Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: F[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[C:4]([F:11])[C:3]=1[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=1.CN.C[CH2:21][N:22](C(C)C)C(C)C>C(#N)C>[F:11][C:4]1[C:3]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=2)=[C:2]([CH2:21][NH2:22])[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=1
Reactant: CCN(C(C)C)C(C)C
Reactant: O=[N+]([O-])c1ccc(F)c(-c2ccccn2)c1F
Agent: CN
Solvent: CC#N
Product: NCc1c([N+](=O)[O-])ccc(F)c1-c1ccccn1
Temperature: 25 °C
Reaction time: 8 h
Yield: 85.7 %

Procedure:
A mixture of 2-(2,6-difluoro-3-nitrophenyl)pyridine (1.0 g, 4.2 mmol), methylamine (2.24 mL, 4.24 mmol, 2M in THF) and DIPEA (0.75 mL, 4.2 mmol) in acetonitrile (10 mL) was stirred overnight at RT. The mixture was concentrated in vacuo and the resulting residue was purified by chromatography (Si—PPC, gradient 0-40% EtOAc/cyclohexane) to afford the title compound as a yellow solid (0.89 g, 84%). 1H NMR (CDCl3, 400 MHz): δ 8.74 (1H, ddd, 5.0, 2.1, 1.0 Hz) 8.46 (1H, br s) 8.27 (1H, dd, 9.5, 6.2 Hz), 7.80 (1H, td, 7.8, 2.1 Hz), 7.47 (1H, dq, 4.0, 1.2 Hz), 7.34 (1H, dd, 9.5, 8.2 Hz), 2.36 (3H, d, 5.3 Hz)
Reaction SMILES: C([O:8][CH2:9][N:10]1[C:18]2[C:13](=[CH:14][C:15]([C:19]([OH:21])=[O:20])=[CH:16][CH:17]=2)[CH:12]=[CH:11]1)C1C=CC=CC=1.[H][H]>C(O)C.[Pd]>[OH:8][CH2:9][N:10]1[C:18]2[C:13](=[CH:14][C:15]([C:19]([OH:21])=[O:20])=[CH:16][CH:17]=2)[CH:12]=[CH:11]1
Reactant: O=C(O)c1ccc2c(ccn2COCc2ccccc2)c1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: O=C(O)c1ccc2c(ccn2CO)c1
Yield: 46.5 %

Procedure:
The 1-benzyloxymethyl-1H-indole-5-carboxylic acid (380 mg) obtained in Intermediate Example 47 was suspended in ethanol (6.5 ml). 10% Palladium on carbon (190 mg) was added thereto and stirred for 47 hours at 60° C. in a hydrogen atmosphere. Insoluble matter was removed by filtration, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (eluting solvent; dichloromethane:methanol 50:1) to give the title compound (120 mg, Y.:48%).
Reaction SMILES: [CH:1]([CH:3]1[CH2:8][CH2:7][CH:6]2[O:9][CH:5]2[CH2:4]1)=[CH2:2].[CH3:10][O:11][SiH:12]([O:15][CH3:16])[O:13][CH3:14]>[H+].[H+].Cl[Pt-2](Cl)(Cl)(Cl)(Cl)Cl>[O:9]1[CH:6]2[CH:5]1[CH2:4][CH:3]([CH2:1][CH2:2][Si:12]([O:15][CH3:16])([O:13][CH3:14])[O:11][CH3:10])[CH2:8][CH2:7]2
Reactant: C=CC1CCC2OC2C1
Reactant: CO[SiH](OC)OC
Agent: Cl[Pt-2](Cl)(Cl)(Cl)(Cl)Cl
Agent: [H+]
Product: CO[Si](CCC1CCC2OC2C1)(OC)OC
Temperature: 89 °C
Reaction time: 0.3 h
Yield: 90 %

Procedure:
The apparatus of Example B was charged with 148.8 g (1.2 mol) of 1-vinyl-3,4-epoxycyclohexane, 1.3 g of a carboxylic acid promoter, and 0.15 ml Of 10% chloroplatinic acid catalyst solution. The flask contents were heated to 89° C. and dropwise addition of 122.8 g (1.0 mol) of trimethoxysilane was begun. The reaction temperature was controlled at 90°-95° C. with an ice bath. Reaction was maintained at that temperature for half an hour after completion of addition, which took 18 minutes. Analysis by gas chromatography showed a yield of 90% of 2-(3,4-epoxycyclohexyl)ethyltrimethoxysilane. This example demonstrates a standard preparation of 2-(3,4-epoxycyclohexylethyltrimethoxysilane using commercial chloroplatinic acid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]([CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH:25]([CH3:28])[C:26]#[N:27])[O:11][C:12]=2[C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=2)=[CH:4][CH:3]=1.[N-:29]=[N+:30]=[N-:31].[Na+].Cl.C(N(CC)CC)C>CN(C)C=O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:9]=[C:10]([CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH:25]([C:26]3[NH:31][N:30]=[N:29][N:27]=3)[CH3:28])[O:11][C:12]=2[C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=2)=[CH:6][CH:7]=1
Reactant: CC(C#N)CCCCCc1nc(-c2ccc(Cl)cc2)c(-c2ccc(Cl)cc2)o1
Reactant: [N-]=[N+]=[N-]
Agent: Cl
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(CCCCCc1nc(-c2ccc(Cl)cc2)c(-c2ccc(Cl)cc2)o1)c1nnn[nH]1
Yield: 55 %

Procedure:
4.45 g of (RS)-7-[4,5-bis(4-chlorophenyl)-2-oxazolyl]-2-methylheptanenitrile in 40 cm3 of dimethylformamide are treated with twice 2.1 g of sodium azide and twice 4.4 g of triethylamine hydrochloride under the (time and temperature) conditions defined in Example 1. After treatment, the product of the reaction is chromatographed on a column 2.8 cm in diameter containing 115 g of silica gel (50 to 200μ). The column is eluted with 1.2 liters of diisopropyl ether and then with 2.8 liters of a diisopropyl ether/ethyl acetate (80:20 by volume) mixture, collecting 200 cm3 fractions. The fractions from the last eluent mixture are concentrated to dryness under reduced pressure (0.2 kPa). 2.7 g (55%) of (RS)-5-{7-[4,5-bis(4-chlorophenyl)-2-oxazolyl]-2-heptyl}-1H-tetrazole are obtained in the form of white crystals, melting point 144° C.
Reaction SMILES: [NH:1]1[CH:5]=[N:4][N:3]=[N:2]1.[H-].[Na+].[CH2:8]([N:14]1[C:23]2[C:18](=[CH:19][C:20]([CH3:24])=[CH:21][CH:22]=2)[C:17]([O:25][CH3:26])=[C:16]([CH2:27]Br)[C:15]1=[O:29])[CH2:9][CH2:10][CH2:11][CH2:12][CH3:13]>CN(C)C=O.C(OC(=O)C)C>[CH2:8]([N:14]1[C:23]2[C:18](=[CH:19][C:20]([CH3:24])=[CH:21][CH:22]=2)[C:17]([O:25][CH3:26])=[C:16]([CH2:27][C:5]2[NH:4][N:3]=[N:2][N:1]=2)[C:15]1=[O:29])[CH2:9][CH2:10][CH2:11][CH2:12][CH3:13]
Reactant: c1nnn[nH]1
Reactant: CCCCCCn1c(=O)c(CBr)c(OC)c2cc(C)ccc21
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCCCCCn1c(=O)c(Cc2nnn[nH]2)c(OC)c2cc(C)ccc21
Temperature: 25 °C
Reaction time: 2 h
Yield: 52.2 %

Procedure:
A solution of tetrazole (0.17 g) in dimethylformamide (2 ml) at ice-bath temperature under nitrogen was stirred with 60% sodium hydride (0.1 g) for 5 mins and then a solution of 1-hexyl-3-bromomethyl-4-methoxy-6-methyl-2(1H)-quinolinone (Example 14, 0.73 g) in dimethylformamide (8 ml) was added to it. The reaction mixture was stirred at room temperature for 2 hours, diluted with ethylacetate and then washed several times with water. The organic layer was dried and evaporated under reduced pressure. The resulting crude reaction product was chromatographed on silica-gel (30 g). Elution with 10% to 20% ethylacetatedichloromethane gave 1-hexyl-3-(1-tetrazolylmethyl)-4-methoxy-6-methyl-2(1H)-quinolinone (0.37 g). That this compound was obtained was confirmed by the spectral data: MS: m/e 355 (M.+); NMR (CDCl3): δ4.18 (s, 3H, OCH3), 5.68 (s, 2H, CH2), 9.14 (s, 1H, CH=).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:16])/[CH:5]=[C:6](/[O:8][C:9]1[CH:10]=[N:11][C:12]([CH3:15])=[CH:13][CH:14]=1)\[CH3:7])[CH3:2].[Br:17]N1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(Cl)(Cl)(Cl)Cl>[CH2:1]([O:3][C:4](=[O:16])/[CH:5]=[C:6](/[O:8][C:9]1[CH:10]=[N:11][C:12]([CH3:15])=[CH:13][CH:14]=1)\[CH2:7][Br:17])[CH3:2]
Reactant: O=C1CCC(=O)N1Br
Reactant: CCOC(=O)/C=C(\C)Oc1ccc(C)nc1
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: CCOC(=O)/C=C(\CBr)Oc1ccc(C)nc1
Yield: 43.7 %

Procedure:
To a stirred mixture of (E)-3-(6-methyl-pyridin-3-yloxy)-but-2-enoic acid ethyl ester (3.50 g, 0.016 mol) in carbon tetrachloride (25 mL) under a nitrogen atmosphere was added N-bromosuccinimide (4.23 g, 0.024 mol) and benzoyl peroxide (383 mg, 0.002 mol). Nitrogen gas was bubbled through the mixture for 5 min, and the resulting mixture was heated to reflux for 4 h. The reaction mixture was then placed in the refrigerator overnight. The solids formed were removed by filtration and the filtrate concentrated in vacuo. The crude product obtained was purified using flash column chromatography (silica gel (100-200 mesh), ethyl acetate/hexanes) to afford (E)-4-bromo-3-(6-methyl-pyridin-3-yloxy)-but-2-enoic acid ethyl ester (2.10 g, 44%) as a yellow oil.
Reaction SMILES: [C:1]([NH:4][C:5]1[N:6]=[C:7]([OH:27])[C:8]2[CH:14]=[C:13]([CH:15]=[C:16]([C:18]3[CH:23]=[CH:22][C:21]([C:24](O)=O)=[CH:20][CH:19]=3)[CH3:17])[CH:12]=[N:11][C:9]=2[N:10]=1)(=[O:3])[CH3:2].CN1CCOCC1.C1(NP(Cl)(=O)OC2C=CC=CC=2)C=CC=CC=1.[NH2:52][C@H:53]([C:61]([O:63][CH2:64][CH3:65])=[O:62])[CH2:54][CH2:55][C:56]([O:58][CH2:59][CH3:60])=[O:57]>CN1CCCC1=O>[C:1]([NH:4][C:5]1[N:6]=[C:7]([OH:27])[C:8]2[CH:14]=[C:13]([CH:15]=[C:16]([C:18]3[CH:19]=[CH:20][C:21]([CH2:24][NH:52][C@H:53]([C:61]([O:63][CH2:64][CH3:65])=[O:62])[CH2:54][CH2:55][C:56]([O:58][CH2:59][CH3:60])=[O:57])=[CH:22][CH:23]=3)[CH3:17])[CH:12]=[N:11][C:9]=2[N:10]=1)(=[O:3])[CH3:2]
Reactant: CCOC(=O)CC[C@H](N)C(=O)OCC
Reactant: CC(=O)Nc1nc(O)c2cc(C=C(C)c3ccc(C(=O)O)cc3)cnc2n1
Agent: O=P(Cl)(Nc1ccccc1)Oc1ccccc1
Solvent: CN1CCOCC1
Solvent: CN1CCCC1=O
Product: CCOC(=O)CC[C@H](NCc1ccc(C(C)=Cc2cnc3nc(NC(C)=O)nc(O)c3c2)cc1)C(=O)OCC
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 0.2 g of 2-acetamido-4-hydroxy-6-[2-(4-carboxyphenyl)prop-1-enyl]pyrido[2,3-d]pyrimidine in 50 mL of N-methylpyrrolidinone containing 0.18 g of N-methylmorpholine was added 0.22 g of phenyl N-phenylphosphoramidochloridate in a single portion. After stirring the mixture at room temperature for 1 hour, 0.20 g of diethyl L-glutamate was added. The reaction mixture was stirred overnight, the solvent was removed under reduced pressure and the residue was triturated with chloroform. The mixture was filtered and the filtrate was evaporated under reduced pressure. The residue was subjected to preparative thin layer chromatography on silica gel using a 5% methanol in chloroform mixture as the eluent. This gave 74.6 mg (25%) of the title compound as a pale yellowish solid; NMR (CDCl3, 250 MHz) d 1.22 (t, 3H, J=7.1 Hz), 1.30 (t, 3H J=7.1 Hz), 2.11-2.57 (m, 10H), 4.14 (q, 2H, J=7.1 Hz), 4.24 (q, 2H, J=7.1 Hz), 4.75-4.83 (m, 1H), 6.86 (brs, 1H), 7.18 (brs, 1H), 7.57 (d, 2H, J=8.42 Hz), 7.84 (d, 2H, J=8.42 Hz), 8.50 (d, 1H, J=2.01 Hz), 8.96 (brs, 1H), 10.34 (brs, 1H).
Reaction SMILES: [CH2:1]([N:5]1[C:9](=[O:10])[C:8](Cl)=[C:7]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[S:6]1(=[O:19])=[O:18])[CH2:2][CH2:3][CH3:4].[N:20]1([C:26]2[CH:31]=[CH:30][C:29]([CH2:32][NH2:33])=[CH:28][CH:27]=2)[CH2:25][CH2:24][O:23][CH2:22][CH2:21]1>>[CH2:1]([N:5]1[C:9](=[O:10])[C:8]([NH:33][CH2:32][C:29]2[CH:28]=[CH:27][C:26]([N:20]3[CH2:25][CH2:24][O:23][CH2:22][CH2:21]3)=[CH:31][CH:30]=2)=[C:7]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[S:6]1(=[O:19])=[O:18])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCN1C(=O)C(Cl)=C(c2ccccc2)S1(=O)=O
Reactant: NCc1ccc(N2CCOCC2)cc1
Product: CCCCN1C(=O)C(NCc2ccc(N3CCOCC3)cc2)=C(c2ccccc2)S1(=O)=O

Procedure:
The title compound was prepared from 2-butyl-4-chloro-5-phenylisothiazol-3(2H)-one 1,1-dioxide and 1-(4-morpholin-4-ylphenyl)methanamine in a similar manner as described for e.g. Example 6 and 7. 1H NMR (500 MHz, CDCl3): δ 7.52-7.48 (m, 2H), 7.46-7.40 (m, 3H), 6.94 (d, 2H), 6.81 (d, 2H), 5.47 (t, 1H), 3.95 (d, 2H), 3.87 (t, 4H), 3.72 (t, 2H), 3.15 (t, 4H), 1.88-1.80 (m, 2H), 1.52-1.42 (m, 2H), 0.99 (t, 3H); 13C NMR (125 MHz, CDCl3): δ 159.2, 151.3, 135.8, 131.8, 129.9, 128.9, 128.8, 127.6, 125.1, 115.9, 108.0, 67.0, 49.4, 48.1, 40.4, 30.5, 20.3, 13.8; Mass Spectrum: M+H+ 456.
Reaction SMILES: [Br:1][C:2]1[CH:14]=[CH:13][C:12]([C:15](=[O:17])[NH2:16])=[C:11]2[C:3]=1[C:4]1[CH:5]=[CH:6][C:7]([C:18]([O:20][CH2:21][CH3:22])=[O:19])=[CH:8][C:9]=1[NH:10]2.C1C(=O)N([Cl:30])C(=O)C1>C(Cl)(Cl)(Cl)Cl.CN(C=O)C>[Br:1][C:2]1[C:14]([Cl:30])=[CH:13][C:12]([C:15](=[O:17])[NH2:16])=[C:11]2[C:3]=1[C:4]1[CH:5]=[CH:6][C:7]([C:18]([O:20][CH2:21][CH3:22])=[O:19])=[CH:8][C:9]=1[NH:10]2
Reactant: CCOC(=O)c1ccc2c(c1)[nH]c1c(C(N)=O)ccc(Br)c12
Reactant: O=C1CCC(=O)N1Cl
Solvent: CN(C)C=O
Solvent: ClC(Cl)(Cl)Cl
Product: CCOC(=O)c1ccc2c(c1)[nH]c1c(C(N)=O)cc(Cl)c(Br)c12
Yield: 65 %

Procedure:
A mixture of ethyl 5-bromo-8-carbamoyl-9H-carbazole-2-carboxylate [synthesized according to the procedure described in U.S. Pat. No. 8,084,620, Intermediate 48-1] (0.100 g, 0.277 mmol) and NCS (recrystallized from toluene; 0.037 g, 0.277 mmol) in CCl4 (10 mL) and DMF (2 mL) was stirred at room temperature for 112 h. The mixture was filtered, and the collected precipitate was washed with CCl4 and dried overnight under vacuum. The residue was purified by column chromatography on silica gel (40 g), eluting with hexanes, then with EtOAc-hexanes (30%, then 50%), to give ethyl 5-bromo-8-carbamoyl-6-chloro-9H-carbazole-2-carboxylate as a fluffy white solid (0.071 g, 65% yield). Mass spectrum m/z 395, 397, (M+H)+. 1H NMR (400 MHz, DMSO-d6) δ 12.13 (s, 1H), 8.77 (d, J=8.6 Hz, 1H), 8.53 (d, J=1.1 Hz, 1H), 8.36 (br. s., 1H), 8.29 (s, 1H), 7.89 (dd, J=8.4, 1.5 Hz, 1H), 7.74 (br. s., 1H), 4.38 (q, J=7.0 Hz, 2H), 1.38 (t, J=7.0 Hz, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[N:14]=[C:13]([NH:15][CH:16]3[CH2:21][CH2:20][N:19](C(OC(C)(C)C)=O)[CH2:18][CH2:17]3)[NH:12][N:11]=2)[CH:5]=[C:6]([Cl:8])[CH:7]=1.[C:29]([OH:35])([C:31]([F:34])([F:33])[F:32])=[O:30].C(Cl)Cl>>[F:32][C:31]([F:34])([F:33])[C:29]([OH:35])=[O:30].[Cl:8][C:6]1[CH:5]=[C:4]([NH:9][C:10]2[N:14]=[C:13]([NH:15][CH:16]3[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]3)[NH:12][N:11]=2)[CH:3]=[C:2]([Cl:1])[CH:7]=1
Reactant: CC(C)(C)OC(=O)N1CCC(Nc2nc(Nc3cc(Cl)cc(Cl)c3)n[nH]2)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Clc1cc(Cl)cc(Nc2n[nH]c(NC3CCNCC3)n2)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 96 %

Procedure:
Tert-butyl 4-(3-(3,5-dichlorophenylamino)-1H-1,2,4-triazol-5-ylamino)piperidine-1-carboxylate (180 mg, 0.42 mmol) was dissolved in 30% TFA/methylene chloride (10 mL) and the mixture was stirred at rt for 30 min. Removal of solvent under reduced pressure gave a solid, which was washed with diethyl ether (10 mL) to give 178 mg (96%) of desired product as an off-white solid. MS +m/z: 327.0 (M+H)+
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8]Cl)=[CH:4][N:3]=1.[F:10][CH:11]([F:14])[CH2:12][NH2:13].C(N(CC)CC)C>C(#N)C>[Cl:1][C:2]1[N:3]=[CH:4][C:5]([CH2:8][NH:13][CH2:12][CH:11]([F:14])[F:10])=[CH:6][CH:7]=1
Reactant: ClCc1ccc(Cl)nc1
Reactant: NCC(F)F
Solvent: CC#N
Solvent: CCN(CC)CC
Product: FC(F)CNCc1ccc(Cl)nc1
Yield: 53.9 %

Procedure:
41.57 g (256.6 mmol) of 2-chloro-5-chloromethylpyridine, 20.80 g (256.6 mmol) of 2,2-difluoroethane-1-amine and 35.8 ml (256.6 mmol) of triethylamine in 500 ml of acetonitrile are stirred at 45° C. for 21 hours. The reaction mixture is concentrated under reduced pressure and the residue is then taken up in 1 N aqueous hydrochloric acid and the mixture is washed with ethyl acetate. The aqueous phase is made alkaline using 2.5 N aqueous sodium hydroxide solution and extracted repeatedly with ethyl acetate. Concentration of the organic phase under reduced pressure gives 28.6 g (53% of theory) of N-[(6-chloropyridin-3-yl)methyl]-2,2-difluoroethane-1-amine.
Reaction SMILES: [OH:1][C:2]1[CH:16]=[CH:15][C:5]([CH2:6][CH:7]2[O:11][C:10]([CH3:13])([CH3:12])[O:9][C:8]2=[O:14])=[CH:4][CH:3]=1.[CH2:17]([SiH](CC)CC)[CH3:18].OS(O)(=O)=O>C(Cl)Cl.CCO.Cl[Ti](Cl)(Cl)Cl>[CH2:17]([O:9][C:8](=[O:14])[CH:7]([O:11][CH:10]([CH3:13])[CH3:12])[CH2:6][C:5]1[CH:15]=[CH:16][C:2]([OH:1])=[CH:3][CH:4]=1)[CH3:18]
Reactant: CC[SiH](CC)CC
Reactant: CC1(C)OC(=O)C(Cc2ccc(O)cc2)O1
Agent: Cl[Ti](Cl)(Cl)Cl
Agent: O=S(=O)(O)O
Solvent: CCO
Solvent: ClCCl
Product: CCOC(=O)C(Cc1ccc(O)cc1)OC(C)C
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 69.6 %

Procedure:
A 0° C. solution of 5-(4-hydroxy-benzyl)-2,2-dimethyl-[1,3]dioxolan-4-one (0.20 g, 0.900 mmol) and triethylsilane (1.05 g, 9.0 mmol) in dry CH2Cl2 (10 mL) was treated dropwise with a 1 molar solution of TiCl4 in CH2Cl2 (0.90 mL, 0.900 mmol) under N2. The resultant red slurry was stirred at 0° C. for 15 minutes and then warmed to room temperature for 45 minutes. The reaction mixture was quenched with water and extracted with EtOAc. The organic layer was dried (Na2SO4) and the solvent removed in vacuo to afford 0.320 g of crude acid that was carried on as is. The oil was dissolved in EtOH (25 mL) and treated with conc. H2SO4 (1 mL) and then stirred at room temperature for 17 h under N2. The solvent was removed in vacuo and the oil extracted with EtOAc and water. The organic layer was dried (Na2SO4) and the solvent removed in vacuo to afford crude product that was purified by flash chromatography using 5:1 hexanes:acetone to give 0.158 g (70%) 3-(4-hydroxy-phenyl)-2-isopropoxy-propionic acid ethyl ester. Rf=0.48 (1:1 hexanes:acetone). 1H NMR (500 MHz, CDCl3) δ 7.10 (d, 2H, J=8.80 Hz), 6.73 (d, 2H, J=8.31 Hz), 4.79 (bs, 1H) 4.20-4.12 (m, 2H), 3.99 (dd, 1H, J=8.31 Hz, J=4.89 Hz), 3.49 (hp, 1H, J=5.87 Hz), 2.95-2.83 (m, 2H), 1.23 (t, 3H, J=6.85 Hz), 1.14 (d, 3H, J=6.36 Hz), 0.97 (d, 3H, J=6.36 Hz); MS (ES−) Calc'd for C14H19O4 (M−1) 251. Found m/z 251 (100%). 97.6% ee by chiral HPLC assay (Chiralcel OJ, 4.6×250 mm, 90/10 heptane/IPA eluent, 1 mL/min, 266 nm).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([C:7]2[CH:12]=[CH:11][C:10]([NH:13][C:14]([C:16]3[N:17]=[C:18]([C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=4)[O:19][C:20]=3[C:21]([F:24])([F:23])[F:22])=[O:15])=[CH:9][CH:8]=2)[CH2:3][CH2:2]1.[O:31]=[C:32]1[NH:36][C:35](=[O:37])[CH:34]([CH2:38][C:39](O)=[O:40])[S:33]1.C(N(CC)CC)C.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1>CN(C=O)C>[O:31]=[C:32]1[NH:36][C:35](=[O:37])[CH:34]([CH2:38][C:39]([N:1]2[CH2:6][CH2:5][CH:4]([C:7]3[CH:8]=[CH:9][C:10]([NH:13][C:14]([C:16]4[N:17]=[C:18]([C:25]5[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=5)[O:19][C:20]=4[C:21]([F:22])([F:23])[F:24])=[O:15])=[CH:11][CH:12]=3)[CH2:3][CH2:2]2)=[O:40])[S:33]1
Reactant: O=C(Nc1ccc(C2CCNCC2)cc1)c1nc(-c2ccccc2)oc1C(F)(F)F
Reactant: O=C(O)CC1SC(=O)NC1=O
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: O=C1NC(=O)C(CC(=O)N2CCC(c3ccc(NC(=O)c4nc(-c5ccccc5)oc4C(F)(F)F)cc3)CC2)S1
Yield: 90.1 %

Procedure:
2-Phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid (4-piperidin-4-yl-phenyl)-amide (60.1 mg, 0.149 mmol), (2,4-dioxo-thiazolidin-5-yl)-acetic acid (26.2 mg, 0.149 mmol), triethylamine (63 uL, 0.448 mmol) and BOP (63.2 mg, 0.149 mmol) in 1 mL DMF were reacted as above. The crude product was purified by flash chromatography to yield 2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid (4-{1-[2-(2,4-dioxo-thiazolidin-5-yl)-acetyl]-piperidin-4-yl}-phenyl)-amide as a white solid (76.9 mg, 90%). ES-MS calcd for C27H23F3N4O5S (m/e) 572.57, obsd 573 (M+H).
Reaction SMILES: [CH3:1][C@:2]1([CH2:13][CH:14]=[O:15])[CH2:4][C@H:3]1[CH:5]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[CH3:6].COC1CCCC1.[BH4-].[Na+].S(=O)(=O)(O)O>CO>[CH3:1][C@:2]1([CH2:13][CH2:14][OH:15])[CH2:4][C@H:3]1[CH:5]([C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1)[CH3:6]
Reactant: CC(c1ccccc1)[C@@H]1C[C@]1(C)CC=O
Agent: O=S(=O)(O)O
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: COC1CCCC1
Product: CC(c1ccccc1)[C@@H]1C[C@]1(C)CCO
Temperature: 20 °C
Yield: 94 %

Procedure:
under a nitrogen atmosphere, 2-[(1R*,2S*)-1-methyl-2-(1-phenylethyl)cyclopropyl]acetaldehyde (a diastereomer mixture with a component ratio of 1:2, 0.20 g, 0.99 mmol), cyclopentyl methyl ether (4 ml), and sodium borohydride (0.05 g, 1.3 mmol) were placed into a 30-ml flask equipped with a stirring apparatus, a dropping funnel, and a thermometer, and methanol (0.05 g) was added with stirring at 20° C., followed by stirring at the same temperature for 60 minutes. Next, a 5% aqueous sulfuric acid solution (1.3 g) was added. After stirring for 10 minutes, the aqueous layer was separated, and the organic layer was washed twice with water (2 ml). The solvent was recovered under reduced pressure to obtain a condensed residue. This residue was purified by silica gel column chromatography (hexane:ethyl acetate=8:2) to obtain 2-[(1R*,2S*)-1-methyl-2-(1-phenylethyl)cyclopropyl]ethanol (a diastereomer mixture with a component ratio of 1:2, 0.19 g, 0.93 mmol, 94% yield).
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=1.[I:10]I>[NH4+].[OH-].O>[OH:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][C:3]=1[I:10]
Reactant: N#Cc1ccc(O)cc1
Reactant: II
Agent: [NH4+]
Agent: [OH-]
Solvent: O
Product: N#Cc1ccc(O)c(I)c1
Reaction time: 6 h
Yield: 80.1 %

Procedure:
To a solution of 4-hydroxybenzonitrile (0.5 g; 4.18 mmol) in 25% NH4OH (22 ml) a solution of I2 (1.06 g; 4.18 mmol) and KI (3.41 g; 20.54 mmol) in H2O (5 ml) was added at once with stirring. The stirring was continued for 6 h, during which time the mixture turn from black into colourless. The precipitate formed was filtered off and filtrate was evaporated to dryness under reduced pressure. The residue was treated with H2O (3 ml). The precipitate formed was filtered off, washed with cold H2O (3×2 ml), and dried in vacuo to give the title compound (0.82 g; 80%), as colourless solid. 1H-NMR (CDCl3) 7.96 (d, 1H, 1.9 Hz); 7.53 (dd, 1H, J=1.9 Hz, 8.5 Hz); 7.03 (d, 1H, J=8.5 Hz); 6.03 (s, 1H);
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[C:4]([CH3:9])[CH:3]=1.N1C=CC=CC=1.[C:16](Cl)(=[O:18])[CH3:17]>ClCCl>[C:16]([O:8][C:5]1[CH:6]=[CH:7][C:2]([Br:1])=[CH:3][C:4]=1[CH3:9])(=[O:18])[CH3:17]
Reactant: CC(=O)Cl
Reactant: Cc1cc(Br)ccc1O
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(=O)Oc1ccc(Br)cc1C
Temperature: 0 °C
Reaction time: 2 h
Yield: 115.9 %

Procedure:
An ice-cold solution of 4-bromo-2-methylphenol (5.6 g, 30 mmol) and pyridine (6.1 mL, 75 mmol) in 50 mL of anhydrous dichloromethane was treated with a solution of acetyl chloride (2.8 mL, 26 mmol) in 5 mL of anhydrous dichloromethane. After 2 hours, the reaction mixture was concentrated in vacuo. The resulting residue was treated with crushed ice, diluted with 150 mL of dichloromethane, washed with water, dried over sodium sulfate, filtered, and concentrated in vacuo to give 6.9 g of 4-bromo-2-methylphenyl acetate as a light brown oil (quantitative yield).
Reaction SMILES: Cl.[CH2:2]([CH:4]1[CH2:9][CH2:8][CH2:7][CH2:6][N:5]1[C:10]1[CH:18]=[CH:17][C:13]([C:14]([OH:16])=O)=[CH:12][C:11]=1[CH2:19][O:20][CH3:21])[CH3:3].[NH2:22][C:23](=[N:43]O)[C:24]1[CH:33]=[C:32]2[C:27]([CH2:28][CH2:29][N:30]([CH2:34][CH2:35][C:36]([O:38][C:39]([CH3:42])([CH3:41])[CH3:40])=[O:37])[CH2:31]2)=[CH:26][CH:25]=1>CCOC(C)=O>[CH2:2]([CH:4]1[CH2:9][CH2:8][CH2:7][CH2:6][N:5]1[C:10]1[CH:18]=[CH:17][C:13]([C:14]2[O:16][N:22]=[C:23]([C:24]3[CH:33]=[C:32]4[C:27]([CH2:28][CH2:29][N:30]([CH2:34][CH2:35][C:36]([O:38][C:39]([CH3:42])([CH3:41])[CH3:40])=[O:37])[CH2:31]4)=[CH:26][CH:25]=3)[N:43]=2)=[CH:12][C:11]=1[CH2:19][O:20][CH3:21])[CH3:3]
Reactant: CC(C)(C)OC(=O)CCN1CCc2ccc(C(N)=NO)cc2C1
Reactant: CCC1CCCCN1c1ccc(C(=O)O)cc1COC
Agent: Cl
Solvent: CCOC(C)=O
Product: CCC1CCCCN1c1ccc(-c2nc(-c3ccc4c(c3)CN(CCC(=O)OC(C)(C)C)CC4)no2)cc1COC

Procedure:
Title compound was prepared following general procedure 2 starting from Intermediate 22 (188 mg; 0.6 mmol) and Intermediate 25 (182 mg; 0.6 mmol). The reaction mixture was diluted with EtOAc, washed with water and brine and evaporated under vacuum.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH:9]=[O:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Br:11]Br>ClCCl>[Br:11][CH:8]([CH2:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)[CH:9]=[O:10]
Reactant: O=CCCc1ccccc1
Reactant: BrBr
Solvent: ClCCl
Product: O=CC(Br)Cc1ccccc1
Yield: 143.6 %

Procedure:
To a solution of 3-phenylpropionaldehyde (13.4 g, purity 90%, 0.09 mol) in dichloromethane at 0° C. was slowly added bromine (13.7 g, 0.085 mol). After 12 h at rt the solvent was evaporated to yield crude title compound (26.0 g (purity about 60%), 81%).