Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]([O-])=O.[Na+].O.[ClH:6].Cl.Cl.[NH2:9][C:10]1[C:15]([NH2:16])=[CH:14][CH:13]=[CH:12][C:11]=1[O:17][CH2:18][CH:19]([OH:33])[CH2:20][NH:21][CH2:22][CH2:23][NH:24][C:25]1[C:30]([CH3:31])=[CH:29][CH:28]=[CH:27][C:26]=1[CH3:32]>C(O)(=O)C>[ClH:6].[ClH:6].[NH:16]1[C:15]2[CH:14]=[CH:13][CH:12]=[C:11]([O:17][CH2:18][CH:19]([OH:33])[CH2:20][NH:21][CH2:22][CH2:23][NH:24][C:25]3[C:30]([CH3:31])=[CH:29][CH:28]=[CH:27][C:26]=3[CH3:32])[C:10]=2[N:9]=[N:1]1
Reactant: Cc1cccc(C)c1NCCNCC(O)COc1cccc(N)c1N
Reactant: O=N[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: Cc1cccc(C)c1NCCNCC(O)COc1cccc2[nH]nnc12
Temperature: 0 °C
Reaction time: 2 h

Procedure:
1.38 g. Sodium nitrite dissolved in 2.2 ml. water are added to a solution, cooled to 0° C., of 9.1 g. 2,3-diamino-1-{2-hydroxy-3-[2-(2,6-dimethylphenylamino)-ethylamino]-propoxy}-benzene trihydrochloride in 12 ml. water and 4.6 ml. glacial acetic acid. After stirring for 2 hours at ambient temperature, the reaction mixture is evaporated to dryness, the residue is taken up in chloroform and the solution is washed with 1M hydrochloric acid and water, dried and evaporated. The residue is recrystallized from ethanol-ethyl acetate, with the addition of active charcoal, to give 2.2 g. (26% of theory) of the desired compound; m.p. 230°-232° C.
Reaction SMILES: [C:1]1([C:6]2[CH:7]=[C:8]([CH:14]=[CH:15][CH:16]=2)[C:9](OCC)=[O:10])[CH2:5][CH2:4][CH2:3][CH:2]=1.[H-].[H-].[H-].[H-].[Li+].[Al+3].[OH-].[Na+]>CCOCC>[C:1]1([C:6]2[CH:7]=[C:8]([CH2:9][OH:10])[CH:14]=[CH:15][CH:16]=2)[CH2:5][CH2:4][CH2:3][CH:2]=1
Reactant: CCOC(=O)c1cccc(C2=CCCC2)c1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Product: OCc1cccc(C2=CCCC2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 64.6 %

Procedure:
A solution of ethyl 3-cyclopent-1-ylbenzoate (4a) (2.5 g, 12 mmol) in ether (25 ml) is added dropwise to a suspension at 0° C. of LiAlH4 (0.57 g, 15 mmol) in ethyl ether (30 ml). The mixture is stirred overnight at room temperature. The reaction mixture is cooled to 0° C. and then 4.1 ml of a 10% aqueous sodium hydroxide solution are added dropwise. The white precipitate formed is filtered under vacuum, the solid washed with ether and then the filtrate concentrated under reduced pressure. The residue is purified by flash chromatography on silica gel (cyclohexane/ethyl acetate: 90/10). The title product (1.35 g) is obtained in the form of a colorless oil.
Reaction SMILES: OO.[N:3]1([CH2:9][CH2:10][NH:11][C:12]2[N:13]=[N+:14]([O-:25])[C:15]3[CH:24]=[C:23]4[C:19]([CH2:20][CH2:21][CH2:22]4)=[CH:18][C:16]=3[N:17]=2)[CH2:8][CH2:7][O:6][CH2:5][CH2:4]1.C([O-])([O-])=[O:27].[Na+].[Na+]>C(O)(C(F)(F)F)=O.O>[N:3]1([CH2:9][CH2:10][NH:11][C:12]2[N:13]=[N+:14]([O-:25])[C:15]3[CH:24]=[C:23]4[C:19]([CH2:20][CH2:21][CH2:22]4)=[CH:18][C:16]=3[N+:17]=2[O-:27])[CH2:8][CH2:7][O:6][CH2:5][CH2:4]1
Reactant: O=C([O-])[O-]
Reactant: [O-][n+]1nc(NCCN2CCOCC2)nc2cc3c(cc21)CCC3
Agent: OO
Agent: [Na+]
Solvent: O
Solvent: O=C(O)C(F)(F)F
Product: [O-][n+]1nc(NCCN2CCOCC2)[n+]([O-])c2cc3c(cc21)CCC3
Temperature: 20 °C
Reaction time: 26 h
Yield: 36 %

Procedure:
H2O2 (70%, 0.50 mL, ca. 10.0 mmol) was added to a stirred solution of 1-oxide 44 (3.00 g, 9.52 mmol) in a mixture of TFA (30 mL) and water (2 mL) at 20° C. Ten more aliquots of 70% H2O2 (0.5 mL) were added in 30 min intervals and the reaction mixture was stirred at 20° C. for 26 h. Water (100 mL) was added and the mixture made basic with Na2CO3. The mixture was extracted with DCM (4×200 mL) and the combined organic fraction was dried and the solvent evaporated. The residue was purified by chromatography, eluting with a gradient (0-5%) of MeOH/DCM, to give 1,4-dioxide 45 (1.13 g, 36%) as a red solid: 1H NMR δ 8.13 (s, 1H, H-9), 8.10 (s, 1H, H-5), 7.38 (br s, 1H, NH), 3.73 (t, J=4.5 Hz, 4H, CH2O), 3.67 (m, 2H, CH2N), 3.03-3.15 (m, 4H, H-6, H-8), 2.68 (t, J=6.0 Hz, 2H, CH2N), 2.53 (t, J=4.5 Hz, 4H, CH2N), 2.17-2.25 (m, 2H, H-7); 13C NMR δ 155.7, 149.4, 145.9, 137.9, 129.7, 115.8, 111.6, 65.9 (2), 56.8, 53.4 (2), 37.7, 33.4, 32.4, 25.6. The hydrochloride salt was crystallised as a red solid: mp (MeOH/DCM) 184-185° C. Anal. calcd for C16H21N5O3.¾HCl: C, 53.5; H, 6.2; N, 19.5. Found: C, 53.9; H, 6.3; N, 19.6%.
Reaction SMILES: [CH3:1][C:2]([C@H:4]1[C@@H:8]2[C@@H:9]3[C@@:22]([CH3:25])([CH2:23][CH2:24][C@@:7]2([C:31]([OH:33])=[O:32])[CH2:6][CH2:5]1)[C@@:21]1([CH3:26])[C@@H:12]([C@:13]2([CH3:30])[C@@H:18]([CH2:19][CH2:20]1)[C:17]([CH3:28])([CH3:27])[C@@H:16]([OH:29])[CH2:15][CH2:14]2)[CH2:11][CH2:10]3)=[CH2:3].C(=O)([O-])[O-].[K+].[K+].[CH2:40](Br)[C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1.C1(C)C=CC=CC=1.C(OCC)C>CN(C)C=O.O>[CH3:3][C:2]([C@H:4]1[C@@H:8]2[C@@H:9]3[C@@:22]([CH3:25])([CH2:23][CH2:24][C@@:7]2([C:31]([O:33][CH2:40][C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=2)=[O:32])[CH2:6][CH2:5]1)[C@@:21]1([CH3:26])[C@@H:12]([C@:13]2([CH3:30])[C@@H:18]([CH2:19][CH2:20]1)[C:17]([CH3:27])([CH3:28])[C@@H:16]([OH:29])[CH2:15][CH2:14]2)[CH2:11][CH2:10]3)=[CH2:1]
Reactant: BrCc1ccccc1
Reactant: C=C(C)[C@@H]1CC[C@]2(C(=O)O)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC[C@H](O)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: Cc1ccccc1
Solvent: CCOCC
Product: C=C(C)[C@@H]1CC[C@]2(C(=O)OCc3ccccc3)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC[C@H](O)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Temperature: 25 °C
Reaction time: 24 h
Yield: 86 %

Procedure:
To a mixture of betulinic acid (2) (500 mg; 1.1 mmol) and potassium carbonate (276 mg; 2.0 mmol) in N,N-dimethylformamide, hereinafter DMF (20 ml), benzylbromide (178 μl; 1.5 mmol) was added and the reaction mixture was stirred at room temperature for 24 h. The course of the reaction was monitored by TLC (toluene/diethyl ether 10:1). The reaction mixture was then diluted with ten-fold excess of water and extracted into ethyl acetate. Combined organic phases were shaken three times with 5% HCl, three times with water, dried with magnesium sulphate and the solvents were evaporated at a rotary vacuum evaporator. The evaporate was purified by column chromatography on silica gel, toluene being the mobile phase. The obtained crude benzyl betulinate (517 mg; 86%) was used without purification in the next step.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:6]=[C:7]([C:11]2[CH:16]=[CH:15][C:14]([N:17]3[CH:21]=[C:20]([C:22]([O:24]CC)=O)[N:19]=[C:18]3[C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=3[C:33]([F:36])([F:35])[F:34])=[CH:13][CH:12]=2)[CH:8]=[CH:9][CH:10]=1)(=[O:4])=[O:3].O1CCOCC1.[NH2:43][NH2:44]>C1(C)C=CC=CC=1>[CH3:1][S:2]([C:5]1[CH:6]=[C:7]([C:11]2[CH:12]=[CH:13][C:14]([N:17]3[CH:21]=[C:20]([C:22]([NH:43][NH2:44])=[O:24])[N:19]=[C:18]3[C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=3[C:33]([F:35])([F:34])[F:36])=[CH:15][CH:16]=2)[CH:8]=[CH:9][CH:10]=1)(=[O:4])=[O:3]
Reactant: CCOC(=O)c1cn(-c2ccc(-c3cccc(S(C)(=O)=O)c3)cc2)c(-c2ccccc2C(F)(F)F)n1
Reactant: NN
Solvent: Cc1ccccc1
Solvent: C1COCCO1
Product: CS(=O)(=O)c1cccc(-c2ccc(-n3cc(C(=O)NN)nc3-c3ccccc3C(F)(F)F)cc2)c1
Temperature: 90 °C
Yield: 69.2 %

Procedure:
To a solution of ethyl 1-(3′-(methylsulfonyl)biphenyl-4-yl)-2-(2-(trifluoromethyl)-phenyl)-1H-imidazole-4-carboxylate (2.63 g, 5.110 mmol) in 8 mL of 1:1 PhMe:Dioxane was added hydrazine (1 mL, 31.86 mmol). The reaction was heated at 90° C. for 12 h and then cooled to room temperature. The reaction was filtered through a small amount of celite to remove a black precipitate and then concentrated and placed on the high vacuum pump. The residue was dissolved in a minimum amount of dichloromethane and slowly added to 200 mL ether with stirring. 100 mL of ether was added and the white precipitate was filtered and rinsed with ether to afford 1-(3′-(methylsulfonyl)biphenyl-4-yl)-2-(2-(trifluoromethyl)-phenyl)-1H-imidazole-4-carbohydrazide (1.77 g, 70%) as a white solid. 1H-NMR (DMSO, 400 MHz) δ 9.21 (s, 1H), 8.16 (s, 1H), 8.14-8.13 (m, 1H), 8.03-8.00 (m, 1H), 7.92-7.89 (m, 1H), 7.85-7.89 (m, 3H), 7.74-7.64 (m, 4H), 7.36 (d, J=8.58 Hz, 2H), 4.44 (brs, 2H), 3.28 (s, 3H); MS (ES): 501.3 [M+H]+ and 523.2 [M+Na]+.
Reaction SMILES: [Li][CH2:2]CCC.[CH2:6]1[CH2:23][O:22][C:8]([C:11]2[C:12]([O:20][CH3:21])=[C:13]([C:16]([F:19])=[CH:17][CH:18]=2)[CH:14]=O)([CH2:9][CH3:10])[O:7]1>[Br-].C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C1COCC1.[Cl-].[Na+].O>[CH2:6]1[CH2:23][O:22][C:8]([C:11]2[C:12]([O:20][CH3:21])=[C:13]([C:16]([F:19])=[CH:17][CH:18]=2)[CH:14]=[CH2:2])([CH2:9][CH3:10])[O:7]1
Reactant: CCC1(c2ccc(F)c(C=O)c2OC)OCCO1
Reactant: [Li]CCCC
Agent: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Agent: [Cl-]
Solvent: C1CCOC1
Solvent: O
Product: C=Cc1c(F)ccc(C2(CC)OCCO2)c1OC
Temperature: 25 °C
Reaction time: 2 h
Yield: 69.2 %

Procedure:
To a suspension of methyltriphenylphosphonium bromide (14.3 g, 40 mmol) in THF (250 ml) at room temperature and under nitrogen was added 16 ml (40 mmol) of 2.5 M n-BuLi. To the almost obtained solution was then added 3-[1,1-(ethylenedioxy)propyl]-6-fluoro-2-methoxybenzaldehyde (10 g, 39.5 mmol) in THF (30 ml). The reaction mixture was then stirred at room temperature for 2 h and poured into a mixture of hexanes and brine. The organic phase was washed two times with brine and one time with water. After evaporation of the solvent, the residue was filtered through a funnel filled with alumina (aluminium oxide 90 acc. Brockmann from Merck) and eluting with EtOAc 1 and hexanes 9 in order to remove the formed triphenylphosphonium oxide. Evaporation of the organic solvent gave a residue which was finally purified on silica gel eluting with EtOAc 1 and hexanes 9 to give 6.9 g (70%) of the title compound with a purity of 94.5% as determined by capillary GC.
Reaction SMILES: [CH2:1]([N:3]([CH2:37][CH3:38])[CH2:4][CH2:5][O:6][C:7]1[CH:12]=[C:11]([CH3:13])[C:10]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([CH2:20][O:21][C:22]3[CH:27]=[CH:26][C:25]([CH2:28][CH2:29][C:30]([O:32]CC)=[O:31])=[C:24]([F:35])[CH:23]=3)[CH:15]=2)=[C:9]([CH3:36])[CH:8]=1)[CH3:2].[OH-].[Na+].[ClH:41].C(=O)([O-])O.[Na+]>C(OCC)(=O)C.O1CCCC1.CO>[ClH:41].[CH2:37]([N:3]([CH2:1][CH3:2])[CH2:4][CH2:5][O:6][C:7]1[CH:8]=[C:9]([CH3:36])[C:10]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([CH2:20][O:21][C:22]3[CH:27]=[CH:26][C:25]([CH2:28][CH2:29][C:30]([OH:32])=[O:31])=[C:24]([F:35])[CH:23]=3)[CH:15]=2)=[C:11]([CH3:13])[CH:12]=1)[CH3:38]
Reactant: CCOC(=O)CCc1ccc(OCc2cccc(-c3c(C)cc(OCCN(CC)CC)cc3C)c2)cc1F
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCN(CC)CCOc1cc(C)c(-c2cccc(COc3ccc(CCC(=O)O)c(F)c3)c2)c(C)c1
Yield: 32 %

Procedure:
To a mixture of ethyl 3-[4-({4′-[2-(diethylamino)ethoxy]-2′,6′-dimethylbiphenyl-3-yl}methoxy)-2-fluorophenyl]propanoate (0.62 g, 1.18 mmol), methanol (5 mL) and tetrahydrofuran (10 mL) was added 1 N aqueous sodium hydroxide solution (2.4 mL) at room temperature with stirring and the mixture was stirred at the same temperature for 2 hrs. The reaction mixture was neutralized with 1 N hydrochloric acid, diluted with ethyl acetate, washed with saturated brine, dried and concentrated under reduced pressure. The residue was purified by preparative HPLC to give a colorless oil. The oil was dissolved in ethyl acetate, neutralized with saturated aqueous sodium hydrogen carbonate, washed with water and saturated brine, dried and concentrated under reduced pressure. The residue was dissolved in ethyl acetate and 4 N hydrogen chloride-ethyl acetate solution was added. The precipitated crystals were collected by filtration, washed and dried to give the title compound (0.20 g, yield 32%) as colorless crystals.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[OH:9].[CH3:10][O:11][CH2:12]OC.O=P12OP3(OP(OP(O3)(O1)=O)(=O)O2)=O.[OH-].[Na+]>ClCCl>[Br:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[O:9][CH2:10][O:11][CH3:12]
Reactant: COCOC
Reactant: Oc1ccc(F)cc1Br
Agent: O=P12OP3(=O)OP(=O)(O1)OP(=O)(O2)O3
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Product: COCOc1ccc(F)cc1Br
Temperature: 25 °C
Reaction time: 2 h
Yield: 98.5 %

Procedure:
2-Bromo-4-fluorophenol (25.0 g, 0.13 mol) was dissolved in dry dichloromethane (100 mL) and dimethoxymethane (115 mL, 1.30 mol). Phosphorus pentoxide (110.8 g, 0.39 mol) was added portion-wise to the solution such that the reaction temperature remained below 40° C. The mixture was stirred vigorously at room temperature for 2 hours and then carefully poured into 1N aqueous NaOH (50 mL). The organic layer was separated, washed with water and then brine, dried over anhydrous MgSO4, filtered and concentrated to give 2-bromo-4-fluoro-1-methoxymethoxy-benzene (30.1 g) as a colorless oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C@@:9]23[CH2:18][CH2:17][CH2:16][CH2:15][C@H:14]2[C:13](=[O:19])[NH:12][C:11](=[O:20])[CH2:10]3)[CH:6]=[CH:7][CH:8]=1.[H-].[Na+].[CH:23]1([CH2:26]Br)[CH2:25][CH2:24]1.O>CN(C)C=O.C1C=CC=CC=1>[CH:23]1([CH2:26][N:12]2[C:11](=[O:20])[CH2:10][C@@:9]3([C:5]4[CH:6]=[CH:7][CH:8]=[C:3]([O:2][CH3:1])[CH:4]=4)[C@H:14]([CH2:15][CH2:16][CH2:17][CH2:18]3)[C:13]2=[O:19])[CH2:25][CH2:24]1
Reactant: BrCC1CC1
Reactant: COc1cccc([C@@]23CCCC[C@H]2C(=O)NC(=O)C3)c1
Agent: [H-]
Agent: [Na+]
Solvent: c1ccccc1
Solvent: CN(C)C=O
Solvent: O
Product: COc1cccc([C@@]23CCCC[C@@H]2C(=O)N(CC2CC2)C(=O)C3)c1
Reaction time: 0.75 h

Procedure:
A solution of 2.0 g (7.3 mmoles) of 4a-(m-methoxyphenyl)-1,3-diketo-trans-decahydroisoquinoline (Ex. 7A) in 50 ml of anhydrous dimethylformamide was added to 35.1 mg of a 55% suspension of sodium hydride in mineral oil in 25 ml of dimethylformamide heated at 70°. Heating was continued for 45 minutes after the addition was complete after which time 1.09 g (8.1 mmoles) of cyclopropylmethyl bromide in 10 ml of dimethylformamide was added. The reaction mixture was heated at 80° for 2 hours and allowed to stand at 25° overnight. It was poured into water and extracted with ether. Evaporation of the ether gave an oil which showed one spot by thin-layer chromatography (silica gel plates, benzene solvent, Rf 0.4, starting material had Rf 0.07) and was identified by nmr as N-cyclopropylmethyl-4a(m-methoxyphenyl)-1,3-diketo-cis-decahydroisoquinoline.
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][N:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6]([CH2:12][CH2:13][CH3:14])=[N:7]2.C(O)C.[F:18][C:19]([F:34])([F:33])[C:20]1[CH:25]=[CH:24][C:23]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)=[C:22]([NH2:32])[CH:21]=1>>[CH2:12]([C:6]1[N:7]=[C:8]2[C:3]([C:2]([NH:32][C:22]3[CH:21]=[C:20]([C:19]([F:18])([F:33])[F:34])[CH:25]=[CH:24][C:23]=3[C:26]3[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=3)=[CH:11][CH:10]=[N:9]2)=[CH:4][CH:5]=1)[CH2:13][CH3:14]
Reactant: CCCc1ccc2c(Cl)ccnc2n1
Reactant: Nc1cc(C(F)(F)F)ccc1-c1ccccc1
Solvent: CCO
Product: CCCc1ccc2c(Nc3cc(C(F)(F)F)ccc3-c3ccccc3)ccnc2n1
Temperature: 100 °C

Procedure:
The product from Example 2g as a 3.15M solution in ethanol (0.078 mL, 0.24 mmol) was reacted with the product from Example 218b (0.057 g, 0.24 mmol) for 64 h at 100° C. following the procedure from Example 1g. Consumption of starting material required periodic addition of the product from Example 2g (0.103 mL, 0.32 mmol) in all, and continued heating at 100° C. (70 hrs.). The crude title compound was purified by HPLC with TFA providing the product as a trifluoroacetic acid salt (0.0058 g, 5%). 1H NMR (300 MHz, DMSO-d6) δ ppm: 0.96 (t, J=7.35 Hz, 3 H) 1.73-1.92 (m, 2 H) 2.90-3.02 (m, 2 H) 6.37 (d, J=6.99 Hz, 1 H) 7.32 (d, J=7.72 Hz, 3 H) 7.48 (dd, J=7.91, 1.65 Hz, 2 H) 7.80 (d, J=8.82 Hz, 1 H) 7.86 (d, J=8.09 Hz, 1 H) 7.94-8.03 (m, 2 H) 8.35 (d, J=6.99 Hz, 1H) 8.91 (d, J=8.82 Hz, 1 H); MS (ESI+) m/z 408.1 (M+H)+; (ESI−) m/z 406.2 (M−H)−.
Reaction SMILES: [C:1]([O:4][CH2:5][C:6]1([OH:24])[CH2:15][C:14]2[C:9](=[C:10]([O:18][CH3:19])[CH:11]=[CH:12][C:13]=2[O:16][CH3:17])[C:8]2(SCCS2)[CH2:7]1)(=[O:3])[CH3:2].O.C([O:28]CC)C>O1CCCC1.CO>[C:1]([O:4][CH2:5][C:6]1([OH:24])[CH2:15][C:14]2[C:9](=[C:10]([O:18][CH3:19])[CH:11]=[CH:12][C:13]=2[O:16][CH3:17])[C:8](=[O:28])[CH2:7]1)(=[O:3])[CH3:2]
Reactant: COc1ccc(OC)c2c1CC(O)(COC(C)=O)CC21SCCS1
Reactant: CCOCC
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: COc1ccc(OC)c2c1CC(O)(COC(C)=O)CC2=O
Reaction time: 1 h
Yield: 70 %

Procedure:
1.9 g of rac-3'-acetoxymethyl-1',2',3',4'-tetrahydro-3'-hydroxy-5',8'-dimethoxyspiro[1,3-dithiolane-2,1'-naphthalene] in 40 ml of tetrahydrofuran were added to a stirred suspension of 6.4 g of mercuric chloride and 6.4 g of mercuric oxide in 200 ml of methanol containing 18 ml of water. After standing at room temperature for 1 hour, ca 150 ml of solvent were removed by evaporation under reduced pressure, 200 ml of dichloromethane were added and the resulting suspension was filtered to remove insoluble material. The filtrate was washed with three 200 ml portions of water, dried over magnesium sulphate and evaporated to give a solid residue. Trituration with diethyl ether gave 1.0 g (70%) of rac-3-acetoxymethyl-1,2,3,4-tetrahydro-3-hydroxy-5,8-dimethoxy-1-oxo-naphthalene in the form of an off-white powder of melting point 124°-126° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=O)[CH:9]([C:11]2[CH:16]=[CH:15][C:14]([S:17][CH3:18])=[CH:13][CH:12]=2)Br)=[CH:4][CH:3]=1.[C:20]1([CH2:26][C:27]([NH2:29])=[S:28])[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.C(CC(C)(C)C)(C)C>C(O)C.C(OCC)(=O)C.C(Cl)Cl>[CH2:26]([C:27]1[S:28][C:9]([C:11]2[CH:16]=[CH:15][C:14]([S:17][CH3:18])=[CH:13][CH:12]=2)=[C:8]([C:5]2[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=2)[N:29]=1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: NC(=S)Cc1ccccc1
Reactant: CSc1ccc(C(Br)C(=O)c2ccc(F)cc2)cc1
Solvent: CCOC(C)=O
Solvent: CCO
Solvent: CC(C)CC(C)(C)C
Product: CSc1ccc(-c2sc(Cc3ccccc3)nc2-c2ccc(F)cc2)cc1
Temperature: 25 °C

Procedure:
To a solution of 2-bromo-l-(4-fluorophenyl)-2-(4-methylthiophenyl)ethanone (Example 1, Step 3) (0.250 g, 0.737 mmol) in ethanol (9 mL) in a 25 mL round bottom flask was added 2-phenylthioacetamide (0.111 g, 0.737 mmol) and the mixture heated to reflux overnight. The reaction was cooled to room temperature, diluted with ethyl acetate (50 mL), washed successively with Na2CO3 (10 % solution) and brine, dried over Na2SO4, filtered and concentrated in vacuo yielding an oil. This oil was dissolved in methylene chloride and isooctane yielding a suspension. The solid was removed by filtration and the filtrate reconcentrated in vacuo yielding 2-benzyl-4-(4-fluorophenyl)-5-(4-methylthiophenyl)thiazole as a yellow oil which was suitable based upon 1H NMR to be used without further purification.
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[C:5]([C:9]2[CH:10]=[C:11]3[C:15](=[C:16]([C:18]([NH2:20])=[O:19])[CH:17]=2)[NH:14][CH:13]=[C:12]3[CH:21]2[CH2:26][CH2:25][N:24]([S:27]([CH2:30][CH2:31][CH2:32][N:33]3[CH2:37][CH2:36][CH2:35][CH2:34]3)(=[O:29])=[O:28])[CH2:23][CH2:22]2)[CH:6]=[CH:7][CH:8]=1)=O.[CH2:38]([NH2:40])[CH3:39].C1COCC1.[BH4-].[Na+]>CO.C(Cl)Cl>[CH2:38]([NH:40][CH2:1][C:3]1[CH:4]=[C:5]([C:9]2[CH:10]=[C:11]3[C:15](=[C:16]([C:18]([NH2:20])=[O:19])[CH:17]=2)[NH:14][CH:13]=[C:12]3[CH:21]2[CH2:26][CH2:25][N:24]([S:27]([CH2:30][CH2:31][CH2:32][N:33]3[CH2:34][CH2:35][CH2:36][CH2:37]3)(=[O:29])=[O:28])[CH2:23][CH2:22]2)[CH:6]=[CH:7][CH:8]=1)[CH3:39]
Reactant: NC(=O)c1cc(-c2cccc(C=O)c2)cc2c(C3CCN(S(=O)(=O)CCCN4CCCC4)CC3)c[nH]c12
Reactant: CCN
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Solvent: ClCCl
Product: CCNCc1cccc(-c2cc(C(N)=O)c3[nH]cc(C4CCN(S(=O)(=O)CCCN5CCCC5)CC4)c3c2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 52 %

Procedure:
To a solution of 5-(3-formylphenyl)-3-(1-{[3-(1-pyrrolidinyl)propyl]sulfonyl}-4-piperidinyl)-1H-indole-7-carboxamide (25 mg, 0.048 mmol) in MeOH/CH2Cl2 (1 mL/1 mL) was added 2M ethyl amine in THF (0.144 mL, 0.288 mmol). The reaction mixture was stirred at room temperature for 2 hours before NaBH4 (12 mg, 0.3 mmol) was added. The reaction mixture was stirred at room temperature overnight and evaporated all the solvent. The residue was purified by using a Gilson semi-preparative HPLC system, eluting with 10% B to 80% B, where A=H2O (0.1% trifluoroacetic acid) and B=CH3CN (0.1% trifluoroacetic acid) pumped at 25 mL/min to give the title compound (11 mg, 52%)
Reaction SMILES: [CH3:1][O:2][C:3](=[O:17])[C:4]1[CH:9]=[CH:8][C:7]([CH2:10]P(OC)(OC)=O)=[CH:6][CH:5]=1.C([N-]C(C)C)(C)C.[Li+].[O:26]([C:31]([N:33]1[CH2:38][CH2:37][C:36](=O)[CH2:35][CH2:34]1)=[O:32])[C:27]([CH3:30])([CH3:29])[CH3:28].O>C1COCC1.C(OCC)(=O)C>[C:27]([O:26][C:31]([N:33]1[CH2:38][CH2:37][C:36](=[CH:10][C:7]2[CH:6]=[CH:5][C:4]([C:3]([O:2][CH3:1])=[O:17])=[CH:9][CH:8]=2)[CH2:35][CH2:34]1)=[O:32])([CH3:30])([CH3:28])[CH3:29]
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Reactant: COC(=O)c1ccc(CP(=O)(OC)OC)cc1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: O
Product: COC(=O)c1ccc(C=C2CCN(C(=O)OC(C)(C)C)CC2)cc1
Temperature: -78 °C
Reaction time: 12 h
Yield: 35 %

Procedure:
The crude product (compound 48) was dissolved in dry THF (200 mL) under N2 and cooled to −78° C. Lithium diisopropylamide (32.7 mL 1.5 M in hexanes, 49 mmol) was added dropwise. The solution was allowed to warm to room temperature. A solution of compound 46 (9.76 g, 49 mmol in 100 mL dry THF) was added to the reaction dropwise and was stirred under N2 for 12 hrs. Water (300 mL) and ethyl acetate (300 mL) were added to the reaction mixture and extracted. The aqueous phase was washed with ethyl acetate (2×300 mL). The combined ethyl acetate was dried over MgSO4 and evaporated to give a crude product, which was purified by silica gel chromatography (0-33% ethyl acetate in hexanes) to provide compound 49 as a white solid (5.64 g, 35%).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5](Br)=[CH:4][N:3]=1.C([Mg]Cl)(C)C.CN(C)[CH:16]=[O:17].O>O1CCCC1>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:16]=[O:17])=[CH:4][N:3]=1
Reactant: Brc1ccc(Br)nc1
Reactant: CN(C)C=O
Agent: CC(C)[Mg]Cl
Solvent: O
Solvent: C1CCOC1
Product: O=Cc1ccc(Br)nc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 66.1 %

Procedure:
To a solution of 2,5-dibromopyridine (2.37 g, 10.0 mmol) in tetrahydrofuran (15 mL) was added isopropylmagnesium chloride (2 mol/L in tetrahydrofuran; 5.0 mL, 10 mmol) under nitrogen atmosphere, and the mixture was stirred at room temperature for 1 h. Dimethylformamide (1.6 mL, 20 mmol) was added, and the mixture was stirred for additional 15 min. Water was added, and the mixture was extracted with ethyl acetate twice. The organic layer was washed with brine and dried on anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (2:1 hexane/ethyl acetate) to afford 2-bromo-5-pyridinecarboxaldehyde (1.23 g, 66%).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]([OH:16])=O)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].ON1[C:22]2[N:23]=[CH:24]C=CC=2N=N1.Cl.CN(C)CCCN=C=NCC.CNC.C(O)C>ClCCl.CN(C)C=O.C(OCC)(=O)C>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14](=[O:16])[N:23]([CH3:24])[CH3:22])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: On1nnc2cccnc21
Reactant: CC(C)(C)OC(=O)N1CCC(C(=O)O)CC1
Agent: CCN=C=NCCCN(C)C
Agent: CNC
Agent: Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: CCO
Product: CN(C)C(=O)C1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 50.8 %

Procedure:
1-(tert-Butoxycarbonyl)piperidine-4-carboxylic acid (8.0 g, 35 mmol) was dissolved in dichloromethane (70 ml) and N,N-dimethylformamide (35 ml). 1-Hydroxy-7-azabenzotriazole (4.75 g, 35 mmol) was added. The solution was cooled to 0° C. N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (6.69 g, 35 mmol) was added. The reaction mixture was stirred for 20 min at 0° C. A 5.6 M solution of dimethylamine in ethanol (37 ml, 209 mmol) was added. The reaction mixture was stirred for 3 days, while it was warming up to room temperature. It was diluted with ethyl acetate (400 ml) and washed with a 10% aqueous solution of sodium hydrogen sulfate (400 ml). The aqueous phase was extracted with ethyl acetate (2×200 ml). The combined organic layers were washed with a saturated aqueous solution of sodium hydrogen carbonate (300 ml) and dried over magnesium sulfate. The solvent was removed in vacuo. The crude product was purified by flash chromatography on silica (300 g), using dichloromethane/methanol 20:1 as eluent, to give 4.56 g of 4-(dimethylcarbamoyl)piperidine-1-carboxylic acid tert-butyl ester.