Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1](=[C:3]1[CH:16]2[CH:11]([CH2:12][CH2:13][CH2:14][CH2:15]2)[CH2:10][C:9]2[C:4]1=[CH:5][CH:6]=[CH:7][CH:8]=2)O.[H][H].[ClH:19]>O1CCCC1.[Pd]>[ClH:19].[NH2:1][CH:3]1[CH:16]2[CH:11]([CH2:12][CH2:13][CH2:14][CH2:15]2)[CH2:10][C:9]2[C:4]1=[CH:5][CH:6]=[CH:7][CH:8]=2
Reactant: [H][H]
Reactant: ON=C1c2ccccc2CC2CCCCC12
Agent: [Pd]
Agent: Cl
Solvent: C1CCOC1
Product: NC1c2ccccc2CC2CCCCC21
Reaction time: 0.5 h

Procedure:
4.3 Parts of a syn-anti-mixture of 9-oximino-1,2,3,4,4a,9,9a,10-octahydroanthracene were dissolved in 40 ml of tetrahydrofuran and 8.7 ml of methanolic hydrochloric acid. 1.3 Parts of a 10% palladium-on-carbon catalyst were added and the mixture was hydrogenated with 896 ml gaseous hydrogen at 30-35° C. and normal pressure within 30 minutes. The catalyst was filtered off, and the filtrate concentrated. 4 Parts of 9-amino-1,2,3,4,4a,9,9a,10-octahydroanthracene hydrochloride, mp. 240-245° C., were obtained. The hydrochloride was dissolved in water, and sodium hydroxide was added to adjust the pH-value to pH 8. The alkaline solution was extracted with ether. The combined etheral phases were dried with Na2SO4, filtered and concentrated. 2.8 Parts (70% of theory) of 9-amino-1,2,3,4,4a,9,9a,10-octahydroanthracene (int. 13), mp. 37-39° C., were obtained. The amine-product consists of a mixture of at least 3 stereochemical isomers.
Reaction SMILES: [CH3:1][C:2]([C:5]1[CH:6]=[C:7]([S:16][C@@H:17]2[CH2:21][O:20][CH2:19][C@H:18]2[OH:22])[CH:8]=[C:9]([C:12]([CH3:15])([CH3:14])[CH3:13])[C:10]=1[OH:11])([CH3:4])[CH3:3].Cl[CH2:24][C:25]([OH:27])=[O:26].[K].Cl>C(O)(C)(C)C>[CH3:15][C:12]([C:9]1[CH:8]=[C:7]([S:16][C@@H:17]2[CH2:21][O:20][CH2:19][C@H:18]2[O:22][CH2:24][C:25]([OH:27])=[O:26])[CH:6]=[C:5]([C:2]([CH3:1])([CH3:3])[CH3:4])[C:10]=1[OH:11])([CH3:13])[CH3:14]
Reactant: CC(C)(C)c1cc(S[C@@H]2COC[C@H]2O)cc(C(C)(C)C)c1O
Reactant: O=C(O)CCl
Agent: Cl
Agent: [K]
Solvent: CC(C)(C)O
Product: CC(C)(C)c1cc(S[C@@H]2COC[C@H]2OCC(=O)O)cc(C(C)(C)C)c1O
Temperature: 25 °C

Procedure:
The compound of Example 2 (3.6 g, 0.011 mole) and chloroacetic acid (2.04 g, 0.022 mole) were added to t-butyl alcohol (40 ml) to which had been added potassium (1.39 g, 0.033 mole) and the reaction mixture was refluxed for 36 hours. The reaction mixture was cooled to room temperature, and 1 N hydrochloric acid (50 ml) was added slowly. The reaction mixture was extracted twice with 100 ml of diethyl ether. The combined diethyl ether extracts were washed with saturated sodium bicarbonate (2×100 ml), 1 N hydrochloric acid (10 ml) and brine (20 ml) dried over anhydrous sodium sulfate, filtered and concentrated in a rotary evaporator to give the crude product as an oil. The product was purified by silica gel chromatography and recrystallized from ethyl acetate-hexane. The structure was supported by NMR and infrared spectroscopy and elemental analysis.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([S:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])=[CH:4][CH:3]=1.[Li]CCCC.CN([CH:26]=[O:27])C>C1COCC1>[CH2:9]([S:8][C:5]1[CH:6]=[CH:7][C:2]([CH:26]=[O:27])=[CH:3][CH:4]=1)[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17]
Reactant: CCCCCCCCCSc1ccc(Br)cc1
Reactant: CN(C)C=O
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CCCCCCCCCSc1ccc(C=O)cc1
Temperature: 0 °C
Yield: 89 %

Procedure:
To a solution of 3.15 g (10.0 mmol) of 1-bromo-4-(nonylthio)benzene in 50 mL anhydrous THF was slowly added 9.4 mL of n-BuLi (1.6 M in hexanes, 15 mmol) at −50° C. The mixture was aged at the same temperature for 1 h before the addition of 2.3 mL of anhydrous DMF. The reaction mixture was allowed to warm to 0° C. and was quenched with 2 N HCl to pH=1. The layers were separated and the aqueous layer was extracted with ethyl acetate (50 mL×2). The combined organic layer and extractions were washed with water and concentrated to oil. Flash chromatography on a Biotage 40M cartridge using 5% ethyl acetate/hexanes afforded 2.35 g (89%) of the title compound as light yellow oil: 1H NMR (500 MHz) δ 0.91 (t, J=7.0, 3H), 1.30-1.76 (m, 14H), 3.03 (t, J=7.4, 2H), 7.37 (d, J=8.5, 2H), 7.78 (d, J=8.5, 2H), 9.95 (s, 1H); LC-1: 4.8 min; ESI-MS 265 (M+H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([C:17]([O:19]C)=[O:18])[CH:15]=2)[NH:10][N:9]=1.Cl>CO.O1CCCC1.[OH-].[Na+]>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([C:17]([OH:19])=[O:18])[CH:15]=2)[NH:10][N:9]=1
Reactant: COC(=O)c1ccc2[nH]nc(-c3ccccc3F)c2c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: O=C(O)c1ccc2[nH]nc(-c3ccccc3F)c2c1
Temperature: 70 °C

Procedure:
A total of 1.6 g of methyl 3-(2-fluorophenyl)-1H-5-indazolecarboxylate was dissolved in 15 ml of a 1:1 solvent mixture of methanol and tetrahydrofuran, 2 ml of 5 N aqueous sodium hydroxide solution was added, followed by heating at 70° C. for 6 hours. After cooling to room temperature, the reaction mixture was added with diluted hydrochloric acid and was extracted with ethyl acetate for two times. The organic layer was washed with water, dried over anhydrous magnesium sulfate and the solvent was evaporated, to give 1.5 9 of the title compound as a colorless powder.
Reaction SMILES: Br[C:2]1[CH:12]=[CH:11][C:5]2[N:6]([CH3:10])[C:7](=[O:9])[NH:8][C:4]=2[C:3]=1[S:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.[CH3:20][N:21]1[CH:26]=[C:25](B2OC(C)(C)C(C)(C)O2)[C:24]2[CH:36]=[CH:37][N:38]([S:39]([C:42]3[CH:47]=[CH:46][C:45]([CH3:48])=[CH:44][CH:43]=3)(=[O:41])=[O:40])[C:23]=2[C:22]1=[O:49]>>[CH3:10][N:6]1[C:5]2[CH:11]=[CH:12][C:2]([C:25]3[C:24]4[CH:36]=[CH:37][N:38]([S:39]([C:42]5[CH:47]=[CH:46][C:45]([CH3:48])=[CH:44][CH:43]=5)(=[O:41])=[O:40])[C:23]=4[C:22](=[O:49])[N:21]([CH3:20])[CH:26]=3)=[C:3]([S:13][C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[C:4]=2[NH:8][C:7]1=[O:9]
Reactant: Cn1c(=O)[nH]c2c(Sc3ccccc3)c(Br)ccc21
Reactant: Cc1ccc(S(=O)(=O)n2ccc3c(B4OC(C)(C)C(C)(C)O4)cn(C)c(=O)c32)cc1
Product: Cc1ccc(S(=O)(=O)n2ccc3c(-c4ccc5c([nH]c(=O)n5C)c4Sc4ccccc4)cn(C)c(=O)c32)cc1

Procedure:
This compound was synthesized according to the procedure of Example 10, Step 5, using 5-bromo-1-methyl-4-(phenylthio)-1,3-dihydro-2H-benzimidazol-2-one and 6-methyl-1-[(4-methylphenyl)sulfonyl]-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one as the starting materials. LCMS calculated for C29H25N4O4S2 (M+H)+: m/z=557.1. found: 557.0.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[OH:9].[CH2:10](Br)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[CH2:10]([O:9][C:3]1[CH:4]=[CH:5][C:6]([F:8])=[CH:7][C:2]=1[F:1])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: BrCc1ccccc1
Reactant: Oc1ccc(F)cc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: Fc1ccc(OCc2ccccc2)c(F)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 24.9 %

Procedure:
To 2,4-difluoro-phenol (35, 7.60 g, 0.0584 mol) in N,N-dimethylformamide (50.0 mL) were added benzyl bromide (8.0 mL, 0.067 mol) and potassium carbonate (9.00 g, 0.0651 mol) under an atmosphere of nitrogen. The reaction was stirred at room temperature overnight. The reaction was poured into water and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated and purified by silica gel column chromatography eluting with 20% ethyl acetate in hexane to give the compound as white solid (525, 3.20 g, 25%).
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5]([C:7](=[N:33][O:34][CH3:35])[C:8]([NH:10][C@H:11]2[C@@H:14]([C:15]([O:17]CC3C=CC([N+]([O-])=O)=CC=3)=[O:16])[N:13]([S:28]([O-:31])(=[O:30])=[O:29])[C:12]2=[O:32])=[O:9])[N:6]=1.[Na+].C(=O)([O-])O.[Na+]>O1CCCC1.O.[Pd]>[NH2:1][C:2]1[S:3][CH:4]=[C:5]([C:7](=[N:33][O:34][CH3:35])[C:8]([NH:10][C@H:11]2[C@@H:14]([C:15]([OH:17])=[O:16])[N:13]([S:28]([OH:31])(=[O:29])=[O:30])[C:12]2=[O:32])=[O:9])[N:6]=1
Reactant: CON=C(C(=O)N[C@@H]1C(=O)N(S(=O)(=O)[O-])[C@@H]1C(=O)OCc1ccc([N+](=O)[O-])cc1)c1csc(N)n1
Agent: [Pd]
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CON=C(C(=O)N[C@@H]1C(=O)N(S(=O)(=O)O)[C@@H]1C(=O)O)c1csc(N)n1

Procedure:
In a mixture of 10 ml of tetrahydrofuran and 10 ml of water is dissolved 155 mg of sodium cis-3-[2-(2-amino-4-thiazolyl)-2-methoxyiminoacetamido]-4-(4-nitrobenzyloxycarbonyl)-2-oxoazetidine-1-sulfonate (syn-isomer). To the solution is added 145 mg of 10% palladium-on-carbon, and the mixture is subjected to catalytic reduction at ambient temperature under normal pressure with stirring. Three hours later, 10 ml of an aqueous solution of 25 mg of sodium hydrogen carbonate is added to the reaction mixture. The catalyst is removed by filtration, and the filtrate is washed with ethyl acetate, and concentrated under reduced pressure. The concentrate is purified by column chromatography on Amberlite XAD-II, followed by lyophilization to give cis-3-[2-(2-amino-4-thiazolyl)-2-methoxyiminoacetamido]-4-carboxy-1-sulfo-2-oxoazetidine.disodium salt (syn-isomer).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([CH2:10][C:11]([NH:13][N:14]=[C:15]1[CH2:20][CH2:19][N:18]([C:21]2[CH:26]=[CH:25][N:24]=[CH:23][CH:22]=2)[CH2:17][CH2:16]1)=[O:12])[CH3:9])=[O:7])([CH3:4])([CH3:3])[CH3:2].C(O)(=O)C.C([BH3-])#N.[Na+]>CO>[C:1]([O:5][C:6]([N:8]([CH2:10][C:11]([NH:13][NH:14][CH:15]1[CH2:20][CH2:19][N:18]([C:21]2[CH:22]=[CH:23][N:24]=[CH:25][CH:26]=2)[CH2:17][CH2:16]1)=[O:12])[CH3:9])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CN(CC(=O)NN=C1CCN(c2ccncc2)CC1)C(=O)OC(C)(C)C
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: CN(CC(=O)NNC1CCN(c2ccncc2)CC1)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 99.4 %

Procedure:
The resultant 1-[(tert-butoxycarbonyl)sarcosinyl]-2-[1-(4-pyridyl)-4-piperidinylidene]hydrazine (1.0 g) was dissolved in methanol (20 ml) and treated with acetic acid (665 mg) with cooling on ice, followed by sodium cyanoborohydride (261 mg) and stirred at room temperature for 30 minutes. The reaction mixture was concentrated and the residue was dissolved in dichloromethane, washed with aqueous sodium bicarbonate and brine, dried and concentrated to obtain 1-[(tert-butoxycarbonyl)sarcosinyl]-2-[1-(4-pyridyl)-4-piperidinyl]hydrazine (1.0 g) as a colorless oil.
Reaction SMILES: [CH:1]#[C:2][CH3:3].[Br:4][C:5]1[CH:6]=[C:7](I)[C:8]([NH2:11])=[N:9][CH:10]=1.C(N(CC)CC)C>C1COCC1.[Cu]I>[Br:4][C:5]1[CH:6]=[C:7]([C:1]#[C:2][CH3:3])[C:8]([NH2:11])=[N:9][CH:10]=1
Reactant: Nc1ncc(Br)cc1I
Reactant: C#CC
Agent: [Cu]I
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC#Cc1cc(Br)cnc1N
Temperature: -40 °C
Reaction time: 0.5 h

Procedure:
Propyne (28 g, 700 mmol) was condensed into a pre-weighed flask cooled to ca. −40° C. containing THF (150 mL). The solution was added via cannula to a cooled (0-5° C.), degassed mixture of 5-bromo-3-iodo-pyridin-2-ylamine (139 g, 465 mmol), bis(triphenylphosphine)dichloropalladium(0) (16.3 g, 23.2 mmol), copper (I) iodide (5.3 g, 27.9 mmol) and triethylamine (141 g, 194 mL, 1.4 mol) in THF (1.25 L). The mixture was stirred at 0-5° C. for 30 minutes then for a further 30 minutes at ambient temperature. The solid was removed by filtration and the cake washed with THF. The filtrate was diluted with ethyl acetate and extracted with 2M hydrochloric acid (×3). The combined acid extract was washed with diethyl ether and then made basic by careful addition of potassium carbonate then extracted with diethyl ether (×3). The combined organic layer was dried (Na2SO4), filtered and evaporated to afford the title compound as a buff solid (91 g, 93%). 1H NMR (400 MHz, CDCl3): 8.01 (d, J=2.4 Hz, 1H), 7.55 (d, J=2.4 Hz, 1H), 4.96 (s, 2H), 2.11 (s, 3H).
Reaction SMILES: Cl[C:2]1[C:7]2[C:8]([I:30])=[N:9][N:10]([C:11]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[C:6]=2[CH:5]=[CH:4][N:3]=1.[CH3:31][OH:32].C[O-].[Na+].O>C1COCC1>[I:30][C:8]1[C:7]2[C:2]([O:32][CH3:31])=[N:3][CH:4]=[CH:5][C:6]=2[N:10]([C:11]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[N:9]=1
Reactant: Clc1nccc2c1c(I)nn2C(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: CO
Agent: C[O-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: COc1nccc2c1c(I)nn2C(c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 50 °C
Reaction time: 2 h

Procedure:
To a solution of 4-chloro-3-iodo-1-trityl-1H-pyrazolo[4,3-c]pyridine (1.7 g) in THF (20 mL) was added sodium methoxide methanol solution (1.5 M, 2.7 mL) at room temperature, and the mixture was stirred at 50° C. for 2 hr. To the reaction mixture was added water, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give the title compound (1.6 g).
Reaction SMILES: [C:1]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1[NH:16][C:17]1[CH:22]=[CH:21][C:20]([OH:23])=[CH:19][C:18]=1[CH3:24])=[CH:13][CH:12]=[CH:11][C:10]=2[CH:25]=[O:26])(=[O:5])[CH2:2][CH2:3][CH3:4].[CH3:27][Mg]I>O1CCCC1.CCOCC>[C:1]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1[NH:16][C:17]1[CH:22]=[CH:21][C:20]([OH:23])=[CH:19][C:18]=1[CH3:24])=[CH:13][CH:12]=[CH:11][C:10]=2[CH:25]([OH:26])[CH3:27])(=[O:5])[CH2:2][CH2:3][CH3:4]
Reactant: C[Mg]I
Reactant: CCCC(=O)c1cnc2c(C=O)cccc2c1Nc1ccc(O)cc1C
Solvent: C1CCOC1
Solvent: CCOCC
Product: CCCC(=O)c1cnc2c(C(C)O)cccc2c1Nc1ccc(O)cc1C
Temperature: 25 °C

Procedure:
3-Butyryl-4-(4-hydroxy-2-methylphenylamino)quinoline-8-carbaldehyde (2.0 g, 6 mmol) was stirred in dry tetrahydrofuran (200 ml) at j-30° C. and treated with a solution of methylmagnesium iodide in ether. Cooling was removed and the mixture was allowed to warm to room temperature. The mixture was washed with saturated ammonium chloride solution (×2) and the aqueous extracted with dichloromethane. The combined organics were dried and evaporated to afford a brown oil which was chromatographed (silica gel, 1% methanol in dichloromethane) to return aldehyde starting material (0.16 g ) and give 3-butyryl-4-(4-hydroxy-2-methyl-phenylamino)-8-(1-hydroxyethyl)quinoline as yellow crystals from ether-petrol (0.45 g, 21.5%), m.p. 182°-4° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][CH3:10])[N:6]=[C:5]([O:11][C:12]2[CH:13]=[CH:14][CH:15]=[C:16]3[C:21]=2[C:19](=[O:20])[O:18][CH:17]3O)[N:4]=1.[CH:23]([Mg]Cl)=[CH2:24].Cl>O1CCCC1>[CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][CH3:10])[N:6]=[C:5]([O:11][C:12]2[CH:13]=[CH:14][CH:15]=[C:16]3[C:21]=2[C:19](=[O:20])[O:18][CH:17]3[CH:23]=[CH2:24])[N:4]=1
Reactant: COc1cc(OC)nc(Oc2cccc3c2C(=O)OC3O)n1
Reactant: C=C[Mg]Cl
Agent: Cl
Solvent: C1CCOC1
Product: C=CC1OC(=O)c2c(Oc3nc(OC)cc(OC)n3)cccc21
Temperature: 25 °C
Reaction time: 16 h

Procedure:
3.6 g of 7-[(4,6-dimethoxy-pyrimidin-2-yl)oxy]-3-hydroxy-phthalide (see Example 84) are placed in 60 ml of absolute tetrahydrofuran at -45° C., and the solution is treated within 10 minutes with 18 ml of a 2M solution of vinylmagnesium chloride solution in tetrahydrofuran. The reaction solution is then stirred for approximately 16 hours at room temperature, a further 6 ml of vinyl-magnesium chloride solution are added and the reaction solution is heated at reflux temperature for a further hour. When it has cooled, the reaction solution is acidified with 1N hydrochloric acid and freed of tetrahydrofuran in a rotary evaporator. The aqueous phase is then extracted with tert-butyl methyl ether, and the organic phase is washed and concentrated by evaporation under reduced pressure. Silica gel chromatography using ethyl acetate/n-hexane (2:3) as eluant yields pure 7-[(4,6-dimethoxy-pyrimidin-2-yl)oxy]-3-vinyl-phthalide, m.p. 94°-97° C.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[N:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH:11]=[O:12].[BH4-].[Na+]>CO.C1COCC1>[N:1]1[C:10]2[C:5](=[N:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH2:11][OH:12]
Reactant: O=Cc1ccc2ncccc2n1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Product: OCc1ccc2ncccc2n1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 78 %

Procedure:
To a solution of 1,5-naphthyridine-2-carbaldehyde (8-3) (1.0 g, 6.32 mmol) in MeOH (15 mL) and THF (15 mL) was added NaBH4 (84 mg, 2.21 mmol). The reaction mixture was stirred at 0° C. for 0.5 h. The mixture was concentrated and purified by chromatography on silica gel to afford the title compound (790 mg).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:8]2[C:14](=O)[N:13]([C@@H:16]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[CH3:17])[CH2:12][CH2:11][CH2:10][O:9]2)[CH:5]=[CH:6][CH:7]=1.CO.[OH-].[Na+]>O1CCCC1>[Br:1][C:2]1[CH:3]=[C:4]([CH:8]2[CH2:14][N:13]([C@@H:16]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[CH3:17])[CH2:12][CH2:11][CH2:10][O:9]2)[CH:5]=[CH:6][CH:7]=1
Reactant: C[C@H](c1ccccc1)N1CCCOC(c2cccc(Br)c2)C1=O
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: C[C@H](c1ccccc1)N1CCCOC(c2cccc(Br)c2)C1
Temperature: 0 °C
Yield: 98.6 %

Procedure:
To a solution of 2-(3-bromo-phenyl)-4-((R)-1-phenyl-ethyl) -[1,4]oxazepan-3-one (diastereomer 1) (9.39 g, 25.1 mmol) in tetrahydrofuran (75 ml) was added 1.0M-borane-tetrahydrofuran complex in tetrahydrofuran (75.0 ml, 75.0 mmol) at 0° C. The mixture was refluxed for 4 hours. The mixture was cooled to 0° C. and methanol (100 ml) and 6.0 N aqueous sodium hydroxide (100 ml) was added carefully. The mixture was refluxed for 2 hours and cooled to room temperature. The solvent was removed under reduced pressure. The residue was partitioned between water and chloroform. The organic layer was washed with brine, dried over sodium sulfate, concentrated in vacuo. The residue was purified by silica gel column chromatography (eluant; hexane/ethyl acetate=4/1) to afford diastereomerically pure 2-(3-bromophenyl)-4-((R)-1-phenyl-ethyl)-[1,4]oxazepane as colorless oil (8.92 g, 99%).
Reaction SMILES: [CH3:1][O:2][C:3]([C@@H:5]1[CH2:13][C:8]2([S:12][CH2:11][CH2:10][S:9]2)[CH2:7][N:6]1C(OCC1C=CC=CC=1)=O)=[O:4].C(OCC)C.[BrH:29]>C(O)(=O)C>[BrH:29].[CH3:1][O:2][C:3]([C@@H:5]1[CH2:13][C:8]2([S:9][CH2:10][CH2:11][S:12]2)[CH2:7][NH:6]1)=[O:4]
Reactant: COC(=O)[C@@H]1CC2(CN1C(=O)OCc1ccccc1)SCCS2
Agent: Br
Solvent: CCOCC
Solvent: CC(=O)O
Product: COC(=O)[C@@H]1CC2(CN1)SCCS2
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Dissolve 3.0 g of 7-benzyloxycarbonyl-1,4-dithia-7-azaspiro[4.4]nonane-8(S)-carboxylic acid methyl ester (3.0 g) in 20 ml of 20% hydrobromic acid in glacial acetic acid and stir the mixture at room temperature for two hours. Add the mixture dropwise to diethyl ether at 0°-5° to give 1,4-dithia-7-azaspiro[4.4]nonane-8(S)-carboxylic acid methyl ester hydrobromide, a brown solid m.g. 156°-158°.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[O:12][N:11]=[CH:10][C:9]=2[CH2:13][CH2:14][C:15]([OH:17])=[O:16])[S:5][C:6]=1[Cl:7].S(=O)(=O)(O)O.[CH3:23]O>>[Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[O:12][N:11]=[CH:10][C:9]=2[CH2:13][CH2:14][C:15]([O:17][CH3:23])=[O:16])[S:5][C:6]=1[Cl:7]
Reactant: O=C(O)CCc1cnoc1-c1cc(Cl)c(Cl)s1
Reactant: CO
Agent: O=S(=O)(O)O
Product: COC(=O)CCc1cnoc1-c1cc(Cl)c(Cl)s1
Yield: 80 %

Procedure:
To a solution of 3-[5-(4,5-dichloro-2-thienyl)-4-isoxazolyl]propionic acid (1.60 g) in methanol (30 ml) was added conc. sulfuric acid (1 ml) and the mixture was heated under reflux for 1 hr. The reaction mixture was concentrated, iced water was poured on the residue and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried (MgSO4) and concentrated. The residue was subjected to silica gel column chromatography, and crystals (1.34 g, yield 80%) of methyl 3-[5-(4,5-dichloro-2-thienyl)-4-isoxazolyl]propionate was obtained from a fraction eluted with ethyl acetate-hexane (1:7, volume ratio). The crystals were recrystallized from diethyl ether-hexane to give a colorless needle. melting point: 49–50° C.
Reaction SMILES: Cl.C[O:3][C:4](=[O:16])[C@@H:5]([NH2:15])[CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([C:13]#[N:14])[CH:8]=1.[Cl:17][C:18]1[CH:26]=[CH:25][C:21]([C:22](O)=[O:23])=[C:20]([NH:27][S:28]([C:31]2[C:32]3[N:33]=[CH:34][CH:35]=[N:36][C:37]=3[CH:38]=[CH:39][CH:40]=2)(=[O:30])=[O:29])[CH:19]=1>>[Cl:17][C:18]1[CH:26]=[CH:25][C:21]([C:22]([NH:15][C@@H:5]([CH2:6][C:7]2[CH:12]=[CH:11][CH:10]=[C:9]([C:13]#[N:14])[CH:8]=2)[C:4]([OH:3])=[O:16])=[O:23])=[C:20]([NH:27][S:28]([C:31]2[C:32]3[N:33]=[CH:34][CH:35]=[N:36][C:37]=3[CH:38]=[CH:39][CH:40]=2)(=[O:29])=[O:30])[CH:19]=1
Reactant: COC(=O)[C@@H](N)Cc1cccc(C#N)c1
Reactant: O=C(O)c1ccc(Cl)cc1NS(=O)(=O)c1cccc2nccnc12
Agent: Cl
Product: N#Cc1cccc(C[C@H](NC(=O)c2ccc(Cl)cc2NS(=O)(=O)c2cccc3nccnc23)C(=O)O)c1

Procedure:
(S)-2-(tert-Butoxycarbonylamino)-3-(3-cyano-phenyl)-propionic acid was treated as in EXAMPLE 2, Part A, to produce (S)-2-amino-3-(3-cyano-phenyl)-propionic acid methyl ester hydrochloride as a white solid. This ester was coupled to 4-chloro-2-(quinoxaline-5-sulfonylamino)-benzoic acid as in EXAMPLE 1, Part C. The resulting methyl ester was hydrolyzed as in EXAMPLE 2, Part E, to afford the title compound. HPLC: RT=8.94 min. MS (ESI−): mass calcd. for C25H18ClN5O5S, 535.07; m/z found, 534/536 [M−H]−. 1H NMR (500 MHz, CDCl3): 11.01 (s, 1H), 9.03 (d, J=1.7, 1H), 8.94 (d, J=1.7, 1H), 8.57 (d, J=7.4, 1H), 8.33 (d, J=8.5, 1H), 7.90 (t, 7.5, 1H), 7.74 (d, J=1.9, 1H), 7.57-7.55 (m, 1H), 7.47-7.41 (m, 3H), 7.12 (d, J=8.4, 1H), 6.93 (dd, J=5.6, 1.9, 1H), 6.40 (d, J=7.3, 1H), 5.02-4.98 (m, 1H), 3.36 (dd, J=14.1, 6.0, 1H), 3.25 (dd, J=14.2, 5.6, 1H).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[CH2:5]2.Cl.[CH2:13]([CH:20]1[CH2:25][CH2:24][N:23]([CH:26]([CH3:30])[C:27](O)=[O:28])[CH2:22][CH2:21]1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>C(OCC)C>[CH2:13]([CH:20]1[CH2:21][CH2:22][N:23]([CH:26]([CH3:30])[C:27]([NH:1][C:2]2[CH:3]=[C:4]3[C:8](=[CH:9][CH:10]=2)[NH:7][C:6](=[O:11])[CH2:5]3)=[O:28])[CH2:24][CH2:25]1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: Nc1ccc2c(c1)CC(=O)N2
Reactant: CC(C(=O)O)N1CCC(Cc2ccccc2)CC1
Agent: Cl
Solvent: CCOCC
Product: CC(C(=O)Nc1ccc2c(c1)CC(=O)N2)N1CCC(Cc2ccccc2)CC1

Procedure:
The title compound is prepared from 5-amino-1,3-dihydro-indol-2-one and 2-(4-benzyl-piperidin-1-yl)-propionic acid hydrochloride (Example 161b) according to the method described in Example 161c. Melting Point: 153-155° C. (diethylether).
Reaction SMILES: C([C:4]1[S:8][C:7]2[S:9][C:10]([C:12]([C:14]3[CH:15]=[C:16]([CH:20]([CH2:24][CH2:25][CH2:26][CH3:27])[C:21]([OH:23])=[O:22])[CH:17]=[CH:18][CH:19]=3)=[O:13])=[CH:11][C:6]=2[CH:5]=1)(O)=O.Cl>N1C2C(=CC=CC=2)C=CC=1.[Cu]>[S:9]1[C:7]2[S:8][CH:4]=[CH:5][C:6]=2[CH:11]=[C:10]1[C:12]([C:14]1[CH:15]=[C:16]([CH:20]([CH2:24][CH2:25][CH2:26][CH3:27])[C:21]([OH:23])=[O:22])[CH:17]=[CH:18][CH:19]=1)=[O:13]
Reactant: CCCCC(C(=O)O)c1cccc(C(=O)c2cc3cc(C(=O)O)sc3s2)c1
Agent: [Cu]
Agent: Cl
Solvent: c1ccc2ncccc2c1
Product: CCCCC(C(=O)O)c1cccc(C(=O)c2cc3ccsc3s2)c1
Temperature: 165 °C
Yield: 106 %

Procedure:
2-{3-(5-Carboxy-thieno[2,3-b]thien-2-yl)carbonyl-phenyl}hexanoic acid (12.5 g) and copper powder (1 g) are suspended in quinoline (100 cc) and heated at 165° C. for 35 minutes. The reaction mixture is then heated to 190° C. over a period of 10 minutes, then cooled, poured into a mixture of 12 N concentrated aqueous hydrochloric acid (120 cc) and distilled water (400 cc), and extracted three times with methylene chloride (total 300 cc). The combined methylene chloride phases are washed twice with a 2 N aqueous solution of hydrogen chloride (total 60 cc), then three times with distilled water (total 90 cc), dried over anhydrous sodium sulphate in the presence of decolourizing charcoal (0.5 g), filtered and evaporated. Crude 2-{3-(thieno[2,3-b]thien-2-yl)carbonyl-phenyl}hexanoic acid (11.8 g) is thus obtained.