Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][N:6]=[CH:7]2.C(=O)(O)[O-].[K+].[CH3:17][O:18][C:19]1[CH:20]=[C:21]([CH:25]=[CH:26][C:27]=1[O:28][CH3:29])[C:22](Cl)=[O:23]>C1C=CC=CC=1>[CH3:17][O:18][C:19]1[CH:20]=[C:21]([CH:25]=[CH:26][C:27]=1[O:28][CH3:29])[C:22]([NH:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][N:6]=[CH:7]2)=[O:23]
Reactant: COc1ccc(C(=O)Cl)cc1OC
Reactant: Nc1cccc2cnccc12
Agent: O=C([O-])O
Agent: [K+]
Solvent: c1ccccc1
Product: COc1ccc(C(=O)Nc2cccc3cnccc23)cc1OC

Procedure:
5-Aminoisoquinoline (8 g.) was dissolved in dry benzene (100 ml) and 0.5 g of dry potassium bicarbonate was added to the solution. A 0.1 mole excess of 3,4-dimethoxybenzoyl chloride was dissolved in dry benzene (50 ml) and this solution was poured into the solution of 5-aminoisoquinoline. A precipitate formed immediately. This was collected by filtration and washed with 10% sodium carbonate solution followed by water. The washings were discarded and the insoluble residue was recrystallized from benzene to yield 11.5 g of 5-(3,4-dimethoxybenzamido)isoquinoline as tan needles, m.p. 193°-194° C.
Reaction SMILES: [CH2:1]1[C:7]2[CH:8]=[CH:9][C:10]([S:12]([NH2:15])(=[O:14])=[O:13])=[CH:11][C:6]=2[CH2:5][CH2:4][NH:3][CH2:2]1.[CH2:16]([N:18]=[C:19]=[O:20])[CH3:17]>CN(C)C=O>[CH2:16]([NH:18][C:19]([N:3]1[CH2:2][CH2:1][C:7]2[CH:8]=[CH:9][C:10]([S:12]([NH2:15])(=[O:14])=[O:13])=[CH:11][C:6]=2[CH2:5][CH2:4]1)=[O:20])[CH3:17]
Reactant: NS(=O)(=O)c1ccc2c(c1)CCNCC2
Reactant: CCN=C=O
Solvent: CN(C)C=O
Product: CCNC(=O)N1CCc2ccc(S(N)(=O)=O)cc2CC1

Procedure:
3.4 G. of 2,3,4,5-tetrahydro-1H-3-benzazepine-7-sulfonamide are dissolved in 50 ml. of dimethylformamide while warming at 60° C. and the solution is then rapidly cooled with an icebath. As soon as a temperature of 20° C. is reached, 1.18 ml. of ethylisocyanate are added dropwise while stirring, and the mixture is subsequently stirred at 25° C. for 0.5 hour. The solution is then concentrated in vacuo on a bath at 80° C. and the crystalline residue is digested with ether. There is obtained 3-ethylcarbamoyl-2,3,4,5-tetrahydro-1H-3-benzazepine-7-sulfonamide.
Reaction SMILES: C([NH:3][C:4]1[CH:29]=[CH:28][C:7]([CH2:8][S:9][C:10]([N:12]2[C@@H:24]([C:25]([OH:27])=[O:26])[CH2:23][C:22]3[C:21]4[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=4)[NH:15][C:14]=3[CH2:13]2)=[S:11])=[CH:6][CH:5]=1)=O.C(O)(=O)CS.Cl>C(O)C>[NH2:3][C:4]1[CH:5]=[CH:6][C:7]([CH2:8][S:9][C:10]([N:12]2[C@@H:24]([C:25]([OH:27])=[O:26])[CH2:23][C:22]3[C:21]4[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=4)[NH:15][C:14]=3[CH2:13]2)=[S:11])=[CH:28][CH:29]=1
Reactant: O=CNc1ccc(CSC(=S)N2Cc3[nH]c4ccccc4c3C[C@@H]2C(=O)O)cc1
Agent: Cl
Agent: O=C(O)CS
Solvent: CCO
Product: Nc1ccc(CSC(=S)N2Cc3[nH]c4ccccc4c3C[C@@H]2C(=O)O)cc1
Reaction time: 2.5 h
Yield: 38.1 %

Procedure:
(3R)-2-[(4-(Formylamino)benzylthio)thiocarbonyl]-1,2,3,4-tetrahydro-β-carboline-3-carboxylic acid (1.46 g) is dissolved in ethanol (34 ml) and thereto is added thioglycolic acid (0.04 ml) and is further added dropwise 6N HCl (34 ml). The mixture is stirred under argon stream for 2.5 hours and then distilled under reduced pressure to remove the solvent. The residue is purified by silica gel column chromatography (solvent, chloroform:methanol:acetic acid=94:5:1-20:10:1) to give the title compound (0.52 g), as pale yellow powder.
Reaction SMILES: [C:1]([OH:12])(=O)/[CH:2]=[CH:3]/[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10].[CH3:13][N:14]1[CH2:20][CH2:19][CH2:18][NH:17][CH2:16][CH2:15]1>>[C:1]([N:17]1[CH2:18][CH2:19][CH2:20][N:14]([CH3:13])[CH2:15][CH2:16]1)(=[O:12])/[CH:2]=[CH:3]/[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10]
Reactant: CN1CCCNCC1
Reactant: CCCCCCC/C=C/C(=O)O
Product: CCCCCCC/C=C/C(=O)N1CCCN(C)CC1

Procedure:
The same procedures as in Example 2 were carried out using (E)-2-decenoic acid and 1-methyl-1,4-diazepane as starting raw materials, to produce an intended compound.
Reaction SMILES: [Br:1][C:2]([CH3:18])([CH3:17])[C:3]([O:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH:15]=[CH2:16])=[O:4].[SH:19][CH2:20][CH2:21][CH2:22][Si:23]([O:30][CH2:31][CH3:32])([O:27][CH2:28][CH3:29])[O:24][CH2:25][CH3:26]>>[Br:1][C:2]([CH3:18])([CH3:17])[C:3]([O:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][S:19][CH2:20][CH2:21][CH2:22][Si:23]([O:30][CH2:31][CH3:32])([O:24][CH2:25][CH3:26])[O:27][CH2:28][CH3:29])=[O:4]
Reactant: C=CCCCCCCCCCOC(=O)C(C)(C)Br
Reactant: CCO[Si](CCCS)(OCC)OCC
Product: CCO[Si](CCCSCCCCCCCCCCCOC(=O)C(C)(C)Br)(OCC)OCC

Procedure:
The 10-undecenyl 2-bromo-2-methylpropanate was reacted with 3-mercaptopropyltriethoxysilane in the same manner as in Example 1 to give 11-(3-(triethoxysilyl)propylthio)undecyl 2-bromo-2-methylpropanate of the chemical formula below (compound 5).
Reaction SMILES: C(OC([N:8]1[CH2:26][CH2:25][C@@H:11]2[N:12]([CH3:24])[C:13]3[C:14]([C:20]([F:23])([F:22])[F:21])=[CH:15][C:16](Br)=[CH:17][C:18]=3[C@@H:10]2[CH2:9]1)=O)(C)(C)C.[CH3:27][O:28][C:29]1[CH:35]=[CH:34][CH:33]=[CH:32][C:30]=1[NH2:31]>>[O:28]([C:29]1[CH:35]=[CH:34][CH:33]=[CH:32][C:30]=1[NH:31][C:16]1[CH:15]=[C:14]([C:20]([F:22])([F:23])[F:21])[C:13]2[N:12]([CH3:24])[C@H:11]3[CH2:25][CH2:26][NH:8][CH2:9][C@H:10]3[C:18]=2[CH:17]=1)[CH3:27]
Reactant: CN1c2c(cc(Br)cc2C(F)(F)F)[C@@H]2CN(C(=O)OC(C)(C)C)CC[C@@H]21
Reactant: COc1ccccc1N
Product: COc1ccccc1Nc1cc2c(c(C(F)(F)F)c1)N(C)[C@H]1CCNC[C@@H]21

Procedure:
The title compound was prepared by following the general coupling procedure as a yellow solid (22 mg, 61%) from (4aS,9bR)-8-bromo-5-methyl-6-trifluoromethyl-1,3,4,4a,5,9b-hexahydro-pyrido[4,3-b]indole-2-carboxylic acid tert-butyl ester (Example 45, 41 mg, 0.095 mmol) and 2-methoxyaniline (37 mg, 0.30 mmol). 1H NMR (CDCl3, 300 MHz) δ (ppm) 1.82–2.00 (m, 2H), 2.58–2.80 (m, 3H), 2.80–3.00 (m, 5H), 3.07 (dd, J=12.9, 5.9 Hz, 1H), 3.15–3.25 (m, 1H), 3.45–3.55 (m, 1H), 3.91 (s, 3H), 5.97 (s, 1H), 6.75–6.90 (m, 3H), 6.99 (dd, J=1.6, 7.5 Hz, 1H), 7.09 (d, J=1.8 Hz, 1H).
Reaction SMILES: [CH2:1]([CH:3]1[CH2:8][CH2:7][CH2:6][CH:5]([CH2:9][CH3:10])[CH:4]1[NH2:11])[CH3:2]>[Pd]>[CH2:1]([C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([CH2:9][CH3:10])[C:4]=1[NH2:11])[CH3:2]
Reactant: CCC1CCCC(CC)C1N
Agent: [Pd]
Product: CCc1cccc(CC)c1N
Yield: 96 %

Procedure:
The procedure described in Example 27 is followed, using a catalyst which contains 1.0% by weight of palladium on a cobalt/aluminum spinel and starting from 2,6-diethylcyclohexylamine. 2,6-Diethylaniline (boiling point=243° C.) is obtained in a yield of 96% of the theory.
Reaction SMILES: [Cl:1][C:2]1[C:7]2[CH:8]=[C:9]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[S:10][C:6]=2[C:5]([CH:17]([OH:19])[CH3:18])=[CH:4][N:3]=1>ClCCl.CCC[N+](CCC)(CCC)CCC.[O-][Ru](=O)(=O)=O>[Cl:1][C:2]1[C:7]2[CH:8]=[C:9]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[S:10][C:6]=2[C:5]([C:17](=[O:19])[CH3:18])=[CH:4][N:3]=1
Reactant: CC(O)c1cnc(Cl)c2cc(-c3ccccc3)sc12
Agent: O=[Ru](=O)(=O)[O-]
Agent: CCC[N+](CCC)(CCC)CCC
Solvent: ClCCl
Product: CC(=O)c1cnc(Cl)c2cc(-c3ccccc3)sc12

Procedure:
To a suspension of 1-(4-chloro-2-phenyl-thieno[3,2-c]pyridin-7-yl)-ethanol 96 (92 mg, 0.32 mmol) and 168 mg of powdered 4A molecular sieves in dichloromethane (35 mL) was added TPAP (11 mg, 0.03 mmol). The resultant mixture was stirred at room temperature for 1 h. After this time, the reaction mixture was diluted with dichloromethane and washed with saturated aqueous sodium thiosulfate (1×) and saturated aqueous copper sulfate (1×). The organic layer was dried over Na2SO4, filtered, and the filtrate was purified by silica gel column chromatography (eluent: hexane:EtOAc, 17:3) to give 97. 1H NMR (400 MHz, CDCl3) δ: 2.79 (s, 3H), 7.40-7.53 (m, 3H), 7.75 (s, 1H), 7.78-7.83 (m, 2H), 8.83 (s, 1H). MS (EI) m/z (M+H+) 288.
Reaction SMILES: C1([C@H]2NC(=O)COC2)C=CC=CC=1.[N+]([O-])(O)=O.[N+:18]([C:21]1[CH:26]=[CH:25][C:24]([C@H:27]2[NH:32][C:31](=[O:33])[CH2:30][O:29][CH2:28]2)=[CH:23][CH:22]=1)([O-])=O>S(=O)(=O)(O)O>[NH2:18][C:21]1[CH:22]=[CH:23][C:24]([C@H:27]2[NH:32][C:31](=[O:33])[CH2:30][O:29][CH2:28]2)=[CH:25][CH:26]=1
Reactant: O=C1COC[C@@H](c2ccc([N+](=O)[O-])cc2)N1
Agent: O=C1COC[C@@H](c2ccccc2)N1
Agent: O=S(=O)(O)O
Solvent: O=[N+]([O-])O
Product: Nc1ccc([C@@H]2COCC(=O)N2)cc1

Procedure:
(R)-5-phenylmorpholin-3-one was allowed to react with nitric acid in concentrated sulfuric acid, and the resulting (R)-5-(4-nitrophenyl)morpholin-3-one (F: 223) was subjected to catalytic hydrogenation in the same manner as shown in Reference Example 3 to obtain (R)-5-(4-aminophenyl)morpholin-3-one. F: 193.
Reaction SMILES: [C:1]([C:5]1[S:9]/[C:8](=[N:10]\[C:11](=[O:21])[C:12]2[CH:17]=[C:16]([Cl:18])[CH:15]=[CH:14][C:13]=2[O:19][CH3:20])/[N:7]([CH2:22][C@@H:23]2[CH2:26][CH2:25][N:24]2C(OC(C)(C)C)=O)[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].FC(F)(F)C(O)=O>C(Cl)Cl>[NH:24]1[CH2:25][CH2:26][C@@H:23]1[CH2:22][N:7]1[CH:6]=[C:5]([C:1]([CH3:4])([CH3:3])[CH3:2])[S:9]/[C:8]/1=[N:10]\[C:11](=[O:21])[C:12]1[CH:17]=[C:16]([Cl:18])[CH:15]=[CH:14][C:13]=1[O:19][CH3:20]
Reactant: COc1ccc(Cl)cc1C(=O)/N=c1\sc(C(C)(C)C)cn1C[C@@H]1CCN1C(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COc1ccc(Cl)cc1C(=O)/N=c1\sc(C(C)(C)C)cn1C[C@H]1CCN1
Temperature: 25 °C
Reaction time: 48 h
Yield: 67.7 %

Procedure:
A solution of Example 15B (295 mg, 0.6 mmol) in CH2Cl2 (5 mL) was treated with trifluoroacetic acid (1 mL) and the reaction mixture was stirred at room temperature for 48 hrs, concentrated on the rotovap and the residue was partitioned between ethyl acetate and saturated NaHCO3. The organic layer was washed with brine, dried (MgSO4), filtered, and concentrated in vacuo. The residue was purified by flash chromatography using an Analogix® Intelliflash280™ (SiO2, 0-15% methanol in CH2Cl2) to afford the title compound (160 mg, 68% yield). MS (DCI) m/z 394 (M+H)+. 1H NMR (300 MHz, DMSO-d6) δ ppm 1.17-1.27 (m, 2H), 1.28-1.35 (s, 9H), 2.05-2.19 (m, 1H), 2.19-2.34 (m, 1H), 3.45-3.61 (m, 1H), 3.72-3.82 (m, 3H), 4.20-4.35 (m, 3H), 7.11 (d, J=8.7 Hz, 1H), 7.30 (s, 1H), 7.45 (dd, J=8.7, 2.8 Hz, 1H), 7.61 (d, J=2.8 Hz, 1H). MS (DCI) m/z 394 (M+H)+.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[C:19]([C@H:20]([CH3:25])[CH2:21][C:22](O)=[O:23])=[C:18]([I:26])[N:17]=[CH:16][N:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N1C=CN=C1)(N1C=CN=C1)=O.Cl.[CH3:40][NH:41][O:42][CH3:43].CN1CCOCC1.[Cl-].[NH4+]>O1CCCC1.O>[I:26][C:18]1[N:17]=[CH:16][N:15]=[C:14]([N:11]2[CH2:10][CH2:9][N:8]([C:6]([O:5][C:1]([CH3:3])([CH3:4])[CH3:2])=[O:7])[CH2:13][CH2:12]2)[C:19]=1[C@@H:20]([CH2:21][C:22]([N:41]([O:42][CH3:43])[CH3:40])=[O:23])[CH3:25]
Reactant: C[C@H](CC(=O)O)c1c(I)ncnc1N1CCN(C(=O)OC(C)(C)C)CC1
Reactant: CNOC
Agent: Cl
Agent: O=C(n1ccnc1)n1ccnc1
Agent: [Cl-]
Solvent: CN1CCOCC1
Solvent: C1CCOC1
Solvent: O
Product: CON(C)C(=O)C[C@@H](C)c1c(I)ncnc1N1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 20 °C
Reaction time: 1 h
Yield: 99 %

Procedure:
Into a solution of (R)-3-(4-(4-(tert-butoxycarbonyl)piperazin-1-yl)-6-iodopyrimidin-5-yl)butanoic acid (100 g, 210 mmol) in tetrahydrofuran (700 mL) was added 1,1′-carbonyldiimidazole (40.9 g, 252 mmol) in portions. The reaction mixture was stirred at 20° C. for 1 h and cooled to 5° C. N,O-dimethylhydroxyamine hydrochloride (41.0 g, 420 mmol) was added in portions followed by N-methylmorpholine (6.94 mL, 63.0 mmol). The mixture was stirred at 5° C. for about 1 h, slowly warmed up to room temperature, and stirred for 24 h. Saturated aqueous ammonium chloride (500 mL) and water (150 mL) were added to get a clear phase separation. The organic layer was washed with saturated aqueous ammonium chloride (500 mL) and brine (200 mL). The residual water was azeotroped off to less than 500 ppm by co-evaporation with tetrahydrofuran. The product, as a solution in tetrahydrofuran was used for the next step without further purification or isolation (weight assay yield: >99%. 1H NMR (300 MHz, CDCl3) δ 8.23 (s, 1H), 3.84 (ddq, J=9.0, 7.2, 5.1 Hz, 1H), 3.72 (s, 3H), 3.61-3.57 (m, 4H), 3.42 (dd, J=16.5, 9.0 Hz, 1H), 3.25-3.21 (m, 4H), 3.17 (s, 3H), 2.76 (dd, J=16.5, 5.1 Hz, 1H), 1.47 (s, 9H), 1.47 (d, J=7.2 Hz, 3H). HRMS calcd. For C19H31IN5O4 [M+H]+: 520.1415. found 520.1413.
Reaction SMILES: OC(C)(C)[CH2:3][C@@:4]1([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[O:9][C:8](=[O:10])[N:7]([C@H:11]([C:13]2[CH:18]=[CH:17][C:16](B3OC(C)(C)C(C)(C)O3)=[CH:15][CH:14]=2)[CH3:12])[CH2:6][CH2:5]1.[C:36]([O-:39])([O-])=O.[Cs+].[Cs+]>O1CCOCC1>[OH:9][C:4]([CH3:5])([CH3:3])[CH2:3][C@@:4]1([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[O:9][C:8](=[O:10])[N:7]([C@H:11]([C:13]2[CH:18]=[CH:17][C:16]([C:14]3[CH:13]=[CH:11][NH:7][C:36](=[O:39])[CH:15]=3)=[CH:15][CH:14]=2)[CH3:12])[CH2:6][CH2:5]1
Reactant: C[C@@H](c1ccc(B2OC(C)(C)C(C)(C)O2)cc1)N1CC[C@](CC(C)(C)O)(c2ccccc2)OC1=O
Reactant: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1COCCO1
Product: C[C@@H](c1ccc(-c2cc[nH]c(=O)c2)cc1)N1CC[C@](CC(C)(C)O)(c2ccccc2)OC1=O
Temperature: 120 °C
Yield: 71 %

Procedure:
To a solution of (S)-6-(2-hydroxy-2-methylpropyl)-6-phenyl-3-((S)-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)ethyl)-1,3-oxazinan-2-one (2.646 g, 5.52 mmol) in 1,4-dioxane (60 mL) were added 4-iodopyridin-2(1K)-one (1.200 g, 5.43 mmol), 2 M Cs2CO3 (14.5 mL), and PdCl2(dppf)nCH2Cl2 (0.230 g, 0.28 mmol). The mixture was degassed and heated, under a nitrogen atmosphere, at 120° C. for 15 h. The mixture was diluted with CH2Cl2, dried over Na2SO4. After the solvents were evaporated, the residue was purified by chromatography on silica gel eluted with MeOH/CH2Cl2 to afford 1.717 g (71%) of (S)-6-(2-hydroxy-2-methylpropyl)-3-((S)-1-(4-(2-oxo-1,2-dihydropyridin-4-yl)phenyl)ethyl)-6-phenyl-1,3-oxazinan-2-one. LC-MS Method 1 tR=1.23 min, m/z 389, 447 (MH+); 1H NMR (400 MHz, CD3OD) δ 7.40 (d, J=6.7 Hz, 1H), 7.31 (d, J=8.2 Hz, 2H), 7.29-7.20 (m, 5H), 6.96 (d, J=8.2 Hz, 2H), 6.57-6.52 (m, 2H), 5.49 (q, J=7.0 Hz, 1H), 2.98-2.93 (m, 1H), 2.47-2.34 (m, 2H), 2.16-2.09 (m, 1H), 2.07 (s, 2H), 1.45 (d, J=7.0 Hz, 3H), 1.19 (s, 3H), 0.87 (s, 3H).
Reaction SMILES: [H][H].[Cl:3][C:4]1[CH:30]=[CH:29][C:7]([C:8]([C:10]2[C:11]([CH3:28])=[C:12]([CH:16]=[CH:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][C:25]([OH:27])=[O:26])[CH:13]=[CH:14][CH:15]=2)=[O:9])=[CH:6][CH:5]=1>C(O)C.[Pt]=O>[Cl:3][C:4]1[CH:5]=[CH:6][C:7]([C:8]([C:10]2[C:11]([CH3:28])=[C:12]([CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][C:25]([OH:27])=[O:26])[CH:13]=[CH:14][CH:15]=2)=[O:9])=[CH:29][CH:30]=1
Reactant: Cc1c(C=CCCCCCCCC(=O)O)cccc1C(=O)c1ccc(Cl)cc1
Reactant: [H][H]
Agent: O=[Pt]
Solvent: CCO
Product: Cc1c(CCCCCCCCCC(=O)O)cccc1C(=O)c1ccc(Cl)cc1
Yield: 80.3 %

Procedure:
Hydrogen was passed through a solution of 6.89 g of the acid of Step A in 100 ml of ethanol in the presence of 140 mg of platinum oxide for 45 minutes and the mixture was then filtered. The filtrate was evaporated to dryness and the residue was treated with ether in the presence of activated carbon and was crystallized from a 1:1 isopropyl ether-petroleum ether mixture to obtain 5.56 g of 10-[3'-(4-chlorobenzoyl)-2'-methyl-phenyl]-decanoic acid melting at 74° C.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[N:8]1[CH2:13][CH2:12][CH2:11][C@H:10]([NH:14]C(=O)OC(C)(C)C)[CH2:9]1.C(OC([NH:29][C:30]1[S:34][C:33]([C:35]2[C:40]([F:41])=[CH:39][CH:38]=[CH:37][N:36]=2)=[N:32][C:31]=1[C:42](O)=[O:43])=O)(C)(C)C>>[NH2:29][C:30]1[S:34][C:33]([C:35]2[C:40]([F:41])=[CH:39][CH:38]=[CH:37][N:36]=2)=[N:32][C:31]=1[C:42]([NH:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[N:8]1[CH2:13][CH2:12][CH2:11][C@H:10]([NH2:14])[CH2:9]1)=[O:43]
Reactant: CC(C)(C)OC(=O)Nc1sc(-c2ncccc2F)nc1C(=O)O
Reactant: CC(C)(C)OC(=O)N[C@H]1CCCN(c2ccncc2N)C1
Product: Nc1sc(-c2ncccc2F)nc1C(=O)Nc1cnccc1N1CCC[C@H](N)C1
Yield: 55 %

Procedure:
Followed the procedure as described in EXAMPLE 1, starting with (S)-tert-butyl 1-(3-aminopyridin-4-yl)piperidin-3-ylcarbamate and 5-(tert-butoxycarbonylamino)-2-(3-fluoropyridin-2-yl)thiazole-4-carboxylic acid. Obtained the desired product as a white solid (50 mg, 55%). 1H NMR (500 MHz, DMSO) δ 9.40 (s, 1H), 8.44 (d, J=4.6 Hz, 1H), 8.21 (d, J=5.2 Hz, 1H), 7.86 (dd, J=25.8, 14.5 Hz, 3H), 7.58-7.40 (m, 1H), 7.13 (d, J=5.2 Hz, 1H), 3.09 (d, J=9.1 Hz, 1H), 3.00 (d, J=12.6 Hz, 2H), 2.59 (dd, J=26.2, 15.4 Hz, 1H), 2.37 (t, J=10.1 Hz, 1H), 1.90 (s, 1H), 1.78 (d, J=15.8 Hz, 2H), 1.14 (d, J=8.7 Hz, 1H). ESIMS m/z=414.1 (M+1).
Reaction SMILES: [Li+].CC([N-]C(C)C)C.[CH2:9]([O:11][C:12]([C:14]1[N:15]=[C:16]([Br:22])[N:17]([CH:19]([CH3:21])[CH3:20])[CH:18]=1)=[O:13])[CH3:10].[C:23]([C:25]1[CH:32]=[CH:31][C:28]([CH:29]=[O:30])=[CH:27][CH:26]=1)#[N:24]>C1COCC1>[CH2:9]([O:11][C:12]([C:14]1[N:15]=[C:16]([Br:22])[N:17]([CH:19]([CH3:21])[CH3:20])[C:18]=1[CH:29]([C:28]1[CH:31]=[CH:32][C:25]([C:23]#[N:24])=[CH:26][CH:27]=1)[OH:30])=[O:13])[CH3:10]
Reactant: N#Cc1ccc(C=O)cc1
Reactant: CCOC(=O)c1cn(C(C)C)c(Br)n1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CCOC(=O)c1nc(Br)n(C(C)C)c1C(O)c1ccc(C#N)cc1
Temperature: -70 °C
Reaction time: 1 h
Yield: 66.5 %

Procedure:
LDA (2 M in THF, 53.6 mL, 107 mmol) was added slowly (over 30 min) to a cold (−78° C.) solution of intermediate A (20 g, 77 mmol) in THF (400 mL) (during the addition, the temperature raised to −70° C.). The mixture was stirred for 1 h at −78° C. A solution of 4-cyanobenzaldehyde (14 g, 107 mmol) in THF (100 mL) was added slowly. The reaction mixture was stirred for 30 min at −78° C., allowed to warm to −20° C. over 1 h, quenched by addition of acetic acid (10 mL), diluted with EtOAc/water, and extracted with EtOAc. The organic extracts were washed with water and brine, dried (Na2SO4), filtered, and concentrated. The residue was purified by flash chromatography (hexane/EtOAc, 1:1), followed by trituration in EtOAc, to provide 20.1 g of the title compound. tR: 0.99 min (LC-MS 2); ESI-MS: 392.2/394.1 [M+H]+ (LC-MS 2); Rf=0.29 (hexane/EtOAc, 1:1).
Reaction SMILES: [BH4-].[Na+].[Cl:3][C:4]1[CH:23]=[CH:22][C:21](/[CH:24]=[C:25]2/[CH:26]=[N:27][CH2:28][CH2:29][CH2:30]/2)=[CH:20][C:5]=1[C:6]([NH:8][CH2:9][C:10]12[CH2:19][CH:14]3[CH2:15][CH:16]([CH2:18][CH:12]([CH2:13]3)[CH2:11]1)[CH2:17]2)=[O:7].Cl>CO>[Cl:3][C:4]1[CH:23]=[CH:22][C:21](/[CH:24]=[C:25]2/[CH2:26][NH:27][CH2:28][CH2:29][CH2:30]/2)=[CH:20][C:5]=1[C:6]([NH:8][CH2:9][C:10]12[CH2:11][CH:12]3[CH2:13][CH:14]([CH2:15][CH:16]([CH2:18]3)[CH2:17]1)[CH2:19]2)=[O:7]
Reactant: O=C(NCC12CC3CC(CC(C3)C1)C2)c1cc(/C=C2/C=NCCC2)ccc1Cl
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: O=C(NCC12CC3CC(CC(C3)C1)C2)c1cc(/C=C2\CCCNC2)ccc1Cl
Temperature: 25 °C
Reaction time: 4 h
Yield: 51.9 %

Procedure:
Sodium borohydride (0.009 g) in methanol (0.5 ml) was added to a solution of 2-chloro-5-[(E)-(5,6-dihydro-3(4H)-pyridinylidene)methyl]-N-(tricyclo[3.3.1.13,7]dec-1-ylmethyl)-benzamide (0.046 g, Example 88a,) in methanol (1.5 ml). The reaction mixture was stirred for 4 h under an atmosphere of nitrogen at room temperature. Concentrated hydrochloric acid (0.01 ml) was added and the mixture was evaporated under reduced pressure. An aqueous solution of sodium hydroxide (2M, 2 ml) was added to rebasify the residue followed by water (10 ml) and dichloromethane (10 ml). The layers were partitioned and the aqueous layer was extracted further with dichloromethane (2×10 ml). The organic extracts were combined, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure to give the title compound as a white powder (0.024 g).
Reaction SMILES: C([O:5][C:6](=[O:30])[CH2:7][N:8]1[C:12]2[CH:13]=[C:14]([Cl:17])[CH:15]=[CH:16][C:11]=2[N:10]([S:18]([C:21]2[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][CH:22]=2)(=[O:20])=[O:19])[C:9]1=[O:29])(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[Cl:17][C:14]1[CH:15]=[CH:16][C:11]2[N:10]([S:18]([C:21]3[CH:22]=[CH:23][C:24]([O:27][CH3:28])=[CH:25][CH:26]=3)(=[O:20])=[O:19])[C:9](=[O:29])[N:8]([CH2:7][C:6]([OH:30])=[O:5])[C:12]=2[CH:13]=1
Reactant: COc1ccc(S(=O)(=O)n2c(=O)n(CC(=O)OC(C)(C)C)c3cc(Cl)ccc32)cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COc1ccc(S(=O)(=O)n2c(=O)n(CC(=O)O)c3cc(Cl)ccc32)cc1
Temperature: 25 °C

Procedure:
1.10 g (2.43 mmol) of tert-butyl[6-chloro-3-(4-methoxybenzenesulfonyl)-2-oxo-2,3-dihydrobenzimidazol-1-yl]acetate (XIIg) were dissolved in dichloromethane (40 ml) and, while stirring at room temperature, trifluoroacetic acid (20 ml) was added. The reaction solution was stirred for 2 h and then the solvent and excess trifluoroacetic acid were removed in vacuo. The residue was taken up again in toluene, concentrated in vacuo and then dried in vacuo. Yield: 0.82 g (95%) of white solid
Reaction SMILES: [C:1]1([CH3:11])[CH:6]=[CH:5][C:4]([S:7]([OH:10])(=[O:9])=[O:8])=[CH:3][CH:2]=1.[Cl:12]Cl>>[Cl:12][C:2]1[CH:3]=[C:4]([S:7]([OH:10])(=[O:8])=[O:9])[CH:5]=[CH:6][C:1]=1[CH3:11]
Reactant: ClCl
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Product: Cc1ccc(S(=O)(=O)O)cc1Cl

Procedure:
In a typical process for preparing an aqueous solution of an alkali metal salt of 2-chloro-5-amino-4-toluene sulfonic acid, toluene is first reacted with sulfuric acid to produce para-toluene sulfonic acid as the principal product. The sulfonic acid is then reacted with chlorine to produce 2-chloro-para-toluene sulfonic acid as a principal product which is reacted with a mixture of 50 percent nitric acid and 50 percent sulfuric acid to produce 2-chloro-5-nitro-para-toluene sulfonic acid. The nitrated product is then neutralized in an aqueous lime slurry which is subsequently filtered. The aqueous nitrated product is then iron reduced to form an amine and the reaction mixture is neutralized with sodium hydroxide to a pH of about 9.5-10.5 and the resulting solution is subsequently filtered.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:12]([CH2:16][CH:17]2[CH2:21][CH2:20][CH2:19][CH2:18]2)[C:13]([OH:15])=O)[CH:5]=[CH:6][C:7]=1[S:8]([CH3:11])(=[O:10])=[O:9].C(Cl)(=O)C(Cl)=O.C(N(CC)C(C)C)(C)C.[NH2:37][C:38]1[CH:47]=[CH:46][C:45]2[C:40](=[CH:41][CH:42]=[CH:43][CH:44]=2)[N:39]=1>C(Cl)Cl.CN(C)C=O.O1CCCC1>[Br:1][C:2]1[CH:3]=[C:4]([CH:12]([CH2:16][CH:17]2[CH2:21][CH2:20][CH2:19][CH2:18]2)[C:13]([NH:37][C:38]2[CH:47]=[CH:46][C:45]3[C:40](=[CH:41][CH:42]=[CH:43][CH:44]=3)[N:39]=2)=[O:15])[CH:5]=[CH:6][C:7]=1[S:8]([CH3:11])(=[O:9])=[O:10]
Reactant: Nc1ccc2ccccc2n1
Reactant: CS(=O)(=O)c1ccc(C(CC2CCCC2)C(=O)O)cc1Br
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CS(=O)(=O)c1ccc(C(CC2CCCC2)C(=O)Nc2ccc3ccccc3n2)cc1Br
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 91.5 %

Procedure:
A solution of 2-(3-bromo-4-methanesulfonyl-phenyl)-3-cyclopentyl-propionic acid (prepared as in Example 24, 100 mg, 0.266 mmol) in methylene chloride (8 mL) was treated with dry N,N-dimethylformamide (2 drops). The reaction mixture was cooled to 0° C. and then treated dropwise with a 2M solution of oxalyl chloride in methylene chloride (0.15 mL, 0.29 mmol). The reaction mixture was stirred at 0° C. for 10 min and then stirred at 25° C. for 30 min. The reaction mixture was then treated with N,N-diisopropylethylamine (0.11 mL, 0.63 mmol) followed by a solution of 2-aminoquinoline (92 mg, 0.56 mmol) in dry tetrahydrofuran (3 mL). The resulting reaction mixture was stirred at 25° C. for 17 h. The reaction mixture was concentrated in vacuo. The resulting residue was adsorbed onto silica gel (Merck Silica gel 60, 230-400 mesh) and then purified via Biotage chromatography (FLASH 40S, Silica, 3/2 hexanes/ethyl acetate) to afford the 2-(3-bromo-4-methanesulfonyl-phenyl)-3-cyclopentyl-N-quinolin-2-yl-propionamide (122 mg, 92%) as a white foam; mp 95-100° C. EI-HRMS m/e calcd for C24H25BrN2O3S (M+) 500.0769, found 500.0775.