Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: B.CSC.[C:5]([CH2:8][C:9]1[CH:10]=[C:11]([CH:15]=[CH:16][C:17]=1[Cl:18])[C:12](O)=[O:13])(O)=[O:6]>C1COCC1>[Cl:18][C:17]1[CH:16]=[CH:15][C:11]([CH2:12][OH:13])=[CH:10][C:9]=1[CH2:8][CH2:5][OH:6]
Reactant: O=C(O)Cc1cc(C(=O)O)ccc1Cl
Agent: B
Solvent: CSC
Solvent: C1CCOC1
Product: OCCc1cc(CO)ccc1Cl
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of borane-methyl sulfide complex (2M in THF, 12.0 mL) was added portionwise over 3 minutes to a suspension of 3-(carboxymethyl)-4-chlorobenzoic acid (example 75, step a) (2.06 g) in dry THF (30 mL) at room temperature. The resulting effervescing dense suspension was stirred at room temperature for 1 hour, then heated to reflux for 1 hour. The cooled mixture was quenched by the portionwise addition of methanol (10 mL) over 2 minutes. The solution was stirred at room temperature for 30 minutes and then concentrated onto silica and purified by flash chromatography on silica eluted with 5% methanol in dichloromethane to afford the subtitled compound as a white solid. Yield 0.983 g.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][N:5]=[C:4]([C:8]([NH:10][C:11]2[CH:16]=[CH:15][C:14]([S:17](=[O:24])(=[O:23])[NH:18][CH2:19][CH2:20][O:21][CH3:22])=[CH:13][C:12]=2[CH3:25])=[O:9])[CH:3]=1.C(NC(C)C)(C)C.[CH:33]1([CH2:36][NH:37][CH:38]2[CH2:43][CH2:42][CH2:41][CH2:40][CH2:39]2)[CH2:35][CH2:34]1>C(O)C>[CH:38]1([N:37]([CH2:36][CH:33]2[CH2:34][CH2:35]2)[C:2]2[N:7]=[CH:6][N:5]=[C:4]([C:8]([NH:10][C:11]3[CH:16]=[CH:15][C:14]([S:17]([NH:18][CH2:19][CH2:20][O:21][CH3:22])(=[O:24])=[O:23])=[CH:13][C:12]=3[CH3:25])=[O:9])[CH:3]=2)[CH2:39][CH2:40][CH2:41][CH2:42][CH2:43]1
Reactant: C1CCC(NCC2CC2)CC1
Reactant: COCCNS(=O)(=O)c1ccc(NC(=O)c2cc(Cl)ncn2)c(C)c1
Solvent: CC(C)NC(C)C
Solvent: CCO
Product: COCCNS(=O)(=O)c1ccc(NC(=O)c2cc(N(CC3CC3)C3CCCCC3)ncn2)c(C)c1
Temperature: 160 °C
Yield: 84.3 %

Procedure:
A solution of 6-chloro-N-(4-(N-(2-methoxyethyl)sulfamoyl)-2-methylphenyl)pyrimidine-4-carboxamide (Intermediate 38, 100 mg; 0.26 mmol) and diisopropylamine (91 mL; 0.52 mmol) in ethanol (2.5 ml) was treated with N-(cyclopropylmethyl)cyclohexanamine (54.4 mg; 0.33 mmol). The mixture was heated to 160° C. in a microwave for 1 hour and the solvent removed in vacuo. The residue was purified by column chromatography (silica) eluting with petroleum ether containing increasing amounts of EtOAc to give the title compound as a white solid (110 mg, 84%).
Reaction SMILES: [C:1]([C:3]1[S:4][C:5]2[C:11]([C:12]#[N:13])=[C:10](/[N:14]=[CH:15]/[N:16](C)C)[CH:9]=[CH:8][C:6]=2[N:7]=1)#[N:2].N[C:20]1[CH:21]=[C:22]([CH:25]=[CH:26][CH:27]=1)[C:23]#[N:24].[K+].[Br-]>C(Cl)Cl.CCOC(C)=O>[C:23]([C:22]1[CH:21]=[C:20]([NH:13][C:12]2[C:11]3[C:10](=[CH:9][CH:8]=[C:6]4[N:7]=[C:3]([C:1]#[N:2])[S:4][C:5]4=3)[N:14]=[CH:15][N:16]=2)[CH:27]=[CH:26][CH:25]=1)#[N:24]
Reactant: N#Cc1cccc(N)c1
Reactant: CN(C)/C=N/c1ccc2nc(C#N)sc2c1C#N
Agent: [Br-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: N#Cc1cccc(Nc2ncnc3ccc4nc(C#N)sc4c23)c1
Yield: 40 %

Procedure:
Prepared from VII and 3-aminobenzonitrile. Flash chromatography eluent (DCM-EtOAc, 5:5). Yield: 40%; yellow solid; mp>260° C.; IR (KBr) νmax/cm−1 3240, 3171, 3088, 2228, 1623, 1591, 1555, 1509, 1465, 1393, 1273, 1229, 1149, 969, 919, 825; 1H NMR (300 MHz, DMSO-d6) δ 8.54 (d, 1H, J=9.0 Hz), 8.43 (s, 1H), 7.74 (m, 2H), 7.55-7.53 (m, 3H); HRMS calcd for C17H9N6S (M+H+): 329.0609, found 329.0600.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[C:10]1[NH:15][C:14](=[O:16])[C:13]2=[C:17]([CH3:25])[N:18]=[C:19]([CH:20]3[CH2:24][CH2:23][CH2:22][CH2:21]3)[N:12]2[N:11]=1)[CH3:2].[S:26]([Cl:30])(=O)(=[O:28])[OH:27]>>[CH2:1]([O:3][C:4]1[CH:9]=[CH:8][C:7]([S:26]([Cl:30])(=[O:28])=[O:27])=[CH:6][C:5]=1[C:10]1[NH:15][C:14](=[O:16])[C:13]2=[C:17]([CH3:25])[N:18]=[C:19]([CH:20]3[CH2:24][CH2:23][CH2:22][CH2:21]3)[N:12]2[N:11]=1)[CH3:2]
Reactant: O=S(=O)(O)Cl
Reactant: CCOc1ccccc1-c1nn2c(C3CCCC3)nc(C)c2c(=O)[nH]1
Product: CCOc1ccc(S(=O)(=O)Cl)cc1-c1nn2c(C3CCCC3)nc(C)c2c(=O)[nH]1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
At 0° C., 7.0 g (20.7 mmol) of 2-(2-ethoxyphenyl)-5-methyl-7-cyclopentyl-3H-imidazo[5,1-f][1,2,4]-triazin-4-one (Example 15A) are added carefully to 24.1 g (207 mmol) of chlorosulphuric acid. The mixture is allowed to warm to room temperature and stirred overnight. The solution is carefully added to 200 ml of ice-water and extracted twice with dichloromethane. The combined organic phases are dried over sodium sulphate and the solvent is distilled off under reduced pressure. The sulphonyl chloride is dried under reduced pressure and reacted further to the sulphonamides without further purification.
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([NH:11][C:12]2[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[C:14]([O:20][CH3:21])[CH:13]=2)[C:5]2[N:10]=[CH:9][S:8][C:6]=2[N:7]=1.[F:22]/[C:23](/[C:35]1[CH:40]=[CH:39][CH:38]=[C:37](B2OC(C)(C)C(C)(C)O2)[CH:36]=1)=[CH:24]\[C:25]1[CH:34]=[CH:33][C:28]([C:29]([O:31][CH3:32])=[O:30])=[CH:27][CH:26]=1.C([O-])([O-])=O.[Na+].[Na+].O>O1CCOCC1.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>[CH3:21][O:20][C:14]1[CH:13]=[C:12]([NH:11][C:4]2[C:5]3[N:10]=[CH:9][S:8][C:6]=3[N:7]=[C:2]([C:39]3[CH:40]=[C:35](/[C:23](/[F:22])=[CH:24]/[C:25]4[CH:26]=[CH:27][C:28]([C:29]([O:31][CH3:32])=[O:30])=[CH:33][CH:34]=4)[CH:36]=[CH:37][CH:38]=3)[N:3]=2)[CH:17]=[CH:16][C:15]=1[O:18][CH3:19]
Reactant: COc1ccc(Nc2nc(Cl)nc3scnc23)cc1OC
Reactant: COC(=O)c1ccc(/C=C(\F)c2cccc(B3OC(C)(C)C(C)(C)O3)c2)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: COC(=O)c1ccc(/C=C(\F)c2cccc(-c3nc(Nc4ccc(OC)c(OC)c4)c4ncsc4n3)c2)cc1
Yield: 41.6 %

Procedure:
To a stirred solution of 5-chloro-N-(3,4-dimethoxyphenyl)thiazolo[5,4-d]pyrimidin-7-amine (100 mg, 0.31 mmol) and (Z)-methyl 4-(2-fluoro-2-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)vinyl)benzoate (150 mg, 0.39 mmol) in 25 mL of 1,4-dioxane were added Na2CO3 (64 mg, 0.6 mmol) and 3 mL of water at room temperature. Then the mixture was degassed with nitrogen for 15 minutes. Pd(PPh3)4 (20 mg, 0.017 mmol) was added in one portion and the reaction mixture was stirred at reflux for 18 hours under nitrogen. The solvent was evaporated and the residue was purified by silica gel chromatography (200-300 mesh, eluting with a mixture of petroleum ether and ethyl acetate=1:1) to give (Z)-methyl 4-(2-(3-(7-(3,4-dimethoxyphenylamino)thiazolo[5,4-d]pyrimidin-5-yl)phenyl)-2-fluorovinyl)benzoate (70 mg, 42%) as a yellow sold. 543 [M+H]+, tR=1.88 min.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][C:10]=1[O:11][CH3:12])[CH2:7][N:6](CC1C=CC(OC)=CC=1)[CH2:5]2.C1(OC)C=CC=CC=1>FC(F)(F)C(O)=O>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][C:10]=1[O:11][CH3:12])[CH2:7][NH:6][CH2:5]2
Reactant: COc1ccc(CN2Cc3cc(Cl)c(OC)cc3C2)cc1
Solvent: COc1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: COc1cc2c(cc1Cl)CNC2
Yield: 70.6 %

Procedure:
A solution of 5-chloro-6-methoxy-2-(4-methoxy-benzyl)-2,3-dihydro-1H-isoindole (600 mg) and anisole (0.3 ml) in trifluoroacetic acid (6 ml) was heated at 180° C. (50 W) for 40 minutes in a CEM discover microwave synthesiser. The reaction mixture was evaporated and re-evaporated with toluene. The crude material was partitioned between DCM and water, the aqueous layer washed with DCM (×3) then evaporated and re-evaporated with toluene to give 5-chloro-6-methoxy-2,3-dihydro-1H-isoindole (256 mg) as green crystals. MS: [M+H]+ 184
Reaction SMILES: [O:1]=[C:2]1[NH:6][C@H:5]([C:7]([OH:9])=O)[CH2:4][S:3]1.Cl.[CH3:11][CH:12]([C@H:18]1[CH2:23][CH2:22][C@H:21]([CH2:24][NH2:25])[CH2:20][CH2:19]1)[CH2:13][O:14][N+:15]([O-:17])=[O:16]>>[CH3:11][CH:12]([C@H:18]1[CH2:23][CH2:22][C@H:21]([CH2:24][NH:25][C:7]([C@@H:5]2[CH2:4][S:3][C:2](=[O:1])[NH:6]2)=[O:9])[CH2:20][CH2:19]1)[CH2:13][O:14][N+:15]([O-:17])=[O:16]
Reactant: CC(CO[N+](=O)[O-])[C@H]1CC[C@H](CN)CC1
Reactant: O=C1N[C@H](C(=O)O)CS1
Agent: Cl
Product: CC(CO[N+](=O)[O-])[C@H]1CC[C@H](CNC(=O)[C@@H]2CSC(=O)N2)CC1

Procedure:
91 mg of the desired-compound were obtained as a colorless oil using similar procedures to those in Example 3 by using 76.9 mg of (4R)-2-oxo-4-thiazolidinecarboxylic acid and 110 mg of trans-4-(1-methyl-2-nitroxyethyl)cyclohexylmethylamine hydrochloride.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:8]=[C:9]([Cl:13])[C:10]=1[O:11][CH3:12])[CH:6]=O.[C:14]([O:19]CC)(=[O:18])/[CH:15]=[CH:16]/[CH3:17].CC(C)([O-])C.[K+].Cl>CN1CCCC1=O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:6]=[CH:17][CH:16]=[CH:15][C:14]([OH:19])=[O:18])[CH:8]=[C:9]([Cl:13])[C:10]=1[O:11][CH3:12]
Reactant: COc1cc(C=O)cc(Cl)c1OC
Reactant: C/C=C/C(=O)OCC
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: CN1CCCC1=O
Product: COc1cc(C=CC=CC(=O)O)cc(Cl)c1OC

Procedure:
To a solution containing 10.0 g of 3,4-dimethoxy-5-chlorobenzaldehyde and 8.3 ml of ethyl crotonate in 65 ml of N-methylpyrrolidone 6.7 g of potassium tert.-butoxide was added with stirring. The solution was stirred for 0.5 h more at 20° C. and the solution was poured then to a mixture of ice and hydrochloric acid and extracted with ether. The ether extract was washed with water and extracted then with NaHCO3 -solution. The aqueous phase was acidified with hydrochloric acid and the semisolid product was separated and washed with water. Yield 7.3 g (55%).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([C:9]2[C:10](=[O:23])[C:11](=[CH:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=3)[CH2:12][C:13]=2[O:14][CH3:15])=[C:4]([CH3:24])[CH:3]=1>C(O)(=O)C.[Zn]>[Br:1][C:2]1[CH:3]=[C:4]([CH3:24])[C:5]([C:9]2[C:10](=[O:23])[CH:11]([CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=3)[CH2:12][C:13]=2[O:14][CH3:15])=[C:6]([CH3:8])[CH:7]=1
Reactant: COC1=C(c2c(C)cc(Br)cc2C)C(=O)C(=Cc2ccccn2)C1
Agent: [Zn]
Solvent: CC(=O)O
Product: COC1=C(c2c(C)cc(Br)cc2C)C(=O)C(Cc2ccccn2)C1
Temperature: 27.5 °C
Reaction time: 6.5 h

Procedure:
To a solution of 2-(4-bromo-2,6-dimethylphenyl)-3-methoxy-5-[1-pyridin-2-ylmethylidene]cyclopent-2-enone (2.8 g, 7.3 mmol) in acetic acid (30 ml) is added zinc powder (2.3 g, 36.5 mmol) at 25-30°C. The resulting suspension is stirred at 25-30°C. for 6-7 hours, then filtered through a bed of diatomaceous earth and washed with methanol (20 ml×2). The filtrate is concentrated under vacuum, water is added and the crude product is extracted with ethyl acetate (50 ml×3). The combined organic fractions are washed with distilled water, brine, dried over sodium sulfate, filtered and the filtrate concentrated in vacuo. The crude is purified by flash column chromatography to afford rac-2-(4-bromo-2,6-dimethylphenyl)-3-methoxy-5-pyridin-2-ylmethylcyclopent-2-enone.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][C@H:3]([CH2:7][OH:8])[CH2:2]1.[CH:9]1([CH:15]=O)[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].Cl>O1CCCC1.C(O)(=O)C>[CH:9]1([CH2:15][N:1]2[CH2:6][CH2:5][CH2:4][C@H:3]([CH2:7][OH:8])[CH2:2]2)[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]1
Reactant: O=CC1CCCCC1
Reactant: OC[C@H]1CCCNC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: OC[C@H]1CCCN(CC2CCCCC2)C1
Reaction time: 21 h
Yield: 59.9 %

Procedure:
To a solution of 900 mg of (3S)-3-piperidylmethanol in 60 ml of tetrahydrofuran, 1.05 g of cyclohexanecarbaldehyde, 0.54 ml of acetic acid and 2.5 g of sodium triacetoxyborohydride were successively added at room temperature by the order stated, followed by 21 hours' stirring at the same temperature. The reaction liquid was rendered acidic with 1N hydrochloric acid and washed with chloroform. The aqueous layer was rendered basic with 4N aqueous sodium hydroxide solution, followed by extraction with chloroform and drying over anhydrous sodium sulfate. Distilling the solvent off under reduced pressure, 990 mg of the title compound was obtained.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([C:20]([NH:22][C@H:23]([C:39]([NH:41][C@H:42]([C:52]([NH:54][C@@H:55]([C:57]([OH:59])=[O:58])[CH3:56])=[O:53])[CH2:43][O:44][CH2:45][C:46]1[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=1)=[O:40])[CH2:24][C:25]1[CH:30]=[CH:29][C:28]([O:31][CH2:32][C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)=[CH:27][CH:26]=1)=[O:21])[CH2:10][C:11]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[NH:13][CH:12]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:60]O>C(N(CC)CC)C>[CH3:60][O:58][C:57](=[O:59])[C@@H:55]([CH3:56])[NH:54][C:52](=[O:53])[C@H:42]([CH2:43][O:44][CH2:45][C:46]1[CH:47]=[CH:48][CH:49]=[CH:50][CH:51]=1)[NH:41][C:39](=[O:40])[C@H:23]([CH2:24][C:25]1[CH:30]=[CH:29][C:28]([O:31][CH2:32][C:33]2[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=2)=[CH:27][CH:26]=1)[NH:22][C:20](=[O:21])[C@H:9]([CH2:10][C:11]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[NH:13][CH:12]=1)[NH:8][C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7]
Reactant: C[C@@H](NC(=O)[C@H](COCc1ccccc1)NC(=O)[C@H](Cc1ccc(OCc2ccccc2)cc1)NC(=O)[C@H](Cc1c[nH]c2ccccc12)NC(=O)OC(C)(C)C)C(=O)O
Reactant: CO
Solvent: CCN(CC)CC
Product: COC(=O)[C@@H](C)NC(=O)[C@H](COCc1ccccc1)NC(=O)[C@H](Cc1ccc(OCc2ccccc2)cc1)NC(=O)[C@H](Cc1c[nH]c2ccccc12)NC(=O)OC(C)(C)C
Reaction time: 48 h

Procedure:
Nα-t-Butoxycarbonyl-L-tryptophyl-O-benzyl-L-tyrosyl-O-benzyl-L-seryl-D-alanine resin, 7.1 g., prepared in Example 1 is mixed with methanol, 600 ml., and triethylamine, 60 ml., at room temperature for 2 days. After filtration and evaporation, the crude product, 2.7 g., is chromatographed on silica gel with chloroform-methanol-water (60:30:5) to yield 1.9 g., m.p. 178°-182° C.
Reaction SMILES: [CH3:1][C@H:2]1[CH2:7][NH:6][CH2:5][C@@H:4]([CH3:8])[NH:3]1.Cl[S:10]([C:13]1[CH:14]=[CH:15][C:16]([O:22][CH2:23][CH3:24])=[C:17]([CH:21]=1)[C:18]([OH:20])=[O:19])(=[O:12])=[O:11]>O>[CH2:23]([O:22][C:16]1[CH:15]=[CH:14][C:13]([S:10]([N:6]2[CH2:5][C@@H:4]([CH3:8])[NH:3][C@@H:2]([CH3:1])[CH2:7]2)(=[O:12])=[O:11])=[CH:21][C:17]=1[C:18]([OH:20])=[O:19])[CH3:24]
Reactant: CCOc1ccc(S(=O)(=O)Cl)cc1C(=O)O
Reactant: C[C@@H]1CNC[C@H](C)N1
Solvent: O
Product: CCOc1ccc(S(=O)(=O)N2C[C@@H](C)N[C@@H](C)C2)cc1C(=O)O
Yield: 70.1 %

Procedure:
In a 250 ml three-neck flask, 52.6 g (0.23 mol) of cis-2,6-dimethylpiperazine was added to the suspension of compound (II) (53 g, 0.20 mol) in water (170 ml) at about 10° C. with stirring, at the same time the temperature of reacting mixture was kept below 20° C. The reaction was then stirred at 10° C. for another 2 hours. The precipitate was filtered, ice-water washed, dried, and refluxed in acetone for 1 hour, and purified, gave 48 g compound (III) (yield 70%) as white crystalline, m.p. 260.5-273.0° C. (Dec.). HNMR(DMSO) δ: 7.72-7.75(2H, H-4 and H-6 on benzene ring), 7.26-7.28(1H, H-3 on benzene ring), 4.12-4.17(2H, —CH2— on —OCH2CH3), 3.5-3.53(2H, —CH2— on piperazine ring), 2.89-2.92(2H, —CH— on piperazine ring), 1.80-1.86(2H, —CH2— on piperazine ring), 1.31-1.34(3H, —CH3 on —OCH2CH3), 1.0-1.04(6H, two —CH3 groups on piperazine ring).
Reaction SMILES: [OH:1][N:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[N:4]=[N:3]1.[CH2:11]([C:18]1[CH:23]=[CH:22][C:21]([C:24]2[CH:32]=[CH:31][C:27]([C:28](O)=[O:29])=[CH:26][CH:25]=2)=[CH:20][CH:19]=1)[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17].Cl.C(N=C=NCCCN(C)C)C.O>ClCCl>[CH2:11]([C:18]1[CH:23]=[CH:22][C:21]([C:24]2[CH:32]=[CH:31][C:27]([C:28]([N:4]3[C:5]4[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=4[N+:2]([O-:1])=[N:3]3)=[O:29])=[CH:26][CH:25]=2)=[CH:20][CH:19]=1)[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17]
Reactant: CCCCCCCc1ccc(-c2ccc(C(=O)O)cc2)cc1
Reactant: On1nnc2ccccc21
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Solvent: O
Product: CCCCCCCc1ccc(-c2ccc(C(=O)n3n[n+]([O-])c4ccccc43)cc2)cc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a suspension of 1-hydroxybenzotriazole (501 mg) and 4-(4-heptylphenyl)benzoic acid (1 g) in dichloromethane (30 ml) was added 1-ethyl-3-(3'-dimethylaminopropyl) carbodiimide hydrochloride (WSCD.HCl) (839 mg), and stirred for 3 hours at ambient temperature. The reaction mixture was added to water. The organic layer was separated, and dried over magnesium sulfate. The magnesium sulfate was filtered off, and the filtrate was evaporated under reduced pressure to give 1-[4-(4-heptylphenyl)benzoyl]benzotriazole 3-oxide. To a solution of The Starting Compound (2.49 g) and 1-[4-(4-heptylphenyl)benzoyl]benzotriazole 3-oxide in N,N-dimethylformamide (25 ml) was added 4-(N,N-dimethylamino)pyridine (381 mg), and stirred for 12 hours at ambient temperature. The reaction mixture was pulverized with ethyl acetate. The precipitate was collected by filtration, and dried under reduced pressure. The residue was dissolved in water, and subjected to column chromatography on ion exchange resin (DOWEX-5WX4) eluting with water. The fraction containing the object compound were combined, and subjected to column chromatography on ODSD (YMC-gel.ODS-AM.S-50) eluting with 30% acetonitrile aqueous solution. The fractions containing the object compound were combined, and evaporated under reduced pressure to remove acetonitrile. The residue was lyophilized to give The Object Compound (32) (1.99 g).
Reaction SMILES: C([O:8][N:9]1[C:14](=[O:15])[C:13]2[CH:16]=[C:17]([F:25])[C:18]([N:20]3[CH2:24][CH2:23][CH2:22][CH2:21]3)=[N:19][C:12]=2[N:11]([C:26]2[CH:31]=[CH:30][C:29]([O:32][CH3:33])=[CH:28][CH:27]=2)[C:10]1=[O:34])C1C=CC=CC=1>C1COCC1.[Pd]>[F:25][C:17]1[C:18]([N:20]2[CH2:21][CH2:22][CH2:23][CH2:24]2)=[N:19][C:12]2[N:11]([C:26]3[CH:31]=[CH:30][C:29]([O:32][CH3:33])=[CH:28][CH:27]=3)[C:10](=[O:34])[N:9]([OH:8])[C:14](=[O:15])[C:13]=2[CH:16]=1
Reactant: COc1ccc(-n2c(=O)n(OCc3ccccc3)c(=O)c3cc(F)c(N4CCCC4)nc32)cc1
Agent: [Pd]
Solvent: C1CCOC1
Product: COc1ccc(-n2c(=O)n(O)c(=O)c3cc(F)c(N4CCCC4)nc32)cc1
Yield: 86.9 %

Procedure:
Using the method of Example 56, 20% Pd/C (20 mg), 3-benzyloxy-6-fluoro-1-(4-methoxyphenyl)-7-pyrrolidin-1-yl-1H-pyrido[2,3-d]pyrimidine-2,4-dione (Example U-4, 0.16 g, 0.34 mmol) were combined in 15 mL of THF, to give 0.11 g of the title compound as a solid.
Reaction SMILES: [C:1]1([CH:7]2[CH2:12][CH2:11][CH:10]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[CH:9]=[CH:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.ClC1C=CC=C(C(OO)=[O:27])C=1.C([O-])([O-])=O.[K+].[K+]>C(Cl)Cl>[O:27]1[CH:11]2[CH:10]([C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=3)[CH2:9][CH2:8][CH:7]([C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)[CH:12]12
Reactant: C1=CC(c2ccccc2)CCC1c1ccccc1
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Product: c1ccc(C2CCC(c3ccccc3)C3OC23)cc1
Reaction time: 2 h
Yield: 60.9 %

Procedure:
3,6-Diphenylcyclohex-1-ene (50 mg, 0.21 mmol), m-chloroperbenzoic acid (55%, 200 mg, 0.64 mmol), and K2CO3 (150 mg, 1.09 mmol) were stirred in CH2Cl2 (10 mL) for 24 hours. The reaction mixture was filtered and washed with CH2Cl2 (40 mL). The filtrate and aqueous Na2S2O3 solution (10%, 10 mL) were stirred for 2 hours. The organic phase was washed with saturated NaHCO3 solution and H2O and dried over anhydrous magnesium sulfate. Preparative thin-layer chromatography (silica gel, 2 mm, developed with 10:1 hexane/EtOAc) gave 1,2-epoxy-3,6-diphenylcyclohexane (32 mg, 60% yield) as a colorless oil along with recovery of starting material (10 mg, 20%). 1,2-Epoxy-3,6-diphenylcyclohexane: 1H NMR (200 MHz, CDCl3) δ 7.20-7.45 (m, 10 H), 3.45 (s, 2 H), 3.37 (t, J=6.4 Hz, 2 H), 1.67-1.88 (m, 2 H), 1.37-1.58 (m, 2 H); 13C NMR (50 MHz), 143.2, 128.6, 128.0, 126.5, 56.2, 39.9, 25.0.
Reaction SMILES: [CH2:1]([N:8]1[CH2:12][CH2:11][C:10](=O)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CC1[N:20]=CC(COP(O)(O)=O)=C(C=O)C=1O.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>O>[CH2:1]([N:8]1[CH2:12][CH2:11][CH:10]([NH2:20])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C1CCN(Cc2ccccc2)C1
Reactant: Cc1ncc(COP(=O)(O)O)c(C=O)c1O
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: O
Product: NC1CCN(Cc2ccccc2)C1

Procedure:
In the same manner as in Example 12, a cell-dispersion solution was prepared. Into a flask in which substrates, that is, 900 mg of 1-benzyl-3-pyrrolidinone and 928.2 mg of (S)-α-phenethylamine were added in advance, 3 ml of the cell-dispersion solution, 3.7 mg of pyridoxal phosphate, and 3 mL of a 1M potassium phosphate buffer (pH 6.8) were introduced. The whole volume was adjusted to 30 mL by adding deionized water therein. This was reacted at 30° C. for 16 hours with stirring. After the reaction is completed, 1-benzyl-3-aminopyrrolidine thus produced in the reaction mixture was analyzed via HPLC with the conditions described below. This showed that 1-benzyl-3-aminopyrrolidine was produced with a conversion rate of 75.1%, and it had a (S) configuration and optical purity of 79.2% e.e.
Reaction SMILES: [C:1]([C@@H:4]1[CH2:7][C@H:6]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[C:5]1([CH3:16])[CH3:15])(=[O:3])C.[O:17]1CCOCC1>>[C:11]([O:10][C:8]([C@H:6]1[CH2:7][C@@H:4]([C:1]([OH:3])=[O:17])[C:5]1([CH3:16])[CH3:15])=[O:9])([CH3:14])([CH3:13])[CH3:12]
Reactant: C1COCCO1
Reactant: CC(=O)[C@@H]1C[C@H](C(=O)OC(C)(C)C)C1(C)C
Product: CC(C)(C)OC(=O)[C@H]1C[C@@H](C(=O)O)C1(C)C
Reaction time: 3 h
Yield: 78 %

Procedure:
A stirred solution of (1S,3R)-tert-butyl 3-acetyl-2,2-dimethylcyclobutanecarboxylate (2.4 g, 10.62 mmol) in dioxane (270 ml) aqueous NaOBr solution (about 180 ml) was added slowly at about 0° C. and stirred at the same temperature for about 3 hours then allowed to stirred at room temperature for about 4 hours (the yellow colored solution turned to white color). After completion of the reaction (monitored by TLC), the reaction mixture was washed with methyl t-butyl ether (3×150 ml), the aqueous layer was adjusted pH (2-3) with 1N HCl and the aqueous layer was extracted with EtOAc and dried over Na2SO4 and the solvent was evaporated to afford title compound as an off white liquid. Wt: 1.9 g; Yield: 78%; 1H NMR (300 MHZ, CDCl3): δ 2.82-2.67 (m, 2H), 2.57-2.50 (m, 1H), 2.04-1.98 (m, 1H), 1.42 (s, 9H), 1.34 (s, 3H), 1.05 (s, 3H); IR (KBr, cm−1): 3205, 1731, 1694, 1460, 1371, 1236, 1157, 1108, 846, 721; Mass: [M+Na]+ 251 (40%).
Reaction SMILES: C([O:4][C@H:5]([CH3:30])[CH2:6][CH2:7][CH2:8][CH2:9][N:10]1[C:19](=[O:20])[C:18]2[N:17](COCC)[C:16]([NH:25][CH2:26][CH2:27]O)=[N:15][C:14]=2[N:13]([CH3:29])[C:11]1=[O:12])(=O)C.S(Cl)([Cl:33])=O>>[OH:4][C@H:5]([CH3:30])[CH2:6][CH2:7][CH2:8][CH2:9][N:10]1[C:19](=[O:20])[C:18]2[NH:17][C:16]([NH:25][CH2:26][CH2:27][Cl:33])=[N:15][C:14]=2[N:13]([CH3:29])[C:11]1=[O:12]
Reactant: CCOCn1c(NCCO)nc2c1c(=O)n(CCCC[C@@H](C)OC(C)=O)c(=O)n2C
Reactant: O=S(Cl)Cl
Product: C[C@@H](O)CCCCn1c(=O)c2[nH]c(NCCCl)nc2n(C)c1=O
Temperature: 25 °C
Reaction time: 3 h
Yield: 69 %

Procedure:
A mixture of (R)-1-(5-acetoxyhexyl)-7-ethoxymethyl-8-(2-hydroxyethylamino)-3-methylxanthine (3.95 g, 9.3 mmol) and thionyl chloride (25 ml) was stirred at room temperature for 3 hours. After concentrating under reduced pressure to remove unreacted thionyl chloride, ethanol (100 ml) and a 1.0 M solution of hydrogen chloride in diethyl ether (10.0 ml) were added. After the mixture was stirred at 75-80° C. for 16 hours, concentrating under reduced pressure provided (R)-1-(5-hydroxyhexyl)-8-(2-chloroethylamino)-3-methylxanthine (2.2 g, 69% yield) as a white powder.