Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][P:4]([CH2:24][NH:25][C:26]([C@@H:28]([NH:33][C:34]([C@@H:36]1[CH2:40][CH2:39][CH2:38][N:37]1C(OCC1C=CC=CC=1)=O)=[O:35])[CH2:29][CH:30]([CH3:32])[CH3:31])=[O:27])([CH2:6][CH:7]([C:12](=[O:23])[NH:13][C@H:14]([C:19](=[O:22])[NH:20][CH3:21])[CH2:15][CH:16]([CH3:18])[CH3:17])[CH2:8][CH:9]([CH3:11])[CH3:10])=[O:5])[CH3:2].C(N(CC)CC)C.[C:58](Cl)(=[O:65])[C:59]1[CH:64]=[CH:63][CH:62]=[CH:61][CH:60]=1>C(O)C.Cl.ClCCl.[Pd]>[CH2:1]([O:3][P:4]([CH2:24][NH:25][C:26](=[O:27])[C@H:28]([CH2:29][CH:30]([CH3:32])[CH3:31])[NH:33][C:34](=[O:35])[C@@H:36]1[CH2:40][CH2:39][CH2:38][N:37]1[C:58](=[O:65])[C:59]1[CH:64]=[CH:63][CH:62]=[CH:61][CH:60]=1)([CH2:6][CH:7]([C:12](=[O:23])[NH:13][C@H:14]([C:19](=[O:22])[NH:20][CH3:21])[CH2:15][CH:16]([CH3:17])[CH3:18])[CH2:8][CH:9]([CH3:11])[CH3:10])=[O:5])[CH3:2]
Reactant: O=C(Cl)c1ccccc1
Reactant: CCOP(=O)(CNC(=O)[C@H](CC(C)C)NC(=O)[C@@H]1CCCN1C(=O)OCc1ccccc1)CC(CC(C)C)C(=O)N[C@@H](CC(C)C)C(=O)NC
Agent: [Pd]
Agent: Cl
Solvent: ClCCl
Solvent: CCO
Solvent: CCN(CC)CC
Product: CCOP(=O)(CNC(=O)[C@H](CC(C)C)NC(=O)[C@@H]1CCCN1C(=O)c1ccccc1)CC(CC(C)C)C(=O)N[C@@H](CC(C)C)C(=O)NC
Temperature: 0 °C
Reaction time: 16 h

Procedure:
0.36 g of benzyl(S)-2-[[(S)-1-[[[ethoxy[(RS)-4-methyl-2-[[(S)-3-methyl-1-(methylcarbamoyl)butyl]carbamoyl]pentyl]phosphinyl]methyl]carbamoyl]-3-methylbutyl]carbamoyl]-1-pyrrolidinecarboxylate was dissolved in 5 ml of ethanol containing 0.5 ml of 1 M hydrochloric acid. The solution was hydrogenated over 5% palladium-on-charcoal for 2 hours. After filtration and evaporation of the filtrate, the residue was re-evaporated with toluene until a white solid was obtained. This solid was dissolved in 6 ml of dichloromethane. The solution was cooled to 0° C. and treated with 0.15 ml of triethylamine and 0.064 ml of benzoyl chloride. The mixture was stirred at room temperature for 16 hours and the solvent was then removed by evaporation. The residue was dissolved in ethyl acetate. The mixture was filtered and the filtrate was evaporated to give a pale yellow gum. Chromatography on silica gel using 3% ethanol in chloroform for the elution followed by evaporation yielded 0.32 g of [[ [N-(1-benzoyl-L-prolyl)-L-leucyl]amino]methyl][(RS)-4-methyl-2-[[(S)-3-methyl-1-(methylcarbamoyl)butyl]carbamoyl]pentyl]phosphinic acid ethyl ester in the form of a white foam.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].O.[CH:15]([CH:17]1[CH2:19][CH2:18]1)=O.C([BH3-])#N.[Na+]>C1COCC1.C(O)(=O)C>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([CH2:15][CH:17]2[CH2:19][CH2:18]2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: O=CC1CC1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CC(=O)O
Solvent: O
Product: CC(C)(C)OC(=O)N1CCN(CC2CC2)CC1
Temperature: 20 °C
Reaction time: 14 h
Yield: 79.7 %

Procedure:
To a solution of 1-tert-butyloxycarbonylpiperazine (2.24 g, 12.0 mmol) in THF (10 ml) were added water (0.15 ml), acetic acid (3.60 ml), formylcyclopropane (1.35 ml, 18.1 mmol), and sodium cyanoborohydride (18 ml of a 1M solution in THF, 18 mmol). The mixture was stirred at 20° C. for 14 hours. The mixture is concentrated under reduced pressure, and the residue is mixed with water (80 ml) and 1 N aqueous hydrochloric acid (40 ml). After washing with ethyl acetate (20 ml) the aqueous phase is made basic by addition of potassium carbonate (approx. 20 g) and extracted with ethyl acetate (4×30 ml). The combined extracts were dried with magnesium sulphate and concentrated under reduced pressure, to yield 2.3 g (80%) of the title compound as a colourless oil.
Reaction SMILES: [CH3:1][N:2]1[CH:6]2[N:7]([CH3:14])[C:8]3[C:13]([C:5]2([CH3:15])[CH2:4][CH2:3]1)=[CH:12][CH:11]=[CH:10][CH:9]=3.N1C=CC=CC=1.[BrH:22].[NH+]1C=CC=CC=1.O>C(Cl)Cl>[Br:22][C:11]1[CH:12]=[C:13]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH3:14])[CH:6]1[N:2]([CH3:1])[CH2:3][CH2:4][C:5]21[CH3:15]
Reactant: Br
Reactant: CN1CCC2(C)c3ccccc3N(C)C12
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Solvent: O
Solvent: c1ccncc1
Product: CN1CCC2(C)c3cc(Br)ccc3N(C)C12
Temperature: 0 °C

Procedure:
To a chilled (0° C.) solution of 1,2,3,3a,8,8a-hexahydro-1,3a,8-trimethylpyrrolo[2,3-b]indole (1.41 g) in methylene chloride (20 ml) was added pyridine (1.41 ml) under an atmosphere of N2. Solid pyridinium hydrobromide perbromide (2.23 g) was added with stirring to the mixture and the resulting solution was maintained at 0° C. for 1 hour. The mixture was poured into water (100 ml) and the aqueous and organic phases separated. The organic phase was washed twice with 50 ml portions of brine and 50 ml portions of saturated sodium bicarbonate and then with 50 ml of brine. After drying the organic phase over Na2SO4 and filtering, the solvent was removed under reduced pressure. The resulting oil was purified using column chromatography on silica gel with 10% methanol in ethyl acetate as eluent. The appropriate fractions were combined, evaporated and repurified using column chromatography on silica gel with 5% methanol in ethyl acetate as eluant to afford 1.5 g of 5-bromo-1,2,3,3a,8,8a-hexahydro-1,3a,8-trimethylpyrrolo[2,3-b]indole, as an oil.
Reaction SMILES: CO.[N+:3]([C:6]1[S:10][C:9]([C:11]([O:13][CH3:14])=[O:12])=[CH:8][CH:7]=1)([O-])=O>[Fe].O>[NH2:3][C:6]1[S:10][C:9]([C:11]([O:13][CH3:14])=[O:12])=[CH:8][CH:7]=1
Reactant: COC(=O)c1ccc([N+](=O)[O-])s1
Agent: [Fe]
Solvent: O
Solvent: CO
Product: COC(=O)c1ccc(N)s1
Temperature: 70 °C
Yield: 254.5 %

Procedure:
3.6 g of iron powder, 1.4 g of FeSO4.7H2O, 25 ml of methanol and 8 ml of water were successively introduced into a three-necked flask. 940 mg (5 mmol) of methyl 5-nitro-2-thiophenecarboxylate were then added and the mixture was heated at 70° C. for eight hours. The reaction medium was filtered on celite, the filtrate evaporated, and taken up in water and ethyl ether. The organic phase was decanted, dried over magnesium sulfate and evaporated. The residue obtained was purified by chromatography on a silica column eluted with dichloromethane; 2 g (77%) of the expected compound of melting point 110°-112° C. were obtained.
Reaction SMILES: [CH3:1][C:2]1([O:8][C:9](=[O:12])[NH:10]N)[CH2:7][CH2:6][O:5][CH2:4][CH2:3]1.CC(O)=O.N([O-])=O.[Na+].N[C@@H:22]([C:26]([OH:28])=[O:27])[C@H:23]([CH3:25])[OH:24].C([O-])([O-])=O.[Na+].[Na+].Cl>O.CCOC(C)=O.O1CCOCC1>[OH:24][C@@H:23]([CH3:25])[C@@H:22]([NH:10][C:9]([O:8][C:2]1([CH3:1])[CH2:7][CH2:6][O:5][CH2:4][CH2:3]1)=[O:12])[C:26]([OH:28])=[O:27]
Reactant: C[C@H](O)[C@@H](N)C(=O)O
Reactant: CC1(OC(=O)NN)CCOCC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: O=N[O-]
Solvent: CC(=O)O
Solvent: C1COCCO1
Solvent: O
Product: C[C@H](O)[C@@H](NC(=O)OC1(C)CCOCC1)C(=O)O
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 80 %

Procedure:
In a round bottomed flask equipped with a magnetic stirrer (4-methyltetrahydropyran-4-yl)-N-aminocarbamate (0.540 g, 3.10 mmol), H2O (10 mL) and CH3COOH (0.35 mL, 6.20 mmol) were sequentially added. The resulting mixture was cooled to 0° C. and NaNO2 (0.354 g, 3.72 mmol) dissolved in H2O (2 mL) was added dropwise. The cloudy mixture was stirred for 1.5 h at rt. Dioxane (20 mL) followed by the D-threonine salt solution [prepared from D-threonine (0.554 g, 4.65 mmol) solution in H2O (4 mL) and Na2CO3 (1.34 g, 12.40 mmol)] were added to the mixture. After being left overnight at 45° C., the crude mixture was then cooled to rt, then H2O (30 mL) and AcOEt (80 mL) were added and, while maintaining a vigorous stirring, the pH was adjusted to 2 with 2M HCl solution. The phases were separated and the aqueous one washed with AcOEt (2×50 mL). The combined organic liquors were dried over Na2SO4 and concentrated to leave a light yellow oil (0.647 g, 80%), which was used in the next step without purification. MS (ESI) m/z: 284.1 [M−Na]+. 1H NMR (DMSO-d6): δ 1.09 (d, J=6.3 Hz, 3H), 1.47 (s, 3H), 1.63 (m, 2H), 1.99 (m, 2H), 3.61 (m, 5H), 3.90 (dd, J=9.4, 6.3 Hz, 1H), 4.09 (m, 1H), 6.53 (d, J=9.4 Hz, 1H), 12.20 (bs, 1H).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:16])[C:4]([C:7]1[CH:12]=[CH:11][C:10]([C:13](Cl)=[O:14])=[CH:9][CH:8]=1)([CH3:6])[CH3:5].[NH2:17][C:18]1[CH:33]=[CH:32][C:31]([Cl:34])=[CH:30][C:19]=1[C:20]([NH:22][C:23]1[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][N:24]=1)=[O:21]>C(Cl)Cl.CN(C1C=CN=CC=1)C>[CH3:1][O:2][C:3](=[O:16])[C:4]([C:7]1[CH:12]=[CH:11][C:10]([C:13](=[O:14])[NH:17][C:18]2[CH:33]=[CH:32][C:31]([Cl:34])=[CH:30][C:19]=2[C:20](=[O:21])[NH:22][C:23]2[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][N:24]=2)=[CH:9][CH:8]=1)([CH3:6])[CH3:5]
Reactant: Nc1ccc(Cl)cc1C(=O)Nc1ccc(Cl)cn1
Reactant: COC(=O)C(C)(C)c1ccc(C(=O)Cl)cc1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: COC(=O)C(C)(C)c1ccc(C(=O)Nc2ccc(Cl)cc2C(=O)Nc2ccc(Cl)cn2)cc1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a solution of 2-(4-chlorocarbonyl-phenyl)-2-methyl-propionic acid methyl ester (240.0 mg, 1.0 mmol) in CH2Cl2 at 0° C. was added TEA (3.0 mmol) followed by addition of 2-amino-5-chloro-N-(5-chloro-pyridin-2-yl)-benzamide (281 mg, 1.0 mmol) and DMAP (cat. 10 mg). The resulted mixture was stirred at 0° C. for 1 hr and rt over night. Solvent was evaporated and HPLC purification gave 2{4-[4-Chloro-2-(5-chloro-pyridin-2-ylcarbamoyl)-phenylcarbamoyl]-phenyl}-2-methyl-propionic acid methyl ester as white solid. MS found: (M+1)+=486.2.
Reaction SMILES: C(ON=O)CC(C)C.N[C:10]1[S:11][C:12]([C:41]([C:43]2[CH:48]=[CH:47][CH:46]=[CH:45][C:44]=2[Cl:49])=[O:42])=[C:13]([C:15]2[N:16]=[N:17][N:18]([CH2:26][C:27]3[CH:32]=[C:31]([C:33]([F:36])([F:35])[F:34])[CH:30]=[C:29]([C:37]([F:40])([F:39])[F:38])[CH:28]=3)[C:19]=2[C:20]2[CH:21]=[N:22][CH:23]=[CH:24][CH:25]=2)[N:14]=1>C1COCC1.CCOC(C)=O>[F:40][C:37]([F:38])([F:39])[C:29]1[CH:28]=[C:27]([CH:32]=[C:31]([C:33]([F:36])([F:34])[F:35])[CH:30]=1)[CH2:26][N:18]1[C:19]([C:20]2[CH:21]=[N:22][CH:23]=[CH:24][CH:25]=2)=[C:15]([C:13]2[N:14]=[CH:10][S:11][C:12]=2[C:41]([C:43]2[CH:48]=[CH:47][CH:46]=[CH:45][C:44]=2[Cl:49])=[O:42])[N:16]=[N:17]1
Reactant: Nc1nc(-c2nnn(Cc3cc(C(F)(F)F)cc(C(F)(F)F)c3)c2-c2cccnc2)c(C(=O)c2ccccc2Cl)s1
Agent: CC(C)CCON=O
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: O=C(c1ccccc1Cl)c1scnc1-c1nnn(Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)c1-c1cccnc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Add isoamylnitrite (29 μL, 0.21 mmol) to a solution of {2-amino-4-[1-(3,5-bis-trifluoromethyl-benzyl)-5-pyridin-3-yl-1H-[1,2,3]triazol-4-yl]-thiazol-5-yl}-(2-chloro-phenyl)-methanone (63 mg, 0.103 mmol) in THF (1.5 mL). Stir the solution at RT for 30 min. then warm to reflux for an additional 30 min. Cool solution to RT and dilute with EtOAc (30 mL). Wash the organic solution with saturated NaHCO3 (15 mL) and brine (15 mL) then dry, filter, and concentrate. Purify the crude material by flash chromatography then triturate with ether (2×0.3 mL) and dry to give the title compound: MS (IS) 594.1 (M+1), MS (ES−) 592.0 (M−1); 1HNMR (400 MHz, CDCl3): δ 9.17 (s, 1H), 8.60 (d, 1H, J=5.0), 8.50 (s, 1H), 7.97 (s, 1H), 7.76 (s, 1H), 7.65 (s, 2H), 7.41 (m, 2H), 7.24 (m, 2H), 7.19 (m, 1H), 5.77 (s, 2H).
Reaction SMILES: Br.[C:2]([C:6]1[CH:11]=[CH:10][C:9](/[C:12](/[C:31]2[N:36]=[C:35]([O:37]C)[C:34]([CH2:39][CH2:40][C:41]([OH:43])=[O:42])=[CH:33][CH:32]=2)=[CH:13]\[C@H:14]2[CH2:18][CH2:17][C:16](=[O:19])[N:15]2[CH2:20][C:21]2[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][C:22]=2[O:29][CH3:30])=[CH:8][CH:7]=1)([CH3:5])([CH3:4])[CH3:3].O>O1CCOCC1>[C:2]([C:6]1[CH:7]=[CH:8][C:9](/[C:12](/[C:31]2[NH:36][C:35](=[O:37])[C:34]([CH2:39][CH2:40][C:41]([OH:43])=[O:42])=[CH:33][CH:32]=2)=[CH:13]\[C@H:14]2[CH2:18][CH2:17][C:16](=[O:19])[N:15]2[CH2:20][C:21]2[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][C:22]=2[O:29][CH3:30])=[CH:10][CH:11]=1)([CH3:5])([CH3:3])[CH3:4]
Reactant: COc1ccc(CN2C(=O)CC[C@@H]2/C=C(\c2ccc(C(C)(C)C)cc2)c2ccc(CCC(=O)O)c(OC)n2)c(OC)c1
Agent: Br
Solvent: C1COCCO1
Solvent: O
Product: COc1ccc(CN2C(=O)CC[C@@H]2/C=C(\c2ccc(C(C)(C)C)cc2)c2ccc(CCC(=O)O)c(=O)[nH]2)c(OC)c1
Temperature: 65 °C
Reaction time: 2 h
Yield: 91.2 %

Procedure:
48% hydrobromic acid (1.7 mL) was added to a solution of 3-(6-{(E)-1-(4-tert-butylphenyl)-2-[(2R)-1-(2,4-dimethoxybenzyl)-5-oxopyrrolidin-2-yl]ethenyl}-2-methoxypyridin-3-yl)propanoic acid (172 mg) in 1,4-dioxane (1.7 mL), and the mixture was stirred at 65° C. for two hours. Water was added to the reaction solution, followed by extraction with ethyl acetate. The organic layer was washed with brine and dried over anhydrous magnesium sulfate, after which the solvent was evaporated under reduced pressure. The resulting residue was purified by silica gel column chromatography (chloroform:methanol=10:0→9:1) to give 3-(6-{(E)-1-(4-tert-butylphenyl)-2-[(2R)-1-(2,4-dimethoxybenzyl)-5-oxopyrrolidin-2-yl]ethenyl}-2-oxo-1,2-dihydropyridin-3-yl)propanoic acid as a yellow oil (153 mg).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:11][CH2:12][O:13][CH:14]2[CH2:19][CH2:18][CH2:17][CH2:16][O:15]2)=[CH:6][CH:5]=1)([O-])=O.C([O-])=O.[NH4+]>CCO.[Pd]>[O:15]1[CH2:16][CH2:17][CH2:18][CH2:19][CH:14]1[O:13][CH2:12][CH2:11][O:10][C:7]1[CH:6]=[CH:5][C:4]([NH2:1])=[CH:9][CH:8]=1
Reactant: O=[N+]([O-])c1ccc(OCCOC2CCCCO2)cc1
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CCO
Product: Nc1ccc(OCCOC2CCCCO2)cc1
Temperature: 40 °C
Reaction time: 2 h

Procedure:
To a solution of 2-({2-[(4-nitrophenyl)oxy]ethyl}oxy)tetrahydro-2H-pyran (Intermediate 17) (1.33 g, 5 mmol) in EtOH (50 mL) was added Pd/C (catalytic amount) and ammonium formiate (0.9 g, 10 eq). The reaction was stirred to 40° C. for 2 hours. After filtration on celite, the solvent was evaporated and the residue was poured in water, extracted with ether and dried over sodium sulphate and evaporated. The title compound was obtained as a dark oil (0.8 g, 68%). LC/MS: m/z 238 (M+H)+, Rt: 2.38 min.
Reaction SMILES: [CH:1]1[C:13]2[CH:12]([CH2:14][O:15][C:16](=[O:53])[NH:17][C@H:18]3[CH2:22][C@@H:21]([C:23](=[O:35])[NH:24][C@H:25]4[C:34]5[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=5)[CH2:28][CH2:27][CH2:26]4)[N:20]([C:36](=[O:52])[C@@H:37]([NH:44]C(OC(C)(C)C)=O)[CH:38]4[CH2:43][CH2:42][CH2:41][CH2:40][CH2:39]4)[CH2:19]3)[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.[ClH:54]>O1CCOCC1>[ClH:54].[CH:1]1[C:13]2[CH:12]([CH2:14][O:15][C:16](=[O:53])[NH:17][C@H:18]3[CH2:22][C@@H:21]([C:23](=[O:35])[NH:24][C@H:25]4[C:34]5[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=5)[CH2:28][CH2:27][CH2:26]4)[N:20]([C:36](=[O:52])[C@@H:37]([NH2:44])[CH:38]4[CH2:43][CH2:42][CH2:41][CH2:40][CH2:39]4)[CH2:19]3)[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1
Reactant: CC(C)(C)OC(=O)N[C@H](C(=O)N1C[C@@H](NC(=O)OCC2c3ccccc3-c3ccccc32)C[C@H]1C(=O)N[C@@H]1CCCc2ccccc21)C1CCCCC1
Agent: Cl
Solvent: C1COCCO1
Product: N[C@H](C(=O)N1C[C@@H](NC(=O)OCC2c3ccccc3-c3ccccc32)C[C@H]1C(=O)N[C@@H]1CCCc2ccccc21)C1CCCCC1

Procedure:
To a stirred solution of {(3S,5S)-1-((S)-2-tert-butoxycarbonylamino-2-cyclohexyl-acetyl)-5-[(R)-(1,2,3,4-tetrahydro-naphthalen-1-yl)carbamoyl]-pyrrolidin-3-yl}-carbamic acid 9H-fluoren-9-ylmethyl ester (Intermediate 23) (6.5 g, 9.03 mmol) in dioxane (25 mL) at 0° C. was added 4 M HCl in dioxane (50 mL) dropwise and then the cooling bath removed. After 6 h the mixture was evaporated and the residue was triturated with ether to provide the title compound (5.58 g) as a white solid. LC-MS: 621 (M+H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:10](I)=[CH:9][N:8]([Si](C(C)C)(C(C)C)C(C)C)[C:5]2=[N:6][CH:7]=1.C([Mg]Cl)(C)C.[CH2:27]([N:29]1[C:33]([CH:34]=[O:35])=[CH:32][C:31]([NH:36][CH2:37][C:38]2[CH:43]=[CH:42][C:41]([F:44])=[CH:40][CH:39]=2)=[N:30]1)[CH3:28]>O1CCCC1>[Cl:1][C:2]1[CH:3]=[C:4]2[C:10]([CH:34]([C:33]3[N:29]([CH2:27][CH3:28])[N:30]=[C:31]([NH:36][CH2:37][C:38]4[CH:43]=[CH:42][C:41]([F:44])=[CH:40][CH:39]=4)[CH:32]=3)[OH:35])=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1
Reactant: CC(C)[Si](C(C)C)(C(C)C)n1cc(I)c2cc(Cl)cnc21
Reactant: CCn1nc(NCc2ccc(F)cc2)cc1C=O
Agent: CC(C)[Mg]Cl
Solvent: C1CCOC1
Product: CCn1nc(NCc2ccc(F)cc2)cc1C(O)c1c[nH]c2ncc(Cl)cc12
Temperature: -20 °C
Yield: 55.9 %

Procedure:
5-Chloro-3-iodo-1-triisopropylsilanyl-1H-pyrrolo[2,3-b]pyridine (629, 0.15 g, 0.34 mmol) was dissolved in tetrahydrofuran (3 mL, 40 mmol) and the solution was cooled to −20° C. 2 M isopropylmagnesium chloride in tetrahydrofuran (200 μL) was added dropwise and the reaction was stirred and allowed to warm to −5° C. After the reaction was cooled to −20° C., 2-ethyl-5-(4-fluoro-benzylamino)-2H-pyrazole-3-carbaldehyde (530, 0.043 g, 0.17 mmol, prepared as described in Example 47, Scheme 162, Step 5) in tetrahydrofuran (4 mL) was added to the mixture. The reaction was stirred to −5° C., then concentrated, ethyl acetate was added and the mixture was washed with sodium bicarbonate saturated solution and brine. After drying over anhydrous sodium sulfate, the solvent was removed under reduced pressure. Purification with silica gel column chromatography eluting with a gradient of ethyl acetate (5-80%) in hexanes gave the desired compound (630, 0.038 g, 40%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][C:9]2[N:13]([CH3:14])[N:12]=[N:11][N:10]=2)=[N:6][CH:7]=1.[CH3:15]C([O-])(C)C.[K+].IC>C1COCC1>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]([CH3:15])[C:9]2[N:13]([CH3:14])[N:12]=[N:11][N:10]=2)=[N:6][CH:7]=1
Reactant: Cn1nnnc1Nc1ccc(Br)cn1
Reactant: CC(C)(C)[O-]
Agent: [K+]
Solvent: CI
Solvent: C1CCOC1
Product: CN(c1ccc(Br)cn1)c1nnnn1C
Temperature: 70 °C
Yield: 31.4 %

Procedure:
5-bromo-N-(1-methyl-1H-tetrazol-5-yl)pyridine-2-amine (1 g, 3.9 mmol) was dissolved in 50 mL THF, potassium tert-butylate (0.88 g, 7.8 mmol) and iodomethane (1.1 g, 7.8 mmol) were added slowly. The reaction was heated to 70° C. and reacted for 12 h. After filtration and concentration, 330 mg of product was obtained by separation on a silica gel column (dichloromethane:methanol=100:1), at a yield of 31%.
Reaction SMILES: Cl[C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][C:3]=1[N+:11]([O-:13])=[O:12].[CH3:14][NH2:15]>>[CH3:14][NH:15][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][C:3]=1[N+:11]([O-:13])=[O:12]
Reactant: O=C(O)c1ccc(Cl)c([N+](=O)[O-])c1
Reactant: CN
Product: CNc1ccc(C(=O)O)cc1[N+](=O)[O-]
Temperature: 87.5 °C
Reaction time: 5 h

Procedure:
A mixture of 4-chloro-3-nitrobenzoic acid compound of formula-8 (200 g) and methyl amine (660 ml) was taken into autoclave and heated to 85-90° C. and stirred for 5 hours under pressure of 2.0-2.5 kg. After completion of the reaction, the reaction mixture was cooled to 25-35° C. Quenched the reaction mixture with water and then acidified with hydrochloric acid. Filtered the precipitated solid and then dried to get title compound.
Reaction SMILES: [Br:1][C:2]1[C:3]([CH2:10][CH3:11])=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH:5]=[O:6].[BH4-].[Na+]>CO>[Br:1][C:2]1[C:3]([CH2:10][CH3:11])=[C:4]([CH2:5][OH:6])[CH:7]=[CH:8][CH:9]=1
Reactant: CCc1c(Br)cccc1C=O
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CCc1c(Br)cccc1CO
Temperature: 25 °C
Reaction time: 2 h
Yield: 59.4 %

Procedure:
To a solution of 3-bromo-2-ethylbenzaldehyde (5 g, 23.47 mmol) in Methanol (50 mL) was added NaBH4 (1.776 g, 46.9 mmol) at 0° C. The reaction solution was stirred at room temperature for 2 hours. The solvent was removed in vacuo and the residue was dissolved in ethyl acetate, washed with water, dried over sodium sulphate, concentrated and purified by ISCO column chromatography to afford (3-bromo-2-ethylphenyl)methanol (D133) (3 g) as an oil. MS (ES): C9H11BrO requires 213.99. found 197.0 (M+H+-18).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([CH3:11])[N:10]=1)[C:5](O)=[O:6].C1N=CN(C(N2C=NC=C2)=O)C=1.Cl.[CH3:25][NH:26][O:27][CH3:28]>C(Cl)Cl>[CH3:28][O:27][N:26]([CH3:25])[C:5](=[O:6])[C:4]1[CH:3]=[C:2]([CH3:1])[N:10]=[C:9]([CH3:11])[CH:8]=1
Reactant: CNOC
Reactant: Cc1cc(C(=O)O)cc(C)n1
Agent: Cl
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: ClCCl
Product: CON(C)C(=O)c1cc(C)nc(C)c1
Reaction time: 20 h

Procedure:
To 2,6-dimethylisonicotinic acid (1.00 g, 6.61 mmol) in DCM (8.3 mL), CDI (1.18 g, 7.27 mmol) was added and the mixture was stirred for 45 minutes after which N,O-dimethylhydroxylamine hydrochloride (0.71 g, 7.3 mmol) was added and the mixture was stirred for 20 hours. The reaction mixture was quenched with 0.3 M aqueous solution of NaOH and partitioned between water and DCM. The aqueous layer was extracted with DCM, washed with aqueous saturated solution of NaCl, dried (MgSO4) and concentrated. The crude product was purified by flash column chromatography (silica gel, 0-100% EtOAc-DCM) to provide the title compound.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10]([C:12]2[CH:20]=[C:19]3[C:15]([CH2:16][CH2:17][NH:18]3)=[CH:14][CH:13]=2)=[O:11])=[CH:5][CH:4]=1)#[N:2].[Cl:21][C:22]1[CH:23]=[CH:24][C:25]([O:32][CH3:33])=[C:26]([S:28](Cl)(=[O:30])=[O:29])[CH:27]=1>>[C:1]([C:3]1[CH:4]=[CH:5][C:6]([NH:9][C:10]([C:12]2[CH:20]=[C:19]3[C:15]([CH2:16][CH2:17][N:18]3[S:28]([C:26]3[CH:27]=[C:22]([Cl:21])[CH:23]=[CH:24][C:25]=3[O:32][CH3:33])(=[O:29])=[O:30])=[CH:14][CH:13]=2)=[O:11])=[CH:7][CH:8]=1)#[N:2]
Reactant: N#Cc1ccc(NC(=O)c2ccc3c(c2)NCC3)cc1
Reactant: COc1ccc(Cl)cc1S(=O)(=O)Cl
Product: COc1ccc(Cl)cc1S(=O)(=O)N1CCc2ccc(C(=O)Nc3ccc(C#N)cc3)cc21

Procedure:
1-(5-Chloro-2-methoxy-benzenesulfonyl)-2,3-dihydro-1H-indole-6-carboxylic acid [4-(1H-tetrazol-5-yl)-phenyl]-amide, MS (ISP), m/e=509.1 (M−H), was prepared in analogy to example 13, steps 1 to 4. Step 1 was performed using 4-amino-benzonitrile and yielded 1H-indole-6-carboxylic acid (4-cyano-phenyl)-amide which was reduced to 2,3-dihydro-1H-indole-6-carboxylic acid (4-cyano-phenyl)-amide in step 2. This was coupled with 5-chloro-2-methoxy benzenesulfonyl chloride in step 3, yielding 1-(5-chloro-2-methoxy-benzenesulfonyl)-2,3-dihydro-1H-indole-6-carboxylic acid (4-cyano-phenyl)-amide, which was converted to 1-(5-chloro-2-methoxy-benzenesulfonyl)-2,3-dihydro-1H-indole-6-carboxylic acid [4-(1H-tetrazol-5-yl)-phenyl]-amide by reaction with ammonium azide in step 4.
Reaction SMILES: O=[C:2]1[CH2:7][CH2:6][N:5]([C:8]2[CH:13]=[CH:12][C:11]([NH:14][S:15]([C:18]3[S:19][C:20]([S:23]([C:26]4[CH:31]=[CH:30][C:29]([C:32]([F:35])([F:34])[F:33])=[CH:28][N:27]=4)(=[O:25])=[O:24])=[CH:21][CH:22]=3)(=[O:17])=[O:16])=[CH:10][CH:9]=2)[CH2:4][CH2:3]1.[NH2:36][CH2:37][C@H:38]([OH:48])[CH2:39][O:40][C:41]1[CH:46]=[CH:45][C:44]([OH:47])=[CH:43][CH:42]=1>>[OH:48][C@H:38]([CH2:39][O:40][C:41]1[CH:46]=[CH:45][C:44]([OH:47])=[CH:43][CH:42]=1)[CH2:37][NH:36][CH:2]1[CH2:7][CH2:6][N:5]([C:8]2[CH:13]=[CH:12][C:11]([NH:14][S:15]([C:18]3[S:19][C:20]([S:23]([C:26]4[CH:31]=[CH:30][C:29]([C:32]([F:35])([F:33])[F:34])=[CH:28][N:27]=4)(=[O:25])=[O:24])=[CH:21][CH:22]=3)(=[O:16])=[O:17])=[CH:10][CH:9]=2)[CH2:4][CH2:3]1
Reactant: NC[C@H](O)COc1ccc(O)cc1
Reactant: O=C1CCN(c2ccc(NS(=O)(=O)c3ccc(S(=O)(=O)c4ccc(C(F)(F)F)cn4)s3)cc2)CC1
Product: O=S(=O)(Nc1ccc(N2CCC(NC[C@H](O)COc3ccc(O)cc3)CC2)cc1)c1ccc(S(=O)(=O)c2ccc(C(F)(F)F)cn2)s1

Procedure:
The title compound was prepared from 5-(5-trifluoromethyl-pyridine-2-sulfonyl)-thiophene-2-sulfonic acid [4-(4-oxo-piperidin-1-yl)-phenyl]-amide (which was obtained in Example 229) and 4-((2S)-3-amino-2-hydroxy-propoxyl)-phenol (which was obtained in Example 5) according to the procedure of Example 278 as a grey solid; 1H NMR (300 MHz, DMSO-d6) δ 1.25–1.45 (m, 2 H), 1.70–1.95 (m, 2 H), 2.50–2.85 (m, 5 H), 3.54 (brd, J=12.4 Hz, 2 H), 3.65–3.95 (m, 3 H), 6.60–6.90 (m, 8 H), 7.92 (d, J=1.6 Hz, 1 H), 8.41 (d, J=8.3 Hz, 1 H), 8.48 (d, J=1.6 Hz, 1 H), 8.61 (dd, J=8.3, 2.0 Hz, 1 H), 8.89 (s, 1 H), 9.23 (s, 1 H); MS (ES) m/z: 713.1 (MH+); HRMS Calcd. for C30H32F3N4O7S3 (MH+): 713.1385. Found: 713.1407.