Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[N:7]([CH2:8][CH2:9][CH3:10])[C:6](=[O:11])[N:5]([CH2:12][CH2:13][CH3:14])[C:4](=[O:15])[C:3]=1[NH:16][C:17]([CH:19]1[CH2:25][CH:24]2[O:26][CH:21]([CH:22]=[CH:23]2)[CH2:20]1)=O>[OH-].[Na+].CO>[CH:21]12[O:26][CH:24]([CH:23]=[CH:22]1)[CH2:25][CH:19]([C:17]1[NH:16][C:3]3[C:4](=[O:15])[N:5]([CH2:12][CH2:13][CH3:14])[C:6](=[O:11])[N:7]([CH2:8][CH2:9][CH3:10])[C:2]=3[N:1]=1)[CH2:20]2
Reactant: CCCn1c(N)c(NC(=O)C2CC3C=CC(C2)O3)c(=O)n(CCC)c1=O
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CCCn1c(=O)c2[nH]c(C3CC4C=CC(C3)O4)nc2n(CCC)c1=O
Temperature: 25 °C
Yield: 58.1 %

Procedure:
A solution of 8-oxa-bicyclo[3.2.1]oct-6-ene-3-carboxylic acid (6-amino-2,4-dioxo-1,3-dipropyl-1,2,3,4-tetrahydro-pyrimidin-5-yl)-amide (0.185 mmol, 0.067 g) in 20% NaOH (1.23 ml) and MeOH (6.2 ml) was stirred and refluxed overnight. The reaction was cooled to room temperature and then concentrated to remove MeOH. The aqueous residue was extracted with Et2O and these extracts discarded. The aqueous was acidified (pH 2-3) with conc. HCl and then extracted with EtOAc. The combined EtOAc extracts were washed with H2O and brine and dried (MgSO4). Filtration and evaporation followed by flash column chromatography, eluting with 1:1 EtOAc/CH2Cl2, provided the title compound (0.037 g, 58%) as a beige solid. 1H NMR (300 MHz, CDCl3): 0.93-0.99 (m, 6H), 1.62-1.83 (m, 6H), 2.14-2.25 (m, 2H), 3.40-3.51 (m, 1H), 4.05-1.10 (m, 4H), 4.86 (br s, 2H), 6.25 (s, 2H).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:13]=[CH:14][C:15]=1F)[C:5]([NH:7]C[Si](C)(C)C)=[O:6]>CN(C=O)C.C(OCC)(=O)C.[C-]#N.[Zn+2].[C-]#N.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>[C:5]([NH2:7])(=[O:6])[C:4]1[CH:13]=[CH:14][CH:15]=[CH:2][CH:3]=1
Reactant: C[Si](C)(C)CNC(=O)c1ccc(F)c(Br)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [C-]#N
Agent: [Zn+2]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: NC(=O)c1ccccc1
Temperature: 90 °C
Reaction time: 4 h
Yield: 200.9 %

Procedure:
3-bromo-4-fluoro-N-[(trimethylsilyl)methyl]benzamide (5.0 g) was dissolved in DMF, and zinc cyanide (1.4 g) and tetrakis(triphenylphosphine)palladium (1.9 g) were added thereto under argon atmosphere. The reaction mixture was stirred for 4 hours at 90° C. The reaction mixture was returned to room temperature. The mixture was diluted with ethyl acetate and washed with a saturated aqueous sodium hydrogen carbonate solution, subsequently dried over magnesium sulfate. After filtering the reaction mixture, the solvent was distilled off under reduced pressure, and the resulting mixture was purified by silica gel chromatography, to obtain 3-cyano-4-fluoro-N-[trimethylsilyl)methyl]benzamide (4.0 g) at a yield of 97%.
Reaction SMILES: [CH3:1][C:2]1([CH3:18])[O:17][C:6]2=[CH:7][C:8]3[C:9]([CH3:16])=[CH:10][C:11]([CH3:15])=[N:12][C:13]=3[CH:14]=[C:5]2[CH:4]=[CH:3]1.ClC1C=CC=[C:22]([C:26]([O:28]O)=[O:27])C=1.CO.S([O-])([O-])(=O)=S.[Na+].[Na+]>C(Cl)(Cl)Cl>[C:26]([O:28][CH2:15][C:11]1[CH:10]=[C:9]([CH3:16])[C:8]2[CH:7]=[C:6]3[O:17][C:2]([CH3:18])([CH3:1])[CH:3]=[CH:4][C:5]3=[CH:14][C:13]=2[N:12]=1)(=[O:27])[CH3:22]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: Cc1cc(C)c2cc3c(cc2n1)C=CC(C)(C)O3
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: CO
Product: CC(=O)OCc1cc(C)c2cc3c(cc2n1)C=CC(C)(C)O3
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 64 %

Procedure:
To a solution of 2,2,7,9-tetramethyl-2H-pyrano[2,3-g]quinoline (3.0 g, 12.5 mmol) in chloroform (30.0 mL), a solution of m-chloroperbenzoic acid (4.76 g, 27.6 mmol) in chloroform (12 mL)-methanol (3 mL) was added dropwise at room temperature, and the resulting mixture was stirred at room temperature for 30 minutes. Upon the completion of the reaction, aqueous sodium thiosulfate solution was added to the reaction solution, and it was extracted. The resulting organic phase was washed with sodium hydrogencarbonate and then with aqueous sodium chloride solution, and dried over anhydrous magnesium sulfate. After distilling off the solvent, acetic anhydride (12 mL) was added to the residue, and the resulting mixture was stirred at 150° C. for 1 hour. Upon the completion of the reaction, acetic anhydride was distilled off, the residue was neutralized with aqueous sodium carbonate solution, extracted with chloroform, and the resulting organic phase was washed with aqueous sodium chloride solution, and dried over anhydrous magnesium sulfate. After distilling off the solvent, the residue was purified by medium pressure column chromatography (hexane/ethyl acetate=2/1) and the aimed product was obtained (yield: 64%).
Reaction SMILES: [CH3:1][C:2]1([CH3:23])[O:6][C@@H:5]([CH2:7][O:8][C:9]2[CH:10]=[C:11]([C:19]([O:21]C)=[O:20])[CH:12]=[C:13]([CH:18]=2)[C:14]([O:16]C)=[O:15])[CH2:4][O:3]1.[OH-].[Na+]>CO>[CH3:1][C:2]1([CH3:23])[O:6][C@@H:5]([CH2:7][O:8][C:9]2[CH:18]=[C:13]([C:14]([OH:16])=[O:15])[CH:12]=[C:11]([CH:10]=2)[C:19]([OH:21])=[O:20])[CH2:4][O:3]1
Reactant: COC(=O)c1cc(OC[C@H]2COC(C)(C)O2)cc(C(=O)OC)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CC1(C)OC[C@H](COc2cc(C(=O)O)cc(C(=O)O)c2)O1

Procedure:
1.40 g of dimethyl (S)-5-(2,2-dimethyl-[1,3]dioxolan-4-ylmethoxy)-isophthalate were stirred at room temperature for 16 hours with 4 ml of sodium hydroxide solution (28%) in 50 ml of methanol. After neutralization with 6N hydrochloric acid, the methanol was distilled off in a water-jet vacuum. The residue was poured on to ice-water, extracted with methylene chloride, the combined methylene chloride phases were washed with water, dried over magnesium sulfate, filtered and evaporated. There was obtained (S)-5-(2,2-dimethyl-[1,3]dioxolan-4-ylmethoxy)-isophthalic acid, MS: m/z 296 ([M]+).
Reaction SMILES: [CH:1](=O)[C:2]1[CH:12]=[C:9]([O:10][CH3:11])[C:7]([OH:8])=[C:4]([O:5][CH3:6])[CH:3]=1.[C:14]([NH:17][CH2:18][C:19]([OH:21])=[O:20])(=[O:16])[CH3:15].C([O-])(=O)C.[Na+].C(OC(=O)C)(=O)C>>[C:14]([NH:17][C:18](=[CH:1][C:2]1[CH:12]=[C:9]([O:10][CH3:11])[C:7]([OH:8])=[C:4]([O:5][CH3:6])[CH:3]=1)[C:19]([OH:21])=[O:20])(=[O:16])[CH3:15]
Reactant: CC(=O)NCC(=O)O
Reactant: COc1cc(C=O)cc(OC)c1O
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)OC(C)=O
Product: COc1cc(C=C(NC(C)=O)C(=O)O)cc(OC)c1O
Temperature: 90 °C
Reaction time: 1 h
Yield: 31.7 %

Procedure:
A 1.8 g (9.88 mmol) of syringaldehyde, 1.4 g (12.0 mmol) of N-acetylglycine, 1 g (12.2 mmol) of sodium acetate and 5 ml of acetic anhydride were stirred at 120° C. for 6 hours. A precipitate was washed with water and ethanol in this order and dried under reduced pressure. To the product was added 80 ml of 0.1N hydrochloric acid, and the mixture was stirred at 90° C. for 1 hour. A crystal formed was washed with water and acetone in this order to give 880 mg (yield 31.7%) of objective αacetylamino-3,5-dimethoxy-4-hydroxycinnamic acid.
Reaction SMILES: S(Cl)(Cl)=O.[CH3:5][C:6]1[O:7][CH2:8][CH2:9][S:10][C:11]=1[C:12]([OH:14])=O.[NH2:15][C:16]1[CH:17]=[CH:18][C:19]([Cl:29])=[C:20]([CH:28]=1)[C:21]([O:23][CH2:24][CH2:25][CH2:26][CH3:27])=[O:22].C(N(CC)CC)C>C(Cl)Cl>[Cl:29][C:19]1[CH:18]=[CH:17][C:16]([NH:15][C:12]([C:11]2[S:10][CH2:9][CH2:8][O:7][C:6]=2[CH3:5])=[O:14])=[CH:28][C:20]=1[C:21]([O:23][CH2:24][CH2:25][CH2:26][CH3:27])=[O:22]
Reactant: CC1=C(C(=O)O)SCCO1
Reactant: CCCCOC(=O)c1cc(N)ccc1Cl
Solvent: O=S(Cl)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCCOC(=O)c1cc(NC(=O)C2=C(C)OCCS2)ccc1Cl
Temperature: 25 °C
Reaction time: 8 h
Yield: 41 %

Procedure:
Thionyl chloride (4.4 g, 0.037 mole) was added to a stirred mixture of 5,6-dihydro-2-methyl-1,4-oxathiin-3-carboxylic acid (5.0 g, 0.031 mole) and methylene chloride (50 ml). The mixture was warmed to 35°-40° C. for about 3 hours, left stirring overnight at room temperature, and evaporated under reduced pressure. The solid residue, crude 5,6-dihydro-2-methyl-1,4-oxathiin-3-carbonyl chloride, was dissolved in methylene chloride (50 ml) and the solution treated dropwise at 5°-10° C. over 2 hours with a solution of butyl 5-amino-2-chlorobenzoate (6.1 g, 0.031 mole) and triethylamine (3.6 g, 0.036 mole) in methylene chloride (50 ml). The reaction mixture was stirred at room temperature for a further 3 hours and then worked up by washing in sequence with water (50 ml), dilute hydrochloric acid (3.5%, 50 ml), water (50 ml), dilute sodium hydroxide (2%, 25 ml) and water (50ml). Evaporation of the solvent left an oil, which slowly solidified. Recrystallization from methanol (50 ml) gave beige crystals, m.p. 71°-73° C. (4.7 g, 41% yield).
Reaction SMILES: FC([Si:5]([CH3:8])([CH3:7])[CH3:6])(F)F.[Si:9]([O:16][C@H:17]1[CH2:22][CH2:21][C@H:20]2[C@@:23]3([CH:47]=[CH2:48])[C@H:32]([C@@H:33]([CH2:35][CH2:36][CH2:37][CH2:38][C:39](=[O:44])[C:40]([F:43])([F:42])[F:41])[CH2:34][C@:18]12[CH3:19])[C:31]1[CH:30]=[CH:29][C:28]([O:45][CH3:46])=[CH:27][C:26]=1[CH2:25][CH2:24]3)(C(C)(C)C)([CH3:11])[CH3:10]>>[C:18]([C@H:19]1[CH2:22][CH2:21][C@H:20]2[C@@:23]3([CH:47]=[CH2:48])[C@H:32]([C@@H:33]([CH2:35][CH2:36][CH2:37][CH2:38][C:39]([C:40]([F:43])([F:42])[F:41])([O:44][Si:5]([CH3:6])([CH3:7])[CH3:8])[C:40]([F:41])([F:42])[F:43])[CH2:34][C@:18]12[CH2:17][O:16][SiH:9]([CH3:11])[CH3:10])[C:31]1[CH:30]=[CH:29][C:28]([O:45][CH3:46])=[CH:27][C:26]=1[CH2:25][CH2:24]3)([CH3:20])([CH3:19])[CH3:17]
Reactant: C[Si](C)(C)C(F)(F)F
Reactant: C=C[C@@]12CCc3cc(OC)ccc3[C@H]1[C@@H](CCCCC(=O)C(F)(F)F)C[C@]1(C)[C@@H](O[Si](C)(C)C(C)(C)C)CC[C@H]12
Product: C=C[C@@]12CCc3cc(OC)ccc3[C@H]1[C@@H](CCCCC(O[Si](C)(C)C)(C(F)(F)F)C(F)(F)F)C[C@]1(CO[SiH](C)C)[C@@H](C(C)(C)C)CC[C@@H]21

Procedure:
In the reaction with (trifluoromethyl)-trimethylsilane analogously to instructions 1.1, 200 mg of alcohol 16a yields 200 mg of the column-chromatographically stable trimethylsilyl ether 17a as a light yellow, viscous mass (GC-MS: m/z theor.: 720, pract.: 720). The latter is, without the reaction with tetrabutylammonium fluoride-trihydrate being performed, used in the next stage.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][CH2:5][C:6]1([CH2:16][CH3:17])[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[NH:8][C:7]1=[O:15].[Cl:18][C:19]1[CH:20]=[C:21]([N:26]2[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]2)[CH:22]=[CH:23][C:24]=1[F:25]>>[Cl:18][C:19]1[CH:20]=[C:21]([N:26]2[CH2:31][CH2:30][N:29]([CH2:2][CH2:3][CH2:4][CH2:5][C:6]3([CH2:16][CH3:17])[C:14]4[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=4)[NH:8][C:7]3=[O:15])[CH2:28][CH2:27]2)[CH:22]=[CH:23][C:24]=1[F:25]
Reactant: Fc1ccc(N2CCNCC2)cc1Cl
Reactant: CCC1(CCCCCl)C(=O)Nc2ccccc21
Product: CCC1(CCCCN2CCN(c3ccc(F)c(Cl)c3)CC2)C(=O)Nc2ccccc21

Procedure:
The title compound is prepared according to process H by applying processing method 1 starting from 3-(4-chlorobutyl)-3-ethyl-1,3-dihydro-2H-indol-2-one and 1-(3-chloro-4-fluoro-phenyl)-piperazine.
Reaction SMILES: [CH2:1]([N:8]([CH2:22][CH:23](OCC)[O:24]CC)[C:9](=[O:21])[CH2:10][CH2:11][O:12][CH2:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.ClCCl>O1CCOCC1>[CH2:1]([N:8]([CH2:22][CH:23]=[O:24])[C:9](=[O:21])[CH2:10][CH2:11][O:12][CH2:13][CH2:14][C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(CN(Cc1ccccc1)C(=O)CCOCCc1ccccc1)OCC
Agent: Cl
Solvent: ClCCl
Solvent: C1COCCO1
Product: O=CCN(Cc1ccccc1)C(=O)CCOCCc1ccccc1

Procedure:
N-Benzyl-N-(2,2-diethoxyethyl)-3-phenethyloxy-propanamide (Example 4a), 0.3 g) was dissolved in anhydrous dioxane (7 mL) and treated with concentrated hydrochloric acid (2 mL) at ambient temperature. The resultant solution was stirred at ambient temperature for 2.5 hours. The reaction mixture was poured into dichloromethane (20 mL) and washed with water (2×20 mL) and brine (20 mL). The organic layer was isolated, dried over anhydrous magnesium sulphate, filtered and concentrated to give the sub-titled compound (0.19 g) as a viscous oil.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH:12]([C:13]([OH:17])([CH3:16])[CH:14]=[CH2:15])[CH2:11][O:10]C1(C)C)=[O:7])([CH3:4])([CH3:3])[CH3:2].O.C1(C)C=CC(S(O)(=O)=O)=CC=1>CO.C(=O)(O)[O-].[Na+]>[C:1]([O:5][C:6](=[O:7])[NH:8][CH:12]([CH2:11][OH:10])[C:13]([OH:17])([CH3:16])[CH:14]=[CH2:15])([CH3:4])([CH3:2])[CH3:3]
Reactant: C=CC(C)(O)C1COC(C)(C)N1C(=O)OC(C)(C)C
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CO
Product: C=CC(C)(O)C(CO)NC(=O)OC(C)(C)C
Reaction time: 0.5 h
Yield: 100.1 %

Procedure:
To a solution of 4-(1-hydroxy-1-methyl-allyl)-2,2-dimethyl-oxazolidine-3-carboxylic acid tert-butyl ester (compound of formula II, 3.3 g, 12.1 mmol, prepared as in Ageno, G.; Banfi, L.; Cascio, G.; Guanti, G.; Manghisi, E.; Riva, R.; Rocca, V. Tetrahedron, 1995, 29, 8121) in 100 ml of methanol was added p-toluenesulfonic acid monohydrate (0.215 g, 1.1 mmol). After stirring for about 30 minutes at a temperature of about 20° C. to about 25° C., the mixture was diluted with saturated aqueous sodium bicarbonate and was concentrated in vacuo. The residue was diluted with water and was extracted 3 times into ethyl acetate. The combined organic layers were dried over sodium sulfate, filtered and concentrated in vacuo to afford 2.8 g of (2-Hydroxy-1-hydroxymethyl-2-methyl-but-3-enyl)-carbamic acid tert-butyl ester (compound of formula III) as a colorless syrup.
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([CH3:11])[C:3]=1[C:4]([OH:6])=[O:5].[CH3:12]N(C=O)C.C(Cl)(=O)C(Cl)=O>ClCCl>[CH3:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([CH3:11])[C:3]=1[C:4]([O:6][CH3:12])=[O:5]
Reactant: Cc1cccc(C)c1C(=O)O
Reactant: CN(C)C=O
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Product: COC(=O)c1c(C)cccc1C
Temperature: 0 °C
Reaction time: 3 h

Procedure:
To a cooled (0° C.) solution of 2,6-dimethylbenzoic acid (20.2 g, 134 mmol) in dichloromethane (200 mL) is added DMF (1 mL) followed by oxalyl chloride (14 mL, 162 mmol). On complete addition, the cold bath is removed and stirring continued for 3 h. The resulting solution is concentrated under vacuum and the residue added slowly to a cooled (0° C.) solution comprising methanol (200 mL) and triethylamine (40 mL). On complete addition the reaction mixture is stirred for 30 min. then poured into hydrochloric acid solution (400 mL, 2N) which is then extracted with ether. The ether extract is washed with hydrochloric acid solution (1N), sokium bicarbonate solution and brine; then dried over MgSO4 and concentrated to give the title compound which is used without further purification. MS (EI) 164 (M)+.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:8](Cl)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[CH:12]1([CH2:15][NH2:16])[CH2:14][CH2:13]1>ClCCl>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:16][CH2:15][CH:12]2[CH2:14][CH2:13]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: NCC1CC1
Reactant: O=S(=O)(Cl)c1ccc(Br)cc1
Solvent: ClCCl
Product: O=S(=O)(NCC1CC1)c1ccc(Br)cc1
Yield: 26.5 %

Procedure:
According to general procedure C, 4-Bromobenzene sulfonyl chloride (0.40 g, 1.56 mmol) and cyclopropylmethylamine (0.35 mL, 3.90 mmol) were stirred together in dry dichloromethane (5 mL) for 16 hours. 4-bromo-N-(cyclopropylmethyl)benzenesulfonamide (0.12 g) was provided after purification. MS (ESI) m/z 290. HPLC purity 100.0% at 210-370 nm, 9.0 min.; the Xterra® RP18 column, 3.5μ, 150×4.6 mm column, 1.2 mL/min., 85/15-5/95 (ammonium formate buffer pH=3.5/ACN+MeOH) for 10 min., hold 4 min.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9]2[CH:14]=[CH:13][C:12]([C:15]34[CH2:24][CH:19]5[CH2:20][CH:21]([CH2:23][CH:17]([CH2:18]5)[CH2:16]3)[CH2:22]4)=[CH:11][CH:10]=2)=[CH:4][C:3]=1[N:25]([CH3:33])[C:26](=[O:32])[O:27][C:28]([CH3:31])([CH3:30])[CH3:29].[O:34]=[C:35]1[NH:39][C:38](=[O:40])[CH:37]([CH2:41][C:42]2[CH:52]=[CH:51][C:45]([O:46][CH2:47][C:48](O)=[O:49])=[CH:44][CH:43]=2)[S:36]1.C(P(=O)(OCC)OCC)#N.C(N(CC)CC)C>O1CCCC1>[O:34]=[C:35]1[NH:39][C:38](=[O:40])[CH:37]([CH2:41][C:42]2[CH:43]=[CH:44][C:45]([O:46][CH2:47][C:48]([NH:1][C:2]3[CH:7]=[CH:6][C:5]([O:8][C:9]4[CH:10]=[CH:11][C:12]([C:15]56[CH2:24][CH:19]7[CH2:18][CH:17]([CH2:23][CH:21]([CH2:20]7)[CH2:22]5)[CH2:16]6)=[CH:13][CH:14]=4)=[CH:4][C:3]=3[N:25]([CH3:33])[C:26](=[O:32])[O:27][C:28]([CH3:29])([CH3:30])[CH3:31])=[O:49])=[CH:51][CH:52]=2)[S:36]1
Reactant: CN(C(=O)OC(C)(C)C)c1cc(Oc2ccc(C34CC5CC(CC(C5)C3)C4)cc2)ccc1N
Reactant: O=C(O)COc1ccc(CC2SC(=O)NC2=O)cc1
Agent: CCOP(=O)(C#N)OCC
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CN(C(=O)OC(C)(C)C)c1cc(Oc2ccc(C34CC5CC(CC(C5)C3)C4)cc2)ccc1NC(=O)COc1ccc(CC2SC(=O)NC2=O)cc1
Yield: 86.1 %

Procedure:
In a similar manner to that described in Example (2-1), a reaction was carried out using t-butyl N-{2-amino-5-[4-(1-adamantyl)phenoxy]phenyl}-N-methylcarbamate (1.34 g), 4-(2,4-dioxothiazolidin-5-ylmethyl)phenoxyacetic acid (0.93 g), diethyl cyanophosphonate (0.54 g), triethylamine (0.33 g) and anhydrous tetrahydrofuran (20 ml) and the reaction mixture was purified to give the desired product (1.83 g).
Reaction SMILES: C[O:2][C:3](=[O:19])[CH:4]([C:11]1[CH:16]=[CH:15][C:14]([C:17]#[N:18])=[CH:13][CH:12]=1)[CH2:5][CH:6]1[CH2:10][CH2:9][CH2:8][CH2:7]1.[OH-].[Li+].Cl>O1CCCC1.O.CO>[C:17]([C:14]1[CH:13]=[CH:12][C:11]([CH:4]([CH2:5][CH:6]2[CH2:10][CH2:9][CH2:8][CH2:7]2)[C:3]([OH:19])=[O:2])=[CH:16][CH:15]=1)#[N:18]
Reactant: COC(=O)C(CC1CCCC1)c1ccc(C#N)cc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: N#Cc1ccc(C(CC2CCCC2)C(=O)O)cc1
Temperature: 25 °C
Reaction time: 6 h
Yield: 59.2 %

Procedure:
A solution of 2-(4-cyano-phenyl)-3-cyclopentyl-propionic acid methyl ester (65.0 mg, 0.25 mmol) in tetrahydrofuran/water/methanol (2.5 mL, 3:1:1) was treated with a 1N aqueous lithium hydroxide solution (0.27 mL, 0.27 mmol). The reaction was stirred at 25° C. for 6 h. At this time, the reaction was acidified to pH=1 with a 1N aqueous hydrochloric acid solution and extracted with chloroform/methanol (9:1, 3×25 mL). The combined organic layers were dried over sodium sulfate, filtered, and concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 230-400 mesh, 80/20 hexanes/ethyl acetate) afforded 2-(4-cyano-phenyl)-3-cyclopentyl-propionic acid (36.0 mg, 58.6%) as a white solid: mp 126-128° C.; EI-HRMS m/e calcd for C15H17NO2 (M+) 243.1259 found 243.1268.
Reaction SMILES: Cl.Cl.Cl.[O:4]1[C:12]2[CH:11]=[CH:10][N:9]=[C:8]([N:13]3[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][C@H:21]4[CH2:26][CH2:25][C@H:24]([NH2:27])[CH2:23][CH2:22]4)[CH2:15][CH2:14]3)[C:7]=2[CH2:6][CH2:5]1.[N:28]1([C:33]2[CH:41]=[CH:40][C:36]([C:37](O)=[O:38])=[CH:35][CH:34]=2)[CH:32]=[CH:31][CH:30]=[N:29]1>>[O:4]1[C:12]2[CH:11]=[CH:10][N:9]=[C:8]([N:13]3[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][C@H:21]4[CH2:26][CH2:25][C@H:24]([NH:27][C:37](=[O:38])[C:36]5[CH:35]=[CH:34][C:33]([N:28]6[CH:32]=[CH:31][CH:30]=[N:29]6)=[CH:41][CH:40]=5)[CH2:23][CH2:22]4)[CH2:15][CH2:14]3)[C:7]=2[CH2:6][CH2:5]1
Reactant: O=C(O)c1ccc(-n2cccn2)cc1
Reactant: N[C@H]1CC[C@H](CCN2CCN(c3nccc4c3CCO4)CC2)CC1
Agent: Cl
Product: O=C(N[C@H]1CC[C@H](CCN2CCN(c3nccc4c3CCO4)CC2)CC1)c1ccc(-n2cccn2)cc1

Procedure:
The title compound, white solid (109 mg, 87%), MS (ISP) m/z=501.3 [(M+H)+], mp 229° C., was prepared in accordance with the general method of example 32 from trans-4-{2-[4-(2,3-dihydrofuro[3,2-c]pyridin-4-yl)-piperazin-1-yl]-ethyl}-cyclohexanamine trihydrochloride (intermediate C) (110 mg, 0.25 mmol) and 4-pyrazol-1-yl-benzoic acid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C@:9]([OH:19])([C@H:16]([SH:18])[CH3:17])[CH2:10][N:11]1[CH:15]=[N:14][CH:13]=[N:12]1.C(N(CC)CC)C.[C:27](Cl)(=[O:31])[CH:28]([CH3:30])[CH3:29]>ClCCl>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C@:9]([OH:19])([C@H:16]([S:18][C:27](=[O:31])[CH:28]([CH3:30])[CH3:29])[CH3:17])[CH2:10][N:11]1[CH:15]=[N:14][CH:13]=[N:12]1
Reactant: CC(C)C(=O)Cl
Reactant: C[C@@H](S)[C@](O)(Cn1cncn1)c1ccc(F)cc1F
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)C(=O)S[C@H](C)[C@](O)(Cn1cncn1)c1ccc(F)cc1F
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 78.6 %

Procedure:
In dichloromethane (5 ml) was dissolved (2R,3R)-2-(2,4-difluorophenyl)-3-mercapto-1-(1H-1,2,4-triazol-1-yl)-2-butanol (143 mg), followed by addition of triethylamine (0.076 ml) and isobutyryl chloride (58.6 mg) under ice-cooling. The mixture was stirred at room temperature for 15 minutes, and then the solvent was distilled off under reduced pressure. The residue was purified by silica gel chromatography (eluent:hexane-ethyl acetate=1:2). The desired fraction was concentrated to give (2R,3R)-2-(2,4-difluorophenyl)-3-isobutyrylthio-1-(1H-1,2,4-triazol-1-yl)-2-butanol (compound 62, 140 mg) as a colorless syrup. This product was treated with 4N hydrochloric acid (in ethyl acetate) to give the hydrochloride, which was then crystallized from ether to give compound 62 hydrochloride (156 mg) as a colorless powder. m.p. 129°-138° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[C:9](I)[CH:10]=1)[NH:7][N:6]=[CH:5]2.B(O)(O)[C:13]1[S:21][C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH:14]=1.COCCOC.C([O-])([O-])=O.[Na+].[Na+]>O>[S:21]1[C:13]([C:9]2[CH:10]=[C:2]([Br:1])[CH:3]=[C:4]3[C:8]=2[NH:7][N:6]=[CH:5]3)=[CH:14][C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][C:20]1=2
Reactant: Brc1cc(I)c2[nH]ncc2c1
Reactant: OB(O)c1cc2ccccc2s1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Product: Brc1cc(-c2cc3ccccc3s2)c2[nH]ncc2c1
Temperature: 90 °C
Reaction time: 0.5 h
Yield: 70 %

Procedure:
A mixture of 5-bromo-7-iodo-1H-indazole (Preparation #22a, 30.0 g, 92.9 mmol) and thianapthene-2-boronic acid (21.5 g, 120.7 mmol), DME (480 mL), water (48 mL), Na2CO3 (29.5 g, 279 mmol) and tetrakis triphenylphosphine palladium (0) (8.6 g, 7.43 mmol) was heated at about 90° C. in an oil bath under an atmosphere of nitrogen for about 15 hours. The solvent was removed under reduced pressure and the residue was suspended in a mixture of ethyl acetate (600 mL) and water (300 mL). The mixture was stirred for about 30 minutes and the resulting solid was collected by filtration and dried to yield 7-Benzo[b]thiophen-2-yl-5-bromo-1H-indazole (21.4 g, 70%); (DMSO-d6, 400 MHz) δ 13.63 (s, 1H), 8.24 (s, 1H), 8.05-8.09 (m, 3H), 7.92 (d, 1H), 7.65 (s, 1H), 7.16 (m, 2H); RP-HPLC (Table 1, Method e) Rt=2.69 min; m/z: (M−H)− 328.4.
Reaction SMILES: [CH:1]1([CH2:6][OH:7])[CH2:5][CH2:4][CH2:3][CH2:2]1.[H-].[Na+].[CH2:10]([O:17][C:18]1[CH:19]=[CH:20][C:21]2[O:27][CH2:26][CH2:25][CH:24](Br)[C:23](=[O:29])[C:22]=2[CH:30]=1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>O1CCCC1>[CH2:10]([O:17][C:18]1[CH:19]=[CH:20][C:21]2[O:27][CH2:26][CH2:25][CH:24]([O:7][CH2:6][CH:1]3[CH2:5][CH2:4][CH2:3][CH2:2]3)[C:23](=[O:29])[C:22]=2[CH:30]=1)[C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1
Reactant: O=C1c2cc(OCc3ccccc3)ccc2OCCC1Br
Reactant: OCC1CCCC1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: O=C1c2cc(OCc3ccccc3)ccc2OCCC1OCC1CCCC1

Procedure:
To a solution of 1.5 g of (cyclopentyl)methanol in 50 ml of tetrahydrofuran is added 720 mg of 50% sodium hydride. After stirring until evolution of H2 is substantially complete (about 30 minutes), a solution of 4.5 g of crude 7-benzyloxy-4-bromo-3,4-dihydro-1-benzoxepin-5 (2H)-one is added. The reaction is allowed to stir at room temperature for 5 hours. The tetrahydrofuran is evaporated in vacuo, and the residue dissolved in ethyl acetate and washed with water. The ethyl acetate layer is dried over sodium sulfate and evaporated in vacuo to yield present title product.