Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8](=[O:10])[C:7]([CH3:12])([CH3:11])[C:6]=2[CH:13]=1.[CH3:14][N:15](C)C=O>>[C:14]([C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8](=[O:10])[C:7]([CH3:12])([CH3:11])[C:6]=2[CH:13]=1)#[N:15]
Reactant: CC1(C)C(=O)Oc2ccc(Br)cc21
Reactant: CN(C)C=O
Product: CC1(C)C(=O)Oc2ccc(C#N)cc21
Yield: 45 %

Procedure:
5-Bromo-2,3-dihydro-3,3-dimethylbenzofuran-2-one (39.2 g, 0.162 mole) was treated with cuprous cyanide (17.9 g, 0.2 mole) in dimethyl formamide (40 ml) (as in example 2). Recrystallisation (twice) of the product from ethanol yielded 14 g (45%) title product m.p. 138°-140° C.
Reaction SMILES: O[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][C:5]([C:11]([F:14])([F:13])[F:12])=[CH:4][N:3]=1.P(Cl)(Cl)([Cl:17])=O.N1C2C(=CC=CC=2)C=CC=1.[OH-].[Na+]>>[Cl:17][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][C:5]([C:11]([F:14])([F:13])[F:12])=[CH:4][N:3]=1
Reactant: O=[N+]([O-])c1cc(C(F)(F)F)cnc1O
Reactant: O=P(Cl)(Cl)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: c1ccc2ncccc2c1
Product: O=[N+]([O-])c1cc(C(F)(F)F)cnc1Cl
Temperature: 25 °C
Yield: 85.9 %

Procedure:
A mixture of 5.22 g of 2-hydroxy-3-nitro-5-(trifluoromethyl)pyridine, 4.2 g of phosphorus oxychloride and 2.0 g of quinoline was refluxed with heating for 5.5 hours. The reaction mixture was cooled down to room temperature, then, the reaction mixture was poured into ice water. This mixture was neutralized with a sodium hydroxide aqueous solution, then, the mixture was extracted with ethyl acetate twice. The combined organic layers were washed with water and saturated saline, dried over magnesium sulfate, then, concentrated under reduced pressure. The residue was subjected to silica gel column chromatography, to obtain 4.88 g of 2-chloro3-nitro-5-(trifluoromethyl)pyridine.
Reaction SMILES: [CH2:1]([NH:17][C:18]1[CH:28]=[CH:27][C:21]([CH2:22][CH2:23][C:24]([OH:26])=[O:25])=[CH:20][CH:19]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16].C(N1C=CN=C1)(N1C=CN=C1)=O.[C:41]1(O)[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1.[H-].[Na+]>O1CCCC1>[CH2:1]([NH:17][C:18]1[CH:19]=[CH:20][C:21]([CH2:22][CH2:23][C:24]([O:26][C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=2)=[O:25])=[CH:27][CH:28]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16]
Reactant: CCCCCCCCCCCCCCCCNc1ccc(CCC(=O)O)cc1
Reactant: Oc1ccccc1
Agent: O=C(n1ccnc1)n1ccnc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCCCCCCCCCCCCCCCNc1ccc(CCC(=O)Oc2ccccc2)cc1

Procedure:
A solution of 0.05 mole of 4-(hexadecylamino)hydrocinnamic acid and 0.05 mole of 1,1'-carbonyldiimidazole in 50 ml. of tetrahydrofuran is treated with 0.052 mole of phenol and a trace of sodium hydride. The reaction is heated to reflux for 3 hours, then cooled, filtered and evaporated in vacuo providing phenyl 4-(hexadecylamino)hydrocinnamate.
Reaction SMILES: [CH:1]1[C:2]([I:10])=[CH:3][C:4]([I:9])=[C:5]([OH:8])[C:6]=1[I:7].[F:11][C:12]([F:23])([C:16]([F:22])([Br:21])[C:17]([F:20])([F:19])[Br:18])[C:13](Cl)=[O:14]>N1C=CC=CC=1>[I:7][C:6]1[CH:1]=[C:2]([I:10])[CH:3]=[C:4]([I:9])[C:5]=1[O:8][C:13](=[O:14])[C:12]([F:11])([F:23])[C:16]([F:22])([Br:21])[C:17]([F:20])([F:19])[Br:18]
Reactant: O=C(Cl)C(F)(F)C(F)(Br)C(F)(F)Br
Reactant: Oc1c(I)cc(I)cc1I
Solvent: c1ccncc1
Product: O=C(Oc1c(I)cc(I)cc1I)C(F)(F)C(F)(Br)C(F)(F)Br
Temperature: 50 °C
Yield: 45.2 %

Procedure:
100 grams of triiodophenol were dissolved in 100 ml of pyridine with warming to 50° C. 75 grams of 2,2,3,4,4-pentafluoro-3,4-dibromo-butyryl chloride were added dropwise through a dropping funnel with stirring at such a rate that the temperature did not rise above 65° C. The mixture was stirred at 50° C. for an additional 30 minutes, then overnight at room temperature. The mixture was washed in a separatory funnel three times with 500 ml of DI water, then filtered through a column of silica and the solvent evaporated. The material was then chromatographed on a column of silica using FREON 113 (trichlorotrifluroethane) as eluent. Chromatography on silica gave 75.5 grams of material 99% pure. The material solidified at room temperature and has a melting point of 50° C. I.R.(ν, in cm-1)=3050, 3090 (Ar--H); 1800 (C=O); 1570, 1415 (Ar C=C). m/e 62 (47%, C5H2); 69 (18%, CF3); 129 (22%, CF2Br); 131 (70%, CF2Br and C3F5); 189 (60%, C5H2I); 344 (56%, C6H2I2O); 471 (100%, C6H2I3O).
Reaction SMILES: [CH3:1][C:2]([O:11][OH:12])([CH2:4][CH2:5][C:6]([CH3:10])([O:8][OH:9])[CH3:7])[CH3:3].CN([Si:16](N(C)C)([CH3:18])[CH3:17])C>CCOCC>[CH3:17][Si:16]1([CH3:18])[O:12][O:11][C:2]([CH3:1])([CH3:3])[CH2:4][CH2:5][C:6]([CH3:10])([CH3:7])[O:8][O:9]1
Reactant: CN(C)[Si](C)(C)N(C)C
Reactant: CC(C)(CCC(C)(C)OO)OO
Solvent: CCOCC
Product: CC1(C)CCC(C)(C)OO[Si](C)(C)OO1
Temperature: 16 °C
Reaction time: 1 h
Yield: 97.8 %

Procedure:
Into a 250 ml flask equipped with a magnetic stirring bar, addition funnel and calcium sulfate drying tube is placed a solution of 10.84g (0.06 mole, 98.66% pure) of 2,5-dimethyl-2,5-dihydroperoxyhexane in 120 ml of anhydrous ether. The solution is cooled to 16° C. and a solution of 8.77g (0.06 mole) of bis(dimethylamino) dimethylsilane in 30 ml of anhydrous ether is added slowly dropwise. The reaction temperature is maintained between 15° and 20° by use of an ice bath and by adjusting the rate of addition. After the addition is complete, the solution is stirred at room temperature for one hour. The solution is filtered to remove a small amount of suspended solid. The solvent is removed by distillation yielding 13.75g of 3,3,6,6,9,9-hexamethyl-1,2,4,5-tetraoxa-3-silacyclononane (theoretical yield 14.05g, 97.9%; A.O. analysis 13.32%, theoretical 13.67%, 97.4% pure). The infrared spectrum of the reaction product of this example is identical to the spectrum of material produced in Example 1.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][NH:4][C:5]([N:7]([CH2:17][CH2:18][CH3:19])[CH:8]1[O:16][CH2:15][C@H:13]([OH:14])[C@H:11]([OH:12])[C@H:9]1[OH:10])=[O:6].C(=O)([O-])[O-].[Na+].[Na+].[N+:26]([O-])([N+]([O-])=O)=[O:27]>O1CCCC1.C(Cl)Cl>[Cl:1][CH2:2][CH2:3][N:4]([N:26]=[O:27])[C:5]([N:7]([CH2:17][CH2:18][CH3:19])[CH:8]1[O:16][CH2:15][C@H:13]([OH:14])[C@H:11]([OH:12])[C@H:9]1[OH:10])=[O:6]
Reactant: O=[N+]([O-])[N+](=O)[O-]
Reactant: CCCN(C(=O)NCCCl)C1OC[C@H](O)[C@H](O)[C@H]1O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: C1CCOC1
Product: CCCN(C(=O)N(CCCl)N=O)C1OC[C@H](O)[C@H](O)[C@H]1O
Yield: 75.9 %

Procedure:
3.0 g of 1-(2-chloroethyl)-3-n-propyl-3-L-arabinopyranosylurea are dissolved in a mixture of 80 ml of tetrahydrofuran and 80 ml of methylene chloride, and 15 g of sodium carbonate are added thereto. 5 g of nitrogen tetroxide gas are introduced into the mixture for 10 minutes under ice-cooling. The mixture is treated in the same manner as described in Example 2. 2.5 g of 1-(2-chloroethyl)-1-nitroso-3-n-propyl-3-L-arabinopyranosylurea are thereby obtained as yellow caramel.
Reaction SMILES: [C:1]12([CH2:11][OH:12])[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.C(N(CC)CC)C.[CH3:20][S:21](Cl)(=[O:23])=[O:22]>C(Cl)Cl>[CH3:20][S:21]([O:12][CH2:11][C:1]12[CH2:8][CH:7]3[CH2:6][CH:5]([CH2:4][CH:3]([CH2:9]3)[CH2:2]1)[CH2:10]2)(=[O:23])=[O:22]
Reactant: OCC12CC3CC(CC(C3)C1)C2
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CS(=O)(=O)OCC12CC3CC(CC(C3)C1)C2
Temperature: 0 °C

Procedure:
A mixture of 3 g of adamantan-1-ylmethanol and 5 ml of triethylamine in 50 ml of DCM is cooled to 0° C., 2 ml of methanesulfonyl chloride are added dropwise, and the mixture is left to stir while allowing the temperature to return to AT. A mixture of water/ice is added to the reaction mixture, the mixture is extracted with DCM, the organic phase is dried over Na2SO4, and the solvent is evaporated off under vacuum. 2 g of the expected compound are obtained.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([Cl:13])[CH:11]=2)[C:6]([C:14]([N:16]2[CH2:21][CH2:20][N:19]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=3[F:28])[CH2:18][CH2:17]2)=[O:15])=[CH:5]1.[S:29](Cl)([CH3:32])(=[O:31])=[O:30].C(N(CC)CC)C>C(Cl)Cl>[Cl:13][C:10]1[CH:11]=[C:12]2[C:7]([C:6]([C:14]([N:16]3[CH2:17][CH2:18][N:19]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=4[F:28])[CH2:20][CH2:21]3)=[O:15])=[CH:5][N:4]2[CH2:3][CH2:2][NH:1][S:29]([CH3:32])(=[O:31])=[O:30])=[CH:8][CH:9]=1
Reactant: NCCn1cc(C(=O)N2CCN(c3ccccc3F)CC2)c2ccc(Cl)cc21
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CS(=O)(=O)NCCn1cc(C(=O)N2CCN(c3ccccc3F)CC2)c2ccc(Cl)cc21

Procedure:
[1-(2-Amino-ethyl)-6-chloro-1H-indol-3-yl]-[4-(2-fluoro-phenyl)-piperazin-1-yl]-methanone (preparation described herein), was treated with mesylchloride (1.05 eq) and triethylamine (1.05 eq) in CH2Cl2 under argon at RT to give after purification by prep. HPLC the title compound.
Reaction SMILES: [NH:1]1[C:5]([C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=2[CH2:12][NH2:13])=[CH:4][N:3]=[CH:2]1.N1C=CC=CC=1.[C:20](Cl)(=[O:22])[CH3:21]>ClCCl>[NH:3]1[CH:4]=[C:5]([C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=2[CH2:12][NH:13][C:20](=[O:22])[CH3:21])[N:1]=[CH:2]1
Reactant: CC(=O)Cl
Reactant: NCc1ccccc1-c1cnc[nH]1
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(=O)NCc1ccccc1-c1c[nH]cn1
Temperature: 25 °C
Reaction time: 16 h
Yield: 12.6 %

Procedure:
To a solution of (2-(1H-imidazol-5-yl)phenyl)methanamine (77 mg, 0.445 mmol) in dichloromethane (3 mL) was added pyridine (0.11 mL, 1.33 mmol) and acetyl chloride (76 μL, 1.07 mmol). The reaction was stirred at room temperature for 16 h. The solvent was removed under reduced pressure. The crude product was dissolved in methanol (4 mL) and refluxed for 2 h. The solution was concentrated and the residue was purified by flash column chromatography (silica gel, 5%-20% MeOH/DCM as eluent) to afford the desired product as a white solid (12 mg, 0.056 mmol, 13%). 1H NMR: 2.01 (s, 3H), 4.44 (d, 2H, J=6.3 Hz), 7.21 (d, 1H, J=1.2 Hz), 7.27-7.30 (m, 2H), 7.41-7.48 (m, 2H), 7.73 (d, 1H, J=0.9 Hz), 7.96 (s, 1H).
Reaction SMILES: [CH3:1][C:2]1[CH:13]=[CH:12][C:5]2[NH:6][C:7](=[O:11])[O:8][C:9](=[O:10])[C:4]=2[CH:3]=1.[H-].[Na+].[CH2:16](Br)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>CN(C=O)C>[CH2:16]([N:6]1[C:5]2[CH:12]=[CH:13][C:2]([CH3:1])=[CH:3][C:4]=2[C:9](=[O:10])[O:8][C:7]1=[O:11])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: Cc1ccc2[nH]c(=O)oc(=O)c2c1
Reactant: BrCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1ccc2c(c1)c(=O)oc(=O)n2Cc1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 96.9 %

Procedure:
A solution of Compound 11 (25 g, 141 mmol) in DMF was added slowly to a suspension of NaH (60% in mineral oil, 6.21 g, 155 mmol) in DMF and further stirred at room temperature for 1 h. Then, neat benzyl bromide (19.53 mL, 155 mmol) was added and the solution further stirred at room temperature for 3 h. The solution was poured into ice water, and the solids formed were filtered, washed several times by water, and dried. The solid was suspended in hexane, sonicated briefly, filtered, and washed by hexane to yield 36.5 g (97%) of white solids. M.P. 150° C. 1H NMR (DMSO-d6): δ 2.32 (s, 3H), 5.27 (s, 2H), 7.15 (d, J=8.7 Hz, 1H), 7.26–7.39 (m, 5H), 7.54 (dd, J=1.5, 8.7 Hz, 1H), 7.83 (d, J=1.5 Hz, 1H). Anal. (C16H13NO3) C, H, N.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:13]=[C:12]2[C:8]([CH2:9][C:10](=[O:14])[NH:11]2)=[CH:7][CH:6]=1)=[O:4].[CH3:15][O:16][C:17](OC)(OC)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.CC(OC(C)=O)=O>>[CH3:15][O:16][C:17]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=[C:9]1[C:8]2[C:12](=[CH:13][C:5]([C:3]([O:2][CH3:1])=[O:4])=[CH:6][CH:7]=2)[NH:11][C:10]1=[O:14]
Reactant: COC(OC)(OC)c1ccccc1
Reactant: COC(=O)c1ccc2c(c1)NC(=O)C2
Solvent: CC(=O)OC(C)=O
Product: COC(=O)c1ccc2c(c1)NC(=O)C2=C(OC)c1ccccc1

Procedure:
Alternatively, the 6-methoxycarbonyl-2-oxindole may be reacted directly with trimethylorthobenzoate in the presence of acetanhydride to obtain the “enolether” (methyl 3-[methoxy(phenyl)methylene]-2-oxoindoline-6-carboxylate). This alternative embodiment is described in the General Synthesis Scheme as step II′ and may be carried out as described above for step IIb.
Reaction SMILES: O[C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][N:8]=[C:9]2[N:12]2[CH2:17][CH2:16][N:15]3[CH2:18][CH2:19][CH2:20][CH2:21][CH:14]3[CH2:13]2)=[CH:4][CH:3]=1.[S:22](Cl)(=[O:25])(=[O:24])[NH2:23].C(=O)([O-])O.[Na+]>CN1CCCC1=O>[CH2:13]1[N:12]([C:9]2[C:10]3[C:5](=[CH:4][CH:3]=[C:2]([S:22](=[O:25])(=[O:24])[NH2:23])[CH:11]=3)[CH:6]=[CH:7][N:8]=2)[CH2:17][CH2:16][N:15]2[CH2:18][CH2:19][CH2:20][CH2:21][CH:14]12
Reactant: Oc1ccc2ccnc(N3CCN4CCCCC4C3)c2c1
Reactant: NS(=O)(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN1CCCC1=O
Product: NS(=O)(=O)c1ccc2ccnc(N3CCN4CCCCC4C3)c2c1
Temperature: 25 °C
Yield: 66.2 %

Procedure:
In 3 ml of N-methylpyrrolidone, 105 mg of 7-hydroxy-1-octahydropyrido[1,2-a]pyrazin-2-ylisoquinoline as synthesized in Production Example 84 was dissolved, and to the solution 1.00 g of sulfamoyl chloride was added, followed by an hour's stirring at room temperature. The solution was neutralized with saturated aqueous sodium hydrogencarbonate solution, extracted with chloroform, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified on silica gel column chromatography (25% aqueous ammonia:methanol:chloroform=1:10:90) to provide 85 mg (75%) of 1-octahydropyrido[1,2-a]pyrazin-2-yl-7-sulfamoylisoquinoline.
Reaction SMILES: [C:1]([O:5][C:6](=[O:16])[NH:7][CH2:8][CH2:9][NH:10][C:11]([C:14]#[N:15])([CH3:13])[CH3:12])([CH3:4])([CH3:3])[CH3:2].[H-].[H-].[H-].[H-].[Li+].[Al+3].C[CH2:24][O:25]CC.CCN(C(C)C)C(C)C.ClC(OC1C=CC([N+]([O-])=O)=CC=1)=O>C1COCC1>[C:1]([O:5][C:6](=[O:16])[NH:7][CH2:8][CH2:9][N:10]1[C:11]([CH3:13])([CH3:12])[CH2:14][NH:15][C:24]1=[O:25])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C#N)NCCNC(=O)OC(C)(C)C
Reactant: CCOCC
Agent: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Agent: [Al+3]
Agent: [H-]
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)NCCN1C(=O)NCC1(C)C
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 53 %

Procedure:
{2-[(Cyano-dimethyl-methyl)-amino]-ethyl}-carbamic acid tert-butyl ester (0.74 g., 3.3 mmol) was dissolved in THF (2 mL), cooled in an ice bath, and a 1.0 M solution of LiAlH4 in Et2O (6.5 mL, 6.5 mmol) was added dropwise. The resulting suspension was stirred in the ice bath for 3 h and then quenched (i. 0.17 mL of water; ii. 0.17 mL of 4 M aqueous NaOH; iii. 0.84 mL of water). The resulting mixture was diluted with THF (50 mL) and stirred for 15 min. The mixture was filtered and the filtrate concentrated to give an oil. The oil was dissolved in THF (10 mL), DIPEA (1.4 mL) was added, and the mixture was stirred in an ice bath. A solution of p-nitrophenyl chloroformate (800 mg, 4.0 mmol) in THF (8 mL) was added dropwise and the resulting yellow solution was stirred for 16 h. The mixture was concentrated, dissolved in DCM (50 mL) and washed with 0.5 M HCl (50 mL) followed by saturated aqueous NaHCO3 solution (50 mL). The organic layer was dried (Na2SO4), concentrated and purified by flash chromatography (EtOAc) to give the product as a pale yellow gum (450 mg, 54%).
Reaction SMILES: [C:1]([C:5]1[N:10]=[CH:9][C:8]([C:11]2[N:12]([C:32]([N:34]3[CH2:39][C@@H:38]4[C@@H:36]([CH:37]4[C:40](O)=[O:41])[CH2:35]3)=[O:33])[C@@:13]([C:25]3[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=3)([CH3:24])[C@@:14]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=3)([CH3:16])[N:15]=2)=[C:7]([O:43][CH2:44][CH3:45])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH3:46][O:47][C@H:48]1[CH2:52][CH2:51][NH:50][CH2:49]1>>[C:1]([C:5]1[N:10]=[CH:9][C:8]([C:11]2[N:12]([C:32]([N:34]3[CH2:39][C@@H:38]4[C@@H:36]([CH:37]4[C:40]([N:50]4[CH2:51][CH2:52][C@H:48]([O:47][CH3:46])[CH2:49]4)=[O:41])[CH2:35]3)=[O:33])[C@@:13]([C:25]3[CH:26]=[CH:27][C:28]([Cl:31])=[CH:29][CH:30]=3)([CH3:24])[C@@:14]([C:17]3[CH:18]=[CH:19][C:20]([Cl:23])=[CH:21][CH:22]=3)([CH3:16])[N:15]=2)=[C:7]([O:43][CH2:44][CH3:45])[CH:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CCOc1cc(C(C)(C)C)ncc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)N1C[C@@H]2C(C(=O)O)[C@@H]2C1
Reactant: CO[C@H]1CCNC1
Product: CCOc1cc(C(C)(C)C)ncc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)N1C[C@@H]2C(C(=O)N3CC[C@H](OC)C3)[C@@H]2C1

Procedure:
In a manner analogous to the method described in examples 99, (1S,5R)-3-[(4S,5R)-2-(6-tert-butyl-4-ethoxy-pyridin-3-yl)-4,5-bis-(4-chloro-phenyl)-4,5-dimethyl-4,5-dihydro-imidazole-1-carbonyl]-3-aza-bicyclo[3.1.0]hexane-6-carboxylic acid (prepared from the ethyl ester, example 135) was coupled with (S)-3-methoxy-pyrrolidine (Aldrich) to give the title compound. HR-MS (ES, m/z) calculated for C40H48Cl2N5O4 [(M+H)+] 708.3078, observed 708.3072.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([CH3:8])[CH:5]=[C:4]([CH3:9])[N:3]=1.[ClH]1C=CC=C1[S:15]([N:18]=[C:19]=[O:20])(=[O:17])=[O:16].[NH:21]1[CH:25]=[CH:24][CH:23]=[C:22]1[C:26]([O:28][CH3:29])=[O:27].[Cl-].[Al+3].[Cl-].[Cl-]>[N+](C)([O-])=O.O>[CH3:9][C:4]1[CH:5]=[C:6]([CH3:8])[N:7]=[C:2]([NH:1][C:19]([NH:18][S:15]([C:24]2[CH:23]=[C:22]([C:26]([O:28][CH3:29])=[O:27])[NH:21][CH:25]=2)(=[O:17])=[O:16])=[O:20])[N:3]=1
Reactant: COC(=O)c1ccc[nH]1
Reactant: Cc1cc(C)nc(N)n1
Agent: [Al+3]
Agent: [Cl-]
Solvent: O
Solvent: C[N+](=O)[O-]
Product: COC(=O)c1cc(S(=O)(=O)NC(=O)Nc2nc(C)cc(C)n2)c[nH]1
Reaction time: 0.5 h

Procedure:
To a stirred suspension of 2.58 g (0.021 mol) of 2-amino-4,6-dimethylpyrimidine in 75 ml dry nitromethane at -10° was added dropwise, via syringe, under nitrogen, 2.0 ml (0.023 mol) of chlorolsulfonyl isocyanate at such a rate to maintain the temperature below 0°. The resulting clear solution was stirred 0.5 hour at -5° to -10°, then treated dropwise with a solution of 2.29 g (0.021 mole) of methyl pyrrole-2-carboxylate in 25 ml dry nitromethane. Upon completion of the addition, 2.95 gm (0.022 mole) of aluminum (III) chloride was added in one portion. The reaction mixture was heated at reflux for 2 hours, then allowed to stand overnight at ambient temperatures. The mixture was poured into 300 ml H2O and the two phase system extracted with three portions of CH2Cl2. The organic solutions were washed with water, dried over MgSO4 and evaporated to a tan foam which was triturated with minimal CH2Cl2 to afford the product as a white solid, m.p. 202°-204°.
Reaction SMILES: [OH:1][C@H:2]1[CH2:19][CH2:18][C@@:17]2([CH3:20])[C@@H:4]([CH2:5][CH2:6][C@:7]3([CH3:49])[C@@H:16]2[CH2:15][CH2:14][C@H:13]2[C@@:8]3([CH3:48])[CH2:9][CH2:10][C@@:11]3([C:27]([NH:29][CH2:30][CH2:31][CH:32]4[O:37][C:36]([CH3:39])([CH3:38])[O:35][CH:34]([CH2:40][C:41]([O:43][C:44]([CH3:47])([CH3:46])[CH3:45])=[O:42])[CH2:33]4)=[O:28])[CH2:23][CH2:22][C@@H:21]([C:24]([CH3:26])=[CH2:25])[C@@H:12]32)[C:3]1([CH3:51])[CH3:50].CC1C=CN=C(N)C=1C.[CH3:61][C:62]1([CH3:69])[CH2:66][C:65](=[O:67])[O:64][C:63]1=[O:68]>N1C=CC=CC=1.C(OCC)(=O)C>[C:44]([O:43][C:41](=[O:42])[CH2:40][CH:34]1[O:35][C:36]([CH3:38])([CH3:39])[O:37][CH:32]([CH2:31][CH2:30][NH:29][C:27]([C@:11]23[CH2:23][CH2:22][C@@H:21]([C:24]([CH3:26])=[CH2:25])[C@@H:12]2[C@@H:13]2[C@@:8]([CH3:48])([CH2:9][CH2:10]3)[C@@:7]3([CH3:49])[C@@H:16]([C@:17]4([CH3:20])[C@@H:4]([CH2:5][CH2:6]3)[C:3]([CH3:51])([CH3:50])[C@@H:2]([O:1][C:65](=[O:67])[CH2:66][C:62]([CH3:69])([CH3:61])[C:63]([OH:68])=[O:64])[CH2:19][CH2:18]4)[CH2:15][CH2:14]2)=[O:28])[CH2:33]1)([CH3:47])([CH3:46])[CH3:45]
Reactant: CC1(C)CC(=O)OC1=O
Reactant: C=C(C)[C@@H]1CC[C@]2(C(=O)NCCC3CC(CC(=O)OC(C)(C)C)OC(C)(C)O3)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: Cc1ccnc(N)c1C
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Product: C=C(C)[C@@H]1CC[C@]2(C(=O)NCCC3CC(CC(=O)OC(C)(C)C)OC(C)(C)O3)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC[C@H](OC(=O)CC(C)(C)C(=O)O)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12

Procedure:
To a stirred solution of tert-butyl 2-(6-(2-((1R,3aS,5aR,5bR,7aR,9S,11aR,11bR,13aR,13bR)-9-hydroxy-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)icosahydro-1H-cyclopenta[a]chrysene-3a-carboxamido)ethyl)-2,2-dimethyl-1,3-dioxan-4-yl)acetate (Example 79, 0.5 g, 0.80 mmol) in pyridine (5 ml), dimethyl amino pyridine (0.2 g, 1.6 mmol) and 3,3-dimethyldihydrofuran-2,5-dione (0.82 ml) were added. Contents were refluxed for about 16 hours. After completion of the reaction, the reaction mixture was diluted with ethyl acetate (30 ml). The organic layer was washed with 5% aqueous HCl, water followed by brine, dried over Na2SO4 and concentrated under reduced pressure. The residue was purified by silica gel column chromatography using 5% MeOH in DCM as eluent to furnish the title compound (0.25 g) as a white solid. 1H NMR (300 MHz, CDCl3): 0.95-1.16 (m, 19H); 1.23-1.78 (m, 23H); 2.15-2.59 (m, 11H); 2.77-3.58 (m, 16H); 4.33-4.70 (m, 4H); 5.58-5.60 (s, 1H); 5.78-5.80 (s, 1H); 7.44-7.47 (s, 1H); ES Mass: 806 [M+Na].
Reaction SMILES: [I:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[C:5]([I:10])=[CH:4][C:3]=1[OH:11].C(=O)([O-])[O-].[K+].[K+].Br[CH2:19][C:20]#[N:21]>CC(C)=O>[I:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[C:5]([I:10])=[CH:4][C:3]=1[O:11][CH2:19][C:20]#[N:21]
Reactant: N#CCBr
Reactant: COc1cc(I)c(O)cc1I
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: COc1cc(I)c(OCC#N)cc1I
Temperature: 60 °C
Reaction time: 8 h
Yield: 91.9 %

Procedure:
2,5-Diiodo-4-methoxy-phenol (2.8 g, 7.5 mmol) and potassium carbonate (2.1 g) were added to 30 mL of stirring acetone at room temperature and under nitrogen. Bromoacetonitrile (0.575 mL, 8.25 mmol) was added, and the reaction mixture was heated to 60° C. and stirred under nitrogen for 8 hours, then stirred for 18 hours under nitrogen at room temperature. The reaction mixture concentrated under reduced pressure, and the residue was poured into water and extracted into EtOAc. The combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was chromatographed on 150 g of flash silica (5%-20% EtOAc/hexanes) to give 2.86 g of (2,5-Diiodo-4-methoxy-phenoxy)-acetonitrile, MS (M+H)=416.
Reaction SMILES: [CH2:1]([O:8][N:9]([CH2:12][C:13]1([C:19]([OH:21])=O)[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1)[CH:10]=[O:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH:22]([C:24]1[N:29]=[C:28]([C:30]([F:33])([F:32])[F:31])[CH:27]=[CH:26][N:25]=1)[NH2:23].CN1CCOCC1.C1C=NC2N(O)N=NC=2C=1.Cl.CN(C)CCCN=C=NCC>CN(C=O)C>[CH2:1]([O:8][N:9]([CH2:12][C:13]1([C:19]([NH:23][NH:22][C:24]2[N:29]=[C:28]([C:30]([F:32])([F:31])[F:33])[CH:27]=[CH:26][N:25]=2)=[O:21])[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18]1)[CH:10]=[O:11])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: NNc1nccc(C(F)(F)F)n1
Reactant: O=CN(CC1(C(=O)O)CCCCC1)OCc1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2cccnc21
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Product: O=CN(CC1(C(=O)NNc2nccc(C(F)(F)F)n2)CCCCC1)OCc1ccccc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 45.6 %

Procedure:
To a mixture of 1-[(Benzyloxy-formyl-amino)-methyl]-cyclohexanecarboxylic acid (0.10 g, 0.34 mmol), 2-hydrazino-4-(trifluoromethyl)pyrimidine (0.06 g, 0.34 mmol), NMM (0.17 g, 1.7 mmol) and HOAt (0.046 g, 0.34 mmol) in DMF (2 mL) at room temperature was added 1-[3-(dimethylamino)-propyl]-3-ethylcarbodiimide hydrochloride (0.067 g, 0.34 mmol). After stirring at room temperature 18 h, the reaction mixture was then purified by preparative, reverse-phase HPLC to afford the title compound as a white solid (0.070 g, 47%). MH+452.
Reaction SMILES: [CH:1]1[CH:2]=[CH:3][C:4]([CH2:7][CH2:8][C:9]([C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:16]=2O)=[O:10])=[CH:5][CH:6]=1>[Pd]>[C:4]1([CH:7]=[CH:8][C:9]([C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=2)=[O:10])[CH:3]=[CH:2][CH:1]=[CH:6][CH:5]=1
Reactant: O=C(CCc1ccccc1)c1ccccc1O
Agent: [Pd]
Product: O=C(C=Cc1ccccc1)c1ccccc1

Procedure:
Hydrogenation of 1.06 g (4.38 mmol) of chalcone with catalytic amount of 10% Pd/C gives the dihydrochalcone after purification on silica gel chromatography. 1H NMR (300 MHz, CD3OD): δ 7.91 (d, d, J=1.8, 8.4 Hz, 1H), 7.50 (d, d, d, J=1.8, 7.2, 9.0 Hz, 1H), 6.97-6.92 (m, 2H), 5.83 (s, 1H), 3.34 (t, J=7.8 Hz, 2H), 2.96 (t, J=7.2 Hz, 2H), 2.13 (s, 3H); 1.87 (s, 3H).