Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1]N1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1.[F:27][C:28]1[CH:37]=[CH:36][C:35]2[C:30](=[CH:31][CH:32]=[C:33]([O:42][CH3:43])[C:34]=2[C:38]([F:41])([F:40])[F:39])[C:29]=1[CH3:44]>C(Cl)(Cl)(Cl)Cl>[Br:1][CH2:44][C:29]1[C:30]2[C:35](=[C:34]([C:38]([F:40])([F:41])[F:39])[C:33]([O:42][CH3:43])=[CH:32][CH:31]=2)[CH:36]=[CH:37][C:28]=1[F:27]
Reactant: O=C1CCC(=O)N1Br
Reactant: COc1ccc2c(C)c(F)ccc2c1C(F)(F)F
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: COc1ccc2c(CBr)c(F)ccc2c1C(F)(F)F
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
A suspension of N-bromosuccinimide (6.93 g, 1.1 eq), benzoyl peroxide (38 mg) and 2-fluoro-6-methoxy-1-methyl-5-(trifluoromethyl)naphthalene (9.14 g, 35.39 mmol) in carbontetrachloride (160 mL) was heated to reflux with stirring under a dry nitrogen atmosphere for 1.5 hours. The reaction mixture was cooled to room temperature and filtered. The solid was washed with carbon tetrachloride (3×30 mL). The solvent was removed from the combined CCl4 phases to provide the product as a white solid in quantitative yield. A small portion of this solid was recrystallized from hexane:ethylacetate, m.p. 97°-100° C.
Reaction SMILES: CC1C=CC(S(OS(C2C=CC(C)=CC=2)(=O)=O)(=O)=O)=CC=1.FC(F)(F)C1C=CC=CC=1.[F:32][C:33]1[C:38]([F:39])=[CH:37][CH:36]=[CH:35][C:34]=1[C@@H:40]1[CH2:51][CH2:50][C:49](=[O:52])[C:43]2=[N+:44]([O-])[CH:45]=[CH:46][CH:47]=[C:42]2[CH2:41]1.[CH3:53][C:54]([NH2:57])([CH3:56])[CH3:55]>C(OCC)(=O)C.C(Cl)Cl>[C:54]([NH:57][C:45]1[N:44]=[C:43]2[C:49](=[O:52])[CH2:50][CH2:51][C@@H:40]([C:34]3[CH:35]=[CH:36][CH:37]=[C:38]([F:39])[C:33]=3[F:32])[CH2:41][C:42]2=[CH:47][CH:46]=1)([CH3:56])([CH3:55])[CH3:53]
Reactant: CC(C)(C)N
Reactant: O=C1CC[C@@H](c2cccc(F)c2F)Cc2ccc[n+]([O-])c21
Agent: Cc1ccc(S(=O)(=O)OS(=O)(=O)c2ccc(C)cc2)cc1
Solvent: FC(F)(F)c1ccccc1
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CC(C)(C)Nc1ccc2c(n1)C(=O)CC[C@@H](c1cccc(F)c1F)C2
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 37.9 %

Procedure:
At 0° C., the 4-methylbenzenesulfonic anhydride (0.930 g, 2.85 mmol) was added to the trifluoro-toluene (3 mL)/CH2Cl2 (3.00 mL) suspension of (R)-6-(2,3-difluorophenyl)-9-oxo-6,7,8,9-tetrahydro-5H-cyclohepta[b]pyridine 1-oxide (0.412 g, 1.424 mmol) and 2-methylpropan-2-amine (0.604 mL, 5.70 mmol). The reaction was stirred at 0° C. for 30 min before diluted with ethyl acetate. The crude was washed by NaOH (1N) twice and the ethyl acetate layer was separated, dried (Na2SO4), filtered and concentrated. Flash column by ethyl acetate in hexane from 0 to 40% to 60% gave the desired product (0.1861 g, 38%). MS (ESI)[M+H+]=345.1; 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 7.18 (d, J=8.56 Hz, 1H) 6.95-7.10 (m, 2H) 6.82-6.95 (m, 1H) 6.60 (d, J=8.56 Hz, 1H) 4.95 (br. s., 1H) 3.45-3.58 (m, 1H) 2.91-3.05 (m, 3H) 2.73-2.85 (m, 1H) 2.13-2.27 (m, 1H) 1.95-2.11 (m, 1H) 1.43 (s, 9H).
Reaction SMILES: [CH2:1]([O:8][C@H:9]([CH3:19])[C:10]([N-]N1CCOCC1)=[O:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:20]([Li])([CH3:22])[CH3:21].[Cl-].[NH4+]>C1COCC1.CCCCC>[CH2:1]([O:8][C@@H:9]([C:10](=[O:11])[CH:20]([CH3:22])[CH3:21])[CH3:19])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: C[C@@H](OCc1ccccc1)C(=O)[N-]N1CCOCC1
Reactant: [Li]C(C)C
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCCCC
Product: CC(C)C(=O)[C@@H](C)OCc1ccccc1
Reaction time: 3 h
Yield: 94 %

Procedure:
To a stirred solution of (R)-2-benzyloxypropionyl N-morpholinyl amide (10 mmol) in THF (20 mL) under nitrogen atmosphere at −78° C. was added dropwise isopropyl lithium (15 mmol) in pentane. The reaction mixture was stirred at −78 C for 3 h (monitored by tlc). The reaction mixture was poured into saturated ammonium chloride solution and then extracted with ethyl acetate (3×25 mL). The combined extract was washed with water (2×25 mL), dried over Na2SO4 and concentrated in vacuo. The residue was purified by passing through a short silica gel column using a 0-25% gradient of ether and n-pentane as eluents to give pure 20a as a colorless liquid in 94% yield. 1H NMR (400 MHz, CDCl3): δ 1.08 (3H, d); 1.10 (3H, d); 1.36 (3H, d); 3.02 (1H, m); 4.06 (1H, q); 4.46 (2H, dd); 7.33-7.34 (5H, m). MS (ESI) m/z 207.13 (M+H+).
Reaction SMILES: C(O[N:5]1[C:11](=[O:12])[C:10]2[CH:13]=[CH:14][CH:15]=[CH:16][C:9]=2[CH:8]([CH2:17][CH2:18][C:19]([O:21][CH3:22])=[O:20])[C:7]2[CH:23]=[CH:24][CH:25]=[CH:26][C:6]1=2)(=O)C.F[C:28](F)(F)[C:29](O)=[O:30].[NH2:34][CH2:35][C:36]1[CH:41]=[CH:40][C:39]([NH:42][C:43]([NH:45][CH2:46][C:47]2[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=2)=[O:44])=[CH:38][CH:37]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>>[CH2:46]([NH:45][C:43]([NH:42][C:39]1[CH:38]=[CH:37][C:36]([CH2:35][NH:34][C:29](=[O:30])[CH2:28][N:5]2[C:11](=[O:12])[C:10]3[CH:13]=[CH:14][CH:15]=[CH:16][C:9]=3[CH:8]([CH2:17][CH2:18][C:19]([O:21][CH3:22])=[O:20])[C:7]3[CH:23]=[CH:24][CH:25]=[CH:26][C:6]2=3)=[CH:41][CH:40]=1)=[O:44])[C:47]1[CH:48]=[CH:49][CH:50]=[CH:51][CH:52]=1
Reactant: COC(=O)CCC1c2ccccc2C(=O)N(OC(C)=O)c2ccccc21
Reactant: O=C(O)C(F)(F)F
Reactant: NCc1ccc(NC(=O)NCc2ccccc2)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Product: COC(=O)CCC1c2ccccc2C(=O)N(CC(=O)NCc2ccc(NC(=O)NCc3ccccc3)cc2)c2ccccc21

Procedure:
Coupling of 11-(3-methoxy-3-oxopropyl)-6-oxo-6,11-dihydro-5H-dibenzo[b,e]azepin-5-yl acetate (70) with N-(4-(aminomethyl)phenyl-N′-benzylurea (trifluoroacetate) (58) using HATU as coupling reagent afforded 140 mg; ESI-MS [M+K+]=629.2, [M+H+]: 591.25, 296.1.
Reaction SMILES: [CH:1]1(N=C=NC2CCCCC2)CCCC[CH2:2]1.[CH3:16][C:17]1[S:21][C:20]([C:22]([OH:24])=[O:23])=[CH:19][CH:18]=1.C(O)C.CN(C1C=CC=CN=1)C>ClCCl>[CH3:16][C:17]1[S:21][C:20]([C:22]([O:24][CH2:1][CH3:2])=[O:23])=[CH:19][CH:18]=1
Reactant: C(=NC1CCCCC1)=NC1CCCCC1
Reactant: Cc1ccc(C(=O)O)s1
Agent: CN(C)c1ccccn1
Solvent: ClCCl
Solvent: CCO
Product: CCOC(=O)c1ccc(C)s1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
To a stirred solution of 15.9 g (77.4 mmol) of 1,3-dicyclohexylcarbodiimide in 40 mL dichloromethane was added 10 g (70.3 mmol) of 5-methyl-2-thiophenecaboxylic acid and 4.85 g (105.5 mmol) of anhydrous ethanol. 0.86 g of dimethylaminopyridine was then added and the suspension stirred at room temperature for 20 hours. The resulting white precipitate was removed by filtration. The filtrate was washed with water, dried (MgSO4), filtered and concentrated under reduced pressure. The residue was purified by bulb-to-bulb distillation (bp=95° C., 3 mm Hg) to give the title compound as a clear, pale yellow oil.
Reaction SMILES: [CH2:1]([N:8]1[C:12]([CH2:13][NH:14][C:15](=[O:25])[CH2:16][NH:17]C(=O)OC(C)(C)C)=[C:11]([C:26]2[CH:27]=[C:28]3[C:32](=[CH:33][CH:34]=2)[NH:31][N:30]=[CH:29]3)[N:10]=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl>O1CCCC1.C(OCC)C>[CH2:1]([N:8]1[C:12]([CH2:13][NH:14][C:15](=[O:25])[CH2:16][NH2:17])=[C:11]([C:26]2[CH:27]=[C:28]3[C:32](=[CH:33][CH:34]=2)[NH:31][N:30]=[CH:29]3)[N:10]=[N:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)NCC(=O)NCc1c(-c2ccc3[nH]ncc3c2)nnn1Cc1ccccc1
Agent: Cl
Solvent: CCOCC
Solvent: C1CCOC1
Product: NCC(=O)NCc1c(-c2ccc3[nH]ncc3c2)nnn1Cc1ccccc1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
Example 143C (66 mg, 0.217 mmol), N-(tert-butoxycarbonyl)-glycine (39 mg, 0.223 mmol), and HATU (85 mg, 0.224 mmol) were combined in methylene chloride (2.5 mL). Diisopropylethylamine (150 μL, 0.865 mmol) was added and the mixture was stirred at ambient temperature overnight. The mixture was absorbed on silica gel and purified by silica gel chromatography eluting with a gradient of 0-6% methanol in dichloromethane to afford tert-butyl 2-((1-benzyl-4-(1H-indazol-5-yl)-1H-1,2,3-triazol-5-yl)methylamino)-2-oxoethylcarbamate. This carbamate was dissolved in tetrahydrofuran (2 mL) and 0.5 mL of a solution of 1 N hydrochloric acid in diethyl ether was added and the mixture was stirred for 20 minutes at room temperature. The solvents were removed under reduced pressure, and diethyl ether was added to the mixture and stirred at room temperature overnight. The solvent was decanted, and the resulting residue was dried under a stream of nitrogen to afford the title compound as a hydrochloride salt. 1H NMR (300 MHz, DMSO-d6) δ ppm 13.21 (s, 1H) 9.02 (t, J=5.09 Hz, 1H) 8.11-8.16 (m, 2H) 8.06 (s, 2H) 7.75-7.82 (m, 1H) 7.64 (d, J=8.82 Hz, 1H) 7.30-7.45 (m, 3H) 7.23-7.31 (m, 2H) 5.72 (s, 2H) 4.57 (d, J=5.09 Hz, 2H) 3.41 (q, J=5.76 Hz, 2H). MS (ESI+) m/z 362.1 (M+H)+.
Reaction SMILES: [H-].[Na+].[O:3]=[C:4]([CH3:11])[CH2:5][C:6]([O:8][CH2:9][CH3:10])=[O:7].[F:12][C:13]([F:23])([F:22])[C:14]1[CH:21]=[CH:20][C:17]([CH2:18]Br)=[CH:16][CH:15]=1>C(COC)OC>[O:3]=[C:4]([CH3:11])[CH:5]([CH2:18][C:17]1[CH:16]=[CH:15][C:14]([C:13]([F:12])([F:22])[F:23])=[CH:21][CH:20]=1)[C:6]([O:8][CH2:9][CH3:10])=[O:7]
Reactant: FC(F)(F)c1ccc(CBr)cc1
Reactant: CCOC(=O)CC(C)=O
Agent: [H-]
Agent: [Na+]
Solvent: COCCOC
Product: CCOC(=O)C(Cc1ccc(C(F)(F)F)cc1)C(C)=O
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
Sodium hydride (60% dispersion in mineral oil, 1.5 g, 38.4 mmol) was added in portions over 2 minutes to an ice-cooled, stirring solution of ethyl 3-oxobutanoate (5 g, 38.4 mmol) in dry dimethoxyethane (65 mL). After 30 minutes, a solution of 4-(trifluoromethyl)benzyl bromide (9.2 g, 38.4 mmol) in dry dimethoxyethane (10 mL) was added dropwise over 2 minutes. The flask was removed from the cooling bath. After 2 hours, water (10 mL) was added. The mixture was partitioned between half-saturated aqueous sodium chloride solution (50 mL) and ethyl acetate (150 mL). The layers were separated. The organic layer was dried with magnesium sulfate and the dried solution was filtered. The filtrate was concentrated and the residue was purified by flash-column chromatography on silica gel eluting with hexanes-ethyl acetate to provide the title compound as a colorless liquid.
Reaction SMILES: [CH2:1]([O:4][CH2:5][C:6]1[C:11](I)=[CH:10][CH:9]=[CH:8][C:7]=1[F:13])[CH:2]=[CH2:3]>CC#N.CCN(CC)CC>[F:13][C:7]1[CH:8]=[CH:9][CH:10]=[C:11]2[C:6]=1[CH2:5][O:4][CH2:1][C:2]2=[CH2:3]
Reactant: C=CCOCc1c(F)cccc1I
Solvent: CC#N
Solvent: CCN(CC)CC
Product: C=C1COCc2c(F)cccc21
Temperature: 80 °C

Procedure:
2-(Allyloxymethyl)-1-fluoro-3-iodobenzene (1 g) was dissolved in 20 mL of CH3CN and 2.4 mL of Et3N. The reaction solution was vacuum degassed three times, followed by the addition of Pd(OAc)2 (37.6 mg) and PPh3 (89.8 mg). The resulting mixture was heated at 80° C. for 16 hours. The reaction mixture was cooled to room temperature and diluted with Et2O. The organic layer was washed with 1N HCl, 10% aqueous NaHCO3, brine, and then dried over Na2SO4. After filtration, the filtrate was concentrated to dryness to offer a brown oil, which was purified by flash chromatography to offer 200 mg of the title compound.
Reaction SMILES: [C:1](OC(=O)C)(=[O:3])C.[N:8]1([C:14]2[N:15]=[CH:16][C:17]3[C:23](=[O:24])[C:22]([C:25]([OH:27])=[O:26])=[CH:21][NH:20][C:18]=3[N:19]=2)[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1>C(O)=O>[CH:1]([N:11]1[CH2:10][CH2:9][N:8]([C:14]2[N:15]=[CH:16][C:17]3[C:23](=[O:24])[C:22]([C:25]([OH:27])=[O:26])=[CH:21][NH:20][C:18]=3[N:19]=2)[CH2:13][CH2:12]1)=[O:3]
Reactant: CC(=O)OC(C)=O
Reactant: O=C(O)c1c[nH]c2nc(N3CCNCC3)ncc2c1=O
Solvent: O=CO
Product: O=CN1CCN(c2ncc3c(=O)c(C(=O)O)c[nH]c3n2)CC1
Temperature: 50 °C

Procedure:
Formic acid (140 ml) was added dropwise to acetic anhydride (200 ml) cooled on an ice both. The solution was heated at 50° C. for 15 minutes and then cooled to 5° C. To the solution, 5,8-dihydro-2-(1-piperazinyl)-5-oxopyrido[2,3-d]pyrimidine-6-carboxylic acid (70 g) was added. The mixture was heated at 80° C. for 3 hours and then cooled. The crystals precipitated were collected by filtration and washed with ethyl ether to give 5,8-dihydro-2-(4-formyl-1-piperazinyl)-5-oxopyrido [2,3-d]pyrimidine-6-carboxylic acid (72.5 g). m.p. above 300° C.
Reaction SMILES: [CH2:1]([C:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][C:10]=2[NH:12][C:13]([C:15]2[N:19]3[CH:20]=[CH:21][CH:22]=[CH:23][C:18]3=[N:17][CH:16]=2)=[O:14])[N:5]([CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[C:27]([CH:31]=O)[N:26]=2)[N:4]=1)[CH3:2].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[N:47]1([C:53]([O:55][C:56]([CH3:59])([CH3:58])[CH3:57])=[O:54])[CH2:52][CH2:51][NH:50][CH2:49][CH2:48]1>ClCCl.CO>[CH2:1]([C:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][C:10]=2[NH:12][C:13]([C:15]2[N:19]3[CH:20]=[CH:21][CH:22]=[CH:23][C:18]3=[N:17][CH:16]=2)=[O:14])[N:5]([CH2:24][C:25]2[N:26]=[C:27]([CH2:31][N:50]3[CH2:51][CH2:52][N:47]([C:53]([O:55][C:56]([CH3:59])([CH3:58])[CH3:57])=[O:54])[CH2:48][CH2:49]3)[CH:28]=[CH:29][CH:30]=2)[N:4]=1)[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: CCc1nn(Cc2cccc(C=O)n2)c2cccc(NC(=O)c3cnc4ccccn34)c12
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Solvent: CO
Product: CCc1nn(Cc2cccc(CN3CCN(C(=O)OC(C)(C)C)CC3)n2)c2cccc(NC(=O)c3cnc4ccccn34)c12
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 45 %

Procedure:
To a mixture of N-(3-ethyl-1-((6-formylpyridin-2-yl)methyl)-1H-indazol-4-yl)imidazo[1,2-a]pyridine-3-carboxamide (20 mg, 0.0471 mmol) and sodium triacetoxyborohydride (49.9 mg, 0.236 mmol) in a 1:1 mixture of dichloromethane/methanol (1 mL) was added tert-butyl piperazine-1-carboxylate (10.5 mg, 0.0565 mmol). The mixture was stirred for 30 minutes at ambient temperature. The solvent was removed under reduced pressure and the residue was purified using preparative thin layer chromatography on silica, eluting with 12% methanol and 0.5% ammonium hydroxide in dichloromethane to give the desired product (12.6 mg).
Reaction SMILES: [CH3:1][C:2]([CH3:37])([CH2:34][CH:35]=[CH2:36])[C:3]([C:5]1[C:13]2[C:8](=[N:9][CH:10]=[C:11]([C:14]3[CH:19]=[C:18]([O:20][CH3:21])[C:17]([O:22][CH3:23])=[C:16]([O:24][CH3:25])[CH:15]=3)[N:12]=2)[N:7](COCC[Si](C)(C)C)[CH:6]=1)=[O:4].O.O.O.C([O-])(=O)C.[Na+]>ClCCl.FC(F)(F)C(O)=O>[CH3:1][C:2]([CH3:37])([CH2:34][CH:35]=[CH2:36])[C:3]([C:5]1[C:13]2[C:8](=[N:9][CH:10]=[C:11]([C:14]3[CH:19]=[C:18]([O:20][CH3:21])[C:17]([O:22][CH3:23])=[C:16]([O:24][CH3:25])[CH:15]=3)[N:12]=2)[NH:7][CH:6]=1)=[O:4]
Reactant: C=CCC(C)(C)C(=O)c1cn(COCC[Si](C)(C)C)c2ncc(-c3cc(OC)c(OC)c(OC)c3)nc12
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Solvent: O=C(O)C(F)(F)F
Product: C=CCC(C)(C)C(=O)c1c[nH]c2ncc(-c3cc(OC)c(OC)c(OC)c3)nc12
Reaction time: 96 h
Yield: 50.2 %

Procedure:
A solution of 2,2-dimethyl-1-[2-(3,4,5-trimethoxy-phenyl)-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazin-7-yl]-pent-4-en-1-one (0.127 g, 0.242 mmol) in 4 mL of dichloromethane and 1 mL of trifluoroacetic acid was stirred for 3 h, then concentrated. The residue was taken up in 2 mL of ethanol (not all dissolves) and treated with sodium acetate trihydrate (0.329 g, 2.42 mmol). The mixture was stirred for 4 d, then concentrated to a residue. Column chromatography (0→5% MeOH/CH2Cl2) afforded 0.048 g (50%) of 2,2-dimethyl-1-[2-(3,4,5-trimethoxy-phenyl)-5H-pyrrolo[2,3-b]pyrazin-7-yl]-pent-4-en-1-one as a white solid.
Reaction SMILES: [H-].[Na+].Cl[C:4]1[C:13]2[C:8](=[C:9]([F:14])[CH:10]=[CH:11][CH:12]=2)[N:7]=[CH:6][N:5]=1.[CH3:15][C:16]1[CH:21]=[CH:20][C:19]([CH2:22][CH2:23][OH:24])=[CH:18][CH:17]=1>CN(C=O)C>[F:14][C:9]1[CH:10]=[CH:11][CH:12]=[C:13]2[C:8]=1[N:7]=[CH:6][N:5]=[C:4]2[O:24][CH2:23][CH2:22][C:19]1[CH:20]=[CH:21][C:16]([CH3:15])=[CH:17][CH:18]=1
Reactant: Cc1ccc(CCO)cc1
Reactant: Fc1cccc2c(Cl)ncnc12
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1ccc(CCOc2ncnc3c(F)cccc23)cc1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a mixture of 0.6 g of sodium hydride (50%, suspension in oil) and 2 g of 4-chloro-8-fluoroquinazoline in 20 ml of DMF was added 1.64 g of 2-(4-methylphenyl)ethanol, and the mixture was stirred for one hour. Then the mixture was poured into ice water. The solid was collected by filtration. Yield: 0.7 g (20.5%). M.P. 72°-74° C.
Reaction SMILES: Cl.[NH2:2][OH:3].C(=O)(O)[O-].[Na+].[CH:9]1([C:15]#[N:16])[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]1.C1(C)C=CC=CC=1>C(O)(C)C>[OH:3][NH:2][C:15]([CH:9]1[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]1)=[NH:16]
Reactant: N#CC1CCCCC1
Reactant: NO
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CC(C)O
Product: N=C(NO)C1CCCCC1
Reaction time: 0.21 h

Procedure:
To a solution of 1.9 g (27.4 mmol) of hydroxylamine hydrochloride in 22 mL of isopropyl alcohol, 3.3 g (40.3 mmol) of sodium bicarbonate was added. The resulting mixture was stirred at 25° C. to 30° C. for 10-15 min. 2.0 g (18.3 mmol) of cyclohexanecarbonitrile was added and stirred at 80° C. to 85° C. for 3-4 h. After the reaction period, the reaction mass was cooled to 25° C. to 30° C., filtered and washed with 10 mL of isopropyl alcohol. The filtrate was collected and distilled out completely to obtain a crude residue. The residue was chased with 5 mL of toluene, to yield the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH3:12])[C:5]2[O:9][C:8](S)=[N:7][C:6]=2[CH:11]=1.[NH:13]1[CH2:19][CH2:18][CH2:17][NH:16][CH2:15][CH2:14]1.C(OCC)(=O)C.Cl>C1(C)C=CC=CC=1.O>[Cl:1][C:2]1[CH:3]=[C:4]([CH3:12])[C:5]2[O:9][C:8]([N:13]3[CH2:19][CH2:18][CH2:17][NH:16][CH2:15][CH2:14]3)=[N:7][C:6]=2[CH:11]=1
Reactant: Cc1cc(Cl)cc2nc(S)oc12
Reactant: C1CNCCNC1
Agent: Cl
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Solvent: O
Product: Cc1cc(Cl)cc2nc(N3CCCNCC3)oc12
Temperature: 25 °C

Procedure:
Under nitrogen atmosphere, a suspension of 5-chloro-2-mercapto-7-methylbenzoxazole (70 g, 35 mol) in toluene (1.4 L) was added with homopiperazine (70 g, 0.35 mol) with stirring, and then the mixture was heated under reflux for 3 hours. The reaction mixture was cooled to room temperature, and poured into a mixture of ethyl acetate (0.7 L) and water (0.7 L). The mixture was added dropwise with 6 N hydrochloric acid (55 mL) with stirring to adjust its pH to 7.5. The separated organic layer was washed with water (1.2 L). The remaining organic layer was added with water (1.2 L), and then added dropwise with 6 N hydrochloric acid with stirring to adjust its pH to 1–1.5. The separated aqueous layer was added with ethyl acetate (1.4 L), and then added with 5 N aqueous sodium hydroxide (180 mL) with stirring to adjust its pH to 8.0. The separated organic layer was washed with water (1.4 L), and dried anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure to obtain the title compound as a crude product (59 g). A solution of the crude product in ethyl acetate (1.2 L) was added with activated carbon (1.5 g), and the mixture was stirred for 30 minutes at room temperature. Then, the activated carbon was removed by filtration, and the solvent was evaporated under reduced pressure. The resultant solid was added with acetonitrile (177 mL), and was dissolved by warming the mixture to 60 C.° with stirring. The resultant uniform solution was left stand for cooling to room temperature over 1 hour, and then further cooled to 5 C.° The deposited crystals were collected by filtration, and dried under reduced pressure at 40 C.° for 4 hours to obtain the title compound (34 g).
Reaction SMILES: [CH:1]([N-]C(C)C)([CH3:3])[CH3:2].[Li+].CN1C(=O)N(C)CCC1.[CH:18]1([C:28]([O:30][CH3:31])=[O:29])[CH2:23][CH2:22][CH2:21][CH:20]([C:24]([O:26][CH3:27])=[O:25])[CH2:19]1.BrCC[Cl:35]>C1COCC1>[Cl:35][CH2:2][CH2:1][CH2:3][C:20]1([C:24]([O:26][CH3:27])=[O:25])[CH2:21][CH2:22][CH2:23][CH:18]([C:28]([O:30][CH3:31])=[O:29])[CH2:19]1
Reactant: COC(=O)C1CCCC(C(=O)OC)C1
Reactant: CC(C)[N-]C(C)C
Reactant: ClCCBr
Agent: [Li+]
Solvent: CN1CCCN(C)C1=O
Solvent: C1CCOC1
Product: COC(=O)C1CCCC(CCCCl)(C(=O)OC)C1
Temperature: -78 °C
Reaction time: 1 h
Yield: 71.1 %

Procedure:
To a pre-cooled (−78° C.) solution of lithium diisopropylamide (36 mL, 78 mmol) in THF (250 mL) was added DMPU (30.5 g, 238 mmol) dropwise (not allowing the temperature to exceed −65° C.), followed by an addition of a solution of dimethyl cyclohexane-1,3-dicarboxylate (11.9 g, 59.5 mmol) in THF (50 mL) at −78° C. over 20 min. After stirring at −78° C. for one hour, 1-bromo-2-chloroethane (11.1 g, 77.4 mmol) was added and the reaction mixture was slowly warmed up to room temperature overnight. After quenched with Sat. NH4Cl (100 mL), the mixture was concentrated under reduced pressure. The resulting residue was diluted with water (200 mL) and extracted with dichloromethane (4×100 mL). The combined organic layer was washed with water (100 mL) and brine (100 mL), dried over MgSO4 and concentrated under reduced pressure. The resulting residue was purified by column chromatography (silica gel, petroleum ether/ethyl acetate: 20/1) to afford 11.7 g (75%) of dimethyl 1-(3-chloropropyl)cyclohexane-1,3-dicarboxylate as a yellow oil. ESI-MS m/z: 263 (M+H)+.
Reaction SMILES: [CH3:1][N:2]([CH2:4][C:5]1[O:9][C:8]([CH2:10][S:11][CH2:12][CH2:13][NH2:14])=[CH:7][CH:6]=1)[CH3:3].[N+](N[C:19]1[NH:24][C:23](=[O:25])[C:22]([CH2:26][C:27]2[CH:28]=[N:29][CH:30]=[CH:31][CH:32]=2)=[CH:21][N:20]=1)([O-])=O>C(O)C>[CH3:3][N:2]([CH2:4][C:5]1[O:9][C:8]([CH2:10][S:11][CH2:12][CH2:13][NH:14][C:19]2[NH:24][C:23](=[O:25])[C:22]([CH2:26][C:27]3[CH:28]=[N:29][CH:30]=[CH:31][CH:32]=3)=[CH:21][N:20]=2)=[CH:7][CH:6]=1)[CH3:1]
Reactant: O=c1[nH]c(N[N+](=O)[O-])ncc1Cc1cccnc1
Reactant: CN(C)Cc1ccc(CSCCN)o1
Solvent: CCO
Product: CN(C)Cc1ccc(CSCCNc2ncc(Cc3cccnc3)c(=O)[nH]2)o1

Procedure:
A solution of 2-(5-dimethylaminomethyl-2-furyl-methylthio)ethylamine (2.25 g, 0.105 mol) and 2-nitroamino-5-(3-pyridylmethyl)-4-pyrimidone (2.47 g, 0.100 mol) in ethanol (12 ml) was boiled under reflux for 22 hours and evaporated to dryness. The residue was washed with water to give 2-[2-(5-dimethylaminomethyl-2-furylmethylthio)ethylamino]-5-(3-pyridylmethyl)-4-pyrimidone and this was treated with dilute ethanolic hydrogen chloride and dried. The residue was recrystallised from methanol/2-propanol and from methanol to give 2-[2-(5-dimethylaminomethyl-2-furylmethylthio)ethylamino]-5-(3-pyridylmethyl)-4-pyrimidone trihydrochloride (2.61 g) m.p. 205°-208°.
Reaction SMILES: N1C=CN=C1.[Cl:6][C:7]1[CH:14]=[C:13]([OH:15])[CH:12]=[CH:11][C:8]=1[CH:9]=[O:10].[C:16]([Si:20]([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)Cl)([CH3:19])([CH3:18])[CH3:17].O>C(Cl)Cl>[Si:20]([O:15][C:13]1[CH:12]=[CH:11][C:8]([CH:9]=[O:10])=[C:7]([Cl:6])[CH:14]=1)([C:16]([CH3:19])([CH3:18])[CH3:17])([C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=1)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: O=Cc1ccc(O)cc1Cl
Reactant: CC(C)(C)[Si](Cl)(c1ccccc1)c1ccccc1
Agent: c1c[nH]cn1
Solvent: ClCCl
Solvent: O
Product: CC(C)(C)[Si](Oc1ccc(C=O)c(Cl)c1)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 107.2 %

Procedure:
To a solution of imidazole (4.28 g, 62.89 mmol) and 2-chloro-4-hydroxybenzaldehyde (8.95 g, 57.16 mmol) in CH2Cl2 (500 ml)was added dropwise a solution of t-butyldiphenylchlorosilane (17.27 g, 62.86 mmol) in CH2Cl2, (200 mL). The solution was stirred overnight at ambient temperature. The mixture was then poured into H2O (500 mL) and the organic layer washed with NaHCO3, H2O, brine, and dried (MgSO4). The solvent was removed in vacuo to provide 24.2 g of the title compound.
Reaction SMILES: [H-].[Na+].C[C:4](P(OC)(O)=O)([C:6]([O-:8])=[O:7])[CH3:5].[CH2:14]([O:21][C:22]1[C:30]2[NH:29][CH:28]=[CH:27][C:26]=2[C:25](C=O)=[CH:24][CH:23]=1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.[CH3:33]N(C)C=O>O1CCCC1>[CH2:14]([O:21][C:22]1[CH:23]=[CH:24][C:25](/[CH:5]=[CH:4]/[C:6]([O:8][CH3:33])=[O:7])=[C:26]2[C:30]=1[NH:29][CH:28]=[CH:27]2)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: COP(=O)(O)C(C)(C)C(=O)[O-]
Reactant: CN(C)C=O
Reactant: O=Cc1ccc(OCc2ccccc2)c2[nH]ccc12
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COC(=O)/C=C/c1ccc(OCc2ccccc2)c2[nH]ccc12
Temperature: 25 °C
Reaction time: 1 h

Procedure:
60% Sodium hydride dispersion (0.10 g, 2.5 mmol) was added to a stirred solution of trimethylphosphonoacetate (0.41 ml, 2.5 mmol) in tetrahydrofuran (10 ml). The pale suspension was stirred for 1 hour at room temperature then a solution of 7-benzyloxyindole-4-carboxaldehyde (0.63 g, 2.5 mmol) in tetrahydrofuran (5 ml) was added followed by dimethylformamide (5 ml) to give a clear solution. The solution was stirred for 1 hour at room temperature then evaporated under high vacuum. The residue in ethyl acetate was washed with dilute hydrochloric acid dried and concentrated to give pale solid.