Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[N:4][C:3]=1[CH2:13][CH2:14][C:15]([C:17]1[CH:22]=[CH:21][C:20]([CH2:23][CH2:24][CH2:25][CH:26]2[O:30][C:29](=[O:31])[NH:28][C:27]2=[O:32])=[CH:19][CH:18]=1)=O.Cl.[NH2:34][OH:35].C([O-])(=O)C.[Na+].CO>O>[OH:35][N:34]=[C:15]([C:17]1[CH:22]=[CH:21][C:20]([CH2:23][CH2:24][CH2:25][CH:26]2[O:30][C:29](=[O:31])[NH:28][C:27]2=[O:32])=[CH:19][CH:18]=1)[CH2:14][CH2:13][C:3]1[N:4]=[C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[O:6][C:2]=1[CH3:1]
Reactant: Cc1oc(-c2ccccc2)nc1CCC(=O)c1ccc(CCCC2OC(=O)NC2=O)cc1
Reactant: NO
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CO
Product: Cc1oc(-c2ccccc2)nc1CCC(=NO)c1ccc(CCCC2OC(=O)NC2=O)cc1
Reaction time: 2 h
Yield: 89.7 %

Procedure:
A mixture of 5-[3-[4-[3-(5-methyl-2-phenyl-4-oxazolyl)propionyl]phenyl]propyl]-2,4-oxazolidinedione (0.28 g), hydroxylamine hydrochloride (0.09 g), sodium acetate (0.11 g) and 80% methanol (20 ml) was stirred under refluxing conditions for 2 hours. The reaction mixture was poured over water; the resulting crystal was collected by filtration to yield 5-[3-[4-[1-hydroxyimino-3-(5-methyl-2-phenyl-4-oxazolyl)propyl]phenyl]propyl]-2,4-oxazolidinedione (0.26 g, 90%), which was then recrystallized from dichloromethane-methanol to yield colorless prisms having a melting point of 185°-186° C.
Reaction SMILES: [CH:1]([C:4]1[C:5]([C:14]([C:16]2[CH:17]=[C:18]([CH:23]=[CH:24][C:25]#[N:26])[CH:19]=[C:20]([CH3:22])[CH:21]=2)=[O:15])=[N:6][C:7]([O:12]C)=[N:8][C:9]=1[O:10]C)([CH3:3])[CH3:2]>C1COCC1.C(Cl)(=O)C(Cl)=O>[CH:1]([C:4]1[C:9](=[O:10])[NH:8][C:7](=[O:12])[NH:6][C:5]=1[C:14]([C:16]1[CH:17]=[C:18]([CH:23]=[CH:24][C:25]#[N:26])[CH:19]=[C:20]([CH3:22])[CH:21]=1)=[O:15])([CH3:3])[CH3:2]
Reactant: COc1nc(OC)c(C(C)C)c(C(=O)c2cc(C)cc(C=CC#N)c2)n1
Agent: O=C(Cl)C(=O)Cl
Solvent: C1CCOC1
Product: Cc1cc(C=CC#N)cc(C(=O)c2[nH]c(=O)[nH]c(=O)c2C(C)C)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 54.7 %

Procedure:
To a stirred solution of 3-[3-(5-isopropyl-2,6-dimethoxy-pyrimidine-4-carbonyl)-5-methyl-phenyl]-acrylonitrile (5.36 g, 15.27 mmol) in anhydrous THF (50 ml), oxalyl chloride (25 ml) was added. The mixture was then refluxed with vigorous stirring for overnight. After cooling to room temperature, the mixture was evaporated in vacuo and the residue was purified by silica gel column chromatography (eluent, EA:hexanes (from 1:1 to 4:1)) to afford 2.7 g (55%) of a white solid. m.p. 233-235° C.; 1H NMR (300 MHz, CD3OD/CDCl3) δ 1.16 (6H, d, J=6.9 Hz), 2.39-2.56 (4H, m), 6.12 (1H, d, J=16.6 Hz), 7.49 (1H, d, J=16.6 Hz), 7.66 (1H, s), 7.83 (1H, s), 7.87 (1H, s); m/z (LC/Mass, EI) 324 (M+H+).
Reaction SMILES: C([N:8]1[C@:12]2([CH3:22])[C:13]3[CH:14]=[CH:15][C:16]([F:21])=[CH:17][C:18]=3[O:19][CH2:20][C@@H:11]2[CH2:10][O:9]1)C1C=CC=CC=1>[Pd].CO>[NH2:8][C@:12]1([CH3:22])[C:13]2[C:18](=[CH:17][C:16]([F:21])=[CH:15][CH:14]=2)[O:19][CH2:20][C@@H:11]1[CH2:10][OH:9]
Reactant: C[C@@]12c3ccc(F)cc3OC[C@@H]1CON2Cc1ccccc1
Agent: [Pd]
Solvent: CO
Product: C[C@@]1(N)c2ccc(F)cc2OC[C@@H]1CO
Reaction time: 24 h
Yield: 94.8 %

Procedure:
10% Palladium on carbon (0.213 g, 0.200 mmol) was added under a nitrogen atmosphere to a solution of rel-(3aR,9bS)-1-benzyl-7-fluoro-9b-methyl-3,3a,4,9b-tetrahydro-1H-chromeno[4,3-c]isoxazole from step F2 (1.2 g, 4.01 mmol), in MeOH (200 mL). The resulting flask was repeatedly flushed with hydrogen gas and vigorously stirred under an atmosphere of hydrogen (double balloon) for 24 h. The reaction mixture was purged with nitrogen, filtered through celite, and concentrated in vacuo. The filtrate was dissolved in MeOH and passed through a 0.45 um filter. The filtrate was concentrated in vacuo and dried under high vacuum to afford rel-((3S,4S)-4-amino-7-fluoro-4-methylchroman-3-yl)methanol (0.80 g, 3.8 mmol, 94% yield) as a viscous oil. The crude product was used for subsequent chemistry without purification or characterization.
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[CH2:3][O:4][NH2:5].[NH2:8][C:9]1[S:10][CH:11]=[C:12]([C:14](=O)[C:15]([OH:17])=[O:16])[N:13]=1>>[NH2:8][C:9]1[S:10][CH:11]=[C:12](/[C:14](=[N:5]/[O:4][CH2:3][C:2]([F:7])([F:6])[F:1])/[C:15]([OH:17])=[O:16])[N:13]=1
Reactant: Nc1nc(C(=O)C(=O)O)cs1
Reactant: NOCC(F)(F)F
Product: Nc1nc(/C(=N/OCC(F)(F)F)C(=O)O)cs1

Procedure:
N.m.r. in solvent B: 5.42 (s, 2H), 7.17 (s, 1H), 7.67 (s, 2H). 11. A suspension of the product from Footnote 10 (4.4 mM) in DMF (40 μl. at 0° C. was dissolved by the addition of 3M HCl in ether (8.8 mM). N-hydroxybenzotriazole (4.4 mM) and t-butyl 7-amino-3-azidomethyl-ceph-3-em-4-carboxylate (4.0 mM) were added to the solution, followed by dropwise addition of a solution of DCCI (4.4 mM) in CH3CN (15 ml.) during 20 minutes. The mixture was left t stir for 23 hours at 0° C. and 1 hour at room temperature. The precipitate was filtered, washed with DMF (3 ml.) and the residue evaporated to dryness. Trituration at 0° C. with aqueous NaHCO3 (5%) yielded a yellow solid which was treated at room temperature with TFA/H2O (15:1) during 2 hours. Evaporation to dryness and purification of the residue by chromatography on Dianion HP 20 resin gave the required product. 12. N.m.r. in solvent B: 3.6 (m, 2H), 4.2 (dd, 2H), 5.25 (d, 1H), 5.5 (s, 2H), 5.9 (d, 1H), 7.25 (s, 1H) 7.7 (s, 2H). 13. This molecule is not tritylated on the 14. The starting material was prepared by condensation of O-(2,2,2-trifluoroethyl)hydroxylamine with 2-(2-aminothiazol-4-yl)glyoxylic acid to give 2-(2-aminothiazol-4-yl)-2-[(Z)-2,2,2-trifluoroethoxyimino]acetic acid.
Reaction SMILES: [N:1]([CH2:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2C=C[CH:14]=[CH:13][CH:12]=2)=[C:7]([O:17][CH3:18])[CH:6]=1)=[N+:2]=[N-:3].C(C1C=CC(CCl)=CC=1OC)CCC>>[N:1]([CH2:4][C:5]1[CH:10]=[CH:9][C:8]([CH2:11][CH2:12][CH2:13][CH3:14])=[C:7]([O:17][CH3:18])[CH:6]=1)=[N+:2]=[N-:3]
Reactant: COc1cc(CN=[N+]=[N-])ccc1-c1ccccc1
Agent: CCCCc1ccc(CCl)cc1OC
Product: CCCCc1ccc(CN=[N+]=[N-])cc1OC
Yield: 36 %

Procedure:
Following the same procedure for the preparation of 4-Azidomethyl-2-methoxy-biphenyl, the title compound is prepared from 1-Butyl-4-chloromethyl-2-methoxy-benzene (crude material from the previous step) in 36% yield (overall yield for 4 steps).
Reaction SMILES: C[O:2][C:3](=[O:38])[CH2:4][C@H:5]1[C:9]2[CH:10]=[CH:11][C:12]([O:14][C@H:15]3[C:23]4[C:18](=[C:19]([CH2:28][N:29]5[CH2:34][CH2:33][N:32]6[NH:35][CH:36]=[CH:37][C:31]6=[CH:30]5)[C:20]([C:24]([F:27])([F:26])[F:25])=[CH:21][CH:22]=4)[CH2:17][CH2:16]3)=[CH:13][C:8]=2[O:7][CH2:6]1.COC(=O)C[C@H]1C2C=CC(O[C@H]3C4C(=C(CBr)C(C(F)(F)F)=CC=4)CC3)=CC=2OC1.N1N2CCNCC2=CC=1>>[NH:35]1[N:32]2[CH2:33][CH2:34][N:29]([CH2:28][C:19]3[C:20]([C:24]([F:27])([F:25])[F:26])=[CH:21][CH:22]=[C:23]4[C:18]=3[CH2:17][CH2:16][C@H:15]4[O:14][C:12]3[CH:11]=[CH:10][C:9]4[C@H:5]([CH2:4][C:3]([OH:38])=[O:2])[CH2:6][O:7][C:8]=4[CH:13]=3)[CH:30]=[C:31]2[CH:37]=[CH:36]1
Reactant: COC(=O)C[C@@H]1COc2cc(O[C@@H]3CCc4c3ccc(C(F)(F)F)c4CN3C=C4C=CNN4CC3)ccc21
Agent: COC(=O)C[C@@H]1COc2cc(O[C@@H]3CCc4c3ccc(C(F)(F)F)c4CBr)ccc21
Agent: c1cc2n(n1)CCNC2
Product: O=C(O)C[C@@H]1COc2cc(O[C@@H]3CCc4c3ccc(C(F)(F)F)c4CN3C=C4C=CNN4CC3)ccc21

Procedure:
The methyl ester of the title compound, {(S)-6-[(R)-4-(6,7-dihydro-pyrazolo[1,5-a]pyrazin-5-ylmethyl)-5-trifluoromethyl-indan-1-yloxy]-2,3-dihydro-benzofuran-3-yl}-acetic acid methyl ester, is prepared from {(S)-6-[(R)-4-bromomethyl-5-trifluoromethyl-indan-1-yloxy]-2,3-dihydro-benzofuran-3-yl}-acetic acid methyl ester and 4,5,6,7-tetrahydro-pyrazolo[1,5-a]pyrazine following a procedure analogous to that described for Intermediate 42. The crude product is directly submitted to the saponification conditions described for Example 1 to give the title compound upon chromatography on reversed phase (HPLC; acetonitrile/water). LC (method 6): tR=1.07 min; Mass spectrum (ESI+): m/z=514 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][CH2:9][C:10]([F:13])([F:12])[F:11])=[CH:4][CH:3]=1.[C:14]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])(=[O:19])[CH2:15][C:16]([O-])=[O:17].Cl.CN(C)CCCN=C=NCC>C(Cl)Cl.C(OCC)(=O)C>[C:21]([O:20][C:14](=[O:19])[CH2:15][C:16]([N:8]([C:5]1[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=1)[CH2:9][C:10]([F:11])([F:12])[F:13])=[O:17])([CH3:24])([CH3:23])[CH3:22]
Reactant: CC(C)(C)OC(=O)CC(=O)[O-]
Reactant: FC(F)(F)CNc1ccc(Cl)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CC(C)(C)OC(=O)CC(=O)N(CC(F)(F)F)c1ccc(Cl)cc1
Reaction time: 1 h

Procedure:
(4-Chlorophenyl) (2,2,2-trifluoroethyl)amine (1.84 g, 8.8 mmol) and mono-t-butyl malonate (1.37 mL, 8.9 mmol) were dissolved in DCM (50 mL) and the solution cooled in an ice bath prior to portion wise addition of 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (1.71 g, 8.9 mmol). After one hour the reaction was complete by TLC and was diluted with ethyl acetate and sequentially washed with 1 N NaOH, 1N HCl, and brine. The organic layer was dried with MgSO4 and concentrated under reduced pressure to give a white solid which was used without further purification. 1H NMR (300 MHz, CDCl3) δ ppm 1.40 (9H, s), 3.13 (2H, s), 4.34 (2H, q, J=8.7 Hz), 7.22 (2H, m), 7.41 (2H, m).
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[Cl:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][NH:16][C:17]([C:19]2[NH:20][C:21]3[C:26]([CH:27]=2)=[CH:25][C:24]([NH:28]C(=O)OC(C)(C)C)=[CH:23][CH:22]=3)=[O:18])=[C:11]([F:36])[C:10]=1[O:37][C:38]1[CH:43]=[C:42]([C:44]#[N:45])[CH:41]=[C:40]([Cl:46])[CH:39]=1>ClCCl>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[NH2:28][C:24]1[CH:25]=[C:26]2[C:21](=[CH:22][CH:23]=1)[NH:20][C:19]([C:17]([NH:16][CH2:15][C:12]1[CH:13]=[CH:14][C:9]([Cl:8])=[C:10]([O:37][C:38]3[CH:43]=[C:42]([C:44]#[N:45])[CH:41]=[C:40]([Cl:46])[CH:39]=3)[C:11]=1[F:36])=[O:18])=[CH:27]2
Reactant: CC(C)(C)OC(=O)Nc1ccc2[nH]c(C(=O)NCc3ccc(Cl)c(Oc4cc(Cl)cc(C#N)c4)c3F)cc2c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: N#Cc1cc(Cl)cc(Oc2c(Cl)ccc(CNC(=O)c3cc4cc(N)ccc4[nH]3)c2F)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 96.8 %

Procedure:
Trifluoroacetic acid (5 mL, 64.9 mmol) was added to a solution of 1,1-dimethylethyl (2-{[({4-chloro-3-[(3-chloro-5-cyanophenyl)oxy]-2-fluorophenyl}methyl)amino]carbonyl}-1H-indol-5-yl)carbamate (1.36 g, 2.39 mmol) in dichloromethane (40 mL). The reaction mixture was stirred at RT overnight. The solvent was evaporated to give the title compound as a beige foam (1.35 g, 97%). 1H NMR (400 MHz, DMSO-d6) δ ppm 11.94 (s, 1H), 9.92 (br. s., 2H), 9.13 (t, 1H), 7.75-7.85 (m, 1H), 7.62 (d, 1H), 7.44-7.57 (m, 4H), 7.40 (t, 1H), 7.23 (d, 1H), 7.16 (dd, 1H), 4.57 (d, 2H). ES-LCMS: m/z 469 (M+H).
Reaction SMILES: [CH2:1]([N:8]1[CH2:16][C:15]2([C:17]([O:19][CH3:20])=[O:18])[CH:10]([C:11](=[O:27])[CH2:12][CH2:13][CH:14]2[C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:28]([C:31]1[CH:36]=[CH:35][C:34]([Mg]Br)=[CH:33][CH:32]=1)([CH3:30])[CH3:29].BrC1C=CC(C(C)C)=CC=1.[Mg]>C(OCC)C>[CH2:1]([N:8]1[CH2:16][C:15]2([C:17]([O:19][CH3:20])=[O:18])[CH:10]([C:11]([C:34]3[CH:35]=[CH:36][C:31]([CH:28]([CH3:30])[CH3:29])=[CH:32][CH:33]=3)([OH:27])[CH2:12][CH2:13][CH:14]2[C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COC(=O)C12CN(Cc3ccccc3)CC1C(=O)CCC2c1ccccc1
Reactant: CC(C)c1ccc([Mg]Br)cc1
Agent: CC(C)c1ccc(Br)cc1
Agent: [Mg]
Solvent: CCOCC
Product: COC(=O)C12CN(Cc3ccccc3)CC1C(O)(c1ccc(C(C)C)cc1)CCC2c1ccccc1
Yield: 41 %

Procedure:
By carrying out the reaction as in Stage A of Example 1, but from 6 g of methyl (3aRS,4SR,7aRS)-2-benzyl-7-oxo-4-phenyloctahydroisoindole-3a-carboxylate in 60 cm3 of dry diethyl ether and from a solution of 4-isopropylphenylmagnesium bromide, prepared at the time of use from 4 g of 4-bromoisopropylbenzene and 0.52 g of magnesium turnings in 7 cm3 of dry diethyl ether, for eighteen hours at room temperature, 3.3 g (41%) of methyl (3aRS,4SR,7RS,7aRS)-2-benzyl-7-(4-isopropylphenyl)-7-hydroxy-4-phenyloctahydroisoindole-3a-carboxylate were obtained, after purification by flash chromatography on silica gel (230-400 mesh), elution being carried out with a gradient of mixtures of cyclohexane and of ethyl acetate (from 98/2 to 80/20 by volume), in the form of a yellow oil, the characteristic of which was as follows:
Reaction SMILES: [OH:1][CH2:2][CH:3]([NH:7][C:8]([N:10]1[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]1)=[O:9])[C:4]([OH:6])=O.[CH:16]1[C:26]2[CH:25]=[CH:24][C:23]3[CH:27]=[CH:28][CH:29]=[CH:30][C:22]=3[C:21](=[C:31]3[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]3)[C:20]=2[CH:19]=[CH:18][CH:17]=1.Cl.C(N=C=NCCCN(C)C)C.C(N(CC)CC)C>ClCCl>[CH:16]1[C:26]2[CH:25]=[CH:24][C:23]3[CH:27]=[CH:28][CH:29]=[CH:30][C:22]=3[C:21](=[C:31]3[CH2:32][CH2:33][N:34]([C:4](=[O:6])[CH:3]([NH:7][C:8]([N:10]4[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]4)=[O:9])[CH2:2][OH:1])[CH2:35][CH2:36]3)[C:20]=2[CH:19]=[CH:18][CH:17]=1
Reactant: C1=Cc2ccccc2C(=C2CCNCC2)c2ccccc21
Reactant: O=C(O)C(CO)NC(=O)N1CCCCC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(NC(CO)C(=O)N1CCC(=C2c3ccccc3C=Cc3ccccc32)CC1)N1CCCCC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
64.0 mg (0.296 mmol) of 3-hydroxy-2-[(1-piperidinylcarbonyl)amino]propionic acid, 80.9 mg (0.296 mmol) of 4-(5H-dibenzo[a,d][7]annulen-5-ylidene)piperidine and 85.1 mg (0.444 mmol) of 1 -ethyl-3-(3′-dimethylaminopropyl)carbodiimide hydrochloride were dissolved in 10 ml of dichloromethane. 0.091 ml (0.651 mmol) of triethylamine was added to the obtained solution, and they were stirred at room temperature overnight. The reaction mixture was concentrated under reduced pressure. Ethyl acetate was added to the residue. After washing with saturated aqueous sodium chloride solution, the reaction product was dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. The resultant product was purified by the silica gel chromatography (dichloromethane: methanol=9:1) to obtain the title compound.
Reaction SMILES: [CH3:1][C:2]([C:5]1[CH:6]=[C:7]([C:22](=[NH:30])[NH:23][O:24][C:25](OCC)=[O:26])[CH:8]=[C:9]([C:18]([CH3:21])([CH3:20])[CH3:19])[C:10]=1[O:11][CH2:12][O:13][CH2:14][CH2:15][O:16][CH3:17])([CH3:4])[CH3:3]>C1(C)C=CC=CC=1>[CH3:4][C:2]([C:5]1[CH:6]=[C:7]([C:22]2[NH:30][C:25](=[O:26])[O:24][N:23]=2)[CH:8]=[C:9]([C:18]([CH3:19])([CH3:20])[CH3:21])[C:10]=1[O:11][CH2:12][O:13][CH2:14][CH2:15][O:16][CH3:17])([CH3:1])[CH3:3]
Reactant: CCOC(=O)ONC(=N)c1cc(C(C)(C)C)c(OCOCCOC)c(C(C)(C)C)c1
Solvent: Cc1ccccc1
Product: COCCOCOc1c(C(C)(C)C)cc(-c2noc(=O)[nH]2)cc1C(C)(C)C

Procedure:
A solution of 5.0 g (0.012 mole) of 3,5-bis(1,1-dimethylethyl)-N-[(ethoxycarbonyl)oxy]-4-[(2-methoxyethoxy)methoxy]benzenecarboximidamide in toluene (150 ml) is stirred at 120°-130° C. for 18 hours. The toluene is evaporated (vacuum) and the residual oil solidifies upon standing. The solid is recrystallized from ethyl acetate and hexane giving 3.1 g (70%) of analytically pure 3-[3,5-bis(1,1-dimethylethyl)-4-[(2-methoxyethoxy)methoxy]phenyl]-1,2,4-oxadiazol-5(4H)-one, mp 112°-114° C.
Reaction SMILES: [C:1]([CH:4]1[CH2:9][CH2:8][CH:7]([CH:10]([CH3:12])[CH3:11])[CH2:6][CH2:5]1)(=[O:3])[CH3:2].C[O-].[Na+]>CO>[C:1]([C@H:4]1[CH2:9][CH2:8][C@H:7]([CH:10]([CH3:12])[CH3:11])[CH2:6][CH2:5]1)(=[O:3])[CH3:2]
Reactant: CC(=O)C1CCC(C(C)C)CC1
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: CC(=O)[C@H]1CC[C@H](C(C)C)CC1

Procedure:
A 12 g quantity of cis-trans mixture of 1-acetyl-4-isopropylcyclohexane and sodium methoxide in an amount equimolar to the mixture are heated in 150 ml of methanol for 6 hours with stirring. The reaction mixture is distilled in a vacuum to remove the solvent, 50 ml of water is added to the residue, and the resulting solution is subjected to extraction with 50 ml of ether three times. The extract is washed with water, dried over anhydrous sodium sulfate and thereafter distilled in a vacuum to remove the solvent. The residue is distilled in a vacuum, giving 9 g of trans-1-acetyl-4-isopropylcyclohexane boiling at 109° to 113° C./18-19 mm Hg.
Reaction SMILES: [NH2:1][C:2]1[C:7]([CH3:8])=[C:6]([O:9][CH3:10])[CH:5]=[CH:4][C:3]=1[C:11](=[O:13])[CH3:12].[CH:14]([C:17]1[N:18]=[C:19]([C:22](Cl)=[O:23])[S:20][CH:21]=1)([CH3:16])[CH3:15].C(C1C=CC(OC)=CC=1NC(C1SC=C(C(C)C)N=1)=O)(=O)C>>[C:11]([C:3]1[C:2]([NH:1][C:22]([C:19]2[S:20][CH:21]=[C:17]([CH:14]([CH3:16])[CH3:15])[N:18]=2)=[O:23])=[C:7]([CH3:8])[C:6]([O:9][CH3:10])=[CH:5][CH:4]=1)(=[O:13])[CH3:12]
Reactant: CC(C)c1csc(C(=O)Cl)n1
Reactant: COc1ccc(C(C)=O)c(N)c1C
Agent: COc1ccc(C(C)=O)c(NC(=O)c2nc(C(C)C)cs2)c1
Product: COc1ccc(C(C)=O)c(NC(=O)c2nc(C(C)C)cs2)c1C
Yield: 66 %

Procedure:
N-(6-Acetyl-2-methyl-3-methoxyphenyl)-4-isopropylthiazole-2-carboxamide 217b was synthesized from compound 201b and compound 214 as a beige solid in 66% yield, according to the procedure as described for compound 217a. MS (ESI, EI+): m/z=333 (MH+).
Reaction SMILES: [CH2:1]([C:4]1[C:9]([OH:10])=[C:8]([Br:11])[CH:7]=[C:6]([F:12])[C:5]=1[N:13]1[C:18](=[O:19])[CH:17]=[C:16]([C:20]([F:23])([F:22])[F:21])[N:15]([CH3:24])[C:14]1=[O:25])[CH:2]=[CH2:3].O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C(C)=CC=CC=1>[Br:11][C:8]1[C:9]2[O:10][CH:2]([CH3:3])[CH2:1][C:4]=2[C:5]([N:13]2[C:18](=[O:19])[CH:17]=[C:16]([C:20]([F:22])([F:21])[F:23])[N:15]([CH3:24])[C:14]2=[O:25])=[C:6]([F:12])[CH:7]=1
Reactant: C=CCc1c(O)c(Br)cc(F)c1-n1c(=O)cc(C(F)(F)F)n(C)c1=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: Cc1ccccc1C
Product: CC1Cc2c(c(Br)cc(F)c2-n2c(=O)cc(C(F)(F)F)n(C)c2=O)O1
Yield: 97.3 %

Procedure:
3-(2-Allyl-4-bromo-6-fluoro-3-hydroxyphenyl)-1-methyl-6-trifluoromethyl-2,4(1H,3H)-pyrimidine-dione (1.50 g) was dissolved in xylene (15 ml). After p-toluenesulfonic acid monohydrate (0.54 g) was added thereto, it was allowed to react under the refluxing condition for 12 hours. After the completion of the reaction, it was extracted with ethyl acetate, washed with an aqueous sodium hydrogen-carbonate solution and water, and then dried over anhydrous magnesium sulfate. Ethyl acetate was distilled off, and the resulting oily substance was purified by chromatography on silica gel (ethyl acetate:n-hexane=1:3) to obtain the objective 3-(7-bromo-5-fluoro-2-methyl-2,3-dihydro-benzo[b]furan-4-yl)-1-methyl-6-trifluoromethyl-2,4(1H,3H)-pyrimidinedione (1.46 g).
Reaction SMILES: [C:1]1(C2C=CC=CC=2)[CH:6]=[CH:5][CH:4]=[C:3]([CH2:7][N:8]2[C:16]3[C:11](=[C:12]([OH:17])[CH:13]=[CH:14][CH:15]=3)[CH:10]=[C:9]2[CH3:18])[CH:2]=1.[H-].[Na+].Br[CH2:28][C:29]([O:31][CH3:32])=[O:30]>>[CH3:32][O:31][C:29](=[O:30])[CH2:28][O:17][C:12]1[CH:13]=[CH:14][CH:15]=[C:16]2[C:11]=1[CH:10]=[C:9]([CH3:18])[N:8]2[CH2:7][C:3]1[CH:4]=[CH:5][C:6]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)=[CH:1][CH:2]=1
Reactant: COC(=O)CBr
Reactant: Cc1cc2c(O)cccc2n1Cc1cccc(-c2ccccc2)c1
Agent: [H-]
Agent: [Na+]
Product: COC(=O)COc1cccc2c1cc(C)n2Cc1ccc(-c2ccccc2)cc1
Yield: 125 %

Procedure:
Using the procedure described in Example 1, Part E, 1-([1,1'-biphenyl]-3-ylmethyl)-4-hydroxy-2-methyl-1H-indole (970 mg, 3.1 mmol) was treated with 124 mg (3.1 mmol) of 60% NaH/mineral oil and then 0.29 mL (3.1 mmol) of methyl bromoacetate. The product was purified by chromatography over silica gel eluting with 20% EtOAc/hexane, to give 747 mg (63% yield) of [[1-([1,1'-biphenyl]-4-ylmethyl)-2-methyl-1H-indol-4-yl]oxy]acetic acid methyl ester, 164°-167° C.
Reaction SMILES: [H-].[Na+].[F:3][C:4]([F:21])([F:20])[C@H:5]1[CH2:10][CH2:9][C@H:8]([C:11]([N:13]2[CH2:17][CH2:16][CH2:15][C@@H:14]2[CH2:18][OH:19])=[O:12])[CH2:7][CH2:6]1.Br[C:23]1[CH:24]=[N:25][CH:26]=[C:27]([C:29]([F:32])([F:31])[F:30])[CH:28]=1.O>CS(C)=O>[F:30][C:29]([F:32])([F:31])[C:27]1[CH:26]=[N:25][CH:24]=[C:23]([O:19][CH2:18][C@H:14]2[CH2:15][CH2:16][CH2:17][N:13]2[C:11]([C@H:8]2[CH2:7][CH2:6][C@H:5]([C:4]([F:3])([F:20])[F:21])[CH2:10][CH2:9]2)=[O:12])[CH:28]=1
Reactant: O=C([C@H]1CC[C@H](C(F)(F)F)CC1)N1CCC[C@@H]1CO
Reactant: FC(F)(F)c1cncc(Br)c1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: O=C([C@H]1CC[C@H](C(F)(F)F)CC1)N1CCC[C@@H]1COc1cncc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
NaH (60% oil dispersant, 11 mg, 0.27 mmol) was placed on the reaction tube, and a solution of [(2R)-1-{[trans-4-(trifluoromethyl)cyclohexyl]carbonyl}pyrrolidin-2-yl]methanol (68 mg, 0.24 mmol, EXAMPLE 31 Step 1) in DMSO (2.0 mL) was added at ambient temperature. After being stirred for 15 min at room temperature, 3-bromo-5-(trifluoromethyl)pyridine (50 mg, 0.22 mmol) was added to the mixture at ambient temperature. The mixture was heated stepwise with continuous stirring, at room temperature for 19 h, at 50° C. for 3 h, at 80° C. for 15 h, and at 100° C. for 15 h. After cooling to room temperature, water was added to the mixture. The mixture was extracted with ethyl acetate twice and washed with brine. The extracts were combined and dried over sodium sulfate and concentrated in vacuo to give an oil. The residual oil was purified by silica gel preparative thin layer chromatography (TLC) (ethyl acetate/hexane 3:2) to afford 40 mg (43%) of the title compound as a colorless viscous oil.
Reaction SMILES: C([O:5][C:6]([NH:8][C:9]1[CH:10]=[C:11]2[C:19](=[CH:20][CH:21]=1)[NH:18][C:17]1[CH2:16][CH2:15][CH:14]([N:22]([CH3:24])[CH3:23])[CH2:13][C:12]2=1)=O)(C)(C)C.[F:25][C:26]1[CH:34]=[CH:33][C:29](C(Cl)=O)=[CH:28][CH:27]=1>FC(F)(F)C(O)=O>[F:25][C:26]1[CH:34]=[CH:33][C:29]([C:6]([NH:8][C:9]2[CH:10]=[C:11]3[C:19](=[CH:20][CH:21]=2)[NH:18][C:17]2[CH2:16][CH2:15][CH:14]([N:22]([CH3:23])[CH3:24])[CH2:13][C:12]3=2)=[O:5])=[CH:28][CH:27]=1
Reactant: O=C(Cl)c1ccc(F)cc1
Reactant: CN(C)C1CCc2[nH]c3ccc(NC(=O)OC(C)(C)C)cc3c2C1
Solvent: O=C(O)C(F)(F)F
Product: CN(C)C1CCc2[nH]c3ccc(NC(=O)c4ccc(F)cc4)cc3c2C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 96.8 %

Procedure:
A solution of 0.10 gm (0.30 mMol) 6-(t-butoxycarbonyl)amino-3-(dimethyl)amino-1,2,3,4-tetrahydro-9H-carbazole in 1.0 mL trifluoroacetic acid was stirred for 20 minutes at room temperature. The reaction mixture was then concentrated under reduced pressure. The residual oil was then dissolved in 5 mL tetrahydrofuran. To this solution was added 1.5 mL triethylamine followed by 5.0 μL (0.42 mMol) 4-fluorobenzoyl chloride and the solution was stirred for 1 hour at room temperature. The reaction mixture was concentrated under reduced pressure and the residue was dissolved in dichloromethane. This solution was washed with aqueous potassium carbonate and was then concentrated under reduced pressure. The residue was dissolved in dilute aqueous tartaric acid and the solution was extracted well with dichloromethane. The remaining aqueous phase was made basic with dilute aqueous sodium hydroxide and was extracted well with dichloromethane. These organic phases were combined, dried over sodium sulfate and concentrated under reduced pressure. The residue was subjected to silica gel chromatography, eluting with 95:5 chloroform:5% ammonium hydroxide in methanol. Fractions containing the product were combined and concentrated under reduced pressure to give 0.102 gm (95%) of 6-(4-fluorobenzoyl)amino-3-(dimethyl)amino-1,2,3,4-tetrahydro-9H-carbazole.