Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C:3]1[NH:12][C:11]2[C:10](=[O:13])[N:8]([CH3:9])[C:7](=[O:14])[N:6]([CH3:15])[C:5]=2[N:4]=1)[CH3:2].[H-].[Na+].[O:18]([CH2:25][CH2:26][CH2:27]Br)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.O>CN(C)C=O>[CH2:1]([C:3]1[N:12]([CH2:27][CH2:26][CH2:25][O:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:11]2[C:10](=[O:13])[N:8]([CH3:9])[C:7](=[O:14])[N:6]([CH3:15])[C:5]=2[N:4]=1)[CH3:2]
Reactant: BrCCCOc1ccccc1
Reactant: CCc1nc2c([nH]1)c(=O)n(C)c(=O)n2C
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCc1nc2c(c(=O)n(C)c(=O)n2C)n1CCCOc1ccccc1
Reaction time: 0.5 h
Yield: 69 %

Procedure:
A suspension of 8-ethyltheophylline (20.8 g; 0.1 M) in dry dimethylformamide (100 ml) was added to an oil free suspension of sodium hydride (2.4 g; 0.1 M) in dry dimethylformamide (100 ml) and the mixture was stirred for 30 minutes. 3-Phenoxypropylbromide (21.5 g; 0.1 M) was added and the mixture was stirred at room temperature for 24 hours. The resulting suspension was poured into water and the precipitate was filtered off and dried. The solid was crystallised from ethanol to give 8-ethyl-7-(3-phenoxy propyl)theophylline as white prisms 23.6 g (69%) mp 107°-8°.
Reaction SMILES: [O:1]1[CH2:5][CH2:4][CH:3]([CH2:6][NH:7][C:8](SC)=[CH:9][N+:10]([O-:12])=[O:11])[CH2:2]1.[CH3:15][NH2:16]>CO.[OH-].[Na+].C(O)C>[O:1]1[CH2:5][CH2:4][CH:3]([CH2:6][NH:7][C:8]([NH:16][CH3:15])=[CH:9][N+:10]([O-:12])=[O:11])[CH2:2]1
Reactant: CN
Reactant: CSC(=C[N+](=O)[O-])NCC1CCOC1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: CCO
Product: CNC(=C[N+](=O)[O-])NCC1CCOC1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
A mixture comprising 7.0 g of (tetrahydro-3-furanyl)methylamine, 12.5 g of 1,1-bis(methylthio)-2-nitroethylene and 100 ml of acetonitrile was refluxed for 5 hours. The reaction mixture was concentrated under a reduced pressure, and purified by silica gel column chromatography (eluent:ethyl acetate/hexane=1/1) to give 6.6 g of 1-[{tetrahydro-3-furanyl)methyl}amino]-1-methylthio-2-nitroethylene. Then, a mixture comprising 4.0 g of the 1-[{(tetrahydro-3-furanyl)methyl}amino]-1-methylthio-2-nitroethylene obtained above, 6.0 ml of 40% methylamine in methanol solution, 20 ml of 1N aqueous sodium hydroxide solution and 20 ml of ethanol was stirred at room temperature for 5 hours. The resulting reaction mixture was concentrated under a reduced pressure, and purified by silica gel column chromatography (eluent:ethyl acetate/methanol=9/1) to obtain 3.2 g of 1-[{(tetrahydro-3-furanyl)methyl}amino]-1-methylamino-2-nitroethylene.
Reaction SMILES: [CH3:1][C:2]1[C:7]([Cl:8])=[C:6]([OH:9])[C:5]([CH2:10]/[CH:11]=[C:12](/[CH2:14][CH2:15]/[CH:16]=[C:17](/[C@H:19]2[O:24][C:23]([CH3:26])([CH3:25])[C:21](=[O:22])[CH2:20]2)\[CH3:18])\[CH3:13])=[C:4]([OH:27])[C:3]=1[CH:28]=[O:29].[H][H]>[Pd].C(O)C>[Cl:8][C:7]1[C:2]([CH3:1])=[C:3]([C:4]([OH:27])=[C:5]([CH2:10][CH2:11][CH:12]([CH3:13])[CH2:14][CH2:15][CH2:16][CH:17]([CH:19]2[CH2:20][C:21](=[O:22])[C:23]([CH3:25])([CH3:26])[O:24]2)[CH3:18])[C:6]=1[OH:9])[CH:28]=[O:29]
Reactant: C/C(=C\Cc1c(O)c(Cl)c(C)c(C=O)c1O)CC/C=C(\C)[C@@H]1CC(=O)C(C)(C)O1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: Cc1c(Cl)c(O)c(CCC(C)CCCC(C)C2CC(=O)C(C)(C)O2)c(O)c1C=O

Procedure:
An ethanol (201 ml) solution of ascofuranone (1,058 mg, 2.52 mmlo) was stirred in the presence of 5% Pd/C (435 mg) in a hydrogen atmosphere at 0(C for three hours. After the catalyst was separated by filtration with the use of Celite, the filtrate was concentrated to obtain a crude product (1,178 mg). This product was purified by silica gel column chromatography (hexane:ethyl acetate═5:1) to obtain 3-chloro-4,6-dihydroxy-2-methyl-5-[3-methyl-7-(tetrahydro-5,5-dimethyl-4-oxo-2-furanyl)-octyl]benzaldehyde (a diastereomeric mixture, yellow syrup 262 mg, yield 25%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7]([C:12]([NH2:14])=[O:13])=[C:6]2[O:15][CH:16]([CH3:18])[CH3:17].[H-].[Na+].[CH3:21][O:22][CH2:23]Cl>CN(C)C=O.C(OCC)(=O)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[N:8]([CH2:21][O:22][CH3:23])[C:7]([C:12]([NH2:14])=[O:13])=[C:6]2[O:15][CH:16]([CH3:18])[CH3:17]
Reactant: COc1ccc2[nH]c(C(N)=O)c(OC(C)C)c2c1
Reactant: COCCl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COCn1c(C(N)=O)c(OC(C)C)c2cc(OC)ccc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 31.8 %

Procedure:
5-Methoxy-3-(1-methylethoxy)-1H-indole-2-carboxamide (106 mg, 0.43 mmol) in 4 mL of dimethylformamide is added to a suspension of sodium hydride (60% by weight) (30 mg, 0.75 mol) in 2 mL of dimethylformamide. After 1 hour chloromethyl methyl ether (60 μL, 0.79 mmol) is added, and the solution is stirred at room temperature overnight. The reaction mixture is diluted with ethyl acetate and washed with brine. The organic layer is dried over MgSO4. Filtration followed by concentration in vacuo and subsequent chromatography eluting with 1:1 ethyl acetate:hexane gives 40 mg of 5-methoxy-1-methoxymethyl-3-(1-methylethoxy)-1H-indole-2-carboxamide. An analytical sample was obtained by recrystallization from ethyl acetate:hexane; mp 145°-147° C.
Reaction SMILES: [CH2:1]([O:8][C@H:9]1[CH2:13][N:12]([CH:14]2[CH2:19][CH2:18][N:17]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:16][CH2:15]2)[C:11](=[O:27])[C@H:10]1[O:28][C:29]1[CH:34]=[CH:33][C:32](Br)=[CH:31][C:30]=1[F:36])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:37][S:38]([O-:40])=[O:39].[Na+].[C@@H]1(N)CCCC[C@H]1N>CS(C)=O>[CH2:1]([O:8][C@H:9]1[CH2:13][N:12]([CH:14]2[CH2:19][CH2:18][N:17]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:16][CH2:15]2)[C:11](=[O:27])[C@H:10]1[O:28][C:29]1[CH:34]=[CH:33][C:32]([S:38]([CH3:37])(=[O:40])=[O:39])=[CH:31][C:30]=1[F:36])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CS(=O)[O-]
Reactant: CC(C)(C)OC(=O)N1CCC(N2C[C@H](OCc3ccccc3)[C@H](Oc3ccc(Br)cc3F)C2=O)CC1
Agent: N[C@@H]1CCCC[C@H]1N
Agent: [Na+]
Solvent: CS(C)=O
Product: CC(C)(C)OC(=O)N1CCC(N2C[C@H](OCc3ccccc3)[C@H](Oc3ccc(S(C)(=O)=O)cc3F)C2=O)CC1
Temperature: 110 °C
Yield: 53.4 %

Procedure:
Tert-butyl 4-((3S,4S)-4-(benzyloxy)-3-(4-bromo-2-fluorophenoxy)-2-oxopyrrolidin-1-yl)piperidine-1-carboxylate (300 mg, 0.532 mmol) was dissolved in DMSO (5 mL) and degassed for 10 minutes. Sodium methanesulfinate (81.5 mg, 0.799 mmol) and trans-cyclohexane-1,2-diamine (25.6 μL, 0.213 mmol) were added, followed by Cu(I) triflate benzene complex (26.8 mg, 0.0532 mmol) and the reaction was heated to 110° C. overnight. The reaction was cooled, partitioned between water and EtOAc, extracted with EtOAc, washed with brine, dried over Na2SO4, filtered and concentrated. The residue was purified over silica gel (100% EtOAc) to afford tert-butyl 4-((3S,4S)-4-(benzyloxy)-3-(2-fluoro-4-(methylsulfonyl)phenoxy)-2-oxopyrrolidin-1-yl)piperidine-1-carboxylate (160 mg, 0.284 mmol, 53.4% yield).
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:16]([O:18]CC)=[O:17])=[N:4][CH:5]=[C:6]([CH2:8][C:9]2[CH:14]=[CH:13][C:12]([F:15])=[CH:11][CH:10]=2)[CH:7]=1.C([O-])([O-])=O.[Cs+].[Cs+].N[C:28]1[CH:38]=[CH:37][C:31]([C:32]([N:34]([CH3:36])[CH3:35])=[O:33])=[CH:30][CH:29]=1.CC(C)([O-])C.[Na+]>O1CCOCC1.ClCCl.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.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2>[CH3:35][N:34]([CH3:36])[C:32]([C:31]1[CH:37]=[CH:38][C:28]([NH:1][C:2]2[C:3]([C:16]([OH:18])=[O:17])=[N:4][CH:5]=[C:6]([CH2:8][C:9]3[CH:10]=[CH:11][C:12]([F:15])=[CH:13][CH:14]=3)[CH:7]=2)=[CH:29][CH:30]=1)=[O:33]
Reactant: CCOC(=O)c1ncc(Cc2ccc(F)cc2)cc1N
Reactant: CN(C)C(=O)c1ccc(N)cc1
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Solvent: ClCCl
Solvent: C1COCCO1
Product: CN(C)C(=O)c1ccc(Nc2cc(Cc3ccc(F)cc3)cnc2C(=O)O)cc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 94 %

Procedure:
To a dry 100 mL flask under a nitrogen atmosphere was added ethyl 3-amino-5-(4-fluorobenzyl)pyridine-2-carboxylate (89 mg, 0.325 mmol) described in example 1, Cs2CO3 (148 mg, 0.455 mmol), Pd2dba3 (1.5 mg, 0.0016 mmol), and Xantphos (2.8 mg, 0.0049 mmol). Dioxane (15 mL) and 4-amino-N,N-dimethylbenzamide (1.25 mL of a 0.78 M solution in dioxane, 0.975 mmol) were added and the resulting solution was refluxed for 2 hrs. Sodium tert-butoxide (94 mg, 0.975 mmol) was added and the mixture was stirred for 10 minutes. The mixture was cooled to ambient temperature, diluted with dichloromethane, filtered through Celite and concentrated under reduced pressure. Water was added and the aqueous layer was washed with ethyl acetate and then acidified with 1 N hydrochloric acid to a pH of 4. The resulting yellow precipitate was collected by vacuum filtration to yield 3-({4-[(dimethylamino)carbonyl]phenyl}amino)-5-[(4-fluorophenyl)methyl]-2-pyridinecarboxylic acid (120 mg, 94% yield). 1H NMR (CDCl3) δ 7.82 (s, 1 H), 7.46 (s, 1 H), 7.38 (d, J=8.4 Hz, 2 H), 7.13 (d, J=8.4 Hz, 2 H), 7.09-7.05 (m, 2 H), 6.97-6.93 (m, 2 H), 3.88 (s, 2 H), 3.07 (s, 3 H), 2.99 (s, 3 H); MS m/z 392 (M−1).
Reaction SMILES: [CH:1]([N:3]1[C:15]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[C:9]2[C:4]1=[CH:5][CH:6]=[CH:7][CH:8]=2)=[CH2:2].[C:16](OC=C)(=[O:18])[CH3:17].[OH-].[Na+].C(N1C2C=CC=CC=2C2C1=CC=CC=2)=C>O1CCCC1>[CH:1]([N:3]1[C:15]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[C:9]2[C:4]1=[CH:5][CH:6]=[CH:7][CH:8]=2)=[CH2:2].[CH:16]([OH:18])=[CH2:17]
Reactant: C=COC(C)=O
Agent: C=Cn1c2ccccc2c2ccccc21
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: C=CO
Temperature: 60 °C
Reaction time: 3 h

Procedure:
Copoly(N-vinyl carbazole-vinyl acetate) (5.0 g) was dissolved in 100 ml of tetrahydrofuran and 25 ml of I N methanolic sodium hydroxide was added. The solution was stirred for 3 hours at 60° C and precipitated into 600 ml of methanol. The polymer was purified by two additional precipitations from tetrahydrofuran into methanol. The purified polymer was obtained in 90% yield and was found to contain 46.6 mole percent N-vinyl carbazole (calculated from nitrogen analysis).
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH3:15].[NH:16]1[CH2:21][CH2:20][O:19][CH2:18][CH2:17]1>C(#N)C>[CH2:2]([N:16]1[CH2:21][CH2:20][O:19][CH2:18][CH2:17]1)[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH3:15]
Reactant: C1COCCN1
Reactant: CCCCCCCCCCCCCCBr
Solvent: CC#N
Product: CCCCCCCCCCCCCCN1CCOCC1
Temperature: 25 °C
Yield: 93.6 %

Procedure:
In a 250-mL round bottom flask, equipped with a magnetic stirrer, a heating mantle and reflux condenser, were placed 1-bromotetradecane (15.9 g, 57.3 mmol), acetonitrile (75 mL), and morpholine (10 g, 114.7 mmol). The reaction mixture was refluxed for 4 hrs. The reaction mixture was cooled to room temperature and was concentrated to a residue on a rotary evaporator. Water and ethyl acetate were added. The organic phase was separated and washed with saturated sodium chloride solution, and then dried over anhydrous magnesium sulfate. After filtration, the solvent was evaporated to dryness affording 15.2 g (94% yield) of 4-tetradecylmorpholine as a tan oil. This intermediate was subjected to the next step without further purification.
Reaction SMILES: C([O:3][C:4](=[O:23])[CH2:5][CH:6]1[N:11]2[CH:12]=[C:13]([C:15]3[CH:20]=[CH:19][CH:18]=[C:17]([Cl:21])[CH:16]=3)[CH:14]=[C:10]2[C:9](=[O:22])[NH:8][CH2:7]1)C.[OH-].[Li+]>O1CCCC1.O>[Cl:21][C:17]1[CH:16]=[C:15]([C:13]2[CH:14]=[C:10]3[C:9](=[O:22])[NH:8][CH2:7][CH:6]([CH2:5][C:4]([OH:23])=[O:3])[N:11]3[CH:12]=2)[CH:20]=[CH:19][CH:18]=1
Reactant: CCOC(=O)CC1CNC(=O)c2cc(-c3cccc(Cl)c3)cn21
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)CC1CNC(=O)c2cc(-c3cccc(Cl)c3)cn21
Temperature: 25 °C
Reaction time: 18 h
Yield: 85.9 %

Procedure:
To a solution of ethyl[7-(3-chlorophenyl)-1-oxo-1,2,3,4-tetrahydropyrrolo[1,2-a]pyrazin-4-yl]acetate (0.573 g, 1.72 mmol) in a mixture tetrahydrofuran-water (5:1, 10 mL) was added lithium hydroxide (144 mg, 3.44 mmol) and the reaction mixture was stirred at room temperature for 18 h. The THF was evaporated and the aqueous residue diluted with H2O. The aqueous phase was acidified with hydrochloric acid (1 M) until pH<1 and a precipitation occurred; the solid was filtered, washed with water and dried under vacuum to obtain the title compound as an off-white solid (450 mg, 85% yield).
Reaction SMILES: [C:1]([O:4][CH2:5][C:6]1[C:10]2[CH2:11][N:12]([CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH2:13][CH:14]([CH3:15])[C:9]=2[N:8]([CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[C:7]=1[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)(=O)C>CO>[CH2:23]([N:8]1[C:9]2[CH:14]([CH3:15])[CH2:13][N:12]([CH2:16][C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=3)[CH2:11][C:10]=2[C:6]([CH2:5][O:4][CH3:1])=[C:7]1[C:30]1[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=1)[C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1
Reactant: CC(=O)OCc1c2c(n(Cc3ccccc3)c1-c1ccccc1)C(C)CN(Cc1ccccc1)C2
Solvent: CO
Product: COCc1c2c(n(Cc3ccccc3)c1-c1ccccc1)C(C)CN(Cc1ccccc1)C2

Procedure:
3-Acetoxymethyl-1,5-dibenzyl-4,5,6,7-tetrahydro-7-methyl-2-phenyl-1H-pyrrolo[3,2-c]pyridine (200 mg), prepared according to Example 16, was dissolved in methanol (10 ml) by briefly warming. On cooling, the title compound wasobtained as white needles, 125 mg. M.pt. 140°-1° C (Found: C,82.5; H, 7.5; N, 6.4. C30H32N2O requires: C, 82.5; H, 7.4; N, 6.4%).
Reaction SMILES: C[O:2][C:3](=O)[C:4]([N:7]1[CH2:12][CH2:11][CH:10]([S:13][C:14]2[C:15]([F:37])=[CH:16][C:17]3[O:26][CH2:25][CH2:24][N:23]4[C:19](=[N:20][C:21]([C:27]5[N:28]([CH:33]([CH3:35])[CH3:34])[N:29]=[C:30]([CH3:32])[N:31]=5)=[CH:22]4)[C:18]=3[CH:36]=2)[CH2:9][CH2:8]1)([CH3:6])[CH3:5].[H-].[H-].[H-].[H-].[Li+].[Al+3].CCOC(C)=O>C1COCC1>[F:37][C:15]1[C:14]([S:13][CH:10]2[CH2:11][CH2:12][N:7]([C:4]([CH3:6])([CH3:5])[CH2:3][OH:2])[CH2:8][CH2:9]2)=[CH:36][C:18]2[C:19]3[N:23]([CH2:24][CH2:25][O:26][C:17]=2[CH:16]=1)[CH:22]=[C:21]([C:27]1[N:28]([CH:33]([CH3:35])[CH3:34])[N:29]=[C:30]([CH3:32])[N:31]=1)[N:20]=3
Reactant: COC(=O)C(C)(C)N1CCC(Sc2cc3c(cc2F)OCCn2cc(-c4nc(C)nn4C(C)C)nc2-3)CC1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: Cc1nc(-c2cn3c(n2)-c2cc(SC4CCN(C(C)(C)CO)CC4)c(F)cc2OCC3)n(C(C)C)n1
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 73 %

Procedure:
To an ice-cooled solution of 2-{4-[8-fluoro-2-(2-isopropyl-5-methyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-1,3a-diazabenzo[e]azulen-9-ylsulfanyl]piperidin-1-yl}-2-methylpropionic acid methyl ester (0.394 mmol) in THF (20 mL) was added LiAlH4 (1.0M in THF, 0.79 mL) and the mixture was stirred at 0° C. for 5 min. To the reaction mixture was added EtOAc (1 mL) and stirring was continued for 10 min. Volatiles were removed under reduced pressure and the resulting residue was partitioned between DCM (40 mL) and 10% aq. solution of Rochelle's salt (50 mL). The suspension was then filtered through a pad of Celite®. The filtrate was extracted with additional DCM and the combined organic layers were washed with water, then brine, dried and concentrated in vacuo. The resulting residue was purified by column chromatography (Si-PCC, gradient 2-10% 2M NH3/MeOH in DCM) affording 2-{4-[8-Fluoro-2-(2-isopropyl-5-methyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-1,3a-diazabenzo[e]azulen-9-ylsulfanyl]piperidin-1-yl}-2-methylpropan-1-ol (148 mg, 73% over two steps). LCMS: RT 2.17 min [M+H]+ 515.0
Reaction SMILES: [OH-].[Na+].[CH3:3][O:4][CH2:5][CH2:6][O:7][CH2:8][O:9][C:10]1[CH:11]=[C:12]2[C:17](=[CH:18][CH:19]=1)[CH:16]=[C:15]([C:20]([O:22]C)=[O:21])[CH:14]=[CH:13]2.Cl>O1CCCC1.CO.O>[CH3:3][O:4][CH2:5][CH2:6][O:7][CH2:8][O:9][C:10]1[CH:11]=[C:12]2[C:17](=[CH:18][CH:19]=1)[CH:16]=[C:15]([C:20]([OH:22])=[O:21])[CH:14]=[CH:13]2
Reactant: COCCOCOc1ccc2cc(C(=O)OC)ccc2c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: COCCOCOc1ccc2cc(C(=O)O)ccc2c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 93 %

Procedure:
12.9 g (325 mmol) of sodium hydroxide pellets are added to a solution of 16.9 g (58 mmol) of methyl 6-(2-methoxyethoxymethoxy)naphthalene-2-carboxylate in 200 ml of tetrahydrofuran, 20 ml of methanol and a few drops of water, and the reaction medium is stirred at room temperature for 4 hours. Next, aqueous 1N hydrochloric acid solution is added until pH=2 is obtained, and the reaction medium is extracted with ethyl acetate, dried over sodium sulfate, filtered and concentrated under vacuum. The residue obtained is washed with heptane and filtered. 14.9 g of 6-(2-methoxyethoxymethoxy)-2-naphthoic acid are obtained in the form of a white solid, in a yield of 92%.
Reaction SMILES: [CH2:1]([N:3]([CH2:20][CH3:21])[C:4](=[O:19])[CH2:5][C:6](=[O:18])[CH2:7][CH:8]([OH:17])[CH:9]=[CH:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[CH3:2].C([BH3-])#N.[Na+]>CC(C)[O-].CC(C)[O-].CC(C)[O-].[Cl-].[Ti+4]>[CH2:20]([N:3]([CH2:1][CH3:2])[C:4](=[O:19])[CH2:5][CH:6]([OH:18])[CH2:7][CH:8]([OH:17])[CH:9]=[CH:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[CH3:21]
Reactant: CCN(CC)C(=O)CC(=O)CC(O)C=Cc1ccccc1
Agent: [Ti+4]
Agent: CC(C)[O-]
Agent: [BH3-]C#N
Product: CCN(CC)C(=O)CC(O)CC(O)C=Cc1ccccc1
Yield: 69.4 %

Procedure:
By carrying out the reaction as in Example 9 but starting from 530 mg of N,N-diethyl-7-phenyl-5-hydroxy-3-oxo-6-heptenamide (1.83 mmol), 0.51 cm3 of 95% titanium chloride triisopropoxide (2.2 mmol) and from 136.9 mg of 95% sodium cyanoborohydride (2.06 mmol), there is obtained, with a yield of 70%, 370 mg of N,N-diethyl-7-phenyl-3,5-dihydroxy-6-heptenamide for which the syn/anti ratio is equal to 70/30.
Reaction SMILES: [OH-].[K+].[Cl:3][C:4]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:5]=1[CH:6]=[CH:7][NH:8]2.Cl[CH2:14][C:15]1[N:16]=[CH:17][N:18]([C:20]([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH:19]=1>CS(C)=O.O>[Cl:3][C:4]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:5]=1[CH:6]=[CH:7][N:8]2[CH2:14][C:15]1[N:16]=[CH:17][N:18]([C:20]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)([C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=2)[C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[CH:19]=1
Reactant: Clc1cccc2[nH]ccc12
Reactant: ClCc1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CS(C)=O
Product: Clc1cccc2c1ccn2Cc1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Reaction time: 0.5 h

Procedure:
A mixture of powdered KOH (7 mmol) in DMSO (12 mL) at room temperature (rt) under N2 was stirred for 0.5 h. 4-Chloro-1H-indole (Intermediate A1) (1.67 mmol) was added and the mixture was allowed to stir for 2 h at rt. The 4-chloromethyl-1-trityl-1H-imidazole (prepared according to the procedures in: James, L. K. et al; J. Med. Chem. 1997, 20, 721. and Cordi, A. A. et al Eur. J. Med. Chem. 1990, 25, 557, incorporated herein by reference) (Intermediate A2) (1.19 mmol) was added and the mixture was stirred at rt for 18 h. The solution was diluted with H2O and extracted with ethyl acetate. The organic phase was washed with H2O, dried over MgSO4, filtered and evaporated to give the crude product. The residue was purified by chromatography on SiO2 with 1-2% MeOH in CH2Cl2 to give 4-chloro-1-(1-trityl-1H-imidazol-4-ylmethyl)-1H-indole (Intermediate A3). The protected imidazole compound (Intermediate A3) was mixed with H2O (3 mL) and acetic acid (6 mL) and heated to reflux for 1 to 2 h. The mixture was cooled to rt and made basic with 2M NaOH. The aqueous layer was extracted with ethyl acetate (2×15 mL) and the combined organic layers were dried over Na2SO4. This mixture was filtered, freed of solvent and purified by chromatography with 5% NH3:MeOH in CH2Cl2 to give 4-(4-chloro-indol-1-ylmethyl)-1,3-dihydro-imidazole (Intermediate A4) (˜20% over two steps).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH2:11][C:12]#[N:13].[CH:14]1([N:20]=[C:21]=[O:22])[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1>C(O)C>[C:12]([CH2:11][C:5]1[C:4]2[C:8](=[CH:9][CH:10]=[C:2]([NH:1][C:21]([NH:20][CH:14]3[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]3)=[O:22])[CH:3]=2)[NH:7][CH:6]=1)#[N:13]
Reactant: O=C=NC1CCCCC1
Reactant: N#CCc1c[nH]c2ccc(N)cc12
Solvent: CCO
Product: N#CCc1c[nH]c2ccc(NC(=O)NC3CCCCC3)cc12
Reaction time: 1 h
Yield: 55.8 %

Procedure:
To a solution of 7.0 g (0.041 mole) of 5-aminoindole-3-acetonitrile in 100 ml of abs ethanol, at 0° under nitrogen atmosphere, was added 5.23 ml (0.041 mole) of cyclohexylisocyanate dropwise. After stirring at 0° for one hour the product was filtered and recrystallized from ethanol to give 6.78 g (56% yield) of desired product: m.p. 233°-234°; i.r. (Nujol) 3300, 3275, 2245 and 1622 cm-1.
Reaction SMILES: [NH2:1][C:2]1[CH:18]=[CH:17][CH:16]=[CH:15][C:3]=1[O:4][C:5]1[CH:14]=[CH:13][CH:12]=[CH:11][C:6]=1[C:7]([O:9]C)=[O:8].[OH-].[Na+]>CO.O>[NH2:1][C:2]1[CH:18]=[CH:17][CH:16]=[CH:15][C:3]=1[O:4][C:5]1[CH:14]=[CH:13][CH:12]=[CH:11][C:6]=1[C:7]([OH:9])=[O:8]
Reactant: COC(=O)c1ccccc1Oc1ccccc1N
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: Nc1ccccc1Oc1ccccc1C(=O)O
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A mixture of Methyl 2-(2-aminophenoxy)benzoate (9.2 g, 0.038 mol) and sodium hydroxide (3.2 g, 0.08 mol) in 1:1 methanol/water (200 mL) was stirred under argon at room temperature for 3 h. The methanol was evaporated, the aqueous residue was acidified with dilute HCl, extracted with ethyl acetate, dried over anhydrous MgSO4, filtered, and evaporated to give the crude product which was purified by flash chromatography (silica gel, ethyl acetate/hexane/formic acid), and then recrystallized from ethyl acetate/hexane to give the title compound as a white crystalline solid; mp 150°-151° C.
Reaction SMILES: [CH3:1][N:2]([CH3:16])[CH2:3][CH2:4][N:5]([C:8]1[CH:13]=[C:12]([CH3:14])[CH:11]=[C:10]([CH3:15])[N:9]=1)[C:6]#[N:7].[OH-].[Na+].NC(N)=[O:21]>Cl>[CH3:1][N:2]([CH3:16])[CH2:3][CH2:4][N:5]([C:8]1[CH:13]=[C:12]([CH3:14])[CH:11]=[C:10]([CH3:15])[N:9]=1)[C:6]([NH2:7])=[O:21]
Reactant: Cc1cc(C)nc(N(C#N)CCN(C)C)c1
Reactant: NC(N)=O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: Cc1cc(C)nc(N(CCN(C)C)C(N)=O)c1

Procedure:
A solution of N-(2-dimethylaminoethyl)-N-(4,6-dimethyl-2-pyridyl)cyanamide (5.66 g., 0.026 mole) in 6 N hydrochloric acid (60 ml.) is allowed to sit at room temperature for 11/2 hour. The reaction solution was then cooled, made alkaline (pH about 11) with 50% sodium hydroxide solution, and extracted with ether. After washing with water and drying over anhydrous magnesium sulfate, the combined extracts are taken to dryness in vacuum. Recrystallization of the residue from hexane gives 3.90 g. of product urea, m.p. 88°-89° C.
Reaction SMILES: [F:1][C:2]1[CH:8]=[CH:7][CH:6]=[CH:5][C:3]=1[NH2:4].Cl.N([O-])=O.[Na+].[N-:14]=[N+:15]=[N-].[Na+]>O>[F:1][C:2]1[CH:8]=[CH:7][CH:6]=[CH:5][C:3]=1[N:4]=[N+:14]=[N-:15]
Reactant: [N-]=[N+]=[N-]
Reactant: Nc1ccccc1F
Agent: Cl
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Product: [N-]=[N+]=Nc1ccccc1F

Procedure:
A mixture of 4.44g. (0.04 mole) of 2-fluoroaniline in 16 ml. of water and 9 ml. of concentrated HCl, kept at 0°-5° C., was treated with a solution of 2.90g. (0.04 mole) of NaNO2 in 10 ml. of water. The reaction mixture was aged for one-half hour at 0°-5° C. and there was then added slowly to the mixture a solution of 2.6g. (0.04 mole) of NaN3 in 10 ml. of water. The reaction mixture was then allowed to slowly reach room temperature, and it was noted that a gas was evolved. There was then added 40 ml. of petroleum ether, and the reaction mixture was shaken well, after which it was observed to separate into two separate layers. The yellow petroleum ether layer was separated, dried over MgSO4, and concentrated under reduced pressure at a temperature of about 30° C. There was produced 5.5g. of a yellow oil and the structure of the final product was confirmed by IR.