Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:4][C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][C:14]=1[O:15][CH3:16])[N:11]=[CH:10][N:9]=[C:8]2Cl)(=[O:3])[CH3:2].[Br:18][C:19]1[CH:25]=[CH:24][C:22]([NH2:23])=[C:21]([F:26])[CH:20]=1>C(O)(C)C>[C:1]([O:4][C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][C:14]=1[O:15][CH3:16])[N:11]=[CH:10][N:9]=[C:8]2[NH:23][C:22]1[CH:24]=[CH:25][C:19]([Br:18])=[CH:20][C:21]=1[F:26])(=[O:3])[CH3:2]
Reactant: COc1cc2ncnc(Cl)c2cc1OC(C)=O
Reactant: Nc1ccc(Br)cc1F
Solvent: CC(C)O
Product: COc1cc2ncnc(Nc3ccc(Br)cc3F)c2cc1OC(C)=O
Temperature: 83 °C
Reaction time: 8 h
Yield: 84.3 %

Procedure:
A suspension of 4-chloro-7-methoxyquinazolin-6-yl acetate (2.05 g), 4-bromo-2-fluoroaniline (2.11 g, 1.30 eq) and isopropanol (40 mL) was stirred at 83° C. overnight. The reaction mixture was cooled to room temperature and filtered, the residue was washed with 100 mL of isopropanol and dried to afford the desired compound as a solid (2.78 g, 84.50%).
Reaction SMILES: [CH3:1][O:2][C:3]([CH:5](P(OC)(OC)=O)[NH:6][C:7]([O:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:8])=[O:4].[C:23]([CH2:27][CH:28]=O)([CH3:26])([CH3:25])[CH3:24].C1CCN2C(=NCCC2)CC1>C1COCC1.C(Cl)Cl>[CH3:1][O:2][C:3](=[O:4])[C:5]([NH:6][C:7]([O:9][CH2:10][C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1)=[O:8])=[CH:28][CH2:27][C:23]([CH3:26])([CH3:25])[CH3:24]
Reactant: CC(C)(C)CC=O
Reactant: COC(=O)C(NC(=O)OCc1ccccc1)P(=O)(OC)OC
Solvent: C1CCOC1
Solvent: C1CCC2=NCCCN2CC1
Solvent: ClCCl
Product: COC(=O)C(=CCC(C)(C)C)NC(=O)OCc1ccccc1
Reaction time: 16 h
Yield: 94.4 %

Procedure:
N-(Benzyloxycarbonyl)-α-phosphonoglycine trimethyl ester (2 g, 6.0 mmol, 1.0 equiv) was dissolved in dry THF (20 mL). tert-Butylacetaldehyde (0.758 mL, 6.0 mmol, 1.0 equiv) and DBU (0.903 mL, 6.0 mmol, 1.0 equiv) were added and the reaction mixture was stirred for 16 h. The solution was diluted with 100 mL of CH2Cl2 and washed with water (1×50 mL), and brine (1×50 mL). The organic layer was dried over Na2SO4, decanted and concentrated in vacuo to provide 2-benzyloxycarbonylamino-5,5-dimethyl-hex-2-enoic acid methyl ester as a thick oil (1.73 g, 94%) which was used without further purification; MS: 306 (M+1).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[N:10][C:11]=1[CH:12]([O:15][CH3:16])[O:13][CH3:14])[N:8]([C:17]([NH:19][C:20]1[CH:25]=[CH:24][C:23]([C:26]([F:29])([F:28])[F:27])=[CH:22][N:21]=1)=[O:18])[CH2:7][CH2:6][CH2:5]2.[Li]CCCC.[F:35]N(S(C1C=CC=CC=1)(=O)=O)S(C1C=CC=CC=1)(=O)=O>C1COCC1>[CH3:14][O:13][CH:12]([O:15][CH3:16])[C:11]1[N:10]=[C:9]2[C:4]([CH2:5][CH2:6][CH2:7][N:8]2[C:17]([NH:19][C:20]2[CH:25]=[CH:24][C:23]([C:26]([F:29])([F:28])[F:27])=[CH:22][N:21]=2)=[O:18])=[CH:3][C:2]=1[F:35]
Reactant: O=S(=O)(c1ccccc1)N(F)S(=O)(=O)c1ccccc1
Reactant: COC(OC)c1nc2c(cc1Br)CCCN2C(=O)Nc1ccc(C(F)(F)F)cn1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: COC(OC)c1nc2c(cc1F)CCCN2C(=O)Nc1ccc(C(F)(F)F)cn1
Temperature: 25 °C
Reaction time: 0.03 h

Procedure:
A solution of 6-bromo-7-(dimethoxymethyl)-N-(5-(trifluoromethyl)pyridin-2-yl)-3,4-dihydro-1,8-naphthyridine-1(2H)-carboxamide (intermediate 2D, 50 mg, 0.105 mmol) in THF (1 ml) at −78° C. under argon was treated drop wise with n-BuLi (1.5 M in hexane, 0.154 ml, 0.231 mmol). The resulting brown solution was stirred for 2 min, then a solution of N-fluoro-N-(phenylsulfonyl)benzenesulfonamide (80 mg, 0.254 mmol) in THF (0.5 ml) was added. The resulting yellow solution was stirred at −78° C. for 10 min. The reaction mixture was quenched by addition of sat. aq. NH4Cl, warmed to room temperature and extracted with EtOAc (2×). The combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure. The crude material was purified by normal phase chromatography (12 g silica gel cartridge, heptanes/EtOAc 100:0 to 60:40) the product containing fractions were concentrated to give the title compound as a white solid. (UPLC-MS 1) tR 1.25 min; ESI-MS 415.1 [M+H]+.
Reaction SMILES: [CH:1]1[CH:6]=[CH:5][C:4]([NH:7][C:8]2[CH:13]=[CH:12][C:11]([NH2:14])=[CH:10][CH:9]=2)=[CH:3][CH:2]=1.[CH3:15][C:16](=O)[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25].[H][H]>[Pt]=S>[CH3:25][CH:24]([NH:14][C:11]1[CH:12]=[CH:13][C:8]([NH:7][C:4]2[CH:3]=[CH:2][CH:1]=[CH:6][CH:5]=2)=[CH:9][CH:10]=1)[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH3:15]
Reactant: [H][H]
Reactant: Nc1ccc(Nc2ccccc2)cc1
Reactant: CCCCCCCCCC(C)=O
Agent: S=[Pt]
Product: CCCCCCCCCC(C)Nc1ccc(Nc2ccccc2)cc1
Temperature: 120 °C

Procedure:
Para-aminodiphenylamine (184 grams, 1.00 mole), 2-undecanone (221 grams, 1.30 moles) and 6.0 grams (dry weight) of carbon supported platinum sulfide catalyst were charged to a one-liter stirred autoclave. The vessel was sealed, pressurized first with nitrogen and then with hydrogen gas, stirred, and heated to 120° C. until the reaction was completed, as indicated by the cessation of hydrogen absorption. The vessel was cooled, vented, and the contents removed. The catalyst was removed by filtration and the water was separated. The excess ketone reactant was removed by heating in vacuo.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][C:3]2[CH:6]=[C:7]([CH2:10][CH2:11][O:12][CH2:13][CH2:14][N:15]([CH3:19])[CH2:16][CH2:17][OH:18])[CH:8]=[CH:9][C:2]1=2.N1C=CC=CC=1.[C:26](OC(=O)C)(=[O:28])[CH3:27].C(=O)([O-])O.[Na+]>C(Cl)Cl.O>[C:26]([O:18][CH2:17][CH2:16][N:15]([CH2:14][CH2:13][O:12][CH2:11][CH2:10][C:7]1[CH:8]=[CH:9][C:2]2[S:1][CH:5]=[CH:4][C:3]=2[CH:6]=1)[CH3:19])(=[O:28])[CH3:27]
Reactant: CC(=O)OC(C)=O
Reactant: CN(CCO)CCOCCc1ccc2sccc2c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: c1ccncc1
Solvent: ClCCl
Solvent: O
Product: CC(=O)OCCN(C)CCOCCc1ccc2sccc2c1
Temperature: 5 °C
Reaction time: 0.5 h

Procedure:
In 10 mL of methylene chloride is dissolved 1.00 g of 2-{[2-(2-benzo[b]thiophen-5-ylethoxy)ethyl]-(methyl)amino}-1-ethanol. The solution thus obtained is cooled to 5° C., to which are added 0.32 mL of pyridine, 0.37 mL of acetic anhydride and 0.04 g of N,N-dimethylaminopyridine. The mixture is stirred at ambient temperature for 30 minutes. Water is added to the mixture, pH is adjusted to 7.5 with saturated aqueous solution of sodium hydrogen carbonate, and the organic layer is separated. The organic layer is washed with saturated aqueous solution of sodium chloride and dried over anhydrous magnesium sulfate, the solvent is distilled off under reduced pressure, and the residue is purified by column chromatography (eluent: chloroform:methanol=100:1 to 50:1) to obtain 1.14 g of 2-{[2-(2-benzo[b]-thiophen-5-ylethoxy)-ethyl](methyl)amino}ethyl acetate as an oily product.
Reaction SMILES: [C:1]1(=[O:11])[O:6][C:4](=[O:5])[C:3]2=[CH:7][CH:8]=[CH:9][CH:10]=[C:2]12.[CH2:12]([Sn:16](=[O:21])[CH2:17][CH2:18][CH2:19][CH3:20])[CH2:13][CH2:14][CH3:15]>>[C:1]([O-:6])(=[O:11])[C:2]1[C:3](=[CH:7][CH:8]=[CH:9][CH:10]=1)[C:4]([O-:21])=[O:5].[CH2:12]([Sn+2:16][CH2:17][CH2:18][CH2:19][CH3:20])[CH2:13][CH2:14][CH3:15]
Reactant: CCCC[Sn](=O)CCCC
Reactant: O=C1OC(=O)c2ccccc21
Product: CCCC[Sn+2]CCCC
Product: O=C([O-])c1ccccc1C(=O)[O-]

Procedure:
Phthalic anhydride and dibutyltin oxide are introduced into a screw drier in accordance with Example 4b. At the exit, dibutyltin phthalate (compound 1) is obtained as a white free-flowing powder.
Reaction SMILES: [F:1][C:2]([F:23])([F:22])[C:3]1[CH:17]=[C:16]([C:18]([F:21])([F:20])[F:19])[CH:15]=[CH:14][C:4]=1[CH2:5][N:6]1[CH2:11][CH2:10][CH:9]([CH:12]=O)[CH2:8][CH2:7]1.[F:24][C:25]1([F:39])[CH2:30][C@@H:29]([NH:31][C:32]2[CH2:36][S:35][C:34](=[O:37])[N:33]=2)[C@H:28]([OH:38])[CH2:27][CH2:26]1.C([O-])(=O)C.[NH2+]1CCCCC1>CC(O)C>[F:23][C:2]([F:1])([F:22])[C:3]1[CH:17]=[C:16]([C:18]([F:21])([F:20])[F:19])[CH:15]=[CH:14][C:4]=1[CH2:5][N:6]1[CH2:11][CH2:10][CH:9](/[CH:12]=[C:36]2/[C:32]([NH:31][C@@H:29]3[CH2:30][C:25]([F:24])([F:39])[CH2:26][CH2:27][C@H:28]3[OH:38])=[N:33][C:34](=[O:37])[S:35]/2)[CH2:8][CH2:7]1
Reactant: O=CC1CCN(Cc2ccc(C(F)(F)F)cc2C(F)(F)F)CC1
Reactant: O=C1N=C(N[C@@H]2CC(F)(F)CC[C@H]2O)CS1
Agent: C1CC[NH2+]CC1
Agent: CC(=O)[O-]
Solvent: CC(C)O
Product: O=C1N=C(N[C@@H]2CC(F)(F)CC[C@H]2O)/C(=C/C2CCN(Cc3ccc(C(F)(F)F)cc3C(F)(F)F)CC2)S1
Temperature: 75 °C
Reaction time: 8 h
Yield: 71.9 %

Procedure:
To a solution of 1-[2,4-bis(trifluoromethyl)benzyl]piperidine-4-carbaldehyde (777 mg) in 2-propanol (5 mL) were added 4-[trans-(5,5-difluoro-2-hydroxycyclohexyl)amino]-1,3-thiazol-2(5H)-one (860 mg) and piperidinium acetate (339 mg). The reaction mixture was stirred at 75° C. overnight, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) and silica gel column chromatography (NH, methanol/ethyl acetate) to give the title compound (941 mg).
Reaction SMILES: [CH:1]([N:4]1[C:13]2[C:8](=[CH:9][CH:10]=[C:11]([CH3:14])[N:12]=2)[C:7](=[O:15])[C:6]([C:16]([OH:18])=O)=[CH:5]1)([CH3:3])[CH3:2].C(N(CC)CC)C.ClC(OCC)=O.[NH2:32][C:33]1[NH:37][N:36]=[N:35][N:34]=1>CN(C)C=O>[CH:1]([N:4]1[C:13]2[C:8](=[CH:9][CH:10]=[C:11]([CH3:14])[N:12]=2)[C:7](=[O:15])[C:6]([C:16]([NH:32][C:33]2[NH:37][N:36]=[N:35][N:34]=2)=[O:18])=[CH:5]1)([CH3:2])[CH3:3]
Reactant: Nc1nnn[nH]1
Reactant: Cc1ccc2c(=O)c(C(=O)O)cn(C(C)C)c2n1
Agent: CCOC(=O)Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: Cc1ccc2c(=O)c(C(=O)Nc3nnn[nH]3)cn(C(C)C)c2n1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
1,4-Dihydro-1-isopropyl-7-methyl-4-oxo-1,8-naphthyridine-3-carboxylic acid (Example 3b, 0.9 g) was warmed in dimethylformamide (70 ml) and triethylamine (0.7 ml) was added. The solution was cooled to 0° and ethyl chloroformate (0.4 ml) was added and the mixture was kept for 30 minutes. 5-Amino-1H-tetrazol (3.6 g) was added and the mixture was stirred at room temperature for 18 hours and filtered. The filtrate was evaporated and the residue was crystallised from a mixture of dimethylformamide and isopropanol. The product has m.p. > 300° (d) (36%).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6](Cl)[N:5]=[CH:4][N:3]=1.[Br:9][C:10]1[CH:11]=[C:12]([CH:14]=[CH:15][CH:16]=1)[NH2:13].CCN(C(C)C)C(C)C.[CH2:26]([CH2:28][NH2:29])[OH:27]>CCCCO>[Br:9][C:10]1[CH:11]=[C:12]([NH:13][C:6]2[N:5]=[CH:4][N:3]=[C:2]([NH:29][CH2:28][CH2:26][OH:27])[CH:7]=2)[CH:14]=[CH:15][CH:16]=1
Reactant: NCCO
Reactant: Nc1cccc(Br)c1
Reactant: Clc1cc(Cl)ncn1
Solvent: CCN(C(C)C)C(C)C
Solvent: CCCCO
Product: OCCNc1cc(Nc2cccc(Br)c2)ncn1
Temperature: 25 °C
Reaction time: 6 h
Yield: 60 %

Procedure:
100 mg of 4,6-dichloropyrimidine, 127 mg of m-bromoaniline and 103 mg of DIPEA were dissolved in 1 mL of n-BuOH and the mixture obtained was charged into a microwave vial and the vioal obtained was kept in a heating block at 120° C. for 6 hours. The reaction was monitored by TLC and was completed within 6 hours. The mixture obtained was cooled to r.t., 61 mg of ethanolamine and 139 mg of DIPEA were added and the mixture obtained was heated under microwave irradiation for an hour at 200° C. The reaction was finished and crude product was obtained by evaporating n-BuOH. Purification was carried out by column chromatography using EtOAc: MeOH 20:1. 2-(6-(3-Bromophenylamino)pyrimidin-4-ylamino)ethan-1-ol in the form of a colorless solid was obtained.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:15]=[CH:14][C:11]([C:12]#[N:13])=[C:10]([Cl:16])[CH:9]=2)[CH:5]=[N:6][CH:7]=1.[CH3:17][O:18][C:19]1[CH:24]=[CH:23][C:22]([S:25](Cl)(=[O:27])=[O:26])=[CH:21][CH:20]=1>N1C=CC=CC=1>[Cl:16][C:10]1[CH:9]=[C:8]([C:4]2[CH:3]=[C:2]([NH:1][S:25]([C:22]3[CH:21]=[CH:20][C:19]([O:18][CH3:17])=[CH:24][CH:23]=3)(=[O:27])=[O:26])[CH:7]=[N:6][CH:5]=2)[CH:15]=[CH:14][C:11]=1[C:12]#[N:13]
Reactant: N#Cc1ccc(-c2cncc(N)c2)cc1Cl
Reactant: COc1ccc(S(=O)(=O)Cl)cc1
Solvent: c1ccncc1
Product: COc1ccc(S(=O)(=O)Nc2cncc(-c3ccc(C#N)c(Cl)c3)c2)cc1
Yield: 43.1 %

Procedure:
According to General Sulfonylation Procedure 2 in Example 1, to a solution of 4-(5-amino-pyridin-3-yl)-2-chloro-benzonitrile (20 mg, 87 μmol, leg) in anhydrous pyridine (500 μl) was added 4-methoxy-benzenesulfonyl chloride (19.8 mg, 96 μmol, 1.1 eq). The crude product was purified by Isco Cornbiflash® Companion™ flash chromatography system on normal phase (4 g SiO2, flow rate 18 mL/min), eluting with mixtures of dichloromethane/methanol, to give N-[5-(3-chloro-4-cyano-phenyl)-pyridin-3-yl]-4-methoxy-benzenesulfonamide (15 mg, >95% purity, yield: 43%).
Reaction SMILES: Cl[CH2:2][O:3][C:4](=[O:29])[C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:12](=[O:28])[CH2:13][NH:14][C:15]([O:17][CH2:18][C:19]2[CH:24]=[CH:23][C:22]([N+:25]([O-:27])=[O:26])=[CH:21][CH:20]=2)=[O:16])=[CH:7][CH:6]=1.[I-:30].[Na+]>CC(C)=O>[I:30][CH2:2][O:3][C:4](=[O:29])[C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:12](=[O:28])[CH2:13][NH:14][C:15]([O:17][CH2:18][C:19]2[CH:24]=[CH:23][C:22]([N+:25]([O-:27])=[O:26])=[CH:21][CH:20]=2)=[O:16])=[CH:7][CH:6]=1
Reactant: [I-]
Reactant: O=C(CNC(=O)OCc1ccc([N+](=O)[O-])cc1)Nc1ccc(C(=O)OCCl)cc1
Agent: [Na+]
Solvent: CC(C)=O
Product: O=C(CNC(=O)OCc1ccc([N+](=O)[O-])cc1)Nc1ccc(C(=O)OCI)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 49.3 %

Procedure:
A solution of chloromethyl-4[N-(4-nitrobenzyloxycarbonyl)glycylamino]benzoate (1.0 g) in dry acetone (30 ml) was treated with finely-ground sodium iodide (3.6 g) and the mixture stirred at room temperature for 16 h. The mixture was filtered, the filtrate evaporated under reduced pressure and the residue dissolved in dichloromethane (50 ml) and washed with sodium thiosulphate (10%. aq. solution) until colourless. The organic phase was washed with water (20 ml), saturated aqueous NaCl (20 ml) and dried (MgSO4). The solvent was evaporated and the residue crystallised from ethyl acetate to afford the title compound as a white solid (0.600 g), m.p. 162°-4° C.; νmax (Nujol) 3300, 1735, 1690, 1610, and 1525 cm-1 ; δH (CDCl3 /D6 -DMSO) 3.90 (2H, d, J 6 Hz), 5.23 (2H, s), 6.18 (2H, s), 6.18 (2H, s), and 7.35-8.20 (10H, m).
Reaction SMILES: CN([CH2:4][C:5]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[N:7]2[C:14](=[O:25])[CH:15]([CH2:18][C:19]3[N:20]=[CH:21][NH:22][C:23]=3[CH3:24])[CH2:16][CH2:17][C:6]=12)C.C([O-])=O.[NH4+]>[Pd].C(O)C.O.O1CCCC1>[CH3:4][C:5]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[N:7]2[C:14](=[O:25])[CH:15]([CH2:18][C:19]3[N:20]=[CH:21][NH:22][C:23]=3[CH3:24])[CH2:16][CH2:17][C:6]=12
Reactant: Cc1[nH]cnc1CC1CCc2c(CN(C)C)c3ccccc3n2C1=O
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCO
Solvent: O
Product: Cc1[nH]cnc1CC1CCc2c(C)c3ccccc3n2C1=O
Temperature: 75 °C
Reaction time: 1 h
Yield: 60.4 %

Procedure:
A mixture of 8,9-dihydro-10-[(dimethylamino)methyl]-7-[(5-methyl-1H-imidazol-4-yl)methyl]pyrido[1,2-a]indol-6(7H)-one (224 mg), ammonium formate (500 mg), 10% palladium on carbon (210 mg), water (1 ml), ethanol (2 ml) and tetrahydrofuran (1 ml) was heated at 75° C. for 45 minutes and then cooled. Ammonium formate (300 mg), 10% palladium on carbon (100 mg), water (1 ml), and ethanol (2 ml) were added successively to the reaction mixture. Heating at 75° C. was continued for further 1 hour. After cooling, the reaction mixture was filtered and the filtrate was evaporated in vacuo. The residue was diluted with water and extracted three times with chloroform. The chloroform layer was washed with water and brine, dried over anhydrous magnesium sulfate, and evaporated in vacuo. Silica gel column chromatography of the residue (5% methanol-chloroform) gave 8,9-dihydro-10-methyl-7-[(5-methyl-1H-imidazol-4-yl)methyl] pyrido[1,2-a]indol-6(7H)-one (118 mg).
Reaction SMILES: C[O:2][CH:3](OC)[CH2:4][S:5][C:6]1[S:7][C:8]([C:19]2[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=2)=[C:9]([C:11]2[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=2)[N:10]=1.C(O)(=O)C.S(=O)(=O)(O)O.O>C(OCC)(=O)C>[CH3:18][O:17][C:14]1[CH:15]=[CH:16][C:11]([C:9]2[N:10]=[C:6]([S:5][CH2:4][CH:3]=[O:2])[S:7][C:8]=2[C:19]2[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=2)=[CH:12][CH:13]=1
Reactant: COc1ccc(-c2nc(SCC(OC)OC)sc2-c2ccc(OC)cc2)cc1
Agent: O=S(=O)(O)O
Solvent: O
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: COc1ccc(-c2nc(SCC=O)sc2-c2ccc(OC)cc2)cc1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
7.0 g of 2-[4,5-bis-(p-methoxyphenyl)-thiazol-2-ylthio]-acetaldehyde-dimethylacetal are mixed with 50 ml of acetic acid, 25 ml of sulphuric acid and 25 ml of water, stirred vigorously for 30 minutes, and then stirred into 1000 ml of ice-water. The oil which separates is taken up in 200 ml of ethyl acetate. Shaking is carried out with a further 200 ml of ethyl acetate and the combined organic phases are washed with water and then twice with cold sodium bicarbonate solution, dried over magnesium sulphate and concentrated to dryness by evaporation. The crude product is crystallised with diethyl ether. 2-[4,5-bis-(p-methoxyphenyl)-thiazol-2-ylthio]-acetaldehyde having a melting point of 75°-76° is obtained.
Reaction SMILES: [F:1][C:2]([F:15])([CH:12]([F:14])[F:13])[CH2:3][O:4][C:5]1[CH:11]=[CH:10][C:8]([NH2:9])=[CH:7][CH:6]=1.Br[CH2:17][CH2:18][N:19]1[C:23](=[O:24])[C:22]2=[CH:25][CH:26]=[CH:27][CH:28]=[C:21]2[C:20]1=[O:29].C(=O)(O)[O-].[K+].[I-].[K+]>CN(C)C=O>[C:20]1(=[O:29])[N:19]([CH2:18][CH2:17][NH:9][C:8]2[CH:10]=[CH:11][C:5]([O:4][CH2:3][C:2]([F:15])([F:1])[CH:12]([F:13])[F:14])=[CH:6][CH:7]=2)[C:23](=[O:24])[C:22]2=[CH:25][CH:26]=[CH:27][CH:28]=[C:21]12
Reactant: O=C1c2ccccc2C(=O)N1CCBr
Reactant: Nc1ccc(OCC(F)(F)C(F)F)cc1
Agent: O=C([O-])O
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=C1c2ccccc2C(=O)N1CCNc1ccc(OCC(F)(F)C(F)F)cc1
Yield: 41.1 %

Procedure:
A mixture of 4-(2,2,3,3-tetrafluoropropoxy)aniline (7.4 g), N-(2-bromoethyl)phthalimide (9.0 g), potassium bicarbonate (6.9 g), potassium iodide (5.5 g) and N,N-dimethylformamide (80 ml) are refluxed for 22 hours. The solvent was distilled off under reduced pressure. To the residue, ice-water (200 ml) and ethyl acetate (200 ml) were added and fractionated. The ethyl acetate layer was washed with water, dried over anhydrous magnesium sulfate and distilled off under reduced pressure. The residue was purified by silica gel chromatography (eluate; ethyl acetate:hexane=1:2 v/v) and recrystallized from ethyl acetate-diisopropyl ether to give N-(2-phthalimido)ethyl-4-(2,2,3,3-tetrafluoropropoxy)aniline (5.4 g) as white crystals.
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8]([OH:10])=[O:9])=[CH:6][CH:5]=[CH:4][N:3]=1.S(OC)(O[CH3:15])(=O)=O.C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[Cl:1][C:2]1[C:7]([C:8]([O:10][CH3:15])=[O:9])=[CH:6][CH:5]=[CH:4][N:3]=1
Reactant: O=C(O)c1cccnc1Cl
Reactant: COS(=O)(=O)OC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: COC(=O)c1cccnc1Cl
Temperature: 25 °C
Reaction time: 8 h

Procedure:
2-Chloro-3-pyridinecarboxylic acid, methyl ester (11) is prepared as follows: a suspension of 22.06 g (140 mmol) of 2-chloro-3-pyridinecarboxylic acid (10), 14.6 mL (154 mmol) of dimethyl sulfate, 29 g (210 mmol) of anhydrous powdered potassium carbonate, and 140 mL of acetone is stirred at room temperature overnight. The mixture is filtered, the salts are washed with acetone, and the filtrate is concentrated to an oil that is diluted with dichloromethane. The organic phase is washed with saturated aqueous sodium dicarbonate, dried, then filtered through a pad of silica gel (230-400 mesh). The filtrate is concentrated to give an oil that is distilled at 90°-91° C./0.17 mm to leave 19.9 g of the pure product as a colorless oil.
Reaction SMILES: [O:1]=[C:2]1[N:7]([CH2:8][C:9]2[CH:14]=[CH:13][C:12]([C:15]3[C:16]([C:21]#[N:22])=[CH:17][CH:18]=[CH:19][CH:20]=3)=[CH:11][CH:10]=2)[C:6]2[S:23][C:24]([CH2:26][C:27]([F:30])([F:29])[F:28])=[CH:25][C:5]=2[C:4](=[O:31])[NH:3]1.Br[CH2:33][C:34]([C:36]1[CH:41]=[CH:40][C:39]([F:42])=[CH:38][CH:37]=1)=[O:35].CN(C)C=O.[H-].[Na+]>C(OCC)(=O)C>[F:42][C:39]1[CH:40]=[CH:41][C:36]([C:34](=[O:35])[CH2:33][N:3]2[C:4](=[O:31])[C:5]3[CH:25]=[C:24]([CH2:26][C:27]([F:30])([F:29])[F:28])[S:23][C:6]=3[N:7]([CH2:8][C:9]3[CH:10]=[CH:11][C:12]([C:15]4[C:16]([C:21]#[N:22])=[CH:17][CH:18]=[CH:19][CH:20]=4)=[CH:13][CH:14]=3)[C:2]2=[O:1])=[CH:37][CH:38]=1
Reactant: O=C(CBr)c1ccc(F)cc1
Reactant: N#Cc1ccccc1-c1ccc(Cn2c(=O)[nH]c(=O)c3cc(CC(F)(F)F)sc32)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: N#Cc1ccccc1-c1ccc(Cn2c(=O)n(CC(=O)c3ccc(F)cc3)c(=O)c3cc(CC(F)(F)F)sc32)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 55 %

Procedure:
To a mixture of 4′-{[2,4-dioxo-6-(2,2,2-trifluoroethyl)-3,4-dihydrothieno[2,3-d]pyrimidin-1(2H)-yl]methyl}biphenyl-2-carbonitrile (1.5 g), 2-bromo-1-(4-fluorophenyl)ethanone (0.89 g) and N,N-dimethylformamide (50 mL) was added 60% sodium hydride (0.16 g), and the mixture was stirred at room temperature for 2 hr. The reaction mixture was diluted with ethyl acetate, washed successively with 1N hydrochloric acid and saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure. The obtained residue was recrystallized from tetrahydrofuran to give the title compound as colorless crystals (1.08 g, 55%).
Reaction SMILES: [CH:1]([C:3]1[S:7][C:6]2[CH:8]=[C:9]([O:12][CH3:13])[CH:10]=[CH:11][C:5]=2[C:4]=1[O:14][C:15]1[CH:20]=[CH:19][C:18](/[CH:21]=[CH:22]/[C:23]([O:25][CH3:26])=[O:24])=[CH:17][CH:16]=1)=[O:2].[N+:27]([CH:29](S(C1C=CC(C)=CC=1)(=O)=O)[CH:30]([CH3:32])[CH3:31])#[C-:28].C[O-].[Na+]>CO>[CH:30]([C:29]1[N:27]=[CH:28][O:2][C:1]=1[C:3]1[S:7][C:6]2[CH:8]=[C:9]([O:12][CH3:13])[CH:10]=[CH:11][C:5]=2[C:4]=1[O:14][C:15]1[CH:20]=[CH:19][C:18](/[CH:21]=[CH:22]/[C:23]([O:25][CH3:26])=[O:24])=[CH:17][CH:16]=1)([CH3:32])[CH3:31]
Reactant: [C-]#[N+]C(C(C)C)S(=O)(=O)c1ccc(C)cc1
Reactant: COC(=O)/C=C/c1ccc(Oc2c(C=O)sc3cc(OC)ccc23)cc1
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: COC(=O)/C=C/c1ccc(Oc2c(-c3ocnc3C(C)C)sc3cc(OC)ccc23)cc1
Temperature: 80 °C
Yield: 27.2 %

Procedure:
To a solution of (E)-methyl 3-(4-((2-formyl-6-methoxybenzo[b]thiophen-3-yl)oxy)phenyl)acrylate (30 mg, 0.081 mmol) and 1-((l-isocyano-2-methylpropyl)sulfonyl)-4-methylbenzene (38.7 mg, 0.163 mmol) in MeOH (1.5 mL) at room temperature was added NaOMe (13.20 mg, 0.244 mmol) as a solid. The resulting mixture was warmed to 80° C. for 3 h after which time the reaction was quenched by addition of brine and extracted with EtOAc (2×). The combined organic layers were dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The resulting crude material was purified by column chromatography (SiO2, 0-20% EtOAc/Heptane) to afford (E)-methyl 3-(4-((2-(4-isopropyloxazol-5-yl)-6-methoxybenzo[b]thiophen-3-yl)oxy)phenyl)acrylate (10 mg, 0.022 mmol, 27% yield) as a yellow oil. LC/MS (m/z, MH+): 450.0.
Reaction SMILES: C[O:2][C:3](=[O:14])[CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([SH:12])=[CH:8][C:7]=1[CH3:13].Br[CH2:16][C:17]1[CH:22]=[CH:21][C:20]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[CH:19][CH:18]=1>>[C:20]1([C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH:19]=[CH:18][C:17]([CH2:16][S:12][C:9]2[CH:10]=[CH:11][C:6]([O:5][CH2:4][C:3]([OH:2])=[O:14])=[C:7]([CH3:13])[CH:8]=2)=[CH:22][CH:21]=1
Reactant: BrCc1ccc(-c2ccccc2)cc1
Reactant: COC(=O)COc1ccc(S)cc1C
Product: Cc1cc(SCc2ccc(-c3ccccc3)cc2)ccc1OCC(=O)O

Procedure:
The title compound was prepared in the manner analogous to Example 1F using 2C and 1E. MS m/z 379 (M+1).
Reaction SMILES: [CH:1]([Mg]Br)=[CH2:2].[F:5][C:6]1[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:10][C:7]=1[CH:8]=[O:9].[NH4+].[Cl-]>C1COCC1>[CH:1]([CH:8]([C:7]1[CH:10]=[C:11]([C:14]([F:15])([F:16])[F:17])[CH:12]=[CH:13][C:6]=1[F:5])[OH:9])=[CH2:2]
Reactant: O=Cc1cc(C(F)(F)F)ccc1F
Reactant: C=C[Mg]Br
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: C=CC(O)c1cc(C(F)(F)F)ccc1F
Temperature: 25 °C
Reaction time: 2 h

Procedure:
52.6 ml (0.0526 mol) of a 1M solution of vinylmagnesium bromide in THF are added dropwise at a temperature below 25° C. to a solution of 10.1 g (0.0526 mol) of 2-fluoro-5-(trifluoromethyl)benzaldehyde (prepared according to Example P) in 53 ml of anhydrous THF. The mixture is then stirred for 2 h 30 at room temperature. Hydrolysis is carried out with a saturated aqueous NH4Cl solution while cooling between 10° and 20° C.; extraction is carried out with ether and the extract is washed with water, dried over Na2SO4, filtered and evaporated under vacuum. The residue is used without subsequent purification in the following stage. Yd.: 11.6 g (quantitative)