Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][CH:2]([CH3:6])[C:3](=[S:5])[NH2:4].Br[CH2:8][C:9](=O)[C:10]([O:12][CH2:13][CH3:14])=[O:11].[O-]S([O-])(=O)=O.[Mg+2]>CC(C)=O>[CH:2]([C:3]1[S:5][CH:8]=[C:9]([C:10]([O:12][CH2:13][CH3:14])=[O:11])[N:4]=1)([CH3:6])[CH3:1]
Reactant: CCOC(=O)C(=O)CBr
Reactant: CC(C)C(N)=S
Agent: O=S(=O)([O-])[O-]
Agent: [Mg+2]
Solvent: CC(C)=O
Product: CCOC(=O)c1csc(C(C)C)n1
Yield: 86.4 %

Procedure:
A solution of 2.35 g (23 mmol) of 2-methylpropane-thioamide and 2.89 ml (23 mmol) of ethyl bromopyruvate in 75 ml of acetone was treated with excess MgSO4 and heated at reflux for 2.5 h. The resulting mixture was allowed to cool, filtered, and concentrated in vacuo to an oil, which was taken up in chloroform, washed sequentially with aqueous NaHCO3 and brine, dried over Na2SO4, and concentrated. The residue was purified by chromatography on silica gel using chloroform as an eluent to provide 3.96 g (86%) of the desired compound, Rf 0.21 (chloroform) as an oil. 1H NMR (CDCl3) δ1.41 (t, J=8 Hz, 3H), 1.42 (d, J=7 Hz, 6H), 3.43 (heptet, J=7 Hz, 1H), 4.41 (q, J=8 Hz, 2H), 8.05 (s, 1H). Mass spectrum: (M+H)+ =200.
Reaction SMILES: Cl.Cl.[CH2:3]([N:10]1[CH2:15][CH2:14][C@H:13]([CH3:16])[C@H:12]([NH:17][CH3:18])[CH2:11]1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[C:19]1([CH3:46])[CH:24]=[CH:23][C:22]([C:25]([C@@:27]([C:43]([OH:45])=[O:44])([OH:42])[C@@:28]([C:33]([C:35]2[CH:40]=[CH:39][C:38]([CH3:41])=[CH:37][CH:36]=2)=[O:34])([OH:32])[C:29]([OH:31])=[O:30])=[O:26])=[CH:21][CH:20]=1.[OH-].[Na+]>CO>[C:19]1([CH3:46])[CH:24]=[CH:23][C:22]([C:25]([C@@:27]([C:43]([OH:45])=[O:44])([OH:42])[C@@:28]([C:33]([C:35]2[CH:36]=[CH:37][C:38]([CH3:41])=[CH:39][CH:40]=2)=[O:34])([OH:32])[C:29]([OH:31])=[O:30])=[O:26])=[CH:21][CH:20]=1.[CH2:3]([N:10]1[CH2:15][CH2:14][C@@H:13]([CH3:16])[C@@H:12]([NH:17][CH3:18])[CH2:11]1)[C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: CN[C@@H]1CN(Cc2ccccc2)CC[C@@H]1C
Agent: Cc1ccc(C(=O)[C@](O)(C(=O)O)[C@@](O)(C(=O)O)C(=O)c2ccc(C)cc2)cc1
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: CN[C@H]1CN(Cc2ccccc2)CC[C@H]1C
Temperature: 75 °C

Procedure:
To a clean, dry, nitrogen-purged 250 ml flask were charged racemic cis-(1-benzyl-4-methyl-piperidine-3-yl)-methylamine bis hydrochloride (20.0 g, 68.7 mmol), di-p-toluoyl-L-tartaric acid (L-DPTT) (15.9 g, 41.2 mmol) and methanol (100 ml). A solution of sodium hydroxide (5.5 g, 137.3 mmol in water (100 ml)) was added to the reaction at a rate to maintain the temperature below 30° C. The reaction was heated to between 70-80° C. and held at this temperature for at least 60 minutes. The reaction was cooled to 5-15° C. over at least 4 hours and held at this temperature for at least 12 hours. The solids were filtered and washed with a 1:1 mixture of MeOH:water (60 ml). The wet-cake was returned to the 250 ml flask and methanol (100 ml) and water (100 ml) were charged. The reaction was heated to between 70-80° C. and held at this temperature for at least 120 minutes. The reaction was cooled to 5-15° C. over at least 4 hours and held at this temperature for at least 12 hours. The solids were filtered and washed with a 1:1 mixture of MeOH:water (60 ml). The wet-cake was sampled for purity (99.4% ee) to ensure an additional repulp was not necessary. After drying under vacuum at 40-50° C. for at least 24 hours with a slight nitrogen bleed, the title compound (11.9 g, 28.9 mmol) was isolated in 42.1% yield (98.6% enantiomeric excess, 0.63% trans isomer by GC (Cyclosil B column 30 m×I.D. 0.25 mm; Inlet Temp 250; 2.0 ml/min flow rate; 15 min run; 160 C isothermal method.
Reaction SMILES: [Na].[NH:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][C:3]1=[O:11].[C:12](OCC)(=[O:19])[C:13]1[CH:18]=[CH:17][CH:16]=[N:15][CH:14]=1>C(O)C.O>[N:15]1[CH:16]=[CH:17][CH:18]=[C:13]([C:12]([CH:4]2[C:5]3[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=3)[NH:2][C:3]2=[O:11])=[O:19])[CH:14]=1
Reactant: CCOC(=O)c1cccnc1
Reactant: O=C1Cc2ccccc2N1
Agent: [Na]
Solvent: CCO
Solvent: O
Product: O=C1Nc2ccccc2C1C(=O)c1cccnc1
Yield: 18.5 %

Procedure:
To a solution of 2.1 g (0.090 mole) of sodium metal in 100 ml of ethanol, was added 10.0 g (0.075 mole) of 2-oxindole, followed by 13.6 g (0.090 mole) of ethyl nicotinate. The resulting slurry was heated under reflux for 3 hours and then the mixture was cooled and filtered. The residue was discarded, and the filtrate was evaporated in vacuo. The residue thus obtained was dissolved in ca. 150 ml of water, and the aqueous solution was washed with chloroform. To the aqueous solution was then added 5.8 ml of glacial acetic acid and the resulting mixture was cooled in an ice-bath. The solid was recovered by filtration and recrystallized from ethanol to give 3.3 g of the title compound as yellow needles, m.p. 169°-170° C.
Reaction SMILES: [Br:1][CH2:2][CH2:3]Br.[CH3:5][O:6][C:7]([C:9]1[CH:17]=[C:16]2[C:12]([CH2:13][CH2:14][NH:15]2)=[CH:11][CH:10]=1)=[O:8].C(N(CC)CC)C>C(OCC)(=O)C>[Br:1][CH2:2][CH2:3][N:15]1[C:16]2[C:12](=[CH:11][CH:10]=[C:9]([C:7]([O:6][CH3:5])=[O:8])[CH:17]=2)[CH2:13][CH2:14]1
Reactant: BrCCBr
Reactant: COC(=O)c1ccc2c(c1)NCC2
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: COC(=O)c1ccc2c(c1)N(CCBr)CC2
Temperature: 90 °C
Reaction time: 2 h

Procedure:
To 1,2-dibromoethane (15.7 ml) were added 6-methoxycarbonylindoline (2.41 g) and triethylamine (7.8 ml), and the mixture was stirred at 90° C. for 2 hr. Ethyl acetate (150 ml) was added to the reaction mixture, and the mixture was washed with saturated brine (300 ml) and dried over Na2SO4. Ethyl acetate was evaporated under reduced pressure. The obtained residue was purified by column chromatography to give the title compound (1.71 g).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[CH:7][NH:8]2)=[CH:4][C:3]=1[C:11]#[N:12]>CO.N.[Ni]>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[CH:7][NH:8]2)=[CH:4][C:3]=1[CH2:11][NH2:12]
Reactant: N#Cc1cc2cc[nH]c2cc1Cl
Agent: [Ni]
Agent: N
Solvent: CO
Product: NCc1cc2cc[nH]c2cc1Cl
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of 242 (43 mg, 0.24 mmol) in MeOH (10 mL) and 7M NH3 in MeOH (5 mL) was added Raney nickel and the reaction mixture was stirred vigorously under hydrogen (1 atm.) at RT for 3 h. The reaction mixture was filtered through a pad of Celite® and concentrated under reduced pressure to afford (6-chloro-1H-indol-5-yl)methanamine (244) as pale oil: MS (ESI)=164.1 [M−NH2]+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([NH2:14])[CH:9]=2)[CH:5]=[CH:6][CH:7]=1.[CH:15](=O)[CH2:16][CH2:17][CH3:18]>>[CH2:15]([NH:14][C:10]1[CH:9]=[C:8]([C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=2)[CH:13]=[CH:12][CH:11]=1)[CH2:16][CH2:17][CH3:18]
Reactant: CCCC=O
Reactant: Nc1cccc(-c2cccc(Cl)c2)c1
Product: CCCCNc1cccc(-c2cccc(Cl)c2)c1

Procedure:
Following a procedure analogous to that for the synthesis of Intermediate 137, 3′-chlorobiphenyl-3-amine (Oakwood, 15 mg, 0.074 mmol) and butyraldehyde (7 μL, 0.074 mmol) were converted to a crude oil which was used without purification in the preparation of Example 143. 1H NMR (CDCl3) δ 8.17 (d, J=0.9 Hz, 1H), 7.86-7.42 (m, 3H), 7.41-7.07 (m, 3H), 6.78-6.57 (m, 1H), 3.00-2.87 (m, 2H), 1.63-1.46 (m, 2H), 1.47-1.34 (m, 2H), 1.02 (t, J=7.4 Hz, 3H); MS(ESI+) m/z 260.2 (M+H)+.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:23])[CH2:5][N:6]1[C:14]2[C:9](=[CH:10][C:11]([O:15][Si](C(C)(C)C)(C)C)=[CH:12][CH:13]=2)[CH:8]=[CH:7]1)[CH3:2].O.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>C1COCC1.C(OCC)C>[CH2:1]([O:3][C:4](=[O:23])[CH2:5][N:6]1[C:14]2[C:9](=[CH:10][C:11]([OH:15])=[CH:12][CH:13]=2)[CH:8]=[CH:7]1)[CH3:2]
Reactant: CCOC(=O)Cn1ccc2cc(O[Si](C)(C)C(C)(C)C)ccc21
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: O
Solvent: CCOCC
Solvent: C1CCOC1
Product: CCOC(=O)Cn1ccc2cc(O)ccc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 83.2 %

Procedure:
To an ice cold solution of [5-(tert-butyl-dimethyl-silanyloxy)-indol-1-yl]-acetic acid ethyl ester (12.9 g, 38.7 mmol) in THF (130 ml) was added tetrabutylammonium fluoride hydrate (12.5 g, 38.7 mmol). The reaction mixture was stirred for 1 h at RT, diluted with diethyl ether and washed with 1N HCl and water. Evaporation of the solvent under reduced pressure gave 7.07 g (32.2 mmol, 83%) (5-hydroxy-indol-1-yl)-acetic acid ethyl ester.
Reaction SMILES: C(N(CC)CC)C.[C:8](Cl)(=[O:15])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.[C:17]([C:19]1[C:20]([OH:26])=[N:21][C:22]([OH:25])=[CH:23][CH:24]=1)#[N:18]>CN(C)C(=O)C>[C:8]([O:25][C:22]1[N:21]=[C:20]([OH:26])[C:19]([C:17]#[N:18])=[CH:24][CH:23]=1)(=[O:15])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: N#Cc1ccc(O)nc1O
Solvent: CCN(CC)CC
Solvent: CC(=O)N(C)C
Product: N#Cc1ccc(OC(=O)c2ccccc2)nc1O
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 60 %

Procedure:
A 0.51 ml quantity of triethylamine and 0.43 ml of benzoyl chloride were added to a solution of 1.00 g of 3-cyano-2,6-dihydroxypyridine in 40 ml of N,N-dimethylacetamide. The mixture was stirred at room temperature for 15 minutes. To the reaction mixture were added 0.51 ml of triethylamine and 0.43 ml of benzoyl chloride, and the mixture was stirred at room temperature for 15 minutes. The reaction mixture was filtered and the filtrate was concentrated under a reduced pressure. The concentrate was washed with chloroform and with water, giving 1.06 g of the title compound in a yield of 60%.
Reaction SMILES: [F:1][C:2]1[CH:11]=[C:10]([C:12]2[N:17]=[N:16][C:15](S(C)=O)=[N:14][CH:13]=2)[CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].O.[NH2:22][NH2:23]>O1CCCC1>[F:1][C:2]1[CH:11]=[C:10]([C:12]2[N:17]=[N:16][C:15]([NH:22][NH2:23])=[N:14][CH:13]=2)[CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5]
Reactant: NN
Reactant: COC(=O)c1ccc(-c2cnc(S(C)=O)nn2)cc1F
Solvent: O
Solvent: C1CCOC1
Product: COC(=O)c1ccc(-c2cnc(NN)nn2)cc1F
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To a suspension of methyl 2-fluoro-4-[3-(methylsulfinyl)-1,2,4-triazin-6-yl]benzoate (0.19 g, 0.00064 mol) in tetrahydrofuran (20 mL) was added hydrazine hydrate (63 μL, 0.0013 mol) slowly. The mixture was stirred at RT for 1.5 h. The mixture was concentrated under reduced pressure to yield the desired product. Analytical LCMS: (M+H)+=264.1.
Reaction SMILES: [C:1]1(=[O:11])[O:6][C:4](=[O:5])[C:3]2=[CH:7][CH:8]=[CH:9][CH:10]=[C:2]12.[CH3:12][C:13]([CH3:21])([CH:16]([OH:20])[CH:17]([CH3:19])[CH3:18])[CH2:14]O>C1(C)C(C)=CC=CC=1>[CH:17]([CH:16]1[C:13]([CH3:21])([CH3:14])[CH2:12][O:6][C:1](=[O:11])[C:2]2[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=2[C:4](=[O:5])[O:20]1)([CH3:19])[CH3:18]
Reactant: O=C1OC(=O)c2ccccc21
Reactant: CC(C)C(O)C(C)(C)CO
Solvent: Cc1ccccc1C
Product: CC(C)C1OC(=O)c2ccccc2C(=O)OCC1(C)C
Yield: 40 %

Procedure:
Following the procedure of Examples 1 or 2,7-Isopropyl-8,8-dimethyl-8,9-dihydro-7H-6,10-dioxabenzocyclononene-5,11-dione was prepared from a solution of 14.81 g (0.1 mole) of phthalic anhydride and 16.30 g (0.11 mole) of 2,2,4-trimethyl-1,3-pentanediol (TMPD) in 75 mL of xylene. The catalyst was 49.4 mg of FASCAT® 4100 catalyst. Xylene was removed on a rotary evaporator and the residue distilled to give 11.09 g of distillate, b0.5 130-160° C. which was found by vapor phase chromatography (vpc) to consist of 84% of 7-Isopropyl-8,8-dimethyl-8,9-dihydro-7H-6,10-dioxabenzocyclononene-5,11-dione (40% yield). The residue from this distillation weighed 17.65 g.
Reaction SMILES: C(O[C:6]([NH:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][C:15]([NH:17][C:18]1[S:19][C:20]2[CH:26]=[C:25]([O:27][S:28]([C:31]3[CH:36]=[CH:35][C:34]([F:37])=[CH:33][CH:32]=3)(=[O:30])=[O:29])[CH:24]=[CH:23][C:21]=2[N:22]=1)=[O:16])=[O:7])(C)(C)C.NC1SC2C=C(OS(C3C=CC(F)=CC=3)(=O)=O)C=CC=2N=1.C(C(CCCCCN)C(O)=O)([O:61][C:62]([CH3:65])([CH3:64])[CH3:63])=O>>[C:62]([O:61][CH:9]([N:8]=[C:6]=[O:7])[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][C:15]([NH:17][C:18]1[S:19][C:20]2[CH:26]=[C:25]([O:27][S:28]([C:31]3[CH:36]=[CH:35][C:34]([F:37])=[CH:33][CH:32]=3)(=[O:29])=[O:30])[CH:24]=[CH:23][C:21]=2[N:22]=1)=[O:16])([CH3:65])([CH3:64])[CH3:63]
Reactant: CC(C)(C)OC(=O)NCCCCCCC(=O)Nc1nc2ccc(OS(=O)(=O)c3ccc(F)cc3)cc2s1
Reactant: CC(C)(C)OC(=O)C(CCCCCN)C(=O)O
Agent: Nc1nc2ccc(OS(=O)(=O)c3ccc(F)cc3)cc2s1
Product: CC(C)(C)OC(CCCCCC(=O)Nc1nc2ccc(OS(=O)(=O)c3ccc(F)cc3)cc2s1)N=C=O

Procedure:
According to the method of intermediate 46, 4-fluorobenzenesulfonic acid 2-(7-tert-butoxycarbonylaminoheptanoylamino)benzothiazol-6-yl ester is prepared via the action of 4-fluorobenzenesulfonic acid 2-aminobenzothiazol-6-yl ester (intermediate 16, brevetbenzothiazole_V2) with BOC-7-amino-heptanoic acid to give 0.164 g of product.
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[CH3:13][C:14]1[CH:19]=[CH:18][N:17]=[C:16]([S:20][CH3:21])[N:15]=1.[Cl:22][C:23]1[CH:34]=[C:33]([Cl:35])[CH:32]=[CH:31][C:24]=1[C:25](N(OC)C)=[O:26].[NH4+].[Cl-]>C(Cl)Cl.C1COCC1>[Cl:22][C:23]1[CH:34]=[C:33]([Cl:35])[CH:32]=[CH:31][C:24]=1[C:25](=[O:26])[CH2:13][C:14]1[CH:19]=[CH:18][N:17]=[C:16]([S:20][CH3:21])[N:15]=1
Reactant: CSc1nccc(C)n1
Reactant: CON(C)C(=O)c1ccc(Cl)cc1Cl
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Solvent: ClCCl
Product: CSc1nccc(CC(=O)c2ccc(Cl)cc2Cl)n1

Procedure:
To the solution of 85 mL of diisopropylamine (Fluka 38300) and 2.5 L of THF at −75° C. under Argon is added 370 mL (0.55 Mol) of butyl lithium (BuLi; 1.6N in hexanes; Fluka 20160) within 1 h. To this is added 71 g (0.5 Mol) of 4-methyl-2-methylsulfanyl-pyrimidine in 250 mL of CH2Cl2 at −75° C. within 30 min. After this, a solution of 118 g (0.5 Mol) of 2,4dichloro-N-methoxy-N-methyl-benzamide in 250 mL of CH2Cl2 at −75° C. within 30 min followed by letting the mixture warn up to rt. After completion, the reaction mixture is poured onto 7 L of NH4Cl satd. and extracted with ethyl acetate. The combined organic layers are washed with brine, dried and evaporated. The crude product is suspended in hexanes. After filtering off and drying 1-(2,4-dichloro-phenyl)-2-(2-methylsulfanyl-pyrimidin-4-yl)-ethanone is obtained as yellow crystals. Title compound: m.p.: 105-107° C.; ES-MS: 313.0/314.9 [M+H]+.
Reaction SMILES: [BH4-].[Na+].[S:3]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[N:5]=[C:4]1[NH:12][C:13]1[CH:32]=[CH:31][C:16]([O:17][C:18]2[C:19]([C:24]3[CH2:29][CH2:28][CH2:27][C:26](=[O:30])[CH:25]=3)=[N:20][CH:21]=[CH:22][N:23]=2)=[CH:15][C:14]=1[F:33].[Cl-].[NH4+].O>CO>[S:3]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[N:5]=[C:4]1[NH:12][C:13]1[CH:32]=[CH:31][C:16]([O:17][C:18]2[C:19]([C:24]3[CH2:29][CH2:28][CH2:27][CH:26]([OH:30])[CH:25]=3)=[N:20][CH:21]=[CH:22][N:23]=2)=[CH:15][C:14]=1[F:33]
Reactant: O=C1C=C(c2nccnc2Oc2ccc(Nc3nc4ccccc4s3)c(F)c2)CCC1
Agent: [BH4-]
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: CO
Product: OC1C=C(c2nccnc2Oc2ccc(Nc3nc4ccccc4s3)c(F)c2)CCC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Sodium tetrahydroborate (157 mg, 4.16 mmol) was added to a suspension of 3-(3-(4-(benzo[d]thiazol-2-ylamino)-3-fluorophenoxy)pyrazin-2-yl)cyclohex-2-enone (600 mg, 1.387 mmol) in MeOH (20 ml) at RT. The mixture was stirred at RT for 1 h, and was then cooled in an ice-water bath. Saturated aqueous ammonium chloride (5 ml) was added along with distilled water (100 ml). The resulting mixture was extracted with EtOAc (2×100 ml), and the combined organic layers were washed with brine and dried over sodium sulfate. Filtration and concentration under reduced pressure, followed by flash chromatography on silica gel (30% to 60% EtOAc in hexanes) afforded (rac)-3-(3-(4-(benzo[d]thiazol-2-ylamino)-3-fluorophenoxy)pyrazin-2-yl)cyclohex-2-enol as a white solid. MS (ESI, pos. ion) m/z: 435.0 (M+1). IC50 (uM) +++++.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([C:9](=[O:11])[CH3:10])=[C:4]([CH3:12])[CH:3]=1.[CH3:13][CH:14]1[CH2:16][O:15]1>[OH-].[Na+].O>[OH:15][CH:14]([CH3:16])[CH2:13][O:1][C:2]1[CH:3]=[C:4]([CH3:12])[C:5]([C:9](=[O:11])[CH3:10])=[C:6]([CH3:8])[CH:7]=1
Reactant: CC1CO1
Reactant: CC(=O)c1c(C)cc(O)cc1C
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CC(=O)c1c(C)cc(OCC(C)O)cc1C
Temperature: 140 °C
Reaction time: 4 h
Yield: 67.7 %

Procedure:
A pressure glass vessel charged with 1-(4-hydroxy-2,6-dimethylphenyl)ethanone (500 mg, 3.1 mmol, 1.0 equiv) and 2-methyloxirane (0.22 mL, 3.1 mmol, 1.0 equiv) in 50% aqueous NaOH solution (5.0 mL) was stirred at 140° C. for 4.0 h. The mixture was diluted with H2O (20 mL) and extracted with EtOAc. The organic layer was collected, dried over MgSO4(s), and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (30% EtOAc in hexanes as eluant) to provide 1-(4-(2-hydroxypropoxy)-2,6-dimethylphenyl)ethanone (445.9 mg, 2.1 mmol) as yellow oil in 66% yield: 1H NMR (CDCl3, 500 MHz) δ 6.57 (s, 2 H), 4.10-4.20 (brs, 1 H), 3.90-3.93 (m, 2 H), 3.75-3.79 (m, 1 H), 2.45 (s, 3 H), 2.23 (s, 6 H), 1.25-1.28 (m, 3 H); ESI-MS: m/z 223.4 (M+H)+.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])=[N:2]1.C(=O)([O-])[O-].[Cs+].[Cs+].[N+:22]([C:25]1[CH:32]=[CH:31][C:28]([CH2:29]Br)=[CH:27][CH:26]=1)([O-:24])=[O:23]>O1CCCC1>[N+:22]([C:25]1[CH:32]=[CH:31][C:28]([CH2:29][N:1]2[C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[C:3]([CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])=[N:2]2)=[CH:27][CH:26]=1)([O-:24])=[O:23]
Reactant: O=[N+]([O-])c1ccc(CBr)cc1
Reactant: CCOC(=O)Cc1n[nH]c2ccccc12
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1CCOC1
Product: CCOC(=O)Cc1nn(Cc2ccc([N+](=O)[O-])cc2)c2ccccc12
Temperature: 25 °C
Yield: 78 %

Procedure:
Ethyl 2-(1H-indazol-3-yl)acetate (9.78 g, 47.9 mmol) was dissolved in anhydrous tetrahydrofuran (100 mL). Cesium carbonate (46.81 g, 143.7 mmol) was added, and stirred at room temperature for half an hour. Then p-nitro benzyl bromide (10.36 g, 47.96 mmol) was added, reacted for 16 hours, and then the solid was filtered. The filtrate was concentrated, chromatographed on a silica gel column (petroleum ether:ethyl acetate=2:1) to obtain a yellow solid 12.68 g, at a yield of 78.1%.
Reaction SMILES: Cl[C:2]1[CH:11]=[C:10]2[C:5]([C:6]([O:18][CH3:19])=[N:7][C:8]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)=[N:9]2)=[CH:4][CH:3]=1.CC1C2C(=CC([B:31]3[O:35][C:34]([CH3:37])([CH3:36])[C:33]([CH3:39])([CH3:38])[O:32]3)=CC=2)N=C(C2C=CC=CC=2)N=1>>[CH3:19][O:18][C:6]1[C:5]2[C:10](=[CH:11][C:2]([B:31]3[O:35][C:34]([CH3:37])([CH3:36])[C:33]([CH3:39])([CH3:38])[O:32]3)=[CH:3][CH:4]=2)[N:9]=[C:8]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[N:7]=1
Reactant: COc1nc(-c2ccccc2)nc2cc(Cl)ccc12
Reactant: Cc1nc(-c2ccccc2)nc2cc(B3OC(C)(C)C(C)(C)O3)ccc12
Product: COc1nc(-c2ccccc2)nc2cc(B3OC(C)(C)C(C)(C)O3)ccc12

Procedure:
Synthesized from of 7-chloro-4-methoxy-2-phenylquinazoline (189 mg, 0.7 mmol) as 4-methyl-2-phenyl-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)quinazoline; off-white solid. MS (ES+): m/z 347.2 (20) MS (ES+): m/z 281.2 (100) [MH+-82]; HPLC: tR=3.19 min (OpenLynx, polar—5 min).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1([C:9]2[CH:14]=[CH:13][C:12]([C:15]3[CH:20]=[CH:19][C:18]([C:21]4[O:25][N:24]=[C:23]([CH3:26])[C:22]=4[CH:27]([C:29](O)=[O:30])[CH3:28])=[CH:17][CH:16]=3)=[CH:11][CH:10]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2].[C:32]1([CH:38]([NH2:40])[CH3:39])[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1>>[CH2:1]([O:3][C:4]([C:6]1([C:9]2[CH:10]=[CH:11][C:12]([C:15]3[CH:20]=[CH:19][C:18]([C:21]4[O:25][N:24]=[C:23]([CH3:26])[C:22]=4[CH:27]([C:29](=[O:30])[NH:40][CH:38]([C:32]4[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=4)[CH3:39])[CH3:28])=[CH:17][CH:16]=3)=[CH:13][CH:14]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: CC(N)c1ccccc1
Reactant: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4C(C)C(=O)O)cc3)cc2)CC1
Product: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4C(C)C(=O)NC(C)c4ccccc4)cc3)cc2)CC1

Procedure:
Prepared according to the procedure described in Example 33, Step 4, using 1-{4′-[4-(1-carboxy-ethyl)-3-methyl-isoxazol-5-yl]-biphenyl-4-yl}-cyclopropanecarboxylic acid ethyl ester and 1-phenyl-ethylamine.
Reaction SMILES: [C:1]1([CH2:7][N:8]2[CH2:13][CH2:12][CH:11]([SH:14])[CH2:10][CH2:9]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl[CH2:16][C:17](=[O:19])[CH3:18].C(=O)([O-])[O-].[Na+].[Na+]>[I-].C([N+](CCCC)(CCCC)CCCC)CCC.C1(C)C=CC=CC=1>[O:19]=[C:17]([CH3:18])[CH2:16][S:14][CH:11]1[CH2:12][CH2:13][N:8]([CH2:7][C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[CH2:9][CH2:10]1
Reactant: SC1CCN(Cc2ccccc2)CC1
Reactant: CC(=O)CCl
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=C([O-])[O-]
Agent: [I-]
Solvent: Cc1ccccc1
Product: CC(=O)CSC1CCN(Cc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A suspension of 1-(phenylmethyl)piperidine-4-thiol (70 g, prepared in Example 1), chloroacetone (26.9 ml), sodium carbonate (71.6 g) and tetrabutylammonium iodide (31.2 g) in toluene (350 ml) is stirred at room temperature for 4 hours. The insoluble material is filtered off and washed with toluene. After concentration, the filtrate is taken up in dichloromethane and washed with dilute sodium hydroxide and then with a saturated aqueous solution of sodium chloride. After drying over sodium sulfate, the solution is concentrated to give 4-[(2-oxopropyl)thio]-1-(phenylmethyl)piperidine (82.2 g) in the form of an oil, which is sufficiently pure to be used in the next step.
Reaction SMILES: [CH:1]([N-]C(C)C)([CH3:3])[CH3:2].[Li+].[CH3:9][CH:10]([CH3:39])[CH2:11][CH:12]1[CH2:17][C@@H:16]([CH2:18][O:19][C:20]([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[O:15][C:13]1=[O:14].C(Br)C=C>C1COCC1.CN(P(N(C)C)(N(C)C)=O)C>[CH3:9][CH:10]([CH3:39])[CH2:11][C:12]1([C:1]([CH3:3])=[CH2:2])[CH2:17][CH:16]([CH2:18][O:19][C:20]([C:33]2[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=2)([C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=2)[C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)[O:15][C:13]1=[O:14]
Reactant: CC(C)CC1C[C@@H](COC(c2ccccc2)(c2ccccc2)c2ccccc2)OC1=O
Reactant: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: C=CCBr
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: C=C(C)C1(CC(C)C)CC(COC(c2ccccc2)(c2ccccc2)c2ccccc2)OC1=O
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 82.2 %

Procedure:
Lithium diisopropylamide (8.3 mL, 16.6 mmol, 2.0M, heptane/THF/ethylbenzene) is added to a solution of (γS)-α-(2-methylpropyl)-γ-trityloxymethyl-γ-butyrolactone (5.67 g, 13.7 mmol), THF (50 mL), and HMPA (2.9 mL) at -78° C. After stirring for 30 minutes at -78° C., a solution of allyl bromide (1.46 mL, 16.9 mmol) and THF (8.0 mL) is added. The solution is allowed to stir for 4 hours at -78° C. and is then quenched with aqueous ammonium chloride (50 mL). After warming to room temperature, aqueous workup (EtOAc, MgSO4) and purification by flash chromatography (6:1 hexane:EtOAc) to give 5.12 g of the title compound (82%) as a white powder (mp 84°-85° C.).
Reaction SMILES: [CH3:1][C:2]1[CH2:3][CH:4]([OH:8])[CH2:5][C:6]=1[CH3:7].N1C=CC=CC=1.[Cl:15]/[C:16](/[C:26]([F:29])([F:28])[F:27])=[CH:17]\[C@@H:18]1[C@H:20]([C:21](Cl)=[O:22])[C:19]1([CH3:25])[CH3:24]>C(C1C=C(C)C=C(C(C)(C)C)C=1O)(C)(C)C.C1(C)C=CC=CC=1>[Cl:15]/[C:16](/[C:26]([F:27])([F:28])[F:29])=[CH:17]\[C@@H:18]1[C@H:20]([C:21]([O:8][CH:4]2[CH2:5][C:6]([CH3:7])=[C:2]([CH3:1])[CH2:3]2)=[O:22])[C:19]1([CH3:25])[CH3:24]
Reactant: CC1=C(C)CC(O)C1
Reactant: CC1(C)[C@H](/C=C(\Cl)C(F)(F)F)[C@@H]1C(=O)Cl
Agent: Cc1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1
Solvent: c1ccncc1
Solvent: Cc1ccccc1
Product: CC1=C(C)CC(OC(=O)[C@H]2[C@@H](/C=C(\Cl)C(F)(F)F)C2(C)C)C1
Yield: 86.5 %

Procedure:
To a mixture of 3,4-dimethyl-3-cyclopenten-1-ol (175 mg), 2,6-di-tert-butyl-4-methylphenol (5 mg), pyridine (150 mg) and toluene (10 ml), (1RS)-cis-3-(Z-2-chloro-3,3,3-trifluoro-1-propenyl)-2,2-dimethylcyclopropanecarbonyl chloride (395 mg) was added under ice-cooling. The resulting reaction mixture was further allowed to react for 8 hours at room temperature. Then the reaction mixture was subjected to the same post-treatment as in Example 1 to afford 441 mg of 3,4-dimethyl-3-cyclopenten-1-yl (1RS)-cis-3-(Z-2-chloro-3,3,3-trifluoro-1-propenyl)-2,2-dimethylcyclopropanecarboxylate (Compound No. 3). Yield 84% nD25 1.4620