Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1.[Li]CCCC.C([O:15][C:16]1[CH2:20][CH2:19][C:18](=O)[CH:17]=1)C.Cl>C1COCC1>[N:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[C:18]1[CH2:19][CH2:20][C:16](=[O:15])[CH:17]=1
Reactant: Brc1ccccn1
Reactant: CCOC1=CC(=O)CC1
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: O=C1C=C(c2ccccn2)CC1
Reaction time: 0.17 h
Yield: 62 %

Procedure:
To a solution of 2-Bromopyridine (5.00 g, 31.6 mmol) in THF (30 ml) was added dropwise n-BuLi (2.55 M in Hexane, 12.5 mL. 31.9 mmol) at −78° C., and stirred for 10 min. To a reaction mixture was added dropwise 3-ethoxy-2-cyclopentenone (2.00 g, 15.9 mmol) in THF (10 mL) at −78° C., and stirred at 0° C. for 2 h. The reaction mixture was acidified with 2M HCl (10 mL), and aqueous layer was washed with EtOAc. The aqueous layer was basified with 1M NaOH aq., and then extracted with CH2Cl2. The organic layer was washed with brine, and dried over anhyd Na2SO4 followed by the removal of solvent. The crude product was purified by column chromatography (Hexane/EtOAc=1/3) to yield 3-(2-pyridyl)-2-cyclopenten-1-one (1.57 g, 58%) as brown solid.
Reaction SMILES: C([NH:7][C:8]1[NH:13][C:12]2=[N:14][CH:15]=[CH:16][C:11]2=[CH:10][N:9]=1)(=O)C(C)(C)C.C(Cl)Cl>CCO.[Cl-].[Cl-].[Zn+2]>[NH2:7][C:8]1[NH:13][C:12]2=[N:14][CH:15]=[CH:16][C:11]2=[CH:10][N:9]=1
Reactant: CC(C)(C)C(=O)Nc1ncc2ccnc-2[nH]1
Agent: [Cl-]
Agent: [Zn+2]
Solvent: ClCCl
Solvent: CCO
Product: Nc1ncc2ccnc-2[nH]1
Temperature: 80 °C

Procedure:
A suspension of 2-(pivaloylamino)-pyrrolo[2,3-d]pyrimidine and ZnCl2 (3-20 equiv.) in wet EtOH (5 vol % water) was heated to 80° C., and monitored by HPLC. When the reaction reached completion, DCM was added, and the organic layer was washed with sat. aq. NaHCO3 and brine. Drying (Na2SO4) and concentration afforded the desired 2-amino-pyrrolo[2,3-d]pyrimidine.
Reaction SMILES: [C:1]([O:5][C:6](=[O:20])[C:7]1[CH:12]=[CH:11][C:10]([NH:13][CH:14]2[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]2)=[CH:9][CH:8]=1)([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[CH:28]1[C:37]2[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=2)[CH:31]=[CH:30][C:29]=1[S:38](Cl)(=[O:40])=[O:39]>C(Cl)Cl>[C:1]([O:5][C:6](=[O:20])[C:7]1[CH:12]=[CH:11][C:10]([NH:13][CH:14]2[CH2:19][CH2:18][N:17]([S:38]([C:29]3[CH:30]=[CH:31][C:32]4[C:37](=[CH:36][CH:35]=[CH:34][CH:33]=4)[CH:28]=3)(=[O:40])=[O:39])[CH2:16][CH2:15]2)=[CH:9][CH:8]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: O=S(=O)(Cl)c1ccc2ccccc2c1
Reactant: CC(C)(C)OC(=O)c1ccc(NC2CCNCC2)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)c1ccc(NC2CCN(S(=O)(=O)c3ccc4ccccc4c3)CC2)cc1
Temperature: 25 °C
Reaction time: 12 h
Yield: 96.4 %

Procedure:
Compound (49) (0.056 g, 0.2 mmol) and triethylamine (0.14 mL, 1 mmol) were added sequentially to a solution of 2-naphthalene sulfonyl chloride (0.136 g, 0.6 mmol) in CH2Cl2 (5 mL) at 25° C. The mixture was stirred at 25° C. for 12 h then was concentrated under reduced pressure. Purification of the residue by flash column chromatography (gradient elution 0 to 30% EtOAc in hexanes) provided the title compound (0.09 g, 92.5%): TLC (Rf =0.50; 40% EtOAc/Hexanes); 1H NMR (CDCl3) δ 8.35 (s, 1H), 7.98 (m, 3H) 7.73 (m, 5H), 6.43 (d, 2H, J=8.7), 3.86 (d, 2H, J=9.2), 3.78 (s, 1H), 3.60 (m, 1H), 2.60 (t, 2H, J=10.5), 2.11 (d, 2H, J=13.4), 1.60 (m, 2H), 1.54 (s, 9H); 13C NMR (CDCl3) δ 165.9, 149.9, 135.0, 133.2, 132.2, 131.4, 129.3, 129.2, 129.0, 128.9, 128.0, 127.7, 123.0, 121.1, 111.9, 79.9, 49.0, 45.2, 31.7, 28.4; HRMS (FAB) m/z 467.2019 (M+H)+ (C26H30N2O4S requires 467.2005).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][CH:10]1[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][CH2:17][CH2:18][NH2:19])[CH2:11]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH:20](=O)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.[BH4-].[Na+].O>C(O)C>[CH2:20]([NH:19][CH2:18][CH2:17][CH2:16][CH2:15][N:12]1[CH2:13][CH2:14][CH:10]([CH2:9][NH:8][C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])[CH2:11]1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: CC(C)(C)OC(=O)NCC1CCN(CCCCN)C1
Reactant: O=Cc1ccccc1
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: CC(C)(C)OC(=O)NCC1CCN(CCCCNCc2ccccc2)C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 65.3 %

Procedure:
A solution of 4-(3-tert-butoxycarbonylaminomethylpyrrolidin-1-yl)-butylamine (2.0 g) and benzaldehyde (0.86 g) in ethanol (50 ml) was stirred at 70° C. for 3 hr. After cooling, sodium borohydride was added, and the mixture was stirred at room temperature for 2 hr. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with brine, dried and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography to give 1.74 g of N-benzyl-4-(3-tert-butoxycarbonylaminomethylpyrrolidin-1-yl)butylamine.
Reaction SMILES: [NH2:1][C:2]1[N:6]([C:7]2[C:12]([CH3:13])=[CH:11][CH:10]=[CH:9][C:8]=2[Cl:14])[N:5]=[C:4]([CH:15]([CH3:17])[CH3:16])[C:3]=1[C:18]#[N:19].[OH:20]S(O)(=O)=O>>[NH2:1][C:2]1[N:6]([C:7]2[C:12]([CH3:13])=[CH:11][CH:10]=[CH:9][C:8]=2[Cl:14])[N:5]=[C:4]([CH:15]([CH3:17])[CH3:16])[C:3]=1[C:18]([NH2:19])=[O:20]
Reactant: Cc1cccc(Cl)c1-n1nc(C(C)C)c(C#N)c1N
Reactant: O=S(=O)(O)O
Product: Cc1cccc(Cl)c1-n1nc(C(C)C)c(C(N)=O)c1N
Temperature: 25 °C
Reaction time: 24 h
Yield: 53 %

Procedure:
Part C: A mixture of 1.5 g (5.5 mmol) of 5-amino-4-cyano-3-isopropyl-1-(2-chloro-6-methylphenyl)pyrazole in 5 mL conc. H2SO4 was stirred at room temperature for 24 hours. The reaction was slowly quenched with ice and then diluted with water. The solution was made basic with saturated Na2CO3, stirred 2 h and filtered. The solid was recrystallized from hexanes/EtOAc to afford 847 mg (53%) of 5-amino-3-isopropyl-1-(2-chloro-6-methylphenyl)pyrazole-4-carboxamide, mp 72-74° C. Mass Spec. (ES−): 291 (M−H)−.
Reaction SMILES: [CH3:1][C:2]1([CH2:5][CH2:6][C:7](Cl)=[O:8])[CH2:4][CH2:3]1.[NH2:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]([N:19]2[CH2:24][CH2:23][N:22]([CH2:25][C:26]3[CH:31]=[CH:30][C:29]([C:32]([OH:41])([C:37]([F:40])([F:39])[F:38])[C:33]([F:36])([F:35])[F:34])=[CH:28][CH:27]=3)[CH2:21][CH2:20]2)=[O:18])=[CH:13][CH:12]=1.C(N(CC)CC)C>ClCCl>[F:39][C:37]([F:38])([F:40])[C:32]([C:29]1[CH:28]=[CH:27][C:26]([CH2:25][N:22]2[CH2:21][CH2:20][N:19]([C:17]([C:14]3[CH:15]=[CH:16][C:11]([NH:10][C:7](=[O:8])[CH2:6][CH2:5][C:2]4([CH3:1])[CH2:4][CH2:3]4)=[CH:12][CH:13]=3)=[O:18])[CH2:24][CH2:23]2)=[CH:31][CH:30]=1)([OH:41])[C:33]([F:36])([F:35])[F:34]
Reactant: CC1(CCC(=O)Cl)CC1
Reactant: Nc1ccc(C(=O)N2CCN(Cc3ccc(C(O)(C(F)(F)F)C(F)(F)F)cc3)CC2)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC1(CCC(=O)Nc2ccc(C(=O)N3CCN(Cc4ccc(C(O)(C(F)(F)F)C(F)(F)F)cc4)CC3)cc2)CC1
Temperature: 25 °C
Yield: 21.6 %

Procedure:
3-(1-Methylcyclopropyl)propionic acid (1.752 mmol, 0.2 g) was stirred in dichloromethane at 0° C. Oxalyl chloride (8.76 mmol, 0.752 mL, 1.112 g) was added and the reaction stirred overnight. The reaction mixture was concentrated under vacuum to give the intermediate 3-(1-methylcyclopropyl)propanoyl chloride. A mixture of 3-(1-methyl-cyclopropyl)propanoyl chloride (0.813 mmol, 0.119 g), (4-aminophenyl)(4-(4-(1,1,1,3,3,3-hexafluoro-2-hydroxypropan-2-yl)benzyl)piperazin-1-yl)methanone (0.542 mmol, 0.25 g) and triethylamine (1.084 mmol, 0.151 mL, 0.110 g) were stirred in dichloromethane at 0° C. for 1 hour. The reaction mixture was allowed to warm to room temperature. The reaction mixture was washed with water, concentrated under vacuum and purified by acidic prep HPLC to afford the title compound (67 mg). MS (ESI) m/z 572.3 [M+H]+
Reaction SMILES: C1COCC1.[CH3:6][C@H:7]([OH:10])[CH2:8][CH3:9].C(N(CC)CC)C.[C:18]([O:28][C:29]1[CH:37]=[CH:36][C:32]([C:33](Cl)=[O:34])=[CH:31][CH:30]=1)([O:20][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=[O:19]>CCOCC>[CH3:6][CH:7]([O:10][C:33](=[O:34])[C:32]1[CH:31]=[CH:30][C:29]([O:28][C:18]([O:20][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[O:19])=[CH:37][CH:36]=1)[CH2:8][CH3:9]
Reactant: O=C(OCc1ccccc1)Oc1ccc(C(=O)Cl)cc1
Reactant: CC[C@H](C)O
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Solvent: CCOCC
Product: CCC(C)OC(=O)c1ccc(OC(=O)OCc2ccccc2)cc1
Reaction time: 8 h
Yield: 17.4 %

Procedure:
A THF solution of 0.1 mole of (S)-(+)-2-butanol and 0.1 mole of triethylamine was stirred at 0° C., and a THF solution of 0.12 mole of 4-carbobenzoxyoxybenzoic acid chloride was added dropwise. The temperature was returned to the room temperature slowly, and stirring was carried out for 8 hours. After the reaction, the reaction solution was ether extracted, dried, concentrated, and purified by column chromatography, to obtain 5.7 g of 4-carbobenzoxyoxybenzoic acid 1-methylpropyl ester. (yield: 18%)
Reaction SMILES: Cl.[Cl:2][C:3]1[C:8]([C:9]([CH3:14])([CH3:13])[C:10]([OH:12])=O)=[CH:7][CH:6]=[CH:5][N:4]=1.[C:15]([O:19][C:20](=[O:27])[NH:21][C@H:22]1[CH2:25][C@H:24]([NH2:26])[CH2:23]1)([CH3:18])([CH3:17])[CH3:16].C(N(CC)CC)C>ClCCl.O>[C:15]([O:19][C:20](=[O:27])[NH:21][C@H:22]1[CH2:25][C@H:24]([NH:26][C:10](=[O:12])[C:9]([C:8]2[C:3]([Cl:2])=[N:4][CH:5]=[CH:6][CH:7]=2)([CH3:14])[CH3:13])[CH2:23]1)([CH3:18])([CH3:16])[CH3:17]
Reactant: CC(C)(C(=O)O)c1cccnc1Cl
Reactant: CC(C)(C)OC(=O)N[C@H]1C[C@H](N)C1
Agent: Cl
Solvent: O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N[C@H]1C[C@H](NC(=O)C(C)(C)c2cccnc2Cl)C1
Temperature: 25 °C
Reaction time: 21 h

Procedure:
2-(2-Chloropyridin-3-yl)-2-methylpropanoic acid hydrochloride (intermediate 25, 992 mg, 4.20 mmol), tert-butyl(trans-3-aminocyclobutyl)carbamate (939 mg, 5.04 mmol), hatu (2077 mg, 5.46 mmol) and triethylamine (2.4 ml, 16.81 mmol) were dissolved in dichloromethane (8.4 mL). The reaction mixture was stirred at room temperature for 21 hours then diluted with water and extracted with dichloromethane. The organic was washed with saturated ammonium chloride and dried over magnesium sulfate. Evaporation under reduced pressure and purification using silica chromatography (0% to 100% ethyl acetate in hexane gradient) gave tert-butyl(trans-3-(2-(2-chloropyridin-3-yl)-2-methylpropanamido)cyclobutyl)carbamate (1327 mg, 3.61 mmol, 86% yield) as white solid.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][N:6]=[CH:5]2.[I:11]I.[OH-].[K+].OS([O-])=O.[Na+]>CN(C=O)C>[Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][N:6]=[C:5]2[I:11]
Reactant: II
Reactant: Brc1ccc2[nH]ncc2c1
Agent: O=S([O-])O
Agent: [K+]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Brc1ccc2[nH]nc(I)c2c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 131.3 %

Procedure:
To a solution of 5-bromo-1H-indazole (8.00 g, 40.6 mmol) in DMF (200 ml), was added I2 (20.61 g, 81.2 mmol) and KOH (8.54 g, 152.3 mmol) successively. The reaction was stirred at room temperature for 3 h. The mixture was then poured into aqueous NaHSO3 and extracted with Et2O (3×150 ml). The combined organic layers were washed with water (3×150 ml) and brine (3×150 ml). It was dried over anhydrous Na2SO4 and evaporated to dryness to give crude product 5-bromo-3-iodo-1H-indazole (17.21 g).
Reaction SMILES: Br[C:2]1[CH:14]=[CH:13][C:12]2[C:11]3[C:6](=[CH:7][C:8]([Br:15])=[CH:9][CH:10]=3)[C:5]([CH3:17])([CH3:16])[C:4]=2[CH:3]=1.[C:18]1([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1B(O)O.C([O-])([O-])=O.[Na+].[Na+].CCO>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.C1(C)C=CC=CC=1>[C:18]1([C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=2)[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[C:2]1[CH:14]=[CH:13][C:12]2[C:11]3[C:6](=[CH:7][C:8]([Br:15])=[CH:9][CH:10]=3)[C:5]([CH3:17])([CH3:16])[C:4]=2[CH:3]=1
Reactant: CC1(C)c2cc(Br)ccc2-c2ccc(Br)cc21
Reactant: OB(O)c1ccccc1-c1ccccc1
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: Cc1ccccc1
Product: CC1(C)c2cc(Br)ccc2-c2ccc(-c3ccccc3-c3ccccc3)cc21
Temperature: 100 °C
Yield: 63 %

Procedure:
A mixture of 35.2 g (100 mmol) of 2,7-dibromo-9,9-dimethyl-9H-fluorene, 21.8 g (110 mmol) of biphenyl-2-ylboronic acid, 2.31 g (2 mmol) of Tetrakis(triphenylphosphine)palladium, 75 ml of 2M Na2CO3, 150 ml of EtOH and 300 ml toluene was degassed and placed under nitrogen, and then heated at 100° C. for 12 h. After finishing the reaction. The mixture was allowed to cool to room temperature. The organic layer was extracted with ethyl acetate and water, dried with anhydrous magnesium sulfate, the solvent was removed and the residue was purified by column chromatography on silica (hexane-dichloromethane) to give product (26.8 g, 63.0 mmol, 63%) as a white solid. 1H NMR (CDCl3, 400 MHz): δ 7.61 (d, J=7.8 Hz, 1H), 7.55˜7.53 (m, 2H), 7.49˜7.42 (m, 5H), 7.29 (d, J=8.0 Hz, 1H), 7.20˜7.14 (m, 5H), 6.98 (s, 1H), 1.21 (s, 6H)
Reaction SMILES: [OH-].[Na+].[C:3]([O:7][C:8]([NH:10][CH2:11][C:12]([NH:14][C@@:15]1([C:32]([O:34]CC)=[O:33])[CH2:20][C@@H:19]([S:21][C:22]2[NH:26][CH:25]=[N:24][N:23]=2)[C@@H:18]2[C@H:16]1[C@H:17]2[C:27]([O:29]CC)=[O:28])=[O:13])=[O:9])([CH3:6])([CH3:5])[CH3:4]>O1CCCC1.O>[C:3]([O:7][C:8]([NH:10][CH2:11][C:12]([NH:14][C@@:15]1([C:32]([OH:34])=[O:33])[CH2:20][C@@H:19]([S:21][C:22]2[NH:26][CH:25]=[N:24][N:23]=2)[C@@H:18]2[C@H:16]1[C@H:17]2[C:27]([OH:29])=[O:28])=[O:13])=[O:9])([CH3:6])([CH3:4])[CH3:5]
Reactant: CCOC(=O)[C@H]1[C@H]2[C@@H]1[C@](NC(=O)CNC(=O)OC(C)(C)C)(C(=O)OCC)C[C@H]2Sc1nnc[nH]1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)NCC(=O)N[C@@]1(C(=O)O)C[C@@H](Sc2nnc[nH]2)[C@H]2[C@H](C(=O)O)[C@H]21
Temperature: 2.5 °C
Reaction time: 2 h
Yield: 60.1 %

Procedure:
Add 2M sodium hydroxide (4.5 mL, 9 mmol) to a stirred solution of diethyl (1R,2S,4R,5R,6R)-2-[[2-(tert-butoxycarbonylamino)acetyl]amino]-4-(4H-1,2,4-triazol-3-ylsulfanyl)bicyclo[3.1.0]hexane-2,6-dicarboxylate (1.4 g, 2.81 mmol) in tetrahydrofuran (8 mL) at room temperature. Stir the biphasic mixture for 2 hours, dilute the reaction mixture with water (50 mL) and wash with diethyl ether (50 mL). Cool the aqueous layer to 0-5° C., acidify to pH=2 with 2M hydrochloric acid and extract with ethyl acetate (2×60 mL). Combine the organics phases, dry on sodium sulfate and concentrate to give the title compound as a white solid (0.75 g, 1.69 mmol). 1H NMR (D2O) δ 1.18-1.27 (m, 1H), 1.32 (s, 9H), 1.44-1.49 (m, 1H), 2.0-2.6 (m, 1H), 2.12-2.19 (m, 1H), 2.65-2.75 (m, 2H), 3.57-3.68 (m, 2H), 4.12-4.21 (m, 1H), 8.23 (s, 1H) as well as some title compound in the remaining aqueous layer (approximately 1.12 mmol). MS (m/z): 442 (M+1), 464 (M+23).
Reaction SMILES: O[CH2:2][CH2:3][CH2:4][CH:5]1[CH2:10][CH2:9][N:8]([C:11]2[CH:12]=[CH:13][C:14](=[O:17])[NH:15][N:16]=2)[CH2:7][CH2:6]1.[Cl:18]CCl.S(Cl)(Cl)=O>O1CCCC1>[Cl:18][CH2:2][CH2:3][CH2:4][CH:5]1[CH2:10][CH2:9][N:8]([C:11]2[CH:12]=[CH:13][C:14](=[O:17])[NH:15][N:16]=2)[CH2:7][CH2:6]1
Reactant: ClCCl
Reactant: O=c1ccc(N2CCC(CCCO)CC2)n[nH]1
Solvent: O=S(Cl)Cl
Solvent: C1CCOC1
Product: O=c1ccc(N2CCC(CCCCl)CC2)n[nH]1
Reaction time: 8 h
Yield: 100 %

Procedure:
To a stirred and cooled (ice bath) mixture of 2.8 parts of 6-[4-(3-hydroxypropyl)-1-piperidinyl]-3(2H)-pyridazinone, 65 parts of dichloromethane and 45 parts of tetrahydrofuran were added dropwise 2.8 parts of thionyl chloride. Upon complete addition, stirring was continued overnight at room temperature. The whole was evaporated and the residue was taken up in methylbenzene. The organic layer was evaporated again, yielding 3 parts (100%) of 6-[4-(3-chloropropyl)-1-piperidinyl]-3(2H)-pyridazinone as a residue (int. 100).
Reaction SMILES: [CH3:1][C:2]([CH3:32])([CH3:31])[C:3]#[C:4]/[CH:5]=[CH:6]/[CH2:7][CH:8]([CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([O:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([C:26]3[CH:30]=[CH:29][S:28][CH:27]=3)[CH:21]=2)[CH:13]=1)[CH2:9][OH:10].[CH3:33]I.[H-].[Na+].O>CN(C)C=O.C(OCC)C>[CH3:33][O:10][CH2:9][CH:8]([CH2:7]/[CH:6]=[CH:5]/[C:4]#[C:3][C:2]([CH3:32])([CH3:31])[CH3:1])[CH2:11][C:12]1[CH:13]=[C:14]([CH:15]=[CH:16][CH:17]=1)[O:18][CH2:19][C:20]1[CH:21]=[C:22]([C:26]2[CH:30]=[CH:29][S:28][CH:27]=2)[CH:23]=[CH:24][CH:25]=1
Reactant: CI
Reactant: CC(C)(C)C#C/C=C/CC(CO)Cc1cccc(OCc2cccc(-c3ccsc3)c2)c1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CCOCC
Product: COCC(C/C=C/C#CC(C)(C)C)Cc1cccc(OCc2cccc(-c3ccsc3)c2)c1
Yield: 80 %

Procedure:
44.4 mg of (E)-2-(6,6-dimethyl-2-hepten-4-ynyl)-3-[3-[3-(3-thienyl)phenylmethoxy]phenyl]propanol obtained in Example 11 is dissolved in 1 ml of dimethylformamide, 17.4 μl of methyl iodide and 8 mg of 60% oily sodium hydride are added under ice cooling and stirring, and the mixture is stirred at room temperature for 4 hours. Water and ethyl ether are added to the reaction solution for dilution, and the organic layer is taken, washed with saturated saline and dried over anhydrous magnesium sulfate. The desiccating agent is filtered, the solvent is distilled off under reduced pressure, and the residue is purified by silica gel column chromatography [Wako gel C-200, 7 g; hexane/ethyl acetate=19/1] to obtain 39 mg (yield: 80%) of the captioned compound as a colorless oily matter.
Reaction SMILES: CCN(CC)CC.[SH:8][CH2:9][C:10]([OH:12])=[O:11].Cl[C:14]1[CH:19]=[CH:18][C:17]([N+:20]([O-:22])=[O:21])=[CH:16][C:15]=1[N+:23]([O-:25])=[O:24].O>O1CCOCC1>[N+:20]([C:17]1[CH:16]=[C:15]([N+:23]([O-:25])=[O:24])[CH:14]=[CH:19][C:18]=1[S:8][CH2:9][C:10]([OH:12])=[O:11])([O-:22])=[O:21]
Reactant: O=C(O)CS
Reactant: O=[N+]([O-])c1ccc(Cl)c([N+](=O)[O-])c1
Solvent: O
Solvent: CCN(CC)CC
Solvent: C1COCCO1
Product: O=C(O)CSc1ccc([N+](=O)[O-])cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 5 h
Yield: 89.1 %

Procedure:
Et3N (1.5 g, 15 mmol) and mercapto-acetic acid (1 g, 11 mmol) were added to a solution of 1-chloro-2,4-dinitrobenzene (2.26 g, 10 mmol) in 1,4-dioxane (50 mL) at room temperature. After stirring at room temperature for 5 h, H2O (100 mL) was added. The resulting suspension was extracted with ethyl acetate (100 mL×3). The ethyl acetate extract was washed with water and brine, dried over Na2SO4 and concentrated to give 2-(2,4-dinitrophenylthio)-acetic acid (2.3 g, 74%), which was used without further purification.
Reaction SMILES: [C:1]([NH:8][C:9]1[S:10][C:11]2[CH2:22][CH2:21][CH2:20][CH2:19][C:12]=2[C:13]=1[C:14](OCC)=[O:15])(=[O:7])[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].[CH3:23][NH:24][CH3:25]>>[C:1]([NH:8][C:9]1[S:10][C:11]2[CH2:22][CH2:21][CH2:20][CH2:19][C:12]=2[C:13]=1[C:14]([N:24]([CH3:25])[CH3:23])=[O:15])(=[O:7])[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: CNC
Reactant: CCCCCC(=O)Nc1sc2c(c1C(=O)OCC)CCCC2
Product: CCCCCC(=O)Nc1sc2c(c1C(=O)N(C)C)CCCC2

Procedure:
The product of Example 33 and dimethylamine were processed as in Examples 29A and 29B to afford the title compound. 1H NMR (300 MHz, CDCl3) δ ppm 0.88-0.96 (m, 4H), 1.29-1.41 (m, 4H), 1.54-1.72 (m, 3H), 1.73-1.91 (m, 3H), 2.33-2.42 (m, 4H), 2.63-2.71 (m, 2H), 2.92 (s, 3H), 3.05 (s, 3H); MS (DCI/NH3) m/z 323 (M+H)+; anal. calculated for C17H26N2O2S.0.75C8H17NO.0.3H2O: C, 63.46; H, 9.11; N, 8.85. Found: C, 63.15; H, 9.46; N, 8.66.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:11]=[C:12]2C(=O)OC(C)(C)[O:14][C:13]2=[O:21])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].C(O)=O>C(N(CC)CC)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:11][CH2:12][C:13]([OH:21])=[O:14])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: COc1ccc(C=C2C(=O)OC(C)(C)OC2=O)cc1OC
Solvent: O=CO
Solvent: CCN(CC)CC
Product: COc1ccc(CCC(=O)O)cc1OC

Procedure:
After weighing 14.6 g (0.05 mol) of 5-(3,4-dimethoxyphenylmethylene)-2,2-dimethyl-1,3-dioxane-4,6-dione (m.p.: 173° C.) to 50 ml of the mixture of formic acid and triethylamine prepared according to Example 1, the procedure described in Example 1 was followed.
Reaction SMILES: C(N(C(C)C)CC)(C)C.[CH:10]1[CH:19]=[C:18]2[N:12]([CH:13]=[N:14][NH:15][C:16]2=O)[CH:11]=1.P(Cl)(Cl)([Cl:22])=O.C(=O)(O)[O-].[Na+]>C1(C)C=CC=CC=1>[CH:18]1[CH:19]=[C:10]2[C:11]([Cl:22])=[N:12][CH:13]=[N:14][N:15]2[CH:16]=1
Reactant: O=c1[nH]ncn2cccc12
Reactant: O=P(Cl)(Cl)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: Cc1ccccc1
Product: Clc1ncnn2cccc12
Temperature: 100 °C
Yield: 81 %

Procedure:
Diisopropylethylamine (3.5 mL, 20.3 mmol) was added to a solution of pyrrolo[1,2-f][1,2,4]triazin-4(3H)-one (2.5 g, 18.5 mmol) dissolved in toluene (37.5 mL) under nitrogen atmosphere. Subsequently, after adding phosphorus oxychloride (5.1 mL, 55.7 mmol), the mixture was heated for 20 hours at 100° C. The resulting reaction mixture was cooled to 0° C. and, after slowly adding sodium bicarbonate aqueous solution, stirred at room temperature for 30 minutes. The resulting aqueous layer was extracted with ethyl acetate, dried with magnesium sulfate, and then filtered. The filtrate was concentrated in vacuum. The resulting yellow solid product was subjected to the next step without purification (2.31 g, 15.0 mmol, 81% yield).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:15])[C:4]1[CH:9]=[CH:8][C:7]([CH2:10]Br)=[C:6]([N+:12]([O-:14])=[O:13])[CH:5]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Cl:35][C:36]1[CH:43]=[C:42]([N:44]2[CH2:49][CH2:48][O:47][CH2:46][CH2:45]2)[CH:41]=[C:40]([Cl:50])[C:37]=1[CH:38]=O.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[CH3:1][O:2][C:3](=[O:15])[C:4]1[CH:9]=[CH:8][C:7](/[CH:10]=[CH:38]/[C:37]2[C:36]([Cl:35])=[CH:43][C:42]([N:44]3[CH2:45][CH2:46][O:47][CH2:48][CH2:49]3)=[CH:41][C:40]=2[Cl:50])=[C:6]([N+:12]([O-:14])=[O:13])[CH:5]=1
Reactant: COC(=O)c1ccc(CBr)c([N+](=O)[O-])c1
Reactant: O=Cc1c(Cl)cc(N2CCOCC2)cc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(/C=C/c2c(Cl)cc(N3CCOCC3)cc2Cl)c([N+](=O)[O-])c1
Temperature: 95 °C

Procedure:
A mixture of 4-bromomethyl-3-nitrobenzoic acid methyl ester (1.01 g, 3.68 mmol) (from Example 3-8) and triphenylphosphine (1.06 g, 4.05 mmol) in DMF (20 mL) under N2 was heated at 95° C. Upon disappearance of the starting ester by TLC, 2,6-dichloro-4-morpholin-4-yl-benzaldehyde (1.15 g, 4.42 mmol) was added followed by K2CO3 (1.02 g, 7.36 mmol). The mixture was heated at 95° C. for 22.5 h then was allowed to cool to ambient temperature. The mixture was partitioned between EtOAc/DCM (700 mL) and Water (200 mL). The resulting orange precipitate was filtered and the organic phase was dried over Na2SO4 and concentrate under reduced pressure. The residue was triturated with EtOAc/Et2O to yield additional orange solid. The combined orange solids provided 4-[(E)-2-(2,6-dichloro-4-morpholin-4-yl-phenyl)-vinyl]-3-nitrobenzoic acid methyl ester. 1H NMR (400 MHz, DMSO-d6): δ 8.46 (d, J=1.77 Hz, 1H), 8.24 (dd, J=8.27, 1.71 Hz, 1H), 8.11 (d, J=8.21 Hz, 1H), 7.49 (d, J=16.42 Hz, 1H), 7.33 (d, J=16.42 Hz, 1H), 7.10 (s, 2H), 3.91 (s, 3H), 3.67-3.73 (m, 4H), 3.22-3.27 (m, 4H). MS (m/z) 437.1 (M+1).
Reaction SMILES: C([Br:4])(=O)C.[N+]([C:8]1[CH:13]=[CH:12][N:11]([OH:14])[CH2:10][C:9]=1[CH3:15])([O-])=O>>[Br:4][C:8]1[CH:13]=[CH:12][N:11]([OH:14])[CH2:10][C:9]=1[CH3:15]
Reactant: CC1=C([N+](=O)[O-])C=CN(O)C1
Reactant: CC(=O)Br
Product: CC1=C(Br)C=CN(O)C1
Temperature: 50 °C
Reaction time: 2 h
Yield: 86 %

Procedure:
Acetyl bromide (5 mL) was cooled to 0° C. To this was added 4-Nitro-3-methyl-pyridin-1-ol (1000 mg, 6.48 mmol) portionwise while maintaining temperature. After the addition was complete, the reaction was heated to 50° C. and stirred for 2 hours. The reaction was then cooled to 0° C., quenched with ice and neutralized with solid Na2CO3 (pH=8). The neutral aqueous reaction mixture was extracted into DCM. The organic layer was dried (MgSO4), the solvents were removed in vacuo resulting in the title compound as a yellow solid (1.05 mg, 86%). ESI-MS (m/z): Calcd. for C6H6BrNO: 188.0 (M+1); found: 188.0.