Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[F:15][C:16]1[CH:17]=[C:18]([CH:20]=[C:21]([F:24])[C:22]=1[F:23])[NH2:19].[C:25]1(=O)[CH2:29][CH2:28][CH2:27][CH2:26]1.C(=O)([O-])O.[Na+]>ClC(Cl)C.C(O)(=O)C>[CH:25]1([NH:19][C:18]2[CH:17]=[C:16]([F:15])[C:22]([F:23])=[C:21]([F:24])[CH:20]=2)[CH2:29][CH2:28][CH2:27][CH2:26]1
Reactant: Nc1cc(F)c(F)c(F)c1
Reactant: O=C1CCCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(Cl)Cl
Solvent: CC(=O)O
Product: Fc1cc(NC2CCCC2)cc(F)c1F
Reaction time: 3.5 h

Procedure:
Under ice-cooling, 11.5 g of sodium triacetoxyborohydride was added in small portions to a solution of 4.0 g of 3,4,5-trifluoroaniline and 3.6 ml cyclopentanone in 150 ml dichloroethane and 3.1 ml acetic acid, and, after rising to room temperature, stirred for 3.5 hours. Aqueous saturated sodium hydrogen carbonate was added thereto, followed by extraction with chloroform and subsequent drying over anhydrous sodium sulfate. After filtration, the solvent was evaporated under a reduced pressure, and the resulting residue was purified by silica gel column chromatography to obtain 5.4 g of N-cyclopentyl-3,4,5-trifluoroaniline.
Reaction SMILES: [F:1][C:2]1[CH:11]=[C:10](F)[C:9]([F:13])=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].[C-:14]#[N:15].[Na+]>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.CN(C=O)C.CCOC(C)=O>[C:14]([C:10]1[C:9]([F:13])=[CH:8][C:3]([C:4]([O:6][CH3:7])=[O:5])=[C:2]([F:1])[CH:11]=1)#[N:15]
Reactant: [C-]#N
Reactant: COC(=O)c1cc(F)c(F)cc1F
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COC(=O)c1cc(F)c(C#N)cc1F
Temperature: 60 °C
Reaction time: 24 h

Procedure:
Methyl 2,4,5-trifluorobenzoate (DSL Chemicals; 950.61 mg; 5 mmol; 1 eq.), sodium cyanide (306.30 mg; 6.25 mmol; 1.25 eq.) and tetrabutylammonium bromide (2 014.82 mg; 6.25 mmol; 1.25 eq.) were dissolved in DMF (10 mL). The resulting mixture was heated at 60° C. overnight. As the reaction was not complete, sodium cyanide (306.30 mg; 6.25 mmol; 1.25 eq.) was added and the mixture was stirred at 60° C. for additional 24 h. The resulting dark pink solution was diluted with EtOAc and washed with brine several times. It was dried over MgSO4, filtrated and evaporated, resulting into a sticky dark red oil, which was purified by flash chromatography (SiO2 100 g, EtOAc/c-hex 1:9 until 1:1), affording the title product. 1H NMR (DMSO-d6, 300 MHz) δ 7.77 (dd, J=5.45, 8.41 Hz, 1H), 7.42 (dd, J=4.99, 8.88 Hz, 1H), 3.96 (s, 3H). LC/MS (Method A): 463.2 (M−H)−; 465.2 (M+H)+. HPLC (Method A) Rt 3.63 min (Purity: 99.9%).
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([S:11]([NH:14][C:15]2[CH:20]=[CH:19][C:18](I)=[CH:17][C:16]=2[C:22]2[N:26]([CH3:27])[C:25]([CH2:28][CH3:29])=[N:24][N:23]=2)(=[O:13])=[O:12])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].C(Cl)Cl.C(N(CC)CC)C.CN([CH:43]=[O:44])C.[CH3:45][OH:46]>>[CH3:45][O:46][C:43](=[O:44])[C:18]1[CH:19]=[CH:20][C:15]([NH:14][S:11]([C:8]2[CH:9]=[CH:10][C:5]([C:1]([CH3:3])([CH3:4])[CH3:2])=[CH:6][CH:7]=2)(=[O:12])=[O:13])=[C:16]([C:22]2[N:26]([CH3:27])[C:25]([CH2:28][CH3:29])=[N:24][N:23]=2)[CH:17]=1
Reactant: CO
Reactant: CCc1nnc(-c2cc(I)ccc2NS(=O)(=O)c2ccc(C(C)(C)C)cc2)n1C
Reactant: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCc1nnc(-c2cc(C(=O)OC)ccc2NS(=O)(=O)c2ccc(C(C)(C)C)cc2)n1C
Temperature: 80 °C
Reaction time: 8 h

Procedure:
A 15 mL pressure vessel was charged with 4-tert-butyl-N-[4-iodo-2-(5-ethyl-4-methyl-4H-[1,2,4]triazol-3-yl)-phenyl]-benzenesulfonamide (prepared according to general procedure C, 551 mg, 1.05 mmol), [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) complex with CH2Cl2 (1:1) (86 mg, 0.105 mmol), triethylamine (290 μL, 2.1 mmol), and DMF/MeOH (4:1) (5 mL). The vessel was placed under an atmosphere of CO (50 p.s.i.), heated to 80° C., and stirred overnight. The following day, the volatiles were removed in vacuo, the residue dissolved in EtOAc, and the organics washed twice with 1 M HCl. The aqueous solution was then extracted three times with EtOAc. The EtOAc extractions were then pooled together and washed with brine. The organic solvent was then removed and the resultant residue was purified by silica gel chromatography to afford 4-(4-tert-butyl-benzenesulfonylamino)-3-(5-ethyl-4-methyl-4H-[1,2,4]triazol-3-yl)-benzoic acid methyl ester as a yellow foam: MS (ES) M+H expected 457.2, found 457.1.
Reaction SMILES: [NH2:1][C@H:2]1[CH2:8][CH2:7][C@H:6]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH2:5][N:4]([CH2:15][C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[C:3]1=[O:23].Br[CH:25]([CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][NH:38][C:39]([O:41][C:42]([CH3:45])([CH3:44])[CH3:43])=[O:40])[C:26]([O:28][CH2:29][CH3:30])=[O:27].C1CCCCC1>C(OCC)(=O)C>[C:42]([O:41][C:39]([NH:38][CH2:37][CH2:36][CH2:35][CH2:34][CH2:33][CH2:32][CH2:31][CH:25]([NH:1][C@H:2]1[CH2:8][CH2:7][C@H:6]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH2:5][N:4]([CH2:15][C:16]([O:18][C:19]([CH3:20])([CH3:22])[CH3:21])=[O:17])[C:3]1=[O:23])[C:26]([O:28][CH2:29][CH3:30])=[O:27])=[O:40])([CH3:45])([CH3:44])[CH3:43]
Reactant: CCOC(=O)C(Br)CCCCCCCNC(=O)OC(C)(C)C
Reactant: CC(C)(C)OC(=O)CN1C[C@@H](c2ccccc2)CC[C@H](N)C1=O
Solvent: C1CCCCC1
Solvent: CCOC(C)=O
Product: CCOC(=O)C(CCCCCCCNC(=O)OC(C)(C)C)N[C@H]1CC[C@H](c2ccccc2)CN(CC(=O)OC(C)(C)C)C1=O

Procedure:
1.2 g of t-butyl rel-α-[3(S)-amino-2-oxo-6(R)-phenylperhydroazepin-1-yl]acetate was treated with 2.15 g of ethyl 2-bromo-9-t-butoxycarbonylaminononanoate prepared as described in Preparation 4) in a similar manner to that described in Example 4, to afford a reaction product, which was subjected to column chromatography through silica gel using a mixture of cyclohexane and ethyl acetate in the ratio of 1:1 by volume as the eluent.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:28])[NH:4][CH:5]([C:9]([N:11]1[CH2:15][CH2:14][CH2:13][CH:12]1[C:16]1[NH:17][C:18]([C:21]2[CH:26]=[CH:25][C:24](Br)=[CH:23][CH:22]=2)=[CH:19][N:20]=1)=[O:10])[CH:6]([CH3:8])[CH3:7].[CH3:29][O:30][C:31](=[O:57])[NH:32][CH:33]([C:37]([N:39]1[CH2:43][CH2:42][CH2:41][CH:40]1[C:44]1[NH:45][C:46]([C:49]2[CH:54]=[CH:53][C:52]([C:55]#[CH:56])=[CH:51][CH:50]=2)=[CH:47][N:48]=1)=[O:38])[CH:34]([CH3:36])[CH3:35].C(N(CC)CC)C.N#N>CN(C=O)C.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.[Cu]I>[CH3:1][O:2][C:3](=[O:28])[NH:4][CH:5]([C:9]([N:11]1[CH2:15][CH2:14][CH2:13][CH:12]1[C:16]1[NH:17][C:18]([C:21]2[CH:26]=[CH:25][C:24]([C:56]#[C:55][C:52]3[CH:53]=[CH:54][C:49]([C:46]4[NH:45][C:44]([CH:40]5[CH2:41][CH2:42][CH2:43][N:39]5[C:37](=[O:38])[CH:33]([NH:32][C:31]([O:30][CH3:29])=[O:57])[CH:34]([CH3:36])[CH3:35])=[N:48][CH:47]=4)=[CH:50][CH:51]=3)=[CH:23][CH:22]=2)=[CH:19][N:20]=1)=[O:10])[CH:6]([CH3:8])[CH3:7]
Reactant: C#Cc1ccc(-c2cnc(C3CCCN3C(=O)C(NC(=O)OC)C(C)C)[nH]2)cc1
Reactant: COC(=O)NC(C(=O)N1CCCC1c1ncc(-c2ccc(Br)cc2)[nH]1)C(C)C
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: N#N
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COC(=O)NC(C(=O)N1CCCC1c1ncc(-c2ccc(C#Cc3ccc(-c4cnc(C5CCCN5C(=O)C(NC(=O)OC)C(C)C)[nH]4)cc3)cc2)[nH]1)C(C)C
Temperature: 80 °C
Yield: 47.4 %

Procedure:
A solution of (1-{2-[5-(4-bromo-phenyl)-1H-imidazol-2-yl]-pyrrolidine-1-carbonyl}-2-methyl-propyl)-carbamic acid methyl ester (947 mg, 2.11 mmol), (1-{2-[5-(4-ethynyl-phenyl)-1H-imidazol-2-yl]-pyrrolidine-1-carbonyl}-2-methyl-propyl)-carbamic acid methyl ester (1.00 g, 2.53 mmol), and triethylamine (882 μl, 6.33 mmol) in DMF (13 mL) was degassed with N2 gas for 20 minutes. To the degassed solution was added Pd(PPh3)4 (244 mg, 0.21 mmol) and CuI (40 mg, 0.21 mmol). The pressure flask was sealed then heated at 80° C. overnight. After cooling to room temperature, the reaction was concentrated then diluted with EtOAc and washed with water. The aqueous phase was back-extracted two times then the organic phases were combined and dried over Na2SO4. After concentration, the crude material was purified by silica gel chromatography (0-20% MeOH-EtOAc gradient) then reverse phase preparative HPLC (10-85% MeCN—H2O; 0.1% formic acid modifier) to afford [1-(2-{5-[4-(4-{2-[1-(2-methoxycarbonylamino-3-methyl-butyryl)-pyrrolidin-2-yl]-3H-imidazol-4-yl}-phenylethynyl)-phenyl]-1H-imidazol-2-yl}-pyrrolidine-1-carbonyl)-2-methyl-propyl]-carbamic acid methyl ester (600 mg, 1.00 mmol, 47% yield). 1H-NMR: 400 MHz, (DMSO-d6) δ: 11.84 (s, 2H), 7.75 (d, 4H), (7.56 (s, 2H), 7.47 (d, 4H), 7.28 (d, 2H), 5.06 (m, 2H), 4.06-4.04 (m, 2H), 3.80 (m, 4H), 3.54 (s, 6H), 2.14 (m, 4H) 2.00-1.90 (m, 6H), 0.89 (d, 6H), 0.84 (d, 6H). LCMS-ESI+: calc'd for C42H51N8O6: 763.4 (M+H+). Found: 763.4 (M+H+).
Reaction SMILES: [C:1]([OH:7])(=O)[CH2:2][CH2:3][C:4]#[CH:5].[CH3:8][N:9]1[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]1.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C>CN(C=O)C>[CH3:8][N:9]1[CH2:14][CH2:13][N:12]([C:1](=[O:7])[CH2:2][CH2:3][C:4]#[CH:5])[CH2:11][CH2:10]1
Reactant: CN1CCNCC1
Reactant: C#CCCC(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: C#CCCC(=O)N1CCN(C)CC1
Yield: 28.3 %

Procedure:
4-Pentynoic acid (1.03 g) and N-methylpiperazine (1.0 g) was dissolved in 30 mL of DMF, 1.6 g of HOBt was added to the solution at ice temperature under stirring. After the mixture was stirred at same temperature for 15 minutes, additionally 2.3 g of WSC was added, and the solution was stirred at room temperature overnight. The DMF was removed under reduced pressure from the reaction mixture, then water was added to the residue and the mixture was extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous magnesium sulfate, and then the solvent was removed. The residue was purified by chromatography on silica gel (methylene chloride-methanol-triethylamine 600:20:1) to give 510 mg of 1-(4-methylpiperazin-1-yl)pent-4-yn-1-one as a colorless oil.
Reaction SMILES: [F:1][C:2]([F:31])([F:30])[C:3]1[CH:4]=[C:5]([C@@H:9]([NH:13][C:14]([C:16]2[CH:17]=[N:18][N:19]([C:23]3[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][CH:24]=3)[C:20]=2[CH2:21]Br)=[O:15])[CH2:10][CH2:11][CH3:12])[CH:6]=[CH:7][CH:8]=1.[NH3:32].CO>>[F:1][C:2]([F:31])([F:30])[C:3]1[CH:4]=[C:5]([C@@H:9]([NH:13][C:14]([C:16]2[CH:17]=[N:18][N:19]([C:23]3[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][CH:24]=3)[C:20]=2[CH2:21][NH2:32])=[O:15])[CH2:10][CH2:11][CH3:12])[CH:6]=[CH:7][CH:8]=1
Reactant: N
Reactant: CCC[C@H](NC(=O)c1cnn(-c2ccc(Cl)cc2)c1CBr)c1cccc(C(F)(F)F)c1
Solvent: CO
Product: CCC[C@H](NC(=O)c1cnn(-c2ccc(Cl)cc2)c1CN)c1cccc(C(F)(F)F)c1
Yield: 61 %

Procedure:
5-Bromomethyl-1-(4-chloro-phenyl)-1H-pyrazole-4-carboxylic acid [(S)-1-(3-trifluoromethyl-phenyl)-butyl]-amide (47 mg, 0.091 mmol) is treated with ammonia in methanol (7.0 N solution, 2.0 mL, 14 mmol) and the resultant solution is heated in a microwave at 120° C. for 3 min. The crude reaction mixture is concentrated in vacuo and purified by preparative reverse phase HPLC (eluted with 10 to 90% CH3CN/H2O and 0.1% TFA as additive) to afford 5-aminomethyl-1-(4-chloro-phenyl)-1H-pyrazole-4-carboxylic acid [(S)-1-(3-trifluoromethyl-phenyl)-butyl]-amide (25 mg, 61%).
Reaction SMILES: [Li+:1].[C:2]1([S:8]([O-:11])(=[O:10])=[O:9])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([Li:16])CCC.[C:17]1(=[O:22])[CH2:21][CH2:20][CH2:19][CH2:18]1.C1COCC1>>[Li+:16].[Li+:1].[OH:22][C:17]1([C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[S:8]([O-:11])(=[O:10])=[O:9])[CH2:21][CH2:20][CH2:19][CH2:18]1.[OH:22][C:17]1([C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[S:8]([O-:11])(=[O:10])=[O:9])[CH2:21][CH2:20][CH2:19][CH2:18]1
Reactant: O=C1CCCC1
Reactant: O=S(=O)([O-])c1ccccc1
Reactant: [Li]CCCC
Agent: [Li+]
Solvent: C1CCOC1
Product: O=S(=O)([O-])c1ccccc1C1(O)CCCC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 80169.4 %

Procedure:
A mixture of benzenesulfonic acid lithium salt (32.8 g, 0.20 mmol) and 500 ml THF was stirred in an ice bath while 138 ml (0.22 mol) of n-butyllithium solution (1.6M in hexane) was added. After stirring at room temperature for 1 hour the mixture was recooled to 0° and cyclopentanone (16.8 g, 0.20 mmol) was added dropwise; the reaction mixture was allowed to warm to ambient temperature and stirred for 24 hours. The precipitated product was collected by filtration and dried in a vacuum oven to yield 39.8 g of 2-(1-hydroxycyclopent-1-yl)benzenesulfonic acid dilithium salt.
Reaction SMILES: CS(C)=O.[OH2:5].[Br:6][C:7]1[C:8]([F:34])=[CH:9][C:10]([O:30][CH2:31][O:32][CH3:33])=[C:11]([CH:29]=1)[CH:12]([C:15]1[C:20]([O:21][CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[CH:19][CH:18]=[CH:17][N:16]=1)C#N>CN(C=O)C>[Br:6][C:7]1[C:8]([F:34])=[CH:9][C:10]([O:30][CH2:31][O:32][CH3:33])=[C:11]([CH:29]=1)[C:12]([C:15]1[C:20]([O:21][CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[CH:19][CH:18]=[CH:17][N:16]=1)=[O:5]
Reactant: COCOc1cc(F)c(Br)cc1C(C#N)c1ncccc1OCc1ccccc1
Reactant: O
Solvent: CN(C)C=O
Solvent: CS(C)=O
Product: COCOc1cc(F)c(Br)cc1C(=O)c1ncccc1OCc1ccccc1

Procedure:
By using DMSO/water (10:1), in place of DMF in Reference Example 40, 2-(5-bromo-α-cyano-4-fluoro-2-methoxymethoxybenzyl)-3-benzyloxypyridine (2.53 g) was subjected to oxidative decyanation to afford 2-(5-bromo-4-fluoro-2-methoxymethoxybenzoyl)-3-benzyloxypyridine (2.46 g) (Compound F-9). Physico-chemical properties and spectrum data are shown in Table 22 and Table 23.
Reaction SMILES: Cl.[CH3:2][CH2:3][C:4]1[CH:5]=[CH:6][C:7]([CH2:10][CH2:11][O:12][C:13]2[CH:14]=[CH:15][C:16]([CH2:19][CH:20]3[S:26][C:24](=[O:25])[NH:23][C:21]3=[O:22])=[CH:17][CH:18]=2)=[N:8][CH:9]=1.C(=O)(O)[O-:28].[Na+].ClC1C=CC=C(C(OO)=O)C=1>CN(C)C=O.O.C(Cl)Cl>[O:25]=[C:24]1[NH:23][C:21](=[O:22])[CH:20]([CH2:19][C:16]2[CH:17]=[CH:18][C:13]([O:12][CH2:11][CH2:10][C:7]3[CH:6]=[CH:5][C:4]([CH2:3][CH3:2])=[CH:9][N+:8]=3[O-:28])=[CH:14][CH:15]=2)[S:26]1
Reactant: CCc1ccc(CCOc2ccc(CC3SC(=O)NC3=O)cc2)nc1
Reactant: O=C([O-])O
Agent: Cl
Agent: O=C(OO)c1cccc(Cl)c1
Agent: [Na+]
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: O
Product: CCc1ccc(CCOc2ccc(CC3SC(=O)NC3=O)cc2)[n+]([O-])c1
Temperature: 10 °C
Reaction time: 48 h
Yield: 46.2 %

Procedure:
The hydrochloric acid salt of pioglitazone (3 g, 7.64 mmol) was dissolved in N,N-dimethylformamide (DMF, 50 mL) and neutralized by addition of an aqueous solution of sodium bicarbonate (NaHCO3, 0.641 g, 7.64 mmol in 6 mL water). The reaction mixture was diluted with water and the white solid was filtered off. It was rinsed with water and dried under vacuum. The resulting solid was resuspended in dichloromethane (CH2Cl2), and meta-chloroperbenzoic acid (m-CPBA, 50% by weight, 2.64 g, 7.64 mmol) was added to the mixture while maintaining the temperature at about 10° C. The reaction mixture was stirred at room temperature for 2 days, and then one more equivalent of m-CPBA (2.64 g, 7.64 mmol) was added. The reaction mixture was stirred for 2 h, then diluted with CH2Cl2 (50 mL). The organic layer was washed with 10% Na2S2O3 in water/water (2:1 v:v), then with 1:1 v:v 10% NaHCO3 in water/water (1:1 v:v). The resulting organic mixture was dried over sodium sulfate, filtered and solvent evaporated to give the crude N-oxide, which was further purified by flash chromatography on silica gel (gradient elution: CH2Cl2/10% MeOH in CH2Cl2 from 9:1 to 1:1). Fractions containing the pure N-oxide were pooled and evaporated to give the title compound (1.313 g, 3.53 mmol, 46.2% yield). LC/MS: 373 (M+1)
Reaction SMILES: [Br:1][C:2]1[C:3]([O:9][CH2:10][CH:11]2[CH2:13][CH2:12]2)=[CH:4][C:5]([OH:8])=[N:6][CH:7]=1.[H-].[Na+].[CH3:16][S:17][CH2:18]Cl>CN(C=O)C>[Br:1][C:2]1[C:3]([O:9][CH2:10][CH:11]2[CH2:12][CH2:13]2)=[CH:4][C:5](=[O:8])[N:6]([CH2:16][S:17][CH3:18])[CH:7]=1
Reactant: Oc1cc(OCC2CC2)c(Br)cn1
Reactant: CSCCl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CSCn1cc(Br)c(OCC2CC2)cc1=O
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 49.9 %

Procedure:
To a solution of the title compound from Step 2 (330 mg, 1.35 mmol) in DMF (5 mL) was added NaH (40 mg, 2 mmol, 60% in mineral oil) at 0° C. The mixture was stirred at 0° C. for 30 minutes. Then, chloromethyl methyl sulfide (131 mg, 1.35 mmol) was added. The mixture was warmed to room temperature and stirred for 5 hours. The mixture was quenched with saturated aqueous NH4Cl (30 mL) and extracted with EA (10 mL×3). The combined organic layers were washed with saturated brine (20 mL×2), dried over anhydrous Na2SO4, filtered and concentrated under vacuum. The residue was purified by column chromatography on silica gel (PE:EA=3:1) to afford the title compound (205 mg, 50%) as yellow oil. 1H NMR (CDCl3, 400 MHz) δ 7.60 (s, 1H), 5.86 (s, 1H), 4.96 (s, 1H), 3.84 (d, J=6.8 Hz, 2H), 2.17 (s, 3H), 1.32-1.25 (m, 1H), 0.70-0.67 (m, 2H), 0.41-0.39 (m, 2H).
Reaction SMILES: [N+:1]([C:4]1[CH:42]=[CH:41][C:7]([O:8][CH2:9][CH2:10][CH2:11][O:12][C:13]2[CH:37]=[CH:36][C:16]3[C:17](=[O:35])[CH2:18][C:19]([CH2:28][CH2:29][C:30]([O:32]CC)=[O:31])([CH2:21][CH2:22][C:23]([O:25]CC)=[O:24])[O:20][C:15]=3[C:14]=2[CH2:38][CH2:39][CH3:40])=[CH:6][CH:5]=1)([O-:3])=[O:2].ClC1C=CC(OCCCOC2C=CC3C(=O)CC(CCC(OCC)=O)(CCC(OCC)=O)OC=3C=2CCC)=CC=1>C(OCC)(=O)C.CCCCCC>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]([O:8][CH2:9][CH2:10][CH2:11][O:12][C:13]2[CH:37]=[CH:36][C:16]3[C:17](=[O:35])[CH2:18][C:19]([CH2:28][CH2:29][C:30]([OH:32])=[O:31])([CH2:21][CH2:22][C:23]([OH:25])=[O:24])[O:20][C:15]=3[C:14]=2[CH2:38][CH2:39][CH3:40])=[CH:41][CH:42]=1)([O-:3])=[O:2]
Reactant: CCCc1c(OCCCOc2ccc([N+](=O)[O-])cc2)ccc2c1OC(CCC(=O)OCC)(CCC(=O)OCC)CC2=O
Agent: CCCc1c(OCCCOc2ccc(Cl)cc2)ccc2c1OC(CCC(=O)OCC)(CCC(=O)OCC)CC2=O
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: CCCc1c(OCCCOc2ccc([N+](=O)[O-])cc2)ccc2c1OC(CCC(=O)O)(CCC(=O)O)CC2=O
Yield: 46.2 %

Procedure:
The title compound was prepared by the method of Example 22 substituting the title product of Example 38 (110 mg) for the title product of Example 21. Trituration with ethyl acetate/hexane produced 46 mg of the titled compound as a solid, m.p. 171°-172° C.
Reaction SMILES: [O:1]([CH:9]1[CH2:13][C:12](=[O:14])[C:11]([S:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])=[CH:10]1)[Si](C(C)(C)C)(C)C.C(=O)(O)[O-].[Na+]>C(O)(=O)C.O.O1CCCC1>[OH:1][CH:9]1[CH2:13][C:12](=[O:14])[C:11]([S:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])=[CH:10]1
Reactant: CCCCCCCCSC1=CC(O[Si](C)(C)C(C)(C)C)CC1=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Solvent: C1CCOC1
Product: CCCCCCCCSC1=CC(O)CC1=O
Yield: 78.5 %

Procedure:
4-t-Butyldimethylsiloxy-2-n-octylthiocyclopent-2-en-1-one (90 mg) was dissolved in 5 ml of a mixture of acetic acid, water and tetrahydrofuran in a ratio of 3:1:1, and reacted at room temperature for 48 hours. The reaction mixture was neutralized with sodium bicarbonate, and extracted with ethyl acetate. The extract was treated by conventional methods, and chromatographed on a thin layer plate with cyclohexane/ethyl acetate (4/6) to afford 48 mg of 4-hydroxy-2-n-octylthiocyclopent-2-en-1-one in a yield of 84% showing a single spot. The resulting product had the following characteristics.
Reaction SMILES: [C:1]1([NH:7][C:8]2[N:13]=[C:12](O)[CH:11]=[C:10]([CH:15]3[CH2:17][CH2:16]3)[N:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.P(Cl)(Cl)([Cl:20])=O.Cl.[OH-].[Na+]>O>[C:1]1([NH:7][C:8]2[N:13]=[C:12]([Cl:20])[CH:11]=[C:10]([CH:15]3[CH2:17][CH2:16]3)[N:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: Oc1cc(C2CC2)nc(Nc2ccccc2)n1
Reactant: O=P(Cl)(Cl)Cl
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: Clc1cc(C2CC2)nc(Nc2ccccc2)n1
Temperature: 25 °C

Procedure:
19.6 g (86.3 mmol) of 2-phenylamino-4-hydroxy-6-cyclopropyl-pyrimidine are added to 50 ml (0.55 mol) of phosphorus oxychloride at 75° C. in the course of one hour, while stirring, and the mixture is then refluxed for one hour. When the evolution of hydrogen chloride has ended, the reaction mixture is cooled to room temperature and poured into 200 ml of water, while stirring vigorously, the temperature being kept at about 50° C. by addition of ice. The approximately 400 ml of the pale brown suspension is brought to pH 7 by slow dropwise addition of 220 ml of 30% aqueous sodium hydroxide solution and is extracted three times with 150 ml of ethyl acetate each time. The combined extracts are washed twice with 100 ml of water each time, dried over sodium sulfate and filtered and the solvent is evaporated. The 20.7 of pale brown powder are treated with 400 ml of diethyl ether and the undissolved material is filtered off. After evaporation of the diethyl ether, the residue is recrystallized from diisopropyl ether. The yellowish crystals melt at 127°-128° C. Yield 17.7 g (72.1 mmol; 83.5% of theory).
Reaction SMILES: [OH:1][C:2]1[CH:9]=[C:8]([CH3:10])[CH:7]=[C:6]([CH3:11])[C:3]=1[CH:4]=[O:5].C(N(C(C)C)CC)(C)C.[CH3:21][O:22][CH2:23]Cl.O>ClCCl>[CH3:21][O:22][CH2:23][O:1][C:2]1[CH:9]=[C:8]([CH3:10])[CH:7]=[C:6]([CH3:11])[C:3]=1[CH:4]=[O:5]
Reactant: Cc1cc(C)c(C=O)c(O)c1
Reactant: COCCl
Solvent: ClCCl
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: COCOc1cc(C)cc(C)c1C=O
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a solution of 2-hydroxy-4,6-dimethylbenzaldehyde (0.75 g) and diisopropylethylamine (1.4 mL) in dichloromethane (20 mL) was added chloromethyl methyl ether (0.57 mL), and the mixture was stirred at room temperature for 24 hours. Water was added to the reaction mixture, and the mixture was extracted with diethyl ether. The organic layer was washed with brine and water and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure, and the residue was purified by column chromatography on silica gel (eluent: hexane/ethyl acetate=20/1) to give 2-(methoxymethyloxy)-4,6-dimethylbenzaldehyde (0.57 g).
Reaction SMILES: [N:1]1([C:11]2[CH:20]=[CH:19][C:14]([C:15]([O:17][CH3:18])=[O:16])=[CH:13][CH:12]=2)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[NH:4][CH2:3][CH2:2]1.ClCCl.ClC(Cl)(O[C:28](=[O:34])OC(Cl)(Cl)Cl)Cl.Cl.Cl.[NH:38]1[CH2:42][CH2:41][CH:40]([C:43]2[CH:44]=[N:45][NH:46][CH:47]=2)[CH2:39]1>C(N(CC)CC)C>[NH:45]1[CH:44]=[C:43]([CH:40]2[CH2:41][CH2:42][N:38]([C:28]([N:4]3[C:5]4[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=4)[N:1]([C:11]4[CH:20]=[CH:19][C:14]([C:15]([O:17][CH3:18])=[O:16])=[CH:13][CH:12]=4)[CH2:2][CH2:3]3)=[O:34])[CH2:39]2)[CH:47]=[N:46]1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: c1n[nH]cc1C1CCNC1
Reactant: COC(=O)c1ccc(N2CCNc3ccccc32)cc1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)c1ccc(N2CCN(C(=O)N3CCC(c4cn[nH]c4)C3)c3ccccc32)cc1
Temperature: 4 °C
Reaction time: 4 h
Yield: 242.7 %

Procedure:
2.7 g of methyl 4-(3,4-dihydroquinoxalin-1(2H)-yl)benzoate and 50 ml of dichloromethane are introduced into a three-necked flask equipped with a magnetic stirrer and placed under an inert atmosphere. After cooling to 4° C., 4.2 ml of triethylamine and 1.19 g of triphosgene are successively added. The reaction medium is stirred at ambient temperature for 4 h. 2.11 g of 4-(pyrrolidin-3-yl)-1H-pyrazole dihydrochloride and 1.4 ml of triethylamine are then introduced and the mixture is stirred at ambient temperature for 18 h. The reaction medium is washed with a saturated aqueous sodium hydrogencarbonate solution; the organic phase is dried over sodium sulfate and concentrated under reduced pressure. The residue is chromatographed on silica gel eluted with a gradient of methanol from 1.5% to 3% in dichloromethane. 4.2 g of methyl 4-[4-{[3-(1H-pyrazol-4-yl)pyrrolidin-1-yl]carbonyl}-3,4-dihydroquinoxalin-1(2H)-yl]benzoate are obtained.