Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:5]=[C:6]([Cl:25])[C:7]2[C:8]3[CH2:17][CH2:16][N:15]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:14][CH2:13][C:9]=3[NH:10][C:11]=2[CH:12]=1.Br[CH2:27][C:28]([O:30][CH2:31][CH3:32])=[O:29]>CN(C=O)C>[Cl:3][C:4]1[CH:5]=[C:6]([Cl:25])[C:7]2[C:8]3[CH2:17][CH2:16][N:15]([C:18]([O:20][C:21]([CH3:22])([CH3:24])[CH3:23])=[O:19])[CH2:14][CH2:13][C:9]=3[N:10]([CH2:27][C:28]([O:30][CH2:31][CH3:32])=[O:29])[C:11]=2[CH:12]=1
Reactant: CC(C)(C)OC(=O)N1CCc2[nH]c3cc(Cl)cc(Cl)c3c2CC1
Reactant: CCOC(=O)CBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)Cn1c2c(c3c(Cl)cc(Cl)cc31)CCN(C(=O)OC(C)(C)C)CC2
Reaction time: 0.33 h
Yield: 75.5 %

Procedure:
Sodium hydride (60% dispersion in mineral oil, 0.25 g, 6.3 mmol) was added to a solution of tert-butyl 8,10-dichloro-1,4,5,6-tetrahydroazepino[4,5-b]indole-3(2H)-carboxylate (1.5 g, 4.2 mmol) in DMF (15 mL). After 20 min, ethyl bromoacetate(0.94 mL, 8.4 mmol) was added. The reaction was quenched with saturated aqueous NH4Cl after 1.5 h and extracted with EtOAc (3×20 mL). The combined organic extracts were washed with brine, dried over Na2SO4, decanted, and concentrated. The crude product was purified by column chromatography (Biotage, 40M) with heptane/EtOAc (3:1) followed by crystallization from MeOH/EtOAc to give 1.4 g (78%) of a white solid: mp 144.5-147.0° C.; IR (diffuse reflectance) 2982, 2972, 1748, 1690, 1456, 1411, 1373, 1366, 1352, 1252, 1222, 1202, 1159, 1115, 824cm−1; MS (EI) m/z 440 (M+), 442, 440, 386, 384, 310, 300, 298, 86, 84, 57; Anal. Calcd for C21H26Cl2N2O4: C, 57.15; H, 5.94; N, 6.35; found: C, 57.15; H, 6.04; N, 6.37.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([C:7]2[CH:15]=[CH:14][CH:13]=[C:12]3[C:8]=2[CH2:9][C:10](=[O:16])[NH:11]3)=[CH:3][CH:2]=1.[CH2:17]([O:19][C:20]([C:22]1[NH:23][C:24]([CH:31]=O)=[C:25]2[C:30]=1[CH2:29][CH2:28][CH2:27][CH2:26]2)=[O:21])[CH3:18]>>[CH2:17]([O:19][C:20]([C:22]1[NH:23][C:24]([CH:31]=[C:9]2[C:8]3[C:12](=[CH:13][CH:14]=[CH:15][C:7]=3[C:4]3[CH:5]=[CH:6][N:1]=[CH:2][CH:3]=3)[NH:11][C:10]2=[O:16])=[C:25]2[C:30]=1[CH2:29][CH2:28][CH2:27][CH2:26]2)=[O:21])[CH3:18]
Reactant: CCOC(=O)c1[nH]c(C=O)c2c1CCCC2
Reactant: O=C1Cc2c(cccc2-c2ccncc2)N1
Product: CCOC(=O)c1[nH]c(C=C2C(=O)Nc3cccc(-c4ccncc4)c32)c2c1CCCC2

Procedure:
4-Pyridin-4-yl-1,3-dihydroindol-2-one was condensed with 3-formyl-4,5,6,7-tetrahydro-2H-isoindole-1-carboxylic acid ethyl ester to give the title compound.
Reaction SMILES: Cl[C:2]([O:4][C:5]1[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[CH:7][CH:6]=1)=[O:3].[Si:14]([O:21][C@@H:22]1[C@@H:26]([CH2:27][OH:28])[O:25][C@@H:24]([N:29]2[CH:37]=[C:35]([CH3:36])[C:33](=[O:34])[NH:32][C:30]2=[O:31])[CH2:23]1)([C:17]([CH3:20])([CH3:19])[CH3:18])([CH3:16])[CH3:15]>C(Cl)Cl.N1C=CC=CC=1>[Si:14]([O:21][C@@H:22]1[C@@H:26]([CH2:27][O:28][C:2]([O:4][C:5]2[CH:6]=[CH:7][C:8]([N+:11]([O-:13])=[O:12])=[CH:9][CH:10]=2)=[O:3])[O:25][C@@H:24]([N:29]2[CH:37]=[C:35]([CH3:36])[C:33](=[O:34])[NH:32][C:30]2=[O:31])[CH2:23]1)([C:17]([CH3:20])([CH3:18])[CH3:19])([CH3:15])[CH3:16]
Reactant: Cc1cn([C@H]2C[C@H](O[Si](C)(C)C(C)(C)C)[C@@H](CO)O2)c(=O)[nH]c1=O
Reactant: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Solvent: c1ccncc1
Solvent: ClCCl
Product: Cc1cn([C@H]2C[C@H](O[Si](C)(C)C(C)(C)C)[C@@H](COC(=O)Oc3ccc([N+](=O)[O-])cc3)O2)c(=O)[nH]c1=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 77.5 %

Procedure:
p-Nitrophenyl chloroformate (252 mg, 1.25 mmol) in anhydrous methylene chloride was added to a stirred solution of 3'-O-(t-butyldimethylsilyl)thymidine (356 mg, 10 mmol, Wang et al. Nucleosides Nucleotides 1998, 17, 1033-1051) in anhydrous methylene chloride (4 mL) and pyridine (0.5 mL). The resulting solution was stirred at room temperature overnight, then cooled with ice, quenched with water (2 mL), stirred at 0° C. for 30 min, diluted with methylene chloride, washed with dilute acetic acid, water, then 5% sodium bicarbonate, dried over sodium sulfate, and concentrated to dryness. Chromatography on silica with ethyl acetate-hexanes (1:1 to 3:2) gave 505 mg of the titled compound as a colorless foam.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:29]=[CH:30][CH:31]=1)[CH2:5][C:6]1[O:7][C:8]([CH3:28])=[C:9]([CH3:27])[C:10]=1[C:11]([C:13]1[CH:18]=[C:17]([CH:19]([CH3:21])[CH3:20])[C:16]([O:22]C)=[C:15]([CH:24]([CH3:26])[CH3:25])[CH:14]=1)=[O:12].B(Br)(Br)Br.C(Cl)Cl>C(Cl)Cl>[Br:1][C:2]1[CH:3]=[C:4]([CH:29]=[CH:30][CH:31]=1)[CH2:5][C:6]1[O:7][C:8]([CH3:28])=[C:9]([CH3:27])[C:10]=1[C:11]([C:13]1[CH:14]=[C:15]([CH:24]([CH3:26])[CH3:25])[C:16]([OH:22])=[C:17]([CH:19]([CH3:20])[CH3:21])[CH:18]=1)=[O:12]
Reactant: COc1c(C(C)C)cc(C(=O)c2c(Cc3cccc(Br)c3)oc(C)c2C)cc1C(C)C
Agent: BrB(Br)Br
Solvent: ClCCl
Product: Cc1oc(Cc2cccc(Br)c2)c(C(=O)c2cc(C(C)C)c(O)c(C(C)C)c2)c1C
Yield: 76.2 %

Procedure:
The title compound was prepared according to the procedure in Example 5, step 3 using [2-(3-bromo-benzyl)-4,5-dimethyl-furan-3-yl]-(3,5-diisopropyl-4-methoxy-phenyl)-methanone (1.34 g, 2.78 mmol) and 1M boron tribromide/CH2Cl2 (5.84 mL) in CH2Cl2. Purification on Biotage KP-Sil eluting with 15% acetone/hexane gave 0.995 g (73%) of the title compound. 1H NMR (DMSOd6) δ1.14 (d, 12H), 1.80 (s, 3H), 2.19 (s, 3H), 3.32 (septet, 2H), 3.87 (s, 2H), 7.09 (d, 1H), 7.22 (t, 1H), 7.26 (s, 1H), 7.39 (d, 1H), 7.43 (s, 2H), 9.13 (s, 1H). IR (KBr) 3350, 2950, 1580, 1560 and 1325 cm−1. mass spectrum (EI) m/z 468 (M+). Anal. Calcd. for C26H29BrO3: C, 66.53; H, 6.23; N, 0.00. Found: C, 66.50; H, 6.22; N, 0.08.
Reaction SMILES: [I-].[CH3:2][S+](C)(C)=O.[H-].[Na+].[CH3:9][O:10][C:11]([C:13]1[CH:14]=[CH:15][C:16]2[N:17]([CH:33]=1)[C:18](=[O:32])[C:19]([CH2:30][CH3:31])=[C:20](/[CH:22]=[CH:23]/[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[N:21]=2)=[O:12]>CN(C)C=O>[C:24]1(/[CH:23]=[CH:22]/[C:20]2[N:21]=[C:16]3[CH:15]=[CH:14][C:13]4([CH2:2][CH:33]4[N:17]3[C:18](=[O:32])[C:19]=2[CH2:30][CH3:31])[C:11]([O:10][CH3:9])=[O:12])[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1
Reactant: CCc1c(/C=C/c2ccccc2)nc2ccc(C(=O)OC)cn2c1=O
Reactant: C[S+](C)(C)=O
Agent: [H-]
Agent: [I-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCc1c(/C=C/c2ccccc2)nc2n(c1=O)C1CC1(C(=O)OC)C=C2
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Trimethyl-sulphoxonium iodide (0.7 g) was reacted with 50% sodium hydride (0.15 g) in dimethylformamide (30 ml) under stirring at room temperature for 1 hour, then a solution of 2-trans-(2-phenyl-ethenyl)-3-ethyl-4-oxo-4H-pyrido[1,2-a]pyrimidine-7-carboxylic acid methyl ester, m.p. 214°-216° C., (0.82 g) in dimethyl-formamide (20 ml) was added. The mixture was allowed to react under stirring at room temperature for 3 hours, then it was diluted with ice water and filtered. Crystallization from acetone gave 2-trans-(2-phenyl-ethenyl)-3-ethyl-6,7-methylen-4-oxo-4H-pyrido[1,2-a]pyrimidine-7-carboxylic acid, methyl ester, m.p. 194°-195° C. (0.58 g), which was reacted with 1% KOH in 95% ethanol solution (11 ml) at reflux temperature for 15 minutes. After cooling the reaction mixture was acidified with acetic acid, concentrated in vacuo and diluted with ice water: the precipitate was filtered and washed with water until neutral. Crystallization from acetone gave 0.34 g of 2-trans-(2-phenyl-ethenyl)-3-ethyl-6,7-methylen-4-oxo-4H-pyrido[1,2]pyrimidine-7-carboxylic acid, m.p. 215°-216° C., NMR (CF3COOD) δ: 1.22(m) and 2.93(m)(6,7-CH2 protons), 1.36(t) (CH2CH3), 2.93(m)(CH2 --CH3), 5.51(d.d)(C-6 proton), 7.01(d) (C-9 proton), 7.31(d)(Hβ vinyl proton), 7.63(b.s.)(phenyl protons), 7.76(d)(Hα vinyl proton), 8.26(d)(C-8 proton).
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[N:10]([CH2:12][CH2:13][O:14][C:15]1[CH:20]=[CH:19][C:18]([CH2:21][CH:22](Br)[C:23]([O:25][CH3:26])=[O:24])=[CH:17][CH:16]=1)[CH3:11].[C:28]([O-:31])(=[S:30])[CH3:29].[K+].CN(C)C=O>O>[C:28]([S:30][CH:22]([CH2:21][C:18]1[CH:19]=[CH:20][C:15]([O:14][CH2:13][CH2:12][N:10]([C:2]2[O:1][C:5]3[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=3[N:3]=2)[CH3:11])=[CH:16][CH:17]=1)[C:23]([O:25][CH3:26])=[O:24])(=[O:31])[CH3:29]
Reactant: COC(=O)C(Br)Cc1ccc(OCCN(C)c2nc3ccccc3o2)cc1
Reactant: CC([O-])=S
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)C(Cc1ccc(OCCN(C)c2nc3ccccc3o2)cc1)SC(C)=O
Temperature: 80 °C

Procedure:
A mixture of methyl 3-[4-[2-[N-(2-benzoxazolyl)-N-methylamino]ethoxy]phenyl]-2-bromopropanoate (1.25 g), potassium thioacetate (0.5 g) and dry N,N-dimethylformamide (15 mL) was heated at 80° C. for 18 hours under a nitrogen atmosphere. The mixture was diluted with water (1 L) and extracted with ethyl acetate (3×250 mL). The combined ethyl acetate solutions were washed with water (3×250 mL) and brine (500 mL), dried (MgSO4) and evaporated. The residue was chromatographed on silica gel with 40% ethyl acetate in hexane as eluent to afford the title compound, a gum.
Reaction SMILES: C[Si](I)(C)C.[OH:6][C:7]1[CH:8]=[C:9]([CH:20]=[C:21]([O:23][C@@H:24]([CH3:28])[CH2:25][O:26]C)[CH:22]=1)[C:10]([NH:12][C:13]1[CH:18]=[N:17][C:16]([CH3:19])=[CH:15][N:14]=1)=[O:11].CO.O.O.O.O.O.S([O-])([O-])(=O)=S.[Na+].[Na+]>C(#N)C>[OH:6][C:7]1[CH:8]=[C:9]([CH:20]=[C:21]([O:23][C@@H:24]([CH3:28])[CH2:25][OH:26])[CH:22]=1)[C:10]([NH:12][C:13]1[CH:18]=[N:17][C:16]([CH3:19])=[CH:15][N:14]=1)=[O:11]
Reactant: COC[C@H](C)Oc1cc(O)cc(C(=O)Nc2cnc(C)cn2)c1
Agent: C[Si](C)(C)I
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: O
Solvent: CO
Solvent: CC#N
Product: Cc1cnc(NC(=O)c2cc(O)cc(O[C@@H](C)CO)c2)cn1
Reaction time: 24 h
Yield: 65.6 %

Procedure:
Trimethylsilyl iodide (6.06 mL, 42.75 mmol) was added to a solution of 3-hydroxy-5-{[(1S)-1-methyl-2-(methyloxy)ethyl]oxy}-N-(5-methylpyrazin-2-yl)benzamide (2.71 g, 8.55 mmol) in dry acetonitrile (150 mL) and stirred for 24 hours. Methanol (30 mL) was added to quench the reaction and stirred for 10 minutes. 10% w/v Aqueous sodium thiosulfate pentahydrate (20 mL) was added to the mixture and the organic solvents removed in vacuo. The residue was brought to pH5 with 1M hydrochloric acid and ethyl acetate (80 mL) added. A yellow solid (1.4 g) was separated by filtration. The aqueous filtrate was reextracted into ethyl acetate (2×80 mL) and the combined organic layers dried (MgSO4), filtered and the solvents removed in vacuo. This residue was combined with the yellow solid obtained above and purified by column chromatography, eluting with 5% to 10% methanol in DCM, to give the title compound (1.70 g)
Reaction SMILES: [NH2:1][C:2]1[N:10]=[CH:9][C:8]([Cl:11])=[CH:7][C:3]=1[C:4]([NH2:6])=[O:5].Br[CH2:13][C:14]1[CH:21]=[C:20]([Cl:22])[CH:19]=[CH:18][C:15]=1[C:16]#[N:17]>CN(C)C=O>[ClH:11].[Cl:11][C:8]1[CH:7]=[C:3]([C:4]([NH2:6])=[O:5])[C:2](=[NH:1])[N:10]([CH2:13][C:14]2[CH:21]=[C:20]([Cl:22])[CH:19]=[CH:18][C:15]=2[C:16]#[N:17])[CH:9]=1
Reactant: N#Cc1ccc(Cl)cc1CBr
Reactant: NC(=O)c1cc(Cl)cnc1N
Solvent: CN(C)C=O
Product: Cl
Product: N#Cc1ccc(Cl)cc1Cn1cc(Cl)cc(C(N)=O)c1=N
Temperature: 100 °C
Reaction time: 14 h
Yield: 1.3 %

Procedure:
To a solution of 2-amino-5-chloronicotinamide (0.15 g) in N,N-dimethylformamide (3 ml) was added 2-(bromomethyl)-4-chlorobenzonitrile (0.31 g), and the mixture was stirred at 100° C. for 14 hr. The reaction mixture was quenched with saturated aqueous sodium hydrogen carbonate solution and extracted with ethyl acetate. The extract was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the obtained residue was purified by silica gel chromatography (ethyl acetate:hexane=3:2-4:1). 2N Hydrochloric acid-methanol solution (1 ml) was added to the obtained yellow oil at room temperature, and the obtained precipitate was recrystallized from methanol-ethyl acetate to give the title compound (2 mg).
Reaction SMILES: C1(CC(N[C@H](C(=O)N)CCC(O)=O)=O)C=CC=CC=1.[C:20]1([CH2:26][C:27](Cl)=[O:28])[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.[NH2:30][C@H:31]([C:37]([OH:39])=[O:38])[CH2:32][CH2:33][C:34](=[O:36])[NH2:35]>>[C:20]1([CH2:26][C:27]([NH:30][C@H:31]([C:37]([OH:39])=[O:38])[CH2:32][CH2:33][C:34](=[O:36])[NH2:35])=[O:28])[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: O=C(Cl)Cc1ccccc1
Reactant: NC(=O)CC[C@H](N)C(=O)O
Agent: NC(=O)[C@H](CCC(=O)O)NC(=O)Cc1ccccc1
Product: NC(=O)CC[C@H](NC(=O)Cc1ccccc1)C(=O)O

Procedure:
Phenylacetylisoglutamine can be synthesized by the reaction of phenylacetyl chloride with L-glutamine to yield phenylacetylglutamine, with subsequent heating under vacuum at 160° C. to yield 3-phenylacetylamino-2,6-piperidinedione, which can then be treated with sodium hydroxide. Also, phenylacetylisoglutamine can be prepared by treatment of phenylacetic acid with N,N′-disuccinimidyl carbonate in acetonitrile followed by reaction with L-isoglutamine in the presence of NaHCO3 in a 1:1 acetonitrile/water mixture. However, the second synthesis requires L-isoglutamine, which is expensive, so the former route of synthesis is preferred on economic grounds. In either synthetic pathway, D-glutamine or a racemic mixture of glutamine stereoisomers can be used in place of L-glutamine, or D-isoglutamine or a racemic mixture of isoglutamine stereoisomers can be used in place of L-isoglutamine, yielding the corresponding optical isomer of phenylacetylglutamine. Either optical isomer of phenylacetylisoglutamine, or a mixture thereof in any proportion, can be used in the present invention.
Reaction SMILES: [C:1](Cl)(Cl)=[O:2].[CH3:5][N:6]1[CH:11]=[C:10]([N:12]2[CH2:16][CH2:15][CH2:14][CH2:13]2)[C:9]2[CH:17]=[CH:18][CH:19]=[CH:20][C:8]=2[S:7]1(=[O:22])=[O:21].C(N(CC)CC)C.[NH2:30][C:31]1[C:36](=[O:37])[C:35]2[CH:38]=[CH:39][CH:40]=[CH:41][C:34]=2[O:33][CH:32]=1>C1(C)C=CC=CC=1.O1CCCC1>[CH3:5][N:6]1[C:11]([C:1]([NH:30][C:31]2[C:36](=[O:37])[C:35]3[CH:38]=[CH:39][CH:40]=[CH:41][C:34]=3[O:33][CH:32]=2)=[O:2])=[C:10]([N:12]2[CH2:16][CH2:15][CH2:14][CH2:13]2)[C:9]2[CH:17]=[CH:18][CH:19]=[CH:20][C:8]=2[S:7]1(=[O:22])=[O:21]
Reactant: CN1C=C(N2CCCC2)c2ccccc2S1(=O)=O
Reactant: O=C(Cl)Cl
Reactant: Nc1coc2ccccc2c1=O
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CN1C(C(=O)Nc2coc3ccccc3c2=O)=C(N2CCCC2)c2ccccc2S1(=O)=O
Temperature: -40 °C
Reaction time: 0.5 h

Procedure:
A solution of 2.5 g (0.025 mole) of phosgene in toluene is diluted with 50 ml of dry tetrahydrofurane and then cooled to a temperature of -40° C. A solution of 6.6 g (0.025 mole) of 2-methyl-4-(1-pyrrolidinyl)-2H-1,2-benzothiazine 1,1-dioxide and 2.5 g (0.025 mole) of triethylamine in 200 ml of tetrahydrofurane is then added slowly, with stirring, at a temperature of -40° to +55° C. in the course of 30 minutes. The reaction mixture is stirred for 12 hours at room temperature, then cooled to 10° C., and subsequently a suspension of 6.25 g (0.05 mole) of 3-amino-4-oxo-4H-1-benzopyrane in 100 ml of tetrahydrofurane is added slowly. The temperature of the reaction mixture is allowed to rise to room temperature. The reaction mixture is then stirred for 72 hours and poured into ice-water. The precipitate is collected by suction and crystallised from tetrahydrofurane, affording pure crystalline 2-methyl-N-(4-oxo-4H-1-benzopyran-3-yl)-4-(1-pyrrolidinyl)-2H-1,2-benzothiazine-3-carboxamide 1,1-dioxide. 2-Methyl-3,4-dihydro-4-oxo-N-(6-chloro-7-methyl-4-oxo-4H-1-benzopyran-3-yl)-2H-1,2-benzothiazine-3-carboxamide 1,1-dioxide can be obtained in analogeous manner starting from 2-methyl-N-(6-chloro-7-methyl-4-oxo.4H-1 -benzopyran-3-yl)-4-(1-pyrrolidinyl)-1,2-benzothiazine-3-carboxamide 1,1-dioxide.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N:12]2[CH2:16][CH2:15][C@@H:14]([O:17][C:18]3[CH:19]=[N:20][C:21]([OH:24])=[CH:22][CH:23]=3)[C:13]2=[O:25])[CH:5]=[C:6]2[C:10]=1[CH2:9][CH2:8][C:7]2=[O:11].[CH:26](O)([CH3:28])[CH3:27].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>C1COCC1.C(Cl)Cl.CN1C(=O)CCC1>[F:1][C:2]1[CH:3]=[C:4]([N:12]2[CH2:16][CH2:15][C@@H:14]([O:17][C:18]3[CH:19]=[N:20][C:21]([O:24][CH:26]([CH3:28])[CH3:27])=[CH:22][CH:23]=3)[C:13]2=[O:25])[CH:5]=[C:6]2[C:10]=1[CH2:9][CH2:8][C:7]2=[O:11]
Reactant: CC(C)O
Reactant: O=C1CCc2c(F)cc(N3CC[C@@H](Oc4ccc(O)nc4)C3=O)cc21
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CN1CCCC1=O
Solvent: ClCCl
Solvent: C1CCOC1
Product: CC(C)Oc1ccc(O[C@@H]2CCN(c3cc(F)c4c(c3)C(=O)CC4)C2=O)cn1
Temperature: 40 °C
Reaction time: 12 h

Procedure:
To a mixture of (R)-1-(7-fluoro-3-oxo-indan-5-yl)-3-(6-hydroxy-pyridin-3-yloxy)-pyrrolidin-2-one (60 mg), isopropanol (30 mg) and solvent (THF/DCM/NMP 4:4:1, 5 mL) under argon was added triphenyiphosphine (polymer, 0.4 mmol). After 5 minutes DIAD (51 mg) was added. The mixture was shaken at 40° C. for 12 hours. The mixture was filtered and the filtrate was concentrated. The residue was purified by preparative HPLC to provide Example 2-24. 1H-NMR (400 MHz, DMSO) δ 7.99 (1H, dd, J=11.1, 1.8 Hz), 7.97 (1H, d, J=3.1 Hz), 7.77 (1H, d, J=1.8 Hz), 7.51 (1H, dd, J=9.0, 3.1 Hz), 6.71 (1H, d, J=9.0 Hz), 5.22 (1H, dd, J=8.3, 8.3 Hz), 5.14 (1H, m), 3.96 (1H, m), 3.85 (1H, m), 3.10 (2H, m), 2.72 (2H, m), 2.69 (1H, m), 2.14 (1H, m), 1.27 (6H, d, J=6.2 Hz).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C@@H:12]([CH2:16][CH:17]2[CH2:22][CH2:21][C:20](=[O:23])[CH2:19][CH2:18]2)[C:13](O)=[O:14])[CH:5]=[CH:6][C:7]=1[S:8]([CH3:11])(=[O:10])=[O:9].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.BrN1C(=O)CCC1=O.[NH2:51][C:52]1[CH:57]=[N:56][C:55]([CH3:58])=[CH:54][N:53]=1.N1C(C)=CC=CC=1C>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]([C@@H:12]([CH2:16][CH:17]2[CH2:18][CH2:19][C:20](=[O:23])[CH2:21][CH2:22]2)[C:13]([NH:51][C:52]2[CH:57]=[N:56][C:55]([CH3:58])=[CH:54][N:53]=2)=[O:14])[CH:5]=[CH:6][C:7]=1[S:8]([CH3:11])(=[O:10])=[O:9]
Reactant: Cc1cnc(N)cn1
Reactant: CS(=O)(=O)c1ccc([C@@H](CC2CCC(=O)CC2)C(=O)O)cc1Cl
Agent: O=C1CCC(=O)N1Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Solvent: Cc1cccc(C)n1
Product: Cc1cnc(NC(=O)[C@H](CC2CCC(=O)CC2)c2ccc(S(C)(=O)=O)c(Cl)c2)cn1
Temperature: 25 °C
Reaction time: 4 h
Yield: 48.1 %

Procedure:
A solution of 2(R)-(3-chloro-4-methanesulfonyl-phenyl)-3-(4-oxo-cyclohexyl)-propionic acid (prepared as in Example 60, 263 mg, 0.73 mmol) and triphenylphosphine (250 mg, 0.95 mmol) in methylene chloride (5.0 mL) cooled to 0° C. was treated with N-bromosuccinimide (167 mg, 0.95 mmol) in small portions. After the complete addition of N-bromosuccinimide, the reaction mixture was allowed to warm to 25° C. over 30 min. The bright orange reaction mixture was then treated with 2-amino-5-methylpyrazine (160 mg, 1.46 mmol) and 2,6-lutidine (0.36 mL, 2.92 mmol). The resulting reaction mixture was stirred at 25° C. for 4 h. The reaction mixture was then diluted with methylene chloride (25 mL) and was successively washed with a 10% aqueous hydrochloric acid solution 1×20 mL), a saturated aqueous sodium bicarbonate solution 1×20 mL) and water 1×20 mL), dried over sodium sulfate, filtered, and concentrated in vacuo. Biotage chromatography (FLASH 40S, Silica, 65/35 hexanes/ethyl acetate to 3/7 hexanes/ethyl acetate) afforded 2(R)-(3-chloro-4-methanesulfonyl-phenyl)-N-(5-methyl-pyrazin-2-yl)-3-(4-oxo-cyclohexyl)-propionamide (158 mg, 48%) as a white foam: [α]23589=−41.52° (c=0.33, chloroform); EI-HRMS m/e calcd for C20H21Cl2N3O4S (M+H)+ 450.1249. found 450.1253.
Reaction SMILES: N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O.[CH2:19]([N:26]([CH3:35])[CH2:27][CH2:28][CH:29]([OH:34])[CH2:30][CH:31]([CH3:33])[CH3:32])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.O[C:37]1[C:42]2[CH:43]=[CH:44][S:45][C:41]=2[CH:40]=[CH:39][CH:38]=1.C(P(CCCC)CCCC)CCC>ClCCl.C1(C)C=CC=CC=1>[S:45]1[CH:44]=[CH:43][C:42]2[C:37]([O:34][CH:29]([CH2:30][CH:31]([CH3:32])[CH3:33])[CH2:28][CH2:27][N:26]([CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[CH3:35])=[CH:38][CH:39]=[CH:40][C:41]1=2
Reactant: Oc1cccc2sccc12
Reactant: CC(C)CC(O)CCN(C)Cc1ccccc1
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: ClCCl
Solvent: Cc1ccccc1
Product: CC(C)CC(CCN(C)Cc1ccccc1)Oc1cccc2sccc12
Yield: 59.2 %

Procedure:
Add 1,1′-(azodicarbonyl)dipiperidine (1.6901 g, 6.698 mmol) to a stirred solution of 1-(benzyl-methyl-amino)-5-methyl-hexan-3-ol (1.0463 g, 4.445 mmol), 4-hydroxybenzo-thiophene (1.0027 g, 6.676 mmol), tributylphosphine (1.70 mL, 6.82 mmol), and anhydrous toluene (15 mL). Heat the reaction to 70° C. under nitrogen for 18 hours. Cool the reaction to room temperature and dilute with dichloromethane. Filter off the solid material and concentrate the solvent off on a rotary evaporator to give the crude product. Purify the crude product by flash chromatography on silica gel eluting with 10% ethyl acetate /dichloromethane to yield 0.9674 g (59%) of [3-(benzo[b]thiophen-4-yloxy)-5-methyl-hexyl]-benzyl-methyl-amine: mass spectrum (ion spray) m/z=368.3(M+1); 1H NMR (CDCl3) δ 7.46-7.41 (m, 2H), 7.29-7.21 (m, 7H), 6.83 (d, 1H), 4.66-4.60 (m, 1H), 3.47 (s, 2H), 2.54-2.51 (m, 2H), 2.19 (s, 3H), 2.02-1.71 (m, 4H), 1.49-1.42 (m, 1H), 0.95 (d, 3H), 0.89 (d, 3H).
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[Br:13][C:14]1[CH:15]=[C:16]([C:19]2[NH:20][C:21]3[CH:27]=[C:26]([Cl:28])[C:25]([Cl:29])=[CH:24][C:22]=3[N:23]=2)[S:17][CH:18]=1.CN(C)[CH:32]=[O:33].Cl>O1CCCC1.O>[Br:13][C:14]1[CH:15]=[C:16]([C:19]2[NH:23][C:22]3[CH:24]=[C:25]([Cl:29])[C:26]([Cl:28])=[CH:27][C:21]=3[N:20]=2)[S:17][C:18]=1[CH:32]=[O:33]
Reactant: CN(C)C=O
Reactant: Clc1cc2nc(-c3cc(Br)cs3)[nH]c2cc1Cl
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: O
Solvent: CC(C)NC(C)C
Product: O=Cc1sc(-c2nc3cc(Cl)c(Cl)cc3[nH]2)cc1Br
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 54.7 %

Procedure:
To a solution of diisopropylamine (0.67 mL, 4.8 mmol) in tetrahydrofuran (6 mL) was added n-butyllithium (1.6 mol/L in hexanes; 2.7 mL, 4.3 mmol) at 0° C. under nitrogen atmosphere, and the reaction mixture was cooled to −78° C. 2-(4-Bromothiophen-2-yl)-5,6-dichlorobenzimidazole (500 mg, 1.44 mmol) in tetrahydrofuran (14 mL) was added dropwise followed by the addition of dimethylformamide (0.33 mL, 4.3 mmol), and the mixture was stirred for 30 min. Water and hydrochloric acid (1 mol/L) were added, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and brine, dried on anhydrous sodium sulfate. The solvent was removed under reduced pressure, and the residue was triturated with ethyl acetate to afford 2-(3-bromo-2-formylthiophen-5-yl)-5,6-dichlorobenzimidazole (296 mg, 55%).
Reaction SMILES: [Br:1][C:2]1[C:3]([O:20][CH3:21])=[C:4]([CH2:8][N:9]2C(=O)C3C(=CC=CC=3)C2=O)[CH:5]=[CH:6][CH:7]=1.O.NN>CCO>[Br:1][C:2]1[C:3]([O:20][CH3:21])=[C:4]([CH2:8][NH2:9])[CH:5]=[CH:6][CH:7]=1
Reactant: COc1c(Br)cccc1CN1C(=O)c2ccccc2C1=O
Agent: NN
Solvent: O
Solvent: CCO
Product: COc1c(Br)cccc1CN
Temperature: 90 °C
Yield: 54 %

Procedure:
To a suspension of 2-{[3-bromo-2-(methyloxy)phenyl]methyl}-1H-isoindole-1,3(2H)-dione (26.7 g, 77.2 mmol) in EtOH (300 mL), hydrazine hydrate (7.8 g, 154 mmol) was added, and the reaction mixture was heated to 90° C. for 4 h. After cooled to room temperature, the mixture was filtered and the solid was washed with EtOAc (300 mL×2). The filtrate was concentrated to about 50 mL and filtered again. After removing the solvent, the residue was dissolved in 20 mL of MeOH, and then 1N HCl was added to obtain a white solid. Then the white solid was recrystallized with MeOH-Et2O to obtain 9.0 g of the product. Yield: 46.3%. 1H NMR (400 MHz, D2O) δ 3.79 (s, 3H), 4.13 (s, 2H), 7.02 (t, J=7.6 Hz, 1 H), 7.27 (d, J=8.0 Hz, 1 H), 7.57 (d, J=8.0 Hz, 1 H); 13C NMR (100 MHz, D2O) δ 37.7, 60.2, 115.6, 125.3, 126.6, 128.8, 133.8, 153.7; MS: m/z 254.1 (M+); HPLC: retention time: 7.618 min; purity: 98.8%.