Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([CH2:12][CH2:13][CH2:14][CH2:15][OH:16])[CH:9]([CH3:11])[CH3:10])=[O:7])([CH3:4])([CH3:3])[CH3:2].CC(C)([O-])C.[K+].[F:23][C:24]1[CH:31]=[CH:30][CH:29]=[CH:28][C:25]=1[CH2:26]Br>O1CCCC1.C(Cl)Cl>[F:23][C:24]1[CH:31]=[CH:30][CH:29]=[CH:28][C:25]=1[CH2:26][O:16][CH2:15][CH2:14][CH2:13][CH2:12][N:8]([C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])[CH:9]([CH3:11])[CH3:10]
Reactant: CC(C)N(CCCCO)C(=O)OC(C)(C)C
Reactant: Fc1ccccc1CBr
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: C1CCOC1
Product: CC(C)N(CCCCOCc1ccccc1F)C(=O)OC(C)(C)C
Temperature: -78 °C
Reaction time: 0.67 h
Yield: 77.1 %

Procedure:
A solution of N-(t-butoxycarbonyl)-4-hydroxy-N-isopropylbutylamine (539 mg, 2.33 mmol) in tetrahydrofuran (11 ml) at −40° C. was treated with potassium t-butoxide (1 M in tetrahydrofuran, 2.54 ml, 2.54 mmol). After 40 minutes, the suspension was cooled to −78° C. and treated with a solution of 2-fluorobenzyl bromide (400 mg, 2.12 mmol) in tetrahydrofuran (4 ml). The reaciton was slowly warmed to room temperature and stirred for about five hours. The reaction was diluted with methylene chloride and washed with 1 M potassium carbonate and brine. The organic fraction was dried over sodium sulfate, filtered, and concentrated. The crude oil was purified by liquid chromatography to yield 555 mg (77%) of the title intermediate as a clear oil.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([NH:8][CH:9]2[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]2)[CH:5]=[C:4]([C:15]2[C:23]3[C:18](=[N:19][CH:20]=[C:21]([C:24]4[CH:25]=[N:26][N:27](S(C5C=CC=CC=5)(=O)=O)[CH:28]=4)[CH:22]=3)[N:17](S(C3C=CC=CC=3)(=O)=O)[CH:16]=2)[CH:3]=1.[OH-].[Li+]>O1CCCC1.CO.O.C(OCC)(=O)C>[NH:26]1[CH:25]=[C:24]([C:21]2[CH:22]=[C:23]3[C:15]([C:4]4[CH:3]=[C:2]([Cl:1])[N:7]=[C:6]([NH:8][CH:9]5[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]5)[CH:5]=4)=[CH:16][NH:17][C:18]3=[N:19][CH:20]=2)[CH:28]=[N:27]1
Reactant: O=S(=O)(c1ccccc1)n1cc(-c2cnc3c(c2)c(-c2cc(Cl)nc(NC4CCCCC4)c2)cn3S(=O)(=O)c2ccccc2)cn1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: CO
Product: Clc1cc(-c2c[nH]c3ncc(-c4cn[nH]c4)cc23)cc(NC2CCCCC2)n1
Yield: 23.9 %

Procedure:
A solution of Example 171b (0.110 g, 0.16 mmol) in 18 mL tetrahydrofuran/methanol (2:1) was treated with 1N lithium hydroxide (0.048 g, 2.00 mmol) in 2 mL water at room temperature for 4 hours. The material was diluted with ethyl acetate, washed with brine, dried over MgSO4, filtered, and concentrated. The residue was purified by trituration with diethyl ether/ethyl acetate and filtration to afford 15 mg of the title compound. 1H NMR (400 MHz, DMSO-d6) ppm 1.17-1.44 (m, 5H) 1.56-1.66 (m, 1H) 1.69-1.80 (m, 2H) 1.92-2.01 (m, 2H) 3.66-3.78 (m, 1H) 6.39 (d, J=7.63 Hz, 1H) 6.83 (d, J=6.71 Hz, 2H) 7.95 (s, 1H) 7.95-8.16 (m, 2H) 8.33 (s, 1H) 8.52 (s, 1H) 11.79 (s, 1H) 12.73 (s, 1H). MS (ESI+) m/z 393.7 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4](/[CH:9]=[CH:10]/[C:11]([O:13][C@@H:14]2[CH2:19][C@H:18]([CH3:20])[CH2:17][CH2:16][C@H:15]2[CH:21]([CH3:23])[CH3:22])=[O:12])[CH:5]=[CH:6][C:7]=1[F:8].[CH3:24]S(C)(=O)=C.[I-].[Na+].[OH-].[Na+]>CS(C)=O.O>[F:1][C:2]1[CH:3]=[C:4]([C@@H:9]2[CH2:24][C@H:10]2[C:11]([O:13][C@@H:14]2[CH2:19][C@H:18]([CH3:20])[CH2:17][CH2:16][C@H:15]2[CH:21]([CH3:23])[CH3:22])=[O:12])[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: C=S(C)(C)=O
Reactant: CC(C)[C@@H]1CC[C@@H](C)C[C@H]1OC(=O)/C=C/c1ccc(F)c(F)c1
Agent: [I-]
Agent: [Na+]
Agent: [OH-]
Solvent: CS(C)=O
Solvent: O
Product: CC(C)[C@@H]1CC[C@@H](C)C[C@H]1OC(=O)[C@@H]1C[C@H]1c1ccc(F)c(F)c1
Temperature: 25 °C
Reaction time: 0.83 h

Procedure:
A solution of (1R,2S,5R)-2-isopropyl-5-methylcyclohexyl (E)-3-(3,4-difluorophenyl)-2-propenoate (approximately 8.6 kg) in dimethyl sulfoxide (approximately 27.9 kg) was added with stirring over 20 minutes to a mixture of dimethylsulfoxonium methylide (approximately 2.6 kg, prepared as described above), sodium iodide (approximately 4.2 kg), water (approximately 500 g) and sodium hydroxide (approximately 56 g) in dimethylsulfoxide(27.7 kg) at 25° C. The reaction mixture was stirred for a further 2 hours and 50 minutes at 25° C., then used directly for the preparation of (1R,2S,5R)-2-iopropyl-5-methylcyclohexyl trans-(1R,2R)-2-(3,4-difluorophenyl)cyclopropanecarboxylate.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8]C)=[O:7])=[C:4]([O:12][CH3:13])[C:3]=1[S:14][CH3:15].O.[OH-].[Li+]>CO>[Cl:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([OH:8])=[O:7])=[C:4]([O:12][CH3:13])[C:3]=1[S:14][CH3:15]
Reactant: COC(=O)c1ccc(Cl)c(SC)c1OC
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: COc1c(C(=O)O)ccc(Cl)c1SC
Temperature: 25 °C
Reaction time: 8 h
Yield: 92.2 %

Procedure:
A mixture of methyl 4-chloro-2-methoxy-3-(methylsulphenyl)benzoate (85% pure, 16.9 g) and lithium hydroxide monohydrate (3.85 g) in aqueous methanol was stirred at room temperature overnight. The mixture was evaporated then treated with water and acidified to pH1. It was extracted with ethyl acetate, dried (MgSO4) and filtered. The filtrate was evaporated to dryness to give 4-chloro-2-methoxy-3-(methylsulphenyl)benzoic acid (14.7 g) as a white solid m.p. 121.3°-122.7° C. NMR (CDCl3) 2.45(s,3H), 4.05(s,3H), 7.3(d.1H), 7.95(d,1H) containing only a trace of 4-chloro-3-(choromethylsulphenyl)-2-methoxybenzoic acid (determined by NMR).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[N:6][C:5]([OH:8])=[C:4]2[O:9][C:10]([Cl:12])=[CH:11][C:3]=12.[C:13]([O-])([O-])=O.[K+].[K+].CI>CN(C=O)C>[Br:1][C:2]1[C:3]2[CH:11]=[C:10]([Cl:12])[O:9][C:4]=2[C:5](=[O:8])[N:6]([CH3:13])[CH:7]=1
Reactant: Oc1ncc(Br)c2cc(Cl)oc12
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CI
Product: Cn1cc(Br)c2cc(Cl)oc2c1=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 71.7 %

Procedure:
A 0.2 M solution of 4-bromo-2-chlorofuro[2,3-c]pyridin-7-ol (143 mg, 0.6 mmol) and K2CO3 (200 mg, 1.45 mmol) in DMF stirred at 0° C. under an atmosphere of nitrogen was treated with MeI (99 mg, 0.7 mmol). The ice bath was removed; the mixture was stirred at rt overnight. The reaction mixture was treated water (15 mL) and was extracted with EtOAc (3×10 mL). The combined organic layers were washed with water (15 mL), brine (20 mL), dried over Na2SO4, filtered, and concentrated in vacuo. The residue was purified by chromatography on silica gel using a gradient of EtOAc (10 to 100%) in hexanes to afford the title compound (113 mg, 85%) as a white solid. LCMS (M+H)+=263.
Reaction SMILES: C[Si](C)(C)N[Si](C)(C)C.[Li].[S:11]1[CH:15]=[CH:14][CH:13]=[C:12]1[C:16]#[CH:17].[CH:18](=[O:25])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>O1CCCC1>[S:11]1[CH:15]=[CH:14][CH:13]=[C:12]1[C:16]#[C:17][CH:18]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[OH:25]
Reactant: C#Cc1cccs1
Reactant: O=Cc1ccccc1
Agent: C[Si](C)(C)N[Si](C)(C)C
Agent: [Li]
Solvent: C1CCOC1
Product: OC(C#Cc1cccs1)c1ccccc1
Temperature: 25 °C

Procedure:
Place lithium hexamethyldisilazane (3 mL of a 1M solution in tetrahydrofuran, 3 mmol) under argon atmosphere and cool to 0° C. Add (thiophen-2-yl)acetylene (324 mg, 3 mmol) in tetrahydrofuran (20 mL) and stir at 0° C. until anion formation is complete. Add a solution of benzaldehyde (297 mg, 2.8 mmol) in tetrahydrofuran, remove the ice bath and stir at room temperature until the reaction is complete. Pour onto ethyl ether and water, separate the organic layer and dry (MgSO4). Filter and evaporate the solvent in vacuo. Purify by silica gel chromatography to yield the title compound.
Reaction SMILES: [CH2:1]([C:8]1[CH:20]=[CH:19][C:11]([O:12][CH2:13][C@H:14]2[CH2:18][CH2:17][CH2:16][NH:15]2)=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.Br[CH2:29][CH2:30][CH2:31][C:32]([O:34][CH3:35])=[O:33].O>ClCCl>[CH3:35][O:34][C:32](=[O:33])[CH2:31][CH2:30][CH2:29][N:15]1[CH2:16][CH2:17][CH2:18][C@@H:14]1[CH2:13][O:12][C:11]1[CH:19]=[CH:20][C:8]([CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)=[CH:9][CH:10]=1
Reactant: COC(=O)CCCBr
Reactant: c1ccc(Cc2ccc(OC[C@H]3CCCN3)cc2)cc1
Solvent: O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)CCCN1CCC[C@@H]1COc1ccc(Cc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 24.7 %

Procedure:
To a solution of Example 1 (0.5 g, 1.65 mmol) in dichloromethane (4.8 mL) was added triethylamine (0.46 mL, 3.30 mmol) and methyl 4-bromobutyrate (0.24 mL, 1.90 mmol). The resulting solution was stirred at ambient temperature for 16 hours. Water (25 mL) and dichloromethane (25 mL) were added to the reaction mixture and the crude residue was extracted into dichloromethane. The organic portion was washed with water (25 mL), washed with brine (25 mL), dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The crude product was purified by silica gel flash chromatography using hexane/EtOAc (gradient system) to give the title compound (0.15 g, 24%); 1H NMR (400 MHz, CDCl3); δ 1.66-1.86 (m, 5H), 1.96 (m, 1H), 2.20-2.45 (m, 4H), 2.86 (m, 2H), 3.14 (m, 1H), 3.63 (s, 3H), 3.74 (m, 1H), 3.89 (m, 1H), 3.92 (s, 2H), 6.82 (d, J=8.4 Hz, 2H), 7.08 (d, J=8.0 Hz, 2H), 7.16-7.20 (m, 3H), 7.27 (m, 2H); MS (m/z) 368.4 (M+1); LC (90.6%).
Reaction SMILES: [CH:1]1([O:6][C:7]2[CH:8]=[C:9](/[CH:16]=[CH:17]/[C:18]([O:20][CH3:21])=[O:19])[CH:10]=[CH:11][C:12]=2[N+:13]([O-])=O)[CH2:5][CH2:4][CH2:3][CH2:2]1.C(O)(=O)C.[ClH:26]>CO.C(OCC)C.[Fe]>[ClH:26].[NH2:13][C:12]1[CH:11]=[CH:10][C:9](/[CH:16]=[CH:17]/[C:18]([O:20][CH3:21])=[O:19])=[CH:8][C:7]=1[O:6][CH:1]1[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: COC(=O)/C=C/c1ccc([N+](=O)[O-])c(OC2CCCC2)c1
Agent: [Fe]
Agent: Cl
Solvent: CC(=O)O
Solvent: CCOCC
Solvent: CO
Product: COC(=O)/C=C/c1ccc(N)c(OC2CCCC2)c1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a stirred solution of 2.1 g (7.2 mmol) of methyl 3-(3-cyclopentoxy-4-nitrophenyl)-E-propenoate in 30 mL of methanol was added 6.3 mL (110.1 mmol) of glacial acetic acid and 2.0 g (35.8 mmol) of iron filings. The mixture was warmed to reflux and stirred for 16 hours after which time it was cooled to room temperature, filtered over Celite 545, and concentrated. Liquid chromatography over 200 g of silica gel using 50% ethyl acetate in hexane provided a pure oil. The product was dissolved in anhydrous ethyl ether, subjected to a stream of anhydrous hydrogen chloride gas upon which time an analytically pure, hydrochloride solid formed. The desired solid was collected, washed several times with anhydrous ethyl ether, and dried in vacuo.
Reaction SMILES: Cl.[N:2]1([CH:7]([OH:9])C)[CH2:6][CH2:5][CH2:4][CH2:3]1.[F:10][C:11]1[CH:12]=[C:13](O)[CH:14]=[C:15]([F:17])[CH:16]=1.C(=O)([O-])[O-].[Cs+].[Cs+].[I-].[Na+]>CN(C)C=O>[F:10][C:11]1[CH:12]=[C:13]([CH:14]=[C:15]([F:17])[CH:16]=1)[O:9][CH2:7][N:2]1[CH2:6][CH2:5][CH2:4][CH2:3]1
Reactant: Oc1cc(F)cc(F)c1
Reactant: CC(O)N1CCCC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: Fc1cc(F)cc(OCN2CCCC2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 48.8 %

Procedure:
Add pyrrolidin-1-yl-ethanol hydrochloride (1.5 g) to a mixture of 3,5-difluorophenol (1.0 g), cesium carbonate (8.78 g), sodium iodide (1.15 g) in dry dimethylformamide (20 mL). Stir at room temperature overnight. Concentrate under reduced pressure and the residue is purified by chromatography eluting with ethyl acetate:hexane (1:1) to provide (0.8 g, 50%) of an oil.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].Br[CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10].CN(C=O)C.[CH3:19][N:20]1[C:29]2[C:24](=[CH:25][C:26]([O:30][CH2:31][CH2:32][CH2:33][NH:34][CH2:35][C:36]3[CH:41]=[CH:40][N:39]=[CH:38][CH:37]=3)=[CH:27][CH:28]=2)[CH:23]=[CH:22][C:21]1=[O:42]>C(OCC)(=O)C>[CH2:12]([O:11][C:9](=[O:10])[CH2:8][N:34]([CH2:33][CH2:32][CH2:31][O:30][C:26]1[CH:25]=[C:24]2[C:29](=[CH:28][CH:27]=1)[N:20]([CH3:19])[C:21](=[O:42])[CH:22]=[CH:23]2)[CH2:35][C:36]1[CH:37]=[CH:38][N:39]=[CH:40][CH:41]=1)[CH3:13]
Reactant: Cn1c(=O)ccc2cc(OCCCNCc3ccncc3)ccc21
Reactant: CCOC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCOC(=O)CN(CCCOc1ccc2c(ccc(=O)n2C)c1)Cc1ccncc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Potassium carbonate (1.66 g) and ethyl bromoacetate (1.16 ml) were added to a DMF solution (50 ml) of 1-methyl-6-{3-[(pyridin-4-ylmethyl)amino]propoxy}-1H-quinolin-2-one (1.5 g), and stirred at room temperature overnight. The reaction mixture was added to ice water, and extraction with ethyl acetate was performed. The organic layer was washed with a saturated sodium chloride aqueous solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate: methanol=100:0→85:15). The purified product was condensed under reduced pressure to give the title compound (1.28 g) as a orange oil.
Reaction SMILES: [C:1]1([C:7]2([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[NH:11][C:10](=[O:12])[NH:9][C:8]2=[O:13])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Na+].[C:22]1([S:32](Cl)(=[O:34])=[O:33])[C:31]2[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=2)[CH:25]=[CH:24][CH:23]=1.O>O1CCCC1.C(OCC)(=O)C>[C:22]1([S:32]([N:9]2[C:8](=[O:13])[C:7]([C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)([C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=3)[NH:11][C:10]2=[O:12])(=[O:34])=[O:33])[C:31]2[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=2)[CH:25]=[CH:24][CH:23]=1
Reactant: O=S(=O)(Cl)c1cccc2ccccc12
Reactant: O=C1NC(=O)C(c2ccccc2)(c2ccccc2)N1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: C1CCOC1
Product: O=C1NC(c2ccccc2)(c2ccccc2)C(=O)N1S(=O)(=O)c1cccc2ccccc12
Reaction time: 0.5 h
Yield: 11.4 %

Procedure:
5,5-Diphenylimidazolidine-2,4-dione (0.5 g) was dissolved in tetrahydrofuran (5 mL), and sodium hydride (60%, in oil) (87 mg) was added at 0° C. under ice-cooling. After stirred for 30 minutes, 1-naphthalenesulfonyl chloride (471 mg) was added at 0° C., and the mixture was stirred at room temperature overnight. After water was added carefully, ethyl acetate (100 mL) was added, and the layers were separated. The resulting organic layer was washed with a saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was distilled off. The material was dissolved in ethyl acetate, and purified by silica gel chromatography (hexane:ethyl acetate=3:1 to 2:1) to obtain 100 mg of white powder.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8]([NH:11][CH:12]1[CH2:14][CH2:13]1)(=[O:10])=[O:9].C1N=CN([C:20](N2C=NC=C2)=[O:21])C=1>C(Cl)Cl>[CH:12]1([N:11]2[C:20](=[O:21])[NH:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=3[S:8]2(=[O:10])=[O:9])[CH2:14][CH2:13]1
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: Nc1ccccc1S(=O)(=O)NC1CC1
Solvent: ClCCl
Product: O=C1Nc2ccccc2S(=O)(=O)N1C1CC1
Reaction time: 12 h
Yield: 83.9 %

Procedure:
A solution of 2-amino-N-cyclopropyl-benzenesulfonamide (6.9 g, 32.5 mmol) in CH2Cl2 (50 ml) was treated with CDI (6.5 g, 40 mmol) and stirred for 12 h at reflux. The solution was a washed with HCl (1N), dried over MgSO4 and concentrated to give 6.5 g (84%) of 2-cyclopropyl-1,1-dioxo-1,4-dihydro-2H-1λ6-benzo[1,2,4]thiadiazin-3-one as a brown solid.
Reaction SMILES: [NH:1]1[C:5](=[O:6])[CH2:4][CH:3]2[CH2:7][C:8]3[C:13]([CH:2]12)=[CH:12][CH:11]=[CH:10][CH:9]=3.[H-].[Na+].Cl[C:17]1[CH:22]=[CH:21][C:20]([C:23]#[N:24])=[CH:19][N:18]=1>C1(C)C=CC=CC=1>[O:6]=[C:5]1[N:1]([C:17]2[N:18]=[CH:19][C:20]([C:23]#[N:24])=[CH:21][CH:22]=2)[CH:2]2[C:13]3[C:8]([CH2:7][CH:3]2[CH2:4]1)=[CH:9][CH:10]=[CH:11][CH:12]=3
Reactant: O=C1CC2Cc3ccccc3C2N1
Reactant: N#Cc1ccc(Cl)nc1
Agent: [H-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: N#Cc1ccc(N2C(=O)CC3Cc4ccccc4C32)nc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a suspension of 3,3a,4,8b-tetrahydro-1H-indeno[1,2-b]pyrrol-2-one (1 g, 5.77 mmol) in toluene (15 ml) was added sodium hydride (0.254 g, 6.35 mmol) at 0° C. The batch was warmed to room temperature and 2-chloro-5-cyanopyridine (0.824 g, 5.77 mmol) was added. The batch was stirred at 95° C. for 2 h. After cooling, the batch was added to ice water and extracted with ethyl acetate (2×). The combined organic phases were concentrated and the residue was purified by column chromatography (hexane/ethyl acetate 7/3) to give 6-(2-oxo-3,3a,4,8b-tetrahydroindeno[1,2-b]pyrrol-1-yl)pyridine-3-carbonitrile F20 (1.00 g, 63%). LCMS (method A) 1.68 min; ES+: 276 (M+H+).
Reaction SMILES: [CH3:1][C:2]1[C:3]([CH2:9][N:10]([CH2:16][C:17]2[C:22]([CH:23]([CH3:25])[CH3:24])=[CH:21][CH:20]=[CH:19][N:18]=2)[CH2:11][CH2:12][CH2:13][CH2:14][NH2:15])=[N:4][CH:5]=[C:6]([CH3:8])[CH:7]=1.C[Si]([N:30]=[C:31]=[O:32])(C)C>CC(O)C>[CH3:1][C:2]1[C:3]([CH2:9][N:10]([CH2:16][C:17]2[C:22]([CH:23]([CH3:25])[CH3:24])=[CH:21][CH:20]=[CH:19][N:18]=2)[CH2:11][CH2:12][CH2:13][CH2:14][NH:15][C:31]([NH2:30])=[O:32])=[N:4][CH:5]=[C:6]([CH3:8])[CH:7]=1
Reactant: C[Si](C)(C)N=C=O
Reactant: Cc1cnc(CN(CCCCN)Cc2ncccc2C(C)C)c(C)c1
Solvent: CC(C)O
Product: Cc1cnc(CN(CCCCNC(N)=O)Cc2ncccc2C(C)C)c(C)c1
Yield: 64.6 %

Procedure:
To a solution of N1-(3,5-Dimethyl-pyridin-2-ylmethyl)-N1-{3-isopropyl-pyridin-2-ylmethyl}-butane-1,4-diamine (78 mg, 0.23 mmol) in 2-propanol (2 mL) was added trimethylsilyl-isocyanate (32 μL, 0.24 mmol). The resultant solution was stirred at room temperature overnight then concentrated. Purification of the crude material by radial chromatography on silica gel (1 mm plate, 20:1:1 CH2Cl2-MeOH—NH4OH) provided 57 mg (64%) of the free base of the title compound as a white solid.
Reaction SMILES: [C:1]1([C:7]2[N:16]([CH3:17])[C:15]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[CH:14][C:13](=[O:24])[C:8]=2[C:9]([O:11]C)=[O:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1>[OH-].[Na+]>[C:1]1([C:7]2[N:16]([CH3:17])[C:15]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[CH:14][C:13](=[O:24])[C:8]=2[C:9]([OH:11])=[O:10])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: COC(=O)c1c(-c2ccccc2)n(C)c(-c2ccccc2)cc1=O
Agent: [Na+]
Agent: [OH-]
Product: Cn1c(-c2ccccc2)cc(=O)c(C(=O)O)c1-c1ccccc1

Procedure:
2.5 gms of methyl 2,6-diphenyl-1-methyl-4-oxonicotinate was suspended in 28 mls of 5% aqueous sodium hydroxide 8 hours, cooled, and filtered to remove residual insolubles. The clear basic solution was then acidified with dilute HCl to provide a white precipitate of 2,6-diphenyl-1-methyl-4-oxonicotinic acid. Recrystallization from methylene chloride/ether provided 2.4 gms of product. mp=209°-211° (dec).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:11]=[CH:12][C:13]=1[O:14][CH2:15][C@@H:16]([NH:18][C:19](=[O:40])[CH2:20][C:21]1[CH:26]=[CH:25][C:24]([NH:27][C:28]([NH:30][C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=2[CH3:37])=[O:29])=[C:23]([O:38][CH3:39])[CH:22]=1)[CH3:17])[C:7]([O:9][CH3:10])=[O:8])([O-])=O>CO.C1COCC1.[Pd]>[NH2:1][C:4]1[CH:5]=[C:6]([CH:11]=[CH:12][C:13]=1[O:14][CH2:15][C@@H:16]([NH:18][C:19](=[O:40])[CH2:20][C:21]1[CH:26]=[CH:25][C:24]([NH:27][C:28]([NH:30][C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=2[CH3:37])=[O:29])=[C:23]([O:38][CH3:39])[CH:22]=1)[CH3:17])[C:7]([O:9][CH3:10])=[O:8]
Reactant: COC(=O)c1ccc(OC[C@H](C)NC(=O)Cc2ccc(NC(=O)Nc3ccccc3C)c(OC)c2)c([N+](=O)[O-])c1
Agent: [Pd]
Solvent: CO
Solvent: C1CCOC1
Product: COC(=O)c1ccc(OC[C@H](C)NC(=O)Cc2ccc(NC(=O)Nc3ccccc3C)c(OC)c2)c(N)c1
Yield: 82.3 %

Procedure:
A stirred solution of methyl (S)-3-nitro-4-[2-[3-methoxy-4-[N′-(2-methylphenyl)ureido]phenylacetylamino]-1-propoxy]benzoate (310 mg, 0.56 mmol) in MeOH-THF (10 mL, 1:1, v/v) was hydrogenated over 5% Pd—C (50 mg, 16 wt %) overnight. The mixture was filtered to remove the catalyst and the filtrate was evaporated to give methyl (S)-3-amino-4-[2-[3-methoxy-4-[N′-(2-methylphenyl) ureido]phenylacetylamino]-1-propoxy]benzoate (240 mg) as a gum.
Reaction SMILES: [C:1]([O:5][C:6](=[O:36])[NH:7][C:8]1([C:12]2[CH:17]=[CH:16][C:15](C3C(=O)C4C(=CC=C(F)C=4)OC=3C3C=CC=CC=3)=[CH:14][CH:13]=2)[CH2:11][CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].I[C:38]1[C:47](=[O:48])[C:46]2[C:41](=[C:42]([O:52][CH3:53])[C:43]([N+:49]([O-:51])=[O:50])=[CH:44][CH:45]=2)[O:40][C:39]=1[C:54]1[CH:59]=[CH:58][CH:57]=[CH:56][CH:55]=1>>[C:1]([O:5][C:6](=[O:36])[NH:7][C:8]1([C:12]2[CH:13]=[CH:14][C:15]([C:38]3[C:47](=[O:48])[C:46]4[C:41](=[C:42]([O:52][CH3:53])[C:43]([N+:49]([O-:51])=[O:50])=[CH:44][CH:45]=4)[O:40][C:39]=3[C:54]3[CH:59]=[CH:58][CH:57]=[CH:56][CH:55]=3)=[CH:16][CH:17]=2)[CH2:9][CH2:10][CH2:11]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: COc1c([N+](=O)[O-])ccc2c(=O)c(I)c(-c3ccccc3)oc12
Reactant: CC(C)(C)OC(=O)NC1(c2ccc(-c3c(-c4ccccc4)oc4ccc(F)cc4c3=O)cc2)CCC1
Product: COc1c([N+](=O)[O-])ccc2c(=O)c(-c3ccc(C4(NC(=O)OC(C)(C)C)CCC4)cc3)c(-c3ccccc3)oc12
Yield: 72 %

Procedure:
Following the procedure used to prepare {1-[4-(6-fluoro-4-oxo-2-phenyl-4H-chromen-3-yl)-phenyl]-cyclobutyl}-carbamic acid tert-butyl ester, 3-iodo-8-methoxy-7-nitro-2-phenyl-chromen-4-one was reacted to give the title compound as a yellow solid (390 mg, 72%). LCMS (Method G): RT=4.47 min, [M+H]+=543.
Reaction SMILES: [CH3:1][CH2:2][CH2:3]Br.[OH:5][CH2:6][CH2:7][S:8]([C:11]1[CH:12]=[C:13]([C:26](=[O:43])[CH2:27][CH2:28][C:29]([C:31]2[CH:36]=[C:35]([O:37][CH3:38])[C:34]([O:39][CH3:40])=[C:33]([O:41][CH3:42])[CH:32]=2)=[O:30])[CH:14]=[C:15]([O:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:16]=1[OH:17])(=[O:10])=[O:9].C(=O)([O-])[O-]>CN(C=O)C>[OH:5][CH2:6][CH2:7][S:8]([C:11]1[CH:12]=[C:13]([C:26](=[O:43])[CH2:27][CH2:28][C:29]([C:31]2[CH:32]=[C:33]([O:41][CH3:42])[C:34]([O:39][CH3:40])=[C:35]([O:37][CH3:38])[CH:36]=2)=[O:30])[CH:14]=[C:15]([O:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:16]=1[O:17][CH2:1][CH2:2][CH3:3])(=[O:10])=[O:9]
Reactant: COc1cc(C(=O)CCC(=O)c2cc(OCc3ccccc3)c(O)c(S(=O)(=O)CCO)c2)cc(OC)c1OC
Reactant: CCCBr
Agent: O=C([O-])[O-]
Solvent: CN(C)C=O
Product: CCCOc1c(OCc2ccccc2)cc(C(=O)CCC(=O)c2cc(OC)c(OC)c(OC)c2)cc1S(=O)(=O)CCO
Temperature: 75 °C
Reaction time: 2 h

Procedure:
n-Propyl bromide (1.63 mL, 17.8 mmol) was added to a solution of 1-[3-(2-hydroxyethylsulfonyl)-4-hydroxy-5-benzyloxyphenyl]-4-(3,4,5-trimethoxyphenyl)butan-1,4-dione (5.53 g, 9.91 mmol) in DMF (10 mL) containing postassium carbonate (2.74 g, 19.9 mmol). The mixture was stirred at 75° C. for 2 h, and partitioned between ethyl ether and water. The aqueous layer was re-extracted with ether (2 x) and ethyl acetate. The organic extracts were combined, dried, and evaporated to dryness. The residue was triturated with Et2O to give crystals, which was washed with Et2O containing a small volume of acetone. This material, Rf 0.53 (hexane-ethyl acetate; 1:2, v/v), was used directly in the next experiment without further purification.
Reaction SMILES: [CH2:1]1[O:9][C:8]2[CH:7]=[CH:6][C:5]([CH:10]([CH:16]([CH:18]3[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]3)[OH:17])[C:11]([O:13]CC)=[O:12])=[CH:4][C:3]=2[O:2]1.[OH-].[Na+]>C(O)C>[CH2:1]1[O:9][C:8]2[CH:7]=[CH:6][C:5]([CH:10]([CH:16]([CH:18]3[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]3)[OH:17])[C:11]([OH:13])=[O:12])=[CH:4][C:3]=2[O:2]1
Reactant: CCOC(=O)C(c1ccc2c(c1)OCO2)C(O)C1CCCCC1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=C(O)C(c1ccc2c(c1)OCO2)C(O)C1CCCCC1
Reaction time: 1.5 h
Yield: 37.3 %

Procedure:
To a solution of ethyl (2RS,3RS)-2-(3,4-methylenedioxyphenyl)-3-cyclohexyl-3-hydroxypropionate (4.2 g) in ethanol (50 ml) was added 1M sodium hydroxide solution (26.2 ml) at room temperature. After being stirred for 1.5 hours at the same temperature, the mixture was concentrated in vacuo. The residue was dissolved in 1N hydrochloric acid (50 ml) and ethyl acetate (100 ml) and the organic layer was washed with brine, dried over magnesium sulfate, and concentrated in vacuo. The residue was crystallized from n-hexane to give (2RS,3RS)-2-(3,4-methylenedioxyphenyl)-3-cyclohexyl-3-hydroxypropionic acid (1.43 g).
Reaction SMILES: [NH4+].[Cl-].[Br:3][C:4]1[CH:9]=[C:8]([CH3:10])[C:7]([N+:11]([O-])=O)=[CH:6][N:5]=1>O.[Fe]>[Br:3][C:4]1[N:5]=[CH:6][C:7]([NH2:11])=[C:8]([CH3:10])[CH:9]=1
Reactant: Cc1cc(Br)ncc1[N+](=O)[O-]
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Product: Cc1cc(Br)ncc1N
Temperature: 90 °C

Procedure:
A mixture of NH4Cl (14.9 mmol) and iron powder (18.4 mmol) in H2O (5 mL) was stirred at 90° C. 2-bromo-4-methyl-5-nitropyridine (2.3 mmol) was added in portions. The mixture was stirred at 90° C. for 1 h and 15 min. The reaction was stopped and extracted with EtOAc. The organic layer was dried (Na2SO4) and concentrated to yield the desired product.