Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[S:6][C:5]([C:7](=[O:9])[CH3:8])=[CH:4][CH:3]=1.C(N(C(C)C)CC)(C)C.FC(F)(F)S(O[Si](C)(C)C)(=O)=O.[Br:31]N1C(=O)CCC1=O.C(=O)(O)[O-].[Na+]>ClCCl.O>[Br:31][CH2:8][C:7]([C:5]1[S:6][C:2]([F:1])=[CH:3][CH:4]=1)=[O:9]
Reactant: CC(=O)c1ccc(F)s1
Reactant: O=C1CCC(=O)N1Br
Agent: C[Si](C)(C)OS(=O)(=O)C(F)(F)F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: O=C(CBr)c1ccc(F)s1
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 88.8 %

Procedure:
To a stirred clear amber solution of 1-(5-fluorothiophen-2-yl)ethanone (9.70 g, 67.3 mmol) in dichloromethane (224 mL) at 0° C. under nitrogen is added diisopropylethylamine (14.7 mL, 84.1 mmol) followed by the drop wise addition of trimethylsilyl trifluoromethanesulfonate (13.8 mL, 74.0 mmol) over 10 minutes while maintaining the internal temperature below 5° C. The resulting solution is stirred at 0° C. for 90 minutes. N-bromosuccinimide (13.17 g, 74.0 mmol) is added in one portion and the resulting orange solution is stirred at 0° C. for 1 hour. Dilute aqueous sodium bicarbonate (200 mL of a 1:1 water/saturated aqueous sodium bicarbonate solution) and dichloromethane (50 mL) are added. The phases are separated and the aqueous phase is re-extracted with dichloromethane (150 mL). The combined organic extracts are dried over sodium sulfate, filtered, and concentrated under reduced pressure to give a red oily/amorphous residue. The residue is diluted with hexanes (50 mL) and dichloromethane (5 mL) and filtered to remove solids. The solids are washed with a solution of hexanes/dichloromethane (˜50 mL, 7:3). The combined filtrates are concentrated under reduced pressure and the residue is purified by silica gel chromatography eluting with hexanes/dichloromethane (two-step gradient from 70:30 to 60:40 to 50:50) to give the title compound (13.33 g, 89%). 1H NMR (CDCl3) δ 4.27 (s, 2H), 6.58 (dd, J=1.3, 4.4 Hz, 1H), 7.52 (dd, J=1.5, 4.2 Hz, 1H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]([N:21]3[CH:25]=[CH:24][N:23]=[C:22]3[CH3:26])[O:11][C:12]=2[CH2:13][CH2:14][CH2:15][C:16](OCC)=[O:17])=[CH:4][CH:3]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-].O>O1CCCC1>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:9]=[C:10]([N:21]3[CH:25]=[CH:24][N:23]=[C:22]3[CH3:26])[O:11][C:12]=2[CH2:13][CH2:14][CH2:15][CH2:16][OH:17])=[CH:6][CH:7]=1
Reactant: CCOC(=O)CCCc1oc(-n2ccnc2C)nc1-c1ccc(F)cc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: Cc1nccn1-c1nc(-c2ccc(F)cc2)c(CCCCO)o1
Reaction time: 1 h

Procedure:
Ethyl 4-(4-fluorophenyl)-2-(2-methyl-1-imidazolyl)-5-oxazolebutanoate (2.31 g) was dissolved in 20 ml of tetrahydrofuran, to which was added gradually lithium aluminum hydride (269 mg) under ice-cooling. The resulting mixture was stirred for 1 hour. Water (0.5 ml) was carefully added to the reaction mixture. The resulting mixture was filtered, and the residue on the filter paper was washed with ethyl acetate. The filtrate was concentrated to give crystals of 4-(4-fluorophenyl)-2-(2-methyl-1-imidazolyl)-5-oxazolebutanol. Recrystallization from ethyl acetate gave pale yellow prisms (885 mg, 47%). Melting point 97-98° C.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:15][C@@H:14]([N:16]=[N+]=[N-])[CH2:13][C@H:9]1[C:10]([OH:12])=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2]>O.C(O)C>[C:1]([O:5][C:6]([N:8]1[CH2:15][C@@H:14]([NH2:16])[CH2:13][C@H:9]1[C:10]([OH:12])=[O:11])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1C[C@@H](N=[N+]=[N-])C[C@H]1C(=O)O
Solvent: CCO
Solvent: O
Product: CC(C)(C)OC(=O)N1C[C@@H](N)C[C@H]1C(=O)O
Yield: 91.1 %

Procedure:
Azido acid 5b (1.10 g, 4.29 mmol) was dissolved in 100 ml 10% water/ethanol containing 150 mg Pd/C and hydrogenated at 100 psi for 16 h. The mixture was filtered through a pad of celite, washed with 50 mL of 1:1 water/ethanol and the filtrate concentrated to dryness. This material was recrystallized from water/ethanol to give 900 mg of 6 (84% yield), m.p.=225°-227° C. (decomp.) 1H NMR (D2O) δ 1.40/1.44 (m, 9H), 2.11 (m, 1H), 2.68 (m, 1H), 3.69 (m, 2H), 3.99 (m, 2H), 4.20 (dd, J=9.0/3.9 Hz, 1H). Anal. (C10H18N2O4.H2O) C, H, N.
Reaction SMILES: [Mg].[F:2][C:3]([F:27])([F:26])[O:4][C:5]1[CH:10]=[CH:9][C:8]([C@H:11]2[CH2:16][CH2:15][C@H:14]([C@H:17]3[CH2:22][CH2:21][C@H:20]([CH2:23][CH2:24]Cl)[CH2:19][CH2:18]3)[CH2:13][CH2:12]2)=[CH:7][CH:6]=1.[CH3:28][O:29][Si:30](OC)([O:33][CH3:34])[O:31][CH3:32]>C1COCC1>[F:2][C:3]([F:27])([F:26])[O:4][C:5]1[CH:10]=[CH:9][C:8]([C@H:11]2[CH2:16][CH2:15][C@H:14]([C@H:17]3[CH2:22][CH2:21][C@H:20]([CH2:23][CH2:24][Si:30]([O:33][CH3:34])([O:31][CH3:32])[O:29][CH3:28])[CH2:19][CH2:18]3)[CH2:13][CH2:12]2)=[CH:7][CH:6]=1
Reactant: CO[Si](OC)(OC)OC
Reactant: FC(F)(F)Oc1ccc([C@H]2CC[C@H]([C@H]3CC[C@H](CCCl)CC3)CC2)cc1
Agent: [Mg]
Solvent: C1CCOC1
Product: CO[Si](CC[C@H]1CC[C@H]([C@H]2CC[C@H](c3ccc(OC(F)(F)F)cc3)CC2)CC1)(OC)OC
Reaction time: 2 h

Procedure:
A Grignard reagent was prepared from 100 ml of THF, magnesium (120 mmole) and 1-trifluoromethoxy-4-(trans-4-(trans-4-chloroethylcyclohexyl)cyclohexyl)benzene (100 mmole) under nitrogen atmosphere. A THF 100 ml solution of tetramethoxysilane (150 mmole) was heated to 65° C., and the Grignard reagent was added dropwise thereto. The solution was stirred at the same temperature for 2 hours, and after left standing for cooling, the reaction mixture was filtered. The solvent was distilled off, and then 1-trifluoromethoxy-4-(trans-4-(trans-4-trimethoxysilylethylcyclohexyl)cyclohexyl)benzene (57 mmole) was obtained by distillation under reduced pressure.
Reaction SMILES: Br[CH2:2][C:3]1[N:4]=[C:5]([C:9]2[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[CH:11][CH:10]=2)[O:6][C:7]=1[CH3:8].[F:17][C:18]1[C:26]([OH:27])=[CH:25][CH:24]=[C:23]([F:28])[C:19]=1[C:20]([NH2:22])=[O:21].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[F:17][C:18]1[C:26]([O:27][CH2:2][C:3]2[N:4]=[C:5]([C:9]3[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[CH:11][CH:10]=3)[O:6][C:7]=2[CH3:8])=[CH:25][CH:24]=[C:23]([F:28])[C:19]=1[C:20]([NH2:22])=[O:21]
Reactant: NC(=O)c1c(F)ccc(O)c1F
Reactant: COc1ccc(-c2nc(CBr)c(C)o2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1ccc(-c2nc(COc3ccc(F)c(C(N)=O)c3F)c(C)o2)cc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 89.3 %

Procedure:
To a solution of 4-Bromomethyl-2-(4-methoxy-phenyl)-5-methyl-oxazole (0.10 g, 0.35 mmol) in 2 ml of anhydrous DMF was added 2,6-Difluoro-3-hydroxy-benzamide (0.061 g, 0.35 mmol) and potassium carbonate (0.171 g, 1.05 mmol). The reaction mixture was stirred at 25° C. for 24 h under nitrogen atmosphere. The reaction mixture was evaporated to dryness under reduced pressure and the residue was purified by column chromatography on silica (60-120 M) using ethyl acetate/hexane (50:50) as the eluent to provide the title compound as white solid (0.117 g, 87%). 1H NMR (DMSO-d6, 400 MHz): δ 2.42 (s, 3H), 3.82 (s, 3H), 5.06 (s, 2H), 7.10 (m, 3H), 7.37 (m, 1H), 7.86 (m, 3H) and 8.13 (br s, 1H). MS ES+ (375.12), HPLC (method I) Rt=15.78 min.
Reaction SMILES: CO[C:3](=[O:23])[CH:4]([C:11]1[CH:16]=[CH:15][C:14]([N:17]2[CH2:22][CH2:21][O:20][CH2:19][CH2:18]2)=[CH:13][CH:12]=1)[CH2:5][CH:6]1[CH2:10][CH2:9][CH2:8][CH2:7]1.[CH3:24][NH:25][C:26]([NH2:28])=[O:27].C[O-].[Mg+2].C[O-].CO>>[CH:6]1([CH2:5][CH:4]([C:11]2[CH:16]=[CH:15][C:14]([N:17]3[CH2:18][CH2:19][O:20][CH2:21][CH2:22]3)=[CH:13][CH:12]=2)[C:3]([NH:28][C:26]([NH:25][CH3:24])=[O:27])=[O:23])[CH2:7][CH2:8][CH2:9][CH2:10]1
Reactant: COC(=O)C(CC1CCCC1)c1ccc(N2CCOCC2)cc1
Reactant: CNC(N)=O
Agent: C[O-]
Agent: [Mg+2]
Solvent: CO
Product: CNC(=O)NC(=O)C(CC1CCCC1)c1ccc(N2CCOCC2)cc1
Temperature: 25 °C
Yield: 10.5 %

Procedure:
A mixture of 3-cyclopentyl-2-(4-morpholin-4-yl-phenyl)-propionic acid methyl ester (364.0 mg, 1.15 mmol) and methyl urea (254.8 mg, 3.44 mmol) was treated with a solution of magnesium methoxide in methanol (7.4 wt. %, 6.6 mL, 4.59 mmol). The resulting reaction mixture was heated under reflux for 3 d. The reaction mixture was allowed to cool to 25° C. and then filtered through a pad of celite. The pad of celite was washed well with ethyl acetate until the washings showed the absence of product by thin layer chromatography. The filtrate was then concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 230-400 mesh, 3/1 hexanes/ethyl acetate then 1/1 hexanes/ethyl acetate) afforded 1-[3-cyclopentyl-2-(4-morpholin-4-yl-phenyl)-propionyl]-3-methyl-urea (43.5 mg, 11%) as a white solid: mp 206-207° C.; FAB-HRMS m/e calcd for C20H29N3O3 (M+) 359.2209, found 359.2206.
Reaction SMILES: [C:1]([NH:9][C@@H:10]([CH:32]([CH3:34])[CH3:33])[C:11]([N:13](CC1C=CC=CC=1)[CH2:14][C:15]([NH:17][C@H:18]([CH:23]=[O:24])[CH2:19][C:20]([OH:22])=[O:21])=[O:16])=[O:12])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.NC1CC2C(=CC=CC=2)C1.N[N:46]1[CH2:54][C:53]2[C:48](=[CH:49][CH:50]=[CH:51][CH:52]=2)[CH2:47]1>>[C:1]([NH:9][C@@H:10]([CH:32]([CH3:33])[CH3:34])[C:11]([N:13]([N:46]1[CH2:54][C:53]2[C:48](=[CH:49][CH:50]=[CH:51][CH:52]=2)[CH2:47]1)[CH2:14][C:15]([NH:17][C@H:18]([CH:23]=[O:24])[CH2:19][C:20]([OH:22])=[O:21])=[O:16])=[O:12])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)[C@H](NC(=O)c1ccccc1)C(=O)N(CC(=O)N[C@H](C=O)CC(=O)O)Cc1ccccc1
Reactant: NN1Cc2ccccc2C1
Agent: NC1Cc2ccccc2C1
Product: CC(C)[C@H](NC(=O)c1ccccc1)C(=O)N(CC(=O)N[C@H](C=O)CC(=O)O)N1Cc2ccccc2C1

Procedure:
Compound 756 was prepared by a method similar to the method used to prepare compound 724 and compound 706, except 2-aminoindane was replaced with 2-aminoisoindoline (prepared as described in Eloy, F., Moussebois, C., Bull. Soc. Chim. Belg., 68, pp. 409-421 (1959)). ##STR136##
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[NH:9][C:10](=[O:13])[O:11][CH:12]=2)=[CH:4][CH:3]=1.Cl[C:15](=[O:21])[C:16]([O:18][CH2:19][CH3:20])=[O:17]>[Ti](Cl)(Cl)(Cl)Cl.ClCCl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[NH:9][C:10](=[O:13])[O:11][C:12]=2[C:15](=[O:21])[C:16]([O:18][CH2:19][CH3:20])=[O:17])=[CH:6][CH:7]=1
Reactant: O=c1[nH]c(-c2ccc(Cl)cc2)co1
Reactant: CCOC(=O)C(=O)Cl
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: ClCCl
Product: CCOC(=O)C(=O)c1oc(=O)[nH]c1-c1ccc(Cl)cc1
Temperature: 0 °C
Reaction time: 2 h
Yield: 89 %

Procedure:
Titanium tetrachloride(15.5 g) was added dropwise into a mixture of 4-(4-chlorophenyl)-4-oxazolin-2-one(4.00 g), ethyl chloroglyoxylate(5.58 g) and dichloromethane(30 ml) at room temperature. After stirring for 2 hours, the reaction mixture was poured into ice water, and extracted with ethyl acetate. The ethyl acetate layer was washed with water, and dried(MgSO4). The solvent was evaporated to give ethyl 2-[4-(4-chlorophenyl)-2-oxo-4-oxazolin-5-yl]-2-oxoacetate as crystals(5.38 g, 89%). This was recrystallized from ethyl acetate-hexane to give pale yellow prisms. mp 152-153° C.
Reaction SMILES: [O:1]=[C:2]([C:17]1[CH:18]=[C:19]2[C:24](=[CH:25][CH:26]=1)[NH:23][C:22](=[O:27])[CH2:21][CH2:20]2)[CH2:3][CH2:4][N:5]1[CH2:10][CH2:9][CH:8]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH2:7][CH2:6]1.[H][H]>C(O)C.[C].[Pd]>[OH:1][CH:2]([C:17]1[CH:18]=[C:19]2[C:24](=[CH:25][CH:26]=1)[NH:23][C:22](=[O:27])[CH2:21][CH2:20]2)[CH2:3][CH2:4][N:5]1[CH2:10][CH2:9][CH:8]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH2:7][CH2:6]1
Reactant: O=C1CCc2cc(C(=O)CCN3CCC(c4ccccc4)CC3)ccc2N1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: O=C1CCc2cc(C(O)CCN3CCC(c4ccccc4)CC3)ccc2N1

Procedure:
2.2 Grams of 6-[1-oxo-3-(4-phenyl-1-piperidyl)propyl]-3,4-dihydrocarbostyril and 0.5 g of 5%-palladium carbon were dispersed in 80 ml of ethanol and stirred under 2 atmospheric pressure of hydrogen gas at a room temperature for 5 hours. The reaction mixture was filtered to remove the palladium black and the mother liquor was concentrated under a reduced pressure. The residue thus obtained was recrystallized from ethanol to obtain 1.5 g of 6-[1-hydroxy-3-(4-phenyl-1-piperidyl)-propyl]-3,4-dihydrocarbostyril in colorless plate-like crystals.
Reaction SMILES: I[CH:2]1[CH2:19][C@@:18]2([CH3:20])[C:5]([CH2:6][CH2:7][C@@H:8]3[C@@H:17]2[CH2:16][CH2:15][C@@:13]2([CH3:14])[C@H:9]3[CH2:10][CH2:11][C:12]2=[O:21])=[CH:4][C:3]1=[O:22].C(=O)([O-])[O-].[Li+].[Li+].O>CN(C)C=O>[CH3:14][C@:13]12[CH2:15][CH2:16][C@H:17]3[C@@H:8]([CH2:7][CH2:6][C:5]4[C@:18]3([CH3:20])[CH:19]=[CH:2][C:3](=[O:22])[CH:4]=4)[C@@H:9]1[CH2:10][CH2:11][C:12]2=[O:21]
Reactant: C[C@]12CC(I)C(=O)C=C1CC[C@@H]1[C@@H]2CC[C@]2(C)C(=O)CC[C@@H]12
Agent: O=C([O-])[O-]
Agent: [Li+]
Solvent: CN(C)C=O
Solvent: O
Product: C[C@]12C=CC(=O)C=C1CC[C@@H]1[C@@H]2CC[C@]2(C)C(=O)CC[C@@H]12

Procedure:
412 mg (1 mmol) of 2-iodo-androst-4-ene-3,17-dione of example 9 and 148 mg (2 mmol) of anhydrous lithium carbonate are stirred in 2 ml of dimethylformamide for 1 hour at 120° C. under nitrogen atmosphere. After cooling, it is added to water and extracted with ethyl acetate. The ethyl acetate solution is dried on sodium sulfate and then concentrated by evaporation. The residue is chromatographed on silica gel with ethyl acetate/hexane as mobile solvent. After concentration by evaporation of the fractions, 227 mg (80% of theory) of androsta-1,4-diene-3,17-dione of melting point 138°-139° C. is obtained.
Reaction SMILES: N([O-])=O.[Na+].[C:5]1([C@@H:11]([NH:13][C:14]2[N:19]=[C:18]([N:20]3[C:24]4[CH:25]=[C:26]([NH2:29])[CH:27]=[CH:28][C:23]=4[N:22]=[CH:21]3)[CH:17]=[CH:16][N:15]=2)[CH3:12])[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.[N-:30]=[N+:31]=[N-].[Na+]>O.C(O)(=O)C.C(OCC)(=O)C>[C:5]1([C@@H:11]([NH:13][C:14]2[N:19]=[C:18]([N:20]3[C:24]4[CH:25]=[C:26]([N:29]=[N+:30]=[N-:31])[CH:27]=[CH:28][C:23]=4[N:22]=[CH:21]3)[CH:17]=[CH:16][N:15]=2)[CH3:12])[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=1
Reactant: C[C@H](Nc1nccc(-n2cnc3ccc(N)cc32)n1)c1ccccc1
Reactant: [N-]=[N+]=[N-]
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: C[C@H](Nc1nccc(-n2cnc3ccc(N=[N+]=[N-])cc32)n1)c1ccccc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 73.7 %

Procedure:
A solution of 16.3 mg of NaNO2 in 0.5 mL of H2O was added to a 5° C. solution of 78 mg of 2-[(S)-1-phenylethylamino]-4-[6-aminobenzimidazol-1-yl]pyrimidine in 2 mL acetic acid. The solution was cooled to 0° C. and stirred for 0.5 hours. A solution of 23 mg of NaN3 in 0.5 mL H2O was added and stirred for one hour. The solution was diluted with 100 mL of ethyl acetate and washed with water, saturated NaHCO3 and brine. The organic phase was dried over MgSO4, filtered and concentrated under reduced pressure. The residue was purified by flash chromatography eluting with methanol in methylene chloride to give 62 mg of the title compound. RF: 0.6 (5% MeOH in CH2Cl2). 1H NMR (300 MHz, CD3OD): δ1.57 (d, J=7 Hz, 3H), 5.18 (q, J=8 Hz, 1H), 6.88 (d, J=6 Hz, 1H), 7.05 (dd, J=2.5, 9 Hz, 1H), 7.18 (m, 1H), 7.29 (t, J=6 Hz, 2H), 7.43 (d, J=9 Hz, 2H), 7.65 (d, J=9 Hz, 1H), 8.02 (m, 1H), 8.3 (d, J=6 Hz, 1H), 8.69 (b s, 1H). Mass Spectrum (CH3CN-TFA-NH4HCO2-ESI): 357.2 (M+1).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:18]([OH:20])[CH3:19])[CH:5]=[C:6]([F:17])[C:7]=1[B:8]1[O:12][C:11]([CH3:14])([CH3:13])[C:10]([CH3:16])([CH3:15])[O:9]1.[CH:21]1(C(C2C=C(F)C=C(F)C=2)O)C[CH2:22]1>>[CH:19]1([CH:18]([C:4]2[CH:3]=[C:2]([F:1])[C:7]([B:8]3[O:12][C:11]([CH3:13])([CH3:14])[C:10]([CH3:15])([CH3:16])[O:9]3)=[C:6]([F:17])[CH:5]=2)[OH:20])[CH2:22][CH2:21]1
Reactant: CC(O)c1cc(F)c(B2OC(C)(C)C(C)(C)O2)c(F)c1
Reactant: OC(c1cc(F)cc(F)c1)C1CC1
Product: CC1(C)OB(c2c(F)cc(C(O)C3CC3)cc2F)OC1(C)C

Procedure:
Following the procedure of Intermediate 106, replacing 1-(3,5-difluorophenyl)ethanol with cyclopropyl(3,5-difluorophenyl)methanol (Intermediate 139) provided the title compound.
Reaction SMILES: [CH3:1][C:2]1([C:7]2[O:11][C:10]([CH2:12][N:13]3[CH:17]=[C:16]([NH2:18])[CH:15]=[N:14]3)=[CH:9][CH:8]=2)[O:6]CCO1.[CH3:19][O:20][C:21]1[CH:22]=[C:23]([C:27]2[O:31][CH:30]=[N:29][C:28]=2[C:32](O)=[O:33])[CH:24]=[CH:25][CH:26]=1>>[C:2]([C:7]1[O:11][C:10]([CH2:12][N:13]2[CH:17]=[C:16]([NH:18][C:32]([C:28]3[N:29]=[CH:30][O:31][C:27]=3[C:23]3[CH:24]=[CH:25][CH:26]=[C:21]([O:20][CH3:19])[CH:22]=3)=[O:33])[CH:15]=[N:14]2)=[CH:9][CH:8]=1)(=[O:6])[CH3:1]
Reactant: COc1cccc(-c2ocnc2C(=O)O)c1
Reactant: CC1(c2ccc(Cn3cc(N)cn3)o2)OCCO1
Product: COc1cccc(-c2ocnc2C(=O)Nc2cnn(Cc3ccc(C(C)=O)o3)c2)c1

Procedure:
Following general procedure B followed by either C or D, starting from 1-[5-(2-methyl-[1,3]dioxolan-2-yl)-furan-2-ylmethyl]-1H-pyrazol-4-ylamine and 5-(3-methoxy-phenyl)-oxazole-4-carboxylic acid.
Reaction SMILES: [CH:1]([NH:4][CH:5]([CH3:7])[CH3:6])([CH3:3])[CH3:2].[CH3:8][O:9][C:10]([C:12]1([CH2:18][S:19]([C:22]2[CH:27]=[CH:26][C:25]([O:28][C:29]3[CH:34]=[CH:33][C:32]([Cl:35])=[CH:31][CH:30]=3)=[CH:24][CH:23]=2)(=[O:21])=[O:20])[CH2:17][CH2:16][O:15][CH2:14][CH2:13]1)=[O:11].C([N-]C(C)C)(C)C.[Li+:43].[CH2:44](Br)[C:45]1[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=1>O1CCCC1.Cl>[CH:1]([N-:4][CH:5]([CH3:7])[CH3:6])([CH3:3])[CH3:2].[Li+:43].[CH3:8][O:9][C:10]([C:12]1([CH2:18][S:19]([C:22]2[CH:27]=[CH:26][C:25]([O:28][C:29]3[CH:30]=[CH:31][C:32]([Cl:35])=[CH:33][CH:34]=3)=[CH:24][CH:23]=2)(=[O:20])=[O:21])[CH2:17][CH2:16][O:15][CH2:14][CH:13]1[CH2:44][C:45]1[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=1)=[O:11]
Reactant: CC(C)NC(C)C
Reactant: BrCc1ccccc1
Reactant: COC(=O)C1(CS(=O)(=O)c2ccc(Oc3ccc(Cl)cc3)cc2)CCOCC1
Agent: CC(C)[N-]C(C)C
Agent: Cl
Agent: [Li+]
Solvent: C1CCOC1
Product: COC(=O)C1(CS(=O)(=O)c2ccc(Oc3ccc(Cl)cc3)cc2)CCOCC1Cc1ccccc1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 67 %

Procedure:
Lithium diisopropylamide was prepared by the addition of 2.5M N-butyl lithium (610 μL, 1.53 mmol) in hexanes to a solution of diisopropylamine (200 μL, 1.53 mmol) in tetrahydrofuran (3 mL) at 0° C. and stirring for 20 minutes. Then a solution of 4-[4-(4-chlorophenoxy)phenylsulfonylmethyl]-tetrahydropyran-4-carboxylic acid methyl ester (540 mg, 1.27 mmol) in tetrahydrofuran (1 mL) was added to the solution of lithium diisopropylamide at -78° C., and stirred for an additional 60 minutes. Benzyl bromide (181 μL, 1.53 mmol) of was added to the mixture, stirred for an 50 minutes, warmed to room temperature over 30 minutes, and stirred for an additional 3 hours. The mixture was then diluted with 0.1M aqueous hydrochloric acid (25 mL) and extracted with methylene chloride (2×50 mL). The combined organic layers were dried over magnesium sulfate, concentrated in vacuo, chromatographed over silica gel, eluted with 20% ethyl acetate/hexanes, to afford 3-benzyl-4-[4-(4-chlorophenoxy)phenylsulfonylmethyl]-tetrahydropyran-4-carboxylic acid methyl ester (440 mg, 67%) . IR (KBr) 1736 cm-1 ; 1HNMR (CDCl3) δ 1.78 (dm, J=13.5 Hz, 1H), 2.02-2.17 (m, 2H), 2.39 (dm, J=13.5 Hz, 1H), 3.19-3.23 (m, 2H), 3.37-3.45 (td, J=11.9, 2.4 Hz, 2H), 3.77-3.85 (m, 1H), 3.84 (s, 3H), 3.88-3.98 (m, 2H), 4.07-4.17 (m, 2H), 6.83-6.90 (m, 4H), 6.94 (d, J=8.7 Hz, 2H), 7.08-7.15 (m, 3H), 7.37 (d, J=8.7 Hz, 2H), 7.62 (d, J=8.7 Hz, 2H); FABMS (M+ +H): 515.
Reaction SMILES: [Br:1][C:2]1[CH:15]=[CH:14][C:5]([C:6]([CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])=[O:7])=[CH:4][CH:3]=1.O[CH:17]1[C:30]2[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=2[O:24][C:23]2[C:18]1=[CH:19][CH:20]=[CH:21][CH:22]=2>C(O)C.C(O)(=O)C>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([CH:8]([CH:17]2[C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][C:23]=3[O:24][C:25]3[C:30]2=[CH:29][CH:28]=[CH:27][CH:26]=3)[C:9]([O:11][CH2:12][CH3:13])=[O:10])=[O:7])=[CH:14][CH:15]=1
Reactant: OC1c2ccccc2Oc2ccccc21
Reactant: CCOC(=O)CC(=O)c1ccc(Br)cc1
Solvent: CCO
Solvent: CC(=O)O
Product: CCOC(=O)C(C(=O)c1ccc(Br)cc1)C1c2ccccc2Oc2ccccc21
Reaction time: 72 h

Procedure:
A solution of ethyl 4-bromobenzoylacetate (14.8 g, 0.05 mol) and 9-hydroxyxanthene (10.9 g, 0.06 mol) in ethanol-acetic acid (1:1, 150 ml) was stirred as described in Example 3 (ii) and a white solid collected. The filtrate was stirred a further 3 days and a second crop collected to give ethyl 2-(4-bromobenzoyl)-2-(9H-xanthen-9-yl)acetate.
Reaction SMILES: Br.[NH2:2][CH2:3][C:4]([NH:6][C@H:7]1[CH2:12][CH2:11][CH2:10][CH2:9][C@H:8]1[NH:13][C:14](=[O:25])[C:15]1[CH:20]=[CH:19][C:18]([S:21]([NH2:24])(=[O:23])=[O:22])=[CH:17][CH:16]=1)=[O:5].[Cl:26][C:27]1[CH:28]=[C:29]([S:33](Cl)(=[O:35])=[O:34])[CH:30]=[CH:31][CH:32]=1.CCOC(C)=O>CN(C=O)C>[NH2:24][S:21]([C:18]1[CH:17]=[CH:16][C:15]([C:14]([NH:13][C@@H:8]2[CH2:9][CH2:10][CH2:11][CH2:12][C@@H:7]2[NH:6][C:4](=[O:5])[CH2:3][NH:2][S:33]([C:29]2[CH:30]=[CH:31][CH:32]=[C:27]([Cl:26])[CH:28]=2)(=[O:35])=[O:34])=[O:25])=[CH:20][CH:19]=1)(=[O:23])=[O:22]
Reactant: NCC(=O)N[C@H]1CCCC[C@H]1NC(=O)c1ccc(S(N)(=O)=O)cc1
Reactant: O=S(=O)(Cl)c1cccc(Cl)c1
Agent: Br
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: NS(=O)(=O)c1ccc(C(=O)N[C@@H]2CCCC[C@@H]2NC(=O)CNS(=O)(=O)c2cccc(Cl)c2)cc1
Reaction time: 8 h
Yield: 29.4 %

Procedure:
N-(cis)-{2-[(aminoacetyl)amino]cyclohexyl}-4-(aminosulfonyl)benzamide hydrogen bromide, (61b), (70 mg) was dissolved in DMF (2.5 mL) prior to the addition of 3-chlorobenzenesulfonyl chloride (51 mg). After stirring overnight, EtOAc was added and the solution was washed with 1N HCl. The EtOAc was dried, filtered, and concentrated. Reverse phase HPLC purification (gradient elution, water/acetonitrile/TFA) of the resulting residue provided the title benzamide (25 mg). MS found: (M+H)+=530.1.
Reaction SMILES: [NH2:1][CH2:2][CH:3]([CH3:6])[CH2:4][OH:5].[C:7]1(=O)[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]1.O.[CH2:15]=[C:16]1[O:20][C:18](=[O:19])[CH2:17]1>C1C=CC=CC=1.C(Cl)Cl>[CH3:6][CH:3]1[CH2:2][N:1]([C:18](=[O:19])[CH2:17][C:16](=[O:20])[CH3:15])[C:7]2([CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]2)[O:5][CH2:4]1
Reactant: O=C1CCCCC1
Reactant: C=C1CC(=O)O1
Reactant: CC(CN)CO
Solvent: ClCCl
Solvent: c1ccccc1
Solvent: O
Product: CC(=O)CC(=O)N1CC(C)COC12CCCCC2
Reaction time: 1 h

Procedure:
A solution of 3-amino-2-methyl propan-1-ol (4) (0.400 g) in dry benzene (10 ml) was treated with cyclohexanone (0.450 g) and heated at reflux in an apparatus with provision for water removal for 5 hours. The product was concentrated to give the crude 3-methyl-1-oxa-5-azospiro[5.5]undecane (5) as a yellow oil; νmax. (CH2Cl2) 3450, 1660 (weak, Schiffs base); 1460, 1450, 1160, 1040 cm-1. This material was redissolved in dry benzene (10 ml) and stirred and cooled in an ice-bath, treated with diketene (0.37 ml) and stirring continued at 0° C. for 1 h followed by room temperature for 1 h. The solvent was evaporated and the residue chromatographed on Kieselgel 60 (<230 mesh ASTM) eluting with hexane grading to 1:1 ethyl acetate/hexane, to give 1-[3-methyl-1-oxa-5-azaspiro[5.5]undecan-5-yl]butan-1,3 -dione (6) (0.400 g) as a yellow oil; νmax (CH2Cl2) 1725, 1640, 1450, 1410, 1550 cm-1 ; δ (ppm, CDCl3) 0.96 (3H, d, J=7 Hz, CH3CH); 1.25-2.70 (10H, m, cyclohexyl); 2.10-2.20 (1H, m, CH3CH); 2.27 (3H, s, C(O)CH3); 3.10 (1H, dd, J=12, 7 Hz, CHaHbN); 3.27 (1H, dd, J=11, 7 Hz, CHaHbO); 3.34 (1H, dd, J=12, 7 Hz, CHAHb N); 3.50 (2H, d, J=2.5 Hz, COCH2CO); 3.94 (1H, dd, J=11, 7 Hz, CHaHbO).
Reaction SMILES: [O:1]=[S:2]1(=[O:28])[CH2:7][CH2:6][CH:5]([C:8]2[C:16]3[C:11](=[C:12]([C:25]([NH2:27])=[O:26])[CH:13]=[C:14]([C:17]4[CH:22]=[CH:21][CH:20]=[C:19]([CH:23]=O)[CH:18]=4)[CH:15]=3)[NH:10][CH:9]=2)[CH2:4][CH2:3]1.Cl.CN.C(O)(=O)C.[C:36]([BH3-])#[N:37].[Na+]>CO.CS(C)=O>[O:28]=[S:2]1(=[O:1])[CH2:3][CH2:4][CH:5]([C:8]2[C:16]3[C:11](=[C:12]([C:25]([NH2:27])=[O:26])[CH:13]=[C:14]([C:17]4[CH:22]=[CH:21][CH:20]=[C:19]([CH2:23][NH:37][CH3:36])[CH:18]=4)[CH:15]=3)[NH:10][CH:9]=2)[CH2:6][CH2:7]1
Reactant: [BH3-]C#N
Reactant: NC(=O)c1cc(-c2cccc(C=O)c2)cc2c(C3CCS(=O)(=O)CC3)c[nH]c12
Agent: CN
Agent: Cl
Agent: [Na+]
Solvent: CS(C)=O
Solvent: CC(=O)O
Solvent: CO
Product: CNCc1cccc(-c2cc(C(N)=O)c3[nH]cc(C4CCS(=O)(=O)CC4)c3c2)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
3-(1,1-Dioxidotetrahydro-2H-thiopyran-4-yl)-5-(3-formylphenyl)-1H-indole-7-carboxamide (0.160 g, 0.404 mmol) was taken up in MeOH (1.802 mL)/DMSO (1.802 mL). Methyl amine HCl (0.136 g, 2.018 mmol) was added followed by acetic acid (0.462 mL, 8.07 mmol). The reaction mixture was allowed to stir at room temperature for 1 hour. Sodium cyanoborohydride (0.051 g, 0.807 mmol) was added and the reaction mixture was allowed to stir for 45 minutes and LCMS then shows conversion to desired product. The reaction mixture was purified through a 500 mg SCX cartridge eluting with MeOH followed by ammonia in methanol. The fractions are concentrated under a stream of nitrogen. The residue was dissolved in DMSO (˜3 mL) and purified via RP-HPLC using an XBridge Prep C18 column with water/acetonitrile (0.1% NH4OH buffer). Obtained 0.023 g (13.85%) of the title compound.