Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [SH:1][C:2]1[S:3][C:4]([SH:7])=[N:5][N:6]=1.[CH3:8][C:9]1[CH:14]2[C:15]([CH3:17])([CH3:16])[CH:12]([CH2:13]2)[CH2:11][CH:10]=1.[C:18]([O:29][CH2:30][CH2:31][CH2:32][CH3:33])(=[O:28])/[CH:19]=[CH:20]\[C:21]([O:23][CH2:24][CH2:25][CH2:26][CH3:27])=[O:22].C(=O)([O-])[O-].[Na+].[Na+]>>[CH:14]12[CH2:13][CH:12]([C:15]1([CH3:17])[CH3:16])[CH2:11][CH2:10][C:9]2([S:1][C:2]1[S:3][C:4]([S:7][CH:19]([C:18]([O:29][CH2:30][CH2:31][CH2:32][CH3:33])=[O:28])[CH2:20][C:21]([O:23][CH2:24][CH2:25][CH2:26][CH3:27])=[O:22])=[N:5][N:6]=1)[CH3:8]
Reactant: CCCCOC(=O)/C=C\C(=O)OCCCC
Reactant: CC1=CCC2CC1C2(C)C
Reactant: Sc1nnc(S)s1
Agent: O=C([O-])[O-]
Agent: [Na+]
Product: CCCCOC(=O)CC(Sc1nnc(SC2(C)CCC3CC2C3(C)C)s1)C(=O)OCCCC
Temperature: 100 °C

Procedure:
2,5-Dimercapto-1,3,4-thiadiazole (35.0 g, 0.23 mol) was charged into a reaction flask along with alpha-pinene (33.85 g, 0.24 mol). The reaction was heated to 100° C. for 1 hour and then cautiously heated to 120° C. The reaction exothermed and was maintained at 155° C. for 20 min. Dibutyl maleate (53.5 g, 0.55 mol) was added and the reaction was maintained at 155° C. for 3 hours. The reaction product was then cooled, charged with sodium carbonate (about 1 g) and stirred. The product was filtered using a filter aid.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH:8]([F:10])[F:9])[CH:3]=1.C([Sn](CCCC)(CCCC)[C:16]([O:18]CC)=[CH2:17])CCC.Cl>C1(C)C=CC=CC=1.C(OCC)(=O)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[F:9][CH:8]([F:10])[C:4]1[CH:3]=[C:2]([C:16](=[O:18])[CH3:17])[CH:7]=[CH:6][CH:5]=1
Reactant: C=C(OCC)[Sn](CCCC)(CCCC)CCCC
Reactant: FC(F)c1cccc(Br)c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: CC(=O)c1cccc(C(F)F)c1
Temperature: 100 °C
Reaction time: 1 h
Yield: 97.9 %

Procedure:
A mixture of 1-bromo-3-(difluoromethyl)benzene (0.72 g, 3.48 mmol), tributyl(1-ethoxyvinyl)tin (1.38 g, 3.83 mmol), dichlorobis(triphenylphosphine)-palladium(II) (0.24 g, 0.35 mmol) in toluene (12 mL) is heated at 100° C. under nitrogen atmosphere for 16 hours. After cooling to room temperature, 2M hydrochloric acid (12 mL) is added to the mixture. Then the resulting mixture is stirred at room temperature for 1 hour. The mixture is diluted with ethyl acetate (100 mL) and washed with water (100 mL). The organic layer is dried over sodium sulfate, and concentrated under reduced pressure. The residue is purified by column chromatography on silica-gel eluting with n-hexane/ethyl acetate (30:1) to give 0.58 g (98% yield) of the title compound as colorless oil.
Reaction SMILES: [C:1](Cl)(Cl)=[O:2].[NH2:5][C:6]1[S:7][C:8]2[CH:14]=[CH:13][C:12]([C:15]([F:18])([F:17])[F:16])=[CH:11][C:9]=2[N:10]=1>C(OCC)(=O)C>[F:18][C:15]([F:16])([F:17])[C:12]1[CH:13]=[CH:14][C:8]2[S:7][C:6]([N:5]=[C:1]=[O:2])=[N:10][C:9]=2[CH:11]=1
Reactant: O=C(Cl)Cl
Reactant: Nc1nc2cc(C(F)(F)F)ccc2s1
Solvent: CCOC(C)=O
Product: O=C=Nc1nc2cc(C(F)(F)F)ccc2s1

Procedure:
A saturated solution of phosgene in ethyl acetate (200 ml) is charged into a glass reaction vessel equipped with a mechanical stirrer, thermometer and reflux condenser. 2-Amino-5-trifluoromethylbenzothiazole (0.1 mole) is added with stirring. After the addition is completed, the reaction mixture is heated at reflux for a period of about 1 hour. After this time the mixture is cooled, and the solid product formed is recovered by filtration. The solid is then dried to yield the desired product 5-trifluoromethylbenzothiazol-2-yl isocyanate dimer.
Reaction SMILES: [CH3:1][C:2]1[N:6]([CH2:7][CH:8]([OH:10])[CH3:9])[N:5]=[C:4]([N+:11]([O-:13])=[O:12])[CH:3]=1.C(N(CC)CC)C.CN(C1C=CC=CN=1)C.[C:30](OC(=O)C)(=[O:32])[CH3:31]>C(Cl)Cl.O>[CH3:9][CH:8]([O:10][C:30](=[O:32])[CH3:31])[CH2:7][N:6]1[C:2]([CH3:1])=[CH:3][C:4]([N+:11]([O-:13])=[O:12])=[N:5]1
Reactant: CC(=O)OC(C)=O
Reactant: Cc1cc([N+](=O)[O-])nn1CC(C)O
Agent: CN(C)c1ccccn1
Solvent: O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)OC(C)Cn1nc([N+](=O)[O-])cc1C
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 64.5 %

Procedure:
A solution of 1-(5-Methyl-3-Nitro-Pyrazol-1-Yl)-Propan-2-ol (440 Mg, 2.5 Mmol) in methylene chloride at 25° C. was treated with triethylamine (1.1 mL, 7.7 mmol), catalytic dimethylaminopyridine and acetic anhydride (0.29 mL, 3.0 mmol). The reaction was stirred at 25° C. for 1.5 h. At this time, the reaction was poured into water and was extracted into methylene chloride. The organics were concentrated in vacuo to afford acetic acid 1-methyl-2-(5-methyl-3-nitro-pyrazol-1-yl)-ethyl ester (440 mg, 75%) as a white solid which was used without further purification; ES+-HRMS m/e calcd for C9H13N3O4 [M+Na+] 250.0798, found 250.0798.
Reaction SMILES: [H-].[Na+].[CH2:3]([NH:12][C:13]1[C:21]2[C:16](=[CH:17][C:18]([Cl:23])=[CH:19][C:20]=2[Cl:22])[N:15]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[C:14]=1[C:31]([O:33][CH2:34][CH3:35])=[O:32])C(C1C=CC=CC=1)=O.[CH2:36](I)[CH3:37].Cl.CN(C)[CH:42]=[O:43]>>[CH2:36]([CH2:37][CH2:3][NH:12][C:13]1[C:21]2[C:16](=[CH:17][C:18]([Cl:23])=[CH:19][C:20]=2[Cl:22])[N:15]([C:24]([O:26][C:27]([CH3:30])([CH3:28])[CH3:29])=[O:25])[C:14]=1[C:31]([O:33][CH2:34][CH3:35])=[O:32])[C:42]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[O:43]
Reactant: CN(C)C=O
Reactant: CCI
Reactant: CCOC(=O)c1c(NCC(=O)c2ccccc2)c2c(Cl)cc(Cl)cc2n1C(=O)OC(C)(C)C
Agent: Cl
Agent: [H-]
Agent: [Na+]
Product: CCOC(=O)c1c(NCCCC(=O)c2ccccc2)c2c(Cl)cc(Cl)cc2n1C(=O)OC(C)(C)C
Temperature: -10 °C
Reaction time: 0.5 h

Procedure:
Suspend sodium hydride (52 mg of a 60% dispersion, 1.73 mmol) in anhydrous dimethylformamide and cool to -10° C. Add, by dropwise addition, a solution of 3-[(phenacyl)amino]-2-carbethoxy-4,6-dichloro-1-tert-butyloxycarbonyl-indole (0.75 g, 1.57 mmol) in dimethylformamide. Stir under a nitrogen atmosphere for 30 minutes. Add ethyl iodide (0.27 g, 1.73 mmol) and stir at -10° C. for 5 hours. Pour into 1N hydrochloric acid (100 mL) and extract into ethyl acetate. Separate the organic phase and dry (MgSO4). Evaporate the solvent in vacuo and purify by flash chromatography (4:1 methylene chloride/ethyl acetate and recrystallize (ethyl acetate/hexane) to give the title compound; mp 110°-11° C.
Reaction SMILES: [Br:1][CH2:2][C:3]1[CH:4]=[C:5]([NH:9][C:10](=[O:33])[CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([O:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32])[CH:13]=2)[CH:6]=[CH:7][CH:8]=1.[CH3:34][C:35]1[S:39][CH:38]=[N:37][CH:36]=1>C1(C)C=CC=CC=1>[Br-:1].[CH3:34][C:35]1[S:39][CH:38]=[N+:37]([CH2:2][C:3]2[CH:8]=[CH:7][CH:6]=[C:5]([NH:9][C:10](=[O:33])[CH2:11][C:12]3[CH:17]=[CH:16][CH:15]=[C:14]([O:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32])[CH:13]=3)[CH:4]=2)[CH:36]=1
Reactant: CCCCCCCCCCCCCCOc1cccc(CC(=O)Nc2cccc(CBr)c2)c1
Reactant: Cc1cncs1
Solvent: Cc1ccccc1
Product: CCCCCCCCCCCCCCOc1cccc(CC(=O)Nc2cccc(C[n+]3csc(C)c3)c2)c1
Product: [Br-]
Yield: 90.2 %

Procedure:
A mixture of 4 g of N-[3-(bromomethyl)phenyl]-3-(tetradecyloxy)benzeneacetamide and 3.84 g of 5-methylthiazole in 40 ml of toluene is refluxed for 1.5 hours under argon, cooled and the solvent evaporated to a residue. The residue is mixed with ether and the solid collected by centrifugation. The solid is washed several times with ether then dried by vacuum to give 4.3 g of the desired product as an off white powder, m.p. 125°-130° C.
Reaction SMILES: I[CH2:2][CH:3]1[O:7][C:6](=[O:8])[N:5]([C:9]2[CH:14]=[C:13]([F:15])[C:12]([C:16]3[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=3)=[C:11]([F:22])[CH:10]=2)[CH2:4]1.[N-:23]=[N+:24]=[N-:25].[Na+].O>CN(C=O)C>[N:23]([CH2:2][CH:3]1[O:7][C:6](=[O:8])[N:5]([C:9]2[CH:14]=[C:13]([F:15])[C:12]([C:16]3[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=3)=[C:11]([F:22])[CH:10]=2)[CH2:4]1)=[N+:24]=[N-:25]
Reactant: [N-]=[N+]=[N-]
Reactant: O=C1OC(CI)CN1c1cc(F)c(-c2cccnc2)c(F)c1
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: [N-]=[N+]=NCC1CN(c2cc(F)c(-c3cccnc3)c(F)c2)C(=O)O1
Reaction time: 2 h

Procedure:
(±)-5-(Iodomethyl)-3-[4-(3-pyridyl)-3,5-difluorophenyl]-2-oxazolidinone (PREPARATION 5, 577 mg, 1.31 mmol) in DMF (dried over 4A sieves, 15 ml) is combined with sodium azide (681 mg, 10.5 mmol, 8 eq). The reaction is placed under an atmosphere of nitrogen and heated to 55°. After 2 hr, the reaction is added to water (100 ml) and then extracted with ethyl acetate (4×25 ml). The combined organic extracts are combined and are washed with water then brine, dried (sodium sulfate), filtered and concentrated under reduced pressure. The crude azide is suitable for reduction without further purification. An analytical sample is prepared by preparative TLC (silica gel) eluting with acetonitrile/chloroform (10/90). The appropriate fractions are pooled and concentrated to give the title compound, mp 97-98°; FTIR (mull) cm-1 3483, 2110, 1746, 1640, 1417, 1237, 1064 and 716; MS (EI, m/z) 331, 274, 258, 232, 217, 190 and 43; NMR (CDCl3) 8.72, 8.63, 7.79, 7.42-7.38, 7.34, 4.90-4.82, 4.11, 3.88, 3.77 and 3.63 δ.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([CH2:16][CH2:17][CH2:18][O:19][CH:20]3[CH2:25][CH2:24][O:23][CH2:22][CH2:21]3)[CH2:14][NH:13][C:12](=O)[CH2:11][CH2:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8].[H-].[H-].[H-].[H-].[Li+].[Al+3]>C1COCC1>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([CH2:16][CH2:17][CH2:18][O:19][CH:20]3[CH2:25][CH2:24][O:23][CH2:22][CH2:21]3)[CH2:10][CH2:11][CH2:12][NH:13][CH2:14]2)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: O=C1CCC(CCCOC2CCOCC2)(c2ccc(Cl)c(Cl)c2)CN1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: Clc1ccc(C2(CCCOC3CCOCC3)CCCNC2)cc1Cl
Temperature: 60 °C
Reaction time: 20 h

Procedure:
Piperidone (6) (42.9 g, 0.111 mol) in dry THF (300 mL) was added to a suspension of LAH (8.4 g, 0.222 mol) in dry THF (500 mL), which was then heated under N2 at 60° C. in an oil bath for 5 hours, then cooled and stirred at room temperature overnight (20 hours). The reaction was quenched by H2O (8.5 mL), 4N NaOH (8.5 mL), and H2O (8.5 mL), respectively. White solid was filtered and washed with Et2O. The filtrate was concentrated, and the crude oil was purified by flash chromatography (CH2Cl2-MeOH/95:5) to give a colorless oil (37.94 g 91.8%).
Reaction SMILES: [F:1][C:2]([F:32])([F:31])[C:3]([CH:18]=[N:19][C:20]1[CH:29]=[CH:28][CH:27]=[C:26]2[C:21]=1[CH:22]=[N:23][C:24]([CH3:30])=[N:25]2)([OH:17])[CH2:4][C:5](C1C=CC(Cl)=CC=1OC)([CH3:7])[CH3:6].B(Br)(Br)Br.[C:37]([O-:40])(O)=O.[Na+].Cl[CH2:43][Cl:44]>>[Cl:44][C:43]1[CH:6]=[CH:5][C:4]([CH:18]([C:3]([OH:17])([CH2:4][C:5]([CH3:6])=[CH2:7])[C:2]([F:32])([F:31])[F:1])[NH:19][C:20]2[CH:29]=[CH:28][CH:27]=[C:26]3[C:21]=2[CH:22]=[N:23][C:24]([CH3:30])=[N:25]3)=[C:3]([O:40][CH3:37])[CH:2]=1
Reactant: COc1cc(Cl)ccc1C(C)(C)CC(O)(C=Nc1cccc2nc(C)ncc12)C(F)(F)F
Reactant: ClCCl
Reactant: O=C([O-])O
Agent: BrB(Br)Br
Agent: [Na+]
Product: C=C(C)CC(O)(C(Nc1cccc2nc(C)ncc12)c1ccc(Cl)cc1OC)C(F)(F)F
Reaction time: 1.5 h
Yield: 62 %

Procedure:
130 mg (0.28 mmol) of 1,1,1,-trifluoro-4-(4-chloro-2-methoxyphenyl)-2-[(2-methyl-quinazol-5-yl)iminomethyl]-4-methyl-pentan-2-ol is introduced into 5 ml of dichloromethane, and 5.6 ml of a 1 M solution of boron tribromide in dichloromethane is added in drops at −70° C. It is allowed to reach −10° C. within 1.5 hours, then 5 ml of a saturated NaHCO3 solution is added, the phases are separated, the aqueous phase is extracted with dichloromethane, the combined organic phases are washed with saturated NaHCO3 solution and saturated NaCl solution and dried with sodium sulfate. After the solvent is removed in a rotary evaporator, the crude product is chromatographed on silica gel (eluant: dichloromethane/methanol 98:2). 80 mg (62%) of the desired product is obtained as a yellow solid.
Reaction SMILES: [C:1]1([SH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Br[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][Cl:15]>>[Cl:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][S:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: ClCCCCCCBr
Reactant: Sc1ccccc1
Product: ClCCCCCCSc1ccccc1

Procedure:
Prepared by Procedure R and Scheme Z using benzenethiol and 1-bromo-6-chlorohexane.
Reaction SMILES: [CH:1]1[N:6]=[C:5](Cl)[C:4]2[N:8]=[CH:9][N:10]([C@@H:11]3[O:15][C@H:14]([CH2:16][OH:17])[C@@H:13]([OH:18])[C@H:12]3[OH:19])[C:3]=2[N:2]=1.[CH2:20]1[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[C:22]([CH2:29][NH2:30])=[CH:21]1.C(N(CC)CC)C>C(O)C>[CH2:20]1[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[C:22]([CH2:29][NH:30][C:5]2[C:4]3[N:8]=[CH:9][N:10]([C:3]=3[N:2]=[CH:1][N:6]=2)[C@@H:11]2[O:15][C@H:14]([CH2:16][OH:17])[C@@H:13]([OH:18])[C@H:12]2[OH:19])=[CH:21]1
Reactant: NCC1=CCc2ccccc21
Reactant: OC[C@H]1O[C@@H](n2cnc3c(Cl)ncnc32)[C@H](O)[C@@H]1O
Solvent: CCN(CC)CC
Solvent: CCO
Product: OC[C@H]1O[C@@H](n2cnc3c(NCC4=CCc5ccccc54)ncnc32)[C@H](O)[C@@H]1O
Yield: 22.3 %

Procedure:
A reaction mixture of 1.4 g of 6-chloropurine riboside, 1.6 g of [1H-inden-3-yl]methylamine as prepared in Example E hereinafter and 1.5 g of triethylamine in 150 ml ethanol is refluxed for 24 hours. Volatiles are evaporated under reduced pressure and residue is purified on Prep-500A using one prepacked silica gel column and 10% methanoldichloromethane as an eluant at a rate of 150 ml/min. Evaporation of solvent from pure fractions affords 0.43 g (22%) of N6 -[1H-inden-3-yl]methyl adenosine having a melting point of 200°-202° C. Anals. calcd. for C20H21N5O4.0.3 CH3OH; Found: C=60.20; H=5.53; N=17.29; C=60.49; H=5.44; N=17.25.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:20])[CH:5]1[CH2:10][CH2:9][N:8]([S:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)(=[O:13])=[O:12])[CH2:7][CH2:6]1)[CH3:2].C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[CH2:31](Br)[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1>O1CCCC1>[CH2:1]([O:3][C:4]([C:5]1([CH2:31][C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[CH2:10][CH2:9][N:8]([S:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)(=[O:12])=[O:13])[CH2:7][CH2:6]1)=[O:20])[CH3:2]
Reactant: CCOC(=O)C1CCN(S(=O)(=O)c2ccccc2)CC1
Reactant: BrCc1ccccc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CCOC(=O)C1(Cc2ccccc2)CCN(S(=O)(=O)c2ccccc2)CC1
Temperature: 25 °C

Procedure:
A solution of ethyl-N-benzenesulfonyl-isonipecotate (5 g, 0.016 mole) in tetrahydrofuran (1 L) at -78° C. was treated with a solution of Lithium bis (trimethylsilyl)amide in tetrahydrofuran (18.5 mL of a 1M solution). The solution was stirred at -60° for 15 minutes at which time benzyl bromide (3.15 g, 0.016 moles) was added and the reaction warmed to room temperature over 1.5 hours. The reaction was concentrated at reduced pressure to @ one quarter volume and then poured into saturated aqueous sodium bicarbonate (1 L) and extracted with ethyl acetate (2×800 mL). The combined extracts were dried over anhydrous magnesium sulfate, filtered, and concentrated at reduced pressure. The residue was chromatographed on silica gel with 30% ethyl acetate/hexane as eluent to give 5.1 g. 1H NMR CDCl3 δ 7.7 (d,=8.5 Hz, 2H), 7.6-7.4 (m, 3H), 7.3-7.2 (m, 3H), 7.1-7.0 (m, 2H), 3.98 (q, J=7 Hz, 2H), 3.65 (m, 2H), 2.78 (s, 2H), 2.35 (dt, J=2.5, 12 Hz, 2H), 2.19 (d, J=12 Hz, 2H), 1.61 (dt, J=4.5, 12 Hz, 2H).
Reaction SMILES: [C:1]1([NH2:8])[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[NH2:7].[CH3:9][C:10]1([S:13][CH2:12]1)[CH3:11]>CCOCC>[NH2:7][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][C:1]=1[NH:8][CH2:9][C:10]([SH:13])([CH3:12])[CH3:11]
Reactant: Nc1ccccc1N
Reactant: CC1(C)CS1
Solvent: CCOCC
Product: CC(C)(S)CNc1ccccc1N
Temperature: 80 °C
Yield: 26.4 %

Procedure:
o-Phenylenediamine (15.31 g, 1.42×10-1 mol, 100M %) and 12.46 g (1.42×10-1 mol, 100M %) isobutylene sulfide (Snyder et al, J Am Chem Soc 69: 2672-2674, 1947) were mixed in a Parr bomb and heated in an oven at 80° C. for 18 hr. The bomb was cooled to room temperature and then opened. The crude brown oil contained some solid. The mixture was dissolved in 150 ml ether (some white solid did not dissolve), washed with saturated aqueous NaCl solution, and the solvent was removed on the rotary evaporator. The oily residue was placed on flash silica in a 600 ml sintered glass funnel and eluted with 500 ml portions of hexane, 90% hexane/ether, twice with 80% hexane/ether and twice with 50% hexane/ether. Evaporation of the first 50:50 hexane/ether fraction gave 7.36 g (26.5%) of 2-amino-1-(2-mercapto-2-methylpropylamino)benzene as a waxy crystalline product, mp 38°-40° C.
Reaction SMILES: [NH2:1][C@@H:2]([CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][CH2:15][C:16]2[N:17]=[C:18]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[O:19][C:20]=2[CH3:21])=[CH:9][CH:8]=1)[C:3]([OH:5])=[O:4].[C:28]1([C:34](=[O:45])[CH2:35][C:36](=O)[CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH3:43])[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>>[CH2:37](/[C:36](/[NH:1][C@@H:2]([CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][CH2:15][C:16]2[N:17]=[C:18]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[O:19][C:20]=2[CH3:21])=[CH:9][CH:8]=1)[C:3]([OH:5])=[O:4])=[CH:35]/[C:34](=[O:45])[C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=1)[CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH3:43]
Reactant: CCCCCCCC(=O)CC(=O)c1ccccc1
Reactant: Cc1oc(-c2ccccc2)nc1CCOc1ccc(C[C@H](N)C(=O)O)cc1
Product: CCCCCCC/C(=C/C(=O)c1ccccc1)N[C@@H](Cc1ccc(OCCc2nc(-c3ccccc3)oc2C)cc1)C(=O)O

Procedure:
The title compound was prepared as described above for the preparation of Example 2, from 102 mg (0.28 mmol) of Intermediate 45 and 69 mg (0.28 mmol) of Intermediate 19 to yield 77 mg of Example 45: TLC (EtOAc/MeOH , 713): Rf=0.56; 1H NMR (DMSO-d6, 400 MHz) δ11.55 (d, 1H, J=9.6), 7.86 (d, 2H, J=6.8), 7.76 (d, 2H, J=6.4), 7.46. (m, 3H), 7.38 (m, 3H), 7.10 (d, 2H, J=8.4), 6.78 (d, 2H, J=8.4), 5.5 (s, 1H), 4.10 (t, 2H, J=6.6), 4.0 (m, 1H), 3.16 (m, 1H), 2.86 (t, 2H, J=6.5), 2.69 (dd, 1H, J=13.6, 9.6), 2.31 (s, 3H), 1.87 (m, 2H), 1.25-1.1 (m, 10H), 0.78 (t, 3H, J=6.8); low resolution MS (ES+)m/e 595.1 (MH+).
Reaction SMILES: [NH2:1][C:2]1[N:10]=[C:9]2[C:5]([NH:6][CH:7]=[N:8]2)=[C:4](Cl)[N:3]=1.[Na].[CH2:13]([OH:17])[CH2:14][CH2:15][CH3:16]>>[NH2:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][NH:8]2)=[C:4]([O:17][CH2:13][CH2:14][CH2:15][CH3:16])[N:3]=1
Reactant: CCCCO
Reactant: Nc1nc(Cl)c2[nH]cnc2n1
Agent: [Na]
Product: CCCCOc1nc(N)nc2[nH]cnc12

Procedure:
The title compound was prepared in a manner analogous to the preparation of the compound of Example 11a, using 2-amino-6-chloropurine (Sigma, lot #69F4064, 4.4 g, 25.9 mmol) and sodium (Aldrich, lot #9621CL, 3 g, 129.5 mmol) in 250 mL n-butanol to give 4.4 g (21.2 mmol, 82%). mp=165° C.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:18]=[CH:19][CH:20]=1)[CH2:7][N:8]1[CH:12]=[C:11]([CH2:13][CH2:14][C:15](O)=[O:16])[N:10]=[N:9]1)([O-:3])=[O:2].NOS(O)(=O)=O.[N+](C1C=C(C=CC=1)CN1C=C(C=CC(O)=O)N=N1)([O-])=O>>[N+:1]([C:4]1[CH:5]=[C:6]([CH:18]=[CH:19][CH:20]=1)[CH2:7][N:8]1[CH:12]=[C:11]([CH:13]=[CH:14][CH:15]=[O:16])[N:10]=[N:9]1)([O-:3])=[O:2]
Reactant: O=C(O)CCc1cn(Cc2cccc([N+](=O)[O-])c2)nn1
Agent: NOS(=O)(=O)O
Agent: O=C(O)C=Cc1cn(Cc2cccc([N+](=O)[O-])c2)nn1
Product: O=CC=Cc1cn(Cc2cccc([N+](=O)[O-])c2)nn1
Yield: 22 %

Procedure:
3-[1-(3-nitrobenzyl)-1,2,3-triazol-4-yl]-propionic acid (m.p. 147°-150° C.; prepared by reduction by means of hydroxylamine-O-sulphonic acid of 3-[1-(3-nitrobenzyl)-1,2,3-triazol-4-yl]-acrylic acid (m.p. 155°-158° C.), which is obtained by oxidation of the corresponding 3-[1-(3-nitrobenzyl)-1,2,3-triazol-4-yl]-acrolein (m.p. 136°-140° C.):
Reaction SMILES: [C:1]([N:4]1[CH2:11][C:10]2[CH:12]=[C:13]([C:16]3[CH:24]=[CH:23][CH:22]=[CH:21][C:17]=3[C:18](O)=[O:19])[CH:14]=[CH:15][C:9]=2[CH:8]=[CH:7][C:6]2[CH:25]=[C:26]([Cl:29])[CH:27]=[CH:28][C:5]1=2)(=[O:3])[CH3:2].C(Cl)(=O)C(Cl)=O.C([O-])([O-])=O.[K+].[K+].[N:42]1[CH:47]=[CH:46]C=NN=1>C(Cl)Cl.CN(C=O)C.O>[C:1]([N:4]1[CH2:11][C:10]2[CH:12]=[C:13]([C:16]3[CH:24]=[CH:23][CH:22]=[CH:21][C:17]=3[C:18]3[O:19][CH:46]=[CH:47][N:42]=3)[CH:14]=[CH:15][C:9]=2[CH:8]=[CH:7][C:6]2[CH:25]=[C:26]([Cl:29])[CH:27]=[CH:28][C:5]1=2)(=[O:3])[CH3:2]
Reactant: c1cnnnc1
Reactant: CC(=O)N1Cc2cc(-c3ccccc3C(=O)O)ccc2C=Cc2cc(Cl)ccc21
Agent: O=C(Cl)C(=O)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: O
Solvent: CN(C)C=O
Product: CC(=O)N1Cc2cc(-c3ccccc3-c3ncco3)ccc2C=Cc2cc(Cl)ccc21
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 15.5 %

Procedure:
To a mixture of Example 222 (20 mg, 0.05 mmol) in CH2Cl2 (1 mL) was added one drop of DMF. The solution was cooled to 0° C., oxalyl chloride (3 μl, 0.055 mmol) was added and the reaction mixture was stirred for 30 minutes. The reaction mixture was concentrated to a yellow solid, taken up in sulfolane and treated with K2CO3 (14 mg, 0.1 mmol) and 1,2,3-triazine (3 μl, 0.05 mmol). The mixture was heated at 140° C. for 5 hours, then water was added. The resulting mixture was filtered, and the solid was purified by preparative reversed-phase HPLC to give the title compound (3.3 mg, 15%). HPLC Rt=2.36 (b) min. m/z=427 (M+H+).
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:10]([OH:12])=O)=[N:4][CH:5]=[CH:6][C:7]=1[O:8][CH3:9].[CH3:13][NH2:14].[CH:15]1([N:19]2[CH2:24][CH2:23][CH:22]([O:25][C:26]3[CH:33]=[CH:32][C:29]([CH:30]=O)=[CH:28][CH:27]=3)[CH2:21][CH2:20]2)[CH2:18][CH2:17][CH2:16]1>>[CH:15]1([N:19]2[CH2:24][CH2:23][CH:22]([O:25][C:26]3[CH:33]=[CH:32][C:29]([C:30]4[N:14]([CH3:13])[C:10](=[O:12])[C:3]5[N:4]=[CH:5][CH:6]=[C:7]([O:8][CH3:9])[C:2]=5[N:1]=4)=[CH:28][CH:27]=3)[CH2:21][CH2:20]2)[CH2:18][CH2:17][CH2:16]1
Reactant: COc1ccnc(C(=O)O)c1N
Reactant: CN
Reactant: O=Cc1ccc(OC2CCN(C3CCC3)CC2)cc1
Product: COc1ccnc2c(=O)n(C)c(-c3ccc(OC4CCN(C5CCC5)CC4)cc3)nc12

Procedure:
The entitled compound was obtained as a pale yellow solid (m.p. 182.2-205.2° C.), according to the method of Example 15 but starting from 3-amino-4-methoxypyridin-2-carboxylic acid, methylamine and 4-[(1-cyclobutyl-4-piperidinyl)oxy]benzaldehyde.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]([CH2:25][CH:26]([CH3:28])[CH3:27])[S:9]([C:12]2[CH:13]=[N:14][C:15]([NH:18][CH:19]3[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]3)=[CH:16][CH:17]=2)(=[O:11])=[O:10])=[CH:4][CH:3]=1.CCN(C(C)C)C(C)C.[CH3:38][S:39](Cl)(=[O:41])=[O:40].C([O-])(O)=O.[Na+]>C(Cl)Cl.O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]([CH2:25][CH:26]([CH3:28])[CH3:27])[S:9]([C:12]2[CH:13]=[N:14][C:15]([NH:18][CH:19]3[CH2:24][CH2:23][N:22]([S:39]([CH3:38])(=[O:41])=[O:40])[CH2:21][CH2:20]3)=[CH:16][CH:17]=2)(=[O:11])=[O:10])=[CH:4][CH:3]=1
Reactant: CC(C)CN(c1ccc(F)cc1)S(=O)(=O)c1ccc(NC2CCNCC2)nc1
Reactant: CS(=O)(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: ClCCl
Product: CC(C)CN(c1ccc(F)cc1)S(=O)(=O)c1ccc(NC2CCN(S(C)(=O)=O)CC2)nc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 4-{5-[(4-fluoro-phenyl)-isobutyl-sulfamoyl]-pyridin-2-ylamino}-piperidine-1-carboxylic acid tert-butyl ester (66 mg, 130 μmol) in DCM (8 mL) was added TFA (2 mL) and the reaction was stirred at room temperature for 30 minutes. The reaction was concentrated and purified by SCX column eluting with 2M NH3 in MeOH to give 6-(piperidin-4-ylamino)-pyridine-3-sulfonic acid (4-fluoro-phenyl)-isobutyl-amide (41 mg, 101 μmol). To a solution of 6-(piperidin-4-ylamino)-pyridine-3-sulfonic acid (4-fluoro-phenyl)-isobutyl-amide (41 mg, 101 μmol) in DCM (5 mL) was added DIPEA (35 μL, 202 μmol) followed by methane sulfonylchloride (1 mL of a 78 μL, 1 mmol solution in 10 mL of DCM) and the reaction stirred at room temperature for 30 minutes. Water and saturated NaHCO3 were then added, extracted, filtered through a phase separator, concentrated and purified by silica gel column chromatography (0-50% EtOAc in cyclohexane) to give the title compound (49 mg). 1H NMR (400 MHz, DMSO): δ 8.03 (d, J=2.52 Hz, 1H), 7.54 (d, J=7.47 Hz, 1H), 7.35 (dd, J=8.95, 2.54 Hz, 1H), 7.17 (t, J=8.01 Hz, 4H), 6.51 (d, J=8.98 Hz, 1H), 3.91 (br s, 1H), 3.51 (d, J=11.88 Hz, 2H), 3.25 (d, J=7.31 Hz, 2H), 2.86 (m, 5H), 1.97 (d, J=12.65 Hz, 2H), 1.44-1.49 (m, 2H), 0.82 (d, J=6.63 Hz, 6H). LCMS (m/z, Method B) ES+ 485.0 [M+1]+.