Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[OH:9].C(=O)([O-])[O-].[K+].[K+].F[C:17]1[CH:22]=[CH:21][C:20]([N+:23]([O-:25])=[O:24])=[CH:19][C:18]=1[CH3:26].CN(C=O)C>O>[CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[O:9][C:17]1[CH:22]=[CH:21][C:20]([N+:23]([O-:25])=[O:24])=[CH:19][C:18]=1[CH3:26]
Reactant: Cc1cc([N+](=O)[O-])ccc1F
Reactant: Cc1cccc(C)c1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1cc([N+](=O)[O-])ccc1Oc1c(C)cccc1C
Yield: 91.1 %

Procedure:
A solution of 2,6-dimethylphenol (0.87 g, 7.1 mmol), potassium carbonate (0.98 g, 7.1 mmol), 2-fluoro-5-nitrotoluene (1.0 g, 6.4 mmol) and DMF (20 mL) was stirred at 100° C. for 2 h. The reaction mixture was diluted with 100 mL water and extracted with 250 mL EtOAc. The organic layer was washed with brine, dried with sodium sulfate and concentrated to provide the crude titled compound (1.5 g, 92%). This material was used without purification: MS (ESI): mass calcd. for C15H15NO3, 257.3; m/z found, 258.1 [M+H]+. 1H NMR (400 MHz, CDCl3): 8.16 (dd, J=2.8, 0.7 Hz, 1H), 7.92 (dd, J=9.1, 2.7 Hz, 1H), 7.18-7.07 (m, 3H), 6.33 (d, J=9.0 Hz, 1H), 2.50 (s, 3H), 2.09 (s, 6H).
Reaction SMILES: F[C:2](F)(F)[C:3](O)=[O:4].[NH:8]1[CH2:13][CH2:12][CH:11]([CH2:14][NH:15][C:16]([N:18]2[CH2:22][CH:21]([CH2:23][C:24]([CH3:27])([CH3:26])[CH3:25])[C:20]3([C:35]4[C:30](=[CH:31][C:32]([Cl:36])=[CH:33][CH:34]=4)[NH:29][C:28]3=[O:37])[CH:19]2[C:38]2[CH:43]=[CH:42][CH:41]=[C:40]([Cl:44])[C:39]=2[F:45])=[O:17])[CH2:10][CH2:9]1.C(N(CC)CC)C.C(Cl)(=O)C>O1CCCC1>[C:3]([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][NH:15][C:16]([N:18]2[CH2:22][CH:21]([CH2:23][C:24]([CH3:27])([CH3:26])[CH3:25])[C:20]3([C:35]4[C:30](=[CH:31][C:32]([Cl:36])=[CH:33][CH:34]=4)[NH:29][C:28]3=[O:37])[CH:19]2[C:38]2[CH:43]=[CH:42][CH:41]=[C:40]([Cl:44])[C:39]=2[F:45])=[O:17])[CH2:10][CH2:9]1)(=[O:4])[CH3:2]
Reactant: CC(C)(C)CC1CN(C(=O)NCC2CCNCC2)C(c2cccc(Cl)c2F)C12C(=O)Nc1cc(Cl)ccc12
Reactant: O=C(O)C(F)(F)F
Solvent: CC(=O)Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(=O)N1CCC(CNC(=O)N2CC(CC(C)(C)C)C3(C(=O)Nc4cc(Cl)ccc43)C2c2cccc(Cl)c2F)CC1

Procedure:
In a manner similar to the method described in Example 26, rac-(2′S,3′S,4′S)-6-chloro-2′-(3-chloro-2-fluoro-phenyl)-4′-(2,2-dimethyl-propyl)-2-oxo-1,2-dihydro-spiro[indole-3,3′-pyrrolidine]-1′-carboxylic acid (piperidin-4-ylmethyl)-amide trifluoroacetic acid (25 mg, 0.04 mmol) was reacted with triethylamine and acetyl chloride (3.2 mg, 0.04 mmol) in tetrahydrofuran to give rac-(2′S,3′S,4′S)-6-chloro-2′-(3-chloro-2-fluoro-phenyl)-4′-(2,2-dimethyl-propyl)-2-oxo-1,2-dihydro-spiro[indole-3,3′-pyrrolidine]-1′-carboxylic acid (1-acetyl-piperidin-4-ylmethyl)-amide as a white solid (Yield, 17 mg, 77%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C@@H:12]([CH2:25][CH:26]2[CH2:30][CH2:29][CH2:28][CH2:27]2)[C:13]([NH:15][C:16]2[CH:20]=[CH:19][N:18]([CH2:21][C:22]([OH:24])=O)[N:17]=2)=[O:14])[CH:5]=[CH:6][C:7]=1[S:8]([CH3:11])(=[O:10])=[O:9].[C:31](Cl)(=O)C(Cl)=O.N1C(C)=CC=CC=1C.COCCN1C=CC(N)=N1>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]([C@@H:12]([CH2:25][CH:26]2[CH2:30][CH2:29][CH2:28][CH2:27]2)[C:13]([NH:15][C:16]2[CH:20]=[CH:19][N:18]([CH2:21][CH2:22][O:24][CH3:31])[N:17]=2)=[O:14])[CH:5]=[CH:6][C:7]=1[S:8]([CH3:11])(=[O:9])=[O:10]
Reactant: O=C(Cl)C(=O)Cl
Reactant: CS(=O)(=O)c1ccc([C@@H](CC2CCCC2)C(=O)Nc2ccn(CC(=O)O)n2)cc1Cl
Agent: COCCn1ccc(N)n1
Solvent: Cc1cccc(C)n1
Solvent: ClCCl
Product: COCCn1ccc(NC(=O)[C@H](CC2CCCC2)c2ccc(S(C)(=O)=O)c(Cl)c2)n1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 41 %

Procedure:
2-(R)-(3-Chloro-4-methanesulfonyl-phenyl)-3-cyclopentyl-propionic acid (prepared as in PCT WO 2004/052869 A1, Example 1, 469 mg, 1.42 mmol,) was suspended in methylene chloride (7 mL) and a 2.0 M solution of oxalyl chloride in methylene chloride (710 mL, 1.42 mmol) was added and the reaction stirred at 25° C. for 10 min. The solution was chilled to 0° C. and 2,6-lutidine (331 μL, 2.84 mmol) was added dropwise. The reaction continued to stir at 0° C. for 10 min. The 1-(2-methoxy-ethyl)-1H-pyrazol-3-ylamine (200 mg, 1.42 mmol) was added as a pre-dissolved reaction in methylene chloride (7 mL), the ice bath was removed and the reaction continued to stir at 25° C. for 25 min. The reaction was diluted with methylene chloride (100 mL), washed with water (2×30 mL), saturated aqueous brine solution (1×20 mL), dried over magnesium sulfate and concentrated in vacuo to a beige foam. Purification by flash column chromatography (Merck silica gel 60, 40-63 μm; 0% ethyl acetate/methylene chloride to 20% ethyl acetate/methylene chloride) afforded 2-(R)-(3-chloro-4-methanesulfonyl-phenyl)-3-cyclopentyl-N-[1-(2-methoxy-ethyl)-1H-pyrazol-3-yl]-propionamide (262 mg, 41%) as a white powder: ESI-LRMS m/e calcd for C21H28ClN3O4S [M+] 453.15, found 454.26 [M+H+]; 1H NMR (400 MHz, CDCl3) δ ppm 1.05-1.23 (m, 2H, CH2), 1.45-1.92 (m, 8H, 4×CH2), 2.14-2.33 (m, 1H, CH), 3.26 (s, 3H, SO2CH3), 3.31 (s, 3H, OCH3), 3.53 (t, J=7.6 Hz, 1H, CH), 3.67 (t, J=5.2 Hz, 2H, OCH2), 4.13 (t, J=5.2 Hz, 2H, NCH2), 6.65 (d, Jo=2.3 Hz, 1H, Ar), 7.33 (d, Jo=2.3 Hz, 1H, Ar), 7.45 (dd, Jo=8.2, Jm=1.7 Hz. 1H, Ar), 7.58 (d, Jm=1.7 Hz, 1H, Ar), 7.81 (s, 1 H, NH), 8.08 (d, Jo=8.2 Hz, 1H, Ar).
Reaction SMILES: [Cl:1][C:2]1[CH:26]=[CH:25][C:5]([O:6][C:7]2[C:15]([C:16]3[C:17]([O:22][CH3:23])=[N:18][CH:19]=[CH:20][CH:21]=3)=[CH:14][C:10]([C:11](O)=[O:12])=[C:9]([F:24])[CH:8]=2)=[C:4]([O:27][CH3:28])[CH:3]=1.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C.[CH3:62][S:63]([NH2:66])(=[O:65])=[O:64]>C(Cl)Cl.CN(C)C=O>[Cl:1][C:2]1[CH:26]=[CH:25][C:5]([O:6][C:7]2[C:15]([C:16]3[C:17]([O:22][CH3:23])=[N:18][CH:19]=[CH:20][CH:21]=3)=[CH:14][C:10]([C:11]([NH:66][S:63]([CH3:62])(=[O:65])=[O:64])=[O:12])=[C:9]([F:24])[CH:8]=2)=[C:4]([O:27][CH3:28])[CH:3]=1
Reactant: CS(N)(=O)=O
Reactant: COc1cc(Cl)ccc1Oc1cc(F)c(C(=O)O)cc1-c1cccnc1OC
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: ClCCl
Product: COc1cc(Cl)ccc1Oc1cc(F)c(C(=O)NS(C)(=O)=O)cc1-c1cccnc1OC
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 113.1 %

Procedure:
A mixture of 4-(4-chloro-2-methoxyphenoxy)-2-fluoro-5-(2-methoxypyridin-3-yl)benzoic acid (Preparation 15, 0.070 g, 0.114 mmol), O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (0.112 g, 0.294 mmol) and N,N-diisopropylethylamine (191 μL, 1.09 mmol) in DCM (10 mL) and dimethylformamide (1.1 mL) was stirred at room temperature for 10 minutes, then methyl sulfonamide (0.0397 g, 0.417 mmol) was added. The reaction was heated at 45° C. for 18 hours under a nitrogen atmosphere, then cooled to room temperature and concentrated in vacuo to afford a pale brown residue. This was partitioned between aqueous hydrochloric acid (0.5 M, 10 mL) and DCM (25 mL). The organic extract was washed with aqueous hydrochloric acid (0.5 M, 2×10 mL), dried over sodium sulfate and concentrated in vacuo to afford a pale brown gum (0.062 g). The crude product was purified by preparative A-HPLC to afford the title compound (26.7 mg):
Reaction SMILES: [CH3:1][C:2]1([CH3:32])[C:6]([CH3:8])([CH3:7])[O:5][B:4]([C:9]2[CH:22]=[CH:21][C:20]3[C:19]4[C:14](=[CH:15][C:16]([B:23]5[O:27][C:26]([CH3:29])([CH3:28])[C:25]([CH3:31])([CH3:30])[O:24]5)=[CH:17][CH:18]=4)C[CH2:12][C:11]=3[CH:10]=2)[O:3]1.BrC1C=CC2C3C(=CC(Br)=CC=3)CC=2C=1>>[CH3:1][C:2]1([CH3:32])[C:6]([CH3:8])([CH3:7])[O:5][B:4]([C:9]2[CH:22]=[CH:21][C:20]3[C:19]4[C:14](=[CH:15][C:16]([B:23]5[O:27][C:26]([CH3:29])([CH3:28])[C:25]([CH3:30])([CH3:31])[O:24]5)=[CH:17][CH:18]=4)[CH2:12][C:11]=3[CH:10]=2)[O:3]1
Reactant: CC1(C)OB(c2ccc3c(c2)CCc2cc(B4OC(C)(C)C(C)(C)O4)ccc2-3)OC1(C)C
Agent: Brc1ccc2c(c1)Cc1cc(Br)ccc1-2
Product: CC1(C)OB(c2ccc3c(c2)Cc2cc(B4OC(C)(C)C(C)(C)O4)ccc2-3)OC1(C)C

Procedure:
Followed the procedure used to prepare 4,4,5,5-tetramethyl-2-[7-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-9,10-dihydro-phenanthren-2-yl]-[1,3,2]dioxaborolane, except that 2,7-dibromofluorene was used instead of 2,7-dibromo-9,10-dihydro-phenanthrene. 1H-NMR (300 MHz, CDCl3). δ 8.01 (s, 2H), 7.84 (s, 4H), 3.90 (s, 2H), 1.38 (s, 24H).
Reaction SMILES: [CH3:1][CH:2]([N:4]1[C:12](/[CH:13]=[CH:14]/[CH:15]([OH:23])[CH2:16][CH:17]([OH:22])[CH2:18][C:19](O)=[O:20])=[C:11]([C:24]2[CH:25]=[CH:26][C:27]([F:30])=[CH:28][CH:29]=2)[C:10]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]1=2)[CH3:3].[NH2:31][OH:32].O.CO>C1COCC1>[F:30][C:27]1[CH:28]=[CH:29][C:24]([C:11]2[C:10]3[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=3)[N:4]([CH:2]([CH3:3])[CH3:1])[C:12]=2/[CH:13]=[CH:14]/[C@@H:15]([OH:23])[CH2:16][C@@H:17]([OH:22])[CH2:18][C:19]([NH:31][OH:32])=[O:20])=[CH:25][CH:26]=1
Reactant: NO
Reactant: CC(C)n1c(/C=C/C(O)CC(O)CC(=O)O)c(-c2ccc(F)cc2)c2ccccc21
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: CC(C)n1c(/C=C/[C@@H](O)C[C@@H](O)CC(=O)NO)c(-c2ccc(F)cc2)c2ccccc21
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of fluvastatin (100 mg, 0.25 mmol, in the lactone form) in THF (1 mL) was added 50% hydroxylamine in H2O (0.12 mL, 1.91 mmol). The mixture was stirred at ambient temperature for 16 h, and concentrated under reduced pressure. The residue was extracted with CH2Cl2. The organic layer was washed with brine, dried over MgSO4, filtered, concentrated, and purified by flash chromatography (silica gel; CH2Cl2/MeOH/NEt3 (89:1:9 to 5:5:1)) to give fluva-HA (30 mg, 30%). C24H27FN2O4; white foam; TLC (CH2C1-2/MeOH (9:1)) Rf=0.13; 1H NMR (CDCl3, 400 MHz) δ 7.57-7.59 (1H, d, J=8.4 Hz), 7.41-7.44 (3H, m), 7.13-7.19 (3H, m), 6.99-7.03 (1H, t), 6.69-6.73 (1H, d, J=14.8 Hz), 5.74-5.79 (1H, dd, J=16.4 Hz), 4.95 (1H, br s), 4.39-4.42 (1H, m), 4.21-4.24 (1H, m), 2.24-2.25 (2H, m), 1.64-1.73 (6H, m), 1.32-1.36 (2H, m) ppm; ESI-HRMS calcd for C24H28FN2O4: 427.2033. found: m/z 427.2034 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[C:3](=[O:18])[N:4]([CH2:9][C:10]2[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][CH:11]=2)[CH:5]=[C:6]([Cl:8])[CH:7]=1.C[O:20][C:21]([C:23]1[CH:27]=[C:26]([Br:28])[N:25]([CH:29]([CH3:31])[CH3:30])[C:24]=1[CH:32]([C:34]1[CH:39]=[CH:38][C:37]([Cl:40])=[CH:36][CH:35]=1)O)=O.ClC1C=C(C=CC=1[F:49])N.ClC(N(C)C)=C(C)C>C(Cl)Cl.CO.CCN(CC)CC>[Br:28][C:26]1[N:25]([CH:29]([CH3:31])[CH3:30])[C:24]2[CH:32]([C:34]3[CH:39]=[CH:38][C:37]([Cl:40])=[C:36]([F:49])[CH:35]=3)[N:1]([C:2]3[C:3](=[O:18])[N:4]([CH2:9][C:10]4[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][CH:11]=4)[CH:5]=[C:6]([Cl:8])[CH:7]=3)[C:21](=[O:20])[C:23]=2[CH:27]=1
Reactant: COC(=O)c1cc(Br)n(C(C)C)c1C(O)c1ccc(Cl)cc1
Reactant: Nc1ccc(F)c(Cl)c1
Reactant: COc1ccc(Cn2cc(Cl)cc(N)c2=O)cc1
Agent: CC(C)=C(Cl)N(C)C
Solvent: CO
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1ccc(Cn2cc(Cl)cc(N3C(=O)c4cc(Br)n(C(C)C)c4C3c3ccc(Cl)c(F)c3)c2=O)cc1

Procedure:
The title compound was prepared in analogy to the procedure described for Intermediate D but in the step corresponding to Step D2,5-bromo-2-[(4-chloro-3-fluoro-phenyl)-hydroxy-methyl]-1-isopropyl-1H-pyrrole-3-carboxylic acid methyl ester (Step AZ1) and 3-amino-5-chloro-1-(4-methoxy-benzyl)-1H-pyridin-2-one (Step AH1) were used instead of 5-bromo-2-[(4-chloro-phenyl)-hydroxy-methyl]-1-isopropyl-1H-pyrrole-3-carboxylic acid methyl ester and 3-chloro-4-fluoroaniline respectively. Moreover, in this step, the procedures described for Steps H3 and H2 using 1-chloro-N,N,2-trimethylpropenylamine and Et3N were used. The title compound (containing some of the corresponding 2-chloro analog) was obtained as a yellow-brown solid. tR: 7.83 min (HPLC 2); ESI-MS: tR=1.36 min, [M+H]+ 618/620/622 (LC-MS 1); TLC: Rf=0.50 (98:2 CH2Cl2/MeOH).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:9]=[C:10]=[S:11])[CH:5]=[CH:6][C:7]=1[CH3:8].Cl.[NH2:13][CH2:14][C:15]([NH2:17])=[O:16].[CH2:18](N(CC)CC)[CH3:19]>C(Cl)(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10](=[S:11])[NH:13][CH2:14][C:15]([NH2:17])=[O:16])[CH:5]=[CH:6][C:7]=1[CH3:8].[Cl:1][C:2]1[CH:3]=[C:4]([N:9]2[C:15](=[O:16])[CH2:14][N:13]=[C:10]2[S:11][CH2:18][CH3:19])[CH:5]=[CH:6][C:7]=1[CH3:8]
Reactant: Cc1ccc(N=C=S)cc1Cl
Reactant: CCN(CC)CC
Reactant: NCC(N)=O
Agent: Cl
Solvent: ClC(Cl)Cl
Product: CCSC1=NCC(=O)N1c1ccc(C)c(Cl)c1
Product: Cc1ccc(NC(=S)NCC(N)=O)cc1Cl

Procedure:
2-[3-(3-Chloro-4-methylphenyl)-thioureido]-acetamide was prepared by the procedure described Example 11 using 18.36 g of 3-chloro-4-methylphenyl-isothiocyanate, 11.05 g of glycinamide hydrochloride, 10.1 g of triethyl amine, and 300 mL of chloroform. 22.0 Grams of the desired product was obtained, m.p. 167°-169° C. (dec.). Mass spectrum (EI, M.+) m/z 257/259. 1H-NMR (DMSO-d6 ; 400 MHz) δ9.93 (s, 1 H), 7.80 (t, 1 H), 7.73 (s, 1 H), 7.52 (s, 1 H), 7.25 (m, 2 H), 7.16 (s, 1 H), 4.07 (d, 2 H), and 2.27 ppm (s, 3 H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([OH:12])[C:6](=[CH:10][CH:11]=1)[C:7]([OH:9])=O.[C:13](Cl)(=[O:17])[O:14][CH2:15][CH3:16].[NH2:19][CH2:20][CH2:21][S:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30].Cl>C(Cl)Cl.C(N(CC)CC)C>[CH2:15]([O:14][C:13]([O:12][C:5]1[CH:4]=[C:3]([O:2][CH3:1])[CH:11]=[CH:10][C:6]=1[C:7]([NH:19][CH2:20][CH2:21][S:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30])=[O:9])=[O:17])[CH3:16]
Reactant: CCOC(=O)Cl
Reactant: COc1ccc(C(=O)O)c(O)c1
Reactant: CCCCCCCCSCCN
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCCCCCCSCCNC(=O)c1ccc(OC)cc1OC(=O)OCC
Temperature: -15 °C
Reaction time: 1.5 h

Procedure:
In the meantime, 3.36 g of 4-methoxysalicylic acid was dispersed in 30 ml of methylene chloride under argon atmosphere, and the dispersion was cooled to -15° C. To the dispersion were added 4.47 g of triethylamine and 4.58 g of ethyl chlorocarbonate, and the mixture was agitated for 1.5 hours. To the mixture was added the 2-aminoethyl-n-octylsulfide which had been dissolved in 10 ml of methylene chloride, and the mixture was agitated at -15° C. for 2 hours. The reaction mixture was poured into 1N aqueous hydrochloric acid, and the mixture was extracted with methylene chloride. The organic layer was washed with saturated aqueous solution of sodium bicarbonate, and dried over anhydrous sodium sulfate. The solvent was distilled off in evacuated atomosphere, and the residue was subjected to column chromatography using silica gel. There was obtained 6.37 g of 2-(2'-ethoxycarbonyloxy-4'-methoxybenzoylamino)ethyl-n-octylsulfide, which was dissolved in 100 ml of methanol. To the solution was added 23 ml of 1N aqueous solution of sodium hydroxide, and the mixture was agitated for 35 minutes. The solvent was distilled off in evacuated atomosphere, and the residue was subjected to column chromatography using silica gel. There was obtained 3.55 g of 2-(2'-hydroxy-4'-methoxybenzoylamino)ethyl-n-octylsulfide.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:10]2[CH:18]([CH:19]3[CH2:23][CH2:22][CH2:21][CH2:20]3)[CH:17]3[C:12]([C:13]4[CH:27]=[CH:26][C:25]([C:28]([OH:30])=[O:29])=[CH:24][C:14]=4[CH2:15][CH2:16]3)=[N:11]2)[CH:5]=[CH:6][C:7]=1[C:8]#[N:9].[C:31]([O:35][CH3:36])(=[O:34])[CH2:32]O>>[Cl:1][C:2]1[CH:3]=[C:4]([N:10]2[CH:18]([CH:19]3[CH2:20][CH2:21][CH2:22][CH2:23]3)[CH:17]3[C:12]([C:13]4[CH:27]=[CH:26][C:25]([C:28]([O:30][CH2:32][C:31]([O:35][CH3:36])=[O:34])=[O:29])=[CH:24][C:14]=4[CH2:15][CH2:16]3)=[N:11]2)[CH:5]=[CH:6][C:7]=1[C:8]#[N:9]
Reactant: COC(=O)CO
Reactant: N#Cc1ccc(N2N=C3c4ccc(C(=O)O)cc4CCC3C2C2CCCC2)cc1Cl
Product: COC(=O)COC(=O)c1ccc2c(c1)CCC1C2=NN(c2ccc(C#N)c(Cl)c2)C1C1CCCC1

Procedure:
The title compound was prepared from (±)-(3SR,3aRS)-2-(3-chloro-4-cyanophenyl)-3-cyclopentyl-3,3a,4,5-tetrahydro-2H-benzo[g]indazole-7-carboxylic acid, Example 15 and methyl glycolate according to Method E. 1H NMR (400 MHz, CDCl3) δ ppm 1.20-1.69 (m, 7H), 1.72-1.84 (m, 1H), 1.89-2.03 (m, 1H), 2.06-2.20 (m, 1H), 2.26-2.36 (m, 1H), 2.86-2.99 (m, 1H), 3.07-3.18 (m, 1H), 3.49 (ddd, J=13.70, 9.40, 4.83 Hz, 1H), 3.82 (s, 3H), 4.65 (dd, J=9.53, 5.50 Hz, 1H), 4.89 (s, 2H) 7.03 (dd, J=8.73, 2.01 Hz, 1H), 7.31 (d, J=1.88 Hz, 1H), 7.46 (d, J=8.86 Hz, 1H), 7.95-8.01 (m, 2H), 8.17 (d, J=8.86 Hz, 1H). ES-MS m/z 492 (M+H).
Reaction SMILES: Br[C:2]1[N:7]=[CH:6][CH:5]=[CH:4][N:3]=1.[CH2:8]([OH:14])[CH2:9][CH2:10][CH2:11][C:12]#[CH:13].C1(NC2CCCCC2)CCCCC1.C(#N)C>[Cu]I.CCOCC>[N:3]1[CH:4]=[CH:5][CH:6]=[N:7][C:2]=1[C:13]#[C:12][CH2:11][CH2:10][CH2:9][CH2:8][OH:14]
Reactant: C#CCCCCO
Reactant: Brc1ncccn1
Agent: [Cu]I
Agent: C1CCC(NC2CCCCC2)CC1
Solvent: CC#N
Solvent: CCOCC
Product: OCCCCC#Cc1ncccn1
Temperature: 25 °C
Reaction time: 1 h
Yield: 83.1 %

Procedure:
A mixture of 2-bromopyrimidine (3.96 g), 5-hexynol (2.44 g), dicyclohexylamine (4 g), BTPC (250 mg), copper (I) iodide (25 mg) and acetonitrile (40 ml) was stirred at ambient temperature under nitrogen for 1 h (temp. rose to ~45°). Ether (120 ml) was added, the mixture was filtered and the filtrate was evaporated in vacuo to an oil which was purified by FCC. Elution with ether followed by System C (17:3) gave the title compound as a pale yellow oil (3.64 g), t.l.c. (System C 17:3) Rf 0.34.
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5]([CH2:7][N:8]2[C:12](=[O:13])/[C:11](=[CH:14]/[C:15]3[CH:16]=[C:17]4[C:21](=[CH:22][CH:23]=3)[N:20]([CH2:24][C:25]3[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][C:26]=3[C:32]([F:35])([F:34])[F:33])[N:19]=[CH:18]4)/[S:10][C:9]2=[O:36])[N:6]=1.[C:37](OC(=O)C)(=[O:39])[CH3:38]>>[Cl:31][C:28]1[CH:29]=[CH:30][C:25]([CH2:24][N:20]2[C:21]3[C:17](=[CH:16][C:15](/[CH:14]=[C:11]4/[C:12](=[O:13])[N:8]([CH2:7][C:5]5[N:6]=[C:2]([NH:1][C:37](=[O:39])[CH3:38])[S:3][CH:4]=5)[C:9](=[O:36])[S:10]/4)=[CH:23][CH:22]=3)[CH:18]=[N:19]2)=[C:26]([C:32]([F:35])([F:34])[F:33])[CH:27]=1
Reactant: CC(=O)OC(C)=O
Reactant: Nc1nc(CN2C(=O)S/C(=C\c3ccc4c(cnn4Cc4ccc(Cl)cc4C(F)(F)F)c3)C2=O)cs1
Product: CC(=O)Nc1nc(CN2C(=O)S/C(=C\c3ccc4c(cnn4Cc4ccc(Cl)cc4C(F)(F)F)c3)C2=O)cs1

Procedure:
N-(4-{[(5Z)-5-({1-[4-Chloro-2-(trifluoromethyl)benzyl]-1H-indazol-5-yl}methylidene)-2,4-dioxo-1,3-thiazolidin-3-yl]methyl}-1,3-thiazol-2-yl)acetamide was prepared from (5Z)-3-[(2-amino-1,3-thiazol-4-yl)methyl]-5-({1-[4-chloro-2-(trifluoromethyl)benzyl]-1H-indazol-5-yl}methylidene)-1,3-thiazolidine-2,4-dione (from Example 400) and acetic anhydride following General Procedure U.
Reaction SMILES: [NH2:1][C:2]1[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][C:3]=1[O:4][CH2:5][C:6]1[CH:15]=[CH:14][C:9]([C:10]([O:12][CH3:13])=[O:11])=[CH:8][CH:7]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH:43]1([S:48](Cl)(=O)=[O:49])[CH2:47][CH2:46][CH2:45][CH2:44]1.O>C(Cl)Cl.N1C=CC=CC=1>[CH:43]1([S:48]([NH:1][C:2]2[CH:19]=[CH:18][C:17]([C:20]([F:21])([F:22])[F:23])=[CH:16][C:3]=2[O:4][CH2:5][C:6]2[CH:7]=[CH:8][C:9]([C:10]([O:12][CH3:13])=[O:11])=[CH:14][CH:15]=2)=[O:49])[CH2:47][CH2:46][CH2:45][CH2:44]1
Reactant: O=S(=O)(Cl)C1CCCC1
Reactant: COC(=O)c1ccc(COc2cc(C(F)(F)F)ccc2N)cc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: c1ccncc1
Solvent: ClCCl
Solvent: O
Product: COC(=O)c1ccc(COc2cc(C(F)(F)F)ccc2NS(=O)C2CCCC2)cc1
Temperature: 25 °C
Reaction time: 6 h
Yield: 75.9 %

Procedure:
To a solution of methyl 4-(2-amino-5-trifluoromethylphenoxymethyl)benzoate (300 mg) in methylene chloride (3.0 ml), pyridine (187 μml) and triphenylphosphine (315 mg) were added in a stream of argon. At 0° C., cyclopentylsulfonylchloride (202 mg) was added dropwise thereto. The mixture was stirred for 6 hours at room temperature. To the reaction mixture, water was added. The mixture was extracted with ethyl acetate, washed, dried over and concentrated with the reduced pressure. The residue was purified on silica gel column chromatography (hexane:AcOEt=2:1→1:1) to give the title compound (309 mg) having the following physical data.
Reaction SMILES: [CH3:1][C:2]1[CH2:7][C:6]([CH3:9])([CH3:8])[NH:5][C:4]([CH3:11])([CH3:10])N=1.CC(C)=[O:14]>>[CH3:10][C:4]1([CH3:11])[NH:5][C:6]([CH3:9])([CH3:8])[CH2:7][C:2](=[O:14])[CH2:1]1
Reactant: CC(C)=O
Reactant: CC1=NC(C)(C)NC(C)(C)C1
Product: CC1(C)CC(=O)CC(C)(C)N1
Temperature: 60 °C

Procedure:
5.0 g. of Acetonine was dissolved in a mixed solvent comprising 19 g. of acetone and 9.5 g. of another solvent listed below. The solution was added with a catalyst listed below and the mixture was heated at 60°C. for 10 hours in a sealed equipment to effect the reaction. After completion of the reaction, the reaction mixture was purified in the same manner as in Example 1 to obtain triacetonamine in a yield as shown hereinbelow.
Reaction SMILES: [C:1]([C:4]1[C:12]([CH2:13]/[CH:14]=[C:15](\[CH3:21])/[CH2:16][CH2:17][C:18]([OH:20])=[O:19])=[C:11]([O:22][CH3:23])[C:10]([CH3:24])=[C:9]2[C:5]=1[C:6](=[O:25])[O:7][CH2:8]2)([OH:3])=[O:2].[C:26]1(C)C=CC(S(O)(=O)=O)=CC=1>CO>[C:1]([C:4]1[C:12]([CH2:13]/[CH:14]=[C:15](\[CH3:21])/[CH2:16][CH2:17][C:18]([O:20][CH3:26])=[O:19])=[C:11]([O:22][CH3:23])[C:10]([CH3:24])=[C:9]2[C:5]=1[C:6](=[O:25])[O:7][CH2:8]2)([OH:3])=[O:2]
Reactant: COc1c(C)c2c(c(C(=O)O)c1C/C=C(\C)CCC(=O)O)C(=O)OC2
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CO
Product: COC(=O)CC/C(C)=C/Cc1c(OC)c(C)c2c(c1C(=O)O)C(=O)OC2
Yield: 930 %

Procedure:
A solution of 3.88 g (11.1 mmol) of (E)-6-(4-carboxy-1,3-dihydro-6-methoxy-7-methyl-3-oxoisobenzofuran-5-yl)-4-methyl-4-hexenoic acid and 0.2 g (1.0 mmol) of p-toluenesulfonic acid in methanol (60 ml) was stirred at room temperature for 8 hours. The solvent was evaporated under reduced pressure. The residue was dissolved in ethyl acetate, and this solution was washed twice with water, once with brine, and dried over magnesium sulfate. The solvent was evaporated under reduced pressure to give a solid which was recrystallized from ethyl acetate to give 3.37 g (9.3 mmol) of methyl (E)-6-(4-carboxy-1,3-dihydro-6-methoxy-7-methyl-3-oxoisobenzofuran-5-yl)-4-methyl-4-hexenoate as a white solid, mp 169°-170° C.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[NH:7][CH:8]=[C:9]([CH2:11][NH:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:10]=1)=[O:5])[CH3:2].C(N(CC)C(C)C)(C)C.[C:28](Cl)(=[O:30])[CH3:29]>C(Cl)Cl>[CH2:1]([O:3][C:4]([C:6]1[NH:7][CH:8]=[C:9]([CH2:11][N:12]([C:28](=[O:30])[CH3:29])[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:10]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1cc(CNc2ccccc2)c[nH]1
Reactant: CC(=O)Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)c1cc(CN(C(C)=O)c2ccccc2)c[nH]1
Temperature: 0 °C

Procedure:
4-Phenylaminomethyl-1H-pyrrole-2-carboxylic acid ethyl ester (183) (0.1523 g, 0.623 mmol) was weighed out into a 10 mL flask. A stir bar and septum were added, and the flask was purged with nitrogen. The amine was dissolved in methylene chloride (1.6 mL, 0.4 M) and then the flask was cooled to 0° C. N,N-diisopropyl ethyl amine (0.1194 mL, 0.686 mmol) was added, then acetyl chloride (0.0488 mL, 0.686 mmol) was added slowly by syringe to the stirring 0° C. solution. The reaction was then allowed to warm to room temperature. When the reaction was judged complete by HPLC (35 min) the reaction was diluted with methylene chloride and quenched with water. The organic phase was removed, washed with brine, dried with Na2SO4, filtered and concentrated en vacuo. The crude product was sufficiently pure by HPLC and NMR analysis that it was used in the next step without further purification (0.1625 g, 91%, white crystalline solid). 1H (CD3OD, 400 MHz): δ 11.22 (1H, broad s), 7.43-7.31 (3H, m), 7.08 (2H, dd, J=7.0, 1.5 Hz), 6.75 (1H, d, J=1.5 Hz), 6.68 (1H, d, J=1.5 Hz), 4.70 (2H, s), 4.24 (2H, q, J=7.0 Hz), 1.81 (3H, s), 1.31 (3H, t, J=7.0 Hz) ppm. 13C (CD3OD, 100 MHz): δ 172.47, 162.64, 143.86, 130.68, 129.34, 129.27, 124.50, 124.33, 122.19, 116.72, 61.16, 46.60, 22.64, 14.75 ppm. DEPT (CD3OD, 100 MHz): CH3 carbons: 22.64, 14.75; CH2 carbons: 61.16, 46.60; CH carbons: 130.68, 129.34, 129.27, 124.33, 116.72 ppm. HPLC: 8.738 min.