Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][C:5]([C:7]1[CH:12]=[CH:11][C:10]([CH2:13][CH:14]([C:20]([O:22][CH2:23][CH3:24])=[O:21])[C:15]([O:17][CH2:18][CH3:19])=[O:16])=[CH:9][CH:8]=1)=[O:6].C(=O)([O-])[O-].[K+].[K+].[N:31]1[CH:36]=[CH:35][C:34]([C:37]([OH:50])([C:44]2[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=2)[C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)=[CH:33][CH:32]=1>O.C(OCC)(=O)C.C1(C)C=CC=CC=1>[OH:50][C:37]([C:44]1[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1)([C:38]1[CH:39]=[CH:40][CH:41]=[CH:42][CH:43]=1)[CH:34]1[CH2:35][CH2:36][N:31]([CH2:2][CH2:3][CH2:4][C:5]([C:7]2[CH:12]=[CH:11][C:10]([CH2:13][CH:14]([C:20]([O:22][CH2:23][CH3:24])=[O:21])[C:15]([O:17][CH2:18][CH3:19])=[O:16])=[CH:9][CH:8]=2)=[O:6])[CH2:32][CH2:33]1
Reactant: OC(c1ccccc1)(c1ccccc1)c1ccncc1
Reactant: CCOC(=O)C(Cc1ccc(C(=O)CCCCl)cc1)C(=O)OCC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Solvent: O
Product: CCOC(=O)C(Cc1ccc(C(=O)CCCN2CCC(C(O)(c3ccccc3)c3ccccc3)CC2)cc1)C(=O)OCC
Temperature: 25 °C
Reaction time: 168 h
Yield: 97.3 %

Procedure:
Mix together [4-(4-chloro-1-oxobutyl)phenyl]methyl-propanedioic acid, diethyl ester (380 mg, 1.1 mmol), potassium carbonate (450 mg, 3.2 mmol), α-(4-pyridyl)benzhydrol (500 mg, 1.9 mmol), water (4 mL) and toluene (10 mL). Heat the mixture to reflux. After 7 days, cool to room temperature. Add ethyl acetate and water. Wash the organic phase with brine, dry over anhydrous magnesium sulfate and concentrate. Purify by flash chromatography (200 g of silica gel, 10% methanol/chloroform as eluent) to give the title compound (627 mg, 99%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][C:10]=1[NH2:11])[NH:7][C:6](=[O:12])[CH2:5]2.N1CCCCC1.Cl[C:20]([C@@H:22]([O:24][C:25](=[O:27])[CH3:26])[CH3:23])=[O:21]>O1CCCC1>[F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][C:10]=1[NH:11][C:20]([CH:22]([O:24][C:25](=[O:27])[CH3:26])[CH3:23])=[O:21])[NH:7][C:6](=[O:12])[CH2:5]2
Reactant: Nc1cc2c(cc1F)CC(=O)N2
Reactant: CC(=O)O[C@@H](C)C(=O)Cl
Solvent: C1CCOC1
Solvent: C1CCNCC1
Product: CC(=O)OC(C)C(=O)Nc1cc2c(cc1F)CC(=O)N2
Temperature: -40 °C
Reaction time: 8 h
Yield: 98.8 %

Procedure:
The stirred solution of 5-fluoro-6-amino-1,3-dihydro-indol-2-one (450 mg, 2.71 mmol) in 10 ml of tetrahydrofuran was added with piperidine (0.4 ml). The mixture was cooled to −40° C. in an acetone-dry ice bath and added with (S)-acetic acid 1-chlorocarbonyl-ethyl ester (423 mg, 2.71 mmol) in 10 ml of tetrahydrofuran dropwise. Upon the completion of the addition, the resulting mixture was stirred at the room temperature overnight until the precipitate was formed. The solid was filtered, washed with water and recrystallized from methanol to give acetic acid 1-(5-fluoro-2-oxo-2,3-dihydro-1H-indol-6-ylcarbamoyl)-ethyl ester (750 mg, 99%) as a white solid.
Reaction SMILES: [CH:1]([C:4]1[CH:11]=[CH:10][C:7]([CH2:8]Cl)=[CH:6][CH:5]=1)([CH3:3])[CH3:2].[NH:12]1[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]1>C1COCC1>[CH:1]([C:4]1[CH:11]=[CH:10][C:7]([CH2:8][N:12]2[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]2)=[CH:6][CH:5]=1)([CH3:3])[CH3:2]
Reactant: C1CNCCN1
Reactant: CC(C)c1ccc(CCl)cc1
Solvent: C1CCOC1
Product: CC(C)c1ccc(CN2CCNCC2)cc1

Procedure:
Synthesized according to General Procedure A: 4-isopropylbenzyl chloride (4{19}, 5 g, 29.6 mmol, 1 equiv.), piperazine (15.3 g, 177.9 mmol, 6 equiv.), THF (64.9 mL). Purification with flash column chromatography on silica gel (4:1 EtOAc:MeOH) afforded 5{19} (5.82 g, 90%) as a white solid. 1H-NMR (500 MHz, CDCl3): δ 7.21 (d, 2H, J=8.0 Hz), 7.14 (d, 2H, J=8.0 Hz), 4.15 (q, 2H, J=7.0 Hz), 3.43 (s, 2H), 2.89-2.84 (m, 5H), 2.39 (br s, 4H), 2.25 (br s, 1H), 1.22 (d, 6H, J=6.5 Hz). 13C-NMR (125 MHz, CDCl3): δ 147.3, 135.0, 128.9, 125.9, 63.2, 54.1, 45.7, 33.5, 23.8.
Reaction SMILES: Cl[C:2]1[CH:9]=[N:8][CH:7]=[C:6]([Cl:10])[C:3]=1[C:4]#[N:5].[CH3:11][O:12][C:13]1[CH:14]=[C:15](B(O)O)[CH:16]=[CH:17][CH:18]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].CN(C)C(=O)C>C(OCC)(=O)C.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Pd]>[Cl:10][C:6]1[CH:7]=[N:8][CH:9]=[C:2]([C:17]2[CH:16]=[CH:15][CH:14]=[C:13]([O:12][CH3:11])[CH:18]=2)[C:3]=1[C:4]#[N:5]
Reactant: COc1cccc(B(O)O)c1
Reactant: N#Cc1c(Cl)cncc1Cl
Agent: [Pd]
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CC(=O)N(C)C
Product: COc1cccc(-c2cncc(Cl)c2C#N)c1
Temperature: 110 °C
Yield: 42.4 %

Procedure:
A mixture of 3,5-dichloroisonicotinonitrile (2 g, 11.56 mmol), 3-methoxyphenylboronic acid (1.932 g, 12.72 mmol), potassium phosphate (4.91 g, 23.12 mmol) and palladium tetrakis(triphenylphosphine) (0.668 g, 0.578 mmol) was pumped and backfilled with nitrogen 3 times. N,N-dimethylacetamide (30 mL) was added. The mixture was again pumped and backfilled with nitrogen 3 times. After heating to 110° C. for 15 h, the mixture was diluted with ethyl acetate (300 mL), washed with water (50 mL), brine (50 mL) and dried (MgSO4) and concentrated. Silica gel chromatography, loading with dichloromethane-hexanes (1:1) and eluting with 5-30% ethyl acetate in hexanes, gave 3-chloro-5-(3-methoxyphenyl)isonicotinonitrile as white solid (1.20 g, 43% yield). MS (ES+) m/z: 245 (M+H); LC retention time: 3.13 min (analytical HPLC Method A).
Reaction SMILES: [OH:1][C:2]1[C:3]([C:12](Cl)=[O:13])=[CH:4][C:5]2[C:10]([CH:11]=1)=[CH:9][CH:8]=[CH:7][CH:6]=2.[NH2:15][C:16]1[CH:25]=[CH:24][C:19]2=[N:20][C:21](=[O:23])[N:22]=[C:18]2[CH:17]=1.O.C([O-])(=O)C.[Na+]>C1(C)C=CC=CC=1>[OH:1][C:2]1[C:3]([C:12]([NH:15][C:16]2[CH:25]=[CH:24][C:19]3=[N:20][C:21](=[O:23])[N:22]=[C:18]3[CH:17]=2)=[O:13])=[CH:4][C:5]2[C:10]([CH:11]=1)=[CH:9][CH:8]=[CH:7][CH:6]=2
Reactant: Nc1ccc2c(c1)=NC(=O)N=2
Reactant: O=C(Cl)c1cc2ccccc2cc1O
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: O
Solvent: Cc1ccccc1
Product: O=C1N=c2ccc(NC(=O)c3cc4ccccc4cc3O)cc2=N1
Yield: 86 %

Procedure:
CS 178560 describes the reaction of a solution of 3-hydroxy-2-naphthoyl chloride in toluene with 5-aminobenzimidazolone in the 30-fold amount of water in the presence of sodium acetate to give 3-hydroxy-N-benzimida-zolon-5-yl-2-naphthamide in 86% yield.
Reaction SMILES: C([O:3][C:4](=[O:30])[CH2:5][C:6]1[CH:7]=[C:8]([C:20]2[CH:25]=[CH:24][C:23]([C:26]([F:29])([F:28])[F:27])=[CH:22][CH:21]=2)[CH:9]=[C:10]([O:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:11]=1)C.O.O[Li].O>C1COCC1>[CH2:13]([O:12][C:10]1[CH:11]=[C:6]([CH2:5][C:4]([OH:30])=[O:3])[CH:7]=[C:8]([C:20]2[CH:25]=[CH:24][C:23]([C:26]([F:28])([F:29])[F:27])=[CH:22][CH:21]=2)[CH:9]=1)[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: CCOC(=O)Cc1cc(OCc2ccccc2)cc(-c2ccc(C(F)(F)F)cc2)c1
Agent: [Li]O
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)Cc1cc(OCc2ccccc2)cc(-c2ccc(C(F)(F)F)cc2)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 93.7 %

Procedure:
To a solution of (5-benzyloxy-4′-trifluoromethyl-biphenyl-3-yl)-acetic acid ethyl ester (120 g, 0.29 mol) in THF (1.2 L) was added water (240 mL), LiOH.H2O (16 g, 0.32 mol) and the resulting mixture was stirred at room temperature for 16 h. The solution was filtered and concentrated in vacuo to remove THF. The resulting thick liquid was acidified to pH 2 by adding 2N aqueous HCl solution and the white suspension was mechanically stirred for 1 h at room temperature. The wet white product was recovered after filtration and dissolved in EtOAc (500 mL). The organic layer was separated from water, dried (MgSO4) and concentrated in vacuo to obtain (5-benzyloxy-4′-trifluoromethyl-biphenyl-3-yl)-acetic acid (105 g, 94%).
Reaction SMILES: [CH2:1]([C:3]1[C:4](=[O:19])[NH:5][C:6](=[O:18])[NH:7][C:8]=1[O:9][C:10]1[CH:15]=[C:14]([CH3:16])[CH:13]=[C:12]([CH3:17])[CH:11]=1)[CH3:2].[C:20]1([CH3:37])[CH:25]=[CH:24][C:23](S(OCC2CCCCC2)(=O)=O)=[CH:22][CH:21]=1>>[CH:20]1([CH2:37][N:7]2[C:8]([O:9][C:10]3[CH:11]=[C:12]([CH3:17])[CH:13]=[C:14]([CH3:16])[CH:15]=3)=[C:3]([CH2:1][CH3:2])[C:4](=[O:19])[NH:5][C:6]2=[O:18])[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1
Reactant: Cc1ccc(S(=O)(=O)OCC2CCCCC2)cc1
Reactant: CCc1c(Oc2cc(C)cc(C)c2)[nH]c(=O)[nH]c1=O
Product: CCc1c(Oc2cc(C)cc(C)c2)n(CC2CCCCC2)c(=O)[nH]c1=O
Yield: 51.9 %

Procedure:
5-Ethyl-6-(3,5-dimethylphenoxy)-2,4-pyrimidinedione and (cyclohexyl)methyl para-toluenesulfonate were reacted by the same way with the example 1 to obtain the titled compound (185 mg, yield: 51.9%).
Reaction SMILES: [Cl:1][CH2:2][C:3](Cl)=[O:4].C(=O)([O-])[O-].[K+].[K+].[N+:12]([C:15]1[CH:21]=[CH:20][C:18]([NH2:19])=[CH:17][CH:16]=1)([O-:14])=[O:13]>CN(C=O)C>[Cl:1][CH2:2][C:3]([NH:19][C:18]1[CH:20]=[CH:21][C:15]([N+:12]([O-:14])=[O:13])=[CH:16][CH:17]=1)=[O:4]
Reactant: Nc1ccc([N+](=O)[O-])cc1
Reactant: O=C(Cl)CCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=C(CCl)Nc1ccc([N+](=O)[O-])cc1
Reaction time: 8 h

Procedure:
Chloroacetyl chloride (11 ml) was added dropwise to a stirred mixture of potassium carbonate (18.8 g) and 4-nitroaniline (15 g) in DMF (100 ml) maintained at 0°. The mixture was then allowed to stand overnight at room temperature and poured into crushed ice. A yellow solid was recovered and crystallised from toluene containing isopropyl alcohol (10%) to give the title compound (10 g), MP: 180°.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16]3[C:11](=[CH:12][C:13]([O:17][C@@H:18]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)[C@H:19]([NH2:21])[CH3:20])=[CH:14][CH:15]=3)[CH:10]=[N:9]2)=[CH:4][CH:3]=1.C(N(CC)CC)C.C([O:38][C:39]([CH3:44])([CH3:43])[C:40](Cl)=[O:41])(=O)C>ClCCl>[F:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[C:16]3[C:11](=[CH:12][C:13]([O:17][C@H:18]([C:22]4[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=4)[C@@H:19]([NH:21][C:40](=[O:41])[C:39]([OH:38])([CH3:44])[CH3:43])[CH3:20])=[CH:14][CH:15]=3)[CH:10]=[N:9]2)=[CH:6][CH:7]=1
Reactant: CC(=O)OC(C)(C)C(=O)Cl
Reactant: C[C@@H](N)[C@@H](Oc1ccc2c(cnn2-c2ccc(F)cc2)c1)c1ccccc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C[C@H](NC(=O)C(C)(C)O)[C@H](Oc1ccc2c(cnn2-c2ccc(F)cc2)c1)c1ccccc1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
To a stirred solution of (1S,2R)-1-{[1-(4-fluorophenyl)-1H-indazol-5-yl]oxy}-1-phenylpropan-2-amine (18 mg, 50 μmol) in dichloromethane (2 ml) was added triethylamine (100 μl), followed by 2-chloro-1,1-dimethyl-2-oxoethyl acetate (24 mg, 150 μmol). The stirring was continued for 20 min at r.t., then the solvent was removed under reduced pressure, and the residue dissolved in ethanol (1 ml). Aqueous sodium hydroxide solution (1 M, 1 ml) was added, and the mixture was stirrer at 80° C. for 30 min. Then it was cooled to r.t., acidified with TFA, and concentrated under reduced pressure. The product was purified by semi-prep. HPLC. Yield 22 mg (96%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:10]2[CH:11]=[N:12][CH:13]=[C:14]([C@@H:16]3[CH2:20][CH2:19][CH2:18][NH:17]3)[CH:15]=2)=[O:9])=[CH:4][CH:3]=1.[C:21]([O:25][C:26]([NH:28][C@@H:29]([CH2:33][C:34]1[CH:39]=[CH:38][C:37]([NH:40][C:41]([O:43][CH2:44][CH:45]2[C:57]3[CH:56]=[CH:55][CH:54]=[CH:53][C:52]=3[C:51]3[C:46]2=[CH:47][CH:48]=[CH:49][CH:50]=3)=[O:42])=[CH:36][CH:35]=1)[C:30](O)=[O:31])=[O:27])([CH3:24])([CH3:23])[CH3:22].C(N(C(C)C)C(C)C)C.N1(O)C2C=CC=CC=2N=N1>CN(C=O)C.C(OCC)(=O)C>[CH:47]1[C:46]2[CH:45]([CH2:44][O:43][C:41](=[O:42])[NH:40][C:37]3[CH:38]=[CH:39][C:34]([CH2:33][C@H:29]([NH:28][C:26]([O:25][C:21]([CH3:23])([CH3:22])[CH3:24])=[O:27])[C:30]([N:17]4[CH2:18][CH2:19][CH2:20][C@H:16]4[C:14]4[CH:13]=[N:12][CH:11]=[C:10]([C:8](=[O:9])[C:5]5[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=5)[CH:15]=4)=[O:31])=[CH:35][CH:36]=3)[C:57]3[C:52](=[CH:53][CH:54]=[CH:55][CH:56]=3)[C:51]=2[CH:50]=[CH:49][CH:48]=1
Reactant: O=C(c1ccc(F)cc1)c1cncc([C@@H]2CCCN2)c1
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccc(NC(=O)OCC2c3ccccc3-c3ccccc32)cc1)C(=O)O
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N[C@@H](Cc1ccc(NC(=O)OCC2c3ccccc3-c3ccccc32)cc1)C(=O)N1CCC[C@H]1c1cncc(C(=O)c2ccc(F)cc2)c1
Reaction time: 16 h

Procedure:
To a solution of (4-fluoro-phenyl)-((S)-5-pyrrolidin-2-yl-pyridin-3-yl)-methanone (1.0 g, 3.7 mmol), (S)-2-tert-butoxycarbonylamino-3-[4-(9H-fluoren-9-ylmethoxycarbonylamino)-phenyl]-propionic acid (2.21 g, 4.4 mmol) and ethyldiisopropylamine (3 mL) in DMF (20 mL) was added a solution of 2-(1H-benzo[d][1,2,3]triazol-1-yl)-1,1,3,3-tetramethylisouronium hexafluorophosphate(V) (1.67 g, 4.4 mmol) and 1H-benzo[d][1,2,3]triazol-1-ol (0.6 g, 4.4 mmol) in DMF (10 mL) and the reaction mixture was shaken for 16 hours. The reaction mixture was diluted with ethyl acetate (300 ml), washed sequentially with brine (2×) (300 mL), saturated aqueous bicarbonate solution (300 mL), brine (300 mL), water (300 mL), and brine (300 mL), then dried over Na2SO4/MgSO4, and concentrated in vacuo to provide the crude product [4-((S)-2-tert-butoxycarbonylamino-3-{(S)-2-[5-(4-fluoro-benzoyl)-pyridin-3-yl]-pyrrolidin-1-yl}-3-oxo-propyl)-phenyl]-carbamic acid 9H-fluoren-9-ylmethyl ester as a light yellow foam.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][C:5]([OH:7])=[O:6].[N+:8]([C:11]1[CH:21]=[CH:20][C:14]([CH2:15][O:16][C:17](Cl)=[O:18])=[CH:13][CH:12]=1)([O-:10])=[O:9]>[OH-].[Na+].CCOCC>[N+:8]([C:11]1[CH:12]=[CH:13][C:14]([CH2:15][O:16][C:17]([NH:1][CH2:2][CH2:3][CH2:4][C:5]([OH:7])=[O:6])=[O:18])=[CH:20][CH:21]=1)([O-:10])=[O:9]
Reactant: O=C(Cl)OCc1ccc([N+](=O)[O-])cc1
Reactant: NCCCC(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: CCOCC
Product: O=C(O)CCCNC(=O)OCc1ccc([N+](=O)[O-])cc1
Reaction time: 2 h

Procedure:
A 3.10 g portion of 4-aminobutyric acid was dissolved in 15 ml of 2N sodium hydroxide, to the solution were simultaneously added dropwise 6.48 g of p-nitrobenzyloxycarbonyl chloride dissolved in ether and 7.5 ml of 4N sodium hydroxide while cooling on an ice-bath. After 2 hours of stirring at the same temperature, the solution was washed with ether, the resulting aqueous layer was adjusted to acidic with concentrated hydrochloric acid, and a precipitated. solid material was collected by filtration, washed with water and then dried to yield 7.64 g of 4-(p-nitrobenzyloxycarbonyl)aminobutyric acid.
Reaction SMILES: C(OC([NH:8][C:9]([NH:25]C(OC(C)(C)C)=O)=[N:10][C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([C:17]2[C:22]([O:23][CH3:24])=[CH:21][CH:20]=[CH:19][N:18]=2)[CH:12]=1)=O)(C)(C)C.[ClH:33]>ClCCl.O1CCOCC1>[ClH:33].[ClH:33].[CH3:24][O:23][C:22]1[C:17]([C:13]2[CH:12]=[C:11]([NH:10][C:9]([NH2:25])=[NH:8])[CH:16]=[CH:15][CH:14]=2)=[N:18][CH:19]=[CH:20][CH:21]=1
Reactant: COc1cccnc1-c1cccc(N=C(NC(=O)OC(C)(C)C)NC(=O)OC(C)(C)C)c1
Agent: Cl
Solvent: ClCCl
Solvent: C1COCCO1
Product: COc1cccnc1-c1cccc(NC(=N)N)c1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of N,N′-bis(tert-butoxycarbonyl)-N″-(3-(3-methoxypyridin-2-yl)phenyl)guanidine (200 mg) in dichloromethane (2 ml) was added a solution of hydrogen chloride in 1,4-dioxane (4N, 4 ml), and the mixture was stirred at room temperature for 18 hours. The solvent was evaporated under reduced pressure. To the residue was added 5% ethanol in ethyl acetate (100 ml), and the precipitate was collected by filtration and dried under reduced pressure to give 3-(3-methoxypyridin-2-yl)phenylguanidine dihydrochloride (135 mg).
Reaction SMILES: Cl[C:2]1[C:7]([C:8]#[N:9])=[C:6]([C:10]2[CH:15]=[CH:14][C:13]([O:16][CH2:17][CH2:18][OH:19])=[CH:12][CH:11]=2)[C:5]([C:20]#[N:21])=[C:4]([S:22][CH2:23][C:24]2[N:25]=[C:26]([C:29]3[CH:34]=[CH:33][C:32]([Cl:35])=[CH:31][CH:30]=3)[S:27][CH:28]=2)[N:3]=1.[CH:36]1([NH2:40])[CH2:39][CH2:38][CH2:37]1>CN(C=O)C>[Cl:35][C:32]1[CH:31]=[CH:30][C:29]([C:26]2[S:27][CH:28]=[C:24]([CH2:23][S:22][C:4]3[C:5]([C:20]#[N:21])=[C:6]([C:10]4[CH:11]=[CH:12][C:13]([O:16][CH2:17][CH2:18][OH:19])=[CH:14][CH:15]=4)[C:7]([C:8]#[N:9])=[C:2]([NH:40][CH:36]4[CH2:39][CH2:38][CH2:37]4)[N:3]=3)[N:25]=2)=[CH:34][CH:33]=1
Reactant: NC1CCC1
Reactant: N#Cc1c(Cl)nc(SCc2csc(-c3ccc(Cl)cc3)n2)c(C#N)c1-c1ccc(OCCO)cc1
Solvent: CN(C)C=O
Product: N#Cc1c(NC2CCC2)nc(SCc2csc(-c3ccc(Cl)cc3)n2)c(C#N)c1-c1ccc(OCCO)cc1

Procedure:
At RT, 80 mg (0.15 mmol) of 2-chloro-6-({(2-(4-chlorophenyl)-1,3-thiazol-4-yl)methyl}sulfanyl)-4-(4-(2-hydroxyethoxy)phenyl)pyridine-3,5-dicarbonitrile (Example 2A) and 26 μl (0.30 mmol) of cyclobutanamine were stirred in 1.5 ml of DMF overnight. The reaction mixture was then purified by preparative HPLC (acetonitrile/water). This gave 56 mg (65% of theory) of the target compound.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11](B(O)O)=[CH:10][C:9]=2[F:17])=[CH:4][CH:3]=1.Br[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[S:25]([NH:28][CH:29]1[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]1)(=[O:27])=[O:26].C([O-])([O-])=O.[K+].[K+].C1COCC1>CCOC(C)=O.C(P(C(C)(C)C)[C-]1C=CC=C1)(C)(C)C.[C-]1(P(C(C)(C)C)C(C)(C)C)C=CC=C1.[Fe+2].[Pd](Cl)Cl>[NH2:1][C:2]1[N:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([C:19]3[C:20]([S:25]([NH:28][CH:29]4[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]4)(=[O:27])=[O:26])=[CH:21][CH:22]=[CH:23][CH:24]=3)=[CH:10][C:9]=2[F:17])=[CH:4][CH:3]=1
Reactant: O=S(=O)(NC1CCCCC1)c1ccccc1Br
Reactant: Nc1ccc(-c2ccc(B(O)O)cc2F)cn1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: CC(C)(C)P([c-]1cccc1)C(C)(C)C
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: Nc1ccc(-c2ccc(-c3ccccc3S(=O)(=O)NC3CCCCC3)cc2F)cn1
Temperature: 25 °C
Reaction time: 16 h
Yield: 11 %

Procedure:
A mixture of (4-(6-aminopyridin-3-yl)-3-fluorophenyl)boronic acid (75 mg, 0.32 mmol), 2-bromo-N-cyclohexylbenzenesulfonamide (0.11 g, 0.36 mmol), 1,1′-bis[di-tert-butylphosphino)ferrocene]palladium(II) chloride (11 mg, 0.016 mmol), K2CO3 (2 M, 1.6 mL, sparged with nitrogen) and THF (2 mL, sparged with nitrogen) were combined in a sealed vessel under nitrogen. The mixture was vigorously stirred at rt for 16 hours, then diluted with EtOAc. The aqueous phase was removed and the organic layer was dried and concentrated. The residue was subjected to FCC to provide the title compound (15 mg, 11%). MS (CI): mass calcd. for C23H24FN3O2S, 425.16; m/z found, 426.1 [M+H]+. 1H NMR (500 MHz, DMSO-d6) δ 8.20-8.14 (s, 1H), 8.05-7.96 (m, 1H), 7.70-7.57 (m, 3H), 7.55-7.47 (m, 1H), 7.44-7.35 (m, 2H), 7.30-7.20 (m, 2H), 6.59-6.52 (d, J=8.6, 1H), 6.23-6.11 (s, 2H), 2.83-2.69 (d, J=7.4, 1H), 1.68-1.52 (m, 4H), 1.49-1.38 (s, 1H), 1.19-0.92 (m, 6H).
Reaction SMILES: S(=O)(=O)(O)O.[C:6]1([C:19]([OH:21])=[O:20])[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:9]([C:16]([OH:18])=[O:17])=[CH:8][CH:7]=1.C(=O)([O-])[O-].[Na+].[Na+]>CC(O)C>[CH:6]([O:17][C:16]([C:9]1[C:10]2[C:15](=[CH:14][CH:13]=[CH:12][CH:11]=2)[C:6]([C:19]([O:21][CH:9]([CH3:10])[CH3:8])=[O:20])=[CH:7][CH:8]=1)=[O:18])([CH3:15])[CH3:7]
Reactant: O=C(O)c1ccc(C(=O)O)c2ccccc12
Agent: O=C([O-])[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: CC(C)O
Product: CC(C)OC(=O)c1ccc(C(=O)OC(C)C)c2ccccc12
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 76.5 %

Procedure:
Under a nitrogen stream, sulfuric acid (8 mL) was added dropwise over 3 hours to a solution of naphthalene-1,4-dicarboxylic acid (1.107 g, 5.12 mmol) in 2-propanol (60 mL) while heating to reflux. The resultant solution was cooled to room temperature and then saturated aqueous sodium carbonate was added thereto. The mixture was then stirred for 10 minutes at room temperature. The resultant mixture was twice extracted with dichloromethane. After drying the organic layer over anhydrous magnesium sulfate, solvent was removed by distillation under reduced pressure. The resulting residue was purified by silica gel column chromatography (developing solution=ethyl acetate:n-hexane (15:85)), to thereby obtain the titled compound (588 mg, 38%).
Reaction SMILES: C([O:3][C:4](=O)[CH2:5][C:6]1([CH2:13][N+:14]([O-])=O)[CH2:10][C@@H:9]([CH3:11])[C@H:8]([CH3:12])[CH2:7]1)C>CO.[Ni]>[CH3:12][C@H:8]1[C@H:9]([CH3:11])[CH2:10][C:6]2([CH2:13][NH:14][C:4](=[O:3])[CH2:5]2)[CH2:7]1
Reactant: CCOC(=O)CC1(C[N+](=O)[O-])C[C@@H](C)[C@H](C)C1
Agent: [Ni]
Solvent: CO
Product: C[C@@H]1CC2(CNC(=O)C2)C[C@H]1C
Reaction time: 4 h
Yield: 99.7 %

Procedure:
The nitroester (3) (0.83 g, 3.4 mmol) was dissolved in methanol (30 mL) and shaken over Raney nickel catalyst under an atmosphere of hydrogen (40 psi) at 30° C. After 4 hours, the catalyst was removed by filtration through celite. The solvent was removed in vacuo to give 567 mg (99%) of a pale yellow oil which solidified on standing.
Reaction SMILES: [CH3:1][C:2]1[O:6][N:5]=[C:4](C=O)[CH:3]=1.[CH2:9]([O:11][C:12](=[O:18])[CH2:13][C:14]([CH2:16][Cl:17])=[O:15])[CH3:10]>>[CH2:9]([O:11][C:12](=[O:18])[C:13](=[C:4]1[CH:3]=[C:2]([CH3:1])[O:6][NH:5]1)[C:14](=[O:15])[CH2:16][Cl:17])[CH3:10]
Reactant: CCOC(=O)CC(=O)CCl
Reactant: Cc1cc(C=O)no1
Product: CCOC(=O)C(C(=O)CCl)=C1C=C(C)ON1

Procedure:
79.5 g of 5-methylisoxazole-3-aldehyde were reacted with 4-chloroacetoacetic acid ethyl ester as described in Example 24. A crude product, which was chromatographically pure, was obtained. This isomer ratio was 2:1.
Reaction SMILES: B(F)(F)F.[BH4-].[Na+].[F:7][C:8]1[CH:13]=[CH:12][C:11]([CH3:14])=[C:10]([CH:15]=[C:16]([N+:18]([O-])=O)[CH3:17])[CH:9]=1>C1COCC1>[F:7][C:8]1[CH:13]=[CH:12][C:11]([CH3:14])=[C:10]([CH2:15][CH:16]([NH2:18])[CH3:17])[CH:9]=1
Reactant: CC(=Cc1cc(F)ccc1C)[N+](=O)[O-]
Agent: FB(F)F
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Cc1ccc(F)cc1CC(C)N
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 84.3 %

Procedure:
Borontrifluoride diethyletherate (272.68 g, 1.921 mol) was added dropwise through an additional funnel to a mixture of NaBH4 (58.14 g, 1.537 mol) in 600 mL of anhydrous THF cooled in a cooling bath under an argon atmosphere. After addition, the mixture was warmed to rt and continued to stir for 30 minutes. A solution of 4-fluoro-1-methyl-2-(2-nitroprop-1-enyl)benzene (60 g, 0.307 mol) in 200 mL of anhydrous THF was added dropwise through an additional funnel to the above mixture. The resulting reaction mixture was heated at reflux for 6-7 h under an argon atmosphere. After the end of the reaction was established by TLC, the reaction mixture was cooled to rt, quenched by water, acidified by concentrated HCl, and heated to 80° C. for 4 h. The mixture was washed with diethyl ether twice. The aqueous layer was separated, basified with 10% aqueous NaOH solution, and extracted with diethyl ether until no or a little product is left in aqueous layer. The combined extracts were dried over anhydrous MgSO4, filtered, evaporated and purified by a silica gel column chromatography using CH2Cl2 and methanol (85:15 v/v) as eluent to give 43.3 g of the designed compound as off-white solid. 1H NMR (500 MHz, DMSO-d6) δ 7.89 (br s, 2H, NH2), 7.22-7.20 (m, 1H, ArH), 7.03-6.96 (m, 2H, ArH), 3.40-3.34 (m, 1H, CH), 2.91-2.87 (m, 1H, CH), 2.69-2.65 (m, 1H, CH), 2.24 (s, 3H, CH3), 1.10 (d, J=6.5 Hz, 3H, CH3); Mass (ESI, positive) m/z 168.0 [M+H]+.