Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[CH2:2][C:3](=[O:7])[CH:4]([CH3:6])[CH3:5].[Cl:8][C:9]1[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][CH:10]=1.C(=O)([O-])[O-].[K+].[K+]>C(C(C)=O)C>[Cl:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH2:2][C:3](=[O:7])[CH:4]([CH3:6])[CH3:5])=[CH:11][CH:10]=1
Reactant: CC(C)C(=O)CBr
Reactant: Oc1ccc(Cl)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: CC(C)C(=O)COc1ccc(Cl)cc1
Yield: 73.8 %

Procedure:
338 g (2.77 mols) of 1-bromo-3-methyl-butan-2-one were rapidly added dropwise to a mixture of 357 g (2.78 mols) of 4-chlorophenol and 483 g (3.5 mols) of potassium carbonate in 2.5 liters of methyl ethyl ketone. The mixture was heated under reflux for 16 hours and then filtered. The filtrate was concentrated by stripping off the solvent under reduced pressure, the residue was taken up in methylene chloride and the organic phase was washed twice with 2N aqueous sodium hydroxide solution, once with water and once with saturated aqueous sodium chloride solution. After drying, the organic phase was concentrated by stripping off the solvent. The residue which remained was distilled under a high vacuum. 435 g (74% of theory) of 1-(4-chlorophenoxy)-3-methyl-butan-2-one were obtained in this manner.
Reaction SMILES: [SH:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][CH:3]=1.[H-].[Na+].Cl[CH:15]([C:22]1[C:27]([CH3:28])=[CH:26][C:25]([CH3:29])=[CH:24][C:23]=1[CH3:30])[CH2:16][N:17]1[CH:21]=[CH:20][N:19]=[CH:18]1>CN(C)C=O>[CH3:28][C:27]1[CH:26]=[C:25]([CH3:29])[CH:24]=[C:23]([CH3:30])[C:22]=1[CH:15]([S:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:10][CH:11]=1)[CH2:16][N:17]1[CH:21]=[CH:20][N:19]=[CH:18]1
Reactant: COC(=O)c1ccc(S)cc1
Reactant: Cc1cc(C)c(C(Cl)Cn2ccnc2)c(C)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(SC(Cn2ccnc2)c2c(C)cc(C)cc2C)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 80.3 %

Procedure:
947 mg of methyl 4-mercaptobenzoate were dissolved in 6 ml of dry dimethylformamide, and 245 mg of a 55% w/w suspension of sodium hydride in mineral oil were added, whilst ice-cooling, to the resulting solution. The mixture was then stirred at room temperature for 30 minutes. 1.4 g of 1-[2-chloro-2-(2,4,6-trimethylphenyl)ethyl]imidazole dissolved in 7 ml of dry dimethylformamide was added to the solution, and the mixture was then heated at 60° to 65° C. for 20 hours. At the end of this time, the resulting mixture was treated and purified similarly to the procedure described in Example 1, to give 1.72 g of the title compound as an oil.
Reaction SMILES: [NH2:1][CH:2]([CH2:28][C:29]1[CH:34]=[CH:33][C:32]([C:35]#[N:36])=[CH:31][CH:30]=1)[C:3]([N:5]1[CH2:10][CH2:9][CH:8]([N:11]([CH:25]2[CH2:27][CH2:26]2)[S:12]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([C:21]([F:24])([F:23])[F:22])[CH:16]=2)(=[O:14])=[O:13])[CH2:7][CH2:6]1)=[O:4].CI.[CH3:39]N(C=O)C.[H-].[Na+]>C(OCC)(=O)C>[C:35]([C:32]1[CH:31]=[CH:30][C:29]([CH2:28][CH:2]([NH:1][CH3:39])[C:3]([N:5]2[CH2:6][CH2:7][CH:8]([N:11]([CH:25]3[CH2:26][CH2:27]3)[S:12]([C:15]3[CH:20]=[CH:19][CH:18]=[C:17]([C:21]([F:22])([F:24])[F:23])[CH:16]=3)(=[O:13])=[O:14])[CH2:9][CH2:10]2)=[O:4])=[CH:34][CH:33]=1)#[N:36]
Reactant: CN(C)C=O
Reactant: N#Cc1ccc(CC(N)C(=O)N2CCC(N(C3CC3)S(=O)(=O)c3cccc(C(F)(F)F)c3)CC2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CI
Solvent: CCOC(C)=O
Product: CNC(Cc1ccc(C#N)cc1)C(=O)N1CCC(N(C2CC2)S(=O)(=O)c2cccc(C(F)(F)F)c2)CC1

Procedure:
A mixture of N-{1-[2-amino-3-(4-cyanophenyl)propionyl]piperidin-4-yl}-N-cyclopropyl-3-trifluoromethylbenzenesulfonamide (see Example 13, 300 mg, 0.58 mmol), MeI (830 mg, 5.9 mmol), and DMF (5 mL) was treated with NaH (67 mg, 60% mineral oil, 1.8 mmol) at room temperature for 20 hours. The reaction mixture was diluted with ethyl acetate (20 mL), and washed with water (5 mL) and brine (5 mL). The organic layer was evaporated and the residue was purified by column (silica gel, EtOAc/hexane 1/1) to give the title compound N-{1-[3-(4-cyanophenyl)-2-methylamino-propionyl]piperidin-4-yl}-N-cyclopropyl-3-trifluoromethyl-benzenesulfonamide (26) as free base, which was dissolved in 1,4-dioxane (4 mL), and treated with HCl solution (4N in 1,4-dioxane, 1 mL). The resulting mixture was triturated with ethyl ether (10 mL), and the precipitated material was collected by filtration, washed with ethyl ether (2×5 mL), and dried under vacuum for 12 hours to afford the title compound 26 as a HCl-salt (white solid, 0.2 g, yield 65%). 1H NMR (HCl-salt, CD3OD): δ 8.12-8.19 (m, 2H), 8.03 (d, 1H, J=9.2 Hz), 7.86 (dd, 1H, J=7.7 & 7.8 Hz), 7.77 (dd, 2H, J=4.3 & 8.1 Hz), 7.49 (dd, 2H, J=1.9 & 8.3 Hz), 4.76-4.79 (m, 1H), 4.52-4.59 (m, 1H), 3.96-4.06 (m, 1H), 3.6-3.7 (m, 1H), 3.34-3.38 (m, 1H), 3.06-3.14 (m, 2H), 2.68-2.72 (m, 3H, NCH3), 2.34-2.65 (m, 2H), 1.52-2.02 (m, 4H), 0.62-0.92 (m, 4H). LC: 100%. MS (e/z): 535 (m+1).
Reaction SMILES: C([O:5][CH2:6][CH:7]([O:16][CH2:17][CH2:18][O:19][CH:20]([CH3:22])[CH3:21])[CH2:8][O:9][CH2:10][CH2:11][O:12][CH:13]([CH3:15])[CH3:14])(C)(C)C.ClCCl.C(=O)([O-])[O-].[K+].[K+]>C(OCC)C>[CH:20]([O:19][CH2:18][CH2:17][O:16][CH:7]([CH2:8][O:9][CH2:10][CH2:11][O:12][CH:13]([CH3:15])[CH3:14])[CH2:6][OH:5])([CH3:22])[CH3:21]
Reactant: CC(C)OCCOCC(COC(C)(C)C)OCCOC(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: CCOCC
Product: CC(C)OCCOCC(CO)OCCOC(C)C

Procedure:
Compound 32 was prepared as described for 29. The reagents used were as follows, compound 26 (g, mol.), tetrafluoroboric acid-diethyl ether complex ml of a 54% solution in diethyl ether), dichloromethane (100 ml) and excess potassium carbonate. the final yield was a colorless liquid (g, %), (bpt. °C., torr.): 1H-NMR (CDCl3), d, (ppm). Mass spectroscopy, m/e M+.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[C:2]1[C:10]([O:12][CH2:13][CH3:14])=[O:11].O=P(Cl)(Cl)Cl.CN([CH:23]=[O:24])C>>[CH2:13]([O:12][C:10]([C:2]1[NH:1][C:9]2[C:4]([C:3]=1[CH:23]=[O:24])=[CH:5][CH:6]=[CH:7][CH:8]=2)=[O:11])[CH3:14]
Reactant: CN(C)C=O
Reactant: CCOC(=O)c1cc2ccccc2[nH]1
Solvent: O=P(Cl)(Cl)Cl
Product: CCOC(=O)c1[nH]c2ccccc2c1C=O

Procedure:
Ethyl indole-2-carboxylate (10 g, 52.8 mmol) was formylated using POCl3 (1.3 equiv.) and DMF (1.3 equiv.) as above to give 3-formyl-1H-indole-2-carboxylic acid ethyl ester as a white solid.
Reaction SMILES: [CH3:1][CH:2]1[S:6][C:5]([NH:7][C@H:8]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[Cl:16])[CH3:9])=[N:4][C:3]1=[O:17].Br[C:19]1[CH:26]=[CH:25][C:22]([C:23]#[N:24])=[CH:21][CH:20]=1.CC1(C2C=CC(C#N)=CC=2)SC(N[C@H](C2C=CC=CC=2C(F)(F)F)C)=NC1=O>>[Cl:16][C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=1[C@@H:8]([NH:7][C:5]1[S:6][C:2]([C:19]2[CH:26]=[CH:25][C:22]([C:23]#[N:24])=[CH:21][CH:20]=2)([CH3:1])[C:3](=[O:17])[N:4]=1)[CH3:9]
Reactant: CC1SC(N[C@@H](C)c2ccccc2Cl)=NC1=O
Reactant: N#Cc1ccc(Br)cc1
Agent: C[C@H](NC1=NC(=O)C(C)(c2ccc(C#N)cc2)S1)c1ccccc1C(F)(F)F
Product: C[C@H](NC1=NC(=O)C(C)(c2ccc(C#N)cc2)S1)c1ccccc1Cl

Procedure:
The title compound was prepared from the reaction of 5-methyl-2-((S)-1-(2-chlorophenyl)ethylamino)thiazol-4(5H)-one with 4-bromobenzonitrile using the procedure described for 2a. MS (ESI, pos. ion) m/z: 370 (M+1).
Reaction SMILES: [O:1]=[C:2]1[CH2:6][CH2:5][CH2:4][N:3]1[CH2:7][C:8]([O:10]CC)=O.[CH:13]([N:16]([CH:20]([CH3:22])[CH3:21])[CH2:17][CH2:18][NH2:19])([CH3:15])[CH3:14]>>[CH3:14][CH:13]([N:16]([CH:20]([CH3:22])[CH3:21])[CH2:17][CH2:18][NH:19][C:8](=[O:10])[CH2:7][N:3]1[CH2:4][CH2:5][CH2:6][C:2]1=[O:1])[CH3:15]
Reactant: CCOC(=O)CN1CCCC1=O
Reactant: CC(C)N(CCN)C(C)C
Product: CC(C)N(CCNC(=O)CN1CCCC1=O)C(C)C

Procedure:
From 17.1 g. of ethyl 2-oxo-1-pyrrolidineacetate and 21 g. of 2-(diisopropylamino)ethylamine [J.A.C.S. 78, 486 (1956)], following the procedure of Example 1, there is obtained N-[2-[bis(1-methylethyl)amino]ethyl]-2-oxo-1-pyrrolidineacetamide; b.p. 164° C./0.15 mm.
Reaction SMILES: [CH3:1][S:2]([N:5]1[C:13]2[C:8](=[CH:9][CH:10]=[C:11]([N+:14]([O-])=O)[CH:12]=2)[CH:7]=[CH:6]1)(=[O:4])=[O:3]>CO.[Pt]=O>[CH3:1][S:2]([N:5]1[C:13]2[C:8](=[CH:9][CH:10]=[C:11]([NH2:14])[CH:12]=2)[CH:7]=[CH:6]1)(=[O:4])=[O:3]
Reactant: CS(=O)(=O)n1ccc2ccc([N+](=O)[O-])cc21
Agent: O=[Pt]
Solvent: CO
Product: CS(=O)(=O)n1ccc2ccc(N)cc21
Reaction time: 1 h

Procedure:
A mixture of N-methanesulfonyl-6-nitroindole (2.52 g, 10.5 mmol, from above) and platinum oxide (119 mg, 0.52 mmol) in 100 ml of methanol was hydrogenated in a Parr apparatus for approximately 1 hr until a constant pressure was obtained (42 psi H2 initially). The catalyst was removed by filtration (Whatman GF/F filter) and the filtrate was concentrated by rotary evaporation to give N-methanesulfonyl-6-aminoindole, an oil which solidified on standing under an argon atmosphere.
Reaction SMILES: CC1(C)C(C)(C)OB([C:9]2[CH:13]=[CH:12][O:11][C:10]=2[CH3:14])O1.Cl[C:17]1[CH:18]=[C:19]([N:23]2[CH2:28][C@H:27]([CH3:29])[O:26][C@H:25]([CH3:30])[CH2:24]2)[CH:20]=[CH:21][CH:22]=1.O.C(=O)([O-])[O-].[Na+].[Na+]>O1CCOCC1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:29][C@H:27]1[O:26][C@@H:25]([CH3:30])[CH2:24][N:23]([C:19]2[CH:20]=[CH:21][CH:22]=[C:17]([C:9]3[CH:13]=[CH:12][O:11][C:10]=3[CH3:14])[CH:18]=2)[CH2:28]1
Reactant: Cc1occc1B1OC(C)(C)C(C)(C)O1
Reactant: C[C@@H]1CN(c2cccc(Cl)c2)C[C@H](C)O1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: Cc1occc1-c1cccc(N2C[C@@H](C)O[C@@H](C)C2)c1
Temperature: 100 °C

Procedure:
4,4,5,5-Tetramethyl-2-(2-methyl-3-furanyl)-1,3,2-dioxaborolane (1.645 g, 7.91 mmol) was added to a solution of cis-4-(3-chlorophenyl)-2,6-dimethylmorpholine (1.785 g, 7.91 mmol) in a mixture of 1,4-dioxane (17 mL), water (2.83 mL) and sodium carbonate (1.676 g, 15.82 mmol). The solution was degassed using argon gas and then charged with tetrakis(triphenylphosphine)palladium(0) (0.914 g, 0.791 mmol). After addition, the reaction mixture was stirred and heated in the microwave at 100° C. for 48 hours. Crude LC/MS showed desired product and only 26% of starting material can be seen. The reaction mixture was washed with ethyl acetate (200 mL), water (100 mL), filtered and then evaporated to dryness. The residue was dissolved in dichloromethane (˜10 ml) and purified on silica by using a Biotage SP4 chromatographic system (65i cartridge, eluted with 0-50% ethyl acetate in isohexanes). Fractions containing pure product were combined and concentrated under reduced pressure to give the title compound as a colourless oil (0.74 g, 2.59 mmol, 32.8% yield). LC/MS [M+H]+=272.
Reaction SMILES: [CH3:1][NH2:2].[OH:3][C:4]1[CH:5]=[C:6]([CH:9]=[CH:10][C:11]=1[O:12][CH3:13])[CH:7]=O.[BH4-].[Na+]>C(O)C>[CH3:13][O:12][C:11]1[CH:10]=[CH:9][C:6]([CH2:7][NH:2][CH3:1])=[CH:5][C:4]=1[OH:3]
Reactant: CN
Reactant: COc1ccc(C=O)cc1O
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: CNCc1ccc(OC)c(O)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 74.8 %

Procedure:
Methylamine (40% aqueous solution, 2.2 mL, 25 mmol) is added to a solution of 3-hydroxy-4-methoxybenzaldehyde (3.0 g, 20 mmol) in ethanol (35 mL). The resulting slurry is stirred for 30 minutes at room temperature. Then the solvents were evaporated under reduced pressure. The resulting solid is dissolved in methanol (300 mL) and sodium borohydride (0.90 g, 24 mmol) is added. The reaction mixture is stirred for 2 hours at room temperature and then concentrated under reduced pressure. The residue is partitioned between saturated aqueous potassium carbonate solution and ethyl acetate. The aqueous phase is extracted 3× with ethyl acetate, and the combined extracted were concentrated under reduced pressure to give 2-methoxy-5-methylaminomethyl-phenol as a granular white solid (2.5 g, 75%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2([CH:12]3[C:21]4[C:16](=[CH:17][CH:18]=[C:19]([O:22][CH2:23][CH2:24][NH:25][S:26]([CH2:29][CH2:30][CH3:31])(=[O:28])=[O:27])[CH:20]=4)[CH2:15][CH2:14][NH:13]3)[CH2:11][CH2:10][CH2:9]2)[CH:5]=[CH:6][CH:7]=1.[CH2:32]([N:34](CC)CC)[CH3:33].BrCC#N>ClCCl>[Cl:1][C:2]1[CH:3]=[C:4]([C:8]2([CH:12]3[C:21]4[C:16](=[CH:17][CH:18]=[C:19]([O:22][CH2:23][CH2:24][NH:25][S:26]([CH2:29][CH2:30][CH3:31])(=[O:28])=[O:27])[CH:20]=4)[CH2:15][CH2:14][N:13]3[CH2:33][C:32]#[N:34])[CH2:9][CH2:10][CH2:11]2)[CH:5]=[CH:6][CH:7]=1
Reactant: CCCS(=O)(=O)NCCOc1ccc2c(c1)C(C1(c3cccc(Cl)c3)CCC1)NCC2
Reactant: CCN(CC)CC
Agent: N#CCBr
Solvent: ClCCl
Product: CCCS(=O)(=O)NCCOc1ccc2c(c1)C(C1(c3cccc(Cl)c3)CCC1)N(CC#N)CC2
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
N-[2-({1-[1-(3-Chlorophenyl)cyclobutyl]-1,2,3,4-tetrahydroisoquinolin-7-yl}oxy)ethyl]propane-1-sulfonamide (70 mg, 0.14 mmol, cf. example 49) was dissolved in dry dichloromethane (0.5 mL). Triethylamine (35.5 mg, 0.35 mmol) was added and the reaction mixture was stirred at room temperature for 30 min. After addition of 2-bromoacetonitrile (20 mg, 0.168 mmol) stirring at room temperature was continued over night. The reaction mixture was diluted with dichloromethane and washed with aqueous saturated NaHCO3 solution (5 mL) and water (5 mL). The organic phase was dried (MgSO4) and the solvent was evaporated in vacuo. The crude product was purified by flash chromatography (silica, dichloromethane then dichloromethane:methanol=200:1). Yield: 35 mg (0.07 mmol, 50%).
Reaction SMILES: C(OC(=O)[NH:7][CH2:8][C:9]#[C:10][C:11]1[CH:29]=[N:28][C:14]2[NH:15][CH2:16][CH2:17][N:18]([CH2:19][C:20]3[CH:25]=[C:24]([Cl:26])[CH:23]=[CH:22][C:21]=3[Cl:27])[C:13]=2[CH:12]=1)(C)(C)C.FC(F)(F)C(O)=O.[OH-].[Na+]>C(Cl)Cl>[Cl:27][C:21]1[CH:22]=[CH:23][C:24]([Cl:26])=[CH:25][C:20]=1[CH2:19][N:18]1[CH2:17][CH2:16][NH:15][C:14]2[N:28]=[CH:29][C:11]([C:10]#[C:9][CH2:8][NH2:7])=[CH:12][C:13]1=2
Reactant: CC(C)(C)OC(=O)NCC#Cc1cnc2c(c1)N(Cc1cc(Cl)ccc1Cl)CCN2
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: NCC#Cc1cnc2c(c1)N(Cc1cc(Cl)ccc1Cl)CCN2
Yield: 37 %

Procedure:
{3-[1-(2,5-Dichlorobenzyl)-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl]prop-2-ynyl}carbamic acid tert-butyl ester (19 mg), trifluoroacetic acid (250 μL) and CH2Cl2 (1 mL) were stirred under nitrogen at room temperature for 1.5 hours. 2 N NaOH (2 mL) and CH2Cl2 (approx. 10 mL) were added. The organic phase was isolated, washed twice with H2O, washed once with brine, dried over sodium sulfate, filtered and then purified by normal phase column chromatography, eluting with 5% methanol in methylene chloride, to give the title compound as an off-white solid (37% yield). M.p.=183° C., LCMS: m/z=347.35 (M+H+), 1H-NMR (CDCl3, 400 MHz) δ 3.42 (2H, t, J=4.8 Hz), 3.61 (4H, m), 4.41 (2H, s), 5.04 (1H, bs), 6.42 (1H, s), 7.21 (2H, m), 7.34 (1H, d, J=8.3 Hz), 7.59 (1H, s, J=1.0 Hz).
Reaction SMILES: [CH3:1][C:2]1[C:10]2[C:5](=[CH:6][C:7]([N+:11]([O-])=O)=[CH:8][CH:9]=2)[NH:4][N:3]=1.C([O-])=O.[NH4+]>C(O)C.O.CCOC(C)=O.[Fe]>[NH2:11][C:7]1[CH:6]=[C:5]2[C:10]([C:2]([CH3:1])=[N:3][NH:4]2)=[CH:9][CH:8]=1
Reactant: Cc1n[nH]c2cc([N+](=O)[O-])ccc12
Agent: [Fe]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CCOC(C)=O
Solvent: CCO
Solvent: O
Product: Cc1n[nH]c2cc(N)ccc12
Temperature: 90 °C
Yield: 81.9 %

Procedure:
To a solution of 3-methyl-6-nitroindazole (0.4 g, 2.24 mmol) in ethanol (EtOH) (10 mL) and H2O (5 mL) was added Iron (0.63 g, 11.22 mmol) and ammonium formate (1.4 g, 22.4 mmol). After heating at 90° C. for 2 h, the mixture was diluted with EtOAc, excess iron was removed by filtration, and the filtrate was washed sequentially with water, sat. NaHCO3, and brine, before it was dried and concentrated to give 6-amino-3-methylindazole (0.27 g).
Reaction SMILES: [C@H:1]12[CH2:7][C@H:4]([NH:5][CH2:6]1)[CH2:3][N:2]2[C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9].C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.[CH3:29][C:30]([CH3:47])([CH3:46])[C@@H:31]([C:43](O)=[O:44])[NH:32]C(OCC1C=CC=CC=1)=O.CN1CCOCC1.C([O-])=O.[NH4+]>C(Cl)Cl.O.C([O-])([O-])=O.[Na+].[Na+].[Pd].C(O)C>[CH3:29][C:30]([CH3:47])([CH3:46])[C@@H:31]([C:43]([N:5]1[CH2:6][C@@H:1]2[CH2:7][C@H:4]1[CH2:3][N:2]2[C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])=[O:44])[NH2:32]
Reactant: CC(C)(C)OC(=O)N1C[C@@H]2C[C@H]1CN2
Reactant: CC(C)(C)[C@H](NC(=O)OCc1ccccc1)C(=O)O
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: O=C[O-]
Solvent: CCO
Solvent: ClCCCl
Solvent: O
Product: CC(C)(C)OC(=O)N1C[C@@H]2C[C@H]1CN2C(=O)[C@@H](N)C(C)(C)C
Temperature: 25 °C
Reaction time: 18 h
Yield: 95.3 %

Procedure:
To a solution of 1,1-dimethylethyl (1S,4S)-2,5-diazabicyclo[2.2.1]heptane-2-carboxylate (11.25 g, 57.6 mmol) in CH2Cl2 (567 mL) was added EDC (40.8 g, 213 mmol), HOBt (10.86 g, 70.9 mmol), 3-methyl-N-{[(phenylmethyl)oxy]carbonyl}-L-valine (18.82 g, 70.9 mmol), and NMM (37.4 g, 340 mmol). The reaction mixture was stirred at room temperature for 18 h. The reaction was diluted with water (75 ml) and sat. Na2CO3 (75 ml). Stirring was continued for an additional 0.5 h then the two layers were separated. The organic solution was washed with sat. NaHCO3, 1N HCl, sat. NaHCO3, and brine. The organic layer was passed over a phase separator and concentrated under reduced pressure. To the residue was added ethanol (567 ml), 10% Pd/C (6.04 g) and ammonium formate (35.8 g, 567 mmol). The solution was stirred at room temperature for 18 h and then filtered over a pad of celite. The resulting solution was concentrated to afford an off white residue. The residue was dissolved in CH2Cl2 and washed with sat. Na2CO3. The layers were separated and the aqueous layer was extracted three times with CH2Cl2. The combined CH2Cl2 extracts were passed over a phase separator and concentrated to afford the desired product (17.1 g, 54.9 mmol) as an off white residue. LCMS (m/z): 312.2 (M+H).
Reaction SMILES: [O:1]=[C:2]1[CH:7]2[CH2:8][CH:4]([CH2:5][CH:6]2[C:9]([OH:11])=O)[O:3]1.[CH2:12]([O:14][C:15]([C:17]1([NH2:22])[CH2:19][CH:18]1[CH:20]=[CH2:21])=[O:16])[CH3:13].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C.C(Cl)Cl>[CH2:12]([O:14][C:15]([C:17]1([NH:22][C:9]([CH:6]2[CH2:5][CH:4]3[CH2:8][CH:7]2[C:2](=[O:1])[O:3]3)=[O:11])[CH2:19][CH:18]1[CH:20]=[CH2:21])=[O:16])[CH3:13]
Reactant: C=CC1CC1(N)C(=O)OCC
Reactant: O=C(O)C1CC2CC1C(=O)O2
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: C=CC1CC1(NC(=O)C1CC2CC1C(=O)O2)C(=O)OCC
Temperature: 25 °C
Reaction time: 1 h
Yield: 99.2 %

Procedure:
To a solution of 3-oxo-2-oxa-bicyclo[2.2.1]heptane-5-carboxylic acid (857 mg, 5.5 mmol), in DMF (14 ml) and DCM (25 ml) at room temperature, was added 1-amino-2-vinylcyclopropanecarboxylic acid ethyl ester (1.15 g, 6.0 mmol), HATU (2.29 g, 6.0 mmol) and DIPEA (3.82 ml, 22 mmol). The reaction was stirred under N2-atmosphere at ambient temperature for 1 h. LC/MS analysis showed complete conversion and the reaction mixture was concentrated in vacuo. The residue was re-dissolved in DCM (100 ml) and 0.1 M HCl (aq) and the layers separated. The organic phase was washed with NaHCO3 (aq) and brine, dried (MgSO4) and filtered. Removal of the solvent in vacuo afforded the title compound (1.6 g, 99%). LC/MS (Method A): tR=2.46 min, >95%, m/z (ESI+)=294(MH+)
Reaction SMILES: [C:1]([S:4][CH2:5]/[C:6](=[CH:10]/[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)/[C:7]([OH:9])=O)(=[O:3])[CH3:2].[NH2:17][CH2:18][CH2:19][C:20]([O:22][CH3:23])=[O:21]>>[O:9]=[C:7]([NH:17][CH2:18][CH2:19][C:20]([O:22][CH3:23])=[O:21])/[C:6](/[CH2:5][S:4][C:1](=[O:3])[CH3:2])=[CH:10]\[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: CC(=O)SC/C(=C/c1ccccc1)C(=O)O
Reactant: COC(=O)CCN
Product: COC(=O)CCNC(=O)/C(=C\c1ccccc1)CSC(C)=O
Yield: 60 %

Procedure:
The (E)-2-acetylthiomethyl-3-phenylpropenoic acid described in Example 1 (step C) is coupled with methyl β-alaninate according to the experimental procedure described in Example 1 (step D). Yield: 60% (after flash chromatography, eluent: ether/petroleum ether 6/4) m.p. 54° C. IR (nujol): 3280, 1720, 1680, 1630, 1610 cm-1 1H NMR: 7.20, (s, 5H); 6.80 (s, 1H); 5.90 (broad s, 1H); 3.85 (s, 2H); 3.50 (s, 3H); 3.60 to 3.30 (m, 2H); 2.35 (t, 2H, J=5.30 Hz); 2.25 (s, 3H). Microanalysis: C16H19O4NS Calc. % C=59.79 H=5.96 N=4.36 Found. % C=59.67 H=6.28 N=4.47
Reaction SMILES: [Si:1]([O:8][C:9]1[CH:15]=[CH:14][C:12]([NH2:13])=[CH:11][CH:10]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].I[C:17]1[CH:18]=[N:19][N:20]([CH:22]2[CH2:26][CH2:25][O:24][CH2:23]2)[CH:21]=1>O1CCCC1>[Si:1]([O:8][C:9]1[CH:15]=[CH:14][C:12]([NH:13][C:17]2[CH:18]=[N:19][N:20]([CH:22]3[CH2:26][CH2:25][O:24][CH2:23]3)[CH:21]=2)=[CH:11][CH:10]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: CC(C)(C)[Si](C)(C)Oc1ccc(N)cc1
Reactant: Ic1cnn(C2CCOC2)c1
Solvent: C1CCOC1
Product: CC(C)(C)[Si](C)(C)Oc1ccc(Nc2cnn(C3CCOC3)c2)cc1

Procedure:
4-[tert-Butyl(dimethyl)silyl]oxyaniline (0.92 g, 3.48 mmol) and 4-iodo-1-tetrahydrofuran-3-yl-pyrazole (0.78 g, 3.48 mmol) dissolved in anhydrous tetrahydrofuran (20 mL) are stirred for one hour at ambient temperature in the presence of sodium tert-butylate (1.7 mL, 2M solution in THF) and chloro(2-di-tert-butylphosphino-2′,4′,6′-triisopropyl-1,1′-biphenyl)[2-(2-aminoethyl)phenyl]palladium(II) (84 mg, 0.122 mmol). The reaction mixture is filtered over Celite and then evaporated to dryness. The residue is crystallised from a mixture of heptane/ethyl acetate, filtered and washed with heptane and then purified by chromatography over silica gel using dichloromethane and methanol as eluants to yield the expected product.
Reaction SMILES: [NH:1]1[CH:6]=[CH:5][C:4](=[C:7]2[C:15](=[O:16])[C:14]3[CH2:13][CH2:12][CH2:11][CH2:10][C:9]=3[C:8]2=O)[CH:3]=[CH:2]1.O.[NH2:19][NH2:20]>>[N:1]1[CH:6]=[CH:5][C:4]([CH2:7][C:8]2[C:9]3[CH2:10][CH2:11][CH2:12][CH2:13][C:14]=3[C:15](=[O:16])[NH:20][N:19]=2)=[CH:3][CH:2]=1
Reactant: O=C1C2=C(CCCC2)C(=O)C1=C1C=CNC=C1
Reactant: NN
Solvent: O
Product: O=c1[nH]nc(Cc2ccncc2)c2c1CCCC2

Procedure:
A mixture of 0.773 g (3.4 mmol) 2-[4(1H)-pyridinylidene]-4,5,6,7-tetrahydro-inden-1,3-dione and 5 ml hydrazine hydrate is heated for 4 h under reflux. The title compound is obtained after cooling to 0° C., filtration, washing of the filter residue with water, then ether, and drying under HV (8 h, 100° C.); m.p. 193-194° C.; ESI-MS: (M+H)+=242.
Reaction SMILES: [Br:1][C:2]1[C:10]([CH3:11])=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][C:3]=1[S:12](Cl)(=O)=O>Cl.O.C(O)(=O)C>[Br:1][C:2]1[C:10]([CH3:11])=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][C:3]=1[SH:12]
Reactant: Cc1cc(C(=O)O)cc(S(=O)(=O)Cl)c1Br
Agent: Cl
Solvent: CC(=O)O
Solvent: O
Product: Cc1cc(C(=O)O)cc(S)c1Br
Temperature: 80 °C
Reaction time: 4 h

Procedure:
A solution of stannous chloride (196 g, 0.86 mol) in concentrated hydrochloric acid (250 mL) and water (55 mL) was added to a stirred suspension of compound of Example 1c (68 g, 0.217 mol) in acetic acid (580 mL) at 80° C., over a period of 20 min. The reaction mixture was stirred at 80° C. for 4 h. The reaction mixture was cooled, poured into water (500 mL) with stirring and digested at 80° C. for 30 min. The solid was filtered, washed with water till filtrate was neutral and dried to obtain the title compound. Yield: 48 g (90%); 1H NMR (DMSO-d6, 300 MHz): δ 2.40 (s, 3H, CH3), 7.70 (s, 1H, Ar), 7.84 (s, 1H, Ar); MS: m/e (ES−) 491 (M−1).