Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]=[CH:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[CH2:9]([O:11][SiH:12]([O:16][CH2:17][CH3:18])[O:13][CH2:14][CH3:15])[CH3:10]>[H+].[H+].Cl[Pt-2](Cl)(Cl)(Cl)(Cl)Cl.C(O)(C)C>[CH2:1]([Si:12]([O:16][CH2:17][CH3:18])([O:13][CH2:14][CH3:15])[O:11][CH2:9][CH3:10])[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: CCO[SiH](OCC)OCC
Reactant: C=Cc1ccccc1
Agent: Cl[Pt-2](Cl)(Cl)(Cl)(Cl)Cl
Agent: [H+]
Solvent: CC(C)O
Product: CCO[Si](CCc1ccccc1)(OCC)OCC
Temperature: 50 °C
Yield: 1.5 %

Procedure:
130 mg Of styrene and 217 mg of triethoxysilane were placed in a glass reaction tube and 0.01 ml of an isopropyl alcohol solution of chloroplatinic acid (platinum content: 0.02 Wt. %) was added to this mixture. The reaction tube was sealed with Teflon tape and heated for 30 minutes in an oil bath at 50° C. When the tube contents were analyzed by GC-MS following cooling, the conversion rate of styrene was 3% and phenethyltriethoxysilane was produced at a yield of 1.5%. The yield of (α-methylbenzyl) triethoxysilane was 0.5%.
Reaction SMILES: [CH:1]1([C:7]2[S:23][C:10]3[N:11]=[C:12]([CH3:22])[N:13]=[C:14]([CH2:15][NH:16][C:17]([CH3:21])([CH3:20])[CH2:18][OH:19])[C:9]=3[CH:8]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C1N=CN([C:29](N2C=NC=C2)=[O:30])C=1>C(Cl)Cl>[CH:1]1([C:7]2[S:23][C:10]3[N:11]=[C:12]([CH3:22])[N:13]=[C:14]([CH2:15][N:16]4[C:17]([CH3:20])([CH3:21])[CH2:18][O:19][C:29]4=[O:30])[C:9]=3[CH:8]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: Cc1nc(CNC(C)(C)CO)c2cc(C3CCCCC3)sc2n1
Reactant: O=C(n1ccnc1)n1ccnc1
Solvent: ClCCl
Product: Cc1nc(CN2C(=O)OCC2(C)C)c2cc(C3CCCCC3)sc2n1
Temperature: 25 °C
Reaction time: 6 h
Yield: 91.1 %

Procedure:
To a mixture of 2-{[(6-cyclohexyl-2-methylthieno[2,3-d]pyrimidin-4-yl)methyl]amino}-2-methylpropan-1-ol (55 mg) and DCM was added CDI (40 mg), followed by stirring at room temperature for 6 hours. The reaction mixture was concentrated under reduced pressure. The residue was purified by silica gel column (hexane/EtOAc) to obtain 3-[(6-cyclohexyl-2-methylthieno[2,3-d]pyrimidin-4-yl)methyl]-4,4-dimethyl-1,3-oxazolidin-2-one (54 mg).
Reaction SMILES: C([O:3][C:4](=O)[CH:5]=[C:6]1[CH2:9][CH:8]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([Br:16])[CH:11]=2)[CH2:7]1)C.[BH4-].[Na+]>>[Br:16][C:12]1[CH:11]=[C:10]([CH:8]2[CH2:7][CH:6]([CH2:5][CH2:4][OH:3])[CH2:9]2)[CH:15]=[CH:14][CH:13]=1
Reactant: CCOC(=O)C=C1CC(c2cccc(Br)c2)C1
Agent: [BH4-]
Agent: [Na+]
Product: OCCC1CC(c2cccc(Br)c2)C1
Temperature: 67 °C
Yield: 51.1 %

Procedure:
[3-(3-Bromo-phenyl)-cyclobutylidene]-acetic acid ethyl ester (1.3 g, 4.48 mmol) was suspended in poly(ethylene glycol) (Average MW 400, 15 mL) and sodium borohydride (650 mg, 17.2 mmol) was added portionwise. The slurry was warmed to 67° C. for one hour, then cooled to room temperature and partitioned between 2N hydrochloric acid and diethylether. The ether extracts were purified by column chromatography (EtOAc in hexanes) to afford 584 mg of an oil (52%). 1H NMR (400 MHz, DMSO-d6) δ ppm 1.19-1.29 (m, 1H) 1.31-1.38 (m, 1H) 1.47-1.52 (m, 1H) 1.59-1.68 (m, 1H) 1.97-2.32 (m, 2H) 2.34-2.41 (m, 1H) 4.22-4.31 (m, 1H) 3.23-3.39 (m, 3H) 7.15-7.24 (m, 2H) 7.29-7.38 (m, 2H); MS (EI) m/z 254 [M+·].
Reaction SMILES: C(O[CH:4]=[C:5]([C:8]#[N:9])[C:6]#[N:7])C.Cl.[Cl:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[NH:18][NH2:19]>CCO>[NH2:9][C:8]1[N:18]([C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=2[Cl:11])[N:19]=[CH:4][C:5]=1[C:6]#[N:7]
Reactant: NNc1ccccc1Cl
Reactant: CCOC=C(C#N)C#N
Agent: Cl
Solvent: CCO
Product: N#Cc1cnn(-c2ccccc2Cl)c1N

Procedure:
At RT, 2-(ethoxymethylene)malononitrile (5.77 g, 47.2 mmol) was added in portions to a stirred suspension of 1-(2-chlorophenyl)hydrazine hydrochloride (8.05 g, 45.0 mmol) and TEA (6.58 ml, 47.2 mmol) in absolute EtOH (56 mL). The mixture was heated to reflux for 1 h. The volatile solvents were removed under reduced pressure. The brown reside was dissolved in EtOAc, washed with water followed by saturated NaHCO3 solution. The organic layer was dried over sodium sulfate, filtered, and concentrated under reduced pressure to obtain 5-amino-1-(2-chlorophenyl)-1H-pyrazole-4-carbonitrile as a rusty crystalline solid. MS (ESI, pos.ion) m/z: 219.0 (M+1).
Reaction SMILES: [C:1]([C:5]1[CH:42]=[CH:41][C:8]([CH2:9][O:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2/[CH:17]=[CH:18]/[CH:19]([CH2:31][CH2:32][C:33]2[CH:38]=[CH:37][C:36]([C:39]#[N:40])=[CH:35][CH:34]=2)[CH2:20][C:21]2[CH:30]=[CH:29][C:24]([C:25]([O:27]C)=[O:26])=[CH:23][CH:22]=2)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[OH-].[Li+].Cl>C1COCC1.O>[C:1]([C:5]1[CH:42]=[CH:41][C:8]([CH2:9][O:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2/[CH:17]=[CH:18]/[CH:19]([CH2:31][CH2:32][C:33]2[CH:38]=[CH:37][C:36]([C:39]#[N:40])=[CH:35][CH:34]=2)[CH2:20][C:21]2[CH:22]=[CH:23][C:24]([C:25]([OH:27])=[O:26])=[CH:29][CH:30]=2)=[CH:7][CH:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(=O)c1ccc(CC(/C=C/c2ccccc2OCc2ccc(C(C)(C)C)cc2)CCc2ccc(C#N)cc2)cc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)c1ccc(COc2ccccc2/C=C/C(CCc2ccc(C#N)cc2)Cc2ccc(C(=O)O)cc2)cc1
Temperature: 60 °C
Reaction time: 12 h
Yield: 90 %

Procedure:
A solution of 1.1 g (1.97 mmol) of methyl-4-{(3E)-4-{2-[(4-tert-butylbenzyl)oxy]phenyl}-2-[2-(4-cyanophenyl)ethyl]but-3-en-1-yl}benzoate from Example 102A in 7.20 ml of THF and 3.60 ml of water is mixed with 189 mg (7.89 mmol) of lithium hydroxide and stirred at 60° C. for 12 h. The reaction mixture is adjusted to pH 34 with 1 M hydrochloric acid and concentrated. The residue is taken up on silica gel and purified by chromatography (mobile phase: cyclohexane/ethyl acetate 1:1, with 0.1% formic acid). 990 mg (1.77 mmol, 97% purity, 90% yield) of a solid are isolated.
Reaction SMILES: [OH:1][C:2]([C:30]1[CH:31]=[C:32]2[C:37](=[CH:38][CH:39]=1)[CH:36]=[C:35]([C:40](OC)=[O:41])[CH:34]=[CH:33]2)([C:6]1[N:7]=[CH:8][N:9](C(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[CH:10]=1)[CH:3]([CH3:5])[CH3:4].OC(C1C=C2C(=CC=1)C=C(C(O)=O)C=C2)(C1N=C[N:52]([C:54]([C:67]2[CH:72]=[CH:71][CH:70]=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)C=1)C(C)C.C1(N)CCCC1>>[CH:54]1([NH:52][C:40]([C:35]2[CH:34]=[CH:33][C:32]3[C:37](=[CH:38][CH:39]=[C:30]([C:2]([OH:1])([C:6]4[N:7]=[CH:8][NH:9][CH:10]=4)[CH:3]([CH3:4])[CH3:5])[CH:31]=3)[CH:36]=2)=[O:41])[CH2:67][CH2:72][CH2:71][CH2:70]1
Reactant: COC(=O)c1ccc2cc(C(O)(c3cn(C(c4ccccc4)(c4ccccc4)c4ccccc4)cn3)C(C)C)ccc2c1
Reactant: CC(C)C(O)(c1ccc2cc(C(=O)O)ccc2c1)c1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Agent: NC1CCCC1
Product: CC(C)C(O)(c1ccc2cc(C(=O)NC3CCCC3)ccc2c1)c1c[nH]cn1

Procedure:
In a manner to that described in Example 9-(i), methyl 6-(1-hydroxy-2-methyl-1-(1-trityl-1H-imidazol-4-yl)propyl)-2-naphthoate (2.83 g) was converted to 6-(1-hydroxy-2-methyl-1-(1-trityl-1H-imidazol-4-yl)propyl)-2-naphthoic acid, which was reacted with cyclopentylamine (0.16 ml) in a similar manner as described in Example 24-(i) to give the titled compound (509 mg) as a colorless powder.
Reaction SMILES: [C:1]([O:5][C:6](=[O:21])[CH2:7][N:8]1[C:12]2=[N:13][CH:14]=[CH:15][CH:16]=[C:11]2[C:10]([C:17](=[NH:20])[NH:18]O)=[N:9]1)([CH3:4])([CH3:3])[CH3:2].CC(OC(C)=O)=O>[Pd].CC(O)=O>[C:1]([O:5][C:6](=[O:21])[CH2:7][N:8]1[C:12]2=[N:13][CH:14]=[CH:15][CH:16]=[C:11]2[C:10]([C:17](=[NH:18])[NH2:20])=[N:9]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)Cn1nc(C(=N)NO)c2cccnc21
Agent: [Pd]
Solvent: CC(=O)OC(C)=O
Solvent: CC(=O)O
Product: CC(C)(C)OC(=O)Cn1nc(C(=N)N)c2cccnc21

Procedure:
[3-(N-Hydroxycarbamimidoyl)-pyrazolo[3,4-b]pyridin-1-yl]-acetic acid tert-butyl ester (6.17 g) in a 100 mL vial was charged with AcOH (45 mL) and Ac2O (4.3 mL). The resultant mixture was stirred at room temperature for 1 h at this time the initial suspension became a clear solution. To this solution was added Pd/C (10%, 900 mg) and stirred under 1 atm H2 balloon, and resultant mixture was stirred over night at room temperature. The reaction mixture was filtered through a pad of celite washed with DCM/MeOH. Evaporation of the solvent gave (3-amidino-pyrazolo[3,4-b]pyridin-1-yl)-acetic acid tert-butyl ester which was used without further purification.
Reaction SMILES: S(=O)(=O)(O)O.CO[C@@H:8]1[O:30][C:29]([CH2:41][O:42][C:43](=[O:50])[C:44]2[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=2)([CH2:31][O:32][C:33](=[O:40])[C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[C@@H:19]([O:20][C:21](=[O:28])[C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[C@H:9]1[O:10][C:11](=[O:18])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.[C:51]([OH:54])(=[O:53])[CH3:52]>C(OC(=O)C)(=O)C.C(OCC)(=O)C.O>[C:51]([O:54][C@@H:8]1[O:30][C:29]([CH2:41][O:42][C:43](=[O:50])[C:44]2[CH:45]=[CH:46][CH:47]=[CH:48][CH:49]=2)([CH2:31][O:32][C:33](=[O:40])[C:34]2[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=2)[C@@H:19]([O:20][C:21](=[O:28])[C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)[C@H:9]1[O:10][C:11](=[O:18])[C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1)(=[O:53])[CH3:52]
Reactant: CO[C@@H]1OC(COC(=O)c2ccccc2)(COC(=O)c2ccccc2)[C@@H](OC(=O)c2ccccc2)[C@H]1OC(=O)c1ccccc1
Reactant: CC(=O)O
Agent: O=S(=O)(O)O
Solvent: CC(=O)OC(C)=O
Solvent: O
Solvent: CCOC(C)=O
Product: CC(=O)O[C@@H]1OC(COC(=O)c2ccccc2)(COC(=O)c2ccccc2)[C@@H](OC(=O)c2ccccc2)[C@H]1OC(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 15 h

Procedure:
Sulfuric acid (97%, 75 mL) was added to a solution of 1-O-methyl-2,3,5-tri-O-benzoyl-4-C-(benzoyloxymethyl)-β-D-ribofuranose (1.7 g, 2.8 mmoles) in a mixture of acetic acid (6.7 mL) and acetic anhydride (0.67 mL) at 0° C. The reaction mixture was stirred at 25° C. for 15 h and diluted with ethyl acetate (50 mL) and water (10 mL). This solution was washed with brine (3 times), with a saturated aqueous solution of sodium bicarbonate, dried over sodium sulfate, filtered, and the filtrate was evaporated to dryness. The residue was subjected to silica gel chromatography [ethanol (0–2%) in dichloromethane] to give 1.4 g of the titled compound as a white solid.
Reaction SMILES: [C:1]1([CH2:7][C:8]([OH:10])=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N1C=CN=C1)(N1C=CN=C1)=O.[OH:23][C:24]1[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][C:25]=1[NH2:26]>ClCCl>[C:1]1([CH2:7][C:8]([NH:26][C:25]2[CH:27]=[C:28]([Cl:31])[CH:29]=[CH:30][C:24]=2[OH:23])=[O:10])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: Nc1cc(Cl)ccc1O
Reactant: O=C(O)Cc1ccccc1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: ClCCl
Product: O=C(Cc1ccccc1)Nc1cc(Cl)ccc1O
Reaction time: 1 h

Procedure:
Phenylacetic acid (20 g, 0.15 mol) in dichloromethane (120 ml) was treated with 1,1′-carbonyl diimidazole (25 g, 0.15 mol). After 1 hour, a solution of 2-hydroxy-5-chloroaniline in dichloromethane was added. The mixture was stirred overnight and processed in the usual manner to give 31.2 g of the title compound as a crystalline solid.
Reaction SMILES: [CH2:1]([C:3]1[C:4]([CH:29]([OH:49])[C:30]2[N:34](COCC[Si](C)(C)C)[C:33]3[CH:43]=[CH:44][C:45]([C:47]#[N:48])=[CH:46][C:32]=3[N:31]=2)=[C:5]2[C:9](=[C:10]([CH3:12])[CH:11]=1)[N:8]([S:13]([C:16]1[CH:22]=[CH:21][C:19]([CH3:20])=[CH:18][CH:17]=1)(=[O:15])=[O:14])[CH:7]=[C:6]2[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[CH3:2].C(C1C(C(O)C2N(COCC[Si](C)(C)C)C3C=C(C#N)C=CC=3N=2)=C2C(=C(C)C=1)N(S(C1C=CC(C)=CC=1)(=O)=O)C=C2C1C=CC=CC=1)C>Cl.CO.CCOC(C)=O>[CH2:1]([C:3]1[C:4]([CH:29]([OH:49])[C:30]2[NH:34][C:33]3[CH:43]=[CH:44][C:45]([C:47]#[N:48])=[CH:46][C:32]=3[N:31]=2)=[C:5]2[C:9](=[C:10]([CH3:12])[CH:11]=1)[N:8]([S:13]([C:16]1[CH:22]=[CH:21][C:19]([CH3:20])=[CH:18][CH:17]=1)(=[O:15])=[O:14])[CH:7]=[C:6]2[C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1)[CH3:2]
Reactant: CCc1cc(C)c2c(c(-c3ccccc3)cn2S(=O)(=O)c2ccc(C)cc2)c1C(O)c1nc2cc(C#N)ccc2n1COCC[Si](C)(C)C
Agent: CCc1cc(C)c2c(c(-c3ccccc3)cn2S(=O)(=O)c2ccc(C)cc2)c1C(O)c1nc2ccc(C#N)cc2n1COCC[Si](C)(C)C
Agent: Cl
Solvent: CO
Solvent: CCOC(C)=O
Product: CCc1cc(C)c2c(c(-c3ccccc3)cn2S(=O)(=O)c2ccc(C)cc2)c1C(O)c1nc2cc(C#N)ccc2[nH]1
Temperature: 60 °C
Reaction time: 17 h

Procedure:
A solution of a mixture of (±)-2-((5-ethyl-7-methyl-3-phenyl-1-tosyl-1H-indol-4-yl)(hydroxy)methyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazole-5-carbonitrile and (±)-2-((5-ethyl-7-methyl-3-phenyl-1-tosyl-1H-indol-4-yl)(hydroxy)methyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazole-6-carbonitrile (25 mg, 0.036 mmol) in 1M HCl in MeOH (2 mL) was stirred at 60° C. for 17 h. The reaction mixture was cooled to room temperature. The reaction mixture was diluted with EtOAc. The mixture was successively washed by 5% aq. NaHCO3, H2O and brine, dried over Na2SO4, and filtered. Concentration of the filtrate gave the title compound, which was used in the next reaction without any further purification. MS (ESI+) m/z 561.2 (M+H).
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[N:14]([CH2:15][CH2:16][O:17][CH3:18])[C:13]3[C:19]([O:29][CH3:30])=[CH:20][C:21]([CH2:27]O)=[C:22]([C:23]([F:26])([F:25])[F:24])[C:12]=3[N:11]=2)=[CH:6][CH:5]=1)([CH3:3])[CH3:2].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(Br)(Br)(Br)[Br:51]>C1COCC1>[Br:51][CH2:27][C:21]1[CH:20]=[C:19]([O:29][CH3:30])[C:13]2[N:14]([CH2:15][CH2:16][O:17][CH3:18])[C:10]([C:7]3[CH:8]=[CH:9][C:4]([CH:1]([CH3:3])[CH3:2])=[CH:5][CH:6]=3)=[N:11][C:12]=2[C:22]=1[C:23]([F:24])([F:26])[F:25]
Reactant: COCCn1c(-c2ccc(C(C)C)cc2)nc2c(C(F)(F)F)c(CO)cc(OC)c21
Reactant: BrC(Br)(Br)Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COCCn1c(-c2ccc(C(C)C)cc2)nc2c(C(F)(F)F)c(CBr)cc(OC)c21
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 89.5 %

Procedure:
To a solution of 655 mg (1.52 mmol) [2-(4-isopropyl-phenyl)-7-methoxy-1-(2-methoxy-ethyl)-4-trifluoromethyl-1H-benzoimidazol-5-yl]-methanol in 10 ml THF, 604 mg (2.28 mmol) triphenylphosphine and 764 mg (2.28 mmol) carbon tetrabromide are added at 0° C. The mixture is stirred at 0° C. for 10 min and 30 min at room temperature. Then the reaction mixture is poured on water and extracted (3×) with ethyl acetate. The combined organic layers are washed with water (2×) and brine, dried over MgSO4, filtered and concentrated in vacuo. The residue is purified by flash-chromatography on silica gel (hexane:EtOAc=2:1−>1:1) to afford 660 mg of the title compound as a colorless crystalline solid.
Reaction SMILES: [C:1]([N:5]1[C:14]2[C:9](=[CH:10][C:11]([I:15])=[CH:12][CH:13]=2)[C:8](=[O:16])[C:7]([C:17]([O:19]CC)=O)=[CH:6]1)([CH3:4])([CH3:3])[CH3:2].[Cl:22][C:23]1[CH:30]=[CH:29][C:26]([CH2:27][NH2:28])=[CH:25][CH:24]=1>>[C:1]([N:5]1[C:14]2[C:9](=[CH:10][C:11]([I:15])=[CH:12][CH:13]=2)[C:8](=[O:16])[C:7]([C:17]([NH:28][CH2:27][C:26]2[CH:29]=[CH:30][C:23]([Cl:22])=[CH:24][CH:25]=2)=[O:19])=[CH:6]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CCOC(=O)c1cn(C(C)(C)C)c2ccc(I)cc2c1=O
Reactant: NCc1ccc(Cl)cc1
Product: CC(C)(C)n1cc(C(=O)NCc2ccc(Cl)cc2)c(=O)c2cc(I)ccc21
Temperature: 25 °C
Yield: 88.7 %

Procedure:
A slurry of 1.11 g of ethyl 1-(tert-butyl)-6-iodo-4-oxo-1,4-dihydro-3-quinolinecarboxylate from Preparation No. 9 in 2.0 g of 4-chlorobenzylamine is heated under argon at 160° C. for 18 hours, then cooled to room temperature and triturated with 1N HCl. The solid is filtered, washed well with water, and dried under vacuum. Flash chromatography using 20% ethyl acetate in dichloromethane provides 1.22 g of the title compound as a white solid.
Reaction SMILES: [CH3:1][CH:2]([OH:9])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].[OH2:10].[C:11]1([CH3:21])C=CC(S(O)(=O)=O)=C[CH:12]=1.C1C2NC3C(=CC=CC=3)SC=2C=CC=1>C1(C)C=CC=CC=1>[C:21]([O:9][CH:2]([CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8])[CH3:1])(=[O:10])[CH:11]=[CH2:12]
Reactant: CCCCCCC(C)O
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: O
Agent: c1ccc2c(c1)Nc1ccccc1S2
Solvent: Cc1ccccc1
Product: C=CC(=O)OC(C)CCCCCC

Procedure:
A mixture of 2-octanol (268.51 grams, 2.1 mol), AA (183.75 grams, 2.6 mol), p-toluenesulfonic acid monohydrate (5.00 grams, 26 mmol), toluene (250 grams) and phenothiazine (1.0 grams) was heated to reflux. Water was separated from the toluene/water azeotrope using a Dean Stark distillation trap. After six hours at reflux a total of 37 milliliters of water was collected in the trap. The reaction mixture was washed with 1 Molar aqueous sodium hydroxide (200 milliliters), then concentrated under reduced pressure. The remaining oil was distilled under reduced pressure (65-67° C. at 2 mmHg) to give the product as a colorless oil. (Yield: 248.6 grams)
Reaction SMILES: [CH2:1]([NH:5][C:6]1[CH:11]=[CH:10][C:9]([CH:12]([CH3:14])[CH3:13])=[CH:8][CH:7]=1)[CH2:2][CH2:3][CH3:4].[CH:15]([C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([CH:24]([CH3:26])[CH3:25])[C:19]=1[N:27]=[C:28]=[O:29])([CH3:17])[CH3:16]>>[CH2:1]([N:5]([C:6]1[CH:7]=[CH:8][C:9]([CH:12]([CH3:13])[CH3:14])=[CH:10][CH:11]=1)[C:28]([NH:27][C:19]1[C:18]([CH:15]([CH3:16])[CH3:17])=[CH:23][CH:22]=[CH:21][C:20]=1[CH:24]([CH3:26])[CH3:25])=[O:29])[CH2:2][CH2:3][CH3:4]
Reactant: CC(C)c1cccc(C(C)C)c1N=C=O
Reactant: CCCCNc1ccc(C(C)C)cc1
Product: CCCCN(C(=O)Nc1c(C(C)C)cccc1C(C)C)c1ccc(C(C)C)cc1
Yield: 35 %

Procedure:
By the reaction and treatment in the same manner as in Example 2 using butyl(4-isopropylphenyl)amine (1.8 g) and 2,6-diisopropylphenyl isocyanate (2.7 g) as starting materials, N-butyl-N′-(2,6-diisopropylphenyl)-N-(4-isopropylphenyl)urea (1.3 g) was obtained.
Reaction SMILES: [NH:1]1[C:9]2[CH:8]=[CH:7][CH:6]=[C:5]([CH2:10]O)[C:4]=2[CH:3]=[CH:2]1.C1(P([N:26]=[N+:27]=[N-:28])(C2C=CC=CC=2)=O)C=CC=CC=1.N12CCCN=C1CCCCC2>O1CCCC1>[N:26]([CH2:10][C:5]1[CH:6]=[CH:7][CH:8]=[C:9]2[C:4]=1[CH:3]=[CH:2][NH:1]2)=[N+:27]=[N-:28]
Reactant: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Reactant: OCc1cccc2[nH]ccc12
Solvent: C1CCOC1
Solvent: C1CCC2=NCCCN2CC1
Product: [N-]=[N+]=NCc1cccc2[nH]ccc12
Reaction time: 5 h
Yield: 1810.1 %

Procedure:
To a solution of 1H-indole-4-methanol (Example 17; 71 mg, 0.48 mmol) in tetrahydrofuran (1 mL) at 0° C. was added diphenylphosphoryl azide (156 μL, 0.72 mmol) followed by 1,8-diazabicyclo[5.4.0]undec-7-ene (87.4 μL, 0.58 mmol). The cooling bath was removed and the solution was allowed to stir for 5 h. After the solvent was evaporated, ethyl acetate was added and the solution was washed with 1N hydrochloric acid solution and brine, dried (MgSO4), filtered and concentrated. The residual material was chromatographed over silica gel (12% ethyl acetateihexanes) to give 4-(azidomethyl)-1H-indole (1.496 g, 88% yield) as an oil.
Reaction SMILES: Cl[CH:2]([C:9]1[N:10]=[N:11][CH:12]=[CH:13][CH:14]=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[H][H].[O-2].[Mg+2]>C(O)C.[Pd]>[CH2:2]([C:9]1[N:10]=[N:11][CH:12]=[CH:13][CH:14]=1)[C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1
Reactant: ClC(c1ccccc1)c1cccnn1
Reactant: [H][H]
Agent: [Pd]
Agent: [Mg+2]
Agent: [O-2]
Solvent: CCO
Product: c1ccc(Cc2cccnn2)cc1
Yield: 93.8 %

Procedure:
A solution of (±) 3-α-chlorobenzylpyridazine (2.05 g.) in ethanol (50 ml.) was treated with hydrogen, in the presence of magnesium oxide (0.4 g.) and palladium on charcoal (5% Pd; 0.2 g.), for 1 hour at ambient temperature and normal atmospheric pressure. The solution was then filtered and the filtrate was evaporated to dryness. The residue was dissolved in hot chloroform (100 ml.), cooled, washed with water (50 ml.), dried over magnesium sulphate and evaporated to give 3-benzylpyridazine (1.6 g.), m.p. 61°-64° C., in the form of a light brown coloured solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[N:4]=[CH:5][C:6]2[CH:12]=[CH:11][C:10](=[O:13])[N:9]([CH2:14][CH:15]=O)[C:7]=2[N:8]=1.[O:17]1[C:26]2[CH:25]=[C:24]([CH2:27][N:28]([CH:36]3[CH2:41][CH2:40][NH:39][CH2:38][CH2:37]3)[C:29](=[O:35])[O:30][C:31]([CH3:34])([CH3:33])[CH3:32])[N:23]=[CH:22][C:21]=2[O:20][CH2:19][CH2:18]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)([O-])O.[Na+]>ClCCl.C(Cl)(Cl)Cl.C(O)(=O)C>[O:17]1[C:26]2[CH:25]=[C:24]([CH2:27][N:28]([CH:36]3[CH2:41][CH2:40][N:39]([CH2:15][CH2:14][N:9]4[C:7]5[N:8]=[C:3]([O:2][CH3:1])[N:4]=[CH:5][C:6]=5[CH:12]=[CH:11][C:10]4=[O:13])[CH2:38][CH2:37]3)[C:29](=[O:35])[O:30][C:31]([CH3:34])([CH3:33])[CH3:32])[N:23]=[CH:22][C:21]=2[O:20][CH2:19][CH2:18]1
Reactant: COc1ncc2ccc(=O)n(CC=O)c2n1
Reactant: CC(C)(C)OC(=O)N(Cc1cc2c(cn1)OCCO2)C1CCNCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: CC(=O)O
Solvent: ClCCl
Product: COc1ncc2ccc(=O)n(CCN3CCC(N(Cc4cc5c(cn4)OCCO5)C(=O)OC(C)(C)C)CC3)c2n1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 66.1 %

Procedure:
To a solution of 0.33 g of (2-methoxy-7-oxopyrido(2,3-d)pyrimidin-8(7H)-yl)acetaldehyde in 15 mL of dichloromethane, a solution of 0.53 g of tert-butyl (2,3-dihydro(1,4)dioxino(2,3-c)pyridin-7-ylmethyl)(piperidin-4-yl)carbamate in 5.3 mL of dichloromethane, and 87 μL of acetic acid were added, and the mixture was stirred at room temperature for 1 hour 30 minutes. To the reaction mixture, 0.40 g of sodium triacetoxyborohydride was added, and the mixture was stirred for 2 hours 30 minutes. After leaving overnight, the mixture was stirred at room temperature for 4 hours. Chloroform and a saturated aqueous sodium hydrogen carbonate solution were added to the reaction mixture, the organic layer was separated, and the aqueous layer was extracted with chloroform. The organic layer and the extract were combined, the resultant solution was washed with a saturated aqueous sodium chloride solution and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The resultant residue was purified by silica gel column chromatography using gradient elution with chloroform:methanol=50:1 to 10:1 to obtain 0.55 g of tert-butyl (2,3-dihydro(1,4)dioxino(2,3-c)pyridin-7-ylmethyl)(1-(2-(2-methoxy-7-oxopyrido(2,3-d)pyrimidin-8(7H)-yl)ethyl)piperidin-4-yl)carbamate as a light yellow foam.
Reaction SMILES: [SH:1][C:2]1[C:3](=[O:11])[N:4]([CH2:8][CH2:9][CH3:10])[CH:5]=[CH:6][N:7]=1.[Cl:12][C:13]1[CH:20]=[CH:19][C:16]([CH2:17]Br)=[CH:15][CH:14]=1.C(=O)([O-])[O-].[K+].[K+].O>O1CCCC1>[Cl:12][C:13]1[CH:20]=[CH:19][C:16]([CH2:17][S:1][C:2]2[C:3](=[O:11])[N:4]([CH2:8][CH2:9][CH3:10])[CH:5]=[CH:6][N:7]=2)=[CH:15][CH:14]=1
Reactant: Clc1ccc(CBr)cc1
Reactant: CCCn1ccnc(S)c1=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Product: CCCn1ccnc(SCc2ccc(Cl)cc2)c1=O
Yield: 88 %

Procedure:
500 mg (2.30 mM) of 3-mercapto-1-propylpyrazin-2(1H)-one, 319.2 μl (1.21 mM) of 4-chlorobenzylbromide and 637 mg (4.6 mM) of potassium carbonate in 4 ml of tetrahydrofurane were stirred overnight at room temperature. Water was added and the aqueous layer was extracted with ethyle acetate. The organic layer was separated and washed with water, dried on anhydrous sodium sulfate and evaporated under vacuum, to give an oil which was purified by silica gel column chromatography, using dichloromethane/dimethylketone (98/2) as eluant, to give 600 mg of 3-[(4-chlorobenzyl)thio]-1-propylpyrazin-2(1H)-one. Yield: 88%.
Reaction SMILES: CO.[ClH:3].[NH:4]1[CH2:9][CH2:8][CH:7](/[CH:10]=[CH:11]/[C:12]2[CH:20]=[CH:19][C:15]([C:16]([NH2:18])=[O:17])=[CH:14][CH:13]=2)[CH2:6][CH2:5]1.[H][H]>[C].[Pd].O>[ClH:3].[NH:4]1[CH2:9][CH2:8][CH:7]([CH2:10][CH2:11][C:12]2[CH:13]=[CH:14][C:15]([C:16]([NH2:18])=[O:17])=[CH:19][CH:20]=2)[CH2:6][CH2:5]1
Reactant: NC(=O)c1ccc(/C=C/C2CCNCC2)cc1
Reactant: [H][H]
Agent: [Pd]
Agent: Cl
Solvent: CO
Solvent: O
Product: NC(=O)c1ccc(CCC2CCNCC2)cc1
Yield: 56 %

Procedure:
10% Palladium-carbon (catalytic amount) was added to a methanol (15 ml)/water (5 ml) solution containing 4-[(E)-2-piperidin-4-ylvinyl]benzamide hydrochloride (800 mg), followed by stirring in a hydrogen gas atmosphere at room temperature under normal pressure for 4 hours. The catalyst was removed by filtration, and the resulting filtrate was concentrated under reduced pressure. The resulting solid was recrystallized from ethanol/acetonitrile to obtain 4-(2-piperidin-4-ylethyl)benzamide hydrochloride (451 mg) (Reference Example 58).