Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1]S(OCC1CCOCC1)(=O)=O.[H-].[Na+].[O:15]1[CH2:20][CH2:19][CH:18]([CH2:21][N:22]2[C:30]3[C:25](=[CH:26][C:27]([C:31]([OH:33])=[O:32])=[CH:28][CH:29]=3)[C:24]([C:34]([CH:36]3[C:38]([CH3:40])([CH3:39])[C:37]3([CH3:42])[CH3:41])=[O:35])=[CH:23]2)[CH2:17][CH2:16]1.N>CN(C=O)C>[O:15]1[CH2:20][CH2:19][CH:18]([CH2:21][N:22]2[C:30]3[C:25](=[CH:26][C:27]([C:31]([O:33][CH3:1])=[O:32])=[CH:28][CH:29]=3)[C:24]([C:34]([CH:36]3[C:38]([CH3:40])([CH3:39])[C:37]3([CH3:42])[CH3:41])=[O:35])=[CH:23]2)[CH2:17][CH2:16]1
Reactant: CS(=O)(=O)OCC1CCOCC1
Reactant: CC1(C)C(C(=O)c2cn(CC3CCOCC3)c3ccc(C(=O)O)cc23)C1(C)C
Agent: N
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)c1ccc2c(c1)c(C(=O)C1C(C)(C)C1(C)C)cn2CC1CCOCC1
Yield: 44 %

Procedure:
The product of Example 114A (1.5 g, 5.1 mmol), the product of Example 18A (10 mmol), and NaH (60% dispersion in mineral oil, 0.61 g, 15 mmol) in 40 mL of DMF were processed as described in Example 1D to provide the title compound (0.89 g, 2.2 mmol, 44% yield) and 1-(tetrahydro-2H-pyran-4-ylmethyl)-3-[(2,2,3,3-tetramethylcyclopropyl)carbonyl]-1H-indole-5-carboxylic acid as a minor product (0.21 g, 0.55 mmol, 11% yield, MS (DCI/NH3) m/z 384 (M+H)+ for the carboxylic acid). Data for Example 114B (major product): 1H NMR (CDCl3, 300 MHz) δ ppm 1.33 (s, 6H), 1.36 (s, 6H), 1.40-1.58 (m, 4H), 1.95 (s, 1H), 2.06-2.24 (m, 1H), 3.34 (dt, J=11.6, 2.5 Hz, 2H), 3.92 (s, 3H), 3.94-4.01 (m, 2H), 4.06 (d, J=7.1 Hz, 2H), 7.36 (d, J=8.8 Hz, 1H), 7.66 (s, 1H), 8.00 (dd, J=8.5, 1.7 Hz, 1H), 9.12 (dd, J=1.7, 0.7 Hz, 1H); MS (DCI/NH3) m/z 398 (M+H)+; Anal. Calculated for C24H31NO4: C, 72.52; H, 7.86; N, 3.52. Found: C, 72.53; H, 7.90; N, 3.48.
Reaction SMILES: Cl.[NH2:2][O:3][CH2:4][CH2:5][CH3:6].[C:7]([CH:10]1[CH2:13][N:12]([C:14](=[O:34])/[CH:15]=[CH:16]/[C:17]2[CH:18]=[C:19]3[C:30](=[N:31][CH:32]=2)[NH:29][C:28](=[O:33])[C:21]2([CH2:26][CH2:25][N:24]([CH3:27])[CH2:23][CH2:22]2)[CH2:20]3)[CH2:11]1)(=O)[CH3:8]>CO.ClCCl>[CH3:27][N:24]1[CH2:25][CH2:26][C:21]2([CH2:20][C:19]3[C:30](=[N:31][CH:32]=[C:17](/[CH:16]=[CH:15]/[C:14](=[O:34])[N:12]4[CH2:11][CH:10](/[C:7](=[N:2]/[O:3][CH2:4][CH2:5][CH3:6])/[CH3:8])[CH2:13]4)[CH:18]=3)[NH:29][C:28]2=[O:33])[CH2:22][CH2:23]1
Reactant: CCCON
Reactant: CC(=O)C1CN(C(=O)/C=C/c2cnc3c(c2)CC2(CCN(C)CC2)C(=O)N3)C1
Agent: Cl
Solvent: ClCCl
Solvent: CO
Product: CCCO/N=C(\C)C1CN(C(=O)/C=C/c2cnc3c(c2)CC2(CCN(C)CC2)C(=O)N3)C1
Reaction time: 8 h

Procedure:
1-(Aminooxy)propane hydrochloride (10.5 mg, 0.093 mmol) was added to a solution of (E)-6-(3-(3-acetylazetidin-1-yl)-3-oxoprop-1-enyl)-1′-methyl-1H-spiro[[1,8]naphthyridine-3,4′-piperidin]-2(4H)-one (20.0 mg, 0.052 mmol) in methanol/dichloromethane (1.5 mL, 9:1) at room temperature. The reaction mixture was stirred overnight. After concentration to dryness, the residue was purified by chromatography on silica gel using chloroforme/methanol (9:1) as eluent. Triturations in acetone allowed isolation of the title product as a white solid (9 mg, 39%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16]3[C:11](=[CH:12][C:13]([O:17][C@H:18]([C:22]4[CH:27]=[CH:26][CH:25]=[C:24]([O:28][CH3:29])[CH:23]=4)[C@@H:19]([NH2:21])[CH3:20])=[CH:14][CH:15]=3)[CH:10]=[N:9]2)=[CH:4][CH:3]=1.[OH:30][C@@H:31]([CH3:35])[C:32](O)=[O:33]>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[C:16]3[C:11](=[CH:12][C:13]([O:17][C@H:18]([C:22]4[CH:27]=[CH:26][CH:25]=[C:24]([O:28][CH3:29])[CH:23]=4)[C@@H:19]([NH:21][C:32](=[O:33])[C@@H:31]([OH:30])[CH3:35])[CH3:20])=[CH:14][CH:15]=3)[CH:10]=[N:9]2)=[CH:6][CH:7]=1
Reactant: C[C@H](O)C(=O)O
Reactant: COc1cccc([C@@H](Oc2ccc3c(cnn3-c3ccc(F)cc3)c2)[C@H](C)N)c1
Product: COc1cccc([C@@H](Oc2ccc3c(cnn3-c3ccc(F)cc3)c2)[C@H](C)NC(=O)[C@H](C)O)c1

Procedure:
Prepared as described in Example 110 using (1R,2S)-1-{[1-(4-fluorophenyl)-1H-indazol-5-yl]oxy}-1-(3-methoxyphenyl)propan-2-amine (6a, 39 mg, 1000 μmol) and (2S)-2-hydroxypropanoic acid (18 mg, 20 μmol). Yield 17 mg (37%).
Reaction SMILES: [CH2:1]([O:8][C@H:9]([CH3:20])[CH:10]([OH:19])[C:11]#[C:12][C:13]1[CH:14]=[N:15][CH:16]=[CH:17][CH:18]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Si:21](Cl)([C:24]([CH3:27])([CH3:26])[CH3:25])([CH3:23])[CH3:22].N1C=CN=C1.O>CN(C)C=O>[CH2:1]([O:8][C@H:9]([CH3:20])[CH:10]([O:19][Si:21]([C:24]([CH3:27])([CH3:26])[CH3:25])([CH3:23])[CH3:22])[C:11]#[C:12][C:13]1[CH:14]=[N:15][CH:16]=[CH:17][CH:18]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: C[C@@H](OCc1ccccc1)C(O)C#Cc1cccnc1
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Solvent: O
Product: C[C@@H](OCc1ccccc1)C(C#Cc1cccnc1)O[Si](C)(C)C(C)(C)C

Procedure:
(3RS,4R)-4-Benzyloxy-1-pyridin-3-yl-pent-1-yn-3-ol (Example 30b), 1.745 g) was stirred in dimethylformamide (20 ml) with tert-butyldimethylsilyl chloride (1.18 g) and imidazole (0.89 g) at room temperature for 22 hours. Water was added and the reaction was extracted with diethyl ether. The organic phases were combined, washed with brine, dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo. Purification by flash chromatography on silica gel, eluting with 4:1 isohexane/ethyl acetate gave the subtitle compound as an oil (2.014 g).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[N:6]([C:10]2[CH:15]=[CH:14][C:13]([N+:16]([O-:18])=[O:17])=[C:12]([NH2:19])[CH:11]=2)[CH:7]=[CH:8][CH:9]=1)=[O:4].CC1(C)[O:26][C:25]([C:27]2[CH:28]=[C:29]([CH:32]=[CH:33][CH:34]=2)[C:30]#[N:31])=[CH:24][C:23](=O)[O:22]1>>[CH3:1][O:2][C:3]([C:5]1[N:6]([C:10]2[CH:15]=[CH:14][C:13]([N+:16]([O-:18])=[O:17])=[C:12]([NH:19][C:23](=[O:22])[CH2:24][C:25]([C:27]3[CH:34]=[CH:33][CH:32]=[C:29]([C:30]#[N:31])[CH:28]=3)=[O:26])[CH:11]=2)[CH:7]=[CH:8][CH:9]=1)=[O:4]
Reactant: COC(=O)c1cccn1-c1ccc([N+](=O)[O-])c(N)c1
Reactant: CC1(C)OC(=O)C=C(c2cccc(C#N)c2)O1
Product: COC(=O)c1cccn1-c1ccc([N+](=O)[O-])c(NC(=O)CC(=O)c2cccc(C#N)c2)c1

Procedure:
The title compound was prepared from 1-(3-amino-4-nitro-phenyl)-1H-pyrrole-2-carboxylic acid methyl ester (Example F9) and 3-(2,2-dimethyl-6-oxo-6H-[1,3]dioxin-4-yl)-benzonitrile (Example L1) according to the general procedure M. Obtained as a yellow solid (840 mg).
Reaction SMILES: [C:1]([O:5][C:6](=[O:19])[NH:7][CH2:8][CH2:9][CH2:10][NH:11][C:12]([N:14]=[CH:15]N(C)C)=[S:13])([CH3:4])([CH3:3])[CH3:2].[Cl:20][C:21]1[CH:30]=[CH:29][CH:28]=[CH:27][C:22]=1[C:23](=[O:26])[CH2:24]Br>>[C:1]([O:5][C:6](=[O:19])[NH:7][CH2:8][CH2:9][CH2:10][NH:11][C:12]1[S:13][C:24]([C:23](=[O:26])[C:22]2[CH:27]=[CH:28][CH:29]=[CH:30][C:21]=2[Cl:20])=[CH:15][N:14]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: CN(C)C=NC(=S)NCCCNC(=O)OC(C)(C)C
Reactant: O=C(CBr)c1ccccc1Cl
Product: CC(C)(C)OC(=O)NCCCNc1ncc(C(=O)c2ccccc2Cl)s1

Procedure:
The title compound was synthesised from [3-(3-Dimethylaminomethylene-thioureido)-propyl]-carbamic acid tert-butyl ester and 2-chloro phenacylbromide (commercially available) according to the procedure described for Example 25. MS (m/e): 395.8 (MH+, 100%).
Reaction SMILES: Cl[CH2:2][C:3]([N:5]1[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[NH:9][C:8](=[O:16])[C:7]2[N:17]([CH3:21])[CH:18]=[C:19]([CH3:20])[C:6]1=2)=[O:4].C(N(CC)CC)C.[CH2:29]([N:31]([CH2:34][CH:35]1[CH2:40][CH2:39][CH2:38][CH2:37][NH:36]1)[CH2:32][CH3:33])[CH3:30]>CN(C)C=O>[CH2:29]([N:31]([CH2:34][CH:35]1[CH2:40][CH2:39][CH2:38][CH2:37][N:36]1[CH2:2][C:3]([N:5]1[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[NH:9][C:8](=[O:16])[C:7]2[N:17]([CH3:21])[CH:18]=[C:19]([CH3:20])[C:6]1=2)=[O:4])[CH2:32][CH3:33])[CH3:30]
Reactant: CCN(CC)CC1CCCCN1
Reactant: Cc1cn(C)c2c1N(C(=O)CCl)c1ccccc1NC2=O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCN(CC)CC1CCCCN1CC(=O)N1c2ccccc2NC(=O)c2c1c(C)cn2C

Procedure:
A mixture of 4-(chloroacetyl)-1,3-dimethyl-1,4,9,10-tetrahydropyrrolo[3,2-b][1,5]-benzodiazepin-10-one (2.0 g, 0.0066 mol), dimethylformamide (30 ml), triethylamine (1 ml, 0.0071 mol) and 2-[(diethylamino)methyl]piperidine (1.7 g, 0.01 mol) is heated to 30°-40° C. for two hours with stirring. The solvent is distilled off under water jet vacuum, the residue taken up in water (10 ml), made alkline with potassium carbonate and extracted exhaustively with dichloromethane. The combined methylene chloride extracts are dried over sodium sulfate and concentrated. The crude product thus obtained is purified by chromatography on silica gel using dichloromethane/methanol (9:1 v/v). After recrystallization from ethyl acetate/methanol (95:5) the desired compound (1.4 g) is obtained in the form of colorless crystals, Mp. 176°-178° C.
Reaction SMILES: [NH2:1][CH:2]([CH2:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][CH:14]=1)[CH:3]([C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([F:11])[CH:6]=1)[OH:4].[C:23]1([C:34](O)=[O:35])[CH:24]=[CH:25][CH:26]=[C:27]2[CH2:33][CH2:32][CH2:31][CH:30]=[CH:29][C:28]=12.Cl.C(N=C=NCCCN(C)C)C.ON1C2C=CC=CC=2N=N1>C(#N)C.O>[F:11][C:7]1[CH:6]=[C:5]([CH:3]([OH:4])[CH:2]([NH:1][C:34]([C:23]2[CH:24]=[CH:25][CH:26]=[C:27]3[CH2:33][CH2:32][CH2:31][CH:30]=[CH:29][C:28]=23)=[O:35])[CH2:12][C:13]2[CH:14]=[CH:15][C:16]([C:19]([F:22])([F:20])[F:21])=[CH:17][CH:18]=2)[CH:10]=[CH:9][CH:8]=1
Reactant: NC(Cc1ccc(C(F)(F)F)cc1)C(O)c1cccc(F)c1
Reactant: O=C(O)c1cccc2c1C=CCCC2
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CC#N
Product: O=C(NC(Cc1ccc(C(F)(F)F)cc1)C(O)c1cccc(F)c1)c1cccc2c1C=CCCC2
Temperature: 25 °C
Reaction time: 8 h
Yield: 81.6 %

Procedure:
To a solution of (1RS,2SR)-2-amino-1-(3-fluorophenyl)-3-(4-(trifluoromethyl)phenyl)-1-propanol (167 mg, 0.53 mmol) in acetonitrile (20 ml) were added 6,7-dihydro-5H-benzo[a]cycloheptene-1-carboxylic acid (100 mg, 0.53 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (153 mg, 0.80 mmol) and 1-hydroxy-1H-benzotriazole (81 mg, 0.53 mmol) and the mixture was stirred overnight at room temperature. The reaction solution was diluted with water (100 ml) and extracted with ethyl acetate (100 ml×2). The extract was washed successively with 1N hydrochloric acid, 1N aqueous sodium hydroxide solution and saturated brine, dried over anhydrous magnesium sulfate and evaporated under reduced pressure. The residue was recrystallized from ethyl acetate-hexane to give the title compound (209 mg, 81%).
Reaction SMILES: [I-].[CH2:2]([O:4][CH:5]([O:13][CH2:14][CH3:15])[C:6]1[CH:11]=[CH:10][N+:9]([CH3:12])=[CH:8][CH:7]=1)[CH3:3].[OH-:16].[K+].C1(C)C=CC=CC=1>O.[Fe-3](C#N)(C#N)(C#N)(C#N)(C#N)C#N.[K+].[K+].[K+]>[CH3:12][N:9]1[CH:8]=[CH:7][C:6]([CH:5]([O:4][CH2:2][CH3:3])[O:13][CH2:14][CH3:15])=[CH:11][C:10]1=[O:16]
Reactant: CCOC(OCC)c1cc[n+](C)cc1
Reactant: [OH-]
Agent: N#C[Fe-3](C#N)(C#N)(C#N)(C#N)C#N
Agent: [I-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: O
Product: CCOC(OCC)c1ccn(C)c(=O)c1
Temperature: 40 °C
Reaction time: 0.5 h
Yield: 53.6 %

Procedure:
4-(Diethoxymethyl)-1-methylpyridinium iodide (3.43 g, 10.6 mmol) was dissolved in water (70 mL). To this, a solution of potassium ferricyanide (38.4 g, 117 mmol) in water (85 mL) was added dropwise under a nitrogen atmosphere at 0° C. over 1 hour. To this, an aqueous solution (16 mL) of potassium hydroxide (9.40 g, 167 mmol) was added dropwise at the same temperature over 30 minutes. To this, toluene (100 mL) was added and the mixture was stirred at 40° C. for 30 minutes. Then, extraction with dichloromethane was performed, followed by drying over anhydrous sodium sulfate. The solvent was evaporated off under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate) to give 1-methyl-4-(diethoxymethyl)-2(1H)-pyridone (1.20 g, yield: 53%).
Reaction SMILES: [CH2:1]([C:8]1[CH:15]=[CH:14][C:11]([CH2:12]O)=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:16]1(=[O:26])[NH:20][C:19](=[O:21])[C:18]2=[CH:22][CH:23]=[CH:24][CH:25]=[C:17]12.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>O1CCCC1>[CH2:1]([C:8]1[CH:15]=[CH:14][C:11]([CH2:12][N:20]2[C:19](=[O:21])[C:18]3=[CH:22][CH:23]=[CH:24][CH:25]=[C:17]3[C:16]2=[O:26])=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: OCc1ccc(Cc2ccccc2)cc1
Reactant: O=C1NC(=O)c2ccccc21
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: O=C1c2ccccc2C(=O)N1Cc1ccc(Cc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 72.6 %

Procedure:
To a solution of 4-benzoylbenzoic acid (2.00 g) in trifluoroacetic acid (30 mL) was added dropwise triethylsilane (3.53 mL), and the resulting mixture was stirred at room temperature for 3 hours. The reaction mixture was concentrated under reduced pressure, and then n-hexane was added to the residue. The precipitate was collected by filtration, washed with n-hexane and dried under reduced pressure at 60° C. to give 4-benzylbenzoic acid (1.66 g). To an ice-cold suspension of lithium aluminium hydride (0.315 g) in tetrahydrofuran (45 mL) was added dropwise a solution of 4-benzylbenzoic acid (1.60 g) in tetrahydrofuran (30 mL), and the resulting mixture was stirred at room temperature for 4.5 hours. The reaction was quenched by sequential addition of water (0.320 mL), 15% aqueous sodium hydroxide (0.320 mL) and water (0.320 mL). The insoluble material was filtered out and the filtrate was concentrated under reduced pressure to give 4-benzylbenzyl alcohol (1.56 g). 4-Benzylbenzylalcohol (1.56 g) was dissolved in tetrahydrofuran (39 mL). After addition of phthalimide (1.39 g) and triphenylphosphine (2.68 g), diisopropylazodicarboxylate (40% toluene solution, 5.17 g) was added dropwise, and the resulting mixture was stirred at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure and the residue was purified by column chromatography on silica gel (eluent: hexane/ethyl acetate=5/1) to give the title compound (1.87 g).
Reaction SMILES: Cl.[CH3:2][O:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[N:10]1[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]1.[C:16]([NH2:20])(=[O:19])[CH:17]=[CH2:18].C(=O)([O-])[O-].[K+].[K+]>O>[CH3:2][O:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[N:10]1[CH2:15][CH2:14][N:13]([CH2:18][CH2:17][C:16]([NH2:20])=[O:19])[CH2:12][CH2:11]1
Reactant: C=CC(N)=O
Reactant: COc1ccccc1N1CCNCC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: COc1ccccc1N1CCN(CCC(N)=O)CC1
Temperature: 80 °C
Yield: 89501 %

Procedure:
A mixture of 1-(2-methoxyphenyl)piperazine hydrochloride (22 g, 96.2 mmol), acrylamide (7.5 g, 106 mmol) and potassium carbonate (20 mL, 5M, 100 mmol) in 110 mL of water was heated at 80° C. for 2 hours to give a suspension. The suspension was allowed to cool to room temperature and filtered. The filtered residue was washed with water (3×30 mL) and dried under reduced pressure at 85° C. for 16 hours to give 3-[4-(2-methoxyphenyl)-piperazin-1-yl]propionamide (22.67 g, 86.1 mol), m.p. 145°-146° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][N:3]=1.Cl[C:10]1[C:19]2[C:14](=[CH:15][C:16]([O:22][CH3:23])=[C:17]([O:20][CH3:21])[CH:18]=2)[N:13]=[CH:12][CH:11]=1.O>CN(C)C1C=CN=CC=1.ClC1C=CC=CC=1Cl>[Cl:1][C:2]1[N:3]=[CH:4][C:5]([O:8][C:10]2[C:19]3[C:14](=[CH:15][C:16]([O:22][CH3:23])=[C:17]([O:20][CH3:21])[CH:18]=3)[N:13]=[CH:12][CH:11]=2)=[CH:6][CH:7]=1
Reactant: COc1cc2nccc(Cl)c2cc1OC
Reactant: Oc1ccc(Cl)nc1
Agent: CN(C)c1ccncc1
Solvent: Clc1ccccc1Cl
Solvent: O
Product: COc1cc2nccc(Oc3ccc(Cl)nc3)c2cc1OC
Temperature: 140 °C
Reaction time: 2 h
Yield: 67.1 %

Procedure:
2-Chloro-5-hydroxypyridine (100 mg), 4-chloro-6,7-dimethoxyquinoline (861 mg), and 4-dimethylaminopyridine (283 mg) were suspended in o-dichlorobenzene (5 ml), and the suspension was stirred at 140° C. for 2 hr. The reaction solution was cooled to room temperature, water was then added to the reaction solution, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was then washed with water and saturated brine and was dried over anhydrous magnesium sulfate. The solvent was removed by distillation under the reduced pressure, and the residue was purified by column chromatography using acetone-hexane to give the title compound (164 mg, yield 67%).
Reaction SMILES: C(N(C(C)C)CC)(C)C.[CH3:10][CH:11]([CH3:18])[CH2:12]/[CH:13]=[CH:14]/[C:15](=[O:17])[CH3:16].[CH3:19][CH2:20][O:21][C:22]([CH2:24][N+:25]([O-:27])=[O:26])=[O:23].Cl>C(#N)C>[CH2:12]([CH:13]([CH2:14][C:15](=[O:17])[CH3:16])[CH:24]([N+:25]([O-:27])=[O:26])[C:22]([O:21][CH2:20][CH3:19])=[O:23])[CH:11]([CH3:18])[CH3:10]
Reactant: CCOC(=O)C[N+](=O)[O-]
Reactant: CC(=O)/C=C/CC(C)C
Agent: Cl
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)C(C(CC(C)=O)CC(C)C)[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Diisopropylethylamine (7.9 mL) was added to the acetonitrile solution (50 mL) of (3E)-6-methylhept-3-en-2-one (6.25 g) and nitro ethyl acetate (5 mL) under argon gas atmosphere, and the reaction mixture was stirred at room temperature overnight. 1N hydrochloric acid was added to the reaction mixture, and the reaction mixture was extracted with ethyl acetate. The organic layer was washed by water and a saturated aqueous solution of sodium chloride, and dried with anhydrous magnesium sulfate. The organic layer was concentrated under reduced pressure. The obtained residue was purified by column chromatography on silica gel (n-hexane/ethyl acetate=95/5→75/25) to obtain the title compound (9.88 g) having the following physical data.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([CH3:19])=[C:6]([CH:18]=1)[O:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:10][N:9]=1.C([O:23][B:24](OC(C)C)[O:25]C(C)C)(C)C.C1COCC1.[Li]CCCC>C1(C)C=CC=CC=1>[CH3:19][C:5]1[CH:4]=[CH:3][C:2]([B:24]([OH:25])[OH:23])=[CH:18][C:6]=1[O:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:10][N:9]=1
Reactant: Cc1ccc(Br)cc1Oc1ccc(C(F)(F)F)cn1
Reactant: CC(C)OB(OC(C)C)OC(C)C
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: Cc1ccc(B(O)O)cc1Oc1ccc(C(F)(F)F)cn1
Temperature: -40 °C
Reaction time: 1 h
Yield: 126.8 %

Procedure:
2-(5-Bromo-2-methylphenoxy)-5-(trifluoromethyl)pyridine (1 g, 0.003 mol) and triisopropylborate (0.8 mL, 0.003 mol) were dissolved in toluene (20 mL) and THF (5 mL) and cooled to −78° C. under a N2 atmosphere. n-BuLi (2.69 mL, 0.003 mol) was added while maintaining the reaction at −70° C. and then the reaction was stirred for 1 h at −40° C. Gradually the temperature was increased to −20-0° C. and then the reaction was quenched with 2N HCl. The reaction mixture was warmed to RT, concentrated and extracted with EtOAc. The organic extract was dried over Na2SO4 and concentrated under reduced pressure to give the title compound (1.13 g). m/z (296.4, 298.3, M− H−).
Reaction SMILES: [C:1]([O:5][C:6](=[O:13])[CH2:7][CH2:8][NH:9][CH:10]([CH3:12])[CH3:11])([CH3:4])([CH3:3])[CH3:2].[Cl:14][C:15]1[N:20]=[C:19](Cl)[C:18]([N+:22]([O-:24])=[O:23])=[CH:17][N:16]=1.C(=O)(O)[O-].[K+]>O.C(OCC)C>[C:1]([O:5][C:6](=[O:13])[CH2:7][CH2:8][N:9]([C:17]1[C:18]([N+:22]([O-:24])=[O:23])=[CH:19][N:20]=[C:15]([Cl:14])[N:16]=1)[CH:10]([CH3:11])[CH3:12])([CH3:4])([CH3:3])[CH3:2]
Reactant: O=[N+]([O-])c1cnc(Cl)nc1Cl
Reactant: CC(C)NCCC(=O)OC(C)(C)C
Agent: O=C([O-])O
Agent: [K+]
Solvent: CCOCC
Solvent: O
Product: CC(C)N(CCC(=O)OC(C)(C)C)c1nc(Cl)ncc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 3 h
Yield: 92.8 %

Procedure:
A solution of 0.935 g (0.005 mole) of 3-isopropylamino-propanoic acid tert-butyl ester in 20 mL of water was added dropwise to a solution of 0.97 g (0.005 mole) of 2,4-dichloro-5-nitro-pyrimidine in 20 mL of ethyl ether. At 0 degrees, 1.0 g (0.010 mole) of potassium bicarbonate was added. The mixture was stirred at ambient temperature for 3 hours. The layers were then separated, and the aqueous layer extracted twice with 30 mL of ether. The combined organic layers were dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. Purification by silica gel chromatography, eluting with hexanes-ethyl acetate (100:0-80:20) gave 1.6 g of 3-[(2-chloro-5-nitro-pyrimidin-4-yl)-isopropyl-amino]-propanoic acid tert-butyl ester (IV-43).
Reaction SMILES: [CH:1](=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N+:9]([CH3:12])([O-:11])=[O:10]>>[C:2]1([C@H:1]([OH:8])[CH2:12][N+:9]([O-:11])=[O:10])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C[N+](=O)[O-]
Reactant: O=Cc1ccccc1
Product: O=[N+]([O-])C[C@@H](O)c1ccccc1
Yield: 84 %

Procedure:
Further, the present inventors has reported in Tetrahedron Letters (1993) Vol. 34, p. 2657 that the reaction between benzaldehyde and nitromethane under a catalyst of lanthanum-lithium-(R)-binaphthol complex at −50° C. gives (S)-1-phenyl-2-nitro ethanol in a yield of 84% (40% e.e.), and when carried out under a catalyst of samarium-lithium-(R)-binaphthol complex at −40° C., the reaction gives the same compound in a yield of 90% (62% e.e.) ((R) or (S) in the name of each compound represents R or S isomer, respectively, showing the compound's configuration).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[C:10]([O:12][CH3:13])[CH:11]=1)[N:8]([CH3:14])[C:7](=[CH2:15])[C:6]2([CH3:17])[CH3:16].COC1C=C2C(=CC=1)N(CCCCCC)C1(C=[CH:38][C:37]3[CH:40]=[C:41]([N+:46]([O-:48])=[O:47])[CH:42]=[C:43]([O:44][CH3:45])[C:36]=3[S:35]1)C2(C)C>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[C:10]([O:12][CH3:13])[CH:11]=1)[N:8]([CH3:14])[C:7]1([CH:15]=[CH:38][C:37]3[CH:40]=[C:41]([N+:46]([O-:48])=[O:47])[CH:42]=[C:43]([O:44][CH3:45])[C:36]=3[S:35]1)[C:6]2([CH3:17])[CH3:16]
Reactant: CCCCCCN1c2ccc(OC)cc2C(C)(C)C12C=Cc1cc([N+](=O)[O-])cc(OC)c1S2
Reactant: C=C1N(C)c2c(OC)cc(OC)cc2C1(C)C
Product: COc1cc(OC)c2c(c1)C(C)(C)C1(C=Cc3cc([N+](=O)[O-])cc(OC)c3S1)N2C
Yield: 147 %

Procedure:
3.4 g of the indoline and 3.2 g of the 3-methoxy-5-nitrosalicylaldehyde obtained in Example 2 were reacted in the same manner as in Example 2 to obtain 4.3 g of intended 5',7'-dimethoxy-1',3',3'-trimethyl-6-nitro-8-methoxyspiro[2H-1-benzothiopyran-2,2'-indoline] (yield 69%, melting point 131° C.).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]([N:10]2[CH2:15][CH2:14][N:13]([C:16]3[C:21]([CH3:22])=[CH:20][C:19]([CH2:23][CH3:24])=[CH:18][N:17]=3)[CH2:12][CH2:11]2)=[O:9])=[C:4]([F:25])[CH:3]=1.[CH3:26][N:27]1[C:31](=[O:32])[C:30]([CH3:34])([CH3:33])[NH:29][C:28]1=[O:35]>>[CH2:23]([C:19]1[CH:20]=[C:21]([CH3:22])[C:16]([N:13]2[CH2:14][CH2:15][N:10]([C:8]([C:5]3[CH:6]=[CH:7][C:2]([N:29]4[C:30]([CH3:34])([CH3:33])[C:31](=[O:32])[N:27]([CH3:26])[C:28]4=[O:35])=[CH:3][C:4]=3[F:25])=[O:9])[CH2:11][CH2:12]2)=[N:17][CH:18]=1)[CH3:24]
Reactant: CCc1cnc(N2CCN(C(=O)c3ccc(Br)cc3F)CC2)c(C)c1
Reactant: CN1C(=O)NC(C)(C)C1=O
Product: CCc1cnc(N2CCN(C(=O)c3ccc(N4C(=O)N(C)C(=O)C4(C)C)cc3F)CC2)c(C)c1
Yield: 4.3 %

Procedure:
Using (4-bromo-2-fluorophenyl)[4-(5-ethyl-3-methylpyridin-2-yl)piperazin-1-yl]methanone (163 mg) described in Preparation Example 211 and 3,5,5-trimethylimidazolidine-2,4-dione (63 mg) described in Preparation Example 218 and by the reaction and treatment in the same manner as in Example 536, the title compound (8 mg) was obtained.