Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:16]=[CH:15][CH:14]=[C:13]3[C:9]=2[CH2:10][C:11](=[O:17])[NH:12]3)[CH:5]=[CH:6][CH:7]=1.[CH3:18][C:19]1[CH:23]=[C:22]([CH3:24])[NH:21][C:20]=1[CH:25]=O>C(O)C.N1CCCCC1>[CH3:18][C:19]1[CH:23]=[C:22]([CH3:24])[NH:21][C:20]=1[CH:25]=[C:10]1[C:9]2[C:13](=[CH:14][CH:15]=[CH:16][C:8]=2[C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([F:1])[CH:3]=2)[NH:12][C:11]1=[O:17]
Reactant: Cc1cc(C)c(C=O)[nH]1
Reactant: O=C1Cc2c(cccc2-c2cccc(F)c2)N1
Solvent: CCO
Solvent: C1CCNCC1
Product: Cc1cc(C)c(C=C2C(=O)Nc3cccc(-c4cccc(F)c4)c32)[nH]1
Temperature: 25 °C
Reaction time: 72 h
Yield: 44.5 %

Procedure:
To a solution of 4-(3-fluoro-phenyl)-1,3-dihydro-indol-2-one (56.8 mg, 0.25 mmol) and 3,5-dimethyl-1H-pyrrole-2-carbaldehyde (32 mg, 0.26 mmol) in ethanol (2 mL) was added piperidine (3 drops). The reaction mixture was stirred at room temperature for three days. A yellow solid product was precipitated out, filtered, washed by ethanol for three times, and dried under high vacuum to provide pure product 3-(3,5-Dimethyl-1H-pyrrol-2-ylmethylene)-4-(3-fluoro-phenyl)-1,3-dihydro-indol-2-one as a yellow solid (37 mg, 46%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[CH2:7][C@H:8]3[NH:19][CH2:18][CH2:17][C@@:14]4([C:15]=2[CH:16]=1)[C@H:9]3[CH2:10][C:11]([CH3:21])([CH3:20])[O:12][CH2:13]4.[CH2:22](Br)[CH:23]=[CH2:24].C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[CH2:24]([N:19]1[CH2:18][CH2:17][C@@:14]23[C:15]4[CH:16]=[C:3]([O:2][CH3:1])[CH:4]=[CH:5][C:6]=4[CH2:7][C@@H:8]1[C@@H:9]2[CH2:10][C:11]([CH3:21])([CH3:20])[O:12][CH2:13]3)[CH:23]=[CH2:22]
Reactant: C=CCBr
Reactant: COc1ccc2c(c1)[C@]13CCN[C@H](C2)[C@@H]1CC(C)(C)OC3
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: C=CCN1CC[C@]23COC(C)(C)C[C@H]2[C@H]1Cc1ccc(OC)cc13

Procedure:
A mixture of 3-methoxy-7,7-dimethyl-6-oxamorphinan (XI, prepared in Example 3) (0.005 m), allyl bromide (0.006 m) and potassium carbonate (2 g) in 20 ml of acetonitrile is heated at reflux for 18 hours. The mixture is filtered and the filtrate concentrated. The residue is treated with water and extracted with ethyl acetate. The extracts are dried (Na2SO4) and concentrated to give the title compound.
Reaction SMILES: [N:1]1([CH2:7][CH2:8][CH:9]2[CH2:18][CH2:17][C:16]3[C:11](=[CH:12][CH:13]=[C:14]([O:19][CH2:20][C:21]4[CH:29]=[CH:28][C:24]([C:25]([O-])=[O:26])=[CH:23][CH:22]=4)[CH:15]=3)[CH2:10]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:30][O:31][C:32]1[CH:33]=[C:34]([CH:36]=[CH:37][C:38]=1[O:39][CH3:40])[NH2:35].C1C=CC2N(O)N=NC=2C=1.C(=O)([O-])[O-].[K+].[K+]>CN(C1C=CN=CC=1)C.CN(C=O)C>[CH3:30][O:31][C:32]1[CH:33]=[C:34]([NH:35][C:25](=[O:26])[C:24]2[CH:23]=[CH:22][C:21]([CH2:20][O:19][C:14]3[CH:15]=[C:16]4[C:11](=[CH:12][CH:13]=3)[CH2:10][CH:9]([CH2:8][CH2:7][N:1]3[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]3)[CH2:18][CH2:17]4)=[CH:29][CH:28]=2)[CH:36]=[CH:37][C:38]=1[O:39][CH3:40]
Reactant: O=C([O-])c1ccc(COc2ccc3c(c2)CCC(CCN2CCCCC2)C3)cc1
Reactant: COc1ccc(N)cc1OC
Agent: CN(C)c1ccncc1
Agent: O=C([O-])[O-]
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: COc1ccc(NC(=O)c2ccc(COc3ccc4c(c3)CCC(CCN3CCCCC3)C4)cc2)cc1OC
Reaction time: 12 h
Yield: 81.7 %

Procedure:
WSCD (free form, 0.2 ml) was added to DMF solution (3 ml) of 4-[[2-(2-piperidinoethyl)-6-tetralinyl]oxymethyl]benzoate (300 mg), 3,4-dimethoxyaniline (120 mg), HOBt (120 mg) and DMAP (100 mg) at room temperature, which was stirred for 12 hours. 10% aqueous potassium carbonate solution was added to the reaction mixture, and the resulting crystals were collected by filtration. The crystals were washed with water, then dried. The crystals were purified using alumina column chromatography (development solvent; THF), and recrystallized (THF-IPE) to give the titled compound (330 mg).
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[SH:10].Cl[CH2:12][C:13]1[N:17]=[C:16]([C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([O:24][CH3:25])[CH:19]=2)[O:15][N:14]=1.C(=O)([O-])[O-].[K+].[K+].C(OCC)(=O)C>CN(C=O)C.CCCCCC>[CH3:25][O:24][C:20]1[CH:19]=[C:18]([C:16]2[O:15][N:14]=[C:13]([CH2:12][S:10][C:2]3[NH:3][C:4]4[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=4[N:1]=3)[N:17]=2)[CH:23]=[CH:22][CH:21]=1
Reactant: COc1cccc(-c2nc(CCl)no2)c1
Reactant: Sc1nc2ccccc2[nH]1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CCCCCC
Solvent: CN(C)C=O
Product: COc1cccc(-c2nc(CSc3nc4ccccc4[nH]3)no2)c1

Procedure:
1H-Benzoimidazole-2-thiol (150 mg, 1 mmol) was added to a solution of the 3-chloromethyl-5-(3-methoxy-phenyl)-[1,2,4]oxadiazole (30 mg, 0.13 mmol) and potassium carbonate (50 mg, 0.36 mmol) in DMF (2 ml) at room temperature. The solvent was removed in vacuo and the product obtained by flash chromatography using 20-100% ethyl acetate in hexane. 1H NMR (CDCl3), δ (ppm): 7.71 (d, 1H), 7.62 (d, 1H), 7.53 (m, 2H), 7.42 (t, 1H), 7.18 (overlapping, m, 3H), 4.52 (s, 2H), 3.87 (s, 3H).
Reaction SMILES: [C:1]1([C:7]2[C:15]3[C:10](=[CH:11][CH:12]=[C:13]([Cl:16])[CH:14]=3)[N:9]([CH2:17][CH2:18][NH2:19])[C:8]=2[C:20](OCC)=[O:21])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[CH3:10][N:9]([CH3:17])[CH2:8][CH2:7][CH2:1][N:19]1[CH2:18][CH2:17][N:9]2[C:10]3[CH:11]=[CH:12][C:13]([Cl:16])=[CH:14][C:15]=3[C:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)=[C:8]2[C:20]1=[O:21]
Reactant: CCOC(=O)c1c(-c2ccccc2)c2cc(Cl)ccc2n1CCN
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CN(C)CCCN1CCn2c(c(-c3ccccc3)c3cc(Cl)ccc32)C1=O
Temperature: 25 °C
Reaction time: 56 h

Procedure:
To a stirred solution of ethyl 3-phenyl-5-chloro-1-(2-aminoethyl)indole-2-carboxylate (6 grams, 0.019 mole) in 50 ml dimethyl formamide is added potassium carbonate, powdered, 3.4 grams (0.025 mole), followed by 2.45 grams (0.02 mole) distilled dimethylaminopropyl chloride. The solution is stirred 56 hours at room temperature, then heated at 100°-120° C. for 4 hours. After cooling, the suspension is poured into 200 ml ice-water and extracted with dichloromethane. The extract is washed with saline, then dried over sodium sulfate, filtered and concentrated. The residue, which contains considerable dimethyl formamide, is poured into water (300 ml). A solid is formed and is separated by decantation. The residue is crystallized from acetone.
Reaction SMILES: C(N(CC)CC)C.[O:8]1[CH2:13][CH2:12][CH2:11][CH:10]([NH2:14])[CH2:9]1.Cl.[C:16]([O:20][C:21]([NH:23][C@@H:24]([CH3:37])[C:25]([NH:27][N:28]1[CH:32]=[CH:31][CH:30]=[C:29]1[C:33](OC)=[O:34])=[O:26])=[O:22])([CH3:19])([CH3:18])[CH3:17].C[Al](C)C.C(C(C(C([O-])=O)O)O)([O-])=O.[Na+].[Na+]>C1(C)C=CC=CC=1.O>[O:26]=[C:25]([NH:27][N:28]1[CH:32]=[CH:31][CH:30]=[C:29]1[C:33](=[O:34])[NH:14][CH:10]1[CH2:11][CH2:12][CH2:13][O:8][CH2:9]1)[C@@H:24]([NH:23][C:21](=[O:22])[O:20][C:16]([CH3:19])([CH3:18])[CH3:17])[CH3:37]
Reactant: COC(=O)c1cccn1NC(=O)[C@H](C)NC(=O)OC(C)(C)C
Reactant: NC1CCCOC1
Agent: C[Al](C)C
Agent: Cl
Agent: O=C([O-])C(O)C(O)C(=O)[O-]
Solvent: O
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: C[C@H](NC(=O)OC(C)(C)C)C(=O)Nn1cccc1C(=O)NC1CCCOC1
Temperature: 80 °C
Reaction time: 2 h

Procedure:
Anhydrous triethylamine (600 μl, 4.31 mmols) was added to a solution of tetrahydro-2H-pyran-3-amine.HCl (600 mg, 4.36 mmols) in toluene (10 ml) and it was stirred at room temperature for 30 min. A solution of (S)-methyl 1-(2-(tert-butoxycarbonylamino)propanamido)-1H-pyrrole-2-carboxylate (900 mg, 2.90 mmols) in toluene (36 ml) and a 2M solution of trimethylaluminium in toluene (7 ml, 14 mmols) were added. The solution obtained was stirred at 80° C. for 2 h. Water (70 ml) and a 0.5M sodium tartrate solution (35 ml) were added. It was extracted with ethylacetate. The combined organic layers were washed with water and brine. It was dried, filtered and concentrated in vacuum. The title compound was obtained (750 mg, 68%).
Reaction SMILES: [CH3:1][C:2]([CH3:19])([O:4][C:5]([NH:7][C@@H:8]([CH2:12][CH:13]1[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1)[C:9]([OH:11])=O)=[O:6])[CH3:3].C(N1C=CN=C1)(N1C=CN=C1)=O.Cl.[CH3:33][NH:34][O:35][CH3:36].C(N(CC)CC)C>O1CCCC1>[CH3:19][C:2]([CH3:1])([O:4][C:5]([NH:7][C@@H:8]([CH2:12][CH:13]1[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1)[C:9]([N:34]([O:35][CH3:36])[CH3:33])=[O:11])=[O:6])[CH3:3]
Reactant: CNOC
Reactant: CC(C)(C)OC(=O)N[C@@H](CC1CCCCC1)C(=O)O
Agent: Cl
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CON(C)C(=O)[C@H](CC1CCCCC1)NC(=O)OC(C)(C)C

Procedure:
To a solution of (S)-α-[[(1,1-dimethylethoxy)-carbonyl]amino]cyclohexanepropanoic acid (93 g., 343 mmole) in dry tetrahydrofuran (1 1.) was added a 20% molar excess of 1,1'-carbonyldiimidazole over a period of less than 10 minutes with very efficient stirring to keep the internal temperature below 30° . After stirring for 30 minutes, N,O-dimethylhydroxylamine hydrochloride (36.8 g., 377 mmole) was added, followed by triethylamine (38.2 g., 377 mmole). After stirring at room temperature for 4 hours, the reaction mixture was filtered and the resulting filtrate was concentrated in vacuo. The amber colored residue (100 g.) was dissolved in ether (900 ml.) and poured into 1N HCl (1 l.). The acidic aqueous phase was separated, further extracted with ether and the combined ethereal solutions were washed with water, saturated sodium bicarbonate, water, and brine, then dried (MgSO4) to give (S)-α-[[(1,1-dimethylethoxy)-carbonyl]amino]-N-methoxy-N-methylcyclohexane-propanamide as a colorless oil. [α]D =-12.9° (c=1, methanol). TLC (silica gel; 1:1, ethyl acetate:hexanes) Rf =0.58.
Reaction SMILES: [NH2:1][C:2]1[C:7]([OH:8])=[CH:6][C:5]([Cl:9])=[CH:4][N:3]=1.Br[CH2:11][C:12]1[CH:13]=[C:14]([CH:19]=[CH:20][CH:21]=1)[C:15]([O:17][CH3:18])=[O:16]>>[NH2:1][C:2]1[C:7]([O:8][CH2:11][C:12]2[CH:13]=[C:14]([CH:19]=[CH:20][CH:21]=2)[C:15]([O:17][CH3:18])=[O:16])=[CH:6][C:5]([Cl:9])=[CH:4][N:3]=1
Reactant: COC(=O)c1cccc(CBr)c1
Reactant: Nc1ncc(Cl)cc1O
Product: COC(=O)c1cccc(COc2cc(Cl)cnc2N)c1

Procedure:
The title compound was prepared using the method of Preparation 22 from 2-amino-5-chloro-3-pyridinol and methyl 3-(bromomethyl)benzoate to give a tan solid:
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:11]=[CH:12][CH:13]=1)[CH2:5][NH:6][S:7]([CH3:10])(=[O:9])=[O:8].Br[CH2:15][C:16]([O:18]C)=[O:17].C([O-])([O-])=O.[K+].[K+]>CC(C)=O>[CH3:10][S:7]([NH:6][CH2:5][C:4]1[CH:3]=[C:2]([CH:13]=[CH:12][CH:11]=1)[O:1][CH2:15][C:16]([OH:18])=[O:17])(=[O:9])=[O:8]
Reactant: COC(=O)CBr
Reactant: CS(=O)(=O)NCc1cccc(O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CS(=O)(=O)NCc1cccc(OCC(=O)O)c1
Temperature: 25 °C
Reaction time: 68 h
Yield: 72.9 %

Procedure:
A mixture of N-(3-hydroxy-benzyl)-methanesulfonamide (6.000 g, 29.82 mmol), methyl bromoacetate (4.562 g, 29.82 mmol), K2CO3 (4.121 g, 29.82 mmol), and acetone (250 mL) was stirred at room temperature for 68 h. The solids were removed by filtration and the solution was concentrated in vacuo. Purification by flash chromatography (1:1 hexanes:EtOAc) provided the title compound (5.637 g). 1H NMR (400 MHz, CDCl3) δ 7.25 (m, 1H), 6.96 (m, 1H), 6.89 (s, 1H), 6.82 (m, 1H), 4.63 (m, 3H), 4.28 (m, 2H), 3.80 (s, 3H), 2.86 (s, 3H); MS 274 (M+1).
Reaction SMILES: C1[O:15][CH:4]([C:5]2[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=2[O:11][CH2:12][CH2:13]Cl)OC1.[C:16]1([N:22]2[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]2)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[C:16]1([N:22]2[CH2:27][CH2:26][N:25]([CH2:13][CH2:12][O:11][C:6]3[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=3[CH:4]=[O:15])[CH2:24][CH2:23]2)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: c1ccc(N2CCNCC2)cc1
Reactant: ClCCOc1ccccc1C1OCCO1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=Cc1ccccc1OCCN1CCN(c2ccccc2)CC1
Reaction time: 18 h
Yield: 42.8 %

Procedure:
A suspension of 2.29 g of 2-(2-chloroethyloxy)benzaldehyde ethyleneacetal, 1.73 g of N-phenylpiperazine, 1.50 g of anhyrous potassium carbonate and 15 ml of dimethylformamide is stirred at 70°-80° C. for about 18 hours under argon atmosphere. The reaction mixture is concentrated under reduced pressure to remove dimethylformamide. Water is added to the residue, and the aqueous mixture is extracted with ether. The extract is washed with water, dried and concentrated under reduced pressure to remove solvent. The residue is dissolved in 10 ml of methanol, and 10% hydrochloric acid is added thereto. The mixture is heated at 60° to 70° C. for 10 to 20 minutes, and then is made alkaline with 10% sodium hydroxide solution and extracted with ether. The extract is washed with water, dried and concentrated under reduced pressure to remove solvent. The residue is purified by silica gel chromatography (solvent, ethyl acetate:chloroform=2:8). 1.33 g of 2-[2-(4-phenylpiperazin-1-yl)ethyloxy]benzaldehyde are obtained as a colorless oil.
Reaction SMILES: C(N(CC)CC)C.[CH3:8][S:9](Cl)(=[O:11])=[O:10].O1CCCC1.[Cl:18][C:19]1[CH:20]=[CH:21][C:22]([CH2:25][OH:26])=[N:23][CH:24]=1>O>[CH3:8][S:9]([O:26][CH2:25][C:22]1[CH:21]=[CH:20][C:19]([Cl:18])=[CH:24][N:23]=1)(=[O:11])=[O:10]
Reactant: CS(=O)(=O)Cl
Reactant: OCc1ccc(Cl)cn1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Solvent: O
Product: CS(=O)(=O)OCc1ccc(Cl)cn1
Reaction time: 0.5 h
Yield: 99 %

Procedure:
Triethylamine (12 mL) and methanesulfonyl chloride (5.7 mL) were added to tetrahydrofuran (150 mL) solution of 5-chloro-2-hydroxymethylpyridine (12.77 g) under cooling with ice, and stirred for 30 minutes under cooling with ice. After addition of water (150 mL), the reaction liquid was extracted with ethyl acetate (150 mL+150 mL), and the organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. Concentrating the solvent under reduced pressure, the residue was crystallized from ethyl acetate-diisopropyl ether mixed solvent to provide the title compound (14.65 g, 99%).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1I.[F:9][C:10]([F:21])([F:20])[C:11]1[CH:16]=[CH:15][C:14](B(O)O)=[CH:13][CH:12]=1.C(=O)([O-])[O-].[Na+].[Na+]>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>[Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:14]1[CH:15]=[CH:16][C:11]([C:10]([F:21])([F:20])[F:9])=[CH:12][CH:13]=1
Reactant: OB(O)c1ccc(C(F)(F)F)cc1
Reactant: Brc1ccccc1I
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+]
Product: FC(F)(F)c1ccc(-c2ccccc2Br)cc1
Temperature: 85 °C
Reaction time: 32 h
Yield: 67.1 %

Procedure:
An oven dried Schlenk tube was evacuated and backfilled with argon and charged with tetrakis(triphenylphosphine)palladium (289 mg, 0.25 mmol, 5.0 mol %), 2-bromoiodobenzene (0.83 mL, 6.50 mmol), 4-(trifluoromethyl)phenylboronic acid (950 mg, 5.0 mmol), and sodium carbonate (2.86 g, 27.0 mmol). The tube was evacuated and backfilled with argon. To the tube was added (degassed) dimethoxyethane (45 mL), ethanol (2 mL), and water (15 mL) through a rubber septum. The reaction mixture was heated to 85° C. with stirring for 32 hours. The reaction mixture was then diluted with 2:1 hexane/ethyl acetate (100 mL) and poured into a separatory funnel. The mixture was washed with water (80 mL), and brine (80 mL). The organic layer was dried over anhydrous sodium sulfate, decanted, and concentrated in vacuo. The crude material was purified by flash chromatography on silica gel to afford 1.01 g (67%) of the product.
Reaction SMILES: [CH2:1]([C:3](=[CH2:6])[CH:4]=O)[CH3:2].[NH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[OH:14].[N+](C1C=CC=CC=1O)([O-])=O.[OH-].[NH4+]>Cl.C(Cl)Cl>[CH2:1]([C:3]1[CH:4]=[N:7][C:8]2[C:13]([CH:6]=1)=[CH:12][CH:11]=[CH:10][C:9]=2[OH:14])[CH3:2]
Reactant: C=C(C=O)CC
Reactant: Nc1ccccc1O
Agent: Cl
Agent: O=[N+]([O-])c1ccccc1O
Agent: [NH4+]
Solvent: ClCCl
Product: CCc1cnc2c(O)cccc2c1
Temperature: 100 °C
Reaction time: 2 h

Procedure:
2-Ethylacrolein (161.5 g) is added over a two hour period to a stirred mixture of o-aminophenol (296 g, 1.0 mol) and o-nitrophenol in 37% aqeuous hydrochloric acid (296 g) at a temperature of 100° C. The reaction mixture is allowed to stir at 100° C. for two hours and is then cooled to room temperature. Methylene chloride is added to the cooled reaction mixture and the pH of the mixture is adjusted to pH 7.0 with concentrated ammonium hydroxide while stirring. The organic phase is removed and concentrated under reduced pressure. Vaccum distillation of the residue at 5 mm Hg collecting the distillate having a vapor temperature of 130° C. to 165° C. gives 3-ethyl-8-hydroxyquinoline of 93% to 98% purity as determined by assay using high performance liquid chromatograph.
Reaction SMILES: [CH:1]1([N:4]2[CH2:9][CH2:8][N:7]([C:10]3[CH:15]=[CH:14][C:13]([N+:16]([O-])=O)=[CH:12][CH:11]=3)[CH2:6][CH2:5]2)[CH2:3][CH2:2]1>CO.[Pd]>[CH:1]1([N:4]2[CH2:5][CH2:6][N:7]([C:10]3[CH:15]=[CH:14][C:13]([NH2:16])=[CH:12][CH:11]=3)[CH2:8][CH2:9]2)[CH2:3][CH2:2]1
Reactant: O=[N+]([O-])c1ccc(N2CCN(C3CC3)CC2)cc1
Agent: [Pd]
Solvent: CO
Product: Nc1ccc(N2CCN(C3CC3)CC2)cc1
Reaction time: 4 h

Procedure:
A mixture of 1-cyclopropyl-4-(4-nitrophenyl)piperazine (1.1 g, 4.4 mmol), 10% Pd/C (100 mg) in methanol (50 mL) is stirred under a hydrogen atmosphere (balloon) for 4 h. The catalyst is filtered off through a pad of Celite and the methanol solution is evaporated to give a oily product that became a reddish-brown solid on standing (0.9 g, 93%). The compound is used in the next step without further purification. LCMS-ESI (m/z): calcd for C13H19N3, 217.1; [M+H]+ found, 218.4.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][O:4][CH2:5][C:6]1[NH:7][C:8]([CH3:28])=[C:9]([C:24]([O:26][CH3:27])=[O:25])[CH:10]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[Cl:23])[C:11]=1[C:12]([O:14][CH2:15][CH3:16])=[O:13].CS[C:31]1[NH:36][C:35](=[O:37])[CH:34]=[CH:33][N:32]=1>C(O)C>[Cl:23][C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=1[CH:10]1[C:9]([C:24]([O:26][CH3:27])=[O:25])=[C:8]([CH3:28])[NH:7][C:6]([CH2:5][O:4][CH2:3][CH2:2][NH:1][C:31]2[NH:36][C:35](=[O:37])[CH:34]=[CH:33][N:32]=2)=[C:11]1[C:12]([O:14][CH2:15][CH3:16])=[O:13]
Reactant: CCOC(=O)C1=C(COCCN)NC(C)=C(C(=O)OC)C1c1ccccc1Cl
Reactant: CSc1nccc(=O)[nH]1
Solvent: CCO
Product: CCOC(=O)C1=C(COCCNc2nccc(=O)[nH]2)NC(C)=C(C(=O)OC)C1c1ccccc1Cl

Procedure:
2-[2-Aminoethoxymethyl]-3-ethoxycarbonyl-4-(2-chlorophenyl)-5-methoxycarbonyl-6-methyl-1,4-dihydropyridine (0.75 g) and 2-methylthio-3H-pyrimid-4-one (0.5 g) were dissolved in ethanol (5 ml) and heated under reflux for 20 hours. The solvent was evaporated and the residue was partitioned between ethyl acetate and water. The organic layer was separated, washed with 2N hydrochloric acid to remove any unreacted amine, and then with dilute sodium hydroxide solution. It was then washed with water, dried, filtered and evaporated to give a yellow gum. Chromatography on silica "Kieselgel 60H" (Trade Mark) eluting with ethyl acetate gave the title compound, which was recrystallised from ethyl acetate, yield 171 mg, m.p. 148°-150°.
Reaction SMILES: [O:1]=[S:2]1(=[O:39])[CH2:7][CH2:6][CH:5]([C:8]2[CH:13]=[CH:12][C:11]([NH:14][C:15]([C:17]3[N:18](COCC[Si](C)(C)C)[CH:19]=[C:20]([C:22]#[N:23])[N:21]=3)=[O:16])=[C:10]([N:32]3[CH2:37][CH2:36][CH:35]([CH3:38])[CH2:34][CH2:33]3)[CH:9]=2)[CH2:4][CH2:3]1>C(O)(C(F)(F)F)=O.C(Cl)Cl>[O:39]=[S:2]1(=[O:1])[CH2:3][CH2:4][CH:5]([C:8]2[CH:13]=[CH:12][C:11]([NH:14][C:15]([C:17]3[NH:18][CH:19]=[C:20]([C:22]#[N:23])[N:21]=3)=[O:16])=[C:10]([N:32]3[CH2:37][CH2:36][CH:35]([CH3:38])[CH2:34][CH2:33]3)[CH:9]=2)[CH2:6][CH2:7]1
Reactant: CC1CCN(c2cc(C3CCS(=O)(=O)CC3)ccc2NC(=O)c2nc(C#N)cn2COCC[Si](C)(C)C)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC1CCN(c2cc(C3CCS(=O)(=O)CC3)ccc2NC(=O)c2nc(C#N)c[nH]2)CC1
Temperature: 25 °C
Reaction time: 4 h
Yield: 90 %

Procedure:
A solution of 4-cyano-1-(2-trimethylsilanyl-ethoxymethyl)-1H-imidazole-2-carboxylic acid [4-(1,1-dioxo-hexahydro-1λ6-thiopyran-4-yl)-2-(4-methyl-piperidin-1-yl)-phenyl]-amide (as prepared in the previous step, 19.0 mg, 0.0330 mmol) in 1 mL of 2:1 TFA/DCM was stirred at RT for 4 h. Removal of the solvent under reduced pressure followed by flash chromatography of the residue on silica gel (10-20% EtOAc/DCM) gave 13.2 mg (90%) of the title compound as a white solid: 1H-NMR (CDCl3; 400 MHz): δ 12.00 (s, 1H), 10.29 (s, 1H), 8.33 (d, 1H, J=8.3 Hz), 7.76 (d, 1H, J=2.3 Hz), 7.12 (dd, 1H, J=8.3, 1.7 Hz), 7.06 (d, 1H, J=1.7 Hz), 3.14-3.22 (m, 4H), 3.01 (d, 2H, J=12.0 Hz), 2.68-2.83 (m, 3H), 2.38-2.53 (m, 2H), 2.23 (d, 2H, J=14.5 Hz), 1.50-1.85 (m, 5H), 1.09 (d, 3H, J=5.8 Hz). Mass spectrum (ESI, m/z): Calcd. for C22H27N5O3S, 442.2 (M+H), found 442.2.
Reaction SMILES: [CH3:1][O:2][C:3]([CH:5]1[CH2:9][CH2:8][CH2:7][CH:6]1[C:10]([OH:12])=O)=[O:4].Cl.[NH2:14][CH2:15][C:16]#[N:17].F[P-](F)(F)(F)(F)F.N1([PH+](N2CCCC2)N2CCCC2)CCCC1.C(N(CC)CC)C>CN(C)C=O>[C:15]([CH2:16][NH:17][C:10]([C@@H:6]1[CH2:7][CH2:8][CH2:9][C@H:5]1[C:3]([O:2][CH3:1])=[O:4])=[O:12])#[N:14]
Reactant: N#CCN
Reactant: COC(=O)C1CCCC1C(=O)O
Agent: C1CCN([PH+](N2CCCC2)N2CCCC2)C1
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COC(=O)[C@@H]1CCC[C@H]1C(=O)NCC#N
Temperature: 0 °C
Reaction time: 3 h

Procedure:
Cyclopentane-1,2-dicarboxylic acid monomethyl ester (2.21 g, 12.8 mmol), 2-aminoacetonitrile hydrochloride (1.48 g, 16.0 mmol) and benzotriazol-1-yloxy)tripyrrolidinophosphonium hexafluorophosphate (PyBOP) (7.34 g, 14.1 mmol) were dissolved in dimethylformamide (26 mL) and the reaction mixture was cooled to 0° C. Triethylamine (4.9 mL, 35 mmol) was added and the reaction mixture was stirred at ambient temperature for 3 h. The reaction mixture was partitioned between water (150 mL) and ethyl acetate (100 mL). The product was extracted into ethyl acetate, washed with saturated sodium chloride aqueous solution, dried over anhydrous sodium sulfate and concentrated. The residue was chromatographed on silica gel with 3:2 ethyl acetate:hexanes eluent to give methyl trans-2-{[(cyanomethyl)amino]carbonyl}cyclopentanecarboxylate as a colorless solid.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([OH:10])[C:3]=1[CH:4]=[O:5].I[CH2:12][CH3:13].C([O-])([O-])=O.[K+].[K+].CCOCC>CN(C=O)C>[Cl:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([O:10][CH2:12][CH3:13])[C:3]=1[CH:4]=[O:5]
Reactant: CCI
Reactant: O=Cc1c(O)cccc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOCC
Product: CCOc1cccc(Cl)c1C=O
Temperature: 80 °C

Procedure:
A mixture of commercially available 2-chloro-6-hydroxybenzaldehyde (2.000 g; 12.80 mmol), iodoethane (3.985 g; 25.50 mmol), and K2CO3 (2.119 g; 15.30 mmol) in anh. DMF (35 ml) was heated to 80° C., under nitrogen, for 1 h. Et2O was added and the organic layer was washed with water, dried over anh. MgSO4, filtered, and concentrated to dryness under reduced pressure affording 2-chloro-6-ethoxybenzaldehyde as a yellow solid. LC-MS (conditions A): tR=0.75 min.; [M+H]+: 185.39 g/mol.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]([CH3:15])[CH2:10][C:11](=[O:14])[NH:12][N:13]=2)=[CH:4][C:3]=1[N+:16]([O-])=O>CO.[Pd]>[NH2:16][C:3]1[CH:4]=[C:5]([C:8]2[CH:9]([CH3:15])[CH2:10][C:11](=[O:14])[NH:12][N:13]=2)[CH:6]=[CH:7][C:2]=1[NH2:1]
Reactant: CC1CC(=O)NN=C1c1ccc(N)c([N+](=O)[O-])c1
Agent: [Pd]
Solvent: CO
Product: CC1CC(=O)NN=C1c1ccc(N)c(N)c1

Procedure:
100 g of 6-(4-amino-3-nitrophenyl)-5-methyl-2,3,4,5-tetrahydropyridazin-3-one are dissolved in 2 1 of methanol and hydrogenated over 20 g of 5% palladium-on-charcoal at 20° and 1 bar until absorption ceases. Filtration and evaporation give 6-(3,4-diaminophenyl)-5-methyl-2,3,4,5-tetrahydropyridazin-3-one, m.p. 195°-196°.