Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[C:7]([N+:8]([O-])=O)=[CH:6][N:5]=[C:4]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH:3]=1>C(O)C.[C].[Pd]>[NH2:8][C:7]1[C:2]([CH3:1])=[CH:3][C:4]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[N:5][CH:6]=1
Reactant: CCOC(=O)c1cc(C)c([N+](=O)[O-])cn1
Agent: [Pd]
Solvent: CCO
Product: CCOC(=O)c1cc(C)c(N)cn1
Temperature: 25 °C
Reaction time: 8 h
Yield: 98.9 %

Procedure:
A mixture of ethyl 4-methyl-5-nitropyridine-2-carboxylate (3.23 g) and 10% palladium-carbon powder (0.65 g) in ethanol (50 mL) was stirred at room temperature under a hydrogen atmosphere overnight. The insoluble material was removed by filtration, and the filtrate was concentrated under reduced pressure to give the title compound (2.74 g).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][N:3]=1.C([Cu])#N.C[N:13]([CH:15]=[O:16])C>Cl>[F:8][C:5]1[CH:6]=[CH:7][C:2]([C:15]([NH2:13])=[O:16])=[N:3][CH:4]=1
Reactant: CN(C)C=O
Reactant: Fc1ccc(Br)nc1
Agent: N#C[Cu]
Agent: Cl
Product: NC(=O)c1ccc(F)cn1
Temperature: 100 °C
Reaction time: 15.5 h
Yield: 31.2 %

Procedure:
Take up 2-bromo-5-fluoropyridine (0.750 g, 4.26 mmol) and CuCN (0.954 g, 10.7 mmol) in DMF (10.7 mL). Heat to reflux for 5 hours. Cool the reaction mixture to 100° C. Add a solution of FeCl36H2O (0.654 g) in 10% HCl solution (30 mL) and stir for 15.5 hours. Cool the reaction mixture to 80° C. and filter. Add 1.0 N NaOH until the reaction mixture becomes basic and extract with dichloromethane (3×200 mL). Wash the organic layer with brine (1×75 mL), dry over Na2SO4, filter and concentrate to give the title compound (0.186 g, 31.2%): TOF MS EI+ 140.0 (M)+, base peak EI+ 97.0 (M−CONH)+, HRMS calcd for C6H5N2OF 140.0386, found 140.0378, time 3.40 min; HPLC [YMC-Pack Pro C-18 (150×4.6 mm, S-5 microm), acetonitrile in water containing 0.01% concentrated HCl at 1.0 mL/min, 30-99% over 19 min], tR=7.5 min, 100% purity.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7].[OH:8][C:9]1[CH:10]=[C:11]([CH:14]=[C:15]([OH:18])[C:16]=1[OH:17])[CH:12]=[O:13]>>[CH2:2]([O:8][C:9]1[CH:10]=[C:11]([CH:14]=[C:15]([O:18][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7])[C:16]=1[O:17][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7])[CH:12]=[O:13])[CH2:3][CH2:4][CH2:5][CH2:6][CH3:7]
Reactant: CCCCCCBr
Reactant: O=Cc1cc(O)c(O)c(O)c1
Product: CCCCCCOc1cc(C=O)cc(OCCCCCC)c1OCCCCCC

Procedure:
The title compound was prepared according to the method described in Example 9 above from 1-bromohexan and 3,4,5-trihydroxy-benzaldehyde.
Reaction SMILES: Cl[C:2](=[N:6][NH:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([Cl:14])[CH:9]=1)[C:3](=[O:5])[CH3:4].[Cl:15][C:16]1[CH:21]=[CH:20][C:19]([SH:22])=[CH:18][CH:17]=1>>[Cl:15][C:16]1[CH:21]=[CH:20][C:19]([S:22][C:2](=[N:6][NH:7][C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([Cl:14])[CH:9]=2)[C:3](=[O:5])[CH3:4])=[CH:18][CH:17]=1
Reactant: Sc1ccc(Cl)cc1
Reactant: CC(=O)C(Cl)=NNc1cccc(Cl)c1
Product: CC(=O)C(=NNc1cccc(Cl)c1)Sc1ccc(Cl)cc1
Yield: 95.9 %

Procedure:
The reaction of 2.23 g of 1-chloro-1-[(3-chlorophenyl) hydrazono]-2-propanone with 1.72 g of 4-chlorothiophenol as Example 11 yielded 3.14 g of 1-[(4-chlorophenyl)thio]-1-[(3-chlorophenyl)hydrazono]-2-propanone, mp 128°-131° C.
Reaction SMILES: Br[C:2]1[S:3][C:4]([CH3:7])=[CH:5][CH:6]=1.[C:8]1([CH2:14][N:15]2[CH2:19][CH:18]=[C:17](B3OC(C)(C)C(C)(C)O3)[CH2:16]2)[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.[F-].[Cs+]>C1COCC1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:7][C:4]1[S:3][C:2]([C:17]2[CH2:16][N:15]([CH2:14][C:8]3[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=3)[CH2:19][CH:18]=2)=[CH:6][CH:5]=1
Reactant: Cc1ccc(Br)s1
Reactant: CC1(C)OB(C2=CCN(Cc3ccccc3)C2)OC1(C)C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cs+]
Agent: [F-]
Solvent: C1CCOC1
Product: Cc1ccc(C2=CCN(Cc3ccccc3)C2)s1
Temperature: 80 °C
Reaction time: 1.5 h

Procedure:
The title compound can be prepared through a coupling palladium mediated reaction, e.g. starting from 2-bromo-5-methylthiophene and 1-(phenylmethyl)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,5-dihydro-1H-pyrrole. For example, to a solution of 2-bromo-5-methylthiophene (1.3 eq.) in THF, 1-(phenylmethyl)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,5-dihydro-1H-pyrrole (1 eq.), tetrakis(triphenylphosphine)palladium(0) (5% mol) and cesium fluoride (4 eq.) may be added at room temperature. The resulting mixture should be stirred at 80° C. for 1.5 hours. After cooling the solvent should be evaporated under reduced pressure and the residue partitioned between dichloromethane and sodium hydroxyde (1M). The organic phase should be evaporated under reduced pressure and the crude product purified by flash chromatography to give the title compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]2[CH2:9][CH2:10][CH2:11][CH:12]([NH:14][CH2:15][CH2:16][O:17][CH3:18])[CH2:13][C:7]=2[CH:6]=[CH:5][C:4]=1[NH2:19].Cl[C:21]1[N:26]=[C:25]([NH:27][C@@H:28]2[C@@H:33]3[CH2:34][C@@H:30]([CH:31]=[CH:32]3)[C@@H:29]2[C:35]([NH2:37])=[O:36])[C:24]([Cl:38])=[CH:23][N:22]=1>>[Cl:38][C:24]1[C:25]([NH:27][C@@H:28]2[C@@H:33]3[CH2:34][C@@H:30]([CH:31]=[CH:32]3)[C@@H:29]2[C:35]([NH2:37])=[O:36])=[N:26][C:21]([NH:19][C:4]2[CH:5]=[CH:6][C:7]3[CH2:13][CH:12]([NH:14][CH2:15][CH2:16][O:17][CH3:18])[CH2:11][CH2:10][CH2:9][C:8]=3[C:3]=2[O:2][CH3:1])=[N:22][CH:23]=1
Reactant: NC(=O)[C@@H]1[C@H](Nc2nc(Cl)ncc2Cl)[C@H]2C=C[C@@H]1C2
Reactant: COCCNC1CCCc2c(ccc(N)c2OC)C1
Product: COCCNC1CCCc2c(ccc(Nc3ncc(Cl)c(N[C@H]4[C@@H](C(N)=O)[C@@H]5C=C[C@H]4C5)n3)c2OC)C1

Procedure:
The title compound was prepared from 1-methoxy-N(6)-(2-methoxyethyl)-6,7,8,9-tetrahydro-5H-benzocyclohepten-2,6-diamine (200 mg, 0.8 mmol) and (1S,2S,3R,4R)-3-(2,5-dichloropyrimidin-4-ylamino)-bicyclo[2.2.1]hept-5-ene-2-carboxylic acid amide (290 mg, 0.76 mmol) in an analogous manner to Example 946 to afford a tan solid (30 mg, 8%). Mp: 98-99° C. LCMS (m/e) 527 (M+1); 1H-NMR (CDCl3, 400 MHz) δ 8.20 (m, 1H), 7.92 (s, 1H), 7.43 (s, 1H), 7.00 (d, J=8 Hz, 1H), 6.91 (d, J=8 Hz, 1H), 6.40 (m, 1H), 6.35 (m, 1H), 5.70 (br s, 1H), 5.56 (br s, 1H), 4.37 (m, 1H), 3.73 (s, 3H), 3.52 (m, 2H), 3.37 (s, 3H), 3.10 (m, 2H), 2.96-2.82 (m, 5H), 2.62 (m, 2H), 2.51 (d, J=8 Hz, 1H), 2.25 (d, J=8 Hz, 1H), 2.10 (m, 1H), 1.96 (m, 1H), 1.77 (m, 2H), 1.64 (d, J=8 Hz, 1H), 1.50 (m, 1H).
Reaction SMILES: C[O:2][C:3]([C@H:5]1[CH2:10][CH2:9][C@H:8]([O:11][C:12]([N:14]2[CH2:18][C@@H:17]([N:19]([CH2:32][C:33]3[CH:38]=[C:37]([C:39]([F:42])([F:41])[F:40])[CH:36]=[C:35]([C:43]([F:46])([F:45])[F:44])[CH:34]=3)[C:20]3[N:25]=[CH:24][C:23]([C:26]4[CH:27]=[N:28][N:29]([CH3:31])[CH:30]=4)=[CH:22][N:21]=3)[CH2:16][C@H:15]2[CH2:47][CH3:48])=[O:13])[CH2:7][CH2:6]1)=[O:4].O.[OH-].[Li+].O.CO>C1COCC1>[C:3]([CH:5]1[CH2:10][CH2:9][CH:8]([O:11][C:12]([N:14]2[CH2:18][C@@H:17]([N:19]([CH2:32][C:33]3[CH:34]=[C:35]([C:43]([F:44])([F:45])[F:46])[CH:36]=[C:37]([C:39]([F:41])([F:42])[F:40])[CH:38]=3)[C:20]3[N:21]=[CH:22][C:23]([C:26]4[CH:27]=[N:28][N:29]([CH3:31])[CH:30]=4)=[CH:24][N:25]=3)[CH2:16][C@H:15]2[CH2:47][CH3:48])=[O:13])[CH2:7][CH2:6]1)([OH:4])=[O:2]
Reactant: CC[C@@H]1C[C@H](N(Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)c2ncc(-c3cnn(C)c3)cn2)CN1C(=O)O[C@H]1CC[C@H](C(=O)OC)CC1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: CC[C@@H]1C[C@H](N(Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)c2ncc(-c3cnn(C)c3)cn2)CN1C(=O)OC1CCC(C(=O)O)CC1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
(2R,4S)-4-{(3,5-Bis-trifluoromethyl-benzyl)-[5-(1-methyl-1H-pyrazol-4-yl)-pyrimidin-2-yl]-amino}-2-ethyl-pyrrolidine-1-carboxylic acid trans-4-methoxycarbonyl-1-cyclohexyl ester (0.101 mmol; 69 mg) and lithium hydroxide monohydrate (0.381 mmol; 16 mg) are dissolved in THF (1 mL), water (0.5 mL) and MeOH (0.1 mL). The solution is stirred for 3 hours at room temperature. The reaction mixture is quenched with aqueous 1M HCl (0.95 mL) and stirred for 15 minutes. To the mixture is added dichloromethane and the organic layer is separated and then concentrated under reduced pressure. The desired product, (2R,4S)-4-{(3,5-Bis-trifluoromethyl-benzyl)-[5-(1-methyl-1H-pyrazol-4-yl)-pyrimidin-2-yl]-amino}-2-ethyl-pyrrolidine-1-carboxylic acid 4-carboxy-cyclohexyl ester, is obtained in 90% yield (60 mg); ESI-MS m/z: 669 [M+1]+, Retention time 2.13 min (condition A).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:9]2[C:17](=[O:18])[C:16]3[C@@H:15]4[C:19]([CH3:21])([CH3:20])[C@@:12]([CH3:22])([CH2:13][CH2:14]4)[C:11]=3[NH:10]2)[CH:5]=[C:6]([Cl:8])[CH:7]=1.I[CH3:24].C>CN(C)C=O.C(O)C.C(OCC)C>[Cl:1][C:2]1[CH:3]=[C:4]([N:9]2[C:17](=[O:18])[C:16]3[C@@H:15]4[C:19]([CH3:21])([CH3:20])[C@@:12]([CH3:22])([CH2:13][CH2:14]4)[C:11]=3[N:10]2[CH3:24])[CH:5]=[C:6]([Cl:8])[CH:7]=1
Reactant: CI
Reactant: CC1(C)[C@@H]2CC[C@@]1(C)c1[nH]n(-c3cc(Cl)cc(Cl)c3)c(=O)c12
Solvent: CCO
Solvent: CN(C)C=O
Solvent: CCOCC
Product: Cn1c2c(c(=O)n1-c1cc(Cl)cc(Cl)c1)[C@H]1CC[C@]2(C)C1(C)C
Temperature: 95 °C
Reaction time: 8 h
Yield: 18.8 %

Procedure:
A mixture of (4S,7R)-2-(3,5-dichloro-phenyl)-7,8,8-trimethyl-1,2,4,5,6,7-hexahydro-4,7-methano-indazol-3-one (Intermediate 45; 200 mg, 0.59 mmol) and iodomethane (180 μL, 2.9 mmol) in dimethylformamide (3 mL) was heated at 95° C. for 7 h and then stirred overnight at room temperature. The solvent was evaporated, dichloromethane (50 mL) was added and the solution was washed with water (3×25 mL), saturated aqueous sodium thiosulfate (25 mL), and brine (25 mL). The solution was dried (magnesium sulfate), filtered, evaporated, and purified by column chromatography, eluting with 20% ethyl acetate/petroleum ether, and dried under high vacuum overnight to give a pale orange solid. This was dissolved in ethanol and the solution was treated with charcoal, then filtered through Celite (washing the Celite well with ethanol) and evaporated to give a brown solid. The brown solid was dissolved in ethyl ether and the solution was cooled in a freezer for 1 h. The solid was filtered off and washed with ether to give (4S,7R)-2-(3,5-dichloro-phenyl)-1,7,8,8-tetramethyl-1,2,4,5,6,7-hexahydro-4,7-methano-indazol-3-one (39 mg, 19%). ES(+)-MS (M+H) 351.
Reaction SMILES: [ClH:1].[CH3:2][O:3][C:4](=[O:14])[C@@H:5]1[CH2:9][CH2:8][CH2:7][N:6]1[C:10](=[O:13])[CH2:11][NH2:12].[CH2:15]1[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH2:17][C:16]1=O.C(N(CC)CC)C.[Na]>CO>[ClH:1].[CH3:2][O:3][C:4](=[O:14])[C@@H:5]1[CH2:9][CH2:8][CH2:7][N:6]1[C:10](=[O:13])[CH2:11][NH:12][CH:16]1[CH2:15][C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH2:17]1
Reactant: O=C1Cc2ccccc2C1
Reactant: COC(=O)[C@@H]1CCCN1C(=O)CN
Agent: Cl
Agent: [Na]
Solvent: CO
Solvent: CCN(CC)CC
Product: COC(=O)[C@@H]1CCCN1C(=O)CNC1Cc2ccccc2C1
Temperature: 25 °C
Yield: 37 %

Procedure:
Glycyl-L-proline methylester hydrochloride (16.0 g, 72.1 m mole) was dissolved in methanol (150 ml), and Indan-2-on (4.75 g, 36.0 m mole) and triethylamine (1.8 g, 18.0 m mole) were added thereto. Sodium syanoborohydride (2.27 g, 36.0 m mole) was gradually added thereto while cooling with ice and stirring. The mixture was stirred for 1 hour while cooling with ice and next for 5 hours at room temperature. A little insoluble material was separated by filtration, and the filtrate was concentrated under reduced pressure. To the residue, water (100 ml) and ethyl ether (100 ml) were added, and the solution was adjusted to pH 1.5 with 6N hydrochloric acid while stirring to dissolve it. The ethyl ether layer was removed, and the remaining water layer was washed with ethyl ether (100 ml). The desired product was extracted from the water layer with chloroform (100 ml×3 times). The thus obtained chloroform as extracted was concentrated under reduced pressure. To thus produced tar-like residue ethyl ether and 5% sodium bicarbonate (200 ml) were added and the mixture was stirred to dissolve the solid matter. The aqueous layer was removed and the ethyl ether layer was washed with aqueous solution saturated with sodium chloride. To the ethyl ether layer water (150 ml) was added, and the solution was adjusted to pH 1.5 with 6N hydrochloric acid while stirring and ethyl ether was removed. The water layer was washed with ethyl ether (100 ml) and to the water layer chloroform (200 ml) was added. The solution was adjusted to pH 8.0 with sodium bicarbonate while stirring. The aqueous layer was removed, and chloroform layer was dried with anhydrous sodium sulfate, and the sodium sulfate was sepa rated by filtration. Separately, anhydrous hydrogen chloride gas was brown into the chloroform, and thus obtained hydrogen chloride chloroform solution was added to the above mentioned chloroform layer. After checking the solution acidic enough, the chloroform was removed off under reduced pressure, to yield N-(2-indanyl) glycyl-L-proline methylester hydrochloride (4.50 g, 13.3 m mole, yield: 37%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:12]([NH2:14])=[O:13])[C:5](=[CH:9][C:10]=1[F:11])[C:6]([OH:8])=O>C1(C)C=CC=CC=1>[F:11][C:10]1[CH:9]=[C:5]2[C:6](=[O:8])[NH:14][C:12](=[O:13])[C:4]2=[CH:3][C:2]=1[F:1]
Reactant: NC(=O)c1cc(F)c(F)cc1C(=O)O
Solvent: Cc1ccccc1
Product: O=C1NC(=O)c2cc(F)c(F)cc21

Procedure:
One part of the 4,5-difluorophthalamic acid was heated to 170° C. for a period of 30 minutes, then cooled, dissolved in toluene and crystallized therefrom. The crystalline product was separated by filtration to yield 0.56 parts of 4,5-difluorophthalimide, having a melting range of 154°-156° C. The structure was confirmed by C13 nuclear magnetic resonance analysis.
Reaction SMILES: [C:1]([O:5][C:6](=[O:24])[N:7]([C:9]([C:16]1[CH:21]=[CH:20][C:19]([Cl:22])=[C:18]([Cl:23])[CH:17]=1)([CH2:13][NH:14][CH3:15])[CH2:10][CH:11]=[CH2:12])[CH3:8])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[C:32](Cl)(=[O:36])[CH:33]([CH3:35])[CH3:34]>C(#N)C>[C:1]([O:5][C:6](=[O:24])[N:7]([C:9]([C:16]1[CH:21]=[CH:20][C:19]([Cl:22])=[C:18]([Cl:23])[CH:17]=1)([CH2:13][N:14]([C:32](=[O:36])[CH:33]([CH3:35])[CH3:34])[CH3:15])[CH2:10][CH:11]=[CH2:12])[CH3:8])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)C(=O)Cl
Reactant: C=CCC(CNC)(c1ccc(Cl)c(Cl)c1)N(C)C(=O)OC(C)(C)C
Solvent: CCN(CC)CC
Solvent: CC#N
Product: C=CCC(CN(C)C(=O)C(C)C)(c1ccc(Cl)c(Cl)c1)N(C)C(=O)OC(C)(C)C
Reaction time: 1 h
Yield: 64 %

Procedure:
tert-Butyl[1-(3,4-dichlorophenyl)-1-methylaminomethyl-3-butenyl]methylcarbamate (2.0 g) produced in Example 4 was dissolved in acetonitrile (40 mL). Under cooling with ice, triethylamine (1.49 mL) and isobutyryl chloride (1.12 mL) was added thereto. Under cooling with ice, the mixture was stirred for 1 hour. The reaction mixture was concentrated under reduced pressure, and water was added to the residue, followed by extraction with ethyl acetate. The organic layer was washed with saturated brine, dried over sodium sulfate anhydrate, and concentrated under reduced pressure. The residue was purified through silica gel column chromatography (n-hexane:ethyl acetate=3:1), to thereby give the title compound (1.53 g, 64%).
Reaction SMILES: P(Cl)(Cl)([Cl:3])=O.[NH2:6][C:7]1[CH:12]=[C:11](O)[N:10]=[C:9]([NH:14][C:15]2[CH:22]=[CH:21][C:18]([C:19]#[N:20])=[CH:17][CH:16]=2)[N:8]=1.C(=O)([O-])[O-].[K+].[K+]>O>[NH2:6][C:7]1[CH:12]=[C:11]([Cl:3])[N:10]=[C:9]([NH:14][C:15]2[CH:22]=[CH:21][C:18]([C:19]#[N:20])=[CH:17][CH:16]=2)[N:8]=1
Reactant: N#Cc1ccc(Nc2nc(N)cc(O)n2)cc1
Reactant: O=P(Cl)(Cl)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: N#Cc1ccc(Nc2nc(N)cc(Cl)n2)cc1
Temperature: 97 °C

Procedure:
1500 ml of phosphorus oxychloride and 300 g of 4-(4-Amino-6-hydroxypyrimidin-2-ylamino)benzonitrile at 27±3° C. were added to the reaction vessel and heated to 97±3° C.; and maintained at same temperature for 7 hrs. After completion of the reaction, ˜50% of phosphorous oxychloride was distilled off under vacuum at 83±2° C. and the reaction mixture was cooled to 30±5° C. In a clean RB flask were added 1000 g of ice and 1000 mL of water and such was slowly added the above obtained reaction mass. The pH of the reaction mass was adjusted to 9.0±0.5 with 50% potassium carbonate solution in water at 5±5° C. The reaction mixture was stirred, filtered and the obtained solid was washed with 600 ml of water and suck dried. The wet solid was charged into a RB flask at 27±3° C. to which was added 600 ml of water. The resulting wet solid was taken into a RB flask and 600 ml of water was added, stirred, and filtered. The obtained solid was washed with water and suck dried. 3000 ml of ethyl acetate was charged into a RB flask and to this was added the obtained solid and heated to 43±3° C. The reaction mass was stirred for 20 mins and filtered hot. The residue was washed with ethyl acetate and filtrate (1) collected at 27±3° C. The obtained solid was again taken in RB flask to which was added 1500 ml of ethyl acetate and heated to 43±3° C., stirred and the hot reaction mass filtered and the filtrate (2) collected. Both filtrates (1) and (2) were taken and distilled off solvent at 47±3° C. To the residue was added 900 ml of heptane and cooled to 27±3° C. and was again added 1100 ml of heptane, stirred, the solid filtered and suck dried, and the solid was washed with heptane. The obtained solid was dried under vacuum. To the obtained 190 g of crude was added 380 ml of dimethyl formamide and 20.4 ml of 1,8-diazabicycloundec-7-ene under stirring at 27±3° C. and the reaction mass heated to 47±3° C. To the obtained clear solution was added 760 ml of water and stirred for 1 hr. The reaction mass was cooled and filtered. The solid was washed with 760 mL of water twice and suck dried. The solid was washed with 48 ml of chilled methanol and the solid suck dried. The obtained solid was further dried under vacuum to yield the title compound.
Reaction SMILES: CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.I[C:44]1[CH:49]=[CH:48][CH:47]=[CH:46][N:45]=1.[SH:50][C:51]1[CH:52]=[C:53]([CH:57]=[CH:58][CH:59]=1)[C:54]([OH:56])=[O:55].C(N(CC)C(C)C)(C)C>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].O1CCOCC1>[N:45]1[CH:46]=[CH:47][CH:48]=[CH:49][C:44]=1[S:50][C:51]1[CH:52]=[C:53]([CH:57]=[CH:58][CH:59]=1)[C:54]([OH:56])=[O:55]
Reactant: O=C(O)c1cccc(S)c1
Reactant: Ic1ccccn1
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1COCCO1
Product: O=C(O)c1cccc(Sc2ccccn2)c1
Temperature: 100 °C
Reaction time: 8 h
Yield: 66 %

Procedure:
Xantphos (3.75 g) and Pd2(dba)3 (2.97 g) were added in that order to a dioxane (150 mL) solution of 2-iodopyridine (7.31 g), 3-mercaptobenzoic acid (5.0 g) and N,N-diisopropylethylamine (11.30 mL), and stirred overnight in a nitrogen atmosphere at 100° C. After left cooled, the reaction solution was evaporated under reduced pressure, then ethyl acetate was added to the residue, washed three times with aqueous saturated ammonium chloride solution, and dried with sodium sulfate. The drying agent was removed through filtration, and the solvent was evaporated off under reduced pressure. The residue was purified through silica gel column chromatography (methanol/chloroform=from 0% to 20%, gradient) to give the intended product (4.95 g, 66%) as a brown solid.
Reaction SMILES: [C:1](Cl)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:10]([C:14]1[CH:29]=[CH:28][C:17]([C:18]([NH:20][C:21]2[C:22]([NH2:27])=[CH:23][CH:24]=[CH:25][CH:26]=2)=[O:19])=[CH:16][CH:15]=1)([CH3:13])([CH3:12])[CH3:11]>>[C:1]([NH:27][C:22]1[C:21]([NH:20][C:18](=[O:19])[C:17]2[CH:28]=[CH:29][C:14]([C:10]([CH3:12])([CH3:11])[CH3:13])=[CH:15][CH:16]=2)=[CH:26][CH:25]=[CH:24][CH:23]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)c1ccc(C(=O)Nc2ccccc2N)cc1
Reactant: O=C(Cl)c1ccccc1
Product: CC(C)(C)c1ccc(C(=O)Nc2ccccc2NC(=O)c2ccccc2)cc1
Yield: 53.7 %

Procedure:
Using the procedure described in Example 93, Part A, benzoyl chloride (0.80 mmol) and N1-(4-tert-butylbenzoyl)-1,2-benzenediamine (0.75 mmol) yielded 150 mg (54%) of the title compound.
Reaction SMILES: [SH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([N+:12]([O-:14])=[O:13])=[C:5]2[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.[C:21](=O)([O-])[O-].[K+].[K+].Cl>O1CCOCC1.O.CI>[CH3:21][S:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([N+:12]([O-:14])=[O:13])=[C:5]2[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: O=[N+]([O-])c1cnc2ccc(S)cc2c1-c1ccccc1
Reactant: O=C([O-])[O-]
Agent: Cl
Agent: [K+]
Solvent: O
Solvent: CI
Solvent: C1COCCO1
Product: CSc1ccc2ncc([N+](=O)[O-])c(-c3ccccc3)c2c1
Reaction time: 2.5 h

Procedure:
To a solution of 6-mercapto-3-nitro-4-phenylquinoline (1.55 g) in dioxane (30 ml) were added a solution of potassium carbonate (1.14 g) in water (10 ml) and methyl iodide (1.17 g), and the whole was stirred for 2.5 hrs. at room temperature. After dilution with water, the mixture was acidified with hydrochloric acid, and the precipitating crystals were collected by filtration and recrystallized from acetone to give 6-methylthio-3-nitro-4-phenylquinoline as yellow needles. Yield 1.39 g (85.3%). m.p. 131°-133° C.
Reaction SMILES: C[O:2][C:3]([C:5]1[C:6]2[N:28]([CH2:29][C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)[C:27](=[O:36])[NH:26][C:7]=2[C:8]([N:11]([CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[N:9][CH:10]=1)=O.[NH2:37][CH2:38][CH:39]1[CH2:41][CH2:40]1>>[CH:39]1([CH2:38][NH:37][C:3]([C:5]2[C:6]3[N:28]([CH2:29][C:30]4[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=4)[C:27](=[O:36])[NH:26][C:7]=3[C:8]([N:11]([CH2:12][C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[CH2:19][C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=3)=[N:9][CH:10]=2)=[O:2])[CH2:41][CH2:40]1
Reactant: NCC1CC1
Reactant: COC(=O)c1cnc(N(Cc2ccccc2)Cc2ccccc2)c2[nH]c(=O)n(Cc3ccccc3)c12
Product: O=C(NCC1CC1)c1cnc(N(Cc2ccccc2)Cc2ccccc2)c2[nH]c(=O)n(Cc3ccccc3)c12
Temperature: 120 °C
Reaction time: 8 h

Procedure:
1-benzyl-4-dibenzylamino-2-oxo-2,3-dihydro-1H-imidazo[4,5,c]pyridine-7-carboxylic acid methyl ester (50 mg, 0.1 mmol) was suspended in 2 mL of (aminomehtyl) cyclopropane and the mixture was stirred at 120° C. overnight. The excess of amine was removed in vacuo and the gum was partitioned in water (20 mL) and ethyl acetate (50 mL), the organic layer was isolated, dried over MgSO4 and the solvent was removed in vacuo. The residue was purified by column chromatography on silica gel using 5% of methanol in dichloromethane to give 10 mg of the title compound as a yellow gum.
Reaction SMILES: Cl.[F:2][C:3]1[CH:16]=[CH:15][C:6]([C:7]([CH:9]2[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]2)=[O:8])=[CH:5][CH:4]=1.Cl.Cl[C:19]1[CH:24]=[CH:23][N:22]=[CH:21][CH:20]=1.C(N(CC)CC)C>C1(C)C(C)=CC=CC=1>[F:2][C:3]1[CH:4]=[CH:5][C:6]([C:7]([CH:9]2[CH2:14][CH2:13][N:12]([C:19]3[CH:24]=[CH:23][N:22]=[CH:21][CH:20]=3)[CH2:11][CH2:10]2)=[O:8])=[CH:15][CH:16]=1
Reactant: Clc1ccncc1
Reactant: O=C(c1ccc(F)cc1)C1CCNCC1
Agent: Cl
Solvent: Cc1ccccc1C
Solvent: CCN(CC)CC
Product: O=C(c1ccc(F)cc1)C1CCN(c2ccncc2)CC1
Temperature: 145 °C
Yield: 41.5 %

Procedure:
A stirred mixture of 4-(4-fluorobenzoyl)piperidine, hydrochloride salt (3.90 g), 4-chloropyridine, hydrochloride salt (2.85 g) and triethylamine (4.90 ml) in xylene (75 ml) was heated at 145° C. for 27 hours. The solvent was evaporated and the residue partitioned between methylene chloride (150 ml) and water (100 ml), the pH being adjusted to ˜10 with 0.880 ammonia. The aqueous phase was extracted with a further methylene chloride (50 ml). The combined organic phases were washed with water, dried (Mg SO4) and evaporated. The residue was purified by column chromatography using a 19:1 mixture of methylene chloride and methanol as eluent to give 4-(4-fluorobenzoyl)-1-(4-pyridyl)piperidine (1.89 g);