Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CN(C)C=O.[N:6]1([C:11]2[CH:19]=[CH:18][C:14]([C:15]([OH:17])=O)=[CH:13][CH:12]=2)[CH:10]=[CH:9][N:8]=[CH:7]1.[C:20]1([N:26]2[CH2:31][CH2:30][N:29]([CH2:32][C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)[CH:28]([CH2:39][NH2:40])[CH2:27]2)[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.C(Cl)Cl>C(N(CC)CC)C.CO>[N:6]1([C:11]2[CH:12]=[CH:13][C:14]([C:15]([NH:40][CH2:39][CH:28]3[CH2:27][N:26]([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)[CH2:31][CH2:30][N:29]3[CH2:32][C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)=[O:17])=[CH:18][CH:19]=2)[CH:10]=[CH:9][N:8]=[CH:7]1
Reactant: O=C(O)c1ccc(-n2ccnc2)cc1
Reactant: NCC1CN(c2ccccc2)CCN1Cc1ccccc1
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: CO
Product: O=C(NCC1CN(c2ccccc2)CCN1Cc1ccccc1)c1ccc(-n2ccnc2)cc1
Reaction time: 1 h

Procedure:
To N,N-dimethylformamide (200 mL) under nitrogen atmosphere add 4-(1H-imidazol-1-yl)benzoic acid (7.0 g, 37 mmol) and 1,1-carbonyldiimidazole (6.0 g, 37 mmol) and stir for 1 h. Add 4-phenyl-1-(phenylmethyl)-2-piperazinemethanamine (9.5 g, 34 mmol) and stir. Monitor the progress of the reaction by thin-layer chromatography. Upon completion of the reaction remove the solvent in vacuo. To the oil add water (100 mL), a saturated solution of sodium bicarbonate (30 mL) and methylene chloride (200 mL) and stir for 1 h. Separate the layers and extract the aqueous layer with methylene chloride. Concentrate the combined organic layers to give an oil. Flash chromatograph the oil on silica (1000 g) with a mixture of methylene chloride, methanol, triethylamine (97/2/1). Combine and concentrate the fractions containing product. Recrystallize the solid from ethyl acetate/hexane to provide the title compound.
Reaction SMILES: [CH:1]1([C:7]2[C:8]3[CH:9]=[CH:10][C:11]([C:32]([NH:34][S:35]([N:38]([CH2:40][CH:41](OC)[O:42]C)[CH3:39])(=[O:37])=[O:36])=[O:33])=[CH:12][C:13]=3[N:14]3[C:21]=2[C:20]2[CH:22]=[CH:23][CH:24]=[CH:25][C:19]=2[O:18][CH2:17][CH:16]([CH2:26][O:27][CH2:28][CH2:29][NH:30][CH3:31])[CH2:15]3)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(O)(C(F)(F)F)=O.O>C(Cl)Cl>[CH:1]1([C:7]2[C:8]3[CH:9]=[CH:10][C:11]([C:32]([NH:34][S:35]([N:38]([CH3:39])[CH2:40][CH:41]=[O:42])(=[O:36])=[O:37])=[O:33])=[CH:12][C:13]=3[N:14]3[C:21]=2[C:20]2[CH:22]=[CH:23][CH:24]=[CH:25][C:19]=2[O:18][CH2:17][CH:16]([CH2:26][O:27][CH2:28][CH2:29][NH:30][CH3:31])[CH2:15]3)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: CNCCOCC1COc2ccccc2-c2c(C3CCCCC3)c3ccc(C(=O)NS(=O)(=O)N(C)CC(OC)OC)cc3n2C1
Solvent: O
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CNCCOCC1COc2ccccc2-c2c(C3CCCCC3)c3ccc(C(=O)NS(=O)(=O)N(C)CC=O)cc3n2C1
Temperature: 40 °C
Reaction time: 0.67 h

Procedure:
A solution of (7R or 7S)-14-cyclohexyl-N-{[(2,2-dimethoxyethyl)(methyl)amino]sulfonyl}-7-{[2-(methylamino)ethoxy]methyl}-7,8-dihydro-6H-indolo[1,2-e][1,5]benzoxazocine-11-carboxamide (0.05 M) in DCM was treated with an excess of TFA and H2O (>50 eq of each). The mixture was stirred at 40° C. for 40 min. The solution was allowed to cool to RT and used in the next step. (ES+) m/z 597 (M+H)+.
Reaction SMILES: [F-:1].C([N+](CCCC)(CCCC)CCCC)CCC.[F:19][C:20]1[CH:21]=[C:22]([CH:32]=[C:33]([F:39])[C:34]=1[O:35][CH2:36][C:37]#[CH:38])[C:23]([N:25]1[CH:31]2[CH:26]1[CH2:27][CH2:28][CH2:29][CH2:30]2)=[O:24].[Cl-].[NH4+]>O1CCCC1>[F:1][CH:31]1[CH2:30][CH2:29][CH2:28][CH2:27][CH:26]1[NH:25][C:23](=[O:24])[C:22]1[CH:21]=[C:20]([F:19])[C:34]([O:35][CH2:36][C:37]#[CH:38])=[C:33]([F:39])[CH:32]=1
Reactant: C#CCOc1c(F)cc(C(=O)N2C3CCCCC32)cc1F
Reactant: [F-]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: C#CCOc1c(F)cc(C(=O)NC2CCCCC2F)cc1F
Temperature: 25 °C
Reaction time: 1 h

Procedure:
At room temperature, 1.2 ml of tetrabutylammonium fluoride (1M tetrahydrofuran solution) was added dropwise to a mixture of 4 ml of tetrahydrofuran and 291 mg of 7-[3,5-difluoro-4-(2-propynyloxy)benzoyl]-7-azabicyclo[4.1.0]heptane. This mixture was stirred at room temperature for 1 hour. Then, an aqueous saturated ammonium chloride solution was added to the reaction mixture, and this was extracted with ethyl acetate. The organic layer was dried over magnesium sulfate, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to obtain 0.13 g of N-(2-fluorocyclohexyl)-3,5-difluoro-4-(2-propynyloxy)benzamide (hereinafter, described as the compound 114 of the present invention) represented by the formula:
Reaction SMILES: [S:1]1[C:9]2[C:8](=[O:10])[CH:7]=[CH:6][NH:5][C:4]=2[CH:3]=[CH:2]1.[N+:11]([O-])([OH:13])=[O:12]>C(O)(=O)CC.CCOCC>[N+:11]([C:7]1[C:8](=[O:10])[C:9]2[S:1][CH:2]=[CH:3][C:4]=2[NH:5][CH:6]=1)([O-:13])=[O:12]
Reactant: O=[N+]([O-])O
Reactant: O=c1cc[nH]c2ccsc12
Solvent: CCOCC
Solvent: CCC(=O)O
Product: O=c1c([N+](=O)[O-])c[nH]c2ccsc12
Yield: 78 %

Procedure:
To a solution of 3.1 g of thieno[3,2-b]pyridin-7(4H)-one 13 in 90 ml of propionic acid is added 1.5 ml of fuming nitric acid at 110° C. with stirring and the mixture is refluxed for 1 hour. The cooled mixture is diluted with 50 ml of ether and the resulting crystals are collected by filtration, washed with water and ether-methanol, and dried to give 3.13 g (78%) of Compound 14. Recrystallization from dimethyl sulfoxide-methanol affords colorless crystals melting at 328°-331° C. (dec.).
Reaction SMILES: C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C.[F:20][C:21]1[CH:22]=[C:23]([CH:27]=[C:28]([F:31])[C:29]=1[F:30])[C:24]([OH:26])=O.CCN=C=NCCCN(C)C.Cl.Cl.[C:45]1([C:63]2[CH:68]=[CH:67][CH:66]=[CH:65][CH:64]=2)[CH:50]=[CH:49][C:48]([NH:51][C:52](=[O:62])[CH2:53][C:54](=[O:61])[N:55]2[CH2:60][CH2:59][NH:58][CH2:57][CH2:56]2)=[CH:47][CH:46]=1>CN(C=O)C.O>[C:45]1([C:63]2[CH:68]=[CH:67][CH:66]=[CH:65][CH:64]=2)[CH:46]=[CH:47][C:48]([NH:51][C:52](=[O:62])[CH2:53][C:54](=[O:61])[N:55]2[CH2:56][CH2:57][N:58]([C:24](=[O:26])[C:23]3[CH:27]=[C:28]([F:31])[C:29]([F:30])=[C:21]([F:20])[CH:22]=3)[CH2:59][CH2:60]2)=[CH:49][CH:50]=1
Reactant: O=C(O)c1cc(F)c(F)c(F)c1
Reactant: O=C(CC(=O)N1CCNCC1)Nc1ccc(-c2ccccc2)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=C(CC(=O)N1CCN(C(=O)c2cc(F)c(F)c(F)c2)CC1)Nc1ccc(-c2ccccc2)cc1
Temperature: 10 °C
Reaction time: 8 h
Yield: 43.6 %

Procedure:
HOBt (34 mg, 0.25 mmol) and DIPEA (67.9 mg, 0.51 mmol) were added to a stirred solution of 3,4,5-trifluorobenzoic acid (37 mg, 0.21 mmol) in DMF (2 mL). The reaction mixture was cooled to 10° C. and EDCI.HCl (48 mg, 0.25 mmol) followed by N-biphenyl-4-yl-3-oxo-3-piperazin-1-yl-propionamide hydrochloride (75 mg, 0.2 mmol) were added. The reaction mixture was stirred at room temperature overnight then diluted with water. The resulting precipitate was filtered and purified by column chromatography using silica gel 60-120 mesh (40% ethyl acetate in hexane) to afford 42 mg (42%) of N-Biphenyl-4-yl-3-oxo-3-[4-(3,4,5-trifluoro-benzoyl)-piperazin-1-yl]-propionamide. LCMS: 482.16 (M+1)+ 94.2%, 1H NMR: (CDCl3): δ 9.5 (s, 1H), 7.58 (m, 6H), 7.43 (t, 2H), 7.34 (m, 1H), 7.08 (t, 2H), 3.7 (bs, 8H), 3.54 (s, 2H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4](/[C:8](/[CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])=[CH:9]\[CH:10]=O)[CH:5]=[CH:6][CH:7]=1.[C:17]([CH:21]=P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)([O:19][CH3:20])=[O:18]>ClCCl>[CH3:20][O:19][C:17](=[O:18])/[CH:21]=[CH:10]/[CH:9]=[C:8](\[C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([F:1])[CH:3]=1)/[CH2:12][CH2:13][CH2:14][CH2:15][CH3:16]
Reactant: COC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: CCCCC/C(=C/C=O)c1cccc(F)c1
Solvent: ClCCl
Product: CCCCC/C(=C/C=C/C(=O)OC)c1cccc(F)c1

Procedure:
As described in Example 99, (Z)-3-(3-fluorophenyl)-2-octenal (6.2 g) was treated with (carbomethoxymethylene)triphenylphosphorane (10.5 g) in dichloromethane (50 mL) for 4 days at room temperature. The ester was isolated in the usual way and furnished 6.6 g of (2E,4Z)-5-(3-fluorophenyl)-2,4-decadienoic acid methyl ester as an oil.
Reaction SMILES: [Si:1](Cl)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[Br:9][C:10]1[CH:15]=[C:14]([CH3:16])[C:13]([CH2:17][CH:18]([OH:24])[CH2:19][C:20]([O:22][CH3:23])=[O:21])=[C:12]([CH3:25])[CH:11]=1.N1C=CN=C1>ClCCl.CCOC(C)=O>[Br:9][C:10]1[CH:11]=[C:12]([CH3:25])[C:13]([CH2:17][CH:18]([O:24][Si:1]([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2])[CH2:19][C:20]([O:22][CH3:23])=[O:21])=[C:14]([CH3:16])[CH:15]=1
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: COC(=O)CC(O)Cc1c(C)cc(Br)cc1C
Agent: c1c[nH]cn1
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: COC(=O)CC(Cc1c(C)cc(Br)cc1C)O[Si](C)(C)C(C)(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 69.9 %

Procedure:
TBS-Cl (1291 mg, 4.28 mmol) was added to a solution of 2A (860 mg, 2.86 mmol) and imidazole (389 mg, 5.71 mmol) in dichloromethane (20 mL) and stirred overnight at rt. The reaction was diluted with EtOAc, washed with water and brine, dried over Na2SO4 and concentrated. The crude product was purified by flash chromatography (loading in chloroform, 0% to 50% ethyl acetate in hexane over 15 min using a 40 g silica gel cartridge) to yield 2B (830 mg, 1.998 mmol, 70.0% yield) as a clear oil. 1H NMR (500 MHz, chloroform-d) δ ppm 7.15 (2H, s), 4.28-4.36 (1H, m), 3.68 (3H, s), 2.82 (2H, ddd, J=53.09, 13.89, 7.02 Hz), 2.53 (2H, ddd, J=57.43, 15.06, 6.19 Hz), 2.33 (6H, s), 0.80 (9H, s), −0.10 (3H, s), −0.32 (3H, s).
Reaction SMILES: C([Li])CCC.[CH3:6][C:7]1([CH3:17])[CH2:16][CH2:15][C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[O:8]1.[C:18](=[O:20])=[O:19].C(OCC)C>CCCCCC.C(OCC)C>[CH3:6][C:7]1([CH3:17])[CH2:16][CH2:15][C:14]2[C:9](=[C:10]([C:18]([OH:20])=[O:19])[CH:11]=[CH:12][CH:13]=2)[O:8]1
Reactant: CC1(C)CCc2ccccc2O1
Reactant: O=C=O
Agent: [Li]CCCC
Solvent: CCOCC
Solvent: CCCCCC
Product: CC1(C)CCc2cccc(C(=O)O)c2O1
Temperature: 0 °C

Procedure:
To a solution of 1.6M n-butyllithium in hexane and 150 ml of diethyl ether were added a solution of 27 g of 2,2-dimethylchroman in diethyl ether over a one hour period at room temperature. The solution was then heated at reflux 160 minutes, cooled, and poured into dry ice/diethyl ether. The mixture was allowed to come to room temperature, poured into ice water, and layers separated. The organic layer was washed with water, dried over sodium sulfate, and concentrated in vacuo to provide 21 g of solid. The aqueous layer was acidified and the resulting precipitate extracted into diethyl ether/ethyl acetate. The organic extract was washed with water, dried over sodium sulfate, and concentrated in vacuo to provide 9 g of solid. The two isolated solids were combined and chromatographed over silica gel eluting with 10% ethyl acetate in toluene. The appropriate fractions were combined and concentrated in vacuo to provide 9.8 g of the desired title intermediate, m.p. 90°-92° C.
Reaction SMILES: [H-].[Na+].CN(C)C=O.[F:8][C:9]1[CH:35]=[CH:34][C:12]([O:13][C:14]2[C:22]3[N:21]=[C:20](S(C)(=O)=O)[NH:19][C:18]=3[CH:17]=[C:16]([O:27][C:28]3[CH:29]=[N:30][CH:31]=[CH:32][CH:33]=3)[CH:15]=2)=[CH:11][CH:10]=1.[NH:36]1[CH:40]=[N:39][CH:38]=[N:37]1>C(OCC)(=O)C>[F:8][C:9]1[CH:35]=[CH:34][C:12]([O:13][C:14]2[C:22]3[N:21]=[C:20]([N:36]4[CH:40]=[N:39][CH:38]=[N:37]4)[NH:19][C:18]=3[CH:17]=[C:16]([O:27][C:28]3[CH:29]=[N:30][CH:31]=[CH:32][CH:33]=3)[CH:15]=2)=[CH:11][CH:10]=1
Reactant: CS(=O)(=O)c1nc2c(Oc3ccc(F)cc3)cc(Oc3cccnc3)cc2[nH]1
Reactant: c1nc[nH]n1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Fc1ccc(Oc2cc(Oc3cccnc3)cc3[nH]c(-n4cncn4)nc23)cc1
Temperature: 160 °C
Reaction time: 8 h

Procedure:
5.0 mg of sodium hydride was added to a dimethylformamide (0.5 ml) solution of 16 mg of 4-(4-fluoro-phenoxy)-2-methanesulfonyl-6-(pyridin-3-yloxy)-1H-benzimidazole, and then 10.4 mg of [1,2,4]triazole was added to it, and the reaction liquid was stirred overnight at 160° C. The reaction liquid was diluted with ethyl acetate, washed with water and saturated saline in order, and dried with anhydrous magnesium sulfate. The solvent was evaporated away under reduced pressure, and the resulting residue was purified through partitioning thin-layer chromatography (Kieselgel™ 60F254, Art 5744 (by Merck), ethyl acetate) to obtain the entitled compound.
Reaction SMILES: [CH2:1]([N:5]([S:15]([C:18]1[CH:23]=[CH:22][C:21]([CH3:24])=[CH:20][CH:19]=1)(=[O:17])=[O:16])[C@H:6]([C:12]([OH:14])=[O:13])[CH2:7][CH2:8][CH2:9][CH2:10][NH2:11])[CH:2]([CH3:4])[CH3:3].[C:25]([O:29][C:30]([N:32]([CH3:44])[C@H:33]([C:41](O)=[O:42])[CH2:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)=[O:31])([CH3:28])([CH3:27])[CH3:26]>>[CH3:24][C:21]1[CH:22]=[CH:23][C:18]([S:15]([N:5]([C@H:6]([C:12]([OH:14])=[O:13])[CH2:7][CH2:8][CH2:9][CH2:10][NH:11][C:41]([C@@H:33]([N:32]([C:30]([O:29][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:31])[CH3:44])[CH2:34][C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)=[O:42])[CH2:1][CH:2]([CH3:3])[CH3:4])(=[O:17])=[O:16])=[CH:19][CH:20]=1
Reactant: CN(C(=O)OC(C)(C)C)[C@@H](Cc1ccccc1)C(=O)O
Reactant: Cc1ccc(S(=O)(=O)N(CC(C)C)[C@@H](CCCCN)C(=O)O)cc1
Product: Cc1ccc(S(=O)(=O)N(CC(C)C)[C@@H](CCCCNC(=O)[C@H](Cc2ccccc2)N(C)C(=O)OC(C)(C)C)C(=O)O)cc1

Procedure:
The title compound was prepared from Nα-isobutyl-Nα-(4-methylbenzenesulfonyl)-L-lysine (100 mg, 0.29 mmol, example 1, step E) as described in general procedure Bc using commercially available Nα-tert-butoxycarbonyl-Nα-methyl-L-phenylalanine (83 mg, 0.3 mmol). The final product was triturated with ether to yield 176 mg (90%) of the desired material.
Reaction SMILES: [N:1]([C:4]1[C:13]([S:14][CH2:15][C:16]2[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=2)=[CH:12][C:7]([C:8]([O:10][CH3:11])=[O:9])=[C:6]([NH:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=2[F:31])[C:5]=1[F:32])=[N+]=[N-]>[Pd].[Ni]>[NH2:1][C:4]1[C:13]([S:14][CH2:15][C:16]2[CH:17]=[CH:18][C:19]([O:22][CH3:23])=[CH:20][CH:21]=2)=[CH:12][C:7]([C:8]([O:10][CH3:11])=[O:9])=[C:6]([NH:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=2[F:31])[C:5]=1[F:32]
Reactant: COC(=O)c1cc(SCc2ccc(OC)cc2)c(N=[N+]=[N-])c(F)c1Nc1ccccc1F
Agent: [Ni]
Agent: [Pd]
Product: COC(=O)c1cc(SCc2ccc(OC)cc2)c(N)c(F)c1Nc1ccccc1F

Procedure:
Methyl 4-azido-3-fluoro-2-((2-fluorophenyl)amino)-5-((4-methoxy benzyl)thio)benzoate can be hydrogenated in the presence of appropriate catalyst (such as Pd/C, Pt, Ni) in appropriate solvent. The reaction normally completes within several hours (1-12 h, prefer 3-10 h). Methyl 4-amino-3-fluoro-2-((2-fluorophenyl)amino)-5-((4-methoxybenzyl)thio)benzoate is obtained after conventional workup.
Reaction SMILES: CS([O:5][C@H:6]1[CH2:11][CH2:10][C@H:9]([C:12]([F:15])([F:14])[CH3:13])[CH2:8][CH2:7]1)(=O)=O.O[C:17]1[CH:18]=[C:19]2[C:24](=[CH:25][CH:26]=1)[CH:23]=[C:22]([CH2:27][N:28]1[CH2:31][CH:30]([C:32]([O:34]C)=[O:33])[CH2:29]1)[CH:21]=[CH:20]2.C([O-])([O-])=O.[Cs+].[Cs+].Cl>C(O)(C)(C)C.CC(=O)CC>[F:14][C:12]([C@H:9]1[CH2:10][CH2:11][C@H:6]([O:5][C:17]2[CH:18]=[C:19]3[C:24](=[CH:25][CH:26]=2)[CH:23]=[C:22]([CH2:27][N:28]2[CH2:29][CH:30]([C:32]([OH:34])=[O:33])[CH2:31]2)[CH:21]=[CH:20]3)[CH2:7][CH2:8]1)([F:15])[CH3:13]
Reactant: COC(=O)C1CN(Cc2ccc3cc(O)ccc3c2)C1
Reactant: CC(F)(F)[C@H]1CC[C@H](OS(C)(=O)=O)CC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC(C)(C)O
Solvent: CCC(C)=O
Product: CC(F)(F)[C@H]1CC[C@H](Oc2ccc3cc(CN4CC(C(=O)O)C4)ccc3c2)CC1
Temperature: 110 °C
Reaction time: 16 h

Procedure:
(trans)-4-(1,1-difluoroethyl)cyclohexyl methanesulfonate (WO 2010051030) (0.98 mmol, 236 mg, 1.0 eq.), methyl 1-((6-hydroxynaphthalen-2-yl)methyl)azetidine-3-carboxylate (1.17 mmol, 317 mg, 1.2 mmol) and Cs2CO3 (4.41 mmol, 1.4 g, 4.5 eq.) were dissolved in t-butanol (4 mL) and 2-butanone (2 mL). The mixture was stirred at 110° C. for 16 h. 1 M aq. HCl solution was added to the mixture to adjust pH=6. Then the mixture was extracted with EtOAc. The organic layer was purified by silica gel column chromatography using DCM/CH3OH (10/1) as eluent to give product (7 mg, 1.8%) as a white solid. ESI-MS (M+1)+: 404.1. HPLC: 89.46%. 1H NMR (400 MHz, CD3OD) δ: 7.89 (s, 1H), 7.86-7.81 (m, 2H), 7.46 (dd, 1H), 7.31 (s, 1H), 7.19 (dd, 1H), 4.47 (s, 2H), 4.43-4.41 (m, 1H), 4.21 (d, 4H), 3.45˜3.41 (m, 1H), 2.32-2.30 (m, 2H), 2.02-1.99 (m, 2H), 1.64-1.54 (m, 3H), 1.51-1.45 (m, 3H), 1.36-1.28 (m, 2H).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([CH2:10][C:11]#[N:12])=[CH:2]1.[CH3:13][C:14]([CH3:19])([CH3:18])[C:15](Cl)=[O:16].[H-].[Na+]>CN(C=O)C>[CH3:13][C:14]([CH3:19])([CH3:18])[C:15]([N:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([CH2:10][C:11]#[N:12])=[CH:2]1)=[O:16]
Reactant: N#CCc1c[nH]c2ccccc12
Reactant: CC(C)(C)C(=O)Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)C(=O)n1cc(CC#N)c2ccccc21
Yield: 38.7 %

Procedure:
Using the procedure of subpart A above, the N-alkylation reaction of 10.2 g (65 mmol) of commercially available (1H-indol-3-yl)-acetonitrile (5) (1H-indol-3-yl)-acetonitrile (Acros Organics, Belgium) with 8.7 ml (71 mmol) of trimethylacetyl chloride and 3.4 g (85 mmol) of NaH (60% dispersion in oil) as a base in 115 ml of DMF yielded 6.6 g (38.7%) of [1-(2,2-dimethyl-propionyl)-1H-indol-3-yl]-acetonitrile (6) as a yellow oil after chromatographic purification.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[CH2:7]([O:9][C:10](=[O:23])[NH:11][C:12]1[CH:17]=[C:16]([Br:18])[N:15]=[C:14]([Br:19])[C:13]=1[N+:20]([O-:22])=[O:21])[CH3:8].[CH2:24](Br)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.[I-].[Na+]>CC(C)=O>[CH2:7]([O:9][C:10](=[O:23])[N:11]([CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[C:12]1[CH:17]=[C:16]([Br:18])[N:15]=[C:14]([Br:19])[C:13]=1[N+:20]([O-:22])=[O:21])[CH3:8]
Reactant: CCOC(=O)Nc1cc(Br)nc(Br)c1[N+](=O)[O-]
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCOC(=O)N(Cc1ccccc1)c1cc(Br)nc(Br)c1[N+](=O)[O-]
Reaction time: 36 h

Procedure:
Potassium carbonate (5.57 g) was added to a stirred solution of (2,6-dibromo-3-nitro-pyridin-4-yl)-carbamic acid ethyl ester (7.44 g) in acetone (100 ml) then benzyl bromide (2.87 ml) was added, followed by sodium iodide (3.63 g). The mixture was left to stir under nitrogen for 36 hours. The reaction mixture was filtered to remove precipitated white solids, concentrated in vacuo, and then partitioned between ethyl acetate (100 ml) and water (100 ml). The organics were dried (MgSO4) and evaporated to a yellow oil. This crude oil was adsorbed onto silica gel and then purified by chromatography on Isco Companion on a silica column (80 g, Redisep) eluting with EtOAc:heptane, increasing the gradient linearly from 10:90 to 50:50. This provided the title compound (7.50 g) as a yellow oil.
Reaction SMILES: Cl.[Br:2][C:3]1[C:4]([C:22]#[N:23])=[N:5][N:6]([CH2:20][CH3:21])[C:7]=1[CH2:8][C:9]([NH:12]C(=O)OC(C)(C)C)([CH3:11])[CH3:10]>C(O)C>[NH2:12][C:9]([CH3:10])([CH3:11])[CH2:8][C:7]1[N:6]([CH2:20][CH3:21])[N:5]=[C:4]([C:22]#[N:23])[C:3]=1[Br:2]
Reactant: CCn1nc(C#N)c(Br)c1CC(C)(C)NC(=O)OC(C)(C)C
Agent: Cl
Solvent: CCO
Product: CCn1nc(C#N)c(Br)c1CC(C)(C)N
Temperature: 25 °C
Reaction time: 48 h
Yield: 100.8 %

Procedure:
Hydrogen chloride (21 mL of a 3.6 M solution in ethanol) was added to a solution of tert-butyl 2-(4-bromo-3-cyano-1-ethyl-1H-pyrazol-5-yl)-1,1-dimethylethylcarbamate (5.6 g, 15 mmol), prepared in Example 1244, in ethanol (75 mL), and the reaction was stirred at room temperature for two days and concentrated under reduced pressure. The residue was suspended in water (50 mL), and aqueous sodium hydroxide (50% w/w) was added to adjust the mixture to pH 12. The basic mixture was extracted with dichloromethane (2×50 mL), and the combined extracts were dried over sodium sulfate, filtered, and concentrated under reduced pressure to provide 4.1 g of 5-(2-amino-2-methylpropyl)-4-bromo-1-ethyl-1H-pyrazole-3-carbonitrile as a colorless oil.
Reaction SMILES: O[C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][CH:8]=[C:9]2[CH2:12][CH2:13][NH:14][C:15](=[O:22])[C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[CH:4][CH:3]=1.[OH-].[K+].CN(C)C(Cl)=[S:28].CCCCCC>O.O1CCCC1>[SH:28][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][CH:8]=[C:9]2[CH2:12][CH2:13][NH:14][C:15](=[O:22])[C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[CH:4][CH:3]=1
Reactant: CN(C)C(=S)Cl
Reactant: O=C(NCCc1cccc2ccc(O)cc12)c1ccccc1
Agent: [K+]
Agent: [OH-]
Solvent: CCCCCC
Solvent: C1CCOC1
Solvent: O
Product: O=C(NCCc1cccc2ccc(S)cc12)c1ccccc1

Procedure:
The product obtained in Step A (9 mmol) is added, with stirring, to a solution of potassium hydroxide (10 mmol) dissolved in 15 ml of water and 16 ml of tetrahydrofuran. The solution is cooled using a bath of ice and salt, and dimethylthiocarbamoyl chloride (9 mmol) dissolved in tetrahydrofuran (15 ml) is added dropwise with stirring. After stirring for half an hour while maintaining the cold temperature, the reaction mixture is extracted with chloroform. The organic phases are combined, dried over magnesium sulphate, filtered and then concentrated under reduced pressure. The residue is taken up in diphenyl ether (10 ml) and refluxed for one hour under a nitrogen atmosphere. The diphenyl ether is removed by evaporation under reduced pressure until a solution of about 2 ml has been obtained. The 2 ml of distillate, which are still hot, are poured carefully into 50 ml of hexane to yield, after cooling, a solid which is isolated by filtration. The solid collected in that manner is added to a solution of potassium hydroxide (380 mg) dissolved in a water/methanol mixture (1 ml/10 ml). The solution is refluxed for 12 hours and then cooled and concentrated under reduced pressure. The residue is taken up in 20 ml of chloroform and extracted 3 times with water. The organic phase is dried over magnesium sulphate, filtered and concentrated under reduced pressure. The residue is chromatographed over silica gel to yield the title product.
Reaction SMILES: [CH2:1]([C@@H:8]1[CH2:13][C@@H:12]([N:14]([CH2:21][C:22]2[C:31]3[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=3)[N:25]=[CH:24][CH:23]=2)[C:15](=[O:20])[C:16]([F:19])([F:18])[F:17])[CH2:11][CH2:10][NH:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:32][O:33][C:34]1[CH:35]=[C:36]([CH:40]=[C:41]([O:43][CH3:44])[CH:42]=1)[C:37](O)=[O:38].O=C1N(P(Cl)(N2CCOC2=O)=O)CCO1.C(N(CC)CC)C>>[CH2:1]([C@@H:8]1[CH2:13][C@@H:12]([N:14]([CH2:21][C:22]2[C:31]3[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=3)[N:25]=[CH:24][CH:23]=2)[C:15](=[O:20])[C:16]([F:18])([F:19])[F:17])[CH2:11][CH2:10][N:9]1[C:37](=[O:38])[C:36]1[CH:40]=[C:41]([O:43][CH3:44])[CH:42]=[C:34]([O:33][CH3:32])[CH:35]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(N(Cc1ccnc2ccccc12)[C@H]1CCN[C@H](Cc2ccccc2)C1)C(F)(F)F
Reactant: COc1cc(OC)cc(C(=O)O)c1
Agent: O=C1OCCN1P(=O)(Cl)N1CCOC1=O
Solvent: CCN(CC)CC
Product: COc1cc(OC)cc(C(=O)N2CC[C@H](N(Cc3ccnc4ccccc34)C(=O)C(F)(F)F)C[C@H]2Cc2ccccc2)c1

Procedure:
200 mg (0.467 mmol) of (2R*,4S*)-2-benzyl-N-(4-quinolylmethyl)-N-trifluoroacetyl-4-piperidinamine are reacted with 102 mg (0.561 mmol) of 3,5-dimethoxybenzoic acid, 143 mg (0.561 mmol) of bis(2-oxo-3-oxazolidinyl)phosphinic chloride and 144 μl (1.03 mmol) of triethylamine in analogy to Example 4. The title compound is obtained as white foam. TLC: methylene chloride/methanol/conc. ammonia (1000:50:1) Rf =0.31, FD-MS: M+ =591.
Reaction SMILES: C([O:3][C:4]([C:6]1([S:14]([C:17]2[CH:22]=[CH:21][C:20]([O:23][C:24]3[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][CH:25]=3)=[CH:19][CH:18]=2)(=[O:16])=[O:15])[CH2:11][CH2:10][N:9]([CH2:12][CH3:13])[CH2:8][CH2:7]1)=[O:5])C>C1COCC1.CO.[OH-].[Na+]>[Cl:30][C:27]1[CH:26]=[CH:25][C:24]([O:23][C:20]2[CH:19]=[CH:18][C:17]([S:14]([C:6]3([C:4]([OH:5])=[O:3])[CH2:11][CH2:10][N:9]([CH2:12][CH3:13])[CH2:8][CH2:7]3)(=[O:15])=[O:16])=[CH:22][CH:21]=2)=[CH:29][CH:28]=1
Reactant: CCOC(=O)C1(S(=O)(=O)c2ccc(Oc3ccc(Cl)cc3)cc2)CCN(CC)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: CCN1CCC(C(=O)O)(S(=O)(=O)c2ccc(Oc3ccc(Cl)cc3)cc2)CC1

Procedure:
4-[4-(4-Chloro-phenoxy)-benzenesulfonyl]-1-ethyl-piperidine-4-carboxylic acid was prepared starting from 4-[4-(4-chloro-phenoxy)-benzenesulfonyl]-1-ethyl-piperidine-4-carboxylic acid ethyl ester (3.02 g, 6.7 mmol) dissolved in THF:methanol (3:1 150 ml) and 10 N NaOH (20 ml). The resulting reaction mixture was worked up as outlined in example 83. Yield 1.8 g (65%); white solid; mp 184° C.; MS:423.9 (M+H)+