Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:41]=[CH:40][CH:39]=[CH:38][C:4]=1[CH2:5][NH:6][C:7]([C:9]1[N:13]([C:14]2[N:19]=[C:18]([CH2:20][NH:21][C:22](=[O:33])[C@@H:23]([NH:25]C(=O)OC(C)(C)C)[CH3:24])[CH:17]=[CH:16][CH:15]=2)[N:12]=[C:11]([C:34]([F:37])([F:36])[F:35])[CH:10]=1)=[O:8].FC(F)(F)C(O)=O>C(Cl)Cl>[NH2:25][C@@H:23]([CH3:24])[C:22]([NH:21][CH2:20][C:18]1[N:19]=[C:14]([N:13]2[C:9]([C:7]([NH:6][CH2:5][C:4]3[CH:38]=[CH:39][CH:40]=[CH:41][C:3]=3[O:2][CH3:1])=[O:8])=[CH:10][C:11]([C:34]([F:35])([F:37])[F:36])=[N:12]2)[CH:15]=[CH:16][CH:17]=1)=[O:33]
Reactant: COc1ccccc1CNC(=O)c1cc(C(F)(F)F)nn1-c1cccc(CNC(=O)[C@H](C)NC(=O)OC(C)(C)C)n1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COc1ccccc1CNC(=O)c1cc(C(F)(F)F)nn1-c1cccc(CNC(=O)[C@H](C)N)n1
Temperature: 21 °C
Reaction time: 2 h
Yield: 69 %

Procedure:
To a stirred solution of 50 (28 mg, 0.049 mmol) in CH2Cl2 (1 mL) was added trifluoroacetic acid (0.056 mL, 0.728 mmol). The resulting solution was allowed to stir at 21° C. for 2 h and evaporated to dryness. Water was added and the precipitate was removed by filtration. The aqueous phase was then lyophilized. The title product 51 (16.1 mg, 56.1% yield) was isolated as a white solid. 1H NMR: (CD3OD) o(ppm): 7.99 (t, 1H, J=8.0 Hz), 7.73 (d, 1H, J=8.0 Hz), 7.38 (d, 1H, J=7.6 Hz), 7.26 (d, 2H, J=7.6 Hz), 7.09 (s, 1H), 6.96 (d, 1H, J=7.6 Hz), 6.91 (t, 1H, J=7.6 Hz), 4.51 (dd, 2H, J=15.2, 23.6 Hz), 4.32 (dd, 2H, J=16, 54.4 Hz), 3.95 (q, 1H, J=7.2 Hz), 3.80 (s, 3H), 1.51 (d, 3H, J=6.8 Hz). LRMS (ESI): calc. 476.5; found 477.5 (MH)+.
Reaction SMILES: [NH:1]([C:41]([O:43][C:44]([CH3:47])([CH3:46])[CH3:45])=[O:42])[C@H:2]([C:8]([NH:10][C@H:11]([C:23]([NH:25][C@H:26]([C:31]([O:33]CC1C=CC=CC=1)=[O:32])[CH2:27][CH:28]([CH3:30])[CH3:29])=[O:24])[CH2:12][CH2:13][C:14](=[O:22])[O:15][CH:16]1[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1)=[O:9])[CH2:3][CH2:4][C:5](=[O:7])[NH2:6].C(OCC)C.CCCCCC>C1COCC1.[C].[Pd]>[NH:1]([C:41]([O:43][C:44]([CH3:46])([CH3:45])[CH3:47])=[O:42])[C@H:2]([C:8]([NH:10][C@H:11]([C:23]([NH:25][C@H:26]([C:31]([OH:33])=[O:32])[CH2:27][CH:28]([CH3:30])[CH3:29])=[O:24])[CH2:12][CH2:13][C:14](=[O:22])[O:15][CH:16]1[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1)=[O:9])[CH2:3][CH2:4][C:5](=[O:7])[NH2:6]
Reactant: CC(C)C[C@H](NC(=O)[C@H](CCC(=O)OC1CCCCC1)NC(=O)[C@H](CCC(N)=O)NC(=O)OC(C)(C)C)C(=O)OCc1ccccc1
Agent: [Pd]
Solvent: CCOCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CC(C)C[C@H](NC(=O)[C@H](CCC(=O)OC1CCCCC1)NC(=O)[C@H](CCC(N)=O)NC(=O)OC(C)(C)C)C(=O)O
Yield: 98.5 %

Procedure:
21.0 Grams of Boc-Gln-Glu(OcHex)-Leu-OBzl was dissolved in 200 ml of THF, and the solution was subjected to catalytic reduction in the presence of 2.00 g of 5%-palladium-carbon as the catalyst. After the reduction was finished, the catalyst was removed by filtration, and the filtrate was concentrated under reduced pressure. To the residue thus obtained was added diethyl ether-n-hexane to crystallize to obtaine 17.86 g (yield: 98.5%) of the above-mentioned objective product.
Reaction SMILES: [CH:1]1([N:6]2[CH2:12][C:11]3([CH2:15][CH2:14][CH2:13]3)[C:10](=[O:16])[N:9]([CH3:17])[C:8]3[CH:18]=[N:19][C:20]([NH:22][C:23]4[CH:31]=[CH:30][C:26]([C:27](O)=[O:28])=[CH:25][C:24]=4[O:32][CH3:33])=[N:21][C:7]2=3)[CH2:5][CH2:4][CH2:3][CH2:2]1.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.Cl.Cl.[NH2:67][CH:68]1[CH:73]2[CH2:74][CH2:75][N:70]([CH2:71][CH2:72]2)[CH2:69]1>CN(C=O)C>[CH:1]1([N:6]2[CH2:12][C:11]3([CH2:13][CH2:14][CH2:15]3)[C:10](=[O:16])[N:9]([CH3:17])[C:8]3[CH:18]=[N:19][C:20]([NH:22][C:23]4[CH:31]=[CH:30][C:26]([C:27]([NH:67][CH:68]5[CH:73]6[CH2:74][CH2:75][N:70]([CH2:71][CH2:72]6)[CH2:69]5)=[O:28])=[CH:25][C:24]=4[O:32][CH3:33])=[N:21][C:7]2=3)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: COc1cc(C(=O)O)ccc1Nc1ncc2c(n1)N(C1CCCC1)CC1(CCC1)C(=O)N2C
Reactant: NC1CN2CCC1CC2
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COc1cc(C(=O)NC2CN3CCC2CC3)ccc1Nc1ncc2c(n1)N(C1CCCC1)CC1(CCC1)C(=O)N2C
Temperature: 25 °C
Reaction time: 3 h

Procedure:
4-(9′-Cyclopentyl-5′-methyl-6′-oxo-5′,6′,8′,9′-tetrahydrospiro[cyclobutane-1,7′-pyrimido[4,5-b][1,4]diazepine]-2′-ylamino)-3-methoxybenzoic acid (Intermediate 7) (15 mg, 0.033 mmol), DIPEA (12 μl, 0.066 mmol, 2 eq) and TBTU (12 mg, 0.036 mmol, 1.1 eq) were added to 0.5 mL DMF and the resulting solution stirred at rt for 5 min before the addition of 3-aminoquinuclidine dihydrochloride (8 mg, 0.04 mmol, 1.2 eq) and DIPEA (13 μL). The RM was then stirred at rt for 3 hours before purifying by preparative RP-HPLC-MS (Preparative—2) to provide (±)-4-(9′-cyclopentyl-5′-methyl-6′-oxo-5′,6′,8′,9′-tetrahydrospiro[cyclobutane-1,7′-pyrimido[4,5-b][1,4]diazepine]-2′-ylamino)-3-methoxy-N-(quinuclidin-3-yl)benzamide.
Reaction SMILES: [SH:1][C:2]1[N:7]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([C:14]([F:17])([F:16])[F:15])[CH:9]=2)[CH:5]=[CH:4][N:3]=1.[OH-].[Na+].[CH3:20]I>>[CH3:20][S:1][C:2]1[N:7]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([C:14]([F:17])([F:15])[F:16])[CH:9]=2)[CH:5]=[CH:4][N:3]=1
Reactant: FC(F)(F)c1cccc(-c2ccnc(S)n2)c1
Reactant: CI
Agent: [Na+]
Agent: [OH-]
Product: CSc1nccc(-c2cccc(C(F)(F)F)c2)n1
Temperature: 25 °C

Procedure:
A solution of 4.75 g. of 2-mercapto-4-(m-trifluoromethylphenyl)pyrimidine in 50 ml. of 1 N sodium hydroxide is cooled to near 0° C. in an ice bath and 2.90 g. of methyliodide is added. After the reaction mixture is allowed to warm to room temperature, the product is removed by filtration, m.p. 89°-90° C.
Reaction SMILES: [CH:1]1([C@H:6]([N:11]=[C:12]=[O:13])[C:7]([O:9][CH3:10])=[O:8])[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH2:14]([C@@H:19]1[CH2:23][CH2:22][CH2:21][C@H:20]1[OH:24])[CH2:15][CH2:16][CH:17]=[CH2:18]>C1(C)C=CC=CC=1.CN(C1C=CN=CC=1)C.CCOC(C)=O.Cl>[CH:1]1([C@H:6]([NH:11][C:12]([O:24][C@@H:20]2[CH2:21][CH2:22][CH2:23][C@H:19]2[CH2:14][CH2:15][CH2:16][CH:17]=[CH2:18])=[O:13])[C:7]([O:9][CH3:10])=[O:8])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: COC(=O)[C@@H](N=C=O)C1CCCC1
Reactant: C=CCCC[C@@H]1CCC[C@H]1O
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: C=CCCC[C@@H]1CCC[C@H]1OC(=O)N[C@H](C(=O)OC)C1CCCC1
Temperature: 85 °C
Reaction time: 5 h
Yield: 75 %

Procedure:
A solution of methyl (2S)-cyclopentyl(isocyanato)acetate (1.57 g, 8.56 mmol) and (1R,2R)-2-pent-4-en-1-ylcyclopentanol (Intermediate A9) (1.20 g, 7.78 mmol) in PhMe (56 mL) was treated portionwise with DMAP (0.95 g, 7.78 mmol). The resulting mixture was stirred for 5 hours at 85° C., then cooled to 20° C., and diluted with EtOAc and HCl(aq.) (1N). The organic layer was separated, washed with brine, and dried over Na2SO4. Filtration and removal of the volatiles gave a residue that was purified by column chromatography (gradient elution, 4-40% Et2O/petroleum ether) to afford the title compound (1.97 g, 76%) as an oil. LCMS (ES+) m/z, 338 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][NH:10][CH3:11])=[CH:5][CH:4]=1.Cl[S:13]([C:16]1[CH:25]=[CH:24][C:19]([C:20]([O:22]C)=[O:21])=[CH:18][CH:17]=1)(=[O:15])=[O:14]>>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][N:10]([CH3:11])[S:13]([C:16]2[CH:17]=[CH:18][C:19]([C:20]([OH:22])=[O:21])=[CH:24][CH:25]=2)(=[O:15])=[O:14])=[CH:5][CH:4]=1
Reactant: COC(=O)c1ccc(S(=O)(=O)Cl)cc1
Reactant: CNCc1ccc(OC)cc1
Product: COc1ccc(CN(C)S(=O)(=O)c2ccc(C(=O)O)cc2)cc1

Procedure:
Prepared as in example 5-27 from 1-(4-methoxyphenyl)-N-methylmethanamine and methyl 4-(chlorosulfonyl)-benzoate (Example 5-10c). MS (M−H, 335.1); 1H NMR (400 MHz, DMSO-d6): δ, ppm: 2.51 (s, 3H), 3.71 (s, 3H), 4.05 (s, 2H), 6.88 (d, 2H), 7.18 (d, 2H), 7.91 (d, 2H); 8.13 (d, 2H). Elemental analysis: (found): C, 57.47%; H, 4.77%; and N, 4.31%. (theoretical): C, 57.30%; H, 5.11%; and N, 4.18%.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:4]=[C:5]([CH:26]=[CH:27][CH:28]=1)[C:6]([N:8]([CH2:17][C:18]1[CH:23]=[C:22]([Cl:24])[CH:21]=[C:20]([Cl:25])[CH:19]=1)[CH2:9][C:10]1[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=1)=[O:7].[F:29][C:30]1[CH:37]=[CH:36][C:33]([CH:34]=O)=[CH:32][CH:31]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C([O-])(O)=O.[Na+]>C(Cl)Cl.CC(O)C>[Cl:25][C:20]1[CH:19]=[C:18]([CH:23]=[C:22]([Cl:24])[CH:21]=1)[CH2:17][N:8]([CH2:9][C:10]1[CH:11]=[CH:12][C:13]([F:16])=[CH:14][CH:15]=1)[C:6](=[O:7])[C:5]1[CH:26]=[CH:27][CH:28]=[C:3]([CH2:2][NH:1][CH2:34][C:33]2[CH:36]=[CH:37][C:30]([F:29])=[CH:31][CH:32]=2)[CH:4]=1
Reactant: NCc1cccc(C(=O)N(Cc2ccc(F)cc2)Cc2cc(Cl)cc(Cl)c2)c1
Reactant: O=Cc1ccc(F)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(C)O
Product: O=C(c1cccc(CNCc2ccc(F)cc2)c1)N(Cc1ccc(F)cc1)Cc1cc(Cl)cc(Cl)c1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 63 %

Procedure:
To a solution of 3-(aminomethyl)-N-(3,5-dichlorobenzyl)-N-(4-fluorobenzyl)benzamide (0.6 g, 1.44 mmol) in CH2Cl2 (6.0 mL) and 2-propanol (6.0 mL) was added 4-fluorobenzaldehyde (0.16 mL, 1.44 mmol). The resulting mixture was stirred at rt for 1.5 h. The reaction mixture was cooled to ice bath temperature and was added sodium triacetoxyborohydride (0.49 g, 2.30 mmol) under N2 atmosphere. The resulting mixture was stirred at rt for 20 h. To the reaction mixture was added saturated aq NaHCO3 solution and the mixture was stirred for 20 minutes. The mixture was concentrated, and the residue was diluted with ethyl acetate and saturated aq NaHCO3 solution. The organic layer was separated, washed with brine, dried over MgSO4 and concentrated. The residue was purified by flash chromatography on silica gel (ISCO. condition: 24 g column; eluents: 0-25% of ethyl acetate in CH2Cl2, gradient over 40 minutes) to obtain the desired product as colorless oil (0.47, 63%). 1H NMR (CDCl3): δ 7.55-7.29 (m, 7H), 7.17-7.00 (m, 8H), 4.70-4.63 (m, 2H), 4.43-4.36 (m, 2H), 3.82 (s, 2H), 3.77 (s, 2H); MS (ESI): [M+H]+=524.9.
Reaction SMILES: C([O:3][C:4]([C:6]1[N:7]([CH2:26][CH:27]2[CH2:29][CH2:28]2)[CH:8]=[C:9]([NH:11][C:12]([NH:14][C:15]2[CH:20]=[CH:19][C:18]([O:21][C:22]([F:25])([F:24])[F:23])=[CH:17][CH:16]=2)=[O:13])[N:10]=1)=[O:5])C.O.[OH-].[Na+]>C(O)C>[F:25][C:22]([F:23])([F:24])[O:21][C:18]1[CH:19]=[CH:20][C:15]([NH:14][C:12]([NH:11][C:9]2[N:10]=[C:6]([C:4]([OH:5])=[O:3])[N:7]([CH2:26][CH:27]3[CH2:28][CH2:29]3)[CH:8]=2)=[O:13])=[CH:16][CH:17]=1
Reactant: CCOC(=O)c1nc(NC(=O)Nc2ccc(OC(F)(F)F)cc2)cn1CC1CC1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: O=C(Nc1ccc(OC(F)(F)F)cc1)Nc1cn(CC2CC2)c(C(=O)O)n1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
10.6 g (28.1 mmol) of 4-[({[4-(trifluoromethoxy)phenyl]amino}-carbonyl)amino]-1-(cyclopropylmethyl)-1H-imidazole-2-carboxylic acid ethyl ester is suspended in 158 ml of ethanol. While being cooled with ice, 16.4 ml of water and 6 ml (112 mmol) of 50% aqueous sodium hydroxide solution are added. The reaction mixture is stirred for 1 hour at room temperature and then concentrated by evaporation in a vacuum. The residue is taken up in 100 ml of isopropanol and mixed with 100 ml of 1N hydrochloric acid while being cooled with ice. The crystals are suctioned off and dried in a vacuum at 40° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]([OH:13])=[CH:11][C:10]([C:14]3[CH:19]=[CH:18][N:17]=[CH:16][CH:15]=3)=[N:9]2)=[CH:4][CH:3]=1.C([O-])([O-])=O.[Cs+].[Cs+].CN(C=O)C.Br[CH2:32][N:33]1[C:37](=[O:38])[C:36]2[C:39]([CH:45]([CH3:47])[CH3:46])=[CH:40][C:41]([O:43][CH3:44])=[CH:42][C:35]=2[S:34]1(=[O:49])=[O:48]>CO.O>[CH:45]([C:39]1[C:36]2[C:37](=[O:38])[N:33]([CH2:32][O:13][C:12]3[N:8]([C:5]4[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=4)[N:9]=[C:10]([C:14]4[CH:19]=[CH:18][N:17]=[CH:16][CH:15]=4)[CH:11]=3)[S:34](=[O:49])(=[O:48])[C:35]=2[CH:42]=[C:41]([O:43][CH3:44])[CH:40]=1)([CH3:47])[CH3:46]
Reactant: COc1cc(C(C)C)c2c(c1)S(=O)(=O)N(CBr)C2=O
Reactant: Oc1cc(-c2ccncc2)nn1-c1ccc(Cl)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CO
Product: COc1cc(C(C)C)c2c(c1)S(=O)(=O)N(COc1cc(-c3ccncc3)nn1-c1ccc(Cl)cc1)C2=O
Temperature: 25 °C
Reaction time: 4 h
Yield: 49.9 %

Procedure:
A mixture of 1-(4-chlorophenyl)-3-(4-pyridyl)-5-hydroxy pyrazole (406 mg; 1.49 mmol) and Cs2CO3 (243 mg; 0.75 mmol) in methanol (8 ml) was stirred at room temperature for 4 hours. The solvent was concentrated in vacuo, and the residue was dried in vacuo overnight. To the above residue was added 7 ml of DMF and 2-bromomethyl-4-isopropyl-6-methoxy-1,2-benzisothiazol-3(2H)-one 1,1-dioxide (519 mg, 1.49 mmol) and the resulting mixture was stirred at room temperature for 5 hours and poured into water. The above mixture was extracted with methylene chloride (3×), the organic layer was dried over sodium sulfate, and concentrated in vacuo. The residue was purified by column chromatography (silica gel; 33-50% ethyl acetate/hexane; 12-50% methylene chloride/acetone) and recrystallized from methylene chloride/hexane to afford 401 mg (50%) of 4-isopropyl-6-methoxy-2-[1-(4-chlorophenyl)-3-(4-pyridyl) pyrazol-5-yl-oxymethyl]-1,2-benzisothiazol-3(2H)-one 1,1-dioxide (Formula I: R1 =4-Cl--Ph; R2 =4-pyridyl; R3 =H; R4 =CH(CH3)2 ; R5 =6-OCH3) as a white solid, m.p. >190° C. (dec.).
Reaction SMILES: C([O:4][CH2:5][C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][CH:15]=1)[N:12]=[C:11]([CH2:16][CH2:17][CH2:18][CH3:19])[N:10]([CH2:20][C:21]1[CH:26]=[CH:25][C:24]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=3[C:33]3[NH:37][N:36]=[N:35][N:34]=3)=[CH:23][CH:22]=1)[C:9]2=[O:38])(=O)C.[OH-].[Na+].CCCCCC.C(O)(=O)C>CO>[CH2:16]([C:11]1[N:10]([CH2:20][C:21]2[CH:22]=[CH:23][C:24]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=3[C:33]3[NH:34][N:35]=[N:36][N:37]=3)=[CH:25][CH:26]=2)[C:9](=[O:38])[C:8]2[C:13](=[CH:14][CH:15]=[C:6]([CH2:5][OH:4])[CH:7]=2)[N:12]=1)[CH2:17][CH2:18][CH3:19]
Reactant: CCCCc1nc2ccc(COC(C)=O)cc2c(=O)n1Cc1ccc(-c2ccccc2-c2nnn[nH]2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: CCCCCC
Solvent: CO
Product: CCCCc1nc2ccc(CO)cc2c(=O)n1Cc1ccc(-c2ccccc2-c2nnn[nH]2)cc1
Yield: 94.7 %

Procedure:
A solution of 0.2 g (0.38 mmol) of the product of Example 63 was dissolved in 5 mL of MeOH and was treated with 1 mL of 1N NaOH (1.0 mmol) and stirred over night. The resulting solution was extracted with EtOAc (3×10 mL). The organic phase was washed with water (2×5 mL) and brine (1×5 mL) and dried over MgSO4. The mixture was filtered and concentrated in vacuo and the residue was purified by flash chromatography over silica gel eluting with 80:19:1 EtOAc: hexane:acetic acid to give 0.17 g (0.36 mmol) of a white foam, 93% yield. 1H-NMR (CD3OD): 0.88 (t, 3H, J=7.38 Hz), 1.41 (m, 2H), 1.48 (m, 2H), 2.73 (3 line m, 2H, J=8.03 Hz), 4.60 (s, 2H), 5.38 (bs, 2H), 7.08 (m, 4 H), 7.20 (m, 1H), 7.50 (m, 2H), 7.61 (m, 2H), 7.77 (dd, 1H, J=2.0, 9.0 Hz), 8.17 (s, 1H). FABMS m/e: 467 (M+ +1) calc. for C27H26N6O2
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH:7]=[CH:6]2)#[N:2].F[C:13]1[CH:18]=[CH:17][C:16]([N+:19]([O-])=O)=[CH:15][CH:14]=1.[Cl:22][C:23]1[CH:28]=[CH:27][C:26]([N:29]=[C:30]=[O:31])=[CH:25][C:24]=1[C:32]([F:35])([F:34])[F:33]>>[Cl:22][C:23]1[CH:28]=[CH:27][C:26]([NH:29][C:30]([NH:19][C:16]2[CH:17]=[CH:18][C:13]([N:8]3[C:9]4[C:5](=[CH:4][C:3]([C:1]#[N:2])=[CH:11][CH:10]=4)[CH:6]=[CH:7]3)=[CH:14][CH:15]=2)=[O:31])=[CH:25][C:24]=1[C:32]([F:33])([F:34])[F:35]
Reactant: O=C=Nc1ccc(Cl)c(C(F)(F)F)c1
Reactant: O=[N+]([O-])c1ccc(F)cc1
Reactant: N#Cc1ccc2[nH]ccc2c1
Product: N#Cc1ccc2c(ccn2-c2ccc(NC(=O)Nc3ccc(Cl)c(C(F)(F)F)c3)cc2)c1

Procedure:
The title compound can be synthesized from 5-cyanoindole, 4-fluoronitrobenzene and 4-chloro-3-(trifluoromethyl)phenyl isocyanate by using the same techniques as in Example 1.
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]([CH2:32][CH:33]2[CH2:35][CH2:34]2)(=[O:31])=[O:30])=[CH:25][C:21]=1[C:22]([OH:24])=[O:23].[NH:36]1[CH2:41][CH2:40][O:39][CH2:38][CH2:37]1>>[CH:33]1([CH2:32][S:29]([C:26]2[CH:27]=[CH:28][C:20]([N:36]3[CH2:41][CH2:40][O:39][CH2:38][CH2:37]3)=[C:21]([CH:25]=2)[C:22]([OH:24])=[O:23])(=[O:31])=[O:30])[CH2:35][CH2:34]1
Reactant: C1COCCN1
Reactant: O=C(O)c1cc(S(=O)(=O)CC2CC2)ccc1Cl
Agent: CS(=O)(=O)c1ccc(N2CCCC2)c(C(=O)O)c1
Product: O=C(O)c1cc(S(=O)(=O)CC2CC2)ccc1N1CCOCC1
Yield: 27 %

Procedure:
The title compound was synthesised according to the procedure described for the synthesis of 5-Methanesulfonyl-2-pyrrolidin-1-yl-benzoic acid from 2-Chloro-5-cyclopropylmethanesulfonyl-benzoic acid and morpholine and obtained in 27% yield. MS (m/e): 324.2 (MH−, 100%).
Reaction SMILES: [Cl:1][S:2](CC(Cl)=O)(=[O:4])=[O:3].C[OH:10].[CH3:11][CH2:12][O:13][CH2:14]C>>[Cl:1][S:2]([CH2:11][C:12]([O:13][CH3:14])=[O:10])(=[O:4])=[O:3]
Reactant: CO
Reactant: CCOCC
Reactant: O=C(Cl)CS(=O)(=O)Cl
Product: COC(=O)CS(=O)(=O)Cl
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 95 %

Procedure:
To a solution of 2-(chlorosulfonyl)acetyl chloride (1 g, 5.65 mmol) in dry Et2O (5 ml) cooled to 0° C., a solution of methanol (0.286 g, 6.21 mmol) in dry Et2O (1 ml) was added dropwise. After 15 minutes, the mixture was warmed to RT and stirred for 2 hours. The solvent was evaporated and the desired compound was obtained (1 g, 5.36 mmol, 95% yield) and used in the next step without further purification.
Reaction SMILES: [NH2:1][C:2]1[N:9]=[CH:8][CH:7]=[C:6]([Cl:10])[C:3]=1[CH:4]=O.[C:11]([C:14]1[C:19]([C:20]([F:23])([F:22])[F:21])=[CH:18][C:17]([NH2:24])=[CH:16][N:15]=1)(=O)[CH3:12].CC([O-])(C)C.[K+]>C1COCC1>[Cl:10][C:6]1[CH:7]=[CH:8][N:9]=[C:2]2[C:3]=1[CH:4]=[CH:12][C:11]([C:14]1[N:15]=[CH:16][C:17]([NH2:24])=[CH:18][C:19]=1[C:20]([F:23])([F:21])[F:22])=[N:1]2
Reactant: Nc1nccc(Cl)c1C=O
Reactant: CC(=O)c1ncc(N)cc1C(F)(F)F
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: Nc1cnc(-c2ccc3c(Cl)ccnc3n2)c(C(F)(F)F)c1
Temperature: -40 °C
Reaction time: 2 h

Procedure:
Dissolve 2-amino-4-chloronicotinaldehyde (78 mg, 0.5 mmol) and 2-acetyl-5-amino-3-trifluoromethylpyridine (102 mg, 0.5 mmol) in anhydrous THF (5.0 mL) and cool it to −40° C. under N2 atmosphere. Add in portion t-BuOK (112 mg, 1.0 mmol) to the reaction mixture and stir the mixture at −110° C. for 2 hours. Concentrate the reaction mixture under vacuum, dilute the residue with water (20 mL), extract with CH2Cl2 (3×30 mL) and dry (MgSO4). Filter, concentrate under vacuum and purify the crude by column chromatography to afford the title compound product as a yellow solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:26]=[CH:27][C:28]=1[N+:29]([O-:31])=[O:30])[C:6]([C:8]1[N:16]2[C:11]([CH:12]=[CH:13][CH:14]=[CH:15]2)=[C:10]([NH:17][C:18](=[O:24])[O:19][C:20]([CH3:23])([CH3:22])[CH3:21])[C:9]=1[CH3:25])=[O:7].[H-].[Na+].CI.[C:36](=O)(O)[O-].[Na+]>O1CCCC1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:26]=[CH:27][C:28]=1[N+:29]([O-:31])=[O:30])[C:6]([C:8]1[N:16]2[C:11]([CH:12]=[CH:13][CH:14]=[CH:15]2)=[C:10]([N:17]([CH3:36])[C:18](=[O:24])[O:19][C:20]([CH3:23])([CH3:21])[CH3:22])[C:9]=1[CH3:25])=[O:7]
Reactant: O=C([O-])O
Reactant: COc1cc(C(=O)c2c(C)c(NC(=O)OC(C)(C)C)c3ccccn23)ccc1[N+](=O)[O-]
Agent: [H-]
Agent: [Na+]
Solvent: CI
Solvent: C1CCOC1
Product: COc1cc(C(=O)c2c(C)c(N(C)C(=O)OC(C)(C)C)c3ccccn23)ccc1[N+](=O)[O-]
Temperature: 0 °C
Reaction time: 1 h
Yield: 96 %

Procedure:
3.05 g (7.2 mmol) of tert-butyl 3-(3-methoxy-4-nitrobenzoyl)-2-methylindolizin-1-ylcarbamate in solution in 50 ml of tetrahydrofuran are added dropwise to 315 mg (7.9 mmol) of sodium hydride (at 60% as a dispersion in oil) in suspension in 10 ml of tetrahydrofuran, cooled to 0° C. After stirring for 1 hour at 0° C., 0.59 ml (9.5 mmol) of methyl iodide is added while the medium is maintained at 0° C. It is allowed to return to room temperature and it is stirred for 1 hour. The reaction medium is poured over a saturated aqueous sodium bicarbonate solution and extracted with ethyl acetate. The organic phase is separated after settling out, washed with a saturated aqueous sodium chloride solution, dried over sodium sulphate and concentrated under reduced pressure. 3.47 g of an orange-coloured foam are obtained.
Reaction SMILES: Cl.Cl[CH2:3][CH2:4][N:5]1[CH:10]([CH3:11])[CH2:9][CH2:8][CH2:7][C:6]1([CH3:13])[CH3:12].[Br:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[OH:21]>>[Br:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[O:21][CH2:3][CH2:4][N:5]1[CH:10]([CH3:11])[CH2:9][CH2:8][CH2:7][C:6]1([CH3:13])[CH3:12]
Reactant: CC1CCCC(C)(C)N1CCCl
Reactant: Oc1ccccc1Br
Agent: Cl
Product: CC1CCCC(C)(C)N1CCOc1ccccc1Br

Procedure:
The title compound was prepared from 1-(2-chloroethyl)-2,2,6-trimethylpiperidine hydrochloride and 2-bromophenol in a similar manner to Example 2 (b).
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[C:12]([O:14][CH2:15][CH3:16])[C:11]([C:17]([F:20])([F:19])[F:18])=[CH:10][C:9]=1[NH:21][C:22](=[O:38])[CH2:23][C:24](=O)[C:25]1[CH:30]=[CH:29][CH:28]=[C:27]([C:31]2[CH:32]=[N:33][CH:34]=[CH:35][CH:36]=2)[CH:26]=1)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH2:15]([O:14][C:12]1[C:11]([C:17]([F:20])([F:19])[F:18])=[CH:10][C:9]2[NH:21][C:22](=[O:38])[CH2:23][C:24]([C:25]3[CH:30]=[CH:29][CH:28]=[C:27]([C:31]4[CH:32]=[N:33][CH:34]=[CH:35][CH:36]=4)[CH:26]=3)=[N:7][C:8]=2[CH:13]=1)[CH3:16]
Reactant: CCOc1cc(NC(=O)OC(C)(C)C)c(NC(=O)CC(=O)c2cccc(-c3cccnc3)c2)cc1C(F)(F)F
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCOc1cc2c(cc1C(F)(F)F)NC(=O)CC(c1cccc(-c3cccnc3)c1)=N2

Procedure:
The title compound was prepared from {5-ethoxy-2-[3-oxo-3-(3-pyridin-3-yl-phenyl)-propionylamino]-4-trifluoromethyl-phenyl}-carbamic acid tert-butyl ester (Example M166) (265 mg, 0.488 mmol) by treatment with TFA in CH2Cl2 according to the general procedure N. Obtained as a white solid (154 mg, 74%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH:11]=[C:10]([C:18]([OH:20])=O)[N:9]=1.C(N(CC)CC)C.ClC(OCC)=O.[CH3:34][NH:35][CH2:36][C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1>C(Cl)(Cl)Cl>[CH3:34][N:35]([CH2:36][C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1)[C:18]([C:10]1[N:9]=[C:8]([C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[Cl:1])[C:17]2[C:12]([CH:11]=1)=[CH:13][CH:14]=[CH:15][CH:16]=2)=[O:20]
Reactant: CNCc1ccccc1
Reactant: O=C(O)c1cc2ccccc2c(-c2ccccc2Cl)n1
Agent: CCOC(=O)Cl
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: CN(Cc1ccccc1)C(=O)c1cc2ccccc2c(-c2ccccc2Cl)n1
Yield: 64.8 %

Procedure:
Operations are carried out as for Example 7, starting from 2.83 g of 1-(2-chloro phenyl) isoquinoline 3-carboxylic acid, 1.15 g of triethylamine, 1.24 g of ethyl chloroformate and 1.56 g of N-methyl benzylamine in 100 ml of chloroform. 2.5 g of N-methyl N-phenylmethyl 1-(2-chloro phenyl) isoquinoline 3-carboxamide, melting at 128° C., are obtained.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH:10]([NH:13][CH2:14][CH2:15][C:16]([O:18][CH3:19])=[O:17])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Cl:20][C:21]1[CH:28]=[CH:27][C:24]([CH:25]=O)=[CH:23][CH:22]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(O)(=O)C>ClC(Cl)C>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH:10]([N:13]([CH2:25][C:24]2[CH:27]=[CH:28][C:21]([Cl:20])=[CH:22][CH:23]=2)[CH2:14][CH2:15][C:16]([O:18][CH3:19])=[O:17])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: O=Cc1ccc(Cl)cc1
Reactant: COC(=O)CCNC1CCN(C(=O)OC(C)(C)C)C1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CC(Cl)Cl
Product: COC(=O)CCN(Cc1ccc(Cl)cc1)C1CCN(C(=O)OC(C)(C)C)C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 3-(2-methoxycarbonyl-ethylamino)-pyrrolidine-1-carboxylic acid tert-butyl ester (0.73 g, 2.68 mmol) in dichloroethane (10.0 mL) was added 4-chlorobenzaldehyde (0.42 g, 2.95 mmol), sodium triacetoxy borohydride (1.71 g, 8.04 mmol) and catalytic acetic acid and the resulting mixture was stirred at room temperature overnight. The reaction mixture was concentrated, dissolved in dichloromethane and washed with saturated aqueous sodium bicarbonate. The combined organics were washed with brine and dried over sodium sulfate. The crude product was purified on silica using gradient elution from hexane/ethyl acetate (15%) to hexane/ethyl acetate (50%). 1H-NMR (CDCl3) δ: 1.35 (9H, s), 1.80 (1H, m), 1.90 (1H, m), 2.40 (2H, t), 2.85 (2H, t), 3.00-3.80 (7H, m), 4.70 (1H, d), 7.20 (4H, m). ESI-MS m/z: 397 (M+1), UV retention time: 1.99 min.