Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([O:11][CH2:12][CH2:13][CH2:14][N:15]2[CH2:20][CH2:19][N:18]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=3OC)[CH2:17][CH2:16]2)[C:10]2[CH2:9][CH2:8][CH2:7][CH2:6][C:5]=2[CH:4]=[CH:3][CH:2]=1.[C:29]1(O)C2CCCCC=2C=CC=1.ClCCCN1CCN(C2C=CC=CC=2OC)CC1.C1(N)C(F)=C(F)C(F)=C(N)C=1F.Cl.Cl>>[CH3:29][C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=1[N:18]1[CH2:19][CH2:20][N:15]([CH2:14][CH2:13][CH2:12][O:11][C:1]2[C:10]3[CH2:9][CH2:8][CH2:7][CH2:6][C:5]=3[CH:4]=[CH:3][CH:2]=2)[CH2:16][CH2:17]1
Reactant: Oc1cccc2c1CCCC2
Reactant: COc1ccccc1N1CCN(CCCOc2cccc3c2CCCC3)CC1
Agent: COc1ccccc1N1CCN(CCCCl)CC1
Agent: Cl
Agent: Nc1c(F)c(N)c(F)c(F)c1F
Product: Cc1ccccc1N1CCN(CCCOc2cccc3c2CCCC3)CC1

Procedure:
1-[3-(5,6,7,8-tetrahydronaphth-1-yloxy)-propyl]-4-(2-methoxyphenyl)-piperazine from 5,6,7,8-tetrahydro-1-naphthol and 1-(3-chloropropyl)-4-(2-methoxyphenyl)-piperazine; yield 48% of theory; m.p. of the dihydrochloride 202°-203°C. (decomp.).
Reaction SMILES: [C:1]([C:5]1[CH:38]=[CH:37][C:8]([C:9]([NH:11][C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([C:18]3[N:19]=[C:20]([NH:26][C:27]4[CH:32]=[CH:31][C:30]([CH2:33][CH2:34][OH:35])=[CH:29][CH:28]=4)[C:21](=[O:25])[N:22]([CH3:24])[CH:23]=3)[C:13]=2[CH3:36])=[O:10])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].C(N(C(C)C)CC)(C)C.[S:48](Cl)([CH3:51])(=[O:50])=[O:49].[OH-].[Na+]>C(Cl)Cl>[C:1]([C:5]1[CH:38]=[CH:37][C:8]([C:9]([NH:11][C:12]2[C:13]([CH3:36])=[C:14]([C:18]3[N:19]=[C:20]([NH:26][C:27]4[CH:28]=[CH:29][C:30]([CH2:33][CH2:34][O:35][S:48]([CH3:51])(=[O:50])=[O:49])=[CH:31][CH:32]=4)[C:21](=[O:25])[N:22]([CH3:24])[CH:23]=3)[CH:15]=[CH:16][CH:17]=2)=[O:10])=[CH:7][CH:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: Cc1c(NC(=O)c2ccc(C(C)(C)C)cc2)cccc1-c1cn(C)c(=O)c(Nc2ccc(CCO)cc2)n1
Reactant: CS(=O)(=O)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: Cc1c(NC(=O)c2ccc(C(C)(C)C)cc2)cccc1-c1cn(C)c(=O)c(Nc2ccc(CCOS(C)(=O)=O)cc2)n1
Temperature: 25 °C

Procedure:
A solution of 5-bromo-3-[4-(2-hydroxy-ethyl)-phenylamino]-1-methyl-1H-pyrazin-2-one (2) (1.2 g; 2.35 mmol) in CH2Cl2 (30 mL) was cooled to 0° C. and 1.5 mL of diisopropylethyl amine was added. A second solution containing 0.75 mL mesyl chloride in 3 mL CH2Cl2 was added dropwise to the stirring reaction solution under N2 and the reaction allowed to warm to rt for 1 hr. 0.1N Sodium hydroxide was then added carefully to the reaction, and the layers separated. The CH2Cl2 layer was washed with brine and dried over solid sodium sulfate, then filtered and evaporated to a light red-brown oil (1.5 g). The crude methanesulfonic acid 2-(4-{6-[3-(4-tert-butyl-benzoylamino)-2-methyl-phenyl]-4-methyl-3-oxo-3,4-dihydro-pyrazin-2-ylamino}-phenyl)-ethyl ester (3) was used directly in subsequent reactions.
Reaction SMILES: [NH2:1][C:2]1[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][C:3]=1[CH:4]=[C:5]1[C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=2[C:7](=[O:14])[O:6]1.[OH-].[Na+].Cl>C(O)C>[Cl:19][C:16]1[CH:15]=[C:3]2[C:2](=[CH:18][CH:17]=1)[NH:1][C:5]([C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=1[C:7]([OH:6])=[O:14])=[CH:4]2
Reactant: Nc1ccc(Cl)cc1C=C1OC(=O)c2ccccc21
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=C(O)c1ccccc1-c1cc2cc(Cl)ccc2[nH]1
Temperature: 25 °C
Reaction time: 1 h
Yield: 84.8 %

Procedure:
To a solution of 3-(2-amino-5-chlorobenzylidene)-2-benzofuran-1(3H)-one (466 mg) in ethanol (3.5 mL) was added a 1 M aqueous sodium hydroxide solution (3.4 mL) at room temperature, followed by heating with reflux for 45 minutes. The reaction mixture was acidified by adding of 1 M hydrochloric acid under ice-cooling, and stirred at room temperature for 1 hour. The resulting precipitate was separated by filtration and the filtrate was extracted with diethyl ether. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure to obtain 2-(5-chloro-1H-indol-2-yl)benzoic acid (395 mg).
Reaction SMILES: [C:1]([C:3]1[CH:11]=[CH:10][C:6]([C:7]([NH2:9])=[O:8])=[CH:5][C:4]=1[N+:12]([O-])=O)#[CH:2].[Cl-].[NH4+]>[Fe].O1CCCC1>[C:1]([C:3]1[CH:11]=[CH:10][C:6]([C:7]([NH2:9])=[O:8])=[CH:5][C:4]=1[NH2:12])#[CH:2]
Reactant: C#Cc1ccc(C(N)=O)cc1[N+](=O)[O-]
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: C#Cc1ccc(C(N)=O)cc1N
Yield: 59.4 %

Procedure:
5 g (26.3 mmol) 4-Ethynyl-3-nitrobenzamide (Compound XII-1) and 75 ml tetrahydrofuran were added into a 150 ml four-necked flask, mechanically stirred to dissolve, and added with 10 ml aqueous solution of 10 g (186.9 mmol) ammonium chloride, then 10 g (178.5 mmol) iron powder was added portionwise and reacted at room temperature for 4 hours until the reaction was completed. The mixture was filtrated, and the filter cake was washed with tetrahydrofuran. The filtrate was extracted with ethyl acetate and the organic phase was washed with water, dried over anhydrous sodium sulfate, decolorized with activated charcoal, filtered, and concentrated to precipitate a solid, which was filtrated and dried to obtain 4-ethynyl-3-aminobenzamide (Compound XI-1, gray solid), 2.4 g, yield 59.4%.
Reaction SMILES: [C:1]([S:4][CH2:5][CH:6]([CH:10]([C:12]1[CH:17]=[CH:16][C:15]([OH:18])=[CH:14][CH:13]=1)[CH3:11])[C:7]([OH:9])=O)(=[O:3])[CH3:2].[CH2:19]([O:26][C:27](=[O:31])[C@H:28]([CH3:30])[NH2:29])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>>[CH2:19]([O:26][C:27](=[O:31])[C@H:28]([CH3:30])[NH:29][C:7](=[O:9])[CH:6]([CH2:5][S:4][C:1](=[O:3])[CH3:2])[CH:10]([C:12]1[CH:17]=[CH:16][C:15]([OH:18])=[CH:14][CH:13]=1)[CH3:11])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: CC(=O)SCC(C(=O)O)C(C)c1ccc(O)cc1
Reactant: C[C@H](N)C(=O)OCc1ccccc1
Product: CC(=O)SCC(C(=O)N[C@@H](C)C(=O)OCc1ccccc1)C(C)c1ccc(O)cc1
Yield: 69 %

Procedure:
Using the procedure described in Example 60, but starting with 2-acetylthiomethyl-3-(4-hydroxyphenyl)butanoic acid and alanine benzyl ester, N-[2-acetylthiomethyl-3-(4-hydroxyphenyl)-1-oxobutyl]alanine benzyl ester is obtained in a 69% yield, the characteristics of which are as follows: Rf= 0.22 [hexane/ethyl acetate (65:35 by volume)].
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[O:3][C:4]1[CH:10]=[CH:9][C:7]([NH2:8])=[CH:6][CH:5]=1.[Br:13][C:14]1[CH:15]=[CH:16][C:17]2[N:18]([CH:20]=[C:21]([C:23](OCC)=[O:24])[N:22]=2)[CH:19]=1>>[Br:13][C:14]1[CH:15]=[CH:16][C:17]2[N:18]([CH:20]=[C:21]([C:23]([NH:8][C:7]3[CH:9]=[CH:10][C:4]([O:3][C:2]([F:11])([F:12])[F:1])=[CH:5][CH:6]=3)=[O:24])[N:22]=2)[CH:19]=1
Reactant: Nc1ccc(OC(F)(F)F)cc1
Reactant: CCOC(=O)c1cn2cc(Br)ccc2n1
Product: O=C(Nc1ccc(OC(F)(F)F)cc1)c1cn2cc(Br)ccc2n1

Procedure:
The title compound was prepared by essentially following the same procedures described for Intermediate I, using 4-(trifluoromethoxy)aniline and ethyl 6-bromoimidazo[1,2-a]pyridine-2-carboxylate as starting materials.
Reaction SMILES: [F:1][C:2]1[C:11]([F:12])=[C:10]([OH:13])[C:9]([N+:14]([O-:16])=[O:15])=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].C(=O)([O-])[O-].[Cs+].[Cs+].[CH3:23][N:24]([CH3:28])[C:25](Cl)=[S:26].O>CN(C)C=O>[CH3:7][O:6][C:4](=[O:5])[C:3]1[CH:8]=[C:9]([N+:14]([O-:16])=[O:15])[C:10]([O:13][C:25](=[S:26])[N:24]([CH3:28])[CH3:23])=[C:11]([F:12])[C:2]=1[F:1]
Reactant: COC(=O)c1cc([N+](=O)[O-])c(O)c(F)c1F
Reactant: CN(C)C(=S)Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)c1cc([N+](=O)[O-])c(OC(=S)N(C)C)c(F)c1F
Temperature: 85 °C
Reaction time: 1 h

Procedure:
A solution of methyl 2,3-difluoro-4-hydroxy-5-nitrobenzoate in N,N-dimethylformamide is treated with one molar equivalent of cesium carbonate and warmed to 85° C. for 30 minutes. The stirring mixture is then treated dropwise rapidly with a solution comprised of a slight excess of N,N-dimethylthiocarbamoyl chloride in N,N-dimethylformamide. The reaction mixture is stirred at room temperature for one hour, or may be warmed over a steam bath for one hour. The mixture is then poured into water and extracted with ethyl acetate. The organic phase is washed with 5% aqueous sodium hydroxide, water, and brine, and is then dried with a drying agent like magnesium sulfate of sodium sulfate. The solvent is then removed in vacuo to give a crude product. The compound is purified by ordinary methods such as chromatography or crystallization from an appropriate solvent.
Reaction SMILES: [F:1][C:2]([F:8])([F:7])[S:3](O)(=[O:5])=[O:4].[NH2:9][C:10]1[CH:35]=[CH:34][C:13]([O:14][CH2:15][CH2:16][CH2:17][N:18]2[CH2:23][CH2:22][N:21]([C:24]3[N:29](C)[C:28](=[O:31])[N:27](C)[C:26](=[O:33])[CH:25]=3)[CH2:20][CH2:19]2)=[CH:12][CH:11]=1.C(=O)([O-])[O-].[K+].[K+]>ClCCl>[F:1][C:2]([F:8])([F:7])[S:3]([NH:9][C:10]1[CH:35]=[CH:34][C:13]([O:14][CH2:15][CH2:16][CH2:17][N:18]2[CH2:19][CH2:20][N:21]([C:24]3[NH:29][C:28](=[O:31])[NH:27][C:26](=[O:33])[CH:25]=3)[CH2:22][CH2:23]2)=[CH:12][CH:11]=1)(=[O:5])=[O:4]
Reactant: Cn1c(N2CCN(CCCOc3ccc(N)cc3)CC2)cc(=O)n(C)c1=O
Reactant: O=S(=O)(O)C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Product: O=c1cc(N2CCN(CCCOc3ccc(NS(=O)(=O)C(F)(F)F)cc3)CC2)[nH]c(=O)[nH]1
Yield: 62.5 %

Procedure:
5 ml of a dichloromethane solution containing 0.65 ml of anhydrous trifluoromethanesulfonic acid was added at -78° C. to 25 ml of a dichloromethane solution containing 1.3 g of 6-[4-(3-[4-aminophenoxy]propyl)piperazin-1-yl]-1,3-dimethyl-2,4(1H,3H)-pyrimidinedione obtained in Example 6, and the temperature of the solution was then gradually elevated to room temperature, while it was stirred. 20 ml of dichloromethane and a 2% aqueous potassium carbonate solution were added to the reaction solution, followed by stirring until insolubles were dissolved therein. After the separation of the resultant organic layer, the aqueous layer was neutralized and then extracted with chloroform (50 ml×2), and the extract layers were joined and mixed with the organic layer previously obtained. The mixture was dried over sodium sulfate and then concentrated to obtain 1.1 g (yield: 62.5%) of 6-[4-(3-[4-trifluoromethanesulfonylaminophenoxy]propyl)piperazin-1-yl]-2,4(1H,3H)-pyrimidinedione in a crystalline state.
Reaction SMILES: C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[C:15]1([C:21]2[CH:34]=[CH:33][C:24]([C:25]([NH:27][CH2:28][CH2:29][CH2:30][CH:31]=O)=[O:26])=[CH:23][CH:22]=2)[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.[CH3:35][O:36][C:37]1[CH:46]=[C:45]2[C:40]([CH2:41][CH2:42][NH:43][CH2:44]2)=[CH:39][CH:38]=1.ClCCl>ClCCCl>[CH3:35][O:36][C:37]1[CH:46]=[C:45]2[C:40]([CH2:41][CH2:42][N:43]([CH2:31][CH2:30][CH2:29][CH2:28][NH:27][C:25](=[O:26])[C:24]3[CH:33]=[CH:34][C:21]([C:15]4[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=4)=[CH:22][CH:23]=3)[CH2:44]2)=[CH:39][CH:38]=1
Reactant: COc1ccc2c(c1)CNCC2
Reactant: O=CCCCNC(=O)c1ccc(-c2ccccc2)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Solvent: ClCCl
Product: COc1ccc2c(c1)CN(CCCCNC(=O)c1ccc(-c3ccccc3)cc1)CC2
Reaction time: 16 h
Yield: 82.7 %

Procedure:
Sodium triacetoxyborohydride (4.66 g, 22 mmol) was added to a stirred mixture of 4-(4-phenylbenzoylamino)butyraldehyde (3.92 g, 15 mmol) and 7-methoxy-1,2,3,4-tetrahydroisoquinoline [Daniel J. Sall et al., J. Med. Chem., 1987, 30, 2208] (2.40 g, 14.7 mmol) in 1,2-dichloroethane (200 ml) at room temperature. After stirring for 16 h, dichloromethane (100 ml) was added and the mixture was then washed with saturated aqueous K2CO3 (2×100 ml) and brine (100 ml). Drying (Na2SO 4) and evaporation in vacuo afforded a viscous oil which was chromatographed on silica gel, eluting with ethyl acetate, to give the title compound as a pale pink solid (5.04 g, 83%).
Reaction SMILES: [F:1][C:2]1([F:23])[CH2:6][N:5]([C:7]2[CH:12]=[CH:11][C:10]([N+:13]([O-:15])=[O:14])=[C:9]([C:16]([F:19])([F:18])[F:17])[CH:8]=2)[C@H:4]([C:20]([OH:22])=[O:21])[CH2:3]1.S(Cl)(Cl)=O.[CH3:28]O>>[F:23][C:2]1([F:1])[CH2:6][N:5]([C:7]2[CH:12]=[CH:11][C:10]([N+:13]([O-:15])=[O:14])=[C:9]([C:16]([F:19])([F:18])[F:17])[CH:8]=2)[C@H:4]([C:20]([O:22][CH3:28])=[O:21])[CH2:3]1
Reactant: CO
Reactant: O=C(O)[C@@H]1CC(F)(F)CN1c1ccc([N+](=O)[O-])c(C(F)(F)F)c1
Solvent: O=S(Cl)Cl
Product: COC(=O)[C@@H]1CC(F)(F)CN1c1ccc([N+](=O)[O-])c(C(F)(F)F)c1
Temperature: 0 °C
Yield: 48 %

Procedure:
(S)-4,4-difluoro-1-(4-nitro-3-(trifluoromethyl)phenyl)pyrrolidine-2-carboxylic acid (600 mg, 1.76 mmol) was dissolved in methanol (10 mL), cooled to 0° C., and treated dropwise with thionyl chloride (840 mg, 515 μL, 7.08 mmol). The reaction mixture was heated at 50° C. over 48 h. The reaction mixture was evaporated in vacuo and the residue was purified by silica gel column chromatography (0-60% ethyl acetate in hexane) to obtain (S)-methyl 4,4-difluoro-1-(4-nitro-3-(trifluoromethyl)phenyl)pyrrolidine-2-carboxylate (300 mg, 48% yield). 1H NMR (400 MHz, DMSO-d6) δ 8.12 (d, J=9.2 Hz, 1H), 7.04 (d, J=2.6 Hz, 1H), 6.97 (dd, J=9.2, 2.7 Hz, 1H), 5.19 (dd, J=9.8, 1.9 Hz, 1H), 4.14-3.99 (m, 2H), 3.69 (s, 3H), 3.11-2.95 (m, 1H), 2.78 (t, J=14.6 Hz, 1H).
Reaction SMILES: [CH:1]1([NH:6][C:7]2[CH:8]=[C:9]([F:25])[CH:10]=[C:11]3[C:15]=2[NH:14][C:13]([C:16]2[S:17][CH2:18][C@@H:19]([CH2:21][C:22](O)=[O:23])[N:20]=2)=[CH:12]3)[CH2:5][CH2:4][CH2:3][CH2:2]1.[C:26]([N:29]1[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]1)(=[O:28])[CH3:27]>>[C:26]([N:29]1[CH2:34][CH2:33][N:32]([C:22](=[O:23])[CH2:21][C@@H:19]2[CH2:18][S:17][C:16]([C:13]3[NH:14][C:15]4[C:11]([CH:12]=3)=[CH:10][C:9]([F:25])=[CH:8][C:7]=4[NH:6][CH:1]3[CH2:2][CH2:3][CH2:4][CH2:5]3)=[N:20]2)[CH2:31][CH2:30]1)(=[O:28])[CH3:27]
Reactant: O=C(O)C[C@@H]1CSC(c2cc3cc(F)cc(NC4CCCC4)c3[nH]2)=N1
Reactant: CC(=O)N1CCNCC1
Product: CC(=O)N1CCN(C(=O)C[C@@H]2CSC(c3cc4cc(F)cc(NC5CCCC5)c4[nH]3)=N2)CC1
Yield: 55 %

Procedure:
The compound (100 mg, 0.28 mmol) prepared in Example 37 and 1-acetylpiperazine instead of 1-methylpiperazine were reacted according to the same procedure as Example 84 to give the title compound (60 mg, Yield 55%).
Reaction SMILES: [F:1][C:2]([F:20])([F:19])[CH2:3][C:4]1[NH:5][C:6]2[C:11]([CH:12]=1)=[C:10]([C:13]([F:16])([F:15])[F:14])[C:9]([C:17]#[N:18])=[CH:8][CH:7]=2.C([O-])([O-])=O.[Cs+].[Cs+].[F:27][C:28]([F:47])([F:46])[C:29]1[CH:30]=[C:31]([C:39]2[O:43][N:42]=[C:41]([CH2:44]Cl)[N:40]=2)[CH:32]=[C:33]([C:35]([F:38])([F:37])[F:36])[CH:34]=1.CC#N>CCOC(C)=O>[F:47][C:28]([F:27])([F:46])[C:29]1[CH:30]=[C:31]([C:39]2[O:43][N:42]=[C:41]([CH2:44][N:5]3[C:6]4[C:11](=[C:10]([C:13]([F:16])([F:15])[F:14])[C:9]([C:17]#[N:18])=[CH:8][CH:7]=4)[CH:12]=[C:4]3[CH2:3][C:2]([F:1])([F:19])[F:20])[N:40]=2)[CH:32]=[C:33]([C:35]([F:37])([F:36])[F:38])[CH:34]=1
Reactant: N#Cc1ccc2[nH]c(CC(F)(F)F)cc2c1C(F)(F)F
Reactant: FC(F)(F)c1cc(-c2nc(CCl)no2)cc(C(F)(F)F)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Solvent: CCOC(C)=O
Product: N#Cc1ccc2c(cc(CC(F)(F)F)n2Cc2noc(-c3cc(C(F)(F)F)cc(C(F)(F)F)c3)n2)c1C(F)(F)F
Temperature: 50 °C
Reaction time: 24 h
Yield: 18.3 %

Procedure:
A mixture of the indole (0.040 g, 0.14 mmol) from step A, Cs2CO3 (0.054 g, 0.16 mmol), 5-[3,5-bis(trifluoromethyl)phenyl]-3-(chloromethyl)-1,2,4-oxadiazole (0.091 g, 0.27 mmol) and CH3CN (4 mL) was stirred at 50° C. for 24 h. The mixture was diluted with EtOAc (25 mL) and washed with water (15 mL) and brine (15 mL). Drying (MgSO4), filtration, and concentration was followed by purification (SiO2, 0-30% EtOAc in hexanes) to afford the title compound (0.015 g, 19%) as an off-white solid: 1H NMR (400 MHz, CDCl3) δ 8.48 (s, 2H), 8.10 (s, 1H), 7.80 (d, J=8.6 Hz, 1H), 7.65 (d, J=8.6 Hz, 1H), 6.96 (s, 1H), 5.58 (s, 2H), 3.94 (q, 2H); MS m/z 585 (M−H).
Reaction SMILES: [Na].[CH:2]1([N:7]2[C:11]([NH2:12])=[C:10]([C:13]([NH2:15])=[O:14])[C:9]([CH2:16][CH3:17])=[N:8]2)[CH2:6][CH2:5][CH2:4][CH2:3]1.[S:18]1[CH:22]=[CH:21][CH:20]=[C:19]1[CH2:23][C:24](OCC)=O.Cl>C(O)C.O>[CH:2]1([N:7]2[C:11]3=[N:12][C:24]([CH2:23][C:19]4[S:18][CH:22]=[CH:21][CH:20]=4)=[N:15][C:13](=[O:14])[C:10]3=[C:9]([CH2:16][CH3:17])[NH:8]2)[CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: CCc1nn(C2CCCC2)c(N)c1C(N)=O
Reactant: CCOC(=O)Cc1cccs1
Agent: Cl
Agent: [Na]
Solvent: O
Solvent: CCO
Product: CCc1[nH]n(C2CCCC2)c2nc(Cc3cccs3)nc(=O)c1-2
Temperature: 25 °C
Yield: 40.3 %

Procedure:
Sodium (414 mg) was dissolved in ethanol (45 ml) and then 1-cyclopentyl-3-ethyl-5-amino-1H-pyrazole-4-carboxamide (2 g, 9 mmol), followed by ethyl 2-thienylacetate (3.1 g, 18 mmol) were added. The reaction mixture was refluxed overnight, cooled to room temperature and the ethanol was stripped. Water, followed by 2N HCl were added to the residue and the product was collected by filtration, and washed with water. The product was recrystallized from ethyl acetate and dried at 90° C. and 0.2 mm Hg to afford 1.19 g of 1-cyclopentyl-3-ethyl-6-(2-thienylmethyl)pyrazolo[3,4-d]pyrimidin-4-one, m.p. 173-174° C.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1([N:13]2[CH:17]=[CH:16][CH:15]=[C:14]2[C:18](=[O:23])[C:19]([Cl:22])([Cl:21])[Cl:20])[CH2:11][C:10](=[O:12])[NH:9][C:7]1=[O:8])=[O:5])[CH3:2].[Br:24]Br.C(=O)(O)[O-].[Na+]>C(Cl)(Cl)Cl>[Br:24][C:16]1[CH:15]=[C:14]([C:18](=[O:23])[C:19]([Cl:22])([Cl:20])[Cl:21])[N:13]([C:6]2([C:4]([O:3][CH2:1][CH3:2])=[O:5])[CH2:11][C:10](=[O:12])[NH:9][C:7]2=[O:8])[CH:17]=1
Reactant: BrBr
Reactant: CCOC(=O)C1(n2cccc2C(=O)C(Cl)(Cl)Cl)CC(=O)NC1=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Product: CCOC(=O)C1(n2cc(Br)cc2C(=O)C(Cl)(Cl)Cl)CC(=O)NC1=O
Reaction time: 0.5 h
Yield: 33.1 %

Procedure:
To a stirred solution of 2-ethoxycarbonyl-2-(2-trichloroacetylpyrrol-1-yl)succinimide (6.0 g) in chloroform (30 ml) was added dropwise a solution of bromine (6.9 g) in chloroform (18 ml) under ice cooling. The resulting mixture was stirred under ice cooling for 30 minutes, poured into aqueous sodium bicarbonate solution, and extracted with chloroform. The extracts were dried over sodium sulfate and concentrated under reduced pressure. The residue was chromatographed on silica gel using chloroform/methanol (2000:1) as the eluent. Fractions containing the title compound were pooled and evaporated under reduced pressure. The residue was recrystallized from ethyl acetate/n-hexane to give the title compound (2.4 g, 36.4%) as colorless crystals, mp 196°-198° C.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:7]=[C:8]([C:12](=[O:14])[CH3:13])[CH:9]=[CH:10][CH:11]=1.[CH3:15][CH:16]([CH3:32])[C:17]([NH:19][C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([CH:26]2[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]2)[CH:21]=1)=[O:18]>>[C:12]([C:8]1[CH:7]=[C:6]([CH:11]=[CH:10][CH:9]=1)[O:5][CH2:4][CH2:3][CH2:2][N:29]1[CH2:30][CH2:31][CH:26]([C:22]2[CH:21]=[C:20]([NH:19][C:17](=[O:18])[CH:16]([CH3:15])[CH3:32])[CH:25]=[CH:24][CH:23]=2)[CH2:27][CH2:28]1)(=[O:14])[CH3:13]
Reactant: CC(=O)c1cccc(OCCCCl)c1
Reactant: CC(C)C(=O)Nc1cccc(C2CCNCC2)c1
Product: CC(=O)c1cccc(OCCCN2CCC(c3cccc(NC(=O)C(C)C)c3)CC2)c1

Procedure:
Prepared by Procedure G and Scheme B1 using 1-[3-(3-chloropropoxy)phenyl]ethanone and 2-methyl-N-[3-(4-piperidinyl)phenyl]propanamide: ESMS m/e: 423.2 (M+H)+.
Reaction SMILES: [C:1]([NH:4][CH2:5][CH2:6][NH:7][C:8](=[S:11])SC)(=[O:3])[CH3:2].O.[NH2:13][NH2:14]>C(O)C>[C:1]([NH:4][CH2:5][CH2:6][NH:7][C:8](=[S:11])[NH:13][NH2:14])(=[O:3])[CH3:2]
Reactant: CSC(=S)NCCNC(C)=O
Reactant: NN
Solvent: CCO
Solvent: O
Product: CC(=O)NCCNC(=S)NN
Temperature: 4 °C

Procedure:
A solution of methyl N-(2-acetamidoethyl)-dithiocarbamate (57.7 g) and hydrazine hydrate (14.6 cc) in absolute ethanol (300 cc) is heated under reflux for 2 hours. The mixture is then cooled to 4° C. and is filtered, and the insoluble matter is dried at 30° C. under 0.05 mm Hg. (4-(2-Acetamidoethyl)-thiosemicarbazide (39.5 g) is obtained in the form of white crystals (instantaneous m.p. [Kofler]=171° C.).
Reaction SMILES: CC1(C)CCCC(C)(C)N1.C(=O)=O.[F:14][C:15]1[CH:20]=[N:19][CH:18]=[CH:17][N:16]=1.[O:21]1[CH2:26][CH2:25][C:24](=[O:27])[CH2:23][CH2:22]1>C1COCC1.CCCCCC>[F:14][C:15]1[C:20]([C:24]2([OH:27])[CH2:25][CH2:26][O:21][CH2:22][CH2:23]2)=[N:19][CH:18]=[CH:17][N:16]=1
Reactant: Fc1cnccn1
Reactant: O=C1CCOCC1
Agent: CC1(C)CCCC(C)(C)N1
Agent: O=C=O
Solvent: C1CCOC1
Solvent: CCCCCC
Product: OC1(c2nccnc2F)CCOCC1
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
A 2.5M solution of nbuli (4.49 mL, 11.22 mmol)/hexane in THF (3 mL) was first cooled to −78° C. To the cooled solution was added dropwise, 2,2,6,6-tetramethylpiperidine (2.065 mL, 12.24 mmol). The dry ice bath was then switched to a 0° C. bath. The reaction mixture was stirred for 10 min at 0° C. and then the dry ice bath was switched back to recool the reaction mixture to −78° C. To the cooled solution was added 2-fluoropyrazine (1 g, 10.20 mmol), dropwise. After 5 min of stirring at −78° C., a solution of dihydro-2H-pyran-4(3H)-one (0.937 mL, 10.20 mmol) in 0.6 mL of THF was added dropwise. The resulting mixture was allowed to gradually warm to room temperature overnight. Reaction was quenched with saturated NH4Cl and extracted with EtOAc. Purification by Biotage (0-100% EtOAc/hexane) produced product.
Reaction SMILES: [OH-].[Li+].CO.O.[F:6][C:7]1[CH:12]=[CH:11][C:10]([CH2:13][O:14][C:15]2[CH:31]=[CH:30][C:29]([CH:32]=[O:33])=[CH:28][C:16]=2[C:17]([O:19]CC2C=CC(F)=CC=2)=[O:18])=[CH:9][CH:8]=1>O1CCCC1>[F:6][C:7]1[CH:8]=[CH:9][C:10]([CH2:13][O:14][C:15]2[CH:31]=[CH:30][C:29]([CH:32]=[O:33])=[CH:28][C:16]=2[C:17]([OH:19])=[O:18])=[CH:11][CH:12]=1
Reactant: O=Cc1ccc(OCc2ccc(F)cc2)c(C(=O)OCc2ccc(F)cc2)c1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: O=Cc1ccc(OCc2ccc(F)cc2)c(C(=O)O)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Lithium hydroxide (0.75 g, 31.4 mmol), methanol (25 ml) and water (25 ml) were added to a solution of (4-fluorophenyl)methyl 2-{[(4-fluorophenyl)methyl]oxy}-5-formylbenzoate (may be prepared as described in Description 104; 4 g, 10.46 mmol) in tetrahydrofuran (100 ml). The mixture was stirred at room temperature overnight. The mixture was evaporated to half volume, diluted with water (100 ml) and acidified with 1M aqueous hydrochloric acid to adjust the pH to 1. The mixture was stirred at room temperature and the solid formed was filtered, washed with water (50 ml) and air dried under vacuum to yield the title compound as a white solid. 2.85 g.