Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([C:8]([OH:11])([CH3:10])[CH3:9])[CH:5]=[C:4]([F:12])[C:3]=1[C:13]1[S:17][C:16]([NH:18][C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([C:25](=[O:28])[CH2:26][F:27])[N:20]=2)=[C:15]([C:29]([NH2:31])=[O:30])[CH:14]=1.[BH4-].[Na+]>CO>[F:1][C:2]1[CH:7]=[C:6]([C:8]([OH:11])([CH3:9])[CH3:10])[CH:5]=[C:4]([F:12])[C:3]=1[C:13]1[S:17][C:16]([NH:18][C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([CH:25]([OH:28])[CH2:26][F:27])[N:20]=2)=[C:15]([C:29]([NH2:31])=[O:30])[CH:14]=1
Reactant: CC(C)(O)c1cc(F)c(-c2cc(C(N)=O)c(Nc3cccc(C(=O)CF)n3)s2)c(F)c1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CC(C)(O)c1cc(F)c(-c2cc(C(N)=O)c(Nc3cccc(C(O)CF)n3)s2)c(F)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
In a dry flask, 5-[2,6-difluoro-4-(1-hydroxy-1-methylethyl)phenyl]-2-{[6-(fluoroacetyl)pyridin-2-yl]amino}thiophene-3-carboxamide (33.6 mg, 0.08 mmol) was taken up in methanol (0.75 ml) at room temperature. Sodium borohydride (6 mg, 0.15 mmol) was added in small portions and the reaction mixture was stirred at room temperature overnight. The reaction was quenched with aqueous sodium bicarbonate and extracted three times with ethyl acetate. All organic layers were combined, dried over anhydrous magnesium sulfate, filtered, and concentrated. The crude residue was purified by silica gel chromatography (0-100% ethyl acetate/hexanes) to afford the title compound.
Reaction SMILES: [C:1](O)(=O)[CH:2]([CH3:4])[CH3:3].C(=O)(O)O.[NH:11]([C:13](=[NH:15])[NH2:14])[NH2:12].[N+]([O-])(O)=O>O>[CH:2]([C:1]1[N:14]=[C:13]([NH2:15])[NH:11][N:12]=1)([CH3:4])[CH3:3]
Reactant: N=C(N)NN
Reactant: CC(C)C(=O)O
Agent: O=C(O)O
Solvent: O
Solvent: O=[N+]([O-])O
Product: CC(C)c1n[nH]c(N)n1
Temperature: 110 °C
Reaction time: 75 h
Yield: 64.7 %

Procedure:
To a solution of isobutyric acid (25 g, 283.75 mmol) in water (25 mL) was added hydrazinecarboximidamide carbonic acid salt (15 g, 110.29 mmol) and HNO3 (0.3 mL), and the reaction mixture was stirred for 75 h at 110° C. The resulting mixture was concentrated under vacuum. The residue was applied onto a silica gel column (dichloromethane/methanol (15:1)) to afford 3-isopropyl-1H-1,2,4-triazol-5-amine as a white solid (9 g, 65%).
Reaction SMILES: [CH2:1]([OH:10])[C@@H:2]([OH:9])[CH:3]([OH:8])[C@H:4]([OH:7])[CH2:5][OH:6]>P([O-])([O-])([O-])=O>[CH2:5]([OH:6])[C@@H:4]([C@H:3]([C@@H:2]([CH2:1][OH:10])[OH:9])[OH:8])[OH:7]
Reactant: OC[C@@H](O)C(O)[C@H](O)CO
Agent: O=P([O-])([O-])[O-]
Product: OC[C@@H](O)[C@H](O)[C@@H](O)CO
Reaction time: 24 h

Procedure:
D-arabitol was dissolved in 0.1 M phosphate buffer (pH 6.0) to a concentration of 5% (w/v). The washed microbial cells as obtained above was added thereto to about 10% (w/v) in terms of the wet weight. A 10-ml portion of the thus-obtained reaction mixture was added to a test tube and allowed to react at 30° C. with shaking. After 24 hours, the microbial cells were removed by centrifugation and xylitol thus produced was determined by HPLC. The results are shown in Table 6. As shown in Table 6, xylitol was produced and accumulated from D-arabitol.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:18]2[CH:23]=[C:22]([Cl:24])[CH:21]=[CH:20][C:19]=2[O:25][CH2:26]C(O)=O)[CH:5]=[CH:6][C:7]=1[C:8]([N:10]1[C@@H:15](C)[CH2:14][CH2:13]C[C@H]1C)=[O:9].[O:30]1CCCN1>>[Cl:1][C:2]1[CH:3]=[C:4]([C:18]2[CH:23]=[C:22]([Cl:24])[CH:21]=[CH:20][C:19]=2[O:25][CH3:26])[CH:5]=[CH:6][C:7]=1[C:8]([N:10]1[CH2:15][CH2:14][CH2:13][O:30]1)=[O:9]
Reactant: C1CNOC1
Reactant: C[C@@H]1CCC[C@H](C)N1C(=O)c1ccc(-c2cc(Cl)ccc2OCC(=O)O)cc1Cl
Product: COc1ccc(Cl)cc1-c1ccc(C(=O)N2CCCO2)c(Cl)c1

Procedure:
The sub-title compound was prepared by the method of example 21 step b) using the product of example 21 step a) and isoxazolidine.
Reaction SMILES: N([O-])=O.[Na+].S(=O)(=O)(O)O.[ClH:10].[NH+]1C=CC=CC=1.N[C:18]1[C:23]([C:24]#[N:25])=[CH:22][C:21]([C:26]#[N:27])=[CH:20][N:19]=1.N([O-])=O.NC1C=CC=CN=1>C(O)(=O)C>[Cl:10][C:18]1[C:23]([C:24]#[N:25])=[CH:22][C:21]([C:26]#[N:27])=[CH:20][N:19]=1
Reactant: Cl
Reactant: N#Cc1cnc(N)c(C#N)c1
Agent: Nc1ccccn1
Agent: O=N[O-]
Agent: O=S(=O)(O)O
Solvent: CC(=O)O
Product: N#Cc1cnc(Cl)c(C#N)c1
Temperature: 0 °C

Procedure:
Acetic acid (37 mL) was added over 10 min to sodium nitrite (13.4 g, 0.194 mol) with stirring. Concentrated sulfuric acid (12.3 mL) was added over 5 min to the resulting thick slurry which was then cooled to 0° C. In a separate flask, pyridinium hydrochloride (14.4 g, 0.125 mol) was added to a stirred mixture of 2-amino-3,5-dicyanopyridine (4.0 g, 27.75 mmol) in acetic acid (55 mL) and the resulting mixture was cooled to 0° C. to give a thick slurry. The nitrite slurry was added to the aminopyridine slurry over 5 min with stirring at 0° C. Acetic acid (50 mL) was added and the thick slurry was warmed to rt. After 1 h at rt the mixture was warmed to 50° C. and after a further 1 h, it was poured into an ice/water mixture (500 mL). The aqueous mixture was extracted with methylene chloride (4 times) and the combined extracts were dried (Na2SO4) and evaporated to a yellow solid. The crude product was purified by chromatography on silica (chloroform/methanol gradient, 1-3% methanol) to give the title compound as a solid:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([F:15])=[CH:11][C:10]=2[F:16])[CH:5]=[CH:4][C:3]=1[C:17]([C:19]1[CH:24]=[C:23]([N:25]2[CH:29]=[C:28]([CH2:30][CH2:31][N:32]3[CH2:37][CH2:36]O[CH2:34][CH2:33]3)[N:27]=[N:26]2)[CH:22]=[CH:21][C:20]=1[CH3:38])=[O:18].ClC1C=C(NC2C=CC(F)=CC=2F)C=CC=1C(C1C=[C:46]([N:51]2C=C(CCOS(C3C=CC(C)=CC=3)(=O)=O)N=N2)C=CC=1C)=O.CN1CCNCC1>>[Cl:1][C:2]1[CH:7]=[C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([F:15])=[CH:11][C:10]=2[F:16])[CH:5]=[CH:4][C:3]=1[C:17]([C:19]1[CH:24]=[C:23]([N:25]2[CH:29]=[C:28]([CH2:30][CH2:31][N:32]3[CH2:37][CH2:36][N:51]([CH3:46])[CH2:34][CH2:33]3)[N:27]=[N:26]2)[CH:22]=[CH:21][C:20]=1[CH3:38])=[O:18]
Reactant: Cc1ccc(S(=O)(=O)OCCc2cn(-c3ccc(C)c(C(=O)c4ccc(Nc5ccc(F)cc5F)cc4Cl)c3)nn2)cc1
Reactant: Cc1ccc(-n2cc(CCN3CCOCC3)nn2)cc1C(=O)c1ccc(Nc2ccc(F)cc2F)cc1Cl
Agent: CN1CCNCC1
Product: Cc1ccc(-n2cc(CCN3CCN(C)CC3)nn2)cc1C(=O)c1ccc(Nc2ccc(F)cc2F)cc1Cl

Procedure:
The reaction was carried out similarly as described in the preparation of compound 138, using compound 435 (0.24 mmol) and 1-methyl-piperazine (0.5 mL). The crude product was purified by continuous gradient flash chromatography using MeOH/DCM 0:100 to 15:85 as the eluent to afford the title compound as yellow foam.
Reaction SMILES: [NH2:1][C:2]1[N:6]([C:7]2[CH:8]=[C:9]([CH:16]=[CH:17][C:18]=2[CH3:19])[C:10]([NH:12][CH:13]2[CH2:15][CH2:14]2)=[O:11])[N:5]=[CH:4][C:3]=1[C:20](=[O:27])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.[I:28]C1C=C(C=CC=1)C(C(=CNC1C=CC=CC=1)C#N)=O.CCN(C(C)C)C(C)C>C(O)C>[NH2:1][C:2]1[N:6]([C:7]2[CH:8]=[C:9]([CH:16]=[CH:17][C:18]=2[CH3:19])[C:10]([NH:12][CH:13]2[CH2:14][CH2:15]2)=[O:11])[N:5]=[CH:4][C:3]=1[C:20](=[O:27])[C:21]1[CH:22]=[CH:23][CH:24]=[C:25]([I:28])[CH:26]=1
Reactant: Cc1ccc(C(=O)NC2CC2)cc1-n1ncc(C(=O)c2ccccc2)c1N
Reactant: N#CC(=CNc1ccccc1)C(=O)c1cccc(I)c1
Solvent: CCO
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccc(C(=O)NC2CC2)cc1-n1ncc(C(=O)c2cccc(I)c2)c1N
Temperature: 160 °C
Yield: 70 %

Procedure:
To a stirred solution of N-cyclopropyl-3-hydrazino-4-methyl-benzamide, trifluoroacetic acid salt 6 (648 mg, 1.74 mmol, 1.0 eq) in 2 mL of ethanol was added 2-(3-iodo-benzoyl)-3-phenylamino-acrylonitrile 2 (550 mg, 1.74 mmol, preparation: International Patent Application Publication No. WO 02/57101 A1, pg. 84) and DIEA (0.50 mL, 2.9 mmol). The mixture was heated to 160° C. for 40 min using microwave. The mixture was concentrated in vacuo. The crude product was purified by silica gel column chromatography (EtOAc/hex, gradient 1/1 to 2/1) to give 3-[5-Amino-4-(3-iodo-benzoyl)-pyrazol-1-yl]-N-cyclopropyl-4-methyl-benzamide 7 (589 mg, 70%) as a white solid. MS m/z 497 [M+H]+; 1H NMR (300 MHz, CDCl3) δ0.60 (m, 2H), 0.86 (m, 2H), 2.24 (s, 3H), 2.87 (m, 1H), 5.81 (bs, 2H), 6.35 (bs, 1H), 7.25 (dd, J1=J2=7.8 Hz, 1H), 7.45 (d, J=8.1 Hz, 1H), 7.69 (d, J=1.7 Hz, 1H), 7.80 (m, 3H), 7.89 (m, 1H), 8.00 (s, 1H) ppm.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.[CH3:14][C:15](OC(C)=O)=[O:16]>>[C:15]([NH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1)(=[O:16])[CH3:14]
Reactant: CC(=O)OC(C)=O
Reactant: Nc1ccccc1-c1ccccc1
Product: CC(=O)Nc1ccccc1-c1ccccc1
Reaction time: 0.17 h

Procedure:
2-Aminobiphenyl a (21.9289 g, 130 mmol) was dissolved in Ac2O (30 mL, 318 mmol) and stirred 10 minutes. An additional portion of Ac2O (10 mL, 106 mmol) was added then stirred for 10 more minutes. The sample was poured onto ice. The resulting solid was vacuum filtered and washed with H2O to give N-acetyl-2-aminobiphenyl b (26.955 g, 128 mmol, 98%).
Reaction SMILES: C(P(C(C)(C)C)C1C=CC2C(=CC=CC=2)C=1C1C2C(=CC=CC=2)C=CC=1)(C)(C)C.[C:30]1([C:36]2[CH:37]=[CH:38][C:39]3[N:40]([C:42]([CH2:45][OH:46])=[N:43][N:44]=3)[N:41]=2)[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1.Cl[C:48]1[C:57]2[C:52](=[CH:53][C:54]([O:58][CH3:59])=[CH:55][CH:56]=2)[N:51]=[CH:50][C:49]=1[F:60].C(=O)([O-])[O-].[Cs+].[Cs+]>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C1(C)C=CC=CC=1>[F:60][C:49]1[CH:50]=[N:51][C:52]2[C:57]([C:48]=1[O:46][CH2:45][C:42]1[N:40]3[N:41]=[C:36]([C:30]4[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=4)[CH:37]=[CH:38][C:39]3=[N:44][N:43]=1)=[CH:56][CH:55]=[C:54]([O:58][CH3:59])[CH:53]=2
Reactant: COc1ccc2c(Cl)c(F)cnc2c1
Reactant: OCc1nnc2ccc(-c3ccccc3)nn12
Agent: [Pd]
Agent: CC(C)(C)P(c1ccc2ccccc2c1-c1cccc2ccccc12)C(C)(C)C
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: Cc1ccccc1
Product: COc1ccc2c(OCc3nnc4ccc(-c5ccccc5)nn34)c(F)cnc2c1
Temperature: 25 °C

Procedure:
A sealable tube was charged with Pd2 dba3 (0.20 g, 0.22 mmol), racemic-2-(di-t-butylphosphino)-1,1′-binaphthyl (0.18 g, 0.44 mmol), (6-phenyl-[1,2,4]triazolo[4,3-b]pyridazin-3-yl)methanol (0.100 g, 0.44 mmol), 4-chloro-3-fluoro-7-methoxyquinoline (0.14 g, 0.66 mmol), cesium carbonate (0.29 g, 0.88 mmol), and toluene and sealed. The mixture was heated at 100 C for 12 h. The mixture was allowed to cool to rt and the solid filtered, and rinsed with toluene. The solid was stirred with a mixture of EA, MeOH, CH2Cl2 and filtered. The filtrate was purified via flash chromatography using a MeOH in CH2Cl2 gradient. The resulting solid was triturated with CH2Cl2/Hexanes then purified by prep hplc. The title compound was collected as a white solid. M/Z=402.1 [M+H], calc 401.3994 for C22H16FN5O2.
Reaction SMILES: [OH:1][C:2]1[CH:12]=[CH:11][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:4][C:3]=1[CH2:13][C:14](=[CH2:16])[CH3:15]>C(O)C.[Pd]>[OH:1][C:2]1[CH:12]=[CH:11][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:4][C:3]=1[CH2:13][CH:14]([CH3:15])[CH3:16]
Reactant: C=C(C)Cc1cc(C(=O)OCC)ccc1O
Agent: [Pd]
Solvent: CCO
Product: CCOC(=O)c1ccc(O)c(CC(C)C)c1
Temperature: 25 °C
Reaction time: 41 h

Procedure:
Ethyl 4-hydroxy-3-methallylbenzoate (25.5 g) was dissolved in ethanol (250 ml) and then, with 10% palladium charcoal (2.6 g) added thereto, this mixture was stirred at room temperature for 41 hours under a hydrogen gas atmosphere. After the reaction mixture was filtered, the filtrate was concentrated under a vacuum, thereby yielding 25.6 g of the aimed oily compound.
Reaction SMILES: [CH:1]1([C:7]2([NH2:14])[CH2:12][CH2:11][CH2:10][N:9]([CH3:13])[CH2:8]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:15][O:16][C:17]1[CH:25]=[C:24]([C:26]([F:29])([F:28])[F:27])[CH:23]=[C:22]([S:30][CH3:31])[C:18]=1[C:19](Cl)=[O:20]>>[CH:1]1([C:7]2([NH:14][C:19](=[O:20])[C:18]3[C:22]([S:30][CH3:31])=[CH:23][C:24]([C:26]([F:29])([F:27])[F:28])=[CH:25][C:17]=3[O:16][CH3:15])[CH2:12][CH2:11][CH2:10][N:9]([CH3:13])[CH2:8]2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: CN1CCCC(N)(C2CCCCC2)C1
Reactant: COc1cc(C(F)(F)F)cc(SC)c1C(=O)Cl
Product: COc1cc(C(F)(F)F)cc(SC)c1C(=O)NC1(C2CCCCC2)CCCN(C)C1

Procedure:
In analogy to the procedure described for the synthesis of example 16, the title compound was prepared from rac-3-cyclohexyl-1-methyl-piperidin-3-ylamine (Example A.11) and 2-methoxy-6-methylsulfanyl-4-trifluoromethyl-benzoyl chloride (Example B6). MS (m/e): 445.2 (MH+).
Reaction SMILES: O[CH2:2][CH2:3][S:4][CH:5](C)[C:6](=[O:21])[C:7](=[N:13][O:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])[C:8]([O:10][CH2:11][CH3:12])=[O:9].C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[O:21]1[C:6]([C:7](=[N:13][O:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])[C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:5][S:4][CH2:3][CH2:2]1
Reactant: CCCCCCON=C(C(=O)OCC)C(=O)C(C)SCCO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: CCCCCCON=C(C(=O)OCC)C1=CSCCO1
Yield: 68.9 %

Procedure:
Ethyl 4-(2-hydroxyethylthio)-3-oxo-2-n-hexyloxyiminovalerate (300 g.), p-toluenesulfonic acid (42.0 g.) and toluene (2.5 l.) were treated in a similar manner to that of Example I-(ii) and refluxed under heating for 1.5 hours. The resultant solution was treated in a similar manner to that of Example I-(ii) to give ethyl 2-(2,3-dihydro-1,4-oxathiin-6-yl)-2-n-hexyloxyiminoacetate (mixture of syn isomer and anti isomer, 186.8 g.).
Reaction SMILES: [C:1]([CH:3]1[CH2:5][NH:4]1)#[N:2].Cl[C:7]([O:9][CH2:10][CH3:11])=[O:8]>>[C:1]([CH:3]1[CH2:5][N:4]1[C:7]([O:9][CH2:10][CH3:11])=[O:8])#[N:2]
Reactant: CCOC(=O)Cl
Reactant: N#CC1CN1
Product: CCOC(=O)N1CC1C#N

Procedure:
In an analogous manner, by reacting 2-cyano-aziridine with ethyl chloroformate, there is obtained ethyl 2-cyano-1-aziridine-carboxylate; b.p. 70°-75°C./0.01 mm.Hg.
Reaction SMILES: C([O:8][C:9]1[CH:10]=[C:11]([C:23]2([C:26]#[N:27])[CH2:25][CH2:24]2)[CH:12]=[CH:13][C:14]=1[O:15]CC1C=CC=CC=1)C1C=CC=CC=1>CO.[Pd]>[OH:8][C:9]1[CH:10]=[C:11]([C:23]2([C:26]#[N:27])[CH2:24][CH2:25]2)[CH:12]=[CH:13][C:14]=1[OH:15]
Reactant: N#CC1(c2ccc(OCc3ccccc3)c(OCc3ccccc3)c2)CC1
Agent: [Pd]
Solvent: CO
Product: N#CC1(c2ccc(O)c(O)c2)CC1
Temperature: 25 °C
Reaction time: 4 h
Yield: 91.7 %

Procedure:
To a solution of 1-(3,4-bis-benzyloxy-phenyl)-cyclopropanecarbonitrile (10 g, 28 mmol) in MeOH (50 mL) was added Pd/C (0.5 g) under nitrogen atmosphere. The mixture was stirred under hydrogen atmosphere (1 atm) at room temperature for 4 h. The catalyst was filtered off through a celite pad and the filtrate was evaporated under vacuum to give 1-(3,4-dihydroxy-phenyl)-cyclopropanecarbonitrile (4.5 g, 92%). 1H NMR (DMSO 400 MHz) δ 9.06 (br s, 2H), 6.67-6.71 (m, 2H), 6.54 (dd, J=2.4, 8.4 Hz, 1H), 1.60-1.57 (m, 2H), 1.30-1.27 (m, 2H).
Reaction SMILES: [CH2:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][NH:2]1.[NH:11]1[C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=2[N:13]=[C:12]1[CH2:20][N:21]([CH2:32][C:33]1[CH:40]=[CH:39][C:36]([CH:37]=O)=[CH:35][CH:34]=1)[CH:22]1[C:31]2[N:30]=[CH:29][CH:28]=[CH:27][C:26]=2[CH2:25][CH2:24][CH2:23]1.CC(O)=O.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>C1COCC1>[NH:11]1[C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=2[N:13]=[C:12]1[CH2:20][N:21]([CH2:32][C:33]1[CH:40]=[CH:39][C:36]([CH2:37][N:2]2[CH2:3][CH2:4][C:5]3[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=3)[CH2:1]2)=[CH:35][CH:34]=1)[CH:22]1[C:31]2[N:30]=[CH:29][CH:28]=[CH:27][C:26]=2[CH2:25][CH2:24][CH2:23]1
Reactant: c1ccc2c(c1)CCNC2
Reactant: O=Cc1ccc(CN(Cc2nc3ccccc3[nH]2)C2CCCc3cccnc32)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: c1ccc2c(c1)CCN(Cc1ccc(CN(Cc3nc4ccccc4[nH]3)C3CCCc4cccnc43)cc1)C2
Temperature: 25 °C
Reaction time: 2 h
Yield: 78.4 %

Procedure:
Using General Procedure B: To a stirred solution of 1,2,3,4-tetrahydroisoquinoline (49 mg, 0.37 mmol), 4-{[(1H-benzimidazol-2-ylmethyl)-(5,6,7,8-tetrahydro-quinolin-8-yl)-amino]-methyl}-benzaldehyde (140 mg, 0.34 mmol), and AcOH 0.020 mL, 0.35 mmol) in THF (3.5 mL) was added NaBH(OAc)3 (94 mg, 0.44 mmol) and the mixture was stirred at room temperature for 2 h. Purification of the crude material by column chromatography on silica gel (500:5:1 CH2Cl2/MeOH/NH4OH) afforded a colourless foam (137 mg).
Reaction SMILES: [CH:1]1([C:4](=[O:26])[CH2:5][C:6]([C:8]2[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:10][C:9]=2[S:18][C:19]2[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][CH:20]=2)=[O:7])[CH2:3][CH2:2]1.[CH2:27]([O:29][CH:30](OCC)OCC)[CH3:28]>C(OC(=O)C)(=O)C>[CH:1]1([C:4](=[O:26])[C:5](=[CH:30][O:29][CH2:27][CH3:28])[C:6]([C:8]2[CH:13]=[CH:12][C:11]([C:14]([F:15])([F:16])[F:17])=[CH:10][C:9]=2[S:18][C:19]2[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][CH:20]=2)=[O:7])[CH2:3][CH2:2]1
Reactant: CCOC(OCC)OCC
Reactant: O=C(CC(=O)C1CC1)c1ccc(C(F)(F)F)cc1Sc1ccc(Cl)cc1
Solvent: CC(=O)OC(C)=O
Product: CCOC=C(C(=O)c1ccc(C(F)(F)F)cc1Sc1ccc(Cl)cc1)C(=O)C1CC1

Procedure:
A mixture of 3-cyclopropyl-1-[2-(4-chlorophenylsulphenyl)-4-trifluoromethylphenyl]propan-1,3-dione (2.9 g) and triethylorthoformate (2.3 g) in acetic anhydride (2.4 g) was heated at reflux for 75 minutes. The reaction mixture was concentrated to give 3-cyclopropyl- 1-[2-(4-chlorophenylsulphenyl)-4-trifluoromethylphenyl]-2-ethoxymethylenepropan-1,3-dione as a red oil which was used without further purification.
Reaction SMILES: [H-].[Na+].[NH2:3][C:4]1[N:5]=[N:6][CH:7]=[CH:8][CH:9]=1.[N+](C1C=CC([O:19][C:20]([N:22]2[CH2:25][CH:24]([O:26][C:27]3[CH:32]=[CH:31][C:30]([Br:33])=[CH:29][N:28]=3)[CH2:23]2)=O)=CC=1)([O-])=O.C(=O)(O)[O-].[Na+]>CN(C=O)C>[N:6]1[CH:7]=[CH:8][CH:9]=[C:4]([NH:3][C:20]([N:22]2[CH2:23][CH:24]([O:26][C:27]3[CH:32]=[CH:31][C:30]([Br:33])=[CH:29][N:28]=3)[CH2:25]2)=[O:19])[N:5]=1
Reactant: O=C(Oc1ccc([N+](=O)[O-])cc1)N1CC(Oc2ccc(Br)cn2)C1
Reactant: Nc1cccnn1
Agent: O=C([O-])O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=C(Nc1cccnn1)N1CC(Oc2ccc(Br)cn2)C1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 80.1 %

Procedure:
To an ice-bath cooled solution of sodium hydride (60 wt % in mineral oil, (0.946 g, 23.6 mmol) in DMF (21 mL) under nitrogen atmosphere was added (dropwise) a solution of 3-aminopyridazine (1.24 g, 13.01 mmol) in DMF (21 mL). After several minute a solution of 3-(5-bromo-pyridin-2-yloxy)-azetidine-1-carboxylic acid 4-nitro-phenyl ester (Example 10, step 3; 4.66 g, 11.83 mmol) in DMF (17 mL) was added. After 5 min the cooling bath was removed and reaction allowed to warm to ambient temperature and stir for 1.5 hr. Saturated sodium bicarbonate solution (500 mL) was added and the mixture was extracted with EtOAc (4×400 mL). Combined organic phases were washed with sat sodium chloride solution (500 mL), dried over sodium sulphate and filtered. The filtrate solvents were removed in vacuo to afford a crude product that was triturated with diethyl ether to afford the title compound (3.32 g, 80%) as a colourless solid.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[C:7](=O)[CH2:6][CH2:5]2.[CH:12]([N-:15]C(C)C)(C)C.[Li+].C(OP(C#N)(=O)OCC)C>C1COCC1>[Br:1][C:2]1[CH:3]=[C:4]2[C:8]([C:7]([C:12]#[N:15])=[CH:6][CH2:5]2)=[CH:9][CH:10]=1
Reactant: CC(C)[N-]C(C)C
Reactant: O=C1CCc2cc(Br)ccc21
Agent: CCOP(=O)(C#N)OCC
Agent: [Li+]
Solvent: C1CCOC1
Product: N#CC1=CCc2cc(Br)ccc21
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of 5-bromo-2,3-dihydro-1H-inden-1-one (1 g, 4.74 mmol) in anhydrous THF (15 ml) at −10° C. was added 2M lithium diisopropylamide in THF (0.242 ml, 0.483 mmol) dropwise. The resulting mixture was stirred at −10° C. for 15 min before diethylcyanophosphonate (0.791 ml, 5.21 mmol) was added dropwise. Following the addition, the mixture was allowed to warm to room temperature, and was stirred at room temperature for 3 h. The mixture was cooled to −78° C. and borontrifluoride diethyl etherate (1.196 ml, 9.52 mmol) was added dropwise. Following the addition, the mixture was stirred at −78° C. for 1 h and was then allowed to warm to room temperature and was stirred at room temperature for 16 h. The mixture was concentrated in vacuo, and the residue was partitioned between EtOAc (50 mL) and H2O (2×50 mL). The organic layer was dried over Na2SO4, filtered and concentrated in vacuo, and the crude product was purified by column chromatography on silica gel using 9:1 EtOAc:hexanes as the eluent. The title compound was obtained as an tan solid (0.72 g, 69%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:11][C:12]([N:14]([CH3:16])[CH3:15])=[O:13])[CH:5]=[CH:6][C:7]=1[CH:8]([CH3:10])[CH3:9].C1(C)C=CC(S(O)(=O)=O)=CC=1.[O:28]1CCOC[CH2:29]1>C1C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[C:4]([N:11]2[C:12](=[O:13])[N:14]([CH3:15])[CH2:16][O:28][CH2:29]2)[CH:5]=[CH:6][C:7]=1[CH:8]([CH3:9])[CH3:10]
Reactant: C1COCCO1
Reactant: CC(C)c1ccc(NC(=O)N(C)C)cc1Cl
Agent: *CO*
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: c1ccccc1
Product: CC(C)c1ccc(N2COCN(C)C2=O)cc1Cl

Procedure:
N-(3-Chloro-4-isopropyl-phenyl)-N',N'-dimethylurea (22.65 g.=0.1 mol) is dissolved in a solvent mixture comprising dioxane (50 cc.) and benzene (80 cc.). After adding p-toluenesulphonic acid (1 g.) and polyoxymethylene (8.1 g.), the solution is heated under reflux for 1 hour in a flask equipped with a Dean and Stark apparatus with a reflux condenser. 3.7 cc. of aqueous phase are collected.
Reaction SMILES: CC1CC[O:4]C1.[C:7]([CH2:9][CH:10]([CH3:15])[C:11]([O:13][CH3:14])=[O:12])#[N:8]>>[C:7]([CH2:9][CH:10]([CH3:15])[C:11]([O:13][CH3:14])=[O:12])(=[O:4])[NH2:8]
Reactant: CC1CCOC1
Reactant: COC(=O)C(C)CC#N
Product: COC(=O)C(C)CC(N)=O

Procedure:
A process for producing 3-methyltetrahydrofuran, wherein in a first step, prussic acid is reacted with methyl methacrylate to produce methyl 3-cyanoisobutyrate. The methyl 3-cyanoisobutyrate is then reacted with water and sulfuric acid to produce a resultant product which is reacted with a C1 -C8 aliphatic alcohol to produce a methylsuccinic acid ester. The methylsuccinic acid ester is catalytically hydrogenated to prepare the 3-methyltetrahydrofuran. Alternatively, the methyl 3-cyanoisobutyrate is hydrated to produce methyl 3-carbamoylisobutyrate, which is then reacted with a formic acid ester to form a methylsuccinic acid ester and formamide and the resultant methylsuccinic acid ester is catalytically hydrogenated. The 3-methyltetrahydrofuran is produced in high selectivity and in a commercially advantageous manner from inexpensive reactants. The 3-methyltetrahydrofuran is useful as a commoner for producing polyether glycol, which is utilized as starting raw material for preparing spandex fiber.
Reaction SMILES: Cl[C:2]1([C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([O:25][CH3:26])[CH:20]=2)[CH:7]2[CH2:8][CH2:9][CH:3]1[CH2:4][N:5]([CH2:10][C:11]1[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=1)[CH2:6]2.C(O)(C)(C)C.[Na].CO>O1CCOCC1>[CH3:18][O:17][C:14]1[CH:13]=[CH:12][C:11]([CH2:10][N:5]2[CH2:4][CH:3]3[CH:2]([C:19]4[CH:24]=[CH:23][CH:22]=[C:21]([O:25][CH3:26])[CH:20]=4)[CH:7]([CH2:8][CH2:9]3)[CH2:6]2)=[CH:16][CH:15]=1
Reactant: COc1ccc(CN2CC3CCC(C2)C3(Cl)c2cccc(OC)c2)cc1
Agent: [Na]
Solvent: C1COCCO1
Solvent: CO
Solvent: CC(C)(C)O
Product: COc1ccc(CN2CC3CCC(C2)C3c2cccc(OC)c2)cc1
Temperature: 110 °C
Yield: 35 %

Procedure:
8-Chloro-3-(4-methoxy-benzyl)-8-(3-methoxy-phenyl)-3-aza-bicyclo[3.2.1]octane (2.46 g, 6.61 mmol) and t-butanol (9.48 mL, 99.1 mmol) in dioxane (25 mL) was heated to a gentle reflux with an oil bath (110° C.). Sodium (1.52 g, 66.1 mmol) was pre-washed sequentially with hexanes/ethanol/THF/hexanes then added portionwise to the above refluxing mixture over 20 min. The reaction mixture was heated overnight then cooled to room temperature. To this was added methanol (50 mL) to quench residual sodium. The solvent was removed in vacuo, and the product was partitioned between water (100 mL) and EtOAc (100 mL). The layers were separated and the product was further extracted with EtOAc (3×40 mL), washed with saturated aqueous NaCl solution (1×50 mL), dried over Na2SO4, filtered and concentrated to a light brown oil. Flash chromatography provided the title compound (780 mg, 35%). (TLC 20% EtOAc/hexanes Rf 0.60); 1H NMR (400 MHz, CDCl3) δ 7.29 (d, J=8.7 Hz, 2H), 7.23 (t, J=7.7 Hz, 1H), 6.89 (d, J=8.7 Hz, 2H), 6.88 (m, 1H), 6.84 (s, 1H), 6.74 (dd, J=7.9, 2.5 Hz, 1H), 3.82 (s, 3H), 3.81 (s, 3H), 3.52 (s, 2H), 2.86 (dd, J=10.8, 3.7 Hz, 2H), 2.75 (s, 1H), 2.51 (br s, 2H), 2.28 (d, J=10.0 Hz, 2H), 1.79 (dd, J=12.7, 5.8 Hz, 2H), 1.63 (m, 2H); GCMS m/z 337 (M)+.