Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C@H:12]([CH2:13]O)[CH2:11][O:10][C:9]1([CH3:16])[CH3:15])=[O:7])([CH3:4])([CH3:3])[CH3:2].[SH:17][C:18]1[S:19][C:20]2[CH:26]=[CH:25][CH:24]=[CH:23][C:21]=2[N:22]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>C1COCC1.CCOC(C)=O>[C:1]([O:5][C:6]([N:8]1[C@H:12]([CH2:13][S:17][C:18]2[S:19][C:20]3[CH:26]=[CH:25][CH:24]=[CH:23][C:21]=3[N:22]=2)[CH2:11][O:10][C:9]1([CH3:16])[CH3:15])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: Sc1nc2ccccc2s1
Reactant: CC(C)(C)OC(=O)N1[C@H](CO)COC1(C)C
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1[C@H](CSc2nc3ccccc3s2)COC1(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 89.4 %

Procedure:
To a stirred, cooled (0° C.) solution of (R)-4-hydroxymethyl-2,2-dimethyl-oxazolidine-3-carboxylic acid tert-butyl ester (1.36 g; CAS 108149-65-1), 2-mercaptobenzothiazole (1.48 g) and triphenylphosphine (2.32 g) in THF (80 ml) under an argon atmosphere was added diethyl azodicarboxylate (4.1 ml; 40% solution in toluene). The mixture (soon turning to a yellow suspension, slowly warming up to r.t.) was stirred for 18 h overnight, then diluted with EtOAc and washed with sat. aq. Na2CO3. The aqueous phase was back extracted with EtOAc. The combined organics were washed with brine, dried over MgSO4, filtered and concentrated. The crude product was purified by column chromatography (SiO2; gradient: cyclohexane ->cyclohexane/EtOAc 85:15) to give (S)-4-(benzothiazol-2-ylsulfanyl-methyl)-2,2-dimethyl-oxazolidine-3-carboxylic acid tert-butyl ester (2.0 g) as light yellow viscous oil.
Reaction SMILES: [Cl:1][C:2]1[S:6][C:5]2[C:7]3([O:24][CH2:25][C:26]([F:28])([F:27])[C:4]=2[CH:3]=1)[CH2:12][CH2:11][N:10]([CH2:13][C:14]1[C:15]([C:19]([O:21][CH2:22][CH3:23])=[O:20])=[N:16][NH:17][CH:18]=1)[CH2:9][CH2:8]3.C(=O)([O-])[O-].[K+].[K+].F[C:36]1[C:41]([F:42])=[CH:40][CH:39]=[CH:38][N:37]=1.C(Cl)Cl>CN(C)C=O>[Cl:1][C:2]1[S:6][C:5]2[C:7]3([O:24][CH2:25][C:26]([F:27])([F:28])[C:4]=2[CH:3]=1)[CH2:8][CH2:9][N:10]([CH2:13][C:14]1[C:15]([C:19]([O:21][CH2:22][CH3:23])=[O:20])=[N:16][N:17]([C:36]2[C:41]([F:42])=[CH:40][CH:39]=[CH:38][N:37]=2)[CH:18]=1)[CH2:11][CH2:12]3
Reactant: CCOC(=O)c1n[nH]cc1CN1CCC2(CC1)OCC(F)(F)c1cc(Cl)sc12
Reactant: Fc1cccnc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CCOC(=O)c1nn(-c2ncccc2F)cc1CN1CCC2(CC1)OCC(F)(F)c1cc(Cl)sc12
Temperature: 60 °C
Yield: 65.6 %

Procedure:
To a solution of ethyl 4-[(2-chloro-4,4-difluoro-spiro[5H-thieno[2,3-c]pyran-7,4′-piperidine]-1′-yl)methyl]-1H-pyrazole-3-carboxylate (22.5 g, 52.10 mmoles) in Dimethylformamide (225.00 mL) is added Potassium Carbonate (10.80 g, 78.14 mmoles) and 2,3-difluoropyridine (7.19 g, 62.52 mmoles) and the resulting suspension is stirred at 60° C. 15 h. Then, reaction mixture is poured over Ice/brine (30 mL) and CH2Cl2 (50 mL) is added to the resulting suspension. Solution is washed with H2O (2×50 mL). Organics are dried over sodium sulfate and concentrated to give a crude which is purified via SiO2 filtration eluting with 2-propanol/CH2Cl2 mixtures to give 18 g of the title compound. MS (m/z): 527 (M+1).
Reaction SMILES: [C:1]12[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=1)[NH:6]C(=O)O[C:2]2=O.C1(C)C=CC(S(O)(=O)=O)=CC=1.C(O)(=O)C.[C:28]([NH:31][NH2:32])(=[O:30])[CH3:29]>C1(C)C=CC=CC=1>[NH2:6][C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][C:1]=1[C:2]1[O:30][C:28]([CH3:29])=[N:31][N:32]=1
Reactant: CC(=O)NN
Reactant: O=c1[nH]c2ccccc2c(=O)o1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CC(=O)O
Solvent: Cc1ccccc1
Product: Cc1nnc(-c2ccccc2N)o1
Temperature: 120 °C
Reaction time: 4 h

Procedure:
A mixture of isatoic anhydride (16.3 g, 0.1 mol), p-toluenesulfonic acid (0.2 g, 1.1 mmol), glacial acetic acid (10 ml), acethydrazide (7.4 g, 0.1 mol) and dry toluene (90 ml) was stirred at 120° C. for 4 h, cooledto room temperature and poured into ice water. Toluene (500 ml) was added, and the phases were separated. The aqueous phase was extracted with CH2Cl2 (2×100 ml).
Reaction SMILES: [OH:1][C@H:2]1[C@@H:8]([C:9]2[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[CH:11][CH:10]=2)[CH2:7][C:6]2[CH:17]=[C:18]([S:21][CH3:22])[CH:19]=[CH:20][C:5]=2[NH:4][C:3]1=[O:23].ClC1C=C(C=CC=1)C(OO)=[O:29]>C(Cl)Cl.C(OCC)(=O)C>[OH:1][C@H:2]1[C@@H:8]([C:9]2[CH:10]=[CH:11][C:12]([O:15][CH3:16])=[CH:13][CH:14]=2)[CH2:7][C:6]2[CH:17]=[C:18]([S:21]([CH3:22])=[O:29])[CH:19]=[CH:20][C:5]=2[NH:4][C:3]1=[O:23]
Reactant: COc1ccc([C@H]2Cc3cc(SC)ccc3NC(=O)[C@H]2O)cc1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: COc1ccc([C@H]2Cc3cc(S(C)=O)ccc3NC(=O)[C@H]2O)cc1
Reaction time: 0.5 h
Yield: 57.1 %

Procedure:
A solution of (cis)-1,3,4,5-Tetrahydro-3-hydroxy-7-methylthio-4-(4-methoxyphenyl)-2H-1-benzazepin-2-one (1.0 g, 3.04 mmol) in dry methylene chloride (30 ml) at 5° C. was treated with m-chloroperoxybenzoic acid (0.615 g, 3.04 mmol). After 30 minutes, the reaction was complete and the reaction mixture was diluted with ethyl acetate, washed with saturated sodium hydrogen carbonate, water, and brine. The organic layer was filtered and concentrated in vacuo to give a solid residue (1.02×g). Trituration with hot ethyl acetate, cooling and filtration afforded the product (600 mg), m.p. 214°14 216° C. The mother liquors were concentrated in vacuo and chromatographed on LPS-1 silica (methylene chloride/methanol). The product fractions were combined and concentrated in vacuo, and the residue crystallized from ethyl acetate to give an additional 200 mg of product.
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[C:8]([CH:10]([CH3:12])[CH3:11])[CH:7]=[C:6]([CH:13]([CH3:15])[CH3:14])[C:5]=1[OH:16])([CH3:3])[CH3:2].[H-].[Na+].Br[CH2:20][C:21]([OH:23])=[O:22]>O1CCCC1>[CH3:14][CH:13]([C:6]1[CH:7]=[C:8]([CH:10]([CH3:12])[CH3:11])[CH:9]=[C:4]([CH:1]([CH3:3])[CH3:2])[C:5]=1[O:16][CH2:20][C:21]([OH:23])=[O:22])[CH3:15]
Reactant: CC(C)c1cc(C(C)C)c(O)c(C(C)C)c1
Reactant: O=C(O)CBr
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)c1cc(C(C)C)c(OCC(=O)O)c(C(C)C)c1
Reaction time: 16 h
Yield: 61.9 %

Procedure:
A solution of 2,4,6-triisopropylphenol (4.0 g, 18 mmol) in 50 mL tetrahydrofuran was added dropwise to a suspension of sodium hydride (1.52 g, 38 mmol) in 25 mL tetrahydrofuran. The resulting pale green suspension was stirred for 30 minutes before a solution of bromoacetic acid (2.52 g, 18 mmol) in 50 mL tetrahydrofuran was added dropwise. The resulting thick suspension was stirred for 16 hours and then concentrated in vacuo. The residue was partitioned between 1N HCl and dichloromethane, the organic extract was dried over MgSO4, filtered, and concentrated to give a yellow solid. Recrystallized from hexanes to give 3.1 g of [2,4,6-tris(1-methylethyl)phenoxy]acetic acid, mp 105°-108° C.
Reaction SMILES: C([O:4][C@H:5]1[CH2:22][CH2:21][C@@:20]2([CH3:23])[C@@H:7]([CH2:8][CH2:9][C@:10]3([CH3:62])[C@@H:19]2[CH2:18][CH2:17][C@H:16]2[C@@:11]3([CH3:61])[CH2:12][CH2:13][C@@:14]3([C:30](=[O:60])[NH:31][C@H:32]([C@H:40]([OH:59])[CH2:41][N:42]4[C@H:51]([C:52](=[O:58])[NH:53][C:54]([CH3:57])([CH3:56])[CH3:55])[CH2:50][C@H:49]5[C@H:44]([CH2:45][CH2:46][CH2:47][CH2:48]5)[CH2:43]4)[CH2:33][C:34]4[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=4)[CH2:26][CH2:25][C@@H:24]([C:27]([CH3:29])=[CH2:28])[C@@H:15]32)[C:6]1([CH3:64])[CH3:63])(=O)C.C1COCC1.[OH-].[Na+]>CO>[C:54]([NH:53][C:52]([C@@H:51]1[CH2:50][C@H:49]2[C@H:44]([CH2:45][CH2:46][CH2:47][CH2:48]2)[CH2:43][N:42]1[CH2:41][C@@H:40]([OH:59])[C@@H:32]([NH:31][C:30]([C@:14]12[CH2:26][CH2:25][C@@H:24]([C:27]([CH3:29])=[CH2:28])[C@@H:15]1[C@@H:16]1[C@@:11]([CH3:61])([CH2:12][CH2:13]2)[C@@:10]2([CH3:62])[C@@H:19]([C@:20]3([CH3:23])[C@@H:7]([CH2:8][CH2:9]2)[C:6]([CH3:63])([CH3:64])[C@@H:5]([OH:4])[CH2:22][CH2:21]3)[CH2:18][CH2:17]1)=[O:60])[CH2:33][C:34]1[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=1)=[O:58])([CH3:55])([CH3:56])[CH3:57]
Reactant: C=C(C)[C@@H]1CC[C@]2(C(=O)N[C@@H](Cc3ccccc3)[C@H](O)CN3C[C@H]4CCCC[C@H]4C[C@H]3C(=O)NC(C)(C)C)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC[C@H](OC(C)=O)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: C=C(C)[C@@H]1CC[C@]2(C(=O)N[C@@H](Cc3ccccc3)[C@H](O)CN3C[C@H]4CCCC[C@H]4C[C@H]3C(=O)NC(C)(C)C)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC[C@H](O)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Temperature: 25 °C
Reaction time: 6 h
Yield: 71.4 %

Procedure:
(1R,3aS,5aR,5bR,7aR,9S,11aR,11bR,13aR,13bR)-3a-((2S,3R)-4-((3S,4aS,8aS)-3-(tert-butylcarbamoyl)octahydroisoquinolin-2(1H)-yl)-3-hydroxy-1-phenylbutan-2-ylcarbamoyl)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)icosahydro-1H-cyclopenta[a]chrysen-9-yl acetate (Example 29, 0.5 g) in MeOH:THF (8:8 ml) and cooled the contents to 0° C. then sodium hydroxide (0.12 g in 4 ml water) was added and the contents were stirred for about 6 hours at room temperature, and the completion of the reaction was monitored by TLC. The reaction mixture was evaporated under reduced pressure, the residue was taken in water and extracted with DCM. The organic layer was dried over Na2SO4 and concentrated under reduced pressure. The residue was purified by silica gel column chromatography using 5% methanol in DCM as eluent to furnish the title compound (0.34 g) as a white solid. 1H NMR (300 MHz, CDCl3): 0.57-0.97 (m, 19H); 1.18-1.21 (m, 8H); 1.25-1.41 (m, 12H); 1.49-1.62 (m, 8H); 1.65-1.82 (m, 10H); 1.85-1.98 (m, 4H); 2.56-2.69 (m, 2H); 2.88-3.06 (m, 3H); 3.29-3.38 (m, 1H); 3.89-3.90 (m, 1H); 4.25-4.70 (m, 4H); 5.78 (s, 1H); 6.12-6.15 (d, J=9 Hz, 1H); 7.19-7.29 (m, 6H); ES Mass: 839 (100%), [M+1] 840.
Reaction SMILES: [CH3:1][C:2]([Si:5]([CH3:16])([CH3:15])[O:6][C:7]1[CH:8]=[C:9]([CH2:13][NH2:14])[CH:10]=[CH:11][CH:12]=1)([CH3:4])[CH3:3].[Cl:17][C:18]1[CH:19]=[C:20]([CH:24]=[C:25]([Cl:28])[C:26]=1[OH:27])[C:21](O)=[O:22].CN([P+](ON1N=NC2C=CC=CC1=2)(N(C)C)N(C)C)C.F[P-](F)(F)(F)(F)F.C(N(C(C)C)CC)(C)C>ClCCl>[Cl:17][C:18]1[CH:19]=[C:20]([C:21]([NH:14][CH2:13][C:9]2[CH:10]=[CH:11][CH:12]=[C:7]([O:6][Si:5]([C:2]([CH3:1])([CH3:3])[CH3:4])([CH3:16])[CH3:15])[CH:8]=2)=[O:22])[CH:24]=[C:25]([Cl:28])[C:26]=1[OH:27]
Reactant: O=C(O)c1cc(Cl)c(O)c(Cl)c1
Reactant: CC(C)(C)[Si](C)(C)Oc1cccc(CN)c1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)[Si](C)(C)Oc1cccc(CNC(=O)c2cc(Cl)c(O)c(Cl)c2)c1
Temperature: 25 °C
Reaction time: 5 h
Yield: 86.2 %

Procedure:
A solution of 3-[[(1,1-dimethylethyl)dimethylsilyl]oxy]benzenemethanamine (Example 8; 5.80 g, 24.5 mmol) in dry dichloromethane (20 mL) was added to a cooled (0° C.) suspension of 3,5-dichloro-4-hydroxybenzoic acid (4.2 g, 20.4 mmol) and BOP reagent (9.80 g, 22.3 mmol) in dry dichloromethane (50 mL). Diisopropylethylamine (10.6 mL, 60.9 mmol) was added slowly, and the cooling bath was removed. The solution was stirred at room temperature for 5 h, then the solvent was evaporated and the residue was dissolved in ethyl acetate. The solution was washed with 1 M HCl (2×100 mL), saturated aqueous sodium hydrogen carbonate (100 mL), and brine (100 mL), dried (MgSO4), filtered, evaporated, and chromatographed (30% ethyl acetate/hexanes) to give 2,6-dichloro-4-[[[[3-[[(1,1-dimethylethyl)dimethylsilyl]oxy]phenyl]methyl]amino]carbonyl]phenol (7.50 g, 87%) as a white solid.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH2:7][C:8]([OH:10])=O)[CH:2]=1.[CH:11]1([CH2:14][N:15]2[C:23]3[N:22]=[C:21]([CH2:24][C:25]4[CH:30]=[CH:29][C:28]([NH:31][CH3:32])=[CH:27][CH:26]=4)[NH:20][C:19]=3[C:18](=[O:33])[N:17]([CH2:34][C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][C:36]=3[F:41])[C:16]2=[O:42])[CH2:13][CH2:12]1.C(N(CC)CC)C>>[CH:11]1([CH2:14][N:15]2[C:23]3[N:22]=[C:21]([CH2:24][C:25]4[CH:26]=[CH:27][C:28]([N:31]([CH3:32])[C:8](=[O:10])[CH2:7][C:3]5[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=5)=[CH:29][CH:30]=4)[NH:20][C:19]=3[C:18](=[O:33])[N:17]([CH2:34][C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][C:36]=3[F:41])[C:16]2=[O:42])[CH2:13][CH2:12]1
Reactant: O=C(O)Cc1cccnc1
Reactant: CNc1ccc(Cc2nc3c([nH]2)c(=O)n(Cc2ccccc2F)c(=O)n3CC2CC2)cc1
Solvent: CCN(CC)CC
Product: CN(C(=O)Cc1cccnc1)c1ccc(Cc2nc3c([nH]2)c(=O)n(Cc2ccccc2F)c(=O)n3CC2CC2)cc1

Procedure:
This compound was prepared by a method similar to that described in example 79 except that commercially available 3-pyridylacetic acid was used in place of N-acetyl-6-amino-2-pyridine carboxylic acid, the reaction was performed using 0.69 equivalents of 3-cyclopropylmethyl-8-[4-(methylamino)-benzyl]-1-(2-fluorobenzyl)-3,7-dihydropurine-2,6-dione and 0.78 equivalents of triethylamine was added as the final reagent to the reaction mixture. The product was purified by chromatography using silica gel eluted with 93:7 chloroform/methanol followed by crystallization from acetonitrile. MS, m/z(M+)=553.2364.
Reaction SMILES: CC1C=CC(S(O[CH2:12][CH:13]2[CH2:17][C:16]3[CH:18]=[C:19]([F:29])[CH:20]=[C:21]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=4[CH3:28])[C:15]=3[O:14]2)(=O)=O)=CC=1.[N-:30]=[N+:31]=[N-:32].[Na+]>>[N:30]([CH2:12][CH:13]1[CH2:17][C:16]2[CH:18]=[C:19]([F:29])[CH:20]=[C:21]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=3[CH3:28])[C:15]=2[O:14]1)=[N+:31]=[N-:32]
Reactant: [N-]=[N+]=[N-]
Reactant: Cc1ccc(S(=O)(=O)OCC2Cc3cc(F)cc(-c4ccccc4C)c3O2)cc1
Agent: [Na+]
Product: Cc1ccccc1-c1cc(F)cc2c1OC(CN=[N+]=[N-])C2

Procedure:
Treatment of (±)-[5-fluoro-7-(2-methylphenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl 4-methylbenzenesulfonate (1.48 g, 3.59 mmol) with sodium azide (0.933 g, 14.35 mmol) generally according to the procedure described for Intermediate 98 gave (±)-2-(azidomethyl)-5-fluoro-7-(2-methylphenyl)-2,3-dihydro-1-benzofuran. Treatment of the azide with palladium on carbon (0.101 g, 10 wt. %) generally according to the procedure described for Example 1 provided 0.555 g (53%) of (±)-1-[5-fluoro-7-(2-methylphenyl)-2,3-dihydro-1-benzofuran-2-yl]methanamine as a white solid, hydrochloride salt. mp 229-234° C.; Anal. calcd. for C16H16FNOHCl.0.1H2O: C, 65.02; H, 5.87; N, 4.74. Found: C, 64.99; H, 5.83; N, 4
Reaction SMILES: [C:1]([C:5]1[N:14]([CH2:15][CH2:16][OH:17])[C:8]2=[CH:9][N:10]=[C:11](Cl)[CH:12]=[C:7]2[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[NH3:18]>CO>[NH2:18][C:11]1[CH:12]=[C:7]2[CH:6]=[C:5]([C:1]([CH3:4])([CH3:3])[CH3:2])[N:14]([CH2:15][CH2:16][OH:17])[C:8]2=[CH:9][N:10]=1
Reactant: N
Reactant: CC(C)(C)c1cc2cc(Cl)ncc2n1CCO
Solvent: CO
Product: CC(C)(C)c1cc2cc(N)ncc2n1CCO
Temperature: 120 °C
Yield: 16 %

Procedure:
In a 100 mL autoclave, a mixture of 2-(2-tert-butyl-5-chloro-1H-pyrrolo[2,3-c]pyridin-1-yl)ethanol (350 mg, 1.39 mmol) and CuSO4.5H2O (35 mg, 1.4 mmol) in aqueous ammonia (14 mL) and CH3OH (7 ml) was heated to 120° C. for 14 h. The mixture was allowed to cool down to 25° C. The methanol was removed by evaporation under vacuum and the resulting mixture was extracted with ethyl acetate (50 mL×3). The combined organic layers were washed with brine, dried over anhydrous Na2SO4 and purified by chromatography on silica gel (5% CH3OH in dichloromethane as eluant) to afford 2-(5-amino-2-tert-butyl-1H-pyrrolo[2,3-c]pyridin-1-yl)ethanol (50 mg, 16%). 1H-NMR (CDCl3, 300 MHz) δ 8.22 (s, 1H), 6.59 (s, 1H), 6.08 (s, 1H), 4.44 (t, J=6.9 Hz, 2H), 3.99 (t, J=6.9 Hz, 2H), 1.45 (s, 9H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6](B2OC(C)(C)C(C)(C)O2)[CH:5]=[CH:4][C:3]=1[C:17]1[N:18]=[CH:19][C:20]([NH2:23])=[N:21][CH:22]=1.Br[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[S:31]([N:34]1[CH2:40][CH2:39][CH2:38][CH2:37][CH2:36][CH2:35]1)(=[O:33])=[O:32]>>[N:34]1([S:31]([C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][C:25]=2[C:6]2[CH:5]=[CH:4][C:3]([C:17]3[N:18]=[CH:19][C:20]([NH2:23])=[N:21][CH:22]=3)=[C:2]([F:1])[CH:7]=2)(=[O:32])=[O:33])[CH2:40][CH2:39][CH2:38][CH2:37][CH2:36][CH2:35]1
Reactant: O=S(=O)(c1ccccc1Br)N1CCCCCC1
Reactant: CC1(C)OB(c2ccc(-c3cnc(N)cn3)c(F)c2)OC1(C)C
Product: Nc1cnc(-c2ccc(-c3ccccc3S(=O)(=O)N3CCCCCC3)cc2F)cn1

Procedure:
The title compound was prepared in a manner similar to that described in Example 448 using 5-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-pyrazin-2-amine and 1-((2-bromophenyl)sulfonyl)azepane. MS (ESI): mass calcd. for C22H23FN4O2S, 426.15; m/z found, 427.2 [M+H]+. 1H NMR (400 MHz, CD3OD) δ 8.37 (s, 1H), 8.21 (s, 1H), 8.02 (d, J=7.9, 1H), 7.96 (t, J=8.2, 1H), 7.66 (m, 1H), 7.60-7.55 (m, 1H), 7.38 (d, J=6.5, 1H), 7.31-7.24 (m, 2H), 1.63-1.52 (m, 12H).
Reaction SMILES: [F-].C([N+](CCCC)(CCCC)CCCC)CCC.[F:19][C:20]1[CH:60]=[CH:59][C:23]([CH2:24][C:25]2[S:29][C:28]([C:30]3[C:35]([Br:36])=[CH:34][N:33]=[C:32]([NH:37][CH2:38][CH2:39][N:40]4[C:44]([CH3:46])([CH3:45])[C:43](=[O:47])[NH:42][C:41]4=[O:48])[N:31]=3)=[CH:27][C:26]=2[CH2:49][CH2:50][O:51][Si](C(C)(C)C)(C)C)=[CH:22][CH:21]=1.O>O1CCCC1>[F:19][C:20]1[CH:60]=[CH:59][C:23]([CH2:24][C:25]2[S:29][C:28]([C:30]3[C:35]([Br:36])=[CH:34][N:33]=[C:32]([NH:37][CH2:38][CH2:39][N:40]4[C:44]([CH3:46])([CH3:45])[C:43](=[O:47])[NH:42][C:41]4=[O:48])[N:31]=3)=[CH:27][C:26]=2[CH2:49][CH2:50][OH:51])=[CH:22][CH:21]=1
Reactant: CC1(C)C(=O)NC(=O)N1CCNc1ncc(Br)c(-c2cc(CCO[Si](C)(C)C(C)(C)C)c(Cc3ccc(F)cc3)s2)n1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: O
Product: CC1(C)C(=O)NC(=O)N1CCNc1ncc(Br)c(-c2cc(CCO)c(Cc3ccc(F)cc3)s2)n1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
Tetrabutylammonium fluoride (5 mL, 1M in tetrahydrofuran, 5.00 mmol) was added slowly to a solution of 1-(2-(4-(5-(4-fluorobenzyl)-4-(2-(tert-butyldimethylsilyloxy)ethyl)thiophen-2-yl)-5-bromopyrimidin-2-ylamino)ethyl)-5,5-dimethylimidazolidine-2,4-dione (1.8 g, 2.66 mmol) in tetrahydrofuran (40 mL) at rt. After stirring at rt for 4 h, 100 mL of water was added. The mixture was extracted with ethyl acetate 3×100 mL). The combined organic layers were washed with brine (100 mL), dried over anhydrous sodium sulfate and filtered. The solvent was removed in vacuo and the product purified by flash chromatography eluting with methanol/dichloromethane (1:30) to give the title compound as a slightly yellow solid (1.2 g, 80%).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[OH:9].[C:10](OC(=O)C)(=[O:12])[CH3:11]>CO>[Cl:8][C:5]1[CH:6]=[CH:7][C:2]([NH:1][C:10](=[O:12])[CH3:11])=[C:3]([OH:9])[CH:4]=1
Reactant: CC(=O)OC(C)=O
Reactant: Nc1ccc(Cl)cc1O
Solvent: CO
Product: CC(=O)Nc1ccc(Cl)cc1O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 91.6 %

Procedure:
To a suspension of 2-amino-5-chlorophenol (1.01 g, 7.0 mmol) in methanol (10 mL) was added acetic anhydride (1.08 g, 10.55 mmol) and the reaction mixture was stirred at room temperature for 30 min. The volatiles were removed in vacuo and the residue was purified by silica gel flash chromatography (hexane:ethyl acetate 5:2) to give the subtitled compound (1.19 g).
Reaction SMILES: [C:1]([S:4][C:5]1[C:10]([CH2:11][CH2:12][C:13]([O:15]CC)=[O:14])=[CH:9][CH:8]=[CH:7][CH:6]=1)(=[O:3])[CH3:2].C([O-])(=O)C.[Na+]>C(O)(C)(C)C>[C:1]([S:4][C:5]1[C:10]([CH2:11][CH2:12][C:13]([OH:15])=[O:14])=[CH:9][CH:8]=[CH:7][CH:6]=1)(=[O:3])[CH3:2]
Reactant: CCOC(=O)CCc1ccccc1SC(C)=O
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(C)(C)O
Product: CC(=O)Sc1ccccc1CCC(=O)O
Temperature: 25 °C

Procedure:
Ten (10.0) or 100.0 mg of racemic ethyl 2-acetylthio-3-benzenepropanoate was added to 1000 μl of 90% tert-butanol and 10% 200 mM sodium acetate buffer (pH 4.0) which contained 10 mg of immobilized lipase from Mucor meihei (Novo). The glass vessel was tightly capped and stirred for 0–40 hours at room temperature. Thirty μl aliquots were-removed to ascertain conversion and optical purity. The aliquots were analyzed using an chiral HPLC column (Chiralcel AD, Daicel Chemical Industries) with a mobile phase of hexane:ethanol:trifluoroacetic acid 98:2:0.1%. The flow rate is 1 ml/minute and detection was at 230 nm. This experiment was also performed in 90% acetonitrile, acetone, and isopropanol as described above. Other racemic esters were also evaluated: butyl, isobutyl, and trifluoroethyl. The results described in Table 1 (above) were obtained.
Reaction SMILES: [C:1]1([S:7]([NH:10][C:11]2[CH:16]=[CH:15][C:14]([N+:17]([O-:19])=[O:18])=[CH:13][CH:12]=2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Na+].Br[CH2:23][C:24]([O:26][CH2:27][CH3:28])=[O:25]>CN(C=O)C>[CH2:27]([O:26][C:24](=[O:25])[CH2:23][N:10]([C:11]1[CH:16]=[CH:15][C:14]([N+:17]([O-:19])=[O:18])=[CH:13][CH:12]=1)[S:7]([C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)(=[O:9])=[O:8])[CH3:28]
Reactant: O=[N+]([O-])c1ccc(NS(=O)(=O)c2ccccc2)cc1
Reactant: CCOC(=O)CBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)CN(c1ccc([N+](=O)[O-])cc1)S(=O)(=O)c1ccccc1

Procedure:
A cold (0° C.) solution of N-phenylsulphonyl-4-nitroaniline (7.39 g, 30 mmol) in DMF (65 mL) was treated with sodium hydride (0.76 g, 32 mmol) portionwise over a period of 1.5 h. A solution of ethyl bromoacetate (4 mL) in DMF (10 mL) was added, and the resultant mixture stirred at RT overnight. The product mixture was concentrated under vacuum, and the residue dissolved in ethyl acetate. The organic extract was washed with brine, dried over magnesium sulfate, filtered and concentrated under vacuum. The residue was subjected to column chromatography on silica gel eluting with 0.5% methanol in chloroform. Collection and concentration of appropriate fractions provided N-4-nitrophenyl-N-phenylsulfonylglycine ethyl ester (4-8a) as a clear gum. ##STR41## Step 2: N-{4-[4-(4-tert-Butyloxycarbonylpiperazin-1-yl)phenylcarbonyl-amino]phenyl}-N-phenylsulfonylglycine ethyl ester (4-10a)
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:16][C:15]2[C:10](=[CH:11][C:12](I)=[C:13]([F:17])[CH:14]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[O:19]1[CH2:24][CH2:23][CH:22]([OH:25])[CH2:21][CH2:20]1>>[C:1]([O:5][C:6]([N:8]1[CH2:16][C:15]2[C:10](=[CH:11][C:12]([O:25][CH:22]3[CH2:23][CH2:24][O:19][CH2:20][CH2:21]3)=[C:13]([F:17])[CH:14]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1Cc2cc(F)c(I)cc2C1
Reactant: OC1CCOCC1
Product: CC(C)(C)OC(=O)N1Cc2cc(F)c(OC3CCOCC3)cc2C1

Procedure:
Prepared in analogy to Example A6(a) from 5-fluoro-6-iodo-1,3-dihydro-isoindole-2-carboxylic acid tert-butyl ester (Example A84(f)) and tetrahydro-4H-pyran-4-ol. Yellow solid. MS (m/e): 282.3 ([M+H-Me2C═CH2]+, 100%).
Reaction SMILES: [N:1]12[CH2:8][CH2:7][CH:4]([CH2:5][CH2:6]1)[CH:3]([OH:9])[CH2:2]2.[F:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[N:17]=[C:18]=[O:19]>>[N:1]12[CH2:8][CH2:7][CH:4]([CH2:5][CH2:6]1)[CH:3]([O:9][C:18](=[O:19])[NH:17][C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=1[F:10])[CH2:2]2
Reactant: OC1CN2CCC1CC2
Reactant: O=C=Nc1ccccc1F
Product: O=C(Nc1ccccc1F)OC1CN2CCC1CC2
Yield: 79 %

Procedure:
3-Quinuclidinol and 2-fluorophenyl isocyanate were used. The reaction solution was evaporated under reduced pressure, and the residual solid was recrystallized from ethyl acetate to afford the title compound (79%) as a white solid: mp 124.0-126.0° C.; FAB LRMS m /z (relatively intensity, %) 265 (MH+, 22), 110 (100).
Reaction SMILES: [F:1][C:2]([F:32])([F:31])[C:3]1[CH:30]=[CH:29][C:6]([CH2:7][N:8]2[CH2:13][CH:12]3[CH:10]([CH2:11]3)[CH:9]2[C:14]([NH:16][C@H:17]([C:19]2[CH:28]=[CH:27][C:22]([C:23]([O:25]C)=[O:24])=[CH:21][CH:20]=2)[CH3:18])=[O:15])=[CH:5][CH:4]=1.O[Li].O>O1CCOCC1.O>[F:31][C:2]([F:1])([F:32])[C:3]1[CH:4]=[CH:5][C:6]([CH2:7][N:8]2[CH2:13][CH:12]3[CH:10]([CH2:11]3)[CH:9]2[C:14]([NH:16][C@H:17]([C:19]2[CH:20]=[CH:21][C:22]([C:23]([OH:25])=[O:24])=[CH:27][CH:28]=2)[CH3:18])=[O:15])=[CH:29][CH:30]=1
Reactant: COC(=O)c1ccc([C@H](C)NC(=O)C2C3CC3CN2Cc2ccc(C(F)(F)F)cc2)cc1
Agent: [Li]O
Solvent: C1COCCO1
Solvent: O
Product: C[C@H](NC(=O)C1C2CC2CN1Cc1ccc(C(F)(F)F)cc1)c1ccc(C(=O)O)cc1
Temperature: 150 °C
Yield: 36.5 %

Procedure:
To a mixture of methyl 4-((1S)-1-(3-(4-(trifluoromethyl)benzyl)-3-azabicyclo[3.1.0]hexane-2-carboxamido)ethyl)benzoate (D153) (84 mg, 0.19 mmol) in a 1:1 mixture dioxane/water, LiOH H2O (12 mg, 0.28 mmol) was added and the reaction heated at 150° C. under microwave irradiation for 5 min. Dioxane was evaporated off and the aqueous phase was acidified with CH3CO2H. The precipitate (58 mg) was filtered off and submitted for chiral HPLC separation (Preparative chromatographic conditions: Column: DAICEL AD-H; Mobile phase: n-heptane/EtOH/TFA 60%/40%/0.2% v/v; DAD: 235 nm). Solvent evaporation of second eluted peak from chiral column, afforded the title compound (E37) (30 mg)