Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: N[C:2]1[C:11]([Cl:12])=[CH:10][C:9]([N:13]([C:18]2[C:37]([CH:38]3[CH2:40][CH2:39]3)=[CH:36][C:21]3[C:22]([C:32](=[O:35])[NH:33][CH3:34])=[C:23]([C:25]4[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=4)[O:24][C:20]=3[CH:19]=2)[S:14]([CH3:17])(=[O:16])=[O:15])=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].CC#N.[BrH:44].N([O-])=O.[Na+]>O>[Br:44][C:2]1[C:11]([Cl:12])=[CH:10][C:9]([N:13]([C:18]2[C:37]([CH:38]3[CH2:40][CH2:39]3)=[CH:36][C:21]3[C:22]([C:32](=[O:35])[NH:33][CH3:34])=[C:23]([C:25]4[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=4)[O:24][C:20]=3[CH:19]=2)[S:14]([CH3:17])(=[O:16])=[O:15])=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5]
Reactant: CNC(=O)c1c(-c2ccc(F)cc2)oc2cc(N(c3cc(Cl)c(N)c(C(=O)OC)c3)S(C)(=O)=O)c(C3CC3)cc12
Reactant: Br
Agent: O=N[O-]
Agent: [Na+]
Solvent: CC#N
Solvent: O
Product: CNC(=O)c1c(-c2ccc(F)cc2)oc2cc(N(c3cc(Cl)c(Br)c(C(=O)OC)c3)S(C)(=O)=O)c(C3CC3)cc12
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a 1 L 3-necked flask equipped with a magnetic stirrer was added 58.0 g (99.0 mmol) of methyl 2-amino-3-chloro-5-(N-(5-cyclopropyl-2-(4-fluorophenyl)-3-(methylcarbamoyl)benzofuran-6-yl)methylsulfonamido)benzoate followed by 500 mL of MeCN and then 500 mL of 48% aqueous HBr. The dark brown solution was cooled to 0° C. in an ice water/brine bath and treated with a solution of 8.20 g (119 mmol) of sodium nitrite in 50 mL of water over a 5 minute period. After 30 minutes LCMS indicated complete consumption of the starting material. The solution was treated with 18.5 g (129 mmol) of CuBr over 2 minutes and then warmed to 50° C. After 30 minutes at 50° C. LCMS indicated complete reaction. The solution was cooled to RT and partitioned between 1 L of EtOAc and 1.5 L of water. The phases were separated and the aqueous solution extracted with EtOAc (2×200 mL). The combined EtOAc solutions were washed with 5% aqueous NaCl (1×1 L), 5% aqueous sodium bisulfite (2×300 mL), saturated aqueous sodium bicarbonate (2×300 mL), saturated aqueous brine (1×300 mL), and dried over sodium sulfate. The drying agent was removed by filtration through a pad of silica gel and the filtrate concentrated to dryness at reduced pressure to give 64.3 g of crude methyl 2-bromo-3-chloro-5-(N-(5-cyclopropyl-2-(4-fluorophenyl)-3-(methylcarbamoyl)benzofuran-6-yl)methylsulfonamido)benzoate as a reddish-brown foam. The crude product was carried forward without further purification. 1H NMR (400 MHz, DMSO-d6) δ ppm 8.50 (q, J=4.29 Hz, 1H) 8.16 (s, 1H) 7.92-8.03 (m, 2H) 7.79 (d, J=2.73 Hz, 1H) 7.65 (d, J=2.73 Hz, 1H) 7.41 (t, J=8.93 Hz, 2H) 7.24 (s, 1H) 3.81-3.89 (m, 3H) 3.45-3.53 (m, 3H) 2.85 (d, J=4.59 Hz, 3H) 2.04-2.16 (m, 1H) 0.71-1.07 (m, 3H) 0.40 (br. s., 1H). LCMS(ESI): 649 (M+H+).
Reaction SMILES: [CH2:1]([O:8][N:9]1[C:15](=[O:16])[N:14]2[CH2:17][C@H:10]1[CH2:11][CH2:12][C@H:13]2[C:18]([OH:20])=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:21][N:22]([C:24](=[O:26])[CH3:25])[NH2:23].ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C>C(Cl)Cl.CN(C)C1C=CN=CC=1>[C:24]([N:22]([CH3:21])[NH:23][C:18]([C@H:13]1[CH2:12][CH2:11][C@H:10]2[CH2:17][N:14]1[C:15](=[O:16])[N:9]2[O:8][CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)=[O:20])(=[O:26])[CH3:25]
Reactant: CC(=O)N(C)N
Reactant: O=C(O)[C@@H]1CC[C@@H]2CN1C(=O)N2OCc1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Product: CC(=O)N(C)NC(=O)[C@H]1CC[C@H]2CN1C(=O)N2OCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 64.2 %

Procedure:
To a solution of (2S,5R)-6-(benzyloxy)-7-oxo-1,6-diazabicyclo[3.2.1]octane-2-carboxylic acid 1 (0.25 g, 0.90 mmol) in dry DCM (30 mL) were added N-methylacetohydrazide 212 (0.14 g, 1.59 mmol), 1-hydroxybenzotriazole (0.19 g, 1.35 mmol), 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (0.26 g, 1.35 mmol) and 4-(dimethylamino)pyridine (0.16 g, 1.35 mmol) at room temperature. The reaction mixture was stirred at room temperature overnight and concentrated under vacuum. The residue was purified by column chromatography to give (2R,5S)—N′-acetyl-6-(benzyloxy)-N′-methyl-7-oxo-1,6-diazabicyclo[3.2.1]octane-2-carbohydrazide 213 (0.20 g, 64%) as a white solid.
Reaction SMILES: [CH3:1][S:2]([CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([N+:11]([O-:13])=[O:12])[CH:6]=1)=[O:3].[F:14][C:15]([F:20])([F:19])[C:16]([NH2:18])=[O:17].[O-2].[Mg+2].C(O)(=O)C.C(O)(=O)C.IC1C=CC=CC=1>C(Cl)Cl.CC([O-])=O.CC([O-])=O.CC([O-])=O.CC([O-])=O.[Rh+2].[Rh+2]>[F:14][C:15]([F:20])([F:19])[C:16]([N:18]=[S:2]([CH3:1])([CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([N+:11]([O-:13])=[O:12])[CH:6]=1)=[O:3])=[O:17]
Reactant: CS(=O)Cc1cccc([N+](=O)[O-])c1
Reactant: NC(=O)C(F)(F)F
Agent: [Rh+2]
Agent: CC(=O)[O-]
Agent: [Mg+2]
Solvent: CC(=O)O
Solvent: Ic1ccccc1
Solvent: ClCCl
Product: CS(=O)(Cc1cccc([N+](=O)[O-])c1)=NC(=O)C(F)(F)F
Temperature: 25 °C
Reaction time: 16 h
Yield: 99.2 %

Procedure:
To a suspension of (rac)-1-[(methylsulfinyl)methyl]-3-nitrobenzene (16.6 g; 83.1 mmol), trifluoroacetamide (18.8 g; 166.1 mmol), magnesium oxide (13.4 g; 332.3 mmol) and rhodium(II)-acetate dimer (1.7 g; 8.3 mmol) in DCM (2290 mL) was added iodobenzene diacetate (40.1 g; 124.6 mmol) at room temperature. The batch was stirred for 16 hours at room temperature, filtered and concentrated. The residue was purified by chromatography (DCM/ethanol 97:3) to give the desired product (25.6 g; 82.4 mmol).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[C:8]([CH3:10])[CH:7]=[C:6]([N+:11]([O-:13])=[O:12])[C:5]=1Cl)([O-:3])=[O:2].Cl.[CH2:16]([O:18][NH2:19])[CH3:17].C(N(CC)CC)C>CO>[N+:1]([C:4]1[CH:9]=[C:8]([CH3:10])[CH:7]=[C:6]([N+:11]([O-:13])=[O:12])[C:5]=1[NH:19][O:18][CH2:16][CH3:17])([O-:3])=[O:2]
Reactant: CCON
Reactant: Cc1cc([N+](=O)[O-])c(Cl)c([N+](=O)[O-])c1
Agent: Cl
Solvent: CO
Solvent: CCN(CC)CC
Product: CCONc1c([N+](=O)[O-])cc(C)cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 70 %

Procedure:
A suspension of 10.0 g. (0.046 mole) of 2,6-dinitro-4-methylchlorobenzene in 100 ml. of methanol was prepared, and to the suspension there was added 7.6 g. (0.092 mole) of ethoxyamine hydrochloride, and 13.9 g. (0.138 mole) of triethylamine. The reaction mixture was stirred for about 30 minutes at room temperature and then heated and stirred for about 2-3 hours, checking samples from the mixture by NMR at half-hour intervals to follow the progress of the reaction. At this time an additional 16.7 g. (0.20 mole) of ethoxyamine hydrochloride was added, and the reaction mixture was stirred and refluxed for about 24 hours. An NMR spectrum of the reaction mixture indicated the presence of the desired product in about 70 percent yield. The reaction product mixture was poured over a mixture of ice and water, and the aqueous mixture filtered. The solid obtained was recrystallized from petroleum ether (b.p. 60°-71° C.) to yield 5.5 g. of product having a melting point of about 64°-66° C. The product was identified by its NMR spectrum as 2,6-dinitro-N-ethoxy-p-toluidine.
Reaction SMILES: FC(F)(F)C(O)=O.[CH2:8]([O:15][C:16](=[O:29])[NH:17][C@@H:18]([CH3:28])[C:19]([C:21]1[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][CH:22]=1)=[O:20])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.C[SiH](C)C1C=CC=CC=1.[OH-].[K+]>CCOC(C)=O.[Cl-].[Na+].O.C1COCC1>[CH2:8]([O:15][C:16](=[O:29])[NH:17][C@@H:18]([CH3:28])[CH:19]([C:21]1[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][CH:22]=1)[OH:20])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: C[C@H](NC(=O)OCc1ccccc1)C(=O)c1ccc(Cl)cc1
Agent: C[SiH](C)c1ccccc1
Agent: [Cl-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: O
Product: C[C@H](NC(=O)OCc1ccccc1)C(O)c1ccc(Cl)cc1
Temperature: 0 °C
Reaction time: 4 h

Procedure:
Trifluoroacetic acid (2 mL) was cooled to −5° C. [(S)-2-(4-Chloro-phenyl)-1-methyl-2-oxo-ethyl]-carbamic acid benzyl ester (0.87 g, 2.7 mmol) was added slowly, followed by dimethylphenylsilane (0.5 mL, 3.3 mmol), and the mixture was stirred for 4 hours. Once no starting material was seen by analytical tlc, the mixture was cooled to 0° C. and treated with 50% aqueous KOH (10 mL), followed by THF. After stirring at mom temperature for 5 hours, only starting material was seen by analytical tlc, and so the solution was diluted with EtOAc and brine. The organic layer was separated and concentrated, and the crude material was purified to give the desired product.
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[C:3]1[CH:4]=[C:5]([OH:13])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.Cl[S:17]([N:20]=C=O)(=[O:19])=[O:18]>C1(C)C=CC=CC=1>[F:1][C:2]([F:14])([F:15])[C:3]1[CH:4]=[C:5]([O:13][S:17](=[O:19])(=[O:18])[NH2:20])[CH:6]=[C:7]([C:9]([F:11])([F:10])[F:12])[CH:8]=1
Reactant: Oc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reactant: O=C=NS(=O)(=O)Cl
Solvent: Cc1ccccc1
Product: NS(=O)(=O)Oc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Yield: 48.1 %

Procedure:
This compound was prepared using the procedure of Example 56 from a mixture of 9.8 g (0.043 mole) of 3,5-bis(trifluoromethyl)phenol and 3.9 ml (0.095 mole) of chlorosulfonyl isocyanate in 50 ml of toluene. The solid product was recrystallized from benzene to yield 6.4 g (48%) of a pale yellow solid, mp 118°-120° C.
Reaction SMILES: [C:1]([C:4]([Cl:11])=[CH:5][CH2:6][C:7]([O:9][CH3:10])=[S:8])(O)=[O:2].C(Cl)(=O)OCC.[BH4-].[Na+].Cl>C1COCC1.N1C=CC=CC=1>[OH:2][CH2:1][C:4]([Cl:11])=[CH:5][CH2:6][C:7]([O:9][CH3:10])=[S:8]
Reactant: COC(=S)CC=C(Cl)C(=O)O
Agent: CCOC(=O)Cl
Agent: Cl
Agent: [BH4-]
Solvent: c1ccncc1
Solvent: C1CCOC1
Product: COC(=S)CC=C(Cl)CO
Temperature: 0 °C
Reaction time: 2 h

Procedure:
A mixture of methyl (2-carboxy-2-chlorovinyl)thioacetate (1) (1.48 g), pyridine (0.65 ml), and ethyl chlorocarbonate (0.6 ml) is stirred in THF at -30° C. for 5 minutes and subsequently at 0° C. for 10 minutes. Sodium borohydride (0.8 g) is added thereto, and the mixture is stirred at 0° C. for 2 hours. The reaction mixture is poured into dil. HCl and extracted with ethyl acetate. The ethyl acetate extract is washed with water, concentrated in vacuo, and chromatographed over silica gel to give methyl (2-hydroxymethyl-2-chlorovinyl)thioacetate (2). Yield: 492 mg.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([OH:8])[CH:5]=[CH:6][CH:7]=1.C(=O)([O-])[O-].[K+].[K+].[C:15]1([CH2:21]Br)[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>CN(C)C=O.O>[C:15]1([CH2:21][O:8][C:4]2[CH:3]=[C:2]([Br:1])[CH:7]=[CH:6][CH:5]=2)[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: BrCc1ccccc1
Reactant: Oc1cccc(Br)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: Brc1cccc(OCc2ccccc2)c1
Temperature: 80 °C
Reaction time: 1 h
Yield: 89.5 %

Procedure:
Under a nitrogen atmosphere, a solution of 50.0 grams (0.29 mole) of 3-bromophenol and 120.0 grams (0.87 mole) of potassium carbonate in 400 mL of N,N-dimethylformamide was stirred, and heated to 80° C. To this was added portionwise, 36.1 mL (0.30 mole) of phenylmethyl bromide during a 20 minute period. Upon completion of addition, the reaction mixture was stirred at 80° C. during a one hour period. After this time, the reaction mixture was allowed to cool to ambient temperature, where it was diluted with 600 mL of water. The mixture was extracted with 600 mL of diethyl ether. The extract was then washed with three 50 mL portions of water, and then it was concentrated under reduced pressure to a residual solid. The solid was recrystallized with 250 mL of methanol, yielding 68.3 grams of 3-(phenylmethoxy)phenyl bromide. The NMR spectrum was consistent with the proposed structure.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[C:5]([N+:9]([O-:11])=[O:10])=[CH:4][N:3]=1.C(N(CC)C(C)C)(C)C.[C:21]([NH:24][CH2:25][CH2:26][NH2:27])(=[O:23])[CH3:22]>O1CCCC1>[Cl:1][C:2]1[N:7]=[C:6]([NH:27][CH2:26][CH2:25][NH:24][C:21](=[O:23])[CH3:22])[C:5]([N+:9]([O-:11])=[O:10])=[CH:4][N:3]=1
Reactant: CC(=O)NCCN
Reactant: O=[N+]([O-])c1cnc(Cl)nc1Cl
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CC(=O)NCCNc1nc(Cl)ncc1[N+](=O)[O-]
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
To a solution of 5.8 g (30 mmol) 2,4-dichloro-5-nitropyrimidine in 120 mL of tetrahydrofuran (THF) at −78° C. under Argon atmosphere was added 5.2 mL (30 mmol) of N,N-diisopropylethylamine followed by 3.1 mL (30 mmol) of N-acetylethylenediamine. The mixture was stirred at −78° C. for 30 min, allowed to warm to room temperature, and stirred for an additional 3 hours. The solvent was removed in vacuo and the residue purified by flash chromatography eluting with EtOAc to provide the compound of formula (2), N-(2-(2-chloro-5-nitropyrimidin-4-ylamino)ethyl)acetamide as pale yellow solid.
Reaction SMILES: Cl.[CH3:2][C:3]1([OH:8])[CH2:7][CH2:6][NH:5][CH2:4]1.C(=O)([O-])[O-].[K+].[K+].[F:15][C:16]1[CH:17]=[C:18]([CH:21]=[C:22]([F:24])[CH:23]=1)[CH2:19]Br>C(#N)C>[F:15][C:16]1[CH:17]=[C:18]([CH:21]=[C:22]([F:24])[CH:23]=1)[CH2:19][N:5]1[CH2:6][CH2:7][C:3]([CH3:2])([OH:8])[CH2:4]1
Reactant: Fc1cc(F)cc(CBr)c1
Reactant: CC1(O)CCNC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CC1(O)CCN(Cc2cc(F)cc(F)c2)C1
Reaction time: 12 h

Procedure:
According to Example 15, 3-methylpyrrolidin-3-ol hydrochloride was synthesized. To a 100 mL reaction flask were added 3-methylpyrrolidin-3-ol hydrochloride (1 g, 7.2 mmol), anhydrous potassium carbonate (2.5 g, 18 mmol) and acetonitrile (15 mL). To the resulting mixture was slowly added a solution of 3,5-difluorobenzyl bromide (1.64 g, 7.9 mmol) in acetonitrile dropwisely at 85° C. The reaction was conducted for 12 hours. After the completion of reaction monitored by TLC, the resulting mixture was evaporated under reduced pressure to remove acetonitrile. To the residue was added a mixed solution of dichloromethane and water for extraction. The organic phase was dried over anhydrous sodium sulfate, and evaporated to remove the solvent to produce a crude product of 1-(3,5-difluorobenzyl)-3-methylpyrrolidin-3-ol (1.8 g), which was directly used in the next step.
Reaction SMILES: [NH2:1][C:2]1[CH:26]=[CH:25][C:5]([C:6]([N:8]2[CH2:13][CH2:12][CH:11]([N:14]3[C:24]4[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=4)[CH2:18][CH2:17][C:15]3=[O:16])[CH2:10][CH2:9]2)=[O:7])=[CH:4][CH:3]=1.CO[CH:29]1[CH2:33][CH2:32][CH:31](OC)O1>C(O)(=O)C>[N:1]1([C:2]2[CH:3]=[CH:4][C:5]([C:6]([N:8]3[CH2:9][CH2:10][CH:11]([N:14]4[C:24]5[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=5)[CH2:18][CH2:17][C:15]4=[O:16])[CH2:12][CH2:13]3)=[O:7])=[CH:25][CH:26]=2)[CH:29]=[CH:33][CH:32]=[CH:31]1
Reactant: COC1CCC(OC)O1
Reactant: Nc1ccc(C(=O)N2CCC(N3C(=O)CCc4ccccc43)CC2)cc1
Solvent: CC(=O)O
Product: O=C(c1ccc(-n2cccc2)cc1)N1CCC(N2C(=O)CCc3ccccc32)CC1

Procedure:
1-[1-(4-Aminobenzoyl)-4-piperidinyl]-3,4-dihydrocarbostyril (500 mg) and 2,5-dimethoxytetrahydrofuran (0.19 ml) are refluxed-with heating for 2 hours in acetic acid. The solvent is concentrated and the residue is purified by silica gel column chromatography (solvent: n-hexane:ethyl acetate=1:1) and recrystallized from n-hexane to give 1-{1-[4-(1-pyrrolyl)benzoyl]-4-piperidinyl}-3,4-dihydrocarbostyril (228 mg) as light gray powder, m.p.: 153°-156° C.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:9][CH:10]([O:13][CH3:14])[O:11][CH3:12])=[C:4]([CH3:15])[C:3]=1[CH3:16].[Mg].C1OC1.[O:21]1[CH2:25][CH2:24][CH2:23][CH2:22]1>>[CH3:12][O:11][CH:10]([O:13][CH3:14])[CH2:9][O:8][C:5]1[CH:6]=[CH:7][C:2]([CH2:23][CH2:22][O:21][CH2:25][CH3:24])=[C:3]([CH3:16])[C:4]=1[CH3:15]
Reactant: C1CCOC1
Reactant: COC(COc1ccc(Br)c(C)c1C)OC
Agent: [Mg]
Solvent: C1CO1
Product: CCOCCc1ccc(OCC(OC)OC)c(C)c1C
Reaction time: 2 h

Procedure:
Grignard reaction was carried out in conventional manner from 5.0 g of 4-bromo-1-(2,2-dimethoxyethoxy)-2,3dimethylbenzene and 0.5 g of magnesium in 30 ml of tetrahydrofuran, and then 1.0 g of ethylene oxide was blown into the reaction mixture at 50° C. Further, the mixture was stirred at the same temperature for 2 hours. Tetrahydrofuran was removed under reduced pressure, and 50 ml of toluene and 50 ml of 1 N hydrochloric acid were added. The organic layer separated was washed with water, and then 5 ml of 20% sodium hydroxide, 4.0 g of diethylsulfate and 0.3 g of tetrabutylammonium chloride were added, followed by heating and stirring at 40° C. for 5 hours. After cooling, the toluene layer was washed with water, dried and then concentrated under reduced pressure The residual oil was purified by column chromatography (Wako Gel C-200, eluant: n-hexane ethyl acetate=10:1) to obtain 3.5 g of the title product.
Reaction SMILES: [CH2:1]([N:4]([CH2:12][C:13]#[C:14][CH3:15])[C:5](=[O:11])[O:6][C:7]([CH3:10])([CH3:9])[CH3:8])[CH:2]=[CH2:3].C[N+]1([O-])CC[O:20][CH2:19]C1>ClCCl.[CH-]=O.[CH-]=O.[C-]#[O+].[C-]#[O+].[C-]#[O+].[C-]#[O+].[C-]#[O+].[C-]#[O+].[Co].[Co+2]>[CH3:15][C:14]1[C:19](=[O:20])[CH2:3][CH:2]2[CH2:1][N:4]([C:5]([O:6][C:7]([CH3:8])([CH3:9])[CH3:10])=[O:11])[CH2:12][C:13]=12
Reactant: C[N+]1([O-])CCOCC1
Reactant: C=CCN(CC#CC)C(=O)OC(C)(C)C
Agent: [Co+2]
Agent: [Co]
Agent: [C-]#[O+]
Solvent: ClCCl
Product: CC1=C2CN(C(=O)OC(C)(C)C)CC2CC1=O
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 63.2 %

Procedure:
Dicobalt octacarbonyl (28.1 g, 82 mmol) was added to a solution of tert-butyl allyl(but-2-yn-1-yl)carbamate (16.4 g, 78 mmol) in dichloromethane (700 mL) at room temperature. The resulting mixture was and stirred under nitrogen for 1.5 h at room temperature, then cooled to 0° C. N-methylmorpholine-N-oxide (55.1 g, 470 mmol) was added in small portions over 1 h. The resultant mixture was stirred at 0° C. for 1 h, at ambient temperature for 2 h and filtered through a silica gel pad. The filter cake was washed with 1:1 mixture of ethyl acetate and hexanes until free of product. The filtrate was concentrated. Silica gel chromatography, eluting with 20-45% ethyl acetate in hexanes, gave tert-butyl 6-methyl-5-oxo-3,3a,4,5-tetrahydrocyclopenta[c]pyrrole-2(1H)-carboxylate (11.7 g, 63% yield). 1H NMR (400 MHz, chloroform-d) δ ppm 4.18 (2 H, d, J=16.29 Hz), 3.92-4.14 (1 H, m), 2.97-3.25 (1 H, m), 2.73-2.87 (1 H, m), 2.52-2.73 (1 H, m), 2.08-2.26 (1 H, m), 1.77 (3 H, s), 1.49 (9 H, s).
Reaction SMILES: [F:1][C:2]1[C:10]([CH3:11])=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[C:4]([N+:12]([O-:14])=[O:13])[CH:3]=1.O=S(Cl)Cl.[CH3:19]O>>[F:1][C:2]1[C:10]([CH3:11])=[CH:9][C:5]([C:6]([O:8][CH3:19])=[O:7])=[C:4]([N+:12]([O-:14])=[O:13])[CH:3]=1
Reactant: Cc1cc(C(=O)O)c([N+](=O)[O-])cc1F
Reactant: CO
Solvent: O=S(Cl)Cl
Product: COC(=O)c1cc(C)c(F)cc1[N+](=O)[O-]

Procedure:
To a solution of the crude 4-fluoro-5-methyl-2-nitrobenzoic acid (5 g) in MeOH (50 mL) was slowly added SOCl2 (3.5 mL, 48 mmol) dropwise and the resulting mixture was refluxed overnight. Then the solvent was removed to give crude methyl 4-fluoro-5-methyl-2-nitrobenzoate (5 g) as a white solid. It was used in the next step without further purification.
Reaction SMILES: [CH2:1]([N:3]([CH3:25])[C:4]1[CH:9]=[C:8]([C:10]2[O:14][N:13]=[C:12]([C:15]3[CH:20]=[C:19]([CH3:21])[C:18]([OH:22])=[C:17]([CH3:23])[CH:16]=3)[N:11]=2)[CH:7]=[C:6]([CH3:24])[N:5]=1)[CH3:2].Cl[CH2:27][C@H:28]([OH:31])[CH2:29][OH:30]>C(O)(C)C.[OH-].[Na+].CC(=O)OCC>[CH2:1]([N:3]([CH3:25])[C:4]1[CH:9]=[C:8]([C:10]2[O:14][N:13]=[C:12]([C:15]3[CH:20]=[C:19]([CH3:21])[C:18]([O:22][CH2:27][C@H:28]([OH:31])[CH2:29][OH:30])=[C:17]([CH3:23])[CH:16]=3)[N:11]=2)[CH:7]=[C:6]([CH3:24])[N:5]=1)[CH3:2]
Reactant: CCN(C)c1cc(-c2nc(-c3cc(C)c(O)c(C)c3)no2)cc(C)n1
Reactant: OC[C@@H](O)CCl
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)O
Solvent: CCOC(C)=O
Product: CCN(C)c1cc(-c2nc(-c3cc(C)c(OC[C@H](O)CO)c(C)c3)no2)cc(C)n1
Yield: 37.2 %

Procedure:
To a solution of 4-{5-[2-(ethyl-methyl-amino)-6-methyl-pyridin-4-yl]-[1,2,4]oxadiazol-3-yl}-2,6-dimethyl-phenol (55 mg, 0.163 mmol) in isopropanol (3 mL) and 3 N aq. NaOH (0.5 mL), (R)-3-chloro-1,2-propanediol (98 mg, 0.894 mmol) is added. The mixture is stirred at 65° C. for 72 h before another portion of (R)-3-chloro-1,2-propanediol (98 mg, 0.894 mmol) is added. Stirring is continued at 65° C. for 4 days before a third portion of (R)-3-chloro-1,2-propanediol (98 mg, 0.894 mmol) is added. After stirring for another 48 h, the mixture is diluted with EA (50 mL) and washed with 1 N aq. NaOH (10 mL) followed by brine (10 mL), dried over MgSO4, filtered and concentrated. The crude product is purified on prep. TLC plates with DCM containing 10% of 7 N NH3 in methanol and 5% of methanol to give (R)-3-(4-{5-[2-(ethyl-methyl-amino)-6-methyl-pyridin-4-yl]-[1,2,4]oxadiazol-3-yl}-2,6-dimethyl-phenoxy)-propane-1,2-diol (25 mg) as a yellow solid; LC-MS: tR=0.73 min; [M+1]+=413.14.
Reaction SMILES: C([O:4][C@H:5]1[CH2:22][CH2:21][C@@:20]2([CH3:23])[C@H:7]([CH2:8][CH2:9][C@@H:10]3[C@@H:19]2[CH2:18][CH2:17][C@@:15]2([CH3:16])[C@:11]3([O:25][CH2:26][O:27][CH2:28][CH3:29])[CH:12]=[CH:13][C:14]2=[O:24])[CH2:6]1)(=O)C.[OH-].[Na+]>CO.O>[OH:4][C@H:5]1[CH2:22][CH2:21][C@@:20]2([CH3:23])[C@H:7]([CH2:8][CH2:9][C@@H:10]3[C@@H:19]2[CH2:18][CH2:17][C@@:15]2([CH3:16])[C@:11]3([O:25][CH2:26][O:27][CH2:28][CH3:29])[CH:12]=[CH:13][C:14]2=[O:24])[CH2:6]1
Reactant: CCOCO[C@]12C=CC(=O)[C@@]1(C)CC[C@H]1[C@H]2CC[C@@H]2C[C@@H](OC(C)=O)CC[C@@]21C
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CCOCO[C@]12C=CC(=O)[C@@]1(C)CC[C@H]1[C@H]2CC[C@@H]2C[C@@H](O)CC[C@@]21C
Yield: 91.1 %

Procedure:
A solution of 6.00 g of 3β-acetoxy-14β-ethoxymethoxy-5β-androst-15-en-17-one and 30 ml of 2N aq. sodium hydroxide in 120 ml of methanol was kept at room temperature for 24 hrs. The mixture was then diluted with water and extracted with dichloromethane. The organic phase was dried over anhydrous sodium sulfate and evaporated to dryness to give 4.90 g of the title compound (II-ac) as a white solid.
Reaction SMILES: Br[C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[CH:4][C:3]=1[Cl:9].[CH3:10][O:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1B(O)O.C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1.O.CC1C(P(C2C(C)=CC=CC=2)C2C(C)=CC=CC=2)=CC=CC=1.CC1C(P(C2C(C)=CC=CC=2)C2C(C)=CC=CC=2)=CC=CC=1.Cl[Pd]Cl>[CH3:10][O:11][C:12]1[C:13]([C:2]2[C:7]([Cl:8])=[CH:6][CH:5]=[CH:4][C:3]=2[Cl:9])=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: COc1ccccc1B(O)O
Reactant: Clc1cccc(Cl)c1Br
Agent: Cl[Pd]Cl
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Agent: O=C([O-])[O-]
Solvent: O
Solvent: C1COCCO1
Product: COc1ccccc1-c1c(Cl)cccc1Cl
Temperature: 100 °C
Yield: 49.2 %

Procedure:
A mixture of 1-bromo-2,6-dichlorobenzene (5.0 g, 0.022 mol), 2-methoxyphenylboronic acid (5.045 g, 0.033 mol) and potassium carbonate (7.65 g, 0.055 mol) in dioxane (130 mL) and water (13 mL) was purged with nitrogen for 20 minutes. Trans-dichlorobis(tri-o-tolylphosphine)palladium (II) (0.87 g, 0.0011 mol) was added and the reaction mixture heated to 100° C. for 36 hours. The cooled reaction mixture was then filtered through celite washing the filter cake with ethyl acetate. The combined organic filtrates were diluted to 500 mL by the addition of ethyl acetate, then washed with 2.0 M aqueous sodium hydroxide (2×350 mL), water (350 mL) and saturated brine (350 mL), dried over magnesium sulfate, filtered and concentrated under reduced pressure to afford a yellow oil. Purification by flash chromatography using a solvent gradient of 0.5 to 2% ethyl acetate in hexane gave 2.74 g (49%) of 2′,6′-dichloro-1,1′-biphenyl-2-yl methyl ether as a white solid. MS (EI) m/z 252 (M+).
Reaction SMILES: Br.C(O)(=O)C.CS(C)=O.[C:10]([NH:15][CH2:16][CH:17]1[CH2:25][C:24]2[C:19](=[CH:20][CH:21]=[C:22]([C:26]3[CH2:27][CH2:28][C:29](=[O:32])[NH:30][N:31]=3)[CH:23]=2)[CH2:18]1)(=[O:14])[CH2:11][CH2:12][CH3:13].C(OC(C)C)(C)C>C(O)(=O)C>[C:10]([NH:15][CH2:16][CH:17]1[CH2:25][C:24]2[C:19](=[CH:20][CH:21]=[C:22]([C:26]3[CH:27]=[CH:28][C:29](=[O:32])[NH:30][N:31]=3)[CH:23]=2)[CH2:18]1)(=[O:14])[CH2:11][CH2:12][CH3:13]
Reactant: CCCC(=O)NCC1Cc2ccc(C3=NNC(=O)CC3)cc2C1
Agent: Br
Solvent: CC(=O)O
Solvent: CC(C)OC(C)C
Solvent: CS(C)=O
Product: CCCC(=O)NCC1Cc2ccc(-c3ccc(=O)[nH]n3)cc2C1
Temperature: 25 °C
Reaction time: 3 h
Yield: 90 %

Procedure:
25 ml of 30% hydrogen bromide-acetic acid and 1 ml of dimethyl sulfoxide were added to 20 ml of a suspension containing 3.13 g of 2-(butyrylamino)methyl-5-[4,5-di-hydropyridazin-3(2H)-on-6-yl]indane suspended in acetic acid. The mixture was stirred at room temperature for 3 hours. Diisopropyl ether was added to the mixture, and crystals precipitated were collected by filtration, washed with water, dried and then recrystallized from methanol to obtain 2.80 g of 2-(butyrylamino)methyl-5-[pyridazin-3(2H)-on-6-yl]indane.