Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F-].C([N+](CCCC)(CCCC)CCCC)CCC.[SH:19][CH2:20][C@:21]12[C:27]([CH3:29])([CH3:28])[C@H:24]([CH2:25][CH2:26]1)[CH2:23][C@@:22]2([C:31]#[C:32][Si](C)(C)C)[OH:30].O>O1CCCC1>[CH3:28][C:27]1([CH3:29])[C@@H:24]2[CH2:25][CH2:26][C@:21]31[C@:22]([OH:30])([CH2:23]2)[C:31](=[CH2:32])[S:19][CH2:20]3
Reactant: CC1(C)[C@@H]2CC[C@@]1(CS)[C@@](O)(C#C[Si](C)(C)C)C2
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: O
Product: C=C1SC[C@]23CC[C@H](C[C@]12O)C3(C)C
Yield: 64.1 %

Procedure:
Tetrabutylammonium fluoride (0.5 mL of a 1.0M solution in tetrahydrofuran) was added to a solution of alcohol 2 (65 mg, 0.23 mmol) in tetrahydrofuran (5 mL) under nitrogen. After two hours water was added to the solution and the resulting mixture extracted with dichloromethane. The combined organic extracts were washed with brine and dried over MgSO4. After filtration and removal of the solvents under reduced pressure, chromatography with 5% ethyl acetate in petrol gave sulfide 3 (31 mg, 64%), [a]20D−90.5 (c 2.10 in CHCl3); umax (thin film)/cm−1 3483 (OH), 2942 (CH), 1701 (C═C), 1627 (C═C); dH (250 MHz; CDCl3) 0.97 (3H, s, CH3), 1.01-1.16 (1H, m), 1.27 (3H, s, CH3), 1.50-1.83 (4H, m), 1.96-2.10 (2H, m), 2.14 (1H, br s, OH), 2.52 (1H, d, J 9.0, CHHS), 3.22 (1H, d, J 9.0, CHHS), 4.93 (1H, d, J 1.0, ═CHH), 5.12 (1H, d, J 1.0, ═CHH); dC (63 MHz; CDCl3) 22.02 (CH3), 22.05 (CH3), 26.89 (CH2), 31.95 (CH2), 32.07 (CH2), 37.38 (CH2), 46.25 (C), 50.79 (CH), 61.68 (C), 93.20 (C), 101.39 (CH2), 151.81 (C); m/z (EI) 210 (M+, 30%), 108 (57), 95 (100), 81 (27), (Found; M+, 210.1085. C12H18OS requires 210.1078).
Reaction SMILES: OC[C@H:3]1[CH2:7][CH2:6][CH2:5][N:4]1[CH2:8][CH:9]([C:17]1[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=1)OC1CCCCO1.C(N([CH2:30][CH3:31])CC)C.CS(Cl)(=O)=O.Cl[CH2:38][Cl:39]>>[Cl:39][C@H:38]1[CH2:6][CH2:7][CH2:3][N:4]([CH2:8][CH:9]([C:17]2[CH:18]=[CH:19][C:20]([O:23][CH3:24])=[CH:21][CH:22]=2)[CH:31]2[CH2:30][CH2:18][CH2:19][CH2:20][O:23]2)[CH2:5]1
Reactant: CCN(CC)CC
Reactant: COc1ccc(C(CN2CCC[C@@H]2CO)OC2CCCCO2)cc1
Reactant: ClCCl
Agent: CS(=O)(=O)Cl
Product: COc1ccc(C(CN2CCC[C@H](Cl)C2)C2CCCCO2)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 80 %

Procedure:
To a solution of 5.70 g (17.0 mmol) of (2R)-(+)-2-hydroxymethyl-1-[4'-methoxyphenyl (2-tetrahydropyranyloxy)ethyl]pyrrolidine and 4.74 ml of triethylamine (40.0 mmol) in dichloromethane (100 ml) was added 2.37 ml (30.6 mmol) of methanesulfonylchloride and the mixture was stirred at room temperature for 16 hours. The mixture was diluted with dichloromethane and the solution was washed with water and saturated aqueous sodium chloride, dried over anhydrous sodium sulfate, and concentrated in vacuo. The residue was purified by silicagel column chromatography ((ethyl acetate)) to give 5.01 g (80%) of (3S)-(-)-3-chloro-[4-methoxyphenyl(2-tetrahydropyranyl)ethyl]piperidine as yellow oil.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[C:6]([NH:10][C:11]([C:13]2[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=2)=[NH:12])[CH:7]=[CH:8][CH:9]=1)[CH3:2].C(=O)(O)[O-].[Na+].Br[CH2:26][C:27](=O)[C:28]([O:30][CH2:31][CH3:32])=[O:29]>O1CCOCC1>[CH2:1]([O:3][C:4]1[CH:5]=[C:6]([N:10]2[CH:26]=[C:27]([C:28]([O:30][CH2:31][CH3:32])=[O:29])[N:12]=[C:11]2[C:13]2[CH:14]=[CH:15][C:16]([F:19])=[CH:17][CH:18]=2)[CH:7]=[CH:8][CH:9]=1)[CH3:2]
Reactant: CCOc1cccc(NC(=N)c2ccc(F)cc2)c1
Reactant: CCOC(=O)C(=O)CBr
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1COCCO1
Product: CCOC(=O)c1cn(-c2cccc(OCC)c2)c(-c2ccc(F)cc2)n1
Temperature: 25 °C

Procedure:
To a mixture of the compound from Step A and 0.80 g (9.5 mmol) of sodium bicarbonate in 10 mL of 1,4-dioxane was added 0.60 mL (4.8 mmol) of ethyl bromopyruvate. The reaction mixture was refluxed overnight. After cooling to room temperature, the solid was filtered off and the filtrate was concentrated in vacuo. Flash chromatography on a Biotage Horizon® system (silica gel, 0 to 30% ethyl acetate in hexanes gradient then 30% ethyl acetate in hexanes) gave the title compound as a viscous yellow oil. LC/MS 355.3 (M+1).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([OH:22])[CH:9]([NH2:21])[CH2:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:13][CH:12]=2)=[CH:4][CH:3]=1.[Br:23][CH2:24][C:25](Br)=[O:26].C(=O)([O-])O.[Na+]>C(OCC)(=O)C.O>[Br:23][CH2:24][C:25]([NH:21][CH:9]([CH2:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:13][CH:12]=1)[CH:8]([C:5]1[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=1)[OH:22])=[O:26]
Reactant: O=C(Br)CBr
Reactant: NC(Cc1ccc(C(F)(F)F)cc1)C(O)c1ccc(F)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Product: O=C(CBr)NC(Cc1ccc(C(F)(F)F)cc1)C(O)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 83.1 %

Procedure:
To a solution of (1RS,2RS)-1-(4-fluorophenyl)-1-hydroxy-3-(4-(trifluoromethyl)phenyl)-2-propylamine (2.0 g, 5.54 mmol) in ethyl acetate (50 ml) were added bromoacetyl bromide (723 ml, 8.30 mmol) and saturated aqueous sodium hydrogen carbonate (50 ml) and the mixture was stirred at room temperature for 3 hrs. The reaction solution was diluted with water (100 ml) and extracted with ethyl acetate (200 ml×2). The extract was washed with saturated brine, dried over anhydrous magnesium sulfate and evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=2:1-1:1). Recrystallization from ethyl acetate-hexane gave the title compound (2.0 g, 83%).
Reaction SMILES: S(Cl)(Cl)=O.[OH:5][C:6]([CH3:11])([CH3:10])[C:7](O)=[O:8].[NH2:12][C:13]1[S:14][C:15]([C:18]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[O:19])=[N:16][N:17]=1.O>CN(C)C(=O)C>[C:20]1([C:18]([C:15]2[S:14][C:13]([NH:12][C:7](=[O:8])[C:6]([OH:5])([CH3:11])[CH3:10])=[N:17][N:16]=2)=[O:19])[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1
Reactant: CC(C)(O)C(=O)O
Reactant: Nc1nnc(C(=O)c2ccccc2)s1
Solvent: O
Solvent: CC(=O)N(C)C
Solvent: O=S(Cl)Cl
Product: CC(C)(O)C(=O)Nc1nnc(C(=O)c2ccccc2)s1
Temperature: -10 °C
Reaction time: 1 h

Procedure:
Thionyl chloride (60 μl, 0.82 mmol) is added to 2-hydroxyisobutyric acid (82.9 mg, 0.796 mmol) in 5.0 ml of N,N-dimethylacetamide at -20°/-15° C. and the mixture is stirred at -15°/-10° C. for one hour. After adding 2-amino-5-(phenylcarbonyl)-1,3,4-thiadiazole (97.5 mg, 0.475 mmol) and equilibrating the reaction mixture to room temperature, it is stirred overnight. The reaction mixture is poured into 75 ml of water and subjected to extraction with 3×25 ml of ethyl acetate. The combined organic phases are dried over magnesium sulfate and filtered and the solvent is distilled off. The oil which remains is purified by flash chromatography (eluent: 33.% v/v ethyl acetate in petroleum ether (40/60)).
Reaction SMILES: [CH2:1]([C:5]1[N:9]([S:10]([N:13]([CH3:15])[CH3:14])(=[O:12])=[O:11])[CH:8]=[CH:7][N:6]=1)[CH2:2][CH2:3][CH3:4].C([Li])CCC.[CH:21](OC)=[O:22]>O1CCCC1.CCCCCC>[CH2:1]([C:5]1[N:9]([S:10]([N:13]([CH3:15])[CH3:14])(=[O:12])=[O:11])[C:8]([CH:21]=[O:22])=[CH:7][N:6]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1nccn1S(=O)(=O)N(C)C
Reactant: COC=O
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CCCCc1ncc(C=O)n1S(=O)(=O)N(C)C
Temperature: -70 °C
Reaction time: 1 h
Yield: 76 %

Procedure:
1.25 g of 2-butyl-3-dimethylaminosulfonylimidazole was dissolved in 25 ml of tetrahydrofuran and cooled to -70° C., and 3.3 ml of n-butyllithium, 1.6 n in hexane, was added. After 1 hour, 0.64 ml of methyl formate was added, and the mixture was heated to room temperature and stirred for 17 hours at this temperature. The mixture was then concentrated, methylene chloride/water was added and the mixture was neutralized by adding 10 percent strength sulfuric acid. The organic phase was dried with Na2SO4 and concentrated by evaporation to give 1.35 g of crude product in the form of a yellow oil, which was purified by chromatography over methylene chloride/methanol/hexane 90:5:5 to give 0.99 g of product. The yield was 76 percent. Other data concerning the roduct was:
Reaction SMILES: Cl[C:2](Cl)(Cl)[CH2:3][N+:4]([O-:6])=[O:5].[CH2:9]([N:11](CC)[CH2:12]C)C.CNC.[Cl:19][C:20]1[N:25]=[CH:24][C:23]([CH2:26][NH2:27])=[CH:22][CH:21]=1>O1CCCC1>[Cl:19][C:20]1[N:25]=[CH:24][C:23]([CH2:26][NH:27][C:2]([N:11]([CH3:12])[CH3:9])=[CH:3][N+:4]([O-:6])=[O:5])=[CH:22][CH:21]=1
Reactant: O=[N+]([O-])CC(Cl)(Cl)Cl
Reactant: NCc1ccc(Cl)nc1
Reactant: CCN(CC)CC
Agent: CNC
Solvent: C1CCOC1
Product: CN(C)C(=C[N+](=O)[O-])NCc1ccc(Cl)nc1
Temperature: 0 °C
Yield: 81.3 %

Procedure:
To a solution of 2.10 g (0.0118 mol) of 1,1,1-trichloro-2-nitroethane in 30 ml of tetrahydrofuran was dropwise added a solution of 1.2 g (0.0118 mol) of triethylamine in 2 ml of tetrahydrofuran under cooling to 0° C. and with stirring. To the mixture which was stirred for 30 minutes was dropwise added a solution of 0.99 g (0.011 mol) of 50% dimethylamine and 2.4 g (0.0237 mol) of triethylamine in 5 ml of tetrahydrofuran at -43° C.--38° C. The mixture was stirred for 30 minutes at the same temperature and 1.0 g (0.007 mol) of 6-chloro-3-pyridylmethylamine was dropwise added. The mixture was allowed to stand until rising to room temperature, stirred for 30 minutes and then filtered. The filtrate was concentrated, and 1,2-dichloroethane was added to the residue. The mixture was again filtered to remove insoluble substance. The filtrate was concentrated and the residue was purified by silica gel column chromatography using acetone to obtain 1.46 g (81.0%) of 1-(6-chloro-3-pyridylmethyl)amino-1-dimethylamino- 2-nitroethylene as yellow crystals. mp. 124°-125° C.
Reaction SMILES: F[C:2]1[N:7]=[CH:6][C:5]([CH:8]2[CH2:12][N:11]([CH3:13])[C:10](=[O:14])[CH2:9]2)=[CH:4][CH:3]=1.[OH-].[NH4+:16]>>[NH2:16][C:2]1[N:7]=[CH:6][C:5]([CH:8]2[CH2:12][N:11]([CH3:13])[C:10](=[O:14])[CH2:9]2)=[CH:4][CH:3]=1
Reactant: [NH4+]
Reactant: CN1CC(c2ccc(F)nc2)CC1=O
Agent: [OH-]
Product: CN1CC(c2ccc(N)nc2)CC1=O
Temperature: 140 °C

Procedure:
To 4-(6-fluoropyridin-3-yl)-1-methylpyrrolidin-2-one(100 mg, 0.515 mmol) was added ammonium hydroxide (2 mL, 15.41 mmol). The reaction mixture was heated in heating block at 140° C. for 48h. LC-MS shows 80% product. Reaction mixture was evaporated. Azeotrope with Toluene (x=3) and proceed for next step. LCMS (m/z): 192.2 (MH+), 0.256 min.
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[S:3]([O:6]S(C(F)(F)F)(=O)=O)(=[O:5])=[O:4].[CH3:16][C:17]([N:20]1[C:24]2[NH:25][C:26](=O)[CH:27]=[C:28]([C:29]([O:31][CH2:32][CH3:33])=[O:30])[C:23]=2[C:22]([CH3:35])=[N:21]1)([CH3:19])[CH3:18]>N1C=CC=CC=1.CCOC(C)=O>[CH3:19][C:17]([N:20]1[C:24]2[N:25]=[C:26]([O:6][S:3]([C:2]([F:15])([F:14])[F:1])(=[O:5])=[O:4])[CH:27]=[C:28]([C:29]([O:31][CH2:32][CH3:33])=[O:30])[C:23]=2[C:22]([CH3:35])=[N:21]1)([CH3:16])[CH3:18]
Reactant: CCOC(=O)c1cc(=O)[nH]c2c1c(C)nn2C(C)(C)C
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Product: CCOC(=O)c1cc(OS(=O)(=O)C(F)(F)F)nc2c1c(C)nn2C(C)(C)C
Temperature: 25 °C
Reaction time: 16 h

Procedure:
Trifluoromethanesulfonic anhydride (0.457 mL, 2.70 mmol) was added dropwise to a solution of ethyl 1-(1,1-dimethylethyl)-3-methyl-6-oxo-6,7-dihydro-1H-pyrazolo[3,4-b]pyridine-4-carboxylate (500 mg, 1.803 mmol) in pyridine (10 mL), and the reaction mixture was stirred at room temperature for 16 h. The contents were diluted with EtOAc and washed with saturated NaHCO3, and then brine. The organic layer was dried over MgSO4, filtered, and concentrated in vacuo. The crude residue was purified via silica gel chromatography (0% to 100% DCM:Hex) to afford the final product as a solid, 670 mg (91%). LCMS E-S (M+H)=410.0. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.38 (t, J=7.07 Hz, 3H), 1.71 (s, 9H), 2.58 (s, 3H), 4.46 (q, J=7.07 Hz, 2H), 7.63 (s, 1H).
Reaction SMILES: N1C=CC=C(CNC(C2(CC3C=CC=CC=3)CCNCC2)=O)C=1.Cl.C(OC([N:32]1[CH2:37][CH2:36][C:35]([CH2:41][C:42]2[CH:47]=[CH:46][C:45]([Cl:48])=[CH:44][CH:43]=2)([C:38]([OH:40])=O)[CH2:34][CH2:33]1)=O)(C)(C)C.[Cl:49][C:50]1[CH:57]=[CH:56][CH:55]=[CH:54][C:51]=1[CH2:52][NH2:53]>>[Cl:49][C:50]1[CH:57]=[CH:56][CH:55]=[CH:54][C:51]=1[CH2:52][NH:53][C:38]([C:35]1([CH2:41][C:42]2[CH:43]=[CH:44][C:45]([Cl:48])=[CH:46][CH:47]=2)[CH2:34][CH2:33][NH:32][CH2:37][CH2:36]1)=[O:40]
Reactant: CC(C)(C)OC(=O)N1CCC(Cc2ccc(Cl)cc2)(C(=O)O)CC1
Reactant: NCc1ccccc1Cl
Agent: Cl
Agent: O=C(NCc1cccnc1)C1(Cc2ccccc2)CCNCC1
Product: O=C(NCc1ccccc1Cl)C1(Cc2ccc(Cl)cc2)CCNCC1

Procedure:
In analogy to the procedure described for the synthesis of 4-benzyl-piperidine-4-carboxylic acid (pyridin-3-ylmethyl)-amide; hydrochloride (intermediate 1) the title compound was prepared from 4-(4-chloro-benzyl)-piperidine-1,4-dicarboxylic acid mono-tert-butyl ester (commercially available) and 2-chloro-benzylamine (commercially available) with subsequent cleavage of the protecting group under acidic conditions. The title compound was purified on silica eluting with a gradient formed from DCM and methanol and the free base was liberated under basic conditions. MS (m/e): 377.1 (MH+).
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][C:5]2[C:6](=[O:9])[CH2:7][O:8][C:4]=2[C:3]=1[CH2:12][N:13]1[CH2:18][CH2:17][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:15][CH2:14]1.CO.[C:28]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O.C1(C)C=CC=CC=1>C1COCC1>[CH3:28][O:1][C:2]1[CH:11]=[CH:10][C:5]2[C:6](=[O:9])[CH2:7][O:8][C:4]=2[C:3]=1[CH2:12][N:13]1[CH2:14][CH2:15][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:17][CH2:18]1
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Reactant: CC(C)(C)OC(=O)N1CCN(Cc2c(O)ccc3c2OCC3=O)CC1
Agent: CCOC(=O)N=NC(=O)OCC
Solvent: C1CCOC1
Solvent: CO
Solvent: Cc1ccccc1
Product: COc1ccc2c(c1CN1CCN(C(=O)OC(C)(C)C)CC1)OCC2=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 25.7 %

Procedure:
A solution of tert-butyl 4-[(6-hydroxy-3-oxo-2,3-dihydrobenzofuran-7-yl)methyl]piperazine-1-carboxylate (0.400 g, 1.15 mmol) obtained in Example A16, Step 1, methanol (0.0442 g, 1.38 mmol) and triphenylphosphine (0.454 g, 1.73 mmol) in THF (8 mL) was added with a solution of a 40% solution of diethyl azodicarboxylate in toluene (0.901 g, 2.07 mmol) in THF (2 mL), and the mixture was stirred overnight at room temperature. The reaction mixture was concentrated, and the resulting residue was purified by silica gel column chromatography (chloroform/ethyl acetate) to obtain tert-butyl 4-[(6-methoxy-3-oxo-2,3-dihydrobenzofuran-7-yl)methyl]piperazine-1-carboxylate (0.107 g, 25%).
Reaction SMILES: [H-].[Na+].[OH:3][NH:4][C:5](=[NH:12])[C:6]1[CH:11]=[CH:10][N:9]=[CH:8][CH:7]=1.C[O:14][C:15]([C@H:17]1[CH2:21][CH2:20][C@@H:19]([CH2:22]O)[CH2:18]1)=O>C1COCC1>[N:9]1[CH:10]=[CH:11][C:6]([C:5]2[N:12]=[C:22]([C@@H:19]3[CH2:20][CH2:21][C@H:17]([CH2:15][OH:14])[CH2:18]3)[O:3][N:4]=2)=[CH:7][CH:8]=1
Reactant: COC(=O)[C@H]1CC[C@@H](CO)C1
Reactant: N=C(NO)c1ccncc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: OC[C@H]1CC[C@@H](c2nc(-c3ccncc3)no2)C1
Reaction time: 18 h

Procedure:
Sodium hydride (10 mg of a 60% dispersion in oil, 2.5 mmol) was added to a solution of N-hydroxyisonicotinamidine (344 mg, 2.5 mmol) in anhydrous THF (3 ml) and the mixture heated under reflux for 1 h. cis-Methyl-3-hydroxymethylcyclopentane-1-carboxylate (396 mg, 2.5 mmol) was added in one portion and heating was continued for 18 h. After cooling, the solution was filtered through celite and the filtrate concentrated in vacuo. The residue was purified by flash chromatography (IH-EtOAc, 1:1 to 0:1) to afford the title compound: RT=2.59 min, m/z (ES+)=246.1 [M+H]+.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[OH:11][CH:12]1[CH2:17][CH2:16][CH2:15][N:14]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH:13]1[CH3:25].C(N(CC)C(C)C)(C)C>ClCCl>[CH3:25][CH:13]1[C:12](=[O:11])[CH2:17][CH2:16][CH2:15][N:14]1[C:18]([O:20][C:21]([CH3:22])([CH3:24])[CH3:23])=[O:19]
Reactant: CC1C(O)CCCN1C(=O)OC(C)(C)C
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CS(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: CC1C(=O)CCCN1C(=O)OC(C)(C)C
Temperature: -78 °C
Reaction time: 0.17 h

Procedure:
A solution of oxalyl chloride (4.06 mL, 46.5 mmol) in 50 mL of dichloromethane was cooled to −78° C. and 4.95 mL (69.8 mmol) of dimethyl sulfoxide was added slowly and the mixture was stirred at −78° C. for 10 min. Then a solution of 5.00 g (23.3 mmol) of tert-butyl 3-hydroxy-2-methylpiperidine-1-carboxylate (Step B) in 5 mL of dichloromethane was added dropwise to above mixture. The mixture was stirred at −78° C. for 20 min, then 40.5 mL (232 mmol) of N,N-diisopropylethylamine was added to the mixture. The reaction was warmed to ambient temperature and continued to stir at ambient temperature for 1 h. The mixture was partitioned between dichloromethane and water. The aqueous phase was extracted with three potions of dichloromethane. The combined organic layers were washed with brine, dried over magnesium sulfate, and concentrated. Purification by flash chromatography on a Biotage®D system (silica gel, eluting with 10% ethyl acetate/hexane to 30% ethyl acetate/hexane) gave the title compound. LC/MS 214 (M+1).
Reaction SMILES: [CH:1]([N:4]1[CH:8]([C:9]2[CH:10]=[C:11]([C:15]3[CH:20]=[CH:19][CH:18]=[C:17]([S:21]([CH3:24])(=[O:23])=[O:22])[CH:16]=3)[CH:12]=[CH:13][CH:14]=2)[CH2:7][NH:6][C:5]1=[O:25])([CH3:3])[CH3:2].[H-].[Na+].[CH3:28][C:29]1[O:33][N:32]=[CH:31][C:30]=1[S:34](Cl)(=[O:36])=[O:35]>>[CH:1]([N:4]1[CH:8]([C:9]2[CH:10]=[C:11]([C:15]3[CH:20]=[CH:19][CH:18]=[C:17]([S:21]([CH3:24])(=[O:22])=[O:23])[CH:16]=3)[CH:12]=[CH:13][CH:14]=2)[CH2:7][N:6]([S:34]([C:30]2[CH:31]=[N:32][O:33][C:29]=2[CH3:28])(=[O:36])=[O:35])[C:5]1=[O:25])([CH3:3])[CH3:2]
Reactant: CC(C)N1C(=O)NCC1c1cccc(-c2cccc(S(C)(=O)=O)c2)c1
Reactant: Cc1oncc1S(=O)(=O)Cl
Agent: [H-]
Agent: [Na+]
Product: Cc1oncc1S(=O)(=O)N1CC(c2cccc(-c3cccc(S(C)(=O)=O)c3)c2)N(C(C)C)C1=O

Procedure:
In analogy to example 13, step 2,1-isopropyl-5-(3′-methanesulfonyl-biphenyl-3-yl)-imidazolidin-2-one (example 13, step 1) was reacted with sodium hydride and 5-methyl-4-isoxazolesulfonyl chloride to give 3-isopropyl-4-(3′-methanesulfonyl-biphenyl-3-yl)-1-(5-methyl-isoxazole-4-sulfonyl)-imidazolidin-2-one as a light brown solid. MS: 502.4 ([M−H]−)
Reaction SMILES: [SH:1][C:2]1[CH:7]=[CH:6][N:5]=[CH:4][CH:3]=1.[H-].[Na+].Cl[C:11]1[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][C:12]=1[N+:19]([O-:21])=[O:20]>C(O)C.O1CCOCC1>[CH3:18][O:17][C:14]1[CH:15]=[CH:16][C:11]([S:1][C:2]2[CH:7]=[CH:6][N:5]=[CH:4][CH:3]=2)=[C:12]([N+:19]([O-:21])=[O:20])[CH:13]=1
Reactant: Sc1ccncc1
Reactant: COc1ccc(Cl)c([N+](=O)[O-])c1
Agent: [H-]
Agent: [Na+]
Solvent: CCO
Solvent: C1COCCO1
Product: COc1ccc(Sc2ccncc2)c([N+](=O)[O-])c1
Temperature: 100 °C
Reaction time: 0.08 h
Yield: 21.5 %

Procedure:
1.11 g of 4-mercaptopyridine was dissolved in 5 ml of ethanol, and 52.8 mg of sodium hydride was added little by little. The mixture was stirred for 5 minutes, and then a solution of 1.87 g of 4-chloro-3-nitroanisole in 5 ml of dioxane was added. The mixture was heated under reflux at 100° C. for 15 hours. The solvent was evaporated, and 2N hydrochloric acid was added to the residue. The residue was washed with ether, made alkaline by adding an aqueous solution of sodium hydroxide, and extracted with methylene chloride. The extract was washed with a saturated aqueous solution of sodium chloride. The solvent was evaporated. The resulting residue was subjected to silica gel column chromatography. The column was eluted with a 5:3 mixture of hexane and acetone, and the eluate was recrystallized from acetone-hexane to give 562 mg (yield 21.4%) of 4-(4-methoxy-2-nitrophenyl)thiopyridine as orange needles having a melting point of 57° to 59° C.
Reaction SMILES: [C:1]1(=O)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH:8]1([NH2:11])[CH2:10][CH2:9]1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].CC(O)=O.Cl>ClC(Cl)C.O>[CH:8]1([NH:11][CH:1]2[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]2)[CH2:10][CH2:9]1
Reactant: NC1CC1
Reactant: O=C1CCCCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: CC(Cl)Cl
Solvent: O
Solvent: CC(=O)O
Product: C1CCC(NC2CC2)CC1
Temperature: 25 °C
Reaction time: 10 h

Procedure:
To cyclohexanone (1.0 mL, 10 mmol) in dichloroethane (30 mL) was added cyclopropylamine (0.70 mL, 10 mmol), NaBH(OAc)3 (3.18 g, 15 mmol) and AcOH (0.57 mL, 10 mmol). The reaction was stirred at room temperature for 10 h. The reaction mixture was poured into water (60 mL) and acidified to pH 2 with 5 N HCl followed by removal of the organic portion. The aqueous portion was brought to pH>12 with 5 N NaOH and extracted with CH2Cl2 (3×30 mL). The collected organic extracts were dried with Na2SO4 and the volatile organics were removed in vacuo to afford the desired intermediate.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[S:10][C:9]([CH:11]=O)=[CH:8][CH:7]=1.[NH2:13][C:14]1[S:15][C:16]([NH2:29])=[C:17]([C:24]([O:26][CH2:27][CH3:28])=[O:25])[C:18]=1[C:19]([O:21][CH2:22][CH3:23])=[O:20].[C:30](O)([C:32](F)(F)F)=O>C(O)(C)C>[S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[S:10][C:30]([CH:32]=[N:13][C:14]2[S:15][C:16]([N:29]=[CH:11][C:9]3[S:10][C:6]([C:2]4[S:1][CH:5]=[CH:4][CH:3]=4)=[CH:7][CH:8]=3)=[C:17]([C:24]([O:26][CH2:27][CH3:28])=[O:25])[C:18]=2[C:19]([O:21][CH2:22][CH3:23])=[O:20])=[CH:8][CH:7]=1
Reactant: O=Cc1ccc(-c2cccs2)s1
Reactant: O=C(O)C(F)(F)F
Reactant: CCOC(=O)c1c(N)sc(N)c1C(=O)OCC
Solvent: CC(C)O
Product: CCOC(=O)c1c(N=Cc2ccc(-c3cccs3)s2)sc(N=Cc2ccc(-c3cccs3)s2)c1C(=O)OCC

Procedure:
5-(Thiophen-2-yl)thiophene-2-carbaldehyde (75 mg) was added to diethyl 2,5-diaminothiophene-3,4-dicarboxylate (49 mg) and the solution was refluxed in isopropanol for four hours in the presence of a catalytic amount of TFA. The title compound was isolated as a red powder (58 mg, 50%) following column chromatography. M.p.: 130°-132° C. 1H-NMR (300 MHz, [D] acetone): δ=8.69 (s, 2H), 7.76 (d, 2H, 3J=4.1 Hz), 7.66 (d, 2H, 3J=6.1 Hz), 7.53 (d, 2H, 3J=3.7 Hz), 7.46 (d, 2H, 3J=4.0 Hz), 7.16 (t, 2H, 3J=3.6 Hz), 4.26 (q, 4H, 3J=6). 9 Hz), 1.30 (t, 6H, 3J=7.3 Hz). 13C-NMR (60 MHz, [D] acetone): δ=173.0, 163.0, 152.8, 140.9, 136.4, 131.6, 129.2, 129.0, 127.3, 126.2, 125.2, 123.9, 66.3, 13.8. EI-MS: m/z 610.9 ([M]+, 100%).
Reaction SMILES: Cl[C:2]1[N:7]2[N:8]=[C:9](C)[CH:10]=[C:6]2[N:5]=[C:4]([NH:12][C:13](=[O:24])[C:14]2[CH:19]=[CH:18][C:17]([C:20]([OH:23])([CH3:22])[CH3:21])=[CH:16][CH:15]=2)[CH:3]=1.[NH:25]1[CH2:30][CH2:29][CH:28]([C:31]([O:33][CH3:34])=[O:32])[CH2:27][CH2:26]1>O1CCOCC1.CS(C)=O.CO>[OH:23][C:20]([C:17]1[CH:16]=[CH:15][C:14]([C:13]([NH:12][C:4]2[CH:3]=[C:2]([N:25]3[CH2:30][CH2:29][CH:28]([C:31]([O:33][CH3:34])=[O:32])[CH2:27][CH2:26]3)[N:7]3[N:8]=[CH:9][CH:10]=[C:6]3[N:5]=2)=[O:24])=[CH:19][CH:18]=1)([CH3:22])[CH3:21]
Reactant: Cc1cc2nc(NC(=O)c3ccc(C(C)(C)O)cc3)cc(Cl)n2n1
Reactant: COC(=O)C1CCNCC1
Solvent: C1COCCO1
Solvent: CS(C)=O
Solvent: CO
Product: COC(=O)C1CCN(c2cc(NC(=O)c3ccc(C(C)(C)O)cc3)nc3ccnn23)CC1
Temperature: 25 °C
Yield: 11.4 %

Procedure:
A solution of N-(7-chloropyrazolo[1,5-a]pyrimidin-5-yl)-4-(2-hydroxypropan-2-yl)benzamide (2D, 500 mg, 1.51 mmol) and methyl piperidine-4-carboxylate (390 mg, 3.05 mmol) in Dioxane (15 mL) was stirred at 100° C. overnight. After cooling to room temperature, the mixture was diluted with a few drops of DMSO and methanol, and was then purified by preparatory HPLC, 30-40% (MeCN/H2O gradient+0.01% TFA). Lyophilization of the combined fractions gave the titled compound as a yellow solid (75 mg, 28%). 1H NMR (DMSO-d6) δ: 10.89 (s, 1H), 8.09 (d, J=2.3 Hz, 1H), 8.00 (d, J=8.6 Hz, 2H), 7.60 (d, J=8.6 Hz, 2H), 7.44 (s, 1H), 6.35 (d, J=2.3 Hz, 1H), 5.18 (s, 1H), 4.29-4.44 (m, 2H), 3.65 (s, 3H), 3.17 (d, J=5.3 Hz, 2H), 2.67-2.82 (m, 1H), 1.98-2.11 (m, 2H), 1.70-1.88 (m, 2H), 1.46 (s, 6H). ESI-MS: m/z 438.0 (M+H)+.
Reaction SMILES: [N+:1]([C:4]1[CH:13]=[CH:12][CH:11]=[C:10]2[C:5]=1[CH:6]=[CH:7][C:8](Cl)=[N:9]2)([O-])=O.[CH3:15][C:16]1[O:20][C:19]([CH2:21][NH2:22])=[CH:18][CH:17]=1.[CH:23]([C:25]1[CH:33]=[CH:32][CH:31]=[C:30]2[C:26]=1[CH:27]=[CH:28][NH:29]2)=O>>[NH:29]1[C:30]2[C:26](=[C:25]([CH2:23][NH:1][C:4]3[C:5]4[CH:6]=[CH:7][C:8]([NH:22][CH2:21][C:19]5[O:20][C:16]([CH3:15])=[CH:17][CH:18]=5)=[N:9][C:10]=4[CH:11]=[CH:12][CH:13]=3)[CH:33]=[CH:32][CH:31]=2)[CH:27]=[CH:28]1
Reactant: O=[N+]([O-])c1cccc2nc(Cl)ccc12
Reactant: O=Cc1cccc2[nH]ccc12
Reactant: Cc1ccc(CN)o1
Product: Cc1ccc(CNc2ccc3c(NCc4cccc5[nH]ccc45)cccc3n2)o1

Procedure:
The title compound, MS: m/e=383.1 (M+H+), was prepared from 5-nitro-2-chloroquinoline, 5-methyl-2-furanmethanamine and 4-formylindole as described in example 26.