Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O-])([O-])=O.[Cs+].[Cs+].[Cl:7][C:8]1[CH:13]=[C:12](F)[CH:11]=[CH:10][C:9]=1[C:15]1[S:19][C:18]([N:20]([CH3:31])[CH:21]2[CH2:26][C:25]([CH3:28])([CH3:27])[NH:24][C:23]([CH3:30])([CH3:29])[CH2:22]2)=[N:17][N:16]=1.[NH:32]1[CH:36]=[CH:35][CH:34]=[N:33]1>CN(C=O)C.C(Cl)Cl>[Cl:7][C:8]1[CH:13]=[C:12]([N:32]2[CH:36]=[CH:35][CH:34]=[N:33]2)[CH:11]=[CH:10][C:9]=1[C:15]1[S:19][C:18]([N:20]([CH3:31])[CH:21]2[CH2:26][C:25]([CH3:28])([CH3:27])[NH:24][C:23]([CH3:30])([CH3:29])[CH2:22]2)=[N:17][N:16]=1
Reactant: c1cn[nH]c1
Reactant: CN(c1nnc(-c2ccc(F)cc2Cl)s1)C1CC(C)(C)NC(C)(C)C1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CN(c1nnc(-c2ccc(-n3cccn3)cc2Cl)s1)C1CC(C)(C)NC(C)(C)C1
Temperature: 25 °C
Reaction time: 96 h

Procedure:
Cs2CO3 (128 mg, 0.392 mmol) was added to a stirred solution of 5-(2-chloro-4-fluorophenyl)-N-methyl-N-(2,2,6,6-tetramethylpiperidin-4-yl)-1,3,4-thiadiazol-2-amine (50 mg, 0.131 mmol) and 1H-pyrazole (13 mg, 0.196 mmol) in DMF (1.3 mL). The reaction mixture was stirred at room temperature for 4 days then warmed to 60° C. and stirred for an additional 18 hours. The reaction mixture was diluted with DCM (10 mL), filtered through celite, and the DCM was removed in vacuo to afford the crude product as a pale brown liquid. The crude material was purified by UV directed preparative HPLC under acidic conditions (formic acid modified), collecting at 324 nm. The product containing fractions were combined and loaded onto a 1 g SCX cartridge (pre-wet with MeOH). The cartridge was washed with MeOH (10 mL) then flushed with 10% DCM in [7M NH3 in MeOH] (10 mL). The DCM/MeOH/NH3 was removed in vacuo to afford the title compound as a clear glass-like solid (37 mg, 66% yield). LC-MS: Rt 0.97 min; MS m/z 431.5 [M+H]+ [Method A]. 1H NMR (400 MHz, DMSO-d6) δ ppm 8.67 (d, J=2.53 Hz, 1H), 8.14 (dd, J=5.56, 3.03 Hz, 2H), 7.97-8.02 (m, 1H), 7.83 (d, J=1.52 Hz, 1H), 6.64-6.60 (m, 1H), 4.37 (tt, J=12.25, 3.16 Hz, 1H), 3.02 (s, 3H), 1.63 (dd, J=12.13, 3.03 Hz, 2H), 1.45 (t, J=12.13 Hz, 2H), 1.21 (s, 6H), 1.09 (s, 6H).
Reaction SMILES: [NH2:1][CH:2]([CH2:12][C:13]1[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=1)[CH:3]([C:5]1[CH:10]=[CH:9][C:8]([F:11])=[CH:7][CH:6]=1)[OH:4].[C:20]1([C:30](Cl)=[O:31])[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH:23]=[CH:22][CH:21]=1.C(=O)([O-])O.[Na+]>C(OCC)(=O)C.O>[F:11][C:8]1[CH:7]=[CH:6][C:5]([CH:3]([OH:4])[CH:2]([NH:1][C:30]([C:20]2[C:29]3[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=3)[CH:23]=[CH:22][CH:21]=2)=[O:31])[CH2:12][C:13]2[CH:14]=[CH:15][C:16]([F:19])=[CH:17][CH:18]=2)=[CH:10][CH:9]=1
Reactant: O=C(Cl)c1cccc2ccccc12
Reactant: NC(Cc1ccc(F)cc1)C(O)c1ccc(F)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Product: O=C(NC(Cc1ccc(F)cc1)C(O)c1ccc(F)cc1)c1cccc2ccccc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 72.1 %

Procedure:
To a solution of (1RS,2SR)-2-amino-1,3-bis(4-fluorophenyl)-1-propanol (450 mg, 1.71 mmol) in ethyl acetate (15 ml) were added 1-naphthoyl chloride (386 ml, 2.56 mmol) and saturated aqueous sodium hydrogen carbonate (15 ml) and the mixture was stirred overnight at room temperature. The reaction solution was diluted with water (100 ml) and extracted with ethyl acetate (100 ml×2). The extract was washed with saturated brine, dried over anhydrous magnesium sulfate and evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:acetone=1:1). Recrystallization from ethyl acetate-hexane gave the title compound (515 mg, 72%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH2:8][OH:9])[CH:5]=[CH:6][CH:7]=1.CN(C=O)C.[H-].[Na+].Cl[CH2:18][C:19]1[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=1>CCOC(C)=O.O>[Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH2:8][O:9][CH2:18][C:19]2[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=2)[CH:3]=1
Reactant: COc1ccc(CCl)cc1
Reactant: OCc1cccc(Br)c1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccc(COCc2cccc(Br)c2)cc1
Reaction time: 0.17 h
Yield: 97.5 %

Procedure:
(3-Bromophenyl)methanol (500 mg) was mixed with DMF (10 ml), and sodium hydride (55% suspended in oil) was added thereto at 0° C., followed by stirring for 10 minutes under ice-cooling. 1-(Chloromethyl)-4-methoxybenzene (520 mg) was added to the reaction mixture, followed by stirring at room temperature for 2 hours. Water and EtOAc were added to the reaction mixture, and the organic layer was dried over MgSO4 and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (CHCl3/hexane) to obtain 1-bromo-3-{[(4-methoxybenzyl)oxy]methyl}benzene (801 mg).
Reaction SMILES: Br[C:2]1[CH:24]=[CH:23][C:5]2[C:6]3[N:7]([CH:11]=[C:12]([C:14]4[N:18]([CH:19]([CH3:21])[CH3:20])[N:17]=[C:16]([CH3:22])[N:15]=4)[N:13]=3)[CH2:8][CH2:9][O:10][C:4]=2[CH:3]=1.C([O-])(=O)C.[K+].[CH3:30][N:31]1[CH:35]=[CH:34][C:33](B2OC(C)(C)C(C)(C)O2)=[N:32]1>C(#N)C.CCOC(C)=O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH:19]([N:18]1[C:14]([C:12]2[N:13]=[C:6]3[C:5]4[CH:23]=[CH:24][C:2]([C:34]5[CH:33]=[N:32][N:31]([CH3:30])[CH:35]=5)=[CH:3][C:4]=4[O:10][CH2:9][CH2:8][N:7]3[CH:11]=2)=[N:15][C:16]([CH3:22])=[N:17]1)([CH3:21])[CH3:20]
Reactant: Cn1ccc(B2OC(C)(C)C(C)(C)O2)n1
Reactant: Cc1nc(-c2cn3c(n2)-c2ccc(Br)cc2OCC3)n(C(C)C)n1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: CC(=O)[O-]
Agent: [K+]
Solvent: CC#N
Solvent: CCOC(C)=O
Product: Cc1nc(-c2cn3c(n2)-c2ccc(-c4cnn(C)c4)cc2OCC3)n(C(C)C)n1
Temperature: 150 °C
Yield: 54.9 %

Procedure:
A microwave vial was charged with a suspension of 9-bromo-2-(1-isopropyl-3-methyl-1H-1,2,4-triazol-5-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine 411 (0.239 mg, 0.617 mmol) in 3.0 ml ACN/1.0 mL water. To this suspension was added potassium acetate (182 mg, 1.85 mmol) and 1-methylpyrazole boronic acid pinacol ester (154 mg, 740 mmol). The reaction suspension was degassed by bubbling nitrogen through the stirred mixture via a syringe. After several minutes the syringe was removed and tetrakis(triphenylphosphine)palladium(0) (57 mg, 56 mmol) was added and the reaction vial was quickly sealed. The sealed vial was flash heated in a microwave at 150° C. for 30 minutes. The cooled reaction was diluted with EtOAc and the organic solution was washed with water ×1, saline ×1 and dried (Na2SO4) before concentration in vacuo. The crude residue was purified by preparative RP-HPLC to give 132 mg of 423 (55% theoretical yield). 1H NMR (400 MHz, DMSO) δ 8.36 (d, J=8.4 Hz, 1H), 8.20 (s, 1H), 7.90 (d, J=23.3 Hz, 2H), 7.36 (dd, J=8.4, 1.6 Hz, 1H), 7.25 (d, J=1.6 Hz, 1H), 5.83 (dt, J=13.3, 6.6 Hz, 1H), 4.51 (s, 4H), 3.87 (s, 3H), 2.25 (s, 3H), 1.47 (d, J=6.6 Hz, 6H)
Reaction SMILES: N1C=CN=C1.C1(OP(Cl)(Cl)=O)C=CC=CC=1.[C:17]([O:21][C:22]([NH:24][C@H:25]([C:33]([OH:35])=O)[CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)=[O:23])([CH3:20])([CH3:19])[CH3:18].Cl.[CH3:37][NH:38][O:39][CH3:40]>C(Cl)Cl>[CH3:40][O:39][N:38]([CH3:37])[C:33](=[O:35])[C@H:25]([CH2:26][C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1)[NH:24][C:22]([O:21][C:17]([CH3:18])([CH3:19])[CH3:20])=[O:23]
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)C(=O)O
Reactant: CNOC
Agent: Cl
Agent: O=P(Cl)(Cl)Oc1ccccc1
Agent: c1c[nH]cn1
Solvent: ClCCl
Product: CON(C)C(=O)[C@H](Cc1ccccc1)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 100.3 %

Procedure:
To a solution of 44.2 g (0.65 mole) of imidazole in methylene chloride (300 ml) is added with stirring 19.4 ml (0.13 mole) of phenyldichlorophosphate. The mixture is stirred at room temperature for 0.5 hour, and then cooled to 0° C. A solution of 34.5 g (0.13 mole) of N-t-butoxycarbonyl-L-phenylalanine in 10 methylene chloride (120 ml) is added, and the mixture is stirred at 0° C. for 1 hr. N,O-dimethylhydroxylamine hydrochloride (15.2 g, 0,156 mole) is then added in small portions. The resulting mixture is stirred at 0° C. for 5 hours and at room temperature for 16 hours. The final suspension is diluted with 400 ml of methylene chloride, washed with 1N hydrochloric acid (2×200 ml), water (200 ml), saturated potassium carbonate solution (200 ml), and brine (200 ml), and dried over anhydrous magnesium sulfate. Removal of solvents gives 40.2 g of the title compound as a pale yellow oil, [α]D26 +22°±1 (c, 1.052, CHCl3).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][CH2:11][C:12](=[O:16])[C:13]([OH:15])=[O:14])=[CH:5][CH:4]=1.[OH-].[Na+].C(OC(C)C)(C)C.C1(C)C=CC=CC=1CCN>C1COCC1.C(#N)C.O.C(N(CC)CC)C>[OH:16][C@H:12]([CH2:11][CH2:10][CH2:9][C:6]1[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:8][CH:7]=1)[C:13]([OH:15])=[O:14]
Reactant: COc1ccc(CCCC(=O)C(=O)O)cc1
Agent: Cc1ccccc1CCN
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CC(C)OC(C)C
Solvent: CCN(CC)CC
Product: COc1ccc(CCC[C@@H](O)C(=O)O)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 47.1 %

Procedure:
5-(4-Methoxyphenyl)-2-oxopentanoic acid (62.7 g) was dissolved in THF (1 L) and triethylamine (46.8 ml) was added thereto. A solution of (−)-DIP-Cl (100 g) in THF (600 ml) was added dropwise thereto while maintaining the temperature at −25° C. to −35° C. The resulting mixture was warmed up to room temperature and stirred for 2 hours, and then water (500 ml) was added thereto at 20° C. or lower. A 6N aqueous sodium hydroxide solution (120 ml) was added thereto and stirred for 15 minutes. Thereafter, diisopropyl ether (300 ml) was added thereto to effect separation into two layers. The aqueous layer was washed twice with diisopropyl ether (300 ml) and then a 6N aqueous hydrochloric acid solution was added thereto, followed by extraction with ethyl acetate. The organic layer was washed with a saturated aqueous sodium chloride solution and then dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure to obtain a crude product. The crude product was dissolved in acetonitrile (640 ml), followed by adding thereto (+)-tolylethylamine (39 g), and the resulting mixture was heated under reflux to dissolve the amine completely. Crystals were precipitated at room temperature and collected by filtration. A 1N aqueous hydrochloric acid solution was added to the crystals obtained, followed by extraction with ethyl acetate. The organic layer was washed with a saturated aqueous sodium chloride solution and then dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure and the residue was crystallized from a mixed solvent of diisopropyl ether and hexane (1/1) to obtain (2R)-2-hydroxy-5-(4-methoxyphenyl)pentanoic acid (29.8 g, 98% e.e.).
Reaction SMILES: [CH3:1][C:2]1([CH3:27])[C:6]([C:7]2[CH:12]=[C:11]([C:13](OC)=[O:14])[C:10]([F:17])=[CH:9][C:8]=2[C:18]2[CH:23]=[C:22]([O:24][CH3:25])[CH:21]=[CH:20][C:19]=2[F:26])=[CH:5][CH2:4][CH2:3]1.[H-].[H-].[H-].[H-].[Li+].[Al+3].[OH-].[Na+]>C1COCC1>[CH3:1][C:2]1([CH3:27])[C:6]([C:7]2[CH:12]=[C:11]([CH2:13][OH:14])[C:10]([F:17])=[CH:9][C:8]=2[C:18]2[CH:23]=[C:22]([O:24][CH3:25])[CH:21]=[CH:20][C:19]=2[F:26])=[CH:5][CH2:4][CH2:3]1
Reactant: COC(=O)c1cc(C2=CCCC2(C)C)c(-c2cc(OC)ccc2F)cc1F
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: COc1ccc(F)c(-c2cc(F)c(CO)cc2C2=CCCC2(C)C)c1
Temperature: 0 °C
Reaction time: 0.75 h
Yield: 82.3 %

Procedure:
To a cooled solution of 66.43G (0.92 g, 2.47 mmol) in dry THF (15 mL) at 0° C. was added LAH (1.0 M in THF) (5.0 mL, 5.0 mmol) dropwise. Upon complete addition, the reaction was maintained at 0° C. and was monitored by TLC and LCMS. After 45 minutes, 1N NaOH was added to quench the reaction (gas evolution occurred). The resulting solution was extracted three times with EtOAc. After drying over anhydrous magnesium sulfate, filtration, and concentration, the residue was purified by flash chromatography (silica gel 60, eluted with 0%-50% EtOAc in hexanes). Fractions containing the desired product were combined and concentrated to provide 66.43H as a colorless oil (0.70 g, 82% yield). 1H NMR (500 MHz, CDCl3) δ ppm 7.30 (1H, m), 7.05 (1H, dd, J=10.6, 1.1 Hz), 6.97 (1H, t, J=8.9 Hz), 6.83 (2H, m), 5.52 (1H, td, J=2.4, 0.9 Hz), 4.81 (2H, s), 3.76 (3H, s), 2.25 (2H, td, J=7.1, 2.4 Hz), 1.76 (1H, br. s.), 1.69 (2H, m), 0.85 (6H, s).
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=O)=[CH:4][C:3]=1[N+:10]([O-:12])=[O:11].Cl.[NH2:14][OH:15].C([O-])(=O)C.[Na+]>C(O)C.O>[F:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[N:14][OH:15])=[CH:4][C:3]=1[N+:10]([O-:12])=[O:11]
Reactant: O=Cc1ccc(F)c([N+](=O)[O-])c1
Reactant: NO
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: O=[N+]([O-])c1cc(C=NO)ccc1F
Temperature: 25 °C
Reaction time: 6 h
Yield: 89.5 %

Procedure:
In a mixture of ethanol (20 mL) and water (10 mL), 4-fluoro-3-nitrobenzaldehyde (2 g), hydroxylamine hydrochloride (1.07 g) and sodium acetate (1.45 g) were dissolved, and the mixture was stirred at room temperature for 6 hours. The reaction mixture was added to water, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain 2-fluoro-5-hydroxyiminomethylnitrobenzene (1.95 g).
Reaction SMILES: [H-].[Na+].[CH:3]([C:5]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[NH:7][C:6]=1[C:14]([O:16][CH2:17][CH3:18])=[O:15])=[O:4].[CH3:19][O:20][C:21]1[CH:22]=[C:23]([CH:26]=[CH:27][CH:28]=1)[CH2:24]Br.O>CS(C)=O>[CH:3]([C:5]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[N:7]([CH2:24][C:23]2[CH:26]=[CH:27][CH:28]=[C:21]([O:20][CH3:19])[CH:22]=2)[C:6]=1[C:14]([O:16][CH2:17][CH3:18])=[O:15])=[O:4]
Reactant: COc1cccc(CBr)c1
Reactant: CCOC(=O)c1[nH]c2ccccc2c1C=O
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: CCOC(=O)c1c(C=O)c2ccccc2n1Cc1cccc(OC)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 81.5 %

Procedure:
Sodium hydride (60% dispersion in mineral oil, 2.40 g, 60.0 mmol) was cooled to 0° C., and anhydrous methyl sulfoxide (75.0 mL, 1.06 mol) was added. The mixture was stirred at 0° C. for 15 minutes before a solution of ethyl 3-formyl-1H-indole-2-carboxylate (10.9 g, 50.2 mmol, Lit. J. Heterocyclic Chem. 1997, 34, 1431.) in 75 mL of methyl sulfoxide was added over a 20 minute period. The resulting solution was warmed to room temperature and stirred for 1 hour. 3-Methoxybenzylbromide (9.8 mL, 70.0 mmol) was added, and the solution was heated at 60° C. for 16 hours. The solution was cooled and poured into water (500 mL). The aqueous solution was extracted with ethyl acetate (3×), and the combined organic extracts were washed with 1 N hydrochloric acid (2×), water, and brine. The solution was dried over anhydrous magnesium sulfate and concentrated in vacuo. Trituration of the residue with 33% hexane/Et2O provided the title compound as a solid (13.8 g, 81%). The product had: 1H NMR (300 MHz, acetone-d6) δ 10.61 (s, 1 H), 8.43 (d, 1 H), 7.61 (d, 1 H), 7.30-7.45 (m, 2 H), 7.19 (dd, 1 H), 6.80 (dd, 1 H), 6.63-6.74 (m, 2 H), 5.88 (s, 2 H), 4.48 (dq, 2 H), 3.70 (s, 3 H), 1.37 (t, 3 H); mass spectroscopy gave MH+=338.1 (calc'd exact mass for C20H19NO4=337.13).
Reaction SMILES: Cl[S:2]([C:5]1[CH:14]=[CH:13][C:8]([C:9]([O:11][CH3:12])=[O:10])=[CH:7][CH:6]=1)(=[O:4])=[O:3].[CH3:15][N:16]1[C:24]2[C:19](=[CH:20][C:21]([CH2:25][NH2:26])=[CH:22][CH:23]=2)[CH:18]=[CH:17]1>>[CH3:15][N:16]1[C:24]2[C:19](=[CH:20][C:21]([CH2:25][NH:26][S:2]([C:5]3[CH:14]=[CH:13][C:8]([C:9]([O:11][CH3:12])=[O:10])=[CH:7][CH:6]=3)(=[O:4])=[O:3])=[CH:22][CH:23]=2)[CH:18]=[CH:17]1
Reactant: Cn1ccc2cc(CN)ccc21
Reactant: COC(=O)c1ccc(S(=O)(=O)Cl)cc1
Product: COC(=O)c1ccc(S(=O)(=O)NCc2ccc3c(ccn3C)c2)cc1

Procedure:
The titled compound was prepared according to the procedure described in step-1 of Example 1 from methyl 4-(chlorosulfonyl)benzoate and (1-methyl-1H-indol-5-yl)methanamine.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[CH2:7][CH2:6][CH2:5]2.[Br:11]N1C(=O)CCC1=O>CN(C)C=O>[NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][C:10]=1[Br:11])[CH2:7][CH2:6][CH2:5]2
Reactant: O=C1CCC(=O)N1Br
Reactant: Nc1ccc2c(c1)CCC2
Solvent: CN(C)C=O
Product: Nc1cc2c(cc1Br)CCC2
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 68.3 %

Procedure:
5-Aminoindan (3.0 g, 22.5 mmol) was dissolved in 10 ml of anhydrous dimethylformamide. A solution of N-bromosuccinimide (4.0 g, 22.5 mmol) in 10 ml anhydrous dimethylformamide was added, and the reaction mixture was stirred at room temperature for 1.5 hours. The reaction mixture was partitioned between ethyl acetate and water, and the separated organic layer washed twice with H2O, then with brine. Drying over Na2SO4 followed by filtration and evaporation of solvent gave a dark brown oil as the crude product. Purification by flash chromatography (50% EtOAc/hexane) provided 5-amino-6-bromoindan (3.26 g, 68% yield), a compound of Formula 2 where X is bromo, as a brown oil which crystallized into a brown solid.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].C([O:14][C:15](=O)[C:16]1[C:21]([CH3:22])=[CH:20][CH:19]=[C:18]([CH3:23])[C:17]=1[N:24]([CH2:36][C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1)[S:25]([C:28]1[CH:33]=[CH:32][C:31]([O:34][CH3:35])=[CH:30][CH:29]=1)(=[O:27])=[O:26])C1C=CC=CC=1.O.O.O.O.O.S([O-])([O-])(=O)=O.[Na+].[Na+]>C1COCC1>[CH2:36]([N:24]([C:17]1[C:18]([CH3:23])=[CH:19][CH:20]=[C:21]([CH3:22])[C:16]=1[CH2:15][OH:14])[S:25]([C:28]1[CH:33]=[CH:32][C:31]([O:34][CH3:35])=[CH:30][CH:29]=1)(=[O:27])=[O:26])[C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1
Reactant: COc1ccc(S(=O)(=O)N(Cc2ccccc2)c2c(C)ccc(C)c2C(=O)OCc2ccccc2)cc1
Agent: O=S(=O)([O-])[O-]
Agent: [Al+3]
Agent: [H-]
Solvent: C1CCOC1
Solvent: O
Product: COc1ccc(S(=O)(=O)N(Cc2ccccc2)c2c(C)ccc(C)c2CO)cc1
Reaction time: 3 h
Yield: 87.6 %

Procedure:
To a slurry of 21 lmg (5.04 mmol) of lithium aluminum hydride in 6 ml of dry THF under nitrogen, was added dropwise a solution of 649 mg (1.26 mmol) of the product of Example 288 in 6 ml of dry THF. The reaction mixture was stirred for 3 hr and then sodium sulfate pentahydrate was slowly added until sizzling stopped and thick solid formed. The solid was filtered and the filtrate was concentrated in vacuo to provide 454 mg (87%) of the desired product as a white solid after trituration with hexane. Electrospray Mass Spec 412 (M+H).
Reaction SMILES: Br[C:2]1[N:6]2[CH2:7][CH2:8][N:9]([C:11]([C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([C:19]([F:22])([F:21])[F:20])[C:14]=3[Cl:23])=[O:12])[CH2:10][C:5]2=[N:4][N:3]=1.[Na].[CH3:25][OH:26]>>[Cl:23][C:14]1[C:15]([C:19]([F:22])([F:21])[F:20])=[CH:16][CH:17]=[CH:18][C:13]=1[C:11]([N:9]1[CH2:8][CH2:7][N:6]2[C:2]([O:26][CH3:25])=[N:3][N:4]=[C:5]2[CH2:10]1)=[O:12]
Reactant: CO
Reactant: O=C(c1cccc(C(F)(F)F)c1Cl)N1CCn2c(Br)nnc2C1
Agent: [Na]
Product: COc1nnc2n1CCN(C(=O)c1cccc(C(F)(F)F)c1Cl)C2

Procedure:
3-Bromo-7-{[2-chloro-3-(trifluoromethyl)phenyl]carbonyl}-5,6,7,8-tetrahydro[1,2,4]triazolo[4,3-a]pyrazine (0.250 g, 0.610 mmol, see Example 1 for methods of preparation) was added to a solution of sodium (0.042 g, 1.831 mmol) in methanol (8 mL), under argon and refluxed for 1 hour. More sodium (0.040 g) was added and the reaction was refluxed for 22 hours. The reaction was quenched with water and extracted with Dichloromethane (three times), the combined organics were dried and evaporated, and the residue was purified on the mass-directed automated (preparative) HPLC (MDAP) and triturated with diethyl ether to give 7-{[2-chloro-3-(trifluoromethyl)phenyl]carbonyl}-3-(methyloxy)-5,6,7,8-tetrahydro[1,2,4]triazolo[4,3-a]pyrazine (0.082 g) as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:13]([O:14][CH2:15][C:16]([F:19])([F:18])[F:17])=[CH:12][N:11]=[C:10]([C:20]([OH:22])=O)[CH:9]=2)=[CH:4][CH:3]=1.[CH3:23][CH:24]([C:26]1[S:27][CH:28]=[C:29]([CH2:31][NH2:32])[N:30]=1)[CH3:25]>>[CH:24]([C:26]1[S:27][CH:28]=[C:29]([CH2:31][NH:32][C:20]([C:10]2[CH:9]=[C:8]([C:5]3[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=3)[C:13]([O:14][CH2:15][C:16]([F:18])([F:19])[F:17])=[CH:12][N:11]=2)=[O:22])[N:30]=1)([CH3:25])[CH3:23]
Reactant: O=C(O)c1cc(-c2ccc(Cl)cc2)c(OCC(F)(F)F)cn1
Reactant: CC(C)c1nc(CN)cs1
Product: CC(C)c1nc(CNC(=O)c2cc(-c3ccc(Cl)cc3)c(OCC(F)(F)F)cn2)cs1

Procedure:
The title compound was synthesized in analogy to Example 1, using 4-(4-chloro-phenyl)-5-(2,2,2-trifluoro-ethoxy)-pyridine-2-carboxylic acid (example D) and 2-(1-methylethyl)-4-thiazole-methanamine, as starting materials; LC-MS (UV peak area/ESI) 80%, 470.902 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][O:9][Si:10]([CH:17]([CH3:19])[CH3:18])([CH:14]([CH3:16])[CH3:15])[CH:11]([CH3:13])[CH3:12])=[CH:4][C:3]=1[NH:20][C@@H:21]1[CH2:26][CH2:25][C@H:24]([C:27]([O:29][CH3:30])=[O:28])[CH2:23][CH2:22]1.CCO.[N:34]#[C:35]Br>C(Cl)Cl>[NH2:34][C:35]1[N:20]([C@@H:21]2[CH2:22][CH2:23][C@H:24]([C:27]([O:29][CH3:30])=[O:28])[CH2:25][CH2:26]2)[C:3]2[CH:4]=[C:5]([CH2:8][O:9][Si:10]([CH:17]([CH3:19])[CH3:18])([CH:11]([CH3:12])[CH3:13])[CH:14]([CH3:16])[CH3:15])[CH:6]=[CH:7][C:2]=2[N:1]=1
Reactant: N#CBr
Reactant: COC(=O)[C@H]1CC[C@@H](Nc2cc(CO[Si](C(C)C)(C(C)C)C(C)C)ccc2N)CC1
Solvent: ClCCl
Solvent: CCO
Product: COC(=O)[C@H]1CC[C@@H](n2c(N)nc3ccc(CO[Si](C(C)C)(C(C)C)C(C)C)cc32)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 99.9 %

Procedure:
A round bottom flask under nitrogen atmosphere was charged with cis-methyl 4-(2-amino-5-((triisopropylsilyloxy)methyl)phenylamino)cyclohexanecarboxylate (2.5 g, 5.75 mmol) and EtOH (23.96 mL) To this was added cyanogen bromide (0.914 g, 8.63 mmol), and the reaction mixture was stirred overnight at RT. The reaction mixture was diluted with DCM (80 mL) and washed with 1N aqueous NaOH (50 mL). The organic layer was collected, dried over sodium sulfate, and concentrated to dryness to afford cis-methyl 4-(2-amino-6-((triisopropylsilyloxy)methyl)-1H-benzo[d]imidazol-1-yl)cyclohexanecarboxylate as a brown solid (2.64 g, 100% yield). MS m/z=460.2 [M+H]. Calc'd for C25H41N3O3Si: 459.3.
Reaction SMILES: [CH:1]1[C:6]([S:7]([C:10]2[CH:15]=[CH:14][C:13]3C(OC(=O)[C:12]=3[CH:11]=2)=O)(=[O:9])=O)=[CH:5][C:4]2C(OC(=O)[C:3]=2[CH:2]=1)=O>C1CCCCC1>[CH:13]1[CH:12]=[C:11]2[C:5]3[C:6]([S:7](=[O:9])[C:10]2=[CH:15][CH:14]=1)=[CH:1][CH:2]=[CH:3][CH:4]=3
Reactant: O=C1OC(=O)c2cc(S(=O)(=O)c3ccc4c(c3)C(=O)OC4=O)ccc21
Solvent: C1CCCCC1
Product: O=S1c2ccccc2-c2ccccc21

Procedure:
The cyclohexane extracts (containing DSDA) were combined and concentrated to an oil which was added hot (over 70° C.) in a thin stream over 5 min to a very vigorously agitated solution of 1.1 N aqueous sodium hydroxide (300 ml) at 95° C. Granules of DBTO were rapidly formed. The DBTO slurry was agitated vigorously at 90°-95° C. for 10-15 minutes, then cooled to 30° C. and filtered. The DBTO cake was thoroughly washed with water (3×100 ml) and dried (25-33% loss on drying).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH2:7][CH2:6][CH2:5]2.[F:12][C:13]([F:30])([F:29])[CH:14]1[CH2:16][N:15]1[S:17]([C:20]1[C:25]([CH3:26])=[CH:24][C:23]([CH3:27])=[CH:22][C:21]=1[CH3:28])(=[O:19])=[O:18]>C1COCC1>[CH3:28][C:21]1[CH:22]=[C:23]([CH3:27])[CH:24]=[C:25]([CH3:26])[C:20]=1[S:17]([NH:15][CH:14]([CH2:16][N:8]1[C:9]2[C:4](=[CH:3][C:2]([CH3:1])=[CH:11][CH:10]=2)[CH2:5][CH2:6][CH2:7]1)[C:13]([F:30])([F:12])[F:29])(=[O:18])=[O:19]
Reactant: Cc1cc(C)c(S(=O)(=O)N2CC2C(F)(F)F)c(C)c1
Reactant: Cc1ccc2c(c1)CCCN2
Solvent: C1CCOC1
Product: Cc1cc(C)c(S(=O)(=O)NC(CN2CCCc3cc(C)ccc32)C(F)(F)F)c(C)c1
Temperature: 130 °C

Procedure:
A mixture of 46 mg (0.31 mmol) of 6-methyl-1,2,3,4-tetrahydroquinoline and 91.5 mg (0.31 mmol) of 2-trifluoromethyl-1-(2,4,6-trimethylbenzenesulfonyl)aziridine in 1.5 mL of anhydrous THF was heated at 130° C. in a sealed tube for 18 hours. The mixture was concentrated and the residue was purified by silica gel chromatography eluting with ethyl acetate-hexanes (gradient) to afford 65 mg (47%), m.p. 143° C.-144° C.