Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CC(C)([O-])C.[K+].Cl[C:23]1[CH:28]=[CH:27][C:26]([O:29][CH2:30][CH3:31])=[CH:25][C:24]=1[N+:32]([O-:34])=[O:33].O>CN(C)C=O>[CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([O:15][C:23]2[CH:28]=[CH:27][C:26]([O:29][CH2:30][CH3:31])=[CH:25][C:24]=2[N+:32]([O-:34])=[O:33])=[CH:13][CH:14]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Oc1ccc(OCc2ccccc2)cc1
Reactant: CCOc1ccc(Cl)c([N+](=O)[O-])c1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOc1ccc(Oc2ccc(OCc3ccccc3)cc2)c([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 69.2 %

Procedure:
To a solution of 4-(benzyloxy)phenol (5.68 g, 28.4 mmol) in N,N-dimethylformamide (100 ml) was added potassium tert-butoxide (3.50 g, 31.2 mmol), and after stirring for 10 minutes, 1-chloro-4-ethoxy-2-nitrobenzene (5.73 g, 28.4 mmol) was added to the reaction solution, followed by stirring at 150° C. for 2 hours. The reaction solution was cooled to room temperature, poured into water and extracted with ethyl acetate. The organic layer was washed with water and a saturated aqueous sodium chloride solution, and after drying, the solvent was evaporated under reduced pressure. The resulting crude crystals were recrystallized from methanol to give 4-[4-(benzyloxy)phenoxy]-3-nitrophenetole (7.18 g).
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH:4]([O:7][C:8]2[C:13]([NH2:14])=[CH:12][CH:11]=[CH:10][N:9]=2)[CH2:3][CH2:2]1.Cl[C:16]1[C:17]2[C:24]([CH3:25])=[C:23]([C:26]([O:28][CH3:29])=[O:27])[S:22][C:18]=2[N:19]=[CH:20][N:21]=1.C1(C)C=CC(S(O)(=O)=O)=CC=1.[OH-].[NH4+].O>O1CCOCC1>[CH3:25][C:24]1[C:17]2[C:16]([NH:14][C:13]3[C:8]([O:7][CH:4]4[CH2:5][CH2:6][O:1][CH2:2][CH2:3]4)=[N:9][CH:10]=[CH:11][CH:12]=3)=[N:21][CH:20]=[N:19][C:18]=2[S:22][C:23]=1[C:26]([O:28][CH3:29])=[O:27]
Reactant: Nc1cccnc1OC1CCOCC1
Reactant: COC(=O)c1sc2ncnc(Cl)c2c1C
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: [NH4+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: COC(=O)c1sc2ncnc(Nc3cccnc3OC3CCOCC3)c2c1C
Temperature: 25 °C
Yield: 47.2 %

Procedure:
2-(Tetrahydro-2H-pyran-4-yloxy)pyridin-3-amine (0.99 g, 5.10 mmol), methyl 4-chloro-5-methylthieno[2,3-d]pyrimidine-6-carboxylate (1.237 g, 5.10 mmol) and para-toluene sulfonic acid (0.097 g, 0.51 mmol) were heated at reflux in anhydrous 1,4-dioxane (20 mL) for 16 hours. The solution was cooled to ambient temperature and poured into a stirred solution of ammonium hydroxide/water (1:4). The precipitate was filtered off, washed with water, diethyl ether and dried. The product was purified by reverse phase preparative HPLC to yield grey solid (0.963 g, 47%).
Reaction SMILES: [Br:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][C:3]=1[CH3:12].C1C(=O)N([Br:20])C(=O)C1.O>C(Cl)(Cl)Cl>[Br:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][C:3]=1[CH2:12][Br:20]
Reactant: O=C1CCC(=O)N1Br
Reactant: COC(=O)c1ccc(Br)c(C)c1
Solvent: ClC(Cl)Cl
Solvent: O
Product: COC(=O)c1ccc(Br)c(CBr)c1
Temperature: 70 °C
Reaction time: 48 h

Procedure:
To a solution of methyl 4-bromo-3-methylbenzoate (50 g; 218 mmol) in CHCl3 (1 L) were added NBS (46.6 g; 262 mmol) in one portion and α,α′-azoisobutyronitrile (0.72 g; 4.37 mmol). The reaction mixture was stirred at 70° C. for 2 days. It was cooled down to RT and water was added. The organic layer was washed with aq. NaHCO3, then brine, dried over MgSO4 and concentrated in vacuo. The residue was washed with n-pentane to afford the title compound as a yellow solid. 1H NMR (DMSO-d6) δ 8.24 (d, J=1.9 Hz, 1H), 7.88-7.82 (m, 2H), 4.87 (s, 2H), 3.91 (s, 3H). HPLC (Method A): Rt 4.44 min (purity 97.9%).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([OH:19])=[C:13]([CH:18]=1)[C:14]([O:16][CH3:17])=[O:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:20]([O-])([O-])=O.[K+].[K+].IC.O>CN(C=O)C>[CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([O:19][CH3:20])=[C:13]([CH:18]=1)[C:14]([O:16][CH3:17])=[O:15])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C([O-])[O-]
Reactant: COC(=O)c1cc(OCc2ccccc2)ccc1O
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CI
Solvent: O
Product: COC(=O)c1cc(OCc2ccccc2)ccc1OC
Temperature: 25 °C
Reaction time: 8 h
Yield: 92.9 %

Procedure:
To a mixture of methyl 5-(benzyloxy)-2-hydroxybenzoate (10.6 g, 41.1 mmol) and K2CO3 (11.3 g, 82.2 mmol) in DMF (100 mL) was added iodomethane (2.60 mL, 49.3 mmol) drop wise over 5 minutes. The resulting mixture was stirred at room temperature overnight. The reaction mixture was poured into water (400 mL), filtered, and collected the solid. The solid was dissolved in EtOAc (300 mL), washed with water (50 mL) and brine (100 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to give methyl 5-(benzyloxy)-2-methoxybenzoate (10.4 g, 98%) as a yellow solid.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[CH3:11][C:12]([Si:15]([CH3:35])([CH3:34])[O:16][C:17]1[CH:22]=[C:21]([CH2:23][OH:24])[CH:20]=[CH:19][C:18]=1[CH2:25][P:26](=[O:33])([O:30][CH2:31][CH3:32])[O:27][CH2:28][CH3:29])([CH3:14])[CH3:13].C(N(CC)CC)C>C(Cl)Cl>[CH3:11][C:12]([Si:15]([CH3:35])([CH3:34])[O:16][C:17]1[CH:22]=[C:21]([CH:23]=[O:24])[CH:20]=[CH:19][C:18]=1[CH2:25][P:26](=[O:33])([O:27][CH2:28][CH3:29])[O:30][CH2:31][CH3:32])([CH3:14])[CH3:13]
Reactant: CCOP(=O)(Cc1ccc(CO)cc1O[Si](C)(C)C(C)(C)C)OCC
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: CS(C)=O
Product: CCOP(=O)(Cc1ccc(C=O)cc1O[Si](C)(C)C(C)(C)C)OCC
Temperature: -30 °C
Reaction time: 0.5 h

Procedure:
A solution of oxalylchloride (0.6 g, 6.7 mmol) in 20 mL methylene chloride is cooled to -70° C. Dimethylsulfoxide (0.6 mL, 8.4 mmol) is added dropwise. The solution is warmed to -30° C. then cooled to -70° C. A solution of diethyl [[2-[[(1,1-dimethylethyl)dimethylsilyl]oxy]-4-(hydroxymethyl)phenyl]methyl]phosphonate (1.73 g, 4.45 mmol) from Preparation 18 in methylenechloride (15 mL) is added to the reaction mixture. The reaction mixture is stirred for 0.5 hours then warmed to -35° C. Triethylamine (4.7 mL, 33.5 mmol) is added and the mixture allowed to warm to room temperature. Methylenechloride (400 mL) is added and the organic phase is washed with 100 mL H2O. The organic phase is dried (MgSO4) and concentrated. The residue is passed through a 200-g silica gel plug using 5% MeOH/CH2Cl2 as the eluent. An oil of diethyl [[2-[[(1,1-dimethylethyl)dimethylsilyl]oxy]-4-formylphenyl]methyl]phosphonate is obtained (1.67 g, 97%).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([NH2:8])[CH:5]=[CH:4][N:3]=1.C[Al](C)C.CCCCCCC.C([O:22][C:23]([C:25]1[N:26]=[C:27]([CH3:37])[S:28][C:29]=1[NH:30][C:31]1[CH:32]=[N:33][CH:34]=[CH:35][CH:36]=1)=O)C>O1CCOCC1>[CH3:1][C:2]1[CH:7]=[C:6]([NH:8][C:23]([C:25]2[N:26]=[C:27]([CH3:37])[S:28][C:29]=2[NH:30][C:31]2[CH:32]=[N:33][CH:34]=[CH:35][CH:36]=2)=[O:22])[CH:5]=[CH:4][N:3]=1
Reactant: CCOC(=O)c1nc(C)sc1Nc1cccnc1
Reactant: Cc1cc(N)ccn1
Agent: C[Al](C)C
Solvent: C1COCCO1
Solvent: CCCCCCC
Product: Cc1cc(NC(=O)c2nc(C)sc2Nc2cccnc2)ccn1
Temperature: 25 °C
Reaction time: 1 h
Yield: 41 %

Procedure:
A solution of 2-methyl-pyridin-4-ylamine (0.10 g, 0.91 mmol) in dry dioxane (2.00 ml) was added to a 2N solution of trimethylaluminium in heptane (0.46 ml, 0.91 mmol). The mixture was stirred at room temperature for 1 h, then 2-methyl-5-(pyridin-3-ylamino)-thiazole-4-carboxylic acid ethyl ester (0.08 g, 0.30 mmol) was added and the reaction mixture was irradiated in a microwave oven at 150° C. for 15 min. The mixture was quenched with water (1.00 ml) and diluted with dichloromethane. After drying with sodium sulphate, the solvent was evaporated. The residue was purified by flash chromatography (dichloromethane/methanol) yielding the title compound (0.04 g, 41%) as a yellow solid, MS (ISP): m/e=326.1 (M+H+).
Reaction SMILES: [C:1]1(B(O)O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:10]([C:12]1[CH:17]=[CH:16][C:15]([NH:18][CH:19]([C:25]2[CH:30]=[C:29]([OH:31])[CH:28]=[C:27]([CH2:32][CH3:33])[CH:26]=2)[C:20]([O:22][CH2:23][CH3:24])=[O:21])=[CH:14][CH:13]=1)#[N:11].N1C=CC=CC=1>C(Cl)Cl.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[C:10]([C:12]1[CH:17]=[CH:16][C:15]([NH:18][CH:19]([C:25]2[CH:30]=[C:29]([O:31][C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)[CH:28]=[C:27]([CH2:32][CH3:33])[CH:26]=2)[C:20]([O:22][CH2:23][CH3:24])=[O:21])=[CH:14][CH:13]=1)#[N:11]
Reactant: CCOC(=O)C(Nc1ccc(C#N)cc1)c1cc(O)cc(CC)c1
Reactant: OB(O)c1ccccc1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCOC(=O)C(Nc1ccc(C#N)cc1)c1cc(CC)cc(Oc2ccccc2)c1
Reaction time: 60 h
Yield: 81.4 %

Procedure:
Copper(II) acetate (223 mg, 1.20 mmol), phenylboronic acid (164 mg, 1.32 mmol) and molecular sieve 4 Å were added to a solution of the ethyl (RS)-(4-cyano-phenylamino)-(3-ethyl-5-hydroxy-phenyl)-acetate (390 mg, 1.20 mmol) obtained in Example 200.1 in CH2Cl2 (12 ml). Pyridine (476 mg, 6.01 mmol) was added dropwise and the mixture was stirred for 60 h. under an atmosphere of air. The reaction mixture was concentrated and the residue was purified by chromatography (SiO2, CH2Cl2). There were obtained 391 mg (81%) of ethyl (RS)-(4-cyano-phenylamino)-(3-ethyl-5-phenoxy-phenyl)-acetate as beige crystals; MS: 401 ([M+H]+).
Reaction SMILES: CCOC(/N=N/C(OCC)=O)=O.[CH3:13][C:14]([CH3:58])([CH2:56][CH3:57])[CH2:15][C:16]1[N:17]=[C:18]([CH2:40][CH:41]([C:43]2[CH:48]=[CH:47][C:46]([C:49]3[CH:54]=[CH:53][C:52]([F:55])=[CH:51][N:50]=3)=[CH:45][CH:44]=2)O)[N:19]([C:21]([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH:20]=1.[CH3:59][NH:60][S:61]([C:64]1[CH:69]=[CH:68][C:67]([N+:70]([O-:72])=[O:71])=[CH:66][CH:65]=1)(=[O:63])=[O:62].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>O1CCCC1>[CH3:13][C:14]([CH3:58])([CH2:56][CH3:57])[CH2:15][C:16]1[N:17]=[C:18]([CH2:40][CH:41]([N:60]([CH3:59])[S:61]([C:64]2[CH:65]=[CH:66][C:67]([N+:70]([O-:72])=[O:71])=[CH:68][CH:69]=2)(=[O:62])=[O:63])[C:43]2[CH:48]=[CH:47][C:46]([C:49]3[CH:54]=[CH:53][C:52]([F:55])=[CH:51][N:50]=3)=[CH:45][CH:44]=2)[N:19]([C:21]([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH:20]=1
Reactant: CNS(=O)(=O)c1ccc([N+](=O)[O-])cc1
Reactant: CCC(C)(C)Cc1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)c(CC(O)c2ccc(-c3ccc(F)cn3)cc2)n1
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CCC(C)(C)Cc1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)c(CC(c2ccc(-c3ccc(F)cn3)cc2)N(C)S(=O)(=O)c2ccc([N+](=O)[O-])cc2)n1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
DEAD (1.3 mL, 8.2 mmol) was added to an ambient temperature solution of 2-[4-(2,2-dimethylbutyl)-1-trityl-1H-imidazol-2-yl]-1-[4-(5-fluoropyridin-2-yl)phenyl]ethanol (2.5 g, 4.1 mmol), N-methyl-4-nitrobenzenesulfonamide (1.8 g, 8.2 mmol) and triphenylphosphine (2.7 g, 10.2 mmol) in tetrahydrofuran (20 mL). After stirring at ambient temperature overnight, the reaction mixture was concentrated. Chromatography over silica eluting with 0-60% ethyl acetate/hexane afforded N-{2-[4-(2,2-dimethylbutyl)-1-trityl-1H-imidazol-2-yl]-1-[4-(5-fluoropyridin-2-yl)phenyl]ethyl}-N-methyl-4-nitrobenzenesulfonamide.
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[C:10]([NH:12][CH2:13][CH2:14][NH2:15])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.C(N(CC)CC)C.[CH3:23][CH:24]([CH3:31])/[CH:25]=[CH:26]/[S:27](Cl)(=[O:29])=[O:28]>C(#N)C.ClCCl>[CH3:23][CH:24]([CH3:31])/[CH:25]=[CH:26]/[S:27]([NH:15][CH2:14][CH2:13][NH:12][C:10]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=[C:2]([CH3:1])[CH:11]=1)(=[O:29])=[O:28]
Reactant: Cc1cc(NCCN)c2ccccc2n1
Reactant: CC(C)/C=C/S(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: CC#N
Solvent: ClCCl
Product: Cc1cc(NCCNS(=O)(=O)/C=C/C(C)C)c2ccccc2n1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 41.3 %

Procedure:
To a solution of N1-(2-methylquinolin-4-yl)ethane-1,2-diamine (161 mg, 0.800 mmol) and triethylamine (0.350 ml, 2.51 mmol) in acetonitrile (5 ml) was added a solution of (E)-3-methylbut-1-ene-1-sulfonyl chloride (102 mg of step D) in dichloromethane (1 ml). The mixture was stirred 30 minutes at room temperature, concentrated under reduced pressure and the residue was purified by column chromatography over aluminum oxide using a gradient of methanol (2-10%) in dichloromethane to yield 83 mg of an off-white foam (0.25 mmol; 13% over 4 steps).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[CH:4][C:3]=1[C@:12]12[CH2:17][C@H:16]1[CH2:15][NH:14][CH2:13]2.Br[CH2:19][CH2:20][CH2:21][Cl:22]>O1CCCC1.C(N(C(C)C)CC)(C)C>[Cl:22][CH2:21][CH2:20][CH2:19][N:14]1[CH2:15][C@H:16]2[C@:12]([C:3]3[CH:4]=[CH:5][C:6]([C:8]([F:11])([F:10])[F:9])=[CH:7][C:2]=3[F:1])([CH2:17]2)[CH2:13]1
Reactant: Fc1cc(C(F)(F)F)ccc1[C@@]12CNC[C@@H]1C2
Reactant: ClCCCBr
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: Fc1cc(C(F)(F)F)ccc1[C@]12C[C@H]1CN(CCCCl)C2

Procedure:
To a solution of (1S,5R)-1-[2-fluoro-4-(trifluoromethyl)phenyl]-3-azabicyclo[3.1.0]hexane (300 mg) in dry tetrahydrofuran (3 mL), diisopropylethylamine (0.65 mL) and 1-bromo-3-chloropropane (1.01 mL) were added and the resulting mixture was refluxed for 3 hours.
Reaction SMILES: Cl[C:2]1[CH:11]=[C:10]2[C:5]([C:6]([OH:12])=[CH:7][CH:8]=[N:9]2)=[CH:4][N:3]=1.CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.CCN(C(C)C)C(C)C.[CH2:64]([SH:71])[C:65]1[CH:70]=[CH:69][CH:68]=[CH:67][CH:66]=1>O.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].O1CCOCC1>[CH2:64]([S:71][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([OH:12])=[CH:7][CH:8]=[N:9]2)=[CH:4][N:3]=1)[C:65]1[CH:70]=[CH:69][CH:68]=[CH:67][CH:66]=1
Reactant: Oc1ccnc2cc(Cl)ncc12
Reactant: SCc1ccccc1
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: O
Solvent: C1COCCO1
Solvent: CCN(C(C)C)C(C)C
Product: Oc1ccnc2cc(SCc3ccccc3)ncc12
Temperature: 80 °C
Yield: 22.6 %

Procedure:
A screw cap vial was charged with 7-chloro-1,6-naphthyridin-4-ol (0.500 g, 2.77 mmol), Xantphos (0.080 g, 0.138 mmol), tris(dibenzylideneacetone)dipalladium (0.063 g, 0.069 mmol), 1,4-dioxane (5.54 mL) and DIPEA (0.963 mL, 5.54 mmol). The vial was purged with argon, sealed and heated to 80° C. for 10 minutes. The reaction was cooled to room temperature and benzyl mercaptan (0.385 mL, 3.25 mmol) was added and the reaction was continued heating at 80° C. for an additional 30 minutes. The reaction was cooled to room temperature, diluted with water and extracted with DCM (3×). The combined organics were washed with water and brine, dried over magnesium sulfate, filtered and concentrated. The resulting material was concentrated, dissolved in minimal DCM and purified via column chromatography (silica gel 40 g, gradient elution 0 to 50% EtOAc:Heptane) to afford 0.168 g of 7-(benzylthio)-1,6-naphthyridin-4-ol. m/z (ESI) 269.1 (M+H)+.
Reaction SMILES: BrBr.[CH:3]([O:16][C:17]([C:19]1[N:20]2[CH:23]([S:24][CH2:25][C:26]=1[CH:27]=[CH:28]N(C)C)[CH:22]([NH:32][C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])[C:21]2=[O:40])=[O:18])([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[N:41]1[CH:46]=[CH:45][CH:44]=[C:43]([NH:47][C:48]([NH2:50])=[S:49])[CH:42]=1>C(Cl)Cl.O1CCCC1.O>[CH:3]([O:16][C:17]([C:19]1[N:20]2[CH:23]([S:24][CH2:25][C:26]=1[C:27]1[S:49][C:48]([NH:47][C:43]3[CH:42]=[N:41][CH:46]=[CH:45][CH:44]=3)=[N:50][CH:28]=1)[CH:22]([NH:32][C:33]([O:35][C:36]([CH3:38])([CH3:37])[CH3:39])=[O:34])[C:21]2=[O:40])=[O:18])([C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: CN(C)C=CC1=C(C(=O)OC(c2ccccc2)c2ccccc2)N2C(=O)C(NC(=O)OC(C)(C)C)C2SC1
Reactant: NC(=S)Nc1cccnc1
Agent: BrBr
Solvent: O
Solvent: ClCCl
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)NC1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(c3cnc(Nc4cccnc4)s3)CSC12
Reaction time: 0.17 h

Procedure:
A solution of bromine (35.96 g) in dry methylene chloride (40 cc) is added dropwise to a solution, cooled to -75° C., of 2-benzhydryloxycarbonyl-7-t-butoxycarbonylamino-3-(2-dimethylamino-vinyl)-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene, E-form, (107.1 g) in dry tetrahydrofuran (600 cc). The mixture is stirred at this temperature for 10 minutes and pyrid-3-yl-thiourea (30.64 g) dissolved in a mixture (400 cc) of water and tetrahydrofuran (50:50 by volume) is then added. The cooling bath is removed and the mixture is stirred at 20° C. for 17 hours. The brown solution is diluted with ethyl acetate (1.5 liters) and is then washed successively with distilled water (1 liter), a half-saturated sodium bicarbonate solution (1 liter), distilled water (1 liter) and a saturated sodium chloride solution (500 cc). The organic phase is dried over anhydrous magnesium sulphate. After evaporation of the solvent under reduced pressure (30 mm Hg; 4 kPa) at 30° C., the residue is chromatographed on a column (height: 46 cm, diameter: 8.1 cm) of silica gel (0.06-0.20 mm), elution being carried out successively with a mixture (5 liters) of cyclohexane and ethyl acetate (50:50 by volume), a mixture (5 liters) of cyclohexane and ethyl acetate (25:75 by volume) and ethyl acetate (7 liters), 1 liter fractions being collected. Fractions 8 to 17, containing the pure product, are combined and concentrated to a residual volume of 250 cc. A yellow suspension is obtained, which is kept at 5° C. for 12 hours. The solid is filtered off, washed with ethyl ether (3×100 cc) and dried under reduced pressure (1 mm Hg; 0.13 kPa). 2-Benzhydryloxycarbonyl-7-t-butoxycarbonylamino-3-[2-(pyrid-3-yl-amino)-thiazol-5-yl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene (14.5 g) is thus obtained in the form of a yellow powder.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6](=[O:12])C(=O)[NH:8]2)=[CH:4][CH:3]=1.[OH-:13].[Na+].Cl>OO>[NH2:8][C:9]1[CH:10]=[C:2]([Br:1])[CH:3]=[CH:4][C:5]=1[C:6]([OH:12])=[O:13]
Reactant: O=C1Nc2cc(Br)ccc2C1=O
Reactant: [OH-]
Agent: Cl
Agent: OO
Agent: [Na+]
Product: Nc1cc(Br)ccc1C(=O)O
Temperature: 0 °C
Reaction time: 2 h
Yield: 21.1 %

Procedure:
To a 500 mL round bottom flask, 6-bromo-1H-indole-2,3-dione (50 g, 0.2192 mol) and NaOH (20 g in 250 mL water) were added and the reaction vessel was cooled to 0° C. To this reaction mixture, 30% hydrogen peroxide (50 mL) was slowly added. The reaction mixture was stirred at 0° C. for 2 hours. The reaction mixture was then acidified with 2N HCl (pH 6) at 0° C. to afford the solid compound. The solid material was collected by filtration and dried to obtain the title compound (10 g, 21%). 1H NMR (300 MHz, DMSO-d6): δ 7.59 (d, J=8.7 Hz, 1H), 6.96 (d, J=2.1 Hz, 1H), 6.65 (dd, f=8.7 Hz, f′=1.8 Hz, 1H) LC-MS (ESI): Calculated mass: 215.0; Observed mass [M+H]+: 217.9. (RT: 0.83 min).
Reaction SMILES: C([O:4][CH2:5][C:6]([N:8]([C:38]1[CH:43]=[CH:42][C:41]([Cl:44])=[CH:40][CH:39]=1)[C@H:9]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[N:12]([C:19]([C:21]2[CH:26]=[CH:25][C:24]([CH2:27][CH2:28][CH2:29][C:30]([CH3:36])([CH3:35])[C:31]([O:33]C)=[O:32])=[CH:23][CH:22]=2)=[O:20])[C@@H:11]([CH3:37])[CH2:10]1)=[O:7])(=O)C.[OH-].[Na+]>CO.O1CCCC1.O>[Cl:44][C:41]1[CH:40]=[CH:39][C:38]([N:8]([C:6](=[O:7])[CH2:5][OH:4])[C@H:9]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[N:12]([C:19]([C:21]3[CH:26]=[CH:25][C:24]([CH2:27][CH2:28][CH2:29][C:30]([CH3:36])([CH3:35])[C:31]([OH:33])=[O:32])=[CH:23][CH:22]=3)=[O:20])[C@@H:11]([CH3:37])[CH2:10]2)=[CH:43][CH:42]=1
Reactant: COC(=O)C(C)(C)CCCc1ccc(C(=O)N2c3ccccc3[C@H](N(C(=O)COC(C)=O)c3ccc(Cl)cc3)C[C@@H]2C)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: C[C@H]1C[C@@H](N(C(=O)CO)c2ccc(Cl)cc2)c2ccccc2N1C(=O)c1ccc(CCCC(C)(C)C(=O)O)cc1
Temperature: 45 °C
Yield: 69.9 %

Procedure:
Methyl 5-(4-{[(2S,4R)-4-[[(acetyloxy)acetyl](4-chlorophenyl)amino]-2-methyl-3,4-dihydroquinolin-1(2H)-yl]carbonyl}phenyl)-2,2-dimethylpentanoate (100 mg, 0.16 mmol, 1 eq.) was dissolved in methanol/tetrahydrofuran (2/1) (2 ml). A solution of sodium hydroxide (32 mg, 0.81 mmol, 5 eq.) in water (1 ml) was added and reaction mixture heated to 45° C. for 8 h and at room temperature for 20 h. The mixture was concentrated and the residue was acidified with a 1N HCl aqueous solution and extracted with ethyl acetate. The organic layer was washed with brine, dried over magnesium sulfate, filtered and concentrated to give the crude acid. Purification by silica gel chromatography gave pure 5-(4-{[(2S,4R)-4-[(4-chlorophenyl)(glycoloyl)amino]-2-methyl-3,4-dihydroquinolin-1(2H)-yl]carbonyl}phenyl)-2,2-dimethylpentanoic acid (63 mg, 70%).
Reaction SMILES: [O:1]=[C:2]([C@@H:6]1[CH2:20][C@H:19]2[C@@H:9]([CH2:10][C:11]3[C:21]4[C:14](=[CH:15][CH:16]=[CH:17][C:18]2=4)[NH:13][CH:12]=3)[N:8]([CH3:22])[CH2:7]1)[CH2:3][CH:4]=O.Cl.[NH2:24]O>C(O)(=O)C>[CH3:22][N:8]1[C@H:9]2[C@@H:19]([C:18]3[CH:17]=[CH:16][CH:15]=[C:14]4[C:21]=3[C:11]([CH2:10]2)=[CH:12][NH:13]4)[CH2:20][C@@H:6]([C:2]2[O:1][N:24]=[CH:4][CH:3]=2)[CH2:7]1
Reactant: NO
Reactant: CN1C[C@H](C(=O)CC=O)C[C@@H]2c3cccc4[nH]cc(c34)C[C@H]21
Agent: Cl
Solvent: CC(=O)O
Product: CN1C[C@H](c2ccno2)C[C@@H]2c3cccc4[nH]cc(c34)C[C@H]21
Temperature: 25 °C
Reaction time: 20 h

Procedure:
A mixture of 5 g (0.017 mole) of 3-oxo-3-(6-methylergolin-8β-yl)-propionaldehyde in 100 ml of glacial acetic acid and 5 g of hydroxylamine hydrochloride was stirred for 20 hours at room temperature and then poured in ice-cold water. After basification with ammonium hydroxide, the solid which separated was filtered and dissolved in ethyl acetate. The organic solution was washed with brine, dried and the solvent was removed, and the residue was crystallized twice from acetone affording the title compound, 1.8 g; m.p. 132°-134° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([CH:12]([N:14]1C(=O)C3C(=CC=CC=3)C1=O)[CH3:13])[C:6]([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][N:26]=1)=[N:5]2.C(O)C.O.NN>>[F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([CH:12]([NH2:14])[CH3:13])[C:6]([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][N:26]=1)=[N:5]2
Reactant: CC(c1nc2ccc(F)cc2nc1-c1ccccn1)N1C(=O)c2ccccc2C1=O
Agent: NN
Solvent: CCO
Solvent: O
Product: CC(N)c1nc2ccc(F)cc2nc1-c1ccccn1
Temperature: 95 °C
Reaction time: 1 h
Yield: 97.3 %

Procedure:
To a heterogeneous mixture of 2-(1-(6-fluoro-3-(pyridin-2-yl)quinoxalin-2-yl)ethyl)isoindoline-1,3-dione (47.26 g, 118.6 mmol) in ethanol (768.3 ml, 118.6 mmol) was added hydrazine, monohydrate (28.77 ml, 593.1 mmol) and the mixture was stirred at 95° C. for 1 h. The hetereogeneous reaction mixture went into solution after 15 min, but voluminous white ppt followed. After 1 h the mixture was cooled to rt. The precipitate was broken up with a spatula, filtered and washed with EtOAc (3×250 mL portions). The filtrate was concentrated under reduced pressure. The residue was redissolved in EtOAc (600 mL) and water (300 mL). The organic layer was separated and the aqueous layer was extracted with EtOAc (100 mL×3). The combined organic layer were dried over MgSO4, filtered, and concentrated under reduced pressure to give 1-(6-fluoro-3-(pyridin-2-yl)quinoxalin-2-yl)ethanamine (30.95 g, 97.25% yield) as a brown solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 8.75 (dq, J=4.7, 0.9 Hz, 1H), 8.20 (dd, J=9.0, 5.9 Hz, 1H), 7.98-8.11 (m, 2H), 7.91 (dd, J=9.4, 2.7 Hz, 1H), 7.78-7.86 (m, 1H), 7.56-7.61 (m, 1H), 4.66 (q, J=6.7 Hz, 1H), 2.08 (br. S, 2H), 1.35 (d, J=6.7 Hz, 3H). Mass Spectrum (ESI) m/e=269.0 (M+1). [Chiral HPLC] (Chiralpak AD-H column, 0.46×250 mm, 5 um) using 10% isocratic of isopropanol in hexane as eluent: two peaks at 9.350 min and at 10.678 min at 254 nm, (Chiralpak OD-H column, 0.46×250 mm, 5 um) using 10% isocratic of isopropanol in hexane as eluent: two peaks at 9.69 min and at 11.22 min at 254 nm.