Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CS[C:3](=[C:6]([C:12]([O:14]CC)=O)[C:7]([O:9][CH2:10][CH3:11])=[O:8])[S:4][CH3:5].[F:17][C:18]1[CH:23]=[CH:22][C:21]([NH:24][C:25]([C:27]2[CH:32]=[CH:31][C:30]([S:33][CH3:34])=[CH:29][CH:28]=2)=[NH:26])=[CH:20][CH:19]=1.[K+].[Br-]>>[F:17][C:18]1[CH:23]=[CH:22][C:21]([N:24]2[C:12](=[O:14])[C:6]([C:7]([O:9][CH2:10][CH3:11])=[O:8])=[C:3]([S:4][CH3:5])[N:26]=[C:25]2[C:27]2[CH:32]=[CH:31][C:30]([S:33][CH3:34])=[CH:29][CH:28]=2)=[CH:20][CH:19]=1
Reactant: CCOC(=O)C(C(=O)OCC)=C(SC)SC
Reactant: CSc1ccc(C(=N)Nc2ccc(F)cc2)cc1
Agent: [Br-]
Agent: [K+]
Product: CCOC(=O)c1c(SC)nc(-c2ccc(SC)cc2)n(-c2ccc(F)cc2)c1=O
Yield: 15.7 %

Procedure:
The title compound was prepared from diethyl [bis(methylthio)methylene]malonate (0.88 g, 3.3 mmol) and N-(4-fluorophenyl)-4-(methylthio)benzenecarboximidamide (0.87 g, 3.3 mmol) (prepared according to the procedure described in preparation 5) by following the procedure described in example 41 (0.22 g, yield 15.7%, mp 151-155° C., purity 99.72% by HPLC). 1H-NMR (CDCl3):δ 1.37-1.40 (t, 3H), 2.45 (s, 3H), 2.55 (s, 3H), 4.38-4.43 (q, 2H), 7.02-7.07 (m, 4H), 7.11-7.14 (m, 2H), 7.22-7.26 (m, 2H). IR (KBr) cm−1: 3360, 3072, 2978, 2924, 1694 (—C═O). MS m/z:431.2 (M+).
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:7]=[C:8]([NH:12][C:13]2[N:18]=[C:17]([C:19]3[CH:24]=[CH:23][N:22]=[C:21]([Cl:25])[CH:20]=3)[CH:16]=[CH:15][N:14]=2)[CH:9]=[CH:10][CH:11]=1)=[O:5])C.[OH-].[Li+]>C(O)C.O>[C:4]([C:6]1[CH:7]=[C:8]([NH:12][C:13]2[N:18]=[C:17]([C:19]3[CH:24]=[CH:23][N:22]=[C:21]([Cl:25])[CH:20]=3)[CH:16]=[CH:15][N:14]=2)[CH:9]=[CH:10][CH:11]=1)([OH:5])=[O:3]
Reactant: CCOC(=O)c1cccc(Nc2nccc(-c3ccnc(Cl)c3)n2)c1
Agent: [Li+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: O=C(O)c1cccc(Nc2nccc(-c3ccnc(Cl)c3)n2)c1
Temperature: 25 °C
Yield: 95.7 %

Procedure:
A mixture of N-[3-ethoxycarbonyl-phenyl]-4-(2-chloro-4-pyridyl)-2-pyrimidineamine (860 mg, 2.43 mmol), lithium hydroxide (233 mg, 9.70 mmol) in ethanol (20 mL) and water (5 mL) is heated to reflux for 1 hour before cooling to room temperature. The mixture is concentrated, dissolved in water and acidified with 10% hydrochloric acid. The solid is collected by filtration and washed with water, methanol and dried to give N-[3-carboxy-phenyl]-4-(2-chloro-4-pyridyl)-2-pyrimidineamine (760 mg); ESI-MS (m/z): 327.0 (M++H).
Reaction SMILES: [C:1]([NH:4][C:5]1[C:6]2[CH:13]=[CH:12][N:11]([C@@H:14]3[O:26][C@H:25]([CH2:27][O:28][C:29](=[O:31])[CH3:30])[C@@H:20]([O:21][C:22](=[O:24])[CH3:23])[C@@:15]3([CH3:32])[O:16][C:17](=[O:19])[CH3:18])[C:7]=2[N:8]=[CH:9][N:10]=1)(=[O:3])[CH3:2].[Br:33]N1C(=O)CCC1=O>CN(C=O)C>[C:1]([NH:4][C:5]1[C:6]2[C:13]([Br:33])=[CH:12][N:11]([C@@H:14]3[O:26][C@H:25]([CH2:27][O:28][C:29](=[O:31])[CH3:30])[C@@H:20]([O:21][C:22](=[O:24])[CH3:23])[C@@:15]3([CH3:32])[O:16][C:17](=[O:19])[CH3:18])[C:7]=2[N:8]=[CH:9][N:10]=1)(=[O:3])[CH3:2]
Reactant: O=C1CCC(=O)N1Br
Reactant: CC(=O)Nc1ncnc2c1ccn2[C@@H]1O[C@H](COC(C)=O)[C@@H](OC(C)=O)[C@@]1(C)OC(C)=O
Solvent: CN(C)C=O
Product: CC(=O)Nc1ncnc2c1c(Br)cn2[C@@H]1O[C@H](COC(C)=O)[C@@H](OC(C)=O)[C@@]1(C)OC(C)=O
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a pre-cooled (0° C.) solution of the compound from Step A (460 mg, 1.00 mmol) in DMF is added N-bromosuccinimide (178 mg, 1.0 mmol) in DMF. The resulting solution is stirred at 0° C. for 30 min then at room temperature for another 30 min. The reaction is quenched by addition of methanol and evaporated in vacuo. The resulting crude mixture is purified on silica gel using ethyl acetate/hexane as the eluent. Fractions containing the desired product are pooled and evaporated in vacuo to give the desired product.
Reaction SMILES: C(OC([NH:8][CH2:9][CH2:10][N:11]([C:15](=[O:20])[C:16]([F:19])([F:18])[F:17])[CH2:12][CH:13]=[CH2:14])=O)(C)(C)C.[F:21][C:22]([F:27])([F:26])[C:23]([OH:25])=[O:24]>C(Cl)Cl>[F:21][C:22]([F:27])([F:26])[C:23]([OH:25])=[O:24].[F:17][C:16]([F:18])([F:19])[C:15]([N:11]([CH2:12][CH:13]=[CH2:14])[CH2:10][CH2:9][NH2:8])=[O:20]
Reactant: C=CCN(CCNC(=O)OC(C)(C)C)C(=O)C(F)(F)F
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: C=CCN(CCN)C(=O)C(F)(F)F
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Dissolve N-(t-butyloxycarbonyl)-N'-(trifluoroacetyl)-N'-(allyl)-ethylenediamine (1.95 mmol) in methylene chloride (7 mL) and add trifluoroacetic acid (2.6mL). Stir at room temperature for 1 hour then evaporate the solvent in vacuo to give N'-(trifluoroacetyl)-N'-(allyl)-ethylenediamine trifluoroacetate.
Reaction SMILES: Cl.Cl.[O:3]1[C:7]2[CH:8]=[CH:9][CH:10]=[C:11]([CH:12]3[CH2:17][CH2:16][N:15]([CH2:18][CH2:19][C@H:20]4[CH2:25][CH2:24][C@H:23]([NH2:26])[CH2:22][CH2:21]4)[CH2:14][CH2:13]3)[C:6]=2[CH2:5][CH2:4]1.[F:27][C:28]([F:36])([F:35])[C@H:29]([OH:34])[CH2:30][C:31](O)=[O:32]>>[O:3]1[C:7]2[CH:8]=[CH:9][CH:10]=[C:11]([CH:12]3[CH2:17][CH2:16][N:15]([CH2:18][CH2:19][C@H:20]4[CH2:21][CH2:22][C@H:23]([NH:26][C:31](=[O:32])[CH2:30][C@@H:29]([OH:34])[C:28]([F:36])([F:35])[F:27])[CH2:24][CH2:25]4)[CH2:14][CH2:13]3)[C:6]=2[CH2:5][CH2:4]1
Reactant: O=C(O)C[C@@H](O)C(F)(F)F
Reactant: N[C@H]1CC[C@H](CCN2CCC(c3cccc4c3CCO4)CC2)CC1
Agent: Cl
Product: O=C(C[C@@H](O)C(F)(F)F)N[C@H]1CC[C@H](CCN2CCC(c3cccc4c3CCO4)CC2)CC1

Procedure:
The title compound, white solid (84 mg, 72%), MS (ISP) m/z=469.4 [(M+H)+], mp 189° C., was prepared in accordance with the general method of example 1 from trans-4-{2-[4-(2,3-dihydro-benzofuran-4-yl)-piperidin-1-yl]-ethyl}-cyclohexylamine dihydrochloride (intermediate B) (100 mg, 0.25 mmol) and (R)-4,4,4-trifluoro-3-hydroxy-butyric acid.
Reaction SMILES: CC(C)(OC([NH:7][C@H:8]([C:24]([N:26]1[CH2:31][CH2:30][N:29]([C:32]2[CH:37]=[CH:36][N:35]=[CH:34][CH:33]=2)[CH2:28][CH2:27]1)=[O:25])[CH2:9][CH2:10][CH2:11][CH2:12][NH:13][C:14]([O:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=[O:15])=O)C.FC(F)(F)C(O)=O.C(=O)([O-])O.[Na+]>C(Cl)Cl>[C:18]1([CH2:17][O:16][C:14]([NH:13][CH2:12][CH2:11][CH2:10][CH2:9][C@@H:8]([C:24]([N:26]2[CH2:27][CH2:28][N:29]([C:32]3[CH:33]=[CH:34][N:35]=[CH:36][CH:37]=3)[CH2:30][CH2:31]2)=[O:25])[NH2:7])=[O:15])[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: CC(C)(C)OC(=O)N[C@@H](CCCCNC(=O)OCc1ccccc1)C(=O)N1CCN(c2ccncc2)CC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: N[C@@H](CCCCNC(=O)OCc1ccccc1)C(=O)N1CCN(c2ccncc2)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a mixture of 24.2 g (46 mmol) of 1-[N2-(1,1-dimethylethoxycarbonyl)-N6-(phenylmethoxycarbonyl)-L-lysyl]-4-(4-pyridinyl)piperazine and 150 ml of methylene chloride were added 50 ml of trifluoroacetic acid and the reaction mixture was stirred overnight at room temperature. The reaction mixture was neutralised by the addition of saturated aqueous sodium hydrogen carbonate solution, the organic phase was dried and evaporated down in vacuo. 12 g (62% of theory) of the desired compound were obtained as a colourless oil.
Reaction SMILES: [I:1][C:2]1[CH:11]=[CH:10][CH:9]=[CH:8][C:3]=1[C:4]([NH:6][NH2:7])=[O:5].N1C=CC=CC=1.[C:18](Cl)(=[O:20])[CH3:19]>ClCCl>[C:18]([NH:7][NH:6][C:4](=[O:5])[C:3]1[CH:8]=[CH:9][CH:10]=[CH:11][C:2]=1[I:1])(=[O:20])[CH3:19]
Reactant: CC(=O)Cl
Reactant: NNC(=O)c1ccccc1I
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(=O)NNC(=O)c1ccccc1I
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 76.8 %

Procedure:
2-Iodobenzohydrazide (1.38 g, 5.27 mmol) obtained in Step 1 of Example 114 was dissolved in dichloromethane (50 mL), and the mixture was stirred at 0° C. for 1.5 hours after adding pyridine (0.639 mL, 7.90 mmol) and acetyl chloride (0.412 mL, 5.79 mmol). The precipitated solid was filtered off, and the resulting solid was dried under reduced pressure to give N′-acetyl-2-iodobenzohydrazide (1.23 g, 77%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:14]=[CH:15][C:16]=1[O:17][CH3:18])[CH2:6][NH:7][CH2:8][CH:9](OC)OC.[CH:19]1[C:24]([CH:25]=O)=[CH:23][C:22]2[O:27][CH2:28][O:29][C:21]=2[CH:20]=1.[ClH:30]>>[ClH:30].[CH3:18][O:17][C:16]1[CH2:15][C:14]2[C:5](=[CH:4][C:3]=1[O:2][CH3:1])[CH:6]=[N:7][C:8]1=[C:9]3[C:19](=[CH:24][C:25]=21)[CH:20]=[C:21]1[O:29][CH2:28][O:27][C:22]1=[CH:23]3
Reactant: O=Cc1ccc2c(c1)OCO2
Reactant: COc1ccc(CNCC(OC)OC)cc1OC
Agent: Cl
Product: COC1=C(OC)Cc2c3c(ncc2=C1)=c1cc2c(cc1=C3)OCO2
Temperature: 100 °C
Reaction time: 3 h

Procedure:
Concentrated HCl (20 mL) was added to a mixture of amine 12a (2.17 g, 8.51 mmol) and piperonal (10b, 3.0 g, 0.020 mol). The reaction mixture was stirred at 100° C. for 3 h. The reaction mixture was then cooled and washed with ether (50 mL×3). Then it was brought to a basic pH with NH4OH. The mixture was extracted with chloroform (50 mL×4), washed with water (100 mL), dried (Na2SO4) and concentrated. The residue was dissolved in a mixture of organic solvents (50 mL diethyl ether, 100 mL dichloromethane, 100 mL chloroform). The mixture was filtered and HCl (2 M in ether, 40 mL) was added to the filtrate. The yellow precipitate that formed (0.806 g, 26%) was collected by filtration, mp 238-240° C. 1H NMR (300 MHz D2O) δ 8.30 (s, 1H), 6.91 (s, 1H), 6.69 (s, 1H), 6.44 (s, 1H), 6.39 (s, 1H), 5.94 (s, 2H), 3.78 (s, 3H), 3.77 (s, 3H), 3.00 (s, 2H); low resolution ESIMS m/z (rel intensity) 322 (100, M+); IR (KBr) 3429, 3032, 2611, 1623, 1551, 1504, 1489, 1430, 1413, 1379, 1331, 1296, 1273, 1226, 1206, 1172, 1036, 977, 933, 837, 776, 724 cm−1. Anal. Calcd for C19H16NO4Cl(H2O)0.85: C, 61.17; H, 4.78; N, 3.75. Found: C, 61.19; H, 4.77; N, 3.56.
Reaction SMILES: C[O:2][C:3]([C:5]1([CH:13]=[N:14][O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH2:10][CH2:9][C:8]([CH3:12])([CH3:11])[CH2:7][CH2:6]1)=[O:4].O.[OH-].[Li+].Cl>C1COCC1.O>[CH2:16]([O:15][N:14]=[CH:13][C:5]1([C:3]([OH:4])=[O:2])[CH2:10][CH2:9][C:8]([CH3:12])([CH3:11])[CH2:7][CH2:6]1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: COC(=O)C1(C=NOCc2ccccc2)CCC(C)(C)CC1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CC1(C)CCC(C=NOCc2ccccc2)(C(=O)O)CC1
Temperature: 60 °C

Procedure:
A mixture of 1-(benzyloxyimino-methyl)-4,4-dimethyl-cyclohexanecarboxylic acid methyl ester (1.83 g, 6.04 mmol) and lithium hydroxide monohydrate (2.53 g, 60.4 mmol) in THF (60 mL) and water (30 mL) was heated at 60° C. for 18 h. The reaction mixture was acidified to pH 5 with 3N aqueous HCl and was extracted with dichloromethane (50 mL×6). The combined organic layers were dried (MgSO4) and were evaporated in vacuo to yield the title compound as a pale yellow oil. (1.47 g, 84%). MH+290.
Reaction SMILES: [Cl:1][C:2]1[CH:14]=[CH:13][C:5]([C:6]([CH2:8][CH2:9][C:10]([OH:12])=[O:11])=[O:7])=[CH:4][CH:3]=1.[CH3:15][N:16]1[CH2:21][CH2:20][CH:19](O)[CH2:18][CH2:17]1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([C:8](=[CH:15][N:16]([CH3:21])[CH3:17])[CH2:9][C:10]([O:12][CH:19]2[CH2:20][CH2:21][N:16]([CH3:15])[CH2:17][CH2:18]2)=[O:11])=[O:7])=[CH:13][CH:14]=1
Reactant: O=C(O)CCC(=O)c1ccc(Cl)cc1
Reactant: CN1CCC(O)CC1
Product: CN(C)C=C(CC(=O)OC1CCN(C)CC1)C(=O)c1ccc(Cl)cc1

Procedure:
35.1 g of 1-methyl-4-piperidyl 3-p-chlorobenzoyl-4-dimethylamino-3-butenoate [obtainable by esterification of 3-p-chlorobenzoyl-propionic acid with 1-methyl-piperidin-4-ol to produce 1-methyl-4-piperidyl 3-p-chloro-benzoylpropionate and subsequent reaction of the latter with dimethylformamide dimethyl acetal in the presence of acetic acid at 120°] and 12 g of phenylhydrazine are warmed for 4 hours at 100°. The reaction mixture is subjected to the customary working up (benzene/water) and 1-methyl-4-piperidyl 5-p-chlorophenyl-1-phenyl-pyrazol-4-yl-acetate is obtained; m.p. 90°-93°. Hydrochloride, m.p. 234°-235°.
Reaction SMILES: [CH3:1][N:2]([C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([CH3:12])[N:7]=1)[C:3](Cl)=[S:4].[Cl:13][C:14]1[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][C:15]=1[CH3:21].C(=O)([O-])[O-].[K+].[K+].O>C(C(C)=O)C>[CH3:1][N:2]([C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([CH3:12])[N:7]=1)[C:3](=[S:4])[O:20][C:17]1[CH:18]=[CH:19][C:14]([Cl:13])=[C:15]([CH3:21])[CH:16]=1
Reactant: Cc1cccc(N(C)C(=S)Cl)n1
Reactant: Cc1cc(O)ccc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Solvent: O
Product: Cc1cccc(N(C)C(=S)Oc2ccc(Cl)c(C)c2)n1
Temperature: 25 °C
Yield: 34.8 %

Procedure:
A mixture of 2.01 g of N-methyl-N-(6-methyl-2-pyridyl)thiocarbamoylchloride, 1.43 g of 4-chloro-3-methylphenol, and 1.38 g of potassium carbonate in 50 ml of methyl ethyl ketone was refluxed for 48 hours. After the reaction mixture was cooled to room temperature, it was poured into cold water and the product was extracted with benzene. The benzene solution, successively washed with water and brine, was dried over anhydrous magnesium sulfate. The residue obtained by the removal of benzene under reduced pressure was chromatographed through silica gel column using hexane-ethyl acetate (3/1, V/V) as an eluent to give 1.07 g of pure O-4-chloro-3-methylphenyl N-methyl-N-(6-methyl-2-pyridyl)thiocarbamate as solid in the yield of 35%. A part of the solid was recrystallized from benzene-hexane and crystalls having melting point of 134° to 136° C. were obtained.
Reaction SMILES: [CH:1]12[CH:6]([NH:7][C:8]([O:10][CH2:11][C:12]3[O:16][N:15]=[C:14]([C:17]([O:19][CH2:20][CH3:21])=[O:18])[CH:13]=3)=[O:9])[CH:5]1[CH2:4][NH:3][CH2:2]2.C(N(CC)C(C)C)(C)C.Cl[C:32]1[CH:41]=[CH:40][C:39]2[C:34](=[CH:35][CH:36]=[C:37]([F:42])[CH:38]=2)[N:33]=1>FC(F)(F)C([O-])=O>[F:42][C:37]1[CH:38]=[C:39]2[C:34](=[CH:35][CH:36]=1)[N:33]=[C:32]([N:3]1[CH2:4][CH:5]3[CH:1]([CH:6]3[NH:7][C:8]([O:10][CH2:11][C:12]3[O:16][N:15]=[C:14]([C:17]([O:19][CH2:20][CH3:21])=[O:18])[CH:13]=3)=[O:9])[CH2:2]1)[CH:41]=[CH:40]2
Reactant: Fc1ccc2nc(Cl)ccc2c1
Reactant: CCOC(=O)c1cc(COC(=O)NC2C3CNCC32)on1
Agent: O=C([O-])C(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)c1cc(COC(=O)NC2C3CN(c4ccc5cc(F)ccc5n4)CC32)on1
Yield: 36.5 %

Procedure:
Starting from 1.55 g (3.79 mmol) of ethyl 5-{[(3-azabicyclo[3.1.0]hex-6-ylcarbamoyl)oxy]methyl}isoxazole-3-carboxylate in trifluoroacetate form, 1.98 ml (11.37 mmol) of N,N-diisopropylethylamine, and 0.68 g (3.79 mmol) of 2-chloro-6-fluoro-quinoline, and eluting with a 99/1 to 98/2 mixture of dichloromethane and methanol, 0.61 g (36%) of product is obtained in the form of an orange oil.
Reaction SMILES: [CH3:1][S:2]([NH:5][C:6]1[CH:14]=[CH:13][CH:12]=[C:11]2[C:7]=1[C:8](=[O:24])[N:9]([CH2:16][C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[C:10]2=[O:15])(=[O:4])=[O:3].Cl.Cl[CH2:27][CH2:28][N:29]1[CH2:34][CH2:33][O:32][CH2:31][CH2:30]1.C([O-])([O-])=O.[K+].[K+]>C(#N)C>[O:32]1[CH2:33][CH2:34][N:29]([CH2:28][CH2:27][N:5]([C:6]2[CH:14]=[CH:13][CH:12]=[C:11]3[C:7]=2[C:8](=[O:24])[N:9]([CH2:16][C:17]([O:19][C:20]([CH3:21])([CH3:23])[CH3:22])=[O:18])[C:10]3=[O:15])[S:2]([CH3:1])(=[O:3])=[O:4])[CH2:30][CH2:31]1
Reactant: ClCCN1CCOCC1
Reactant: CC(C)(C)OC(=O)CN1C(=O)c2cccc(NS(C)(=O)=O)c2C1=O
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CC(C)(C)OC(=O)CN1C(=O)c2cccc(N(CCN3CCOCC3)S(C)(=O)=O)c2C1=O
Temperature: 75 °C
Reaction time: 8 h
Yield: 99 %

Procedure:
A mixture of tert-butyl 2-(4-(methylsulfonamido)-1,3-dioxoisoindolin-2-yl)acetate (196 mg, 0.553 mmol) (prepared with an analogous procedure to that described in, Example 29, Scheme 29, Steps 1, 2, 3, 4 for the preparation of Compound 160), 4-(2-chloroethyl)morpholine hydrochloride (108 mg, 0.581 mmol), and K2CO3 (168 mg, 1.217 mmol) in acetonitrile (10 ml) was stirred at 75° C. overnight. The solvent was removed under vacuum, and the residue was taken up in a EtOAc/DCM/Et2O mixture and filtered through Na2SO4 to remove the inorganic salts. After evaporation of the solvent, tert-butyl 2-(4-(N-(2-morpholinoethyl)methylsulfonamido)-1,3-dioxoisoindolin-2-yl)acetate was obtained (256 mg, 0.548 mmol, 99% yield, MS/ESI+ 467 [MH]+).
Reaction SMILES: [NH2:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([O:12][C:13]2[C:22]3[NH:21][C:20](=[O:23])[C:19]([C:24]([F:27])([F:26])[F:25])=[N:18][C:17]=3[N:16]=[CH:15][CH:14]=2)=[CH:4][CH:3]=1.[F:28][C:29]1[CH:34]=[CH:33][C:32]([C:35]([F:38])([F:37])[F:36])=[CH:31][C:30]=1[N:39]=[C:40]=[O:41]>>[F:28][C:29]1[CH:34]=[CH:33][C:32]([C:35]([F:38])([F:37])[F:36])=[CH:31][C:30]=1[NH:39][C:40]([NH:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([O:12][C:13]2[C:22]3[NH:21][C:20](=[O:23])[C:19]([C:24]([F:27])([F:26])[F:25])=[N:18][C:17]=3[N:16]=[CH:15][CH:14]=2)=[CH:4][CH:3]=1)=[O:41]
Reactant: Nc1ccc(Oc2ccnc3nc(C(F)(F)F)c(=O)[nH]c23)c2ccccc12
Reactant: O=C=Nc1cc(C(F)(F)F)ccc1F
Product: O=C(Nc1cc(C(F)(F)F)ccc1F)Nc1ccc(Oc2ccnc3nc(C(F)(F)F)c(=O)[nH]c23)c2ccccc12

Procedure:
Method F2 was used with 8-(4-aminonaphthalen-1-yloxy)-3-(trifluoromethyl)pyrido[2,3-b]pyrazin-2(1H)-one and 1-fluoro-2-isocyanato-4-(trifluoromethyl)benzene to afford the title compound was obtained as a slightly yellow solid (5 mg, 5%).
Reaction SMILES: [F:1][C:2]([F:8])([F:7])[CH2:3][C:4](O)=[O:5].Cl.C(N=C=NCCCN(C)C)C.ON1C2N=CC=CC=2N=N1.[NH2:31][C:32]1([C:35]([NH:37][C@@H:38]([C:40]2[CH:45]=[CH:44][C:43]([C:46]3[C:47]([C:53]([OH:55])=[O:54])=[C:48]([F:52])[CH:49]=[CH:50][CH:51]=3)=[CH:42][CH:41]=2)[CH3:39])=[O:36])[CH2:34][CH2:33]1.C(N(CC)C(C)C)(C)C>C(Cl)Cl>[F:52][C:48]1[CH:49]=[CH:50][CH:51]=[C:46]([C:43]2[CH:42]=[CH:41][C:40]([C@H:38]([NH:37][C:35]([C:32]3([NH:31][C:4](=[O:5])[CH2:3][C:2]([F:8])([F:7])[F:1])[CH2:34][CH2:33]3)=[O:36])[CH3:39])=[CH:45][CH:44]=2)[C:47]=1[C:53]([OH:55])=[O:54]
Reactant: O=C(O)CC(F)(F)F
Reactant: C[C@@H](NC(=O)C1(N)CC1)c1ccc(-c2cccc(F)c2C(=O)O)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2cccnc21
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: C[C@@H](NC(=O)C1(NC(=O)CC(F)(F)F)CC1)c1ccc(-c2cccc(F)c2C(=O)O)cc1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
To a solution of trifluoropropionic acid (128 mg, 1.0 mmol) in DCM (1 mL), 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (229 mg, 1.2 mmol) and 1-hydroxy-7-azabenzotriazole (136 mg, 1.0 mmol) were added. The resulting solution was stirred at room temperature for 20 minutes, then 4′-((1R)-1-{[(1-aminocyclopropyl)carbonyl]amino}ethyl)-3-fluoro-1,1′-biphenyl-2-carboxylic acid (171 mg, 0.5 mmol) in 1 mL DCM was added, followed by N,N-diisopropylethylamine until pH=10 was achieved. The reaction mixture was stirred at ambient temperature under N2 for 2 hours, concentrated under vacuum and then partitioned between water and ethyl acetate. The organic extract was washed with brine, dried over anhydrous magnesium sulfate, filtered and concentrated under vacuum. The residue was subjected to column chromatography on silica gel eluted with 40% MeOH in CHCl3. Collection and concentration of appropriate fractions provided 3-fluoro-4′-{(1R)-1-[({1-[(3,3,3-trifluoropropanoyl)amino]cyclopropyl}carbonyl)-amino]ethyl}-1,1′-biphenyl-2-carboxylic acid as a white powder.
Reaction SMILES: [CH2:1]([O:8][CH:9]1[CH2:12][CH:11]([C:13](O)=[O:14])[CH2:10]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O.C(=O)([O-])O.[Na+]>O1CCCC1>[CH2:1]([O:8][CH:9]1[CH2:12][CH:11]([CH2:13][OH:14])[CH2:10]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(O)C1CC(OCc2ccccc2)C1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: OCC1CC(OCc2ccccc2)C1
Yield: 93.8 %

Procedure:
3-benzyloxy-cyclobutanecarboxylic acid (1.67 g) in dry tetrahydrofuran (100 mL) was treated with borane-dimethylsulfide complex (1.3 mL) at 50° C. for 16 hours. Water (4 mL) and saturated sodium hydrogen carbonate (3 mL) were added and the mixture was extracted with ethyl acetate. The organic extracts were washed with brine, dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel, eluting with ethyl acetate in cyclohexane (0 to 1:1 by volume) to give the title compound (1.46 g). 1H NMR (400 MHz, CHCl3-d): δ 7.29 (d, 5H), 4.36 (d, 2H), 4.08 (t, 1H), 3.91-3.82 (m, 1H), 3.53 (t, 2H), 2.39-2.30 (m, 1H), 2.33-2.22 (m, 1H), 2.10-2.02 (m, 2H), 1.72-1.63 (m, 1H).
Reaction SMILES: [CH3:1][N:2]1[CH2:15][CH2:14][C:5]2[NH:6][C:7]3[CH:8]=[CH:9][C:10]([CH3:13])=[CH:11][C:12]=3[C:4]=2[CH2:3]1.[F:16][C:17]([F:30])([F:29])[C:18]1[N:23]=[CH:22][C:21](/[CH:24]=[CH:25]\[C:26]([OH:28])=[O:27])=[CH:20][CH:19]=1.[OH-].[K+]>CN1C(=O)CCC1>[F:29][C:17]([F:16])([F:30])[C:18]1[N:23]=[CH:22][C:21]([CH2:24][CH:25]([N:6]2[C:7]3[CH:8]=[CH:9][C:10]([CH3:13])=[CH:11][C:12]=3[C:4]3[CH2:3][N:2]([CH3:1])[CH2:15][CH2:14][C:5]2=3)[C:26]([OH:28])=[O:27])=[CH:20][CH:19]=1
Reactant: O=C(O)/C=C\c1ccc(C(F)(F)F)nc1
Reactant: Cc1ccc2[nH]c3c(c2c1)CN(C)CC3
Agent: [K+]
Agent: [OH-]
Solvent: CN1CCCC1=O
Product: Cc1ccc2c(c1)c1c(n2C(Cc2ccc(C(F)(F)F)nc2)C(=O)O)CCN(C)C1

Procedure:
The title compound is prepared from a mixture of 2,3,4,5-tetrahydro-2,8-dimethyl-1H-pyrido[4,3-b]indole, (Z)-3-(6-(trifluoromethyl)pyridin-3-yl)acrylic acid and KOH (5-7 equiv) in NMP at a temperature ranging between 25 deg C. to 100 deg C. The product obtained is isolated by preparative HPLC.
Reaction SMILES: [Br:1][C:2]1[C:10]2[S:9][C:8]([C:11]([OH:13])=O)=[CH:7][C:6]=2[CH:5]=[CH:4][CH:3]=1.[ClH:14].Cl.[NH2:16][C@@H:17]1[CH:22]2[CH2:23][CH2:24][N:19]([CH2:20][CH2:21]2)[CH2:18]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C>CN(C=O)C>[ClH:14].[N:19]12[CH2:24][CH2:23][CH:22]([CH2:21][CH2:20]1)[CH:17]([NH:16][C:11]([C:8]1[S:9][C:10]3[C:2]([Br:1])=[CH:3][CH:4]=[CH:5][C:6]=3[CH:7]=1)=[O:13])[CH2:18]2
Reactant: N[C@H]1CN2CCC1CC2
Reactant: O=C(O)c1cc2cccc(Br)c2s1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=C(NC1CN2CCC1CC2)c1cc2cccc(Br)c2s1

Procedure:
903.8 mg (3.52 mmol) of 7-bromo-1-benzothiophene-2-carboxylic acid (Example 7A), 700 mg (3.52 mmol) of (R)-3-aminoquinuclidine dihydrochloride, 1604.0 mg (4.22 mmol) of HATU, 1635.7 mg (12.66 mmol) of N,N-diisopropylethylamine and 7.0 ml of DMF are reacted by general method C. The reaction mixture is purified by preparative HPLC. The product is dissolved in a 1:1 mixture of 4 M hydrogen chloride in dioxane and 1N hydrochloric acid and then concentrated and dried under high vacuum. 1087 mg (77% of theory) of the title compound are obtained.
Reaction SMILES: [O:1]=[C:2]1[C:11]2[NH:12][CH:13]=[C:14]([C:15]([OH:17])=O)[C:10]=2[C:9]2[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=2[NH:3]1.[CH3:18][N:19]1CCOCC1.Cl.CN>C(OCC)C>[CH3:18][NH:19][C:15]([C:14]1[C:10]2[C:9]3[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=3[NH:3][C:2](=[O:1])[C:11]=2[NH:12][CH:13]=1)=[O:17]
Reactant: O=C(O)c1c[nH]c2c(=O)[nH]c3ccccc3c12
Reactant: CN1CCOCC1
Agent: CN
Agent: Cl
Solvent: CCOCC
Product: CNC(=O)c1c[nH]c2c(=O)[nH]c3ccccc3c12
Yield: 7.3 %

Procedure:
This compound is prepared according to synthesis 79 from 37 mg (0.17 mmol) of 4-oxo-4,5-dihydro-3H-pyrrolo[2,3-c]quinoline-1-carboxylic acid (synthesis 75), 108 μL (0.99 mmol) of N-methylmorpholine and 17 mg (0.25 mmol) of methylamine hydrochloride. After trituration in diethyl ether, 3 mg (7%) of N-(methyl)-4-oxo-4,5-dihydro-3H-pyrrolo[2,3-c]quinoline-1-carboxamide are obtained in the form of a light brown solid.