Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][NH2:7])=[CH:4][CH:3]=1.[CH3:10][O:11][C:12](=[O:33])[C:13]1[CH:18]=[CH:17][C:16]([C:19]2[N:20]=[C:21](Cl)[C:22]3[CH:27]=[C:26]([C:28]([F:31])([F:30])[F:29])[S:25][C:23]=3[N:24]=2)=[CH:15][CH:14]=1>>[CH3:10][O:11][C:12](=[O:33])[C:13]1[CH:18]=[CH:17][C:16]([C:19]2[N:20]=[C:21]([NH:7][CH2:6][C:5]3[CH:8]=[CH:9][C:2]([F:1])=[CH:3][CH:4]=3)[C:22]3[CH:27]=[C:26]([C:28]([F:31])([F:30])[F:29])[S:25][C:23]=3[N:24]=2)=[CH:15][CH:14]=1
Reactant: NCc1ccc(F)cc1
Reactant: COC(=O)c1ccc(-c2nc(Cl)c3cc(C(F)(F)F)sc3n2)cc1
Product: COC(=O)c1ccc(-c2nc(NCc3ccc(F)cc3)c3cc(C(F)(F)F)sc3n2)cc1

Procedure:
The reaction procedure as above wherein 4-fluorobenzylamine is reacted with 4-(4-chloro-6-trifluoromethyl-thieno-[2,3-d]-pyrimidin-2-yl)-benzoic acid methylester yields 4-[4-(4-fluorobenzylamino)-6-trifluoromethyl-thieno-[2,3-d]-pyrimidin-2-yl]-benzoic acid methylester.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:10]=[C:11]([N+:13]([O-:15])=[O:14])[CH:12]=1)[C:7](Cl)=[O:8])([O-:3])=[O:2].[CH2:16]([OH:32])[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31]>>[CH2:16]([O:32][C:7](=[O:8])[C:6]1[CH:5]=[C:4]([N+:1]([O-:3])=[O:2])[CH:12]=[C:11]([N+:13]([O-:15])=[O:14])[CH:10]=1)[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31]
Reactant: O=C(Cl)c1cc([N+](=O)[O-])cc([N+](=O)[O-])c1
Reactant: CCCCCCCCCCCCCCCCO
Product: CCCCCCCCCCCCCCCCOC(=O)c1cc([N+](=O)[O-])cc([N+](=O)[O-])c1
Yield: 90 %

Procedure:
Using 3,5-dinitrobenzoyl chloride (60.6 g, 263.0 mmol) and hexadecyl alcohol (63.9 g, 263.9 mmol), n-hexadecyl-3,5-dinitrobenzoate was obtained (103.2 g, yield: 90%) in the same manner as in Example 1.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N+:8]([O-:10])=[O:9].[CH2:11]([NH2:19])[CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>ClCCCl>[C:13]1([CH2:12][CH2:11][NH:19][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=2[N+:8]([O-:10])=[O:9])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: O=[N+]([O-])c1ccccc1Cl
Reactant: NCCc1ccccc1
Solvent: ClCCCl
Product: O=[N+]([O-])c1ccccc1NCCc1ccccc1
Yield: 97.5 %

Procedure:
1-Chloro-2-nitrobenzene (2 g, 12.7 mmol), phenethylamine (5.1 mL, 40.6 mmol), and N,N-diispropylethylamine (2.8 mL, 15.3 mmol) were dissolved in 1,2-dichloroethane (20 mL) and heated at reflux for 16 hrs. The mixture was concentrated to an oil which was dissolved in EtOAc (200 mL), washed with dilute HCl (3×50 mL), dried over Na2SO4, filtered and concentrated to dryness to give the title compound (3.0g, 97%): 1H NMR (400 MHz, CDCl3) δ 3.0-3.1 (2H, t), 3.5-3.65 (2H, q), 6.65-6.7 (1H, t), 6.85-6.9 (1H, d), 7.25-7.4 (5H, m), 7.45-7.5 (1H, t), 8.15-8.2 (1H, d).
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][C:8]([C@H:10]3[C@H:15]4[CH2:16][C@H:12]([CH2:13][CH2:14]4)[C@H:11]3[C:17]([N:19]([CH3:21])[CH3:20])=[O:18])=[CH:9][C:4]=2[CH:3]=[CH:2]1.C([N-]C(C)C)(C)C.[Li+].C1C=CC(S(N(S(C2C=CC=CC=2)(=O)=O)[F:40])(=O)=O)=CC=1.O>O1CCCC1>[F:40][C:2]1[S:1][C:5]2[CH:6]=[CH:7][C:8]([C@H:10]3[C@H:15]4[CH2:16][C@H:12]([CH2:13][CH2:14]4)[C@H:11]3[C:17]([N:19]([CH3:21])[CH3:20])=[O:18])=[CH:9][C:4]=2[CH:3]=1
Reactant: CN(C)C(=O)[C@@H]1[C@H]2CC[C@H](C2)[C@@H]1c1ccc2sccc2c1
Reactant: O=S(=O)(c1ccccc1)N(F)S(=O)(=O)c1ccccc1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: CN(C)C(=O)[C@@H]1[C@H]2CC[C@H](C2)[C@@H]1c1ccc2sc(F)cc2c1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a stirred solution of (1S,2R,3S,4R)-3-(1-benzothien-5-yl)-N,N-dimethylbicyclo [2,2,1]heptane-2-carboxamide (200 mg, 0.67 mmol) in dry tetrahydrofuran (5 mL) at −78° C. was added lithium diisopropylamide (1.67 mL, 3.35 mmol). The mixture was stirred at this temperature for 1 hour before N-fluorobenzene sulfonimide (2.3 mL, 3.35 mmol) was added. The mixture was stirred for another 10 minutes at this temperature before it was allowed to warm to room temperature. After 1 hour, water was added and the layers were separated. The aqueous phase was extracted with ethyl acetate (2×10 mL) and the extracts were washed with water (2×10 mL) dried over magnesium sulphate and evaporated in-vacuo. Column chromatography with 20% ethyl acetate in hexane provided (1S,2R,3S,4R)-3-(2-fluoro-1-benzothien-5-yl)-N,N-dimethylbicyclo[2,2,1]heptane-2-carboxamide.
Reaction SMILES: [OH:1][C:2]1[N:6]([C:7]2[CH:12]=[CH:11][C:10]([CH3:13])=[C:9]([CH3:14])[CH:8]=2)[N:5]=[C:4]([CH3:15])[C:3]=1[C:16](=O)[CH3:17].[CH3:19][CH:20]([NH:22][C:23]([C:25]1[S:26][C:27]([C:30]([NH:32][NH2:33])=[O:31])=[CH:28][CH:29]=1)=[O:24])[CH3:21].O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C(O)(C)C>[CH:20]([NH:22][C:23]([C:25]1[S:26][C:27]([C:30]([NH:32][NH:33][C:16](=[C:3]2[C:2](=[O:1])[N:6]([C:7]3[CH:12]=[CH:11][C:10]([CH3:13])=[C:9]([CH3:14])[CH:8]=3)[N:5]=[C:4]2[CH3:15])[CH3:17])=[O:31])=[CH:28][CH:29]=1)=[O:24])([CH3:21])[CH3:19]
Reactant: CC(C)NC(=O)c1ccc(C(=O)NN)s1
Reactant: CC(=O)c1c(C)nn(-c2ccc(C)c(C)c2)c1O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CC(C)O
Solvent: O
Product: CC1=NN(c2ccc(C)c(C)c2)C(=O)C1=C(C)NNC(=O)c1ccc(C(=O)NC(C)C)s1
Temperature: 90 °C
Yield: 43 %

Procedure:
1-(5-Hydroxy-3-methyl-1-(3,4-dimethylphenyl)-1H-pyrazol-4-yl)-ethanone (30 mg, 0.123 mmol, synthesized in accordance with patent document 25), 5-hydrazinocarbonyl-thiophene-2-carboxylic acid 2-propylamide prepared in Reference Synthetic Example 1 and p-toluenesulfonic acid monohydrate (2 mg) in isopropanol (1 mL) were heated at 90° C. overnight under reflux. After cooling, chloroform-ether was added, and the resulting crystals were collected by filtration, washed with chloroform-ether and dried to give 24 mg of the desired product (yield 43%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5](B(O)O)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].I[C:15]1[C:23]2[C:18](=[N:19][CH:20]=[N:21][C:22]=2[NH2:24])[N:17]([CH:25]([CH3:27])[CH3:26])[N:16]=1.C([O-])([O-])=O.[Na+].[Na+]>CCO.COCCOC.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>[CH:25]([N:17]1[C:18]2=[N:19][CH:20]=[N:21][C:22]([NH2:24])=[C:23]2[C:15]([C:5]2[CH:6]=[CH:7][C:8]([O:9][CH3:10])=[C:3]([O:2][CH3:1])[CH:4]=2)=[N:16]1)([CH3:27])[CH3:26]
Reactant: COc1ccc(B(O)O)cc1OC
Reactant: CC(C)n1nc(I)c2c(N)ncnc21
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: COCCOC
Product: COc1ccc(-c2nn(C(C)C)c3ncnc(N)c23)cc1OC
Temperature: 80 °C
Yield: 59.7 %

Procedure:
A solution of 3,4-Dimethoxyphenylboronic acid (24 mg, 0.13 mmol) in EtOH (3.3 ml) was added to a solution of 3-iodo-1-isopropyl-1H-pyrazolo[3,4-d]pyrimidin-4-amine (20 mg, 0.07 mmol) in DME (12 ml). Pd(PPh3)4 (16 mg, 0.014 mmol) and saturated Na2CO3 (1.9 ml) were added and the reaction was heated to 80° C. under an argon atmosphere overnight. After cooling, the reaction was extracted with saturated NaCl and CH2Cl2. Organic phases were combined, concentrated in vacuo and purified by RP-HPLC (MeCN:H2O:0.1% TFA) to yield BA23 (13.1 mg, 60% yield). ESI-MS (M+H)+ m/z calcd 314.0, found 314.1.
Reaction SMILES: [CH3:1][N:2]([CH3:7])[CH2:3][CH2:4][NH:5][CH3:6].C(=O)([O-])[O-].[K+].[K+].Br[CH2:15][C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17].C(OCC)(=O)C>C(#N)C>[CH3:1][N:2]([CH3:7])[CH2:3][CH2:4][N:5]([CH3:6])[CH2:15][C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17]
Reactant: CC(C)(C)OC(=O)CBr
Reactant: CNCCN(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: CCOC(C)=O
Product: CN(C)CCN(C)CC(=O)OC(C)(C)C
Reaction time: 12 h
Yield: 72.3 %

Procedure:
A solution of N,N,N′-trimethylethylenediamine (899 mg, Tokyo Kasei Kogyo) in acetonitrile (31 ml) was cooled to 0° C., added with potassium carbonate (2.21 g, and then slowly added dropwise with tert-butyl bromoacetate (1.56 g, Wako Pure Chemical Industries), and the mixture was stirred at the same temperature for 12 hours. The reaction mixture was added with ethyl acetate, and the insoluble solids were removed by filtration through Celite. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel chromatography (methanol:chloroform=1:10) to obtain the title compound (1.25 g).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:14])[CH:5]([C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([OH:13])[CH:8]=1)[CH3:6])[CH3:2].[N+:15]([O-])([OH:17])=[O:16].O>C(O)(=O)C>[CH2:1]([O:3][C:4](=[O:14])[CH:5]([C:7]1[CH:12]=[CH:11][C:10]([N+:15]([O-:17])=[O:16])=[C:9]([OH:13])[CH:8]=1)[CH3:6])[CH3:2]
Reactant: O=[N+]([O-])O
Reactant: CCOC(=O)C(C)c1cccc(O)c1
Solvent: O
Solvent: CC(=O)O
Product: CCOC(=O)C(C)c1ccc([N+](=O)[O-])c(O)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of 2-(3-Hydroxy-phenyl)-propionic acid ethyl ester (19.0 g) in acetic acid (150 mL) was added nitric acid (11.3 g) at room temperature. The reaction mixture was stirred for 1 h at room temperature and added water. The mixture was extracted with EtOAc and the organic layer was dried over magnesium sulfate, filtered and concentrated in vacuo. The resulting residue was chromatographed on silica gel (n-Hex:EtOAc=10:1) to afford the product as yellow solid. (6.08 g, 26.0%)
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([S:11]([CH:14]2[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]2)(=[O:13])=[O:12])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].Br[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[C:27]([F:30])([F:29])[F:28]>>[C:1]([C:5]1[CH:6]=[CH:7][C:8]([S:11]([CH:14]2[CH2:15][CH2:16][N:17]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=3[C:27]([F:30])([F:29])[F:28])[CH2:18][CH2:19]2)(=[O:13])=[O:12])=[CH:9][CH:10]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: FC(F)(F)c1ccccc1Br
Reactant: CC(C)(C)c1ccc(S(=O)(=O)C2CCNCC2)cc1
Product: CC(C)(C)c1ccc(S(=O)(=O)C2CCN(c3ccccc3C(F)(F)F)CC2)cc1
Yield: 17 %

Procedure:
Using the procedure from Example 7A, 4-[(4-tert-butylphenyl)sulfonyl]piperidine (100 mg, 0.36 mmol) was reacted with 2-bromobenzotrifluoride (59 μl, 0.43 mmol) to afford the title compound (26 mg), a white solid, in 17% yield.
Reaction SMILES: [C:1]([O:5][C:6](=[O:27])[NH:7][CH:8]1[C:14]2[CH:15]=[CH:16][C:17]([O:19][CH2:20][CH:21]3[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]3)=[CH:18][C:13]=2[CH2:12][CH2:11][CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].C1C(=O)N([Br:35])C(=O)C1>CC#N>[C:1]([O:5][C:6](=[O:27])[NH:7][CH:8]1[C:14]2[CH:15]=[C:16]([Br:35])[C:17]([O:19][CH2:20][CH:21]3[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26]3)=[CH:18][C:13]=2[CH2:12][CH2:11][CH2:10][CH2:9]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: O=C1CCC(=O)N1Br
Reactant: CC(C)(C)OC(=O)NC1CCCCc2cc(OCC3CCCCC3)ccc21
Solvent: CC#N
Product: CC(C)(C)OC(=O)NC1CCCCc2cc(OCC3CCCCC3)c(Br)cc21
Reaction time: 1.5 h
Yield: 88.6 %

Procedure:
To (2-cyclohexylmethoxy-6,7,8,9-tetrahydro-5H-benzocyclohepten-5-yl)-carbamic acid tert-butyl ester (7.93 g, 21.2 mmol) in CH3CN (300 mL) was added NBS (3.96 g, 22.3 mmol). The mixture was stirred for 1.5 h, then blown dry under a stream of N2. The residue was resuspended in CCl4, filtered, and concentrated to a solid. The solid was recrystallized from CH3CN to yield a white solid (8.5 g, 88%). MS [M−H]− 452, m.p. 142-144° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:11][C:12]([OH:14])=O)[CH:6]=[C:7]([O:9][CH3:10])[CH:8]=1.[F:15][C:16]1[CH:17]=[C:18]([C:22]2[C:23]([NH2:31])=[N:24][N:25]3[CH:30]=[CH:29][CH:28]=[N:27][C:26]=23)[CH:19]=[CH:20][CH:21]=1>>[CH3:10][O:9][C:7]1[CH:6]=[C:5]([CH2:11][C:12]([NH:31][C:23]2[C:22]([C:18]3[CH:19]=[CH:20][CH:21]=[C:16]([F:15])[CH:17]=3)=[C:26]3[N:27]=[CH:28][CH:29]=[CH:30][N:25]3[N:24]=2)=[O:14])[CH:4]=[C:3]([O:2][CH3:1])[CH:8]=1
Reactant: COc1cc(CC(=O)O)cc(OC)c1
Reactant: Nc1nn2cccnc2c1-c1cccc(F)c1
Product: COc1cc(CC(=O)Nc2nn3cccnc3c2-c2cccc(F)c2)cc(OC)c1

Procedure:
3,5-Dimethoxyphenylacetic acid and the product from Example 128A were processed as using the method analogous to that described in example 104 to afford the title compound. 1H NMR (300 MHz, DMSO-d6) δ ppm 10.40-10.51 (bs, 1H), 9.11 (dd, J=7.0, 1.8 Hz, 1H), 8.65 (dd, J=4.1, 1.7 Hz, 1H), 7.59 (ddd, J=11.2, 2.6, 1.6 Hz, 1H), 7.52 (d, J=7.9 Hz, 1H), 7.26-7.34 (m, 1H), 7.16 (dd, J=7.0, 4.1 Hz, 1H), 7.02-7.09 (m, 1H), 6.46-6.54 (m, 2H), 6.38-6.43 (m, 1H), 3.67-3.77 (bs, 6H), 3.59-3.62 (bs, 2H); MS (ESI) m/z 407 (M+H)+. Anal. calculated for C22H19FN4O3: C, 65.02; H, 4.71; N, 13.79. Found C, 64.80; H, 4.54; N, 13.77.
Reaction SMILES: [NH3:1].[CH3:2][C:3]1[CH:11]=[C:10]([CH3:12])[CH:9]=[CH:8][C:4]=1[C:5](Cl)=[O:6]>C(Cl)(Cl)Cl>[CH3:2][C:3]1[CH:11]=[C:10]([CH3:12])[CH:9]=[CH:8][C:4]=1[C:5]([NH2:1])=[O:6]
Reactant: Cc1ccc(C(=O)Cl)c(C)c1
Reactant: N
Solvent: ClC(Cl)Cl
Product: Cc1ccc(C(N)=O)c(C)c1
Reaction time: 0.33 h

Procedure:
Saturated with anhydrous ammonia, a solution of 50 g (0.3 mole) of 2,4-dimethylbenzoyl chloride and 500 ml of AR chloroform, while maintaining a temperature of 15°. Stirred for 20 min., then filtered, washed with cold distilled water and oven-dried at 60° to give 29.1 g, m.p. 184°-186°.
Reaction SMILES: [CH3:1][N:2]1[C:6]2=[N:7][CH:8]=[CH:9][CH:10]=[C:5]2[N:4]=[C:3]1[CH2:11][OH:12].O[C:14]1[CH:21]=[CH:20][C:17]([CH:18]=[O:19])=[CH:16][CH:15]=1.C(P(CCCC)CCCC)CCC.N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O>C1(C)C=CC=CC=1>[CH:18]([C:17]1[CH:20]=[CH:21][C:14]([O:12][CH2:11][C:3]2[N:2]([CH3:1])[C:6]3=[N:7][CH:8]=[CH:9][CH:10]=[C:5]3[N:4]=2)=[CH:15][CH:16]=1)=[O:19]
Reactant: Cn1c(CO)nc2cccnc21
Reactant: O=Cc1ccc(O)cc1
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: Cc1ccccc1
Product: Cn1c(COc2ccc(C=O)cc2)nc2cccnc21
Yield: 45.2 %

Procedure:
A procedure similar to that described in Preparation 4 was repeated, except that 500 mg of 3-methyl-3H-imidazo[4,5-b]pyridin-2-ylmethanol (prepared as described in Preparation 15), 374 mg of 4-hydroxybenzaldehyde, 0.76 ml of tributylphosphine, 773 mg of 1,1'-(azodicarbonyl)dipiperidine and 12 ml of toluene were used, and that the product was purified by column chromatography through silica gel, using a gradient elution method, with mixtures of ethyl acetate and methanol in ratios ranging from 1:0 to 50:1 by volume as the eluent, to give 0.37 g of the title compound, melting at 124-125° C.
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[NH:9][C:8]([B:11]1[O:15][C:14]([CH3:17])([CH3:16])[C:13]([CH3:19])([CH3:18])[O:12]1)=[CH:7]2.[CH2:20](C1C=CC=C2C=1NC=C2)[CH3:21]>>[CH2:20]([C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[NH:9][C:8]([B:11]1[O:15][C:14]([CH3:17])([CH3:16])[C:13]([CH3:19])([CH3:18])[O:12]1)=[CH:7]2)[CH3:21]
Reactant: CCc1cccc2cc[nH]c12
Reactant: CC1(C)OB(c2cc3cccc(Cl)c3[nH]2)OC1(C)C
Product: CCc1cccc2cc(B3OC(C)(C)C(C)(C)O3)[nH]c12

Procedure:
Prepared according to a procedure analogous to that described for 7-chloro-2-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-indole using 7-ethyl-1H-indole.
Reaction SMILES: C([O-])([O-])=O.[K+].[K+].[CH3:7][C:8]1[CH:13](/[CH:14]=[CH:15]/[C:16]([CH3:18])=[O:17])[C:12]([CH3:20])([CH3:19])[CH2:11][CH2:10][CH:9]=1.[H][H]>CC(O)C>[CH3:7][C:8]1[CH:13](/[CH:14]=[CH:15]/[CH:16]([OH:17])[CH3:18])[C:12]([CH3:19])([CH3:20])[CH2:11][CH2:10][CH:9]=1
Reactant: [H][H]
Reactant: CC(=O)/C=C/C1C(C)=CCCC1(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)O
Product: CC1=CCCC(C)(C)C1/C=C/C(C)O
Yield: 100 %

Procedure:
Under a nitrogen atmosphere, 64 mg of RuCl2 [(S)-DM-BINAP][(S)-DAIPEN], 720 mg of K2CO3, 100 mL of IPA, and 20 g of α-ionone as a racemic form were mixed. After deaeration, the obtained mixture was subjected to an asymmetric hydrogenation at 30° C. and a hydrogen pressure of 3 MPa for 21 hours. The reaction pressure was returned to the constant pressure. It was confirmed by GC that the raw material disappeared, and a post-treatment was then carried out by a conventional method, to give 20.2 g of desired optically active α-ionol (100% yield; 90% e.e.; 0% d.e.).
Reaction SMILES: [C:1]([C:3]1[CH:11]=[C:10]([C:12]#[N:13])[CH:9]=[C:8]2[C:4]=1[CH:5]=[C:6]([C:14]([O:16]CC)=[O:15])[NH:7]2)#[N:2].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>C(O)C.O>[C:1]([C:3]1[CH:11]=[C:10]([C:12]#[N:13])[CH:9]=[C:8]2[C:4]=1[CH:5]=[C:6]([C:14]([OH:16])=[O:15])[NH:7]2)#[N:2]
Reactant: CCOC(=O)c1cc2c(C#N)cc(C#N)cc2[nH]1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Solvent: O
Solvent: CCO
Product: N#Cc1cc(C#N)c2cc(C(=O)O)[nH]c2c1
Yield: 56.6 %

Procedure:
To a stirred solution of ethyl 4,6-dicyano-1H-indole-2-carboxylate (I-2a: 500 mg, 2.09 mmol) in ethanol (10 mL) was added LiOHH2O (176 mg, 4.18 mmol) and heated to reflux for 6 h. Ethanol was evaporated under reduced pressure and the residue was washed with diethyl ether. The solid formed was dissolved in water (20 mL), acidified with saturated citric acid solution and filtered. The solid was further washed with water and dried under vacuum to afford 250 mg (57%) of 4,6-dicyano-1H-indole-2-carboxylic acid (I-2b) as a light brown solid.
Reaction SMILES: [CH3:1][NH:2][O:3][CH3:4].C(N(CC)CC)C.[C:12]12[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=1)[NH:17]C(=O)O[C:13]2=[O:14]>C(O)C>[CH3:1][N:2]([O:3][CH3:4])[C:13](=[O:14])[C:12]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[NH2:17]
Reactant: O=c1[nH]c2ccccc2c(=O)o1
Reactant: CNOC
Solvent: CCN(CC)CC
Solvent: CCO
Product: CON(C)C(=O)c1ccccc1N
Yield: 99.1 %

Procedure:
N,O-Dimethylhydroxylamine (102.5 g) was dissolved in 90% ethanol (40 ml). To the solution were added triethylamine (106 g) and isatoic anhydride (74 g). The mixture was heated for 1.5 hour under reflux. The reaction mixture was concentrated, to which was added a saturated aqueous saline solution, followed by extraction with ethyl acetate (500 ml). The organic layer was washed with water and dried over anhydrous sodium sulfate. The solvent was distilled off to leave N-methyl-N-methyloxy-2-aminobenzamide (81 g) as a yellow oily product. This compound (6.8 g) and 1-[(tert-butoxycarbonylamino-1-methyl)ethyl]-3-bromobenzene (10 g) were dissolved in tetrahydrofuran (200 ml). The solution was cooled to −80° C. or below, to which was added dropwise, while stirring, n-butyl lithium (1.6 mol/L) (128 ml) over 1.5 hour. To the reaction mixture was added water (200 ml), which was subjected to extraction with ethyl acetate (300 ml). The organic layer was washed with water and dried over anhydrous sodium sulfate. The solvent was distilled off, and the residue was purified by means of a silica gel column chromatography to give 2-amino-3′-(1-tert-butoxycarbonylamino-1-methyl)ethyl-benzophenone (2.2 g) as a yellow oily product.
Reaction SMILES: C([NH:8][C@H:9]1[CH2:14][CH2:13][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:11][C@H:10]1[O:22][CH2:23][CH3:24])C1C=CC=CC=1.C([O-])=O.[NH4+]>[Pd].CO>[NH2:8][C@H:9]1[CH2:14][CH2:13][N:12]([C:15]([O:17][C:18]([CH3:19])([CH3:20])[CH3:21])=[O:16])[CH2:11][C@H:10]1[O:22][CH2:23][CH3:24]
Reactant: CCO[C@@H]1CN(C(=O)OC(C)(C)C)CC[C@@H]1NCc1ccccc1
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CO
Product: CCO[C@@H]1CN(C(=O)OC(C)(C)C)CC[C@@H]1N
Yield: 77.1 %

Procedure:
The same operation as in Example (90d) was performed using tert-butyl cis(±)-4-(benzylamino)-3-ethoxypiperidine-1-carboxylate obtained in Example (112c) (4.06 g, 12.1 mmol), 10% Pd/C (wet, 1.1 g), ammonium formate (2.87 g, 46 mmol) and methanol (30 mL), to obtain 2.28 g of the title compound as a colorless oily substance (94%).
Reaction SMILES: Cl[CH2:2][C:3]1[O:4][C:5]2[C:11]([O:12][CH3:13])=[C:10]([O:14][CH3:15])[CH:9]=[C:8]([CH2:16][C:17]3[C:18]([NH2:24])=[N:19][C:20]([NH2:23])=[N:21][CH:22]=3)[C:6]=2[CH:7]=1.[H-].[Na+].[NH:27]([C:31]1[CH:36]=[CH:35][C:34]([SH:37])=[CH:33][CH:32]=1)[C:28]([CH3:30])=[O:29]>C(O)=O>[NH2:23][C:20]1[N:19]=[C:18]([NH2:24])[C:17]([CH2:16][C:8]2[C:6]3[CH:7]=[C:3]([CH2:2][S:37][C:34]4[CH:33]=[CH:32][C:31]([NH:27][C:28](=[O:29])[CH3:30])=[CH:36][CH:35]=4)[O:4][C:5]=3[C:11]([O:12][CH3:13])=[C:10]([O:14][CH3:15])[CH:9]=2)=[CH:22][N:21]=1
Reactant: COc1cc(Cc2cnc(N)nc2N)c2cc(CCl)oc2c1OC
Reactant: CC(=O)Nc1ccc(S)cc1
Agent: [H-]
Agent: [Na+]
Solvent: O=CO
Product: COc1cc(Cc2cnc(N)nc2N)c2cc(CSc3ccc(NC(C)=O)cc3)oc2c1OC

Procedure:
formic acid salt (20 mg) was obtained by reacting 5-(2-chloromethyl-6,7-dimethoxy-benzofuran-4-ylmethyl)-pyrimidine-2,4-diamine (52 mg, 0.151 mmol), NaH (12 mg, 0.303 mmol), and 4-acetaminothiophenol (56 mg, 0.303 mmol).
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([NH2:11])=[CH:7][CH:6]=1)(=[O:4])=[O:3].C[Al](C)C.[C:16](#[N:26])[C:17]1[CH:25]=[CH:24][C:23]2[O:22][CH2:21][O:20][C:19]=2[CH:18]=1>C1(C)C=CC=CC=1.C(Cl)(Cl)Cl>[CH2:21]1[O:22][C:23]2[CH:24]=[CH:25][C:17]([C:16](=[NH:26])[NH:11][C:8]3[CH:9]=[CH:10][C:5]([S:2]([CH3:1])(=[O:3])=[O:4])=[CH:6][CH:7]=3)=[CH:18][C:19]=2[O:20]1
Reactant: CS(=O)(=O)c1ccc(N)cc1
Reactant: N#Cc1ccc2c(c1)OCO2
Agent: C[Al](C)C
Solvent: ClC(Cl)Cl
Solvent: Cc1ccccc1
Product: CS(=O)(=O)c1ccc(NC(=N)c2ccc3c(c2)OCO3)cc1
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
To a suspension of (4-methylsulfonyl)aniline (2.82 g, 16.5 mmol) in toluene (150 mL), trimethylaluminum (2M solution in toluene, 12.5 mL, 24.7 mmol) was added over 15 minutes. The reaction mixture was warmed to room temperature and stirred for 2.5 hours. A solution of piperonylonitrile (4.85 g, 33 mmol) in toluene (100 mL) was added over 10 minutes and the reaction mixture was heated to 90-95° C. After 20 hours, the reaction mixture was cooled to room temperature and poured over a slurry of silica gel in chloroform. After filtration, the residue was washed with a mixture of methylene chloride/methanol (2/1). The combined filtrates were concentrated in vacuo and the resulting yellowish solid was stirred with a mixture of hexane/ether (2/1, 1000 mL). The product was filtered and washed with more of hexane/ether (2/1). The pale yellow solid 3,4-methylenedioxy-N-[4-(methylsulfonyl)phenyl]benzenecarboximidamide (4.8 g, 91%) was used in the next reaction without further purification: mp (DSC) 214° C. Anal. Calc'd. for C15H14N2SO4: C, 56.59, H, 4.43, N, 8.80. Found: C, 56.33, H, 4.28, N, 8.66.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][N:10]2[C:15](=[O:16])[C:14](/[CH:17]=[CH:18]/[C:19]([O:21][CH2:22][CH2:23][CH2:24][CH3:25])=[O:20])=[CH:13][C:12]([O:26]CC3C=CC(OC)=CC=3)=[N:11]2)=[CH:5][CH:4]=1.O1CCOCC1>C(O)C.[Pd]>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][N:10]2[C:15](=[O:16])[C:14]([CH2:17][CH2:18][C:19]([O:21][CH2:22][CH2:23][CH2:24][CH3:25])=[O:20])=[CH:13][C:12](=[O:26])[NH:11]2)=[CH:5][CH:4]=1
Reactant: CCCCOC(=O)/C=C/c1cc(OCc2ccc(OC)cc2)nn(Cc2ccc(OC)cc2)c1=O
Agent: [Pd]
Solvent: C1COCCO1
Solvent: CCO
Product: CCCCOC(=O)CCc1cc(=O)[nH]n(Cc2ccc(OC)cc2)c1=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 89 %

Procedure:
A solution of butyl (2E)-3-[2-{[4-(methyloxy)phenyl]methyl}-6-({[4-(methyloxy)phenyl]methyl}oxy)-3-oxo-2,3-dihydro-4-pyridazinyl]-2-propenoate) (838 mg) in ethanol (15 ml)/1,4-dioxane (10 ml) was treated with 10% Pd/C (400 mg) and stirred under hydrogen at atmospheric pressure and rt for 2 h. The catalyst was filtered off using kieselguhr and the filtrate was evaporated and redissolved in 1,4-dioxane and the solution evaporated to dryness to give the product as a colourless oil (0.56 g, 89%).