Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1](OC(=O)C)(=[O:3])[CH3:2].S(=O)(=O)(O)O.[CH:13]([OH:26])([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>ClCCl>[C:1]([O:26][CH:13]([C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)OC(C)=O
Reactant: OC(c1ccccc1)c1ccccc1
Agent: O=S(=O)(O)O
Solvent: ClCCl
Product: CC(=O)OC(c1ccccc1)c1ccccc1
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
108.3 g (1.05 mol; 1.05 eq) of acetic anhydride are diluted in 370 ml of dichloromethane at 20° C. The solution obtained is cooled to 0±2° C. before introducing 2.8 ml of a 96% sulphuric acid solution in a time of about 10 minutes. After stirring for about 10 minutes, 184.2 g (1 mol, 1 eq) of benzhydrol are introduced in portions at 0° C.±2° C. in 60±15 minutes. The reaction medium is maintained in contact for 2 hours at this temperature.
Reaction SMILES: [CH:1]1([NH2:6])[CH2:5][CH2:4][CH2:3][CH2:2]1.[Cl:7][CH2:8][CH2:9][N:10]=[C:11]=[O:12]>C1COCC1>[Cl:7][CH2:8][CH2:9][NH:10][C:11]([NH:6][CH:1]1[CH2:5][CH2:4][CH2:3][CH2:2]1)=[O:12]
Reactant: NC1CCCC1
Reactant: O=C=NCCCl
Solvent: C1CCOC1
Product: O=C(NCCCl)NC1CCCC1
Temperature: 25 °C
Yield: 99.9 %

Procedure:
A 0° C. solution of cyclopentylamine (4.63 mL, 47.0 mmol) in THF (235 mL) was treated drop-wise with 2-chloroethyl isocyanate (4.41 mL, 51.7 mmol) which was allowed to warm to RT, then concentrated to dryness. The solid was suspended in toluene and concentrated again to dryness to afford 1-(2-chloroethyl)-3-cyclopentylurea (8.95 g, 100%) as an off-white solid. 1H NMR (400 MHz, DMSO-d6): δ 6.01 (d, J=7.3 Hz, 1 H), 5.91 (t, J=5.8 Hz, 1 H), 3.85-3.76 (m, 1 H), 3.54 (t, J=6.2 Hz, 2 H), 3.27 (q, J=6.1 Hz, 2 H), 1.78-1.69 (m, 2 H), 1.62-1.53 (m, 2 H), 1.51-1.42 (m, 2 H), 1.30-1.20 (m, 2 H); MS (ESI) m/z: 191.1 (M+H+).
Reaction SMILES: [CH2:1]([C:3]1[C:4]([C:12]2[O:13][CH:14]=[CH:15][CH:16]=2)=[N:5][C:6]([NH2:11])=[N:7][C:8]=1[S:9][CH3:10])[CH3:2].C1(C2[O:25]N2S(C2C=CC=CC=2)(=O)=O)C=CC=CC=1>ClCCl>[CH2:1]([C:3]1[C:4]([C:12]2[O:13][CH:14]=[CH:15][CH:16]=2)=[N:5][C:6]([NH2:11])=[N:7][C:8]=1[S:9]([CH3:10])=[O:25])[CH3:2]
Reactant: CCc1c(SC)nc(N)nc1-c1ccco1
Reactant: O=S(=O)(c1ccccc1)N1OC1c1ccccc1
Solvent: ClCCl
Product: CCc1c(-c2ccco2)nc(N)nc1S(C)=O
Reaction time: 16 h
Yield: 45.4 %

Procedure:
To a stirred suspension of 350 mg (1.49 mmol) 5-ethyl-4-furan-2-yl-6-methylsulfanyl-pyrimidin-2-ylamine in 15 ml dichloromethane was added 780 mg (3.00 mmol) 3-phenyl-2-(phenylsulfonyl)oxaziridine and stirring continued for 16 hours at room temperature. The reaction mixture was then partitioned between dichloromethane and water and the phases separated. The organic phase was dried over sodium sulfate and concentrated in vacuo. Chromatography (ethyl acetate then methanol/ethyl acetate 1/5) afforded 170 mg (46%) 5-ethyl-4-furan-2-yl-6-methanesulfinyl-pyrimidin-2-ylamine as a yellow crystalline solid. ES-MS m/e (%): 252 (M+H+, 100).
Reaction SMILES: [CH2:1](OC(=O)C)C.Cl.C[N:9]([CH2:17][CH2:18][N:19]([CH2:41][C:42]1[CH:47]=[CH:46][N:45]=[CH:44][CH:43]=1)[CH2:20][CH2:21][CH2:22][O:23][C:24]1[CH:40]=[CH:39][C:27]2[N:28]([CH3:38])[C:29](=[O:37])[C:30]([CH3:36])([CH3:35])[C:31](=[O:34])[N:32]([CH3:33])[C:26]=2[CH:25]=1)C(=O)OC(C)(C)C>C(OCC)(=O)C>[CH3:38][N:28]1[C:29](=[O:37])[C:30]([CH3:35])([CH3:36])[C:31](=[O:34])[N:32]([CH3:33])[C:26]2[CH:25]=[C:24]([O:23][CH2:22][CH2:21][CH2:20][N:19]([CH2:18][CH:17]([NH2:9])[CH3:1])[CH2:41][C:42]3[CH:43]=[CH:44][N:45]=[CH:46][CH:47]=3)[CH:40]=[CH:39][C:27]1=2
Reactant: CN(CCN(CCCOc1ccc2c(c1)N(C)C(=O)C(C)(C)C(=O)N2C)Cc1ccncc1)C(=O)OC(C)(C)C
Reactant: CCOC(C)=O
Agent: Cl
Product: CC(N)CN(CCCOc1ccc2c(c1)N(C)C(=O)C(C)(C)C(=O)N2C)Cc1ccncc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A 4N-hydrogen chloride ethyl acetate solution (3.2 ml) was added to an ethyl acetate solution (30 ml) of tert-butyl methyl-(2-{pyridin-4-ylmethyl-[3-(1,3,3,5-tetramethyl-2,4-dioxo-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepin-7-yloxy)propyl]amino}ethyl)carbamate (1.43 g, 2.5 mmol) and stirred at room temperature overnight. The reaction mixture was concentrated under reduced pressure. The residue was dissolved in dichloromethane, and trifluoroacetic acid (3 ml) was added thereto. Stirring was conducted at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure, and the residue was dissolved in a dichloromethane-methanol mixture solvent. Polymer-bonded quaternary ammonium carbonate (PL-HcO3MP) was added thereto to neutralize the mixture. The resulting reaction mixture was filtered. The filtrate was concentrated under reduced pressure to thereby obtain 1.44 g (yield: quantitative) of 1,3,3,5-tetramethyl-7-{3-[(2-methyl aminoethyl)pyridin-4-ylmethylamino]propoxy}-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione as a pale brown oil.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:27])[CH:4]([CH2:24][CH2:25][CH3:26])[N:5]1[C:11]2[CH:12]=[CH:13][C:14]([Br:16])=[CH:15][C:10]=2[C:9]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=2)=[N:8][CH2:7][C:6]1=O.P12(SP3(SP(SP(S3)(S1)=S)(=S)S2)=S)=[S:29].N1C=CC=CC=1>C(Cl)Cl.O>[CH3:1][O:2][C:3](=[O:27])[CH:4]([CH2:24][CH2:25][CH3:26])[N:5]1[C:11]2[CH:12]=[CH:13][C:14]([Br:16])=[CH:15][C:10]=2[C:9]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=2)=[N:8][CH2:7][C:6]1=[S:29]
Reactant: S=P12SP3(=S)SP(=S)(S1)SP(=S)(S2)S3
Reactant: CCCC(C(=O)OC)N1C(=O)CN=C(c2ccccn2)c2cc(Br)ccc21
Solvent: O
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCCC(C(=O)OC)N1C(=S)CN=C(c2ccccn2)c2cc(Br)ccc21

Procedure:
A mixture of 0.01 mole of 7-bromo-2,3-dihydro-α-propyl-5-(2-pyridyl)-2-oxo-1H-1,4-benzodiazepin-1-acetic acid methyl ester, 0.0105 mole of phosphorus pentasulfide and 100 ml. of pyridine is heated under reflux for about 24 hours. The mixture is evaporated and the residue thus obtained is dissolved in methylene chloride-water. The organic layer is separated, washed with saturated sodium bicarbonate solution, dried over anhydrous magnesium sulfate and evaporated to remove the solvent. The residue thus obtained is chromatographed on silica gel and eluted to give 7-bromo-2,3-dihydro-α-propyl-5-(2-pyridyl)-2-thioxo-1H-1,4-benzodiazepin-1-acetic acid methyl ester.
Reaction SMILES: [CH:1]1([O:6][C:7]2[CH:8]=[C:9]([CH:15]([C:20]#[C:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[CH2:16][C:17]([OH:19])=[O:18])[CH:10]=[CH:11][C:12]=2[O:13][CH3:14])[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH2:28](O)[CH2:29][CH3:30]>OS(O)(=O)=O>[CH2:28]([O:18][C:17](=[O:19])[CH2:16][CH:15]([C:9]1[CH:10]=[CH:11][C:12]([O:13][CH3:14])=[C:7]([O:6][CH:1]2[CH2:5][CH2:4][CH2:3][CH2:2]2)[CH:8]=1)[C:20]#[C:21][C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1)[CH2:29][CH3:30]
Reactant: COc1ccc(C(C#Cc2ccccc2)CC(=O)O)cc1OC1CCCC1
Reactant: CCCO
Agent: O=S(=O)(O)O
Product: CCCOC(=O)CC(C#Cc1ccccc1)c1ccc(OC)c(OC2CCCC2)c1

Procedure:
A solution of (+/-)-3-(3-cyclopentyloxy-4-methoxyphenyl)-3-phenylethynylpropionic acid (200 mg, 0.55 mmol) in n-propanol (15 ml) and conc. H2SO4 (1 drop) was heated at 95° for 5 hr. The solvents were evaporated, the residue taken up in Et2O, washed with H2O, aqueous K2CO3, dried and the solvent evaporated. The residue was purified by flash chromatography (alumina, neutral, activity 1, Et2O), and gave the titled compound as an oil, 125 mg (56%). 1H NMR (400 MHz, CDCl3) δ 7.40 (m, 2 H), 7.28 (m, 3 H), 6.98 (m, 2 H), 6.84 (d, 1 H), 4.80 (m, 1 H), 4.36 (t, 1 H), 4.06 (t, 2 H), 3.82 (s, 3 H), 2.90 (d of d, 1 H), 2.78 (d of d, 1 H), 1.78-1.96 (m, 6 H), 1.64 (m, 4 H), 0.90 (t, 3 H).
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[CH2:5]([CH2:12][C:13](=[O:15])[CH3:14])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.[Cl:16][C:17]1[CH:25]=[CH:24][C:20]([C:21](Cl)=[O:22])=[CH:19][CH:18]=1>C(=S)=S>[Cl:16][C:17]1[CH:25]=[CH:24][C:20]([C:21]([C:9]2[CH:10]=[CH:11][C:6]([CH2:5][CH2:12][C:13](=[O:15])[CH3:14])=[CH:7][CH:8]=2)=[O:22])=[CH:19][CH:18]=1
Reactant: CC(=O)CCc1ccccc1
Reactant: O=C(Cl)c1ccc(Cl)cc1
Agent: [Al+3]
Agent: [Cl-]
Solvent: S=C=S
Product: CC(=O)CCc1ccc(C(=O)c2ccc(Cl)cc2)cc1
Reaction time: 8 h

Procedure:
To a vigorously stirred solution of aluminum chloride (0.2 mole) in carbon disulphide (200 ml.) at 0° C. was added a mixture of benzylacetone (0.1 mole) and p-chlorobenzoyl chloride (0.1 mole) throughout 20 minutes. After a further hour at 0° C., the reaction was allowed to reach room temperature and left overnight. The supernatant carbon disulphide was decanted off and the crude, brown residual oil, was poured carefully onto a mixture of ice and concentrated hydrochloric acid. Work-up in the usual way afforded an oil, which, after trituration with acetone and re-crystallisation from benzene/60°-80° C. petrol, gave pure 4-[4-(p-chlorobenzoyl)phenyl]-2-butanone as colourless needles, m.pt. 91°-2° C.
Reaction SMILES: [Br:1][C:2]1[C:3]([C:18]#[N:19])=[C:4]([NH:8][S:9]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)(=[O:11])=[O:10])[CH:5]=[CH:6][CH:7]=1.C([Sn]([N:33]=[N+:34]=[N-:35])(CCCC)CCCC)CCC>ClC1C=CC=CC=1Cl.CCOCC>[Br:1][C:2]1[C:3]([C:18]2[NH:35][N:34]=[N:33][N:19]=2)=[C:4]([NH:8][S:9]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)(=[O:11])=[O:10])[CH:5]=[CH:6][CH:7]=1
Reactant: N#Cc1c(Br)cccc1NS(=O)(=O)c1ccccc1
Reactant: CCCC[Sn](CCCC)(CCCC)N=[N+]=[N-]
Solvent: Clc1ccccc1Cl
Solvent: CCOCC
Product: O=S(=O)(Nc1cccc(Br)c1-c1nnn[nH]1)c1ccccc1
Yield: 76.6 %

Procedure:
A solution of N-(3-Bromo-2-cyanophenyl)-benzenesulfonamide (Intermediate 21, 0.22 g) and tributyltin azide (0.43 g) in 1,2-dichlorobenzene (1.5 mL) was heated by microwave irradiation at 130° C. for 2 hours. The mixture was diluted with ether and extracted with aqueous 1M sodium hydroxide. The aqueous solution was acidified with 1N hydrochloric acid to pH 1 and then extracted with ethyl acetate. The organic solution was washed with brine and then dried with sodium sulfate, filtered and the filtrate was evaporated. The residue was triturated with ether and the solid was collected by filtration to give the title compound as a colorless solid (0.19 g).
Reaction SMILES: [N+:1]([C:4]1[C:5]([O:18][CH3:19])=[C:6]([C:10]2[CH:11]=[C:12]([C:15]([OH:17])=[O:16])[S:13][CH:14]=2)[CH:7]=[CH:8][CH:9]=1)([O-])=O.C([O-])=O.[NH4+]>C(OCC)(=O)C.[Pd]>[NH2:1][C:4]1[C:5]([O:18][CH3:19])=[C:6]([C:10]2[CH:11]=[C:12]([C:15]([OH:17])=[O:16])[S:13][CH:14]=2)[CH:7]=[CH:8][CH:9]=1
Reactant: COc1c(-c2csc(C(=O)O)c2)cccc1[N+](=O)[O-]
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CCOC(C)=O
Product: COc1c(N)cccc1-c1csc(C(=O)O)c1
Yield: 113.4 %

Procedure:
4-(3-Nitro-2-methoxy-phenyl)-thiophene-2-carboxylic acid 51a (400 mg, 1.45 mmol) was dissolved in 30 mL of ethyl acetate followed by addition of 100 mg of palladium on carbon and ammonium formate (360 mg, 5.8 mmol). The mixture was heated to reflux for 3 hours. The reaction was monitored by TLC until the disappearance of the starting materials. The mixture was filtered to remove palladium on carbon and concentrated under reduced pressure to obtain the title compound 4-(3-amino-2-methoxy-phenyl)-thiophene-2-carboxylic acid 51b (410 mg) as a brown oil, which was directly used in the next step.
Reaction SMILES: [CH3:1][Li].[CH3:3][CH:4]([CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[C:5]([OH:7])=O>CCOCC>[CH3:3][CH:4]([CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[C:5](=[O:7])[CH3:1]
Reactant: CC(Cc1ccccc1)C(=O)O
Reactant: [Li]C
Solvent: CCOCC
Product: CC(=O)C(C)Cc1ccccc1
Temperature: 25 °C

Procedure:
1.4 M Methyl lithium (34.8 mL, 48.72 mmol) was added over 70 min to a stirring 0° C. solution of α-methylhydrocinnamic acid (4.0019 g, 24.36 mmol) in dry Et2O (122 mL, 0.2 M): The ice bath was removed, and the reaction was allowed to stir at room temperature for 2 additional hours. The reaction was the poured into rapidly stirring ice water containing aq. HCl. The organic layer was removed, washed with NaHCO3 and brine, then dried with Na2SO4, filtered, concentrated, and purified by silica gel chromatography (Combiflash column, 95:5 Hexanes:EtOAc) to achieve pure 59 (2.3038 g, 58.3%): 1H (CDCl3, 400 MHz): δ 7.28 (2H, t, J=7.3 Hz), 7.20 (1H, t, J=7.3 Hz), 7.16 (2H, d, J=7.3 Hz), 3.00 (1H, dd, J=13.7, 6.8 Hz), 2.83 (1H, app sex, 7.0 Hz), 2.56 (1H, dd, J=13.7, 7.8 Hz), 2.08 (3H, s), 1.09 (3H, d, J=6.8 Hz) ppm. 13C (CDCl3, 100 MHz): δ 211.99, 139.53, 128.79, 128.28, 126.10, 48.65, 38.75, 28.74, 16.10 ppm. DEPT (CDCl3, 100 MHz): CH3 carbons: 28.74, 16.10; CH2 carbons: 38.75; CH carbons: 128.79, 128.28, 126.10, 48.65 ppm. HPLC: 10.229 min. (Note: SM has HPLC retention time of 9.225 min.)
Reaction SMILES: CC1(C)CCCC(C)(C)N1.C([Li])CCC.[Cl:16][C:17]1[N:22]=[C:21]([O:23][CH3:24])[CH:20]=[CH:19][N:18]=1.[CH:25](OCC)=[O:26]>O1CCCC1>[Cl:16][C:17]1[N:22]=[C:21]([O:23][CH3:24])[C:20]([CH:25]=[O:26])=[CH:19][N:18]=1
Reactant: COc1ccnc(Cl)n1
Reactant: CCOC=O
Agent: CC1(C)CCCC(C)(C)N1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: COc1nc(Cl)ncc1C=O
Temperature: 0 °C
Reaction time: 0.75 h
Yield: 48.3 %

Procedure:
2,2,6,6-Tetramethylpiperidine (2.7 ml, 2.25 g, 16.0 mmol) was added to a solution of n-butyl lithium (n-BuLi) (10 ml, 16.0 mmol, 1.6M in hexanes) in tetrahydrofuran (THF) (100 ml) at -78° C. The solution was allowed to warm to 0° C. and stirred for 45 minutes, cooled to -78° C. and 2-chloro-4-methoxypyrimidine (726 mg, 5.04 mmol) in THF (20 ml) was added dropwise. The solution was then stirred for 1 hour. Then, ethyl formate (0.50 ml, 0.46 g, 6.2 mmol) in THF (20 ml) was added dropwise and the solution was stirred for 1.5 hours. The reaction mixture was quenched with acetic acid (HOAc) (conc.) at -78° C., diluted with water and extracted with ethyl acetate (EtOAc) (3 times). The combined extracts were washed with saturated brine, dried (MgSO4), filtered and concentrated in vacuo to give 1.06 g of crude material. Preparative radial chromatography (SiO2 ; hexane/EtOAc gradient elution) afforded 420 mg (48%) of 2-chloro-4-methoxypyrimidine-5-carboxaldehyde.
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][C:6]([CH2:12][C:13](OC)=[O:14])=[CH:7][CH:8]=2)[N:3]=1.[H-].[H-].[H-].[H-].[Li+].[Al+3].O.O.O.O.O.O.O.O.O.O.S([O-])([O-])(=O)=O.[Na+].[Na+]>C1COCC1>[CH3:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][C:6]([CH2:12][CH2:13][OH:14])=[CH:7][CH:8]=2)[N:3]=1
Reactant: COC(=O)Cc1ccc2ccc(C)nc2c1
Agent: O=S(=O)([O-])[O-]
Agent: [Al+3]
Agent: [H-]
Solvent: C1CCOC1
Solvent: O
Product: Cc1ccc2ccc(CCO)cc2n1
Temperature: 0 °C
Reaction time: 3 h
Yield: 46.8 %

Procedure:
methyl 2-(2-methylquinolin-7-yl)acetate (5.78 g, 26.9 mmol) in THF (50 mL) was added 1M LAH (40.3 mL, 40.3 mmol) in THF at 0° C., followed by stirring at 0° C. for 3 hours. Sodium sulfate decahydrate (10.0 g) was added and stirred at ambient temperature for 30 minutes. The solid was removed by filtration and washed with ethyl acetate (100 mL). The filtrate was concentrated and the residue obtained was purified by flash chromatography (ethyl acetate) on silica gel to give 2-(2-methylquinolin-7-yl)ethanol (2.35 g, 12.6 mmol, 47% yield) as a solid.
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH:4]=[CH:5][C:6]1[CH:7]=[C:8]2[C:12](=[CH:13][CH:14]=1)[NH:11][CH:10]=[C:9]2[CH2:15][C@H:16]1[CH2:20][CH2:19][CH2:18][N:17]1[CH3:21]>[Pd].C(Cl)Cl>[OH:1][CH2:2][CH2:3][CH2:4][CH2:5][C:6]1[CH:7]=[C:8]2[C:12](=[CH:13][CH:14]=1)[NH:11][CH:10]=[C:9]2[CH2:15][C@H:16]1[CH2:20][CH2:19][CH2:18][N:17]1[CH3:21]
Reactant: CN1CCC[C@@H]1Cc1c[nH]c2ccc(C=CCCO)cc12
Agent: [Pd]
Solvent: ClCCl
Product: CN1CCC[C@@H]1Cc1c[nH]c2ccc(CCCCO)cc12

Procedure:
Obtained from the title compound of Example 17 by a procedure similar to that described in Example 2, but using 10% palladium on charcoal as catalyst, as a foam. Rf 0.14 (SS 7). Found: C,71.04; H,8.27; N,8.61. C18H26N2O; 0.33 CH2Cl2 requires C,70.47; H,8.59; N,8.97%.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][CH:9]=[CH:8][C:3]=1[C:4]([NH:6][NH2:7])=[O:5].[OH:12][C:13]1[CH:22]=[CH:21][C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[C:14]=1[CH:23]=O>C1(C)C=CC=CC=1>[NH2:1][C:2]1[CH:11]=[CH:10][CH:9]=[CH:8][C:3]=1[C:4]([NH:6][N:7]=[CH:23][C:14]1[C:15]2[C:20](=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH:21]=[CH:22][C:13]=1[OH:12])=[O:5]
Reactant: O=Cc1c(O)ccc2ccccc12
Reactant: NNC(=O)c1ccccc1N
Solvent: Cc1ccccc1
Product: Nc1ccccc1C(=O)NN=Cc1c(O)ccc2ccccc12

Procedure:
The hydrazone is prepared by refluxing 30.2 g (0.20 mol) o-aminobenzhydrazide, 34.4 g (0.20 mol) 2-hydroxy-1-naphthaldehyde and 250 ml toluene in a 500 ml flask for 1 hour. The solid formed is collected on a filter and washed with hot ethanol yielding 40 g of yellow 2-hydroxy-1-naphthaldehyde-o-aminobenzoyl hydrazone, melting at 188°-191° C.
Reaction SMILES: [C:1]([C:3]1[C:4]([N:6]([CH3:11])[C:7](=[O:10])[C:8]=1Cl)=[O:5])#[N:2].[CH3:12][OH:13]>>[C:1]([C:3]1[C:4]([N:6]([CH3:11])[C:7](=[O:10])[C:8]=1[O:13][CH3:12])=[O:5])#[N:2]
Reactant: CN1C(=O)C(Cl)=C(C#N)C1=O
Reactant: CO
Product: COC1=C(C#N)C(=O)N(C)C1=O
Yield: 88 %

Procedure:
43 parts of 2-cyano-3-chloro-N-methylmaleimide are introduced into 100 parts by volume of methanol, the mixture is heated at the boil for fifteen minutes and then cooled, and thereafter the precipitate is filtered off under suction, washed with a small amount of methanol and dried. 37 parts (88% of theory) of 2-cyano-3-methoxy-N-methylmaleimide of melting point 123°-125° C. are obtained. IR (KBr): 2220, 1720, 1640 cm-1.
Reaction SMILES: [NH2:1][C@H:2]1[CH2:7][CH2:6][CH2:5][CH2:4][C@H:3]1[NH:8][C:9](=[O:26])[C:10]1[C:15]([C:16]([F:19])([F:18])[F:17])=[CH:14][C:13]([C:20]([F:23])([F:22])[F:21])=[CH:12][C:11]=1[O:24][CH3:25].[CH:27](=O)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>>[CH2:27]([NH:1][CH:2]1[CH2:7][CH2:6][CH2:5][CH2:4][CH:3]1[NH:8][C:9](=[O:26])[C:10]1[C:15]([C:16]([F:19])([F:18])[F:17])=[CH:14][C:13]([C:20]([F:21])([F:22])[F:23])=[CH:12][C:11]=1[O:24][CH3:25])[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: O=Cc1ccccc1
Reactant: COc1cc(C(F)(F)F)cc(C(F)(F)F)c1C(=O)N[C@@H]1CCCC[C@@H]1N
Product: COc1cc(C(F)(F)F)cc(C(F)(F)F)c1C(=O)NC1CCCCC1NCc1ccccc1

Procedure:
The title compound, colorless gum, MS: m/e=475.3 [(M+H)+], was prepared in accordance with the general method of example 11 from cis-N-(2-amino-cyclohexyl)-2-methoxy-4,6-bis-trifluoromethyl-benzamide (intermediate H) and benzaldehyde.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[C:5]([C:10]3[N:14]=[C:13]([C:15]4[CH:16]=[N:17][C:18]([CH2:21][CH2:22][CH3:23])=[CH:19][CH:20]=4)[O:12][N:11]=3)[CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.C(OC1C=C(C2ON=C(C3C=CC=C4C=3C=CN4)N=2)C=CC=1OCC)C>>[NH:1]1[C:9]2[C:4](=[C:5]([C:10]3[N:14]=[C:13]([C:15]4[CH:16]=[N:17][C:18]([CH2:21][CH2:22][CH3:23])=[CH:19][CH:20]=4)[O:12][N:11]=3)[CH:6]=[CH:7][CH:8]=2)[CH2:3][CH2:2]1
Reactant: CCCc1ccc(-c2nc(-c3cccc4[nH]ccc34)no2)cn1
Agent: CCOc1ccc(-c2nc(-c3cccc4[nH]ccc34)no2)cc1OCC
Product: CCCc1ccc(-c2nc(-c3cccc4c3CCN4)no2)cn1
Yield: 19 %

Procedure:
When the product of Step C was substituted for 5-(3,4-diethoxyphenyl)-3-(1H-indol-4-yl)-1,2,4-oxadiazole in Example 34, Step C, the similar process afforded the title compound in 19% yield, as creamy solid. 1H-NMR (CDCl3) 1.01 (m, 3H); 1.7-1.9 (m, 2H); 2.87 (m, 2H); 3.46 (tr, 2H, J=9 Hz); 3.64 (tr, 2H, J=9 Hz); 3.9 (broad s, 1H); 6.76 (d, 1H, J=6 Hz); 7.16 (m, 1H); 7.33 (d, 1H, J=9 Hz); 7.53 (dd, 1H, J=2, 9 Hz); 8.35 (dd, 1H, 3, 9 Hz); 9.33 (d, 1H, J=3 Hz).
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:18])=[C:4]([CH:14]([OH:17])[CH2:15][OH:16])[C:5]([O:11][CH2:12][CH3:13])=[C:6]([C:8](=[O:10])[CH3:9])[CH:7]=1.C(N(CC)C(C)C)(C)C.[Si:28](Cl)([C:31]([CH3:34])([CH3:33])[CH3:32])([CH3:30])[CH3:29]>ClCCCl>[Si:28]([O:16][CH2:15][CH:14]([C:4]1[C:5]([O:11][CH2:12][CH3:13])=[C:6]([C:8](=[O:10])[CH3:9])[CH:7]=[C:2]([Cl:1])[C:3]=1[F:18])[OH:17])([C:31]([CH3:34])([CH3:33])[CH3:32])([CH3:30])[CH3:29]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: CCOc1c(C(C)=O)cc(Cl)c(F)c1C(O)CO
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCCl
Product: CCOc1c(C(C)=O)cc(Cl)c(F)c1C(O)CO[Si](C)(C)C(C)(C)C
Temperature: 80 °C
Yield: 80 %

Procedure:
1-[5-Chloro-3-(1,2-dihydroxyethyl)-2-ethoxy-4-fluorophenyl]ethanone (700 mg, 2 mmol) (from Step 2, peak 2) was stirred in 1,2-dichloroethane (6 mL) with N,N-diisopropylethylamine (4.0 mL, 23 mmol) and a 1.0 M solution of tert-butyldimethylsilyl chloride in 1,2-dichloroethane (7.6 mL) was added. The mixture was heated to 80° C. for 3 hours and cooled to rt. Evaporation and purification on silica gel using ethyl acetate in hexanes (0-50%) gave the desired compound 800 mg, 80%. LCMS calculated for C18H28ClFO4SiNa (M+Na)+: m/z=413.1; found: 413.1.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH2:8][OH:9])[N:3]=1.[CH3:10][N:11]1[CH2:16][CH2:15][N:14]([C:17](=[O:22])[CH2:18][CH2:19][C:20]#[CH:21])[CH2:13][CH2:12]1.C(N)(C)(C)C>[Cu]I.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CN(C=O)C>[OH:9][CH2:8][C:4]1[N:3]=[C:2]([C:21]#[C:20][CH2:19][CH2:18][C:17]([N:14]2[CH2:15][CH2:16][N:11]([CH3:10])[CH2:12][CH2:13]2)=[O:22])[CH:7]=[CH:6][CH:5]=1
Reactant: C#CCCC(=O)N1CCN(C)CC1
Reactant: OCc1cccc(Br)n1
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Solvent: CC(C)(C)N
Product: CN1CCN(C(=O)CCC#Cc2cccc(CO)n2)CC1
Temperature: 80 °C
Reaction time: 6 h
Yield: 73 %

Procedure:
To a 50 mL round-bottom flask, 484 mg of 2-bromopyridine-6-methanol, 510 mg of 1-(4-methylpiperazin-1-yl)pent-4-yn-1-one, 20 mg of BHT, 162 mg of copper(I) iodide, 118 mg of tetrakis(triphenylphosphine)palladium (0), 375 mg of t-butylamine and 7.5 mL of DMF were added, and the mixture was stirred under argon atmosphere at 80° C. for 6 hours. The DMF was removed under reduced pressure, then saturated aqueous sodium bicarbonate was added thereto, and the mixture was extracted with chloroform. The organic layer was washed with brine, dried over anhydrous magnesium sulfate, and then the solvent was removed. The residue was purified by chromatography on silica gel (methylene chloride-methanol-triethylamine=600:20:1) to give 540 mg of 5-(6-hydroxymethylpyridin-2-yl)-1-(4-methylpiperazin-1-yl)pent-4-yn-1-one as a yellow oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:12]2[S:13][C:14]3[CH:20]=[C:19]([O:21][CH3:22])[CH:18]=[CH:17][C:15]=3[N:16]=2)[CH:6]=[CH:7][C:8]=1[N+:9]([O-])=O.O.O.[Sn](Cl)Cl.CCCCCC.C1COCC1>CCO>[NH2:9][C:8]1[CH:7]=[CH:6][C:5]([C:12]2[S:13][C:14]3[CH:20]=[C:19]([O:21][CH3:22])[CH:18]=[CH:17][C:15]=3[N:16]=2)=[CH:4][C:3]=1[O:2][CH3:1]
Reactant: COc1ccc2nc(-c3ccc([N+](=O)[O-])c(OC)c3)sc2c1
Agent: Cl[Sn]Cl
Solvent: CCO
Solvent: C1CCOC1
Solvent: O
Product: COc1ccc2nc(-c3ccc(N)c(OC)c3)sc2c1
Yield: 91.8 %

Procedure:
Prepared as described in the Nitro Reduction section using 2-(3-methoxy-4-nitrophenyl)-6-methoxybenzothiazole (0.5 g, 1.56 mmol) and tin (II) dichloride dihydrate (2.61 g, 11.58 mmol) in EtOH (35 ml) to give the title compound (0.41 g, 91%) as a pale orange solid after work-up and flash chromatography (2:1 Hexane/THF).