Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([C@@H:9]2[C:14]([C:15]#[N:16])=[C:13]([CH3:17])[N:12]([C:18]3[CH:23]=[CH:22][CH:21]=[C:20]([C:24]([F:27])([F:26])[F:25])[CH:19]=3)[C:11](=[O:28])[NH:10]2)=[C:5]([N+:29]([O-])=O)[CH:4]=1)#[N:2]>C(O)C.[Pd]>[NH2:29][C:5]1[CH:4]=[C:3]([C:1]#[N:2])[CH:8]=[CH:7][C:6]=1[C@@H:9]1[C:14]([C:15]#[N:16])=[C:13]([CH3:17])[N:12]([C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([C:24]([F:27])([F:26])[F:25])[CH:19]=2)[C:11](=[O:28])[NH:10]1
Reactant: CC1=C(C#N)[C@@H](c2ccc(C#N)cc2[N+](=O)[O-])NC(=O)N1c1cccc(C(F)(F)F)c1
Agent: [Pd]
Solvent: CCO
Product: CC1=C(C#N)[C@@H](c2ccc(C#N)cc2N)NC(=O)N1c1cccc(C(F)(F)F)c1
Reaction time: 2 h

Procedure:
Under argon, (4R)-4-(4-cyano-2-nitrophenyl)-6-methyl-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2,3,4-tetrahydropyrimidine-5-carbonitrile (39.5 g, 92.4 mmol) was dissolved in ethanol (1975 ml). 10% Palladium on activated carbon (19.8 g) was then added, and the mixture was hydrogenated at RT and atmospheric pressure for 2 h (strictly monitored by TLC). The reaction mixture was then filtered through kieselguhr. The filtrate was concentrated and the crude product obtained was subjected to flash chromatography on silica gel (mobile phase: ethyl acetate/cyclohexane 2:1). The title compound was obtained as a solid (25.5 g, 68% of theory).
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH3:12])=[N:4][C:5]2[N:6]([N:9]=[CH:10][CH:11]=2)[C:7]=1Cl.C1OCCOCCOCCOCCOCCOC1.[F-:31].[K+].O>CC#N>[Cl:1][C:2]1[C:3]([CH3:12])=[N:4][C:5]2[N:6]([N:9]=[CH:10][CH:11]=2)[C:7]=1[F:31]
Reactant: Cc1nc2ccnn2c(Cl)c1Cl
Reactant: [F-]
Agent: C1COCCOCCOCCOCCOCCO1
Agent: [K+]
Solvent: CC#N
Solvent: O
Product: Cc1nc2ccnn2c(F)c1Cl
Reaction time: 17 h

Procedure:
A mixture of 6,7-dichloro-5-methylpyrazolo[1,5-a]pyrimidine (1.00 equivalent), 18-crown-6 (5 mol %), and KF (3.00 equivalents) in MeCN is heated under reflux with stirring. After 17 hours, the reaction mixture is poured into water, extracted with EtOAc, dried (MgSO4), and concentrated. The product is purified by flash chromatography as necessary.
Reaction SMILES: C(O)(C(F)(F)F)=O.[F:8][C:9]1([F:46])[CH2:11][CH:10]1[C:12]([NH:14][C:15]1[CH:16]=[C:17]2[C:21](=[CH:22][CH:23]=1)[N:20](C1CCCCO1)[N:19]=[C:18]2[C:30]1[NH:34][C:33]2[CH:35]=[CH:36][C:37]([N:39]3[CH2:44][CH2:43][CH:42]([CH3:45])[CH2:41][CH2:40]3)=[CH:38][C:32]=2[N:31]=1)=[O:13]>C(Cl)Cl>[F:46][C:9]1([F:8])[CH2:11][CH:10]1[C:12]([NH:14][C:15]1[CH:16]=[C:17]2[C:21](=[CH:22][CH:23]=1)[NH:20][N:19]=[C:18]2[C:30]1[NH:34][C:33]2[CH:35]=[CH:36][C:37]([N:39]3[CH2:40][CH2:41][CH:42]([CH3:45])[CH2:43][CH2:44]3)=[CH:38][C:32]=2[N:31]=1)=[O:13]
Reactant: CC1CCN(c2ccc3[nH]c(-c4nn(C5CCCCO5)c5ccc(NC(=O)C6CC6(F)F)cc45)nc3c2)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC1CCN(c2ccc3[nH]c(-c4n[nH]c5ccc(NC(=O)C6CC6(F)F)cc45)nc3c2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 79.3 %

Procedure:
TFA (0.432 mL, 5.61 mmol) was added to solution of 2,2-difluoro-N-(3-(5-(4-methylpiperidin-1-yl)-1H-benzo[d]imidazol-2-yl)-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-5-yl)cyclopropanecarboxamide (30 mg, 0.056 mmol) in CH2Cl2 (5 mL). The reaction mixture was stirred overnight at room temperature, and then the solvent was removed in vacuo. Purification by flash chromatography (5% CH3OH/CH2Cl2) afforded the title compound (20 mg) as an off-white solid. 1H NMR: (400 MHz, CD3OD): δ 8.48 (d, 1H, J=1.2 Hz), 7.43 (dd, 1H, J=1.2 and 8.8 Hz), 7.55 (m, 2H), 7.20 (d, 1H, J=2.0 Hz), 7.06 (dd, 1H, J=2.0 and 9.2 Hz), 3.59 (m, 2H), 2.73 (m, 3H), 2.13 (m, 1H), 1.89-1.77 (m, 3H), 1.53-1.37 (m, 3H), 1.00 (d, 3H, J=6.0 Hz); ESI-MS [M+H]+: 451.2.
Reaction SMILES: [CH3:1][CH:2]([CH3:12])[C:3]([NH:5][C:6]1[CH:10]=[CH:9][N:8]([CH3:11])[CH:7]=1)=[O:4].[H-].[Na+].I[CH3:16].O>CN(C)C=O>[CH3:16][N:5]([C:6]1[CH:10]=[CH:9][N:8]([CH3:11])[CH:7]=1)[C:3](=[O:4])[CH:2]([CH3:12])[CH3:1]
Reactant: CC(C)C(=O)Nc1ccn(C)c1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)C(=O)N(C)c1ccn(C)c1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
2-Methyl-N-(1-methylpyrrol-3-yl)propanamide (2.50 g, 0.015 mol) in dry dimethylformamide (10 ml) was cooled to below 0° C. and stirred under nitrogen during the addition of 50% sodium hydride/oil (0.73 g, 0.0152 mol). After the addition, the mixture was stirred at 0° C. for 30 minutes and then brought to 15° C. when iodomethane (4.30 g, 0.0302 mol) was added. The mixture was stirred at room temperature overnight and then poured into water (200 ml) and the mixture extracted with ether (4 × 50 ml). The combined extracts were washed with water (3 × 50 ml) and dried over magnesium sulphate. The solvent was removed in vacuo to leave a solid which separated from pentane at -10° C as white flakes (2.11 g, 78%).
Reaction SMILES: [I:1][C:2]1[C:19](=[O:20])[N:18]([CH3:21])[C:5]2[CH2:6][CH2:7][N:8](C(=O)C(F)(F)F)[CH2:9][CH:10]([CH3:11])[C:4]=2[CH:3]=1.C([O-])([O-])=O.[K+].[K+]>CO>[I:1][C:2]1[C:19](=[O:20])[N:18]([CH3:21])[C:5]2[CH2:6][CH2:7][NH:8][CH2:9][CH:10]([CH3:11])[C:4]=2[CH:3]=1
Reactant: CC1CN(C(=O)C(F)(F)F)CCc2c1cc(I)c(=O)n2C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: CC1CNCCc2c1cc(I)c(=O)n2C
Temperature: 60 °C
Yield: 55.4 %

Procedure:
A mixture of 3-iodo-1,5-dimethyl-7-(trifluoroacetyl)-1,5,6,7,8,9-hexahydro-2H-pyrido[2,3-d]azepin-2-one (41.9 mg, 101 μmol), K2CO3 (28.0 mg, 202 μmol) and MeOH (8 ml) was heated for 5 h at 60° C. The reaction mixture was concentrated in vacuo and purified by column chromatography to furnish 17.8 mg (55%) of 3-iodo-1,5-dimethyl-1,5,6,7,8,9-hexahydro-2H-pyrido[2,3-d]azepin-2-one. 1H-NMR (DMSO-d6) δ 7.83 (s, 1H), 3.57 (s, 3H), 2.99 (m, 2H), 2.87 (ddd, 1H), 2.78 (m, 3H), 2.47 (dd, 1H), 1.15 (d, 3H) ppm.
Reaction SMILES: [CH2:1]([N:8]1[N:12]=[N:11][C:10]([C@@H:13]2[C@@H:17]([OH:18])[C@@H:16]([OH:19])[C@H:15]([N:20]3[CH:28]=[N:27][C:26]4[C:21]3=[N:22][C:23]([Cl:44])=[N:24][C:25]=4[NH:29][CH2:30][CH:31](C3C=CC=CC=3)[C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)[O:14]2)=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.N[C@@H](CC1C=CC=CC=1)[CH2:47][OH:48]>>[CH2:31]([C@H:30]([NH:29][C:25]1[N:24]=[C:23]([Cl:44])[N:22]=[C:21]2[C:26]=1[N:27]=[CH:28][N:20]2[C@H:15]1[C@H:16]([OH:19])[C@H:17]([OH:18])[C@@H:13]([C:10]2[N:11]=[N:12][N:8]([CH2:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)[N:9]=2)[O:14]1)[CH2:47][OH:48])[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1
Reactant: O[C@@H]1[C@H](O)[C@@H](c2nnn(Cc3ccccc3)n2)O[C@H]1n1cnc2c(NCC(c3ccccc3)c3ccccc3)nc(Cl)nc21
Reactant: N[C@H](CO)Cc1ccccc1
Product: OC[C@H](Cc1ccccc1)Nc1nc(Cl)nc2c1ncn2[C@@H]1O[C@H](c2nnn(Cc3ccccc3)n2)[C@@H](O)[C@H]1O

Procedure:
The title compound is prepared in an analogous fashion to (2R,3S,4R,5R)-2-(2-benzyl-2H-tetrazol-5-yl)-5-[2-chloro-6-(2,2-diphenylethylamino)-purin-9-yl]-tetrahydro-furan-3,4-diol (WO 99/38877) by replacing 2,2-diphenylethylamine with (S)-2-amino-3-phenyl-propan-1-ol
Reaction SMILES: [I:1][C:2]1[C:7]([OH:8])=[CH:6][C:5]([CH3:9])=[CH:4][N:3]=1.[O-]CC.[Na+].[Na].[CH2:15](Cl)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>O.CO.O.CS(C)=O.C(O)C>[I:1][C:2]1[C:7]([O:8][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[CH:6][C:5]([CH3:9])=[CH:4][N:3]=1
Reactant: Cc1cnc(I)c(O)c1
Reactant: ClCc1ccccc1
Agent: CC[O-]
Agent: [Na+]
Agent: [Na]
Solvent: O
Solvent: CO
Solvent: CS(C)=O
Product: Cc1cnc(I)c(OCc2ccccc2)c1
Yield: 94 %

Procedure:
2-Iodo-3-hydroxy-5-methylpyridine (13.5 g, 57.4 m.mole) was added to a solution of sodium ethoxide (57.4 m.mole, prepared freshly from sodium and dry ethanol (100 ml). Dry dimethyl sulfoxide (250 ml) was added, and the ethanol was removed by distillation under reduced pressure. Benzyl chloride (7.27 g, 57.4 mole) was added portionwise with cooling and then the mixture was heated at 90°-100° for 15 hours. The dimethyl sulfoxide was boiled off under reduced pressure, water was added (100 ml) and the product was extracted from this with chloroform. After drying with magnesium sulfate and evaporation under reduced pressure, a crude product was obtained (17.62 g, 94% yield) a tiny portion of which, after heating in water and the recrystallising from methanol-water, gave 2-iodo-3-benzyloxy-5-methylpyridine which was pure by N.M.R. (mp 83°-5°).
Reaction SMILES: [H-].[Na+].[OH:3][CH:4]1[CH2:13][C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C@:6]([CH3:18])([C:14]([F:17])([F:16])[F:15])[O:5]1.[CH3:19]N(C=O)C>>[CH3:19][O:3][CH:4]1[CH2:13][C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C@:6]([CH3:18])([C:14]([F:15])([F:17])[F:16])[O:5]1
Reactant: C[C@@]1(C(F)(F)F)OC(O)Cc2ccccc21
Reactant: CN(C)C=O
Agent: [H-]
Agent: [Na+]
Product: COC1Cc2ccccc2[C@](C)(C(F)(F)F)O1
Temperature: 25 °C
Reaction time: 1 h
Yield: 98 %

Procedure:
To a stirred mixture of sodium hydride (3.47 g, 0.145 mol) in DMF (50 mL) was added (1R)-hydroxy-1-methyl-1-trifluoromethylisochroman (28.0 g, 0.121 mol) solution in DMF (370 mL) at 0° C., then the mixture was stirred at room temperature for 1 hr. The reaction mixture was quenched with water and diluted with saturated aqueous ammonium chloride. This was extracted with ethyl acetate-toluene (4:1). The organic fraction was washed with water and brine, and dried over magnesium sulfate. The solvent was removed in vacuo, the residue was purified by column chromatography on silica-gel eluted with hexane and ethyl acetate (40:1) to give the title compound as a colorless oil (29.1 g, 98%). The 1H-NMR spectra of this material was identical with that of racemate.
Reaction SMILES: [N:1]1([C:7]2[N:12]=[CH:11][NH:10][C:9](=[O:13])[CH:8]=2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[C:14]([C:16]1[CH:17]=[C:18]([CH:21]=[CH:22][CH:23]=1)[CH:19]=O)#[N:15]>>[O:13]=[C:9]1[NH:10][CH:11]=[N:12][C:7]([N:1]2[CH2:6][CH2:5][N:4]([CH2:19][C:18]3[CH:17]=[C:16]([CH:23]=[CH:22][CH:21]=3)[C:14]#[N:15])[CH2:3][CH2:2]2)=[CH:8]1
Reactant: O=c1cc(N2CCNCC2)nc[nH]1
Reactant: N#Cc1cccc(C=O)c1
Product: N#Cc1cccc(CN2CCN(c3cc(=O)[nH]cn3)CC2)c1

Procedure:
3-[4-(6-Oxo-1,6-dihydro-pyrimidin-4-yl)-piperazin-1-ylmethyl]-benzonitrile was prepared using Procedure A from 6-piperazin-1-yl-3H-pyrimidin-4-one (Intermediate 4) and 3-cyanobenzaldehyde. Mass spectrum (ES) MH+=296.
Reaction SMILES: [CH3:1][S:2]([C:4]1[S:8][C:7]([N:9]2[CH:14]([OH:15])[CH2:13][CH2:12][N:11]([CH2:16][C:17]#[CH:18])[C:10]2=[O:19])=[N:6][N:5]=1)=[O:3].[CH3:20][C:21]1[CH:26]=[C:25]([Br:27])[CH:24]=[CH:23][C:22]=1[N:28]=[C:29]=[O:30]>C(N(CC)CC)C>[CH3:1][S:2]([C:4]1[S:8][C:7]([N:9]2[CH:14]([O:15][C:29](=[O:30])[NH:28][C:22]3[CH:23]=[CH:24][C:25]([Br:27])=[CH:26][C:21]=3[CH3:20])[CH2:13][CH2:12][N:11]([CH2:16][C:17]#[CH:18])[C:10]2=[O:19])=[N:6][N:5]=1)=[O:3]
Reactant: C#CCN1CCC(O)N(c2nnc(S(C)=O)s2)C1=O
Reactant: Cc1cc(Br)ccc1N=C=O
Solvent: CCN(CC)CC
Product: C#CCN1CCC(OC(=O)Nc2ccc(Br)cc2C)N(c2nnc(S(C)=O)s2)C1=O
Reaction time: 1 h

Procedure:
Tetrahydro-1-(5-methylsulfinyl-1,3,4-thiadiazol-2-yl)-3-propargyl-6-hydroxy-2(1H)-pyrimidinone (0.05 mole) and 2-methyl-4-bromophenyl isocyanate (3.5 ml; 0.06 mole) are charged into a glass reaction vessel equipped with a mechanical stirrer. The mixture is stirred and triethylamine (1 drop) is added thereto. After the addition is completed the reaction mixture is allowed to stand for a period of about 1 hour. The mixture is then washed with hexane and is dried to yield the desired product tetrahydro-1-(5-methylsulfinyl-1,3,4-thiadiazol-2-yl)-3-propargyl-6-[N-(2-methyl-4-bromophenyl)carbamoyloxy]-2(1H)-pyrimidinone.
Reaction SMILES: [S:1]([CH:5]([CH2:17][C:18]([O:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])=[O:19])[C:6]([O:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])=[O:7])([OH:4])(=[O:3])=[O:2].[Na].C(O)(C)C.[OH-].[Cu+2:35].[OH-]>O>[S:1]([CH:5]([CH2:17][C:18]([O:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])=[O:19])[C:6]([O:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])=[O:7])([OH:4])(=[O:3])=[O:2].[Cu:35]
Reactant: [Cu+2]
Agent: CCCCCCCCOC(=O)CC(C(=O)OCCCCCCCC)S(=O)(=O)O
Agent: [Na]
Agent: [OH-]
Solvent: CC(C)O
Solvent: O
Product: [Cu]

Procedure:
Into a fritted column was added: 12 g (12 meq H+) ion exchange resin (Amberlite® IR 120 brand). Resin beads were washed with 100 ml deionized water. Into a 50 ml beaker were added: 7 g (10 meq) sodium dioctyl sulfosuccinate (Triton® GR-5M brand), 7 g water, and 7 g isopropanol. The surfactant solution was run through the column and collected in a 100 ml beaker containing: 0.5 g (10 meq Cu) copper hydroxide and 20 g water. The effluent/copper hydroxide mixture was swirl mixed while collecting the effluent. A 10 g water rinse of the column was added to the copper mixture. Extraction of the beaker's contents was done with 2×25 ml toluene, the toluene solubles were dried with molecular sieve, rotary evaporator stripping removed the toluene, and the resulting solids were vacuum dried overnight at room temperature.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([CH2:8][CH:9]([CH3:11])[CH3:10])[CH:5]=[CH:4][C:3]=1[C:12]1[C:13]([S:18]([NH:21][C:22]2[O:26][N:25]=[C:24]([CH3:27])[C:23]=2[CH3:28])(=[O:20])=[O:19])=[CH:14][CH:15]=[CH:16][CH:17]=1.[CH3:29][C:30]([CH3:32])=O>>[CH3:27][C:24]1[C:23]([CH3:28])=[C:22]([NH:21][S:18]([C:13]2[C:12]([C:3]3[CH:4]=[CH:5][C:6]([CH2:8][CH:9]([CH3:11])[CH3:10])=[CH:7][C:2]=3[NH:1][CH:30]([CH3:32])[CH3:29])=[CH:17][CH:16]=[CH:15][CH:14]=2)(=[O:20])=[O:19])[O:26][N:25]=1
Reactant: Cc1noc(NS(=O)(=O)c2ccccc2-c2ccc(CC(C)C)cc2N)c1C
Reactant: CC(C)=O
Product: Cc1noc(NS(=O)(=O)c2ccccc2-c2ccc(CC(C)C)cc2NC(C)C)c1C
Temperature: 25 °C
Reaction time: 3 h

Procedure:
The title compound was prepared from the compound of Example 32 and acetone as described for Example 58, with stirring at room temperature for 3 hours. Workup afforded the title compound as a light yellow gum.
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][C:5]=1[CH3:11])([CH3:3])[CH3:2].N1C=CC=CC=1.[C:18](Cl)(=[O:20])[CH3:19]>ClCCl>[C:18]([O:10][C:7]1[CH:8]=[CH:9][C:4]([CH:1]([CH3:3])[CH3:2])=[C:5]([CH3:11])[CH:6]=1)(=[O:20])[CH3:19]
Reactant: Cc1cc(O)ccc1C(C)C
Reactant: CC(=O)Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(=O)Oc1ccc(C(C)C)c(C)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 110.2 %

Procedure:
4-Isopropyl-3-methylphenol (1.00 g) was dissolved in dichloromethane (10 ml) to prepare a solution. Pyridine (724 mg) and acetyl chloride (615 mg) were added to the solution, and the mixture was stirred at room temperature overnight. The solvent was removed by distillation under the reduced pressure, water was then added to the residue, and the mixture was extracted with chloroform. The chloroform layer was washed with water and was dried over anhydrous magnesium sulfate, and the solvent was removed by distillation under the reduced pressure. The residue was dried under the reduced pressure to give 4-isopropyl-3-methylphenyl acetate (1.41 g, yield 100%).
Reaction SMILES: [CH3:1][C:2]1([CH3:31])[C:10]2[C:5](=[CH:6][C:7]([N+:22]([O-:24])=[O:23])=[C:8]([NH:11][C:12](=[O:21])[CH2:13][CH2:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[CH:9]=2)[N:4]([CH2:25][CH2:26][CH2:27][CH2:28][CH3:29])[C:3]1=[O:30].[C:32]([O-])([O-])=O.[K+].[K+].CI>CN(C)C=O>[CH3:31][C:2]1([CH3:1])[C:10]2[C:5](=[CH:6][C:7]([N+:22]([O-:24])=[O:23])=[C:8]([N:11]([CH3:32])[C:12](=[O:21])[CH2:13][CH2:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[CH:9]=2)[N:4]([CH2:25][CH2:26][CH2:27][CH2:28][CH3:29])[C:3]1=[O:30]
Reactant: O=C([O-])[O-]
Reactant: CCCCCN1C(=O)C(C)(C)c2cc(NC(=O)CCc3ccccc3)c([N+](=O)[O-])cc21
Agent: [K+]
Solvent: CI
Solvent: CN(C)C=O
Product: CCCCCN1C(=O)C(C)(C)c2cc(N(C)C(=O)CCc3ccccc3)c([N+](=O)[O-])cc21
Temperature: 75 °C
Reaction time: 48 h

Procedure:
To a solution of N-(3,3-dimethyl-6-nitro-2-oxo-1-pentyl-2,3-dihydro-1H-indol-5-yl)-3-phenyl-propionamide (142 mg) in dry N,N-dimethylformamide (6 ml) is added K2CO3 (163 mg; 1.18 mmol) and methyl iodide (45 μl; 0.72 mmol). The mixture is stirred at 75° C. for 2 days. After an aqueous work-up the compound is obtained.
Reaction SMILES: [Na].[CH2:2]([SH:5])[CH:3]=[CH2:4].[CH3:6][O:7][C:8]1[N:9]=[N:10][C:11](Cl)=[CH:12][CH:13]=1>CO>[CH3:6][O:7][C:8]1[N:9]=[N:10][C:11]([S:5][CH2:2][CH:3]=[CH2:4])=[CH:12][CH:13]=1
Reactant: C=CCS
Reactant: COc1ccc(Cl)nn1
Agent: [Na]
Solvent: CO
Product: C=CCSc1ccc(OC)nn1

Procedure:
1.15 g(0.05 mol) of metallic sodium was dissolved in 50 ml of absolute methanol and then mixed with 4.98 ml(0.05 mol) of allylmercaptan. To this mixture was added 7.23 g(0.05 mol) of 3-methoxy-6-chloropyridazine. The reaction solution was refluxed for 24 hours and then treated according to the same manner as Example 1 to obtain the title compound as a freezing pale white crystal.
Reaction SMILES: [K+].[Br-].[C:3]1([CH3:13])[CH:8]=[CH:7][C:6]([S:9]([OH:12])(=[O:11])=[O:10])=[CH:5][CH:4]=1.[CH2:14]([N:21]([CH3:36])[S:22]([NH:25][C:26]1[CH:31]=[CH:30][C:29]([C:32](=[O:35])[CH2:33][NH2:34])=[CH:28][CH:27]=1)(=[O:24])=[O:23])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>>[C:3]1([CH3:13])[CH:4]=[CH:5][C:6]([S:9]([OH:12])(=[O:10])=[O:11])=[CH:7][CH:8]=1.[NH2:34][CH2:33][CH:32]([C:29]1[CH:28]=[CH:27][C:26]([NH:25][S:22]([N:21]([CH2:14][C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH3:36])(=[O:24])=[O:23])=[CH:31][CH:30]=1)[OH:35]
Reactant: CN(Cc1ccccc1)S(=O)(=O)Nc1ccc(C(=O)CN)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: [Br-]
Agent: [K+]
Product: CN(Cc1ccccc1)S(=O)(=O)Nc1ccc(C(O)CN)cc1

Procedure:
Infared (pelletized with KBr): 690, 770, 820, 1130, 1160, 1220, 1340, 1520, 1620, 3100 cm.31 1. Prepared from N-benzyl-N'-(4-glycylphenyl)-N-methylsulfamide para-toluenesulfonate.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH:14]=[CH:15][C:16]=1[CH:17]=O)[C:12]#[N:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Br-].[C:20]([CH2:25][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)(OCC)=[O:21].CC(C)([O-])C.[K+].Cl>CN(C)C=O>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH:14]=[CH:15][C:16]=1[CH2:17][CH2:25][CH2:20][OH:21])[CH2:12][NH2:13])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: N#Cc1ccc(C=O)c(OCc2ccccc2)c1
Reactant: CCOC(=O)C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [Br-]
Solvent: CN(C)C=O
Product: NCc1ccc(CCCO)c(OCc2ccccc2)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 18.8 %

Procedure:
3-Benzyloxy-4-formylbenzonitrile (0.93 g) and (carboethoxymethyl)triphenylphosphonium bromide (2.52 g) were suspended in N,N-dimethylformamide (10 mL). To the reaction mixture was added potassium t-butoxide (0.66 g), and the mixture was stirred at room temperature for 18 hours. To the reaction mixture was added 1 mol/L hydrochloric acid, and the resulting mixture was extracted with ethyl acetate. The organic layer was washed with brine and dried over anhydrous magnesium sulfate. The filtrate was concentrated under reduced pressure. The obtained residue was dissolved in tetrahydrofuran (10 mL), and the mixture was added dropwise to a suspension of lithium aluminum hydride (0.20 g) in tetrahydrofuran (15 mL) under ice-cooling. The mixture was stirred at 60° C. for 2 hours. After mixture was cooled in an ice bath, and to the reaction mixture were added dropwise ethanol and water successively, and then added diethyl ether. To the reaction mixture was added anhydrous sodium sulfate, and the insoluble material was removed by filtration. The filtrate was concentrated under reduced pressure to give the title compound (0.20 g).
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH2:11][O:12][C:13]1[CH:18]=[CH:17][C:16]([CH2:19][C:20]([O:22][C:23]2([C:26]([O:28]C)=O)[CH2:25][CH2:24]2)=[O:21])=[CH:15][CH:14]=1.CN(C=O)C>>[OH:28][C:26]1[C:23]2([CH2:25][CH2:24]2)[O:22][C:20](=[O:21])[C:19]=1[C:16]1[CH:15]=[CH:14][C:13]([O:12][CH2:11][C:2]2[CH:3]=[CH:4][C:5]3[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=3)[N:1]=2)=[CH:18][CH:17]=1
Reactant: COC(=O)C1(OC(=O)Cc2ccc(OCc3ccc4ccccc4n3)cc2)CC1
Solvent: CN(C)C=O
Product: O=C1OC2(CC2)C(O)=C1c1ccc(OCc2ccc3ccccc3n2)cc1
Temperature: 25 °C
Reaction time: 12 h
Yield: 81.5 %

Procedure:
To a 0° C. solution of methyl 1-(2-(4-(quinolin-2-ylmethoxy)phenyl)acetoxy)cyclopropanecarboxylate (2.0 g, 6.825 mmol) in DMF (20 mL) NaI (49 mg, 20.477 mol) was added and the mixture stirred at RT for 12 h. After complete consumption of the starting material (by TLC), the reaction mixture was quenched with ice water (3 mL) and the aqueous layer was extracted with EtOAc (2×50 mL). The combined organic layers were washed with water (30 mL) and brine (20 mL), dried over anhydrous Na2SO4, filtered, and concentrated in vacuo to afford crude 7-hydroxy-6-(4-(quinolin-2-ylmethoxy)phenyl)-4-oxaspiro[2.4]hept-6-en-5-one (2.0 g, 83%) as a light yellow color solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9](=O)[C:10]([C:12]2[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=2)=O)=[CH:5][CH:4]=1.[Br:21][C:22]1[CH:23]=[C:24]([NH2:29])[C:25]([NH2:28])=[CH:26][CH:27]=1>C(O)(=O)C>[Br:21][C:22]1[CH:23]=[C:24]2[C:25](=[CH:26][CH:27]=1)[N:28]=[C:9]([C:6]1[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=1)[C:10]([C:12]1[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=1)=[N:29]2
Reactant: COc1ccc(C(=O)C(=O)c2ccc(OC)cc2)cc1
Reactant: Nc1ccc(Br)cc1N
Solvent: CC(=O)O
Product: COc1ccc(-c2nc3ccc(Br)cc3nc2-c2ccc(OC)cc2)cc1
Yield: 47.5 %

Procedure:
A solution of 1,2-bis(4-methoxyphenyl)ethane-1,2-dione (540 mg, 2.00 mmol, 1.00 equiv) and 4-bromobenzene-1,2-diamine (380 mg, 2.03 mmol, 1.10 equiv) in acetic acid (5 mL) was stirred for 3 h at 130° C. in an oil bath, then quenched by the addition of water (30 mL). The solids were collected by filtration and washed with water (20 mL). The solid was dried in an oven under reduced pressure, yielding 400 mg (48%) of 6-bromo-2,3-bis(4-methoxyphenyl)quinoxaline as a brown solid.
Reaction SMILES: Cl[C:2]1[C:11]([C:12]([OH:14])=[O:13])=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([Cl:15])[CH:8]=2)[N:3]=1.[NH2:16][C@@H:17]([CH2:21][C:22]1[CH:27]=[CH:26][C:25]([O:28][C:29]2[CH:34]=[CH:33][N:32]=[C:31]([Cl:35])[CH:30]=2)=[CH:24][CH:23]=1)[C:18]([OH:20])=[O:19]>CS(C)=O>[C:18]([C@@H:17]([NH:16][C:2]1[C:11]([C:12]([OH:14])=[O:13])=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([Cl:15])[CH:8]=2)[N:3]=1)[CH2:21][C:22]1[CH:23]=[CH:24][C:25]([O:28][C:29]2[CH:34]=[CH:33][N:32]=[C:31]([Cl:35])[CH:30]=2)=[CH:26][CH:27]=1)([OH:20])=[O:19]
Reactant: O=C(O)c1cc2cc(Cl)ccc2nc1Cl
Reactant: N[C@@H](Cc1ccc(Oc2ccnc(Cl)c2)cc1)C(=O)O
Solvent: CS(C)=O
Product: O=C(O)c1cc2cc(Cl)ccc2nc1N[C@@H](Cc1ccc(Oc2ccnc(Cl)c2)cc1)C(=O)O

Procedure:
In close analogy to the procedure described in Example 109c, 2,6-dichloroquinoline-3-carboxylic acid is reacted with (S)-2-amino-3-[4-(2-chloro-pyridin-4-yloxy)-phenyl]-propionic acid (prepared by analogy to Example 109a,b) in DMSO to provide the title compound in good yield.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]2[N:13]=[C:12]([CH:14]([F:16])[F:15])[CH:11]=[C:10]([C:17]3[CH:22]=[CH:21][C:20]([C:23]([F:26])([F:25])[F:24])=[CH:19][CH:18]=3)[N:9]=2)[CH:5]=[CH:4][N:3]=1.[NH2:27][C:28]1[CH:33]=[CH:32][C:31](B2OC(C)(C)C(C)(C)O2)=[CH:30][N:29]=1>>[F:15][CH:14]([F:16])[C:12]1[CH:11]=[C:10]([C:17]2[CH:22]=[CH:21][C:20]([C:23]([F:26])([F:25])[F:24])=[CH:19][CH:18]=2)[N:9]=[C:8]([C:6]2[CH:5]=[CH:4][N:3]=[C:2]([C:31]3[CH:30]=[N:29][C:28]([NH2:27])=[CH:33][CH:32]=3)[CH:7]=2)[N:13]=1
Reactant: FC(F)c1cc(-c2ccc(C(F)(F)F)cc2)nc(-c2ccnc(Cl)c2)n1
Reactant: CC1(C)OB(c2ccc(N)nc2)OC1(C)C
Product: Nc1ccc(-c2cc(-c3nc(-c4ccc(C(F)(F)F)cc4)cc(C(F)F)n3)ccn2)cn1

Procedure:
The title compound was prepared from 2-(2-chloro-pyridin-4-yl)-4-difluoromethyl-6-(4-trifluoromethyl-phenyl)-pyrimidine (example E.10) (0.19 g, 0.5 mmol) and commercially available 2-amino-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (0.14 g, 0.65 mmol) according to the general procedure VI. Obtained as a light yellow solid (0.021 g, 9%). MS (ISP) 444.4 [(M+H)+]; mp 210° C.