Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[C:10]2[C:5](=[N:6][C:7]([CH3:13])=[CH:8][C:9]=2[CH2:11][OH:12])[S:4][C:3]=1[C:14]([NH2:16])=[O:15].[CH:17](=O)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.O.C(OCC)(=O)C>C(O)(=O)C>[OH:12][CH2:11][C:9]1[C:10]2[C:2]3[NH:1][CH:17]([C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)[NH:16][C:14](=[O:15])[C:3]=3[S:4][C:5]=2[N:6]=[C:7]([CH3:13])[CH:8]=1
Reactant: O=Cc1ccccc1
Reactant: Cc1cc(CO)c2c(N)c(C(N)=O)sc2n1
Solvent: CCOC(C)=O
Solvent: O
Solvent: CC(=O)O
Product: Cc1cc(CO)c2c3c(sc2n1)C(=O)NC(c1ccccc1)N3
Temperature: 25 °C
Yield: 11.7 %

Procedure:
To a solution of 3-amino-4-hydroxymethyl-6-methyl-thieno[2,3-b]pyridine-2-carboxamide (100 mg, 0.42 mmol) in acetic acid (2 mL) was added benzaldehyde (53 mg, 0.50 mmol) and the mixture was heated to reflux for 16 h. After cooling to room temperature, water (2 mL) and ethyl acetate (2 mL) were added to it. The reaction was further extracted with ethyl acetate (2 mL×3). The combined organic layers were washed with brine, dried over Na2SO4 and evaporated under reduced pressure. The residue was purified by preparative HPLC to give the title compound, 4-hydroxymethyl-2-methyl-6-phenyl-6,7-dihydro-5H-9-thia-1,5,7-triaza-fluoren-8-one (16 mg, 12%).
Reaction SMILES: [CH3:1][C:2]1([CH3:37])[C:11]2[C:6](=[CH:7][C:8]([NH:12][C:13]([N:15]3[CH2:20][CH2:19][N:18]([C:21]4[C:26]([C:27]([F:30])([F:29])[F:28])=[CH:25][CH:24]=[CH:23][N:22]=4)[CH2:17][CH2:16]3)=[O:14])=[CH:9][CH:10]=2)[CH:5](C(=O)C(F)(F)F)[NH:4][CH2:3]1.C(=O)([O-])[O-].[K+].[K+]>CO.O>[CH3:1][C:2]1([CH3:37])[C:11]2[C:6](=[CH:7][C:8]([NH:12][C:13]([N:15]3[CH2:20][CH2:19][N:18]([C:21]4[C:26]([C:27]([F:29])([F:28])[F:30])=[CH:25][CH:24]=[CH:23][N:22]=4)[CH2:17][CH2:16]3)=[O:14])=[CH:9][CH:10]=2)[CH2:5][NH:4][CH2:3]1
Reactant: CC1(C)CNC(C(=O)C(F)(F)F)c2cc(NC(=O)N3CCN(c4ncccc4C(F)(F)F)CC3)ccc21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: O
Product: CC1(C)CNCc2cc(NC(=O)N3CCN(c4ncccc4C(F)(F)F)CC3)ccc21
Temperature: 50 °C

Procedure:
A suspension of N-(4,4-dimethyl-1-trifluoroacetyl-1,2,3,4-tetrahydroisoquinol-7-yl)-4-(3-trifluoromethyl-2-pyridyl)-piperazine-1-carboxamide (30 mg, 0.057 mmol) and potassium carbonate (48 mg, 0.348 mmol) in methanol (4 ml) and water (4 ml) was heated at 50° C. for 6 h. After this period, the solvents were evaporated in vacuo and the residue partitioned between DCM (30 ml) and water (30 ml). The aqueous layer was re-extracted with DCM (2×30 ml) and then the combined organic layers dried (Na2SO4) and the solvents evaporated in vacuo to give the title compound as a white solid. 1H NMR (400 MHz, DMSO) δ (ppm): 8.45 (dd, 1H), 7.89 (dd, 1H), 7.22 (d, 1H), 7.10 (dd, 1H), 7.00-7.05 (m, 2H), 6.55 (s, 1H), 3.95 (s, 2H), 3.60-3.65 (m, 4H), 3.30-3.32 (m, 4H), 2.82 (s, 2H), 2.00 (br-s, 1H), 1.23 (s, 6H). MS (ES): MH+ 434.
Reaction SMILES: CC1(C)[O:9][C:8](=[O:10])[C:5]2([CH2:7][CH2:6]2)[C:4](=[O:11])O1.[CH:13]1([CH2:19][NH2:20])[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1>C(O)C>[CH:13]1([CH2:19][N:20]2[CH2:6][CH2:7][CH:5]([C:8]([OH:9])=[O:10])[C:4]2=[O:11])[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1
Reactant: CC1(C)OC(=O)C2(CC2)C(=O)O1
Reactant: NCC1CCCCC1
Solvent: CCO
Product: O=C(O)C1CCN(CC2CCCCC2)C1=O
Yield: 86.4 %

Procedure:
This compound was prepared according to general method 1 starting from 6,6-dimethyl-5,7-dioxaspiro[2.5]octane-4,8-dione (0.250 g, 1.47 mmol) and cyclohexylmethanamine (0.574 mL; 4.41 mmol) in ethanol (3 mL). 1-(cyclohexylmethyl)-2-oxopyrrolidine-3-carboxylic acid 0.286 g (86%) was obtained as a yellow solid.
Reaction SMILES: C(N[C@H:5]([C:13]([OH:15])=[O:14])[CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)(=O)C.[CH3:16][C:17]1[O:18]C(=O)C(=CC2C=CC=CC=2)[N:21]=1>O>[NH:21]([C:12]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[CH:6]=[CH:5][C:13]([OH:15])=[O:14])[C:17]([CH3:16])=[O:18]
Reactant: CC1=NC(=Cc2ccccc2)C(=O)O1
Reactant: CC(=O)N[C@@H](Cc1ccccc1)C(=O)O
Solvent: O
Product: CC(=O)Nc1ccccc1C=CC(=O)O

Procedure:
The invention relates to a process for the preparation of N-acetylphenylalanine by opening the ring of 2-methyl-4-benzylidene-1,3-oxazolin-5-one with water to give 2-acetaminocinnamic acid and subsequent catalytic hydrogenation of the latter.
Reaction SMILES: [C:1]([C:3]1[CH2:20][CH2:19][C@@:18]2([CH3:21])[C:5](=[CH:6][CH2:7][C@@H:8]3[C@@H:17]2[CH2:16][CH2:15][C@@:13]2([CH3:14])[C@H:9]3[CH2:10][CH2:11][C@@H:12]2[C:22](O)=[O:23])[CH:4]=1)#[N:2].[CH3:25][O:26][C:27]1[CH:28]=[C:29]([C:35]([NH2:38])([CH3:37])[CH3:36])[CH:30]=[C:31]([O:33][CH3:34])[CH:32]=1>>[CH3:34][O:33][C:31]1[CH:30]=[C:29]([C:35]([NH:38][C:22]([C@H:12]2[CH2:11][CH2:10][C@H:9]3[C@H:8]4[C@H:17]([CH2:16][CH2:15][C@:13]23[CH3:14])[C@:18]2([CH3:21])[C:5]([CH:4]=[C:3]([C:1]#[N:2])[CH2:20][CH2:19]2)=[CH:6][CH2:7]4)=[O:23])([CH3:36])[CH3:37])[CH:28]=[C:27]([O:26][CH3:25])[CH:32]=1
Reactant: C[C@]12CC[C@H]3[C@@H](CC=C4C=C(C#N)CC[C@@]43C)[C@@H]1CC[C@@H]2C(=O)O
Reactant: COc1cc(OC)cc(C(C)(C)N)c1
Product: COc1cc(OC)cc(C(C)(C)NC(=O)[C@H]2CC[C@H]3[C@@H]4CC=C5C=C(C#N)CC[C@]5(C)[C@H]4CC[C@]23C)c1
Yield: 98 %

Procedure:
Following a procedure similar to that described in Preparation 16a, but using 3-cyanoandrosta-3,5-diene-17β-carboxylic acid [prepared as described in Example 1(b)] and 1-(3,5-dimethoxyphenyl)-1-methylethylamine as starting materials, in relative proportions similar to those used in that Preparation, the title compound was obtained in a yield of 98%.
Reaction SMILES: [NH2:1][C:2]1[C:10]([O:11][CH3:12])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].C1C(=O)N([Br:20])C(=O)C1>CO>[NH2:1][C:2]1[C:10]([O:11][CH3:12])=[CH:9][C:8]([Br:20])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5]
Reactant: COc1cccc(C(=O)O)c1N
Reactant: O=C1CCC(=O)N1Br
Solvent: CO
Product: COc1cc(Br)cc(C(=O)O)c1N
Temperature: 0 °C
Reaction time: 8 h
Yield: 99.7 %

Procedure:
To a solution of 2-amino-3-(methyloxy)benzoic acid (15.0 g, 89.7 mmol) in MeOH (100 mL) was added NBS (16.8 g, 94.2 mmol) at −5° C. The reaction was kept stirring at 0° C. overnight, then put into the ice water under the condition of stirring. A precipitate formed and was filtered out using Celite, and dried in vacuo to afford 2-amino-5-bromo-3-(methyloxy)benzoic acid (22.0 g, 99%). 1H NMR (400 MHz, CDCl3) δ 7.65 (s, 1H), 6.93 (s, 1H), 3.87 (s, 3H).
Reaction SMILES: C(O[C:4]([C:6]1[C:7]([OH:24])=[C:8]2[C:16]([Cl:17])=[CH:15][N:14]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[C:9]2=[C:10]([C:12]#[N:13])[N:11]=1)=[O:5])C.[NH2:25][CH2:26][C:27]([OH:29])=[O:28].C[O-].[Na+].CO>>[Cl:17][C:16]1[C:8]2[C:9](=[C:10]([C:12]#[N:13])[N:11]=[C:6]([C:4]([NH:25][CH2:26][C:27]([OH:29])=[O:28])=[O:5])[C:7]=2[OH:24])[N:14]([C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH:15]=1
Reactant: CCOC(=O)c1nc(C#N)c2c(c(Cl)cn2-c2ccccc2)c1O
Reactant: NCC(=O)O
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: N#Cc1nc(C(=O)NCC(=O)O)c(O)c2c(Cl)cn(-c3ccccc3)c12

Procedure:
Prepared in analogy to that of Example 1(e) from 3-chloro-7-cyano-4-hydroxy-1-phenyl-1H-pyrrolo[2,3-c]pyridine-5-carboxylic acid ethyl ester, glycine and NaOMe/HOMe. The title compound, ESI MS (m/z): 369 (M−1)−.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[C:9](=O)[C:10](=[N:18]O)[C:11](=O)[C:12]([O:14][CH2:15][CH3:16])=[O:13].Cl.[CH3:22][NH:23][NH2:24]>CO>[NH2:18][C:10]1[C:11]([C:12]([O:14][CH2:15][CH3:16])=[O:13])=[N:24][N:23]([CH3:22])[C:9]=1[C:3]1[C:2]([Cl:1])=[CH:7][CH:6]=[CH:5][C:4]=1[Cl:8]
Reactant: CCOC(=O)C(=O)C(=NO)C(=O)c1c(Cl)cccc1Cl
Reactant: CNN
Agent: Cl
Solvent: CO
Product: CCOC(=O)c1nn(C)c(-c2c(Cl)cccc2Cl)c1N
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of ethyl 4-(2,6-dichlorophenyl)-3-(hydroxyimino)-2,4-dioxobutanoate (14 g, 44 mmol) in MeOH (400 mL) at 0° C., add dropwise-concentrated HCl (10 mL) followed by methyl hydrazine (2.02 g, 44 mmol). Stir the reaction mixture at ambient temperature for 8 h and concentrate in vacuo. Partition the residue between EtOAc (400 mL) and saturated aqueous NaHCO3 (150 mL) and separate the layers. Add water (200 mL) to the organic layer, followed by sodium hydrosulfite (150 g) and stir the resulting mixture vigorously for 4 h. Separate the organic phase, wash with water (200 mL), brine (200 mL), dry over MgSO4 and evaporate to obtain the title compound.
Reaction SMILES: C(N(CCC)[C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:12](=[O:27])[C:13]2[CH:18]=[CH:17][C:16]([CH2:19][NH:20][CH2:21][C:22]3[NH:23][CH:24]=[CH:25][N:26]=3)=[CH:15][CH:14]=2)=[CH:7][CH:6]=1)CC.[N:31]1[CH:36]=[CH:35][C:34]([CH:37]=O)=[CH:33][CH:32]=1.[C:39]([BH3-])#[N:40].[Na+].C(=O)(O)[O-].[Na+]>CO.C(O)(=O)C>[CH2:6]([N:40]([CH2:39][C:5]1[CH:6]=[CH:7][C:8]([NH:11][C:12](=[O:27])[C:13]2[CH:14]=[CH:15][C:16]([CH2:19][N:20]([CH2:21][C:22]3[NH:23][CH:24]=[CH:25][N:26]=3)[CH2:37][C:34]3[CH:35]=[CH:36][N:31]=[CH:32][CH:33]=3)=[CH:17][CH:18]=2)=[CH:9][CH:10]=1)[CH2:7][CH2:8][CH3:9])[CH2:5][CH3:10]
Reactant: [BH3-]C#N
Reactant: CCCN(CCC)c1ccc(NC(=O)c2ccc(CNCc3ncc[nH]3)cc2)cc1
Reactant: O=Cc1ccncc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: CCCN(CCC)Cc1ccc(NC(=O)c2ccc(CN(Cc3ccncc3)Cc3ncc[nH]3)cc2)cc1
Temperature: 25 °C
Reaction time: 65 h

Procedure:
The compound (100 mg) obtained in Example 47-3 was dissolved in methanol (5.0 ml) and added with pyridin-4-aldehyde (manufactured by Tokyo Kasei Kogyo Co., Ltd.) (44.8 μl), followed by the addition of sodium cyanoborohydride (44.9 mg). Then, the reaction solution was adjusted to about pH 5 with acetic acid, followed by stirring at room temperature for 65 hours. The reaction solution was added with a saturated aqueous sodium bicarbonate solution and then extracted with chloroform. The organic layer was washed with saturated saline solution and then dried with anhydrous sodium sulfate. Subsequently, the solvent was distilled off. The resulting crude product was purified through silica gel column chromatography (chloroform/methanol) and treated with hydrochloric acid, thereby obtaining hydrochloride (106 mg) of the subject compound as a white solid.
Reaction SMILES: CO[C:3]1[CH:8]=[CH:7][C:6]([CH2:9]CCN)=[CH:5][CH:4]=1.C1(C[CH2:20][CH2:21][NH2:22])CCCCC1.[O:23]1CCOCC1>>[CH:6]1([CH2:9][O:23][CH2:20][CH2:21][NH2:22])[CH2:5][CH2:4][CH2:3][CH2:8][CH2:7]1
Reactant: NCCCC1CCCCC1
Reactant: COc1ccc(CCCN)cc1
Reactant: C1COCCO1
Product: NCCOCC1CCCCC1

Procedure:
A solution of 1.18 g (7.1 mmol) 3-(4-methoxyphenyl)propylamine in 50 mL of dioxane was hydrogenated at 138 bar and at 160° C. for 16 h in the presence of 0.5 g of 5% Ru/Al2O3. The catalyst was removed by filtration and the filtrate was concentrated to dryness. Preparative HPLC of the crude product by elution with 10% (10% concd NH4OH in MeOH)--CH2Cl2 furnished 723.5 mg (59%) of the cis/trans mixture of cyclohexylpropylamine (c/t=~3:1 by 1H NMR): 1H NMR (CDCl3, cis-isomer only) δ 3.37 (br s, 1H), 3.27 (s, 3H), 2.64 (t, J=7.0 Hz, 2H), 2.10-0.87 (M, 15H); FDMS 172 (M+1).
Reaction SMILES: [CH:1](C1C2C(=CC=CC=2)C=CC=1)=[CH2:2].[CH:13]([C:15]1C2C(=CC=CC=2)C=CC=1)=[O:14].C[Mg]I.[C:28]1([CH:34]([C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)[CH3:35])[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1.C(Cl)(=O)C>>[C:28]1([CH:34]([C:36]2[CH:37]=[CH:38][CH:39]=[CH:40][C:41]=2[CH:1]=[CH2:2])[CH3:35])[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1.[C:28]1([CH:34]([C:36]2[CH:37]=[CH:38][CH:39]=[CH:40][C:41]=2[C:13](=[O:14])[CH3:15])[CH3:35])[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: C=Cc1cccc2ccccc12
Reactant: CC(c1ccccc1)c1ccccc1
Reactant: O=Cc1cccc2ccccc12
Agent: C[Mg]I
Solvent: CC(=O)Cl
Product: C=Cc1ccccc1C(C)c1ccccc1
Product: CC(=O)c1ccccc1C(C)c1ccccc1

Procedure:
For instance, vinylnaphthalene is prepared by reacting formylnaphthalene with a Grignard reagent such as methylmagnesium iodide, and then dehydrating. Phenyl(vinylphenyl)ethane is prepared by reacting diphenylethane with acetyl chloride in the presence of a Friedel-Crafts catalyst to obtain phenyl(acetylphenyl)ethane, reducing by sodium borohydride, and then dehydrating. Phenyl(isopropenylphenyl)ethane is prepared by reacting phenyl(formylphenyl)ethane with a Grignard reagent such as methylmagnesium iodide, and then dehydrating. 1,2-Diphenylethylene is prepared by reacting benzaldehyde with benzylmagnesium bromide, and then dehydrating. 1,2-Diphenylpropene is also prepared by a similar method. 1,1-Diphenylethylene is prepared by reacting diphenyl ketone with a Grignard reagent such as methylmagnesium iodide, and then dehydrating.
Reaction SMILES: [CH3:1][C:2]1([CH3:22])[C:7]2[CH:8]=[C:9]([C:12]3[N:16]([CH2:17][CH3:18])[C:15]([C:19]#[N:20])=[CH:14][CH:13]=3)[CH:10]=[CH:11][C:6]=2[NH:5][C:4](=O)[O:3]1.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:32])=CC=1>>[CH3:1][C:2]1([CH3:22])[C:7]2[CH:8]=[C:9]([C:12]3[N:16]([CH2:17][CH3:18])[C:15]([C:19]#[N:20])=[CH:14][CH:13]=3)[CH:10]=[CH:11][C:6]=2[NH:5][C:4](=[S:32])[O:3]1
Reactant: CCn1c(C#N)ccc1-c1ccc2c(c1)C(C)(C)OC(=O)N2
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Product: CCn1c(C#N)ccc1-c1ccc2c(c1)C(C)(C)OC(=S)N2

Procedure:
The title compound was prepared according to the procedure for Example 16 from 5-(4,4-dimethyl-2-oxo-1,4-dihydro-2H-3,1-benzoxazin-6-yl)-1-ethyl-1H-pyrrole-2-carbonitrile and Lawesson's reagent. The product was obtained in the form of white needles: mp 212-213° C.; 1H-NMR (DMSO-d6) δ 1.25 (t, 3H, J=7 Hz), 1.68 (s, 6H), 4.07 (q, J=7 Hz, 2H), 6.32 (d, J=3.9 Hz, 1H), 7.07 (d, J=3.9 Hz, 1H), 7.15 (d, J=9 Hz, 1H), 7.42 (m, 2H), 12.33 (s, 1H); MS (ESI) m/z 310 (M−H)−.
Reaction SMILES: [CH:1]1([C:4]2[NH:12][C:11]3[C:10](=S)[NH:9][C:8](=[S:14])[N:7]([CH2:15][CH2:16][CH3:17])[C:6]=3[N:5]=2)[CH2:3][CH2:2]1.[N:18]1[CH:23]=[CH:22][C:21]([CH2:24][NH2:25])=[CH:20][CH:19]=1.Cl.C(=O)(O)[O-].[Na+]>O>[CH:1]1([C:4]2[NH:12][C:11]3[C:10]([NH:25][CH2:24][C:21]4[CH:22]=[CH:23][N:18]=[CH:19][CH:20]=4)=[N:9][C:8](=[S:14])[N:7]([CH2:15][CH2:16][CH3:17])[C:6]=3[N:5]=2)[CH2:3][CH2:2]1
Reactant: CCCn1c(=S)[nH]c(=S)c2[nH]c(C3CC3)nc21
Reactant: NCc1ccncc1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Product: CCCn1c(=S)nc(NCc2ccncc2)c2[nH]c(C3CC3)nc21

Procedure:
5.33 g (20 mmoles) of 8-cyclopropyl-3-n-propyl-2,6-dithioxanthine and 21.3 ml (200 mmoles) of 95% 4-picolylamine were heated under argon to 150-5° C. After 14 hours the cooled solution was poured into 100 ml of water, acidified with 19 ml of 10N HCl and 1N HCl to pH 6, where an orange colored gum was formed. With sodium bicarbonate the mixture was neutralized to pH 7. With time the gum crystallized and the solid is collected and washed. The residue was suspended in acetone and the crystals collected: 3.92 (57.6%) of crude product. The filtrate was evaporated to dryness, dissolved in 40 ml of 0.5N NaOH, extracted 4 times with methylenechloride, and acidified again with 5N HCl to pH 6. Again the gum crystallized over 48 hours and the mixture was neutralized to pH 7 with bicarbonate and the solid collected: 1.75 g (25.7%) of crude product. Both parts were dissolved in 30 ml of methylenechloride and filtered through 30 g of silicagel in a column. 150 mg (2.8%) of starting material was recovered first, then 5.04 g (74.0%) of product was recovered with 5% of methanol, which was dissolved in 32 ml of 1N HCl, treated with 250 mg of charcoal, filtered, and neutralized with 7.5 ml of 2N NaOH and sodium bicarbonate solution to pH 7-8. The water phase was decanted from the gum and the latter washed with water and crystallized from acetone: 4.08 g (59.9%) of thioisoguanine with mp 204-210° C. with decomposition.
Reaction SMILES: Cl[C:2]1[CH:11]=[C:10]([Cl:12])[C:9]2[C:4](=[N:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.[CH3:13][C:14]1[N:19]=[C:18]([Sn](CCCC)(CCCC)CCCC)[CH:17]=[CH:16][CH:15]=1>C1(C)C=CC=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.Cl[Pd]Cl>[Cl:12][C:10]1[C:9]2[C:4](=[N:5][CH:6]=[CH:7][CH:8]=2)[N:3]=[C:2]([C:18]2[CH:17]=[CH:16][CH:15]=[C:14]([CH3:13])[N:19]=2)[CH:11]=1
Reactant: CCCC[Sn](CCCC)(CCCC)c1cccc(C)n1
Reactant: Clc1cc(Cl)c2cccnc2n1
Agent: Cl[Pd]Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: Cc1cccc(-c2cc(Cl)c3cccnc3n2)n1
Temperature: 80 °C
Reaction time: 16 h

Procedure:
A solution of 1.69 g (8.47 mmol) 2,4-dichloro-[1,8]naphthyridine and 3.24 g (8.47 mmol) 6-methyl-2-(tributylstannyl)-pyridine in 8.5 ml toluene under nitrogen was heated to 80° C. Then 178 mg (0.254 mmol) bis-(triphenylphosphine)-palladium(II)-chloride were added. The mixture was stirred for 16 hrs at 80° C. and then cooled to 0° C. in an ice bath. The precipitate was filtered off, washed with ice cold toluene and petrolether and dried in vacuum. This yielded 4-chloro-2-(6-methylpyridin-2-yl)-[18]naphthyridine as gray felted needles; HPLC-MS: 2.25 min, [M+H] 256.
Reaction SMILES: [CH:1]([C@H:4]1[N:9]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:8][CH2:7][N:6]2[C:17]3[CH:23]=[C:22]([S:24]([CH3:27])(=[O:26])=[O:25])[C:21]([C:28](OC)=[O:29])=[CH:20][C:18]=3[N:19]=[C:5]12)([CH3:3])[CH3:2].CC(C[AlH]CC(C)C)C.CCOC(C)=O>C(Cl)Cl>[OH:29][CH2:28][C:21]1[C:22]([S:24]([CH3:27])(=[O:25])=[O:26])=[CH:23][C:17]2[N:6]3[CH2:7][CH2:8][N:9]([C:10]([O:12][C:13]([CH3:15])([CH3:16])[CH3:14])=[O:11])[C@H:4]([CH:1]([CH3:2])[CH3:3])[C:5]3=[N:19][C:18]=2[CH:20]=1
Reactant: COC(=O)c1cc2nc3n(c2cc1S(C)(=O)=O)CCN(C(=O)OC(C)(C)C)[C@@H]3C(C)C
Agent: CC(C)C[AlH]CC(C)C
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CC(C)[C@@H]1c2nc3cc(CO)c(S(C)(=O)=O)cc3n2CCN1C(=O)OC(C)(C)C
Temperature: -78 °C
Reaction time: 3 h
Yield: 74.6 %

Procedure:
To a 50 mL three-necked flask containing (R)-2-tert-butyl 8-methyl 1-isopropyl-7-(methylsulfonyl)-3,4-dihydrobenzo[4,5]imidazo[1,2-a]pyrazine-2,8(1H)-dicarboxylate (250 mg, 0.554 mmol, from preparation 2) in DCM (5 mL) was added DIBAL-H (1.70 mL, 1.67 mmol, 1.0 M in toluene) dropwise at −78° C. under N2. The mixture was stirred at −78° C. for 3 h. The reaction was quenched with sat. aq. ammonium chloride (10 mL) at −78° C. The aqueous layer was extracted with EtOAc (3×20 mL). The combined organic layers were washed with water (15 mL) and brine, and then dried over anhydrous Na2SO4. The mixture was filtered and the filtrate was evaporated under reduced pressure. The residue was purified by column chromatography on silica gel eluting with PE:EtOAc 8:1˜2:1 to give (R)-tert-butyl 8-(hydroxymethyl)-1-isopropyl-7-(methylsulfonyl)-3,4-dihydrobenzo[4,5]imidazo[1,2-a]pyrazine-2(1H)-carboxylate (175 mg, 74.1% yield) as a white solid.
Reaction SMILES: Br[CH:2]=[C:3]1[C:9]2[CH:10]=[CH:11][CH:12]=[C:13]([Cl:14])[C:8]=2[CH2:7][CH2:6][C:5]2[CH:15]=[CH:16][CH:17]=[CH:18][C:4]1=2.[CH3:19][S:20]([NH:23][C:24]1[CH:29]=[CH:28][C:27](B(O)O)=[CH:26][CH:25]=1)(=[O:22])=[O:21]>>[Cl:14][C:13]1[C:8]2[CH2:7][CH2:6][C:5]3[CH:15]=[CH:16][CH:17]=[CH:18][C:4]=3[C:3](=[CH:2][C:27]3[CH:28]=[CH:29][C:24]([NH:23][S:20]([CH3:19])(=[O:22])=[O:21])=[CH:25][CH:26]=3)[C:9]=2[CH:10]=[CH:11][CH:12]=1
Reactant: Clc1cccc2c1CCc1ccccc1C2=CBr
Reactant: CS(=O)(=O)Nc1ccc(B(O)O)cc1
Product: CS(=O)(=O)Nc1ccc(C=C2c3ccccc3CCc3c(Cl)cccc32)cc1

Procedure:
Following procedures essentially as described in Example 219, below, and using 5-bromomethylene-1-chloro-10,11-dihydro-5H-dibenzo[a,d]cycloheptene (100 mg, 0.313 mmol) and 4-methanesulfonylaminophenylboronic acid (74 mg, 0.344 mmol), affords 55 mg (43%) of a mixture of geometric isomers of the title compound as a brown oil. MS (ES) 408 (M−H); HPLC shows 96% purity.
Reaction SMILES: Br[C:2]1[S:3][C:4]([CH:7]=[O:8])=[CH:5][N:6]=1.[CH3:9][C:10]1[N:11]=[CH:12][NH:13][CH:14]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[CH3:9][C:10]1[N:11]=[CH:12][N:13]([C:2]2[S:3][C:4]([CH:7]=[O:8])=[CH:5][N:6]=2)[CH:14]=1
Reactant: O=Cc1cnc(Br)s1
Reactant: Cc1c[nH]cn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1cn(-c2ncc(C=O)s2)cn1
Temperature: 110 °C
Yield: 292.6 %

Procedure:
A mixture of 2-bromo-1,3-thiazole-5-carbaldehyde (10 mg, 0.068 mmol), 4-methyl-1H-imidazole (7.23 mg, 0.088 mmol), potassium carbonate (28.1 mg, 0.203 mmol) and DMF (5 ml) were heated at 110° C. for 1 h. The mixture was purified on silica gel (EtOAc/hexane 8:2) to afford 2-(4-methyl-1H-imidazol-1-yl)-1,3-thiazole-5-carbaldehyde (38.4 mg, 0.199 mmol) as a yellow solid. This aldehyde (38.4 mg, 0.199 mmol) and anhydrous potassium carbonate (110 mg, 0.795 mmol) were placed in a 25-ml flask and placed on high vacuum for 10 min. Under N2, anhydrous MeOH (2 ml) was added. To the suspension was added dimethyl (1-diazo-2-oxopropyl) phosphonate (40 μl, 0.256 mmol). The reaction was stirred at rt for 22 h. The mixture was diluted with DCM, washed with water, dried over sodium sulfate, concentrated to afford crude product, which was used in next step directly.
Reaction SMILES: [Br:1][C:2]1[CH:9]=[C:8](F)[CH:7]=[CH:6][C:3]=1[C:4]#[N:5].C[Si](C)(C)[O-:13].[K+]>CN(C=O)C.C(OCC)(=O)C>[Br:1][C:2]1[CH:9]=[C:8]([OH:13])[CH:7]=[CH:6][C:3]=1[C:4]#[N:5]
Reactant: N#Cc1ccc(F)cc1Br
Reactant: C[Si](C)(C)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: N#Cc1ccc(O)cc1Br
Temperature: 25 °C
Reaction time: 1 h
Yield: 101 %

Procedure:
To a solution of 2-bromo-4-fluoro-benzonitrile (2000 mg, 9.9995 mmol) in DMF (20 mL), potassium trimethylsilanolate (2565.7 mg, 19.999 mmol) was added portionwise and the reaction mixture stirred at room temperature for 1 h. The mixture was diluted with ethyl acetate (100 ml), washed with an aqueous saturated solution of ammonium chloride (100 ml) and brine (3×100 ml), dried over sodium sulphate and concentrated under vacuum to give the title compound (2000 mg) which was used in the next step without purification.
Reaction SMILES: [CH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]=1.[CH:7]1([OH:13])[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]1>O>[CH3:1][C:6]1[CH2:5][CH2:4][CH2:3][CH:2]=1.[CH:7]1([OH:13])[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]1
Reactant: C1=CCCCC1
Solvent: OC1CCCCC1
Solvent: O
Product: CC1=CCCC1

Procedure:
With respect to the manner of the hydration reaction, there is no particular limitation; the reaction can be performed in either of continuous and batchwise manners. The hydration reaction is generally performed as follows. Cyclohexene is added to a catalyst slurry comprising a hydration catalyst and water to effect hydration of cyclohexene in a suspension state to obtain a reaction mixture comprising an aqueous phase comprised of the catalyst slurry and an oil phase comprised of cyclohexanol produced and the cyclohexene remaining unreacted. The oil phase is phase-separated from the aqueous phase, and provided to a separation step. The aqueous phase containing the hydration catalyst can be recycled as the catalyst slurry to the reactor. In the hydration reaction, a small amount of methylcyclopentene is generally formed as a by-product as well as cyclohexanol as the desired intermediate. The oil phase, which contains the cyclohexanol, the methylcyclopentene and the cyclohexene, is separated into a high boiling point component containing cyclohexanol and a low boiling point component containing cyclohexene by a customary method, such as distillation. If desired, the separated cyclohexanol can be further subjected to treatment for isolation, thereby obtaining a cyclohexanol having a desired purity. In such a case, it is preferred that the obtained cyclohexanol has a purity of 99% or more. In general, it is preferred that the unreacted cyclohexene which is separated from cyclohexanol is subjected to treatment for isolation so as to obtain cyclohexene having a desired purity, followed by recycling thereof to the reactor.
Reaction SMILES: [C:1]([N:4]1[CH:9]2[CH2:10][CH2:11][CH:5]1[CH2:6][NH:7][CH2:8]2)(=[O:3])[CH3:2].[CH2:12](Cl)[CH:13]=[CH:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[C:1]([N:4]1[CH:5]2[CH2:11][CH2:10][CH:9]1[CH2:8][N:7]([CH2:12][CH:13]=[CH:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[CH2:6]2)(=[O:3])[CH3:2]
Reactant: ClCC=Cc1ccccc1
Reactant: CC(=O)N1C2CCC1CNC2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CC(=O)N1C2CCC1CN(CC=Cc1ccccc1)C2

Procedure:
N8 -acetyl-3,8-diazabicyclo[3.2.1]octane was reacted with equimolar amounts of cinnamyl chloride, in the presence of potassium carbonate in acetone under reflux, checking the reaction by thin layer chromatography (TLC). When the reaction was completed, the inorganic salt was filtered off and the filtrate evaporated to dryness. The residue was purified by chromatography (1:1 CHCl3 /Ethyl acetate). N8 -Acetyl-N3 -cinnamyl-3,8-diazabicyclo[3.2.1]octane was obtained, the elementary analysis being in accordance with the desired compound.