Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:6]([CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])[C:7](=[O:16])[NH:8][C@H:9]1[CH2:14][CH2:13][CH2:12][CH2:11][C@@H:10]1[OH:15])[C:2]([CH3:5])([CH3:4])C.[CH2:26](NCCCCCCCCC)[C:27](C)(C)[CH3:28].[CH2:41](CCCCCCCCCCN)C1C=CC=CC=1>>[CH2:1]([N:6]([CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:41])[C:7](=[O:16])[NH:8][C@H:9]1[CH2:14][CH2:13][CH2:12][CH2:11][C@@H:10]1[OH:15])[C:2]1[CH:4]=[CH:28][CH:27]=[CH:26][CH:5]=1
Reactant: CCCCCCCCCN(CC(C)(C)C)C(=O)N[C@H]1CCCC[C@@H]1O
Reactant: CCCCCCCCCNCC(C)(C)C
Reactant: NCCCCCCCCCCCc1ccccc1
Product: CCCCCCCCCCN(Cc1ccccc1)C(=O)N[C@H]1CCCC[C@@H]1O
Yield: 85 %

Procedure:
The same procedure for preparing (1S,2S)-2-(3-neopentyl-3-nonylureido)cyclohexanol as in Example 3 was repeated except that the neopentylnonylamine employed in Example 3 was replaced by benzyldecylamine, whereby (1S,2S)-2-(3-benzyl-3-decylureido)cyclohexanol was obtained in a yield of 85%.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([CH:11]2[CH2:16][N:15]([C:17]([N:19]3[CH2:24][CH2:23][O:22][CH2:21][CH2:20]3)=[O:18])[CH2:14][CH:13]([C:25]([OH:27])=O)[CH2:12]2)=[CH:7][CH:6]=1)(=[O:4])=[O:3].[F:28][C:29]1[CH:30]=[C:31]([C:35](=[N:37]O)[NH2:36])[CH:32]=[CH:33][CH:34]=1>>[F:28][C:29]1[CH:30]=[C:31]([C:35]2[N:37]=[C:25]([CH:13]3[CH2:12][CH:11]([C:8]4[CH:9]=[CH:10][C:5]([S:2]([CH3:1])(=[O:4])=[O:3])=[CH:6][CH:7]=4)[CH2:16][N:15]([C:17]([N:19]4[CH2:20][CH2:21][O:22][CH2:23][CH2:24]4)=[O:18])[CH2:14]3)[O:27][N:36]=2)[CH:32]=[CH:33][CH:34]=1
Reactant: NC(=NO)c1cccc(F)c1
Reactant: CS(=O)(=O)c1ccc(C2CC(C(=O)O)CN(C(=O)N3CCOCC3)C2)cc1
Product: CS(=O)(=O)c1ccc(C2CC(c3nc(-c4cccc(F)c4)no3)CN(C(=O)N3CCOCC3)C2)cc1

Procedure:
60 mg (0.151 mmol) of the compound from Example 198A and 35 mg (0.227 mmol) of 3-fluoro-N′-hydroxybenzenecarboximidamide were reacted according to the General Method 2. Yield: 54 mg (67% of theory)
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]2[C:19]3[C:14](=[N:15][CH:16]=[CH:17][CH:18]=3)[NH:13][CH:12]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].[H-].[Na+].[N+:22]([C:25]1[CH:26]=[C:27]([CH:30]=[CH:31][CH:32]=1)[CH2:28]Cl)([O-:24])=[O:23]>CN(C=O)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]2[C:19]3[C:14](=[N:15][CH:16]=[CH:17][CH:18]=3)[N:13]([CH2:28][C:27]3[CH:30]=[CH:31][CH:32]=[C:25]([N+:22]([O-:24])=[O:23])[CH:26]=3)[CH:12]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: COc1ccc(-c2c[nH]c3ncccc23)cc1OC
Reactant: O=[N+]([O-])c1cccc(CCl)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1ccc(-c2cn(Cc3cccc([N+](=O)[O-])c3)c3ncccc23)cc1OC
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 77 %

Procedure:
3-(3,4-Dimethoxy-phenyl)-1H-pyrrolo[2,3-b]pyridine 1 (35 mg, 0.14 mmole) was dissolved in 15 mL of DMF and sodium hydride (60% dispersion in mineral oil, 10 mg, 0.25 mmol) was added in small portion to the reaction mixture. After stirring for 30 minutes, m-nitro-benzyl chloride (30 mg, 0.14 mmole) was added to the reaction mixture and was stirred for 2 hours. The reaction mixture was poured into 50 mL of ice water and was extracted with ethyl acetate. The organic layer was washed with saturated sodium bicarbonate followed by saturated potassium bisulfate and then brine. The resulting solution was dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography (30% ethyl acetate in hexanes) to yield 42 mg (71%) of the titled compound as a white solid. MS(ESI) [M+H+]+=390.1.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.[CH3:9][C:10]([CH3:15])=[CH:11][C:12](Cl)=[O:13].C(N(CC)CC)C>C(OC(C)C)(C)C>[F:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:12](=[O:13])[CH:11]=[C:10]([CH3:15])[CH3:9])=[CH:4][CH:3]=1
Reactant: CC(C)=CC(=O)Cl
Reactant: Oc1ccc(F)cc1
Solvent: CCN(CC)CC
Solvent: CC(C)OC(C)C
Product: CC(C)=CC(=O)Oc1ccc(F)cc1
Reaction time: 1 h
Yield: 90 %

Procedure:
To a solution of the 4-fluorophenol (25.3 g) and dimethylacryloyl chloride (25.9 g) in diisopropyl ether (500 mL) cooled in an ice bath was added triethylamine (35 mL) dropwise over a period of 20 minutes. After 1 hour, the reaction mixture was washed with water and brine, dried over sodium sulfate, and the organic solvent was evaporated in vacuo to give crude ester. Distillation under vacuum gave dimethylacrylate 4-fluorophenyl ester (38.20 g, 87%).
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[CH:3]=[C:2]1[C:10](=[C:13]([C:16]#[N:17])[C:14]#[N:15])SC.[C:18]1([NH:24][NH2:25])[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>>[NH2:15][C:14]1[N:24]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[N:25]=[C:10]([C:2]2[S:1][C:5]3[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=3[CH:3]=2)[C:13]=1[C:16]#[N:17]
Reactant: CSC(=C(C#N)C#N)c1cc2ccccc2s1
Reactant: NNc1ccccc1
Product: N#Cc1c(-c2cc3ccccc3s2)nn(-c2ccccc2)c1N

Procedure:
Using 2.56 g (10 mmol) of (benzothiophen-2-yl) (methylthio)methylenepropanedinitrile and 1.1 g (10 mmol) of phenylhydrazine, the entitled product having a melting point of 260° to 262° C. was obtained in the same manner as in Example 1-(1).
Reaction SMILES: [CH2:1]([CH2:3][NH2:4])[OH:2].[OH-].[K+].[C:7](Cl)(=[O:12])[C:8]([CH3:11])([CH3:10])[CH3:9]>O>[OH:2][CH2:1][CH2:3][NH:4][C:7](=[O:12])[C:8]([CH3:11])([CH3:10])[CH3:9]
Reactant: NCCO
Reactant: CC(C)(C)C(=O)Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Product: CC(C)(C)C(=O)NCCO
Reaction time: 18 h
Yield: 50.8 %

Procedure:
To a stirred 4° aqueous solution containing ethanolamine (610 mg, 10 mmol), KOH (840 mg, 15 mmol) and H2O (15 mL) was added pivaloyl chloride (1.44 g, 12 mmol) whereupon the reaction was allowed to slowly warm to 20°. After stirring for 18 hr, the solution was extracted 4× with EtOAc,. The combined organic layers were washed with brine, dried over Na2SO4 prior to concentration using a rotary evaporator to yield 737 mg of a clear oil.
Reaction SMILES: [CH2:1]([O:3][CH:4]([C:11]1[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=1)[CH2:5][C:6]([O:8][CH2:9][CH3:10])=[O:7])[CH3:2].[Cl:18][C:19]1[CH:24]=[CH:23][C:22]([CH2:25][CH2:26]O)=[CH:21][CH:20]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(C)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>O1CCCC1>[Cl:18][C:19]1[CH:24]=[CH:23][C:22]([CH2:25][CH2:26][O:17][C:14]2[CH:13]=[CH:12][C:11]([CH:4]([O:3][CH2:1][CH3:2])[CH2:5][C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:16][CH:15]=2)=[CH:21][CH:20]=1
Reactant: OCCc1ccc(Cl)cc1
Reactant: CCOC(=O)CC(OCC)c1ccc(O)cc1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: CCOC(=O)CC(OCC)c1ccc(OCCc2ccc(Cl)cc2)cc1
Temperature: 50 °C
Reaction time: 4 h
Yield: 95 %

Procedure:
Ethyl 3-ethoxy-3-(4-hydroxyphenyl)propionate (100 mg, 0.420 mmol) produced in Example 1 (1C) and 2-(4-chlorophenyl)ethanol (99 mg, 0.630 mmol) were dissolved in tetrahydrofuran (10 mL), and triphenylphosphine (178 mg, 0.680 mmol) and a 40% diethyl azodicarboxylate toluene solution (309 μL, 0.680 mmol) were added thereto at room temperature, and then, the resulting mixture was stirred under a nitrogen atmosphere at 50° C. for 4 hours. After the reaction solution was cooled to room temperature, the solvent was distilled off under reduced pressure, and the resulting residue was purified by silica gel column chromatography (hexane:ethyl acetate=100:0 to 95:5 (v/v)), whereby the objective title compound was obtained as a yellow oily substance (151 mg, yield: 95%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH:11][C:12]2[N:13]=[CH:14][C:15]3[CH2:21][C:20](=[O:22])[NH:19][C:18]4[CH:23]=[C:24](I)[CH:25]=[CH:26][C:17]=4[C:16]=3[N:28]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].[CH2:29]([OH:32])[C:30]#[CH:31]>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH:11][C:12]2[N:13]=[CH:14][C:15]3[CH2:21][C:20](=[O:22])[NH:19][C:18]4[CH:23]=[C:24]([C:31]#[C:30][CH2:29][OH:32])[CH:25]=[CH:26][C:17]=4[C:16]=3[N:28]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: COc1ccc(Nc2ncc3c(n2)-c2ccc(I)cc2NC(=O)C3)cc1OC
Reactant: C#CCO
Product: COc1ccc(Nc2ncc3c(n2)-c2ccc(C#CCO)cc2NC(=O)C3)cc1OC

Procedure:
In a manner similar to that described for Method O, 2-(3,4-dimethoxy-phenylamino)-9-iodo-5H,7H-benzo[b]pyrimido[4,5-d]azepin-6-one (I-30) and prop-2-yn-1-ol were converted to I-52 (38%): HRMS Calcd. for C23H20N4O4: 417.1562, Found 417.1551.
Reaction SMILES: [C:1]([O:5][C:6](=[O:19])[C:7]([S:10][C:11]1[S:12][CH:13]=[C:14]([CH2:16][CH2:17][OH:18])[N:15]=1)([CH3:9])[CH3:8])([CH3:4])([CH3:3])[CH3:2].[F:20][C:21]1[CH:26]=[CH:25][C:24]([C:27]2[CH:32]=[CH:31][C:30](O)=[CH:29][CH:28]=2)=[CH:23][CH:22]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>O1CCCC1>[C:1]([O:5][C:6](=[O:19])[C:7]([S:10][C:11]1[S:12][CH:13]=[C:14]([CH2:16][CH2:17][O:18][C:30]2[CH:29]=[CH:28][C:27]([C:24]3[CH:23]=[CH:22][C:21]([F:20])=[CH:26][CH:25]=3)=[CH:32][CH:31]=2)[N:15]=1)([CH3:9])[CH3:8])([CH3:2])([CH3:4])[CH3:3]
Reactant: Oc1ccc(-c2ccc(F)cc2)cc1
Reactant: CC(C)(C)OC(=O)C(C)(C)Sc1nc(CCO)cs1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)C(C)(C)Sc1nc(CCOc2ccc(-c3ccc(F)cc3)cc2)cs1
Temperature: 25 °C
Reaction time: 17 h
Yield: 55.4 %

Procedure:
2-{[4-(2-Hydroxyethyl)-1,3-thiazol-2-yl]thio}-2-methylpropionic acid tert-butyl ester (451 mg) synthesized in Example 4 and 4′-fluorobiphenyl-4-ol (280 mg) were dissolved in tetrahydrofuran (10 mL), triphenylphosphine (430 mg) and diisopropyl azodicarboxylate (40% toluene solution, 0.88 ml) were added under ice-cooling, and the mixture was stirred at room temperature for 17 hr. The reaction mixture was concentrated under reduced pressure, and hexane (about 10 mL) was added. The precipitated crystals were removed by filtration, and the solvent of the filtrate was evaporated under reduced pressure. The residue was purified by silica gel chromatography (elution solvent; hexane:ethyl acetate=4:1) to give the title compound (390 mg) as a colorless oil.
Reaction SMILES: [CH2:1]([O:4][CH2:5][C:6]1[N:11]=[C:10]([CH2:12]O)[CH:9]=[CH:8][CH:7]=1)[CH:2]=[CH2:3].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(Br)(Br)(Br)[Br:34]>ClCCl>[CH2:1]([O:4][CH2:5][C:6]1[CH:7]=[CH:8][CH:9]=[C:10]([CH2:12][Br:34])[N:11]=1)[CH:2]=[CH2:3]
Reactant: BrC(Br)(Br)Br
Reactant: C=CCOCc1cccc(CO)n1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: C=CCOCc1cccc(CBr)n1
Reaction time: 1 h
Yield: 94.3 %

Procedure:
A solution of 6-allyloxymethylpyridine-2-methanol (1.56 g, 8.72 mmol) and triphenylphosphine (2.74 g, 10.5 mmol) in dichloromethane (40 mL) at 0° C. was treated portionwise with CBr4 (4.34 g, 13.1 mmol), stirred for 1 h, concentrated in vacuo and purified by chromatography [SiO2; isohexane:EtOAc (3:1)] to give the title compound (1.99 g, 94%) as a colourless oil: NMR δH (400 MHz, CDCl3) 7.71 (1H, t, J 7.5 Hz), 7.40 (1H, d, J 7.5 Hz), 7.34 (1H, d, J 7.5 Hz), 6.03-5.93 (1H, m), 5.37-5.32 (1H, m), 5.26-5.22 (1H, m), 4.64 (2H, s), 4.54 (2H, s) and 4.14-4.12 (2H, m).
Reaction SMILES: [O:1]1[C:6](=[O:7])[CH:5]=[CH:4][NH:3][C:2]1=[O:8].[C:9](=O)([O-])[O-].[K+].[K+].CI>CC(C)=O>[CH3:9][N:3]1[CH:4]=[CH:5][C:6](=[O:7])[O:1][C:2]1=[O:8]
Reactant: O=C([O-])[O-]
Reactant: O=c1cc[nH]c(=O)o1
Agent: [K+]
Solvent: CI
Solvent: CC(C)=O
Product: Cn1ccc(=O)oc1=O
Temperature: 25 °C
Reaction time: 10 h
Yield: 86.6 %

Procedure:
At room temperature, 1.50 g of 2H-1,3-oxazine-2,6(3H)-dione, 2.19 g of potassium carbonate and 3.77 g of methyl iodide were sequentially added to 30 ml of acetone, and the mixture was stirred for 10 hours under heat refluxing condition. The reaction mixture was cooled to room temperature and filtered. The filtrate was concentrated under reduced pressure, and the resulting solid was dried to obtain 1.46 g of 3-methyl-2H-1,3-oxazine-2,6(3H)-dione represented by the formula:
Reaction SMILES: CN(P(N(C)C)N(C)C)C.Br[C:12](Br)([F:14])[F:13].[Cl:16][C:17]1[CH:18]=[C:19]([C:23]#[C:24][C:25]2[CH2:29][C:28]3([CH2:34][CH2:33][C:32](=O)[CH2:31][CH2:30]3)[O:27][N:26]=2)[CH:20]=[CH:21][CH:22]=1>C1COCC1>[Cl:16][C:17]1[CH:18]=[C:19]([C:23]#[C:24][C:25]2[CH2:29][C:28]3([CH2:34][CH2:33][C:32](=[C:12]([F:14])[F:13])[CH2:31][CH2:30]3)[O:27][N:26]=2)[CH:20]=[CH:21][CH:22]=1
Reactant: O=C1CCC2(CC1)CC(C#Cc1cccc(Cl)c1)=NO2
Reactant: FC(F)(Br)Br
Agent: CN(C)P(N(C)C)N(C)C
Solvent: C1CCOC1
Product: FC(F)=C1CCC2(CC1)CC(C#Cc1cccc(Cl)c1)=NO2
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 13.7 %

Procedure:
A solution of tris-dimethylaminophosphine in 2.6 mL of anhydrous THF was added under a nitrogen atmosphere to a solution of dibromodifluoromethane in 3.9 mL of anhydrous THF at 0° C. over 15 min. The reaction mixture was stirred at r.t. for 30 min. Afterwards, a solution of the Compound of Example 32 (0.275 g, 0.956 mmol) was added dropwise. After overnight resting, the solution was evaporated and taken up with EtOAc. Washing with water, drying the organic layer with Na2SO4 and evaporating to dryness in vacuo afforded a crude which was purified by means of automated flash chromatography (Isolera®TM-Biotage; gradient Petroleum Ether-EtOAc from 95:5 to 8:2) giving 42 mg of the title compound. Yield: 13.7%.
Reaction SMILES: [CH3:1][CH2:2][C@@H:3]([C:5]([O:7][C@@H:8]1[C@@H:13]2[C@@H:14]([CH2:19][CH2:20][C@@H:21]([OH:29])[CH2:22][C@@H:23]([OH:28])[CH2:24][C:25]([O-:27])=[O:26])[C@@H:15]([CH3:18])[CH:16]=[CH:17][C:12]2=[CH:11][C@@H:10]([OH:30])[CH2:9]1)=[O:6])[CH3:4].[Na+].[Cl-].[Zn+2:33].[Cl-]>O>[CH3:1][CH2:2][C@@H:3]([C:5]([O:7][C@@H:8]1[C@@H:13]2[C@@H:14]([CH2:19][CH2:20][C@@H:21]([OH:29])[CH2:22][C@@H:23]([OH:28])[CH2:24][C:25]([OH:27])=[O:26])[C@@H:15]([CH3:18])[CH:16]=[CH:17][C:12]2=[CH:11][C@@H:10]([OH:30])[CH2:9]1)=[O:6])[CH3:4].[Zn:33]
Reactant: [Zn+2]
Reactant: CC[C@H](C)C(=O)O[C@H]1C[C@H](O)C=C2C=C[C@H](C)[C@H](CC[C@@H](O)C[C@@H](O)CC(=O)[O-])[C@H]21
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Product: CC[C@H](C)C(=O)O[C@H]1C[C@H](O)C=C2C=C[C@H](C)[C@H](CC[C@@H](O)C[C@@H](O)CC(=O)O)[C@H]21
Product: [Zn]

Procedure:
2 equivalents of pravastatin sodium dissolved in de-ionized water are reacted with a solution having 1 equivalent of zinc chloride in de-ionized water. Precipitation of crystalline pravastatin zinc occurs immediately at room temperature. The resultant salt was a 2:1 pravastatin to zinc salt. The preparation and characterization of pravastatin zinc are described more completely in Example 7 of US Application No. 20060034815.
Reaction SMILES: [C:1]([CH2:3][C:4]([O:6]CC)=O)#[N:2].[CH3:9][C:10]1[CH:17]=[CH:16][C:13]([CH2:14][NH2:15])=[CH:12][CH:11]=1>COCCO>[CH3:9][C:10]1[CH:17]=[CH:16][C:13]([CH2:14][NH:15][C:4](=[O:6])[CH2:3][C:1]#[N:2])=[CH:12][CH:11]=1
Reactant: Cc1ccc(CN)cc1
Reactant: CCOC(=O)CC#N
Solvent: COCCO
Product: Cc1ccc(CNC(=O)CC#N)cc1

Procedure:
A solution of 93 g. (0.825 mole) of ethyl cyanoacetate and 100 g. (0.825 mole) of 4-methylbenzylamine in 150 ml. of 2-methoxyethanol is refluxed for 2 hr. After cooling the solid product is isolated by vacuum filtration, washed with pentane and dried to give 90 g. (57.6%) of amide as a white solid: m.p. 124°-6° C.; ν 3220 (NH), 2230 (CN), and 1630 cm.-1 (C=O) δ 8.77 broad, 1H, NH); 7.17 (s, 4H, phenyl protons), 4.28 (d, 2H, benzyl methylene), 3.67 (s, 2H, CH2CO), and 2.28 (s, 3H, CH3).
Reaction SMILES: [NH2:1][C@@H:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C@H:5]([OH:12])[CH2:4][CH2:3]1.[H-].[Na+].[CH2:15]([O:18][CH:19]1[CH2:24][CH2:23][N:22]([C:25]2[N:29]3[CH:30]=[C:31](F)[CH:32]=[CH:33][C:28]3=[N:27][N:26]=2)[CH2:21][CH2:20]1)[CH:16]=[CH2:17].CC(O)=O>CN(C=O)C>[CH2:15]([O:18][CH:19]1[CH2:20][CH2:21][N:22]([C:25]2[N:29]3[CH:30]=[C:31]([O:12][C@H:5]4[C:6]5[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=5)[C@@H:2]([NH2:1])[CH2:3][CH2:4]4)[CH:32]=[CH:33][C:28]3=[N:27][N:26]=2)[CH2:23][CH2:24]1)[CH:16]=[CH2:17]
Reactant: C=CCOC1CCN(c2nnc3ccc(F)cn23)CC1
Reactant: N[C@H]1CC[C@@H](O)c2ccccc21
Agent: [H-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CN(C)C=O
Product: C=CCOC1CCN(c2nnc3ccc(O[C@@H]4CC[C@H](N)c5ccccc54)cn23)CC1
Reaction time: 1 h
Yield: 80.9 %

Procedure:
A suspension of Intermediate A (108 mg, 0.661 mmol) and NaH (60% dispersion in oil, 72.1 mg, 180 mmol) in dry DMF (5 mL) at RT under Ar was stirred for 1 h (CARE: gas evolution). A solution of Intermediate 57a (166 mg, 0.601 mmol) in dry DMF (3 mL) was added and the dark brown solution stirred at 60° C. for 90 min. The solution was concentrated in vacuo, and the residue redissolved in MeOH (5 mL) and AcOH (0.171 mL, 3.00 mmol). The solution was applied to an SCX-2 cartridge (10 g) and was washed with MeOH (100 mL). The product was eluted with 2M NH3 in MeOH (75 mL); concentration in vacuo left a dark brown solid. FCC, using 2-8% [2M NH3 in MeOH] in DCM, gave the title compound as a dark brown oil (204 mg, 81%). LCMS (Method 3): Rt 2.34 min, m/z 420 [MH+].
Reaction SMILES: [C:1]([O:7][CH2:8][C:9]([CH2:22]C)([CH2:20]C)[CH2:10][N:11]([CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[CH3:12])(=[O:6])[CH2:2][C:3]([CH3:5])=O.[NH2:24]/[C:25](/[CH3:31])=[CH:26]\[C:27]([O:29][CH3:30])=[O:28].[F:32][C:33]1[CH:40]=[CH:39][C:38]([N+:41]([O-:43])=[O:42])=[CH:37][C:34]=1[CH:35]=O>CC(O)C>[CH3:5][C:3]1[NH:24][C:25]([CH3:31])=[C:26]([C:27]([O:29][CH3:30])=[O:28])[CH:35]([C:34]2[CH:37]=[C:38]([N+:41]([O-:43])=[O:42])[CH:39]=[CH:40][C:33]=2[F:32])[C:2]=1[C:1]([O:7][CH2:8][C:9]([CH3:20])([CH3:22])[CH2:10][N:11]([CH2:13][C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1)[CH3:12])=[O:6]
Reactant: CCC(CC)(COC(=O)CC(C)=O)CN(C)Cc1ccccc1
Reactant: COC(=O)/C=C(/C)N
Reactant: O=Cc1cc([N+](=O)[O-])ccc1F
Solvent: CC(C)O
Product: COC(=O)C1=C(C)NC(C)=C(C(=O)OCC(C)(C)CN(C)Cc2ccccc2)C1c1cc([N+](=O)[O-])ccc1F
Yield: 261.7 %

Procedure:
To a solution of a mixture 290 mg of 3-(N-benzyl-N-methylamino)-2,2-diethylpropyl acetoacetate and 15 mg of methyl 3-aminocrotonate in 1 ml of 2-propanol was added 168 mg of 2-fluoro-5-nitrobenzaldehyde. The mixture was refluxed for 10 hours. The solvent was distilled off to leave the residue. The residue was purified by a column chromatography (n-hexane:ethyl acetate=2:1) on silica gel to provide 184 mg (yield 34%) of the desirec compound (140).
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([C:8]2[O:9][C:10]3[CH:16]=[CH:15][CH:14]=[CH:13][C:11]=3[N:12]=2)[CH2:4][CH2:3]1.[CH2:17]([Cl:20])[CH:18]=[CH2:19]>>[Cl-:20].[CH2:17]([N+:2]1([CH3:1])[CH2:3][CH2:4][N:5]([C:8]2[O:9][C:10]3[CH:16]=[CH:15][CH:14]=[CH:13][C:11]=3[N:12]=2)[CH2:6][CH2:7]1)[CH:18]=[CH2:19]
Reactant: CN1CCN(c2nc3ccccc3o2)CC1
Reactant: C=CCCl
Product: C=CC[N+]1(C)CCN(c2nc3ccccc3o2)CC1
Product: [Cl-]

Procedure:
Using 435 mg of 2-(4-methyl-1-piperazinyl)benzoxazole and 0.24 ml of allyl chloride, the same treatment of Example 2 was conducted to obtain 504 mg of the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([NH:19][C:20]2[CH:25]=[C:24]([F:26])[C:23](=[O:27])[N:22]([CH3:28])[CH:21]=2)[C:9]2[C:10]([C:16](O)=[O:17])=[N:11][N:12]([CH3:15])[C:13]=2[CH3:14])=[CH:4][CH:3]=1>C(Cl)Cl.CO>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]2[C:9]3[C:10](=[N:11][N:12]([CH3:15])[C:13]=3[CH3:14])[C:16](=[O:17])[N:19]2[C:20]2[CH:25]=[C:24]([F:26])[C:23](=[O:27])[N:22]([CH3:28])[CH:21]=2)=[CH:6][CH:7]=1
Reactant: Cc1c(C(Nc2cc(F)c(=O)n(C)c2)c2ccc(Cl)cc2)c(C(=O)O)nn1C
Solvent: CO
Solvent: ClCCl
Product: Cc1c2c(nn1C)C(=O)N(c1cc(F)c(=O)n(C)c1)C2c1ccc(Cl)cc1

Procedure:
The title compound was prepared in analogy to the procedure described in Example 1 using 4-((4-chlorophenyl)(5-fluoro-1-methyl-6-oxo-1,6-dihydropyridin-3-ylamino)methyl)-1,5-dimethyl-1H-pyrazole-3-carboxylic acid (Step 31.2). tR: 3.64 min (HPLC 1); tR: 0.80 min (LC-MS 2); ESI-MS: 387 [M+H]+ (LC-MS 2); Rf=0.51 (CH2Cl2/MeOH 9:1); 1H NMR (400 MHz, DMSO-d6) δ ppm 2.06 (s, 3H) 3.43 (s, 3H) 3.83 (s, 3H) 6.13 (s, 1H) 7.23-7.29 (m, 2H) 7.33-7.40 (m, 2H) 7.57-7.67 (m, 1H) 7.79 (br. s, 1H).
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[NH:3][CH2:2]1.NC1C=CC=CC=1S.C=O.[C:20]([C:22]1[CH:23]=[C:24]([CH:28]=[C:29]([CH2:33][CH3:34])[C:30]=1[O:31][CH3:32])[C:25](Cl)=[O:26])#[N:21]>ClCCl.C(N(CC)CC)C>[C:20]([C:22]1[CH:23]=[C:24]([CH:28]=[C:29]([CH2:33][CH3:34])[C:30]=1[O:31][CH3:32])[C:25]([N:3]1[C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=2[S:1][CH2:2]1)=[O:26])#[N:21]
Reactant: c1ccc2c(c1)NCS2
Reactant: CCc1cc(C(=O)Cl)cc(C#N)c1OC
Agent: C=O
Agent: Nc1ccccc1S
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCc1cc(C(=O)N2CSc3ccccc32)cc(C#N)c1OC
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
2,3-dihydro-1,3-benzothiazole synthesized from 2-aminobenzenethiol (318 mg) and 37% formalin (0.21 mL) in the same manner as in Example 1 was dissolved in dichloromethane (6 mL), and triethylamine (0.71 mL) and 3-cyano-5-ethyl-4-methoxybenzoyl chloride (387 mg) were added to the solution, and then the mixture was stirred at room temperature for 1.5 hours. The solvent was distilled off under reduced pressure and water was added, and then the mixture was extracted with ethyl acetate. The organic layer was washed with 1N hydrochloric acid, 1N sodium hydroxide and saturated brine, and then dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure and the obtained residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=6:1) to obtain the title compound (498 mg) as a yellow oily substance.
Reaction SMILES: [N:1]1([C:7]2[C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=3[S:9][N:8]=2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[Cl:16][C:17]1[CH:25]=[C:24]2[C:20]([CH2:21][C:22](=[O:26])[NH:23]2)=[CH:19][C:18]=1[CH2:27][CH2:28]Cl.C(=O)([O-])[O-].[K+].[K+]>[I-].[K+].O>[S:9]1[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[C:7]([N:1]2[CH2:6][CH2:5][N:4]([CH2:28][CH2:27][C:18]3[CH:19]=[C:20]4[C:24](=[CH:25][C:17]=3[Cl:16])[NH:23][C:22](=[O:26])[CH2:21]4)[CH2:3][CH2:2]2)=[N:8]1
Reactant: c1ccc2c(N3CCNCC3)nsc2c1
Reactant: O=C1Cc2cc(CCCl)c(Cl)cc2N1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: O
Product: O=C1Cc2cc(CCN3CCN(c4nsc5ccccc45)CC3)c(Cl)cc2N1
Temperature: 90 °C
Yield: 74.9 %

Procedure:
In a 50 ml 3 necked round bottom flask there were placed 1 gram (4.56 mmol) of 3-piperazinylbenzo[d]isothiazole; 2.5 grams (10.86 mmol) of 6-chloro-5-(2-chloroethyl)indolin-2-one; 50 mg of potassium iodide; 1.64 grams (11.88 mmol) of potassium carbonate. The contents of the flask were heated to 90° C. The reaction was monitored by HPLC. After completion of the reaction, 50 ml of DM water was added to the reaction mixture and stirred. The product was filtered off and washed with water and dried to obtain 1.41 grams (75%) of 5-(2-(4-(1,2-benzisothiazol-3-yl)-1-piperazinyl)ethyl)-6-chloro-1,3-dihydro-2H-indol-2-one. The crude product was purified by IPA and/or THF. The product matched the spectra of a standard NMR and showed the correct retention time by HPLC with 98.0% assay. The melting point of the compound was found to be 218° C.-220° C., and was found to conform with the melting point of 218° C.-220° C. as disclosed in U.S. Pat. No. 5,206,366.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([CH:10]2[CH2:15][CH2:14][N:13]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:12][CH2:11]2)=[CH:2]1.[H-].[Na+].[CH3:25]I>CN(C)C=O>[CH3:25][N:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([CH:10]2[CH2:15][CH2:14][N:13]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:12][CH2:11]2)=[CH:2]1
Reactant: CC(C)(C)OC(=O)N1CCC(c2c[nH]c3ccccc23)CC1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cn1cc(C2CCN(C(=O)OC(C)(C)C)CC2)c2ccccc21
Temperature: 25 °C

Procedure:
500 mg tert-butyl 4-(1H-indol-3-yl)-piperidine-1-carboxylate are placed in 8 ml dimethylformamide and 73.3 mg sodium hydride (60% in mineral oil) are added. After 15 min 175 μl methyl iodide are added. The reaction mixture is stirred at ambient temperature. After the reaction is complete the product is purified directly by preparative HPLC (method C). 302 mg of the product are obtained as an oil.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([NH2:8])[C:3]=1I.[F:10][C:11]1[CH:16]=[CH:15][C:14](B(O)O)=[C:13]([C:20](OC)=[O:21])[CH:12]=1>>[Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[C:3]=1[C:14]1[CH:15]=[CH:16][C:11]([F:10])=[CH:12][C:13]=1[C:20](=[O:21])[NH:8]2
Reactant: Nc1nccc(Cl)c1I
Reactant: COC(=O)c1cc(F)ccc1B(O)O
Product: O=c1[nH]c2nccc(Cl)c2c2ccc(F)cc12
Yield: 21.3 %

Procedure:
The title compound was synthesized according to the procedure described for the preparation of Example 1 using 4-chloro-3-iodopyridin-2-amine (1.20 g, 4.72 mmol) and 4-fluoro-2-methoxycarbonylphenylboronic acid (1.03 g, 5.19 mmol) to provide 411 (250 mg, 21% yield) as a solid. LC-MS (M+H=249, obsd.=249).