Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Li+].[OH-].O.[C:4]([O:8][C:9]([N:11]([C:55]([O:57][C:58]([CH3:61])([CH3:60])[CH3:59])=[O:56])[C:12]1[C:21]2[C:16](=[CH:17][C:18]([NH:22][CH:23]3[C:40](=[O:41])[N:39]([CH3:42])[CH2:38][C:37]4[CH:43]=[C:33]([CH:34]=[CH:35][C:36]=4[C:44]([O:46]C)=[O:45])[NH:32][C:31](=[O:48])[O:30][CH2:29][C:28]([F:50])([F:49])[C:27]4[C:51]([CH3:53])=[CH:52][C:24]3=[CH:25][C:26]=4[CH3:54])=[CH:19][CH:20]=2)[CH:15]=[CH:14][N:13]=1)=[O:10])([CH3:7])([CH3:6])[CH3:5].S(=O)(=O)(O)[O-].[Na+]>O1CCOCC1>[C:4]([O:8][C:9]([N:11]([C:55]([O:57][C:58]([CH3:61])([CH3:60])[CH3:59])=[O:56])[C:12]1[C:21]2[C:16](=[CH:17][C:18]([NH:22][CH:23]3[C:40](=[O:41])[N:39]([CH3:42])[CH2:38][C:37]4[CH:43]=[C:33]([CH:34]=[CH:35][C:36]=4[C:44]([OH:46])=[O:45])[NH:32][C:31](=[O:48])[O:30][CH2:29][C:28]([F:50])([F:49])[C:27]4[C:26]([CH3:54])=[CH:25][C:24]3=[CH:52][C:51]=4[CH3:53])=[CH:19][CH:20]=2)[CH:15]=[CH:14][N:13]=1)=[O:10])([CH3:6])([CH3:7])[CH3:5]
Reactant: COC(=O)c1ccc2cc1CN(C)C(=O)C(Nc1ccc3c(N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)nccc3c1)c1cc(C)c(c(C)c1)C(F)(F)COC(=O)N2
Agent: O=S(=O)([O-])O
Agent: [Li+]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: Cc1cc2cc(C)c1C(F)(F)COC(=O)Nc1ccc(C(=O)O)c(c1)CN(C)C(=O)C2Nc1ccc2c(N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)nccc2c1
Reaction time: 4.5 h
Yield: 100 %

Procedure:
To a flask containing LiOH (38.7 mg, 1.617 mmol) was added water (8 mL). A solution of 4C (130 mg, 0.162 mmol) in dioxane (10 mL) was added and the reaction was stirred for 4.5 h. The reaction was partially evaporated to remove the dioxane then transferred to a funnel using H2O (3 mL) and EtOAc (3 mL). To the mixture was added 1N sodium bisulfate (3.23 mL, 3.23 mmol) followed by extraction with EtOAc (4×8 mL). The combined organics were dried (Na2SO4), filtered and concentrated to leave 4D (128 mg, 90% yield) as a white solid. About 10% of the material is mono-boc compound by LC/MS. 19F and MS are consistent with the desired product.
Reaction SMILES: Br[C:2]1[N:7]=[C:6]([NH:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[OH:16])[CH:5]=[N:4][CH:3]=1.[CH3:17][OH:18].[OH-].[Na+].[Cl-].[NH4+]>C(OCC)(=O)C>[CH3:17][O:18][C:2]1[N:7]=[C:6]([NH:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[OH:16])[CH:5]=[N:4][CH:3]=1
Reactant: CO
Reactant: Oc1ccccc1CNc1cncc(Br)n1
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CCOC(C)=O
Product: COc1cncc(NCc2ccccc2O)n1
Temperature: 150 °C

Procedure:
Introduced into a microwave tube are 363 mg (1.29 mmol) of 2-[(6-bromopyrazin-2-ylamino)methyl]phenol, prepared as described previously in Example 12, to which 3 ml of methanol and 103 mg (2.58 mmol, 2 eq) of sodium hydroxide are added. The reaction mixture is then heated for 30 mins in a microwave oven at 150° C. and is then diluted with 50 ml of ethyl acetate. The mixture is neutralized with an ammonium chloride solution to pH=7, decanted and the organic phase is washed twice with 50 ml of water. The organic phase is dried over magnesium sulphate, filtered, and concentrated to dryness. The residue is purified by chromatography over silica with, as eluent, heptane/ethyl acetate (7/3). 2-[(6-Methoxypyrazin-2-ylamino)methyl]phenol is obtained in the form of a white solid.
Reaction SMILES: [NH:1]1[C@@H:9]2[C@@H:4]([CH2:5][CH2:6][CH2:7][CH2:8]2)[CH2:3][C@H:2]1[C:10]([O:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:11].C(N(C(C)C)CC)(C)C.[C:29]1([CH3:44])[CH:34]=[CH:33][C:32]([S:35]([O:38][C@H:39]([CH3:43])[C:40](Cl)=[O:41])(=[O:37])=[O:36])=[CH:31][CH:30]=1>ClCCl>[C:29]1([CH3:44])[CH:30]=[CH:31][C:32]([S:35]([O:38][C@H:39]([CH3:43])[C:40]([N:1]2[C@@H:9]3[C@@H:4]([CH2:5][CH2:6][CH2:7][CH2:8]3)[CH2:3][C@H:2]2[C:10]([O:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[O:11])=[O:41])(=[O:36])=[O:37])=[CH:33][CH:34]=1
Reactant: Cc1ccc(S(=O)(=O)O[C@H](C)C(=O)Cl)cc1
Reactant: O=C(OCc1ccccc1)[C@@H]1C[C@@H]2CCCC[C@@H]2N1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccc(S(=O)(=O)O[C@H](C)C(=O)N2[C@H](C(=O)OCc3ccccc3)C[C@@H]3CCCC[C@@H]32)cc1
Reaction time: 1 h

Procedure:
Introduce into a reactor 200 g of benzyl (2S,3aS,7aS)-octahydro-1H-indole-2-carboxylate and 1.5 liters of dichloromethane, and then bring the temperature of the reaction mixture to 0° C. and add 201 ml of diisopropylethylamine, followed by 202 g of (1R)-2-chloro-1-methyl-2-oxoethyl p-toluenesulphonate. Subsequently, bring the mixture to ambient temperature. After stirring for 1 hour at that temperature, wash the mixture with water. The solution of benzyl (2S,3aS,7aS)-1-[(2R)-2-{p-toluenesulphonyloxy}propionyl]octahydro-1H-indole-2-carboxylate so obtained is used as it is in the following Step.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][C:11]2=[N:14][N:15]([CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21])[C:16]([O:17][CH3:18])=[C:10]2[CH2:9]1)=O)(C)(C)C.C(C(O)=O)(F)(F)F>C(Cl)Cl>[CH3:18][O:17][C:16]1[N:15]([CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21])[N:14]=[C:11]2[CH2:12][CH2:13][NH:8][CH2:9][C:10]=12
Reactant: CCOC(=O)Cn1nc2c(c1OC)CN(C(=O)OC(C)(C)C)CC2
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCOC(=O)Cn1nc2c(c1OC)CNCC2
Temperature: 25 °C
Reaction time: 2 h

Procedure:
In 50 ml of methylene chloride was dissolved 2.73 g (8.40 mmol) of ethyl 5-t-butoxycarbonyl-3-methoxy-4,5,6,7-tetrahydropyrazolo[4,3-c]pyridin-2-acetate, and under ice-cooling, 10 ml of CF3CO2H was added to the solution and the mixture was stirred at room temperature for 2 hours.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:14]=[CH:15][C:16]=1[Cl:17])[CH2:5][N:6]1[CH2:11][CH2:10][O:9][CH:8]([CH2:12][NH2:13])[CH2:7]1.[N:18]1[CH:23]=[CH:22][N:21]=[CH:20][C:19]=1[C:24]1[S:25][CH:26]=[C:27]([CH2:29][C:30](O)=[O:31])[N:28]=1>>[Cl:1][C:2]1[CH:3]=[C:4]([CH:14]=[CH:15][C:16]=1[Cl:17])[CH2:5][N:6]1[CH2:11][CH2:10][O:9][CH:8]([CH2:12][NH:13][C:30](=[O:31])[CH2:29][C:27]2[N:28]=[C:24]([C:19]3[CH:20]=[N:21][CH:22]=[CH:23][N:18]=3)[S:25][CH:26]=2)[CH2:7]1
Reactant: O=C(O)Cc1csc(-c2cnccn2)n1
Reactant: NCC1CN(Cc2ccc(Cl)c(Cl)c2)CCO1
Product: O=C(Cc1csc(-c2cnccn2)n1)NCC1CN(Cc2ccc(Cl)c(Cl)c2)CCO1
Yield: 52.6 %

Procedure:
Example 37 was prepared in an analogous manner to Example 1 using a mixture of Intermediate 1 (0.056 g) and (2-pyrazin-2-yl-1,3-thiazol-4-yl)acetic acid (0.044 g) to give the title compound (0.05 g).
Reaction SMILES: [NH2:1][C:2]1[CH:28]=[CH:27][C:5]([O:6][C:7]2[C:16]3[CH2:15][N:14]([CH2:17][C:18]4[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=4)[C:13](=[O:26])[NH:12][C:11]=3[N:10]=[CH:9][CH:8]=2)=[C:4]([F:29])[CH:3]=1.[Cl:30][C:31]1[C:36]([C:37](Cl)=[O:38])=[CH:35][C:34]([Cl:40])=[CH:33][N:32]=1>N1C=CC=CC=1>[Cl:30][C:31]1[N:32]=[CH:33][C:34]([Cl:40])=[CH:35][C:36]=1[C:37]([NH:1][C:2]1[CH:28]=[CH:27][C:5]([O:6][C:7]2[C:16]3[CH2:15][N:14]([CH2:17][C:18]4[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=4)[C:13](=[O:26])[NH:12][C:11]=3[N:10]=[CH:9][CH:8]=2)=[C:4]([F:29])[CH:3]=1)=[O:38]
Reactant: O=C(Cl)c1cc(Cl)cnc1Cl
Reactant: COc1ccc(CN2Cc3c(Oc4ccc(N)cc4F)ccnc3NC2=O)cc1
Solvent: c1ccncc1
Product: COc1ccc(CN2Cc3c(Oc4ccc(NC(=O)c5cc(Cl)cnc5Cl)cc4F)ccnc3NC2=O)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
57 (50 mg, 0.13 mmol) and 2,5-dichloropyridine-3-carbonyl chloride (29 mg, 0.14 mmol) were suspended in pyridine (1 mL), and stirred overnight at room temperature. The crude product was purified directly via HPLC. LC-MS (M+H=568, obsd.=568).
Reaction SMILES: [H-].[Na+].[NH:3]1[C:11]2[C:6](=[CH:7][C:8]([CH:12]=[O:13])=[CH:9][CH:10]=2)[CH:5]=[CH:4]1.[CH3:14][Si:15]([CH3:22])([CH3:21])[CH2:16][CH2:17][O:18][CH2:19]Cl.Cl>CN(C)C=O>[CH3:14][Si:15]([CH3:22])([CH3:21])[CH2:16][CH2:17][O:18][CH2:19][N:3]1[C:11]2[C:6](=[CH:7][C:8]([CH:12]=[O:13])=[CH:9][CH:10]=2)[CH:5]=[CH:4]1
Reactant: C[Si](C)(C)CCOCCl
Reactant: O=Cc1ccc2[nH]ccc2c1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: C[Si](C)(C)CCOCn1ccc2cc(C=O)ccc21
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a stirred suspension of 5.45, sodium hydride (55%) in mineral oil) in 100 ml N,N-dimethylformamide was added at 0-5° C. a solution of 16.8 g indole-5-carboxaldehyde in 100 ml N,N-dimethylformamide followed by 24.46 ml of 2-(trimethylsilyl)-ethoxymethyl chloride. The reaction mixture was then warmed up to ambient temperature and stirring continued for 16 hours. It was then poured onto ice, neutralized to pH 4 with HCl (1N) and extracted 3 times with ethyl acetate. The combined organic phases were washed with water, dried over magnesium sulfate and evaporated to give a brown oil, which was purified by chromatography (silicagel, eluent: gradient of n-heptane/EtOAc) to yield 25.52 g 1-(2-trimethylsilanyl-ethoxymethyl)-1H-indole-5-carbaldehyde as light yellow oil.
Reaction SMILES: B.CSC.O=[C:6]1[CH:11]([CH2:12][C:13](O)=[O:14])[S:10](=[O:17])(=[O:16])[C:9]2[S:18][C:19]([S:21](=[O:24])(=[O:23])[NH2:22])=[CH:20][C:8]=2[NH:7]1.CO>C(COC)OC>[OH:14][CH2:13][CH2:12][CH:11]1[S:10](=[O:16])(=[O:17])[C:9]2[S:18][C:19]([S:21](=[O:23])(=[O:24])[NH2:22])=[CH:20][C:8]=2[NH:7][CH2:6]1
Reactant: NS(=O)(=O)c1cc2c(s1)S(=O)(=O)C(CC(=O)O)C(=O)N2
Agent: B
Solvent: CO
Solvent: COCCOC
Solvent: CSC
Product: NS(=O)(=O)c1cc2c(s1)S(=O)(=O)C(CCO)CN2
Reaction time: 24 h

Procedure:
Borane-dimethylsulfide (9.5 ml, 10M, 95 mmol) was added to a solution of (2,3-dihydro-2,4,4-trioxo-6-sulfamoyl-1H-thieno-[2,3-b][1,4]thiazin-3-yl)acetic acid (3.25 g, 9.5 mmol) in dimethoxyethane (325 ml) and the resulting solution was heated under reflux for 24 hours. Methanol (100 ml) was added to the cooled reaction mixture, and after stirring for an additional 24 hours, the mixture was evaporated to a thick oil. The oil was partitioned between water and ethyl acetate and the organic layer was washed with brine and dried over sodium sulfate. Removal of the solvent and recrystallization of the residue from water gave 1.5 g. Chromatographic purification over silica gel eluting with CHCl3 /MeOH/NH4OH (70:30:3) gave 3-(2-hydroxyethyl)-2,3-dihydro-4,4-dioxo-6-sulfamoyl-1H-thieno[2,3-b][1,4]thiazine, mp 158°-160° C.
Reaction SMILES: FC1C=CC2N(C(CC3N(C)C=CN=3)=C(C3C=CC(F)=CC=3)N=2)C=1.[Cl:25][C:26]1[CH:31]=[CH:30][C:29]([C:32]2[N:33]=[C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][N:35]3[C:40]=2[CH:41]=O)=[CH:28][CH:27]=1.[CH3:43][C:44]1[O:45][CH:46]=[N:47][N:48]=1>>[Cl:25][C:26]1[CH:27]=[CH:28][C:29]([C:32]2[N:33]=[C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][N:35]3[C:40]=2[CH2:41][C:46]2[O:45][C:44]([CH3:43])=[N:48][N:47]=2)=[CH:30][CH:31]=1
Reactant: O=Cc1c(-c2ccc(Cl)cc2)nc2ccccn12
Reactant: Cc1nnco1
Agent: Cn1ccnc1Cc1c(-c2ccc(F)cc2)nc2ccc(F)cn12
Product: Cc1nnc(Cc2c(-c3ccc(Cl)cc3)nc3ccccn23)o1

Procedure:
The title compound was prepared according to Method C and the experimentals described for compound 199 from 2-(4-chlorophenyl)imidazo[1,2-a]pyridine-3-carbaldehyde and 2-methyl-1,3,4-oxadiazole. M/e+ 325 for C17H14ClN4O (M+H)+; 1H-NMR (400 MHz, CDCl3) δ 8.22 (d, J=6.6 Hz, 1H), 7.80 (d, J=8.4 Hz, 2H), 7.67 (d, J=9.1 Hz, 1H), 7.47 (d, J=8.4 Hz, 2H), 7.27 (t, J=6.9 Hz, 1H), 6.91 (d, J=6.6 Hz, 1H), 4.58 (s, 2H), 2.50 (s, 3H) ppm.
Reaction SMILES: [F:1][C:2]1([F:18])[CH2:7][O:6][C:5]([NH2:8])=[N:4][C@@:3]21[C:16]1[C:11](=[CH:12][CH:13]=[C:14]([NH2:17])[CH:15]=1)[CH2:10][CH2:9]2.[F:19][C:20]1[CH:21]=[CH:22][C:23]([C:26](O)=[O:27])=[N:24][CH:25]=1>>[NH2:8][C:5]1[O:6][CH2:7][C:2]([F:1])([F:18])[C@@:3]2([C:16]3[C:11](=[CH:12][CH:13]=[C:14]([NH:17][C:26](=[O:27])[C:23]4[CH:22]=[CH:21][C:20]([F:19])=[CH:25][N:24]=4)[CH:15]=3)[CH2:10][CH2:9]2)[N:4]=1
Reactant: O=C(O)c1ccc(F)cn1
Reactant: NC1=N[C@@]2(CCc3ccc(N)cc32)C(F)(F)CO1
Product: NC1=N[C@@]2(CCc3ccc(NC(=O)c4ccc(F)cn4)cc32)C(F)(F)CO1
Yield: 17 %

Procedure:
The condensation of (R)-5′,5′-difluoro-2,3,5′,6′-tetrahydrospiro[indene-1,4′-[1,3]oxazine]-2′,6-diamine (intermediate A7.3) and 5-fluoropicolinic acid yielded the title compound (17% yield) as an off-white solid. MS (ISP): m/z=377.2 [M+H]+.
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](O)=[O:7])=[CH:4][C:3]=1[N:11]1[CH:20]=[CH:19][C:18]2[C:13](=[CH:14][C:15]([O:21][CH2:22][CH2:23][N:24]3[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]3)=[CH:16][CH:17]=2)[C:12]1=[O:30].C(Cl)(=O)C(Cl)=O.N1C=CC=CC=1.[NH2:43][C:44]1[CH:48]=[CH:47][O:46][N:45]=1>C(Cl)Cl.CN(C=O)C.C(OCC)(=O)C>[O:46]1[CH:47]=[CH:48][C:44]([NH:43][C:6](=[O:7])[C:5]2[CH:9]=[CH:10][C:2]([CH3:1])=[C:3]([N:11]3[CH:20]=[CH:19][C:18]4[C:13](=[CH:14][C:15]([O:21][CH2:22][CH2:23][N:24]5[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]5)=[CH:16][CH:17]=4)[C:12]3=[O:30])[CH:4]=2)=[N:45]1
Reactant: Nc1ccon1
Reactant: Cc1ccc(C(=O)O)cc1-n1ccc2ccc(OCCN3CCCCC3)cc2c1=O
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: Cc1ccc(C(=O)Nc2ccon2)cc1-n1ccc2ccc(OCCN3CCCCC3)cc2c1=O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
4-Methyl-3-[1-oxo-7-(2-piperidin-1-ylethoxy)isoquinolin-2(1H)-yl]benzoic acid (439 mg) was dissolved in methylene chloride (5 ml) and DMF (3 drops) and cooled to 0° C. under an argon atmosphere. Oxalyl chloride (0.19 ml) was added and the reaction mixture stirred at room temperature for 2 hours. Pyridine (0.90 ml) and 3-aminoisoxazole (0.40 ml) were added and the reaction mixture stirred at room temperature for 2 hours. The reaction mixture was diluted with ethyl acetate, washed with 1N NaOH, dried (magnesium sulfate) and concentrated. Purification by column chromatography on an ion exchange column (isolute SCX column from International Sorbent Technology Limited, Henoed, Mid-Glamorgan, UK) using initially methanol and then a 99:1 mixture of methanol and aqueous ammonia solution to give a solid. The solid was triturated with ethyl acetate to give N-isoxazol-3-yl-4-methyl-3-[1-oxo-7-(2-piperidin-1-ylethoxy)isoquinolin-2(1H)-yl]benzamide as a solid (95 mg); NMR Spectrum: (DMSOd6) 1.40 (m, 2H), 1.45 (m, 4H), 2.15 (s, 3H), 2.49 (m, 4H), 2.70 (m, 2H), 4.15 (m, 2H), 6.75 (d, 1H), 7.05 (d, 1H), 7.25 (d, 1H), 7.43 (d, 1H), 7.60 (d, 1H), 7.68 (d, 1H), 7.73 (d, 1H), 8.00 (s, 1H), 8.05 (d, 1H), 8.85 (s, 1H), 11.50 (s, 1H); Mass Spectrum: M+H+ 473.
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[CH:3]=[C:4]([CH:8]1[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]1)[N+:5]([O-:7])=[O:6].[NH2:16][C@@H:17]([C:22]([CH3:25])([CH3:24])[CH3:23])[C:18]([O:20][CH3:21])=[O:19].C(N(C(C)C)CC)(C)C>C1(C)C=CC=CC=1.C(OCC)(=O)C>[CH:8]1([CH:4]([N+:5]([O-:7])=[O:6])[CH:3]([NH:16][CH:17]([C:22]([CH3:25])([CH3:24])[CH3:23])[C:18]([O:20][CH3:21])=[O:19])[C:2]([F:14])([F:15])[F:1])[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13]1
Reactant: COC(=O)[C@@H](N)C(C)(C)C
Reactant: O=[N+]([O-])C(=CC(F)(F)F)C1CCCCC1
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: Cc1ccccc1
Product: COC(=O)C(NC(C(C1CCCCC1)[N+](=O)[O-])C(F)(F)F)C(C)(C)C
Temperature: 100 °C

Procedure:
A mixture of (3,3,3-trifluoro-1-nitroprop-1-enyl)cyclohexane (3) (0.62 gm), (S)-methyl 2-amino-3,3-dimethylbutanoate (4) (0.656 gm, 1.3 eq) and diisopropylethylamine (0.69 mL) in toluene (15 mL) was heated to 100° C. for 23 hours. After cooling to room temperature, the reaction mixture was diluted with ethyl acetate, and washed successively with 1N hydrochloric acid, water, brine and then dried over anhydrous sodium sulfate. Evaporation to dryness under reduced pressure gave crude methyl 2-(3-cyclohexyl-1,1,1-trifluoro-3-nitropropan-2-ylamino)-3,3-dimethylbutanoate as a mixture of isomers. Separation by silica gel chromatography, eluting with 8% ethyl acetate/hexane, gave two fractions, a faster eluting compound, 5A-1 (0.553 gm) and a slower eluting compound, 5B-1 (0.3 gm). The two compounds are different diastereoisomers of methyl 2-(3-cyclohexyl-1,1,1-trifluoro-3-nitropropan-2-ylamino)-3,3-dimethylbutanoate (5), although the absolute stereochemistry has not yet been established.
Reaction SMILES: [CH:1]([C:4]1[CH:5]=[C:6]([CH:20]=[CH:21][C:22]=1[OH:23])[O:7][C:8]1[C:15]([CH3:16])=[CH:14][C:13]([N+:17]([O-])=O)=[CH:12][C:9]=1[C:10]#[N:11])([CH3:3])[CH3:2]>C(O)C>[NH2:17][C:13]1[CH:14]=[C:15]([CH3:16])[C:8]([O:7][C:6]2[CH:20]=[CH:21][C:22]([OH:23])=[C:4]([CH:1]([CH3:2])[CH3:3])[CH:5]=2)=[C:9]([CH:12]=1)[C:10]#[N:11]
Reactant: Cc1cc([N+](=O)[O-])cc(C#N)c1Oc1ccc(O)c(C(C)C)c1
Solvent: CCO
Product: Cc1cc(N)cc(C#N)c1Oc1ccc(O)c(C(C)C)c1
Yield: 77.2 %

Procedure:
A solution of 2-(3-isopropyl-4-hydroxy-phenoxy)-3-methyl-5-nitrobenzonitrile (215 mg) and stannous chloride (776 mg) in ethanol (5 mL) was refluxed for 2 h, cooled, quenched with saturated aqueous sodium bicarbonate and concentrated in vacuo. The residue was extracted with ethyl acetate, the organics washed with brine, dried over sodium sulfate and concentrated in vacuo. The residue was flash chromatographed (40% ethyl acetate/hexanes) to afford 5-amino-2-(3-isopropyl-4-hydroxy-phenoxy)-3-methyl-benzonitrile as a colorless foam (150 mg).
Reaction SMILES: Cl[C:2]([N:4]1[CH2:7][CH:6]([O:8][C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([C:15]([F:18])([F:17])[F:16])[CH:10]=2)[CH2:5]1)=[O:3].C(=O)([O-])[O-].[K+].[K+].[NH:25]1[CH2:28][CH2:27][CH2:26]1>O1CCCC1>[N:25]1([C:2]([N:4]2[CH2:7][CH:6]([O:8][C:9]3[CH:14]=[CH:13][CH:12]=[C:11]([C:15]([F:18])([F:17])[F:16])[CH:10]=3)[CH2:5]2)=[O:3])[CH2:28][CH2:27][CH2:26]1
Reactant: C1CNC1
Reactant: O=C(Cl)N1CC(Oc2cccc(C(F)(F)F)c2)C1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: O=C(N1CCC1)N1CC(Oc2cccc(C(F)(F)F)c2)C1
Temperature: -70 °C
Reaction time: 0.25 h

Procedure:
A mixture of 5.6 g (0.02 mole) of 1-chlorocarbonyl-3-[3-(trifluoromethyl)phenoxy]azetidine and 3 g (0.027 mole) of potassium carbonate in 50 ml of tetrahydrofuran was treated with 1.26 g (0.022 mole) of azetidine added dropwise to the stirred mixture. After stirring for 15 min, the reaction was treated with 10 g of ice and stirred for an additional 72 hr. The tetrahydrofuran was decanted from the salt-paste and concentrated on a rotary evaporator to yield an oil, 6.3 g. This oil crystallized when cooled to -70° C. and was recrystallized from hexane yielding 5.1 g (85%) of fine white crystals, m.p. 65°-68° C.
Reaction SMILES: C=C1CCCC(C)(C)[C@H]1CC1C=C(OC)C(Br)=C(O[SiH](C)C)C=1C(C)(C)C.[CH2:28]=[C:29]1[C@@H:34]([OH:35])[CH2:33][C@H:32](Br)[C:31]([CH3:38])([CH3:37])[C@H:30]1[CH2:39][C:40]1[CH:45]=[C:44]([O:46][CH3:47])[C:43]([Br:48])=[CH:42][C:41]=1[O:49]C(=O)C.[SiH3]C1C=CC=CC=1O>>[OH:35][C@@H:34]1[CH2:33][CH2:32][C:31]([CH3:37])([CH3:38])[C@@H:30]([CH2:39][C:40]2[CH:45]=[C:44]([O:46][CH3:47])[C:43]([Br:48])=[CH:42][C:41]=2[OH:49])[C:29]1=[CH2:28]
Reactant: C=C1[C@@H](O)C[C@H](Br)C(C)(C)[C@H]1Cc1cc(OC)c(Br)cc1OC(C)=O
Agent: C=C1CCCC(C)(C)[C@H]1Cc1cc(OC)c(Br)c(O[SiH](C)C)c1C(C)(C)C
Agent: Oc1ccccc1[SiH3]
Product: C=C1[C@H](O)CCC(C)(C)[C@H]1Cc1cc(OC)c(Br)cc1O

Procedure:
This set of diastereomeric alcohols was prepared from (2R)-1-methylidene-2-[2'-(tert-butyl)dimethylsilyloxy-4'-bromo-5'-methoxyphenyl]methyl-3,3-dimethylcyclohexane (48) (0.750 g, 1.66 mmol) in the manner previously described for the synthesis of alcohol 54, affording 741 mg (95%) of an inseparable 1:1 mixture of diastereomeric allylic alcohols. A portion (40 mg, 0.085 mmol) of this diastereomeric mixture was subjected to deprotection of the silylphenol in the usual manner, yielding mixture of free phenols, separable by flash column chromatography (silica gel, hexanes lethyl acetate, gradient elution), to give 14.0 mg (46%) of the less polar 1R,3R diastereomer (56), along with 13.0 mg (43%) of the more polar 1S,3R diastereomer (57) as white solids. Data for 56: 1H NMR (400MHz, CDCl3) δ0.93 and 1.12 (2s, 2×3H, geminal-CH3 's), 1.70 (m, 2H, 1-H), 1.94 (m, 3H, 6,3-H), 2.65 and 3.00 (d of ABq, 2H, JAB =14.0 Hz, JA =3.1 Hz, JB =14.0 Hz, benzylic-CH2) 3.84 (s, 3H, OCH3), 4.37 (br s, 1H, 5-H), 4.39 and 4.92 (2s, 2×1H, methylidene-CH2), 6.58 (s, 1H, 6'-H), 7.02 ppm (s, 1H, 3'-H). Data for 57: 1H NMR (400 MHz, CDCl3) δ1.00 and 1.02 (2s, 2×3H, geminal-CH3 's), 2.45 (dd, 1H, J=11.5, 3.2 Hz, 3-H), 2.70 and 2.88 (d of ABq, 2H, JAB =14.1 Hz, JA =13.1 Hz, JB =4.2 Hz, benzylic-CH2) 3.80 (s, 3H, OCH3), 4.40 (br dd, 1H, J13 11.5, 4.5 Hz, 5-H), 4.47 and 4.86 (2s, 2×1H, methylidene-CH2). 6.61 (s, 1H, 6'-H), 7.94 ppm (s, 1H, 3'-H). [Compound 56 is hereinafter also referred to as COMPOUND "R" or 120243]
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([OH:10])[CH:9]=1)[CH:5]=[O:6].C(=O)([O-])[O-].[K+].[K+].CS(O[CH2:22][CH2:23][F:24])(=O)=O>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([O:10][CH2:22][CH2:23][F:24])[CH:9]=1)[CH:5]=[O:6]
Reactant: O=Cc1cc(O)cc(Cl)c1
Reactant: CS(=O)(=O)OCCF
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=Cc1cc(Cl)cc(OCCF)c1
Temperature: 100 °C
Reaction time: 8 h
Yield: 71.4 %

Procedure:
To a solution of 3-chloro-5-hydroxybenzaldehyde (8.2 g, 52.5 mmol; see Example 1(ii) above) and potassium carbonate (9.4 g, 68.2 mmol) in DMF (10 mL) under nitrogen was added a solution of (2-monofluoroethyl) methanesulfonate (9.7 g, 68.2 mmol; see step (i) above) in DMF (120 mL) dropwise at room temperature. The mixture was heated to 100° C. for 5 h and then stirred overnight at room temperature. The reaction was cooled to 0° C., poured into ice-cold 2N HCl and extracted with EtOAc. The combined organic extracts were washed with brine, dried (Na2SO4), filtered and concentrated in vacuo. The brown oil was chromatographed on silica gel eluting with Hex:EtOAc (4:1) to afford the sub-title compound (7.6 g, 71%) as a yellow oil.
Reaction SMILES: [CH2:1]([NH2:5])[CH:2]([CH3:4])[CH3:3].C([CH:8]([C:22]([O-:24])=O)[C:9]([C:19]([O-:21])=O)([OH:18])[C:10](CC)(CC)[C:11]([O-:13])=O)C>CO>[CH2:1]([NH:5][C:11](=[O:13])[CH2:10][C:9]([CH2:8][C:22]([NH:5][CH2:1][CH:2]([CH3:4])[CH3:3])=[O:24])([C:19]([NH:5][CH2:1][CH:2]([CH3:4])[CH3:3])=[O:21])[OH:18])[CH:2]([CH3:4])[CH3:3]
Reactant: CCC(C(=O)[O-])C(O)(C(=O)[O-])C(CC)(CC)C(=O)[O-]
Reactant: CC(C)CN
Solvent: CO
Product: CC(C)CNC(=O)CC(O)(CC(=O)NCC(C)C)C(=O)NCC(C)C
Temperature: 25 °C
Reaction time: 48 h
Yield: 80.3 %

Procedure:
N,N′,N″-tri-iso-butylcitramide was prepared by the reaction of iso-butylamine with triethylcitrate. To a round-bottomed flask were added triethylcitrate (30.001 g; 1 eq), iso-butylamine (24.034 g; 3.03 eq) and methanol (40 mL). The clear light yellow solution stirred for 2 days at room temperature and then additional isobutylamine (3.06 eq) was added. After stirring overnight, a wet white solid was observed. Methanol was removed in vacuo and the solid was triturated using diethylether, collected via filtration and dried in vacuo to give a white powder with no detectable odor (31.09 g; 80.3% yield).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([NH:10]N=C2CCCNC2=O)[CH:5]=[CH:6][C:7]=1[O:8][CH3:9].[CH:19]([OH:21])=O>O>[F:1][C:2]1[CH:3]=[C:4]2[C:5]([C:2]3[CH2:3][CH2:4][NH:10][C:19](=[O:21])[C:7]=3[NH:10]2)=[CH:6][C:7]=1[O:8][CH3:9]
Reactant: COc1ccc(NN=C2CCCNC2=O)cc1F
Reactant: O=CO
Solvent: O
Product: COc1cc2c3c([nH]c2cc1F)C(=O)NCC3
Temperature: 100 °C
Reaction time: 1 h

Procedure:
A mixture of 3-[(3-fluoro-4-methoxyphenyl)hydrazinylidene]piperidin-2-one (a mixture of E and Z isomers) (2.45 g) and formic acid (25.0 mL) was stirred at 100° C. for 1 hour. The reaction mixture was cooled to room temperature, and then water (40.0 mL) was added thereto, followed by extraction with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. The insoluble materials were separated by filtration, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (chloroform:methanol=10:0 to 10:1) to obtain 7-fluoro-6-methoxy-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-1-one (780 mg) as a brown solid.