Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH3:20][O:21][C:22](=[O:32])[C:23]1[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[C:25]([OH:31])[CH:24]=1.CCOC(/N=N/C(OCC)=O)=O.[Cl:45][C:46]1[CH:51]=[C:50]([Cl:52])[CH:49]=[CH:48][C:47]=1[CH2:53][CH2:54]O>C1COCC1>[CH3:20][O:21][C:22](=[O:32])[C:23]1[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[C:25]([O:31][CH2:54][CH2:53][C:47]2[CH:48]=[CH:49][C:50]([Cl:52])=[CH:51][C:46]=2[Cl:45])[CH:24]=1
Reactant: COC(=O)c1ccc(OC)c(O)c1
Reactant: OCCc1ccc(Cl)cc1Cl
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COC(=O)c1ccc(OC)c(OCCc2ccc(Cl)cc2Cl)c1
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
20 g of triphenylphosphine and 10 g of 3-Hydroxy-4-methoxy-benzoic acid methyl ester were dissolved in 200 ml of anhydrous THF. The solution was cooled to 0° C. to 10° C. and a solution of 11.4 ml DEAD in 30 ml anhydrous THF was added dropwise over 20 min. The reaction was warmed to RT and stirred for 45 min. A solution of 11.3 ml 2-(2,4-Dichlorophenyl)-ethanol in 10 ml anhydrous THF was added with cooling. The reaction was stirred at RT for 16 h, and then the solvents were removed under reduced pressure. The residue was treated with n-heptane:ethyl acetate/1:1. The filtrate was dried under reduced pressure. The product was purified by silica gel chromatography, eluting with n-heptane:ethyl acetate/4:1, then n-heptane:ethyl acetate/3:1.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[C:5]([N:9]([CH3:11])[CH3:10])=[CH:4][N:3]=1.Cl.Cl.[NH:14]1[C:18]2[CH2:19][CH2:20][CH2:21][NH:22][C:17]=2[N:16]=[CH:15]1.C(=O)([O-])[O-].[K+].[K+]>C(O)(C)C.O>[Cl:1][C:2]1[N:7]=[C:6]([N:22]2[CH2:21][CH2:20][C:19]3[N:16]=[CH:15][NH:14][C:18]=3[CH2:17]2)[C:5]([N:9]([CH3:11])[CH3:10])=[CH:4][N:3]=1
Reactant: c1nc2c([nH]1)CCCN2
Reactant: CN(C)c1cnc(Cl)nc1Cl
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC(C)O
Product: CN(C)c1cnc(Cl)nc1N1CCc2nc[nH]c2C1
Temperature: 25 °C
Reaction time: 240 h

Procedure:
5 g of 2,4-dichloro-5-dimethylamino-pyrimidine are dissolved in 30 mL isopropanol and combined with 5.82 g 4,5,6,7-tetrahydroimidazopyridine dihydrochloride and 6.06 g potassium carbonate. After 6 and 8 days in each case 1 g of 4,5,6,7-tetrahydroimidazopyridine dihydrochloride and 1 g potassium carbonate are added. In all, the mixture is stirred for 10 days at 25° C. The reaction mixture is diluted with 400 mL water and stirred for 1 h. The precipitate formed is suction filtered, washed and dried.
Reaction SMILES: C([O:8][C:9]1[CH:10]=[C:11]([C:17]2[O:18][CH:19]=[C:20]([CH2:22][CH2:23][C:24]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=3[O:32][CH:33]([CH3:35])[CH3:34])=[O:25])[N:21]=2)[CH:12]=[CH:13][C:14]=1[O:15][CH3:16])C1C=CC=CC=1>CO.[C].[Pd]>[OH:8][C:9]1[CH:10]=[C:11]([C:17]2[O:18][CH:19]=[C:20]([CH2:22][CH2:23][C:24]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=3[O:32][CH:33]([CH3:35])[CH3:34])=[O:25])[N:21]=2)[CH:12]=[CH:13][C:14]=1[O:15][CH3:16]
Reactant: COc1ccc(-c2nc(CCC(=O)c3ccccc3OC(C)C)co2)cc1OCc1ccccc1
Agent: [Pd]
Solvent: CO
Product: COc1ccc(-c2nc(CCC(=O)c3ccccc3OC(C)C)co2)cc1O
Temperature: 25 °C
Reaction time: 1 h
Yield: 77.3 %

Procedure:
The above compound was also obtained by the following method. A 10 g quantity of 2-(3-benzyloxy-4-methoxyphenyl-4-chloromethyloxazole obtained in Reference Example 5 and 5.4 g of 1-(2-isopropoxyphenyl)ethanone were dissolved in 100 ml of tetrahydrofuran, and 2.42 g of sodium hydride was added thereto. After foaming, the reaction mixture was heated and refluxed for 3 hours. After cooling, the reaction mixture was added to ice water, and extraction was performed with ethyl acetate. The organic layer was washed with water, dried over magnesium sulfate, and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=3:1) to give 4.30 g of pale yellow oily 3-[2-(3-benzyloxy-4-methoxyphenyl)oxazol-4-yl]-1-(2-isopropoxyphenyl)propan-1-one. Subsequently, 1.84 g of the obtained 3-[2-(3-benzyloxy-4-methoxyphenyl)oxazol-4-yl]-1-(2-isopropoxyphenyl)propan-1-one was dissolved in 100 ml of methanol. An 800 mg quantity of 10% palladium-carbon powder was added thereto. The mixture was stirred under a hydrogen atmosphere at room temperature for 1 hour. The catalyst was removed by filtration, and the solvent was removed. The residue was then recrystallized from acetone/diisopropyl ether to give 1.15 g of 3-[2-(3-hydroxy-4-methoxyphenyl)oxazol-4-yl]-1-(2-isopropoxyphenyl)propan-1-one.
Reaction SMILES: C(O[C:9]1[C:10]([O:38][CH3:39])=[N:11][C:12]2[C:17]([C:18]=1[Cl:19])=[CH:16][C:15]([C:20]([C:32]1[N:36]([CH3:37])[CH:35]=[N:34][CH:33]=1)([C:22]1[CH:23]=[N:24][C:25]([C:28]([F:31])([F:30])[F:29])=[CH:26][CH:27]=1)[OH:21])=[CH:14][CH:13]=2)C1C=CC=CC=1.[CH3:40][S:41]([C:44]1[CH:49]=[CH:48][C:47](B(O)O)=[CH:46][CH:45]=1)(=[O:43])=[O:42].C([O-])([O-])=O.[K+].[K+]>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[Cl:19][C:18]1[C:17]2[C:12](=[CH:13][CH:14]=[C:15]([C:20]([C:32]3[N:36]([CH3:37])[CH:35]=[N:34][CH:33]=3)([C:22]3[CH:23]=[N:24][C:25]([C:28]([F:30])([F:31])[F:29])=[CH:26][CH:27]=3)[OH:21])[CH:16]=2)[N:11]=[C:10]([O:38][CH3:39])[C:9]=1[C:47]1[CH:48]=[CH:49][C:44]([S:41]([CH3:40])(=[O:43])=[O:42])=[CH:45][CH:46]=1
Reactant: CS(=O)(=O)c1ccc(B(O)O)cc1
Reactant: COc1nc2ccc(C(O)(c3ccc(C(F)(F)F)nc3)c3cncn3C)cc2c(Cl)c1OCc1ccccc1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Product: COc1nc2ccc(C(O)(c3ccc(C(F)(F)F)nc3)c3cncn3C)cc2c(Cl)c1-c1ccc(S(C)(=O)=O)cc1
Temperature: 65 °C

Procedure:
A mixture of 4-chloro-6-(hydroxy(1-methyl-1H-imidazol-5-yl)(6-(trifluoromethyl)pyridin-3-yl)methyl)-2-methoxyquinolin-3-yl trifluoromethanesulfonate (70 mg, 0.12 mmol, Intermediate 11: step g), (4-(methylsulfonyl)phenyl)boronic acid (35 mg, 0.18 mmol), PdCl2(dppf) (9 mg, 0.012 mmol) and K2CO3 (16 mg, 0.12 mmol) was sparged with nitrogen three times. To this mixture was added 1,4-dioxane (2 mL) and water (0.3 mL) and the suspension purged with nitrogen. The resulting solution was heated to 65° C. for 15 hours. The reaction was allowed to cool to room temperature and concentrated to dryness. The residue was dissolved in DMSO, filtered and purified by reverse-phase HPLC (acetonitrile/water+TFA). The acidic fractions were neutralized by diluting with EtOAc and washing with saturated aqueous NaHCO3 followed by water. The organics were dried (MgSO4), filtered and concentrated to dryness to provide the title compound. 1H NMR (400 MHz, CD3OD) δ 8.79-8.76 (m, 1H), 8.24-8.20 (m, 1H), 8.08-8.05 (m, 2H), 8.05-8.01 (m, 1H), 7.96-7.93 (m, 1H), 7.84 (d, J=8.3 Hz, 1H), 7.76-7.72 (m, 2H), 7.65-7.62 (m, 2H), 6.35 (s, 1H), 4.00 (s, 3H), 3.49 (s, 3H), 3.20 (s, 3H); MS (ESI): mass calcd. for C28H22ClF3N4O4S, 602.1; m/z found, 603.2 [M+H]+.
Reaction SMILES: C[Al](C)C.[CH2:5]([NH2:8])[CH2:6][NH2:7].C(O[C:12](=O)[CH2:13][CH2:14][C:15]1[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=1)C>C1(C)C=CC=CC=1>[Cl:21][C:18]1[CH:19]=[CH:20][C:15]([CH2:14][CH2:13][C:12]2[NH:7][CH2:6][CH2:5][N:8]=2)=[CH:16][CH:17]=1
Reactant: CCOC(=O)CCc1ccc(Cl)cc1
Reactant: NCCN
Agent: C[Al](C)C
Solvent: Cc1ccccc1
Product: Clc1ccc(CCC2=NCCN2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 50.9 %

Procedure:
To dry toluene (4 ml) under an inert atmosphere at 0° C. was added a toluene solution of trimethylaluminium (2.45 ml, 4.89 mmol, 2 M solution). A solution of ethylenediamine (0.30 ml, 4.89 mmol) in toluene (1.5 ml) was then added dropwise and the reaction mixture was then allowed to warm to room temperature and stirred for 1 h at this temperature before being re-cooled to 0° C. To this mixture was added dropwise a solution of 3-(4-chloro-phenyl)-propionic acid ethyl ester (0.52 g, 2.45 mmol) in toluene (3 ml). The reaction mixture was then heated at 95° C. for 45 min and then cooled first to room temperature and finally to 0° C. The mixture was quenched by dropwise addition of methanol (1 ml) and when all gas evolution had ceased the mixture was diluted with water and extracted twice with ethyl acetate. The combined organic extracts were dried over sodium sulphate, filtered and concentrated in vacuo. The residue was triturated in ether to yield a white solid (0.26 g, 50%) which was collected by filtration; MS (ISP): 211.0, 209.2 ([M+H]+.).
Reaction SMILES: [Cl:1][C:2]1[N:3]=[N:4][C:5]([Cl:8])=[CH:6][CH:7]=1.[CH2:9]([C:11]([CH2:16][CH3:17])(CO)[CH2:12][OH:13])[CH3:10].S(=O)(=O)(O)O.S(OOS([O-])(=O)=O)([O-])(=O)=O.[NH4+].[NH4+]>[N+]([O-])([O-])=O.[Ag+].O>[Cl:1][C:2]1[N:3]=[N:4][C:5]([Cl:8])=[CH:6][C:7]=1[C:11]([CH2:16][CH3:17])([CH2:12][OH:13])[CH2:9][CH3:10]
Reactant: CCC(CC)(CO)CO
Reactant: Clc1ccc(Cl)nn1
Agent: [Ag+]
Agent: O=S(=O)(O)O
Agent: O=S(=O)([O-])OOS(=O)(=O)[O-]
Solvent: O
Product: CCC(CC)(CO)c1cc(Cl)nnc1Cl
Temperature: 25 °C

Procedure:
Twenty g. of 3,6-dichloropyridazine, 2.3 g. of silver nitrate and 44.4 g. of 2,2-diethyl-1,3-propanediol were slurried in 280 ml. of water and 19.7 g. of sulfuric acid. To the mixture were added, simultaneously, solutions of 61.3 g. of ammonium persulfate in 200 ml. of water and 20 g. of silver nitrate in 40 ml. of water, over a period of 20 minutes at 55°. The mixture heated exothermically to 70°, and it was cooled to ambient temperature after the addition was complete. The aqueous layer was then decanted off, and the solids remaining were slurried twice in 800 ml. of diethyl ether. The resulting solution was shaken with the aqueous layer, and the layers were separated again. The aqueous layer was then made basic to pH 9 with ammonium hydroxide, and was re-extracted with 500 ml. of diethyl ether. The ether was evaporated under vacuum to obtain 46 g. of brown oil, which was purified by high performance liquid chromatography, eluting with 6:1 heptane:ethyl acetate. The product-containing fractions were combined and evaporated under vacuum to obtain, after recrystallization from diethyl ether/heptane, 0.54 g. of the desired product, m.p. 85°-87°.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([OH:9])[CH:5]=[C:6]([CH3:8])[CH:7]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:17][CH2:18][O:19][Si:20]([C:23]([CH3:26])([CH3:25])[CH3:24])([CH3:22])[CH3:21]>CN(C)C=O>[C:23]([Si:20]([O:19][CH2:18][CH2:17][O:9][C:4]1[CH:5]=[C:6]([CH3:8])[CH:7]=[C:2]([CH3:1])[CH:3]=1)([CH3:22])[CH3:21])([CH3:26])([CH3:25])[CH3:24]
Reactant: CC(C)(C)[Si](C)(C)OCCBr
Reactant: Cc1cc(C)cc(O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1cc(C)cc(OCCO[Si](C)(C)C(C)(C)C)c1

Procedure:
To a solution of 3,5-dimethyl-phenol (3.000 g, 24.55 mmol) in N,N-dimethylformamide (120 mL) under nitrogen were added potassium carbonate (16.96 g, 122.7 mmol) and (2-bromoethoxy)-tert-butyldimethylsilane (7.90 mL, 36.8 mmol). The resulting slurry was heated at reflux for 20 hours; then, the solvent was removed under high vacuum. The residue was dissolved in ethyl acetate and the solution was backwashed with 0.2 N aqueous sodium hydroxide, water, and then brine, dried over sodium sulfate, and concentrated. The crude material (5.69 g) was purified by column chromatography (silica gel 230-400 mesh; methylene chloride as eluent) to give tert-butyl-[2-(3,5-dimethyl-phenoxy)-ethoxy]-dimethylsilane as light yellow oil. Yield: 3.72 g (47%).
Reaction SMILES: Br[CH2:2][C:3]#[C:4][CH2:5][CH3:6].[O:7]=[CH:8][C:9]1[CH:17]=[CH:16][C:14]([OH:15])=[C:11]([O:12][CH3:13])[CH:10]=1.C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[CH3:13][O:12][C:11]1[CH:10]=[C:9]([CH:17]=[CH:16][C:14]=1[O:15][CH2:2][C:3]#[C:4][CH2:5][CH3:6])[CH:8]=[O:7]
Reactant: COc1cc(C=O)ccc1O
Reactant: CCC#CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCC#CCOc1ccc(C=O)cc1OC
Yield: 83.3 %

Procedure:
1-Bromopent-2-yne (0.67 mL, 6.6 mmol) was added to a suspension of vanillin (0.50 g, 3.3 mmol) and potassium carbonate (1.37 g, 9.85 mmol) in acetone (5.0 mL) and treated according to Procedure 3. 3-Methoxy-4-(pent-2-ynyloxy)benzaldehyde (0.60 g, 84%) was obtained as a yellow crystalline solid; mp 47-50° C.; δH (400 MHz, CDCl3) 1.11 (t, J=7.6 Hz, 2H, CH2CH3), 2.20 (tq, J=7.6, 2.4 Hz, 3H, CH2CH3), 3.93 (s, 3H, OCH3), 4.83 (t, J=2.4 Hz, 2H, OCH2), 7.13 (d, J5,6=8.0 Hz, 1H, H5), 7.42 (s, 1H, H2), 7.45 (d, J5,6=8.0 Hz, H6), 9.86 (s, 1H, CHO); δC (100 MHz, CDCl3) 12.5, 13.4, 56.0, 57.3, 73.1, 90.7, 109.2, 112.3, 126.4, 130.5, 149.9, 152.5, 190.9; vmax 997, 1136, 1263, 1508, 1586, 1682, 2230, 2298, 2845, 2932 cm−1.
Reaction SMILES: Cl[C:2]1[O:6][N:5]=[C:4]2[C:7]3[C:12]([CH2:13][CH2:14][C:3]=12)=[CH:11][CH:10]=[C:9]([O:15][CH3:16])[CH:8]=3.[NH:17]1[CH2:23][CH2:22][CH2:21][NH:20][CH2:19][CH2:18]1.C([O-])([O-])=O.[K+].[K+]>CN1CCCC1=O.C(Cl)(Cl)Cl.C(Cl)Cl.CO>[N:17]1([C:2]2[O:6][N:5]=[C:4]3[C:7]4[C:12]([CH2:13][CH2:14][C:3]=23)=[CH:11][CH:10]=[C:9]([O:15][CH3:16])[CH:8]=4)[CH2:23][CH2:22][CH2:21][NH:20][CH2:19][CH2:18]1
Reactant: C1CNCCNC1
Reactant: COc1ccc2c(c1)-c1noc(Cl)c1CC2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClC(Cl)Cl
Solvent: CO
Solvent: ClCCl
Product: COc1ccc2c(c1)-c1noc(N3CCCNCC3)c1CC2
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
A stirred mixture of 3-chloro-8-methoxy-4,5-dihydronaphth[1,2-c]isoxazole (2.66 g, 11.32 mmol), homopiperazine (11.40 g, 113.2 mol) and K2CO3 (3.13 g, 22.68 mmol) in 10.0 ml of N-methylpyrrolidinone under N2 was lowered into an oil bath preheated to 150° C. The mixture was heated while stirring under N2 for 20 minutes. At that time, TLC (CH2Cl2) showed no starting material remained. The mixture was removed from the heating bath, allowed to cool to room temperature and diluted with H2O, which caused a solid to precipitate. The crude solid was dried, recrystallized from Et2O and dried in vacuo (0.1 mm) at 85° C., to provide pure product, mp of 106°-109° C., homogeneous by TLC [silica, 1:1 CH3OH:CH2Cl2, Rf=0.18]. The IR (CHCl3), NMR (CDCl3) and Mass Spectrum (M+ =299, EI, 70 eV) were consistent with the structure. The yield was 1.7948 g (6.00 mmol, 53.03%).
Reaction SMILES: Cl.[CH3:2][C:3]([NH2:12])([CH3:11])[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.[Cl:13][C:14]1[CH:19]=[C:18](Cl)[N:17]=[C:16]([NH2:21])[N:15]=1.CCN(C(C)C)C(C)C>CC#N>[Cl:13][C:14]1[N:15]=[C:16]([NH2:21])[N:17]=[C:18]([NH:12][C:3]([CH3:2])([CH3:11])[CH2:4][C:5]2[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=2)[CH:19]=1
Reactant: Nc1nc(Cl)cc(Cl)n1
Reactant: CC(C)(N)Cc1ccccc1
Agent: Cl
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(Cc1ccccc1)Nc1cc(Cl)nc(N)n1
Temperature: 160 °C
Yield: 50.5 %

Procedure:
A mixture of 2-methyl-1-phenyl-2-propanamine hydrochloride (742 mg, 4 mmol), 4,6-dichloro-2-pyrimidinamine (438 mg, 2.67 mmol) and Hunig's base (1.55 g, 12 mmol) in CH3CN (8 mL) was stirred and heated for 6 hours at 160° C. in a Biotage Initiator microwave synthesizer. The mixture was cooled to room temperature and concentrated to dryness. The resulting solids were partitioned between EtOAc and water, and the organic layer was dried over Na2SO4, filtered and concentrated to dryness. Purification by reverse phase chromatography using CH3CN in water from 45% to 65% (0.08% ammonium hydrogen carbonate) in 18 min, afforded the title compound (373 mg) as a white solid. LC-MS (ES) m/z=277.0 [M+H]+.
Reaction SMILES: C(O[C:4](=[O:28])[CH2:5][NH:6][CH2:7][C:8]1[C:17]2[C:12](=[CH:13][C:14]([NH:18][S:19]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)(=[O:21])=[O:20])=[CH:15][CH:16]=2)[CH:11]=[CH:10][CH:9]=1)C.[CH3:29][NH2:30]>CO>[C:22]1([S:19]([NH:18][C:14]2[CH:13]=[C:12]3[C:17](=[CH:16][CH:15]=2)[C:8]([CH2:7][NH:6][CH2:5][C:4]([NH:30][CH3:29])=[O:28])=[CH:9][CH:10]=[CH:11]3)(=[O:21])=[O:20])[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: CCOC(=O)CNCc1cccc2cc(NS(=O)(=O)c3ccccc3)ccc12
Reactant: CN
Solvent: CO
Product: CNC(=O)CNCc1cccc2cc(NS(=O)(=O)c3ccccc3)ccc12
Temperature: 25 °C

Procedure:
[(6-Benzenesulfonylamino-naphthalen-1-ylmethyl)-amino]-acetic acid ethyl ester is added to methylamine in methanol, and the solution is stirred at room temperature, then concentrated under reduced pressure. The oil is dissolved in ethanol and 1N HCl in diethyl ether is added to precipitate 2-[(6-benzenesulfonyl-naphthalen-1-ylmethyl)-amino]-N-methyl-acetamide as a hydrochloride salt.
Reaction SMILES: Cl[CH:2]1[C:11]2[C:6](=[C:7]([Cl:18])[CH:8]=[C:9]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[C:10]=2[CH3:12])[S:5][CH2:4][CH2:3]1.[CH2:19]([SH:21])[CH3:20].C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[CH2:19]([S:21][CH:2]1[C:11]2[C:6](=[C:7]([Cl:18])[CH:8]=[C:9]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[C:10]=2[CH3:12])[S:5][CH2:4][CH2:3]1)[CH3:20]
Reactant: CCS
Reactant: CCOC(=O)c1cc(Cl)c2c(c1C)C(Cl)CCS2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)c1cc(Cl)c2c(c1C)C(SCC)CCS2
Temperature: 25 °C
Reaction time: 48 h
Yield: 139.5 %

Procedure:
0.8 Gram (2.6 mmol) of 4,8-dichloro-5-methyl-6-ethoxycarbonylthiochroman was dissolved in 5 ml of N,N-dimethylformamide, and 0.15 ml (3.1 mmol) of ethanethiol and 0.43 g (3.1 mmol) of potassium carbonate were added. The mixture was stirred at room temperature for 2 days. After the completion of the reaction, 20 ml of water was added, and the reaction mixture was extracted with ethyl acetate twice. An organic layer was washed with water and with a saturated sodium chloride aqueous solution and dried over anhydrous sodium sulfate, and the solvent was distilled off to give 1.2 g (yield 100%) of 4-ethylthio-5-methyl-6-ethoxycarbonyl-8-chlorothiochroman.
Reaction SMILES: [CH3:1][C:2]1[NH:7][C:6](=[O:8])[C:5]([C:9]#[N:10])=[C:4]([C:11]([F:14])([F:13])[F:12])[CH:3]=1.N#N.[ClH:17]>CO.[OH-].[OH-].[Pd+2]>[ClH:17].[ClH:17].[NH2:10][CH2:9][C:5]1[C:6](=[O:8])[NH:7][C:2]([CH3:1])=[CH:3][C:4]=1[C:11]([F:12])([F:13])[F:14]
Reactant: Cc1cc(C(F)(F)F)c(C#N)c(=O)[nH]1
Agent: [Pd+2]
Agent: Cl
Agent: N#N
Solvent: CO
Product: Cc1cc(C(F)(F)F)c(CN)c(=O)[nH]1
Temperature: 23 °C
Reaction time: 18 h
Yield: 100 %

Procedure:
To a solution of 6-methyl-2-oxo-4-(trifluoromethyl)-1,2-dihydropyridine-3-carbonitrile (400 mg, 1.98 mmol) in MeOH (19.8 ml) and HCl (436 ul, 12M) was added 10% Pd(OH)2 (361 mg, 0.257 mmol) under N2 atmosphere. The N2 gas was displaced by H2 gas and the mixture was stirred for 18 h at 23° C. under hydrogen. The H2 gas was displaced by N2 gas. The mixture was filtered through Celite, washed with MeOH and concentrated. The residue was triturated with MeOH-Et2O, collected with Buchner funnel, and dried in vacuo to give the titled compound (433 mg, 100%). 1H NMR (400 MHz, DMSO-d6): δ ppm 2.31 (s, 3H), 3.88 (s, 2H), 6.43 (s, 1H).
Reaction SMILES: C[O-].[Na+].[CH3:4][N:5]([S:31]([CH3:34])(=[O:33])=[O:32])[C:6]1[N:15]=[C:14]([C:16]([O:18][CH3:19])=[O:17])[C:13]([O:20]S(C2C=CC(C)=CC=2)(=O)=O)=[C:12]2[C:7]=1[CH:8]=[CH:9][CH:10]=[N:11]2.C(O)(=O)C>CO.CN(C=O)C>[OH:20][C:13]1[C:14]([C:16]([O:18][CH3:19])=[O:17])=[N:15][C:6]([N:5]([CH3:4])[S:31]([CH3:34])(=[O:33])=[O:32])=[C:7]2[C:12]=1[N:11]=[CH:10][CH:9]=[CH:8]2
Reactant: COC(=O)c1nc(N(C)S(C)(=O)=O)c2cccnc2c1OS(=O)(=O)c1ccc(C)cc1
Agent: C[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CO
Solvent: CC(=O)O
Product: COC(=O)c1nc(N(C)S(C)(=O)=O)c2cccnc2c1O
Temperature: 50 °C

Procedure:
A solution of sodium methoxide (122 mg, 2.26 mmol) in dry methanol (5 mL) was added to methyl 5-[methyl(methylsulfonyl)amino]-8-{[(4-methylphenyl)sulfonyl]oxy}-1,6-naphthyridine-7-carboxylate (420 mg, 0.90 mmol) dissolved in a minimum amount of DMF and the resulting solution was heated to 50° C. for one hour. The reaction was cooled, glacial acetic acid (104 μL, 1.80 mmol) was added and the reaction was concentrated to dryness in vacuo. The resulting residue was triturated with ethanol and the solids were collected by vacuum filtration to give the desired product as a yellow solid.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH2:11][CH2:12][CH2:13]OS(C1C=CC(C)=CC=1)(=O)=O.[NH2:25][CH2:26][C:27]1[CH2:28][O:29][C:30]2[CH:36]=[CH:35][CH:34]=[CH:33][C:31]=2[N:32]=1.C(N(CC)CC)C>C(#N)C>[O:29]1[C:30]2[CH:36]=[CH:35][CH:34]=[CH:33][C:31]=2[NH:32][CH:27]([CH2:26][NH:25][CH2:13][CH2:12][CH2:11][C:5]2[C:4]3[C:8](=[CH:9][CH:10]=[C:2]([F:1])[CH:3]=3)[NH:7][CH:6]=2)[CH2:28]1
Reactant: NCC1=Nc2ccccc2OC1
Reactant: Cc1ccc(S(=O)(=O)OCCCc2c[nH]c3ccc(F)cc23)cc1
Solvent: CCN(CC)CC
Solvent: CC#N
Product: Fc1ccc2[nH]cc(CCCNCC3COc4ccccc4N3)c2c1
Yield: 52.1 %

Procedure:
To a solution of 5-fluoro-3-(3-p-toluenesulfonyloxypropyl)indole (0.52 g, 1.5 mmol) and 3-aminomethyl-1,4-benzoxazine (0.25 g, 1.5 mmol) [prepared in accordance with the procedure set forth in Ind. J. Chem., 13:462-467 (1975)] in acetonitrile (15 mL) was added triethylamine (0.42 mL, 3.0 mmol) at room temperature. The reaction mixture was allowed to reflux 18 h, cooled and concentrated. The crude product was purified by silica gel column chromatography (ethyl acetate/methanol/NH4OH, 98/2/0.5) to afford 265 mg (52%) of the free base.
Reaction SMILES: [CH:1]1([N:7]2[CH2:13][C:12]([F:15])([F:14])[C:11](=[O:16])[N:10]([CH3:17])[C:9]3[CH:18]=[N:19][C:20]([NH:22][C:23]4[CH:37]=[CH:36][C:26]([C:27]([NH:29][N:30]5[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]5)=[O:28])=[CH:25][C:24]=4[O:38][CH3:39])=[N:21][C:8]2=3)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH2:40](Br)[CH3:41].C(N(CC)C(C)C)(C)C>CN(C=O)C>[CH:1]1([N:7]2[CH2:13][C:12]([F:15])([F:14])[C:11](=[O:16])[N:10]([CH3:17])[C:9]3[CH:18]=[N:19][C:20]([NH:22][C:23]4[CH:37]=[CH:36][C:26]([C:27]([NH:29][N:30]5[CH2:35][CH2:34][N:33]([CH2:40][CH3:41])[CH2:32][CH2:31]5)=[O:28])=[CH:25][C:24]=4[O:38][CH3:39])=[N:21][C:8]2=3)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: CCBr
Reactant: COc1cc(C(=O)NN2CCNCC2)ccc1Nc1ncc2c(n1)N(C1CCCCC1)CC(F)(F)C(=O)N2C
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCN1CCN(NC(=O)c2ccc(Nc3ncc4c(n3)N(C3CCCCC3)CC(F)(F)C(=O)N4C)c(OC)c2)CC1
Temperature: 40 °C
Yield: 67.1 %

Procedure:
4-(9-cyclohexyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-3-methoxy-N-(piperazin-1-yl)benzamide (108 mg, 0.2 mmols), ethyl bromide (33 mg, 0.3 mmols) and N,N-diisopropyl ethylamine (106 μL, 0.3 mmols) were mixed in a screw cap vial (5 mL) in DMF (2 mL) heated at 40° C. for 5-8 hrs, then purified to provide the title compound (76.9 mg). 1H NMR (400 MHz, DMSO-d6) δ ppm 0.99 (t, J=7.1 Hz, 3H) 1.14-1.89 (m, 10H) 2.33 (q, J=6.99 Hz, 2H) 2.48 (m, 4H) 2.93 (t, J=4.55 Hz, 4H) 3.31 (s, 3H) 3.93 (s, 3H) 4.06 (t, J=13.22 Hz, 2H) 4.45 (m, 1H). 7.41 (d, J=8.0 Hz, 1H) 7.43 (s, 1H) 7.90 (s, 1H) 8.20 (s, 1H) 8.26 (d, J=8.08 Hz, 1H) 9.38 (s, 1H) [M+H] calculated for C28H38F2N8O3, 572. found 572.
Reaction SMILES: [N:1]1([CH2:6][CH2:7][Cl:8])[CH:5]=[CH:4][CH:3]=[CH:2]1.[Cl-].[F:10][C:11]1[CH:23]=[CH:22][C:14]([CH:15]=[N+:16]2[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]2)=[CH:13][CH:12]=1.FC1C=CC(C=O)=CC=1.N1CCCCC1>>[Cl:8][CH2:7][CH2:6][N:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH:15]([C:14]1[CH:13]=[CH:12][C:11]([F:10])=[CH:23][CH:22]=1)[N:16]1[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1
Reactant: ClCCn1cccc1
Reactant: Fc1ccc(C=[N+]2CCCCC2)cc1
Agent: O=Cc1ccc(F)cc1
Agent: [Cl-]
Solvent: C1CCNCC1
Product: Fc1ccc(C(c2cccn2CCCl)N2CCCCC2)cc1

Procedure:
The preparation was carried out in accordance with general synthesis instructions 4 from 2-pyrrol-1-yl-chloroethane and 1-(4-fluoro-benzylidene)-piperidinium chloride, which had been prepared in accordance with example 3 from 4-fluorobenzaldehyde and piperidine.
Reaction SMILES: [C:1]1([C@@H:7]2[CH2:9][C@H:8]2[CH:10]=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl.[NH2:13][OH:14].C([O-])([O-])=O.[Na+].[Na+]>CCO>[C:1]1([C@@H:7]2[CH2:9][C@H:8]2[CH:10]=[N:13][OH:14])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: NO
Reactant: O=C[C@@H]1C[C@H]1c1ccccc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Product: ON=C[C@@H]1C[C@H]1c1ccccc1
Temperature: 25 °C

Procedure:
A solution of trans-2-phenylcyclopropanecarbaldehyde rac-I-6B (0.89 g, 6.1 mmol) in EtOH (12 mL) and cooled to 0°C. was treated with hydroxylamine hydrochloride (0.43 g, 6.1 mmol) and Na2CO3. The reaction mixture was allowed to warm to rt and stir fo(12 h. The volatiles were removed in vacuo and extracted with EtOAc. The organics were collected, dried over Na2SO4 filtered, and concentrated to afford trans-2-Phenylcyclopropanecarbaldehyde oxime which was used without further purification.