Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O:2][C:3](=[O:34])[CH2:4][CH:5]([C:19]1[CH:24]=[CH:23][C:22]([O:25][CH:26]([F:28])[F:27])=[C:21]([O:29][CH2:30][CH:31]2[CH2:33][CH2:32]2)[CH:20]=1)[N:6]1[CH2:14][C:13]2[C:8](=[C:9]([N+:15]([O-:17])=[O:16])[CH:10]=[CH:11][CH:12]=2)[C:7]1=[O:18].[OH-].[Na+].Cl>CO>[CH:31]1([CH2:30][O:29][C:21]2[CH:20]=[C:19]([CH:5]([N:6]3[CH2:14][C:13]4[C:8](=[C:9]([N+:15]([O-:17])=[O:16])[CH:10]=[CH:11][CH:12]=4)[C:7]3=[O:18])[CH2:4][C:3]([OH:34])=[O:2])[CH:24]=[CH:23][C:22]=2[O:25][CH:26]([F:28])[F:27])[CH2:33][CH2:32]1
Reactant: COC(=O)CC(c1ccc(OC(F)F)c(OCC2CC2)c1)N1Cc2cccc([N+](=O)[O-])c2C1=O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)CC(c1ccc(OC(F)F)c(OCC2CC2)c1)N1Cc2cccc([N+](=O)[O-])c2C1=O
Temperature: 0 °C
Reaction time: 1 h
Yield: 86.5 %

Procedure:
To a suspension of 3-(3-cyclopropylmethoxy-4-difluoromethoxy-phenyl)-3-(7-nitro-1-oxo-1,3-dihydro-isoindol-2-yl)-propionic acid methyl ester (550 mg, 1.2 mmol) in methanol (5 ml) was added dropwise 10 N NaOH (0.23 ml, 2.3 mmol) at 0° C. The mixture was stirred at 0° C. for 1 hour. Then it was allowed to warm up to room temperature and stirred for 2 hours. 4N HCl was added until pH=5. The mixture was extracted with methylene chloride (30 ml) and 1N HCl (30 ml). The organic layer was washed with water (2×30 ml), brine (30 ml) and dried over magnesium sulfate. The solvent was removed in vacuo to give 3-(3-cyclopropylmethoxy-4-difluoromethoxy-phenyl)-3-(7-nitro-1-oxo-1,3-dihydro-isoindol-2-yl)-propionic acid as a yellow solid (480 mg, 90%). 1HNMR (CDCl3): δ 0.31-0.37 (m, 2H), 0.59-0.67 (m, 2H), 1.22-1.28 (m, 1H), 3.11 (dd, J=6.5, 15 Hz, 1H), 3.33 (dd, J=9, 15 Hz, 1H), 3.78-3.87 (m, 2H), 4.18 (d, J=17.5 Hz, 1H), 4.46 (d, J=17.5 Hz, 1H), 5.83 (dd, J=6.5, 9 Hz, 1H), 6.61 (t, JH-F=75 Hz, 1H), 6.91-7.17 (m, 3H), 7.59-7.76 (m, 3H).
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[C:3](=O)[CH2:4][C:5](OCC)=[O:6].[CH3:13][NH:14][NH2:15]>CCOCC>[F:1][C:2]([F:12])([F:11])[C:3]1[N:14]([CH3:13])[N:15]=[C:5]([OH:6])[CH:4]=1
Reactant: CCOC(=O)CC(=O)C(F)(F)F
Reactant: CNN
Solvent: CCOCC
Product: Cn1nc(O)cc1C(F)(F)F
Temperature: 24 °C
Yield: 25.3 %

Procedure:
A flask was charged with 6 kg of ether and 6164.2 g (33.5 mol) of ethyl 4,4,4-trifluoroacetoacetate. With stirring 1542.4 g (33.5 mol) methylhydrazine was added. The temperature was maintained at about 24° C. during the addition. After one additional hour of stirring the reaction was complete. Solvent was stripped to remove most of the ether and the residue was then slurried in 12 1 of chloroform with vigorous stirring. To the slurry was added 50 ml of concentrated sulfuric acid and the mixture was stirred overnight. An additional 100 ml of sulfuric acid was added and the slurry was washed once with 3 1 of water and 5 times with 3 1 of 10% sodium bicarbonate to remove the 5-hydroxy isomer and twice with 3 1 of water. The aqueous layers and undissolved crystals were twice extracted sequentially with 4 1 of chloroform. Chloroform was stripped on a rotary evaporator at 40° C. under vacuum to yield 1405.9 g (25.3% yield) of a solid, m.p. 130°-131° C.
Reaction SMILES: [CH3:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][C:5]([C:11]([CH3:14])([CH3:13])[CH3:12])=[CH:4][C:3]=1[OH:15].[CH2:16](Cl)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[CH2:16]([O:15][C:3]1[CH:4]=[C:5]([C:11]([CH3:12])([CH3:14])[CH3:13])[CH:6]=[C:7]([N+:8]([O-:10])=[O:9])[C:2]=1[CH3:1])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: ClCc1ccccc1
Reactant: Cc1c(O)cc(C(C)(C)C)cc1[N+](=O)[O-]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1c(OCc2ccccc2)cc(C(C)(C)C)cc1[N+](=O)[O-]

Procedure:
This is obtained, by reacting 2-methyl-3-nitro-5-tert.-butylphenol with benzyl chloride in dimethylformamide in the presence of potassium carbonate at 80° C., in the form of yellowish crystals; m.p. 77°-79° C.
Reaction SMILES: CN1CCOCC1.Cl.[NH2:9][C:10]([CH3:15])([CH3:14])[C:11]([NH2:13])=[O:12].[C:16]([O:20][C:21]([N:23]1[C@@H:27]([CH2:28][C@@H:29]([CH:45]([CH3:47])[CH3:46])[CH2:30][C:31]2[CH:36]=[CH:35][C:34]([O:37][CH3:38])=[C:33]([O:39][CH2:40][CH2:41][CH2:42][O:43][CH3:44])[CH:32]=2)[C@H:26]([CH2:48][C@H:49]([C:53](O)=[O:54])[CH:50]([CH3:52])[CH3:51])[O:25][C:24]1([CH3:57])[CH3:56])=[O:22])([CH3:19])([CH3:18])[CH3:17]>CN(C)C=O>[C:16]([O:20][C:21]([N:23]1[C@@H:27]([CH2:28][C@@H:29]([CH:45]([CH3:47])[CH3:46])[CH2:30][C:31]2[CH:36]=[CH:35][C:34]([O:37][CH3:38])=[C:33]([O:39][CH2:40][CH2:41][CH2:42][O:43][CH3:44])[CH:32]=2)[C@H:26]([CH2:48][C@H:49]([C:53](=[O:54])[NH:9][C:10]([C:11](=[O:12])[NH2:13])([CH3:15])[CH3:14])[CH:50]([CH3:51])[CH3:52])[O:25][C:24]1([CH3:56])[CH3:57])=[O:22])([CH3:19])([CH3:18])[CH3:17]
Reactant: CC(C)(N)C(N)=O
Reactant: COCCCOc1cc(C[C@@H](C[C@H]2[C@H](C[C@H](C(=O)O)C(C)C)OC(C)(C)N2C(=O)OC(C)(C)C)C(C)C)ccc1OC
Agent: Cl
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Product: COCCCOc1cc(C[C@@H](C[C@H]2[C@H](C[C@H](C(=O)NC(C)(C)C(N)=O)C(C)C)OC(C)(C)N2C(=O)OC(C)(C)C)C(C)C)ccc1OC
Temperature: 40 °C
Reaction time: 192 h

Procedure:
106 μl of 4-methyl-morpholine, 66 mg of 2-aminoisobutyric acid amide hydrochloride and 91 mg of O-benztriazol-1-yl-N,N,N','-tetramethyluronium hexafluorophosphate (HBTU) are added in succession to 119 mg of 3-tert-butoxycarbonyl-5(S)-(2(S)-carboxy-3-methyl-butyl)-4(S)-{2(S)-isopropyl-3-[4-methoxy-3-(3-methoxypropyloxy)-phenyl]-propyl}-2,2-dimethyl-1,3-oxazolidine (Example 124 c) in 8 ml of dimethylformamide. The reaction mixture is stirred for 8 days at 40° C. The mixture is concentrated by evaporation and the residue is partitioned between ethyl acetate and saturated sodium chloride solution. The organic phases are concentrated by evaporation and the residue is purified by means of FC (60 g of silica gel, dichloromethane/methanol=95:5). The title compound is obtained: Rf (dichloromethane/methanol=95:5)=0.30.
Reaction SMILES: [CH3:1][C:2]([CH3:12])=[CH:3][N:4]1[CH:8]=[CH:7][C:6]([C:9]([OH:11])=O)=[N:5]1.[NH2:13][C@@H:14]([CH3:31])[CH2:15][N:16]1[CH:20]=[CH:19][C:18]([C:21]2[CH:28]=[C:27]([F:29])[C:24]([C:25]#[N:26])=[C:23]([Cl:30])[CH:22]=2)=[N:17]1>C(Cl)Cl>[Cl:30][C:23]1[CH:22]=[C:21]([C:18]2[CH:19]=[CH:20][N:16]([CH2:15][C@@H:14]([NH:13][C:9]([C:6]3[CH:7]=[CH:8][N:4]([CH:3]=[C:2]([CH3:1])[CH3:12])[N:5]=3)=[O:11])[CH3:31])[N:17]=2)[CH:28]=[C:27]([F:29])[C:24]=1[C:25]#[N:26]
Reactant: C[C@H](N)Cn1ccc(-c2cc(F)c(C#N)c(Cl)c2)n1
Reactant: CC(C)=Cn1ccc(C(=O)O)n1
Solvent: ClCCl
Product: CC(C)=Cn1ccc(C(=O)N[C@@H](C)Cn2ccc(-c3cc(F)c(C#N)c(Cl)c3)n2)n1
Yield: 77.8 %

Procedure:
The title compound was prepared using the procedure described in Example 3(h) starting from 1-(2-methyl-prop-1-en-1-yl)-1H-pyrazole-3-carboxylic acid (1.076 mmol, 179 mg) and (S)-4-(1-(2-aminopropyl)-1H-pyrazol-3-yl)-2-chloro-6-fluoro-benzonitrile (0.897 mmol, 250 mg) using DCM (5 ml) as the solvent. The mixture was diluted with DCM, washed with 1M Na2CO3 and water. The organic phase was dried, filtered and evaporated. The product was purified by flash chromatography. 298 mg of the title compound was obtained. 1H-NMR (400 MHz, DMSO-d6): δ 1.12 (d, 3H), 1.80 (d, 3H), 1.84 (d, 3H), 4.27-4.50 (m, 3H), 6.66 (d, 1H), 6.77-6.80 (m, 1H), 7.01 (d, 1H), 7.83 (d, 1H), 7.85-7.89 (m, 2H), 7.95-7.98 (m, 1H), 8.15 (d, 1H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5](F)=[C:6]([CH:9]=1)[CH:7]=[O:8].[Br:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[OH:18].C(=O)([O-])[O-].[K+].[K+]>CC(N(C)C)=O.C(OCC)(=O)C>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([O:18][C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=2[Br:11])=[C:6]([CH:9]=1)[CH:7]=[O:8]
Reactant: Oc1ccccc1Br
Reactant: O=Cc1cc(Br)ccc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CC(=O)N(C)C
Product: O=Cc1cc(Br)ccc1Oc1ccccc1Br
Temperature: 120 °C
Reaction time: 12 h
Yield: 46.1 %

Procedure:
To a solution of 5-bromo-2-fluorobenzaldehyde (0.203 g, 1 mmol) in DMA (2.5 mL) were added 2-bromophenol (0.182 g, 1.05 mmol) and potassium carbonate (0.138 g, 1 mmol), followed by stirring at 120° C. for 12 hours. The reaction solution was diluted with ethyl acetate, washed with brine, dried over MgSO4, and concentrated. The residue was purified through column chromatography (20% ethyl acetate/hexane) and concentrated to obtain the object compound (0.164 g, 46%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([NH2:8])[C:3]=1I.C[O:11][C:12](=O)[C:13]1[CH:18]=[C:17]([O:19][CH2:20][CH2:21][CH2:22][N:23]2[CH2:28][CH2:27][O:26][CH2:25][CH2:24]2)[CH:16]=[CH:15][C:14]=1B1OC(C)(C)C(C)(C)O1>>[Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[C:3]=1[C:14]1[CH:15]=[CH:16][C:17]([O:19][CH2:20][CH2:21][CH2:22][N:23]3[CH2:24][CH2:25][O:26][CH2:27][CH2:28]3)=[CH:18][C:13]=1[C:12](=[O:11])[NH:8]2
Reactant: COC(=O)c1cc(OCCCN2CCOCC2)ccc1B1OC(C)(C)C(C)(C)O1
Reactant: Nc1nccc(Cl)c1I
Product: O=c1[nH]c2nccc(Cl)c2c2ccc(OCCCN3CCOCC3)cc12
Yield: 23.3 %

Procedure:
The title compound was synthesized according to the procedure described for the preparation of Example 1 using 4-chloro-3-iodopyridin-2-amine (350 mg, 1.38 mmol) and 5-(3-morpholin-4-yl-propoxy)-2-(4,4,5,5-tetramethyl[1,3,2]-dioxaborolan-2-yl)-benzoic acid methyl ester (697 mg, 1.72 mmol) to provide 226 (120 mg, 23% yield) as a white solid. LC-MS (M+H=374, obsd.=374).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]2[C:12]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=3)([C:13]#[N:14])[CH:11]([CH2:22][C:23]([CH3:26])([CH3:25])[CH3:24])[NH:10][CH:9]2[C:27](O)=[O:28])[CH:5]=[CH:6][CH:7]=1.[CH3:30][O:31][C:32]1[CH:33]=[C:34]([CH2:40][CH2:41][NH:42][CH3:43])[CH:35]=[CH:36][C:37]=1[O:38][CH3:39].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>C(Cl)Cl>[CH3:30][O:31][C:32]1[CH:33]=[C:34]([CH2:40][CH2:41][N:42]([CH3:43])[C:27]([CH:9]2[CH:8]([C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=3)[C:12]([C:15]3[CH:16]=[CH:17][C:18]([Cl:21])=[CH:19][CH:20]=3)([C:13]#[N:14])[CH:11]([CH2:22][C:23]([CH3:25])([CH3:24])[CH3:26])[NH:10]2)=[O:28])[CH:35]=[CH:36][C:37]=1[O:38][CH3:39]
Reactant: CNCCc1ccc(OC)c(OC)c1
Reactant: CC(C)(C)CC1NC(C(=O)O)C(c2cccc(Cl)c2)C1(C#N)c1ccc(Cl)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COc1ccc(CCN(C)C(=O)C2NC(CC(C)(C)C)C(C#N)(c3ccc(Cl)cc3)C2c2cccc(Cl)c2)cc1OC
Yield: 47.1 %

Procedure:
In a manner similar to the method described in Example 1e, rac-(2R,3R,4R,5S)-3-(3-chloro-phenyl)-4-(4-chloro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid (86.2 mg, 0.20 mmol) prepared in Example 1d was reacted with [2-(3,4-dimethoxy-phenyl)-ethyl]-methyl-amine (58.6 mg, 0.3 mmol), HATU (76.0 mg, 0.2 mmol) and iPr2NEt (0.1 mL, 0.55 mmol) in CH2Cl2 (2 mL) to give rac-(2R,3R,4R,5S)-3-(3-chloro-phenyl)-4-(4-chloro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid [2-(3,4-dimethoxy-phenyl)-ethyl]-methyl-amide (57.3 mg, 48.26%) as a white powder.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:6]=[C:7](B(O)O)[CH:8]=[CH:9][CH:10]=1)=[O:4].P([O-])([O-])([O-])=O.[K+].[K+].[K+].Br[C:23]1[S:27][C:26]([S:28]([NH2:31])(=[O:30])=[O:29])=[CH:25][CH:24]=1.O1CCOCC1>CN(C=O)C>[CH3:1][O:2][C:3](=[O:4])[C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([C:23]2[S:27][C:26]([S:28](=[O:30])(=[O:29])[NH2:31])=[CH:25][CH:24]=2)[CH:6]=1
Reactant: NS(=O)(=O)c1ccc(Br)s1
Reactant: COC(=O)c1cccc(B(O)O)c1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: CN(C)C=O
Product: COC(=O)c1cccc(-c2ccc(S(N)(=O)=O)s2)c1
Temperature: 85 °C
Reaction time: 8 h
Yield: 53.5 %

Procedure:
1,1′-Bis(diphenylphosphino)ferrocene-palladium(II) dichloride-dichloromethane complex (272 mg, 0.33 mmol), 3-methoxycarbonylphenylboronic acid (898 mg, 4.99 mmol), and tripotassium phosphate (1.41 g, 6.64 mmol) were added to a solution of commercially available 5-bromothiophene-2-sulfonamide (805 mg, 3.33 mmol) in mixture of 1,4-dioxane (10 mL) and DMF (1 mL), followed by stirring at 85° C. overnight in an argon atmosphere. The reaction solution was concentrated. A saturated aqueous solution of sodium chloride was added to the residue, followed by extraction with methylene chloride and drying over anhydrous sodium sulfate. The solvent was distilled off, and methanol was added to the residue. The precipitated solid was filtered off. The residue obtained by distilling the solvent off was subjected to purification by silica gel column chromatography to obtain 3-(5-sulfamoyl-2-thienyl)benzoic acid methyl ester (529 mg, 1.78 mmol) (yield: 53%).
Reaction SMILES: [OH-].[Na+].CO.C([O:7][C:8]([C:10]1[C:14]([C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[C:17]([Cl:22])[CH:16]=2)=[CH:13][S:12][C:11]=1[N:23]1[C:31](=[O:32])[C:30]2[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=2)[C:24]1=[O:33])=[O:9])C.Cl>O>[Cl:22][C:17]1[CH:16]=[C:15]([C:14]2[C:10]([C:8]([OH:9])=[O:7])=[C:11]([N:23]3[C:24](=[O:33])[C:25]4[C:30](=[CH:29][CH:28]=[CH:27][CH:26]=4)[C:31]3=[O:32])[S:12][CH:13]=2)[CH:20]=[CH:19][C:18]=1[Cl:21]
Reactant: CCOC(=O)c1c(-c2ccc(Cl)c(Cl)c2)csc1N1C(=O)c2ccccc2C1=O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: O=C(O)c1c(-c2ccc(Cl)c(Cl)c2)csc1N1C(=O)c2ccccc2C1=O
Yield: 92 %

Procedure:
To a solution of NaOH (1.4 mmol) in a 1:1 mixture of methanol:H2O (6 mL) was added 4-(3,4-dichlorophenyl)-2-(1,3-dioxo-1,3-dihydroisoindol-2-yl)-thiophene-3-carboxylic acid ethyl ester (0.7 mmol, Example 6 & 7, Part C). The mixture was heated to reflux for 90 min, then diluted with water (12 mL), chilled in an ice bath, and acidified with concentrated HCl. The product that precipitated was collected by filtration, washed with water, and dried, affording the desired compound as a white solid in 92% yield.
Reaction SMILES: [CH2:1]([NH2:5])/[CH:2]=[CH:3]/[CH3:4].Cl.Br[CH2:8][C:9]([O:11][CH3:12])=[O:10].CCN(CC)CC>C(#N)C>[CH2:1]([NH:5][CH2:8][C:9]([O:11][CH3:12])=[O:10])/[CH:2]=[CH:3]/[CH3:4]
Reactant: COC(=O)CBr
Reactant: C/C=C/CN
Agent: Cl
Solvent: CC#N
Solvent: CCN(CC)CC
Product: C/C=C/CNCC(=O)OC
Temperature: 25 °C
Reaction time: 1 h
Yield: 19.8 %

Procedure:
A suspension of (E)-2-buten-1-amine.HCl (5.37 g, 49.9 mmol) (Chem. Ber., 1984;117:1250) in acetonitrile (100 mL) was treated with methyl bromoacetate (4.72 mL, 49.9 mmol) and Et3N (14.0 mL, 99.8 mmol) and stirred at room temperature for 1 hour. The suspension was then heated at reflux overnight. Solution occurred at reflux temperature. After cooling, the precipitated Et3NHCl was filtered off and the solvent removed under reduced pressure leaving 5.0 g of the crude product. Chromatography on silica gel, eluting with CHCl3/MeOH (98:2) gave 1.41 g (19.8% yield) of the pure product as an oil.
Reaction SMILES: [OH:1][CH:2]([CH2:10][OH:11])[CH2:3][N:4]1[CH2:9][CH2:8][NH:7][CH2:6][CH2:5]1.[C:12]([C:14]1[CH:19]=[CH:18][N:17]=[N:16][C:15]=1[Cl:20])#[N:13]>O1CCOCC1.Cl.C(O)(C)C>[ClH:20].[ClH:20].[C:12]([C:14]1[CH:19]=[CH:18][N:17]=[N:16][C:15]=1[N:7]1[CH2:8][CH2:9][N:4]([CH2:3][CH:2]([OH:1])[CH2:10][OH:11])[CH2:5][CH2:6]1)#[N:13]
Reactant: N#Cc1ccnnc1Cl
Reactant: OCC(O)CN1CCNCC1
Agent: Cl
Solvent: CC(C)O
Solvent: C1COCCO1
Product: N#Cc1ccnnc1N1CCN(CC(O)CO)CC1

Procedure:
Grams 6.9 of 1-(2,3-dihydroxypropyl)piperazine and 3.0 g of 4-cyano-3-chloropyridazine in 60 ml dioxane were refluxed for 2 hours. The reaction mixture was settled, the supernatant liquor evaporated to dryness and the residue, which formed, was dissolved in 10 ml concentrated hydrochloric acid and diluted with 10 volumes of isopropanol. A precipitate was obtained formed by a gummy oil, which solidified afterwards giving 5.9 g of 3-[4-(4-cyanopyridazin-3-yl)piperazin-1yl]propane-1,2-diol dihydrochloride which melted at 128°-130° C.
Reaction SMILES: [NH2:1][C:2]1[CH:29]=[CH:28][C:5]([O:6][C:7]2[CH:12]=[CH:11][N:10]=[C:9]([NH:13][C:14]([N:16]3[CH2:21][CH2:20][CH:19]([CH2:22][N:23]4[CH2:27][CH2:26][CH2:25][CH2:24]4)[CH2:18][CH2:17]3)=[O:15])[CH:8]=2)=[CH:4][CH:3]=1.[F:30][C:31]1[CH:36]=[CH:35][C:34]([NH:37][C:38]([C:40]2([C:43](O)=[O:44])[CH2:42][CH2:41]2)=[O:39])=[CH:33][CH:32]=1.C(N(CC)CC)C.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1>CN(C)C=O>[F:30][C:31]1[CH:32]=[CH:33][C:34]([NH:37][C:38]([C:40]2([C:43]([NH:1][C:2]3[CH:29]=[CH:28][C:5]([O:6][C:7]4[CH:12]=[CH:11][N:10]=[C:9]([NH:13][C:14]([N:16]5[CH2:17][CH2:18][CH:19]([CH2:22][N:23]6[CH2:27][CH2:26][CH2:25][CH2:24]6)[CH2:20][CH2:21]5)=[O:15])[CH:8]=4)=[CH:4][CH:3]=3)=[O:44])[CH2:42][CH2:41]2)=[O:39])=[CH:35][CH:36]=1
Reactant: Nc1ccc(Oc2ccnc(NC(=O)N3CCC(CN4CCCC4)CC3)c2)cc1
Reactant: O=C(O)C1(C(=O)Nc2ccc(F)cc2)CC1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: O=C(Nc1cc(Oc2ccc(NC(=O)C3(C(=O)Nc4ccc(F)cc4)CC3)cc2)ccn1)N1CCC(CN2CCCC2)CC1
Reaction time: 1 h
Yield: 63.8 %

Procedure:
4-(Pyrrolidin-1-ylmethyl)piperidine-1-carboxylic acid [4-(4-aminophenoxy)pyridin-2-yl]amide (125 mg) was dissolved in N,N-dimethylformamide (2 ml), and 1-(4-fluorophenylcarbamoyl)cyclopropanecarboxylic acid (176 mg), triethylamine (0.11 ml) and (1H-1,2,3-benzotriazol-1-yloxy)[tri(dimethylamino)]phosphonium hexafluorophosphate (349 mg) were added thereto in this order at room temperature, followed by stirring for 1 hr. Liquid-liquid separation was carried out after addition of ethyl acetate and a saturated aqueous solution of sodium hydrogencarbonate to the reaction mixture. The organic layer was washed with brine, and dried over anhydrous sodium sulfate. The solvent was concentrated under reduced pressure, and the resultant residue was purified by silica gel column chromatography (Fuji Silysia NH, eluent; heptane:ethyl acetate=1:5, then ethyl acetate). The solvent was concentrated under reduced pressure, and the resultant residue was suspended in diethyl ether (4 ml) and hexane (4 ml). The solid was collected by filtration and dried under aeration to provide the titled compound as white powder (121.2 mg, 63.8%).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[C:7]([O:12][CH3:13])[CH:8]=[CH:9][CH:10]=2)[N:5]=[C:4]([CH3:14])[CH:3]=1.[Cl:15][C:16]1[CH:21]=[CH:20][C:19]([CH:22]([NH2:29])[C:23]2[CH:28]=[CH:27][N:26]=[CH:25][CH:24]=2)=[CH:18][CH:17]=1.CN(C)C=O>C(#N)C>[Cl:15][C:16]1[CH:21]=[CH:20][C:19]([CH:22]([NH:29][C:2]2[C:11]3[C:6](=[C:7]([O:12][CH3:13])[CH:8]=[CH:9][CH:10]=3)[N:5]=[C:4]([CH3:14])[CH:3]=2)[C:23]2[CH:28]=[CH:27][N:26]=[CH:25][CH:24]=2)=[CH:18][CH:17]=1
Reactant: NC(c1ccncc1)c1ccc(Cl)cc1
Reactant: COc1cccc2c(Cl)cc(C)nc12
Solvent: CN(C)C=O
Solvent: CC#N
Product: COc1cccc2c(NC(c3ccncc3)c3ccc(Cl)cc3)cc(C)nc12

Procedure:
Preparation was made using a similar procedure as described in example 19, method 19.2. Starting materials were 4-chloro-8-methoxy-2-methylquinoline and C-(4-chlorophenyl)-C-pyridin-4-yl-methylamine. Acetonitrile was used as solvent instead of dimethylformamide.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]=[C:9]=[O:10])=[CH:4][CH:3]=1.[NH2:11][C:12](=[N:15][C:16](=O)[O:17]C)[S:13][CH3:14].C[O-].[Na+].Cl>C(Cl)Cl>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16](=[O:17])[NH:15][CH:12]([S:13][CH3:14])[NH:11][C:9]2=[O:10])=[CH:4][CH:3]=1
Reactant: Cc1ccc(N=C=O)cc1
Reactant: COC(=O)N=C(N)SC
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: ClCCl
Product: CSC1NC(=O)N(c2ccc(C)cc2)C(=O)N1
Reaction time: 2 h
Yield: 80.9 %

Procedure:
4-Methylphenylisocyanate (19.0 g.) was added during 10 minutes to a solution of methyl N-[1-amino-1-(methylthio)methylene]carbamate (21.2 g.) in methylene chloride (200 ml.). After 2 hours of stirring, sodium methoxide [obtained by dissolving sodium (3.5 g.) in methanol (30 ml.)] was added at 15°-20° C. The subsequent mixture was stirred at that temperature for 18 hours and the resultant solid collected by filtration and dissolved in water (200 ml.). The solution obtained was acidified with concentrated hydrochloric acid and the solid which formed was collected by filtration, washed well with water and dried to give 3-(4-methylphenyl)-6-methylthiotetrahydro-1,3,5-triazine-2,4-dione (29 g., 81%), m.p. 276°-278° C.
Reaction SMILES: [CH3:1][C:2]1[CH:30]=[CH:29][CH:28]=[CH:27][C:3]=1[C:4]([NH:6][C:7]1[C:16]2[CH2:15][CH2:14][CH2:13][CH2:12][C:11]=2[C:10]([S:17](=[O:26])(=[O:25])[NH:18][CH:19]2[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]2)=[CH:9][CH:8]=1)=[O:5].[C:31](Cl)(=[O:35])[CH2:32][CH2:33][CH3:34].C(N(CC)CC)C>C1COCC1>[C:31]([N:22]1[CH2:23][CH2:24][CH:19]([NH:18][S:17]([C:10]2[C:11]3[CH2:12][CH2:13][CH2:14][CH2:15][C:16]=3[C:7]([NH:6][C:4](=[O:5])[C:3]3[CH:27]=[CH:28][CH:29]=[CH:30][C:2]=3[CH3:1])=[CH:8][CH:9]=2)(=[O:26])=[O:25])[CH2:20][CH2:21]1)(=[O:35])[CH2:32][CH2:33][CH3:34]
Reactant: Cc1ccccc1C(=O)Nc1ccc(S(=O)(=O)NC2CCNCC2)c2c1CCCC2
Reactant: CCCC(=O)Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCCC(=O)N1CCC(NS(=O)(=O)c2ccc(NC(=O)c3ccccc3C)c3c2CCCC3)CC1
Reaction time: 18 h
Yield: 34.6 %

Procedure:
To a 25° C. mixture of sulfonamide (26) (134 mg, 0.29 mmol) in THF (10 mL) was added butyryl chloride (77 mg, 0.725 mmol) and triethylamine (367 mg, 3.625 mmol). The mixture was stirred for 18 hours, followed by filtration to remove the precipitate. The filtrate was concentrated in vacuo and purified via chromatography, resulting in the title compound as white solid (50 mg). 1H NMR (300 MHz, MeOD) δ 7.91 (d, 1H), 7.55 (m, 2H), 7.41 (m, 1H), 7.31 (m, 2H), 4.30 (m, 1H), 3.89 (m, 1H), 3.21 (m, 2H), 3.09 (m, 1H), 2.85 (m, 2H), 2.61 (m, 1H), 2.55 (s, 3H), 2.34 (t, 2H), 1.88 (m, 7H), 1.62 (m, 2H), 1.39 (m, 2H), 0.95 (t, 3H) ); LC/MS (M +H)+ m/z 498.
Reaction SMILES: CO[C:3]1[CH:8]=[CH:7][N:6]=[CH:5][C:4]=1[N+:9]([O-:11])=[O:10].[CH:12]1([NH2:15])[CH2:14][CH2:13]1.CCN(C(C)C)C(C)C>C(O)C>[CH:12]1([NH:15][C:3]2[CH:8]=[CH:7][N:6]=[CH:5][C:4]=2[N+:9]([O-:11])=[O:10])[CH2:14][CH2:13]1
Reactant: NC1CC1
Reactant: COc1ccncc1[N+](=O)[O-]
Solvent: CCN(C(C)C)C(C)C
Solvent: CCO
Product: O=[N+]([O-])c1cnccc1NC1CC1
Temperature: 0 °C
Yield: 71.7 %

Procedure:
4-Methoxy-3-nitropyridine 5-a (CAS 31872-62-5) (200 g, 1300 mmol), cyclopropyl-amine (CAS 765-30-0) (185.5 g, 3250 mmol) and DIEA (CAS 7087-68-5) (336 g, 2600 mmol) in dry ethanol (800 mL) was refluxed for 3 hours. The mixture was cooled to 0° C. The solid was collected by filtration. The filter cake was washed with cold ethanol (150 mL). The solid was dried to afford compound 5-b as a white powder (167 g, 72%).
Reaction SMILES: C(N(C(C)C)CC)(C)C.[Cl:10][C:11]1[CH:12]=[C:13]([CH:17]=[CH:18][C:19]=1[N+:20]([O-:22])=[O:21])[C:14]([OH:16])=O.[NH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>C(#N)C>[Cl:10][C:11]1[CH:12]=[C:13]([CH:17]=[CH:18][C:19]=1[N+:20]([O-:22])=[O:21])[C:14]([NH:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)=[O:16]
Reactant: Nc1ccccc1
Reactant: O=C(O)c1ccc([N+](=O)[O-])c(Cl)c1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: O=C(Nc1ccccc1)c1ccc([N+](=O)[O-])c(Cl)c1
Temperature: 80 °C
Reaction time: 8 h
Yield: 49.2 %

Procedure:
Diisopropylethylamine (0.65 mL, 3.7 mmol) was added to a mixture of 3-chloro-4-nitro-benzoic acid (0.2 g, 0.992 mmol), aniline (0.1 mL, 1.1 mmol) and HBTU (0.42 g, 1.1 mmol) in acetonitrile (20 mL) and the reaction mixture was stirred at 80° C. for 8 hours and then at room temperature for 62 hours. The resulting mixture was then partitioned between water and ethyl acetate, the organic layer was separated and the aqueous layer was extracted twice with ethyl acetate. The combined organic extracts were washed with brine, dried over anhydrous sodium sulfate, filtered and evaporated under reduced pressure. The crude residue was purified on a silica gel plug (hexane/EtOAc, 80/20) to afford 135 mg (49% yield) of 3-chloro-4-nitro-N-phenyl-benzamide as a yellow solid.