Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:10]=[C:11]([C:17]#[N:18])[C:12](=[O:16])[NH:13][C:14]=2[CH3:15])=[CH:5][CH:4]=1.B(Br)(Br)Br.[Cl-].[NH4+]>ClCCl>[OH:2][C:3]1[CH:4]=[CH:5][C:6]([C:9]2[CH:10]=[C:11]([C:17]#[N:18])[C:12](=[O:16])[NH:13][C:14]=2[CH3:15])=[CH:7][CH:8]=1
Reactant: COc1ccc(-c2cc(C#N)c(=O)[nH]c2C)cc1
Agent: BrB(Br)Br
Agent: [Cl-]
Agent: [NH4+]
Solvent: ClCCl
Product: Cc1[nH]c(=O)c(C#N)cc1-c1ccc(O)cc1
Temperature: 25 °C
Reaction time: 6 h
Yield: 46 %

Procedure:
To a stirred solution of 5-(4-Methoxy-phenyl)-6-methyl-2-oxo-1,2-dihydro-pyridine-3-carbonitrile (5, 10.0 g, 41.6 mmol) in dichloromethane (200 mL) was added dropwise at 0° C. a solution of boron tribromide (11.8 mL, 125 mmol) in DCM (125 mL). The reaction mixture was stirred for 6 h at ambient temperature, poured into a mixture of ice and saturated ammonium chloride solution (100 mL) and stirred for 1 h at room temperature. The formed precipitate was filtered off, rinsed with water and re-dissolved in aqueous sodium hydroxide (2 N, 400 mL). The aqueous solution was washed with ethyl acetate (100 mL), acidified to pH 4 with aqueous hydrochloric acid (2 N) and extracted with ethyl acetate (3×200 mL). The combined organic phases were washed with brine (2×200 mL), dried (MgSO4) and evaporated to dryness to give 5-(4-hydroxy-phenyl)-6-methyl-2-oxo-1,2-dihydro-pyridine-3-carbonitrile (6) as a yellow solid (3.25 g, 46% yield, 92% pure by LC-MS and 1H NMR), 1H NMR (400 MHz; CDCl3): δ 7.70 (s, 1H); 7.13 (m, 2H); 6.68 (m, 2H); 1.71 (s, 3H).
Reaction SMILES: C[Si](C)(C)[C:3]#[C:4][C:5]1[CH2:10][CH2:9][CH:8]([NH:11][C:12](=[O:18])[O:13][C:14]([CH3:17])([CH3:16])[CH3:15])[CH2:7][CH:6]=1.[F-].C([N+](CCCC)(CCCC)CCCC)CCC.C([O-])([O-])=O.[Na+].[Na+]>C1COCC1>[C:4]([C:5]1[CH2:10][CH2:9][CH:8]([NH:11][C:12](=[O:18])[O:13][C:14]([CH3:16])([CH3:15])[CH3:17])[CH2:7][CH:6]=1)#[CH:3]
Reactant: CC(C)(C)OC(=O)NC1CC=C(C#C[Si](C)(C)C)CC1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=C([O-])[O-]
Agent: [F-]
Solvent: C1CCOC1
Product: C#CC1=CCC(NC(=O)OC(C)(C)C)CC1
Temperature: -15 °C
Reaction time: 0.67 h
Yield: 98.7 %

Procedure:
A solution of tert-butyl 4-(2-(trimethylsilyl)ethynyl)cyclohex-3-enylcarbamate (112 mg, 0.38 mmol) in THF was cooled to −15° C., treated with 1.0 M tetrabutylammonium fluoride in THF (Aldrich, 440 μL, 0.44 mmol) and the mixture stirred at −15° C. for 40 min. The mixture was treated with 5% Na2CO3 (25 mL) and extracted with ether. The ether extract was washed with 5% Na2CO3 and brine, dried (MgSO4) and concentrated in vacuo to give the title compound (83 mg, 99%) as a brown oil. 1H NMR (DMSO-d6) δ 6.09 (s, 1H), 4.51 (s, 1H), 3.77 (s, 1H), 2.82 (s, 1H), 2.47 (d, 1H, J=18.3 Hz), 2.35-2.16 (m, 2H), 2.04-1.79 (m, 2H), 1.72-1.51 (m, 1H), 1.43 (s, 9H).
Reaction SMILES: [CH3:1][C:2]1[N:6]([CH2:7][C:8]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[CH:11]=[CH:10][CH:9]=2)[C:5]2[CH:18]=[C:19]([N:25]3[CH2:30][CH2:29][O:28][CH2:27][CH2:26]3)[CH:20]=[C:21]([C:22]([OH:24])=O)[C:4]=2[N:3]=1.C[N:32](C=O)C.C(Cl)(=O)C(Cl)=O>C(Cl)Cl>[CH3:1][C:2]1[N:6]([CH2:7][C:8]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[CH:11]=[CH:10][CH:9]=2)[C:5]2[CH:18]=[C:19]([N:25]3[CH2:30][CH2:29][O:28][CH2:27][CH2:26]3)[CH:20]=[C:21]([C:22]([NH2:32])=[O:24])[C:4]=2[N:3]=1
Reactant: Cc1nc2c(C(=O)O)cc(N3CCOCC3)cc2n1Cc1cccc2ccccc12
Reactant: CN(C)C=O
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Product: Cc1nc2c(C(N)=O)cc(N3CCOCC3)cc2n1Cc1cccc2ccccc12
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 79 %

Procedure:
To a solution of 2-methyl-6-(4-morpholinyl)-1-(1-naphthalenylmethyl)-1H-benzimidazole-4-carboxylic acid, prepared as described in Example 20 (100 mg) in DCM (20 mL) was added a drop of DMF. The solution was then cooled to 0° C. and then Oxalyl chloride (64 mg) was then added. The mixture was stirred at room temperature for 30 min. The solvent was removed in-vacuo to afford a white solid that used directly in the next step. To the solid dissolved in dry DCM (20 mL) was bubbled in NH3 at 0° C. for 5 min. The mixture was then concentrated in-vacuo to afford the desired product as a white solid (79 mg, 79%). 1H NMR (300 MHz, DMSO-d6): δ ppm 2.47 (s, 3H), 3.05 (t, 4H, J=4.5 Hz), 3.69 (t, 4H, J=4.5 Hz), 6.05 (s, 2H), 6.35 (d, 1H, J=7.5 Hz), 7.23 (s, 1H), 7.34 (t, 1H, J=7.5 Hz), 7.53 (s, 1H), 7.60-7.74 (m, 3H), 7.86 (d, 1H, J=7.5 Hz), 8.01 (d, 1H, J=9.0 Hz), 8.24 (d, 1H, J=9.0 Hz), 9.22 (s, 1H); LC-MS: m/e=401 [M+1]+.
Reaction SMILES: [H-].[Na+].[CH2:3]1[O:5][CH:4]1[CH2:6][OH:7].[CH2:8](Cl)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.O>CN(C=O)C.[Na+].[I-]>[CH2:8]([O:7][CH2:6][C@@H:4]1[CH2:3][O:5]1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: ClCc1ccccc1
Reactant: OCC1CO1
Agent: [H-]
Agent: [I-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: c1ccc(COC[C@@H]2CO2)cc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 78.6 %

Procedure:
A slurry of NaH (267 g) and NaI (26.5 g) in DMF (3000 mL) was cooled to between −15° C. and −10° C. with ice-brine mixture. A solution of glycidol (480 g) in DMF (1000 mL) was added with stirring for 10 minutes. BnCl (745.5 g) in DMF (800 mL) was added (slightly exothermic) and the reaction was warmed to room temperature followed by stirring for approximately 16 hours. The solution was stirred for a further time period until HPLC analysis showed less than 1% of BnCl remained. The reaction was cooled to −5° C. and water (4 L) was added. MBTE (5 L) was added with stirring for 30 minutes. The organic and aqueous layers were separated and two additions of MBTE (5 L; 3.5 L) were used to extract the aqueous layer. The combined organic layer was washed with brine (1.8 L (×2)) and dried over Na2SO4 for 1 hour. The organic layer was concentrated to dryness, distilled under vacuum (5 mm Hg, 85° C.) to give the product as a yellow liquid (760 g). 1H NMR (CDCl3, 400 MHz): δ 7.27-7.37 (m, 5H), 4.51 (s, 2H), 3.74 (dd, 1H), 3.29 (dd, 1H), 3.14 (m, 1H), 2.72 (dd, 1H), 2.55 (dd, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]1[CH2:13][C:12](=[O:14])[C:11](=[C:15](O)[CH3:16])[C:10](=O)[CH2:9]1.[C:19]1([NH:25][NH2:26])[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>C(O)C>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]1[CH2:9][C:10]2[C:11](=[C:15]([CH3:16])[N:25]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[N:26]=2)[C:12](=[O:14])[CH2:13]1
Reactant: CC(O)=C1C(=O)CC(c2ccccc2Cl)CC1=O
Reactant: NNc1ccccc1
Solvent: CCO
Product: Cc1c2c(nn1-c1ccccc1)CC(c1ccccc1Cl)CC2=O
Yield: 76.2 %

Procedure:
A solution of 5-(2-chlorophenyl)-2-(1-hydroxyethylidene)cyclohexane-1,3-dione (1.0 g) and phenylhydrazine (0.43 g) in ethanol (20 ml) was refluxed for 2 hours. Under reduced pressure, the solvent was evaporated, and the resulting crystals were recrystallized from ethyl acetate-hexane to give 6-(2-chlorophenyl)-3-methyl-2-phenyl-4,5,6,7-tetrahydroindazol-4-one (0.97 g) as colorless crystals.
Reaction SMILES: [BH4-].[Na+].[C:3]([C:6]1[CH:11]=[N:10][CH:9]=[CH:8][N:7]=1)(=[O:5])[CH3:4].O.Cl>C(O)C>[OH:5][CH:3]([C:6]1[CH:11]=[N:10][CH:9]=[CH:8][N:7]=1)[CH3:4]
Reactant: CC(=O)c1cnccn1
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: CC(O)c1cnccn1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 91.1 %

Procedure:
Sodium borohydride (0.69 g) was added in portions to a stirred solution of acetylpyrazine (1.49 g) in ethanol (300 mL) at 0° C. The mixture was allowed to warm to room temperature and stirred for 20 min, then water (100 mL) was added and the mixture adjusted to pH 7 with 1N hydrochloric acid. The neutralized solution was concentrated in vacuo to a volume of 200 mL, saturated with sodium chloride, and extracted with ethyl acetate (3×500 mL). The organic extracts were dried (Na2 SO4) and concentrated to give a solid which was washed with dichloromethane (4×100 mL). The dichloromethane washings were concentrated to give 2-(1-hydroxyethyl)pyrazine (1.38 g) as a colorless oil.
Reaction SMILES: [F:1][C:2]([F:29])([F:28])[C:3]1[CH:4]=[C:5]([NH:13][C:14]([N:16]2[CH2:21][CH2:20][N:19]([C:22]3[C:26](Cl)=[N:25][S:24][N:23]=3)[CH2:18][CH2:17]2)=[O:15])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.CC(C)([O-])C.[K+].C(O)(C)(C)C.[F:41][C:42]1[CH:47]=[C:46]([CH2:48][OH:49])[CH:45]=[CH:44][N:43]=1>CO>[F:1][C:2]([F:29])([F:28])[C:3]1[CH:4]=[C:5]([NH:13][C:14]([N:16]2[CH2:21][CH2:20][N:19]([C:22]3[C:26]([O:49][CH2:48][C:46]4[CH:45]=[CH:44][N:43]=[C:42]([F:41])[CH:47]=4)=[N:25][S:24][N:23]=3)[CH2:18][CH2:17]2)=[O:15])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1
Reactant: OCc1ccnc(F)c1
Reactant: O=C(Nc1cc(C(F)(F)F)cc(C(F)(F)F)c1)N1CCN(c2nsnc2Cl)CC1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CO
Solvent: CC(C)(C)O
Product: O=C(Nc1cc(C(F)(F)F)cc(C(F)(F)F)c1)N1CCN(c2nsnc2OCc2ccnc(F)c2)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 13.5 %

Procedure:
To a solution of 4-(4-chloro-[1,2,5]thiadiazol-3-yl)-piperazine-1-carboxylic acid (3,5-bis-trifluoromethyl-phenyl)-amide (117.7 mg, 0.265 mmol, prepared in Example 10b) and 1M solution of potassium tert-butoxide in tert-butanol (0.75 mL, 0.75 mmol) was added 2-Fluoro-4-pyridinemethanol (65.6 mg, 0.516 mmol, prepared in Example 15a). The resulting suspension was stirred at room temperature for 2 h. The crude reaction mixture was diluted with methanol and purified by preparative HPLC (50 mM NH4OAc(aq), Acetonitrile system). The pure fractions were combined and the acetonitrile was removed in vacuo. The remaining aqueous solution was made basic with NaHCO3 and the free based product was extracted into EtOAc. The organic phase was concentrated in vacuo, and the solids were re-dissolved in acetonitrile/water and lyophilized to obtain pure product 4-[4-(2-Fluoro-pyridin-4-ylmethoxy)-[1,2,5]thiadiazol-3-yl]-piperazine-1-carboxylic acid (3,5-bis-trifluoromethyl-phenyl)-amide. (19.0 mg, 13.5% yield). 1H NMR (CDCl3) 8.26 (d, 1H), 7.88 (s, 2H), 7.53 (s, 1H), 7.22 (d, 1H), 6.98 (s, 1H), 6.88 (s, 1H), 5.53 (s, 2H), 3.73-3.50 (m, 8H) ppm.
Reaction SMILES: C(S)C.[Li].[C:5]([C:7]1[CH:8]=[C:9]([C:18]2[S:19][C:20]3[C:26]([O:27]C)=[CH:25][CH:24]=[CH:23][C:21]=3[N:22]=2)[CH:10]=[CH:11][C:12]=1[O:13][CH2:14][CH:15]([CH3:17])[CH3:16])#[N:6].Cl>CN(C=O)C>[C:5]([C:7]1[CH:8]=[C:9]([C:18]2[S:19][C:20]3[C:26]([OH:27])=[CH:25][CH:24]=[CH:23][C:21]=3[N:22]=2)[CH:10]=[CH:11][C:12]=1[O:13][CH2:14][CH:15]([CH3:17])[CH3:16])#[N:6]
Reactant: COc1cccc2nc(-c3ccc(OCC(C)C)c(C#N)c3)sc12
Agent: Cl
Agent: [Li]
Solvent: CCS
Solvent: CN(C)C=O
Product: CC(C)COc1ccc(-c2nc3cccc(O)c3s2)cc1C#N
Temperature: 25 °C
Reaction time: 1 h
Yield: 11.9 %

Procedure:
Ethane thiol (0.45 mL, 6.08 mmol) was added to lithium metal (14 mg, 2.02 mmol), and the mixture was stirred for one hour at room temperature. To tire mixture were then added dry DMF (5 mL) and 2-(3-cyano-4-isobutyloxyphenyl)-7-methoxy-1,3-benzothiazole (150 mg, 0.44 mmol). The resulting mixture was stirred at 80° C. for 8.5 hours, cooled to room temperature, and, after addition of icewater (10 mL), made to pH 7 by addition of aqueous 1M hydrochloric acid. The mixture was then extracted with ethyl acetate (20 mL). The ethyl acetate portion was washed successively with water (10 mL) and aqueous saturated brine (10 mL), dried over anhydrous sodium sulfate, and placed under reduced pressure to distill the solvent off. The residue was purified by silica, gel column chromatography (ethyl acetate/hexane=1/3), and suspended in hexane. The obtained crystalline product was collected by filtration, washed with hexane, and dried in air, to give 17 mg (yield 12%) of the desired compound in the form of a pale yellow crystalline product.
Reaction SMILES: C([N:4]1[C:18]2[C:19]3[C@H:6]([CH2:7][C@@H:8]4[C@@H:13]([C:14]=3[C:15]([N+:20]([O-:22])=[O:21])=[CH:16][CH:17]=2)[CH2:12][C@H:11]([NH:23][C:24](=[O:30])[N:25]([CH2:28][CH3:29])[CH2:26][CH3:27])[CH2:10][N:9]4[CH3:31])[CH2:5]1)(=O)C.O>NN.C(Cl)(Cl)Cl>[CH3:31][N:9]1[C@H:8]2[C@@H:13]([C:14]3[C:15]([N+:20]([O-:22])=[O:21])=[CH:16][CH:17]=[C:18]4[C:19]=3[CH:6]([CH2:7]2)[CH2:5][NH:4]4)[CH2:12][C@H:11]([NH:23][C:24](=[O:30])[N:25]([CH2:28][CH3:29])[CH2:26][CH3:27])[CH2:10]1
Reactant: CCN(CC)C(=O)N[C@H]1C[C@@H]2c3c([N+](=O)[O-])ccc4c3[C@H](C[C@H]2N(C)C1)CN4C(C)=O
Agent: NN
Solvent: ClC(Cl)Cl
Solvent: O
Product: CCN(CC)C(=O)N[C@H]1C[C@@H]2c3c([N+](=O)[O-])ccc4c3C(CN4)C[C@H]2N(C)C1
Yield: 59.4 %

Procedure:
One millimole of 3-(1-acetyl-2,3β-dihydro-6-methyl-12-nitro-8α-ergolinyl)-1,1-diethylurea is heated in a mixture of 2 ml of anhydrous hydrazine and 2 ml of chloroform for 3 hours to 50° C., poured into water, extracted with methylene chloride, the organic phase is dried, and evaporated under vacuum, yielding 230 mg of 3-(2,3-dihydro-6-methyl-12-nitro-8α-ergolinyl)-1,1-diethylurea. Yield: 25%. [α]D =+538° (0.5% in methanol) as the tartaric acid salt.
Reaction SMILES: [CH3:1][C:2]1([C:7]2[S:8][C:9]([CH2:12][N:13]3[CH:17]=[C:16]([NH2:18])[CH:15]=[N:14]3)=[CH:10][N:11]=2)[O:6]CCO1.[C:19]1([C:25]2[O:29][CH:28]=[N:27][C:26]=2[C:30](O)=[O:31])[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>>[C:2]([C:7]1[S:8][C:9]([CH2:12][N:13]2[CH:17]=[C:16]([NH:18][C:30]([C:26]3[N:27]=[CH:28][O:29][C:25]=3[C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=3)=[O:31])[CH:15]=[N:14]2)=[CH:10][N:11]=1)(=[O:6])[CH3:1]
Reactant: O=C(O)c1ncoc1-c1ccccc1
Reactant: CC1(c2ncc(Cn3cc(N)cn3)s2)OCCO1
Product: CC(=O)c1ncc(Cn2cc(NC(=O)c3ncoc3-c3ccccc3)cn2)s1

Procedure:
Following general procedure B followed by C, starting from 1-[2-(2-methyl-[1,3]dioxolan-2-yl)-thiazol-5-ylmethyl]-1H-pyrazol-4-ylamine and 5-phenyl-oxazole-4-carboxylic acid. LC-MS-conditions 02: tR=0.98 min; [M+H]+=393.91.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH2:8][CH2:9][S:10][C:11]2[CH:20]=[CH:19][CH:18]=[CH:17][C:12]=2[C:13]([O:15][CH3:16])=[O:14])[CH:5]=[CH:6][CH:7]=1.[CH2:21]([N:28]([CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH3:38])[C:29](=[O:32])[CH2:30]Br)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.C([O-])([O-])=O.[K+].[K+]>C(#N)C>[CH2:21]([N:28]([CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH3:38])[C:29](=[O:32])[CH2:30][O:1][C:2]1[CH:3]=[C:4]([CH2:8][CH2:9][S:10][C:11]2[CH:20]=[CH:19][CH:18]=[CH:17][C:12]=2[C:13]([O:15][CH3:16])=[O:14])[CH:5]=[CH:6][CH:7]=1)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: COC(=O)c1ccccc1SCCc1cccc(O)c1
Reactant: CCCCCCN(Cc1ccccc1)C(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCCCCCN(Cc1ccccc1)C(=O)COc1cccc(CCSc2ccccc2C(=O)OC)c1
Yield: 89.5 %

Procedure:
Methyl 2-{[2-(3-hydroxyphenyl)ethyl]thio}benzoate (129 mg, 0.447 mmol), N-benzyl-2-bromo-N-hexylacetamide (154 mg, 0.492 mmol) and potassium carbonate, anhydrous (93 mg, 0.671 mmol) were mixed in acetonitrile (10 ml). The mixture was heated to reflux overnight and then evaporated to dryness. Water and ethyl acetate were added into the residue. The two phases were separated. The organic phase was washed with brine and dried with magnesium sulphate and then evaporated. Chromatography of the residue on a column (ISOLUTE® SI, 2 g/6 ml) using ethyl acetate/heptane (10:90, then 25:75) as eluant gave 208 mg the desired product, yield 89.5%.
Reaction SMILES: [F:1][C:2]1[C:11]2[O:10][CH2:9][CH:8]([CH2:12]OS(C3C=CC(C)=CC=3)(=O)=O)[O:7][C:6]=2[CH:5]=[C:4]([S:24]([CH3:27])(=[O:26])=[O:25])[CH:3]=1.[CH2:28]([NH:31][CH2:32][CH2:33][CH3:34])[CH2:29][CH3:30]>C(#N)C>[F:1][C:2]1[C:11]2[O:10][CH2:9][CH:8]([CH2:12][N:31]([CH2:32][CH2:33][CH3:34])[CH2:28][CH2:29][CH3:30])[O:7][C:6]=2[CH:5]=[C:4]([S:24]([CH3:27])(=[O:25])=[O:26])[CH:3]=1
Reactant: Cc1ccc(S(=O)(=O)OCC2COc3c(F)cc(S(C)(=O)=O)cc3O2)cc1
Reactant: CCCNCCC
Solvent: CC#N
Product: CCCN(CCC)CC1COc2c(F)cc(S(C)(=O)=O)cc2O1

Procedure:
Preparation according to Example 42 using [5-fluoro-7-(methylsulfonyl)-2,3-dihydro-1,4-benzodioxin-2-yl]methyl-4-methylbenzenesulfonate (0.005 g, 0.012 mmol), N-propylpropan-1-amine (0.5 ml), ACN (2.5 ml). MS m/z (rel. intensity, 70 eV) 345 (M+, 0.5), 316 (21), 115 (8), 114 (bp), 112 (6).
Reaction SMILES: [C:1]([O:5][C@H:6]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:7](OCC)=[O:8])([CH3:4])([CH3:3])[CH3:2].[H-].[H-].[H-].[H-].[Li+].[Al+3]>O1CCCC1>[C:1]([O:5][C@H:6]([C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1)[CH2:7][OH:8])([CH3:4])([CH3:2])[CH3:3]
Reactant: CCOC(=O)[C@H](OC(C)(C)C)c1ccccc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CC(C)(C)O[C@@H](CO)c1ccccc1
Temperature: 0 °C
Reaction time: 2 h
Yield: 92.3 %

Procedure:
Into a 50-mL round-bottom flask was placed tetrahydrofuran (10 mL), 117.2 (500 mg, 2.12 mmol, 1.00 equiv) and LiAlH4 (81 mg, 2.13 mmol, 1.01 equiv). The resulting solution was stirred for 2 h at 0° C. in a water/ice bath. The reaction was then quenched by the addition of 20 mL of ethyl acetate. The resulting mixture was concentrated under vacuum. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (1:5). Purification afforded 0.38 g (92%) of (2R)-2-(tert-butoxy)-2-phenylethan-1-ol (117.3) as a white solid.
Reaction SMILES: C(O)C.[Cl-].[NH4+].[CH3:6][C:7]1[CH:12]=[C:11]([CH3:13])[CH:10]=[CH:9][C:8]=1[N:14]1[CH2:19][CH2:18][N:17]([C:20]([C:22]2[CH:27]=[CH:26][C:25]([N+:28]([O-])=O)=[CH:24][C:23]=2[NH:31][S:32]([CH3:35])(=[O:34])=[O:33])=[O:21])[CH2:16][CH2:15]1>[Fe].O>[NH2:28][C:25]1[CH:26]=[CH:27][C:22]([C:20]([N:17]2[CH2:16][CH2:15][N:14]([C:8]3[CH:9]=[CH:10][C:11]([CH3:13])=[CH:12][C:7]=3[CH3:6])[CH2:19][CH2:18]2)=[O:21])=[C:23]([NH:31][S:32]([CH3:35])(=[O:34])=[O:33])[CH:24]=1
Reactant: Cc1ccc(N2CCN(C(=O)c3ccc([N+](=O)[O-])cc3NS(C)(=O)=O)CC2)c(C)c1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCO
Solvent: O
Product: Cc1ccc(N2CCN(C(=O)c3ccc(N)cc3NS(C)(=O)=O)CC2)c(C)c1
Temperature: 60 °C
Yield: 107.9 %

Procedure:
Methyl 2-amino-4-nitrobenzoate (600 mg) and triethylamine (2.9 mL) were dissolved in tetrahydrofuran (11 mL), methanesulfonyl chloride (0.51 mL) was added under ice-cooling, and the mixture was stirred at room temperature overnight. Water was added to the reaction mixture, and the mixture was extracted with chloroform. The organic layer was washed with saturated brine, and the solvent was evaporated. Methanol (18 mL) and 1N aqueous sodium hydroxide solution (9.1 mL) were added to the obtained residue, and the mixture was stirred at 50° C.-60° C. After completion of the reaction, to the reaction mixture was added aqueous sodium hydroxide solution, and the mixture was partitioned with ethyl acetate. The aqueous layer was neutralized with diluted hydrochloric acid, and the precipitated solid was collected by filtration to give 2-methanesulfonylamino-4-nitrobenzoic acid (358 mg). Using the obtained 2-methanesulfonylamino-4-nitrobenzoic acid (358 mg) and 1-(2,4-dimethylphenyl)piperazine (262 mg) and by the reaction and treatment in the same manner as in Preparation Example 111, N-{2-[4-(2,4-dimethylphenyl)piperazine-1-carbonyl]-5-nitrophenyl}methanesulfonamide (330 mg) was obtained. Then, to a solution of ethanol (5.4 mL) and water (1.8 mL) were added ammonium chloride (528 mg) and iron (379 mg), and the obtained N-{2-[4-(2,4-dimethylphenyl)piperazine-1-carbonyl]-5-nitrophenyl}methanesulfonamide (267 mg) was added while stirring at 60° C. After completion of the reaction, the insoluble material was collected by filtration, and the filtrate was concentrated. To the obtained residue was added aqueous sodium hydrogen carbonate solution, and the mixture was extracted with ethyl acetate. The solvent was evaporated from the organic layer to give the title compound (268 mg).
Reaction SMILES: [CH:1]1([C:4]2[CH2:8][C:7](=[O:9])[NH:6][N:5]=2)[CH2:3][CH2:2]1.[CH3:10][C:11]1[CH:12]=[C:13]([CH:17]=O)[NH:14][C:15]=1[CH3:16].N1CCCCC1>C(O)C>[CH:1]1([C:4]2[C:8](=[CH:17][C:13]3[NH:14][C:15]([CH3:16])=[C:11]([CH3:10])[CH:12]=3)[C:7](=[O:9])[NH:6][N:5]=2)[CH2:3][CH2:2]1
Reactant: Cc1cc(C=O)[nH]c1C
Reactant: O=C1CC(C2CC2)=NN1
Solvent: C1CCNCC1
Solvent: CCO
Product: Cc1cc(C=C2C(=O)NN=C2C2CC2)[nH]c1C

Procedure:
A reaction mixture of 3-cyclopropyl-2-pyrazolin-5-one (790 mg, 6.3 mmol), 4,5-dimethylpyrrole-2-carboxaldehyde (800 mg, 6.5 mmol), and piperidine 100 mg, in ethanol 50 mL was stirred at 90° C. for 3.5 h. The solvent was removed under reduced pressure. The solid residue was purified by flash column chromatography using (3:7) ethyl acetate:hexane as the mobile phase, then further purified by recrystallization from toluene.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]3[N:22]=[C:21]([NH:23][CH3:24])[CH:20]=[CH:19][C:10]=3[C:11]3[C:17]([CH3:18])=[N:16][O:15][C:12]=3[CH2:13][N:14]=2)=[CH:4][CH:3]=1.N1C[CH2:28][CH2:27][CH2:26]1>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]3[N:22]=[C:21]([N:23]4[CH2:28][CH2:27][CH2:26][CH2:24]4)[CH:20]=[CH:19][C:10]=3[C:11]3[C:17]([CH3:18])=[N:16][O:15][C:12]=3[CH2:13][N:14]=2)=[CH:4][CH:3]=1
Reactant: CNc1ccc2c(n1)C(c1ccc(Cl)cc1)=NCc1onc(C)c1-2
Reactant: C1CCNC1
Product: Cc1noc2c1-c1ccc(N3CCCC3)nc1C(c1ccc(Cl)cc1)=NC2

Procedure:
A procedure similar to 6-(4-chlorophenyl)-N,1-dimethyl-4H-isoxazolo[5,4-c]pyrido[3,2-e]azepin-8-amine (Compound 241) was followed, except that pyrrolidine was used instead of methylamine (33% in EtOH). LC/MS m/z 379 [M+H]+; 1H NMR (400 MHz, DMSO-d6) δ 7.92 (d, J=8.93 Hz, 1H), 7.43 (td, J=2.20, 8.70 Hz, 2H), 7.36 (td, J=2.20, 8.70 Hz, 2H), 6.79 (d, J=8.93 Hz, 1H), 4.62 (br. s, 2H), 3.30-3.25 (m, 4H), 2.47 (s, 3H), 1.96-1.83 (m, 4H).
Reaction SMILES: [CH3:1][C:2](=[CH:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=1)[C:3]([O:5][CH2:6][CH3:7])=[O:4].C([O-])=O.[NH4+]>C(O)C.O.[C].[Pd]>[CH3:1][CH:2]([CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=1)[C:3]([O:5][CH2:6][CH3:7])=[O:4]
Reactant: CCOC(=O)C(C)=Cc1ccccn1
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: O
Solvent: CCO
Product: CCOC(=O)C(C)Cc1ccccn1
Yield: 90.9 %

Procedure:
Ethyl 2-methyl-3-(2-pyridyl)acrylate (7.8 g, 41.0 mmol) was dissolved in ethanol (80 ml), and 10% palladium-carbon (1.0 g) and a solution of ammonium formate (11.2 g, 178 mmol) in water (20 ml) was added thereto. The mixture was refluxed for 2 hrs. Palladium-carbon was filtered off. The reaction mixture was combined with water, concentrated under reduced pressure to the half amount and extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was evaporated to give the titled compound (7.2 g, 91%).
Reaction SMILES: C([C:3]([C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([O:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=2[CH3:29])[C:17]=1[O:30]C)([CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH3:15])[C:4]([O:6]CC)=[O:5])#N.I>C(O)(=O)C>[OH:30][C:17]1[C:18]([O:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=2[CH3:29])=[CH:19][CH:20]=[CH:21][C:16]=1[CH:3]([CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH3:15])[C:4]([OH:6])=[O:5]
Reactant: CCCCCCCC(C#N)(C(=O)OCC)c1cccc(Oc2ccccc2C)c1OC
Agent: I
Solvent: CC(=O)O
Product: CCCCCCCC(C(=O)O)c1cccc(Oc2ccccc2C)c1O
Yield: 76.3 %

Procedure:
A mixture of ethyl 2-cyano-2-[2-methoxy-3-(o-tolyloxy)phenyl]-n-nonanoate (6.7 g), hydriodic acid (58%, 10 ml) and acetic acid (30 ml) was refluxed under heating for 45 hours. The reaction mixture was concentrated under reduced pressure, and the residue was poured into water and extracted with diethyl ether. The extract was washed with aqueous sodium hydrogen sulfite and water in turn, dried and evaporated under reduced pressure. To the residue were added potassium hydroxide (5 g) and methanol (30 ml), and the mixture was refluxed under heating for an hour. After evaporation, the residue was dissolved in water, and the aqueous solution was washed with diethyl ether, acidified with conc. hydrochloric acid and then extracted with diethyl ether. The extract was washed with water, dried and evaporated under reduced pressure. The residue was purified by column chromatography (silica gel 90 g, benzene-ethyl acetate 1:1) to give 2-[2-hydroxy-3-(o-tolyloxy)phenyl]-n-nonanoic acid (4.3 g).