Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([S:3]([CH3:6])(=[O:5])=[O:4])=[CH2:2].Cl.[C:8]([O:12][C:13]([NH:15][CH2:16][CH2:17][NH2:18])=[O:14])([CH3:11])([CH3:10])[CH3:9].C(N(CC)CC)C>CO>[CH3:6][S:3]([CH2:1][CH2:2][N:15]([CH2:16][CH2:17][NH2:18])[C:13]([O:12][C:8]([CH3:9])([CH3:10])[CH3:11])=[O:14])(=[O:5])=[O:4]
Reactant: C=CS(C)(=O)=O
Reactant: CC(C)(C)OC(=O)NCCN
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CO
Product: CC(C)(C)OC(=O)N(CCN)CCS(C)(=O)=O
Temperature: 25 °C
Reaction time: 18 h
Yield: 82.1 %

Procedure:
Methyl vinyl sulfone (0.42 mL, 4.8 mmol) was added dropwise to a cooled solution of N-tert-butyloxycarbonyl-1,2-ethylenediamine hydrochloride (1.00 g, 5.1 mmol) and triethylamine (1.4 mL, 10.7 mmol) in methanol (20 mL). The reaction was stirred at room temperature for 18 h and concentrated. Purification of the crude residue by chromatography over silica gel using 0-5% methanol in methylene chloride gave 2-(N-tert-butyloxycarbonyl-2-aminoethylamino)ethyl methyl sulfone (1.05 g, 77%).
Reaction SMILES: [NH2:1][C@@H:2]([C:20]([NH:22][CH2:23][C:24]([O:26][CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)=[O:25])=[O:21])[CH2:3][CH2:4][CH2:5][NH:6][C:7](=[NH:19])[NH:8][S:9]([C:12]1[CH:18]=[CH:17][C:15]([CH3:16])=[CH:14][CH:13]=1)(=[O:11])=[O:10].[CH2:34]([S:41](Cl)(=[O:43])=[O:42])[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1>CN(C=O)C>[CH2:34]([S:41]([NH:1][C@@H:2]([C:20]([NH:22][CH2:23][C:24]([O:26][CH2:27][C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=1)=[O:25])=[O:21])[CH2:3][CH2:4][CH2:5][NH:6][C:7](=[NH:19])[NH:8][S:9]([C:12]1[CH:13]=[CH:14][C:15]([CH3:16])=[CH:17][CH:18]=1)(=[O:11])=[O:10])(=[O:43])=[O:42])[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1
Reactant: Cc1ccc(S(=O)(=O)NC(=N)NCCC[C@@H](N)C(=O)NCC(=O)OCc2ccccc2)cc1
Reactant: O=S(=O)(Cl)Cc1ccccc1
Solvent: CN(C)C=O
Product: Cc1ccc(S(=O)(=O)NC(=N)NCCC[C@@H](NS(=O)(=O)Cc2ccccc2)C(=O)NCC(=O)OCc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 30 %

Procedure:
The oily residue of the compound of Example 9 was dissolved in 5 mL of DMF, cooled to 0° C. and neutralized with 1 mL of TEA. To the solution was added BnSO2Cl (397 mg, 2.0 mmol) and the solution was stirred at 0° C. for 3 h and 25° C. for 3 h. DMF was removed and residue was dissolved in 100 mL of EtOAc and 20 mL of water. The organic layer was separated, washed with sat. NaHCO3 (10 mL), water (10 mL), 1N HCl (10 mL) and sat. NaCl (3×10 mL), dried with MgSO4, filtered and evaporated. The solid residue was purified by column chromatography on silica gel (EtOAc) to give the title compound (328 mg, 30% yield) as a powder. ES-MS (M+H)+630.5
Reaction SMILES: [O:1]1[C:5]2([CH2:10][CH2:9][C:8](=O)[CH2:7][CH2:6]2)[O:4][CH2:3][CH2:2]1.Cl.C[O:14][C:15](=O)[CH2:16][CH2:17][CH2:18][NH2:19].C(N(CC)CC)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCl>[O:1]1[C:5]2([CH2:10][CH2:9][CH:8]([N:19]3[CH2:18][CH2:17][CH2:16][C:15]3=[O:14])[CH2:7][CH2:6]2)[O:4][CH2:3][CH2:2]1
Reactant: O=C1CCC2(CC1)OCCO2
Reactant: COC(=O)CCCN
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C1CCCN1C1CCC2(CC1)OCCO2
Temperature: 25 °C
Yield: 50.6 %

Procedure:
Dissolve 1,4-dioxaspiro{4.5}decan-8-one (100 g, 640.3 mmol), methyl-4-aminobutyrate hydrochloride (98.5 g, 640.3 mmol), triethylamine (90 mL, 640.3 mmol) and dichloromethane (2 L) and stir at room temperature. Add Sodium triacetoxyborohydride (135.7 g, 640.3 mmol) stir 17 h at room temperature. Quench with water (1 L), separate, wash the aqueous layer with dichloromethane (3×500 mL), combine the organic phases and dry over anhydrous sodium sulfate, filter and concentrate. Purify the material on a 1.5 kg silica column, 6 inches in diameter, and eluted with 8:2 hexanes/ethyl acetate to 95:5 ethyl acetate/methanol to give 73 g of the title compound as a waxy brown solid. 1H NMR (CDCl3) δ 3.99-4.10 (m, 1H), 3.93 (s, 4H), 3.32-3.36 (m, 2H), 2.36-2.40 (m, 2H), 1.94-2.03 (m, 2H), 1.65-1.83 (m, 8H).
Reaction SMILES: [O:1]([C:8]1[CH:9]=[C:10](Br)[CH:11]=[CH:12][CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Mg].II.C(O[CH2:22][C:23]([F:35])=[CH:24][C:25]1([C:28]2[CH:33]=[CH:32][C:31]([Cl:34])=[CH:30][CH:29]=2)[CH2:27][CH2:26]1)(=O)C>O1CCCC1.O>[Cl:34][C:31]1[CH:30]=[CH:29][C:28]([C:25]2([CH:24]=[C:23]([F:35])[CH2:22][C:10]3[CH:11]=[CH:12][CH:13]=[C:8]([O:1][C:2]4[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=4)[CH:9]=3)[CH2:26][CH2:27]2)=[CH:33][CH:32]=1
Reactant: CC(=O)OCC(F)=CC1(c2ccc(Cl)cc2)CC1
Reactant: Brc1cccc(Oc2ccccc2)c1
Agent: II
Agent: [Mg]
Solvent: C1CCOC1
Solvent: O
Product: FC(=CC1(c2ccc(Cl)cc2)CC1)Cc1cccc(Oc2ccccc2)c1
Temperature: 25 °C
Yield: 21.7 %

Procedure:
A Grignard reagent, prepared from 3-phenoxyphenyl bromide (0.33 g) in dry tetrahydrofuran (2 ml) and magnesium (30 mg) under nitrogen using iodine as an initiator at ca 40 C for 50 min, was cooled to room temperature then treated with cuprous bromide (ca 20 mg) for 10 min. After cooling to -78° C., a solution of 1-(3-acetoxy-2-fluoroprop-1-enyl)-1-(4-chlorophenyl)cyclopropane (Example 17) (0.32 g) in tetrahydrofuran was added slowly with stirring, then the mixture was allowed to warm to room temperature overnight. The mixture was treated with water (4 ml), then extracted with diethyl ether (3×20 ml). The combined organic extracts were washed with water (2×10 ml), dried, and evaporated under reduced pressure. The residue was purified by preparative thin layer chromatography (solvent: diethyl ether/hexane; 1:9) and then preparative high performance liquid chromatography (column: C18; solvent: methanol; flow rate: 8 ml/min) to afford 1-(4-chlorophenyl)-1-(2-fluoro-3-(3-phenoxyphenyl)prop-1-enyl)cyclopropane (98 mg, 22%).
Reaction SMILES: [CH2:1]([C:3]1[CH:57]=[CH:56][C:6]([CH2:7][C:8]2[C:16]3[C:11](=[CH:12][CH:13]=[C:14]([C@@H:17]4[O:46][C@H:45]([CH2:47][O:48]CC5C=CC=CC=5)[C@@H:36]([O:37]CC5C=CC=CC=5)[C@H:27]([O:28]CC5C=CC=CC=5)[C@H:18]4[O:19]CC4C=CC=CC=4)[CH:15]=3)[NH:10][CH:9]=2)=[CH:5][CH:4]=1)[CH3:2].[OH-].[Na+]>C1COCC1.O>[CH2:1]([C:3]1[CH:57]=[CH:56][C:6]([CH2:7][C:8]2[C:16]3[C:11](=[CH:12][CH:13]=[C:14]([C@@H:17]4[O:46][C@H:45]([CH2:47][OH:48])[C@@H:36]([OH:37])[C@H:27]([OH:28])[C@H:18]4[OH:19])[CH:15]=3)[NH:10][CH:9]=2)=[CH:5][CH:4]=1)[CH3:2]
Reactant: CCc1ccc(Cc2c[nH]c3ccc([C@@H]4O[C@H](COCc5ccccc5)[C@@H](OCc5ccccc5)[C@H](OCc5ccccc5)[C@H]4OCc4ccccc4)cc23)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CCc1ccc(Cc2c[nH]c3ccc([C@@H]4O[C@H](CO)[C@@H](O)[C@H](O)[C@H]4O)cc23)cc1
Temperature: 25 °C
Yield: 85 %

Procedure:
3-(4-Ethylbenzyl)-5-(2,3,4,6-tetra-O-benzyl-β-D-glucopyranosyl)-1H-indole: Part E (0.68 g, 0.78 mmol) was dissolved in THF (15 mL) and 25% aqueous sodium hydroxide (5 mL) and the resulting solution was brought to reflux for 3 h. After cooling to room temperature, the mixture was diluted with water (30 mL), and extracted with ethyl acetate. The organic extracts were washed with water and brine, dried over anhydrous sodium sulfate and concentrated in vacuo. The crude product was purified by chromatography on silica gel eluting with ethyl acetate/hexane (1:3) to provide the title compound (0.5 g, 85%) as white solid. G. 3-(4-Ethylbenzyl)-5-(β-D-glucopyranosyl)-1H-indole: A solution of Part F (0.30 g, 0.4 mmol) in ethanol (10 mL) and ethyl acetate (20 mL) was hydrogenated over 10% Pearlman's catalyst (0.30 g) under 14 psi of H2 for 40 h. The catalyst was removed by filtration and the filtrate was concentrated in vacuo. The crude product was purified by chromatography on silica gel eluting with methanol/chloroform (10:100) to provide the titled compound (0.04 g, 25%) as a white solid. 1HNMR (300 MHz, CD3OD) δ 7.51 (s, 1H), 7.32 (d, J=8.52 Hz, 1H), 7.19–7.15 (m, 3H), 7.06 (d, J=7.87 Hz, 2H), 6.95 (s, 1H), 4.18–4.15 (m, 1H), 4.04 (s, 2H), 3.87 (d, J=12.2 Hz, 1H), 3.71–3.65 (m, 1H), 3.53–3.48 (m, 2H), 3.45–3.41 (m, 2H), 2.58 (q, J=7.58 Hz, 2H), 1.19 (t, J=7.65 Hz, 3H). MS: m/z (M+Na) 420.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[N:9]=[C:10]([NH2:13])[S:11][CH:12]=1.[Cl:14][C:15]1[C:20]([Cl:21])=[C:19]([Cl:22])[CH:18]=[CH:17][C:16]=1[S:23](Cl)(=[O:25])=[O:24]>>[Cl:14][C:15]1[C:20]([Cl:21])=[C:19]([Cl:22])[CH:18]=[CH:17][C:16]=1[S:23]([NH:13][C:10]1[S:11][CH:12]=[C:8]([C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[Cl:1])[N:9]=1)(=[O:25])=[O:24]
Reactant: O=S(=O)(Cl)c1ccc(Cl)c(Cl)c1Cl
Reactant: Nc1nc(-c2ccccc2Cl)cs1
Product: O=S(=O)(Nc1nc(-c2ccccc2Cl)cs1)c1ccc(Cl)c(Cl)c1Cl

Procedure:
The title compound was prepared from 4-(2-chlorophenyl)-1,3-thiazol-2-amine (57 mg) and 2,3,4-trichlorobenzenesulfonyl chloride (76 mg) as described in the synthetic METHOD B to give a white solid (64.8 mg) with purity >90%: MS (pos) m/z 453.3, 455.3, 457.2.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([NH2:9])=[CH:5][CH:4]=1.OC=[C:12]1[CH2:17][CH2:16][CH2:15][CH2:14][C:13]1=[O:18]>>[CH3:1][O:2][C:3]1[CH:8]=[C:7]2[C:6](=[CH:5][CH:4]=1)[NH:9][C:12]1[C:13](=[O:18])[CH2:14][CH2:15][CH2:16][C:17]2=1
Reactant: O=C1CCCCC1=CO
Reactant: COc1ccc(N)cc1
Product: COc1ccc2[nH]c3c(c2c1)CCCC3=O

Procedure:
6-Methoxy-2,3,4,9-tetrahydro-1H-carbazol-1-one was prepared from p-anisidine and 2-(hydroxymethylene)cyclohexanone in a similar manner as described in Example 1 to give a tan solid. 1H-NMR (CDCl3): δ 8.77 (br s, 1H), 7.32 (d, 1H), 7.06 (d, 1H), 7.03 (s, 1H), 3.88 (s, 3H), 2.98 (t, 2H), 2.66 (t, 2H), 2.28 (quint, 2H); MS m/z 216 (M+1).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([CH:13]2[CH2:18][CH2:17][C:16](=O)[CH2:15][CH2:14]2)=[C:6]2[C:10]=1[C:9](=[O:11])[N:8]([CH3:12])[CH2:7]2.[CH3:20][NH:21][CH3:22].C1COCC1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[NH2:1][C:2]1[CH:3]=[CH:4][C:5]([CH:13]2[CH2:18][CH2:17][CH:16]([N:21]([CH3:22])[CH3:20])[CH2:15][CH2:14]2)=[C:6]2[C:10]=1[C:9](=[O:11])[N:8]([CH3:12])[CH2:7]2
Reactant: CN1Cc2c(C3CCC(=O)CC3)ccc(N)c2C1=O
Reactant: CNC
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Solvent: C1CCOC1
Product: CN1Cc2c(C3CCC(N(C)C)CC3)ccc(N)c2C1=O
Temperature: 25 °C
Reaction time: 24 h
Yield: 58 %

Procedure:
A solution of 7-amino-2-methyl-4-(4-oxocyclohexyl)-2,3-dihydro-1H-isoindol-1-one (100.0 mg, 0.3871 mmol) in 1,2-Dichloroethane (2.0 mL) was charged with 2.0 M of dimethylamine in THF (0.2903 mL, 0.5807 mmol) and sodium triacetoxyborohydride (164.1 mg, 0.7743 mmol). The reaction mixture was stirred at rt for 24 hours. The reaction mixture was quenched with NaHCO3 (10 mL) and extracted with EtOAc (20 mL). The organic layer was washed with brine (10 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to yield a light yellow oil. The crude material was purified by silica gel chromatography on the combi-flash Rf system using DCM/7M NH3 in MeOH (100:0→90:10) as eluent. The fractions containing product were combined and concentrated under reduced pressure to yield a light yellow solid, 64.7 mg (58% yield). 1H NMR (CDCl3, 400 MHz): δ=1.53 (d, J=11.12 Hz, 4 H), 1.91 (d, J=11.12 Hz, 2 H), 2.08 (d, J=14.65 Hz, 2 H), 2.31 (br. s., 6 H), 2.45 (br. s., 1 H), 2.48-2.58 (m, 1 H), 3.14 (s, 3 H), 4.30 (s, 2 H), 5.07 (br. s., 2 H), 6.57 (d, J=8.34 Hz, 1 H), 7.26 (br. s., 1 H). MS (ES+): m/z 288.21 [MH+] (TOF, polar).
Reaction SMILES: [CH3:1][CH:2]([CH3:23])[CH2:3][C@H:4]([NH:8][C:9]([N:11]1[CH2:16][CH2:15][N:14]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH2:13][CH2:12]1)=[O:10])[C:5]([OH:7])=O.[C:24]([O:28][C:29](=[O:47])[C@@H:30]([NH2:46])[CH2:31][C:32]1[CH:37]=[CH:36][C:35]([O:38][CH2:39][C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=2)=[CH:34][CH:33]=1)([CH3:27])([CH3:26])[CH3:25]>>[C:24]([O:28][C:29](=[O:47])[CH:30]([NH:46][C:5](=[O:7])[CH:4]([NH:8][C:9]([N:11]1[CH2:16][CH2:15][N:14]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH2:13][CH2:12]1)=[O:10])[CH2:3][CH:2]([CH3:1])[CH3:23])[CH2:31][C:32]1[CH:37]=[CH:36][C:35]([O:38][CH2:39][C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=2)=[CH:34][CH:33]=1)([CH3:27])([CH3:25])[CH3:26]
Reactant: CC(C)(C)OC(=O)[C@@H](N)Cc1ccc(OCc2ccccc2)cc1
Reactant: CC(C)C[C@H](NC(=O)N1CCN(c2ccccc2)CC1)C(=O)O
Product: CC(C)CC(NC(=O)N1CCN(c2ccccc2)CC1)C(=O)NC(Cc1ccc(OCc2ccccc2)cc1)C(=O)OC(C)(C)C
Yield: 46 %

Procedure:
A solution of the product from Example AG ((2S)-4-methyl-2-[(4-phenyl-piperazine-1-carbonyl)-amino]-pentanoic acid) (0.93 g, 2.9 mmol) and the product from Example A ((S)-2-amino-3-(4-benzyloxy-phenyl)-propionic acid tert-butyl ester) (1.0 g, 2.9 mmol) were coupled according to the procedure described in Example AH. The reaction mixture was purified by chromatography (silica gel, 1:1 EtOAc/heptane) to give the title compound as a white crystals (0.84 g, 46%), mp=67-69° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[OH:12])[O:8][CH:7]=[C:6]([C:13]1[CH:22]=[CH:21][C:16]3[O:17][CH2:18][CH2:19][O:20][C:15]=3[CH:14]=1)[C:5]2=O.O.[NH2:25][NH2:26]>C(O)C>[Cl:1][C:2]1[CH:3]=[C:4]([C:5]2[C:6]([C:13]3[CH:22]=[CH:21][C:16]4[O:17][CH2:18][CH2:19][O:20][C:15]=4[CH:14]=3)=[CH:7][NH:26][N:25]=2)[C:9]([OH:8])=[CH:10][C:11]=1[OH:12]
Reactant: NN
Reactant: O=c1c(-c2ccc3c(c2)OCCO3)coc2cc(O)c(Cl)cc12
Solvent: O
Solvent: CCO
Product: Oc1cc(O)c(-c2n[nH]cc2-c2ccc3c(c2)OCCO3)cc1Cl

Procedure:
This compounds was synthesised in the same manner as described above. 6-Chloro-3-(2,3-dihydro-benzo[1,4]dioxin-6-yl)-7-hydroxy-chromen-4-one (0.1 g, 0.30 mmol), hydrazine hydrate (4 ml), ethanol (10 ml). The quenched reaction was extracted into ethyl acetate (2×30 ml), washed (water), dried (MgSO4), and the solvent remove to give 4-Chloro-6-[4-(2,3-dihydro-benzo[1,4]dioxin-6-yl)-1H-pyrazol-3-yl]-benzene-1,3-diol as an off white solid (0.031 g, 30%); Rf 0.6 Cf SM 0.8 ethyl acetate/hexane (75/25).
Reaction SMILES: [CH2:1]([O:3][CH2:4][CH2:5][N:6]1[C:10]2=[N:11][CH:12]=[CH:13][CH:14]=[C:9]2[N:8]=[C:7]1[CH2:15][N:16]1[CH2:21][CH2:20][N:19]([CH2:22][C:23]#[N:24])[CH2:18][CH2:17]1)[CH3:2].N.[H][H]>[Ni].CO>[CH2:1]([O:3][CH2:4][CH2:5][N:6]1[C:10]2=[N:11][CH:12]=[CH:13][CH:14]=[C:9]2[N:8]=[C:7]1[CH2:15][N:16]1[CH2:17][CH2:18][N:19]([CH2:22][CH2:23][NH2:24])[CH2:20][CH2:21]1)[CH3:2]
Reactant: [H][H]
Reactant: CCOCCn1c(CN2CCN(CC#N)CC2)nc2cccnc21
Agent: [Ni]
Agent: N
Solvent: CO
Product: CCOCCn1c(CN2CCN(CCN)CC2)nc2cccnc21
Yield: 52.1 %

Procedure:
A mixture of 41.8 parts of 4-[[3-(2-ethoxyethyl)-3H-imidazo-[4,5-b]pyridin-2-yl]methyl]-1-piperazineacetonitrile and 1100 parts of methanol, saturated with ammonia was hydrogenated at normal pressure and at room temperature with 20 parts of Raney nickel catalyst. After the calculated amount of hydrogen was taken up, the catalyst was filtered off and the filtrate was evaporated. The residue was converted into the (E)-2-butenedioate salt in 2-propanol. The salt was filtered off and crystallized from a mixture of acetonitrile and 2-propanol. The product was filtered off and dried, yielding 37.4 parts (52.1%) of 4-[[3-(2-ethoxyethyl)-3H-imidazo[4,5-b]pyridin-2-yl]methyl]-1-piperazineethanamine; mp. 159.8° C. (compound 128).
Reaction SMILES: [N:1]([CH2:4][CH3:5])=[C:2]=[O:3].[F:6][C:7]([F:26])([F:25])[C:8]1[CH:9]=[C:10]([S:14]([N:17]2[CH2:22][CH2:21][CH:20]([O:23][NH2:24])[CH2:19][CH2:18]2)(=[O:16])=[O:15])[CH:11]=[CH:12][CH:13]=1.N1C=CC=CC=1>C(Cl)Cl>[CH2:4]([NH:1][C:2]([NH:24][O:23][CH:20]1[CH2:21][CH2:22][N:17]([S:14]([C:10]2[CH:11]=[CH:12][CH:13]=[C:8]([C:7]([F:26])([F:6])[F:25])[CH:9]=2)(=[O:15])=[O:16])[CH2:18][CH2:19]1)=[O:3])[CH3:5]
Reactant: NOC1CCN(S(=O)(=O)c2cccc(C(F)(F)F)c2)CC1
Reactant: CCN=C=O
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCNC(=O)NOC1CCN(S(=O)(=O)c2cccc(C(F)(F)F)c2)CC1
Temperature: 25 °C
Reaction time: 17 h
Yield: 63.6 %

Procedure:
Isocyanatoethane (53.0 mg, 0.74 mmol) was added to a solution of O-(1-(3-(trifluoromethyl)phenylsulfonyl)piperidin-4-yl)hydroxylamine (200 mg, 0.62 mmol) and pyridine (98 mg, 1.23 mmol) in CH2Cl2 (4 ml) and stirred at room temperature for 17 hours. The resulting precipitation was collected, washed with aqueous 1 N HCl solution (10 ml×3), aqueous NaHCO3 solution (10 ml×3), ether (10 ml×2) to give 1-ethyl-3-(1-(3-(trifluoromethyl)phenylsulfonyl)piperidin-4-yloxy)urea (156 mg, 64%) as a white solid: LCMS: 396 [M+1]+. 1H NMR (DMSO-d6) δ: 0.98 (m, 3H), 1.73 (m, 2H), 1.86 (m, 2H), 2.85 (m, 2H), 3.00 (m, 2H), 3.18 (n, 2H), 3.60 (m, 1H), 6.65 (m, 1H), 7.91 (m, 2H), 8.01 (m, 2H), 8.82 (s, 1H).
Reaction SMILES: [NH2:1][C:2]1[N:6]([C:7]2[CH:12]=[CH:11][CH:10]=[C:9](I)[CH:8]=2)[C:5]2[CH:14]=[CH:15][CH:16]=[CH:17][C:4]=2[N:3]=1.[CH3:18][O:19][CH2:20][C:21]1[CH:25]=[CH:24][O:23][C:22]=1[Sn](C)(C)C>>[NH2:1][C:2]1[N:6]([C:7]2[CH:12]=[CH:11][CH:10]=[C:9]([C:22]3[O:23][CH:24]=[CH:25][C:21]=3[CH2:20][O:19][CH3:18])[CH:8]=2)[C:5]2[CH:14]=[CH:15][CH:16]=[CH:17][C:4]=2[N:3]=1
Reactant: COCc1ccoc1[Sn](C)(C)C
Reactant: Nc1nc2ccccc2n1-c1cccc(I)c1
Product: COCc1ccoc1-c1cccc(-n2c(N)nc3ccccc32)c1

Procedure:
2-Amino-1-[3-(3-methoxymethyl-2-furyl)phenyl]benzimidazole was prepared from 1-(2-amino-1-benzimidazolyl)-3-iodobenzene and 3-methoxymethyl-2-trimethylstannylfuran by method C. mp 134°-136° C.
Reaction SMILES: [C:1]([CH:6]1[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][C:7]1=[O:14])([O:3][CH2:4][CH3:5])=[O:2].[I-].[Na+].[H-].[Na+].Br[CH2:20][C:21]([O:23][CH2:24][CH3:25])=[O:22]>C1(C)C=CC=CC=1.O>[C:1]([C:6]1([CH2:20][C:21]([O:23][CH2:24][CH3:25])=[O:22])[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][C:7]1=[O:14])([O:3][CH2:4][CH3:5])=[O:2]
Reactant: CCOC(=O)C1CCCCCCC1=O
Reactant: CCOC(=O)CBr
Agent: [H-]
Agent: [I-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: O
Product: CCOC(=O)CC1(C(=O)OCC)CCCCCCC1=O
Temperature: 110 °C

Procedure:
A solution of 2-carboethoxy-cyclooctanone (92.2 g, 0.5 mole) in toluene (1.6 l) is treated with sodium iodide (1 g) and 60% sodium hydride in mineral oil (23.3 g, 0.58 mole). The mixture is heated at 110° C. The mixture is treated with ethyl α-bromoacetate (98.0 g, 0.58 mole) dropwise and the mixture is warmed to 65° C. for 18 hours. The mixture is cooled and water (500 ml) was added. The layers are separated and the aqueous is extracted with toluene (2×1 l). The extracts are dried (MgSO4) and filtered. The filtrate is concentrated at reduced pressure and distilled to yield pure 2-carboethoxy-2-carboethoxymethylcyclooctanone with a bp of 193°-195° C. at 16 mm.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH2:8][N:9]2[C:21]3[CH:20]=[CH:19][CH:18]=[C:17]([OH:22])[C:16]=3[C:15]3[C:10]2=[CH:11][CH:12]=[CH:13][C:14]=3[C:23](=[O:25])[NH2:24])[CH:5]=[CH:6][CH:7]=1.Br[CH2:27][C:28]([O:30][CH3:31])=[O:29]>CN(C=O)C.C(OCC)(=O)C>[CH3:1][C:2]1[CH:3]=[C:4]([CH2:8][N:9]2[C:21]3[CH:20]=[CH:19][CH:18]=[C:17]([O:22][CH2:27][C:28]([O:30][CH3:31])=[O:29])[C:16]=3[C:15]3[C:10]2=[CH:11][CH:12]=[CH:13][C:14]=3[C:23](=[O:25])[NH2:24])[CH:5]=[CH:6][CH:7]=1
Reactant: Cc1cccc(Cn2c3cccc(O)c3c3c(C(N)=O)cccc32)c1
Reactant: COC(=O)CBr
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COC(=O)COc1cccc2c1c1c(C(N)=O)cccc1n2Cc1cccc(C)c1
Reaction time: 0.05 h
Yield: 65.7 %

Procedure:
40% Methanolic Triton B (0.45 mL, 0.99 mM) was added to a solution of the 9-[(3-methylphenyl)methyl]-4-hydroxy-5-carbamoyl carbazole (100 mg, 0.30 mM) in 8 mL DMF at room temperature. After 3 minutes, methyl bromoacetate (115 mg, 0.72 mM) was added and the resultant mixture stirred at room temperature for 24 hours. The mixture was diluted with ethyl acetate, washed with H2O, and saturated brine, dried over magnesium sulfate, filtered, and concentrated. The residue was purified by column chromatography on silica gel (elution with ethyl acetate) to afford 80 mg (66%) of the {9-[(3-methylphenyl)methyl]-5-carbamoylcarbazol-4-yl}oxyacetic acid, methyl ester as a white solid. 1H NMR (DMSO-d6) δ 7.6 (d, 1H, J=8 Hz), 7.55 (br s, 1H), 7.45-7.0 (m, 8H), 6.9 (d, 1H, J=8 Hz), 6.6 (d, 1H, J=8 Hz), 5.65 (s, 2H), 4.9 (s, 2H), 3.75 (s, 3H), and 2.2 (s, 3H). IR (KBr, cm−1) 3367, 3157, 1760, 1642, 1589, 1499, 1455, 1424, 1328, 1216, 1151, 1102, 772, and 714. MS (FD) m/e 402.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:31]=[CH:32][C:33]=1[O:34][CH3:35])[CH2:6][CH:7]1[C:16]2[C:11](=[CH:12][C:13]([OH:19])=[C:14]([O:17][CH3:18])[CH:15]=2)[CH2:10][CH2:9][N:8]1[CH2:20][C:21]([NH:23][CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)=[O:22].[CH2:36](Br)[CH2:37][CH3:38]>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:31]=[CH:32][C:33]=1[O:34][CH3:35])[CH2:6][CH:7]1[C:16]2[C:11](=[CH:12][C:13]([O:19][CH2:36][CH2:37][CH3:38])=[C:14]([O:17][CH3:18])[CH:15]=2)[CH2:10][CH2:9][N:8]1[CH2:20][C:21]([NH:23][CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)=[O:22]
Reactant: COc1cc2c(cc1O)CCN(CC(=O)NCc1ccccc1)C2Cc1ccc(OC)c(OC)c1
Reactant: CCCBr
Product: CCCOc1cc2c(cc1OC)C(Cc1ccc(OC)c(OC)c1)N(CC(=O)NCc1ccccc1)CC2

Procedure:
prepared by reaction of 2-[1-(3,4-dimethoxy-benzyl)-6-hydroxy-7-methoxy-3,4-dihydro-1H-isoquinolin-2-yl]-N-benzyl-acetamide with propyl bromide
Reaction SMILES: C[O:2][C:3]1[C:8]2[C:9]([CH3:19])=[C:10]([S:12][C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[O:11][C:7]=2[C:6]([O:20]C)=[C:5]([CH3:22])[C:4]=1[CH3:23].B(Br)(Br)Br>C(Cl)Cl>[C:13]1([S:12][C:10]2[O:11][C:7]3[C:6](=[O:20])[C:5]([CH3:22])=[C:4]([CH3:23])[C:3](=[O:2])[C:8]=3[C:9]=2[CH3:19])[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: COc1c(C)c(C)c(OC)c2c(C)c(Sc3ccccc3)oc12
Agent: BrB(Br)Br
Solvent: ClCCl
Product: CC1=C(C)C(=O)c2c(oc(Sc3ccccc3)c2C)C1=O
Temperature: 25 °C

Procedure:
A solution of 4,7-dimethoxy-2-phenylthio-3,5,6-trimethylbenzofuran from Step 2 (200 mg, 0.64 mmol) in CH2Cl2 (10 mL) was cooled to -78° C. and a BBr3 solution (2.8 mL, 2.8 mmol, 1M CH2Cl2) was added dropwise. The reaction was slowly warmed to room temperature then quenched with 25% NH4OAc. Extraction with EtOAc followed by addition of powdered FeCl3 and flash chromatography on silica gel (10% EtOAc/hex) afforded the title compound.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([OH:18])[CH:8]=[CH:9][C:10]=1[O:11][C:12](=[O:17])[C:13]([CH3:16])([CH3:15])[CH3:14])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].[CH2:21]([O:23][CH:24]([O:27][CH2:28][CH3:29])[CH2:25]Br)[CH3:22]>CN(C)C=O>[C:1]([C:5]1[CH:6]=[C:7]([O:18][CH2:25][CH:24]([O:27][CH2:28][CH3:29])[O:23][CH2:21][CH3:22])[CH:8]=[CH:9][C:10]=1[O:11][C:12](=[O:17])[C:13]([CH3:16])([CH3:15])[CH3:14])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)C(=O)Oc1ccc(O)cc1C(C)(C)C
Reactant: CCOC(CBr)OCC
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(COc1ccc(OC(=O)C(C)(C)C)c(C(C)(C)C)c1)OCC
Reaction time: 0.5 h
Yield: 21 %

Procedure:
0.70 g of 3-t-butyl-4-trimethylacetoxyphenol was dissolved in 7 ml of dimethylformamide and the solution was added dropwise into a suspension of 0.13 g of oily sodium hydride in 7 ml of dimethylformamide at 0° C. under a nitrogen stream. After stirring for 30 minutes, 0.50 ml of bromoacetaldehyde diethylacetal was added dropwise and the solution was stirred overnight and allowed to attain room temperature. After the reaction was quenched with a saturated aqueous ammonium chloride solution, the reaction mixture was extracted with water and ethyl acetate and the organic layers were washed with saturated brine, dried over anhydrous magnesium sulfate and then concentrated. The concentrate was purified by silica gel column chromatography (in n-hexane containing 1% -5% ethyl acetate) to give 0.21 g of 3-t-butyl-1-(2,2-diethoxyethoxy)-4-trimethylacetoxybenzene as a white solid (yield 21%).