Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][CH:3]=1.[C:9]1([SH:15])[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>>[C:5]1([CH3:8])[CH:6]=[CH:7][CH:2]=[CH:3][C:4]=1[C:12]1[CH:13]=[CH:14][C:9]([SH:15])=[CH:10][CH:11]=1
Reactant: Cc1ccc(I)cc1
Reactant: Sc1ccccc1
Product: Cc1ccccc1-c1ccc(S)cc1

Procedure:
The general procedure was used to convert 4-iodotoluene and thiophenol to the title product. Purification by flash chromatography (hexane as the eluent) gave the analytically pure product as a clear oil (379 mg, 94% yield). 1H NMR (300 MHz, CDCl3) δ 7.22–7.08 (m, 7H; Ha, Ha′, Hc, Hc′, Hd, Hd′, He) 7.04–7.00 (d, J=7.91, 2H; Hb, Hb′), 2.25 (s, 3H; methyl protons). 13C NMR (75 MHz, CDCl3) δ 137.54 (C4), 137.09 (C1′), 132.24 (C2, C6), 131.24 (C1), 130.03 (C3, C5), 129.72 (C2′, C6′), 128.99 (C3′, C5′), 126.35 (C4′), 21.09 (C7). Anal. Calcd. for C13H12S: C, 77.95; H, 6.04; S, 16.01; Found C, 78.00; H, 6.06; S, 15.88.
Reaction SMILES: C([O:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][C:16]1[C:21](=[O:22])[C:20]([O:23][CH3:24])=[C:19]([O:25][CH3:26])[C:18](=[O:27])[C:17]=1[CH3:28])(=O)C.Cl.C(=O)(O)[O-].[Na+]>CO>[OH:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][C:16]1[C:21](=[O:22])[C:20]([O:23][CH3:24])=[C:19]([O:25][CH3:26])[C:18](=[O:27])[C:17]=1[CH3:28]
Reactant: COC1=C(OC)C(=O)C(CCCCCCCCCCCOC(C)=O)=C(C)C1=O
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Product: COC1=C(OC)C(=O)C(CCCCCCCCCCCO)=C(C)C1=O
Reaction time: 12 h
Yield: 95.9 %

Procedure:
To a solution (200 ml) of 6-(11-acetoxyundecyl)-2,3-dimethoxy-5-methyl-1,4-benzoquinone (4.2 g) in methanol is added concentrated hydrochloric acid (0.1 ml), and the mixture is allowed to stand at room temperature for 12 hours. To the reaction mixture is added sodium bicarbonate (0.2 g) and the solvent is distilled off. The product is dissolved in dichloromethane and the insoluble matter is filtered off. Removal of dichloromethane by distillation gives crude crystals. Recrystallization from hexane-ether (3:1) yields orange-yellow needles of 6-(11-hydroxyundecyl)-2,3-dimethoxy-5-methyl-1,4-benzoquinone (I, n=11) (3.6 g) m.p. 57° C.
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][C:9]2[C:8]([CH:12]=[O:13])=[C:7]([OH:14])[CH:6]=[CH:5][C:4]=2[N:3]=1.C(C1C(O)=CC=C2C=1OC(=O)C([C:28]1[CH:44]=[CH:43][C:31]([C:32]([NH:34][CH2:35][CH2:36][N:37]3[CH2:42][CH2:41]OC[CH2:38]3)=[O:33])=[CH:30][CH:29]=1)=C2C)=O.C([O-])([O-])=O.[K+].[K+]>CC(O)C.O>[OH:14][C:7]1[CH:6]=[CH:5][C:4]2[N:3]=[C:2]([C:28]3[CH:29]=[CH:30][C:31]([C:32]([N:34]4[CH2:35][CH2:36][N:37]([CH3:38])[CH2:42][CH2:41]4)=[O:33])=[CH:43][CH:44]=3)[CH:11]=[CH:10][C:9]=2[C:8]=1[CH:12]=[O:13]
Reactant: O=Cc1c(O)ccc2nc(Cl)ccc12
Reactant: Cc1c(-c2ccc(C(=O)NCCN3CCOCC3)cc2)c(=O)oc2c(C=O)c(O)ccc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC(C)O
Product: CN1CCN(C(=O)c2ccc(-c3ccc4c(C=O)c(O)ccc4n3)cc2)CC1

Procedure:
A mixture of 2-chloro-6-hydroxyquinolin-5-carbaldehyde (3) (104 mg, 0.5 mmol), 4-(4-methylpiperazine-1-carbonyl)phenylboronic acid (4) (198 mg, 0.7 mmol) and K2CO3 (174 mg, 1.25 mmol) in a mixture of i-PrOH and water (6 mL 10:1) was purged with Argon for five minutes in a microwave vessel. A tablet of PdOAc2(Sphos)4 (Aldrich, Cat. No. 694088) was added under an Argon atmosphere then the vessel was sealed and irradiated for 45 min at 165° C. Upon cooling, the reaction mixture was filtered through a silica plug using MeOH. The solution was evaporated and purified by Flash chromatography using 0-5% MeOH in CH2Cl2. The product was recrystallized from CH2Cl2/hexanes to afford the title compound. MS (ESI): 376 (M+H)+. 1H NMR (δ, DMSO (2.5 ppm)): 10.74 (s, 1H), 9.44 8.25, 7.21 and 7.49 (4d, 4×1H), 8.29 and 7.54 (2d, 2×2H), 3.64, 3.38, 2.41 and 2.33 (4 broad s, 4×2H), 2.23 (s, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]([OH:30])[CH:9]([CH2:15][C:16]2[CH:21]=[CH:20][C:19]([CH2:22][C:23]([F:29])([F:28])[C:24]([F:27])([F:26])[F:25])=[CH:18][CH:17]=2)[C:10]([O:12]CC)=[O:11])[CH:5]=[CH:6][CH:7]=1.[OH-].[Na+]>O1CCCC1CCO>[Cl:1][C:2]1[CH:3]=[C:4]([CH:8]([OH:30])[CH:9]([CH2:15][C:16]2[CH:21]=[CH:20][C:19]([CH2:22][C:23]([F:28])([F:29])[C:24]([F:26])([F:27])[F:25])=[CH:18][CH:17]=2)[C:10]([OH:12])=[O:11])[CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)C(Cc1ccc(CC(F)(F)C(F)(F)F)cc1)C(O)c1cccc(Cl)c1
Agent: OCCC1CCCO1
Agent: [Na+]
Agent: [OH-]
Product: O=C(O)C(Cc1ccc(CC(F)(F)C(F)(F)F)cc1)C(O)c1cccc(Cl)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 79.1 %

Procedure:
To a solution of ethyl (2RS,3RS)-3-(3-chlorophenyl)-3-hydroxy-2-[4-(2,2,3,3,3-pentafluoropropyl)benzyl]propionate (3.84 g, 8.52 mmol) in tetrahydrofuran-ethanol (20 ml—20 ml) was added 1N sodium hydroxide (17 ml, 17 mmol) at room temperature, and the mixture was stirred overnight at room temperature. After completion of the reaction, the organic solvent was evaporated under reduced pressure, and the aqueous layer was acidified with 1N hydrochloric acid and extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was recrystallized from hexane-ethyl acetate to give (2RS,3RS)-3-(3-chlorophenyl)-3-hydroxy-2-[4-(2,2,3,3,3-pentafluoropropyl)benzyl]propionic acid (2.85 g, 79%) as colorless crystals.
Reaction SMILES: [CH2:1]([C:11]1[N:12]=[N:13][N:14]([CH2:16][C:17]([O:19]CC)=[O:18])[N:15]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10].C(C1N=NN(C(C2C=CC=CC=2)C(OCC)=O)N=1)CCCCCCCCC>>[CH2:1]([C:11]1[N:12]=[N:13][N:14]([CH2:16][C:17]([OH:19])=[O:18])[N:15]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10]
Reactant: CCCCCCCCCCc1nnn(CC(=O)OCC)n1
Agent: CCCCCCCCCCc1nnn(C(C(=O)OCC)c2ccccc2)n1
Product: CCCCCCCCCCc1nnn(CC(=O)O)n1

Procedure:
When in the general procedure of Example 79 an appropriate amount of ethyl 5-decyl-2H-tetrazole-2-acetate was substituted for ethyl (±)-5-decyl-α-phenyl-2H-tetrazole-2-acetate, the title compound was obtained, mp 83°-86° C.
Reaction SMILES: [CH:1]([CH:4]1[CH:8]2[C:9]3[C:14]([CH:5]1[CH2:6][CH2:7]2)=[CH:13][CH:12]=[CH:11][C:10]=3[NH2:15])([CH3:3])[CH3:2].C[Al](C)C.[F:20][C:21]([F:33])([F:32])[C:22]1[C:23]([C:28](OC)=[O:29])=[N:24][CH:25]=[CH:26][N:27]=1.Cl>ClCCl>[CH:1]([CH:4]1[CH:8]2[C:9]3[C:14]([CH:5]1[CH2:6][CH2:7]2)=[CH:13][CH:12]=[CH:11][C:10]=3[NH:15][C:28]([C:23]1[C:22]([C:21]([F:32])([F:20])[F:33])=[N:27][CH:26]=[CH:25][N:24]=1)=[O:29])([CH3:3])[CH3:2]
Reactant: COC(=O)c1nccnc1C(F)(F)F
Reactant: CC(C)C1C2CCC1c1c(N)cccc12
Agent: C[Al](C)C
Agent: Cl
Solvent: ClCCl
Product: CC(C)C1C2CCC1c1c(NC(=O)c3nccnc3C(F)(F)F)cccc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 80.4 %

Procedure:
To a 1-ml vial containing 9-isopropyl-1,2,3,4-tetrahydro-1,4-methano-naphthalen-5-ylamine (6) (0.1 g, 0.497 mmol) and DCM (Volume: 2 mL) was added a 2.0 M solution of trimethylaluminum (0.017 g, 0.243 mmol). After evolution of gas ceased, methyl 3-(trifluoromethyl)pyrazine-2-carboxylate (8) (0.113 g, 0.546 mmol) was added as a solution in dichloromethane (0.5 ml) and the mixture was stirred at room temperature overnight. The reaction mixture was poured into 2N HCl (5 ml) and after bubbling ceased, was extracted with dichloromethane (2×5 ml) and was passed through a Biotage phase separator. The organic extracts were combined and the solvent was removed. The residue was loaded onto a silica column and was eluted using a ethyl acetate/hexanes gradient to afford the title compound (0.15 g, 80%) as a white solid with 4:1 syn:anti product: mp 173-177° C.; 1H NMR (600 MHz, CDCl3) δ 9.33 (s, 1H), 8.90 (d, J=2.2 Hz, 1H), 8.86 (d, J=2.3 Hz, 1H), 7.97 (d, J=8.4 Hz, 1H), 7.20-7.14 (m, 1H), 7.06 (d, J=7.2 Hz, 1H), 3.40 (s, 1H), 3.28 (s, 1H), 2.02-2.00 (m, 2H), 1.65 (d, J=10.0 Hz, 1H), 1.32-1.18 (m, 2H), 1.05-0.98 (m, 1H), 0.84 (d, J=6.6 Hz, 6H); ESIMS m/z 376.3 ([M+H]+), m/z 374.4 ([M−H])−).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([Br:8])=[CH:4][C:3]=1[C:9]([F:12])([F:11])[F:10].[C:13](OC(=O)C)(=[O:15])[CH3:14]>>[C:13]([NH:1][C:2]1[CH:7]=[CH:6][C:5]([Br:8])=[CH:4][C:3]=1[C:9]([F:12])([F:10])[F:11])(=[O:15])[CH3:14]
Reactant: Nc1ccc(Br)cc1C(F)(F)F
Reactant: CC(=O)OC(C)=O
Product: CC(=O)Nc1ccc(Br)cc1C(F)(F)F
Yield: 99.7 %

Procedure:
A solution of 2-amino-5-bromobenzotrifluoride (1.623 g, 6.76 mmol, Aldrich) in acetic anhydride (10 mL) was stirred at room temperature for 12 h to produce a white needle precipitate. It was filtered to give 1.840 g (99.7%) of title compound. Mp: 140°-2° C., 1HNMR (CDCl3): δ2.212 (s, 3H); 7.358 (s, 1H); 7.659 (d, 1H, J=8.7 Hz); 7.726 (d, 1H, J=1.8 Hz); 8.118 (d, 1H, J=8.4 Hz).
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]2[CH:5]=[CH:6][CH:7]=[C:8]([C:11]([OH:13])=[O:12])[C:9]=2[CH:10]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:20](Br)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.O>CN(C)C=O.C(OCC)(=O)C>[CH2:20]([O:12][C:11]([C:8]1[C:9]2[CH:10]=[C:2]([CH3:1])[NH:3][C:4]=2[CH:5]=[CH:6][CH:7]=1)=[O:13])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: BrCc1ccccc1
Reactant: Cc1cc2c(C(=O)O)cccc2[nH]1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CCOC(C)=O
Product: Cc1cc2c(C(=O)OCc3ccccc3)cccc2[nH]1
Temperature: 80 °C
Reaction time: 2 h

Procedure:
To a solution of 2-methylindole-4-carboxylic acid (690 mg; prepared in Reference Example 10) in N,N-dimethylformamide (10 ml) was added anhydrous potassium carbonate (815 mg) and benzyl bromide (0.7 ml) at room temperature, and the mixture was stirred at 80° C. for 2 hours. To the reaction solution was added water and ethyl acetate, and then extracted. The aqueous layer was extracted with ethyl acetate. The combined organic layer was washed with water and a saturated aqueous solution of sodium chloride, successively, dried and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (hexane—ethyl acetate) to give the title compound (610 mg) having the following physical data.
Reaction SMILES: [C:1]([S:26]([NH:29][CH2:30][CH3:31])(=[O:28])=[O:27])([C:4]([C:7]([C:10]([C:13]([C:16]([C:19]([C:22]([F:25])([F:24])[F:23])([F:21])[F:20])([F:18])[F:17])([F:15])[F:14])([F:12])[F:11])([F:9])[F:8])([F:6])[F:5])([F:3])[F:2].C(N(CC)CC)C.C1C2NC3C(=CC=CC=3)SC=2C=CC=1.[C:53]([O:57][CH2:58][CH3:59])(=[O:56])[CH:54]=[CH2:55]>C1(C)C=CC=CC=1>[C:1]([S:26]([N:29]([CH2:55][CH2:54][C:53]([O:57][CH2:58][CH3:59])=[O:56])[CH2:30][CH3:31])(=[O:27])=[O:28])([C:4]([C:7]([C:10]([C:13]([C:16]([C:19]([C:22]([F:24])([F:25])[F:23])([F:21])[F:20])([F:18])[F:17])([F:15])[F:14])([F:12])[F:11])([F:9])[F:8])([F:6])[F:5])([F:3])[F:2]
Reactant: CCNS(=O)(=O)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F
Reactant: C=CC(=O)OCC
Agent: c1ccc2c(c1)Nc1ccccc1S2
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: CCOC(=O)CCN(CC)S(=O)(=O)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F
Temperature: 97 °C
Yield: 97 %

Procedure:
In a 1-L, three-necked flask, fitted with a condenser, stirrer, and thermometer were placed 263 g (0.5 mole) of C8F17SO2N(C2H5)H, 15 g of triethylamine, 3 g of phenothiazine, 150 g toluene and 90 g (0.9 mole) of ethyl acrylate. The reaction mixture was stirred and heated at reflux (about 97° C.) for 16 hours to yield the known adduct C8F17SO2N(C2H5)C2H4COOC2H5 in 97% yield as shown by H-NMR analysis. The adduct was isolated by stripping off the toluene solvent, triethyl amine and excess ethyl acrylate under water aspirator pressure.
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][C:3]=1[S:10][CH3:11].Cl.[N:13]([O-])=O.[Na+].[Sn](Cl)Cl>C(O)C>[NH:1]([C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][C:3]=1[S:10][CH3:11])[NH2:13]
Reactant: O=N[O-]
Reactant: CSc1cc(C#N)ccc1N
Agent: Cl
Agent: Cl[Sn]Cl
Agent: [Na+]
Solvent: CCO
Product: CSc1cc(C#N)ccc1NN
Yield: 74.4 %

Procedure:
To a solution of 4-amino-3-(methylthio)benzonitrile (71.1 mg) and 5N aqueous hydrochloric acid (2.0 ml)/ethanol (0.5 ml) was added under ice cooling sodium nitrite (32.5 mg) and the resulting mixture was stirred for one and a half hours. To the reaction mixture was added tin(II) chloride (101.4 mg) and the resulting mixture was stirred at 0° C. for two and a half hours. The reaction mixture was filtered, and the mother liquor was basified (pH=about 10) with potassium carbonate and extracted with chloroform (30 ml) three times, and the organic layer was dried over sodium sulfate and then concentrated under reduced pressure to afford 4-hydrazinyl-3-(methylthio)benzonitrile (57.7 mg).
Reaction SMILES: [CH:1]1([O:6][C:7]2[CH:8]=[C:9]([CH:13]=[CH:14][C:15]=2[O:16][CH3:17])[C:10](O)=[O:11])[CH2:5][CH2:4][CH2:3][CH2:2]1.S(Cl)[Cl:19]>C1(C)C=CC=CC=1>[CH:1]1([O:6][C:7]2[CH:8]=[C:9]([CH:13]=[CH:14][C:15]=2[O:16][CH3:17])[C:10]([Cl:19])=[O:11])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: COc1ccc(C(=O)O)cc1OC1CCCC1
Reactant: ClSCl
Solvent: Cc1ccccc1
Product: COc1ccc(C(=O)Cl)cc1OC1CCCC1
Reaction time: 5 h
Yield: 98 %

Procedure:
54 g of 3-cyclopentyloxy-4-methoxybenzoic acid was added to 30 ml of thiochloride and was stirred for 5 hours. 50 ml of toluene was added to the reaction solution and was concentrated under reduced pressure to obtain 58 g of the dense brown title compound (yield: 98%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:13]=[C:12]([CH2:14]O)[S:11][N:10]=2)=[CH:5][CH:4]=1.P(Br)(Br)[Br:17].O>C1(C)C=CC=CC=1>[Br:17][CH2:14][C:12]1[S:11][N:10]=[C:9]([C:6]2[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=2)[N:13]=1
Reactant: BrP(Br)Br
Reactant: COc1ccc(-c2nsc(CO)n2)cc1
Solvent: Cc1ccccc1
Solvent: O
Product: COc1ccc(-c2nsc(CBr)n2)cc1
Temperature: 120 °C
Yield: 58 %

Procedure:
To a solution of [3-(4-methoxyphenyl)-[1,2,4]thiadiazol-5-yl]-methanol (0.07 g, 0.29 mmol) in toluene (10 ml) was added PBr3 (0.041 ml, 0.43 mmol) and the resulting reaction mixture was refluxed at 120° C. for 15 min. After the completion of the reaction (TLC monitoring), the reaction mixture was cooled to 0° C., added water (50 ml) and extracted with ethyl acetate (3×50 ml). The combined organics was washed with saturated NaHCO3 solution, dried over Na2SO4, filtered and concentrated under vacuum to get the desired product (0.048 g, 53%).
Reaction SMILES: [CH3:1][N:2]([CH3:13])[C:3]1[CH:8]=[C:7]([CH3:9])[C:6]([N+:10]([O-])=O)=[CH:5][N:4]=1>C(O)C.[Pd]>[CH3:13][N:2]([CH3:1])[C:3]1[CH:8]=[C:7]([CH3:9])[C:6]([NH2:10])=[CH:5][N:4]=1
Reactant: Cc1cc(N(C)C)ncc1[N+](=O)[O-]
Agent: [Pd]
Solvent: CCO
Product: Cc1cc(N(C)C)ncc1N
Temperature: 25 °C
Reaction time: 48 h
Yield: 119.9 %

Procedure:
To a solution of N,N,4-trimethyl-5-nitropyridin-2-amine (15.7 g, 86.6 mmol) in ethanol (200 ml) was added 10% palladium on carbon (50% wet, 1.57 g), and the mixture was purged with hydrogen and stirred under balloon pressure hydrogen at room temperature for 2 days. The catalyst was removed by filtration, and the filtrate was concentrated in vacuo to give the title compound as a brown solid (15.7 g), which was used next reaction without purification.
Reaction SMILES: Cl[C:2]1[C:7]([CH3:8])=[CH:6][CH:5]=[CH:4][C:3]=1[CH3:9].[CH2:10]([NH2:16])[CH2:11][CH2:12][CH2:13][CH2:14][CH3:15].CC(C)([O-])C.[Na+]>C1(C)C=CC=CC=1.CC([O-])=O.CC([O-])=O.[Pd+2]>[CH3:9][C:3]1[CH:4]=[CH:5][CH:6]=[C:7]([CH3:8])[C:2]=1[NH:16][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH3:15]
Reactant: Cc1cccc(C)c1Cl
Reactant: CCCCCCN
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)(C)[O-]
Solvent: Cc1ccccc1
Product: CCCCCCNc1c(C)cccc1C
Yield: 97.4 %

Procedure:
According to the general procedure B, 2-Chloro-m-xylene (70 mg, 0.50 mmol) reacted with n-hexylamine (80 μl, 0.60 mmol) using 2 mol % of Pd(OAc)2, 4 mol % of Ph5FcP(t-Bu)2, and sodium tert-butoxide (58 mg, 0.60 mmol) in toluene (1.5 ml) at 100° C. to give the title compound (100 mg, 97%) as a colorless oil: 1H-NMR (400 MHz, CDCl3): δ 7.02 (d, 2H, J=7.2 Hz), 6.83 (t, 1H, J=7.2 Hz), 3.00 (t, 2H, J=7.2 and 7.6 Hz), 3.0 (bs, 1H), 2.32 (s, 6H), 1.61 (m, 2H), 1.45-1.31 (m, 6H), 0.93 (t, 3H, J=5.6 and 7.2 Hz). 13C{1H}-NMR (100 MHz, CDCl3): δ 146.37, 129.05, 128.75, 121.52, 48.69, 31.73, 31.14, 26.83, 22.62, 18.54, 14.03. GC/MS(EI): m/z 205 (M+).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C@@H:11]([N:14]=[N+]=[N-])[C@H:10]([OH:17])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]>C(O)C.[Pd]>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C@@H:11]([NH2:14])[C@H:10]([OH:17])[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CC[C@@H](N=[N+]=[N-])[C@H](O)C1
Agent: [Pd]
Solvent: CCO
Product: CC(C)(C)OC(=O)N1CC[C@@H](N)[C@H](O)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 103.2 %

Procedure:
A solution of (3R*,4R*)-4-azido-3-hydroxy-piperidine-1-carboxylic acid tert-butyl ester (2.96 g, 12.23 mmol) in ethanol (50 mL) was flushed out with nitrogen. Palladium (10 wt % on activated carbon) (˜300 mg) was added and the mixture flushed out with hydrogen and then stirred under a hydrogen balloon at room temperature overnight. The reaction mixture was filtered through celite and the filtrate evaporated to give (3R*,4R*)-4-amino-3-hydroxy-piperidine-1-carboxylic acid tert-butyl ester (2.73 g).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:11])[C:7]=1[C@@H:8]([OH:10])[CH3:9].C(N(CC)CC)C.[CH3:19][S:20](Cl)(=[O:22])=[O:21]>ClCCl>[CH3:19][S:20]([O:10][C@H:8]([C:7]1[C:2]([Cl:1])=[CH:3][N:4]=[CH:5][C:6]=1[Cl:11])[CH3:9])(=[O:22])=[O:21]
Reactant: CS(=O)(=O)Cl
Reactant: C[C@H](O)c1c(Cl)cncc1Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C[C@H](OS(C)(=O)=O)c1c(Cl)cncc1Cl
Temperature: 25 °C
Reaction time: 4 h

Procedure:
Dissolve (S)-1-(3,5-dichloropyridin-4-yl)ethanol (5.02 g, 26.14 mmol) in dichloromethane (DCM, 100 mL) and cool the flask in an ice bath. Add triethylamine (TEA, 3.5 mL, 25.11 mmol) followed by the dropwise addition of methanesulfonyl chloride (2.2 mL, 28.42 mmol). Remove the ice bath and allow the reaction to warm to RT. After 4 hours, quench the reaction with water (100 mL) and separate layers. Extract the aqueous layer with DCM (50 mL) followed by 20% isopropyl alcohol (IPA)/chloroform (50 mL). Combine the organic extracts, dry over anhydrous sodium sulfate, filter and concentrate in vacuo. Yield: 7.15 g, (100%). MS (ES) m/z 270 [M+1]+.
Reaction SMILES: [BH4-].[Na+].[C:3]([C:6]1[CH:11]=[CH:10][C:9]([NH:12][C:13](=[O:29])[C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([S:20]([N:23]3[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]3)(=[O:22])=[O:21])[CH:15]=2)=[CH:8][CH:7]=1)(=[O:5])[CH3:4].[Cl-].[NH4+]>C(O)C>[OH:5][CH:3]([C:6]1[CH:7]=[CH:8][C:9]([NH:12][C:13](=[O:29])[C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([S:20]([N:23]3[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28]3)(=[O:21])=[O:22])[CH:15]=2)=[CH:10][CH:11]=1)[CH3:4]
Reactant: CC(=O)c1ccc(NC(=O)c2cccc(S(=O)(=O)N3CCCCC3)c2)cc1
Agent: [BH4-]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCO
Product: CC(O)c1ccc(NC(=O)c2cccc(S(=O)(=O)N3CCCCC3)c2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 98.5 %

Procedure:
Sodium borohydride (8.8 mg) was added to an ethanol (2.0 mL) solution of the compound (30.0 mg) obtained in Example 92, and stirred overnight at room temperature. Aqueous saturated ammonium chloride solution was added to the reaction liquid, extracted three times with ethyl acetate, and dried with sodium sulfate. The drying agent was removed through filtration, and the solvent was evaporated off under reduced pressure. The residue was purified through silica gel column chromatography (ethyl acetate/hexane=from 0% to 80%, gradient) to give the entitled compound (29.7 mg, 98%) as a white solid.
Reaction SMILES: Cl[C:2]1[S:3][CH:4]=[CH:5][C:6]=1[N+:7]([O-:9])=[O:8].C(N(CC)C(C)C)(C)C.[CH2:19]([SH:26])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.O>CS(C)=O.C(OCC)(=O)C>[CH2:19]([S:26][C:2]1[S:3][CH:4]=[CH:5][C:6]=1[N+:7]([O-:9])=[O:8])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: SCc1ccccc1
Reactant: O=[N+]([O-])c1ccsc1Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: CCOC(C)=O
Product: O=[N+]([O-])c1ccsc1SCc1ccccc1
Temperature: 80 °C
Yield: 97 %

Procedure:
A mixture of 2-chloro-3-nitrothiophene (1.00 g, 6.11 mmol), N,N-diisopropylethylamine (2.1 mL, 12.22 mmol) and benzyl mercaptan (0.8 mL, 6.72 mmol) in dimethyl sulfoxide (5 mL) was placed in a sealed tube. The reaction mixture was heated at 80° C. for 1 hour, cooled to room temperature and water (10 mL) was added. The mixture was diluted with ethyl acetate (50 mL) and the organic phase was washed with brine, dried over magnesium sulfate, concentrated in vacuo and dried in vacuo to give 97% yield of the title compound.
Reaction SMILES: [CH2:1]([O:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[CH2:22]O)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14].C(#N)C.P(Br)(Br)[Br:28]>N1C=CC=CC=1>[Br:28][CH2:22][C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=1[O:15][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14]
Reactant: CCCCCCCCCCCCCCOc1ccccc1CO
Reactant: BrP(Br)Br
Solvent: c1ccncc1
Solvent: CC#N
Product: CCCCCCCCCCCCCCOc1ccccc1CBr
Temperature: 0 °C

Procedure:
The title compound is prepared by the procedure of Example 20 using 2.5 g of product from Example 21, 10 ml acetonitrile, 2.11 g of phosphorus tribromide and 0.339 g of pyridine. The reaction is cooled for 10 minutes at 0° C., followed by stirring at room temperature for i hour. The product, 2.58 g, is obtained as cream crystals.
Reaction SMILES: Br.Cl[C:3]1[CH:8]=[CH:7][C:6]([CH2:9][C@@H:10]2[CH2:14][NH:13][C@H:12]([C:15]([OH:17])=[O:16])[CH2:11]2)=[CH:5][CH:4]=1.ClC1C=CC(CC2CN(C(=O)C(C)CC(OC)=O)[C@H](C(O)=O)C2)=CC=1>>[C:6]1([CH2:9][CH:10]2[CH2:14][NH:13][C@H:12]([C:15]([OH:17])=[O:16])[CH2:11]2)[CH:5]=[CH:4][CH:3]=[CH:8][CH:7]=1
Reactant: O=C(O)[C@@H]1C[C@H](Cc2ccc(Cl)cc2)CN1
Agent: Br
Agent: COC(=O)CC(C)C(=O)N1CC(Cc2ccc(Cl)cc2)C[C@H]1C(=O)O
Product: O=C(O)[C@@H]1CC(Cc2ccccc2)CN1

Procedure:
Treatment of this material according to the procedures of Example 21 (c) and (d) yields the corresponding 4-(phenylmethyl)-L-proline product.
Reaction SMILES: [CH2:1]([N:4]1[C:12]2[C:11](=[O:13])[N:10]([CH3:14])[C:9](=[O:15])[N:8]([CH3:16])[C:7]=2[N:6]=[C:5]1Cl)[CH:2]=[CH2:3].[C:18]([O:22][C:23]([N:25]1[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]1)=[O:24])([CH3:21])([CH3:20])[CH3:19].N12CCCN=C1CCCCC2>CN1CCCC1=O>[C:18]([O:22][C:23]([N:25]1[CH2:30][CH2:29][N:28]([C:5]2[N:4]([CH2:1][CH:2]=[CH2:3])[C:12]3[C:11](=[O:13])[N:10]([CH3:14])[C:9](=[O:15])[N:8]([CH3:16])[C:7]=3[N:6]=2)[CH2:27][CH2:26]1)=[O:24])([CH3:21])([CH3:19])[CH3:20]
Reactant: C=CCn1c(Cl)nc2c1c(=O)n(C)c(=O)n2C
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Solvent: CN1CCCC1=O
Solvent: C1CCC2=NCCCN2CC1
Product: C=CCn1c(N2CCN(C(=O)OC(C)(C)C)CC2)nc2c1c(=O)n(C)c(=O)n2C
Temperature: 140 °C
Reaction time: 2 h
Yield: 94.4 %

Procedure:
A mixture of 7-allyl-8-chloro-1,3-dimethyl-3,7-dihydropurine-2,6-dione (1.0 g), piperazine-1-carboxylic acid tert-butyl ester (1.1 g), 1,8-diazabicyclo[5,4,0]undec-7-ene (DBU) (0.59 ml), and 1-methylpyrrolidin-2-one (2 ml) were stirred under nitrogen atmosphere in an oil bath at 140° C. for 2 hours. The reaction mixture was extracted with ethyl acetate and water. The organic layer was washed with water followed by saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography with 10–20% (20% 2-propanol/ethyl acetate)/hexane to give 1.5 g of the title compound.