Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([C:7]2[C:8]3[N:9]([CH:13]=[C:14]([CH2:16][OH:17])[N:15]=3)[N:10]=[CH:11][CH:12]=2)[CH2:3][CH2:2]1.C1C(=O)N([Br:25])C(=O)C1.[O-]S([O-])(=S)=O.[Na+].[Na+]>C(#N)C>[Br:25][C:13]1[N:9]2[N:10]=[CH:11][CH:12]=[C:7]([N:4]3[CH2:3][CH2:2][O:1][CH2:6][CH2:5]3)[C:8]2=[N:15][C:14]=1[CH2:16][OH:17]
Reactant: O=C1CCC(=O)N1Br
Reactant: OCc1cn2nccc(N3CCOCC3)c2n1
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: CC#N
Product: OCc1nc2c(N3CCOCC3)ccnn2c1Br
Temperature: -10 °C
Reaction time: 0.17 h

Procedure:
A suspension of compound 5d (1.0 g, 4.3 mmol) in acetonitrile (100 mL) was stirred at −10° C. (in an ice/salt water bath) for 10 min, followed by addition of NBS (0.68 g, 3.8 mmol) in acetonitrile (20 mL) dropwise via an additional funnel. After the mixture was stirred in the ice-water bath for 2 h, 5% Na2S2O3 solution (10 mL) was added to quench the reaction. The aqueous layer was extracted with DCM (2×100 mL). The combined organic layers were washed with brine, and dried over Na2SO4. The mixture was filtered, and the filtrate was concentrated to leave compound 14a as a white solid. Mass Spectrum (LCMS, ESI pos.): Calcd. for C11H13BrN4O2: 313.0 (M+H). found: 313.1.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:28])[CH2:5][NH:6][C:7]1[CH:12]=[C:11]([Cl:13])[C:10]([O:14][C:15]2[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[C:17]([CH:23]([CH2:25][CH3:26])[CH3:24])[CH:16]=2)=[C:9]([Cl:27])[CH:8]=1)[CH3:2].Br[CH2:30][C:31]([O:33][CH2:34][CH3:35])=[O:32].C(N(C(C)C)CC)(C)C>CN(C=O)C.C(OCC)(=O)C>[CH2:1]([O:3][C:4](=[O:28])[CH2:5][N:6]([C:7]1[CH:12]=[C:11]([Cl:13])[C:10]([O:14][C:15]2[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[C:17]([CH:23]([CH2:25][CH3:26])[CH3:24])[CH:16]=2)=[C:9]([Cl:27])[CH:8]=1)[CH2:30][C:31]([O:33][CH2:34][CH3:35])=[O:32])[CH3:2]
Reactant: CCOC(=O)CNc1cc(Cl)c(Oc2ccc(OC)c(C(C)CC)c2)c(Cl)c1
Reactant: CCOC(=O)CBr
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Product: CCOC(=O)CN(CC(=O)OCC)c1cc(Cl)c(Oc2ccc(OC)c(C(C)CC)c2)c(Cl)c1
Temperature: 0 °C
Yield: 48.1 %

Procedure:
To [4-(3-sec-Butyl-4-methoxy-phenoxy)-3,5-dichloro-phenylamino]-acetic acid ethyl ester (Example 2, step 2) (48.0 g, 0.11 mol), ethyl bromoacetate (188 g, 1.12 mol) and diisopropylethylamine (145.57 g, 1.12 mol) in DMF (480 mL) were stirred at 120° C. for 18 h. The reaction mixture was poured in to ice-water. The product was taken up in ethyl acetate, washed with water, brine, dried over sodium sulphate, filtered and concentrated to give the crude product, which was purified by column chromatography over flash silica gel (hexane:ethyl acetate 90:10) to give pure {[4-(3-sec-Butyl-4-methoxy-phenoxy)-3,5-dichloro-phenyl]-ethoxycarbonylmethyl-amino}-acetic acid ethyl ester (27.1 g, 47% yield).
Reaction SMILES: [C:1]([CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([CH2:13][CH:14]([NH:16][CH2:17][CH:18]([OH:28])[C:19]2[N:20]=[C:21]([C:24]([F:27])([F:26])[F:25])[S:22][CH:23]=2)[CH3:15])=[CH:9][CH:8]=1)([O:3][CH3:4])=[O:2].[C:29]([O:33][CH3:34])(=[O:32])[CH:30]=O.C1(C)C=CC=CC=1.C(OCC)(=O)C>O>[C:1]([CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([CH2:13][CH:14]([N:16]2[CH2:17][CH:18]([C:19]3[N:20]=[C:21]([C:24]([F:26])([F:27])[F:25])[S:22][CH:23]=3)[O:28][CH:30]2[C:29]([O:33][CH3:34])=[O:32])[CH3:15])=[CH:9][CH:8]=1)([O:3][CH3:4])=[O:2]
Reactant: COC(=O)COc1ccc(CC(C)NCC(O)c2csc(C(F)(F)F)n2)cc1
Reactant: COC(=O)C=O
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Solvent: O
Product: COC(=O)COc1ccc(CC(C)N2CC(c3csc(C(F)(F)F)n3)OC2C(=O)OC)cc1

Procedure:
0.52 g (0.0012 mol) of N-[2-(4-carbomethoxymethoxyphenyl)-1-methylethyl]-2-hydroxy-2-(2-trifluoromethylthiazol-4-yl)ethanamine and 0.211 g (0.0024 mol) of methyl glyoxylate and 25 ml toluene are heated at 120° C. for 10 minutes and then boiled under a water trap for 1 hour. The solution is cooled, 50 ml of ethyl acetate are added, and the mixture is shaken with 30 ml of water. The organic phase is separated off, dried over sodium sulphate and concentrated. The residue is purified on a laboratory size B prepacked column (supplied by Merck) using toluene/ethyl acetate=20:1.5 as eluant. Fraction A (diastereomer pairs A and B),
Reaction SMILES: Br[C:2]1[CH:8]=[C:7]([CH3:9])[C:5]([NH2:6])=[C:4]([CH2:10][CH3:11])[CH:3]=1.[C-]#N.[Na+].[I-].[K+].[CH3:17][NH:18]CCNC>C1(C)C=CC=CC=1.[Cu]I.C(OCC)(=O)C.O>[NH2:6][C:5]1[C:7]([CH3:9])=[CH:8][C:2]([C:17]#[N:18])=[CH:3][C:4]=1[CH2:10][CH3:11]
Reactant: CCc1cc(Br)cc(C)c1N
Reactant: CNCCNC
Agent: [Cu]I
Agent: [C-]#N
Agent: [I-]
Solvent: O
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: CCc1cc(C#N)cc(C)c1N
Temperature: 118 °C
Reaction time: 21 h
Yield: 99.2 %

Procedure:
A double-jacketed 4 L-flask is charged with 4-bromo-2-ethyl-6-methyl-aniline (324 g, 1.51 mol), sodium cyanide (100.3 g, 1.97 mol), potassium iodide (50.2 g, 0.302 mol) and copper(I)iodide (28.7 g, 0.151 mol). The flask is evacuated three times and refilled with nitrogen. A solution of N,N′-dimethylethylenediamine (191.5 mL, 1.51 mol) in toluene (750 mL) is added. The mixture is heated to 118° C. and stirred at this temperature for 21 h. The mixture is cooled to 93° C. and water (1250 mL) is added to obtain a solution. Ethyl acetate (1250 mL) is added at 22-45° C. and the layers are separated. The org. phase is washed with 10% aq. citric acid (2×500 mL) and water (500 mL). The separated org. phase is evaporated to dryness to afford 4-amino-3-ethyl-5-methyl-benzonitrile (240 g) as a metallic black solid; 1H NMR (CDCl3): δ1.29 (t, J=7.5 Hz, 3H), 2.19 (s, 3H), 2.52 (q, J=7.3 Hz, 2H), 4.10 (s br, 1H), 7.25 (s, 2H).
Reaction SMILES: Br[CH2:2][CH2:3][C:4]#[C:5][Si:6]([CH3:9])([CH3:8])[CH3:7].[F:10][C:11]1[CH:19]=[CH:18][C:14]2[NH:15][N:16]=[N:17][C:13]=2[CH:12]=1.[OH-].[Na+]>>[F:10][C:11]1[CH:19]=[CH:18][C:14]2=[N:15][N:16]([CH2:2][CH2:3][C:4]#[C:5][Si:6]([CH3:9])([CH3:8])[CH3:7])[N:17]=[C:13]2[CH:12]=1
Reactant: C[Si](C)(C)C#CCCBr
Reactant: Fc1ccc2[nH]nnc2c1
Agent: [Na+]
Agent: [OH-]
Product: C[Si](C)(C)C#CCCn1nc2ccc(F)cc2n1
Temperature: 100 °C
Yield: 100 %

Procedure:
(4-Bromo-but-1-ynyl)-trimethyl-silane (294 mg, 1.43 mmol) was added to a solution of 5-fluoro-1H-benzo[d][1,2,3]triazole (187 mg, 1.36 mmol) in a solution of NaOH (2N, 955 μL). The reaction mixture was heated at 100° C. for 14 hours, then it was cooled down and was extracted with DCM. The organic phase was washed with water, brine, dried over MgSO4, filtered and evaporated to yield 355 mg (1.36 mmol) 5-fluoro-2-(4-trimethylsilanyl-but-3-ynyl)-2H-benzo[d][1,2,3]triazole including the two others isomers.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:15][C:12]2([CH2:14][CH2:13]2)[NH:11][CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].I[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>CS(C)=O>[C:1]([O:5][C:6]([N:8]1[CH2:15][C:12]2([CH2:13][CH2:14]2)[N:11]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCNC2(CC2)C1
Reactant: Ic1ccccc1
Solvent: CS(C)=O
Product: CC(C)(C)OC(=O)N1CCN(c2ccccc2)C2(CC2)C1
Temperature: 120 °C

Procedure:
A stirred solution of 4,7-diaza-spiro[2.5]octane-7-carboxylic acid tert-butyl ester (0.1 g, 0.471 mmol) [C.A.S. 886766-28-5], iodobenzene (0.026 ml, 0.236) and CsOH (0.079 g, 0.471 mmol) in DMSO (1 ml) was heated in a sealed tube at 120° C. for 20 min. After cooling, additional 4,7-diaza-spiro[2.5]octane-7-carboxylic acid tert-butyl ester (2 eq.) was added, and the mixture was then heated at 120° C. for 20 min. The mixture was cooled. The mixture was washed with NH4Cl (aqueous sat. solution) was added and extracted with Et2O. The organic phase was separated, washed with water, dried (Na2SO4) and concentrated in vacuo. The crude product was purified by manifold (Sep-Pak® silica cartridge; DCM as eluent). The desired fractions were collected and concentrated in vacuo to yield intermediate D61 (0.021 g, 31%) as a white solid.
Reaction SMILES: [Br:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([S:12]([CH3:15])(=[O:14])=[O:13])[CH:10]=2)[CH:5]=[CH:4][C:3]=1[NH:16][C:17](=[O:23])[O:18][C:19]([CH3:22])([CH3:21])[CH3:20].[H-].[Na+].[Cl:26][CH:27]=[CH:28][CH2:29]Cl>CN(C=O)C.[Na+].[Cl-]>[Br:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([S:12]([CH3:15])(=[O:14])=[O:13])[CH:10]=2)[CH:5]=[CH:4][C:3]=1[N:16]([CH2:29][CH:28]=[CH:27][Cl:26])[C:17](=[O:23])[O:18][C:19]([CH3:20])([CH3:22])[CH3:21]
Reactant: ClC=CCCl
Reactant: CC(C)(C)OC(=O)Nc1ccc2ccc(S(C)(=O)=O)cc2c1Br
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N(CC=CCl)c1ccc2ccc(S(C)(=O)=O)cc2c1Br
Temperature: 25 °C
Reaction time: 6 h
Yield: 96.8 %

Procedure:
A stirred solution of 203 (2.29 g, 5.72 mmol) in dry DMF (20 mL) was treated portionwise at 0° C. with NaH (275 mg, 60% in oil, 6.88 mmol). The mixture was warmed to room temperature for 30 min, then cooled to 0° C. and treated with 1,3-dichloropropene (1.66 mL, 18 mmol, mixed isomers). The mixture was stirred at room temperature for a further 6 h, then diluted with 10% aqueous NaCl and extracted with EtOAc (×2). The combined organic layers were washed with water (×2), dried, and concentrated to dryness under reduced pressure at 100° C. The residue was chromatographed on silica gel, eluting with CH2Cl2/EtOAc (19:1) to give crude tert-butyl 1-bromo-7-(methylsulfonyl)-2-naphthyl(3-chloro-2-propen-1-yl)carbamate (204) (2.63 g, 97%) as a foam: 1H NMR [(CD3)2SO] (mixture of rotamers and B and Z forms) δ 8.78 (s, 1H), 8.32 (dd, J=8.6, 2.2 Hz, 1H), 8.18, 8.17 (2 d, J=8.7 Hz, 1H), 8.13-8.06 (1, 1H), 7.75, 7.70 (2 d, J=8.7 Hz, 1H), 6.44-6.29 (m, 1H), 6.20-6.01 (m, 1H), 4.58-4.48, 4.43-4.22, 4.16-4.05 (3 m, 21H), 3.35 (s, 3H), 1.50, 1.27 (2 s, 9H). HRMS (FAB) calcd. for C19H2279Br35ClCNO4S (m/z 474.0141, found 474.0143.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:7]=[CH:8][C:9]([N:12]2[CH2:17][CH2:16][CH:15](C(=O)N)[CH2:14][CH2:13]2)=[N:10][CH:11]=1)=[O:5])[CH3:2].FC(F)(F)C(OC1C(OC(=O)C(F)(F)F)=C(I)C=CC=1)=O.O.C(#[N:45])C>>[CH2:1]([O:3][C:4]([C:6]1[CH:7]=[CH:8][C:9]([N:12]2[CH2:17][CH2:16][CH:15]([NH2:45])[CH2:14][CH2:13]2)=[N:10][CH:11]=1)=[O:5])[CH3:2]
Reactant: CC#N
Reactant: CCOC(=O)c1ccc(N2CCC(C(N)=O)CC2)nc1
Agent: O=C(Oc1cccc(I)c1OC(=O)C(F)(F)F)C(F)(F)F
Solvent: O
Product: CCOC(=O)c1ccc(N2CCC(N)CC2)nc1
Temperature: 65 °C

Procedure:
A solution comprising 4-carbamoyl-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-5′-carboxylic acid ethyl ester (step a) (2.04 g, 7.36-mmol) and bis(trifluoroacetoxy) iodobenzene (3.80 g, 8.83 mmol) in acetonitrile (13 ml) is treated with water (5 ml) and heated to 65° C. for 30 hours. The solvent is partially removed in vacuo and the resulting solution is acidified to pH1 using 12 M HCl. The solution is extracted with ethyl acetate and this organic portion is discarded. The aqueous portion is basified to pH 8-9 using 2M potassium carbonate solution and then extracted with ethyl acetate and dichloromethane. The organic portions are washed with brine, dried (Na2SO4) and concentrated in vacuo. The resulting residue is triturated with diethyl ether followed by diethyl ether/ethyl acetate (1:1, 5×0.7 ml) and dried in vacuo to yield the title compound as an off-white solid. MS (ES+) m/e 250 (MH+)
Reaction SMILES: [Br:1][C:2]1[CH:21]=[CH:20][C:5]([CH2:6][NH:7][C:8](=[O:19])[C:9]2[CH:14]=[CH:13][C:12]([F:15])=[CH:11][C:10]=2[N+:16]([O-])=O)=[C:4]([F:22])[CH:3]=1.C(=O)(O)[O-].[Na+]>C(O)C>[NH2:16][C:10]1[CH:11]=[C:12]([F:15])[CH:13]=[CH:14][C:9]=1[C:8]([NH:7][CH2:6][C:5]1[CH:20]=[CH:21][C:2]([Br:1])=[CH:3][C:4]=1[F:22])=[O:19]
Reactant: O=C(NCc1ccc(Br)cc1F)c1ccc(F)cc1[N+](=O)[O-]
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Product: Nc1cc(F)ccc1C(=O)NCc1ccc(Br)cc1F
Yield: 81.3 %

Procedure:
A solution of N-(4-bromo-2-fluorobenzyl)-4-fluoro-2-nitrobenzamide (4.79 g) and stannous chloride (12.24 g) in ethanol (26 ml) was stirred at 70°-80° C. for 30 minutes under an atmosphere of nitrogen. After cooling, the reaction mixture was poured into ice-cold water and neutralized with aqueous saturated sodium bicarbonate. The resulting precipitates were filtered off and washed with ethyl acetate. The filtrate was extracted with ethyl acetate and the extract was washed with water and dried. Removal of the solvent gave 2-amino-N-(4-bromo-2-fluorobenzyl)-4-fluorobenzamide (3.58 g).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([CH3:8])[NH:5][C:4]2=[CH:9][C:10]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)=[N:11][C:3]=12.[CH3:18][C:19]1[O:23][C:22]([CH2:24][NH2:25])=[CH:21][CH:20]=1.C([O-])([O-])=O.[K+].[K+].C(Cl)Cl>O>[CH3:18][C:19]1[O:23][C:22]([CH2:24][NH:25][C:2]2[N:7]=[C:6]([CH3:8])[NH:5][C:4]3[C:3]=2[N:11]=[C:10]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:9]=3)=[CH:21][CH:20]=1
Reactant: Cc1ccc(CN)o1
Reactant: Cc1nc(Cl)c2nc(-c3ccccc3)cc-2[nH]1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: ClCCl
Product: Cc1nc(NCc2ccc(C)o2)c2nc(-c3ccccc3)cc-2[nH]1
Temperature: 140 °C
Reaction time: 2.5 h
Yield: 61.2 %

Procedure:
To a mixture of 4-chloro-2-methyl-6-phenylpyrrolo[3,2-d]pyrimidine (Example 1(e)) (47.6 mg, 0.19 mmol) and 5-methyl-2-furanmethanamine (Acros Chemical Company) (100 μL, 0.98 mmol) was added a solution of K2CO3 (0.11 g, 0.76 mmol) in H2O (1.5 mL). This mixture was stirred at 140° C. in a closed-capped Wheaton vial for 2.5 h. After cooling, CH2Cl2 (10 mL) and H2O (10 mL) were added. The organic solution was removed and the aqueous solution washed with CH2Cl2 (10 mL). The combined organic solutions were washed with saturated NaCl (15 mL), dried over MgSO4, filtered and concentrated under reduced pressure. The residue was purified by flash chromatography (3% MeOH:CHCl3 on silica gel) to give 37 mg (62%) of the title compound as a beige solid. Mp: 125-127.5° C. MS m/z: 319 (M+1), 294, 225, 195, 147. 1H NMR (CD3OD, 400 MHz): δ 2.28 (s, 3), 2.53 (s, 3), 4.72 (s, 2), 5.97 (d, 1, J=3.0), 6.24 (d, 1, J=3.0), 6.66 (s, 1), 7.34 (m, 1), 7.43 (t, 2, J=7.7), 7.71 (dd, 2, J=7.1, 1.4). HRMS: Calcd for M+H, C19H18ON4: 319.1555. Found: 319.1566.
Reaction SMILES: [Br:1]N1C(=O)NC(=O)N(Br)C1=O.[CH2:12]([O:14][C:15]1[CH:16]=[C:17]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=2[F:31])[CH:18]=[CH:19][C:20]=1[C:21]([O:23][CH3:24])=[O:22])[CH3:13].CN(C=O)C>O>[Br:1][C:18]1[CH:19]=[C:20]([C:21]([O:23][CH3:24])=[O:22])[C:15]([O:14][CH2:12][CH3:13])=[CH:16][C:17]=1[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[F:31]
Reactant: O=c1[nH]c(=O)n(Br)c(=O)n1Br
Reactant: CCOc1cc(-c2ccccc2F)ccc1C(=O)OC
Solvent: CN(C)C=O
Solvent: O
Product: CCOc1cc(-c2ccccc2F)c(Br)cc1C(=O)OC
Temperature: 25 °C
Reaction time: 1 h
Yield: 178.9 %

Procedure:
Dibromoisocyanuric acid (0.631 g) was added to a mixture of methyl 3-ethoxy-2′-fluorobiphenyl-4-carboxylate (1.14 g) and DMF (10 mL), and the resultant mixture was stirred at room temperature for 2 hours. Dibromoisocyanuric acid (0.238 g) was further added to the reaction mixture, and the mixture was stirred at room temperature for 1 hour. Water was added to the reaction mixture, followed by extraction with ethyl acetate. The obtained organic layer was washed with water and saturated saline and dried over anhydrous magnesium sulfate, and then, the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane/ethyl acetate) to obtain the title compound (1.39 g).
Reaction SMILES: [CH2:1]([N:3]1[C:7]([OH:8])=[C:6]([C:9](=[O:30])[C:10]2[CH:15]=[CH:14][C:13]([S:16]([CH3:19])(=[O:18])=[O:17])=[C:12]([N:20]3[CH2:25][CH:24]([CH2:26][CH3:27])[O:23][CH:22]([OH:28])[CH2:21]3)[C:11]=2[Cl:29])[CH:5]=[N:4]1)[CH3:2].[C:31](Cl)(=O)C>CO.ClCCl>[CH2:1]([N:3]1[C:7]([OH:8])=[C:6]([C:9](=[O:30])[C:10]2[CH:15]=[CH:14][C:13]([S:16]([CH3:19])(=[O:18])=[O:17])=[C:12]([N:20]3[CH2:25][CH:24]([CH2:26][CH3:27])[O:23][CH:22]([O:28][CH3:31])[CH2:21]3)[C:11]=2[Cl:29])[CH:5]=[N:4]1)[CH3:2]
Reactant: CC(=O)Cl
Reactant: CCC1CN(c2c(S(C)(=O)=O)ccc(C(=O)c3cnn(CC)c3O)c2Cl)CC(O)O1
Solvent: CO
Solvent: ClCCl
Product: CCC1CN(c2c(S(C)(=O)=O)ccc(C(=O)c3cnn(CC)c3O)c2Cl)CC(OC)O1
Reaction time: 1 h

Procedure:
A solution of 1.08 g (2.35 mmol) of 1-ethyl-4-(2-chloro-3-(2-hydroxy-6-ethylmorpholin-4-yl)-4-methylsulfonylbenzoyl)-5-hydroxypyrazole in 5 mL of methanol was added with stirring to a solution of 20 mL of methanol pre-treated with 2 mL of acetyl chloride. After 1 hour, the mixture was diluted with dichloromethane and the resulting solution was washed with water and concentrated by evaporation under reduced pressure. The two component mixture residue obtained was separated and purified by preparative reverse-phase HPLC eluting with 1:1 acetonitrile/water containing 0.1 percent phosphoric acid. The fractions containing each of the two products were combined separately, concentrated by evaporation under reduced pressure and extracted with dichloromethane. The dichloromethane solutions were dried over sodium sulfate and concentrated by evaporation under reduced pressure to obtain the title compound as cis and trans isomers, both as syrups. There was 294 mg (27 percent of theory) of the more polar cis compound and 548 mg (49 percent of theory) of the less polar trans compound. These syrups were separately crystallized from ethanol to obtain the cis and trans isomers of the title compound as brown and off-white crystals, respectively.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[NH:10][C:11]([NH:14][C:15](=[O:28])[C:16]([CH3:27])([S:18]([CH:21]3[CH2:26][CH2:25][O:24][CH2:23][CH2:22]3)(=[O:20])=[O:19])[CH3:17])=[N:12][N:13]=2)=[CH:5][CH:4]=1.[H-].[Na+].[CH3:31]I>C1COCC1>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:10]=[C:11]([NH:14][C:15](=[O:28])[C:16]([CH3:17])([S:18]([CH:21]3[CH2:26][CH2:25][O:24][CH2:23][CH2:22]3)(=[O:20])=[O:19])[CH3:27])[N:12]([CH3:31])[N:13]=2)=[CH:5][CH:4]=1
Reactant: CI
Reactant: COc1ccc(-c2nnc(NC(=O)C(C)(C)S(=O)(=O)C3CCOCC3)[nH]2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COc1ccc(-c2nc(NC(=O)C(C)(C)S(=O)(=O)C3CCOCC3)n(C)n2)cc1
Reaction time: 1 h
Yield: 36.7 %

Procedure:
To a solution of 238 mg (0.58 mmol) of N-[5-(4-methoxy-phenyl)-4H[1,2,4]triazol-3-yl]-2-methyl-2-(tetrahydro-pyran-4-sulfonyl)-propionamide (prepared according to Amide Method A) in anhydrous THF (2 mL) at room temperature are added 94 mg (2.32 mmol) of sodium hydride (60% dispersion in mineral oil). The reaction mixture is stirred for 1 h and then 145 μL (2.32 mmol) of methyl iodide are added. The reaction is stirred at room temperature for 1 h. The reaction mixture is quenched with saturated aqueous NH4Cl solution (5 mL) and extracted with ethyl acetate (3×10 mL). The combined organic extracts are dried over Na2SO4, filtered and the filtrate is concentrated under reduced pressure. The residue is triturated with methanol and the resulting precipitate is purified by mass-directed preparative HPLC (neutral method) to afford 90 mg of N-[5-(4-methoxy-phenyl)-2-methyl-2H-[1,2,4]triazol-3-yl]-2-methyl-2-(tetrahydro-pyran-4-sulfonyl)-propionamide. Yield: 97%, ES-MS: m/z 423 [M+H].
Reaction SMILES: C([O-])(=O)C.[K+].CC1(C)C(C)(C)OB(B2OC(C)(C)C(C)(C)O2)O1.[CH2:24]([O:31][CH2:32][CH2:33][CH2:34][S:35][C:36]1[CH:41]=[CH:40][C:39](Br)=[CH:38][CH:37]=1)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.[CH2:43]([O:45][C:46](=[O:55])/[C:47](/Br)=[CH:48]/[CH:49]1[CH2:53][CH2:52][CH2:51][CH2:50]1)[CH3:44].C(=O)([O-])[O-].[Na+].[Na+]>CN(C=O)C.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].C(OCC)(=O)C>[CH2:43]([O:45][C:46](=[O:55])/[C:47](/[C:39]1[CH:40]=[CH:41][C:36]([S:35][CH2:34][CH2:33][CH2:32][O:31][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)=[CH:37][CH:38]=1)=[CH:48]/[CH:49]1[CH2:53][CH2:52][CH2:51][CH2:50]1)[CH3:44]
Reactant: CCOC(=O)/C(Br)=C/C1CCCC1
Reactant: Brc1ccc(SCCCOCc2ccccc2)cc1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: CC(=O)[O-]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCOC(=O)/C(=C/C1CCCC1)c1ccc(SCCCOCc2ccccc2)cc1
Temperature: 80 °C
Reaction time: 1 h
Yield: 178.4 %

Procedure:
Add potassium acetate (1.7 g, 17.3 mmol), 4,4,5,5,4′,4′,5′,5′-octamethyl-[2,2′]bi[[1,3,2]dioxaborolanyl] (1.6 g, 6.35 mmol) and dichloro[1,1′-bis(diphenylphosphino)ferrocene]palladium (II) dichloromethane adduct (424 mg, 0.58 mmol) to a solution of 1-(3-benzyloxy-propylsulfanyl)-4-bromo-benzene (1.95 g, 5.77 mmol) in 15 mL DMF and stir 1 hour at 80° C. Then add (Z)-2-bromo-3-cyclopentyl-acrylic acid ethyl ester (2.85 g, 11.54 mmol), dichloro[1,1′-bis(diphenylphosphino)ferrocene]palladium (II) dichloromethane adduct (424 mg, 0.58 mmol) and sodium carbonate solution (2 M, 14.0 mL, 28.0 mmol) and stir at 80° C. over night. Add 100 mL ethyl acetate and filter. Wash with water and brine, filter through a hydrophobic filter paper and concentrate. Further purification via silica gel column chromatography, eluting with dichloromethane affords the title compound as yellow oil (4.37 g). MS (m/e): 425 (M+H).
Reaction SMILES: [C:1]([O:5][CH3:6])(=[O:4])[CH:2]=[CH2:3].[CH:7]([NH:10][CH:11]([CH3:13])[CH3:12])([CH3:9])[CH3:8]>CO>[CH:7]([N:10]([CH2:3][CH2:2][C:1]([O:5][CH3:6])=[O:4])[CH:11]([CH3:13])[CH3:12])([CH3:9])[CH3:8]
Reactant: C=CC(=O)OC
Reactant: CC(C)NC(C)C
Solvent: CO
Product: COC(=O)CCN(C(C)C)C(C)C
Reaction time: 24 h
Yield: 99780.8 %

Procedure:
A! Methyl acrilate (89 ml, 0.988 mmole) was slowly dropped into a solution of diisopropylamine (27.7 ml, 0.198 mmole) in methanol (300 ml) at -10° C. The reaction mixture was brought to room temperature and stirred for 24 hours, then the solvent and the methyl acrilate in excess were evaporated off thus obtaining 37 g of crude methyl 3-(N,N-diisopropylamino)propionate (quantitative yield) which was directly employed in the next step.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][N:15]([CH2:39][CH3:40])[CH:16]2[CH2:25][CH2:24][C:23]3[C:18](=[CH:19][C:20]([NH:26][C:27](=[O:38])[C:28]4[CH:33]=[CH:32][C:31]([S:34]([CH3:37])(=[O:36])=[O:35])=[CH:30][CH:29]=4)=[CH:21][CH:22]=3)[CH2:17]2)[CH2:10][CH2:9]1)=O)(C)(C)C.FC(F)(F)C(O)=O>C(Cl)Cl>[CH2:39]([N:15]([CH2:14][CH:11]1[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]1)[CH:16]1[CH2:17][C:18]2[CH:19]=[C:20]([NH:26][C:27](=[O:38])[C:28]3[CH:33]=[CH:32][C:31]([S:34]([CH3:37])(=[O:35])=[O:36])=[CH:30][CH:29]=3)[CH:21]=[CH:22][C:23]=2[CH2:24][CH2:25]1)[CH3:40]
Reactant: CCN(CC1CCN(C(=O)OC(C)(C)C)CC1)C1CCc2ccc(NC(=O)c3ccc(S(C)(=O)=O)cc3)cc2C1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCN(CC1CCNCC1)C1CCc2ccc(NC(=O)c3ccc(S(C)(=O)=O)cc3)cc2C1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 94.4 %

Procedure:
To a solution of 4-({ethyl-[7-(4-methanesulfonyl-benzoylamino)-1,2,3,4-tetrahydro-naphthalen-2-yl]-amino}-methyl)-piperidine-1-carboxylic acid tert-butyl ester (1.33 g, 2.3 mmol) in methylene chloride (30 mL) under a nitrogen atmosphere was added trifluoroacetic acid (10 mL). The reaction was stirred at room temperature for 30 min. and concentrated in-vacuo. The residue was partitioned between EtOAc (50 mL) and 10% aq. KOH (50 mL), the organic layer was separated, dried over MgSO4, filtered, and concentrated to afford N-[7-(ethyl-piperidin-4-ylmethyl-amino)-5,6,7,8-tetrahydro-naphthalen-2-yl]-4-methanesulfonyl-benzamide (1.02 g). [M+H]+=470.