Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:8][C:9]1[CH:23]=[CH:22][C:12]([O:13][CH:14]([CH3:21])[CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17])=[CH:11][CH:10]=1)C1C=CC=CC=1.[H][H]>C(O)C.[Pd]>[OH:8][C:9]1[CH:10]=[CH:11][C:12]([O:13][CH:14]([CH3:21])[CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17])=[CH:22][CH:23]=1
Reactant: [H][H]
Reactant: CCOC(=O)CC(C)Oc1ccc(OCc2ccccc2)cc1
Agent: [Pd]
Solvent: CCO
Product: CCOC(=O)CC(C)Oc1ccc(O)cc1
Yield: 93.5 %

Procedure:
To a solution of the product of step (i) (4.5 g) in absolute ethanol (200 ml) was added 10% palladium-on-charcoal catalyst (1.2 g) and the resulting suspension hydrogenated at ambient temperature and pressure until uptake of hydrogen ceased. The catalyst was removed by filtration through celite and the filtrate was concentrated in vacuo to give ethyl 3-(4-hydroxyphenoxy)butyrate as a low-melting crystalline solid (3.0 g) NMR (d6DMSO) : δ 1.25 (3H,t); 1.8-2.0 (2H,m); 2.5 (2H,t); 3.9 (2H,t); 4.1 (2H,q); 6.7 (4H,m); 8.8 (1H,br.s); m/e 224 (M)+.
Reaction SMILES: [C:1]([C:4]1[S:5]C(Br)=C[CH:8]=1)(=O)[CH3:2].[Br:10][C:11]1[S:15][C:14]([C:16]([CH2:18][C:19]#[N:20])=[O:17])=[CH:13][CH:12]=1.N1CCOCC1.[S]>CC(=O)CC>[NH2:20][C:19]1[S:5][C:4]([CH3:8])=[C:1]([CH3:2])[C:18]=1[C:16]([C:14]1[S:15][C:11]([Br:10])=[CH:12][CH:13]=1)=[O:17]
Reactant: CC(=O)c1ccc(Br)s1
Reactant: N#CCC(=O)c1ccc(Br)s1
Agent: [S]
Solvent: C1COCCN1
Solvent: CCC(C)=O
Product: Cc1sc(N)c(C(=O)c2ccc(Br)s2)c1C
Yield: 51 %

Procedure:
The procedure of Example 1 was followed except that 2-acetyl-5-bromothiophene (Aldrich) was used in place of acetophenone to prepare the corresponding 2-(5-bromothiophene-2-carbonyl)acetonitrile (Steps A and B). 2-Butanone (Aldrich), 2-(5-bromothiophene-2-carbonyl)acetonitrile, morpholine, and sulfur were reacted according to the procedure of Step C, Example 1, to afford the desired compound. Yield: 51%; IR (KBr) cm−1: 3348, 1559, 1448, 1413, 1388, 1318, 1263, 974, 769; 1H NMR (CDCl3):δ 2.16 (s, 6H), 5.90 (bs, 2H), 7.02 (d, J=4 Hz, 1H), 7.11 (d, 1H, J=4 Hz); orange solid, mp: 128–130° C. (petroleum ether).
Reaction SMILES: [CH2:1]([C:5]1[N:6]([C:21]2[CH:26]=[CH:25][C:24]([O:27][C:28]3[CH:33]=[CH:32][C:31]([Cl:34])=[CH:30][CH:29]=3)=[CH:23][CH:22]=2)[CH:7]=[C:8]([C:10]2[CH:15]=[CH:14][C:13]([O:16][CH2:17][C@H:18]3[CH2:20][O:19]3)=[CH:12][CH:11]=2)[N:9]=1)[CH2:2][CH2:3][CH3:4].[CH2:35]([NH2:37])[CH3:36]>CO>[CH2:1]([C:5]1[N:6]([C:21]2[CH:22]=[CH:23][C:24]([O:27][C:28]3[CH:33]=[CH:32][C:31]([Cl:34])=[CH:30][CH:29]=3)=[CH:25][CH:26]=2)[CH:7]=[C:8]([C:10]2[CH:11]=[CH:12][C:13]([O:16][CH2:17][C@H:18]([OH:19])[CH2:20][NH:37][CH2:35][CH3:36])=[CH:14][CH:15]=2)[N:9]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCN
Reactant: CCCCc1nc(-c2ccc(OC[C@H]3CO3)cc2)cn1-c1ccc(Oc2ccc(Cl)cc2)cc1
Solvent: CO
Product: CCCCc1nc(-c2ccc(OC[C@H](O)CNCC)cc2)cn1-c1ccc(Oc2ccc(Cl)cc2)cc1

Procedure:
A solution of 2-butyl-1-[4-(4-chloro-phenoxy)-phenyl]-4-[4-((R)-1-oxiranylmethoxy)-phenyl]-1H-imidazole (50 mg, 0.11 mmol, from intermediate A2) in 4 mL of ethylamine in MeOH (2M) was stirred at 60° C. overnight in a teflon-capped vial. Upon completion (determined by LC/MS), the reaction was dried in vacuo and purified by silica gel flash column chromatography using a gradient of EtOAc to 4% ammonia/MeOH (2.0M) in EtOAc as an eluent to afford (R)-1-(4-{2-butyl-1-[4-(4-chloro-phenoxy)-phenyl]-1H-imidazol-4-yl}-phenoxy)-3-ethylamino-propan-2-ol.
Reaction SMILES: Br[C:2]1[CH:15]=[CH:14][C:5]([CH2:6][CH:7]2[CH2:11][O:10][C:9]([CH3:13])([CH3:12])[O:8]2)=[CH:4][CH:3]=1.CN([CH:19]=[O:20])C>C1COCC1.C(OCC)C>[CH3:12][C:9]1([CH3:13])[O:8][CH:7]([CH2:6][C:5]2[CH:14]=[CH:15][C:2]([CH:19]=[O:20])=[CH:3][CH:4]=2)[CH2:11][O:10]1
Reactant: CN(C)C=O
Reactant: CC1(C)OCC(Cc2ccc(Br)cc2)O1
Solvent: C1CCOC1
Solvent: CCOCC
Product: CC1(C)OCC(Cc2ccc(C=O)cc2)O1
Reaction time: 0.5 h

Procedure:
At −78° C. buthyllithium (3.98 mL, 6.37 mmol, 1.6 M solution in hexanes) is added to a solution of 4-(4-bromo-benzyl)-2,2-dimethyl-[1,3]dioxolane (1.57 g, 5.79 mmol) in THF (50 mL). The reaction mixture is stirred at −78° C. for 2 h before DMF is slowly added (2.12 g, 28.95 mmol). Stirring is continued for 30 min at −78° C., then at rt for 1 h. The mixture is diluted with diethyl ether (200 mL) and washed with sat. aq. NaHCO3 and water. The organic layer is dried over MgSO4 and evaporated to leave 4-(2,2-dimethyl-[1,3]dioxolan-4-ylmethyl)-benzaldehyde (1.29 g) as a pale brownish oil; LC-MS: tR=0.87 min; 1H NMR (CDCl3): δ 9.98 (s, 1H), 7.84-7.79 (m, 2H), 7.47-7.37 (m, 2H), 4.35 (p, J=6.4 Hz, 1H), 4.02 (dd, J=5.9, 8.2 Hz, 1H), 3.65 (dd, J=7.0, 8.2 Hz, 1H), 3.04 (dd, J=7.0, 14.1 Hz, 1H), 2.90 (dd, J=5.9, 13.5 Hz, 1H9, 1.44 8s, 3H), 1.36 (s, 3H).
Reaction SMILES: C[O:2][C:3]1[CH:8]=[CH:7][C:6]([O:9]C)=[CH:5][C:4]=1[C:11]([C:13]1[CH:18]=[CH:17][C:16]([O:19]C)=[CH:15][CH:14]=1)=[O:12].Cl.N1C=CC=CC=1.C(Cl)Cl>Cl>[OH:2][C:3]1[CH:8]=[CH:7][C:6]([OH:9])=[CH:5][C:4]=1[C:11]([C:13]1[CH:18]=[CH:17][C:16]([OH:19])=[CH:15][CH:14]=1)=[O:12]
Reactant: COc1ccc(C(=O)c2cc(OC)ccc2OC)cc1
Agent: Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: O=C(c1ccc(O)cc1)c1cc(O)ccc1O
Reaction time: 1 h

Procedure:
To a cooled solution (0° C.) of 4-methoxybenzoyl chloride (5.1 g, 30 mmol) and 1,4-dimethoxy benzene (4.1 g, 30 mmol) in dichloroethane (100 mL) was added aluminum chloride (4.0 g, 30 mmol) and the reaction mixture was stirred at room temperature for 1 h. The reaction was then quenched with 2N HCl and the organic layer was separated and dried over MgSO4. The organic layer was concentrated to give an oil, which was purified by column chromatography(eluent 20% EtOAc/hexanes) to give an oil (4.7 g, 58% yield). The product, (2,5-dimethoxyphenyl)(4-methoxyphenyl)methanone (4.7 g, 17.2 mmol) and pyridine hydrochloride (20 g) was heated to 200° C. After 1 hr, the reaction was cooled, diluted with 2N HCl and extracted with EtOAc. The organic layer was dried over MgSO4, and concentrated to give an oil residue. The crude product was taken up into CH2Cl2 and a solid crystallized out which was collected by filtration (3.1 g, 78% yield); 1H NMR (DMSO-d6) 10.37 (s, 1H), 9.64 (s, 1H), 9.03 (s, 1H), 7.61 (d, 2H, J=8.6 Hz), 6.86-6.75 (m, 4H), 6.67 (d, 1H); MS m/e 229 (M−H)+.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:12])[C:5]([S:8][C:9](=O)[CH3:10])([CH3:7])[CH3:6])[CH3:2].C[O-].[Na+].CC1C=CC(S([O:26][CH2:27][C@H:28]2COC[CH2:30][O:29]2)(=O)=O)=CC=1>C(O)C>[O:26]1[CH2:27][CH2:28][O:29][CH2:30][C@@H:10]1[CH2:9][S:8][C:5]([CH3:7])([CH3:6])[C:4]([O:3][CH2:1][CH3:2])=[O:12]
Reactant: CCOC(=O)C(C)(C)SC(C)=O
Reactant: Cc1ccc(S(=O)(=O)OC[C@H]2COCCO2)cc1
Agent: C[O-]
Agent: [Na+]
Solvent: CCO
Product: CCOC(=O)C(C)(C)SC[C@H]1COCCO1
Temperature: 130 °C
Yield: 48.2 %

Procedure:
To a solution of 0.27 g (1.42 mmol) of 2-acetylsulfanyl-2-methyl-propionic acid ethyl ester in ethanol (4 mL, degassed) are added 0.31 g (5.7 mmol) of sodium methoxide, followed by 0.39 g (1.42 mmol) of (2R)-1,4-dioxan-2-ylmethyl 4-methylbenzene-1-sulfonate (prepared according to WO2008/119663, F. Hoffmann-La Roche AG) under nitrogen atmosphere. The reaction is heated in a microwave to 130° C. for 0.5 h. The solvent is removed under reduced pressure. The residue is dissolved in DCM (10 mL) and washed with saturated aqueous NaHCO3 solution (10 mL). The aqueous layer is extracted with DCM (10 mL). The combined organic extracts are dried over Na2SO4, filtered and the filtrate is concentrated under reduced pressure. The residue is purified by column chromatography (silica, eluent: heptanes, 20% ethyl acetate) to afford 0.17 g of ethyl 2-{[(2R)-1,4-dioxan-2-ylmethyl]sulfanyl}-2-methylpropanoate (UV purity: 77%). Yield: 61%, m/z 271 [M+Na]; 1H NMR (500 MHz, CHLOROFORM-d) δ ppm 1.29 (3H, t, J=7.17 Hz), 1.49-1.54 (6H, m), 2.59-2.66 (1H, m), 2.70-2.77 (1H, m), 3.28-3.36 (1H, m), 3.55-3.63 (1H, m), 3.64-3.76 (3H, m), 3.77-3.85 (2H, m), 4.18 (2H, q, J=7.17 Hz)
Reaction SMILES: Cl.O1CCOCC1.[O:8]=[S:9]1(=[O:37])[CH2:14][CH2:13][CH:12]([CH2:15][S:16]([C:19]2[CH:20]=[C:21]([C:25](=[O:36])[CH2:26][CH2:27][NH:28]C(=O)OC(C)(C)C)[CH:22]=[CH:23][CH:24]=2)(=[O:18])=[O:17])[CH2:11][CH2:10]1>C(Cl)Cl>[NH2:28][CH2:27][CH2:26][C:25]([C:21]1[CH:22]=[CH:23][CH:24]=[C:19]([S:16]([CH2:15][CH:12]2[CH2:11][CH2:10][S:9](=[O:37])(=[O:8])[CH2:14][CH2:13]2)(=[O:17])=[O:18])[CH:20]=1)=[O:36]
Reactant: CC(C)(C)OC(=O)NCCC(=O)c1cccc(S(=O)(=O)CC2CCS(=O)(=O)CC2)c1
Agent: Cl
Solvent: C1COCCO1
Solvent: ClCCl
Product: NCCC(=O)c1cccc(S(=O)(=O)CC2CCS(=O)(=O)CC2)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
HCl/dioxane (4N, 5 mL) was added at 0° C. to a solution of tert-butyl (3-(3-(((1,1-dioxidotetrahydro-2H-thiopyran-4-yl)methyl)sulfonyl)phenyl)-3-oxopropyl)carbamate (0.40 g, 0.87 mmol) in CH2Cl2 (10 mL) and the reaction mixture was stirred at room temperature for 2 h. The reaction mixture was concentrated under reduced pressure to give after purification by preparative HPLC Example 24 as a white solid. Yield (200 mg, 50%); 1H NMR (400 MHz, DMSO-d6) δ 8.39 (s, 1H), 8.31 (d, J=7.6 Hz, 1H), 8.20 (d, J=7.6 Hz, 1H), 7.88 (m, 4H), 3.56-3.52 (m, 2H), 3.50-3.47 (m, 2H), 3.20-3.17 (m, 4H), 3.05-3.02 (m, 2H), 2.31 (bs, 1H), 2.17-2.14 (m, 2H), 1.85-1.77 (m, 2H); MS: m/z 360.18 [M+H]+.
Reaction SMILES: [C:1]1([CH3:11])[CH:6]=[CH:5][C:4]([S:7](Cl)(=[O:9])=[O:8])=[CH:3][CH:2]=1.[O:12]1[C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=2[O:15][CH2:14][C@@H:13]1[CH2:22][OH:23]>N1C=CC=CC=1>[C:1]1([CH3:11])[CH:6]=[CH:5][C:4]([S:7]([O:23][CH2:22][C@@H:13]2[O:12][C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=3[O:15][CH2:14]2)(=[O:9])=[O:8])=[CH:3][CH:2]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: OC[C@H]1COc2ccccc2O1
Solvent: c1ccncc1
Product: Cc1ccc(S(=O)(=O)OC[C@H]2COc3ccccc3O2)cc1
Temperature: 25 °C
Reaction time: 60 h
Yield: 18.9 %

Procedure:
Toluene-4-sulphonyl chloride (4.2 g) was added at -10° C. under nitrogen to a stirred solution of (S)-1,4-benzodioxan-2-ylmethanol (3.3 g) in pyridine (50 ml) The mixture was allowed to warm to ambient temperature and was stirred for a further 60 hours, then poured onto ice-water (200 ml). The product was extracted into ethyl acetate (3×200 ml) then the combined extracts were washed with dilute hydrochloric acid (100 ml), and water (100 ml), dried over magnesium sulphate, and the solvent removed in vacuo. The resulting orange oil (5.84 g), which solidified slowly on standing, was purified by crystallisation from an ether and petroleum ether (b.p. 40°-60° C.) mixture to yield two batches of a white crystalline solid (2.4 and 1.2 g). The 2.4 g batch was recrystallised 3 times from ethanol, the solid obtained becoming each time less rich in the desired (R)-isomer of the product and was therefore discarded. The mother liquors from these 3 recrystallisations now contained predominantly the desired (R)-isomer of the product so they were combined, the solvent removed in vacuo and the residue recrystallised from ethanol to yield white crystals of (R)-1,4-benzodioxan-2-ylmethyl toluene-4-sulphonate (1.2 g); m.p. 105°-107° C.
Reaction SMILES: [CH2:1]([NH:8][CH2:9][CH2:10][NH2:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:12](N1C=CN=C1)(N1C=CN=C1)=[O:13]>C1(C)C=CC=CC=1>[CH2:1]([N:8]1[CH2:9][CH2:10][NH:11][C:12]1=[O:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: NCCNCc1ccccc1
Solvent: Cc1ccccc1
Product: O=C1NCCN1Cc1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 49.2 %

Procedure:
To a solution of N-benzylethylenediamine (6.0 g, 40 mmol) in toluene (50 ml) at 0° C. was added 1,1′-carbonylbis-1H-imidazole (7.8 g, 48 mmol). After stirring the mixture at room temperature overnight, the reaction mixture was washed with water, 5% aqueous citric acid solution and brine. The organic phase was dried over anhydrous magnesium sulfate, filtered and evaporated under reduced pressure. The residue was recrystallized with warm ethyl acetate and filtered off to give 1-benzylimidazolidin-2-one (3.47 g).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([NH:12][C:13](=[O:17])OCC)[C:6]([O:18][CH3:19])=[N:5]2.[CH3:20][C:21]1[CH:22]=[C:23]([N:28]2[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]2)[CH:24]=[C:25]([CH3:27])[CH:26]=1>>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([NH:12][C:13]([N:31]1[CH2:32][CH2:33][N:28]([C:23]3[CH:24]=[C:25]([CH3:27])[CH:26]=[C:21]([CH3:20])[CH:22]=3)[CH2:29][CH2:30]1)=[O:17])[C:6]([O:18][CH3:19])=[N:5]2
Reactant: CCOC(=O)Nc1nc2ccc(Cl)cc2nc1OC
Reactant: Cc1cc(C)cc(N2CCNCC2)c1
Product: COc1nc2cc(Cl)ccc2nc1NC(=O)N1CCN(c2cc(C)cc(C)c2)CC1
Yield: 85 %

Procedure:
Ethyl N-(6-chloro-3-methoxyquinoxalin-2-yl)carbamate and 1-(3,5-dimethylphenyl)piperazine were reacted by the same way with the example 106 to obtain the titled compound (yield, 85%). 1H NMR (300 MHz, CDCl3): δ 2.29 (s, 6H), 3.25-3.29 (m, 4H), 3.73-3.76 (m, 4H), 4.15 (s, 3H), 6.59 (s, 3H), 7.30-7.49 (m, 3H), 7.74-7.77 (m, 1H).
Reaction SMILES: [O:1]1[C:6]2[CH:7]=[C:8]([O:11][C:12]3[CH:21]=[CH:20][N:19]=[C:18]4[C:13]=3[C:14]3[CH:26]=[CH:25][CH:24]=[CH:23][C:15]=3[C:16](=[O:22])[NH:17]4)[CH:9]=[CH:10][C:5]=2[NH:4][CH2:3][CH2:2]1.[N:27]([C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)=[C:28]=[O:29]>>[C:30]1([NH:27][C:28]([N:4]2[C:5]3[CH:10]=[CH:9][C:8]([O:11][C:12]4[CH:21]=[CH:20][N:19]=[C:18]5[C:13]=4[C:14]4[CH:26]=[CH:25][CH:24]=[CH:23][C:15]=4[C:16](=[O:22])[NH:17]5)=[CH:7][C:6]=3[O:1][CH2:2][CH2:3]2)=[O:29])[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1
Reactant: O=c1[nH]c2nccc(Oc3ccc4c(c3)OCCN4)c2c2ccccc12
Reactant: O=C=Nc1ccccc1
Product: O=C(Nc1ccccc1)N1CCOc2cc(Oc3ccnc4[nH]c(=O)c5ccccc5c34)ccc21
Yield: 7.7 %

Procedure:
The title compound was synthesized according to the procedure described for the preparation of Example 221 using 218 (50 mg, 0.14 mmol) and isocyanato benzene (26 mg, 0.22 mmol) to provide 223 (5 mg, 7% yield) as a tan solid. LC-MS (M+H=465, obsd.=465).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[CH:2]1.[Cl:6][CH:7]([C:9]1[CH:17]=[CH:16][C:12]([C:13](Cl)=[O:14])=[CH:11][CH:10]=1)[CH3:8].Cl>C(Cl)Cl>[S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:13]([C:12]1[CH:16]=[CH:17][C:9]([CH:7]([Cl:6])[CH3:8])=[CH:10][CH:11]=1)=[O:14]
Reactant: CC(Cl)c1ccc(C(=O)Cl)cc1
Reactant: c1ccsc1
Agent: Cl
Solvent: ClCCl
Product: CC(Cl)c1ccc(C(=O)c2cccs2)cc1

Procedure:
To a stirred and cooled (0° C) mixture of 4.2 parts of thiophene, 13 parts of stannic chloride and 40 parts of methylene chloride is added dropwise a solution of 10.2 parts of p-(1-chloroethyl)benzoyl chloride in 20 parts of methylene chloride (exothermic reaction with gaseous hydrogen chloride evolution). After stirring for 2h. 30 the reaction mixture is poured onto a mixture of crushed ice and hydrochloric acid solution. The product is extracted with methylene chloride. The organic layer is separated, washed with alkaline water, dried and evaporated. The solid residue is triturated with hot petroleum-ether. The product is filtered off and crystallized from ethanol, yielding p-(1-chloroethyl)phenyl 2-thienyl ketone.
Reaction SMILES: [CH2:1]([O:8][CH2:9][CH:10]1[CH2:15][CH2:14]C(=O)[CH2:12][CH2:11]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(O[CH:20]([O:24][CH2:25][CH3:26])[O:21][CH2:22][CH3:23])C.C1(C)C=CC(S(O)(=O)=O)=CC=1.C(N(CC)CC)C>C(O)C>[CH2:25]([O:24][C:20]1([O:21][CH2:22][CH3:23])[CH2:12][CH2:11][CH:10]([CH2:9][O:8][CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[CH2:15][CH2:14]1)[CH3:26]
Reactant: O=C1CCC(COCc2ccccc2)CC1
Reactant: CCOC(OCC)OCC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCO
Solvent: CCN(CC)CC
Product: CCOC1(OCC)CCC(COCc2ccccc2)CC1

Procedure:
4-Benzyloxymethylcyclohexanone (168 g, 0.77 mol) is dissolved in ethanol (2000 mL), and then triethylorthoformate (350 mL) and p-toluenesulfonic acid (13.3 g) are added. The resulting mixture is stirred and refluxed for 6 hours. After addition of triethylamine (10.5 mL) at room temperature, the mixture is concentrated (500 mL). After addition of sat. NaHCO3 aq., the resulting mixture is extracted with EtOAc. The water layer is extracted with EtOAc and the combined organic layer is washed with brine, dried over magnesium sulfate, and concentrated under reduced pressure. The crude mixture is purified by short pad silica gel column chromatography to afford (4,4-diethoxycyclohexylmethoxymethyl)benzene.
Reaction SMILES: CC(C)([O-])C.[K+].[F:7][C:8]([F:17])([F:16])/[CH:9]=[CH:10]/[C:11]([O:13][CH2:14][CH3:15])=[O:12].C1(C)C=CC(S([CH2:27][N+:28]#[C-:29])(=O)=O)=CC=1>O1CCCC1>[F:7][C:8]([F:16])([F:17])[C:9]1[C:10]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:27][NH:28][CH:29]=1
Reactant: CCOC(=O)/C=C/C(F)(F)F
Reactant: [C-]#[N+]CS(=O)(=O)c1ccc(C)cc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: CCOC(=O)c1c[nH]cc1C(F)(F)F
Temperature: -60 °C
Reaction time: 0.5 h

Procedure:
A solution of potassium t-butoxide (8.11 g, 0.075 mol) in tetrahydrofuran at -60° C. is treated dropwise with a mixture of ethyl 4,4,4-trifluorocrotonate (10.5 g, 0.063 mol) and p-tolylsulfonylmethylisocyanide (12.2 g, 0.063 mol) in tetrahydrofuran over a 1 hour period, stirred at -60° C. for 30 minutes, allowed to warm to room temperature and quenched with water. The reaction mixture is extracted with ether and ethyl acetate. The combined extracts are washed with brine, dried (MgSO4) and concentrated in vacuo to give a solid residue. Recrystallization from 1,2-dichloroethane affords the title compound as a tan solid, 7.3 g (56%), mp 163°-164° C.
Reaction SMILES: [CH:1]([OH:9])(O)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7].[ClH:10].C1(C)C=CC=CC=1>O>[Cl:10][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][CH2:1][OH:9]
Reactant: CCCCCCC(O)O
Reactant: Cl
Solvent: O
Solvent: Cc1ccccc1
Product: OCCCCCCCCl

Procedure:
A mixture of 44 g of heptane diol, 400 ml of concentrated hydrochloric acid, 150 ml of toluene and 50 ml of water was stirred for two and half hours at reflux. The toluene fraction was removed and 200 ml of toluene were added to the aqueous fraction and the mixture was heated for five hours at 85° C. to 90° C. The toluene was removed and 200 ml of toluene and 100 ml of concentrated hydrochloric acid were added to the aqueous phase. The mixture was heated for five hours, then cooled and the organic fraction was combined with the two preceding toluene fractions. The toluene fraction was washed with water, dried and evaporated to dryness under reduced pressure, then distilled at 70° C. under 0.5 mm of mercury to obtain 37 g of the desired product.
Reaction SMILES: [O:1]1[CH2:16][CH:2]1[CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[N:12]=[N:13][S:14][CH:15]=2)=[CH:7][CH:6]=1.[C:17]([C:20]1[CH:29]=[CH:28][C:23]([O:24][CH2:25][CH2:26][NH2:27])=[CH:22][CH:21]=1)(=[O:19])[NH2:18]>C(O)C>[C:17]([C:20]1[CH:29]=[CH:28][C:23]([O:24][CH2:25][CH2:26][NH:27][CH2:16][CH:2]([OH:1])[CH2:3][O:4][C:5]2[CH:10]=[CH:9][C:8]([C:11]3[N:12]=[N:13][S:14][CH:15]=3)=[CH:7][CH:6]=2)=[CH:22][CH:21]=1)(=[O:19])[NH2:18]
Reactant: NCCOc1ccc(C(N)=O)cc1
Reactant: c1cc(-c2csnn2)ccc1OCC1CO1
Solvent: CCO
Product: NC(=O)c1ccc(OCCNCC(O)COc2ccc(-c3csnn3)cc2)cc1

Procedure:
A mixture of 234 mg. of 4-[4(2,3-epoxypropoxy)phenyl]-1,2,3-thiadiazole, 180 mg. of 4-carbamoylphenoxyethylamine and 5 ml. of ethanol is stirred at room temperature for 68 hours. The formed precipitate is collected by filtration and recrystallized from methanol thus obtaining the pure 4-[4{3-(4-carbamoylphenoxyethylamino)2-hydroxypropoxy}phenyl]-1,2,3-thiadiazole, m.p. 173°-174° C; λmax 255 nm (ε 32,300); ir 3,345, 1605, 1570 cm-1.
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:10]1[C:18]2[C:13](=[CH:14][CH:15]=[C:16]([N+:19]([O-])=O)[CH:17]=2)[N:12]([CH:22]2[CH2:27][CH2:26][CH2:25][CH2:24][O:23]2)[N:11]=1.[H][H]>C(O)C.[Pd]>[NH:3]1[C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=2[N:1]=[C:2]1[C:10]1[C:18]2[C:13](=[CH:14][CH:15]=[C:16]([NH2:19])[CH:17]=2)[N:12]([CH:22]2[CH2:27][CH2:26][CH2:25][CH2:24][O:23]2)[N:11]=1
Reactant: [H][H]
Reactant: O=[N+]([O-])c1ccc2c(c1)c(-c1nc3ccccc3[nH]1)nn2C1CCCCO1
Agent: [Pd]
Solvent: CCO
Product: Nc1ccc2c(c1)c(-c1nc3ccccc3[nH]1)nn2C1CCCCO1
Yield: 60 %

Procedure:
3-(1H-Benzo[d]imidazol-2-yl)-5-nitro-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole (50 mg, 0.137 mmol) was added to 10% Pd/C (10 mg) in ethanol (40 mL) and then pressurized with hydrogen (60 psi) for 6 h at room temperature. The reaction mixture was filtered through Celite, and the solvent was removed in vacuo. Purification by flash chromatography (5% CH3OH/CH2Cl2) afforded the title compound in 60% yield. 1H NMR (400 MHz, CD3OD): δ 7.69 (m, 2H), 7.55 (m, 2H), 7.26 (m, 2H), 7.05 (m, 1H), 5.84 (d, 1H, J=9.2 Hz), 4.00 (m, 1H), 3.82 (m, 1H), 2.65 (m, 1H), 2.14 (m, 2H), 1.78 (m, 3H).
Reaction SMILES: [OH-].[K+].[OH:3][CH2:4][C@H:5]([N:11]1[CH2:16][CH2:15][C@@H:14]([CH2:17][C:18]([OH:20])=[O:19])[CH2:13][C@H:12]1[C:21]1[CH:26]=[CH:25][C:24]([C:27]([F:30])([F:29])[F:28])=[CH:23][CH:22]=1)[CH2:6][CH2:7][CH:8]([CH3:10])[CH3:9].I[CH:32]([CH3:34])[CH3:33].[OH-].[Na+]>CS(C)=O.CO>[CH:32]([O:3][CH2:4][C@H:5]([N:11]1[CH2:16][CH2:15][C@@H:14]([CH2:17][C:18]([OH:20])=[O:19])[CH2:13][C@H:12]1[C:21]1[CH:26]=[CH:25][C:24]([C:27]([F:30])([F:28])[F:29])=[CH:23][CH:22]=1)[CH2:6][CH2:7][CH:8]([CH3:9])[CH3:10])([CH3:34])[CH3:33]
Reactant: CC(C)I
Reactant: CC(C)CC[C@H](CO)N1CC[C@@H](CC(=O)O)C[C@H]1c1ccc(C(F)(F)F)cc1
Agent: [K+]
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: CS(C)=O
Product: CC(C)CC[C@H](COC(C)C)N1CC[C@@H](CC(=O)O)C[C@H]1c1ccc(C(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 13.5 %

Procedure:
Powdered KOH (375 mg, 6.68 mmol) was taken up in dry DMSO (1 ml) at RT under N2. The mixture was stirred for 10 minutes before the addition of {(2S,4R)-1-[(1R)-1-(hydroxymethyl)-4-methylpentyl]-2-[4-(trifluoromethyl)phenyl]piperidin-4-yl acetic}acid (Step 1, 67 mg, 0.167 mmol) in dry DMSO (0.5+0.5+0.5 ml), followed by 2-iodopropane (0.334 ml, 3.34 mmol). After 24 hr MS further 2-iodopropane (0.334 ml, 3.34 mmol) was added and the reaction was maintained at RT for 3 days. The reaction was quenched with saturated aqueous NH4Cl and then partitioned between DCM and H2O. The aqueous layer was extracted with DCM (×3). The combined extracts were evaporated and the residue was diluted with MeOH and loaded on to a SCX cartridge (2 g). The cartridge was eluted with MeOH to wash off the DMSO, then 2N NH3 in MeOH to elute the products. The NH3/MeOH fractions were combined and evaporated. The residue was taken up in MeOH (2 ml) and 4N NaOH (aq, 0.2 ml, 0.8 mmol) was added. The mixture was stirred and heated to 60° C. for 2 hrs. After cooling to RT the MeOH was removed in vacuo and the residue was partitioned between DCM and H2O. 2N HCl (0.5 ml) was added. The pH of the aqueous layer was adjusted to ˜7 with NaHCO3 (aq). The aqueous layer was extracted with DCM (×3). The combined extracts were dried (Na2SO4), filtered and evaporated. The residue was purified by reverse phase HPLC (ABZ+ column) to give the title compound (10 mg) as a colourless solid.
Reaction SMILES: [CH:1]1(Br)[CH2:5][CH2:4][CH2:3][CH2:2]1.[F:7][C:8]1[CH:13]=[CH:12][C:11]([C@H:14]([NH:16][C:17]([C@H:19]2[CH2:24][CH2:23][C@H:22]([NH:25][S:26]([C:29]3[CH:34]=[CH:33][C:32]([OH:35])=[C:31]([O:36][CH3:37])[CH:30]=3)(=[O:28])=[O:27])[CH2:21][CH2:20]2)=[O:18])[CH3:15])=[CH:10][CH:9]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O.C(OCC)(=O)C>[F:7][C:8]1[CH:13]=[CH:12][C:11]([C@H:14]([NH:16][C:17]([C@H:19]2[CH2:24][CH2:23][C@H:22]([NH:25][S:26]([C:29]3[CH:34]=[CH:33][C:32]([O:35][CH:1]4[CH2:5][CH2:4][CH2:3][CH2:2]4)=[C:31]([O:36][CH3:37])[CH:30]=3)(=[O:28])=[O:27])[CH2:21][CH2:20]2)=[O:18])[CH3:15])=[CH:10][CH:9]=1
Reactant: BrC1CCCC1
Reactant: COc1cc(S(=O)(=O)N[C@H]2CC[C@H](C(=O)N[C@H](C)c3ccc(F)cc3)CC2)ccc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COc1cc(S(=O)(=O)N[C@H]2CC[C@H](C(=O)N[C@H](C)c3ccc(F)cc3)CC2)ccc1OC1CCCC1
Temperature: 50 °C

Procedure:
Cyclopentylbromide (10.45 mg, 0.07 mmol) was added to solution of trans-4-(4-hydroxy-3-methoxy-benzenesulfonylamino)-cyclohexanecarboxylic acid [(R)-1-(4-fluoro-phenyl)-ethyl]-amide (Example 2, 31.6 mg, 0.07 mmol) and potassium carbonate (19.4 mg, 0.14 mmol) in dimethylformamide (700 ul). The reaction was heated 50° C. for 16 h, cooled to room temperature, diluted with ethyl acetate and rinsed with 1:1 water:brine. The organic layer was concentrated and purified by reverse-phase chromatography followed by lyophilization to yield title compound (18 mg, 0.035 mmol). MS MH+ 519.1