH2:9]1)(C)(C)C.Cl.O1CCOCC1>CO.C(Cl)Cl>[CH2:27]([O:26][C:23]1[CH:24]=[CH:25][C:20]2[N:21]([C:29]([C:30]3[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=3)=[C:18]([C:15]3[CH:16]=[CH:17][C:12]([C:8]4([NH2:7])[CH2:9][CH2:10][CH2:11]4)=[CH:13][CH:14]=3)[N:19]=2)[CH:22]=1)[CH3:28]
Reactant: CCOc1ccc2nc(-c3ccc(C4(NC(=O)OC(C)(C)C)CCC4)cc3)c(-c3ccccc3)n2c1
Agent: Cl
Solvent: CO
Solvent: C1COCCO1
Solvent: ClCCl
Product: CCOc1ccc2nc(-c3ccc(C4(N)CCC4)cc3)c(-c3ccccc3)n2c1
Temperature: 25 °C
Reaction time: 12 h
Yield: 18.7 %

Procedure:
To a solution of {1-[4-(6-ethoxy-3-phenyl-imidazo[1,2-a]pyridin-2-yl)-phenyl]-cyclobutyl}-carbamic acid tert-butyl ester (255 mg, 0.53 mmol) in MeOH (2.1 mL) and CH2Cl2 (3.4 mL) was added a 4 molar solution of HCl in dioxane (2.6 mL, 10.5 mmol, 20 equiv). The resulting solution was stirred at room temperature for 12 h, then was concentrated under reduced pressure. The remaining material was purified using MPLC (Isolute Flash NH2 reverse phase column; 100% CH2Cl2 for 5 min., gradient to 95% CH2Cl2: 5% MeOH over 15 minutes; gradient to 90% CH2Cl2: 10% MeOH over 15 min.; gradient to 80% CH2Cl2: 20% MeOH over 15 min.; and gradient to 75% CH2Cl2: 25% MeOH over 15 min.) to give 1-[4-(6-ethoxy-3-phenyl-imidazo[1,2-a]pyridin-2-yl)-phenyl]-cyclobutylamine (38 mg, 19%):
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[S:13]1[CH:17]=[CH:16][CH:15]=[C:14]1[CH:18]=[CH:19][C:20]([O:22][CH3:23])=[O:21].[C:24]12([CH2:34][CH2:35][N:36]3[C:40]([CH:41]=[O:42])=[CH:39][N:38]=[C:37]3[CH2:43][CH2:44][CH2:45][CH3:46])[CH2:33][CH:28]3[CH2:29][CH:30]([CH2:32][CH:26]([CH2:27]3)[CH2:25]1)[CH2:31]2.[Cl-].[NH4+]>CCCCCC.O1CCCC1.O>[C:24]12([CH2:34][CH2:35][N:36]3[C:40]([CH:41]([OH:42])[CH:19]([CH2:18][C:14]4[S:13][CH:17]=[CH:16][CH:15]=4)[C:20]([O:22][CH3:23])=[O:21])=[CH:39][N:38]=[C:37]3[CH2:43][CH2:44][CH2:45][CH3:46])[CH2:33][CH:28]3[CH2:29][CH:30]([CH2:32][CH:26]([CH2:27]3)[CH2:25]1)[CH2:31]2
Reactant: CCCCc1ncc(C=O)n1CCC12CC3CC(CC(C3)C1)C2
Reactant: COC(=O)C=Cc1cccs1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: O
Solvent: CCCCCC
Solvent: CC(C)NC(C)C
Product: CCCCc1ncc(C(O)C(Cc2cccs2)C(=O)OC)n1CCC12CC3CC(CC(C3)C1)C2
Reaction time: 0.25 h

Procedure:
Diisopropylamine (0.563 g) was covered with 5 ml of tetrahydrofuran and 2 ml of 2.5M n-butyl lithium in hexane was added. The mixture was stirred for 15 minutes, then methyl 3-(2-thienyl)propenoate (0.89 g) in 3 ml of tetrahydrofuran was added. After 20 minutes, 1.04 g of 1-[2-(1-adamantyl)ethyl]-2-n-butyl-imidazol-5-carboxaldehyde in 3 ml of tetrahydrofuran was added and the mixture was stirred for 30 minutes at -78° C. The mixture was poured into 40 ml of saturated ammonium chloride in water, extracted with ether, dried over magnesium sulfate, filtered, concentrated and chromatographed on silica gel eluting with 70% ethyl acetate and 30% hexane to give methyl 3-[1-(2-(1-adamantyl)ethyl)2-n-butyl-1H-imidazol-5-yl]-3-hydroxy-2-(2-thienylmethyl)propanoate. To 1.27 g of this compound in dichloromethane (25 ml) was added 4-dimethylaminopyridine (1.25 g), then acetic anhydride (2.75 g) was added dropwise. The mixture was stirred for one hour, then poured into water and worked up to give 3-acetoxy-3-[1-(2-(1-adamantyl)ethyl)-2-n-butyl-1H-imidazol-5-yl]-2-(2-thienylmethyl)propanoate.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:18])[CH2:4][CH2:5][CH2:6][O:7][C:8]1[CH:13]=[CH:12][C:11]([CH:14]=[O:15])=[CH:10][C:9]=1[O:16][CH3:17].[N+:19]([O-])([OH:21])=[O:20].O>C(OC(=O)C)(=O)C>[CH3:1][O:2][C:3](=[O:18])[CH2:4][CH2:5][CH2:6][O:7][C:8]1[CH:13]=[C:12]([N+:19]([O-:21])=[O:20])[C:11]([CH:14]=[O:15])=[CH:10][C:9]=1[O:16][CH3:17]
Reactant: COC(=O)CCCOc1ccc(C=O)cc1OC
Reactant: O=[N+]([O-])O
Solvent: O
Solvent: CC(=O)OC(C)=O
Product: COC(=O)CCCOc1cc([N+](=O)[O-])c(C=O)cc1OC
Reaction time: 2.5 h
Yield: 62 %

Procedure:
A solution of the keto-ester (48)(20.00 g, 79.3 mmol) in acetic anhydride (80 mL) was added dropwise to a stirring solution of HNO3 (400 mL) and Ac2O (80 mL) at 0° C. After stirring for 2.5 hours the reaction mixture was poured into iced water (3 L) and allowed to stand at 4° C. for a further 16 hours. The precipitate was collected by filtration and dried under vacuum to provide the nitro compound (49) as a yellow crystalline solid (14.52 g, 62%). Melting Point 70-73° C. 1H NMR (250 MHz, CDCl3) δ 10.4 (s, 2H), 7.61 (s, 1H), 7.40 (s, 1H), 4.21 (t, J=6.2 Hz, 2H), 4.00 (s, 3H), 3.71 (s, 3H), 2.58 (t, J=7.1 Hz, 2H), 2.23 (pent, J=6.3 Hz, 2H). 13C NMR (67.8 MHz, CDCl3) 188.2 (C1), 173.7 (C12), 153.8 (Cquat.), 152.1 (Cquat.), 144.1 (Cquat.), 125.8 (Cquat.), 110.2 (C6), 108.5 (C3), 69.0 (C9), 57.0 (C8), 52.2 (C13), 30.6 (C11), 24.4 (C10). IR (cm−1) 3571, 3485, 2951, 1725, 1689, 1573, 1329, 1172, 1064, 1002, 936, 896, 858, 820, 766, 738, 688, 624. MS (M+1) 298.0. Anal. Calcd for C13H15NO7: C, 52.53; H, 5.09; N, 4.71. Found: C, 52.80; H, 5.03; N, 4.75.
Reaction SMILES: [Br:1][C:2]1[NH:6][C:5]2[CH:7]=[C:8]([Cl:13])[C:9]([Cl:12])=[C:10]([Br:11])[C:4]=2[N:3]=1.C/C(/O[Si](C)(C)C)=N\[Si](C)(C)C.C(O[CH:30]1[O:42][C@H:41]([CH3:43])[C@@H:36]([O:37][C:38](=[O:40])[CH3:39])[C@H:31]1[O:32][C:33](=[O:35])[CH3:34])(=O)C.C[Si](OS(C(F)(F)F)(=O)=O)(C)C>C(#N)C.C(OCC)(=O)C>[Br:1][C:2]1[N:6]([C@@H:30]2[O:42][C@H:41]([CH3:43])[C@@H:36]([O:37][C:38](=[O:40])[CH3:39])[C@H:31]2[O:32][C:33](=[O:35])[CH3:34])[C:5]2[CH:7]=[C:8]([Cl:13])[C:9]([Cl:12])=[C:10]([Br:11])[C:4]=2[N:3]=1
Reactant: CC(=O)OC1O[C@H](C)[C@@H](OC(C)=O)[C@H]1OC(C)=O
Reactant: Clc1cc2[nH]c(Br)nc2c(Br)c1Cl
Agent: C/C(=N\[Si](C)(C)C)O[Si](C)(C)C
Agent: C[Si](C)(C)OS(=O)(=O)C(F)(F)F
Solvent: CC#N
Solvent: CCOC(C)=O
Product: CC(=O)O[C@@H]1[C@H](OC(C)=O)[C@@H](C)O[C@H]1n1c(Br)nc2c(Br)c(Cl)c(Cl)cc21
Temperature: 70 °C
Reaction time: 0.25 h
Yield: 64.2 %

Procedure:
To a suspension of 2,4-dibromo-5,6-dichloro-1H-benzimidazole (0.35 g, 1 mmol), in acetonitrile (5 mL) was added N,O-bis(trimethylsilyl)acetamide (0.25 mL, 1 mmol). The resulting mixture was allowed to stir at 70° C. for 15 min, followed by the addition of 1,2,3-tri-O-acetyl-5-deoxyribofuranose (0.31 g, 1.2 mmol) in acetonitrile (5 mL) and trimethylsilyltrifluoromethane sulfonate (0.25 mL, 1.3 mmol). The mixture was allowed to stir at 70° C. for 30 min and was then allowed to cool to RT. The mixture was diluted with ethyl acetate, washed with a saturated aqueous NaHCO3 solution, dried over NaSO4 and the solvents were removed by rotary evaporation. The product was purified by flash chromatography using methylene chloride then 1:1 methylene chloride/chloroform followed by recrystallization from methanol to provide 0.35 g (63%) of the title compound as white crystals: m.p. 152-154° C.; 1H NMR (DMSO-d6) δ: 8.16 (s, 1H), 6.15 (d, 1H), 5.63 (t, 1H), 5.27 (dd, 1H), 4.26 (m, 1H), 2.13 (s, 3H), 2.02 (s, 3H), 1.51 (d, 3H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([OH:29])[CH2:9][CH2:10][N:11]2[CH2:16][CH2:15][CH:14]([C:17]3[CH:18]=[C:19]([NH:23][C:24](=[O:28])[CH:25]([CH3:27])[CH3:26])[CH:20]=[CH:21][CH:22]=3)[CH2:13][CH2:12]2)=[CH:4][CH:3]=1.[Br:30][C:31]1[CH:36]=[CH:35][C:34](O)=[CH:33][CH:32]=1>>[Br:30][C:31]1[CH:36]=[CH:35][C:34]([O:29][CH:8]([C:5]2[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=2)[CH2:9][CH2:10][N:11]2[CH2:16][CH2:15][CH:14]([C:17]3[CH:18]=[C:19]([NH:23][C:24](=[O:28])[CH:25]([CH3:26])[CH3:27])[CH:20]=[CH:21][CH:22]=3)[CH2:13][CH2:12]2)=[CH:33][CH:32]=1
Reactant: Oc1ccc(Br)cc1
Reactant: CC(C)C(=O)Nc1cccc(C2CCN(CCC(O)c3ccc(F)cc3)CC2)c1
Product: CC(C)C(=O)Nc1cccc(C2CCN(CCC(Oc3ccc(Br)cc3)c3ccc(F)cc3)CC2)c1

Procedure:
Prepared by Procedure A and Scheme AN using N-(3-{1-[3-(4-fluorophenyl)-3-hydroxypropyl]-4-piperidinyl}phenyl)-2-methylpropanamide and 4-bromophenol: ESMS m/e: 553.0 (M+H)+.
Reaction SMILES: [OH:1][CH2:2][CH2:3][C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH2:15][CH2:14][CH:13]([NH:16][C:17]([O:19][CH2:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)=[O:18])[CH2:12][CH2:11]2)=[CH:6][CH:5]=1.[C:27]1([CH3:37])[CH:32]=[CH:31][C:30]([S:33](Cl)(=[O:35])=[O:34])=[CH:29][CH:28]=1.O>N1C=CC=CC=1>[S:33]([O:1][CH2:2][CH2:3][C:4]1[CH:5]=[CH:6][C:7]([N:10]2[CH2:11][CH2:12][CH:13]([NH:16][C:17]([O:19][CH2:20][C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=3)=[O:18])[CH2:14][CH2:15]2)=[CH:8][CH:9]=1)([C:30]1[CH:31]=[CH:32][C:27]([CH3:37])=[CH:28][CH:29]=1)(=[O:35])=[O:34]
Reactant: O=C(NC1CCN(c2ccc(CCO)cc2)CC1)OCc1ccccc1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: c1ccncc1
Solvent: O
Product: Cc1ccc(S(=O)(=O)OCCc2ccc(N3CCC(NC(=O)OCc4ccccc4)CC3)cc2)cc1
Reaction time: 4 h

Procedure:
The N-(4-(2-hydroxyethyl)phenyl)-4-benzyloxycarbonylaminopiperidine (1.38 g, 3.89 mmol) obtained in Example 7 (4) was dissolved in pyridine (7.5 ml), and p-toluenesulfonyl chloride (960 mg, 5.04 mmol) was added thereto under ice-cooling, followed by stirring for 4 hours. Water was added to the reaction mixture, and the precipitate was collected by filtration, thereby obtaining N-(4-(2-tosyloxyethyl)phenyl)-4-benzyloxycarbonylaminopiperidine (1.35 g, 68%) as a yellow solid.
Reaction SMILES: C1CCN2C(=NCCC2)CC1.[F:12][C:13]([F:24])([F:23])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[CH2:20][C:21]#[N:22].[CH2:25]=[O:26].Cl>C1COCC1.O>[F:12][C:13]([F:23])([F:24])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[CH:20]([CH2:25][OH:26])[C:21]#[N:22]
Reactant: C=O
Reactant: N#CCc1ccccc1C(F)(F)F
Agent: Cl
Solvent: C1CCOC1
Solvent: O
Solvent: C1CCC2=NCCCN2CC1
Product: N#CC(CO)c1ccccc1C(F)(F)F
Reaction time: 0.75 h
Yield: 94 %

Procedure:
A 50 μL (0.33 mmol) sample of DBU was injected into a stirred solution of 2-(2-(trifluoromethyl)phenyl)ethanenitrile (0.995 g, 4.86 mmol) and formaldehyde (600 μL of 30%) in THF (3 mL), producing a mild exotherm. After 45 min, the mixture was acidified (3N HCl), diluted with water and extracted with ethyl acetate. The organic phase was water washed, dried (MgSO4) and stripped. The resulting colorless oil was flash chromatographed on silica gel (22 g) eluting with CH2Cl2 →40% ethyl acetate/CH2Cl2. Fractions containing only product (Rf 0.5 (silica gel, EtOAc:hexane=1:4)) were stripped to give 1.08 g (94% yield) of the desired alcohol.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][C:12]2[CH:17]=[C:16]([CH3:18])[N:15]=[C:14](Br)[CH:13]=2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.Br[C:21]1C=C(NS(C2C=CC(NC(=O)C)=CC=2)(=O)=O)C=C(C)[N:22]=1>CN.C(O)C>[NH2:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][C:12]2[CH:13]=[C:14]([NH:22][CH3:21])[N:15]=[C:16]([CH3:18])[CH:17]=2)(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: Cc1cc(NS(=O)(=O)c2ccc(N)cc2)cc(Br)n1
Reactant: CC(=O)Nc1ccc(S(=O)(=O)Nc2cc(C)nc(Br)c2)cc1
Agent: CN
Solvent: CCO
Product: CNc1cc(NS(=O)(=O)c2ccc(N)cc2)cc(C)n1
Yield: 48 %

Procedure:
0.94 g (0.00275 mol) of 4-amino-N-(2-bromo-6-methyl-pyridin-4-yl)-benzenesulfonamide was stirred in 50 ml of 8M methylamine in ethanol in an autoclave at 135° C. for 40 hours. The methylamine was allowed to evaporate, the residue was dissolved in ethanol, treated with 2 g of silica gel, concentrated and the residue was chromatographed on silica gel, firstly with ethyl acetate/hexane 1:1, then 9:1. There was obtained 0.39 g (48%) of 4-amino-N-(2-methyl-6-methylamino-pyridin-4-yl)-benzene-sulfonamide as colourless crystals; m.p.: 173-175° C. 0.081 g (0.00028 mol) thereof was recrystallized from methanol, diethyl ether and hexane, dried in a high vacuum, dissolved in 3 ml of methanol and treated with 2.8 ml of 0.1N NaOH. The methanol was distilled off and the residue was freeze-dried twice. There was obtained 0.084 g (97%) of 4-amino-N-(2-methyl-6-methylamino-pyridin-4-yl)-benzenesulfonamide sodium salt (1:1) as white crystals; MS (ISP): me/e=293 (C13H17N4O2S+). 0.31 g (0.0011 mol) of 4-amino-N-(2-methyl-6-methylamino-pyridin-4-yl)-benzenesulfonamide was dissolved in 2 ml of methanol, treated with 1 ml of 2.4N HCl in diethyl ether and freed from solvent. The residue was dissolved in 1 ml of methanol and slowly added dropwise to diethyl ether while stirring vigorously. A colourless precipitate thereby separated and this was isolated and dried in a high vacuum. There was obtained 0.33 g (87%) of 4-amino-N-(2-methyl-6-methylamino-pyridin-4-yl)-benzenesulfonamide hydrochloride (1:1.86) as white crystals; m.p.: >170° C. (dec.).
Reaction SMILES: [F:1][C:2]([F:16])([F:15])[CH2:3][O:4][C:5]1[CH:14]=[CH:13][CH:12]=[CH:11][C:6]=1[O:7][CH2:8][CH2:9][OH:10].C(=O)(O)[O-].[Na+].[Br-].[K+].Cl[O-].[Na+]>CC1(C)N([O])C(C)(C)CCC1.ClCCl>[F:1][C:2]([F:15])([F:16])[CH2:3][O:4][C:5]1[CH:14]=[CH:13][CH:12]=[CH:11][C:6]=1[O:7][CH2:8][CH:9]=[O:10]
Reactant: OCCOc1ccccc1OCC(F)(F)F
Agent: CC1(C)CCCC(C)(C)N1[O]
Agent: O=C([O-])O
Agent: [Br-]
Solvent: ClCCl
Product: O=CCOc1ccccc1OCC(F)(F)F
Temperature: 0 °C
Yield: 6.8 %

Procedure:
2-[2-(2,2,2-Trifluoro-ethoxy)-phenoxy]-ethanol (XIV) (6 g, 0.025 moles) was added to dichloromethane (60 ml). To this solution sodium bicarbonate (1.2 g, in 10 ml water) was added. Reaction mixture was cooled to 0° C. and potassium bromide (0.24 g in 1 ml of water) and TEMPO (2,2,6,6-Tetramethylpiperidine-1-oxyl) (0.02 g, 0.13 mmole) were added in single lot. To this reaction mixture sodium hypochlorite solution (45 ml of 12.5% w/v) was added over a period of 15 minutes at 0-5° C. Continued stirring of reaction mass at 0-5°. After completion of reaction, organic layer was separated. The aqueous layer was extracted with dichloromethane. Combined organic layer was washed with 10% aqueous sodium hydroxide solution, followed by brine. The organic layer was dried over sodium sulphate. The solvent was evaporated under reduced pressure and the residue was purified by column chromatography on silica gel using a mixture of ethyl acetate and hexane (5/95) as eluent to give 0.40 g of (VIII) as colourless solid, melting at 57-58° C.
Reaction SMILES: [CH2:1]([P:9]([CH2:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)(=O)[OH:10])[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.S(Cl)([Cl:23])(=O)=O>C(Cl)(Cl)(Cl)Cl>[CH2:1]([P:9]([Cl:23])([CH2:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:10])[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: O=P(O)(CCc1ccccc1)CCc1ccccc1
Reactant: O=S(=O)(Cl)Cl
Solvent: ClC(Cl)(Cl)Cl
Product: O=P(Cl)(CCc1ccccc1)CCc1ccccc1

Procedure:
Diphenethylphosphinic acid (1.67 g, 6.1 m mole) was dissolved in carbon tetrachloride (5 ml), and sulfuryl chloride (1.46 g, 10.8 ml) was added thereto, and the mixture was heated while refluxing for 2 hours. It was confirmed that the starting material did not remain by tracement of the NMR spectrum. The solvent and excess sulfuryl chloride were distilled off under reduced pressure to obtain an oily diphenethylphosphinylchloride, which was supplied for the following reaction.
Reaction SMILES: [C:1]([O:5][C:6](=[O:20])[NH:7][C@H:8]([C:10]1[CH:15]=[CH:14][C:13]([C:16](C)=[CH2:17])=[CH:12][C:11]=1[F:19])[CH3:9])([CH3:4])([CH3:3])[CH3:2].C(Cl)Cl.CSC.CC[O:29]C(C)=O.CCCCCCC>O>[C:1]([O:5][C:6](=[O:20])[NH:7][C@H:8]([C:10]1[CH:15]=[CH:14][C:13]([C:16](=[O:29])[CH3:17])=[CH:12][C:11]=1[F:19])[CH3:9])([CH3:4])([CH3:3])[CH3:2]
Reactant: C=C(C)c1ccc([C@H](C)NC(=O)OC(C)(C)C)c(F)c1
Reactant: CCOC(C)=O
Solvent: CCCCCCC
Solvent: CSC
Solvent: O
Product: CC(=O)c1ccc([C@H](C)NC(=O)OC(C)(C)C)c(F)c1
Temperature: -70 °C
Reaction time: 0.5 h
Yield: 23 %

Procedure:
To a round bottom flask containing (S)-tert-butyl(1-(2-fluoro-4-(prop-1-en-2-yl)phenyl)ethyl)carbamate (1.28 g, 4.58 mmol) was added DCM (23 mL). The homogenous solution was cooled to −70° C. in a acetone/dry ice bath. Ozone (g) was then gently bubbled through the solution for 25 min at which time the solution becomes pale blue in color. Dimethyl sulfide (1.02 mL, 13.8 mmol) was then added to the cold solution and mixture gradually allowed to warm to room temperature and stirred for 30 min. Reaction mixture was diluted with a water. Phases partitioned. Aqueous phase extracted with DCM. Organic phases combined, washed with brine, dried (Na2SO4), filtered and concentrated onto silica gel. Silica gel column chromatography (EtOAc/Heptane 0 to 60%) provided (S)-tert-butyl(1-(4-acetyl-2-fluorophenyl)ethyl)carbamate (296 mg, 1.05 mmol, 23% yield) as a colorless oil that crystallizes upon standing. 1H NMR (400 MHz, CDCl3) δ 1.38-1.49 (m, 12H) 2.59 (s, 3H) 5.01 (br. s., 1H) 7.40 (t, J=7.65 Hz, 1H) 7.62 (dd, J=11.20, 1.57 Hz, 1H) 7.71 (dd, J=7.95, 1.54 Hz, 1H). LCMS m/z 267.1 (carboxylic acid fragment+CH3CN) (M+H)+, Rt 0.89 min.
Reaction SMILES: [C:1]1([S:7]([N:10]2[C:18]3[C:13](=[CH:14][CH:15]=[C:16]([C:19]([C:32]4[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=4)([C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=4)[O:20][SiH2:21][C:22]([CH3:25])([CH3:24])[CH3:23])[CH:17]=3)[CH:12]=[CH:11]2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C([N-]C(C)C)(C)C.[Li+].Cl[C:47]([O:49][CH3:50])=[O:48].[Cl-].[NH4+]>O1CCCC1>[CH3:50][O:49][C:47]([C:11]1[N:10]([S:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)(=[O:9])=[O:8])[C:18]2[C:13]([CH:12]=1)=[CH:14][CH:15]=[C:16]([C:19]([C:32]1[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=1)([C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1)[O:20][SiH2:21][C:22]([CH3:24])([CH3:25])[CH3:23])[CH:17]=2)=[O:48]
Reactant: COC(=O)Cl
Reactant: CC(C)(C)[SiH2]OC(c1ccccc1)(c1ccccc1)c1ccc2ccn(S(=O)(=O)c3ccccc3)c2c1
Agent: CC(C)[N-]C(C)C
Agent: [Cl-]
Agent: [Li+]
Solvent: C1CCOC1
Product: COC(=O)c1cc2ccc(C(O[SiH2]C(C)(C)C)(c3ccccc3)c3ccccc3)cc2n1S(=O)(=O)c1ccccc1
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
An anhydrous tetrahydrofuran (THF) solution (20 ml) of crude 1-benzenesulfonyl-6-(tert-butyl-diphenyl-silanyloxymethyl)-1H-indole was cooled to −78° C., and a prepared tetrahydrofuran (THF) solution of lithium diisopropyl amide (LDA) was added thereto. This was stirred at −78° C. for 30 minutes. Methyl chloroformate (0.43 ml, 5.98 mmol) was added thereto, and this was stirred at −78° C. for 30 minutes. An aqueous solution saturated with ammonium chloride was added to the reaction mixture, and this was warmed to room temperature. After ethyl acetate extraction, the organic layer was dried over anhydrous sodium sulfate. The desiccant was removed by filtration and concentration was performed. Then, the residue obtained by concentration under reduced pressure was purified by silica gel column chromatography (hexane/ethyl acetate=98/2 to 4/1). Thus, 1-benzenesulfonyl-6-(tert-butyl-diphenyl-silanyloxymethyl)-1H-indole-2-carboxylic acid methyl ester was obtained as a brown amorphous material (882 mg, 51%).