Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CN(C)C=O.[OH:6][C:7]1[CH:8]=[C:9]2[C:14](=[CH:15][CH:16]=1)[NH:13][C:12](=[O:17])[CH:11]=[CH:10]2.C([O-])([O-])=O.[K+].[K+].[OH:24][CH2:25][CH2:26][N:27]([CH:34]1[CH2:39][CH2:38][CH2:37][CH2:36][CH2:35]1)[C:28](=[O:33])[CH2:29][CH2:30][CH2:31]Cl>C(Cl)(Cl)Cl>[OH:24][CH2:25][CH2:26][N:27]([CH:34]1[CH2:35][CH2:36][CH2:37][CH2:38][CH2:39]1)[C:28]([CH2:29][CH2:30][CH2:31][O:6][C:7]1[CH:8]=[C:9]2[C:14](=[CH:15][CH:16]=1)[NH:13][C:12](=[O:17])[CH:11]=[CH:10]2)=[O:33]
Reactant: O=C(CCCCl)N(CCO)C1CCCCC1
Reactant: O=c1ccc2cc(O)ccc2[nH]1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClC(Cl)Cl
Solvent: CN(C)C=O
Product: O=C(CCCOc1ccc2[nH]c(=O)ccc2c1)N(CCO)C1CCCCC1
Yield: 12.5 %

Procedure:
Into 50 ml of dimethylformamide were added 1.73 g of 6-hydroxycarbostyril, 1.8 g of K2CO3 and 0.5 g of KI. The mixture was heating at 60°-70° C. under stirring, then 3.2 g of N-(2-hydroxyethyl)-N-(4-chlorobutyryl)cyclohexylamine was added dropwise gradually thereto. After the addition operation, the reaction mixture was further stirred at the same temperature for 4 hours. Then the solvent was removed by distillation and the residue thus obtained was dissolved in 200 ml of chloroform and the chloroform layer was washed with a diluted hydrochloric acid, 1% Na OH aqueous solution and water in this order, then dried with anhydrous sodium sulfate. The drying agent was removed by filtration, and the mother liquid was concentrated, then the residue thus obtained was crystallized with petroleum ether. The crystals thus obtained was recrystallized from chloroform-petroleum ether to obtain 0.5 g of 6-{3-[N-(2-hydroxyethyl)-N-cyclohexylaminocarbonyl]propoxy}carbostyril. Melting point: 165°-166° C.
Reaction SMILES: N(OC(C)(C)C)=O.[C:8]([Cu])#[N:9].N[C:12]1[S:13][CH:14]=[C:15]([CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19])[N:16]=1>C(#N)C>[C:8]([C:12]1[S:13][CH:14]=[C:15]([CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19])[N:16]=1)#[N:9]
Reactant: N#C[Cu]
Reactant: CCOC(=O)Cc1csc(N)n1
Agent: CC(C)(C)ON=O
Solvent: CC#N
Product: CCOC(=O)Cc1csc(C#N)n1
Reaction time: 2.5 h
Yield: 25.5 %

Procedure:
To a mixture of tert-butyl nitrite (10 mL, 80 mmol) and CuCN (7.28 g, 80 mmol) in anhydrous acetonitrile (30 mL) was added a solution of ethyl 2-(2-aminothiazol-4-yl)acetate (7.5 g, 40 mmol) in anhydrous acetonitrile (20 mL) dropwise over a period of 1 hour at 50° C., then the mixture was stirred at the temperature for 2.5 hours. The mixture was concentrated in vacuo and the residue was purified by a silica gel column chromatography (PETROLEUM ETHER/EtOAc (V/V)=25/1) to give the title compound as yellowish liquid (2 g, 25%). The compound was characterized by the following spectroscopic data:
Reaction SMILES: [O:1]1C=CC=[C:2]1[C:6]1[CH:7]=[CH:8][C:9]2[CH:10]3[CH2:19][CH2:18][CH2:17][CH:11]3[C:12](=[O:16])[NH:13][C:14]=2[CH:15]=1.I([O-])(=O)(=O)=[O:21].[Na+]>C(#N)C.C(Cl)(Cl)(Cl)Cl.O.O.[Ru](=O)=O>[CH2:19]1[CH:10]2[CH:11]([C:12](=[O:16])[NH:13][C:14]3[CH:15]=[C:6]([C:2]([OH:1])=[O:21])[CH:7]=[CH:8][C:9]=32)[CH2:17][CH2:18]1
Reactant: O=C1Nc2cc(-c3ccco3)ccc2C2CCCC12
Reactant: [O-][I+3]([O-])([O-])[O-]
Agent: O=[Ru]=O
Agent: [Na+]
Solvent: ClC(Cl)(Cl)Cl
Solvent: O
Solvent: CC#N
Product: O=C(O)c1ccc2c(c1)NC(=O)C1CCCC21
Reaction time: 24 h

Procedure:
A suspension of 0.37 g (1.5 mmol) of 7-(2-furanyl)-1,2,3,3a,5,9b-hexahydro-cyclopenta[c]quinolin-4-one is suspended in 50 ml of acetonitrile-carbon tetrachloride-water (2:1:2) and mixed with 4.81 g (22.5 mmol) of sodium periodate and 40 mg (0.3 mmol) of ruthenium(IV) oxide. After 24 hours at room temperature, the batch is diluted with water (100 ml) and extracted with ethyl acetate (3×100 ml). The combined extracts are dried (Na2SO4) and concentrated by evaporation in a vacuum. The residue is dissolved in 100 ml of 0.5 M potassium hydroxide solution. The solution is washed with methyl-tert-butyl ether (2×100 ml), acidified with concentrated hydrochloric acid and extracted with ethyl acetate (3×100 ml). The combined extracts are dried (Na2SO4) and concentrated by evaporation in a vacuum: 213 mg of product.
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:8]([OH:10])=O)=[N:4][CH:5]=[CH:6][N:7]=1.C(Cl)Cl.[Cl:14][C:15]1[CH:21]=[CH:20][CH:19]=[CH:18][C:16]=1[NH2:17].Cl.CN(C)CCCN=C=NCC>CN(C)C1C=CN=CC=1.CN(C)C=O>[Cl:14][C:15]1[CH:21]=[CH:20][CH:19]=[CH:18][C:16]=1[NH:17][C:8]([C:3]1[C:2]([NH2:1])=[N:7][CH:6]=[CH:5][N:4]=1)=[O:10]
Reactant: Nc1nccnc1C(=O)O
Reactant: Nc1ccccc1Cl
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: Nc1nccnc1C(=O)Nc1ccccc1Cl
Temperature: 25 °C
Reaction time: 8 h
Yield: 49.7 %

Procedure:
A mixture of 3-aminopyrazine carboxylic acid (7.0 g, 50.32 mmol), methylene chloride (60 mL), dimethylformamide (40 mL), 4-dimethylaminopyridine (15.37 g, 126 mmol), 2-chloroaniline (5.82 mL, 55.35 mmol), and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (11.58 g, 60.38 mmol) was stirred overnight at ambient temperature. The solvent was removed and the residue was mixed with ethyl acetate and 1 N lithium chloride. The precipitate which formed was filtered and rinsed with 1 N lithium chloride, ethyl acetate, and ether and then air dried to afford 6.22 g (50%) of 3-aminopyrazine-2-carboxylic acid 2-chlorophenylamide as fluffy yellow crystals.
Reaction SMILES: [C:1]([OH:9])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.ClC1C=CC(S(O[N:28]2[C:32]3[CH:33]=[C:34]([Cl:37])[CH:35]=[CH:36][C:31]=3[N:30]=[N:29]2)(=O)=O)=CC=1>ClCCl>[C:1]([O:9][N:28]1[C:32]2[CH:33]=[C:34]([Cl:37])[CH:35]=[CH:36][C:31]=2[N:30]=[N:29]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(O)c1ccccc1
Reactant: O=S(=O)(On1nnc2ccc(Cl)cc21)c1ccc(Cl)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(On1nnc2ccc(Cl)cc21)c1ccccc1
Reaction time: 4 h
Yield: 84.6 %

Procedure:
Benzoic acid (2.4 g) is dissolved in dichloromethane (30 ml), and thereto are added triethylamine (2.8 ml) and further 1-(p-chlorobenzenesulfonyloxy)-6-chloro-1,2,3-benzotriazole (6.9 g) and the mixture is stirred for 4 hours. After the reaction, dichloromethane is distilled off and to the resulting residue are added water and ethyl acetate. The ethyl acetate layer is washed with water, an aqueous sodium hydrogen carbonate and water in order, dried over anhydrous magnesium sulfate and the solvent is distilled off to give white crystals of 1-benzoyloxy-6-chloro-1,2,3-benzotriazole (4.55 g). The product is recrystallized from ethanol to give pure product, melting point: 132° C.
Reaction SMILES: [C:1]([O:4][C:5]1[CH:14]=[CH:13][C:12]([C:15]([CH:17]2[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]2)=O)=[C:7]([O:8]C(=O)C)[CH:6]=1)(=[O:3])[CH3:2]>C(O)(=O)C.[Pd]>[C:1]([OH:4])(=[O:3])[CH3:2].[CH:17]1([CH2:15][C:12]2[CH:13]=[CH:14][C:5]([OH:4])=[CH:6][C:7]=2[OH:8])[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22]1
Reactant: CC(=O)Oc1ccc(C(=O)C2CCCCC2)c(OC(C)=O)c1
Agent: [Pd]
Solvent: CC(=O)O
Product: Oc1ccc(CC2CCCCC2)c(O)c1
Temperature: 50 °C
Reaction time: 16 h

Procedure:
A Parr hydrogenator (1 L) was charged with crude 4-cyclohexylcarbonyl resorcinol diacetate (3.0 g, 60% purity, 5.9 mmol) and acetic acid (50 ml) under nitrogen (Note 7). A suspension of 5% Pd/C (200 mg, Engelhard) in acetic acid (50 ml) was added and the reactor sealed, evacuated and purged with nitrogen (4×). The reactor was pressurized to 100 psi with hydrogen and stirred at 30° C. for 16 h, 50° C. for 16 h, recharged with catalyst (250 mg), pressurized to 200 psi H2 and stirred at 50° C. for 16 h, and finally recharged with catalyst (400 mg), pressurized to 200 psi H2 and stirred at 50° C. for 64 h (Note 8). At this time, GC showed the formation of products at the expense of starting material (Note 9). The reactor was evacuated, purged with nitrogen and the mixture filtered through celite (Note 10). The solvent was removed to give 4-cyclohexylmethyl resorcinol monoacetate as a light amber-colored oil which crystallized upon standing at room temperature (2.76 g).
Reaction SMILES: C([O:5][C:6]([CH:8]1[CH:14]([CH:15]=[CH:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH2:13][CH2:12][CH2:11][CH2:10][N:9]1[S:23]([C:26]1[CH:31]=[CH:30][C:29]([O:32][CH3:33])=[CH:28][CH:27]=1)(=[O:25])=[O:24])=[O:7])(C)(C)C.C(OCC1CCCCN(S(C2C=CC(OC)=CC=2)(=O)=O)C1C(O)=O)(=O)C>>[CH3:33][O:32][C:29]1[CH:28]=[CH:27][C:26]([S:23]([N:9]2[CH2:10][CH2:11][CH2:12][CH2:13][CH:14]([CH:15]=[CH:16][C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=3)[CH:8]2[C:6]([OH:7])=[O:5])(=[O:25])=[O:24])=[CH:31][CH:30]=1
Reactant: COc1ccc(S(=O)(=O)N2CCCCC(C=Cc3ccccc3)C2C(=O)OC(C)(C)C)cc1
Agent: COc1ccc(S(=O)(=O)N2CCCCC(COC(C)=O)C2C(=O)O)cc1
Product: COc1ccc(S(=O)(=O)N2CCCCC(C=Cc3ccccc3)C2C(=O)O)cc1

Procedure:
1-(4-Methoxy-benzenesulfonyl)-3-styryl-azepane-2-carboxylic acid was synthesized from 1-(4-Methoxy-benzenesulfonyl)-3-styryl-azepane-2-carboxylic acid tert-butyl ester in the same manner as the procedures used for the preparation of 3-Acetoxymethyl-1-(4-methoxy-benzenesulfonyl)-azepane-2-carboxylic acid: MS (M+H)+ =416, (M+NH4)+ =433.
Reaction SMILES: [Cl:1][C:2]1[CH:23]=[CH:22][C:5]([C:6]([C:8]2[N:12]([CH3:13])[C:11]([CH2:14][C:15]([O:17]CC#N)=O)=[CH:10][C:9]=2[CH3:21])=[O:7])=[CH:4][CH:3]=1.Cl.[CH3:25][O:26][C:27](=[O:31])[C@H:28]([CH3:30])[NH2:29].C(O)(=O)C.C(N(CC)CC)C>C1COCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([C:8]2[N:12]([CH3:13])[C:11]([CH2:14][C:15]([NH:29][C@H:28]([C:27]([O:26][CH3:25])=[O:31])[CH3:30])=[O:17])=[CH:10][C:9]=2[CH3:21])=[O:7])=[CH:22][CH:23]=1
Reactant: Cc1cc(CC(=O)OCC#N)n(C)c1C(=O)c1ccc(Cl)cc1
Reactant: COC(=O)[C@H](C)N
Agent: Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Solvent: CC(=O)O
Product: COC(=O)[C@H](C)NC(=O)Cc1cc(C)c(C(=O)c2ccc(Cl)cc2)n1C
Yield: 169.8 %

Procedure:
A solution of 10.0 g (0.03 mole) of cyanomethyl [5-(4-chlorobenzoyl)-1,4-dimethyl-1H-pyrrol-2-yl]acetate, 1.6 g (0.015 mole) of alanine methyl ester hydrochloride, 0.3 ml of glacial acetic acid, and 2.1 ml (0.015 mole) triethylamine in 40 ml of THF was heated under reflux for 31/2 hours. A second addition of 1.6 g of alanine methyl ester hydrochloride and 2.1 ml of triethylamine was made. The mixture was heated under reflux for 2 hours. A fourth addition of 2.0 g (0.018 mole) of triethylamine was made. The mixture was heated under reflux for 16 hours. The reaction was partitioned between chloroform and dilute hydrochloric acid. The organic layer was washed with brine and dried over anhydrous magnesium sulfate. The solvent was evaporated in vacuo. The residue was recrystallized from acetonitrile to give 9.6 g of methyl N-{[5-(4-chlorobenzoyl)-1,4-dimethyl-1H-pyrrol-2-yl]acetyl}alaninate, m.p. 163°-165° C. (85% yield).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]([CH3:13])([CH3:12])[C:9](Cl)=[O:10])[CH:5]=[CH:6][CH:7]=1.[CH2:14]([N:21]1[CH2:25][C@@H:24]([C:26]2[CH:31]=[CH:30][C:29]([F:32])=[CH:28][CH:27]=2)[C@H:23]([NH:33][CH3:34])[CH2:22]1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.C(N(C(C)C)C(C)C)C>C(Cl)Cl>[CH2:14]([N:21]1[CH2:25][C@@H:24]([C:26]2[CH:27]=[CH:28][C:29]([F:32])=[CH:30][CH:31]=2)[C@H:23]([N:33]([CH3:34])[C:9](=[O:10])[C:8]([C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=2)([CH3:13])[CH3:12])[CH2:22]1)[C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: CN[C@@H]1CN(Cc2ccccc2)C[C@H]1c1ccc(F)cc1
Reactant: CC(C)(C(=O)Cl)c1cccc(Cl)c1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CN(C(=O)C(C)(C)c1cccc(Cl)c1)[C@@H]1CN(Cc2ccccc2)C[C@H]1c1ccc(F)cc1
Reaction time: 2 h
Yield: 80 %

Procedure:
A solution of 2-(3-chloro-phenyl)-2-methyl-propionyl chloride (the preparation of which is described in DE2659404) (0.10 g, 0.46 mmol) in CH2Cl2 (4 ml) was added drop wise to a stirred solution of rac-[(3S,4R)-1-benzyl-4-(4-fluoro-phenyl)-pyrrolidin-3-yl]-methyl-amine (the preparation of which is described herein above) (0.11 g, 0.38 mmol) and ethyl-diisopropyl-amine (0.10 ml, 0.58 mmol) in CH2Cl2 (5 ml). The reaction mixture was stirred 2 h, concentrated under vacuo and purification by flash chromatography (SiO2, EtOAc/H, 1:3) yielded 0.14 g (80%) of the title product as light yellow oil. ES-MS m/e: 465.2 (M+H+).
Reaction SMILES: [NH2:1][C@H:2]([C:8]([OH:10])=O)[CH2:3][CH2:4][C:5]([OH:7])=[O:6].C1(C)C(S(O)(=O)=O)=CC=CC=1.[C:22]([O:26][C:27](=[O:37])[C@H:28]([C:30]([S:33][C:34](=[O:36])[CH3:35])([CH3:32])[CH3:31])[NH2:29])([CH3:25])([CH3:24])[CH3:23].C(N1CCOCC1)C.C1(N=C=NC2CCCCC2)CCCCC1>ClCCl.CN(C=O)C.ClCCl>[C:22]([O:26][C:27](=[O:37])[C@H:28]([C:30]([S:33][C:34](=[O:36])[CH3:35])([CH3:31])[CH3:32])[NH:29][C:8](=[O:10])[C@H:2]([CH2:3][CH2:4][C:5](=[O:6])[OH:7])[NH2:1])([CH3:23])([CH3:24])[CH3:25]
Reactant: N[C@@H](CCC(=O)O)C(=O)O
Reactant: CC(=O)SC(C)(C)[C@H](N)C(=O)OC(C)(C)C
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CCN1CCOCC1
Agent: Cc1ccccc1S(=O)(=O)O
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CC(=O)SC(C)(C)[C@H](NC(=O)[C@@H](N)CCC(=O)O)C(=O)OC(C)(C)C

Procedure:
A solution of 20 mmoles of pyro-L-glutamic acid and 20 mmoles S-acetyl-penicillamine t-butyl ester toluene sulfonic acid, neutrallized with N-ethyl morpholine, in dichloromethane: DMF (4:1) is cooled in an ice bath with stirring. A solution of 20 mmoles of dicyclohexylcarbodiimide in dichloromethane is added to the above reaction mixture. The reaction mixture is stirred in an ice water bath for 1 hour and then at room temperature overnight. Dicyclohexylurea is removed by filtration and the product is washed in ethyl acetate. Solvents of the combined filtrates are removed under reduced pressure with a rotary evaporator at 40° C. Ethyl acetate is added to the residue and the organic solution is washed until neutral. The organic phase is dried over anhydrous MgSO4, filtered and then the solvent is removed with a rotary evaporator. The material is crystallized from isopropanol and ether, yielding the named product.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:34])[C:4]([C:6]1[C:7]([CH3:33])=[N:8][C:9]2[CH2:10][CH2:11][N:12]([C:23]([O:25][CH2:26][C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)=[O:24])[CH2:13][C:14]=2[C:15]=1[C:16]1[CH:21]=[CH:20][C:19]([CH3:22])=[CH:18][CH:17]=1)=[O:5].[B]1OC2C(=CC=CC=2)O1.C([O-])([O-])=O.[Na+].[Na+]>C1(C)C=CC=CC=1.CCOC(C)=O>[OH:5][CH:4]([C:6]1[C:7]([CH3:33])=[N:8][C:9]2[CH2:10][CH2:11][N:12]([C:23]([O:25][CH2:26][C:27]3[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=3)=[O:24])[CH2:13][C:14]=2[C:15]=1[C:16]1[CH:21]=[CH:20][C:19]([CH3:22])=[CH:18][CH:17]=1)[C:3]([O:2][CH3:1])=[O:34]
Reactant: COC(=O)C(=O)c1c(C)nc2c(c1-c1ccc(C)cc1)CN(C(=O)OCc1ccccc1)CC2
Agent: O=C([O-])[O-]
Agent: [B]1Oc2ccccc2O1
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: COC(=O)C(O)c1c(C)nc2c(c1-c1ccc(C)cc1)CN(C(=O)OCc1ccccc1)CC2
Temperature: -35 °C
Reaction time: 0.5 h
Yield: 50.7 %

Procedure:
A solution of benzyl 3-(2-methoxy-2-oxoacetyl)-2-methyl-4-(p-tolyl)-7,8-dihydro-1,6-naphthyridine-6(5H)-carboxylate (2.53 g, 5.52 mmol) (intermediate 10) and 1M (toluene) R-5,5-diphenyl-2-methyl-3,4-propano-1,3,2-oxazaborlidine (2.21 ml, 2.21 mmol) in toluene (100 ml) was cooled to −35° C. Catecholborane (50 wt % in toluene) (1.65 ml, 7.73 mmol) was added dropwise and the solution stirred at −35° C. for 30 min then at −15° C. for 2 h. The reaction was diluted with EtOAc and stirred vigorously with sat'd Na2CO3 for 1 h. The organic phase was washed with twice with satd Na2CO3, dried (Na2SO4), filtered and concentrated. The resulting oil was purified by flash column chromatography (Biotage; 0%-100% EtOAc/hexane) to provide benzyl 3-(1-hydroxy-2-methoxy-2-oxoethyl)-2-methyl-4-(p-tolyl)-7,8-dihydro-1,6-naphthyridine-6(5H)-carboxylate (1.29 g, 50% yield) as a white foam. 1H NMR (400 MHz, CDCl3) δ ppm 7.20-7.49 (m, 7H), 7.08 (t, J=8.68 Hz, 2H), 5.11 (d, J=15.65 Hz, 3H), 4.22 (br. s., 2H), 3.67-3.89 (m, 5H), 3.14 (d, J=2.45 Hz, 1H), 2.99-3.11 (m, 2H), 2.55 (s, 3H), 2.43 (s, 3H). LCMS (M+H) calcd for C27H29N2O5: 461.20. found: 461.0.
Reaction SMILES: [Cl:1][C:2]1[CH:28]=[CH:27][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12]([CH:16]=[C:17]4[S:21][C:20](SCCC)=[N:19][C:18]4=[O:26])=[CH:13][CH:14]=3)[CH:9]=[N:8]2)=[C:4]([C:29]([F:32])([F:31])[F:30])[CH:3]=1.[N:33]1([CH:38]2[CH2:43][CH2:42][NH:41][CH2:40][CH2:39]2)[CH:37]=[CH:36][CH:35]=[N:34]1>>[Cl:1][C:2]1[CH:28]=[CH:27][C:5]([CH2:6][N:7]2[C:15]3[C:14](=[CH:13][C:12]([CH:16]=[C:17]4[S:21][C:20]([N:41]5[CH2:40][CH2:39][CH:38]([N:33]6[CH:37]=[CH:36][CH:35]=[N:34]6)[CH2:43][CH2:42]5)=[N:19][C:18]4=[O:26])=[CH:11][CH:10]=3)[CH:9]=[N:8]2)=[C:4]([C:29]([F:32])([F:30])[F:31])[CH:3]=1
Reactant: c1cnn(C2CCNCC2)c1
Reactant: CCCSC1=NC(=O)C(=Cc2ccc3c(cnn3Cc3ccc(Cl)cc3C(F)(F)F)c2)S1
Product: O=C1N=C(N2CCC(n3cccn3)CC2)SC1=Cc1ccc2c(cnn2Cc2ccc(Cl)cc2C(F)(F)F)c1

Procedure:
5-[1-(4-Chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-(4-pyrazol-1-yl-piperidin-1-yl)-thiazol-4-one was prepared from 5-[1-(4-Chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-propylsulfanyl-thiazol-4-one and 4-Pyrazol-1-yl-piperidine following General Procedure B.
Reaction SMILES: [K].Cl[B:3]1[O:7][C:6]([CH3:9])([CH3:8])[C:5]([CH3:11])([CH3:10])[O:4]1.O1CCBO1.[CH3:17][CH2:18][CH2:19][CH2:20][CH2:21]C>>[CH2:21]([B:3]1[O:7][C:6]([CH3:9])([CH3:8])[C:5]([CH3:11])([CH3:10])[O:4]1)[CH:20]=[CH:19][CH:18]=[CH2:17]
Reactant: CCCCCC
Reactant: CC1(C)OB(Cl)OC1(C)C
Agent: B1CCOO1
Agent: [K]
Product: C=CC=CCB1OC(C)(C)C(C)(C)O1
Temperature: -78 °C

Procedure:
About 0.55 moles of potassium piperylide is placed in a 2 liter, 3-neck flask with a mechanical stirrer, nitrogen bubbler, and a septum on the third neck. Approximately 340 ml of hexane is added and the flask is cooled to −78° C. in a dry ice/isopropyl alcohol bath. A dioxaborolane solution is prepared by dissolving 89.3 grams of 2-chloro-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (0.55 moles) in 750 ml of hexane. The dioxaborolane solution is added to the flask over about 2 hours while stirring. The mixture is stirred continuously overnight and is slowly warmed to room temperature. The flask contents are filtered and the solids are washed with about 250 ml of hexane. The resulting solution is concentrated by distilling off the hexane at atmospheric pressure. The product is 2-(2,4-pentadienyl)4,4,5,5-tetramethyl-1,3,2-dioxaborolane which is then vacuum distilled at 58° C. and 3 mbar.
Reaction SMILES: [CH:1]([C:3]1[CH:11]=[CH:10][C:6]([C:7](Cl)=[O:8])=[CH:5][CH:4]=1)=O.[C:12]([O:16][CH2:17][CH3:18])(=[O:15])[CH:13]=C>>[CH:7]([C:6]1[CH:10]=[CH:11][C:3]([CH:1]=[CH:13][C:12]([O:16][CH2:17][CH3:18])=[O:15])=[CH:4][CH:5]=1)=[O:8]
Reactant: O=Cc1ccc(C(=O)Cl)cc1
Reactant: C=CC(=O)OCC
Product: CCOC(=O)C=Cc1ccc(C=O)cc1
Yield: 46 %

Procedure:
The procedure described in Example 28 is repeated, except that 8.23 g (0.05 mol) of 4-formylbenzoyl chloride and 6.25 g (0.0625 mol) of ethyl acrylate are used. After a reaction time of 13 hours at 120° C., 4.7 g (0.023 mol) of ethyl 4-formylcinnamate are obtained, corresponding to a yield of 46% of theory; boiling point 137°-140° C./13 Pa.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([C:11]2[C:12](=[O:22])[NH:13][C:14]3[C:19]([C:20]=2[OH:21])=[CH:18][CH:17]=[CH:16][CH:15]=3)=[O:10])=[CH:4][CH:3]=1.[CH3:23][N:24]([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[C:25](Cl)=[O:26]>>[CH3:23][N:24]([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[C:25]([O:21][C:20]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[NH:13][C:12](=[O:22])[C:11]=1[C:9]([NH:8][C:5]1[CH:6]=[CH:7][C:2]([O:1][C:25](=[O:26])[N:24]([CH3:23])[C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)=[CH:3][CH:4]=1)=[O:10])=[O:26]
Reactant: CN(C(=O)Cl)c1ccccc1
Reactant: O=C(Nc1ccc(O)cc1)c1c(O)c2ccccc2[nH]c1=O
Product: CN(C(=O)Oc1ccc(NC(=O)c2c(OC(=O)N(C)c3ccccc3)c3ccccc3[nH]c2=O)cc1)c1ccccc1

Procedure:
The title product was prepared from 4-hydroxy-2-oxo-1,2-dihydro-quinoline-3-carboxylic acid (4-hydroxyphenyl)-amide and N-methyl-N-phenylcarbamoyl chloride. The crude product was subjected to preparative HPLC (6.6%, oil). HPLC-MS: m/z=563.2 (M+1); Rt: 4.46 min.
Reaction SMILES: [Sn](Cl)Cl.[Br:4][C:5]1[C:6]([F:17])=[C:7]2[C:13]([N+:14]([O-])=O)=[CH:12][NH:11][C:8]2=[N:9][CH:10]=1.[OH-].[Na+]>Cl>[Br:4][C:5]1[C:6]([F:17])=[C:7]2[C:13]([NH2:14])=[CH:12][NH:11][C:8]2=[N:9][CH:10]=1
Reactant: O=[N+]([O-])c1c[nH]c2ncc(Br)c(F)c12
Agent: Cl
Agent: Cl[Sn]Cl
Agent: [Na+]
Product: Nc1c[nH]c2ncc(Br)c(F)c12
Temperature: 25 °C
Reaction time: 2 h
Yield: 63.3 %

Procedure:
Tin (II) chloride (10 g, 54 mmol) was slowly added to 5-bromo-4-fluoro-3-nitro-1H-pyrrolo[2,3-b]pyridine (9.0 g, 35 mmol) in 6N HCl (200 mL) at a temperature of about 0° C. to about 5° C., and the reaction was stirred at room temperature for 2 hours. The reaction pH was raised to 7 by addition of 6N NaOH. The aqueous layer was then extracted with CHCl3/i-PrOH (3:1). The combined organic phases were dried (MgSO4) and concentrated in vacuo to yield 5-bromo-4-fluoro-1H-pyrrolo[2,3-b]pyridin-3-amine (5.1 g, 64% yield) as a solid. 1H NMR (400 MHz, (CD3)2SO) δ 11.18 (br s, 1H), 8.13 (d, 1H), 6.66 (d, 1H), 4.21 (s, 2H); LCMS (APCI+) m/z 229.9, 231.9 (M+H)+, Retention time=2.11 minutes (Method 1).
Reaction SMILES: Cl[C:2]1[CH:11]=[C:10]2[N:12]([C:14]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[N:13]=[C:8]3[C:9]2=[C:4]([CH2:5][CH2:6][N:7]3[CH2:33][C:34]2[CH:39]=[CH:38][C:37]([O:40][CH3:41])=[CH:36][CH:35]=2)[N:3]=1.[C:42]1([C@H:48]([NH:50][C:51]([NH2:53])=[O:52])[CH3:49])[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CC(C1C=C(C(C)C)C(C2C(P(C3CCCCC3)C3CCCCC3)=C(OC)C=CC=2OC)=C(C(C)C)C=1)C.C(Cl)Cl>[CH3:41][O:40][C:37]1[CH:36]=[CH:35][C:34]([CH2:33][N:7]2[CH2:6][CH2:5][C:4]3[N:3]=[C:2]([NH:53][C:51]([NH:50][C@@H:48]([C:42]4[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=4)[CH3:49])=[O:52])[CH:11]=[C:10]4[N:12]([C:14]([C:15]5[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=5)([C:21]5[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=5)[C:27]5[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=5)[N:13]=[C:8]2[C:9]=34)=[CH:39][CH:38]=1
Reactant: C[C@@H](NC(N)=O)c1ccccc1
Reactant: COc1ccc(CN2CCc3nc(Cl)cc4c3c2nn4C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: COc1ccc(OC)c(P(C2CCCCC2)C2CCCCC2)c1-c1c(C(C)C)cc(C(C)C)cc1C(C)C
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: ClCCl
Product: COc1ccc(CN2CCc3nc(NC(=O)N[C@H](C)c4ccccc4)cc4c3c2nn4C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1

Procedure:
7-chloro-3-(4-methoxybenzyl)-1-trityl-1,3,4,5-tetrahydropyrazolo[3,4,5-de][1,6]naphthyridine (30 mg, 0.054 mmol), (R)-1-(1-phenylethyl)urea (13.26 mg, 0.081 mmol), cesium carbonate (61.4 mg, 0.188 mmol) and BrettPhos pre-catalyst (4.8 mg) were charged in a 1 dram vial, evacuated and backfilled with nitrogen and taken in 1,4-dioxane (0.4 mL) and heated reaction to 100° C. for 1 hour. The reaction mixture was diluted with DCM, washed with water, brine, dried with sodium sulfate and concentrated. Purification of the residue by flash column (0-75% EtOAc-hexanes) gave (R)-1-(3-(4-methoxybenzyl)-1-trityl-1,3,4,5-tetrahydropyrazolo[3,4,5-de][1,6]naphthyridin-7-yl)-3-(1-phenylethyl)urea. MS ESI calc'd. for C44H40N6O2 [M+H]+ 685. found 685.