Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O:2][C:3]1[CH:12]=[C:11]2[C:6]([CH:7]=[CH:8][C:9]([C:13]#[N:14])=[CH:10]2)=[CH:5][CH:4]=1.[Cl-].[Al+3].[Cl-].[Cl-].C(OCC)(=O)C.Cl>ClC1C=CC=CC=1>[OH:2][C:3]1[CH:12]=[C:11]2[C:6]([CH:7]=[CH:8][C:9]([C:13]#[N:14])=[CH:10]2)=[CH:5][CH:4]=1
Reactant: COc1ccc2ccc(C#N)cc2c1
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: CCOC(C)=O
Solvent: Clc1ccccc1
Product: N#Cc1ccc2ccc(O)cc2c1
Yield: 94 %

Procedure:
To a solution of 7-methoxynaphthalene-2-carbonitrile (6 g) in chlorobenzene (60 ml) was added aluminum chloride (15.3 g) at room temperature and the mixture was heated under refluxing for 30 min. After completion of the reaction, the reaction mixture was ice-cooled and ice, ethyl acetate and conc. hydrochloric acid were added, and the mixture was stirred. The organic layer was separated and concentrated. To the obtained residue was added hexane and the resultant solid was collected by filtration and dried under reduced pressure to give the title compound (5.21 g).
Reaction SMILES: [NH2:1][CH2:2][C:3]([C:10]1[CH:11]=[N:12][CH:13]=[CH:14][CH:15]=1)([O:7][CH2:8][CH3:9])[O:4][CH2:5][CH3:6].[CH3:16][CH:17]([CH3:24])[CH2:18][C:19](=[O:23])[C:20](O)=[O:21]>>[CH2:8]([O:7][C:3]([O:4][CH2:5][CH3:6])([C:10]1[CH:11]=[N:12][CH:13]=[CH:14][CH:15]=1)[CH2:2][NH:1][C:20](=[O:21])[C:19](=[O:23])[CH2:18][CH:17]([CH3:24])[CH3:16])[CH3:9]
Reactant: CC(C)CC(=O)C(=O)O
Reactant: CCOC(CN)(OCC)c1cccnc1
Product: CCOC(CNC(=O)C(=O)CC(C)C)(OCC)c1cccnc1

Procedure:
In a manner analogous to Example 1, by condensing 3-(2-amino-1,1-diethoxyethyl)pyridine with 4-methyl-2-oxo-pentanoic acid there is obtained N-(2,2-diethoxy-2-(3-pyridyl)ethyl]-4-methyl2-oxovaleramide as a colorless, amorphous solid. Acidic hydrolysis yields 4-methyl-N-(nicotinoylmethyl)-2-oxovaleramide and subsequent ring closure yields 3-isobutyl-5-(3-pyridyl)-2(1H)-pyrazinone as a crystalline solid, melting point 195°-196° (from ethyl acetate). The conversion into the corresponding chloride, 2-chloro-3-isobutyl-5-(3-pyridyl)pyrazine, is also effected analogously to Example 1.
Reaction SMILES: [NH2:1][C@@H:2]1[CH2:6][CH2:5][CH2:4][C@:3]1([CH3:11])[C:7]([O:9][CH3:10])=[O:8].[CH2:12]([O:19][C:20]1[CH:25]=[CH:24][C:23]([S:26](Cl)(=[O:28])=[O:27])=[CH:22][CH:21]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>>[CH2:12]([O:19][C:20]1[CH:25]=[CH:24][C:23]([S:26]([NH:1][C@@H:2]2[CH2:6][CH2:5][CH2:4][C@:3]2([CH3:11])[C:7]([O:9][CH3:10])=[O:8])(=[O:28])=[O:27])=[CH:22][CH:21]=1)[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: COC(=O)[C@@]1(C)CCC[C@H]1N
Reactant: O=S(=O)(Cl)c1ccc(OCc2ccccc2)cc1
Product: COC(=O)[C@@]1(C)CCC[C@H]1NS(=O)(=O)c1ccc(OCc2ccccc2)cc1

Procedure:
According to the procedure of Example 47, Step 4, using methyl (1S,2R)-2-amino-1-methylcyclopentanecarboxylate (480 mg, 2.48 mmol) and 4-(benzyloxy)benzene-1-sulfonyl chloride (0.692 g, 2.45 mmol), methyl (1S,2R)-2-({[4-(benzyloxy)phenyl]sulfonyl}amino)-1-methylcyclopentanecarboxylate was obtained (811 mg, 82%) as a colorless solid after purification via column chromatography on silica gel eluting with 25% ethyl acetate/hexane. 1H NMR (400 MHz, CHLOROFORM-D) δ ppm 1.20 (s, 3H) 1.45-1.56 (m, 3H) 1.68-1.77 (m, 1H) 2.10 (ddd, J=12.57, 8.53, 3.66 Hz, 1H) 3.27-3.36 (m, 1H) 3.64-3.67 (m, 3H) 5.10 (s, 2H) 5.61 (d, J=10.11 Hz, 1H) 7.00-7.05 (m, 2H) 7.31-7.43 (m, 5H) 7.78-7.83 (m, 2H).
Reaction SMILES: [CH3:1][S:2]([C:4]1[CH:9]=[CH:8][C:7]([CH3:10])=[CH:6][N:5]=1)=[O:3].C1C(=O)N([Br:18])C(=O)C1>C(Cl)(Cl)(Cl)Cl.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>[Br:18][CH2:10][C:7]1[CH:8]=[CH:9][C:4]([S:2]([CH3:1])=[O:3])=[N:5][CH:6]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1ccc(S(C)=O)nc1
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: CS(=O)c1ccc(CBr)cn1
Temperature: 25 °C
Yield: 28.1 %

Procedure:
To a solution of 0.33 g of 2-methanesulfinyl-5-methyl-pyridine in 20 mL of carbon tetrachloride was added 0.40 g NBS and 6 mg benzoyl peroxide. This mixture was refluxed for 4 hours. The reaction mixture was cooled to room temperature, washed with aqueous sodium hydrogen carbonate solution, dried over sodium sulphate, and concentrated to dryness. Purification by flash chromatography (silica, heptane/ethyl acetate) provided 0.14 g of 5-bromomethyl-2-methanesulfinyl-pyridine.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][NH:4][C:5]1[N:10]2[N:11]=[C:12]([CH3:23])[C:13]([C:14]3[C:19]([CH3:20])=[CH:18][C:17]([Cl:21])=[CH:16][C:15]=3[CH3:22])=[C:9]2[N:8]=[C:7]([CH3:24])[CH:6]=1.[O:25]1[CH2:30][CH2:29][C:28](=O)[CH2:27][CH2:26]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(O)(=O)C>ClC(Cl)C>[O:25]1[CH2:30][CH2:29][CH:28]([NH:1][CH2:2][CH2:3][NH:4][C:5]2[N:10]3[N:11]=[C:12]([CH3:23])[C:13]([C:14]4[C:15]([CH3:22])=[CH:16][C:17]([Cl:21])=[CH:18][C:19]=4[CH3:20])=[C:9]3[N:8]=[C:7]([CH3:24])[CH:6]=2)[CH2:27][CH2:26]1
Reactant: Cc1cc(NCCN)n2nc(C)c(-c3c(C)cc(Cl)cc3C)c2n1
Reactant: O=C1CCOCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CC(Cl)Cl
Product: Cc1cc(NCCNC2CCOCC2)n2nc(C)c(-c3c(C)cc(Cl)cc3C)c2n1
Temperature: 25 °C
Reaction time: 3 h
Yield: 69.2 %

Procedure:
Dissolve 7-(2-aminoethylamino)-2,5-dimethyl-3-(4-chloro-2,6-dimethylphenyl)-pyrazolo [1,5-a] pyrimidine (0.183 g, 5.4×10−4 mol, 339.2 g/mol) in dichloroethane (5 mL) and add tetrahydro-4H-pyran-4-one (0.068 g, 0.060 mL, 100.12 g/mol) and sodium triacetoxyborohydride (0.172 g, 211.94 g/mol). To the resultant slurry, add glacial acetic acid (0.032 mL, 5.4×10−4 mol) and stir at ambient temperature under N2 for 3 hours. Partition between CH2Cl2 (3 mL) and 1.0 N NaOH (10 mL), then separate the layers and chromatograph the CH2Cl2 layer using [10% (2.0M NH3 in MeOH)/90% CH2Cl2] as eluent. Obtained 0.16 g white solid-foam upon evaporation. TLC: Rf=0.65. LCMS=422.5 (MH+); 420.5 (M−). 1H-NMR (CDCl3): 6.67 (s, 2H); 5.79 (d, 1H, J=8.8 Hz); 3.98 (br. d, 2H, J=12 Hz); 3.78 (s, 3H); 3.52 (t, 2H, J=6 Hz); 3.39 (br. t, 2H, J=12 Hz); 3.37 (s, 1H); 3.04 (t, 2H, J=6 Hz); 2.75-2.81 (m, 2H); 2.40 (s, 3H); 2.18 (s, 3H); 2.00 (s, 6H); 1.89 (br. d, 2H, J=12 Hz); 1.47-1.53 (m, 2H).
Reaction SMILES: FC(F)(F)C(O)=O.C(OC([N:15]1[CH2:20][CH2:19][N:18]([C:21](=[O:43])[CH:22]([NH:30][C:31]([C:33]2[NH:34][C:35]3[C:40]([CH:41]=2)=[CH:39][C:38]([Cl:42])=[CH:37][CH:36]=3)=[O:32])[CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH2:17][CH2:16]1)=O)(C)(C)C>>[CH2:23]([CH:22]([NH:30][C:31]([C:33]1[NH:34][C:35]2[C:40]([CH:41]=1)=[CH:39][C:38]([Cl:42])=[CH:37][CH:36]=2)=[O:32])[C:21](=[O:43])[N:18]1[CH2:17][CH2:16][NH:15][CH2:20][CH2:19]1)[C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1
Reactant: CC(C)(C)OC(=O)N1CCN(C(=O)C(Cc2ccccc2)NC(=O)c2cc3cc(Cl)ccc3[nH]2)CC1
Solvent: O=C(O)C(F)(F)F
Product: O=C(NC(Cc1ccccc1)C(=O)N1CCNCC1)c1cc2cc(Cl)ccc2[nH]1
Reaction time: 0.3 h

Procedure:
Trifluoroacetic acid (4 ml) was added to 4-{2-[(5-chloro-1H-indole-2-carbonyl)-amino]-3-phenyl-propionyl}-piperazine-1-carboxylic acid tert-butyl ester (0.6 mmol) at 0° C. and the resulting solution was stirred for 0.3 hours and concentrated. The residue was partitioned between ethyl acetate and 2 N NaOH, the organic layer separated and washed with brine, dried over Na2SO4, concentrated and the resulting solid triturated with ether: Yield 189 mg, 77%; HPLC (60/40) 2.63 minutes (99%);
Reaction SMILES: [N:1]([CH2:4][CH2:5][CH2:6][S:7]([NH:10][CH2:11][C:12]1([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[S:16][C:15]([NH:17][C:18](=[O:23])[C:19]([CH3:22])([CH3:21])[CH3:20])=[N:14][N:13]1[C:24](=[O:29])[C:25]([CH3:28])([CH3:27])[CH3:26])(=[O:9])=[O:8])=[N+]=[N-].O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1COCC1>[NH2:1][CH2:4][CH2:5][CH2:6][S:7]([NH:10][CH2:11][C:12]1([C:30]2[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=2)[S:16][C:15]([NH:17][C:18](=[O:23])[C:19]([CH3:20])([CH3:21])[CH3:22])=[N:14][N:13]1[C:24](=[O:29])[C:25]([CH3:27])([CH3:28])[CH3:26])(=[O:9])=[O:8]
Reactant: CC(C)(C)C(=O)NC1=NN(C(=O)C(C)(C)C)C(CNS(=O)(=O)CCCN=[N+]=[N-])(c2ccccc2)S1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)C(=O)NC1=NN(C(=O)C(C)(C)C)C(CNS(=O)(=O)CCCN)(c2ccccc2)S1
Temperature: 25 °C
Reaction time: 16 h
Yield: 89 %

Procedure:
Next, the resulting N-[5-(3-azidopropanesulfonylamino-methyl)-4-(2,2-dimethylpropionyl)-5-phenyl-4,5-dihydro-1,3,4-thiadiazol-2-yl]-2,2-dimethylpropanamide was dissolved in THF (53 mL), and water (10.6 mL) and triphenylphosphine (1.24 g, 4.73 mmol) were added, then the mixture was stirred at room temperature for 16 hours. The mixture was concentrated under reduced pressure, and water and saturated aqueous sodium hydrogencarbonate were added, then the mixture was extracted with ethyl acetate. The organic layer was extracted with aqueous hydrochloric acid, and the aqueous layer was made basic by adding saturated aqueous sodium hydrogencarbonate, and then extracted with ethyl acetate. The resulting organic layer was concentrated under reduced pressure to give N-[5-(3-aminopropanesulfonylaminomethyl)-4-(2,2-dimethylpropionyl)-5-phenyl-4,5-dihydro-1,3,4-thiadiazol-2-yl]-2,2-dimethylpropanamide (1.29 g, 89%).
Reaction SMILES: [O:1]=[C:2]1[N:8]([CH2:9][C:10]([N:12]([CH:21]([CH3:23])[CH3:22])[C:13]2[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=2)=[O:11])[C:7]2[CH:24]=[CH:25][CH:26]=[CH:27][C:6]=2[NH:5][C:4](=[O:28])[CH2:3]1.C([O-])(=O)C.[K+].Br[C:35]1[CH:40]=[CH:39][N:38]=[CH:37][CH:36]=1.ClCCl>CS(C)=O>[O:1]=[C:2]1[N:8]([CH2:9][C:10]([N:12]([CH:21]([CH3:23])[CH3:22])[C:13]2[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=2)=[O:11])[C:7]2[CH:24]=[CH:25][CH:26]=[CH:27][C:6]=2[N:5]([C:35]2[CH:40]=[CH:39][N:38]=[CH:37][CH:36]=2)[C:4](=[O:28])[CH2:3]1
Reactant: Brc1ccncc1
Reactant: COc1ccc(N(C(=O)CN2C(=O)CC(=O)Nc3ccccc32)C(C)C)cc1
Agent: CC(=O)[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: CS(C)=O
Product: COc1ccc(N(C(=O)CN2C(=O)CC(=O)N(c3ccncc3)c3ccccc32)C(C)C)cc1
Temperature: 100 °C
Yield: 50.4 %

Procedure:
To a stirring solution of 700 mg (1.89 mmol) 2-(2,4-Dioxo-2,3,4,5-tetrahydro-benzo[b][1,4]diazepin-1-yl)-N-isopropyl-N-(4-methoxy-phenyl)-acetamide in DMSO is added 370 mg of Cu powder (5.8 mmol, 3 equiv), 380 mg of potassium acetate (3.88 mmol, 2 equiv) and 500 mg of 4-bromopyridine (3.16 mmol, 1.7 equiv, freshly free-based from the hydrochloride salt). The reaction is heated to 100° C. for 16 h then poured onto ice. Dichloromethane is added, and the mixture is filtered through celite. The filtrate is poured into a separatory funnel containing 100 mL of H2O, and the layers separated. 2 mL of a 30% solution of NH4OH were added to the aqueous layer, and the resulting blue solution is extracted with dichloromethane. The combined organics were dried (Na2SO4), filtered and concentrated. The residue is purified by silica gel flash column chromatography to afford 437 mg of 2-(2,4-Dioxo-5-pyridin-4-yl-2,3,4,5-tetrahydro-benzo[b][1,4]diazepin-1-yl)-N-isopropyl-N-(4-methoxy-phenyl)-acetamide as a white solid: mp. 211°-213° C.; 1H NMR (CDCl3, 400 MHz) δ8.61 (d, br, 2H, J=5.4), 7.43 (d, 1H, J=8.1), 7.36-7.14 (m, 5H), 6.99-6.22 (m, 4H), 5.03 (m, 1H), 4.26 (dd, br, 2H, J=16.6, 28.5), 3.87 (s, 3H), 3.55 (dd, 2H, J=12.0, 36.4), 1.09 (d, 6H, J=6.8); low resolution MS (FAB)m/e 459 (MH+).
Reaction SMILES: CS(O[CH:6]1[CH2:11][CH2:10][N:9]([C:12]2[CH:22]=[CH:21][C:15]([C:16]([O:18][CH2:19][CH3:20])=[O:17])=[CH:14][CH:13]=2)[CH2:8][CH2:7]1)(=O)=O.[N-:23]=[N+:24]=[N-:25].[Na+]>CN(C=O)C.[Cl-].[Na+].O>[N:23]([CH:6]1[CH2:11][CH2:10][N:9]([C:12]2[CH:22]=[CH:21][C:15]([C:16]([O:18][CH2:19][CH3:20])=[O:17])=[CH:14][CH:13]=2)[CH2:8][CH2:7]1)=[N+:24]=[N-:25]
Reactant: [N-]=[N+]=[N-]
Reactant: CCOC(=O)c1ccc(N2CCC(OS(C)(=O)=O)CC2)cc1
Agent: [Cl-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)c1ccc(N2CCC(N=[N+]=[N-])CC2)cc1
Temperature: 80 °C
Yield: 86.5 %

Procedure:
To a solution of ethyl 4-(4-(methylsulfonyloxy)piperidin-1-yl)benzoate (10.5 g, 32.1 mmol) in DMF (50 mL) was added sodium azide (4.17 g, 64.2 mmol). The mixture was heated at 80° C. for 5 hours, cooled to room temperature, diluted with brine (300 mL), and extracted with ethyl acetate (400 mL). The organic phase was washed with brine (2×300 mL), dried over anhydrous MgSO4, filtered, and concentrated, to afford ethyl 4-(4-azidopiperidin-1-yl)benzoate as a yellow solid (7.62 g, 87%).
Reaction SMILES: [CH2:1]([OH:6])[CH2:2][CH2:3][CH2:4][OH:5].[H-].[Na+].[Br:9][C:10]1[C:11]([Cl:28])=[CH:12][C:13](F)=[C:14]([S:16]([N:19]([CH3:26])[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=2)(=[O:18])=[O:17])[CH:15]=1>CN(C=O)C>[Br:9][C:10]1[C:11]([Cl:28])=[CH:12][C:13]([O:5][CH2:4][CH2:3][CH2:2][CH2:1][OH:6])=[C:14]([S:16]([N:19]([CH3:26])[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=2)(=[O:17])=[O:18])[CH:15]=1
Reactant: CN(c1ccccn1)S(=O)(=O)c1cc(Br)c(Cl)cc1F
Reactant: OCCCCO
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CN(c1ccccn1)S(=O)(=O)c1cc(Br)c(Cl)cc1OCCCCO
Temperature: 50 °C
Reaction time: 0.25 h
Yield: 96.8 %

Procedure:
To a solution of 1,4-butanediol (0.315 mL, 3.6 mmol) in DMF (2.5 mL) at ambient temperature was added sodium hydride (60%, 34 mg, 0.85 mmol) and the mixture was stirred for 15 minutes. A solution of 5-bromo-4-chloro-2-fluoro-N-methyl-N-pyridin-2-yl-benzenesulfonamide (0.268 g, 0.71 mmol) in DMF (2.5 mL) was added and the mixture heated at 50° C. for 2 h. The solvent was removed in vacuo and water and DCM were added. The mixture was extracted with DCM. The organic layer was washed with brine and was dried over anhydrous MgSO4. Concentration of the filtrate provided a residue that was purified by silica gel chromatography [eluent: 50% ethyl acetate in hexane] to afford 5-bromo-4-chloro-2-(4-hydroxy-butoxy)-N-methyl-N-pyridin-2-yl-benzenesulfonamide as a solid (0.309 g). MS: 451.0 (M+H)+; tR=2.59 min (method 1).
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]([C:10]2[C:15]([O:16][CH3:17])=[CH:14][CH:13]=[CH:12][N:11]=2)=[O:9])=[CH:6][N:5]=[C:4](S(CC)=O)[N:3]=1.FC(F)(F)C(O)=O.[CH3:29][S:30]([N:33]1[CH2:38][CH2:37][CH:36]([NH2:39])[CH2:35][CH2:34]1)(=[O:32])=[O:31]>>[NH2:1][C:2]1[C:7]([C:8]([C:10]2[C:15]([O:16][CH3:17])=[CH:14][CH:13]=[CH:12][N:11]=2)=[O:9])=[CH:6][N:5]=[C:4]([NH:39][CH:36]2[CH2:37][CH2:38][N:33]([S:30]([CH3:29])(=[O:32])=[O:31])[CH2:34][CH2:35]2)[N:3]=1
Reactant: CS(=O)(=O)N1CCC(N)CC1
Reactant: CCS(=O)c1ncc(C(=O)c2ncccc2OC)c(N)n1
Solvent: O=C(O)C(F)(F)F
Product: COc1cccnc1C(=O)c1cnc(NC2CCN(S(C)(=O)=O)CC2)nc1N

Procedure:
The compound was prepared from (4-amino-2-ethylsulfinyl-pyrimidin-5-yl)-(3-methoxy-pyridin-2-yl)-methanone (Example 195) and 1-methanesulfonyl-piperidin-4-ylamine; compound with trifluoroacetic acid (Example 162) in an analogous manner as described in Example 172. HR-MS (ES, m/z) calculated for C17H23N6O4S [(M+H)+] 407.1496, observed 407.1501.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5](=[O:8])[NH:6][N:7]=1.C([O-])([O-])=O.[K+].[K+].Br[CH2:16][CH2:17][O:18][C:19]1[C:28]2[C:23](=[CH:24][C:25]([O:29][CH3:30])=[CH:26][CH:27]=2)[N:22]=[CH:21][CH:20]=1.O>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5](=[O:8])[N:6]([CH2:16][CH2:17][O:18][C:19]2[C:28]3[C:23](=[CH:24][C:25]([O:29][CH3:30])=[CH:26][CH:27]=3)[N:22]=[CH:21][CH:20]=2)[N:7]=1
Reactant: COc1ccc2c(OCCBr)ccnc2c1
Reactant: O=c1ccc(Cl)n[nH]1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccc2c(OCCn3nc(Cl)ccc3=O)ccnc2c1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 44.5 %

Procedure:
A mixture of 6-chloropyridazin-3(2 H)-one (3000 mg, 22983 μmol), K2CO3 (5000 mg, 36178 μmol), and 4-(2-bromoethoxy)-7-methoxyquinoline (6110 mg, 21656 μmol) in DMF (25 mL) was stirred at room temperature for 1.5 h. H2O (50 mL) was added and the mixture was extracted with CH2Cl2 (3×50 mL). The organic layer was washed with H2O (50 mL), dried over Na2SO4, and concentrated to an orange oil. The oil was diluted with ether (40 mL) and the mixture was concentrated to slurry. Hexane (20 mL) was added and the mixture was agitated at 60° C. for 50 min and cooled to room temperature. The mixture was filtered, washed with ether to give a light tan solid (3.2 g). The filtrate was concentrated and partitioned between H2O (20 mL) and EtOAc (50 mL). The organic layer was washed with H2O and concentrated. The residue was triturated with acetone-hexane (1:2) to give a second crop of product (1.5 g). MS (ESI pos. ion) calc'd for C16H14ClN3O3: 331.1; found 332.1 (MH+). 1H NMR (400 MHz, Chloroform-d) δ ppm 3.93 (s, 3 H) 4.55 (t, J=5.28 Hz, 2 H) 4.67 (t, J=5.38 Hz, 2 H) 6.64 (s, 1 H) 6.94 (d, J=9.59 Hz, 1 H) 7.14 (dd, J=9.10, 2.45 Hz, 1 H) 7.18 (d, J=9.78 Hz, 1 H) 7.34 (d, J=2.54 Hz, 1 H) 8.05 (d, J=9.19 Hz, 1 H) 8.65 (d, J=5.28 Hz, 1 H).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([N:14]([CH3:21])[CH:15]2[CH2:20][CH2:19][O:18][CH2:17][CH2:16]2)[CH2:10][CH2:9]1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH3:21][N:14]([CH:11]1[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]1)[CH:15]1[CH2:20][CH2:19][O:18][CH2:17][CH2:16]1
Reactant: CN(C1CCOCC1)C1CCN(C(=O)OC(C)(C)C)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CN(C1CCNCC1)C1CCOCC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 97.9 %

Procedure:
A mixture of 4-[methyl(tetrahydropyran-4-yl)-amino]-piperidine-1-carboxylic acid tert-butyl ester (101 mg, 0.34 mmol) and TFA (2 mL) in DCM (5 mL) was stirred at room temperature for 2 h. The reaction mixture was loaded onto an Isolute® SCX-2 cartridge which was washed with MeOH/DCM and the product eluted with 2M NH3/MeOH affording Methylpiperidin-4-yl(tetrahydropyran-4-yl)amine as a white solid (66 mg, 97%). 1H NMR (CDCl3, 300 MHz): δ 4.05-3.97 (m, 2H); 3.38 (td, J=10.9, 3.8 Hz, 2H); 3.19 (d, J=12.1 Hz, 2H); 2.84-2.57 (m, 5H); 2.27 (s, 3H); 1.80-1.49 (m, 8H).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH:11]1[CH2:16][CH2:15][N:14]([CH3:17])[CH2:13][CH2:12]1.[CH3:18][C:19]1[CH:23]=[CH:22][S:21][C:20]=1[C:24](O)=[O:25]>>[CH3:18][C:19]1[CH:23]=[CH:22][S:21][C:20]=1[C:24]([NH:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH:11]1[CH2:16][CH2:15][N:14]([CH3:17])[CH2:13][CH2:12]1)=[O:25]
Reactant: CN1CCC(c2c[nH]c3ccc(N)cc23)CC1
Reactant: Cc1ccsc1C(=O)O
Product: Cc1ccsc1C(=O)Nc1ccc2[nH]cc(C3CCN(C)CC3)c2c1
Yield: 90.5 %

Procedure:
Beginning with 7.0 mg (0.03 mMol) 5-amino-3-(1-methylpiperidin-4-yl)-1H-indole and 12.8 mg (0.09 mMol) 3-methyl-2-thienoic acid, 9.6 mg (90%) of the title compound were recovered.
Reaction SMILES: [NH2:1][C:2]1[CH2:7][CH2:6][CH2:5][C:4](=[O:8])[C:3]=1[CH3:9].C(=O)([O-])[O-].[Na+].[Na+].[I:16]I.S([O-])([O-])=O.[Na+].[Na+].S([O-])([O-])=O>C1COCC1.CO>[NH2:1][C:2]1[CH2:7][CH2:6][CH:5]([I:16])[C:4](=[O:8])[C:3]=1[CH3:9]
Reactant: II
Reactant: CC1=C(N)CCCC1=O
Agent: O=C([O-])[O-]
Agent: O=S([O-])[O-]
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Product: CC1=C(N)CCC(I)C1=O
Temperature: 10 °C
Reaction time: 1 h
Yield: 65 %

Procedure:
50 g (0.4 mol, 1 eq) of 3-amino-2-methyl-2-cyclohexen-1-one and 106 g (1 ml, 2.5 eq) of sodium carbonate are dispensed into the reactor. 480 mL of MeOH is added. The mixture is cooled in an ice bath to 10° C. A solution of iodine in THF, made by dissolving 253 g (1 mol, 2.5 eq) of iodine in 300 ml of THF, is added to above suspension slowly so that the temperature does not exceed 25° C. The resulting dark suspension is stirred for ˜1 h at room temperature and HPLC shows the ending point of reaction (product area percentage at 265 nm was larger than 70%). To the reaction mixture in the ice bath, is added an aqueous saturated solution of sodium sulfite slowly, until the peroxide level is below 3 ppm (by peroxide test strips), and at same time, the sulfite level is below 50 ppm (by sulfite test strips). Approximately 1.5 q of sodium sulfite is used. The suspension is filtered through a celite pad and the pad is washed with 150 mL×3 of THF (washings not optimized). The combined filtrate and washes are concentrated under vacuum until solid crashes out. 250 mL of MTBE is added and the two layer mixture is concentrated again under vacuum until all upper layer evaporates. 250 mL of MTBE and 100 mL of H2O are added and the mixture is stirred at room temperature for 30 minutes. A dark yellow solid crashes out upon stirring and is filtered and washed with water to give 3-amino-6-iodo-2-methyl-2-cyclohexen-1-one 65 g (65% yield).
Reaction SMILES: FC(F)(F)C(O)=O.[S:8]1[CH:12]=[CH:11][C:10]([C:13]2[CH:18]=[CH:17][C:16]([CH:19]([CH3:22])[CH2:20][NH2:21])=[CH:15][CH:14]=2)=[CH:9]1.Cl[C:24]([O:26][CH:27]([CH3:29])[CH3:28])=[O:25]>>[S:8]1[CH:12]=[CH:11][C:10]([C:13]2[CH:18]=[CH:17][C:16]([CH:19]([CH2:22][C:24]([O:26][CH:27]([CH3:29])[CH3:28])=[O:25])[CH2:20][NH2:21])=[CH:15][CH:14]=2)=[CH:9]1
Reactant: CC(C)OC(=O)Cl
Reactant: CC(CN)c1ccc(-c2ccsc2)cc1
Solvent: O=C(O)C(F)(F)F
Product: CC(C)OC(=O)CC(CN)c1ccc(-c2ccsc2)cc1

Procedure:
The title compound was prepared from 2-(4-(3-thienyl)phenyl)propyl amine trifluoroacetate (prepared in example 1) and i-propyl chloroformate in a manner analogous to the procedure described in Example 1.
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH2:50][C:51]2[CH:56]=[CH:55][C:54]([CH2:57][CH3:58])=[CH:53][CH:52]=2)=[CH:4][C:5]([C@H:11]2[C@H:16]([O:17][CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[C@@H:15]([O:25][CH2:26][C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[C@H:14]([O:33][CH2:34][C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=3)[C@@H:13]([CH2:41][O:42][CH2:43][C:44]3[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=3)[O:12]2)=[C:6]([CH:10]=1)[C:7]([OH:9])=[O:8].S(Cl)(Cl)=O.[CH3:63]O>>[Cl:1][C:2]1[C:3]([CH2:50][C:51]2[CH:52]=[CH:53][C:54]([CH2:57][CH3:58])=[CH:55][CH:56]=2)=[CH:4][C:5]([C@H:11]2[C@H:16]([O:17][CH2:18][C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=3)[C@@H:15]([O:25][CH2:26][C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[C@H:14]([O:33][CH2:34][C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=3)[C@@H:13]([CH2:41][O:42][CH2:43][C:44]3[CH:45]=[CH:46][CH:47]=[CH:48][CH:49]=3)[O:12]2)=[C:6]([CH:10]=1)[C:7]([O:9][CH3:63])=[O:8]
Reactant: CO
Reactant: CCc1ccc(Cc2cc([C@@H]3O[C@H](COCc4ccccc4)[C@@H](OCc4ccccc4)[C@H](OCc4ccccc4)[C@H]3OCc3ccccc3)c(C(=O)O)cc2Cl)cc1
Solvent: O=S(Cl)Cl
Product: CCc1ccc(Cc2cc([C@@H]3O[C@H](COCc4ccccc4)[C@@H](OCc4ccccc4)[C@H](OCc4ccccc4)[C@H]3OCc3ccccc3)c(C(=O)OC)cc2Cl)cc1

Procedure:
To a cold (0° C.) stirred solution of 5-chloro-4-(4-ethylbenzyl)-2-((2S,3S,4R,5R,6R)-3,4,5-tris(benzyloxy)-6-(benzyloxymethyl)tetrahydro-2H-pyran-2-yl)benzoic acid (0.15 g, 0.188 mmol) in methanol (10 mL) was added dropwise sulfurous dichloride (0.034 g, 0.021 mL). The mixture was heated to reflux and kept refluxing overnight. The volatiles were removed under reduced pressure, and the residue was quenched with water. The organic phase was separated, and the aqueous phase was extracted with ethyl acetate. The organic phases were combined, washed with saturated sodium bicarbonate, then with water and then with brine, and dried over anhydrous sodium sulfate. After removal of the volatiles, 153 mg of crude solid product was obtained.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]12[CH2:13][C:10]([NH2:14])([CH2:11][CH2:12]1)[CH2:9][CH2:8][CH2:7]2)=[O:5])[CH3:2].C(Cl)Cl.[CH3:18][C:19]1[N:24]=[C:23]([C:25](O)=[O:26])[CH:22]=[N:21][CH:20]=1.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.C(N(CC)CC)C>>[CH2:1]([O:3][C:4]([C:6]12[CH2:13][C:10]([NH:14][C:25]([C:23]3[CH:22]=[N:21][CH:20]=[C:19]([CH3:18])[N:24]=3)=[O:26])([CH2:11][CH2:12]1)[CH2:9][CH2:8][CH2:7]2)=[O:5])[CH3:2]
Reactant: Cc1cncc(C(=O)O)n1
Reactant: CCOC(=O)C12CCCC(N)(CC1)C2
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOC(=O)C12CCCC(NC(=O)c3cncc(C)n3)(CC1)C2
Temperature: 25 °C
Reaction time: 2 h
Yield: 74.7 %

Procedure:
5-Amino-bicyclo[3.2.1]octane-1-carboxylic acid ethyl ester (0.5 g, 2.53 mmol) was dissolved in methylene chloride (10.0 mL, 156 mmol). 6-Methylpyrazine-2-carboxylic acid (0.35 g, 2.53 mmol), benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate (1.12 g, 2.53 mmol) and triethylamine (0.71 mL, 5.07 mmol) in methylene chloride (10.0 mL, 156 mmol) were added. The mixture was stirred at rt for 2 hours. The mixture was concentrated under reduced pressure. The resulting residue was purified on the CombiFlash® system (hexane/ethyl acetate: 100/0 to 30/70 in 8 min, then hexane/ethyl acetate: 30/70) to afford 0.60 g (75%) of the desired product. ESI-MS m/z: 318 (M+H)+