Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([Li])CCC.CCCCCC.[C:12]([O:16][C:17]([C@@:19]1([CH:33]=O)[CH2:23][C:22](=[O:24])[N:21]([C@@H:25]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH3:26])[CH2:20]1)=[O:18])([CH3:15])([CH3:14])[CH3:13].[Cl-].[NH4+]>[Br-].C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.O1CCCC1>[C:12]([O:16][C:17]([C@@:19]1([CH:33]=[CH2:1])[CH2:23][C:22](=[O:24])[N:21]([C@@H:25]([C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=2)[CH3:26])[CH2:20]1)=[O:18])([CH3:14])([CH3:13])[CH3:15]
Reactant: [Li]CCCC
Reactant: C[C@H](c1ccccc1)N1C[C@@](C=O)(C(=O)OC(C)(C)C)CC1=O
Agent: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Agent: [Cl-]
Solvent: CCCCCC
Solvent: C1CCOC1
Product: C=C[C@]1(C(=O)OC(C)(C)C)CC(=O)N([C@H](C)c2ccccc2)C1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
Methyltriphenylphosphonium bromide (187.4 mg, 0.52 mmol) was dissolved in tetrahydrofuran. A 2.62 M solution of n-butyllithium in hexane (0.16 mL, 0.42 mmol) was added dropwise in a nitrogen atmosphere at −78° C., and the mixture was stirred for one hour. After heating to 0° C., a solution of (3S)-3-formyl-5-oxo-1-[(1R)-1-phenylethyl]pyrrolidine-3-carboxylic acid tert-butyl ester (111 mg, 0.35 mmol) in tetrahydrofuran was added dropwise, and the mixture was stirred for one hour. A saturated ammonium chloride solution was added to the reaction solution, followed by extraction with ethyl acetate. The organic layer was washed with water and brine, dried over anhydrous sodium sulfate, and filtered. The solvent was evaporated under reduced pressure, and the resulting residue was subjected to silica gel column chromatography (25% ethyl acetate/hexane) to give 54 mg of the title compound as a yellow oil.
Reaction SMILES: N(C(OC(C)C)=O)=NC(OC(C)C)=O.[CH3:15][C:16]1[CH:21]=[CH:20][C:19]([NH:22][C:23](=[O:36])[C:24]2[CH:29]=[CH:28][CH:27]=[C:26]([N:30]3[CH2:35][CH2:34][O:33][CH2:32][CH2:31]3)[CH:25]=2)=[CH:18][C:17]=1[NH:37][C:38](=[O:46])[C:39]1[CH:44]=[CH:43][C:42]([OH:45])=[CH:41][CH:40]=1.O[CH:48]1[CH2:52][CH2:51][O:50][CH2:49]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C(Cl)Cl>[CH3:15][C:16]1[CH:21]=[CH:20][C:19]([NH:22][C:23](=[O:36])[C:24]2[CH:29]=[CH:28][CH:27]=[C:26]([N:30]3[CH2:35][CH2:34][O:33][CH2:32][CH2:31]3)[CH:25]=2)=[CH:18][C:17]=1[NH:37][C:38](=[O:46])[C:39]1[CH:40]=[CH:41][C:42]([O:45][CH:48]2[CH2:52][CH2:51][O:50][CH2:49]2)=[CH:43][CH:44]=1
Reactant: OC1CCOC1
Reactant: Cc1ccc(NC(=O)c2cccc(N3CCOCC3)c2)cc1NC(=O)c1ccc(O)cc1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: Cc1ccc(NC(=O)c2cccc(N3CCOCC3)c2)cc1NC(=O)c1ccc(OC2CCOC2)cc1
Temperature: 5 °C
Yield: 298.2 %

Procedure:
Di-isopropyl azodicarboxylate (0.21 ml) was added to a stirred mixture of N-[2-methyl-5-(3-morpholinobenzamido)phenyl]-4-hydroxybenzamide (0.15 g), 3-hydroxytetrahydrofuran (0.31 g), triphenyl phosphine (0.275 g) and methylene chloride (5 ml) which had been cooled to 5° C. The resultant mixture was stirred at ambient temperature for 18 hours. The mixture was poured onto a pre-wetted (methylene chloride) ion-exchange column (isolute SCX 5 g column from International Sorbent Technology Limited) and eluted in turn with methylene chloride (40 ml), with methylene chloride (40 ml) containing 20% methanol and with methylene chloride containing 20% methanol and 3% of a saturated aqueous ammonium hydroxide solution. The product so obtained was further purified by column chromatography on silica using a 4:1 mixture of ethyl acetate and methanol as eluent. There was thus obtained the title compound as a solid (0.52 g); Mass Spectrum: M+H+ 502.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:13][C:12](=[O:14])[NH:11][C:10](=[O:15])[CH2:9]2)=[CH:4][C:3]=1[C:16]1[CH2:21][CH2:20][C:19]([CH3:23])([CH3:22])[CH2:18][CH:17]=1.C1CN([P+](Br)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.[K+].[C:49]([C:51]1[N:52]=[C:53]([C:64]([O-])=[O:65])[N:54]([CH2:56][O:57][CH2:58][CH2:59][Si:60]([CH3:63])([CH3:62])[CH3:61])[CH:55]=1)#[N:50].CCN(C(C)C)C(C)C>C(Cl)Cl>[CH3:22][C:19]1([CH3:23])[CH2:20][CH2:21][C:16]([C:3]2[CH:4]=[C:5]([CH:8]3[CH2:9][C:10](=[O:15])[NH:11][C:12](=[O:14])[CH2:13]3)[CH:6]=[CH:7][C:2]=2[NH:1][C:64]([C:53]2[N:54]([CH2:56][O:57][CH2:58][CH2:59][Si:60]([CH3:63])([CH3:62])[CH3:61])[CH:55]=[C:51]([C:49]#[N:50])[N:52]=2)=[O:65])=[CH:17][CH2:18]1
Reactant: CC1(C)CC=C(c2cc(C3CC(=O)NC(=O)C3)ccc2N)CC1
Reactant: C[Si](C)(C)CCOCn1cc(C#N)nc1C(=O)[O-]
Agent: Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Agent: F[P-](F)(F)(F)(F)F
Agent: [K+]
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC1(C)CC=C(c2cc(C3CC(=O)NC(=O)C3)ccc2NC(=O)c2nc(C#N)cn2COCC[Si](C)(C)C)CC1
Yield: 76.3 %

Procedure:
A solution of 140 mg (0.448 mmol) of 4-[4-amino-3-(4,4-dimethyl-cyclohex-1-enyl)-phenyl]-piperidine-2,6-dione (as prepared in the previous step) in CH2Cl2 (10 mL) was treated with 313 mg (0.672 mmol) of PyBroP, 151 mg (0.493 mmol) of 4-cyano-1-(2-trimethylsilanyl-ethoxymethyl)-1H-imidazole-2-carboxylate potassium salt (as prepared in Example 1, step (d)), and 234 μL (1.34 mmol) of DIEA at RT for 30 min. The mixture was diluted with CH2Cl2 (30 mL) and washed with saturated aqueous NaHCO3 (1×30 mL). The organic layer was dried (MgSO4) and concentrated in vacuo. Silica gel chromatography of the residue with 10-42% EtOAc-hexane afforded 192 mg (76%) of the title compound as an off-white solid: Mass spectrum (ESI, m/z): Calcd. for C30H39N5O4Si, 562.3 (M+H), found 562.0.
Reaction SMILES: [CH:1]([O:3][C@@H:4]1[CH2:9][CH2:8][CH2:7][CH2:6][C@@H:5]1[C:10]([CH3:13])([CH3:12])[CH3:11])=[CH2:2].O>CO>[CH:1]([O:3][CH:4]1[CH2:9][CH2:8][CH2:7][CH2:6][CH:5]1[C:10]([CH3:13])([CH3:12])[CH3:11])=[CH2:2]
Reactant: C=CO[C@@H]1CCCC[C@@H]1C(C)(C)C
Solvent: CO
Solvent: O
Product: C=COC1CCCCC1C(C)(C)C
Temperature: 20 °C
Reaction time: 11 h

Procedure:
1.09 g (6.00 mmol) of cis-2-tert-butylcyclohexyl vinyl ether and 199 mg (0.30 mmol) of Co(OAc) (L3) were dissolved in 6.0 ml of methanol under the atmosphere and 540 μL (30 mmol) of water was added to the mixture and the mixture was then stirred at 20° C. After 11 hours, the reaction solution was analyzed by GC, to find that 23% of the cis-2-tert-butylcyclohexyl vinyl ether was left with an optical purity of 92% ee and comprised (1R, 2R) isomers. Further, the reaction solution was purified by silica gel column chromatography to isolate the reaction substrate 2-tert-butylcyclohexyl vinyl ether and the reaction product 2-tert-butylcyclohexanol in a ratio of 22% and 77% respectively. Also, the kre1 value showing the selectivity of reactions at this time was 4.9.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]([NH2:7])[S:5][CH:6]=1.Cl[C:9]1[CH:14]=[C:13]([S:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH:12]=[CH:11][N:10]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].O>C1(C)C=CC=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.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C1(P(C2C=CC=CC=2)C2C3OC4C(=CC=CC=4P(C4C=CC=CC=4)C4C=CC=CC=4)C(C)(C)C=3C=CC=2)C=CC=CC=1>[CH3:1][C:2]1[N:3]=[C:4]([NH:7][C:9]2[CH:14]=[C:13]([S:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[CH:12]=[CH:11][N:10]=2)[S:5][CH:6]=1
Reactant: Cc1csc(N)n1
Reactant: Clc1cc(Sc2ccccc2)ccn1
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: Cc1ccccc1
Product: Cc1csc(Nc2cc(Sc3ccccc3)ccn2)n1
Yield: 70.6 %

Procedure:
Using the method of Example 3, Step B, 4-methylthiazol-2-amine (3.50 mL, 1.40 mmol), 2-chloro-4-(phenylthio)pyridine (0.342 g, 1.54 mmol), potassium phosphate (0.327 g, 1.54 mmol), tris(dibenzylideneacetone)dipalladium(0) (0.0321 g, 0.0350 mmol) and 4,5-bis(diphenylphosphino)-9,9-dimethyl-9H-xanthene (0.0223 g, 0.0385 mmol) were reacted in toluene (4 mL) and water (1.5 mL) to afford 4-methyl-N-(4-(phenylthio)pyridin-2-yl)thiazol-2-amine (0.296 g, 69.8% yield) as off white solid. 1H NMR (CDCl3) δ 8.07 (d, 1H), 7.54 (m, 2H), 7.44 (m, 3H), 6.57 (dd, 1H), 6.45 (d, 1H), 6.32 (d, 1H), 2.24 (d, 3H); Mass spectrum (apci) m/z=300 (100) (M+H).
Reaction SMILES: [C:1]([C:4]1[CH:39]=[CH:38][C:7]([O:8][CH2:9][CH2:10][CH2:11][O:12][C:13]2[C:14]([C:36]#[N:37])=[C:15]([NH:19][C:20]([C:22]3[N:26](CC4C=CC(OC)=CC=4)[N:25]=[N:24][N:23]=3)=[O:21])[CH:16]=[CH:17][CH:18]=2)=[C:6]([CH2:40][CH2:41][C:42]([F:45])([F:44])[F:43])[C:5]=1[OH:46])(=[O:3])[CH3:2]>FC(F)(F)C(O)=O.C1(OC)C=CC=CC=1>[C:1]([C:4]1[CH:39]=[CH:38][C:7]([O:8][CH2:9][CH2:10][CH2:11][O:12][C:13]2[C:14]([C:36]#[N:37])=[C:15]([NH:19][C:20]([C:22]3[NH:26][N:25]=[N:24][N:23]=3)=[O:21])[CH:16]=[CH:17][CH:18]=2)=[C:6]([CH2:40][CH2:41][C:42]([F:43])([F:45])[F:44])[C:5]=1[OH:46])(=[O:3])[CH3:2]
Reactant: COc1ccc(Cn2nnnc2C(=O)Nc2cccc(OCCCOc3ccc(C(C)=O)c(O)c3CCC(F)(F)F)c2C#N)cc1
Solvent: COc1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: CC(=O)c1ccc(OCCCOc2cccc(NC(=O)c3nnn[nH]3)c2C#N)c(CCC(F)(F)F)c1O

Procedure:
A solution of 7.05 g of N-{{3-{3-[4-acetyl-3-hydroxy-2-(3,3,3-trifluoropropyl)-phenoxy]-propoxy}-2-cyanophenyl}}-1-(4-methoxybenzyl)-tetrazole-5-carboxamide in 150 ml of trifluoroacetic acid and 15 ml of anisole is refluxed for 30 minutes. The reaction mixture is concentrated under reduced pressure, about 200 ml of ether and 300 ml of petroleum ether are added and the crystals are filtered off. The N-{{3-{3-[4-acetyl-3-hydroxy-2-(3,3,3-trifluoropropyl)-phenoxy]-propoxy}-2-cyano-phenyl}}-1H-tetrazole-5-carboxamide thus obtained, of melting point 206°-208°, is dissolved hot in 50 ml of acetone, and the calculated amount of triethanolamine in 30 ml of acetone is added. After addition of ether, crystallisation starts. The triethanolammonium salt of N-{{3-{3-[4-acetyl-3-hydroxy-2-(3,3,3-trifluoropropyl)phenoxy]-propoxy}-2-cyano-phenyl}}-1H-tetrazole-5-carboxamide is thus obtained.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[NH:10][CH2:11][CH3:12])[C:5]#[N:6].[F:13][C:14]1[CH:15]=[C:16]([N:20]2[C:24]([CH2:25][C:26](O)=O)=[CH:23][CH:22]=[N:21]2)[CH:17]=[CH:18][CH:19]=1.Cl.CN(C)CCCN=C=NCC>N1C=CC=CC=1>[CH2:11]([N:10]1[C:9]2[CH:8]=[CH:7][C:4]([C:5]#[N:6])=[CH:3][C:2]=2[N:1]=[C:26]1[CH2:25][C:24]1[N:20]([C:16]2[CH:17]=[CH:18][CH:19]=[C:14]([F:13])[CH:15]=2)[N:21]=[CH:22][CH:23]=1)[CH3:12]
Reactant: O=C(O)Cc1ccnn1-c1cccc(F)c1
Reactant: CCNc1ccc(C#N)cc1N
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: c1ccncc1
Product: CCn1c(Cc2ccnn2-c2cccc(F)c2)nc2cc(C#N)ccc21
Temperature: 25 °C
Reaction time: 17.5 h

Procedure:
To a stirring solution of 3-amino-4-ethylaminobenzonitrile (887 mg, 5.5 mmol) and 1-(3-Fluorophenyl)-5-carboxymethylpyrazole (1.10 g, 5 mmol) in pyridine (5 mL) is added 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (1.15 g, 6 mmol). The mixture is stirred at room temperature for 17.5 h, then concentrated. The residue is cooled in an ice bath, aqueous HCl is added with stirring, the precipitate is collected by filtration, rinsed well with water and dried. The solid is added to acetic acid (75 mL) and heated at reflux for 5.5 h. The mixture is cooled, concentrated, and purified by silica gel chromatography to give 1-Ethyl-2-{[2-(3-fluorophenyl)-pyrazol-3-yl]methyl}-5-cyano-1H-benzimidazole. The product is converted to the mesylate salt in acetone. 1H NMR (CDCl3): δ 8.17 (s, 1H), 7.89 (d, J=8.52 Hz, 1H), 7.68-7.75 (m 1H), 7.44-7.54 (m, 2H), 7.37-7.40 (m, 1H), 7.21-7.28 (m, 1H), 6.35 (d, J=1.65 Hz, 1H), 4.65 (8, 2H), 4.29 (q, J=7.14 Hz, 2H), 2.34 (s, 3H), 1.19 (t, J=7.14 Hz, 3H). LCMS 346.0 (MH+), 344.4 (MH−)
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][Si:5]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.C(N(CC)CC)C.[C:31](Cl)(=[O:34])[CH:32]=[CH2:33]>C1C=CC=CC=1>[C:31]([O:1][CH2:2][CH2:3][CH2:4][Si:5]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1)(=[O:34])[CH:32]=[CH2:33]
Reactant: C=CC(=O)Cl
Reactant: OCCC[Si](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CCN(CC)CC
Solvent: c1ccccc1
Product: C=CC(=O)OCCC[Si](c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 6 h
Yield: 87.3 %

Procedure:
32.9 g (91.4 mmol) of compound (C) was added to a 1 N solution of sodium carbonate in ethanol and the mixture was heated at 70° to 80° C. for 3 h to conduct the hydrolysis. 27.7 g (87.1 mmol) of 3-hydroxypropyltriphenylsilane (D) was thus obtained (yield: 95.4%). 250 ml of dry benzene was placed in a flask after replacing air in the flask with a dry inert gas (argon). 5.0 g (15.7 mmol) of compound (D) and 1.9 g of triethylamine were dissolved therein. 50 ml of a solution of 1.6 g (17.7 mmol) of acryloyl chloride in benzene was added slowly thereto. After the completion of the addition, the mixture was stirred at room temperature for 6 h. The reaction solution was washed with a 0.5 N hydrochloric acid, water, a 1 N sodium carbonate solution and water successively and then dried over magnesium sulfate. Benzene was distilled off and the residue was purified according to column chromatography (silica gel/benzene) to obtain 5.1 g (13.7 mmol) of 3-acryloyloxypropyltriphenylsilane in the form of white crystals (yield: 87.3%).
Reaction SMILES: [F:1][C:2]1[CH:21]=[C:20]([F:22])[C:19]([F:23])=[CH:18][C:3]=1[CH2:4][CH:5]1[CH2:7][N@:6]1[C:8]([O:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[O:9].O.[C-:25]#[N:26].[K+].ClCCl>CS(C)=O>[C:25]([CH2:7][C@H:5]([NH:6][C:8](=[O:9])[O:10][CH2:11][C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1)[CH2:4][C:3]1[CH:18]=[C:19]([F:23])[C:20]([F:22])=[CH:21][C:2]=1[F:1])#[N:26]
Reactant: O=C(OCc1ccccc1)N1CC1Cc1cc(F)c(F)cc1F
Reactant: [C-]#N
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Solvent: ClCCl
Product: N#CC[C@@H](Cc1cc(F)c(F)cc1F)NC(=O)OCc1ccccc1
Temperature: 50 °C
Reaction time: 24 h
Yield: 85.7 %

Procedure:
15.78 g of (R)-benzyl 2-(2,4,5-trifluorobenzyl)aziridine-1-carboxylate was dissolved in 63.2 mL of dimethylsulfoxide and 15.8 mL of water in 250 mL flask; then 7.89 g of silicagel was added thereto. 6.40 g of potassiumcyanide was slowly added to the reaction solution, and the resulting reaction solution was stirred for 24 hours at 50° C. The reaction solution was cooled to room temperature, and then 160 mL of dichloromethane and 800 mL of water were added to the cooled reaction solution in order. An organic layer was isolated; washed with 80 mL of water in twice; dehydrated with sodium sulfate; and then concentrated under reduced pressure. 80 mL of diisopropylether was added to the concentrated residue and then the resulting concentrated residue was stirred for 1 hour at room temperature. The resulting solid was decompression-filtered and vacuum-dried to obtain 14.66 g of a title compound.
Reaction SMILES: C(OC([NH:8][NH:9][C:10]([C@H:12]1[CH2:17][CH2:16][CH2:15][N:14]([C:18](=[O:26])[C:19]2[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=2)[CH2:13]1)=[O:11])=O)(C)(C)C.Cl>ClCCl>[F:25][C:22]1[CH:23]=[CH:24][C:19]([C:18]([N:14]2[CH2:15][CH2:16][CH2:17][C@H:12]([C:10]([NH:9][NH2:8])=[O:11])[CH2:13]2)=[O:26])=[CH:20][CH:21]=1
Reactant: CC(C)(C)OC(=O)NNC(=O)[C@H]1CCCN(C(=O)c2ccc(F)cc2)C1
Agent: Cl
Solvent: ClCCl
Product: NNC(=O)[C@H]1CCCN(C(=O)c2ccc(F)cc2)C1
Temperature: 25 °C
Yield: 103.5 %

Procedure:
0.55 g (1.5 mmol) of N′-[1-(4-fluoro-benzoyl)-(S)-piperidine-3-carbonyl]-hydrazinecarboxylic acid-tert-butyl ester were suspended in 5 mL of dichloromethane and, at 0° C., 4 mL of HCl 4N (dioxane solution) were added. The solution was allowed to warm at room temperature and stirred for 1 h30. The solvent was evaporated under reduced pressure to afford 0.412 g of 1-(4-fluoro-benzoyl)-(S)-piperidine-3-carboxylic acid hydrazide as a white solid extremely igroscopic.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:14]2[O:18][N:17]=[C:16]([C:19]3[CH:20]=[CH:21][CH:22]=[C:23]4[C:27]=3[NH:26][CH:25]=[C:24]4[CH2:28][CH2:29][C:30]([O:32]C)=[O:31])[N:15]=2)[CH:5]=[C:6]([O:11][CH2:12][CH3:13])[C:7]=1[O:8][CH2:9][CH3:10].[OH-].[Na+]>O1CCCC1.CO.O>[Cl:1][C:2]1[CH:3]=[C:4]([C:14]2[O:18][N:17]=[C:16]([C:19]3[CH:20]=[CH:21][CH:22]=[C:23]4[C:27]=3[NH:26][CH:25]=[C:24]4[CH2:28][CH2:29][C:30]([OH:32])=[O:31])[N:15]=2)[CH:5]=[C:6]([O:11][CH2:12][CH3:13])[C:7]=1[O:8][CH2:9][CH3:10]
Reactant: CCOc1cc(-c2nc(-c3cccc4c(CCC(=O)OC)c[nH]c34)no2)cc(Cl)c1OCC
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: CCOc1cc(-c2nc(-c3cccc4c(CCC(=O)O)c[nH]c34)no2)cc(Cl)c1OCC
Temperature: 20 °C
Reaction time: 4 h
Yield: 20.6 %

Procedure:
To a solution of methyl 3-(7-{5-[3-chloro-4,5-bis(ethyloxy)phenyl]-1,2,4-oxadiazol-3-yl}-1H-indol-3-yl)propanoate (D70) (20 mg) in tetrahydrofuran (5 mL) and methanol (5 mL) stirred at 20° C. was added a solution of sodium hydroxide (9 mg) in water (5 mL) in one charge. The reaction mixture was stirred at 20° C. for 4 h. The organic solvent was evaporated off and the mixture was acidified with HCl (1 M) solution to pH around 1. Extracted with EtOAc (60 mL), the organic layer was separated and the organic solvent was evaporated off. The residue was purified by Mass Directed Auto Prep to afford 3-(7-{5-[3-chloro-4,5-bis(ethyloxy)phenyl]-1,2,4-oxadiazol-3-yl}-1H-indol-3-yl)propanoic acid (E45) (4 mg) as a TFA salt. δH (DMSO-d6, 400 MHz): 1.34 (3H, t), 1.43 (3H, t), 2.63 (2H, t), 3.00 (2H, t), 4.19 (2H, q), 4.27 (2H, q), 7.21 (1H, t), 7.27 (1H, d), 7.80-7.84 (2H, m), 7.95 (1H, d), 8.01 (1H, d), 10.81 (1H, s), 12.09 (1H, br s). MS (ES): C23H22ClN3O5 requires 455; found 456.2 (M+H+).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[CH:8]=[C:9]([C:11]3[N:12]=[C:13]([CH2:18][N:19]([CH3:21])[CH3:20])[N:14]([CH2:16][CH3:17])[CH:15]=3)[S:10][C:3]=12.[F:22][C:23]1[CH:28]=[C:27]([N+:29]([O-:31])=[O:30])[CH:26]=[CH:25][C:24]=1[OH:32].C(N1C=C(C2SC3C(=NC=CC=3OC3C=CC([N+]([O-])=O)=CC=3F)C=2)N=C1)C>>[CH2:16]([N:14]1[CH:15]=[C:11]([C:9]2[S:10][C:3]3[C:4](=[N:5][CH:6]=[CH:7][C:2]=3[O:32][C:24]3[CH:25]=[CH:26][C:27]([N+:29]([O-:31])=[O:30])=[CH:28][C:23]=3[F:22])[CH:8]=2)[N:12]=[C:13]1[CH2:18][N:19]([CH3:21])[CH3:20])[CH3:17]
Reactant: O=[N+]([O-])c1ccc(O)c(F)c1
Reactant: CCn1cc(-c2cc3nccc(Cl)c3s2)nc1CN(C)C
Agent: CCn1cnc(-c2cc3nccc(Oc4ccc([N+](=O)[O-])cc4F)c3s2)c1
Product: CCn1cc(-c2cc3nccc(Oc4ccc([N+](=O)[O-])cc4F)c3s2)nc1CN(C)C
Yield: 48 %

Procedure:
Starting from the chloride 112 and 2-fluoro-4-nitrophenol and following the same procedure as described above for the synthesis of compound 14 (scheme 4), title compound 113 was obtained as yellow solid in 48% yield. MS (m/z): 442.1 (M+H).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([NH:8][CH3:9])[CH:5]=[C:4]([CH3:10])[C:3]=1[CH2:11][CH2:12][S:13]([N:16]1[CH2:32][CH2:31][C:19]2([N:23]=[C:22]([CH2:24][CH2:25][CH2:26][CH2:27][CH:28]=[CH2:29])[NH:21][C:20]2=[O:30])[CH2:18][CH2:17]1)(=[O:15])=[O:14].[C:33](Cl)(=[O:43])[CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH:41]=[CH2:42].C(Cl)(=O)C(Cl)=O.C(N(CC)CC)C.[Cl-].[NH4+]>C(Cl)Cl.O.CN(C=O)C>[CH2:24]([C:22]1[NH:21][C:20](=[O:30])[C:19]2([CH2:18][CH2:17][N:16]([S:13]([CH2:12][CH2:11][C:3]3[C:4]([CH3:10])=[CH:5][C:6]([N:8]([CH3:9])[C:33](=[O:43])[CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH:41]=[CH2:42])=[CH:7][C:2]=3[CH3:1])(=[O:15])=[O:14])[CH2:32][CH2:31]2)[N:23]=1)[CH2:25][CH2:26][CH2:27][CH:28]=[CH2:29]
Reactant: C=CCCCCC1=NC2(CCN(S(=O)(=O)CCc3c(C)cc(NC)cc3C)CC2)C(=O)N1
Reactant: C=CCCCCCCCC(=O)Cl
Agent: O=C(Cl)C(=O)Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: C=CCCCCCCCC(=O)N(C)c1cc(C)c(CCS(=O)(=O)N2CCC3(CC2)N=C(CCCCC=C)NC3=O)c(C)c1
Temperature: 25 °C
Reaction time: 17 h
Yield: 46.6 %

Procedure:
The resulting crude product 8-[2-(2,6-dimethyl-4-methylamino-phenyl)-ethanesulfonyl]-2-hex-5-enyl-1,3,8-triaza-spiro[4.5]dec-1-en-4-one (160 mg, 0.35 mmol) was dissolved in methylene chloride. 9-Decenoyl chloride (0.35 mmol) (prepared by allowing oxalyl chloride and a catalytic amount of DMF to act on 9-decenoic acid in methylene chloride) and triethylamine (0.195 ml, 1.4 mmol) were added, and the mixture was stirred at room temperature for 17 hours. A saturated aqueous ammonium chloride solution and water were added to the reaction solution, and the resulting mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous sodium sulfate and then concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to give dec-9-enoic acid {4-[2-(2-hex-5-enyl-4-oxo-1,3,8-triaza-spiro[4.5]dec-1-ene-8-sulfonyl)-ethyl]-3,5-dimethyl-phenyl}-methyl-amide (Compound 1443) (100 mg, 48% in two steps).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([C:8]2[O:9][CH:10]=[CH:11][CH:12]=2)[C:5]([C:13]#[N:14])=[C:4](S(C)=O)[N:3]=1.[Br:18][C:19]1[CH:26]=[CH:25][CH:24]=[CH:23][C:20]=1[CH2:21][NH2:22]>COCCOC>[NH2:1][C:2]1[N:3]=[C:4]([NH:22][CH2:21][C:20]2[CH:23]=[CH:24][CH:25]=[CH:26][C:19]=2[Br:18])[C:5]([C:13]#[N:14])=[C:6]([C:8]2[O:9][CH:10]=[CH:11][CH:12]=2)[N:7]=1
Reactant: NCc1ccccc1Br
Reactant: CS(=O)c1nc(N)nc(-c2ccco2)c1C#N
Solvent: COCCOC
Product: N#Cc1c(NCc2ccccc2Br)nc(N)nc1-c1ccco1

Procedure:
From 2-amino-4-furan-2-yl-6-methanesulfinyl-pyrimidine-5-carbonitrile and 2-bromobenzylamine in DME. ES-MS m/e (%): 372 (M{81Br}+H+, 95), 370 (M{79Br}+H+, 100).
Reaction SMILES: BrCCBr.C[Si](C)(C)Cl.Br[CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[C:18](=[CH:23][O:24][CH3:25])[C:19]([O:21][CH3:22])=[O:20].[Cu](C#N)C#N.[Cl-].[Li+].[Cl:33][C:34]1[CH:42]=[CH:41][CH:40]=[CH:39][C:35]=1[C:36](Cl)=[O:37]>O1CCCC1.[Zn]>[Cl:33][C:34]1[CH:42]=[CH:41][CH:40]=[CH:39][C:35]=1[C:36]([CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[C:18](=[CH:23][O:24][CH3:25])[C:19]([O:21][CH3:22])=[O:20])=[O:37]
Reactant: O=C(Cl)c1ccccc1Cl
Reactant: COC=C(C(=O)OC)c1ccccc1CBr
Agent: N#C[Cu]C#N
Agent: C[Si](C)(C)Cl
Agent: [Cl-]
Solvent: C1CCOC1
Solvent: BrCCBr
Product: COC=C(C(=O)OC)c1ccccc1CC(=O)c1ccccc1Cl
Temperature: -78 °C
Reaction time: 3 h
Yield: 34.1 %

Procedure:
700 mg of 1,2-dibromoethane are added to 2.3 g of zinc powder in 20 ml of THF (tetrahydrofuran). Refluxing is carried out until evolution of gas has ended, the mixture is allowed to cool to room temperature (20° C.) and 0.2 ml of trimethylchlorosilane is added. A solution of 10 g (35 mmol) of methyl α-(2-bromomethylphenyl)-β-methoxyacrylate in 40 ml of THF is added dropwise to this solution at 0° C. and stirring is continued for 3 hours at 5° C. Thereafter, the mixture is cooled to -78° C. and a solution of 3.2 g of copper cyanide and 3 g of lithium chloride in 40 ml of THF is added. The mixture is allowed to thaw for 5 minutes at -20° C. and is again cooled to -78° C., and a solution of 6.1 g of 2-chlorobenzoyl chloride in 20 ml of THF is added dropwise. Stirring is carried out overnight at room temperature. The reaction mixture is poured onto water and extracted with ethyl acetate, and the organic phase is dried and evaporated down. Chromatography over silica gel using hexane/ethyl acetate gives 4.1 g of compound No. 5 (Table 2) as a colorless solid of melting point 70°-75° C. Yield: 35%.
Reaction SMILES: [CH3:1][CH:2]1[CH2:8][C:7](=O)[NH:6][C:5]2[CH:10]=[CH:11][CH:12]=[CH:13][C:4]=2[NH:3]1.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:23])=CC=1>C1COCC1>[CH3:1][CH:2]1[CH2:8][C:7](=[S:23])[NH:6][C:5]2[CH:10]=[CH:11][CH:12]=[CH:13][C:4]=2[NH:3]1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: CC1CC(=O)Nc2ccccc2N1
Solvent: C1CCOC1
Product: CC1CC(=S)Nc2ccccc2N1
Temperature: 80 °C
Yield: 123.4 %

Procedure:
A disposable tube was charged with 4-methyl-4,5-dihydro-1H-benzo[b][1,4]diazepin-2(3H)-one (220 mg, 1.248 mmol) in THF (12 mL). Lawesson's Reagent (278 mg, 0.687 mmol) was added, and the solution was stirred at 80° C. 1 h. The solution was concentrated with celite and purified by silica gel chromatography to yield 4-methyl-4,5-dihydro-1H-benzo[b][1,4]diazepine-2(3H)-thione as a yellow foam (0.163 g, 0.848 mmol, 68%).