Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH3:20][C:21]1[CH:22]=[C:23]([O:28][S:29]([C:32]2[CH:33]=[N:34][CH:35]=[CH:36][CH:37]=2)(=[O:31])=[O:30])[CH:24]=[C:25]([OH:27])[CH:26]=1.[CH2:38](O)[CH2:39][CH2:40][OH:41].N(C(OCC)=O)=NC(OCC)=O>O1CCCC1>[CH3:20][C:21]1[CH:22]=[C:23]([O:28][S:29]([C:32]2[CH:33]=[N:34][CH:35]=[CH:36][CH:37]=2)(=[O:31])=[O:30])[CH:24]=[C:25]([CH:26]=1)[O:27][CH2:38][CH2:39][CH2:40][OH:41]
Reactant: OCCCO
Reactant: Cc1cc(O)cc(OS(=O)(=O)c2cccnc2)c1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: Cc1cc(OCCCO)cc(OS(=O)(=O)c2cccnc2)c1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
A solution of triphenylphosphine (1.52 g, 0.0058 mol), 5-methyl-3-(3-pyridinylsulfonyloxy)phenol (1.54 g, 0.0058 mol), as prepared in the preceding step, and 1,3-propanediol (0.42 mL, 0.0058 mol) in anhydrous tetrahydrofuran (50 mL) was treated with diethyl azodicarboxylate (0.92 mL, 0.0058 mol) and allowed to stir at ambient temperature for 3 days. The tetrahydrofuran was evaporated, and the solid residue was treated with hexane. Solvent was decanted and the solid was treated with dichloromethane and diluted with hexane to produce a crystalline solid which was collected by filtration. The filtrate was evaporated to dryness and partitioned between water and diethyl ether. The aqueous layer was separated and extracted with diethyl ether (2×50 mL). The diethyl ether extracts were combined, washed with brine, and dried over anhydrous sodium sulfate. The diethyl ether extract was evaporated to a gum which was purified further by silica gel chromatography using 10% ethyl acetate/90% dichloromethane, followed by 15% ethyl acetate/85% dichloromethane, 20% ethyl acetate/80% dichloromethane, and finally 25% ethyl acetate/75% dichloromethane. The appropriate fractions were combined and evaporated to a gum (1.3 g). 1H-NMR (300 MHz, CDCl3) δ 9.03 (d, 1H), 8.89 (dd, 1H), 8.14 (m, 1H), 6.64 (s, 1H), 6.42 (s, 1H), 6.37 (t, 1H), 4.00 (t, 2H), 3.81 (q, 2H), 2.25 (s, 3H), and 1.99 (pentet, 2H). Mass spectrum (MALDI-TOF, α-cyano-4-hydroxycinnamic acid matrix) calcd. for C15H17NO5S: 278.0 (M-C3H7O+Na). Found: 278.9.
Reaction SMILES: [CH:1]([O:4][C:5]1[CH:35]=[CH:34][C:8]([O:9][C:10]2[S:11][C:12]([C:15]3[CH:20]=[CH:19][C:18]([CH:21]([N:23]4C(=O)C5C(=CC=CC=5)C4=O)[CH3:22])=[CH:17][CH:16]=3)=[CH:13][N:14]=2)=[CH:7][CH:6]=1)([CH3:3])[CH3:2].O.NN>C(Cl)Cl.C(O)C>[CH:1]([O:4][C:5]1[CH:35]=[CH:34][C:8]([O:9][C:10]2[S:11][C:12]([C:15]3[CH:20]=[CH:19][C:18]([CH:21]([NH2:23])[CH3:22])=[CH:17][CH:16]=3)=[CH:13][N:14]=2)=[CH:7][CH:6]=1)([CH3:2])[CH3:3]
Reactant: CC(C)Oc1ccc(Oc2ncc(-c3ccc(C(C)N4C(=O)c5ccccc5C4=O)cc3)s2)cc1
Agent: NN
Solvent: CCO
Solvent: ClCCl
Solvent: O
Product: CC(C)Oc1ccc(Oc2ncc(-c3ccc(C(C)N)cc3)s2)cc1
Temperature: 25 °C
Yield: 99.8 %

Procedure:
To a solution of Example 1E (0.65 g, 0.0013 mol) in a mixture of methylene chloride (20 mL) and ethanol (2 mL) was added hydrazine monohydrate (0.66 g, 0.013 mol) and the mixture was refluxed under nitrogen for 2 hours. The white suspension was cooled to room temperature, concentrated, dissolved in methylene chloride, and filtered. The filtrate was concentrated to give 0.46 g of the title compound, which was used without further purification. 1H NMR (300 MHz, CDCl3) δ ppm 1.35 (d, J=5.88 Hz, 6 H) 139 (d, J=6.62 Hz, 3 H) 4.13 (q, J=6.62 Hz, 1 H) 4.44-4.62 (m, 1 H) 6.86-6.98 (m, 2 H) 7.16-7.25 (m, 2 H) 7.30-7.44 (m, 5 H). MS (ESI), m/z 337.7 (M−17)+.
Reaction SMILES: [NH2:1][C:2]1[C:3]([NH2:18])=[C:4]([CH:9]=[C:10]([N:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)[N:11]=1)[C:5]([O:7][CH3:8])=[O:6].[CH3:19][C:20](O)=O>>[CH3:19][C:20]1[NH:1][C:2]2=[N:11][C:10]([N:12]3[CH2:17][CH2:16][O:15][CH2:14][CH2:13]3)=[CH:9][C:4]([C:5]([O:7][CH3:8])=[O:6])=[C:3]2[N:18]=1
Reactant: COC(=O)c1cc(N2CCOCC2)nc(N)c1N
Reactant: CC(=O)O
Product: COC(=O)c1cc(N2CCOCC2)nc2[nH]c(C)nc12

Procedure:
A solution of methyl 2,3-diamino-6-morpholinoisonicotinate (4.3 g, 17 mmol) in CH3COOH (100 mL) was refluxed for 16 h. LCMS showed no methyl 2,3-diamino-6-morpholinoisonicotinate left and the desired product formed. It was cooled to room temperature and the solvent was removed in vacuo. The residue was then purified by chromatography on silica gel eluted with MeOH/DCM=1/50 to afford the desired product as a black solid (1.07 g, 23%); LC/MS: MS (ES+) m/e 277 (MH+); 1H NMR (300 MHz, CDCl3) δ ppm 2.69 (s, 3H), 3.58 (t, J=4.8 Hz, 4H), 3.86 (t, J=4.8 Hz, 4H), 4.02 (s, 3H), 7.12 (s, 1H).
Reaction SMILES: [C:1]12([CH2:11][CH2:12][N:13]([CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])[C:14](=[O:17])[CH2:15]Br)[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.C(=O)([O-])[O-].[K+].[K+].CI.[NH2:31][CH2:32][CH2:33][C:34]1[CH:39]=[CH:38][N:37]=[CH:36][CH:35]=1>CN(C)C=O.C(OCC)C.O>[C:1]12([CH2:11][CH2:12][N:13]([CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])[C:14](=[O:17])[CH2:15][NH:31][CH2:32][CH2:33][C:34]3[CH:39]=[CH:38][N:37]=[CH:36][CH:35]=3)[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2
Reactant: CCCCCN(CCC12CC3CC(CC(C3)C1)C2)C(=O)CBr
Reactant: NCCc1ccncc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CI
Product: CCCCCN(CCC12CC3CC(CC(C3)C1)C2)C(=O)CNCCc1ccncc1
Temperature: 75 °C
Reaction time: 8 h
Yield: 41.6 %

Procedure:
Next, 2-bromoacetic acid N-[2-(1-adamantyl)ethyl]-N-pentylamide (1.3 g, 3.5 mmol) was dissolved in anhydrous N,N-dimethylformamide (30 ml), potassium carbonate (1.5 g, 11 mmol), methyl iodide (1.6 g, 11 mmol) and 4-(2-aminoethyl)pyridine (0.43 g, 3.5 mmol) were added to the solution, and the mixture was stirred at an external temperature of 75° C. overnight. Water (100 ml) and diethyl ether (100 ml) were added to the reaction mixture, the reaction mixture was distributed, and the diethyl ether layer was washed with water (70 ml) twice and a saturated aqueous sodium chloride solution (120 ml) once successively and dried over anhydrous magnesium sulfate. The diethyl ether layer was concentrated under reduced pressure, and the concentrate was purified by silica gel column chromatography to give 0.6 g (40%) of the titled compound as an oily matter.
Reaction SMILES: F[B-](F)(F)F.N1(O[C:16](N(C)C)=[N+:17](C)[CH3:18])C2C=CC=CC=2N=N1.[CH2:23]([O:30][C:31]([N:33]1[CH2:42][CH2:41][C:40]2[C:35](=[CH:36][C:37]([O:43][C:44]3[CH:49]=[CH:48][C:47]([C:50]([OH:52])=O)=[CH:46][CH:45]=3)=[CH:38][CH:39]=2)[CH2:34]1)=[O:32])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.CNC.CN1CCOCC1>O1CCCC1>[CH2:23]([O:30][C:31]([N:33]1[CH2:42][CH2:41][C:40]2[C:35](=[CH:36][C:37]([O:43][C:44]3[CH:49]=[CH:48][C:47]([C:50](=[O:52])[N:17]([CH3:18])[CH3:16])=[CH:46][CH:45]=3)=[CH:38][CH:39]=2)[CH2:34]1)=[O:32])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: O=C(O)c1ccc(Oc2ccc3c(c2)CN(C(=O)OCc2ccccc2)CC3)cc1
Reactant: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: CNC
Agent: F[B-](F)(F)F
Solvent: CN1CCOCC1
Solvent: C1CCOC1
Product: CN(C)C(=O)c1ccc(Oc2ccc3c(c2)CN(C(=O)OCc2ccccc2)CC3)cc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
2-(1H-Benzotriazol-1-yl)-1,1,3,3-tetramethyluronium tetrafluoroborate (0.44 g) is added to a solution of 7-(4-carboxy-phenoxy)-3,4-dihydro-1H-isoquinoline-2-carboxylic acid benzyl ester, dimethylamine (2 mol/L in tetrahydrofuran, 0.68 mL), and N-methyl-morpholine (0.41 mL) in tetrahydrofuran (20 mL) chilled in an ice bath. The cooling bath is removed and the resulting mixture is stirred at room temperature for 3 h. Then another portion of dimethylamine (2 mol/L in tetrahydrofuran, 0.70 mL) and 2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium tetrafluoroborate (0.20 g) are added and the mixture is further stirred for another 4 h. After adding another portion of dimethylamine (2 mol/L in tetrahydrofuran, 0.30 mL), the mixture ist stirred at room temperature overnight. The mixture is concentrated and the residue is purified by chromatography on silica gel (ethyl acetate) to furnish the title compound.
Reaction SMILES: [O:1]=[C:2]1[CH2:6][CH2:5][CH2:4][N:3]1[C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8].C([N-]C(C)C)(C)C.[Li+].[Br:22][C:23]([CH2:25]Br)=[CH2:24]>C1COCC1>[Br:22][C:23](=[CH2:24])[CH2:25][CH:6]1[CH2:5][CH2:4][N:3]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[C:2]1=[O:1]
Reactant: CC(C)(C)OC(=O)N1CCCC1=O
Reactant: C=C(Br)CBr
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: C=C(Br)CC1CCN(C(=O)OC(C)(C)C)C1=O
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 8.3 %

Procedure:
In a 250 mL round-bottom flask, tert-butyl 2-oxopyrrolidine-1-carboxylate (4.12 g, 22.2 mmol) was combined with 25 mL of THF and cooled to −78° C. Lithium diisopropylamide (1.5M in THF) (14.8 mL, 22.2 mmol) was added slowly and the mixture was agitated for 30 minutes. 2,3-Dibromopropene (2.72 mL, 22.2 mmol) was added and the mixture was agitated overnight and allowed to warm to ambient temperature. The reaction was then quenched with sodium bicarbonate solution and extracted twice with ether. The extracts were washed with brine and evaporated. The crude product was purified by column chromatography, eluting with 20% ethyl acetate/hexane, to provide the title compound (0.560 g, 8.3% yield).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=O)=[CH:4][C:3]=1[N:11]1[CH:15]=[C:14]([C:16]2[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=2)[N:13]=[N:12]1.[NH2:22][C:23]1[C:24]([O:38][CH3:39])=[C:25]([NH:33][S:34]([CH3:37])(=[O:36])=[O:35])[CH:26]=[C:27]([C:29]([CH3:32])([CH3:31])[CH3:30])[CH:28]=1>>[C:29]([C:27]1[CH:26]=[C:25]([NH:33][S:34]([CH3:37])(=[O:36])=[O:35])[C:24]([O:38][CH3:39])=[C:23]([NH:22][C:6](=[O:8])[C:5]2[CH:9]=[CH:10][C:2]([Cl:1])=[C:3]([N:11]3[CH:15]=[C:14]([C:16]4[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=4)[N:13]=[N:12]3)[CH:4]=2)[CH:28]=1)([CH3:32])([CH3:30])[CH3:31]
Reactant: O=C(O)c1ccc(Cl)c(-n2cc(-c3cccnc3)nn2)c1
Reactant: COc1c(N)cc(C(C)(C)C)cc1NS(C)(=O)=O
Product: COc1c(NC(=O)c2ccc(Cl)c(-n3cc(-c4cccnc4)nn3)c2)cc(C(C)(C)C)cc1NS(C)(=O)=O

Procedure:
Example 11 was prepared by coupling 4-chloro-3-(4-pyridin-3-yl-[1,2,3]triazol-1-yl)-benzoic acid with N-(3-amino-5-tert-butyl-2-methoxy-phenyl)-methane-sulfonamide in the same manner as Example 1. ESI MS m/z 555 [C26H27ClN6O4S+H]+.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1([C:10]([O:12]C)=[O:11])[CH2:7][CH:6]1[CH:8]=[CH2:9])=[O:4].COC(=O)CC(OC)=O.BrC/C=C/CBr.[OH-].[K+].Cl>CO.[Cl-].[Cl-].[Ca+2].O.C(OCC)C>[CH3:1][O:2][C:3]([C:5]1([C:10]([OH:12])=[O:11])[CH2:7][CH:6]1[CH:8]=[CH2:9])=[O:4]
Reactant: C=CC1CC1(C(=O)OC)C(=O)OC
Agent: BrC/C=C/CBr
Agent: Cl
Agent: [Ca+2]
Solvent: COC(=O)CC(=O)OC
Solvent: CO
Solvent: O
Product: C=CC1CC1(C(=O)O)C(=O)OC
Reaction time: 12 h
Yield: 82.9 %

Procedure:
36.8 g (0.2 mol) of 2-vinyl cyclopropane-1,1-dicarboxylic acid dimethyl ester, obtainable from malonic acid dimethyl ester and trans-1,4-dibromobut-2-ene (cf U.S. Pat. No. 4,713,478 and U.S. Pat. No. 4,713,479), are dissolved in 65 ml of methanol in a 100 ml two-necked flask with a thermometer, magnetic stirrer and CaCl2 tube, and the solution is cooled to ca 50° C. with iced water. Then 13.3 g (0.2 mol) of KOH are added in portions in such a way that the temperature does not rise above 15° C. In order to complete the reaction, stirring is continued for 12 hours, and then volatile components are removed in a rotary evaporator in vacuo (50 mbar) at 50° C. The oil obtained (ca 43 g) is dissolved in 50 ml of water and is adjusted to a pH of ca 2-3 with concentrated hydrochloric acid accompanied by cooling. The organic phase is taken up in 100 ml of diethyl ether, extracted twice more with in each case 100 ml of diethyl ether, and the combined ether phases are dried over anhydrous Na2SO4. The solution is stabilized with 0.01 g of hydroquinone monomethyl ether, concentrated in vacuo and dried under a medium high vacuum. The result is 28.2 g (83% yield) of a colourless liquid.
Reaction SMILES: [Li]CCCC.Br[C:7]1[CH:15]=[CH:14][C:10]2[O:11][CH2:12][O:13][C:9]=2[CH:8]=1.[O:16]1[C:20]2([CH2:25][CH2:24][C:23](=[O:26])[CH2:22][CH2:21]2)[O:19][CH2:18][CH2:17]1>C1COCC1>[O:11]1[C:10]2[CH:14]=[CH:15][C:7]([C:23]3([OH:26])[CH2:24][CH2:25][C:20]4([O:19][CH2:18][CH2:17][O:16]4)[CH2:21][CH2:22]3)=[CH:8][C:9]=2[O:13][CH2:12]1
Reactant: Brc1ccc2c(c1)OCO2
Reactant: O=C1CCC2(CC1)OCCO2
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: OC1(c2ccc3c(c2)OCO3)CCC2(CC1)OCCO2
Temperature: -78 °C
Reaction time: 0.33 h

Procedure:
A solution of n-BuLi (2.5 M in hexanes, 24 mL, 60 mmol) was dropped slowly into a solution of 5-bromo-benzo[1,3]dioxole (Aldrich, 10.0 g, 50 mmol) in THF (100 mL) at −78° C. over 10 min. The reaction was stirred for additional 20 min. at −78° C. A solution of 1,4-dioxa-spiro[4.5]decan-8-one (Aldrich, 8.60 g, 55 mmol) in THF (20 mL) was slowly dropped into the reaction. After addition, the reaction was stirred for additional 2 hours at −78° C. The reaction was then quenched with diluted NH4Cl solution and warmed to room temperature. The solvent was removed in vacuo and the residue was partitioned between ethyl acetate and water. The organic layer was washed with brine, dried over anhydrous Na2SO4, filtered and concentrated to give a yellow solid, which was then purified by silica gel column on a CombiFlash® system (Teledyne Isco, Inc, Lincoln, Nebr.) using hexanes and ethyl acetate (from 10% ethyl acetate to 100% ethyl acetate) to afford the title compound as a white solid.
Reaction SMILES: [Na].[C:2]1([CH2:8][CH2:9][SH:10])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CS(O[C@H:16]1[CH2:21][CH2:20][C@H:19]2[C@H:22]3[C@H:32]([C:33](=[O:35])[CH2:34][C@:17]12[CH3:18])[C@:30]1([CH3:31])[C:25](=[CH:26][C:27](=[O:36])[CH:28]=[CH:29]1)[CH2:24][CH2:23]3)(=O)=O>C(O)C>[C:2]1([CH2:8][CH2:9][S:10][C@@H:16]2[CH2:21][CH2:20][C@H:19]3[C@H:22]4[C@H:32]([C:33](=[O:35])[CH2:34][C@:17]23[CH3:18])[C@:30]2([CH3:31])[C:25](=[CH:26][C:27](=[O:36])[CH:28]=[CH:29]2)[CH2:24][CH2:23]4)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: SCCc1ccccc1
Reactant: C[C@]12CC(=O)[C@H]3[C@@H](CCC4=CC(=O)C=C[C@@]43C)[C@@H]1CC[C@@H]2OS(C)(=O)=O
Agent: [Na]
Solvent: CCO
Product: C[C@]12CC(=O)[C@H]3[C@@H](CCC4=CC(=O)C=C[C@@]43C)[C@@H]1CC[C@H]2SCCc1ccccc1

Procedure:
To 2.25 gm. of sodium metal dissolved in 180 ml. of ethanol is added 8 ml. of β-phenylethyl mercaptan followed by 3 gm. of 17β-methanesulfonyloxy-1,4-androstadiene-3,11-dione. Heat the reaction at reflux for 48 hours. Obtain a residue in a manner similar to that described in Example 1A. Chromatograph the residue on a 300 gm. silica gel column eluting with chloroform/ethyl acetate (2:1). Combine the desired fractions as determined by thin layer chromatography, evaporate and crystallize the resultant residue from ether/hexane to obtain the title compound; m.p. 112°-115° C.
Reaction SMILES: [N+:1]([O-:4])(O)=[O:2].[CH3:5][C:6]1[N:14]=[C:13]([CH3:15])[CH:12]=[C:11]([OH:16])[C:7]=1[C:8]([OH:10])=[O:9]>S(=O)(=O)(O)O>[CH3:5][C:6]1[N:14]=[C:13]([CH3:15])[C:12]([N+:1]([O-:4])=[O:2])=[C:11]([OH:16])[C:7]=1[C:8]([OH:10])=[O:9]
Reactant: O=[N+]([O-])O
Reactant: Cc1cc(O)c(C(=O)O)c(C)n1
Agent: O=S(=O)(O)O
Product: Cc1nc(C)c([N+](=O)[O-])c(O)c1C(=O)O
Temperature: 0 °C
Yield: 77 %

Procedure:
20 ml of 90% nitric acid is added to 100 ml of 98% sulphuric acid with stirring and cooling. To this solution is added portion-wise 6.9 g (41.1 mmol) of 2,6-dimethyl-4-hydroxy-nicotinic acid. The mixture is stirred at 80° C. for 1 hour, cooled down and added cautiously 300 g of crushed ice. The resulting suspension is filtered off. The cake is washed with water and dried. There is obtained 6.7 g (77%) of a white solid.
Reaction SMILES: CS(C)=O.[H-].[Na+].[Cl:7][C:8]1[CH:13]=[CH:12][C:11]([CH2:14][C:15]#[N:16])=[CH:10][CH:9]=1.Br[CH2:18][CH2:19][O:20][CH2:21][CH2:22]Br>C(OCC)C>[Cl:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2([C:15]#[N:16])[CH2:22][CH2:21][O:20][CH2:19][CH2:18]2)=[CH:10][CH:9]=1
Reactant: BrCCOCCBr
Reactant: N#CCc1ccc(Cl)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CCOCC
Solvent: CS(C)=O
Product: N#CC1(c2ccc(Cl)cc2)CCOCC1
Temperature: 25 °C
Yield: 95.5 %

Procedure:
Into a round-bottom flask under argon fitted with an addition funnel and thermometer was added anhydrous dimethylsulfoxide (60 mL) and sodium hydride (1.17 g, 48.8 mmol, 95%). Then a solution of (4-chlorophenyl)acetonitrile (3.37 g, 22.2 mmol) and 2-bromoethyl ether (90%, 3.41 mL, 24.4 mmol) in diethyl ether (15 mL) was added slowly, while maintaining the reaction temperature at 20-30° C. The reaction mixture was maintained at room temperature for overnight. The reaction mixture was carefully quenched with water (50 mL) and then extracted with hexane (3×100 mL). The organic extracts were combined, washed with water (3×75 mL), brine (50 mL), dried over anhydrous magnesium sulfate, filtered, and concentrated to give a pale yellow oil. The oil was purified by column chromatography on silica gel using hexane/ethyl acetate (80:20) to give 4.7 g of 4-(4-chlorophenyl)tetrahydropyran-4-carbonitrile, as a colorless oil. 1H NMR (CDCl3, 300 MHz): δ 2.00-2.15 (m, 4H); 3.89 (dt, 2H, J1=12.6 Hz, J2=3 Hz); 4.05-4.11 (m, 2H); 7.37-7.45 (m, 4H); 3C NMR (CDCl3, 300 MHz): δ 36.66 (2C), 41.51, 64.98 (2C), 121.40, 127.03, 129.37, 134.31, 138.46.
Reaction SMILES: [S:1]1[C:5]2[C:6]([C:10](OC)=[O:11])=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[N:2]1.[H-].C([Al+]CC(C)C)C(C)C.[OH-].[Na+].Cl>O1CCCC1.CCCCCC.O>[S:1]1[C:5]2[C:6]([CH2:10][OH:11])=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[N:2]1
Reactant: COC(=O)c1cccc2nnsc12
Agent: CC(C)C[Al+]CC(C)C
Agent: Cl
Agent: [H-]
Solvent: CCCCCC
Solvent: C1CCOC1
Solvent: O
Product: OCc1cccc2nnsc12
Reaction time: 0.33 h
Yield: 96.4 %

Procedure:
To a solution of methyl 1,2,3-benzothiadiazole-7-carboxylate (10.0 g, 51.5 mmol) in tetrahydrofuran (200 mL) was added a solution (1 M, 154 mL, 154 mmol) of diisobutylaluminum hydride in hexane at −78° C. and the mixture was stirred for 20 min. The mixture was stirred at room temperature for 1 hr, water and 1 M aqueous sodium hydroxide solution (20 mL) were added at 0° C., and the mixture was stirred at 0° C. for 10 min. To the reaction mixture was added 6 M hydrochloric acid (10 mL) and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by recrystallization (ethyl acetate/methanol) to give the title compound (8.25 g, yield 96%).
Reaction SMILES: Cl[C:2]1[C:3]2[C:10]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)=[C:9]([C:17]([O:19][CH3:20])=[O:18])[S:8][C:4]=2[N:5]=[CH:6][N:7]=1.CCN(C(C)C)C(C)C.[CH2:30]1[C@H:36]2[NH:37][C@H:32]([CH2:33][CH:34]([OH:38])[CH2:35]2)[CH2:31]1>C1COCC1.O>[OH:38][CH:34]1[CH2:33][CH:32]2[N:37]([C:2]3[C:3]4[C:10]([C:11]5[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=5)=[C:9]([C:17]([O:19][CH3:20])=[O:18])[S:8][C:4]=4[N:5]=[CH:6][N:7]=3)[CH:36]([CH2:30][CH2:31]2)[CH2:35]1
Reactant: OC1C[C@H]2CC[C@@H](C1)N2
Reactant: COC(=O)c1sc2ncnc(Cl)c2c1-c1ccccc1
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: C1CCOC1
Product: COC(=O)c1sc2ncnc(N3C4CCC3CC(O)C4)c2c1-c1ccccc1
Reaction time: 8 h
Yield: 43.9 %

Procedure:
To a stirred solution of methyl 4-chloro-5-phenyl-thieno[2,3-d]pyrimidine-6-carboxylate (3.231 g, 10.59 mmol) and DIPEA (2.39 mL, 15.89 mmol) in THF (60 mL) at room temperature was added nortropine (1.682 g, 15.89 mmol) and the reaction left to stir overnight. The reaction was diluted with water (60 mL) and the layers separated. The aqueous layer was acidified to pH 3 and extracted repeatedly with 3:1 chloroform/IPA. The combined organic layers were dried over sodium sulphate, filtered and concentrated under reduced pressure to afford methyl 4-(3-hydroxy-8-azabicyclo[3.2.1]octan-8-yl)-5-phenyl-thieno[2,3-d]pyrimidine-6-carboxylate (1.839 g, 44%). LCMS: Rt=4.23, 396 (M+1).
Reaction SMILES: [C:1]([C:3]1[S:4][C:5]([C:9]([O:11][CH2:12][CH3:13])=[O:10])=[C:6]([CH3:8])[N:7]=1)#[CH:2].C(N(CC)C(C)C)(C)C.[CH2:23]([N:30]=[N+:31]=[N-:32])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>O1CCCC1.[Cu]I>[CH2:23]([N:30]1[CH:2]=[C:1]([C:3]2[S:4][C:5]([C:9]([O:11][CH2:12][CH3:13])=[O:10])=[C:6]([CH3:8])[N:7]=2)[N:32]=[N:31]1)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: [N-]=[N+]=NCc1ccccc1
Reactant: C#Cc1nc(C)c(C(=O)OCC)s1
Agent: [Cu]I
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)c1sc(-c2cn(Cc3ccccc3)nn2)nc1C
Temperature: 25 °C
Reaction time: 17 h
Yield: 98.6 %

Procedure:
To a solution of ethyl 2-ethynyl-4-methylthiazole-5-carboxylate (0.19 g, 0.71 mmol) in tetrahydrofuran (5 mLl) was added copper(I) iodide (0.003 g, 0.014 mmol), N,N-diisopropylethylamine (0.15 mL, 0.74 mmol) and benzylazide (0.11 g, 0.85 mmol). The reaction mixture was stirred at ambient temperature for 17 hours and concentrated in vacuo. The residue was purified by column chromatography (ethyl acetate:hexanes, 1:1) to afford the title compound as a yellow solid (0.23 g, 98%): 1H NMR (300 MHz, CDCl3) δ 7.98 (s, 1H), 7.39-7.26 (m, 5H), 5.54 (s, 2H), 4.30 (q, J=7.1 Hz, 2H), 2.67 (s, 3H), 1.21 (t, J=7.1 Hz, 3H); MS (ES+) m/z 329.3 (M+1).
Reaction SMILES: [CH2:1]([NH:5][C:6](=[O:18])[CH2:7][C@H:8]1[CH2:13][C@@H:12]([CH2:14][OH:15])[O:11][C:10]([CH3:17])([CH3:16])[O:9]1)[CH2:2][CH2:3][CH3:4].CC1(C)N([O])C(C)(C)CCC1.[Br-].[K+].Cl[O-].[Na+]>C(Cl)Cl>[CH2:1]([NH:5][C:6](=[O:18])[CH2:7][C@H:8]1[CH2:13][C@@H:12]([CH:14]=[O:15])[O:11][C:10]([CH3:17])([CH3:16])[O:9]1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCNC(=O)C[C@H]1C[C@@H](CO)OC(C)(C)O1
Agent: CC1(C)CCCC(C)(C)N1[O]
Agent: [Br-]
Agent: [K+]
Solvent: ClCCl
Product: CCCCNC(=O)C[C@H]1C[C@@H](C=O)OC(C)(C)O1

Procedure:
A solution of N-butyl-2-((4R,6S)-6-(hydroxymethyl)-2,2-dimethyl-1,3-dioxan-4-yl) acetamide (6 grams) in methylene chloride (24 ml) was added to a pre-cooled mixture of TEMPO (0.01 gram), methylene chloride (36 ml) and potassium bromide (0.26 grams) at −5 to −15° C. Sodium hypo chlorite (15.6 ml) was added to the reaction mixture at −15 to −5° C. and stirred. After completion of the reaction, quenched it with 10% sodium thio sulfate solution at room temperature and water was added to it. Both organic and aqueous layers were separated and organic layer was washed with water followed by saturated sodium chloride solution. The solvent from organic layer was distilled off under reduced pressure to get the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][CH:8]=[C:7]([CH2:10][CH2:11]I)[C:6]=2[CH:13]=1.[CH3:14][C:15]1[CH:16]=[C:17]2[C:22](=[C:23]([N:25]3[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]3)[CH:24]=1)[N:21]=[CH:20][CH:19]=[CH:18]2>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][CH:8]=[C:7]([CH2:10][CH2:11][N:28]3[CH2:29][CH2:30][N:25]([C:23]4[CH:24]=[C:15]([CH3:14])[CH:16]=[C:17]5[C:22]=4[N:21]=[CH:20][CH:19]=[CH:18]5)[CH2:26][CH2:27]3)[C:6]=2[CH:13]=1
Reactant: Cc1cc(N2CCNCC2)c2ncccc2c1
Reactant: Clc1ccc2occ(CCI)c2c1
Product: Cc1cc(N2CCN(CCc3coc4ccc(Cl)cc34)CC2)c2ncccc2c1

Procedure:
8-{4-[2-(5-chloro-1-benzofuran-3-yl)ethyl]-1-piperazinyl}-6-methyl-quinoline was prepared by generally following the procedure outlined in example 12, step 6, starting from the 2-(5-chloro-1-benzofuran-3-yl)ethyl iodide (306 mg, 1 mmol) and 6-methyl-8-piperazino quinoline (227 mg, 1 mmol). The product was purified by silica-gel column chromatography by initially eluting it with 80% ethyl acetate:hexane and then with 5% methanol:ethyl acetate, yielding a brown oil. Yield: 140 mg (34%); (M+H): 406; 1HNMR (400 MHz, CDCl3): δ□8.82˜8.80 (dd, J1=1.7 Hz, J2=1.7 Hz, 1H), 8.03˜7.80 (dd, J1=1.7 Hz, J2=1.7 Hz 1H), 7.60˜6.70 (m, 7H), 3.48˜2.81 (m, 12H), 2.5 (s, 3H).
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]=[CH:3][CH:2]=1>O=[Pt]=O.C(O)C>[NH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[NH:4][CH2:3][CH2:2]1
Reactant: c1ccc2nccnc2c1
Agent: O=[Pt]=O
Solvent: CCO
Product: c1ccc2c(c1)NCCN2

Procedure:
Quinoxaline was hydrogenated at 60 psi, 50° C. with PtO2 catalyst in ethanol, to produce 1,2,3,4-tetrahydroquinoxaline (THQ).