Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([N:8]1[CH2:17][CH2:16][C:15]2[NH:14][C:13](=[O:18])[CH:12]=[CH:11][C:10]=2[CH2:9]1)C1C=CC=CC=1>CCO.[OH-].[OH-].[Pd+2]>[NH:14]1[C:15]2[CH2:16][CH2:17][NH:8][CH2:9][C:10]=2[CH:11]=[CH:12][C:13]1=[O:18]
Reactant: O=c1ccc2c([nH]1)CCN(Cc1ccccc1)C2
Agent: [Pd+2]
Agent: [OH-]
Solvent: CCO
Product: O=c1ccc2c([nH]1)CCNC2
Reaction time: 8 h

Procedure:
To a solution of 6-benzyl-5,6,7,8-tetrahydro-1,6-naphthyridin-2(1H)-one (400 mg, 1.66 mmol) in EtOH (30 mL) is added 20% Pd(OH)2/C (20 mg) and the mixture is hydrogenated at 50 psi at rt overnight. The catalyst is filtered and the filtrate is concentrated to give the title compound as a light yellow solid. MS (M+1): 151.1
Reaction SMILES: [SH:1][C:2]1[O:3][C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[N:6]=1.CC(O[CH2:15][C:16]1[CH2:25][S:24][C@@H:19]2[C@H:20]([NH2:23])[C:21](=[O:22])[N:18]2[C:17]=1[C:26]([OH:28])=[O:27])=O.COC(C1C(Cl)=C(Cl)C(C(OC)=O)=C(Cl)C=1Cl)=O>C(#N)C>[NH2:23][CH:20]1[C:21](=[O:22])[N:18]2[C:17]([C:26]([OH:28])=[O:27])=[C:16]([CH2:15][S:1][C:2]3[O:3][C:4]4[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=4[N:6]=3)[CH2:25][S:24][C@H:19]12
Reactant: Sc1nc2ccccc2o1
Reactant: CC(=O)OCC1=C(C(=O)O)N2C(=O)[C@@H](N)[C@H]2SC1
Agent: COC(=O)c1c(Cl)c(Cl)c(C(=O)OC)c(Cl)c1Cl
Solvent: CC#N
Product: NC1C(=O)N2C(C(=O)O)=C(CSc3nc4ccccc4o3)CS[C@H]12
Temperature: 10 °C
Reaction time: 0.67 h
Yield: 92.3 %

Procedure:
A 1.66 g quantity of 2-mercaptobenzoxazole, 18 ml of acetonitrile and 2.72 g of 7-ACA were added to 14.9 g of DCPA with stirring under cooling at 10° C., and the reaction was allowed to proceed at 15° to 17° C. for 40 minutes. The reaction solution was cooled with ice and poured into 120 g of ice-water. The precipitate was recovered by filtration, washed with water (20 ml×4) and acetone successively, and dried thereby affording 3.35 g (92.3% of yield) of 7-amino-3-[(benzoxazol-2-yl)thiomethyl]-3-cephem-4-carboxylic acid.
Reaction SMILES: [CH3:1][C:2]([CH3:15])([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[C@@H:3]([C:5](OC)=[O:6])[NH2:4].[H-].[Al+3].[Li+].[H-].[H-].[H-]>C1COCC1>[NH2:4][CH:3]([C:2]([CH3:15])([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[CH3:1])[CH2:5][OH:6]
Reactant: COC(=O)[C@@H](N)C(C)(C)c1ccccc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CC(C)(c1ccccc1)C(N)CO
Temperature: 25 °C
Yield: 63.5 %

Procedure:
To a solution of methyl beta,beta-dimethylphenylalaninate (1.4 g, 6.76 mmol) in THF (20 mL) at 0° C. was added dropwise a solution of lithium aluminum hydride (384 mg, 10.1 mmol) in THF (10 mL). After warming to 25° C. over 12 h, the solution was quenched by sequential addition of H2O (659 uL), 6N NaOH (500 uL) and H2O (2.4 mL). The resulting precipitate was filtered and the pad washed thoroughly with DCM. The filtrate was concentrated and purified via column chromatography (silica, 2-5% MeOH in DCM (1% NH4OH)) yielding the title compound (770 mg, 64%): LCMS (ES) m/e 179 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:20]=[CH:19][C:5]([C:6]([C:8]2[O:9][C:10]3[CH:16]=[CH:15][C:14]([CH:17]=[O:18])=[CH:13][C:11]=3[CH:12]=2)=[O:7])=[CH:4][CH:3]=1.[CH2:21](O)[CH2:22][OH:23].[C@]12(CS(O)(=O)=O)C(C)(C)C(CC1)CC2=O.C(=O)(O)[O-].[Na+]>C1(C)C=CC=CC=1>[O:18]1[CH2:21][CH2:22][O:23][CH:17]1[C:14]1[CH:15]=[CH:16][C:10]2[O:9][C:8]([C:6]([C:5]3[CH:19]=[CH:20][C:2]([F:1])=[CH:3][CH:4]=3)=[O:7])=[CH:12][C:11]=2[CH:13]=1
Reactant: O=Cc1ccc2oc(C(=O)c3ccc(F)cc3)cc2c1
Reactant: OCCO
Agent: CC1(C)C2CC[C@@]1(CS(=O)(=O)O)C(=O)C2
Agent: O=C([O-])O
Agent: [Na+]
Solvent: Cc1ccccc1
Product: O=C(c1ccc(F)cc1)c1cc2cc(C3OCCO3)ccc2o1
Yield: 64.9 %

Procedure:
2-(4-fluorobenzoyl)-1-benzofuran-5-carbaldehyde (500 mg, 1.86 mmol) and ethylene glycol (2.31 g, 37.2 mmol) were suspended in toluene (20 mL) followed by the addition of (1S)-(+)-10-camphorsulfonic acid (30 mg). This suspension was heated under reflux for 2 hours. After allowing the reaction mixture to cool on standing, saturated aqueous sodium bicarbonate solution was poured thereinto followed by extraction with ethyl acetate. The organic layer was separated followed by washing with sat. NaCl and drying over anhydrous magnesium sulfate. The organic layer was filtered using a glass filter and the filtrate was filtered with a glass filter coated with NH-silica gel. This filtrate was concentrated under a reduced pressure to obtain (5-[1,3]-dioxolan-2-yl-benzofuran-2-yl)-(4-fluoro-phenyl)-methanone (377 mg, 65%).
Reaction SMILES: Br[C:2]1[C:3]([NH:31][C@@H:32]2[CH2:36][CH2:35][N:34]([C:37]([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38])[CH2:33]2)=[N:4][C:5]([NH:11][C:12]2[CH:17]=[CH:16][C:15]([N:18]3[CH2:23][CH2:22][CH:21]([N:24]4[CH2:29][CH2:28][N:27]([CH3:30])[CH2:26][CH2:25]4)[CH2:20][CH2:19]3)=[CH:14][CH:13]=2)=[C:6]([C:8](=[O:10])[NH2:9])[N:7]=1.C(=O)([O-])[O-].[Na+].[Na+].O1[CH2:55][CH2:54][O:53][CH2:52]C1>>[C:8]([C:6]1[N:7]=[C:2]([C:14]2[CH:15]=[CH:16][CH:55]=[C:54]([O:53][CH3:52])[C:13]=2[C:12]#[N:11])[C:3]([NH:31][C@@H:32]2[CH2:36][CH2:35][N:34]([C:37]([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38])[CH2:33]2)=[N:4][C:5]=1[NH:11][C:12]1[CH:17]=[CH:16][C:15]([N:18]2[CH2:23][CH2:22][CH:21]([N:24]3[CH2:29][CH2:28][N:27]([CH3:30])[CH2:26][CH2:25]3)[CH2:20][CH2:19]2)=[CH:14][CH:13]=1)(=[O:10])[NH2:9]
Reactant: CN1CCN(C2CCN(c3ccc(Nc4nc(N[C@@H]5CCN(C(=O)OC(C)(C)C)C5)c(Br)nc4C(N)=O)cc3)CC2)CC1
Reactant: C1COCCO1
Agent: O=C([O-])[O-]
Agent: [Na+]
Product: COc1cccc(-c2nc(C(N)=O)c(Nc3ccc(N4CCC(N5CCN(C)CC5)CC4)cc3)nc2N[C@@H]2CCN(C(=O)OC(C)(C)C)C2)c1C#N
Temperature: 100 °C
Reaction time: 3 h

Procedure:
To a mixture of tert-butyl (3R)-3-{[3-bromo-5-carbamoyl-6-({4-[4-(4-methylpiperazin-1-yl)piperidin-1-yl]phenyl}amino)pyrazin-2-yl]amino}pyrrolidine-1-carboxylate (220 mg), neopentyl glycol ester 2-cyano-3-methoxyphenylborate (164 mg), and tetrakistriphenylphosphine palladium (0) (39 mg), dioxane (8.8 mL) was added a 2 M aqueous sodium carbonate solution (836 μL), followed by stirring at 100° C. for 3 hours under an argon atmosphere. After leaving to be cooled, the mixture was subjected to liquid separation by the addition of ethyl acetate and water. The organic phase was dried over anhydrous magnesium sulfate and then the solvent was evaporated. The obtained residue was purified by silica gel column chromatography (eluent; chloroform:methanol:28% aqueous ammonia=1:0:0-200:10:1) to obtain tert-butyl (3R)-3-{[5-carbamoyl-3-(2-cyano-3-methoxyphenyl)-6-({4-[4-(4-methylpiperazin-1-yl)piperidin-1-yl]phenyl}amino)pyrazin-2-yl]amino}pyrrolidine-1-carboxylate (208 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([SH:9])[CH:5]=[C:6]([Cl:8])[CH:7]=1.[OH-].[Na+:11]>>[Cl:1][C:2]1[CH:3]=[C:4]([S-:9])[CH:5]=[C:6]([Cl:8])[CH:7]=1.[Na+:11]
Reactant: Sc1cc(Cl)cc(Cl)c1
Agent: [Na+]
Agent: [OH-]
Product: [S-]c1cc(Cl)cc(Cl)c1

Procedure:
A 4-necked, 1-liter flask equipped with a stirrer, a thermometer, a dropping funnel and a condenser tube was charged with 163.1 g (0.824 mole of 3,5-dichlorothiophenol) of the crude 3,5-dichlorothiophenol (purity 90.4%) prepared by the process of Example 1, and 370 g (0.925 mole) of an aqueous solution of 10 wt % sodium hydroxide. After 15 minutes of reaction at 25° C., the reaction mixture was subjected to separation procedure to give an aqueous solution of sodium 3,5-dichlorothiophenolate.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([C:12]1([NH:20][C:21](=[O:27])[O:22][C:23]([CH3:26])([CH3:25])[CH3:24])[CH2:17][O:16][C:15]([CH3:19])([CH3:18])[O:14][CH2:13]1)[CH:6]=[CH:5]2.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH2:47]([C@H:51]1[CH2:56][CH2:55][C@H:54](O)[CH2:53][CH2:52]1)[CH2:48][CH2:49][CH3:50].N(C(OC(C)C)=O)=NC(OC(C)C)=O>O1CCCC1.C(OCC)(=O)C>[C:23]([O:22][C:21](=[O:27])[NH:20][C:12]1([C:7]2[CH:6]=[CH:5][C:4]3[C:9](=[CH:10][CH:11]=[C:2]([O:1][C@H:54]4[CH2:55][CH2:56][C@@H:51]([CH2:47][CH2:48][CH2:49][CH3:50])[CH2:52][CH2:53]4)[CH:3]=3)[CH:8]=2)[CH2:17][O:16][C:15]([CH3:19])([CH3:18])[O:14][CH2:13]1)([CH3:26])([CH3:25])[CH3:24]
Reactant: CCCC[C@H]1CC[C@H](O)CC1
Reactant: CC(C)(C)OC(=O)NC1(c2ccc3cc(O)ccc3c2)COC(C)(C)OC1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCCC[C@H]1CC[C@@H](Oc2ccc3cc(C4(NC(=O)OC(C)(C)C)COC(C)(C)OC4)ccc3c2)CC1
Temperature: 25 °C
Reaction time: 96 h

Procedure:
[5-(6-Hydroxynaphthalen-2-yl)-2,2-dimethyl-1,3-dioxinan-5-yl]-carbamic acid tert-butyl ester (Example 13, 498 mg, 0.00133 mol, Apex), PS-triphenylphosphine (3.00 mmol/g loading, 689 mg, 0.00207 mol, Aldrich) were slurried in Tetrahydrofuran (10 mL, Acros), then trans-4-butylcyclohexanol (0.255 g, 0.00163 mol, Synthon) and diisopropyl azodicarboxylate (0.315 mL, 0.00160 mol, Acros) was added. The reaction was stirred at room temperature. After 4 d, the mixture was diluted with ethyl acetate, filtered and concentrated and the crude product was taken up into methylene chloride and subjected to silica gel chromatography purification to give the title compound in 353 mg yield (52%).
Reaction SMILES: C1(S([C:9]2[C:18]3[C:13](=[CH:14][C:15]([O:21][CH3:22])=[C:16]([O:19][CH3:20])[CH:17]=3)[N:12]=[CH:11][CH:10]=2)=O)C=CC=CC=1.C1([Mg]Br)C=CC=CC=1.[Br:31][C:32]1[CH:33]=[C:34]2[C:39](=[CH:40][CH:41]=1)[CH:38]=[C:37]([CH:42]=[O:43])[CH:36]=[CH:35]2.[NH4+].[Cl-]>C1COCC1>[Br:31][C:32]1[CH:33]=[C:34]2[C:39](=[CH:40][CH:41]=1)[CH:38]=[C:37]([CH:42]([C:9]1[C:18]3[C:13](=[CH:14][C:15]([O:21][CH3:22])=[C:16]([O:19][CH3:20])[CH:17]=3)[N:12]=[CH:11][CH:10]=1)[OH:43])[CH:36]=[CH:35]2
Reactant: COc1cc2nccc(S(=O)c3ccccc3)c2cc1OC
Reactant: O=Cc1ccc2cc(Br)ccc2c1
Agent: Br[Mg]c1ccccc1
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: COc1cc2nccc(C(O)c3ccc4cc(Br)ccc4c3)c2cc1OC
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
To a solution of 4-benzenesulfinyl-6,7-dimethoxy-quinoline (step b, 1 g, 3.2 mmol) in THF (15 mL) at −10° C., was added phenylmagnesium bromide (1M in THF, 3.5 mL, 3.5 mmol). The reaction was warmed to RT and stirred for 20 min. 6-Bromo-naphthalene-2-carbaldehyde (Step d, 0.75 g, 3.2 mmol) was added in THF. The resulting mixture was stirred at RT for 2 h, then poured into saturated NH4Cl solution and extracted with ethyl acetate 3×. The combined organic layer was washed with brine, dried over Na2SO4, filtered and concentrated in vacuo. The crude was purified by silica gel column chromatography (15-35% acetone/CH2Cl2) to give the titled compound. MS (ESI, pos. ion) m/z: 424.1 (M+1).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([N+:8]([O-])=O)[C:5]([CH3:11])=[CH:4][C:3]=1[O:12][CH2:13][C:14]1([CH3:17])[CH2:16][CH2:15]1.C(O)(=O)C>[Fe].O>[CH3:11][C:5]1[CH:4]=[C:3]([O:12][CH2:13][C:14]2([CH3:17])[CH2:15][CH2:16]2)[C:2]([CH3:1])=[CH:7][C:6]=1[NH2:8]
Reactant: Cc1cc([N+](=O)[O-])c(C)cc1OCC1(C)CC1
Agent: [Fe]
Solvent: O
Solvent: CC(=O)O
Product: Cc1cc(OCC2(C)CC2)c(C)cc1N
Temperature: 80 °C
Reaction time: 1 h
Yield: 88.3 %

Procedure:
A mixture of 0.61 g of 2,5-dimethyl-1-[(1-methylcyclopropyl)methoxy]-4-nitrobenzen e, 0.78 g of iron powder, 21 ml of acetic acid and 3 mL of water was stirred at 80° C. for 1 hour. The reaction mixture was cooled to around room temperature, and then concentrated under reduced pressure. The resulting residue was converted into basic with an aqueous 1 N sodium hydroxide solution, then ethyl acetate was added, and the mixture was filtered. The filtrate was extracted with ethyl acetate, and then the organic layer was washed with water and saturated salt water, and dried over anhydrous magnesium sulfate. The resulting residue was subjected to silica gel column chromatography to obtain 0.47 g of 2,5-dimethyl-4-[(1-methylcyclopropyl)methoxy]phenylamine.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:16]3[C:11](=[CH:12][CH:13]=[C:14]([C:17]4[NH:21][C:20](=[O:22])[O:19][N:18]=4)[CH:15]=3)[N:10](C3CCCCO3)[N:9]=2)=[CH:4][CH:3]=1.Cl.[OH-].[Na+]>O1CCOCC1.CO>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:16]3[C:11](=[CH:12][CH:13]=[C:14]([C:17]4[NH:21][C:20](=[O:22])[O:19][N:18]=4)[CH:15]=3)[NH:10][N:9]=2)=[CH:4][CH:3]=1
Reactant: O=c1[nH]c(-c2ccc3c(c2)c(-c2ccc(F)cc2)nn3C2CCCCO2)no1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: CO
Product: O=c1[nH]c(-c2ccc3[nH]nc(-c4ccc(F)cc4)c3c2)no1
Yield: 19.1 %

Procedure:
To a solution of 3-[3-(4-fluorophenyl)-1-perhydro-2H-pyran-2-yl-1H-indazol-5-yl]-1,2,4-oxadiazolin-5-one (88 mg, 0.23 mmol) in dioxane (4.0 mL) was added 6 N HCl (4.0 mL) at ambient temperature. After stirring for 16 h an additional amount of dioxane (1.0 mL) was added and the reaction mixture was gently heated in a 60° C. oil bath for 4 h after which an additional amount of 6 N HCl (1.0 mL) and several drops of methanol were added and after an additional 4 h of heating the reaction was stopped by slowly pouring into vigorously stirred aqueous 6 N NaOH (6.0 mL). The solution was adjusted to pH=8 with the addition of 4 N HCl and extracted with ethyl acetate. The organic layer was washed with brine, dried over MgSO4 and concentrated in vacuo to give a pale orange solid which was purified by flash chromatography on silica gel eluting with 10% methanol in dichloromethane to give a pale yellow solid which was dissolved in a minimum amount of methanol and precipitated with ethyl ether and hexanes to afford the desired product as a pale powder (13 mg, 19% yield) 1H NMR (DMSO-d6): δ 13.6 (s, 1H), 13.0 (br s, 1H), 8.5 (s, 1H), 8.1–8.0 (m, 2H), 7.8 (q, 2H), 7.3 (t, 2H); ES-MS (m/z) 297 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:8]([OH:10])=O)[S:6][CH:7]=1.[Cl:11][C:12]1[CH:13]=[C:14]2[C:18](=[CH:19][CH:20]=1)[N:17]([C:21]([NH2:23])=[O:22])[C:16](=[O:24])[CH2:15]2>CN(C1C=CN=CC=1)C.S(Cl)(Cl)=O>[Cl:11][C:12]1[CH:13]=[C:14]2[C:18](=[CH:19][CH:20]=1)[N:17]([C:21]([NH2:23])=[O:22])[C:16](=[O:24])[CH:15]2[C:8](=[O:10])[C:5]1[S:6][CH:7]=[C:3]([O:2][CH3:1])[CH:4]=1
Reactant: COc1csc(C(=O)O)c1
Reactant: NC(=O)N1C(=O)Cc2cc(Cl)ccc21
Agent: CN(C)c1ccncc1
Solvent: O=S(Cl)Cl
Product: COc1csc(C(=O)C2C(=O)N(C(N)=O)c3ccc(Cl)cc32)c1

Procedure:
The title compound was prepared according to the procedure of Example 32. A 1.30 g (8.22 mmoles) sample of 4-methoxy-2-thiophenecarboxylic acid (prepared according to Gronowitz, S., Arkiv. for Kemi. 12:239 (1958)) was converted to 1.19 g of pure acid chloride (b.p. 58-60° C., 0.03 mm) with 10 ml of thionyl chloride. The acid chloride was coupled to 1.18 g (5.61 mmoles) of 5-chloro-2-oxindole-1-carboxamide in the presence of 1.73 g (14.15 mmoles) 4-(N,N-dimethylamino)pyridine to give 1.88 g of crude product on acidic workup. Recrystallization gave 1.39 g (3.96 mmoles, 71% yield) of pure 5-chloro-3-(4-methoxy-2-thenoyl)-2-oxindole-1-carboxamide as a yellow solid, m.p. 221-223° C. (acetic acid).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([C:13]2[O:17][N:16]=[C:15]([C:18]3[CH:26]=[CH:25][CH:24]=[C:23]4[C:19]=3[CH2:20][CH2:21][C@@H:22]4[NH:27][C@@H:28]([CH3:33])[C:29](OC)=[O:30])[N:14]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH:10]([CH3:12])[CH3:11])#[N:2].[BH4-].[Na+]>CO.Cl>[OH:30][CH2:29][C@@H:28]([NH:27][C@@H:22]1[C:23]2[C:19](=[C:18]([C:15]3[N:14]=[C:13]([C:5]4[CH:6]=[CH:7][C:8]([O:9][CH:10]([CH3:12])[CH3:11])=[C:3]([CH:4]=4)[C:1]#[N:2])[O:17][N:16]=3)[CH:26]=[CH:25][CH:24]=2)[CH2:20][CH2:21]1)[CH3:33]
Reactant: COC(=O)[C@H](C)N[C@H]1CCc2c(-c3noc(-c4ccc(OC(C)C)c(C#N)c4)n3)cccc21
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CC(C)Oc1ccc(-c2nc(-c3cccc4c3CC[C@@H]4N[C@@H](C)CO)no2)cc1C#N
Temperature: 25 °C
Yield: 41.3 %

Procedure:
To a solution of (S)-methyl 2-(((S)-4-(5-(3-cyano-4-isopropoxyphenyl)-1,2,4-oxadiazol-3-yl)-2,3-dihydro-1H-inden-1-yl)amino)propanoate (33 mg, 0.07 mmol) in MeOH (2 mL) at 0° C. was added NaBH4 (14 mg, 0.4 mmol). The reaction was allowed to warm to room temperature after 1 h. Incremental amounts of NaBH4 (˜10-15 mg each) were added at 1 h intervals until LC/MS indicated >80% conversion to product. The reaction mixture was diluted with 1N HCl and extracted with DCM (2×). The combined organic layers were dried over Na2SO4 and concentrated. The resulting crude solid was dissolved in DCM and chromatographed (MeOH/DCM) to provide 12.1 mg (40%) of 5-(3-((S)-1-(((S)-1-hydroxypropan-2-yl)amino)-2,3-dihydro-1H-inden-4-yl)-1,2,4-oxadia-zol-5-yl)-2-isopropoxybenzonitrile 53. LCMS-ESI (m/z) calculated for C25H26N4O4: 418.5. found 419.1 [M+H]+, tR=2.56 min. 1H NMR (400 MHz, CDCl3) δ 8.24 (d, J=2.2 Hz, 1H), 8.14 (dd, J=8.9, 2.2 Hz, 1H), 7.88 (d, J=7.6 Hz, 1H), 7.28 (d, J=7.5 Hz, 1H), 7.19 (t, J=7.6 Hz, 1H), 6.92 (d, J=9.1 Hz, 1H), 4.69-4.51 (m, 1H), 4.21 (m, 1H), 3.43 (m, 1H), 3.37-3.19 (m, 1H), 3.10 (m, 2H), 2.95-2.78 (m, 1H), 2.46 (dd, J=6.5, 4.6 Hz, 1H), 2.34-2.17 (m, 1H), 1.81-1.65 (m, 1H), 1.28 (d, J=6.1 Hz, 6H), 0.98 (d, J=6.4 Hz, 3H). Chiral HPLC eluting with 10% IPA/hexanes, plus 0.3% TEA, tR=13.72 min.
Reaction SMILES: O[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([NH:12][C:13](=[O:15])[CH3:14])[CH:10]=2)[N:5]=[C:4]([CH3:16])[CH:3]=1.P(Cl)(Cl)([Cl:19])=O.N>>[Cl:19][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([NH:12][C:13](=[O:15])[CH3:14])[CH:10]=2)[N:5]=[C:4]([CH3:16])[CH:3]=1
Reactant: CC(=O)Nc1ccc2nc(C)cc(O)c2c1
Reactant: O=P(Cl)(Cl)Cl
Agent: N
Product: CC(=O)Nc1ccc2nc(C)cc(Cl)c2c1
Temperature: 25 °C
Yield: 145.9 %

Procedure:
N-(4-Hydroxy-2-methyl-6-quinolyl)acetamide (4.32 g, 20 mmol) and phosphorus oxychloride (9.32 ml, 100 mmol) were heated at 100° C. for 15 min. The reaction mixture was cooled to room temperature and poured into ice water. Thereto was added 28% aqueous ammonia to make the solution alkaline. The resulting insoluble matter was collected by filtration, washed with ether and water, dried under reduced pressure at 80° C. to give N-(4-chloro-2-methyl-6-quinolyl)acetamide (6.85 g, crude, yellow solid).
Reaction SMILES: F[C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=[O:5].C(=O)([O-])[O-].[K+].[K+].[CH3:16][CH:17]([SH:19])[CH3:18]>CN(C=O)C>[CH:17]([S:19][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=[O:5])([CH3:18])[CH3:16]
Reactant: CC(C)S
Reactant: O=Cc1ccccc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)Sc1ccccc1C=O
Temperature: 50 °C
Yield: 88.9 %

Procedure:
2-fluoro-benzaldehyde (2.00 g, 16.1 mmol), potassium carbonate (2.45 g, 17.1 mmol) and 2-propanethiol (1.35 g, 17.1 mmol) were dissolved in 10.0 mL, DMF in a 50 mL round-bottomed flask under dry nitrogen, topped with a reflux condenser. The reaction mixture was heated to 50° C. for 48 h. After cooling the mixture was added to 50 mL of saturated potassium carbonate solution, and the mixture was extracted with 3×50 mL portions of ether. The extracts were dried with magnesium sulfate and evaporated. The yellow oil residue of the crude product was further purified by chromatography on silica gel using 95:5 petroleum ether (60-80) and dichloromethane as eluent to afford a yellow oil (2.58 g, 89%).
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[C:7]([C:11]1[CH:16]=[CH:15][C:14]([S:17]([CH2:20][C:21]2[N:22]=[C:23]([C:27]3[CH:35]=[CH:34][C:30]([C:31](O)=[O:32])=[CH:29][CH:28]=3)[O:24][C:25]=2[CH3:26])(=[O:19])=[O:18])=[CH:13][CH:12]=1)([CH3:10])([CH3:9])[CH3:8].[N:36]1[CH:41]=[CH:40][CH:39]=[C:38]([CH2:42][NH2:43])[CH:37]=1>>[C:7]([C:11]1[CH:12]=[CH:13][C:14]([S:17]([CH2:20][C:21]2[N:22]=[C:23]([C:27]3[CH:35]=[CH:34][C:30]([C:31]([NH:43][CH2:42][C:38]4[CH:37]=[N:36][CH:41]=[CH:40][CH:39]=4)=[O:32])=[CH:29][CH:28]=3)[O:24][C:25]=2[CH3:26])(=[O:19])=[O:18])=[CH:15][CH:16]=1)([CH3:9])([CH3:10])[CH3:8]
Reactant: NCc1cccnc1
Reactant: Cc1oc(-c2ccc(C(=O)O)cc2)nc1CS(=O)(=O)c1ccc(C(C)(C)C)cc1
Agent: O=C(Cl)C(=O)Cl
Product: Cc1oc(-c2ccc(C(=O)NCc3cccnc3)cc2)nc1CS(=O)(=O)c1ccc(C(C)(C)C)cc1
Yield: 46.3 %

Procedure:
Method E. Reaction of oxalyl chloride (27 λL, 0.31 mmol) and benzoic acid 23 (85 mg, 0.21 mmol) with subsequent coupling to 3-pyridinylmethylamine (23 λL, 0.23 mmol) gave benzamide 24 (49 mg, 46%) as a white powder: mp (EtOAc) 177-180° C.; 1H NMR δ 9.20 (t, J=5.8Hz, 1 H, CONH), 8.57 (d, J=1.8Hz, 1 H, H-2′), 8.46 (dd, J=4.7, 1.5Hz, 1 H, H-6′), 7.98 (br d, J=8.5Hz, 2 H, H-2, H-6), 7.86 (br d, J=8.5Hz, 2 H, H-3, H-5), 7.73 (br dt, J=7.9, 1.9Hz, 1 H, H-4′), 7.70 (br dd, J=8.6, 1.9Hz, 2 H, H-2″, H-6″), 7.63 (br dd, J=8.6, 1.9Hz, 2 H, H-3″, H-5″), 7.36 (ddd, J=7.89, 4.7, 0.6Hz, 1 H, H-5′), 4.60 (s, 2 H, CH2SO2), 4.51 (d, J=5.8Hz, 2 H, CH2N), 2.14 (s, 3 H, CH3), 1.30 us, 9 H, C(CH3)31; 13C NMR δ 165.4, 157.8, 157.0, 149.8, 148.7, 148.0, 135.4, 135.3, 135.0, 134.8, 128.7, 128.1 (2), 127.9 (2), 125.9 (2), 125.3 (2), 123.3, 52.9, 40.4, 34.8, 30.6 (3), 9.5, one resonance not observed; MS m/z 504.5 (MH+, 100%). Anal. calcd for C28H29N3O4SCH3OH: C, 65.03; H, 6.21; N, 7.84. Found: C, 65.03; H, 5.94; N, 7.99%.
Reaction SMILES: C([CH:3](O)[CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:8][CH:7]=1)C.C(C1N[CH:27]=[CH:28]N=1)(C1NC=CN=1)=O.C([Br:33])C=C>C(#N)C>[CH2:27]([CH:5]([C:6]1[CH:7]=[CH:8][C:9]([C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:10][CH:11]=1)[CH2:4][CH2:3][Br:33])[CH3:28]
Reactant: O=C(c1ncc[nH]1)c1ncc[nH]1
Reactant: C=CCBr
Reactant: CCOC(=O)c1ccc(CCC(O)CC)cc1
Solvent: CC#N
Product: CCOC(=O)c1ccc(C(CC)CCBr)cc1
Yield: 80.1 %

Procedure:
The ethyl 3-(4-carboethoxyphenyl)propanol (1.00 g, 4.80 mmol) was dissolved in 8 ml of dry acetonitrile under nitrogen and treated with carbonyl diimidazole (1.01 g, 6.24 mmol). After ten minutes, allyl bromide (1.66 ml, 19.2 mmol) was added and the reaction was refluxed for 5 hours. After cooling, the mixture was evaporated, slurried in water and extracted twice with 5:1 pentane/diethyl ether solution. The organic extracts were washed with water and then brine, dried over MgSO4 and concentrated to afford 1.15 g (88% yield) of the subtitle compound.
Reaction SMILES: [NH2:1][CH:2](C1C2CCCCC=2C=CC=1)[CH2:3][N:4]1[C:13]([C:14]#[N:15])=[C:12]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([O:22][CH3:23])[CH:10]=2)[C:5]1=[O:24].[C:35](=[O:38])([O-:37])N>>[C:6]([O:37][C:35](=[O:38])[NH:1][CH2:2][CH2:3][N:4]1[C:13]([C:14]#[N:15])=[C:12]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([O:22][CH3:23])[CH:10]=2)[C:5]1=[O:24])([CH3:11])([CH3:7])[CH3:5]
Reactant: COc1ccc2c(=O)n(CC(N)c3cccc4c3CCCC4)c(C#N)c(-c3ccccc3)c2c1
Reactant: NC(=O)[O-]
Product: COc1ccc2c(=O)n(CCNC(=O)OC(C)(C)C)c(C#N)c(-c3ccccc3)c2c1

Procedure:
Compound 56a was prepared essentially according to the procedure described above in Example I for compound 8 by using tert-butyl-N-2-aminoethyl)-carbamate in place of aminoacetaldehyde diethyl acetal in Step D.
Reaction SMILES: [CH:1]([C:3]1[CH:8]=[C:7]([CH:9]([CH3:11])[CH3:10])[C:6]([O:12][S:13](=[O:34])(=[O:33])[NH:14][C:15](=[O:32])[CH2:16][C:17]2[C:22]([CH:23]([CH3:25])[CH3:24])=[CH:21][C:20]([CH:26]([CH3:28])[CH3:27])=[CH:19][C:18]=2[CH:29]([CH3:31])[CH3:30])=[C:5]([CH:35]([CH3:37])[CH3:36])[CH:4]=1)=O.[CH2:38]([NH2:45])[C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[Cl:60]CCl>>[ClH:60].[CH2:38]([NH:45][CH2:1][C:3]1[CH:4]=[C:5]([CH:35]([CH3:36])[CH3:37])[C:6]([O:12][S:13](=[O:33])(=[O:34])[NH:14][C:15](=[O:32])[CH2:16][C:17]2[C:22]([CH:23]([CH3:24])[CH3:25])=[CH:21][C:20]([CH:26]([CH3:27])[CH3:28])=[CH:19][C:18]=2[CH:29]([CH3:31])[CH3:30])=[C:7]([CH:9]([CH3:11])[CH3:10])[CH:8]=1)[C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1
Reactant: CC(C)c1cc(C(C)C)c(CC(=O)NS(=O)(=O)Oc2c(C(C)C)cc(C=O)cc2C(C)C)c(C(C)C)c1
Reactant: ClCCl
Reactant: NCc1ccccc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Product: CC(C)c1cc(C(C)C)c(CC(=O)NS(=O)(=O)Oc2c(C(C)C)cc(CNCc3ccccc3)cc2C(C)C)c(C(C)C)c1
Product: Cl

Procedure:
[(2,4,6-Triisopropyl-phenyl)-acetyl]-sulfamic acid 4-formyl-2,6-diisopropyl-phenyl ester (1.0 g, 1.9 mmol), benzylamine (0.21 mL, 1.9 mmol), and sodium triacetoxyborohydride (0.56 g, 2.6 mmol) were mixed in 100 mL of dichloromethane under a dry air atmosphere for 16 hours. Quenched by adding saturated sodium bicarbonate (50 mL). The resulting white solid was collected by filtration and resuspended in diethyl ether. HCl gas was bubbled through for 30 minutes, and the resulting solution was concentrated in vacuo to give the title compound as a white solid; mp 179-183° C.