Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CS(C)=O.[CH2:5]([C:9]1[N:13]([CH2:14][C:15]2[CH:20]=[CH:19][C:18]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=3[C:27]3[N:31]([C:32]([C:45]4[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=4)([C:39]4[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=4)[C:33]4[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=4)[N:30]=[N:29][N:28]=3)=[CH:17][CH:16]=2)[C:12]([CH2:51]OS(C)(=O)=O)=[C:11]([Cl:57])[N:10]=1)[CH2:6][CH2:7][CH3:8].[N-:58]=[N+:59]=[N-:60].[Na+].[Na+].[Cl-]>CCOC(C)=O>[N:58]([CH2:51][C:12]1[N:13]([CH2:14][C:15]2[CH:20]=[CH:19][C:18]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=3[C:27]3[N:31]([C:32]([C:45]4[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=4)([C:39]4[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=4)[C:33]4[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=4)[N:30]=[N:29][N:28]=3)=[CH:17][CH:16]=2)[C:9]([CH2:5][CH2:6][CH2:7][CH3:8])=[N:10][C:11]=1[Cl:57])=[N+:59]=[N-:60]
Reactant: CCCCc1nc(Cl)c(COS(C)(=O)=O)n1Cc1ccc(-c2ccccc2-c2nnnn2C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Reactant: [N-]=[N+]=[N-]
Agent: [Cl-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: CCCCc1nc(Cl)c(CN=[N+]=[N-])n1Cc1ccc(-c2ccccc2-c2nnnn2C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 86.9 %

Procedure:
To a dimethyl sulfoxide (100 mL) solution of intermediate (11c) (15 g, 20 mmol) was added sodium azide (3.9 g, 60 mmol). The mixture was stirred at room temperature for 20 minutes. EtOAc (500 mL) and saturated aqueous NaCl (100 mL) were added and the layers were separated, retaining the organic layer. The organic was washed an additional three times with saturated aqueous NaCl (100 mL). After drying over sodium sulfate and filtration, the removal of solvent provided intermediate (11d) as a yellow solid (12 g), which was used directly in the next step. MS m/z: [M+H+] calcd for C41H36ClN9, 690.29; found 690.5.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C:16]2[C:11](=[CH:12][C:13]([OH:17])=[CH:14][CH:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(=O)([O-])[O-].[Cs+].[Cs+].[C:24]([CH:28]1[CH2:33][CH2:32][CH:31](OS(C)(=O)=O)[CH2:30][CH2:29]1)([CH3:27])([CH3:26])[CH3:25].ClCCl>C(O)(C)(C)C.CC(=O)CC>[C:1]([O:5][C:6]([N:8]1[C:16]2[C:11](=[CH:12][C:13]([O:17][C@H:31]3[CH2:32][CH2:33][C@H:28]([C:24]([CH3:27])([CH3:26])[CH3:25])[CH2:29][CH2:30]3)=[CH:14][CH:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCc2cc(O)ccc21
Reactant: CC(C)(C)C1CCC(OS(C)(=O)=O)CC1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCC(C)=O
Solvent: ClCCl
Solvent: CC(C)(C)O
Product: CC(C)(C)OC(=O)N1CCc2cc(O[C@H]3CC[C@H](C(C)(C)C)CC3)ccc21
Temperature: 100 °C

Procedure:
A mixture of 5-hydroxy-2,3-dihydro-indole-1-carboxylic acid tert-butyl ester (0.6 g, 2.6 mmol) in tert-butyl alcohol (8 ml) and 2-butanone (4 mL) was added cesium carbonate (2.5 g, 7.7 mmol) followed by methanesulfonic acid 4-tert-butyl-cyclohexyl ester (1.9 g, 7.7 mmol). The mixture was heated in a sealed vial at 100° C. over night to form precipitate. The mixture was treated with dichloromethane and the precipitate was filtered off and the solvent was concentrated. The residue was purified with a silica gel column eluted with ethyl acetate in hexanes from 0 to 30% to give precipitate (0.96 g, yield: 100%). ESI-MS: 373.30 (M)+.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[C:14]([F:17])([F:16])[F:15])[N:5]=[C:4]([NH2:18])[C:3]=1[N+:19]([O-:21])=[O:20].C([O-])([O-])=O.[K+].[K+].[NH:28]1[CH2:33][CH2:32][O:31][CH2:30][CH2:29]1>CN(C=O)C.O>[N:28]1([C:2]2[CH:7]=[C:6]([C:8]3[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=3[C:14]([F:17])([F:16])[F:15])[N:5]=[C:4]([NH2:18])[C:3]=2[N+:19]([O-:21])=[O:20])[CH2:33][CH2:32][O:31][CH2:30][CH2:29]1
Reactant: Nc1nc(-c2ccccc2C(F)(F)F)cc(Cl)c1[N+](=O)[O-]
Reactant: C1COCCN1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: Nc1nc(-c2ccccc2C(F)(F)F)cc(N2CCOCC2)c1[N+](=O)[O-]
Temperature: 80 °C
Reaction time: 8 h

Procedure:
To a solution of 4-chloro-3-nitro-6-(2-trifluoromethyl-phenyl)-pyridin-2-ylamine (900 mg, 2.83 mmol, prepared as described in the Example 1) in DMF (5 mL), K2CO3 (1.90 g, 14.0 mmol) was added followed by addition of morpholine (0.240 mL, 2.80 mmol). The resulting mixture was stirred at 80° C. overnight. The resulting mixture was diluted with water (20 mL) and extracted with EtOAc (3×10 mL). The organic layers were combined, dried (MgSO4) and concentrated. The resulting residue was purified on silica 0:100-50:50 EtOAc/hexanes to yield 4-morpholin-4-yl-3-nitro-6-(2-trifluoromethyl-phenyl)-pyridin-2-ylamine. Mass Spectrum (LCMS, ESI pos.) Calculated For Mass Spectrum (LCMS, ESI pos.) Calculated For C16H15F3N4O3: 369.1 (M+H), Measured: 369.1.
Reaction SMILES: Cl.[CH3:2][NH:3][CH3:4].[C:5]([O:9][C:10]([NH:12][C@@H:13]([CH2:17][CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[C:14](O)=[O:15])=[O:11])([CH3:8])([CH3:7])[CH3:6]>ClCCl.CN(C=O)C>[C:5]([O:9][C:10](=[O:11])[NH:12][C@H:13]([C:14](=[O:15])[N:3]([CH3:4])[CH3:2])[CH2:17][CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)([CH3:8])([CH3:7])[CH3:6]
Reactant: CC(C)(C)OC(=O)N[C@@H](CCc1ccccc1)C(=O)O
Reactant: CNC
Agent: Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CN(C)C(=O)[C@H](CCc1ccccc1)NC(=O)OC(C)(C)C

Procedure:
Dimethylamine hydrochloride (1.0 mmol) and (S)-N-t-butoxycarbonyl-2-amino-4-phenylbutyric acid (0.84 mmol) were coupled according to Procedure A (0-25° C. reaction temperature, 3:1 dichloromethane/DMF reaction solvent) giving the product which was used without further purification. Yield 238 mg, 93%; HPLC (60/40) 5.98 minutes (97%).
Reaction SMILES: [CH2:1]1[C:7]2[CH:8]=[CH:9][C:10]([O:12][C:13]3[CH:21]=[CH:20][C:16]([C:17]([NH2:19])=[O:18])=[CH:15][N:14]=3)=[CH:11][C:6]=2[CH2:5][CH2:4][CH2:3][NH:2]1.C([O-])([O-])=O.[K+].[K+].Br[CH2:29][CH2:30][CH2:31][CH3:32].C(OCC)(=O)C>CN(C=O)C>[CH2:29]([N:2]1[CH2:3][CH2:4][CH2:5][C:6]2[CH:11]=[C:10]([O:12][C:13]3[CH:21]=[CH:20][C:16]([C:17]([NH2:19])=[O:18])=[CH:15][N:14]=3)[CH:9]=[CH:8][C:7]=2[CH2:1]1)[CH2:30][CH2:31][CH3:32]
Reactant: NC(=O)c1ccc(Oc2ccc3c(c2)CCCNC3)nc1
Reactant: CCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCCCN1CCCc2cc(Oc3ccc(C(N)=O)cn3)ccc2C1
Temperature: 95 °C

Procedure:
Mix 6-(2,3,4,5-tetrahydro-1H-benzo[c]azepin-7-yloxy)nicotinamide (Example 447, Part E, 0.350 g, 1.24 mmol), K2CO3 (0.427 g, 3.09 mmol), and 1-bromobutane (0.178 g, 1.30 mmol) in DMF (6.2 mL). Heat at 95° C. for 5.5 hours, then at 50° C. overnight. Cool the reaction mixture to room temperature and add ethyl acetate (100 mL). Wash with water (1×30 mL) and brine (1×30 mL). Dry the organic layer over Na2SO4, filter and concentrate. Purify by flash chromatography eluting with 6% to 20% (2.0 M NH3 in methanol) in ethyl acetate to give the title compound: MS ES+340.2 (M+H)+, HRMS calcd for C20H26N3O2 340.2025 (M+H)+, found 340.2019, time 0.53 min; HPLC [YMC-Pro pack C-18 (150×4.6 mm, S-5 microm), 0.05% TFA/acetonitrile in 0.05% TFA/water at 1.0 mL/min, 10-20% over 5 min, 20-95% over 18 min], tR=9.6 min, 98.3% purity.
Reaction SMILES: [NH2:1][C:2]1[C:3]([N:8]2[CH2:13][CH2:12][N:11]([C:14]([C:16]3[CH:24]=[CH:23][C:19]([C:20](O)=[O:21])=[CH:18][N:17]=3)=[O:15])[CH2:10][CH2:9]2)=[N:4][CH:5]=[CH:6][CH:7]=1.C1(N=C=NC2CCCCC2)CCCCC1.ON1C2C=CC=CC=2N=N1.Br.[NH2:51][CH:52]1[CH2:57][CH2:56][O:55][C:53]1=[O:54]>C(Cl)Cl.C(N(CC)CC)C.O1CCCC1>[NH2:1][C:2]1[C:3]([N:8]2[CH2:9][CH2:10][N:11]([C:14]([C:16]3[CH:24]=[CH:23][C:19]([C:20](=[O:21])[NH:51][CH:52]4[CH2:57][CH2:56][O:55][C:53]4=[O:54])=[CH:18][N:17]=3)=[O:15])[CH2:12][CH2:13]2)=[N:4][CH:5]=[CH:6][CH:7]=1
Reactant: Nc1cccnc1N1CCN(C(=O)c2ccc(C(=O)O)cn2)CC1
Reactant: NC1CCOC1=O
Agent: Br
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: C1CCOC1
Product: Nc1cccnc1N1CCN(C(=O)c2ccc(C(=O)NC3CCOC3=O)cn2)CC1
Reaction time: 2 h
Yield: 71 %

Procedure:
6-[1-(3-amino-2-pyridyl)piperazin-4-yl-carbonyl]nicotinic acid (1 g) was added to a co-solvent of tetrahydrofuran (25 ml) and methylene chloride (15 ml) and with the successive addition of 1.3-dicyclohexylcarbodimide (1.3 g) and 1-hydroxybenzotriazole (0.46 g) at 15° C.˜20° C., the mixture was stirred for 2 hours. A mixture of α-amino-γ-butyrolactone hydrobromide (1.1 g) and triethylamine (0.9 ml) was added again to the mixture at 20° C. and stirred at 20° C.˜25° C. for 3 hours. With the addition of methylene chloride (50 ml), the mixture was washed with water 3 times, dried over magnesium sulfate and concentrated under reduced pressure. The concentrated residue was treated with ether for crystallization and recrystallized with chloroform and tetrahydrofuran to give a desired compound of 1.07 g (yield: 71%).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH:9]1[CH2:14][CH2:13][CH:12]([NH:15][C:16]2[C:17]([CH3:30])=[C:18]([CH:23]=[C:24]([O:26][CH2:27][CH2:28][OH:29])[CH:25]=2)[C:19]([O:21][CH3:22])=[O:20])[CH2:11][CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH:31](=O)[CH3:32].C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClC(Cl)C>[C:1]([O:5][C:6]([NH:8][CH:9]1[CH2:14][CH2:13][CH:12]([N:15]([CH2:31][CH3:32])[C:16]2[C:17]([CH3:30])=[C:18]([CH:23]=[C:24]([O:26][CH2:27][CH2:28][OH:29])[CH:25]=2)[C:19]([O:21][CH3:22])=[O:20])[CH2:11][CH2:10]1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: COC(=O)c1cc(OCCO)cc(NC2CCC(NC(=O)OC(C)(C)C)CC2)c1C
Reactant: CC=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(Cl)Cl
Solvent: CC(=O)O
Product: CCN(c1cc(OCCO)cc(C(=O)OC)c1C)C1CCC(NC(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 89.7 %

Procedure:
To a stirred solution of methyl 3-((4-((tert-butoxycarbonyl)amino)cyclohexyl)amino)-5-(2-hydroxyethoxy)-2-methylbenzoate (2.0 g, 4.7 mmol) and acetaldehyde (0.63 g, 14.2 mmol) in dichloroethane (20 mL) was added acetic acid (1.7 g, 28 mmol) and the reaction mixture stirred at room temperature for 20 minutes. Then sodium triacetoxyborohydride (3.0 g, 14.2 mmol) was added at 0° C. and reaction was stirred at room temperature for 2 h. On completion, the reaction was quenched with aqueous sodium bicarbonate, the organic phase was separated and the aqueous phase extracted with dichloromethane. The combined organic layers were washed with water, dried, concentrated under reduced pressure; Crude material was purified by column chromatography to afford the title compound (1.9 g, 89%).
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][C:5]([CH2:26][C:27]([O:29][CH2:30][CH3:31])=[O:28])([NH:8][C:9]([NH:11][C:12]2[CH:17]=[CH:16][C:15]([CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])=[CH:14][CH:13]=2)=[O:10])[CH2:4][CH2:3]1.[CH3:32][I:33]>C(Cl)Cl>[I-:33].[CH2:30]([O:29][C:27](=[O:28])[CH2:26][C:5]1([NH:8][C:9]([NH:11][C:12]2[CH:17]=[CH:16][C:15]([CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])=[CH:14][CH:13]=2)=[O:10])[CH2:6][CH2:7][N+:2]([CH3:32])([CH3:1])[CH2:3][CH2:4]1)[CH3:31]
Reactant: CI
Reactant: CCCCCCCCc1ccc(NC(=O)NC2(CC(=O)OCC)CCN(C)CC2)cc1
Solvent: ClCCl
Product: CCCCCCCCc1ccc(NC(=O)NC2(CC(=O)OCC)CC[N+](C)(C)CC2)cc1
Product: [I-]
Temperature: 25 °C
Reaction time: 8 h
Yield: 98 %

Procedure:
A solution of ethyl 2-(1-methyl-4-(3-(4-octylphenyl)ureido)piperidin-4-yl)acetate (73 mg, 0.169 mmol) in CH2Cl2 (5 mL) was treated with MeI (0.11 mL, 1.69 mmol) and the reaction stirred overnight at room temperature. The solvent was removed in vacuo to yield crude title compound (95 mg, 98%) which was used without further purification. 1H NMR (400 MHz, CDCl3) δ 8.35 (bs, 1H), 7.42 (d, 2H, J=8.4 Hz), 7.05 (d, 2H, J=8.4 Hz), 6.49 (bs, 1H), 4.39-4.32 (m, 2H), 4.14 (q, 2H, J=7.2 Hz), 3.41-3.34 (m, 5H), 3.21 (s, 2H), 3.20 (s, 3H), 2.64-2.41 (m, 6H), 1.29-1.20 (m, 13H), 0.89 (t, 3H, 6.4 Hz); MS ESI 446.4 [M]+, calcd for [C26H44N3O3]+ 446.65.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:30]=[CH:29][C:8]([CH2:9][N:10]([C:19]2[CH:24]=[CH:23][C:22]([C:25]([O:27][CH3:28])=[O:26])=[CH:21][CH:20]=2)[C:11](=[O:18])[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16]Br)=[CH:7][CH:6]=1)=[O:4].[CH2:31]([O:41][C:42]1[CH:43]=[C:44]([OH:59])[CH:45]=[C:46]([O:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH2:54][CH2:55][CH2:56][CH2:57][CH3:58])[CH:47]=1)[CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH3:40].C([O-])([O-])=O.[K+].[K+]>C1(=O)CCCCC1>[CH3:1][O:2][C:3]([C:5]1[CH:30]=[CH:29][C:8]([CH2:9][N:10]([C:19]2[CH:24]=[CH:23][C:22]([C:25]([O:27][CH3:28])=[O:26])=[CH:21][CH:20]=2)[C:11](=[O:18])[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][O:59][C:44]2[CH:45]=[C:46]([O:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH2:54][CH2:55][CH2:56][CH2:57][CH3:58])[CH:47]=[C:42]([O:41][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH3:40])[CH:43]=2)=[CH:7][CH:6]=1)=[O:4]
Reactant: COC(=O)c1ccc(CN(C(=O)CCCCCBr)c2ccc(C(=O)OC)cc2)cc1
Reactant: CCCCCCCCCCOc1cc(O)cc(OCCCCCCCCCC)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O=C1CCCCC1
Product: CCCCCCCCCCOc1cc(OCCCCCCCCCC)cc(OCCCCCC(=O)N(Cc2ccc(C(=O)OC)cc2)c2ccc(C(=O)OC)cc2)c1
Yield: 84.7 %

Procedure:
A mixture of compound 19b (540 mg, 1.13 mmol), phenol 9 (461 mg, 1.13 mmol), K2CO3 (392 mg, 2.83 mmol), and a catalytic amount of KI in cyclohexanone (6.50 ml) is reacted in analogy to the already described reaction instructions for the synthesis of compound 20a. The subsequent purification through column chromatography (silica gel, ethyl acetate/petroleum ether 1:2) produced 768 mg (85%) of compound 20b as colorless oil. IR (film) 2900, 2830, 1710, 1650, 1590 cm−1; 1H-NMR (CDCl3) δ 8.00 (d, 8.6 Hz, 2H), 7.94 (d, 8.4 Hz, 2H), 7.25 (d, 8.4 Hz, 2H), 7.05 (d, 8.6 Hz, 2H), 6.05 (t, 1.9 Hz, 1H), 6.02 (d, 1.9 Hz, 2H), 4.95 (s, 2H), 3.92 (s, 3H), 3.91-3.82 superimposed signals (3.90, s, 3H and m, 6H), 2.12 (t, 7.4 Hz, 2H), 1.80-1.61 (m, 8H), 1.47-1.20 (m, 30H), 0.88 (t, 6.7 Hz, 6H); MS (FD) m/z 802 (M+). Anal. calc. for C49H71NO8: C, 73.37; H, 8.92; N, 1.75. Found C, 73.25; H, 8.78; N, 1.87.
Reaction SMILES: [NH2:1][S:2]([C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[NH:10][C:9](=[O:14])[CH2:8]2)(=[O:4])=[O:3].[CH2:15]([O:17][C:18]([C:20]([C:22]1[NH:23][CH:24]=[CH:25][CH:26]=1)=O)=[O:19])[CH3:16].C(N(CC)CC)C>C(O)C>[NH2:1][S:2]([C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[NH:10][C:9](=[O:14])[C:8]2=[C:20]([C:22]1[NH:23][CH:24]=[CH:25][CH:26]=1)[C:18]([O:17][CH2:15][CH3:16])=[O:19])(=[O:4])=[O:3]
Reactant: CCOC(=O)C(=O)c1ccc[nH]1
Reactant: NS(=O)(=O)c1ccc2c(c1)CC(=O)N2
Solvent: CCN(CC)CC
Solvent: CCO
Product: CCOC(=O)C(=C1C(=O)Nc2ccc(S(N)(=O)=O)cc21)c1ccc[nH]1
Temperature: 25 °C

Procedure:
Alternatively, a mixture of 5-aminosulfonylindolin-2-one (1.0 g, 4.7 mmol), 2-ethoxycarbonylcarbonylpyrrole (2.5 g, 14.5 mmol) in ethanol (120 mL) was treated with triethylamine (1.0 mL, 7.2 mmol). The reaction mixture was refluxed for 24 hours. The reaction mixture was concentrated to approximately 20 mL, treated with additional triethylamine (0.2 mL, 1.44 mmol) and refluxed for 55 hoursr. The reaction was then cooled to ambient temperature and concentrated. Reverse phase HPLC using acetonitrile/water afforded 5-aminosulfonyl-3-[(pyrrol-2-yl)(ethoxycarbonyl)methylene]indolin-2-one; 1H NMR (400 MHz, DMSO-d6) δ 1.35 (t, 3H), 4.50 (q, 2H), 6.40 (s, 1H), 6.65 (s, 1H), 7.06 (d, 1H), 7.25(s, 2H), 7.48 (br s, 1H), 7.50 (s, 1H), 7.68 (d, 1H), 11.50 (s, 1H) ppm; (45 mg) and 5-aminosulfonyl-3-[(pyrrol-2-yl)(carboxy)methylene]indolin-2-one; 1H NMR (400 MHz, DMSO-d6) δ 6.40 (s, 1H), 6.65 (s, 1H), 7.06 (d, 1H), 7.25 (s, 2H), 7.48 (br s, 1H), 7.68 (d, 1H), 7.85 (s, 1H), 11.50 (s, 1H) ppm; (48 mg).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[C:10]([NH:12][C:13](=[O:18])[C:14]([CH3:17])([CH3:16])[CH3:15])[CH:9]=[CH:8][C:4]=1[C:5](Cl)=[O:6].[CH3:19][NH:20][CH3:21].O>C1COCC1>[CH3:1][O:2][C:3]1[CH:11]=[C:10]([NH:12][C:13](=[O:18])[C:14]([CH3:17])([CH3:16])[CH3:15])[CH:9]=[CH:8][C:4]=1[C:5]([N:20]([CH3:21])[CH3:19])=[O:6]
Reactant: CNC
Reactant: COc1cc(NC(=O)C(C)(C)C)ccc1C(=O)Cl
Solvent: O
Solvent: C1CCOC1
Product: COc1cc(NC(=O)C(C)(C)C)ccc1C(=O)N(C)C
Reaction time: 1 h

Procedure:
2-Methoxy-4-(2',2'-dimethylpropionamido)-benzoyl chloride (1.12 g) in dry THF (10 ml) was added dropwise over 30 minutes to a stirred solution of dimethylamine (1.17 g of a 40% aqueous solution) in THF (15 ml) at 0°-5° C. After completion of the addition the solution was stirred for 1 hour at 5°-10° C., stood at room temperature overnight, poured into water, and extracted with ethyl acetate. The extract was dried and evaporated to give the product as a yellow solid (0.889 g), m.p. 143°-144° C.
Reaction SMILES: [F:1][CH:2]([F:5])[CH2:3]Cl.[CH2:6]([NH2:13])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.C(N(CC)CC)C.Cl>CN1CCCC1=O>[CH2:6]([NH:13][CH2:3][CH:2]([F:5])[F:1])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: FC(F)CCl
Reactant: NCc1ccccc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CN1CCCC1=O
Product: FC(F)CNCc1ccccc1
Yield: 92.7 %

Procedure:
An amount of 10 g (92 mmol) of 2,2-difluoro-1-chloroethane, 5 g (46 mmol) of benzylamine and 5.2 g (51 mmol) of triethylamine are heated in 20.6 g of N-methylpyrrolidone in an autoclave at an internal temperature of 120° C. for 6 hours. Subsequently, 100 g of 1N hydrochloric acid are added and the solvent is removed under vacuum. The residue is taken up in 30 ml of dichloromethane and adjusted to pH 8 with solid sodium hydrogencarbonate. The phases are subsequently separated and the aqueous phase is again extracted with 20 ml of dichloromethane. The organic phase is distilled. An amount of 7.3 g of N-benzyl-2,2-difluoroethanamine is obtained, which corresponds to a yield of 93%, based on benzylamine.
Reaction SMILES: ClC1C(Cl)=C(/C=C(/[N+]([O-])=O)\CC)C=CC=1OCCCC(O)=O.[Cl:23][C:24]1[C:37]([Cl:38])=[C:36](/[CH:39]=[C:40](/[N+:43]([O-:45])=[O:44])\[CH2:41][CH3:42])[CH:35]=[CH:34][C:25]=1[O:26][C:27]1([C:31](O)=[O:32])[CH2:30][CH2:29][CH2:28]1.NCC(O)=O.[NH2:51][CH2:52][CH2:53][C:54]([OH:56])=[O:55]>>[Cl:23][C:24]1[C:37]([Cl:38])=[C:36](/[CH:39]=[C:40](/[N+:43]([O-:45])=[O:44])\[CH2:41][CH3:42])[CH:35]=[CH:34][C:25]=1[O:26][C:27]1([C:31]([NH:51][CH2:52][CH2:53][C:54]([OH:56])=[O:55])=[O:32])[CH2:30][CH2:29][CH2:28]1
Reactant: NCCC(=O)O
Reactant: CC/C(=C\c1ccc(OC2(C(=O)O)CCC2)c(Cl)c1Cl)[N+](=O)[O-]
Agent: CC/C(=C\c1ccc(OCCCC(=O)O)c(Cl)c1Cl)[N+](=O)[O-]
Agent: NCC(=O)O
Product: CC/C(=C\c1ccc(OC2(C(=O)NCCC(=O)O)CCC2)c(Cl)c1Cl)[N+](=O)[O-]

Procedure:
By carrying out the reaction essentially as described in Example 9, except that the (E)-4-[2,3-dichloro-4-(2-nitro-1-butenyl)phenoxy]butyric acid is replaced by an equimolar quantity of (E)-1-[2,3-dichloro-4-(2-nitro-1-butenyl)phenoxy]cyclobutane-1-carboxylic acid and the glycine is replaced by an equimolar quantity of β-alanine, there is obtained N-{(E)-1-[2,3-dichloro-4-(2-nitro-1-butenyl)phenoxy]-cyclobutane-1-carbonyl}-3-aminopropionic acid.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7]2[N:8]([C:16]3[CH:21]=[CH:20][C:19]([S:22]([NH2:25])(=[O:24])=[O:23])=[CH:18][CH:17]=3)[CH:9]=[C:10]([C:12]([F:15])([F:14])[F:13])[N:11]=2)[CH:2]=1.[C:26](OC(=O)C)(=[O:28])[CH3:27].C(N(CC)CC)C>CN(C)C1C=CN=CC=1.O>[N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7]2[N:8]([C:16]3[CH:21]=[CH:20][C:19]([S:22]([NH:25][C:26](=[O:28])[CH3:27])(=[O:23])=[O:24])=[CH:18][CH:17]=3)[CH:9]=[C:10]([C:12]([F:13])([F:14])[F:15])[N:11]=2)[CH:2]=1
Reactant: CC(=O)OC(C)=O
Reactant: NS(=O)(=O)c1ccc(-n2cc(C(F)(F)F)nc2-c2cccnc2)cc1
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: O
Product: CC(=O)NS(=O)(=O)c1ccc(-n2cc(C(F)(F)F)nc2-c2cccnc2)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 89.6 %

Procedure:
A mixture of 4-[2-(pyridin-3-yl)-4-(trifluoromethyl)-1H-imidazol-1-yl]benzenesulfonamide (0.5 g, 1.36 mmol), acetic anhydride (0.42 g, 4.1 mmol), 4-dimethylaminopyridine (DMAP) (0.083 g, 0.68 mmol) and triethylamine (0.17 g, 1.6 mmol) was stirred at room temperature for 16 hours. The reaction mixture was diluted with 50 mL of water and extracted with ethyl acetate. The organic layer was washed with water, brine, dried over magnesium sulfate and filtered. The filtrate was concentrated under vacuum and the residue was recrystallized from ethyl acetate and hexane to afford 0.5 g (90%) of N-[[4-[2-(3-pyridinyl)-4-(trifluoromethyl)-1H-imidazol-1-yl]phenyl]sulfonyl]acetamide as a colorless solid: mp (DSC): 244-246 _C. Anal. Calc'd. for C17H13F3N4O3S: C, 49.76; H, 3.19; N, 13.65; S, 7.81. Found: C, 49.66; H, 3.06; N, 13.53; S, 8.11.
Reaction SMILES: [O:1]([C:3]([C:5]1[CH:10]([C:11]2[CH:16]=[CH:15][C:14]([F:17])=[C:13]([F:18])[CH:12]=2)[N:9]([C:19]([NH:21][CH2:22][CH2:23][CH2:24][C:25]([NH:27][C:28]2[CH:29]=[C:30]([CH:34]3[CH2:39][CH2:38][N:37](C(OC(C)(C)C)=O)[CH2:36][CH2:35]3)[CH:31]=[CH:32][CH:33]=2)=[O:26])=[O:20])[C:8](=[O:47])[NH:7][C:6]=1[CH3:48])=[O:4])[CH3:2].FC(F)(F)C(O)=O>ClCCl>[O:1]([C:3]([C:5]1[CH:10]([C:11]2[CH:16]=[CH:15][C:14]([F:17])=[C:13]([F:18])[CH:12]=2)[N:9]([C:19]([NH:21][CH2:22][CH2:23][CH2:24][C:25](=[O:26])[NH:27][C:28]2[CH:33]=[CH:32][CH:31]=[C:30]([CH:34]3[CH2:39][CH2:38][NH:37][CH2:36][CH2:35]3)[CH:29]=2)=[O:20])[C:8](=[O:47])[NH:7][C:6]=1[CH3:48])=[O:4])[CH3:2]
Reactant: COC(=O)C1=C(C)NC(=O)N(C(=O)NCCCC(=O)Nc2cccc(C3CCN(C(=O)OC(C)(C)C)CC3)c2)C1c1ccc(F)c(F)c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COC(=O)C1=C(C)NC(=O)N(C(=O)NCCCC(=O)Nc2cccc(C3CCNCC3)c2)C1c1ccc(F)c(F)c1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 28.4 %

Procedure:
Into a solution of tert-butyl 4-{3-[(4-{[(5-Methoxylcarbonyl-6-(3,4-difluorophenyl)-4-methyl-2-oxo-3,6-dihydro-1(2H)-pyrimidinyl)carbonyl]amino}butanoyl)amino]phenyl}-1-piperidinecarboxylate (378 mg, 0.579 mmol) in dichloromethane (5.00 mL) at 0° C. was slowly added trifluoroacetic acid (659 mg, 5.79 mmol). The reaction mixture was stirred at room temperature for 10 min and concentrated in vacuo. The residue was dissolved in iso-PrOH/CHCl3 (1:3, 10 mL) and basified to pH 11 with 10% KOH solution, washed with H2O, followed by brine. The organic layer was dried over MgSO4 and concentrated in vacuo. The residue was purified by flash chromatography (dichloromethane:methanol 5:1) to afford the desired product (93.8 mg, 29.3%): 1H NMR (400 MHz, CDCl3) δ 7.46-7.43 (m, 3H), 7.35-7.29 (m, 2H), 7.12-7.06 (m, 3H), 6.63-6.60 (m, 1H), 6.56-6.52 (m, 2H), 3.26 (s, 3H), 3.22 (s, 3H), 2.72 (dt, 6H, J=2.3, 12.3 Hz), 2.66 (tt, 2H, J=3.6, 11.9 Hz), 2.55 (tt, 1H, J=3.8, 11.9 Hz), 1.88-1.82 (m, 1H), 1.75-1.63 (m, 6H); ESMS m/e: 554.3 (M+H)+.
Reaction SMILES: Cl[C:2]1[N:11]=[C:10]2[C:5]([C:6](=[O:17])[C:7]([C:14]([OH:16])=[O:15])=[CH:8][N:9]2[CH2:12][CH3:13])=[CH:4][C:3]=1[F:18].[C:19]([CH2:22][NH:23][CH:24]1[CH2:28][CH2:27][NH:26][CH2:25]1)(=[O:21])[CH3:20].C(N(CC)CC)C>C(O)C>[C:19]([CH2:22][NH:23][CH:24]1[CH2:28][CH2:27][N:26]([C:2]2[N:11]=[C:10]3[C:5]([C:6](=[O:17])[C:7]([C:14]([OH:16])=[O:15])=[CH:8][N:9]3[CH2:12][CH3:13])=[CH:4][C:3]=2[F:18])[CH2:25]1)(=[O:21])[CH3:20]
Reactant: CC(=O)CNC1CCNC1
Reactant: CCn1cc(C(=O)O)c(=O)c2cc(F)c(Cl)nc21
Solvent: CCN(CC)CC
Solvent: CCO
Product: CCn1cc(C(=O)O)c(=O)c2cc(F)c(N3CCC(NCC(C)=O)C3)nc21
Yield: 98.4 %

Procedure:
A mixture containing 7-chloro-1-ethyl-6-fluoro-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acid (5.41 g), 3-(N-acetylmethylamino)pyrrolidine (4.26 g), triethylamine (6.06 g), and ethanol (100 ml) was heated under reflux for 2 hours with stirring. The reaction mixture was concentrated to dryness under reduced pressure. To the residue was added water (70 ml) and acetic acid (15 ml). After cooling the mixture, the precipitate was collected, washed with water, and recrystallized from dimethylformamide. There were obtained 7.4 g of 7-[3-(N-acetylmethylamino)-1-pyrrolidinyl]-1-ethyl-6-fluoro-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acid, m.p. 287°-289° C.