Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([NH:10][CH:11]([CH3:13])[CH3:12])[C:3]=1[C:4]#[N:5].[S:14](Cl)(=[O:17])(=[O:16])[NH2:15]>CC(N(C)C)=O.O>[S:14]([NH2:1])([NH2:15])(=[O:17])=[O:16].[NH2:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([NH:10][CH:11]([CH3:13])[CH3:12])[C:3]=1[C:4]#[N:5]
Reactant: NS(=O)(=O)Cl
Agent: CC(C)Nc1cccc(N)c1C#N
Solvent: CC(=O)N(C)C
Solvent: O
Product: NS(N)(=O)=O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 2-amino-6-(isopropylamino)benzonitrile (Example 90b) (0.09 g, 0.54 mmol) in DMA (3 mL) was added sulfamoyl chloride (0.19 g, 1.62 mmol). The reaction mixture was stirred at room temperature under nitrogen for 2 hours, diluted with H2O (5 mL) and extracted with EtOAc. Solvents of the combined organic phases were evaporated and the residue was purified by preparative thin layer chromatography using a Hexane/EtOAc (3:2) solution as eluant, to give 2-amino-6-(isopropylamino)benzonitrile sulfamide (0.14 g). MS 255 (MH+).
Reaction SMILES: [C:1]([N:11]1[CH2:15][CH2:14][C@H:13]([NH:16][CH:17]2[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]2)[CH2:12]1)([O:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:2].[C:23](Cl)(=[O:27])[CH:24]([CH3:26])[CH3:25]>C(Cl)Cl>[C:1]([N:11]1[CH2:15][CH2:14][C@H:13]([N:16]([CH:17]2[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]2)[C:23](=[O:27])[CH:24]([CH3:26])[CH3:25])[CH2:12]1)([O:3][CH2:4][C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=1)=[O:2]
Reactant: O=C(OCc1ccccc1)N1CC[C@H](NC2CCCCC2)C1
Reactant: CC(C)C(=O)Cl
Solvent: ClCCl
Product: CC(C)C(=O)N(C1CCCCC1)[C@H]1CCN(C(=O)OCc2ccccc2)C1
Temperature: 25 °C
Reaction time: 12 h
Yield: 96 %

Procedure:
To a solution of (3S)-1-Cbz-3-(cyclohexylamino)pyrolidine (4.75 g, 15.1 mmol) and TEA (4.26 mL, 30.2 mmol) in DCM (50 mL) was added dropwise isobutyryl chloride (1.15 mL, 60.3 mmol). The reaction mixture was stirred at rt for 12 h and quenched with 1N HCl solution. The organic material was extracted with DCM (50 mL×2) followed by EtOAc (50 mL×2), and the extracts were washed with a saline, dried over MgSO4, and concentrated in vacuo. The residue was purified by column chomatography (EtOAc/Hex=1/3) to give the title compound (5.40 g, 96.7%).
Reaction SMILES: [CH2:1]1[CH2:8][CH:7]([NH2:9])[C:5](=[O:6])[NH:4][CH2:3][CH2:2]1.C(N(CC)CC)C.[CH3:17][O:18][C:19]1[CH:20]=[CH:21][C:22]2[O:26][C:25]([C:27](Cl)=[O:28])=[CH:24][C:23]=2[CH:30]=1>ClCCl>[CH3:17][O:18][C:19]1[CH:20]=[CH:21][C:22]2[O:26][C:25]([C:27]([NH:9][CH:7]3[CH2:8][CH2:1][CH2:2][CH2:3][NH:4][C:5]3=[O:6])=[O:28])=[CH:24][C:23]=2[CH:30]=1
Reactant: COc1ccc2oc(C(=O)Cl)cc2c1
Reactant: NC1CCCCNC1=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1ccc2oc(C(=O)NC3CCCCNC3=O)cc2c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 61.3 %

Procedure:
To a being cooled solution of DL-α-amino-ε-caprolactam (0.83 g) and triethylamine (1.1 ml) in dichloromethane (12 ml), a solution of (5-methoxybenzofuran-2-yl)carbonyl chloride (1.37 g) in dichloromethane (5 ml) was added dropwise below 10° C. After being stirred for 3 hours at ambient temperature, the appeared precipitates was collected by filtration to give DL-α-(5-methoxybenzofuran-2-yl)carbonylamino-ε-caprolactam (1.20 g).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][N:6]1[C:18]2[C:17]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[N:11]=[C:10]([NH2:19])[C:9]=2[N:8]=[CH:7]1.[CH2:20]([S:25][C:26]1[C:31]([C:32](Cl)=[O:33])=[CH:30][CH:29]=[CH:28][N:27]=1)[CH2:21][CH2:22][CH2:23][CH3:24]>>[NH2:19][C:10]1[C:9]2[N:8]=[CH:7][N:6]([CH2:5][CH2:4][CH2:3][CH2:2][NH:1][C:32](=[O:33])[C:31]3[CH:30]=[CH:29][CH:28]=[N:27][C:26]=3[S:25][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])[C:18]=2[C:17]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[N:11]=1
Reactant: CCCCCSc1ncccc1C(=O)Cl
Reactant: NCCCCn1cnc2c(N)nc3ccccc3c21
Product: CCCCCSc1ncccc1C(=O)NCCCCn1cnc2c(N)nc3ccccc3c21

Procedure:
According to the general method of Example 14, 1-(4-aminobutyl)-1H-imidazo[4,5-c]quinolin-4-amine and 2-(n-pentylthio)pyridine-3-carbonyl chloride were combined to provide N3-[4-(4-amino-1H-imidazo[4,5-c]quinolin-1-yl)butyl]-2-(pentylsulfanyl)nicotinamide as a tan powder, m.p. 158.0-161.0°C. 1H NMR (300 MHz, DMSO-d6) δ 8.47-8.41 (m, 2H), 8.21 (s, 1H), 8.06 (d, J=8.2 Hz, 1H), 7.63 (dd, J=8.3, 1.1 Hz, 1H), 7.54 (dd, J=7.6, 1.8 Hz, 1H), 7.47-7.41 (m, 1H), 7.26-7.21 (m, 1H), 7.08 (dd, J=7.5, 4.8 Hz, 1H), 6.57 (broad s, 2H), 4.64 (t, J=6.9 Hz, 2H), 3.27 (m, 2H), 2.98 (t, J=7.3 Hz, 2H), 1.96 (m, 2H), 1.62-1.46 (m, 4H), 1.35-1.20 (m, 4H), 0.83 (t, J=7.1 Hz, 3H); MS (EI) m/e 462.2196 (462.2202 calcd for C25H30N6OS).
Reaction SMILES: [CH:1]([C@H:4]1[NH:19][C:18](=[O:20])[C@@H:17]([CH2:21][S:22]C(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[NH:16][C:15](=[O:42])[C@@H:14]([CH:43]([CH3:45])[CH3:44])[NH:13][C:12](=[O:46])[CH2:11][C@@H:10](/[CH:47]=[CH:48]/[CH2:49][CH2:50][S:51]C(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[O:9][C:8](=[O:71])[CH2:7][NH:6][C:5]1=[O:72])([CH3:3])[CH3:2]>C(Cl)Cl.CO>[CH:1]([C@H:4]1[NH:19][C:18](=[O:20])[C@@H:17]2[NH:16][C:15](=[O:42])[C@@H:14]([CH:43]([CH3:45])[CH3:44])[NH:13][C:12](=[O:46])[CH2:11][C@@H:10]([CH:47]=[CH:48][CH2:49][CH2:50][S:51][S:22][CH2:21]2)[O:9][C:8](=[O:71])[CH2:7][NH:6][C:5]1=[O:72])([CH3:3])[CH3:2]
Reactant: CC(C)[C@H]1NC(=O)C[C@@H](/C=C/CCSC(c2ccccc2)(c2ccccc2)c2ccccc2)OC(=O)CNC(=O)[C@@H](C(C)C)NC(=O)[C@@H](CSC(c2ccccc2)(c2ccccc2)c2ccccc2)NC1=O
Agent: CC(C)[C@H]1NC(=O)C[C@H]2/C=C/CCSSC[C@@H](NC1=O)C(=O)N[C@H](C(C)C)C(=O)NCC(=O)O2
Solvent: ClCCl
Solvent: CO
Product: CC(C)[C@H]1NC(=O)C[C@H]2C=CCCSSC[C@@H](NC1=O)C(=O)N[C@H](C(C)C)C(=O)NCC(=O)O2

Procedure:
To a vigorously stirred solution of 12 (305 mg, 1.2 mmol) in CH2Cl2/MeOH (9:1, 280 mL) was added dropwise a solution of bis-trityl 8C (120 mg, 0.12 mmol) over 30 minutes. After a further 30 min the reaction was quenched by the addition of sodium thiosulfate (0.05M, 100 mL) followed by brine (10 mL). The organic phase was separated and the aqueous phase extracted with CH2Cl2 (3×15 mL). The combined organic phase was dried (MgSO4), filtered, and concentrated in vacuo to give a white solid. Purification by column chromatography on silica gel (1-4% MeOH/CH2Cl2) gave bicyclic depsipeptide 9C (60 mg, 0.12 mmol, 97%) as a white solid: [α]25D −105.7 (1:1 MeOH/CHCl3, c 0.15); 1H-NMR (400 MHz, CD3OD) δ 5.76-5.63 (m, 3H), 4.52 (dd, J=11.3, 4.7 Hz, 1H), 3.96 (d, J=5.1 Hz, 1H), 3.74 (d, J=17.5 Hz, 1H), 3.38 (d, J=10.9 Hz, 1H), 3.19-3.11 (m, 2H), 3.09-2.96 (m, 3H), 2.90 (dd, J=13.6, 2.5 Hz, 1H), 2.71-2.62 (m, 2H), 2.58-2.44 (m, 1H), 2.31-2.18 (m, 1H), 1.11 (d, J=7.0 Hz, 3H), 1.09 (d, J=7.0 Hz, 3H), 1.01 (d, J=6.6 Hz, 3H), 0.91 (d, J=6.6 Hz, 3H); 13C-NMR (100 MHz, CD3OD) δ 171.8 (C), 171.7 (C), 170.7 (C), 170.4 (C), 168.3 (C), 130.0 (CH), 129.6 (CH), 69.8 (CH), 64.6 (CH), 61.9 (CH), 54.8 (CH), 42.2 (CH2), 39.3 (CH2), 37.5 (CH2), 37.1 (CH2), 32.1 (CH2), 29.2 (CH), 27.3 (CH), 20.6 (CH3), 20.0 (CH3), 19.4 (CH3), 19.0 (CH3); LRMS (ES+) m/z 537 (100%, [M+Na]+), 515 (90%, [M+H]+).
Reaction SMILES: I([O-])(=O)(=O)=[O:2].[Na+].[CH2:7]([C@@:10]1([CH3:31])[CH2:15][C@H:14]([C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([Cl:22])[CH:17]=2)[C@@H:13]([C:23]2[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][CH:24]=2)[NH:12][C:11]1=[O:30])[CH:8]=C.C[Si](C=[N+]=[N-])(C)C.C([O:41][CH2:42]C)C>C(#N)C.C(OCC)(=O)C.O.O.[Ru](Cl)(Cl)Cl>[Cl:22][C:18]1[CH:17]=[C:16]([C@@H:14]2[C@@H:13]([C:23]3[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][CH:24]=3)[NH:12][C:11](=[O:30])[C@:10]([CH2:7][C:8]([O:41][CH3:42])=[O:2])([CH3:31])[CH2:15]2)[CH:21]=[CH:20][CH:19]=1
Reactant: [O-][I+3]([O-])([O-])[O-]
Reactant: C=CC[C@@]1(C)C[C@H](c2cccc(Cl)c2)[C@@H](c2ccc(Cl)cc2)NC1=O
Reactant: CCOCC
Agent: Cl[Ru](Cl)Cl
Agent: C[Si](C)(C)C=[N+]=[N-]
Agent: [Na+]
Solvent: CC#N
Solvent: O
Solvent: CCOC(C)=O
Product: COC(=O)C[C@@]1(C)C[C@H](c2cccc(Cl)c2)[C@@H](c2ccc(Cl)cc2)NC1=O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Sodium periodate (21.03 g, 98 mmol) was added slowly to a solution containing ruthenium(III) chloride hydrate (0.277 g, 1.229 mmol) and (3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methylpiperidin-2-one (4.6 g, 12.29 mmol; Example 71, step D) in acetonitrile (35.1 mL), ethyl acetate (35.1 mL) and water (52.7 mL) while maintaining a temperature below 20° C. The resulting mixture was then stirred for 2 h at room temperature. Next, the reaction was filtered and concentrated, and the resulting residue was further processed by dissolving in ethyl acetate. The organics were washed with water and brine, dried over MgSO4, filtered and concentrated. Next, the residue was dissolved in a small amount of a mixture of ether and methanol (1:1) and a 2M solution of (trimethylsilyl)diazomethane in diethyl ether (12.29 ml, 24.58 mmol) was added. This solution was then allowed to stir at ambient temperature overnight. The solution was concentrated and the resulting residue was purified on silica gel (eluent: hexane/ethyl acetate 0 to 100%, gradient elution) to give the title compound.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([O:9][CH3:10])=[CH:4][C:3]=1[NH:11][CH:12]1[CH2:17][CH2:16][N:15]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:14][CH2:13]1.[C:25](Cl)(Cl)=[O:26].C(N(CC)CC)C>ClCCl>[CH3:10][O:9][C:5]1[C:6]([Cl:8])=[CH:7][C:2]2[NH:1][C:25](=[O:26])[N:11]([CH:12]3[CH2:13][CH2:14][N:15]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:16][CH2:17]3)[C:3]=2[CH:4]=1
Reactant: O=C(Cl)Cl
Reactant: COc1cc(NC2CCN(C(=O)OC(C)(C)C)CC2)c(N)cc1Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1cc2c(cc1Cl)[nH]c(=O)n2C1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
1,1-Dimethylethyl 4-[(2-amino-4-chloro-5-methoxyphenyl)amino]-1-piperidinecarboxylate (D48) (280 mg) was dissolved in 5 ml of dichloromethane at 0° C. and phosgene (20% in toluene, 0.5 ml) and triethylamine (0.3 ml) were added and the mixture was stirred at 0° C. for 1 h, then washed with aqueous citric acid, then water, dried over MgSO4, filtered and evaporated The product was chromatographed on silica gel eluting with methanol-dichloromethane mixtures, crystallised from diethyl ether, and then further purified by MDAP to yield the title compound, 40 mg.
Reaction SMILES: FC(F)(F)S(OS(C(F)(F)F)(=O)=O)(=O)=O.O[CH:17]([O:19][C:20](=[O:23])[CH:21]=[CH2:22])[CH3:18].[CH2:24](N(CC)CC)C.[CH2:31]([OH:42])[CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][OH:41]>ClCCl>[OH:42][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][O:41][CH2:22][C:21](=[CH2:24])[C:20]([O:19][CH2:17][CH3:18])=[O:23]
Reactant: OCCCCCCCCCCO
Reactant: CCN(CC)CC
Reactant: C=CC(=O)OC(C)O
Agent: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Solvent: ClCCl
Product: C=C(COCCCCCCCCCCO)C(=O)OCC
Temperature: 0 °C
Reaction time: 0.75 h
Yield: 20 %

Procedure:
To a solution of 54.7 g trifluoromethanesulphonic anhydride in 210 ml dichloromethane a solution of 25 g (0.192 mol) α-hydroxyethylacrylate and 19.43 g (0.192 mol) triethylamine in 400 ml dichloromethane was added slowly, so that the temperature of the reaction mixture stays below 5° C. The solution was stirred for 45 min at 0° C. before it was added drop wise at room temperature to a solution of 60 g (0.344 mol) 1,10-decandiol in 400 ml dichloromethane. After the reaction mixture was stirred for 12 h at room temperature the solution was successively washed with 2×300 ml of an aqueous sodium carbonate solution (1 n) and 1×400 ml water. The organic layer was dried over magnesium sulphate and filtered. The raw product was prepurified by column chromatography on silica gel with ethyl acetate as eluens. After the raw product was stabilized with 113 mg BHT, it was finally purified by vacuum distillation (>150° C./0.028 mbar). This afforded 11.024 g (yield: 20%) of a clear, colourless product.
Reaction SMILES: [NH2:1][C:2]1[CH:21]=[CH:20][C:5]([O:6][C:7]2[CH:12]=[CH:11][N:10]=[C:9]([NH2:13])[C:8]=2[NH:14][C:15](=[O:19])[O:16][CH2:17][CH3:18])=[CH:4][C:3]=1[F:22].[H-].[Na+].[CH3:25]I>C1COCC1>[NH2:1][C:2]1[CH:21]=[CH:20][C:5]([O:6][C:7]2[CH:12]=[CH:11][N:10]=[C:9]([NH2:13])[C:8]=2[N:14]([CH3:25])[C:15](=[O:19])[O:16][CH2:17][CH3:18])=[CH:4][C:3]=1[F:22]
Reactant: CCOC(=O)Nc1c(Oc2ccc(N)c(F)c2)ccnc1N
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOC(=O)N(C)c1c(Oc2ccc(N)c(F)c2)ccnc1N
Temperature: 0 °C
Reaction time: 0.67 h

Procedure:
Ethyl 4-(4-amino-3-fluorophenoxy)-2-aminopyridin-3-yl-carbamate (6a) (480 mg, 1.6 mmol) was dissolved in dry THF (8 mL) and cooled at 0° C. Sodium hydride (60% in mineral oil, 80 mg, 2.0 mmol) was added, and the reaction mixture was stirred for 40 minutes at 0° C. Methyl iodide (130 μL, 1.8 mmol) was added at 0° C. The ice bath was removed, and the mixture was stirred at room temperature for 18 hours. The solvent was evaporated and the residue partitioned between DCM and distilled water. The organic layer was dried and evaporated, and the residue washed with diethyl ether to afford the title compound as a brown solid.
Reaction SMILES: [CH3:1][N:2]([CH3:20])[C:3]1[CH:8]=[C:7]([NH2:9])[CH:6]=[CH:5][C:4]=1[C:10]1[N:11]=[C:12]2[CH:17]=[CH:16][C:15](=[O:18])[N:14]=[C:13]2[N:19]=1.[C:21](OC(=O)C)(=[O:23])[CH3:22]>>[CH3:1][N:2]([CH3:20])[C:3]1[CH:8]=[C:7]([NH:9][C:21]([CH3:22])=[O:23])[CH:6]=[CH:5][C:4]=1[C:10]1[N:19]=[C:13]2[NH:14][C:15](=[O:18])[CH2:16][CH:17]=[C:12]2[N:11]=1
Reactant: CC(=O)OC(C)=O
Reactant: CN(C)c1cc(N)ccc1C1=NC2=NC(=O)C=CC2=N1
Product: CC(=O)Nc1ccc(C2=NC3=CCC(=O)NC3=N2)c(N(C)C)c1

Procedure:
A quantity of 0.6 gm of 2-(2-dimethylamino-4-amino-phenyl)imidazo[4,5-b]pyridin-5-one is refluxed with 20 ml of acetic anhydride for 30 minutes. After evaporation, 10 ml of concentrated ammnoia and then 20 ml of ice are added. The product precipitated is suction filtered and washed with water.
Reaction SMILES: C(N(CC)CC)C.Cl.Cl.Cl.[NH2:11][CH2:12][CH2:13][C:14]1[N:15]=[CH:16][N:17]([CH2:19][CH2:20][CH2:21][NH:22][C:23]([C:26]2[CH:31]=[CH:30][C:29]([Cl:32])=[CH:28][CH:27]=2)([CH3:25])[CH3:24])[CH:18]=1.[C:33](Cl)(=[O:40])[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1>ClCCl>[Cl:32][C:29]1[CH:30]=[CH:31][C:26]([C:23]([NH:22][CH2:21][CH2:20][CH2:19][N:17]2[CH:18]=[C:14]([CH2:13][CH2:12][NH:11][C:33](=[O:40])[C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)[N:15]=[CH:16]2)([CH3:25])[CH3:24])=[CH:27][CH:28]=1
Reactant: CC(C)(NCCCn1cnc(CCN)c1)c1ccc(Cl)cc1
Reactant: O=C(Cl)c1ccccc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(NCCCn1cnc(CCNC(=O)c2ccccc2)c1)c1ccc(Cl)cc1
Temperature: 0 °C

Procedure:
Triethylamine (0.46 g) was added to a stirred suspension of 3-[4-(2-aminoethyl)imidazol-1-yl]-N-[1-(4-chlorophenyl)-1-methylethyl]propylamine trihydrochloride, (0.65 g) in dichloromethane (25 ml) and the resulting solution cooled to 0° C. A solution of benzoyl chloride (0.21 g) in dichloromethane (10 ml) was added over 20 minutes at 0-5° C. with stirring. The mixture was stirred at ambient temperature for 2.5 hours. The solution was washed with sodium bicarbonate solution, then water, then dried, filtered and evaporated to give N-[2-(1-{3-[1-(4-chlorophenyl)-1-methylethylamino]propyl}imidazol-4-yl)ethyl]benzamide as an oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C@@H:9]2[CH2:14][CH2:13][CH2:12][CH2:11][C@@H:10]2[NH2:15])=[CH:5][C:4]=1[O:16][CH3:17].[CH3:18][O:19][C:20]([C:22]1[CH:30]=[CH:29][C:25]([C:26](Cl)=[O:27])=[CH:24][CH:23]=1)=[O:21]>C(Cl)Cl.C(N(CC)CC)C>[CH3:17][O:16][C:4]1[CH:5]=[C:6]([C@H:9]2[CH2:14][CH2:13][CH2:12][CH2:11][C@H:10]2[NH:15][C:26](=[O:27])[C:25]2[CH:24]=[CH:23][C:22]([C:20]([O:19][CH3:18])=[O:21])=[CH:30][CH:29]=2)[CH:7]=[CH:8][C:3]=1[O:2][CH3:1]
Reactant: COC(=O)c1ccc(C(=O)Cl)cc1
Reactant: COc1ccc([C@@H]2CCCC[C@@H]2N)cc1OC
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)c1ccc(C(=O)N[C@@H]2CCCC[C@@H]2c2ccc(OC)c(OC)c2)cc1
Reaction time: 1 h

Procedure:
2.6 g of (+/−)-cis-1,2-dimethoxy-4-(2-aminocyclohexyl)benzene are dissolved in 20 ml of methylene chloride and 1 ml of triethylamine. At RT, a solution of 2.4 g of 4-methoxycarbonylbenzoyl chloride in 30 ml of methylene chloride is added dropwise over a period of 3 h, and the mixture is stirred for 1 h and then extracted with 50 ml each of water, 2 N hydrochloric acid, sat. sodium bicarbonate solution and once more with water. The organic phase is dried with sodium sulfate, concentrated and crystallized from ethyl acetate. This gives 2.0 g (45.5% of Th.) of the title compound of m.p. 139-143° C.
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]([O:6][CH3:7])=[O:5].CCN(CC)CC.[C:15]1([CH:21]=O)[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>C(Cl)Cl>[CH:21](=[N:2][CH2:3][C:4]([O:6][CH3:7])=[O:5])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: COC(=O)CN
Reactant: O=Cc1ccccc1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)CN=Cc1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of methyl 2-aminoacetate hydrochloride (15.00 g, 116.00 mmol, 1.0 eq) in CH2Cl2 (150 mL) was added Et3N (20 mL, 143.3 mmol, 1.2 eq) and PhCHO (14.6 mL, 143.3 mmol, 1.2 eq) in turn. The reaction mixture was stirred at room temperature overnight, and concentrated in vacuo. The residue was diluted with EtOAc and filtered. The filtrate was concentrated in vacuo to afford the crude product methyl 2-(benzylideneamino)acetate, which was used for the next step without further purification. To a solution of methyl 2-(benzylideneamino)acetate in MeOH (200 mL) at −5° C. was added NaBH4 (2.80 g, 72.8 mmol, 0.55 eq) slowly. The reaction mixture was stirred at −5° C. for 2 h. The reaction mixture was then quenched with water and extracted with EtOAc (100 mL×3). The combined organic phases were washed with water followed by brine, dried over anhydrous Na2SO4 and concentrated in vacuo. The residue was purified by a silica gel column chromatography (20:1 (v/v) PE/EtOAc) to afford the title compound as colorless oil (21.30 g, 99%).
Reaction SMILES: CS(C1C=CC(N2CCCC2)=C(C=1)C(O)=O)(=O)=O.Cl[C:20]1[CH:28]=[CH:27][C:26]([S:29]([CH3:32])(=[O:31])=[O:30])=[CH:25][C:21]=1[C:22]([OH:24])=[O:23].[OH:33][CH:34]1[CH2:39][CH2:38][CH2:37][NH:36][CH2:35]1>>[OH:33][CH:34]1[CH2:39][CH2:38][CH2:37][N:36]([C:20]2[CH:28]=[CH:27][C:26]([S:29]([CH3:32])(=[O:31])=[O:30])=[CH:25][C:21]=2[C:22]([OH:24])=[O:23])[CH2:35]1
Reactant: OC1CCCNC1
Reactant: CS(=O)(=O)c1ccc(Cl)c(C(=O)O)c1
Agent: CS(=O)(=O)c1ccc(N2CCCC2)c(C(=O)O)c1
Product: CS(=O)(=O)c1ccc(N2CCCC(O)C2)c(C(=O)O)c1
Yield: 9 %

Procedure:
The title compound was synthesised according to the procedure described for the synthesis of 5-Methanesulfonyl-2-pyrrolidin-1-yl-benzoic acid (Example Y) from 2-Chloro-5-methanesulfonyl-benzoic acid and rac-3-hydroxy-piperidine and obtained in 9% yield. MS (m/e): 298.1 (M−H 100%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH:7]([CH2:12][OH:13])[CH2:6]2.[C:14]1([CH3:24])[CH:19]=[CH:18][C:17]([S:20](Cl)(=[O:22])=[O:21])=[CH:16][CH:15]=1.C(N([CH2:30][CH3:31])CC)C.Cl>C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[N:8]([S:20]([C:17]1[CH:18]=[CH:19][C:14]([CH3:24])=[CH:15][CH:16]=1)(=[O:22])=[O:21])[CH:7]([CH2:12][O:13][S:20]([C:17]1[CH:18]=[CH:19][C:30]([CH3:31])=[CH:15][CH:16]=1)(=[O:22])=[O:21])[CH2:6]2
Reactant: COc1ccc2c(c1)CC(CO)N2
Reactant: CCN(CC)CC
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: Cl
Solvent: ClCCl
Product: COc1ccc2c(c1)CC(COS(=O)(=O)c1ccc(C)cc1)N2S(=O)(=O)c1ccc(C)cc1
Yield: 76.1 %

Procedure:
(RS)-(5-methoxy-2,3-dihydro-1H-indol-2-yl)-methanol (100 mg, 0.46 mmol), p-toluenesulfonyl chloride (177 mg, 0.93 mmol), triethylamine (0.21 ml, 1.48 mmol) and N,N-dimethylamino pyridine (2 mg) were stirred for 18 hr at RT in CH2Cl2 (5 ml). 1N HCl (10 ml) was added, the mixture extracted with CH2Cl2 (2×25 ml) and the extracts washed with satd. NaCl solution (20 ml) and dried (Na2SO4). The crude material was chromatographed over SiO2 (Merck 230-400 mesh) eluting with EtOAc-cyclohexane-Et3N (9:10:1) to afford the title compound as a yellow oil (172.8 mg, 0.35 mmol, 76%), MS: m/e=488.0 (M+H+).
Reaction SMILES: C[O:2][C:3](=[O:35])[C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11](=[O:34])[CH:12]([C:19]2[CH:24]=[CH:23][C:22]([NH:25]C(C3C=NC=CC=3)=O)=[CH:21][CH:20]=2)[CH2:13][CH:14]2[CH2:18][CH2:17][CH2:16][CH2:15]2)=[N:6][CH:5]=1.[OH-:36].[Li+].[OH2:38]>O1CCCC1>[CH:14]1([CH2:13][CH:12]([C:19]2[CH:24]=[CH:23][C:22]([N+:25]([O-:38])=[O:36])=[CH:21][CH:20]=2)[C:11]([NH:10][C:7]2[CH:8]=[CH:9][C:4]([C:3]([OH:2])=[O:35])=[CH:5][N:6]=2)=[O:34])[CH2:18][CH2:17][CH2:16][CH2:15]1
Reactant: COC(=O)c1ccc(NC(=O)C(CC2CCCC2)c2ccc(NC(=O)c3cccnc3)cc2)nc1
Reactant: [OH-]
Reactant: O
Agent: [Li+]
Solvent: C1CCOC1
Product: O=C(O)c1ccc(NC(=O)C(CC2CCCC2)c2ccc([N+](=O)[O-])cc2)nc1
Temperature: 25 °C
Reaction time: 20 h
Yield: 7.5 %

Procedure:
A solution of 6-(3-cyclopentyl-2-{4-[(pyridine-3-carbonyl)-amino]-phenyl}-propionylamino)-nicotinic acid methyl ester (prepared in Example 16, 87.2 mg, 0.18 mmol) in tetrahydrofuran (8 mL) and water (2 mL) was treated with lithium hydroxide (17.0 mg, 0.41 mmol). The reaction was stirred at 25° C. for 20 h. At this time, the reaction was concentrated in vacuo. The residue was diluted with water (25 mL) and extracted with diethyl ether (1×20 mL). The aqueous layer was acidified to pH=1 with a 3N aqueous hydrochloric acid solution and was extracted with methylene chloride (3×50 mL). The combined organic extracts were washed with water (1×50 mL) and a saturated aqueous sodium chloride solution (2×50 mL), dried over magnesium sulfate, filtered, and concentrated in vacuo. High pressure liquid chromatography (Chromegasphere SI-60, 10 μM, 60 Å, 25 cm×23 cm ID, 100% ethyl acetate with acetic acid) afforded 6-[3-cyclopentyl-2-(4-nitro-phenyl)-propionylamino]-nicotinic acid (6.4 mg, 7.5%) as a pale yellow oil: EI-HRMS m/e calcd for C16H26N4O4 (M+) 458.1954, found 458.1967.
Reaction SMILES: [CH:1]1([NH:4][CH2:5][CH2:6][CH2:7][NH:8][C:9]2[CH:14]=[CH:13][C:12]([S:15]([NH2:18])(=[O:17])=[O:16])=[CH:11][C:10]=2[N+:19]([O-:21])=[O:20])[CH2:3][CH2:2]1.FC(F)(F)S(O[CH2:28][C:29]([F:32])([F:31])[F:30])(=O)=O.C(N(CC)C(C)C)(C)C>ClCCl>[CH:1]1([N:4]([CH2:28][C:29]([F:32])([F:31])[F:30])[CH2:5][CH2:6][CH2:7][NH:8][C:9]2[CH:14]=[CH:13][C:12]([S:15]([NH2:18])(=[O:16])=[O:17])=[CH:11][C:10]=2[N+:19]([O-:21])=[O:20])[CH2:3][CH2:2]1
Reactant: NS(=O)(=O)c1ccc(NCCCNC2CC2)c([N+](=O)[O-])c1
Reactant: O=S(=O)(OCC(F)(F)F)C(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: NS(=O)(=O)c1ccc(NCCCN(CC(F)(F)F)C2CC2)c([N+](=O)[O-])c1
Reaction time: 8 h

Procedure:
To a solution of EXAMPLE 308A (314 mg) in dichloromethane (6 mL) was added 2,2,2-trifluoroethyl trifluoromethanesulfonate (255 mg) and N,N-diisopropylethylamine (258 mg). The mixture was stirred overnight. The mixture was diluted with dichloromethane (300 mL) and washed with aqueous NaHCO3, water, brine and dried over Na2SO4. Filtration and evaporation of solvent gave the title compound.
Reaction SMILES: CS([O-])(=O)=O.[F:6][C:7]([F:33])([C:18]1N2N=C(C3C=NN(C)C=3)C=CC2=[N:20][N:19]=1)[C:8]1[CH:9]=[C:10]2[C:15](=[CH:16][CH:17]=1)[N:14]=[CH:13][CH:12]=[CH:11]2.C(=O)([O-])[O-:35].[Na+].[Na+]>C(OCC)(=O)C.O>[F:6][C:7]([F:33])([C:8]1[CH:9]=[C:10]2[C:15](=[CH:16][CH:17]=1)[N:14]=[CH:13][CH:12]=[CH:11]2)[C:18]([NH:19][NH2:20])=[O:35]
Reactant: Cn1cc(-c2ccc3nnc(C(F)(F)c4ccc5ncccc5c4)n3n2)cn1
Reactant: O=C([O-])[O-]
Agent: CS(=O)(=O)[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Product: NNC(=O)C(F)(F)c1ccc2ncccc2c1

Procedure:
Methanesulphonate (mesylate) salt of the compound of formula (I) (8.7 g) is dissolved in ethyl acetate/water mixture (50/50 vol/vol; 400 mL). Addition of sodium carbonate (2.5 g) liberates the free base form of the compound of formula (I) which crystallises from the solvent mixture. The solids are filtered, washed and dried at 50° C. to provide 6.53 g of Form III.