Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CC(C)([O-])C.[K+].[CH2:7]([O:14][C:15]1[N:16]=[N:17][CH:18]=[C:19]2[C:23]([CH3:24])=[C:22]([CH3:25])[NH:21][C:20]=12)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.C1OCCOCCOCCOCCOCCOC1.[Cl:44][C:45]([Cl:49])=[CH:46][CH2:47]Br>O1CCCC1>[CH2:7]([O:14][C:15]1[N:16]=[N:17][CH:18]=[C:19]2[C:23]([CH3:24])=[C:22]([CH3:25])[N:21]([CH2:47][CH:46]=[C:45]([Cl:49])[Cl:44])[C:20]=12)[C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: Cc1[nH]c2c(OCc3ccccc3)nncc2c1C
Reactant: ClC(Cl)=CCBr
Agent: C1COCCOCCOCCOCCOCCO1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: Cc1c(C)n(CC=C(Cl)Cl)c2c(OCc3ccccc3)nncc12
Temperature: 25 °C
Reaction time: 0.67 h
Yield: 22.6 %

Procedure:
0.13 g (0.0011 mole) of potassium tert-butoxide was added to a suspension of 0.29 g (0.0011 mole) of 7-benzyloxy-2,3-dimethylpyrrolo[2,3-d]pyridazine and 0.03 g (0.0001 mole) of 18-crown-6 in 8 ml of tetrahydrofuran and the resulting mixture was stirred at room temperature for 40 minutes. 0.22 g (0.0011 mole) of 3,3-dichloro-2-propenyl bromide was then added to the mixture and stirred at room temperature for 5 minutes. The reaction mixture was poured into ice-water and the aqueous mixture was extracted with dichloromethane. The extract was dried over anhydrous sodium sulfate and the solvent was distilled off under reduced pressure. The residue was purified by column chromatography through silica gel using a 20:1 mixture of chloroform and methanol as an eluent to give 0.090 g of 7-benzyloxy-1-(3,3-dichloro-2-propenyl)-2,3-dimethylpyrrolo[2,3-d]pyridazine as a yellow powder.
Reaction SMILES: S(=O)(=O)(O)O.[Cl:6][C:7]1[CH:12]=[CH:11][C:10]([CH2:13][CH:14](O)[CH:15]([CH3:17])[CH3:16])=[CH:9][CH:8]=1>O>[Cl:6][C:7]1[CH:12]=[C:11]2[C:10]([CH2:13][CH2:14][C:15]2([CH3:17])[CH3:16])=[CH:9][CH:8]=1
Reactant: CC(C)C(O)Cc1ccc(Cl)cc1
Agent: O=S(=O)(O)O
Solvent: O
Product: CC1(C)CCc2ccc(Cl)cc21
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Concentrated sulfuric acid (45.0 mL) was added to water (5.00 mL) carefully and allowed to cool down to room temperature. 1-(4-chlorophenyl)-3-methylbutan-2-ol (17.8 g, 0.0896 mol) was added portionwise over 30 minutes. After the addition, the mixture was left to stir at room temperature for 2 hours. The mixture was then poured onto ice and the aqueous layer was extracted with ether. The organic phase was washed water and then dried over magnesium sulphate and concentrated to yield crude product. The residue was purified by filtration through a plug of silica, eluting with dichloromethane, to yield the product, 12.6 g (78%). 1H-NMR (400 MHz, CDCl3, δ): 7.10 (m, 3H), 2.85 (t, J=7.2 Hz, 1H), 1.94 (t, J=7.2 Hz, 1H), 1.25 (s, 6H).
Reaction SMILES: [CH2:1]([O:5][C:6]1[CH:7]=[C:8]([NH:12]N)[CH:9]=[CH:10][CH:11]=1)[CH2:2][CH2:3][CH3:4].O=[C:15]1[CH2:20][CH2:19][CH2:18][CH:17]([NH:21][C:22](=[O:24])[CH3:23])[CH2:16]1.CC(O)=O>O>[CH2:1]([O:5][C:6]1[CH:7]=[C:8]2[C:9]([C:20]3[CH2:19][CH2:18][CH:17]([NH:21][C:22](=[O:24])[CH3:23])[CH2:16][C:15]=3[NH:12]2)=[CH:10][CH:11]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CC(=O)NC1CCCC(=O)C1
Reactant: CCCCOc1cccc(NN)c1
Solvent: CC(=O)O
Solvent: O
Product: CCCCOc1ccc2c3c([nH]c2c1)CC(NC(C)=O)CC3
Temperature: 25 °C
Reaction time: 3 h
Yield: 17 %

Procedure:
A mixture of 0.2 mol of 3-n-butyloxyphenylhydrazine, 0.2 mol of N-(3-oxocyclohexyl)acetamide, and 350 ml of glacial HOAc was stirred at room temperature for 3 hr and then refluxed for 2 hr. After pouring into 2.5 l of H2O and stirring overnight, the insoluble material had partly crystallized. The crystalline material was filtered, washed with H2O, and dried (23 g, Fraction A). The remaining insoluble semi-solid was taken up in EtOAc, washed with H2O, dried, and evaporated. The dark residue was triturated with Et2O and filtered (6.7 g, mp 181°-183°, Fraction B). Additional product was extracted from Fraction A by stirring with two 4 l. portions of Et2O. The combined extracts were evaporated and the resulting residue combined with Fraction B and recrystallized twice from Me2CO to yield 10.2 g of the title compound, mp 182°-184°.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[C:12]3([CH2:17][CH2:16][CH2:15][NH:14][CH2:13]3)[C:11](=[O:18])[N:10]([CH:19]([CH3:21])[CH3:20])[CH2:9]2)=[CH:4][CH:3]=1.[C:22]([O:26][C:27]([NH:29][C:30]([CH3:50])([CH3:49])[C:31]([NH:33][C@H:34]([CH2:38][C:39]1[C:47]2[C:42](=[CH:43][CH:44]=[CH:45][CH:46]=2)[N:41]([CH3:48])[CH:40]=1)[C:35](O)=[O:36])=[O:32])=[O:28])([CH3:25])([CH3:24])[CH3:23].CCN(C(C)C)C(C)C.C(P1(=O)OP(CCC)(=O)OP(CCC)(=O)O1)CC>C(#N)C>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]2[C:12]3([CH2:17][CH2:16][CH2:15][N:14]([C:35](=[O:36])[C@H:34]([NH:33][C:31](=[O:32])[C:30]([NH:29][C:27](=[O:28])[O:26][C:22]([CH3:24])([CH3:23])[CH3:25])([CH3:50])[CH3:49])[CH2:38][C:39]4[C:47]5[C:42](=[CH:43][CH:44]=[CH:45][CH:46]=5)[N:41]([CH3:48])[CH:40]=4)[CH2:13]3)[C:11](=[O:18])[N:10]([CH:19]([CH3:21])[CH3:20])[CH2:9]2)=[CH:6][CH:7]=1
Reactant: Cn1cc(C[C@@H](NC(=O)C(C)(C)NC(=O)OC(C)(C)C)C(=O)O)c2ccccc21
Reactant: CC(C)N1CC(c2ccc(F)cc2)C2(CCCNC2)C1=O
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: CC(C)N1CC(c2ccc(F)cc2)C2(CCCN(C(=O)[C@@H](Cc3cn(C)c4ccccc34)NC(=O)C(C)(C)NC(=O)OC(C)(C)C)C2)C1=O
Temperature: 25 °C
Reaction time: 19 h

Procedure:
A mixture comprising 4-(4-fluorophenyl)-2-isopropyl-2,7-diazaspiro[4.5]decan-1-one (ASW MedChem) (243 mg, 0.744 mmol), (R)-2-(2-(tert-butoxycarbonylamino)-2-methylpropanamido)-3-(1-methyl-1H-indol-3-yl)propanoic acid (Intermediate 3D) (300 mg, 0.744 mmol) and DIPEA (0.519 ml, 2.97 mmol) in acetonitrile (3 ml) was treated with ®T3P (50% in DMF, 0.868 ml, 1.487 mmol) and stirred at RT for 19 hours. The reaction mixture was concentrated in vacuo, dissolved in EtOAc and washed with water. The organic portion was dried (MgSO4) and concentrated in vacuo. Purification of the crude product by chromatography on silica eluting with 2% MeOH in DCM afforded the title compound;
Reaction SMILES: [Br:1][CH:2]1[CH2:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([Cl:11])[CH:8]=2)[C:3]1=[O:12].[CH3:13][NH:14][C:15]([NH:17][CH3:18])=[S:16]>CC(C)=O>[BrH:1].[Cl:11][C:7]1[CH:6]=[CH:5][C:4]2[C:3]3([OH:12])[N:17]([CH3:18])[C:15](=[N:14][CH3:13])[S:16][CH:2]3[CH2:10][C:9]=2[CH:8]=1.[Cl:11][C:7]1[CH:6]=[CH:5][C:4]2[C:3]3([OH:12])[N:17]([CH3:18])[C:15](=[N:14][CH3:13])[S:16][CH:2]3[CH2:10][C:9]=2[CH:8]=1
Reactant: O=C1c2ccc(Cl)cc2CC1Br
Reactant: CNC(=S)NC
Solvent: CC(C)=O
Product: Br
Product: CN=C1SC2Cc3cc(Cl)ccc3C2(O)N1C
Temperature: 25 °C
Reaction time: 5 h

Procedure:
2.47 g (10 mmol) of 2-bromo-5-chloro-1-indanone are dissolved in 30 ml of acetone and, at room temperature, a solution of 1.05 g (10 mmol) of N,N′-dimethylthiourea in 10 ml of acetone is added, and the mixture is stirred at room temperature for 5 h. The precipitate is filtered off with suction and dried in vacuo. Crystallization from methanol/diethyl ether results in the hydrobromide of 6-chloro-3-methyl-2-methylimino-2,3,8,8a-tetrahydroindeno[1,2-d]thiazol-3a-ol of melting point 181-183° C.
Reaction SMILES: [OH:1][C:2]1[CH:12]=[CH:11][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:4][CH:3]=1.[CH2:13](Cl)[C:14](=[CH2:16])[CH3:15].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[OH:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:11][C:12]=1[CH2:15][C:14](=[CH2:13])[CH3:16]
Reactant: CCOC(=O)c1ccc(O)cc1
Reactant: C=C(C)CCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: C=C(C)Cc1cc(C(=O)OCC)ccc1O
Reaction time: 40 h
Yield: 89.3 %

Procedure:
Ethyl 4-hydroxybenzoate (50.0 g), methallyl chloride (32.6 g), and potassium carbonate (45.6 g) were refluxed in acetone (150 ml) with stirring for 40 hours. The reaction mixture was filtered and the filtrate was concentrated under a vacuum. The residue, with toluene (150 ml) added thereto, was washed with 2% sodium hydroxide solution and water successively. After being dried over sodium sulfate anhydride, the solution was concentrated under a vacuum. The resulting oily material was dissolved in N,N-dimethylaniline (80 ml) and refluxed with stirring for about 10 hours. The reaction mixture was acidified with concentrated hydrochloric acid while being cooled with ice and then extracted with toluene. The extract was further extracted with 10% aqueous sodium hydroxide solution. The resulting water layer was acidified with concentrated hydrochloric acid and then extracted with toluene. The extract was washed with water, dried over sodium sulfate anhydride, and then concentrated under a vacuum, thereby yielding 59.2 g of the aimed compound.
Reaction SMILES: [CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([N+:20]([O-:22])=[O:21])=[C:11]([N:14]4[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]4)[CH:12]=3)[C:7](=[O:23])[C:6]([C:24]([OH:26])=[O:25])=[CH:5]2)[CH2:3][CH2:2]1.[C:27]([O:31][CH3:32])(=[O:30])[CH:28]=[CH2:29].O>COCCO.CS(C)=O>[CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([N+:20]([O-:22])=[O:21])=[C:11]([N:14]4[CH2:19][CH2:18][N:17]([CH2:29][CH2:28][C:27]([O:31][CH3:32])=[O:30])[CH2:16][CH2:15]4)[CH:12]=3)[C:7](=[O:23])[C:6]([C:24]([OH:26])=[O:25])=[CH:5]2)[CH2:2][CH2:3]1
Reactant: C=CC(=O)OC
Reactant: O=C(O)c1cn(C2CC2)c2cc(N3CCNCC3)c([N+](=O)[O-])cc2c1=O
Solvent: O
Solvent: CS(C)=O
Solvent: COCCO
Product: COC(=O)CCN1CCN(c2cc3c(cc2[N+](=O)[O-])c(=O)c(C(=O)O)cn3C2CC2)CC1
Yield: 75.1 %

Procedure:
537 mg (0.0015) of 1-cyclopropyl-1,4-dihydro-6-nitro-4-oxo-7-(1-piperazinyl)-3-quinolinecarboxylic acid in a mixture of 7.5 ml of glycol monomethyl ether and 3 ml of dimethylsulphoxide are heated under reflux with 2 g of methyl acrylate for 8 hours. 10 ml of water are added to the solution and the precipitate is filtered off with suction, washed with methanol and dried. 0.5 g of 1-cyclopropyl-1,4-dihydro-7-[4-(2-methoxycarbonylethyl)-1-piperazinyl]-6-nitro-4-oxo-3-quinolinecarboxylic acid of decomposition point 208° to 211° C. are obtained.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][C@@H:10]([NH:13][C:14]2[CH:19]=[CH:18][C:17]([N+:20]([O-])=O)=[CH:16][C:15]=2[F:23])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl[C:25]([O:27][CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)=[O:26]>C(OCC)(=O)C.CO.[Pd]>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][C@@H:10]([N:13]([C:25]([O:27][CH2:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)=[O:26])[C:14]2[CH:19]=[CH:18][C:17]([NH:20][C:25]([O:27][CH2:28][C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)=[O:26])=[CH:16][C:15]=2[F:23])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: O=C(Cl)OCc1ccccc1
Reactant: CC(C)(C)OC(=O)N1CC[C@@H](Nc2ccc([N+](=O)[O-])cc2F)C1
Agent: [Pd]
Solvent: CO
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CC[C@@H](N(C(=O)OCc2ccccc2)c2ccc(NC(=O)OCc3ccccc3)cc2F)C1

Procedure:
To a solution of 4 g of (3R)-3-(2-fluoro-4-nitro-phenyl-amino)-pyrrolidine-1-carboxylic acid tert-butyl ester (12.29 mmol) in 100 ml ethyl acetate and 50 ml methanol were added 1 g of Pd/C 10%. The suspension was stirred under hydrogen. The reaction was monitored by TLC. The catalyst was filtered, the filtrate evaporated to dryness, and the residue was dissolved in 100 ml of acetone. 25 ml of a saturated solution of sodium bicarbonate was added, than a 0° C. 3.63 ml of benzyl chloroformate (25.8 mmol). The reaction was stirred over night at rt and monitored by TLC. The acetone was evaporated, the water layer extracted twice with ethyl acetate, the org layer washed with water and brine, dried over Mg sulfate, filtered and the filtrate evaporated to dryness. The residue was purified by chromatography, using a 1/1 ethyl acetate/hexane mixture as eluent.
Reaction SMILES: Cl.[CH3:2][O:3][C:4]([C:6]1[N:7]([CH3:12])[CH:8]=[C:9]([NH2:11])[CH:10]=1)=[O:5].[Cl:13][C:14]1[N:19]=[C:18](Cl)[C:17]([Cl:21])=[CH:16][N:15]=1.C(=O)([O-])[O-].[Na+].[Na+]>CCO>[Cl:13][C:14]1[N:19]=[C:18]([NH:11][C:9]2[CH:10]=[C:6]([C:4]([O:3][CH3:2])=[O:5])[N:7]([CH3:12])[CH:8]=2)[C:17]([Cl:21])=[CH:16][N:15]=1
Reactant: Clc1ncc(Cl)c(Cl)n1
Reactant: COC(=O)c1cc(N)cn1C
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Product: COC(=O)c1cc(Nc2nc(Cl)ncc2Cl)cn1C
Temperature: 40 °C

Procedure:
The mixture of 4-amino-1-methyl-pyrrole-2-carboxylic acid methyl ester hydrochloride (95 mg, 0.5 mmol), 2,4,5-trichloropyrimidine (57 μL, 0.5 mmol), and sodium carbonate (106 mg, 1.0 mmol) in 3 mL of EtOH is heated at 40° C. overnight. The precipitate is filtered, washed by cold EtOH, and dried in vacuo to afford methyl 4-(2,5-dichloropyrimidin-4-ylamino)-1-methyl-1H-pyrrole-2-carboxylate; ESMS m/z 301.0 (M+H+).
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][CH:3]=[N:2]1.Cl[C:7]1[CH:12]=[CH:11][C:10]([C:13]([F:16])([F:15])[F:14])=[CH:9][CH:8]=1>>[F:14][C:13]([F:16])([F:15])[C:10]1[CH:11]=[CH:12][C:7]([N:1]2[CH:5]=[CH:4][CH:3]=[N:2]2)=[CH:8][CH:9]=1
Reactant: FC(F)(F)c1ccc(Cl)cc1
Reactant: c1cn[nH]c1
Product: FC(F)(F)c1ccc(-n2cccn2)cc1

Procedure:
Following General Procedure A (140° C., 24 hours), 1H-pyrazole (102 mg, 1.5 mmol) is coupled with 1-chloro-4-(trifluoromethyl)benzene (134 μL, 1.0 mmol). The crude brown oil is purified by flash chromatography on silica gel (eluent: dichloromethane/hexanes=50/50) to provide 80 mg (38% isolated yield) of the desired product as a white solid.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([N+]([O-])=O)[CH:5]=[C:6]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([CH3:15])[N:10]=2)[N+:7]=1[O-:8].[O-:19][CH2:20][CH3:21].[Na+].[Na]>C(O)C>[CH3:1][C:2]1[CH:3]=[C:4]([O:19][CH2:20][CH3:21])[CH:5]=[C:6]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([CH3:15])[N:10]=2)[N+:7]=1[O-:8]
Reactant: CC[O-]
Reactant: Cc1cccc(-c2cc([N+](=O)[O-])cc(C)[n+]2[O-])n1
Agent: [Na+]
Agent: [Na]
Solvent: CCO
Product: CCOc1cc(C)[n+]([O-])c(-c2cccc(C)n2)c1
Temperature: 70 °C
Reaction time: 0.5 h

Procedure:
6,6'-Dimethyl-4-nitro-2,2'-bipyridine-N-oxide (17) (1.0 g, 4.1 mmoles) was added to sodium ethoxide solution made from (0.19 g, 0.0083 g-atoms) sodium and 25 ml ethanol. The mixture was stirred at 70° C. for 30 minutes. After neutralization with concentrated hydrochloric acid the reaction mixture was filtered and evaporated to dryness. The product was purified by means of flash chromatography (silica, 0%-50% methanol/chloroform).
Reaction SMILES: [CH2:1]([O:3][CH2:4][CH2:5][CH2:6][N:7]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[N:10]=[C:9](O)[C:8]1=[O:18])[CH3:2].C1(C)C=CC=CC=1.S(Cl)([Cl:28])=O>CN(C)C=O>[CH2:1]([O:3][CH2:4][CH2:5][CH2:6][N:7]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[N:10]=[C:9]([Cl:28])[C:8]1=[O:18])[CH3:2]
Reactant: O=S(Cl)Cl
Reactant: CCOCCCn1c(=O)c(O)nc2ccccc21
Solvent: CN(C)C=O
Solvent: Cc1ccccc1
Product: CCOCCCn1c(=O)c(Cl)nc2ccccc21

Procedure:
To 22.5 g of (1), 330 ml of toluene, 10 ml of dimethylformamide and 10 ml of thionyl chloride are added and the resulting mixture is heated to reflux for 2 hours. The mixture is then subjected to filtration during hot and the filtrate is concentrated. The resultant is purified by silica gel column chromatography (ethyl acetate:hexane=1:3-1:2) to obtain 23.5 g of (2) in the form of yellow oil.
Reaction SMILES: [CH2:1]1[CH:9]2[N:4]([CH2:5][CH2:6][CH:7]([C:10]3[C:18]4[C:13](=[CH:14][CH:15]=[CH:16][N:17]=4)[NH:12][CH:11]=3)[CH2:8]2)[CH2:3][CH2:2]1.[C:19]1([S:29](Cl)(=[O:31])=[O:30])[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH:22]=[CH:21][CH:20]=1.C[Si]([N-][Si](C)(C)C)(C)C.[Na+]>C1COCC1>[CH2:1]1[CH:9]2[N:4]([CH2:5][CH2:6][CH:7]([C:10]3[C:14]4[C:13](=[CH:18][N:17]=[CH:16][CH:15]=4)[N:12]([S:29]([C:19]4[C:28]5[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=5)[CH:22]=[CH:21][CH:20]=4)(=[O:31])=[O:30])[CH:11]=3)[CH2:8]2)[CH2:3][CH2:2]1
Reactant: O=S(=O)(Cl)c1cccc2ccccc12
Reactant: c1cnc2c(C3CCN4CCCC4C3)c[nH]c2c1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: C1CCOC1
Product: O=S(=O)(c1cccc2ccccc12)n1cc(C2CCN3CCCC3C2)c2ccncc21

Procedure:
from 3-(octahydro-7-indolizinyl)-1-H-4-azaindole (less polar isomer) (12 mg, 0.05 mmol), 1-naphthalenesulfonyl chloride (20.9 mg, 0.1 mmol) and 1M NaN(TMS)2 (100 μL, 0.10 mmol) in THF (1 mL) at RT.
Reaction SMILES: [O:1]=[C:2]1[CH2:23][CH2:22][C@@:21]2([CH3:24])[C:4]([CH2:5][CH2:6][C@@H:7]3[C@@H:20]2[CH2:19][CH2:18][C@@:17]2([CH3:25])[C@H:8]3[CH2:9][CH2:10][C@@H:11]2[CH:12]([C:14]([OH:16])=[O:15])[CH3:13])=[CH:3]1.[OH-].[Na+].[CH3:28]I.O>CN(P(N(C)C)N(C)C)C>[O:1]=[C:2]1[CH2:23][CH2:22][C@@:21]2([CH3:24])[C:4]([CH2:5][CH2:6][C@@H:7]3[C@@H:20]2[CH2:19][CH2:18][C@@:17]2([CH3:25])[C@H:8]3[CH2:9][CH2:10][C@@H:11]2[CH:12]([C:14]([O:16][CH3:28])=[O:15])[CH3:13])=[CH:3]1
Reactant: CI
Reactant: CC(C(=O)O)[C@H]1CC[C@H]2[C@@H]3CCC4=CC(=O)CC[C@]4(C)[C@H]3CC[C@]12C
Agent: CN(C)P(N(C)C)N(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: COC(=O)C(C)[C@H]1CC[C@H]2[C@@H]3CCC4=CC(=O)CC[C@]4(C)[C@H]3CC[C@]12C
Reaction time: 0.5 h

Procedure:
To a solution of 20 g (0.06 m) of 3-oxopregn-4-ene-20-carboxylic acid in 100 ml of hexamethyl phosphorus triamide is added 5.0 g (0.12 m) of sodium hydroxide as a 25% solution. The solution is stirred for 30 minutes after which 34 g (0.24 m) of methyliodide is added and stirring is continued for an additional 30 minutes. The reaction mixture is poured into 500 ml of water, and the product is collected and recrystallized from acetone to yield methyl 3-oxopregn-4-ene-20-carboxylate, M.P. 175°-177° C.
Reaction SMILES: C1(CBr)CC1.Br[CH2:7][CH:8]1[CH2:11][CH2:10][CH2:9]1.[CH3:12][C:13]1[N:14]=[C:15]([N:23]2[CH2:27][CH2:26][NH:25][C:24]2=[O:28])[S:16][C:17]=1[C:18]([O:20][CH2:21][CH3:22])=[O:19]>>[CH:8]1([CH2:7][N:25]2[CH2:26][CH2:27][N:23]([C:15]3[S:16][C:17]([C:18]([O:20][CH2:21][CH3:22])=[O:19])=[C:13]([CH3:12])[N:14]=3)[C:24]2=[O:28])[CH2:11][CH2:10][CH2:9]1
Reactant: CCOC(=O)c1sc(N2CCNC2=O)nc1C
Reactant: BrCC1CCC1
Agent: BrCC1CC1
Product: CCOC(=O)c1sc(N2CCN(CC3CCC3)C2=O)nc1C
Yield: 88 %

Procedure:
Following the procedure as described in Example 10, making variations as required to replace cyclopropylmethyl bromide with (bromomethyl)cyclobutane to react with ethyl 4-methyl-2-(2-oxoimidazolidin-1-yl)thiazole-5-carboxylate, the title compound was obtained in 88% yield: 1H NMR (300 MHz, CDCl3) δ 4.29-3.96 (m, 4H), 3.60-3.23 (m, 4H), 2.63-2.48 (m, 4H), 2.09-2.02 (m, 2H), 1.93-1.83 (m, 2H), 1.77-1.68 (m, 2H), 1.26 (t, J=7.3 Hz, 3H); MS (ES+) m/z 324.3 (M+1).
Reaction SMILES: P(Cl)(Cl)([Cl:3])=O.CN(C)[CH:8]=[O:9].[N:11]1[CH:16]=[CH:15][CH:14]=[C:13]([N:17]2[C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[CH2:19][C:18]2=O)[CH:12]=1.[OH-].[NH4+]>ClCCl.O.N1C=CC=CC=1>[Cl:3][CH:18]1[CH:19]([CH:8]=[O:9])[C:20]2[C:25](=[CH:24][CH:23]=[CH:22][CH:21]=2)[N:17]1[C:13]1[CH:12]=[N:11][CH:16]=[CH:15][CH:14]=1
Reactant: CN(C)C=O
Reactant: O=P(Cl)(Cl)Cl
Reactant: O=C1Cc2ccccc2N1c1cccnc1
Agent: [NH4+]
Agent: [OH-]
Solvent: O
Solvent: c1ccncc1
Solvent: ClCCl
Product: O=CC1c2ccccc2N(c2cccnc2)C1Cl
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 14 %

Procedure:
Phosphorous oxychloride (500 μL, 5.39 mmol) is added slowly to a stirred solution of dimethylformamide (516 μL) in dichloromethane (516 μL) at 0-5° C. After 15 min, a solution of 1-(pyridin-3-yl)-1,3-dihydroindol-2-one (250 mg, 1.2 mmol) and pyridine (258 μL) in dichloromethane (2 mL) is added. The reaction mixture is warmed to room temperature and stirred for 24 hr. The reaction is diluted with water, made basic with ammonium hydroxide, extracted with dichloromethane and the extract is concentrated. The residue is treated with phosphorous oxychloride (5 mL) and heated at reflux for 2 hr. After cooling to room temperature, the excess phosphorous oxychloride is removed and the residue is treated with ice/water, made basic with ammonium hydroxide and extracted with dichloromethane. The combined extract is washed with brine, dried, filtered and concentrated. The residue is purified by chromatography eluting with pentane-30% ethyl acetate. Product containing fractions are combined and concentrated to afford 2-chloro-1-(pyridin-3-yl)-1,3-dihydroindole-3-carboxaldehyde (42 mg, 14% yield) as a yellow solid. MS 257 (M+H).
Reaction SMILES: [Cl:1][C:2]1[CH:29]=[CH:28][C:5]([C:6]([N:8]2[CH2:14][C:13]3[CH:15]=[CH:16][CH:17]=[CH:18][C:12]=3[N:11]([CH2:19][CH2:20][CH:21]3[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]3)[C:10](=[O:27])[CH2:9]2)=[O:7])=[CH:4][CH:3]=1.CS[C:32]1[NH:33][CH2:34][CH2:35][N:36]=1.C(N(CC)CC)C>CO>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([N:8]2[CH2:14][C:13]3[CH:15]=[CH:16][CH:17]=[CH:18][C:12]=3[N:11]([CH2:19][CH2:20][CH:21]3[CH2:26][CH2:25][N:24]([C:32]4[NH:36][CH2:35][CH2:34][N:33]=4)[CH2:23][CH2:22]3)[C:10](=[O:27])[CH2:9]2)=[O:7])=[CH:28][CH:29]=1
Reactant: O=C(c1ccc(Cl)cc1)N1CC(=O)N(CCC2CCNCC2)c2ccccc2C1
Reactant: CSC1=NCCN1
Solvent: CCN(CC)CC
Solvent: CO
Product: O=C(c1ccc(Cl)cc1)N1CC(=O)N(CCC2CCN(C3=NCCN3)CC2)c2ccccc2C1
Temperature: 70 °C
Reaction time: 8 h

Procedure:
30 mg (0.073 mmol) of 4-(4-chlorobenzoyl)-1-[2-(4-piperidinyl)-ethyl]-1,3,4,5-tetrahydrobenzo[e][1,4]diazepin-2-on obtained in step 1 in Example 168 and 178 mg (0.73 mmol) of 2-methylthio-2-imidazoline were dissolved in 7 ml of methanol. 0.2 mg (1.4 mmol) of triethylamine was added to the obtained solution, and they were stirred at 70° C. overnight. The solvent was evaporated, and the obtained crude product was treated by the reversed phase high-performance liquid chromatography with silica gel chemically bonded with octadodecyl group as the filler and then eluted with a solvent mixture of water and acetonitrile containing 0.1% (V/V) of trifluoroacetic acid. Acetonitrile was evaporated. After the extraction with dichloromethane, the title compound was obtained.
Reaction SMILES: [F:1][C:2]1[CH:15]=[C:14]([N+:16]([O-:18])=[O:17])[CH:13]=[CH:12][C:3]=1[O:4][C:5]1[N:10]=[CH:9][N:8]=[C:7]([NH2:11])[CH:6]=1.Cl[C:20](OC1C=CC=CC=1)=[O:21].Cl.Cl.[N:31]1([CH2:36][CH:37]2[CH2:42][CH2:41][NH:40][CH2:39][CH2:38]2)[CH2:35][CH2:34][CH2:33][CH2:32]1>O1CCCC1.C(N(CC)CC)C.CN(C)C=O>[F:1][C:2]1[CH:15]=[C:14]([N+:16]([O-:18])=[O:17])[CH:13]=[CH:12][C:3]=1[O:4][C:5]1[N:10]=[CH:9][N:8]=[C:7]([NH:11][C:20]([N:40]2[CH2:41][CH2:42][CH:37]([CH2:36][N:31]3[CH2:35][CH2:34][CH2:33][CH2:32]3)[CH2:38][CH2:39]2)=[O:21])[CH:6]=1
Reactant: C1CCN(CC2CCNCC2)C1
Reactant: Nc1cc(Oc2ccc([N+](=O)[O-])cc2F)ncn1
Reactant: O=C(Cl)Oc1ccccc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: O=C(Nc1cc(Oc2ccc([N+](=O)[O-])cc2F)ncn1)N1CCC(CN2CCCC2)CC1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
6-(2-Fluoro-4-nitrophenoxy)pyrimidin-4-ylamine (200 mg) was dissolved in tetrahydrofuran (8 ml) under a nitrogen atmosphere, and then triethylamine (0.334 ml) and phenyl chloroformate (0.301 ml) were added thereto while cooling in an ice water bath, followed by warming to room temperature and stirring for 1.5 hrs. The reaction mixture was partitioned between ethyl acetate (200 ml) and a saturated aqueous solution of sodium hydrogencarbonate (50 ml). The organic layer was washed with a saturated aqueous solution of sodium hydrogencarbonate (50 ml), water (50 ml), brine (100 ml) in this order, and dried over anhydrous sodium sulfate. The solvent was evaporated to give a residue, to which was added N,N-dimethylformamide (8 ml). 4-(Pyrrolidin-1-ylmethyl)piperidine dihydrochloride (771 mg) and triethylamine (0.896 ml) were added thereto, followed by stirring for 4 hrs. The reaction mixture was partitioned between ethyl acetate (100 ml) and a saturated aqueous solution of ammonium chloride (50 ml). The organic layer was washed with a saturated aqueous solution of ammonium chloride (50 ml), water (50 ml), and brine (50 ml) in this order, and dried over anhydrous sodium sulfate. The solvent was evaporated to give a residue, which was then purified by silica gel column chromatography (Fuji Silysia NH, heptane:ethyl acetate=1:1, then ethyl acetate). Fractions containing the target compound were concentrated to provide 4-(pyrrolidin-1-ylmethyl)piperidine-1-carboxylic acid [6-(2-fluoro-4-nitrophenoxy)pyrimidin-4-yl]amide (350 mg) as a pale yellow oil.