Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[I-].[K+].[CH3:9][C:10]1[CH:15]=[C:14]([CH3:16])[CH:13]=[CH:12][C:11]=1[N:17]([CH2:31][CH:32]([CH3:34])[CH3:33])[S:18]([C:21]1[CH:26]=[CH:25][C:24]([O:27][CH2:28][CH2:29]O)=[CH:23][CH:22]=1)(=[O:20])=[O:19].O>CO>[CH3:9][C:10]1[CH:15]=[C:14]([CH3:16])[CH:13]=[CH:12][C:11]=1[N:17]([CH2:31][CH:32]([CH3:33])[CH3:34])[S:18]([C:21]1[CH:22]=[CH:23][C:24]([O:27][CH2:28][CH2:29][N:1]2[CH2:6][CH2:5][O:4][CH2:3][CH2:2]2)=[CH:25][CH:26]=1)(=[O:20])=[O:19]
Reactant: C1COCCN1
Reactant: Cc1ccc(N(CC(C)C)S(=O)(=O)c2ccc(OCCO)cc2)c(C)c1
Agent: [I-]
Agent: [K+]
Solvent: CO
Solvent: O
Product: Cc1ccc(N(CC(C)C)S(=O)(=O)c2ccc(OCCN3CCOCC3)cc2)c(C)c1
Temperature: 150 °C

Procedure:
To a microwave vial was added morpholine (5.10 μL, 0.058 mmol), potassium iodide (19.26 mg, 0.116 mmol), [Cp*IrCl2]2 (0.639 mg, 0.580 μmol), N-(2,4-dimethylphenyl)-4-[(2-hydroxyethyl)oxy]-N-(2-methylpropyl)benzenesulfonamide (43.8 mg, 0.116 mmol), a stirrer bar and water (0.1 mL). The vial was then sealed and the mixture was heated to 150° C. by microwaves (Biotage Initiator) for 3 hours. Reaction mixture was then diluted with methanol (1 mL) and passed down a pre-conditioned sulfonic acid (SCX) solid phase extraction (SPE) cartridge, eluting with methanol and then 2N methanolic ammonia. The fractions from the methanolic ammonia wash were concentrated in vacuo and the residue purified by mass-directed autoprep, using a formic acid modifier. Product containing fractions were evaporated under a stream of nitrogen to provide product, 2.6 mg. LCMS [LCMS1] Rt 1.01 min, m/z (ES+) 447 (M+H).
Reaction SMILES: F[C:2]1[CH:26]=[CH:25][C:5]([C:6]([NH:8][C:9]2[CH:24]=[CH:23][CH:22]=[CH:21][C:10]=2[C:11]([NH:13][C:14]2[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][N:15]=2)=[O:12])=[O:7])=[C:4]([O:27][CH:28]2[CH2:33][CH2:32][N:31]([C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35])[CH2:30][CH2:29]2)[CH:3]=1.[NH:41]1[CH2:45][CH2:44][CH2:43][CH2:42]1>>[N:41]1([C:2]2[CH:26]=[CH:25][C:5]([C:6]([NH:8][C:9]3[CH:24]=[CH:23][CH:22]=[CH:21][C:10]=3[C:11]([NH:13][C:14]3[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][N:15]=3)=[O:12])=[O:7])=[C:4]([O:27][CH:28]3[CH2:33][CH2:32][N:31]([C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35])[CH2:30][CH2:29]3)[CH:3]=2)[CH2:45][CH2:44][CH2:43][CH2:42]1
Reactant: CC(C)(C)OC(=O)N1CCC(Oc2cc(F)ccc2C(=O)Nc2ccccc2C(=O)Nc2ccc(Cl)cn2)CC1
Reactant: C1CCNC1
Product: CC(C)(C)OC(=O)N1CCC(Oc2cc(N3CCCC3)ccc2C(=O)Nc2ccccc2C(=O)Nc2ccc(Cl)cn2)CC1
Temperature: 80 °C
Yield: 90 %

Procedure:
Using methods substantially equivalent to those described in example 4-F except that the reaction was heated to 80° C., 2-[4-(pyrrolidin-1-yl)-2-(1-tert-butoxycarbonyl-piperidin-4-yloxy)benzoylamino]-N-(5-chloropyridin-2-yl)benzamide (101 mg, 0.16 mmol, 90%) was prepared from 2-[4-fluoro-2-(1-tert-butoxycarbonylpiperidin-4-yloxy)-benzoylamino]-N-(5-chloropyridin-2-yl)benzamide and pyrrolidine.
Reaction SMILES: [CH3:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][NH2:7])=[CH:4][CH:3]=1.[C:10](=O)(O)[O-:11].[Na+].C(Cl)(Cl)=O>C(Cl)Cl.C1(C)C=CC=CC=1>[N:7]([CH2:6][C:5]1[CH:8]=[CH:9][C:2]([CH3:1])=[CH:3][CH:4]=1)=[C:10]=[O:11]
Reactant: O=C([O-])O
Reactant: Cc1ccc(CN)cc1
Agent: O=C(Cl)Cl
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: Cc1ccc(CN=C=O)cc1
Temperature: 0 °C
Reaction time: 0.33 h

Procedure:
A mixture of p-methyl benzylamine (25 g, 0.21 mol) in CH2Cl2 (200 mL) and aqueous saturated solution of sodium bicarbonate (200 mL) was cooled to 0° C. and then treated dropwise with a 20% solution of phosgene in toluene (100 mL). The reaction was stirred at room temperature for 20 minutes and then the organic layer removed and the aqueous layer back-extracted with CH2Cl2. The organic layer was dried (Na2SO4) and the solvent removed in vacuo to give 20.6 g 1-isocyanatomethyl-4-methyl-benzene that was utilized directly in the next reaction without purification.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:9](=[O:11])[CH3:10])[CH:5]=[CH:6][C:7]=1[CH3:8].[O:12]=[C:13]([C:19]([O:21][CH2:22][CH3:23])=[O:20])[C:14]([O:16][CH2:17][CH3:18])=[O:15]>>[CH2:17]([O:16][C:14]([C:13]([OH:12])([CH2:10][C:9]([C:4]1[CH:5]=[CH:6][C:7]([CH3:8])=[C:2]([F:1])[CH:3]=1)=[O:11])[C:19]([O:21][CH2:22][CH3:23])=[O:20])=[O:15])[CH3:18]
Reactant: CCOC(=O)C(=O)C(=O)OCC
Reactant: CC(=O)c1ccc(C)c(F)c1
Product: CCOC(=O)C(O)(CC(=O)c1ccc(C)c(F)c1)C(=O)OCC
Temperature: 120 °C
Reaction time: 48 h
Yield: 79.8 %

Procedure:
A mixture of 3′-fluoro-4′-methylacetophenone (4.92 g, 32.3 mmol) and diethyl ketomalonate (6.19 g, 35.6 mmol) was stirred at 120° C. for 48 hours. The temperature of the reaction mixture was allowed to drop back to room temperature, and the mixture was purified by column chromatography on silica gel [silica gel 100 g, chloroform/ethyl acetate (10/1)] to yield the title compound as yellow crystals (8.41 g, 79.3%).
Reaction SMILES: [I-].[C:2]([C:4]1[CH:5]=[N+:6]([CH3:10])[CH:7]=[CH:8][CH:9]=1)#[N:3].[BH4-].[Na+]>CO.O>[C:2]([C:4]1[CH2:5][N:6]([CH3:10])[CH2:7][CH2:8][CH:9]=1)#[N:3]
Reactant: C[n+]1cccc(C#N)c1
Agent: [BH4-]
Agent: [I-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: CN1CCC=C(C#N)C1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 2 (133 g, 0.54 mol) in methanol (1000 ml) and water (200 ml) was added sodium borohydride (41 g, 1.08 mol) in portions at temperatures below 28° C. After the addition the mixture was stirred for 1 hour at room temperature. Most of the methanol was distilled off. To the residue was added saturated ammonium chloride solution (200 ml), and the mixture was extracted three times with ether (300 ml). The combined organic phases were washed once with water and were then extracted three times with 4M hydrochloric acid (300 ml). The colored aqueous phases were kept for 1 hour at room temperature, and pH was then adjusted to 14. The mixture was extracted three times with ether (250 ml), and the combined organic phases were separated from the solid byproducts. The organic phase was washed with 4 portions of saturated sodium chloride solution (200 ml), dried over magnesium sulphate and evaporated. This yielded 17.4 g (0.143 mol, 26%) of crude oily title compound, which was sufficiently pure according to the 1H NMR spectrum.
Reaction SMILES: [H-].[Na+].CN(C=O)C.[OH:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]([C:18]2[CH:19]=[N:20][CH:21]=[CH:22][CH:23]=2)=[O:17])=[CH:12][CH:11]=1.[C:24]([O:27][CH2:28][CH2:29]Br)(=[O:26])[CH3:25]>O>[CH2:28]([O:27][C:24]([CH2:25][O:8][CH2:9][C:10]1[CH:11]=[CH:12][C:13]([C:16]([C:18]2[CH:19]=[N:20][CH:21]=[CH:22][CH:23]=2)=[O:17])=[CH:14][CH:15]=1)=[O:26])[CH3:29]
Reactant: CC(=O)OCCBr
Reactant: O=C(c1ccc(CO)cc1)c1cccnc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)COCc1ccc(C(=O)c2cccnc2)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
150 mg of 60% sodium hydride was gradually added to 10 ml of a DMF solution of 666 mg of 3-[4-(hydroxymethyl)phenylcarbonyl]pyridine under ice cooling. The reaction solution was stirred at room temperature for 1 hour, then 0.4 ml of 2-bromoethyl acetate was added and the mixture was stirred under the same reaction conditions for 3 hours. After the reaction was completed, the reactive product was diluted with water, extracted with ethyl acetate, and the resultant product was washed with brine, then dried over magnesium sulfate, filtered, and concentrated in vacuo to obtain the desired compound in an amount of 336 mg.
Reaction SMILES: [C:1]([CH:4]([C:15]1[CH:24]=[CH:23][C:22]2[C:21]([CH3:26])([CH3:25])[CH2:20][CH2:19][C:18]([CH3:28])([CH3:27])[C:17]=2[CH:16]=1)[C:5]([O:7]CC1C=CC=CC=1)=[O:6])(=[O:3])[NH2:2].O1CCOCC1>[Pd].C(OCC)C>[C:1]([CH:4]([C:15]1[CH:24]=[CH:23][C:22]2[C:21]([CH3:26])([CH3:25])[CH2:20][CH2:19][C:18]([CH3:28])([CH3:27])[C:17]=2[CH:16]=1)[C:5]([OH:7])=[O:6])(=[O:3])[NH2:2]
Reactant: CC1(C)CCC(C)(C)c2cc(C(C(N)=O)C(=O)OCc3ccccc3)ccc21
Agent: [Pd]
Solvent: CCOCC
Solvent: C1COCCO1
Product: CC1(C)CCC(C)(C)c2cc(C(C(N)=O)C(=O)O)ccc21
Reaction time: 4 h

Procedure:
3.9 g (10 mmol) of benzyl α-carbamoyl-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)acetate, 1.2 g of palladium on carbon (10%) and 100 ml of dioxane were introduced into a reactor. The mixture was hydrogenated at room temperature and at a pressure of 7 bar for 4 hours, filtered on celite and the filtrate evaporated to dryness. The residue obtained was taken up in the minimum amount of ethyl ether, filtered and dried. 2.2 g (76%) of the expected acid were recovered.
Reaction SMILES: [NH:1]([C:3]1[CH:11]=[CH:10][CH:9]=[CH:8][C:4]=1[C:5]([OH:7])=O)[NH2:2].O=[CH:13][CH:14]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:15]#[N:16]>C(O)(=O)C>[C:17]1([C:14]2[CH:13]=[N:2][N:1]3[C:3]4[C:4](=[CH:8][CH:9]=[CH:10][CH:11]=4)[C:5](=[O:7])[NH:16][C:15]=23)[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: N#CC(C=O)c1ccccc1
Reactant: NNc1ccccc1C(=O)O
Solvent: CC(=O)O
Product: O=c1[nH]c2c(-c3ccccc3)cnn2c2ccccc12
Temperature: 150 °C

Procedure:
A mixture of 2-hydrazinobenzoic acid (0.15 g, 0.8 mmol) and 3-oxo-2-phenyl-propionitrile (0.116 g, 0.8 mmol) in acetic acid (0.2 mL) was heated in a microwave (Personal Chemistry SmithSynthesizer) at 150° C. for 10 minutes. The precipitated product was filtered, washed with methanol and diethyl ether and dried. 1H NMR (DMSO-d6) δ 12.10 (s, 1H), 8.10-8.19 (m, 3H) 7.88-7.96 (m, 1H), 7.59 (d, J=7.3 Hz, 2H), 7.52 (t, J=7.8 Hz, 1H), 7.42 (t, J=7.6 Hz, 2 Hz), 7.28 (t, J=7.3 Hz, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]2[C@H:13]([O:14][CH2:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[C@@H:12]([O:22][CH2:23][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[C@H:11]([O:30][CH2:31][C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)[C@@H:10]([CH2:38][O:39][CH2:40][C:41]3[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=3)[O:9]2)=[CH:4][C:3]=1[CH:47]([C:52]1[N:53]=[N+:54]([O-])[C:55]2[CH:61]=[C:60]([CH3:62])[CH:59]=[CH:58][C:56]=2[N:57]=1)[C:48]([O:50][CH3:51])=[O:49].[Cl-].[NH4+].CCOC(C)=O>O1CCOCC1.[Zn]>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]2[C@H:13]([O:14][CH2:15][C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=3)[C@@H:12]([O:22][CH2:23][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[C@H:11]([O:30][CH2:31][C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)[C@@H:10]([CH2:38][O:39][CH2:40][C:41]3[CH:42]=[CH:43][CH:44]=[CH:45][CH:46]=3)[O:9]2)=[CH:4][C:3]=1[CH:47]([C:52]1[N:53]=[N:54][C:55]2[CH:61]=[C:60]([CH3:62])[CH:59]=[CH:58][C:56]=2[N:57]=1)[C:48]([O:50][CH3:51])=[O:49]
Reactant: COC(=O)C(c1nc2ccc(C)cc2[n+]([O-])n1)c1cc([C@@H]2O[C@H](COCc3ccccc3)[C@@H](OCc3ccccc3)[C@H](OCc3ccccc3)[C@H]2OCc2ccccc2)ccc1Cl
Agent: [Cl-]
Agent: [NH4+]
Agent: [Zn]
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: COC(=O)C(c1nnc2cc(C)ccc2n1)c1cc([C@@H]2O[C@H](COCc3ccccc3)[C@@H](OCc3ccccc3)[C@H](OCc3ccccc3)[C@H]2OCc2ccccc2)ccc1Cl
Yield: 74.5 %

Procedure:
3-(1-(2-Chloro-5-((2S,3S,4R,5R,6R)-3,4,5-tris(benzyloxy)-6-(benzyloxymethyl)tetrahydro-2H-pyran-2-yl)phenyl)-2-methoxy-2-oxoethyl)-7-methylbenzo[e][1,2,4]triazine 1-oxide (compound 61, 310 mg, 0.36 mmol) was treated with Zn (500 mg, 7.6 mmol) and ammonium chloride (500 mg, 9.34 mmol) in aqueous dioxane at room temperature for 1 day. The reaction mixture was diluted and work-up with EtOAc. After evaporating the volatile solvent under reduced pressure, the residue was purified with silica gel column (Hx/EtOAc=⅓) to afford title compound (228 mg, 75% yield) as white solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:13]([C:14]3[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=3)[S:12][C:11](=[S:22])[N:10]=2)=[CH:5][CH:4]=1.[Br:23][CH:24](Br)[CH3:25]>[OH-].[Na+]>[Br:23][CH2:24][CH2:25][S:22][C:11]1[S:12][C:13]([C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=2)=[C:9]([C:6]2[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=2)[N:10]=1
Reactant: COc1ccc(C2=NC(=S)SC2c2ccc(OC)cc2)cc1
Reactant: CC(Br)Br
Agent: [Na+]
Agent: [OH-]
Product: COc1ccc(-c2nc(SCCBr)sc2-c2ccc(OC)cc2)cc1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
2.0 g of 4,5-bis-(p-methoxyphenyl)-thiazoline-2-thione are dissolved in 10.4 ml of 2 N sodium hydroxide solution. 2.3 g of dibromoethane are added and the mixture is stirred at room temperature for 4 hours. The organic layer is then removed, the aqueous phase is subsequently shaken with 10 ml of toluene, and the combined organic phases are washed twice with 5 ml of 2 N sodium hydroxide solution each time, dried over magnesium sulphate and concentrated to dryness by evaporation under reduced pressure. 2-(2-Bromoethylthio)-4,5-bis-(p-methoxyphenyl)-thiazole, Rf =0.65 (silica gel, toluene/ethyl acetate 10:1) is obtained.
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:16]3[C:15]([OH:17])=[C:14]([C:18]#[N:19])[C:13](=[O:20])[NH:12][C:11]=3[S:10][CH:9]=2)=[CH:4][CH:3]=1.CC1C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C.[CH2:43]([OH:47])[CH2:44][CH:45]=[CH2:46]>CC([O-])=O.CC([O-])=O.[Pd+2].C(N(CC)CC)C>[OH:17][C:15]1[C:16]2[C:8]([C:5]3[CH:6]=[CH:7][C:2]([CH:46]=[CH:45][CH2:44][CH2:43][OH:47])=[CH:3][CH:4]=3)=[CH:9][S:10][C:11]=2[NH:12][C:13](=[O:20])[C:14]=1[C:18]#[N:19]
Reactant: C=CCCO
Reactant: N#Cc1c(O)c2c(-c3ccc(I)cc3)csc2[nH]c1=O
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CCN(CC)CC
Product: N#Cc1c(O)c2c(-c3ccc(C=CCCO)cc3)csc2[nH]c1=O
Temperature: 150 °C

Procedure:
To a stirred suspension of 3-(4-iodo-phenyl)-4-hydroxy-6-oxo-6,7-dihydro-thieno[2,3-b]pyridine-5-carbonitrile (60 mg, 0.15 mmol), triethylamine (0.1 mL), Pd(OAc)2 (3 mg), P(o-Tol)3 (9 mg), and MgO (18 mg, 0.45 mmol) was added 0.1 mL of but-3-en-1-ol in a single portion. The resulting mixture was heated to 150° C. using microwave reactor for 20 min, then filtered, concentrated and purified by reverse phase HPLC to give the titled compound. MS (ESI) m/e 399 (M+H)+; 1H NMR (500 MHz, DMSO-d6): δ 2.35 (q, J=5 Hz, 2H), 3.53 (t, J=5 Hz, 2H), 6.28 (dt, J=15.91, 7.02 Hz, 1H), 6.45 (d, J=15.91 Hz, 1H), 6.60 (s, 1H), 7.27 (d, J=8.42 Hz, 2H), 7.39 (d, J=8.11 Hz, 2H).
Reaction SMILES: [S:1]([C:5]1[CH:11]=[C:10]([S:12](=[O:15])(=[O:14])[NH2:13])[CH:9]=[C:8]([Br:16])[C:6]=1[NH2:7])(=[O:4])(=[O:3])[NH2:2].[Cl:17][CH2:18][C:19](Cl)=O>O1CCOCC1>[Cl:17][CH2:18][C:19]1[NH:2][S:1](=[O:3])(=[O:4])[C:5]2[CH:11]=[C:10]([S:12](=[O:14])(=[O:15])[NH2:13])[CH:9]=[C:8]([Br:16])[C:6]=2[N:7]=1
Reactant: Nc1c(Br)cc(S(N)(=O)=O)cc1S(N)(=O)=O
Reactant: O=C(Cl)CCl
Solvent: C1COCCO1
Product: NS(=O)(=O)c1cc(Br)c2c(c1)S(=O)(=O)NC(CCl)=N2

Procedure:
A mixture of 2,4-disulfamoyl-6-bromoaniline (0.015 mole) and chloroacetyl chloride (0.016 mole) in 50 ml. of dioxane or other inert organic solvent is heated under reflux conditions for about 24 hours and then concentrated to dryness. The residue is dissolved in concentrated sulfuric acid (5 ml. acid/gram), heated in a steam bath at 60°-70° C. for three hours then poured onto ice. The product, 3-chloromethyl-5-bromo-7-sulfamoyl-1,2,4-benzothiadiazine-1,1-dioxide, is purified by recrystallization from a mixture of acetone-alcohol-water.
Reaction SMILES: [Li]CCCC.C(NC(C)C)(C)C.[Cl:13][C:14]1[CH:19]=[CH:18][C:17]([CH2:20][C:21]([O:23][CH3:24])=[O:22])=[CH:16][CH:15]=1.[Li+].CC([N-]C(C)C)C.Br[CH2:34][C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36]>C1COCC1>[Cl:13][C:14]1[CH:15]=[CH:16][C:17]([CH:20]([CH2:34][C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])[C:21]([O:23][CH3:24])=[O:22])=[CH:18][CH:19]=1
Reactant: COC(=O)Cc1ccc(Cl)cc1
Reactant: CC(C)(C)OC(=O)CBr
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Agent: [Li]CCCC
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: COC(=O)C(CC(=O)OC(C)(C)C)c1ccc(Cl)cc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 88.3 %

Procedure:
n-BuLi (1.60M in hexanes, 35.6 mL, 56.9 mmol) was added to a 0° C. solution of diisopropylamine (8.35 mL, 59.6 mmol) in THF (200 mL). The mixture was stirred at 0° C. for 30 minutes and then cooled to −78° C. A solution of methyl 2-(4-chlorophenyl)acetate (10.0 g, 54.2 mmol) in THF (10 mL) was added to the −78° C. LDA solution by syringe, which was then stirred for 45 minutes. Neat tert-butyl bromoacetate (9.60 mL, 65.0 mmol) was added by syringe, and the reaction was stirred for 15 minutes at −78° C. The bath was removed, and the reaction was allowed to warm to room temperature. After stirring an additional 5 hours, the reaction mixture was quenched with saturated NH4Cl solution, and the solvent(s) were removed in vacuo. The oily mixture was extracted with ethyl acetate, and the organics were combined. The organic portion was dried over MgSO4, filtered, and concentrated in vacuo. The crude oil was purified on silica gel (95:5 hexanes:EtOAc) to afford the 4-tert-butyl 1-methyl 2-(4-chlorophenyl)succinate as a pale yellow oil (14.3 g, 88%). 1H NMR (CDCl3, 400 MHz) δ 7.29 (d, J=7.2 Hz, 2H), 7.22 (d, J=7.2 Hz, 2H), 4.00 (dd, J=9.6, 5.6 Hz, 1H), 3.67 (s, 3H), 3.07 (dd, J=16.4, 9.6 Hz, 1H), 2.58 (dd, J=16.8, 6.0 Hz, 1H), 1.40 (m, 3H).
Reaction SMILES: [OH:1][CH2:2][C:3]([CH2:8][OH:9])([CH2:6][OH:7])[CH2:4][OH:5].[C:10]([OH:29])(=O)[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27].N#N>>[C:10]([O:1][CH2:2][C:3]([CH2:8][O:9][C:10](=[O:29])[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])([CH2:6][O:7][C:10](=[O:29])[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])[CH2:4][O:5][C:10](=[O:29])[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])(=[O:29])[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27]
Reactant: OCC(CO)(CO)CO
Reactant: CCCCCCCCCCCCCCCCCC(=O)O
Agent: N#N
Product: CCCCCCCCCCCCCCCCCC(=O)OCC(COC(=O)CCCCCCCCCCCCCCCCC)(COC(=O)CCCCCCCCCCCCCCCCC)COC(=O)CCCCCCCCCCCCCCCCC
Temperature: 215 °C

Procedure:
A 1000 ml round bottomed flask was charged with 619.9 g (0.12 mol) PEG 150 pentaerythritol and 136.3 g (0.48 mol) triple pressed stearic acid. The mass was heated to 100° C. with a N2 sparge, 1.0 g. phosphoric acid and 0.1 g. hypophosphorus acid were charged. The batch was heated to 215° C. while collecting the water of reaction, and maintained until an acid value of 9.9 was reached. The finished material was a white waxy solid having an acid value of 9.9.
Reaction SMILES: [CH:1]1([C:7]([CH:9]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH2:10][CH:11]=O)=[O:8])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:19][O:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[N:27]1[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]1.[Na]>>[CH3:19][O:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[N:27]1[CH2:32][CH2:31][N:30]([CH2:11][CH2:10][CH:9]([C:7]([CH:1]2[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]2)=[O:8])[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH2:29][CH2:28]1
Reactant: O=CCC(C(=O)C1CCCCC1)c1ccccc1
Reactant: COc1ccccc1N1CCNCC1
Agent: [Na]
Product: COc1ccccc1N1CCN(CCC(C(=O)C2CCCCC2)c2ccccc2)CC1
Yield: 79.4 %

Procedure:
Following the procedures described in the Example 1, Step C, the reaction of 3-cyclohexanecarbonyl-3-phenylpropionaldehyde (1.39 mmol) and 2-methoxyphenylpiperazine (1.39 mmol) with sodium triacetoxyboranehydride (1.80 mmol) gave pure product 1-(2-methoxyphenyl)-4-[3-(cyclohexanecarbonyl)-3-(phenyl)propyl]piperazine (464 mg) in 79% yield. The oxalate salt was prepared as described above.
Reaction SMILES: [CH3:1][O:2][NH2:3].[N+:4](/[C:7](=[CH:9]/[CH3:10])/[CH3:8])([O-:6])=[O:5]>>[CH3:1][O:2][NH:3][CH:9]([CH3:10])[CH:7]([N+:4]([O-:6])=[O:5])[CH3:8]
Reactant: CON
Reactant: C/C=C(\C)[N+](=O)[O-]
Product: CONC(C)C(C)[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 95 %

Procedure:
O-Methylhydroxylamine (176 mg, 3.75 mmol) was added to (E)-2-nitro-2-butene (303 mg, 3 mmol) and the resulting mixture was stirred at 25° C. for 10 minutes. Then, the product was isolated and purified by silica gel thin-layer chromatography (eluent: ethyl acetate/hexane=1/5). O-Methyl-N-(α-methyl-β-nitropropyl)hydroxylamine (mixture of diastereomers, yield: 95%)
Reaction SMILES: C[O:2][C:3]([C@H:5]1[CH2:10][CH2:9][C@H:8]([CH2:11][NH:12][S:13]([C:16]2[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][CH:17]=2)(=[O:15])=[O:14])[CH2:7][CH2:6]1)=[O:4].[OH-].[K+].Cl>CO.O>[F:25][C:22]([F:23])([F:24])[C:19]1[CH:18]=[CH:17][C:16]([S:13]([NH:12][CH2:11][C@H:8]2[CH2:7][CH2:6][C@H:5]([C:3]([OH:4])=[O:2])[CH2:10][CH2:9]2)(=[O:14])=[O:15])=[CH:21][CH:20]=1
Reactant: COC(=O)[C@H]1CC[C@H](CNS(=O)(=O)c2ccc(C(F)(F)F)cc2)CC1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: O=C(O)[C@H]1CC[C@H](CNS(=O)(=O)c2ccc(C(F)(F)F)cc2)CC1
Temperature: 25 °C

Procedure:
A solution of 1.09 g (2.87 mmol) of trans-4-[(4-trifluoromethyl-benzenesulfonylamino)-methyl]-cyclohexanecarboxylic acid methyl ester and 569 mg (85%, 8.62 mmol, 3 eq) of KOH in 20 mL of MeOH and 1 mL of H2O were refluxed for 3 h. After cooling to RT, 4.5 mL of 2M aqueous HCl were added and extracted with 3 portions of 20 mL of CH2Cl2. The combined organic phases were washed with H2O, then with brine, dried over anhydrous Na2SO4 and finally evaporated, leaving 1 g (95%) of trans-4-[(4-trifluoromethyl-benzenesulfonylamino)-methyl]-cyclohexanecarboxylic acid as white solid, MS: 364 ((M−H)−).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([N:10]2[CH2:15][CH2:14][C:13]([CH2:22][CH2:23][N:24]3[CH:29]4[CH2:30][CH2:31][CH:25]3[CH2:26][CH:27]([N:32]3[C:36]5[CH:37]=[CH:38][CH:39]=[CH:40][C:35]=5[N:34]=[C:33]3[CH3:41])[CH2:28]4)([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[CH2:12][CH2:11]2)=[O:9])=[CH:4][C:3]=1[S:42]([NH2:45])(=[O:44])=[O:43].[C:46](Cl)(=[O:49])[CH2:47][CH3:48]>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([N:10]2[CH2:11][CH2:12][C:13]([CH2:22][CH2:23][N:24]3[CH:29]4[CH2:30][CH2:31][CH:25]3[CH2:26][CH:27]([N:32]3[C:36]5[CH:37]=[CH:38][CH:39]=[CH:40][C:35]=5[N:34]=[C:33]3[CH3:41])[CH2:28]4)([C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=3)[CH2:14][CH2:15]2)=[O:9])=[CH:4][C:3]=1[S:42]([NH:45][C:46](=[O:49])[CH2:47][CH3:48])(=[O:43])=[O:44]
Reactant: Cc1nc2ccccc2n1C1CC2CCC(C1)N2CCC1(c2ccccc2)CCN(C(=O)c2ccc(Cl)c(S(N)(=O)=O)c2)CC1
Reactant: CCC(=O)Cl
Product: CCC(=O)NS(=O)(=O)c1cc(C(=O)N2CCC(CCN3C4CCC3CC(n3c(C)nc5ccccc53)C4)(c3ccccc3)CC2)ccc1Cl
Yield: 73 %

Procedure:
2-Chloro-5-[(4-{2-[3-(2-methyl-1H-benzimidazol-1-yl)-8-azabicyclo-[3.2.1]oct-8-yl]ethyl}-4-phenylpiperidin-1-yl)carbonyl]-N-propionylbenzene-sulfonamide (16 mg, 73%) was obtained as amorphous solid from 2-chloro-5-[(4-{2-[3-(2-methyl-1H-benzimidazol-1-yl)-8-azabicyclo[3.2.1]oct-8-yl]ethyl}-4-phenyl piperidin-1-yl)carbonyl]benzenesulfonamide and propionyl chloride following the procedure outlined in example 476. 1H NMR (300 MHz, DMSO-d6) δ 7.81-7.56 (m, 3H), 7.49 (d, J=8.4 Hz, 1H), 7.39-7.26 (m, 5H), 7.24-7.08 (m, 3H), 4.80 (br, 1H), 3.99-3.93 (m, 1H), 3.58-3.38 (m, 5H), 3.11-2.99 (m, 1H), 2.47 (m, 4H), 2.22-1.72 (m, 17H), 0.89-0.81 (m, 3H). HRMS m/z (M+H)+ calcd: 702.2881, obsd: 702.2885.
Reaction SMILES: [NH:1]1[C:5]([C:6]2[CH:7]=[C:8]([CH:31]=[C:32]([C:34]([F:37])([F:36])[F:35])[CH:33]=2)[CH2:9][O:10][CH2:11][C:12]2([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[CH2:17][CH2:16][N:15](C(OC(C)(C)C)=O)[CH2:14][CH2:13]2)=[N:4][N:3]=[N:2]1>FC(F)(F)C(O)=O.C(Cl)Cl>[NH:4]1[C:5]([C:6]2[CH:7]=[C:8]([CH:31]=[C:32]([C:34]([F:37])([F:35])[F:36])[CH:33]=2)[CH2:9][O:10][CH2:11][C:12]2([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[CH2:13][CH2:14][NH:15][CH2:16][CH2:17]2)=[N:1][N:2]=[N:3]1
Reactant: CC(C)(C)OC(=O)N1CCC(COCc2cc(-c3nnn[nH]3)cc(C(F)(F)F)c2)(c2ccccc2)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: FC(F)(F)c1cc(COCC2(c3ccccc3)CCNCC2)cc(-c2nnn[nH]2)c1
Reaction time: 1 h

Procedure:
tert-Butyl 4-((3-(1H-tetrazol-5-yl)-5-(trifluoromethyl)benzyloxy)methyl)-4-phenylpiperidine-1-carboxylate (30.0 mg, 0.058 mmol) was dissolved in a trifluoroacetic acid/methylene chloride mixture (1:1, 1 mL) and stirred under nitrogen for 1 h. The solvent was removed in vacuo and the resulting crude mixture passed through a strong cation exchange column. After washing the column with several volumes of methanol, the product was eluted by washing the column with 2 M ammonia in methanol. Concentration afforded 11.0 mg (45%). LC/MS (HPLC method 3): tR=1.89 min, 418.88 (MH)+.