Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].O1CCCC1.[CH3:8][C:9]1[CH:10]=[C:11]([OH:23])[CH:12]=[C:13]([CH3:22])[C:14]=1[S:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=1.[CH3:24][N:25]([CH3:29])[C:26](Cl)=[O:27]>O>[CH3:24][N:25]([CH3:29])[C:26](=[O:27])[O:23][C:11]1[CH:12]=[C:13]([CH3:22])[C:14]([S:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=2)=[C:9]([CH3:8])[CH:10]=1
Reactant: CN(C)C(=O)Cl
Reactant: Cc1cc(O)cc(C)c1Sc1ccccn1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: Cc1cc(OC(=O)N(C)C)cc(C)c1Sc1ccccn1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a stirred suspension of 240 mg. of sodium hydride in 20 ml. of dry tetrahydrofuran is added a solution of 2.31 g. of 3,5-dimethyl-4-(2-pyridylthio)phenol in 30 ml. of dry tetrahydrofuran. After the effervescence has subsided, a solution of 1.1 g. of N,N-dimethylcarbamoyl chloride in 10 ml. of dry tetrahydrofuran is added dropwise. The reaction mixture is stirred at ambient temperature for 16 hours, and then under reflux for 4 hours. The reaction mixture is cooled to room temperature, and then diluted with an excess of water. The product is extracted into ethyl acetate. The ethyl acetate is washed with water, dried using anhydrous magnesium sulfate, and then evaporated in vacuo to give crude 3,5-dimethyl-4-(2-pyridylthio)phenyl N,N-dimethylcarbamate. The crude product can be purified further by recrystallization.
Reaction SMILES: [C:1]([C:4]1[CH:22]=[CH:21][C:7]2[S:8][C:9]([CH3:20])=[C:10]([CH2:11][C:12]3[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][C:13]=3[Cl:19])[C:6]=2[CH:5]=1)([OH:3])=O.C(N1C=CN=C1)(N1C=CN=C1)=O.[CH2:35]([S:40]([NH2:43])(=[O:42])=[O:41])[CH2:36][CH2:37][CH2:38][CH3:39].C1CCN2C(=NCCC2)CC1>CN(C)C=O>[Cl:19][C:13]1[CH:14]=[C:15]([Cl:18])[CH:16]=[CH:17][C:12]=1[CH2:11][C:10]1[C:6]2[CH:5]=[C:4]([C:1](=[O:3])[NH:43][S:40]([CH2:35][CH2:36][CH2:37][CH2:38][CH3:39])(=[O:42])=[O:41])[CH:22]=[CH:21][C:7]=2[S:8][C:9]=1[CH3:20]
Reactant: CCCCCS(N)(=O)=O
Reactant: Cc1sc2ccc(C(=O)O)cc2c1Cc1ccc(Cl)cc1Cl
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CN(C)C=O
Solvent: C1CCC2=NCCCN2CC1
Product: CCCCCS(=O)(=O)NC(=O)c1ccc2sc(C)c(Cc3ccc(Cl)cc3Cl)c2c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 67.7 %

Procedure:
In the same manner as in Example 1, 5-carboxy-3-(2,4-dichlorobenzyl)-2-methylbenzo[b]thiophene (440 mg, 1.25 mmol) was suspended in dimethylformamide and carbonyldiimidazole (305 mg, 1.88 mmol) was added, which was followed by stirring at room temperature for 1 hr. Then, 1-n-pentanesulfonamide (284 mg, 1.88 mmol) and DBU (286 mg, 1.88 mmol) were added and the mixture was refluxed under heating at 100° C. for 15 hr. The reaction mixture was concentrated under reduced pressure and water and 3N hydrochloric acid were added to acidify the mixture. The mixture was extracted with ethyl acetate, and the organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The desiccant was filtered off and the filtrate was concentrated under reduced pressure. The residual oil was purified by silica gel column chromatography (eluent: hexane/ethyl acetate=3/2) and recrystallized from 2-propanol-n-hexane to give 3-(2,4-dichlorobenzyl)-2-methyl-5-(1-n-pentanesulfonylcarbamoyl)benzo[b]thiophene (410 mg, 68%) as colorless crystals.
Reaction SMILES: I[C:2]1[CH:27]=[CH:26][C:5]([C:6]([N:8]([CH3:25])[C@:9]([CH3:24])([C:14]([NH:16][O:17][CH:18]2[CH2:23][CH2:22][CH2:21][CH2:20][O:19]2)=[O:15])[C:10]([NH:12][CH3:13])=[O:11])=[O:7])=[CH:4][CH:3]=1.[C:28]([C:30]1[CH:37]=[CH:36][C:33]([CH:34]=[O:35])=[CH:32][CH:31]=1)#[CH:29].C1COCC1>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I.C(OCC)(=O)C>[CH:34]([C:33]1[CH:36]=[CH:37][C:30]([C:28]#[C:29][C:2]2[CH:27]=[CH:26][C:5]([C:6]([N:8]([CH3:25])[C@:9]([CH3:24])([C:14]([NH:16][O:17][CH:18]3[CH2:23][CH2:22][CH2:21][CH2:20][O:19]3)=[O:15])[C:10]([NH:12][CH3:13])=[O:11])=[O:7])=[CH:4][CH:3]=2)=[CH:31][CH:32]=1)=[O:35]
Reactant: CNC(=O)[C@@](C)(C(=O)NOC1CCCCO1)N(C)C(=O)c1ccc(I)cc1
Reactant: C#Cc1ccc(C=O)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CNC(=O)[C@@](C)(C(=O)NOC1CCCCO1)N(C)C(=O)c1ccc(C#Cc2ccc(C=O)cc2)cc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 74.7 %

Procedure:
TEA (10 mL) was added dropwise to a mixture of (2S)-2-[(4-iodobenzoyl)(methyl)amino]-N,2-dimethyl-N′-(tetrahydro-2H-pyran-2-yloxy)propanediamide (Intermediate 15, 12 g), 4-ethynylbenzaldehyde (4.1 g), PdCl2(PPh3)2 (0.85 g), CuI (0.46 g), and THF (60 mL) at room temperature in a nitrogen atmosphere, and the mixture was stirred for 2 hours and 15 minutes at room temperature. Ethyl acetate (0.20 L), OH type silica gel (12 g), cellpure (5.9 g) and activated carbon (0.60 g) were added, the insolubles were filtered out, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by OH type silica gel column chromatography (ethyl acetate/hexane=50/50, followed by gradient elution with chloroform/acetone=100/0→80/20). Then, ethyl acetate and IPE were added to the resulting solid, and the solid was filtered off and washed with IPE to obtain (2S)-2-[{4-[(4-formylphenyl)ethynyl]benzoyl}(methyl)amino]-N,2-dimethyl-N′-(tetrahydro-2H-pyran-2-yloxy)propanediamide (yellow brown solid) (9.0 g, 76%).
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:16])[C:10]([NH:12][C:13](=[O:15])[CH3:14])=[CH2:11])C1C=CC=CC=1.Br[C:18]1[CH:24]=[CH:23][C:21]([NH2:22])=[C:20]([CH:25]([CH3:27])[CH3:26])[CH:19]=1.BrC1C=CC(N)=C(CC)C=1>>[C:13]([NH:12]/[C:10](=[CH:11]\[C:18]1[CH:24]=[CH:23][C:21]([NH2:22])=[C:20]([CH:25]([CH3:27])[CH3:26])[CH:19]=1)/[C:9]([O:8][CH3:1])=[O:16])(=[O:15])[CH3:14]
Reactant: CC(C)c1cc(Br)ccc1N
Reactant: C=C(NC(C)=O)C(=O)OCc1ccccc1
Agent: CCc1cc(Br)ccc1N
Product: COC(=O)/C(=C/c1ccc(N)c(C(C)C)c1)NC(C)=O

Procedure:
The titled compound was prepared according to the method described in Example 1B substituting 2-acetylamino-acrylic acid methyl ester for 2-acetylamino-acrylic acid benzyl ester and 4-bromo-2-isopropylaniline for 4-bromo-2-ethylaniline.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[NH:6][C:7]2[C:12]([CH:13]=1)=[CH:11][CH:10]=[C:9]([O:14][CH3:15])[CH:8]=2)=[O:4].C([O-])([O-])=O.[K+].[K+].[CH2:22](Br)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>CN(C=O)C.CCOC(C)=O>[CH2:22]([N:6]1[C:7]2[C:12](=[CH:11][CH:10]=[C:9]([O:14][CH3:15])[CH:8]=2)[CH:13]=[C:5]1[C:3]([O:2][CH3:1])=[O:4])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: BrCc1ccccc1
Reactant: COC(=O)c1cc2ccc(OC)cc2[nH]1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COC(=O)c1cc2ccc(OC)cc2n1Cc1ccccc1
Temperature: 25 °C
Reaction time: 40 h

Procedure:
To a solution of methyl6-methoxy-1H-indole-2-carboxylate (Compound 1, 1.0 g, 4.9 mmol) in DMF (10 ml) was added K2CO3 (2.0 g, 14.6 mmol) and benzyl bromide (0.87 ml, 7.3 mmol). The mixture was stirred at room temperature for 40 h and was diluted with EtOAc, washed with H2O, brine, dried over Na2SO4 and concentrated in vacuo. The residue was purified by crystallization from Et2O to yield the title compound as an off-white solid.
Reaction SMILES: [CH:1]([OH:3])=O.C(OC(=O)C)(=O)C.[CH2:11]([C:13]1[CH:19]=[CH:18][CH:17]=[C:16]([CH2:20][CH3:21])[C:14]=1[NH2:15])[CH3:12]>ClCCl>[CH:1]([NH:15][C:14]1[C:16]([CH2:20][CH3:21])=[CH:17][CH:18]=[CH:19][C:13]=1[CH2:11][CH3:12])=[O:3]
Reactant: CCc1cccc(CC)c1N
Reactant: O=CO
Solvent: CC(=O)OC(C)=O
Solvent: ClCCl
Product: CCc1cccc(CC)c1NC=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 74.2 %

Procedure:
A mixture of formic acid (14.361 g, 0.312 mol) and acetic anhydride (12.659 g, 0.124 mol) was stirred at room temperature for 1 h under an argon atmosphere. This mixture was added to a solution of 2,6-diethylaniline (14.924 g, 0.1 mol) in dry dichloromethane (60 ml) at such a rate that the temperature of the reaction mixture was kept between 5 and 10° C. The reaction was stirred at room temperature for 16 h and then refluxed for 4 h. The solvent was evaporated under reduced pressure, the residue was dissolved in CHCl3 (200 mL) and washed with a saturated aqueous NaHCO3 solution (3×200 mL), and water (200 mL). The organic layer was dried over Na2SO4 and the solvent was evaporated under reduced pressure. The remaining yellow solid was washed with hot diethyl ether (2×50 mL) to afford N-formyl-2,6-diethylaniline 8d as a white solid (13.16 g, 74%). 1H NMR (CDCl3, 300 MHz): δ=8.15-8.02 (m, 1H, CHO), 7.86 (broad s, 1H, NH), 7.25-7.06 (m, 3H), 2.65 (q, J=7 Hz, 2H), 2.53 (q, J=7 Hz, 2H), 1.20 (t, J=7 Hz, 3H), 1.14 (t, J=7 Hz, 3H); 13C{1H} NMR (CDCl3, 75 MHz): δ=165.97, 161.00, 142.13, 141.52, 132.15, 131.66, 128.65, 128.37, 127.09, 126.49, 25.18, 25.04, 15.00, 14.62; HRMS (EI+) calculated for C11H15NO [M]+ 177.1154, observed 177.1159.
Reaction SMILES: Cl.CN(C)CCCN=C=NCC.[NH2:13][C:14]1[C:15](=[O:27])[N:16]([CH3:26])[C:17](=[O:25])[N:18]([CH2:21][CH:22]([CH3:24])[CH3:23])[C:19]=1[NH2:20].[CH3:28][O:29][C:30]1[CH:31]=[C:32]2[C:37](=[CH:38][C:39]=1[O:40][CH3:41])[C:36]([CH3:42])=[N:35][CH:34]=[C:33]2[CH2:43][C:44](O)=O>CO.O>[CH3:28][O:29][C:30]1[CH:31]=[C:32]2[C:37](=[CH:38][C:39]=1[O:40][CH3:41])[C:36]([CH3:42])=[N:35][CH:34]=[C:33]2[CH2:43][C:44]1[NH:13][C:14]2[C:15](=[O:27])[N:16]([CH3:26])[C:17](=[O:25])[N:18]([CH2:21][CH:22]([CH3:23])[CH3:24])[C:19]=2[N:20]=1
Reactant: COc1cc2c(CC(=O)O)cnc(C)c2cc1OC
Reactant: CC(C)Cn1c(N)c(N)c(=O)n(C)c1=O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CO
Solvent: O
Product: COc1cc2c(Cc3nc4c([nH]3)c(=O)n(C)c(=O)n4CC(C)C)cnc(C)c2cc1OC
Temperature: 25 °C
Reaction time: 16 h

Procedure:
1-(3-Dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.201 g, 1.30 mmol) is added to 5,6-diamino-1-isobutyl-3-methyl-1H-pyrimidine-2,4-dione (0.223 g, 1.05 mmol)) and (6,7-dimethoxy-1-methyl-isoquinolin4-yl)-acetic acid (0.25 g, 0.96 mmol) in methanol (5 ml) and water (1 ml) and the mixture is stirred at ambient temperature for 16 hours. The methanol is evaporated and the resultant solid collected by filtration, taken into methanol (5 ml) and 5M aqueous sodium hydroxide (0.5 ml) is added. The reaction is heated to reflux for 1 hour, cooled to ambient temperature and evaporated. The residue is dissolved in water and extracted with dichloromethane, the combined organic extracts are dried over sodium sulfate and evaporated to afford 8-(6,7-dimethoxy-1-methyl-isoquinolin4-ylmethyl)-3-isobutyl-1-methyl-3,7-dihydro-purine-2,6-dione, M+ 437.
Reaction SMILES: C([O:5][CH:6]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])N(C)C)(C)(C)C.[CH:15]1[N:16]=[CH:17][N:18]2[CH:23]=[C:22](C(O)=O)[CH:21]=[CH:20][C:19]=12>CN(C)C=O.C1(C)C=CC=CC=1>[CH:15]1[N:16]=[CH:17][N:18]2[CH:23]=[C:22]([C:6]([O:10][C:11]([CH3:12])([CH3:13])[CH3:14])=[O:5])[CH:21]=[CH:20][C:19]=12
Reactant: CN(C)C(OC(C)(C)C)OC(C)(C)C
Reactant: O=C(O)c1ccc2cncn2c1
Solvent: Cc1ccccc1
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)c1ccc2cncn2c1
Temperature: 90 °C

Procedure:
3.37 ml (14.06 mmol) of N,N-dimethylformamide di(tertbutyl)acetal are added to 570 mg (3.52 mmol) of imidazo[1,5-a]pyridine-6-carboxylic acid [described in Bioorg. Med. Chem. Lett., (2002), 12(3), 465-470] in a mixture of 5 ml of dimethylformamide and 5 ml of toluene and the mixture is heated at 90° C. for 6 hours. 3.37 ml (14.06 mmol) of N,N-dimethylformamide di(tert-butyl)acetal are again added to the reaction medium and the mixture is heated at 90° C. for a further 4 hours. The reaction medium is poured onto water and extracted with ethyl acetate. The organic phase is separated by settling, washed with a saturated aqueous sodium chloride solution, dried over sodium sulfate and concentrated under reduced pressure. The product is purified by filtration through a bed of silica, elution being carried out with a mixture of dichloromethane and methanol (98/2). After evaporation, 580 mg of a beige powder are obtained. Melting point: 77° C.; 1H NMR (d6-DMSO): 1.59 (9H, s), 7.71 (1H, d), 7.36 (1H, s), 7.58 (1H, d), 8.56 (1H, s), 9.03 (1H, s).
Reaction SMILES: B(F)(F)F.CSC.C[O:9][C:10]1[CH:11]=[C:12]([C:17]2[N:21]([CH2:22][C:23]#[N:24])[N:20]=[CH:19][C:18]=2[C:25]2[CH:30]=[CH:29][N:28]=[C:27]([C:31]3[CH:32]=[N:33][CH:34]=[CH:35][CH:36]=3)[CH:26]=2)[CH:13]=[C:14]([CH3:16])[CH:15]=1>ClCCl>[OH:9][C:10]1[CH:11]=[C:12]([C:17]2[N:21]([CH2:22][C:23]#[N:24])[N:20]=[CH:19][C:18]=2[C:25]2[CH:30]=[CH:29][N:28]=[C:27]([C:31]3[CH:32]=[N:33][CH:34]=[CH:35][CH:36]=3)[CH:26]=2)[CH:13]=[C:14]([CH3:16])[CH:15]=1
Reactant: COc1cc(C)cc(-c2c(-c3ccnc(-c4cccnc4)c3)cnn2CC#N)c1
Agent: FB(F)F
Solvent: ClCCl
Solvent: CSC
Product: Cc1cc(O)cc(-c2c(-c3ccnc(-c4cccnc4)c3)cnn2CC#N)c1
Reaction time: 24 h

Procedure:
Borontrifluoride-dimethylsulfide (0.13 mL, 1.2 mmol) was dropwise added to a solution of the methoxy compound (45.7 mg, 0.12 mmol) prepared in Example 34 in dichloromethane (4 mL) at room temperature under nitrogen atmosphere, and stirred for 24 hours. The reaction mixture was concentrated by vacuum distillation. The residue was treated in ethyl acetate (100 mL) and brine (50 mL), and the organic layer was dried over anhydrous magnesium sulfate and distilled under vacuum. Purification through column chromatography (silica gel, ethyl acetate) afforded pure hydroxy products (24 mg, 55%).
Reaction SMILES: [Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH3:11])=[C:4](Cl)[N:3]=1.C(N(CC)CC)C.[CH:20]1([NH2:26])[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1>C(#N)C>[Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH3:11])=[C:4]([NH:26][CH:20]2[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]2)[N:3]=1
Reactant: Cn1cnc2c(Cl)nc(Cl)nc21
Reactant: NC1CCCCC1
Solvent: CCN(CC)CC
Solvent: CC#N
Product: Cn1cnc2c(NC3CCCCC3)nc(Cl)nc21
Temperature: 50 °C
Yield: 81.8 %

Procedure:
2,6-Dichloro-9-methyl-9H-purine (1.40 g, 6.93 mmol) was dissolved in acetonitrile (25 mL). Triethylamine (4.81 mL, 34.5 mmol) and cyclohexylamine (0.79 mL, 6.90 mmol) were added and the reaction mixture was stirred at 50° C. over night. The reaction mixture was cooled to room temperature and concentrated in vacuo. Water was added followed by extraction with ethyl acetate. The combined organic phases were dried over magnesium sulphate, filtered and concentrated in vacuo to give (2-chloro-9-methyl-9H-purin-6-yl)-cyclohexyl-amine (1.5 g, 82%) as a crystalline compound.
Reaction SMILES: [Br:1][C:2]([CH3:18])([CH3:17])[C:3]([O:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH:15]=[CH2:16])=[O:4].[SH:19][CH2:20][CH2:21][CH2:22][Si:23]([O:30][CH2:31][CH3:32])([O:27][CH2:28][CH3:29])[O:24][CH2:25][CH3:26]>>[Br:1][C:2]([CH3:18])([CH3:17])[C:3]([O:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][S:19][CH2:20][CH2:21][CH2:22][Si:23]([O:30][CH2:31][CH3:32])([O:24][CH2:25][CH3:26])[O:27][CH2:28][CH3:29])=[O:4]
Reactant: CCO[Si](CCCS)(OCC)OCC
Reactant: C=CCCCCCCCCCOC(=O)C(C)(C)Br
Product: CCO[Si](CCCSCCCCCCCCCCCOC(=O)C(C)(C)Br)(OCC)OCC

Procedure:
The 10-undecenyl 2-bromo-2-methylpropanate was reacted with 3-mercaptopropyltriethoxysilane in the same manner as in Example 1 to give 11-(3-(triethoxysilyl)propylthio)undecyl 2-bromo-2-methylpropanate of the chemical formula below (compound 5).
Reaction SMILES: [H-].[Na+].[F:3][C:4]1[CH:15]=[CH:14][C:7]2[C:8](=[O:13])[O:9][C:10](=O)[NH:11][C:6]=2[CH:5]=1.BrC[C:18]([O:20][CH2:21][CH3:22])=[O:19]>>[F:3][C:4]1[CH:5]=[C:6]([NH:11][CH2:10][C:18]([O:20][CH2:21][CH3:22])=[O:19])[C:7](=[CH:14][CH:15]=1)[C:8]([OH:9])=[O:13]
Reactant: O=c1[nH]c2cc(F)ccc2c(=O)o1
Reactant: CCOC(=O)CBr
Agent: [H-]
Agent: [Na+]
Product: CCOC(=O)CNc1cc(F)ccc1C(=O)O
Temperature: 25 °C
Reaction time: 18 h

Procedure:
Sodium hydride (80% in oil; 1.2 g) was added slowly to a stirred suspension of 7-fluoro-1H-3,1-benzoxazine-2,4-dione (7 g). Effervescence occurred and a clear solution was produced. Ethyl bromoacetate (4.5 ml) was added and the mixture was stirred at room temperature for 18 hours. The solvent was evaporated and the residue was diluted with water. The solid (9.5 g) was filtered off and washed with water and hexane and dried. This solid (5.4 g) was added to a solution of sodium carbonate (5.3 g) in water (60 ml). After stirring for 6 hours the undissolved solid was filtered off. The filtrate was acidified with dilute hydrochloric acid and extracted with ethyl acetate. The extract was washed with water, dried and evaporated. The solid was purified by flash chromatography and recrystallised from diisopropyl ether to give 4-fluoro-N-(ethoxycarbonylmethyl)- anthranilic acid, mp. 123°-125°. (Compound 11).
Reaction SMILES: [F:1][C:2]([F:11])([F:10])[C:3]1[C:7]([CH:8]=[O:9])=[CH:6][NH:5][N:4]=1.[H-].[Na+].Br[CH2:15][C:16]([NH:18][C:19]1[S:23][C:22]2[CH2:24][CH2:25][CH2:26][CH2:27][C:21]=2[C:20]=1[C:28]([NH2:30])=[O:29])=[O:17].O>CN(C=O)C>[CH:8]([C:7]1[C:3]([C:2]([F:1])([F:10])[F:11])=[N:4][N:5]([CH2:15][C:16]([NH:18][C:19]2[S:23][C:22]3[CH2:24][CH2:25][CH2:26][CH2:27][C:21]=3[C:20]=2[C:28]([NH2:30])=[O:29])=[O:17])[CH:6]=1)=[O:9]
Reactant: O=Cc1c[nH]nc1C(F)(F)F
Reactant: NC(=O)c1c(NC(=O)CBr)sc2c1CCCC2
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: NC(=O)c1c(NC(=O)Cn2cc(C=O)c(C(F)(F)F)n2)sc2c1CCCC2
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 95.9 %

Procedure:
3-(trifluoromethyl)pyrazole-4-carbaldehyde (200 mg, 1.22 mmol) was dissolved in DMF (10 mL). NaH (60% [w/w] suspension in oil, 50 mg, 1.25 mmol) was added portionwise and the reaction mixture stirred at RT for 30 min. 2-(2-bromoacetamido)-4,5,6,7-tetrahydrobenzo[b]thiophene-3-carboxamide (386 mg, 1.22 mmol) was added and the reaction mixture heated at 65° C. for 2 h, then allowed to cool to RT. Water (10 mL) was added and the reaction mixture extracted with EtOAc (3×10 mL). The combined EtOAc layers were washed with water (5×10 mL), brine (10 mL), dried over MgSO4, filtered, and the solvent removed under reduced pressure to give the desired product (470 mg, 1.17 mmol, 96%).
Reaction SMILES: C(OC([NH:8][CH:9]([C:11]1[C:12]([O:33][CH2:34][CH3:35])=[C:13]([CH:19]2[CH2:22][N:21]([C:23]([O:25][CH2:26][C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)=[O:24])[CH2:20]2)[C:14]([CH3:18])=[C:15]([Cl:17])[CH:16]=1)[CH3:10])=O)(C)(C)C.Cl.O1CCOCC1.C(Cl)Cl>>[ClH:17].[NH2:8][CH:9]([C:11]1[C:12]([O:33][CH2:34][CH3:35])=[C:13]([CH:19]2[CH2:22][N:21]([C:23]([O:25][CH2:26][C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)=[O:24])[CH2:20]2)[C:14]([CH3:18])=[C:15]([Cl:17])[CH:16]=1)[CH3:10]
Reactant: CCOc1c(C(C)NC(=O)OC(C)(C)C)cc(Cl)c(C)c1C1CN(C(=O)OCc2ccccc2)C1
Agent: Cl
Solvent: C1COCCO1
Solvent: ClCCl
Product: CCOc1c(C(C)N)cc(Cl)c(C)c1C1CN(C(=O)OCc2ccccc2)C1

Procedure:
Benzyl 3-(3-{1-[(tert-butoxycarbonyl)amino]ethyl}-5-chloro-2-ethoxy-6-methylphenyl)azetidine-1-carboxylate (65 mg, 0.13 mmol, second peak from chiral separation in previous step) was treated with 4.0 M HCl in dioxane (0.4 mL, 2 mmol) in methylene chloride (0.4 mL, 6 mmol) at room temperature for 2 hours. The reaction mixture was evaporated to dryness to give benzyl 3-[3-[1-aminoethyl]-5-chloro-2-ethoxy-6-methylphenyl]azetidine-1-carboxylate hydrochloride. LCMS calculated for C22H28ClN2O3 (M+H)+: m/z=4012. found: 403.1. A mixture of the above HCl salt, 6-bromo-9H-purine (31 mg, 0.16 mmol) and DIPEA (0.11 mL, 0.65 mmol) in ethanol (1 mL) was heated at 100° C. overnight. The mixture was diluted with sat. NaHCO3 solution, extracted with dichloromethane. The combined organic layers were dried over MgSO4 and concentrated to give the desired product (83 mg). LCMS calculated for C27H30ClN6O3 (M+H)+: m/z=521.2. found: 521.1.
Reaction SMILES: [C:1]1(=[O:7])[O:6][C:4](=[O:5])[CH:3]=[CH:2]1.S(Cl)(Cl)=O.C(Cl)(Cl)(Cl)Cl.[CH2:17]([OH:19])[CH3:18]>>[C:4]([O:19][CH2:17][CH3:18])(=[O:5])/[CH:3]=[CH:2]/[C:1]([OH:6])=[O:7]
Reactant: O=C1C=CC(=O)O1
Reactant: CCO
Solvent: ClC(Cl)(Cl)Cl
Solvent: O=S(Cl)Cl
Product: CCOC(=O)/C=C/C(=O)O

Procedure:
Maleic anhydride (100.0 g, 1.02 mole) was dissolved in anhydrous ethanol (60 ml, excess) by heating the mixture in an erlenmeyer flask on a steam bath. Thionyl chloride (1.0 ml) was added using a syringe and the mixture heated with stirring for ten minutes. To the turbid mixture was added carbon tetrachloride (100 ml) and the liquid quickly filtered through a Buchner funnel having a coarse glass frit. The solid was discarded. The filtrate was allowed to cool during which the time the ethyl hydrogen fumarate product (92 g, 63%) crystallized.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:6](=[O:17])[S:7][C:8]2[C:13]([C:14]=1[OH:15])=[CH:12][CH:11]=[C:10](Br)[CH:9]=2)=[O:4].[F:18][C:19]([F:30])([F:29])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1B(O)O>>[CH3:1][O:2][C:3]([C:5]1[C:6](=[O:17])[S:7][C:8]2[C:13]([C:14]=1[OH:15])=[CH:12][CH:11]=[C:10]([C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=1[C:19]([F:30])([F:29])[F:18])[CH:9]=2)=[O:4]
Reactant: COC(=O)c1c(O)c2ccc(Br)cc2sc1=O
Reactant: OB(O)c1ccccc1C(F)(F)F
Product: COC(=O)c1c(O)c2ccc(-c3ccccc3C(F)(F)F)cc2sc1=O

Procedure:
4-Hydroxy-2-oxo-7-(2-trifluoromethyl-phenyl)-2H-thiochromene-3-carboxylic acid methyl ester was prepared from 7-bromo-4-hydroxy-2-oxo-2H-thiochromene-3-carboxylic acid methyl ester (Example 5 e) under conditions analogous to Example 7(a) using 2-trifluoromethyl-phenylboronic acid. 1H NMR (200 MHz, CDCl3): δ (ppm)=8.376 (d, 1H), 7.783-7.295 (m, 6H), 4.024 (s, 3H).
Reaction SMILES: [CH3:1][C:2]1[N:6]=[C:5]([CH3:7])[S:4][C:3]=1/[CH:8]=[CH:9]/[C:10](N(C)C)=O.[N+]([O-])(O)=O.[F:19][C:20]1[CH:25]=[C:24]([F:26])[CH:23]=[CH:22][C:21]=1[NH:27][C:28]([NH2:30])=[NH:29].[OH-].[Na+]>COCCO>[F:19][C:20]1[CH:25]=[C:24]([F:26])[CH:23]=[CH:22][C:21]=1[NH:27][C:28]1[N:30]=[C:8]([C:3]2[S:4][C:5]([CH3:7])=[N:6][C:2]=2[CH3:1])[CH:9]=[CH:10][N:29]=1
Reactant: Cc1nc(C)c(/C=C/C(=O)N(C)C)s1
Reactant: N=C(N)Nc1ccc(F)cc1F
Agent: [Na+]
Agent: [OH-]
Solvent: O=[N+]([O-])O
Solvent: COCCO
Product: Cc1nc(C)c(-c2ccnc(Nc3ccc(F)cc3F)n2)s1
Yield: 78.5 %

Procedure:
A mixture of 3-dimethylamino-1-(2,4-dimethyl-thiazol-5-yl)-propenone (1.0 mmol, 0.21 g) and N-(2,4-difluoro-phenyl)-guanidine nitrate (2 mmol, 0.47 g) in 2-methoxyethanol (5 mL) was treated with NaOH (40 mg). After 24 h refluxing under N2 the solvent was evaporated to dryness and the residue was purified by flash chromatography (EtOAc/PE, 2:1) and recrystallisation from EtOAc/PE to afford the title compound as a brown powder (250 mg, 79%). 1H-NMR (300 MHz, CDCl3) δ2.69 (s, 3H, CH3), 2.71 (s, 3H, CH3), 6.93 (d, 1H, J=5.3 Hz, pyrimidinyl-H), 7.01 (m, 2H, Ph-H), 7.58 (m, 2H, Ph-H), 8.40 (d, 1H, J=5.3 Hz, pyrimidinyl-H).
Reaction SMILES: [CH2:1]([S:4]([NH:7][CH:8]1[CH2:16][C:15]2[C:10](=[CH:11][CH:12]=[C:13]([C:17]3[CH:18]=[CH:19][C:20](=[O:23])[NH:21][N:22]=3)[CH:14]=2)[CH2:9]1)(=[O:6])=[O:5])[CH2:2][CH3:3].[CH3:24]I>>[CH2:1]([S:4]([NH:7][CH:8]1[CH2:16][C:15]2[C:10](=[CH:11][CH:12]=[C:13]([C:17]3[CH:18]=[CH:19][C:20](=[O:23])[N:21]([CH3:24])[N:22]=3)[CH:14]=2)[CH2:9]1)(=[O:6])=[O:5])[CH2:2][CH3:3]
Reactant: CCCS(=O)(=O)NC1Cc2ccc(-c3ccc(=O)[nH]n3)cc2C1
Reactant: CI
Product: CCCS(=O)(=O)NC1Cc2ccc(-c3ccc(=O)n(C)n3)cc2C1

Procedure:
2-n-Propylsulfonylamino-5-[pyridazin-3(2H)-on-6-yl]indane and methyl iodide were reacted in the same manner as in Example 91 to obtain 2-n-propylsulfonylamino-5-[2-methylpyridazin-3(2H)-on-6-yl]indane.
Reaction SMILES: [C:1]1([C:7]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[N:8][NH:9][C:10]2[CH:15]=[CH:14][C:13]([CH3:16])=[CH:12][CH:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Br[CH2:24][CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>>[C:17]1([C:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)=[N:8][N:9]([CH2:24][CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[C:10]2[CH:11]=[CH:12][C:13]([CH3:16])=[CH:14][CH:15]=2)[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: Cc1ccc(NN=C(c2ccccc2)c2ccccc2)cc1
Reactant: BrCCc1ccccc1
Product: Cc1ccc(N(CCc2ccccc2)N=C(c2ccccc2)c2ccccc2)cc1

Procedure:
General procedure B was used to convert 1-(diphenylmethylene)-2-p-tolylhydrazine (200 mg, 0.69 mmol; Example 36A) and 2-bromoethylbenzene (210 mg, 0.69 mmol; Aldrich) to the title compound: MS (DCI/NH3) m/z 391 (M+H)+.