Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][N:2]1[C:6](=[O:7])[C:5]2=[CH:8][CH:9]=[CH:10][CH:11]=[C:4]2[C:3]1=[O:12].[F:13][CH:14]([F:17])[CH2:15]O>>[F:13][CH:14]([F:17])[CH2:15][O:1][N:2]1[C:3](=[O:12])[C:4]2[C:5](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6]1=[O:7]
Reactant: OCC(F)F
Reactant: O=C1c2ccccc2C(=O)N1O
Product: O=C1c2ccccc2C(=O)N1OCC(F)F
Yield: 52 %

Procedure:
N-Hydroxyphthalimide and 2,2-difluoro-ethanol were reacted as described for compound LXI in Example 27, affording XCVIII in 52% yield. 400 MHz 1H NMR (DMSO-d6, ppm) 7.92-7.85 (4H, m), 6.34 (1H, tt, J=54.4, 3.9 Hz), 4.46 (2H, td, J=14.1, 3.9 Hz).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([N:8]2[CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)[CH:5]=[CH:6][CH:7]=1.[CH2:14]1[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH2:17][CH2:16][N:15]1[CH2:24][CH:25]([OH:34])[CH2:26][N:27]1[CH2:32][CH2:31][NH:30][CH2:29][C:28]1=[O:33].CC(C1C=C(C(C)C)C(C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)=C(C(C)C)C=1)C.CC([O-])(C)C.[Na+]>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].O1CCOCC1>[CH2:14]1[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH2:17][CH2:16][N:15]1[CH2:24][CH:25]([OH:34])[CH2:26][N:27]1[CH2:32][CH2:31][N:30]([C:2]2[CH:7]=[CH:6][CH:5]=[C:4]([N:8]3[CH2:13][CH2:12][O:11][CH2:10][CH2:9]3)[CH:3]=2)[CH2:29][C:28]1=[O:33]
Reactant: O=C1CNCCN1CC(O)CN1CCc2ccccc2C1
Reactant: Brc1cccc(N2CCOCC2)c1
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Solvent: C1COCCO1
Product: O=C1CN(c2cccc(N3CCOCC3)c2)CCN1CC(O)CN1CCc2ccccc2C1
Temperature: 100 °C
Yield: 1.7 %

Procedure:
4-(3-bromophenyl)morpholine (100 mg, 0.413 mmol), 1-(3-(3,4-dihydroisoquinolin-2(1H)-yl)-2-hydroxypropyl)piperazin-2-one (119 mg, 0.413 mmol), Xphos (20 mg, 0.042 mmol), Pd(dba)2 (10 mg, 0.017 mmol) and NaOtBu (59.0 mg, 0.615 mmol) and dioxane (5 mL) were combined in a three-neck flask with a condenser and magnetic stirring bar, the system was degassed (N2) and dioxane (10 mL) was added. The reaction mixture was heated at 100° C. for 16 h, filtered and concentrated. The residue was purified by preparative HPLC purification. (3.2 mg, yield 1.7%). 1H NMR (MeOD, 400 MHz), δ ppm: 7.21-7.15 (m, 1H), 7.15-7.07 (m, 3H), 7.07-7.00 (m, 1H), 6.58-6.45 (m, 3H), 4.22 (br. s., 1H), 3.86-3.82 (m, 6H), 3.78-3.69 (m, 4H), 3.68-3.59 (m, 1H), 3.56-3.46 (m, 2H), 3.31-3.26 (m, 1H), 3.16-3.12 (m, 4H), 2.98-2.90 (m, 2H), 2.90-2.78 (m, 2H), 2.60 (d, J=6.0 Hz, 2H).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[S:11]([N:14]=[C:15]=[O:16])(=[O:13])=[O:12])=[O:4].[NH2:17][C:18]1[N:23]=[C:22]([F:24])[CH:21]=[C:20]([O:25][C:26]([F:29])([F:28])[F:27])[N:19]=1>ClCCCl>[F:24][C:22]1[CH:21]=[C:20]([O:25][C:26]([F:29])([F:27])[F:28])[N:19]=[C:18]([NH:17][C:15]([NH:14][S:11]([C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[C:3]([O:2][CH3:1])=[O:4])(=[O:12])=[O:13])=[O:16])[N:23]=1
Reactant: COC(=O)c1ccccc1S(=O)(=O)N=C=O
Reactant: Nc1nc(F)cc(OC(F)(F)F)n1
Solvent: ClCCCl
Product: COC(=O)c1ccccc1S(=O)(=O)NC(=O)Nc1nc(F)cc(OC(F)(F)F)n1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
3.6 g (0.015 mol) of 2-methoxycarbonylbenzenesulfonyl isocyanate in 15 ml of 1,2-dichloroethane were added over the course of 15 minutes to a stirred mixture of 2.95 g (0.015 mol) of 2-amino-4-fluoro-6-trifluoromethoxypyrimidine and 100 ml of 1,2-dichloroethane at 25° C., and the mixture was stirred at 25° C. for 12 hours. The solution was concentrated under reduced pressure, and the residue was stirred with 1:1 ether/petroleum ether. Filtration with suction and drying yielded 4.8 g (73.3% of theory) of the title compound of melting point 157°-161° C.
Reaction SMILES: [CH3:1][N:2]1[C:7](SC)=[N:6][C:5](=[O:10])[C:4]([C:11]2[CH:16]=[CH:15][C:14]([CH3:17])=[CH:13][CH:12]=2)=[N:3]1.[Na].[CH3:19][OH:20]>>[CH3:1][N:2]1[C:7]([O:20][CH3:19])=[N:6][C:5](=[O:10])[C:4]([C:11]2[CH:16]=[CH:15][C:14]([CH3:17])=[CH:13][CH:12]=2)=[N:3]1
Reactant: CO
Reactant: CSc1nc(=O)c(-c2ccc(C)cc2)nn1C
Agent: [Na]
Product: COc1nc(=O)c(-c2ccc(C)cc2)nn1C
Yield: 86 %

Procedure:
2-Methyl-3-methylthio-6-(p-methylphenyl)-5-oxo-2,5-dihydro-1,2,4-triazine (1.0 g) was added in a solution of metallic sodium (0.1 g) in methanol (10 ml), and the resultant mixture was stirred at room temperature for 2 hours. After stirring, the resulting mixture was evaporated to dryness to give a crude product. Recrystallization of the crude product from acetone gave 0.8 g of 2-methyl-3-methoxy-6-(p-methylphenyl)-5-oxo-2,5-dihydro-1,2,4-triazine in 86% yield. M.P., 159° C.
Reaction SMILES: [CH3:1][Si:2]([CH3:13])([CH3:12])[C:3]1[CH:4]=[C:5]2[CH2:11][CH2:10][NH:9][C:6]2=[N:7][CH:8]=1>C(Cl)Cl.O=[Mn]=O>[CH3:1][Si:2]([CH3:13])([CH3:12])[C:3]1[CH:4]=[C:5]2[CH:11]=[CH:10][NH:9][C:6]2=[N:7][CH:8]=1
Reactant: C[Si](C)(C)c1cnc2c(c1)CCN2
Agent: O=[Mn]=O
Solvent: ClCCl
Product: C[Si](C)(C)c1cnc2[nH]ccc2c1
Yield: 89.3 %

Procedure:
To a stirred solution of the azaindoline 21 (20 mg, 0.10 mmol) in CH2Cl2 (2 mL) was added oven activated MnO2 (9 mg, 0.10 mmol) in one portion. After 18 h the mixture was filtered through a silica pad. The pad was washed with AcOEt and the combined organic solutions evaporated to afford the azaindole 22 (17 mg, 86%). 1H NMR (400 MHz; CDCl3) δ 0.35 (s, 9H), 6.50 (d, J=3.5 Hz, 1H), 7.35 (d, J=3.5 Hz, 1H), 8.10 (d, J=1.5 Hz, 1H), 8.40 (d, J=1.5 Hz, 1H), 10.62 (br s, NH).
Reaction SMILES: [OH:1][C:2]1[C:9](/[CH:10]=[CH:11]/[CH3:12])=[CH:8][C:5]([C:6]#[N:7])=[CH:4][C:3]=1[N+:13]([O-])=O>C(OCC)(=O)C.[Pd]>[NH2:13][C:3]1[CH:4]=[C:5]([CH:8]=[C:9]([CH2:10][CH2:11][CH3:12])[C:2]=1[OH:1])[C:6]#[N:7]
Reactant: C/C=C/c1cc(C#N)cc([N+](=O)[O-])c1O
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CCCc1cc(C#N)cc(N)c1O
Temperature: 25 °C
Reaction time: 14 h
Yield: 26 %

Procedure:
To a solution of 1.78 g of 4-hydroxy-3-nitro-5-[(1E)-prop-1-en-1-yl]benzonitrile in ethyl acetate (10 ml) was added palladium on carbon (100 mg). This mixture was evacuated and flushed with hydrogen (via balloon) 10 times. The reaction was stirred at room temperature for 14 h under hydrogen. The mixture was then filtered through a plug of Celite, eluting with methanol. After concentration of the eluent in vacuo, the residue was further purified by column chromatography on a Biotage Horizon, eluting with 1 column volume of 100% hexanes followed by a gradient of 0-20% ethyl acetate in hexanes over 10 column volumes to provide the title compound (400 mg, 26%). Mass spectrum (ESI) 177.2 (M+1).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]([C:18]2[S:19][CH:20]=[CH:21][C:22]=2Br)=[N:15][NH:16][CH3:17])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]>COC(O)C>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[C:18]3[S:19][CH:20]=[CH:21][C:22]=3[N:16]([CH3:17])[N:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CNN=C(c1sccc1Br)C1CCN(C(=O)OC(C)(C)C)CC1
Agent: COC(C)O
Product: Cn1nc(C2CCN(C(=O)OC(C)(C)C)CC2)c2sccc21
Temperature: 70 °C
Reaction time: 8 h
Yield: 93 %

Procedure:
4-[(3-Bromo-thiophen-2-yl)-(methyl-hydrazono)-methyl]-piperidine-1-carboxylic acid tert-butyl ester (700 mg, 1.74 mmol) was mixed with Cul (20 mg), CsCO3 (650 mg, 1.15 eq) in methoxyethanol (10 mL). The mixture was heated to 70° C. for 2 hr. then stirred overnight at room temperature. The solvent was stripped on rotary evaporator. The residue was extracted into EtOAc then washed with brine and concentrated down to an oil. This oil was purified via chromatography (eluted with 0–10% MeOH in DCM) yielding 520 mg (68%) of the desired product.
Reaction SMILES: [Cl:1]N1C(=O)CCC1=O.[C:9]([O:12][C:13]1[CH:18]=[CH:17][C:16]([C@H:19]([NH:21][C:22](=[O:24])[CH3:23])[CH3:20])=[CH:15][C:14]=1[O:25][CH3:26])(=[O:11])[CH3:10].S([O-])([O-])(=O)=S.[Na+].[Na+]>CN(C=O)C>[C:9]([O:12][C:13]1[CH:18]=[C:17]([Cl:1])[C:16]([C@H:19]([NH:21][C:22](=[O:24])[CH3:23])[CH3:20])=[CH:15][C:14]=1[O:25][CH3:26])(=[O:11])[CH3:10]
Reactant: O=C1CCC(=O)N1Cl
Reactant: COc1cc([C@@H](C)NC(C)=O)ccc1OC(C)=O
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1cc([C@@H](C)NC(C)=O)c(Cl)cc1OC(C)=O
Temperature: 0 °C
Reaction time: 1 h
Yield: 73.7 %

Procedure:
N-Chlorosuccinimide (2.28 g, 17.1 mmol) was added to a solution of (R)-4-(1-acetamidoethyl)-2-methoxyphenyl acetate (2.86 g, 11.4 mmol) in DMF (50 mL) and the mixture was stirred for 1 hour at 0° C. and then for 15 hours at room temperature. The reaction mixture was poured onto aqueous 20% sodium thiosulfate solution and extracted with DCM 3 times. The combined organic layer was dried over sodium sulfate, filtered and evaporated. The residue was chromatographed on a column of silica gel, eluting with EtOAc-Hexane (1:1) and then MeOH-DCM (1:10), to give a brown solid. The solid was washed with Et2O and dried in vacuo to give the title compound (2.40 g, 74%) as white solid. 1H NMR (270 MHz, CDCl3) δ ppm 1.51 (3H, d, J=7.2 Hz), 2.00 (3H, s), 2.30 (3H, s), 3.83 (3H, s), 5.20-5.40 (1H, m), 5.91 (1H, m), 6.91 (1H, s), 7.06 (1H, s).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][C:6]([C:10]([OH:12])=O)=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.C(N1C=CN=C1)([N:15]1C=CN=C1)=O.[OH-].[NH4+]>CN(C)C=O>[CH:7]1[C:6]([C:10]([NH2:15])=[O:12])=[CH:5][C:4]2[CH:3]=[CH:2][NH:1][C:9]=2[CH:8]=1
Reactant: O=C(O)c1ccc2[nH]ccc2c1
Reactant: O=C(n1ccnc1)n1ccnc1
Agent: [NH4+]
Agent: [OH-]
Solvent: CN(C)C=O
Product: NC(=O)c1ccc2[nH]ccc2c1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of 8.06 gm (50 mMol) indole-5-carboxylic acid in 150 mL dimethylformamide were added 8.11 gm (50 mMol) carbonyldiimidazole and the reaction mixture stirred at ambient temperature for 3 hours. The reaction mixture was then added dropwise to 150 mL concentrated ammonium hydroxide and the reaction mixture was stirred for 18 hours at ambient temperature. The reaction mixture was concentrated under reduced pressure to give a viscous oil which was subjected to silica gel chromatography, eluting with a gradient of dichloromethane containing 0-10% methanol. Fractions shown to contain product were combined and concentrated under reduced pressure to give the title compound as an oil which crystallizes upon standing.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([C:8]([OH:10])=[O:9])[N:3]=1.O=S(Cl)Cl.[CH2:15](O)[CH3:16]>>[NH2:1][C:2]1[N:3]=[C:4]([C:8]([O:10][CH2:15][CH3:16])=[O:9])[CH:5]=[CH:6][CH:7]=1
Reactant: Nc1cccc(C(=O)O)n1
Reactant: CCO
Solvent: O=S(Cl)Cl
Product: CCOC(=O)c1cccc(N)n1
Temperature: 25 °C
Yield: 76 %

Procedure:
To a solution of 2-amino-6-pyridinecarboxylic acid (90; 6.0 g, 43.5 mmol) in ethanol (150 mL) was added SOCl2 (12.0 g, 101 mmol) at 0° C. The resulting reaction mixture was stirred under reflux for 12 h. Upon cooling to room temperature, the reaction mixture was concentrated under reduced pressure. Enough saturated aqueous Na2CO3 solution was added to adjust the pH=9. The mixture was concentrated under reduced pressure and dichloromethane (150 mL) was added to the resulting residue. The mixture was stirred vigorously at room temperature for 30 min and then filtered. The filtrate was concentrated under reduced pressure to afford ethyl 6-aminopicolinate 91 (5.5 g, 76%).
Reaction SMILES: BrBr.COC1C=CC2C(C)CN(C(=O)C(F)(F)F)CCC=2N=1.C([O-])(O)=O.[Na+].[Br:28][C:29]1[C:46]([O:47][CH3:48])=[N:45][C:32]2[CH2:33][CH2:34][N:35](C(=O)C(F)(F)F)[CH2:36][CH:37]([CH3:38])[C:31]=2[CH:30]=1.C([O-])([O-])=O.[K+].[K+]>CO.CCOC(C)=O>[Br:28][C:29]1[C:46]([O:47][CH3:48])=[N:45][C:32]2[CH2:33][CH2:34][NH:35][CH2:36][CH:37]([CH3:38])[C:31]=2[CH:30]=1
Reactant: COc1nc2c(cc1Br)C(C)CN(C(=O)C(F)(F)F)CC2
Agent: BrBr
Agent: COc1ccc2c(n1)CCN(C(=O)C(F)(F)F)CC2C
Agent: O=C([O-])O
Solvent: CO
Solvent: CCOC(C)=O
Product: COc1nc2c(cc1Br)C(C)CNCC2
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Br2 (2.00 ml, 39.2 mmol) was added to a mixture of 2-methoxy-5-methyl-7-(trifluoroacetyl)-6,7,8,9-tetrahydro-5H-pyrido[2,3-d]azepine (113 mg, 392 μmol), Na2HPO4 buffer (40 ml) and MeOH (5 ml). After stirring for 1 h at ambient temperature, the reaction mixture was parted between EtOAc and NaHCO3. The organic phase was washed with brine, dried over Na2SO4 and concentrated in vacuo. Chromatographic purification rendered 152 mg (99%) of 3-bromo-2-methoxy-5-methyl-7-(trifluoroacetyl)-6,7,8,9-tetrahydro-5H-pyrido[2,3-d]azepine. 1H-NMR (CDCl3) δ 7.61 (s, 1H), 4.18-3.82 (m, 5H), 3.63 (m, 1H), 3.56-3.36 (m, 1H), 3.24 (m, 1H), 3.10 (m, 2H), 1.33 (m, 3H) ppm. A mixture of 3-bromo-2-methoxy-5-methyl-7-(trifluoroacetyl)-6,7,8,9-tetrahydro-5H-pyrido[2,3-d]azepine (52.0 mg, 142 μmol) and K2CO3 (100 mg) in MeOH (20 ml) was heated at reflux for 1.5 h. The reaction mixture was parted between EtOAc and NaHCO3. The organic phase was washed with brine, dried over Na2SO4 and concentrated in vacuo. Chromatographic purification rendered 37.5 mg (97%) of 3-bromo-2-methoxy-5-methyl-6,7,8,9-tetrahydro-5H-pyrido[2,3-d]azepine. 1H-NMR (CDCl3) δ 7.55 (s, 1H), 3.97 (s, 3H), 3.10-2.91 (m, 6H), 2.74 (dd, 1H), 1.31 (d, 3H) ppm.
Reaction SMILES: CO[C:3](=O)[C:4]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1OC1C=CC=CC=1)=O.[CH3:20][NH:21][C:22](=[O:40])[C:23]([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1OC1C=CC=CC=1)=[N:24][O:25][CH3:26]>>[CH3:20][NH:21][C:22](=[O:40])/[C:23](/[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1[CH2:3][CH2:4][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[N:24]/[O:25][CH3:26]
Reactant: COC(=O)C(=O)c1ccccc1Oc1ccccc1
Reactant: CNC(=O)C(=NOC)c1ccccc1Oc1ccccc1
Product: CNC(=O)/C(=N/OC)c1ccccc1CCc1ccccc1

Procedure:
Some examples for production of methyl-2-(2-phenoxyphenyl)-2-oxo-acetate, which is the intermediate compound for methyl-2-(2-phenoxyphenyl)-2-methoxyiminoacetamide, are as follows:
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:7]=[N:8][N:9]([CH:15]2[CH2:17][CH2:16]2)[C:10]=1[C:11]([F:14])([F:13])[F:12])=[O:5])C.[Li+].[OH-]>CO.O>[CH:15]1([N:9]2[C:10]([C:11]([F:12])([F:13])[F:14])=[C:6]([C:4]([OH:5])=[O:3])[CH:7]=[N:8]2)[CH2:16][CH2:17]1
Reactant: CCOC(=O)c1cnn(C2CC2)c1C(F)(F)F
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: O=C(O)c1cnn(C2CC2)c1C(F)(F)F
Yield: 105.4 %

Procedure:
To a solution of 1-Cyclopropyl-5-trifluoromethyl-1H-pyrazole-4-carboxylic acid ethyl ester (140 mg, 0.56 mmol) in CH3OH (2 mL) and water (2 mL) was added LiOH (16 mg, 0.67 mmol). The reaction mixture was stirred at reflux overnight, and then the solution was concentrated under reduced pressure to remove the methanol. The residue was diluted with water and the solution was acidified to pH 2 with concentrated HCl. The resulting mixture was then extracted with ethyl acetate three times. The combined organic extracts were concentrated in vacuo to give 1-cyclopropyl-5-trifluoromethyl-1H-pyrazole-4-carboxylic acid (130 mg, quantitative), which was used without further purification.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:13]3[CH2:14][C:15]4[S:16][C:17]([C:20]5[CH:25]=[CH:24][N:23]=[CH:22][CH:21]=5)=[CH:18][C:19]=4[C:12]=3[N:11](COCC[Si](C)(C)C)[N:10]=2)=[CH:5][CH:4]=1.Cl>CO>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([C:9]2[C:13]3[CH2:14][C:15]4[S:16][C:17]([C:20]5[CH:21]=[CH:22][N:23]=[CH:24][CH:25]=5)=[CH:18][C:19]=4[C:12]=3[NH:11][N:10]=2)=[CH:7][CH:8]=1
Reactant: COc1ccc(-c2nn(COCC[Si](C)(C)C)c3c2Cc2sc(-c4ccncc4)cc2-3)cc1
Agent: Cl
Solvent: CO
Product: COc1ccc(-c2n[nH]c3c2Cc2sc(-c4ccncc4)cc2-3)cc1
Temperature: 100 °C
Yield: 96.9 %

Procedure:
6-(4-Methoxy-phenyl)-2-pyridin-4-yl-4-(2-trimethylsilanyl-ethoxymethyl)-4,7-dihydro-1-thia-4,5-diaza-cyclopenta[a]pentalene (0.49 g, 0.98 mmol) was dissolved in MeOH and treated with concentrated HCl (0.3 mL, 9.4 mmol). The reaction mixture was heated at 100° C. for 4 hr. The solution was cooled to room temperature and the resultant precipitate was filtered, washed with MeOH and concentrated under reduced pressure to provide the corresponding 6-(4-Methoxy-phenyl)-2-pyridin-4-yl-4,7-dihydro-1-thia-4,5-diaza-cyclopenta[a]pent alene (0.35 g, 0.95 mmol) as brown solid in 98% yield.
Reaction SMILES: ClN1C(=O)CCC1=O.[Cl:9][C:10]1[CH:15]=[CH:14][C:13]([SH:16])=[CH:12][CH:11]=1.[S:17]1[CH:21]=[CH:20][CH:19]=[C:18]1[Li].C([Li])CCC.S1C=CC=C1>C1(C)C=CC=CC=1.O1CCCC1>[Cl:9][C:10]1[CH:15]=[CH:14][C:13]([S:16][C:18]2[S:17][CH:21]=[CH:20][CH:19]=2)=[CH:12][CH:11]=1
Reactant: Sc1ccc(Cl)cc1
Reactant: [Li]c1cccs1
Agent: O=C1CCC(=O)N1Cl
Agent: [Li]CCCC
Solvent: c1ccsc1
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: Clc1ccc(Sc2cccs2)cc1
Temperature: -15 °C
Reaction time: 1 h

Procedure:
To a suspension of N-chlorosuccinimide (10.78 g) in dry toluene (45 ml) was added dropwise, a solution of 4-chlorothiophenol (9.84 g) in dry toluene (35 ml) at room temperature. After 1 hour, the suspension was filtered, the filter pad washed with toluene (100 ml) and the filtrate evaporated under reduced pressure to give an orange oil. The oil was dissolved in dry tetrahydrofuran (40 ml) and added dropwise to a solution of 2-thienyllithium (prepared by the addition of n-butyllithium (27.2 ml, 2.5M) to thiophene (5.72 g) in dry tetrahydrofuran (60 ml) at -15° C. under nitrogen and stirred for 2 hours) at -15° C. under nitrogen. The solution was stirred for 1 hour, allowed to warm to room temperature and stirred overnight. The reaction mixture was poured onto ice, extracted with ether (3×100 ml), dried over MgSO4 and evaporated under reduced pressure to give a brown oil. The oil was flash chromatographed on a Sorbsil C 60-40/60H column using petroleum ether (40°-60° C.) to give a colourless oil.
Reaction SMILES: [CH2:1]([O:3][CH:4]([O:6][CH:7]([CH:10]([O:23][CH3:24])[C:11]1[CH:16]=[CH:15][C:14]([N:17]2[CH2:22][CH2:21][O:20][CH2:19][CH2:18]2)=[CH:13][CH:12]=1)[C:8]#[N:9])[CH3:5])[CH3:2].[NH2:25][OH:26].Cl.C([O-])(O)=O.[Na+]>CO>[CH2:1]([O:3][CH:4]([O:6][CH:7]([CH:10]([O:23][CH3:24])[C:11]1[CH:16]=[CH:15][C:14]([N:17]2[CH2:18][CH2:19][O:20][CH2:21][CH2:22]2)=[CH:13][CH:12]=1)/[C:8](=[N:25]/[OH:26])/[NH2:9])[CH3:5])[CH3:2]
Reactant: CCOC(C)OC(C#N)C(OC)c1ccc(N2CCOCC2)cc1
Reactant: NO
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Product: CCOC(C)OC(/C(N)=N/O)C(OC)c1ccc(N2CCOCC2)cc1
Temperature: 75 °C
Reaction time: 16 h

Procedure:
To a solution of 2-(1-ethoxyethoxy)-3-methoxy-3-(4-morpholinophenyl)propanenitrile (0.60 g, 1.8 mmol) in anhydr MeOH (10 mL) under argon was added NH2OH.HCl (0.175 g, 2.5 mmol) and NaHCO3 (0.234 g, 2.8 mmol). The reaction was heated briefly at 75° C. then at 60° C. for 16 hrs. After cooling to room temp, the mixture was concentrated in vacuo to give (Z)-2-(1-ethoxyethoxy)-N′-hydroxy-3-methoxy-3-(4-morpholinophenyl)propanimidamide which was used in the next synthetic step without further purification (0.777 g).
Reaction SMILES: [Na].O=C1O[C@H]([C@H](CO)O)C(O)=C1O.[CH2:14]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH2:16][CH:15]1[NH:23][C:24]1[N:25]=[CH:26][C:27]2[CH2:33][N:32]([C:34](=[O:41])[CH2:35][CH2:36][O:37][CH2:38][C:39]#[CH:40])[CH2:31][CH2:30][C:28]=2[N:29]=1.[N:42]([Si](C)(C)C)=[N+:43]=[N-:44]>CN(C)C=O.O.C(OCC)(=O)C.O.O.O.O.O.S([O-])([O-])(=O)=O.[Cu+2]>[CH2:14]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH2:16][CH:15]1[NH:23][C:24]1[N:25]=[CH:26][C:27]2[CH2:33][N:32]([C:34](=[O:41])[CH2:35][CH2:36][O:37][CH2:38][C:39]3[N:42]=[N:43][NH:44][CH:40]=3)[CH2:31][CH2:30][C:28]=2[N:29]=1
Reactant: C[Si](C)(C)N=[N+]=[N-]
Reactant: C#CCOCCC(=O)N1CCc2nc(NC3Cc4ccccc4C3)ncc2C1
Agent: [Cu+2]
Agent: O=C1O[C@H]([C@@H](O)CO)C(O)=C1O
Agent: O=S(=O)([O-])[O-]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CN(C)C=O
Product: O=C(CCOCc1c[nH]nn1)N1CCc2nc(NC3Cc4ccccc4C3)ncc2C1
Yield: 43.5 %

Procedure:
Add copper(II) sulfate pentahydrate (0.037 g; 0.2 equiv; 0.147 mmoles) and L-ascorbic acid sodium salt (0.291 g; 2.0 equiv; 1.47 mmoles) to a solution of 1-[2-(2,3-dihydro-1H-inden-2-ylamino)-7,8-dihydropyrido[4,3-d]pyrimidin-6(5H)-yl]-3-(prop-2-yn-1-yloxy)propan-1-one (0.277 g; 1.0 equiv; 0.74 mmoles) in dimethylformamide (4 mL) and water (4 mL). Evacuate the system twice and backfill with nitrogen. Add azidotrimethylsilane (0.784 mL; 8.0 equiv; 5.89 mmoles) and heat the heterogeneous mixture to 90° C. for 1 hour. Dilute the reaction mixture with water (250 mL) and ethyl acetate (50 mL) and extract with ethyl acetate (3×50 mL). Wash the combined organic extracts with brine (30 mL), dry over sodium sulfate, filter, and concentrate in vacuo to a yellow/orange oil. Purify the crude product by column chromatography (ethyl acetate to 10% methanol in ethyl acetate) to afford the desired 1-[2-(2,3-dihydro-1H-inden-2-ylamino)-7,8-dihydropyrido[4,3-d]pyrimidin-6(5H)-yl]-3-(1H-1,2,3-triazol-4-ylmethoxy)propan-1-one (0.135 g; 44%): MS (m/z): 420 (M+1).
Reaction SMILES: CS[C:3]1[S:4]/[C:5](=[CH:9]\[C:10]2[CH:11]=[C:12]3[C:17](=[CH:18][CH:19]=2)[N:16]=[CH:15][CH:14]=[CH:13]3)/[C:6](=[O:8])[N:7]=1.[CH2:20]([O:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[CH2:29][CH2:30][NH2:31])[CH3:21].CCN(C(C)C)C(C)C>>[CH2:20]([O:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[CH2:29][CH2:30][NH:31][C:3]1[S:4]/[C:5](=[CH:9]\[C:10]2[CH:11]=[C:12]3[C:17](=[CH:18][CH:19]=2)[N:16]=[CH:15][CH:14]=[CH:13]3)/[C:6](=[O:8])[N:7]=1)[CH3:21]
Reactant: CSC1=NC(=O)/C(=C/c2ccc3ncccc3c2)S1
Reactant: CCOc1ccccc1CCN
Solvent: CCN(C(C)C)C(C)C
Product: CCOc1ccccc1CCNC1=NC(=O)/C(=C/c2ccc3ncccc3c2)S1

Procedure:
Similar procedure as described in example 1b was used, starting from 2-methylsulfanyl-5-[1-quinolin-6-yl-meth-(Z)-ylidene]-thiazol-4-one, 2-(2-Ethoxy-phenyl)-ethylamine and DIEA to give 2-[2-(2-ethoxy-phenyl)-ethylamino]-5-[1-quinolin-6-yl-meth-(Z)-ylidene]-thiazol-4-one. LC-MS m/e 404 (MH+).
Reaction SMILES: Br[C:2]1[CH:17]=[CH:16][C:5]([CH2:6][N:7]2[CH2:12][CH2:11][NH:10][CH:9]([CH:13]([CH3:15])[CH3:14])[CH2:8]2)=[CH:4][CH:3]=1.[F:18][C:19]([F:30])([F:29])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1B(O)O.C(=O)([O-])[O-].[Na+].[Na+].C1(C)C=CC=CC=1>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C(O)C>[CH:13]([CH:9]1[NH:10][CH2:11][CH2:12][N:7]([CH2:6][C:5]2[CH:16]=[CH:17][C:2]([C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=3[C:19]([F:30])([F:29])[F:18])=[CH:3][CH:4]=2)[CH2:8]1)([CH3:15])[CH3:14]
Reactant: OB(O)c1ccccc1C(F)(F)F
Reactant: CC(C)C1CN(Cc2ccc(Br)cc2)CCN1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: Cc1ccccc1
Product: CC(C)C1CN(Cc2ccc(-c3ccccc3C(F)(F)F)cc2)CCN1
Temperature: 120 °C

Procedure:
100 mg of 1-(4-bromo-benzyl)-3-isopropyl-piperazine could be combined with 1 equiv. of 2-trifluoromethylphenyl boronic acid, 10 mol % of tetrakis(triphenylphosphine)palladium(0), 2M sodium carbonate solution, toluene and ethanol. The reaction mixture could be heated in a sealed tube at 120° C. overnight. The reaction mixture could be filtered through Celite and concentrated in vacuo. The residue could be diluted with water and extracted with ethyl acetate. The combined organic phases could be washed with brine, dried over sodium sulfate, filtered and concentrated in vacuo. The crude material could be purified by flash chromatography to afford 3-isopropyl-1-(2′-trifluoromethyl-biphenyl-4-ylmethyl)-piperazine.