Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.[C:12]([O:16][C:17]([N:19]1[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]1)=[O:18])([CH3:15])([CH3:14])[CH3:13].C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[C:12]([O:16][C:17]([N:19]1[CH2:24][CH2:23][N:22]([C:2]2[CH:11]=[CH:10][C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[N:3]=2)[CH2:21][CH2:20]1)=[O:18])([CH3:15])([CH3:13])[CH3:14]
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: Clc1ccc2ccccc2n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CC(C)(C)OC(=O)N1CCN(c2ccc3ccccc3n2)CC1

Procedure:
A mixture of 6.1 mmol 2-chloroquinoline, 6.7 mmol piperazine-1-carboxylic acid tert-butyl ester and 12.2 mmol potassium carbonate in 15 ml acetonitrile was refluxed overnight. The reaction mixture is concentrated, water is added and the compound extracted with ethyl acetate. Chromatography (SiO2; cyclohexane/ethyl acetate 9/1) gave the title compound as a colorless solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([CH:9]=O)=[C:7]([O:11][CH3:12])[N:6]=[CH:5][N:4]=1.[CH2:13]([O:15][C:16](=[O:21])[CH2:17][C:18](=[NH:20])[NH2:19])[CH3:14]>C(O)C>[CH2:13]([O:15][C:16]([C:17]1[CH:9]([C:8]2[C:7]([O:11][CH3:12])=[N:6][CH:5]=[N:4][C:3]=2[O:2][CH3:1])[C:17]([C:16]([O:15][CH2:13][CH3:14])=[O:21])=[C:18]([NH2:19])[NH:20][C:18]=1[NH2:19])=[O:21])[CH3:14]
Reactant: CCOC(=O)CC(=N)N
Reactant: COc1ncnc(OC)c1C=O
Solvent: CCO
Product: CCOC(=O)C1=C(N)NC(N)=C(C(=O)OCC)C1c1c(OC)ncnc1OC
Yield: 56 %

Procedure:
Upon heating a solution of 8.4 g 4,6-dimethoxypyrimidine-5-aldehyde and 13.0 g amidinoacetic acid ethyl ester in 150 ml ethanol for two hours, 2,6-diamino-4-(4,6-dimethoxypyrimid-5-yl)-1,4-dihydropyridine-3,5-dicarboxylic acid diethyl ester of m.p. 219° C (ethanol) is obtained.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][CH2:10][N:11]2[CH:15]=[CH:14][N:13]=[CH:12]2)=[CH:4][CH:3]=1.Cl[CH2:17][C:18]1[N:19]=[C:20]([CH:23]=[C:24]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[O:21][CH:22]=1>>[C:31]1([C:24]([C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=2)=[CH:23][C:20]2[O:21][CH:22]=[C:18]([CH2:17][O:1][C:2]3[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][CH2:10][N:11]4[CH:15]=[CH:14][N:13]=[CH:12]4)=[CH:4][CH:3]=3)[N:19]=2)[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=1
Reactant: Oc1ccc(CCCn2ccnc2)cc1
Reactant: ClCc1coc(C=C(c2ccccc2)c2ccccc2)n1
Product: C(=C(c1ccccc1)c1ccccc1)c1nc(COc2ccc(CCCn3ccnc3)cc2)co1
Yield: 88 %

Procedure:
In substantially the same manner as in Working Example 47, 1-[3-(4-hydroxyphenyl)propyl]imidazole was allowed to react with 4-chloromethyl-2-(2,2-diphenyl ethenyl)oxazole to give 2-(2,2-diphenylethenyl)-4-[4-[3-(1-imidazolyl)propyl]phenoxymethyl]oxazole as an oily product. The yield was 88%.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH:12]([CH3:14])[C:11](=NN(C)C)[CH:10]([CH3:19])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C[OH:21]>Cl>[CH2:1]([N:8]1[CH2:13][CH:12]([CH3:14])[C:11](=[O:21])[CH:10]([CH3:19])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CO
Reactant: CC1CN(Cc2ccccc2)CC(C)C1=NN(C)C
Agent: Cl
Product: CC1CN(Cc2ccccc2)CC(C)C1=O

Procedure:
43 (1.7 g, 6.5 mmol) is dissolved in a 1.25M solution of HCl in methanol (20 ml, 25 mmol) and refluxed for 1.5 h The reaction mixture is evaporated under reduced pressure and dried at high vacuum. The residue (1.7 g of a colorless oil) is dissolved in ethyl acetate and treated with 5M NaOH. The organic layers are evaporated under reduced pressure.
Reaction SMILES: Cl.[CH2:2]([O:9][NH2:10])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.C(OCC)C.[OH-].[Na+].[C:18]1([N:24]=[C:25]=[O:26])[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>O>[CH2:2]([O:9][NH:10][C:25]([NH:24][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=[O:26])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: NOCc1ccccc1
Reactant: O=C=Nc1ccccc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCOCC
Product: O=C(NOCc1ccccc1)Nc1ccccc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 82.9 %

Procedure:
Under a nitrogen atmosphere, a flask was charged sequentially with O-benzylhydroxylamine hydrochloride (37.5 g, 0.23 mole), water (40 mL) and diethyl ether (400 mL). The resulting mixture was cooled to 0° C. and a solution of sodium hydroxide (9.4 g, 0.23 mole) in water (40 mL) was added dropwise. After 0.5 hour, phenyl isocyanate (25.5 mL, 0.23 mole) was added. A white precipitate formed. The reaction was maintained at ambient temperature for 2 hours. The precipitate was isolated by filtration, washed with water and dried to provide 46.2 g of 1-benzyloxy-3-phenyl urea as a white crystalline solid.
Reaction SMILES: C[O:2][C:3]([C:5]1[C:6]([C:24]2[CH:29]=[CH:28][C:27]([C:30]([OH:32])=O)=[CH:26][CH:25]=2)=[CH:7][CH:8]=[C:9]([C:11]2[S:12][CH:13]=[C:14]([C:16]3[CH:21]=[CH:20][C:19]([Cl:22])=[C:18]([Cl:23])[CH:17]=3)[N:15]=2)[CH:10]=1)=[O:4].[OH:33][CH:34]1[CH2:39][CH2:38][NH:37][CH2:36][CH2:35]1.C1COCC1.O.[OH-].[Li+]>CO.O>[Cl:23][C:18]1[CH:17]=[C:16]([C:14]2[N:15]=[C:11]([C:9]3[CH:10]=[C:5]([C:3]([OH:2])=[O:4])[C:6]([C:24]4[CH:25]=[CH:26][C:27]([C:30]([N:37]5[CH2:38][CH2:39][CH:34]([OH:33])[CH2:35][CH2:36]5)=[O:32])=[CH:28][CH:29]=4)=[CH:7][CH:8]=3)[S:12][CH:13]=2)[CH:21]=[CH:20][C:19]=1[Cl:22]
Reactant: COC(=O)c1cc(-c2nc(-c3ccc(Cl)c(Cl)c3)cs2)ccc1-c1ccc(C(=O)O)cc1
Reactant: OC1CCNCC1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: O=C(O)c1cc(-c2nc(-c3ccc(Cl)c(Cl)c3)cs2)ccc1-c1ccc(C(=O)N2CCC(O)CC2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 41.3 %

Procedure:
Using the conditions of General Procedure D for Amide Coupling in Parallel Mode, 4-[4-(3,4-dichloro-phenyl)-thiazol-2-yl]-biphenyl-2,4′-dicarboxylic acid 2-methyl ester (which may be prepared as described for Intermediate 8; 100 mg, 0.21 mmol) was reacted with 4-hydroxypiperidine (available from Aldrich Chemical Company, Inc.; 42 mg, 0.42 mmol) to give the crude amide product. The crude amide was hydrolyzed by adding THF (2 mL), water (0.05 mL), MeOH (1 mL), and lithium hydroxide monohydrate (12.3 mg, 0.29 mmol) and stirring the mixture overnight at room temperature. The reaction mixture was concentrated to dryness under vacuum at 40° C. 1 M HCl (3 mL) was added, and the mixture was stirred, concentrated to dryness, and purified using HPLC Purification Conditions A to give 4-[4-(3,4-dichloro-phenyl)-thiazol-2-yl]-4′-(4-hydroxy-piperidine-1-carbonyl)-biphenyl-2-carboxylic acid (48 mg, 52%) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 13.18 (br s, 1H), 8.47 (s, 1H), 8.37 (d, J=1.8 Hz, 1H), 8.34 (d, J=2.0 Hz, 1H), 8.24 (dd, J=8.0, 2.0 Hz, 1H), 8.09 (dd, J=8.3, 2.0 Hz, 1H), 7.76 (d, J=8.5 Hz, 1H), 7.60 (d, J=8.0 Hz, 1H), 7.42-7.49 (m, 4H), 3.73-3.79 (m, 1H), 3.36-3.52 (m, 2H+water peak), 3.15-3.27 (m, 2H), 1.70-1.82 (m, 2H), 1.32-1.47 (m, 2H).
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([C:8]2[CH:14]=[CH:13][C:11]([NH2:12])=[CH:10][CH:9]=2)[CH2:4][CH2:3]1.[C:15]1([C:25]2[C:34]3[N:33]=[CH:32][CH:31]=[N:30][C:29]=3[C:28]([C:35](O)=[O:36])=[CH:27][CH:26]=2)[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH:18]=[CH:17][CH:16]=1.C1(B(O)O)C2C(=CC=CC=2)C=CC=1>C(Cl)Cl.CO>[CH3:1][N:2]1[CH2:3][CH2:4][N:5]([C:8]2[CH:14]=[CH:13][C:11]([NH:12][C:35]([C:28]3[C:29]4[N:30]=[CH:31][CH:32]=[N:33][C:34]=4[C:25]([C:15]4[C:24]5[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=5)[CH:18]=[CH:17][CH:16]=4)=[CH:26][CH:27]=3)=[O:36])=[CH:10][CH:9]=2)[CH2:6][CH2:7]1
Reactant: CN1CCN(c2ccc(N)cc2)CC1
Reactant: O=C(O)c1ccc(-c2cccc3ccccc23)c2nccnc12
Agent: OB(O)c1cccc2ccccc12
Solvent: ClCCl
Solvent: CO
Product: CN1CCN(c2ccc(NC(=O)c3ccc(-c4cccc5ccccc45)c4nccnc34)cc2)CC1
Reaction time: 8 h

Procedure:
The title compound was prepared in analogy to the procedure described in in Step 14.1 but stirring the reaction mixture overnight and using 4-(4-methylpiperazin-1-yl)-aniline (WO2006000420) and 8-naphthalen-1-yl-quinoxaline-5-carboxylic acid. The latter compound was synthesized as described in Steps 1.2-1.7 but using 1-naphtylboronic acid in Step 1.4. Title compound: ESI-MS: 474.0 [M+H]+; tR=4.34 min (System 1); TLC: Rf=0.45 (DCM/MeOH/NH3aq, 94:5:1).
Reaction SMILES: F[C:2]1[C:7]([C:8]2[C:13]([F:14])=[C:12]([F:15])[C:11](F)=[C:10]([F:17])[C:9]=2[F:18])=[C:6]([F:19])[C:5]([F:20])=[C:4]([F:21])[C:3]=1[F:22].[C:23]1([OH:33])[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[CH:26]=[CH:25][CH:24]=1.[C:34](=[O:37])([O-])[O-].[K+].[K+]>CC(N(C)C)=O>[C:23]1([O:33][C:11]2([O:37][C:34]3[C:2]4[C:7](=[CH:6][CH:5]=[CH:4][CH:3]=4)[CH:8]=[CH:9][CH:10]=3)[C:10]([F:17])=[C:9]([F:18])[C:8]([C:7]3[CH:2]=[C:3]([F:22])[C:4]([F:21])=[C:5]([F:20])[C:6]=3[F:19])=[C:13]([F:14])[CH:12]2[F:15])[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[CH:26]=[CH:25][CH:24]=1
Reactant: Fc1c(F)c(F)c(-c2c(F)c(F)c(F)c(F)c2F)c(F)c1F
Reactant: Oc1cccc2ccccc12
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Product: FC1=C(F)C(Oc2cccc3ccccc23)(Oc2cccc3ccccc23)C(F)C(F)=C1c1cc(F)c(F)c(F)c1F
Temperature: 140 °C
Reaction time: 2 h
Yield: 78.8 %

Procedure:
The monomer 4,4,-bis(1-naphthoxy)octafluorobiphenyl (8FNE) was prepared by the following procedure. A 100 mL round bottom flask was charged with decafluorobiphenyl (3.01 g, 0.0090 mole), 1-naphthol (2.60 g, 0.0181 mole), potassium carbonate (2.95 g, 0.0218 mole), and DMAc (40 g). The mixture was heated with stirring at about 140 ° C. for 2 hr and then cooled to room temperature, filtered, and poured into toluene (100 mL). The toluene solution was washed with 5% sodium hydroxide (50 mL) and then twice with deionized water (2×100 mL). After drying with magnesium sulfate and filtering, it was concentrated by rotary evaporation to yield a red solid. The solid was recrystallized from DMAc/water, filtered, and dried to yield 8FNE (3.9 g, 78.8% yield; m.p. 189-191 ° C.; GC/MS m+ /e 582).
Reaction SMILES: [N:1]1[CH:2]=[CH:3][N:4]2[CH:9]=[CH:8][CH:7]=[C:6]([O:10][CH2:11][CH2:12][CH2:13][CH2:14][N:15]3[C:19](=[O:20])[CH2:18][S:17][C:16]3=[O:21])[C:5]=12.[CH:22](=O)[CH2:23][CH2:24][CH3:25].N1CCCCC1>C(O)C>[CH:22](=[C:18]1[S:17][C:16](=[O:21])[N:15]([CH2:14][CH2:13][CH2:12][CH2:11][O:10][C:6]2[C:5]3[N:4]([CH:3]=[CH:2][N:1]=3)[CH:9]=[CH:8][CH:7]=2)[C:19]1=[O:20])[CH2:23][CH2:24][CH3:25]
Reactant: O=C1CSC(=O)N1CCCCOc1cccn2ccnc12
Reactant: CCCC=O
Solvent: C1CCNCC1
Solvent: CCO
Product: CCCC=C1SC(=O)N(CCCCOc2cccn3ccnc23)C1=O

Procedure:
To a solution of 1.22 g (4.0 mmol) of 3-[4-(imidazo-[1,2-a]pyridin-8-yloxy)butyl]thiazolidine-2,4-dione and 0.36 ml (4.0 mmol) of n-butyraldehyde in 20 ml of ethanol, 0.04 ml (0.4 mmol) of piperidine was added, followed by refluxing for 2 hours. After the reaction mixture was cooled, the solvent was distilled off. The residue was dissolved in chloroform, washed with saturated aqueous sodium hydrogen carbonate and dried, after which the solvent was distilled off. The residue was purified by column chromatography (eluent, n-hexane/ethyl acetate=1/4) to yield 1.44 g (quant, yellow oily substance) of the desired product.
Reaction SMILES: N[CH:2]1C2(CC2)CN[CH2:3]1.[C:9]([O:15][CH2:16][CH3:17])(=[O:14])[CH2:10][C:11]([CH3:13])=[O:12].BrCCBr>>[C:11]([C:10]1([C:9]([O:15][CH2:16][CH3:17])=[O:14])[CH2:3][CH2:2]1)(=[O:12])[CH3:13]
Reactant: NC1CNCC12CC2
Reactant: CCOC(=O)CC(C)=O
Solvent: BrCCBr
Product: CCOC(=O)C1(C(C)=O)CC1

Procedure:
Taking 7-amino-5-azaspiro[2,4]heptane as an example, ethyl acetoacetate is first reacted with 1,2-dibromoethane in the presence of a base to give ethyl 1-acetyl-1-cyclopropanecarboxylate. Then, using bromine, the acetyl group of this compound is brominated to give ethyl 1-bromoacetyl-1-cyclopropanecarboxylate. This bromoacetyl compound is then cyclized with benzylamine to give 5-benzyl-4,7-dioxo-5-azaspiro[2,4]heptane. When this compound is reacted with hydroxylamine hydrochloride, the ketone in 7-position is converted to an oxime to give 5-benzyl-7-(hydroxyimino)-4-oxo-5-azaspiro[2,4]heptane. This oxime is reduced with lithium aluminum hydride to give a spiro ring-containing aminopyrrolidine compound, viz., 7-amino-5-benzyl-5-azaspiro[2,4]heptane. When the benzyl group of this compound is eliminated by an ordinary procedure, such as catalytic hydrogenolysis, 7-amino-5-azaspiro[2,4]heptane which is a racemic compound, is obtained When this cleavage of the benzyl group is preceded after the amino group is protected by the reaction of 2-(tert-butoxycarbonylamino)-2-phenylacetonitrile (hereinafter referred to briefly as BOC-ON), 7-tert-butoxycarbonylamino-5-azaspiro[2,4]heptane is obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:26]=[CH:25][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](SC)=[N:19][C:18]4=[O:24])=[CH:13][CH:14]=3)[CH:9]=[N:8]2)=[C:4]([C:27]([F:30])([F:29])[F:28])[CH:3]=1.[N:31]1([CH2:37][CH2:38][OH:39])[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]1>>[Cl:1][C:2]1[CH:26]=[CH:25][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]([N:34]5[CH2:35][CH2:36][N:31]([CH2:37][CH2:38][OH:39])[CH2:32][CH2:33]5)=[N:19][C:18]4=[O:24])=[CH:13][CH:14]=3)[CH:9]=[N:8]2)=[C:4]([C:27]([F:28])([F:29])[F:30])[CH:3]=1
Reactant: OCCN1CCNCC1
Reactant: CSC1=NC(=O)C(=Cc2ccc3c(cnn3Cc3ccc(Cl)cc3C(F)(F)F)c2)S1
Product: O=C1N=C(N2CCN(CCO)CC2)SC1=Cc1ccc2c(cnn2Cc2ccc(Cl)cc2C(F)(F)F)c1

Procedure:
5-[1-(4-Chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-[4-(2-hydroxy-ethyl)-piperazin-1-yl]-thiazol-4-one was prepared from 5-[1-(4-chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-methylsulfanyl-thiazol-4-one and 2-piperazin-1-yl-ethanol following General Procedure C.
Reaction SMILES: Br[C:2]1[CH:11]=[C:10]2[C:5]([C:6]([Cl:22])=[CH:7][N:8]([CH2:13][C:14]3[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=3)[C:9]2=[O:12])=[CH:4][CH:3]=1.O1CCOCC1.[CH2:29]([SH:36])[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1>O.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].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>[CH2:29]([S:36][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([Cl:22])=[CH:7][N:8]([CH2:13][C:14]3[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=3)[C:9]2=[O:12])=[CH:4][CH:3]=1)[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1
Reactant: SCc1ccccc1
Reactant: COc1ccc(Cn2cc(Cl)c3ccc(Br)cc3c2=O)cc1
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: O
Solvent: C1COCCO1
Product: COc1ccc(Cn2cc(Cl)c3ccc(SCc4ccccc4)cc3c2=O)cc1
Temperature: 80 °C
Yield: 89.7 %

Procedure:
A screw cap vial was charged with 7-bromo-4-chloro-2-(4-methoxybenzyl)isoquinolin-1(2H)-one (3.6 g, 9.51 mmol), Xantphos (0.275 g, 0.475 mmol), tris(dibenzylideneacetone)dipalladium (0) (0.218 g, 0.238 mmol), 1,4-Dioxane (9.51 ml) and dipea (3.31 ml, 19.02 mmol). The vial was purged with Argon, sealed and heated to 80° C. for 10 minutes. The reaction was cooled to room temperature and benzyl mercaptan (1.18 ml, 9.98 mmol) was added and the reaction was continued heating at 80° C. for an additional 30 minutes. The reaction was cooled to room temperature, diluted with water and extracted with DCM (3×). The combined organics were washed with water and brine, dried over magnesium sulfate, filtered and concentrated. The resulting material was concentrated, dissolved in minimal DCM and purified via column chromatography (silica gel 40 g, gradient elution 0 to 50% EtOAc:Heptane) to afford 3.60 g of 7-(benzylthio)-4-chloro-2-(4-methoxybenzyl)isoquinolin-1(2H)-one. m/z (ESI) 442.1 (M+H)+.
Reaction SMILES: Br[C:2]1[N:7]=[C:6]([CH:8]([N:11]2[CH:15]=[CH:14][N:13]=[N:12]2)[CH2:9][OH:10])[CH:5]=[CH:4][CH:3]=1.[NH2:16][C:17]1[S:18][C:19]([C:25]2[CH:30]=[CH:29][C:28]([C:31]([OH:34])([CH3:33])[CH3:32])=[CH:27][C:26]=2[F:35])=[CH:20][C:21]=1[C:22]([NH2:24])=[O:23]>>[F:35][C:26]1[CH:27]=[C:28]([C:31]([OH:34])([CH3:32])[CH3:33])[CH:29]=[CH:30][C:25]=1[C:19]1[S:18][C:17]([NH:16][C:2]2[CH:3]=[CH:4][CH:5]=[C:6]([CH:8]([N:11]3[CH:15]=[CH:14][N:13]=[N:12]3)[CH2:9][OH:10])[N:7]=2)=[C:21]([C:22]([NH2:24])=[O:23])[CH:20]=1
Reactant: OCC(c1cccc(Br)n1)n1ccnn1
Reactant: CC(C)(O)c1ccc(-c2cc(C(N)=O)c(N)s2)c(F)c1
Product: CC(C)(O)c1ccc(-c2cc(C(N)=O)c(Nc3cccc(C(CO)n4ccnn4)n3)s2)c(F)c1

Procedure:
The title compound was synthesized from 2-(6-bromopyridin-2-yl)-2-(1H-1,2,3-triazol-1-yl)ethanol (110 mg, 0.41 mmol) and 2-amino-5-[2-fluoro-4-(1-hydroxy-1-methylethyl)phenyl]thiophene-3-carboxamide (120 mg, 0.41 mmol) according to the general procedure in Example 1.
Reaction SMILES: [C:1]([C:5]1[CH:23]=[CH:22][C:8]([C:9]([CH:11]([C:17]([O:19][CH2:20][CH3:21])=[O:18])[C:12]([O:14][CH2:15][CH3:16])=[O:13])=O)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].P(Cl)(Cl)([Cl:26])=O.C(N(C(C)C)CC)(C)C>>[C:1]([C:5]1[CH:23]=[CH:22][C:8]([C:9]([Cl:26])=[C:11]([C:17]([O:19][CH2:20][CH3:21])=[O:18])[C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CCOC(=O)C(C(=O)OCC)C(=O)c1ccc(C(C)(C)C)cc1
Reactant: O=P(Cl)(Cl)Cl
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)C(C(=O)OCC)=C(Cl)c1ccc(C(C)(C)C)cc1
Temperature: 100 °C
Reaction time: 3 h
Yield: 95.5 %

Procedure:
To a mixture of 72.5 g of diethyl 4-t-butyl-benzoylmalonate and 337.7 g of phosphorus oxychloride, 48.9 g of diisopropylethylamine was added, and the resulting mixture was stirred at 100° C. for 3 hours. The reaction mixture was evaporated under reduced pressure, and the resulting solid residue was extracted with diethyl ether, and the still remaining solid was mixed with water and then extracted diethyl ether. The extracts were combined, concentrated under reduced pressure, washed with 1N hydrochloric acid, 1N aqueous sodium hydroxide and water successively and dried over anhydrous sodium sulfate. The insoluble were filtered off, and the solvent was removed by evaporation. The resulting residue was purified by silica gel chromatography (eluent; n-hexane/ethyl acetate=7:1) to give 73.19 g of the title compound as a yellow oily substance.
Reaction SMILES: [C:1]1([CH3:11])[CH:6]=CC(S(O)(=O)=O)=CC=1.[Cl:12][CH2:13][C@H:14]([OH:17])[CH2:15][OH:16]>CC(C)=O>[Cl:12][CH2:13][C@H:14]1[CH2:15][O:16][C:1]([CH3:6])([CH3:11])[O:17]1
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: OC[C@@H](O)CCl
Solvent: CC(C)=O
Product: CC1(C)OC[C@H](CCl)O1
Yield: 7726 %

Procedure:
p-Toluenesulfonic acid (0.86 g) was added to a mixture of (R)-3-chloro-1,2-propanediol (50.13 g, 0.454 mol, optical purity 98.7% e.e.) and acetone (660 ml) and the resulting mixture was stirred for 12 hours at 25C. After completion of the reaction, acetone was removed in vacuo and the crude product was distilled to give 58.11 g of (R)-4-chloromethyl-2,2-dimethyl-1,3-dioxolane (yield 85%, b.p. 63° C. at 25 mmHg).
Reaction SMILES: [CH3:1][NH:2][C:3]1[S:4][CH:5]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[N:7]=1.[H-].[Na+].Br[C:17]1[CH:26]=[CH:25][C:20]([C:21]([O:23][CH3:24])=[O:22])=[CH:19][CH:18]=1.O.[CH3:28]N(C)C=O>>[CH3:28][CH:1]([NH:2][C:3]1[S:4][CH:5]=[C:6]([C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)[N:7]=1)[C:17]1[CH:26]=[CH:25][C:20]([C:21]([O:23][CH3:24])=[O:22])=[CH:19][CH:18]=1
Reactant: COC(=O)c1ccc(Br)cc1
Reactant: CNc1nc(-c2ccccc2)cs1
Reactant: CN(C)C=O
Agent: [H-]
Agent: [Na+]
Solvent: O
Product: COC(=O)c1ccc(C(C)Nc2nc(-c3ccccc3)cs2)cc1
Reaction time: 0.5 h
Yield: 86 %

Procedure:
To a solution of 2-methylamino-4-phenylthiazole (1.76 g) in N,N-dimethylformamide (25 mL) was gradually added sodium hydride (60%, oil, 351 mg) at room temperature and the mixture was stirred for 30 min. Methyl 4-bromobenzoate (2.11 g) was added, and the mixture was further stirred for 1.5 hrs. To the reaction mixture was added water and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated. The residue was subjected to silica gel column chromatography to give methyl 4-[methyl(4-phenyl-2-thiazolyl)aminomethyl]benzoate (2.56 g, 86%) as a yellow oil from a fraction eluted with ethyl acetate-hexane (1:3, v/v).
Reaction SMILES: C([Li])CCC.[C:6]([O:10][C:11]([N:13]1[CH2:25][C@@H:24]([CH3:26])[N:23]2[C@H:15]([CH2:16][C:17]3[C:22]2=[N:21][C:20](Br)=[CH:19][CH:18]=3)[CH2:14]1)=[O:12])([CH3:9])([CH3:8])[CH3:7].[CH2:28]([S:30]SCC)[CH3:29].C([O-])(=O)C.[NH4+]>O1CCCC1.CO.O>[C:6]([O:10][C:11]([N:13]1[CH2:25][C@@H:24]([CH3:26])[N:23]2[C@H:15]([CH2:16][C:17]3[C:22]2=[N:21][C:20]([S:30][CH2:28][CH3:29])=[CH:19][CH:18]=3)[CH2:14]1)=[O:12])([CH3:9])([CH3:8])[CH3:7]
Reactant: C[C@@H]1CN(C(=O)OC(C)(C)C)C[C@H]2Cc3ccc(Br)nc3N21
Reactant: CCSSCC
Agent: CC(=O)[O-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: CCSc1ccc2c(n1)N1[C@H](C2)CN(C(=O)OC(C)(C)C)C[C@H]1C
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 37.6 %

Procedure:
A solution of n-butyl lithium (1.6 M in hexanes, 0.5 mL, 0.8 mmol) in tetrahydrofuran (5 mL) was stirred at −78° C. for 5 min. under an argon atmosphere. A mixture of (4R,9aR)-6-bromo-4-methyl-3,4,9,9a-tetrahydro-1H-2,4a,5-triaza-fluorene-2-carboxylic acid tert-butyl ester (0.2 g, 0.54 mmol) in tetrahydrofuran (5 mL) was added dropwise, maintaining the temperature below −70° C. The resultant dark red solution was left to stir at −78° C. for 30 min then ethyl disulfide (0.13 mL, 1.08 mmol) was added. The mixture was left to stir at −78° C. for 2 h, then left to warm to room temperature over 2 h. Water (1 mL) was added and the mixture was poured onto an isolute HM-N SPE cartridge and eluted with ethyl acetate (10 mL). The eluent was evaporated under reduced pressure and the crude material was purified by reverse phase preparative HPLC (Prep Nova-Pak HR C18 6 mm 60 Å 30 mm×300 mm column, UV detection at 254 nm, mobile phase 95:5 methanol:water and 10 mmol ammonium acetate, gradient 50 methanol to 100% 0 to 10 min then 100% methanol to 13 min, 20 mL/min) to give the title compound (0.071 g, 53% yield) as a pale yellow oil: m/z M+ 350.14 (M+1); HPLC (50% to 80% gradient [95:5 MeOH:water, 10 mmol ammonium acetate] 220 nm XTERRA 2.0 mL/min) 6.21 min.
Reaction SMILES: [CH3:1][CH:2]([C:8](=O)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[C:3]([O:5]CC)=O.[NH2:16][C:17]1[CH:26]=[CH:25][C:20]([C:21]([O:23][CH3:24])=[O:22])=[CH:19][CH:18]=1.C1(C)C=CC(S(O)(=O)=O)=CC=1>C(Cl)(Cl)Cl.C1(OC2C=CC=CC=2)C=CC=CC=1>[CH3:1][CH:2]1[C:3](=[O:5])[C:18]2[C:17](=[CH:26][CH:25]=[C:20]([C:21]([O:23][CH3:24])=[O:22])[CH:19]=2)[N:16]=[C:8]1[C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1
Reactant: CCOC(=O)C(C)C(=O)c1ccccc1
Reactant: COC(=O)c1ccc(N)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: ClC(Cl)Cl
Solvent: c1ccc(Oc2ccccc2)cc1
Product: COC(=O)c1ccc2c(c1)C(=O)C(C)C(c1ccccc1)=N2
Yield: 28.1 %

Procedure:
Ethyl alpha-methylbenzoylacetate (5 grams) and 3.67 grams of methyl p-aminobenzoate are dehydrated (by heating) for three days in 100 ml of chloroform in the presence of 0.7 gram of p-toluenesulfonic acid. p-Toluenesulfonic acid is removed therefrom, the filtrate is concentrated, and purified by silica gel column chromatography to give an oil. The resulting oily product is heated to reflux in 70 ml of diphenyl ether, cooled, and crystals which separate therefrom are collected by filtration and recrystallized from a mixture of dimethyl formamide and water to give 2 grams of methyl 3-methyl-2-phenyl-4-quinolone-6-carboxylate, colorless crystals, melting point above 300° C.