Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1([CH3:25])[C:6]([CH3:10])([CH2:7][CH2:8]O)[C:5](=[O:11])[N:4]([C:12]2[CH:19]=[CH:18][C:15]([C:16]#[N:17])=[C:14]([C:20]([F:23])([F:22])[F:21])[CH:13]=2)[C:3]1=[O:24].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(Br)(Br)(Br)[Br:46]>ClCCl>[CH3:1][C:2]1([CH3:25])[C:6]([CH3:10])([CH2:7][CH2:8][Br:46])[C:5](=[O:11])[N:4]([C:12]2[CH:19]=[CH:18][C:15]([C:16]#[N:17])=[C:14]([C:20]([F:23])([F:22])[F:21])[CH:13]=2)[C:3]1=[O:24]
Reactant: BrC(Br)(Br)Br
Reactant: CC1(C)C(=O)N(c2ccc(C#N)c(C(F)(F)F)c2)C(=O)C1(C)CCO
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: CC1(C)C(=O)N(c2ccc(C#N)c(C(F)(F)F)c2)C(=O)C1(C)CCBr
Reaction time: 1 h
Yield: 37.1 %

Procedure:
To a solution of compound 20a (33 mg, 0.097 mmol) in anhydrous dichloromethane (2 mL) at 0° C. under argon were added triphenylphosphine (50 mg, 0.194 mmol) and carbontetrabromide (64 mg, 0.194 mmol). The solution was allowed to return to room temperature and stirred for 1 hr. The resulting solution was diluted with dichloromethane (25 mL) and filtered on a cotton plug. Purification of the resulting crude product by flash chromatography using a gradient of ethyl acetate/hexane (3:97 to 3:7) as an eluant gave the desired compound 21a (15 mg, 40% for 2 steps). 1H NMR (400 MHz, Acetone-d6) δ: 1.36 (s, 3H), 1.39 (s, 3H), 1.40 (s, 3H), 2.28 (m, 2H), 3.68 (m, 2H), 8.03 (dd, 1H, J1=6.57 Hz, J2=1.84 Hz), 8.14 (d, 1H, J=1.45 Hz), 8.24 (d, 1H, J=8.40 Hz).
Reaction SMILES: [CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:15])=[C:11](F)[CH:12]=3)[C:7](=[O:16])[C:6]([C:17]([OH:19])=[O:18])=[CH:5]2)[CH2:3][CH2:2]1.[CH2:20]([N:22]1[CH2:27][CH2:26][NH:25][CH2:24][CH:23]1[CH3:28])[CH3:21]>>[CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:15])=[C:11]([N:25]4[CH2:26][CH2:27][N:22]([CH2:20][CH3:21])[CH:23]([CH3:28])[CH2:24]4)[CH:12]=3)[C:7](=[O:16])[C:6]([C:17]([OH:19])=[O:18])=[CH:5]2)[CH2:3][CH2:2]1
Reactant: CCN1CCNCC1C
Reactant: O=C(O)c1cn(C2CC2)c2cc(F)c(F)cc2c1=O
Product: CCN1CCN(c2cc3c(cc2F)c(=O)c(C(=O)O)cn3C2CC2)CC1C
Yield: 51 %

Procedure:
The condensation of 1-cyclopropyl-6,7-difluoro-1,4-dihydro-4-oxo-quinoline-3-carboxylic acid with 4-ethyl-3-methylpiperazine was carried out in a similar manner as described in example 1 gave the titled product. Yield 51%, m.p 200° C., C20H24FN3O3, m/z 374 (M+1).
Reaction SMILES: [C:1]([C:5]1[C:14]2[CH:13]=[C:12](/[C:15](/[CH2:20][CH3:21])=[C:16](/[F:19])\[CH:17]=O)[C:11]([O:22][CH2:23][CH3:24])=[CH:10][C:9]=2[C:8]([CH3:26])([CH3:25])[CH2:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].C(P([CH2:33]/[C:34](/[CH3:41])=[CH:35]\[C:36]([O:38][CH2:39][CH3:40])=[O:37])(CC)=O)C>C1COCC1.CN1C(=O)N(C)CCC1>[C:1]([C:5]1[C:14]2[CH:13]=[C:12](/[C:15](/[CH2:20][CH3:21])=[C:16](/[F:19])\[CH:17]=[CH:33]\[C:34](\[CH3:41])=[CH:35]\[C:36]([O:38][CH2:39][CH3:40])=[O:37])[C:11]([O:22][CH2:23][CH3:24])=[CH:10][C:9]=2[C:8]([CH3:25])([CH3:26])[CH2:7][CH:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CCOc1cc2c(cc1/C(CC)=C(/F)C=O)C(C(C)(C)C)=CCC2(C)C
Reactant: CCOC(=O)/C=C(/C)CP(=O)(CC)CC
Solvent: CN1CCCN(C)C1=O
Solvent: C1CCOC1
Product: CCOC(=O)/C=C(C)/C=C/C(F)=C(/CC)c1cc2c(cc1OCC)C(C)(C)CC=C2C(C)(C)C

Procedure:
As described in General Procedure I-1, (E)-3-(8-tert-butyl-3-ethoxy-5,5-dimethyl-5,6-dihydronaphthalen-2-yl)-2-fluoro-pent-2-enal (Compound A-65, 435 mg, 1.21 mmol) reacted with the ylide of ethyl 4-(diethylphosphoryl)-3-methylbut-2Z-enoate (1.07 g, 4.05 mmol) in THF (10 mL) and DMPU (5 mL) to produce the title compound as an oil after purification by flash chromatography (silica gel, 1% to 2% ethyl acetate in hexane).
Reaction SMILES: [N+:1]([C:4]1[CH:13]=[C:12]2[C:7]([CH2:8][CH2:9][CH2:10][C:11]2=[O:14])=[CH:6][CH:5]=1)([O-])=O.Cl.C(N(CC)CC)C.[C:23](Cl)(=[O:25])[CH3:24]>CO.[Fe].C(OCC)(=O)C.O1CCCC1>[C:23]([NH:1][C:4]1[CH:13]=[C:12]2[C:7]([CH2:8][CH2:9][CH2:10][C:11]2=[O:14])=[CH:6][CH:5]=1)(=[O:25])[CH3:24]
Reactant: CC(=O)Cl
Reactant: O=C1CCCc2ccc([N+](=O)[O-])cc21
Agent: [Fe]
Agent: Cl
Solvent: CO
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(=O)Nc1ccc2c(c1)C(=O)CCC2
Reaction time: 1 h
Yield: 84.1 %

Procedure:
7-Nitro-1-tetralone (8.32 g, 0.044 mol) and concentrated hydrochloric acid (24 ml, 0.29 mol) were dissolved in methanol (100 ml), and an iron powder (7.30 g, 0.13 mol) was gradually added over 1 hour. After stirring for 1 hour, the reaction mixture was concentrated. 4N Sodium hydroxide solution and ethyl acetate were added to the residue, and extraction was conducted. The organic layer was dried, and concentrated. Tetrahydrofuran (100 ml) and triethylamine (5.05 g, 0.05 mol) was added to the residue. Further, acetyl chloride (3.92 g, 0.05 mol) was added under ice-cooling. After stirring for 30 minutes, ethyl acetate and 1N hydrochloric acid were added, and extraction was conducted. The organic layer was concentrated, and the residue was purified with silica gel column chromatography (development solvent: ethyl acetate), to give 7-acetylamino-1-tetralone (7.52 g) as a white powder.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Br:8])[CH:3]=1.[CH3:9][N:10]1[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]1.C1CCN2C(=NCCC2)CC1.CC(C)([O-])C.[Na+].N1CCNCC1>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1.C1(C)C=CC=CC=1>[Br:8][C:4]1[CH:3]=[C:2]([N:13]2[CH2:14][CH2:15][N:10]([CH3:9])[CH2:11][CH2:12]2)[CH:7]=[CH:6][CH:5]=1
Reactant: Brc1cccc(Br)c1
Reactant: CN1CCNCC1
Agent: [Pd]
Agent: C1CNCCN1
Agent: CC(C)(C)[O-]
Solvent: C1CCC2=NCCCN2CC1
Solvent: Cc1ccccc1
Product: CN1CCN(c2cccc(Br)c2)CC1
Temperature: 60 °C
Reaction time: 8 h
Yield: 78.4 %

Procedure:
1,3-Dibromobenzene (0.90 ml, 7.49 mmol), N-methylpiperazine (0.28 ml, 2.50 mmol) and anhydrous toluene (7 ml) were added by syringe to a dry, argon filled flask. The solution was thoroughly mixed before BINAP (47 mg) and Pd2 dba3 (23 mg) were delivered and the flask refilled with Argon and DBU (0.93 g, 2.5 equiv.) added via syringe. The reaction mixture was warmed to 60° C. before freshly ground sodium tertbutoxide was added in one portion to start the reaction. The reaction was left stirring at 60° C. overnight and the TLC analysis appeared to show that some piperazine was still present so the reaction was heated to 100° C. and stirred for another 24 hrs after which it was partitioned between EtOAc (20 ml) and water (20 ml). The aqueous layer was extracted again with EtOAc and the combined organics were washed with 1.6M HCl solution (2×10 ml). The acidic solution containing the product was then basified first with a similar volume of 1M NaOH solution to acid solution and then carefully solid sodium bicarbonate was added to make the pH=8.5 before extraction back into EtOAc (2×15 ml), which was washed with brine, dried over MgSO4 and evaporated to dryness to provide 0.50 g (78% yield) of the pure product as a yellow oil.
Reaction SMILES: C([O:4][C@@:5]1([CH2:36][CH3:37])[C:33]2[CH:32]=[C:31]3[N:11]([CH2:12][C:13]4[C:14]3=[N:15][C:16]3[C:17]5[C:18]=4[N:19]([CH2:27][CH2:28][CH2:29][CH3:30])[C:20](=[O:26])[NH:21][C:22]=5[CH:23]=[CH:24][CH:25]=3)[C:10](=[O:34])[C:9]=2[CH2:8][O:7][C:6]1=[O:35])(=O)C.NN.Cl>CO>[CH2:27]([N:19]1[C:18]2=[C:13]3[CH2:12][N:11]4[C:31](=[CH:32][C:33]5[C@:5]([CH2:36][CH3:37])([OH:4])[C:6](=[O:35])[O:7][CH2:8][C:9]=5[C:10]4=[O:34])[C:14]3=[N:15][C:16]3[C:17]2=[C:22]([CH:23]=[CH:24][CH:25]=3)[NH:21][C:20]1=[O:26])[CH2:28][CH2:29][CH3:30]
Reactant: CCCCN1C(=O)Nc2cccc3nc4c(c1c23)Cn1c-4cc2c(c1=O)COC(=O)[C@@]2(CC)OC(C)=O
Agent: Cl
Agent: NN
Solvent: CO
Product: CCCCN1C(=O)Nc2cccc3nc4c(c1c23)Cn1c-4cc2c(c1=O)COC(=O)[C@]2(O)CC
Temperature: 25 °C
Reaction time: 1 h
Yield: 57.6 %

Procedure:
To a solution of (9S)-9-acetoxy-1-butyl-9-ethyl-1H,12H-pyrano[3″,4″:6′,7′]indolizino-[1′,2′:6,5]pyrido[4,3,2-de]quinazoline-2,10,13(3H,9H,15H)-trione (11.5 mg, 0.023 mmol) in MeOH (3 ml) cooled in an ice-bath was added anhydrous hydrazine (100 μl). The mixture was warmed to room temperature and stirred for 1 hr. Aqueous 1 N HCl solution was added dropwise to acidify the reaction mixture and the mixture was stirred for 1 hr. at room temperature. After concentrated under reduced pressure, the obtaining residue was extracted with CH2Cl2 (20 ml×3). The combined CH2Cl2 solution was washed with brine, dried over MgSO4 and evaporated. The residue was purified by column chromatography (dichloromethane/methanol=30/1) to give pure product (6.1 mg, 58%).
Reaction SMILES: [CH:1]([C:3]1[CH:25]=[CH:24][C:6]([O:7][CH2:8][CH2:9][C:10]2[CH:15]=[CH:14][C:13]([NH:16][C:17](=[O:23])[O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[CH:12][CH:11]=2)=[CH:5][CH:4]=1)=O.[S:26]1[CH2:30][C:29](=[O:31])[NH:28][C:27]1=[O:32].C([O-])(=O)C.[NH2+]1CCCCC1.O>C1(C)C=CC=CC=1>[C:19]([O:18][C:17]([NH:16][C:13]1[CH:12]=[CH:11][C:10]([CH2:9][CH2:8][O:7][C:6]2[CH:5]=[CH:4][C:3]([CH:1]=[C:30]3[S:26][C:27](=[O:32])[NH:28][C:29]3=[O:31])=[CH:25][CH:24]=2)=[CH:15][CH:14]=1)=[O:23])([CH3:22])([CH3:20])[CH3:21]
Reactant: CC(C)(C)OC(=O)Nc1ccc(CCOc2ccc(C=O)cc2)cc1
Reactant: O=C1CSC(=O)N1
Agent: C1CC[NH2+]CC1
Agent: CC(=O)[O-]
Solvent: Cc1ccccc1
Solvent: O
Product: CC(C)(C)OC(=O)Nc1ccc(CCOc2ccc(C=C3SC(=O)NC3=O)cc2)cc1
Temperature: 25 °C
Yield: 72.6 %

Procedure:
A solution of 3.41 g (10 mmole) tert-butyl N-{4-[2-(4-formylphenoxy)ethyl]phenyl}carbamate and 1.29 g (11 mmole) 2,4-thiazolidinedione in toluene containing a catalytic amount of piperidinium acetate was refluxed in a Dean-Stark water trap for 3 hours. The reaction was followed by TLC and more 2,4-thiazolidinedione was added during the reaction time. The solution was cooled to room temperature filtered and the precipitate was refluxed in methanol. Another filtration gave 3.2 g (yield 72.6%) 5-(4-[2-(4-tert-butyloxycarbonylaminophenyl)ethoxy]benzylidene)thiazolidine-2,4-dione as a light yellow, solid substance.
Reaction SMILES: [NH2:1][CH:2]1[CH2:6][CH2:5][N:4]([C:7]2[C:16]([F:17])=[CH:15][C:10]([C:11]([O:13][CH3:14])=[O:12])=[C:9]([NH:18][C:19]3[CH:24]=[CH:23][C:22]([F:25])=[CH:21][C:20]=3[F:26])[N:8]=2)[CH2:3]1.[C:27](OC(=O)C)(=[O:29])[CH3:28].C(OCC)C>C(Cl)(Cl)Cl>[C:27]([NH:1][CH:2]1[CH2:6][CH2:5][N:4]([C:7]2[C:16]([F:17])=[CH:15][C:10]([C:11]([O:13][CH3:14])=[O:12])=[C:9]([NH:18][C:19]3[CH:24]=[CH:23][C:22]([F:25])=[CH:21][C:20]=3[F:26])[N:8]=2)[CH2:3]1)(=[O:29])[CH3:28]
Reactant: CC(=O)OC(C)=O
Reactant: COC(=O)c1cc(F)c(N2CCC(N)C2)nc1Nc1ccc(F)cc1F
Solvent: CCOCC
Solvent: ClC(Cl)Cl
Product: COC(=O)c1cc(F)c(N2CCC(NC(C)=O)C2)nc1Nc1ccc(F)cc1F
Yield: 99.4 %

Procedure:
In 6.5 ml of chloroform was dissolved 650 mg of methyl 6-(3-amino-1-pyrrolidinyl)-2-(2,4-difluorophenylamino)-5-fluoronicotinate, and 190 mg of acetic anhydride was added to the resulting solution, after which the resulting mixture was subjected to reaction at room temperature for 10 minutes. The solvent was then removed by distillation under reduced pressure. To the crystalline material thus obtained was added 2 ml of diethyl ether, after which crystals were collected by filtration to obtain 720 mg (yield 99.4%) of methyl 6-(3-acetylamino-1-pyrrolidinyl)-2-(2,4-difluorophenylamino)-5-fluoronicotinate having a melting point of 199°-200° C.
Reaction SMILES: [NH2:1][C@H:2]1[CH2:7][CH2:6][CH2:5][N:4]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:3]1.Br[CH2:16][CH2:17][CH3:18].CCN(C(C)C)C(C)C>CN(C=O)C.CCOC(C)=O>[CH2:16]([NH:1][C@H:2]1[CH2:7][CH2:6][CH2:5][N:4]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:3]1)[CH2:17][CH3:18]
Reactant: CC(C)(C)OC(=O)N1CCC[C@H](N)C1
Reactant: CCCBr
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Product: CCCN[C@H]1CCCN(C(=O)OC(C)(C)C)C1
Yield: 100.3 %

Procedure:
A solution of (S)-tert-butyl 3-aminopiperidine-1-carboxylate (500 mg, 2.49 mmol) and 1-bromopropane (335 mg, 2.74 mmol) and DIEA (0.11 mL, 6.24 mmol) in DMF (4 mL) was heated at 100° C. for overnight. After reaction was shown to be complete as indicated by TLC, the mixture was diluted with EtOAc (30 mL) and washed with water (2×15 mL). The organic layer was separated, dried over Na2SO4, concentrated in vacuo to afford a residue which was purified by column chromatography (silica gel, gradient MeOH in CH2Cl2) to yield the titled intermediate (605 mg, 57%). 1H NMR (400 MHz, DMSO-d6): δ 3.89-3.64 (m, 3H), 2.80-2.66 (m, 2H), 2.50-2.35 (m, 3H), 1.89-1.83 (m, 2H), 1.61-1.58 (m, 2H), 1.38 (s, 9H), 1.35-1.29 9m, 2H), 0.82 (t, J=7.2 Hz, 3H). ES-MS: m/z [M+1]=243.
Reaction SMILES: [OH:1][CH:2]([C:6]1[CH:11]=[CH:10][C:9]([C:12]2[N:16]=[C:15]([C:17]3[O:21][N:20]=[C:19]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)[C:18]=3[C:28]([F:31])([F:30])[F:29])[O:14][N:13]=2)=[CH:8][CH:7]=1)[C:3]([OH:5])=O.Cl.[S:33]1[CH:37]=[CH:36][N:35]=[C:34]1[CH2:38][NH2:39].CN1CCOCC1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[OH:1][CH:2]([C:6]1[CH:11]=[CH:10][C:9]([C:12]2[N:16]=[C:15]([C:17]3[O:21][N:20]=[C:19]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)[C:18]=3[C:28]([F:31])([F:29])[F:30])[O:14][N:13]=2)=[CH:8][CH:7]=1)[C:3]([NH:39][CH2:38][C:34]1[S:33][CH:37]=[CH:36][N:35]=1)=[O:5]
Reactant: O=C(O)C(O)c1ccc(-c2noc(-c3onc(-c4ccccc4)c3C(F)(F)F)n2)cc1
Reactant: NCc1nccs1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Product: O=C(NCc1nccs1)C(O)c1ccc(-c2noc(-c3onc(-c4ccccc4)c3C(F)(F)F)n2)cc1
Reaction time: 1 h
Yield: 62.3 %

Procedure:
(R/S)-2-Hydroxy-2-(4-(5-(3-phenyl-4-(trifluoromethyl)isoxazol-5-yl)-1,2,4-oxadiazol-3-yl)phenyl)acetic acid (Int-V, 23 mg, 0.053 mmol), thiazol-2-ylmethanamine-HCl (12.05 mg, 0.080 mmol), 4-methylmorpholine (21.57 mg, 0.213 mmol), and HATU (26.4 mg, 0.069 mmol) were added to DMF (1 mL). This was stirred for 1 h before it was purified by prep HPLC (YMC S5 20×100 mm, gradient elution with Method 1—MeOH/water containing 0.1% trifluoroacetic acid as defined above 0% B to 100% B over 10 min, 20 mL/min, 220 nM, product retention=11.8 min) to provide (R/S)-2-hydroxy-2-(4-(5-(3-phenyl-4-(trifluoromethyl)isoxazol-5-yl)-1,2,4-oxadiazol-3-yl)phenyl)-N-(thiazol-2-ylmethyl)acetamide (19 mg, 0.033 mmol, 62.3% yield): LCMS=528.2 [M+H]+; 1H NMR (400 MHz, methanol-d4) δ ppm 8.13-8.22 (2 H, m), 7.46-7.78 (9 H, m), 5.22 (1 H, s), 4.67-4.82 (2 H, m); HPLC peak RT=9.5 min (Method A).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:9][C:10]([CH3:21])=[C:11]([C:13]3[C:14](=[O:20])[CH2:15][CH2:16][C:17]=3[O:18][CH3:19])[N:12]=2)=[CH:4][CH:3]=1.C([N-]C(C)C)(C)C.[Li+].[F:30][C:31]1[CH:32]=[CH:33][C:34]([CH:37]=[O:38])=[N:35][CH:36]=1>O1CCCC1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:9][C:10]([CH3:21])=[C:11]([C:13]3[C:14](=[O:20])[CH:15]([CH:37]([C:34]4[CH:33]=[CH:32][C:31]([F:30])=[CH:36][N:35]=4)[OH:38])[CH2:16][C:17]=3[O:18][CH3:19])[N:12]=2)=[CH:4][CH:3]=1
Reactant: O=Cc1ccc(F)cn1
Reactant: COC1=C(c2nc(-c3ccc(Cl)cc3)sc2C)C(=O)CC1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: COC1=C(c2nc(-c3ccc(Cl)cc3)sc2C)C(=O)C(C(O)c2ccc(F)cn2)C1
Temperature: 78 °C
Reaction time: 0.5 h
Yield: 71.9 %

Procedure:
To a solution of 2-[2-(4-Chloro-phenyl)-5-methyl-thiazol-4-yl]-3-methoxy-cyclopent-2-enone (400 mg, 1.25 mmol) in anhydrous tetrahydrofuran (10 ml) at −78° C. under an atmosphere of nitrogen was added lithium diisopropylamide (1.8M in THF/heptanes/ethylbenzene; 0.76 m, 1.37 mmol) dropwise over a period of 5 minutes, and the reaction allowed to stir at 78° C. for 30 minutes. A solution of 5-fluoro-pyridine-2-carbaldehyde (171 mg, 1.37 mmol) in anhydrous tetrahydrofuran (1 ml) was then added dropwise over a period of 5 minutes before the reaction was allowed to warm to room temperature and stirred for a further 30 minutes. The reaction was quenched by the addition of saturated aqueous ammonium chloride solution (50 ml) and extracted with ethyl acetate (50 ml) and the organic later separated, dry loaded onto silica and purified by flash chromatography to give 2-[2-(4-Chloro-phenyl)-5-methyl-thiazol-4-yl]-5-[(5-fluoro-pyridin-2-yl)-hydroxy-methyl]-3-methoxy-cyclopent-2-enone (400 mg).
Reaction SMILES: [OH:1][CH:2]1[CH2:7][CH2:6][CH2:5][CH:4]=[CH:3]1.O[N:9]1[C:13](=[O:14])[C:12]2=[CH:15][CH:16]=[CH:17][CH:18]=[C:11]2[C:10]1=[O:19].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>O1CCCC1>[CH:2]1([O:1][N:9]2[C:10](=[O:19])[C:11]3=[CH:18][CH:17]=[CH:16][CH:15]=[C:12]3[C:13]2=[O:14])[CH2:7][CH2:6][CH2:5][CH:4]=[CH:3]1
Reactant: O=C1c2ccccc2C(=O)N1O
Reactant: OC1C=CCCC1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: O=C1c2ccccc2C(=O)N1OC1C=CCCC1
Temperature: 25 °C
Yield: 65.6 %

Procedure:
A mixture of 3-hydroxycyclohexene (4.0 g), N-hydroxyphthalimide (6.7 g) and triphenyl phosphine (9.2 g) in tetrahydrofuran (200 ml) was stirred at room temperature. After the addition of diethyl azoformate (7.9 g), the resulting mixture was stirred for 20 hours at room temperature. The reaction mixture was evaporated and the residue was subjected to column chromatography on silica gel (80 g), using chloroform as an eluent. The fractions containing the objected compounds were combined and evaporated to give N-(2-cyclohexen-1-yl)oxyphthalimide (6.5 g).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:12]2[O:16][N:15]=[C:14]([C:17]3[CH:18]=[CH:19][C:20]([CH2:23]O)=[N:21][CH:22]=3)[N:13]=2)[CH:5]=[CH:6][C:7]=1[CH2:8][CH:9]([CH3:11])[CH3:10].C(Br)(Br)(Br)Br.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.Cl.[NH:50]1[CH2:53][CH:52]([C:54]([O:56][CH3:57])=[O:55])[CH2:51]1.C(N(CC)C(C)C)(C)C>>[Cl:1][C:2]1[CH:3]=[C:4]([C:12]2[O:16][N:15]=[C:14]([C:17]3[CH:18]=[CH:19][C:20]([CH2:23][N:50]4[CH2:53][CH:52]([C:54]([O:56][CH3:57])=[O:55])[CH2:51]4)=[N:21][CH:22]=3)[N:13]=2)[CH:5]=[CH:6][C:7]=1[CH2:8][CH:9]([CH3:11])[CH3:10]
Reactant: CC(C)Cc1ccc(-c2nc(-c3ccc(CO)nc3)no2)cc1Cl
Reactant: COC(=O)C1CNC1
Agent: BrC(Br)(Br)Br
Agent: Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)C1CN(Cc2ccc(-c3noc(-c4ccc(CC(C)C)c(Cl)c4)n3)cn2)C1

Procedure:
The crude product of the title compound was synthesized by conducting the reaction similar to that mentioned in Example 23 (23g) using {5-[5-(3-chloro-4-isobutylphenyl)-1,2,4-oxadiazol-3-yl]pyridin-2-yl}methanol (0.18 g, 0.54 mmol) that was obtained in Example 26 (26a), carbon tetrabromide (0.36 g, 1.1 mmol), triphenylphosphine (0.28 g, 1.1 mmol), methyl 3-azetidinecarboxylate hydrochloride (0.12 g, 0.81 mmol), and N,N-diisopropylethylamine (0.28 mL, 1.6 mmol). Subsequently, the crude product of the title compound thus obtained was purified by chromatography on a silica gel column using a mixed solvent of ethyl acetate and hexane (2:1 to 3:1) as the eluent to afford the title compound (0.15 g) in a yield of 61% as a white crystalline solid.
Reaction SMILES: O[CH:2]([CH2:7][CH2:8][S:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]([F:19])([F:18])[F:17])=[CH:12][CH:11]=1)[CH2:3][C:4](=[O:6])[CH3:5].ClC(Cl)(Cl)C(O)=O>C1(C)C=CC=CC=1>[F:18][C:16]([F:17])([F:19])[C:13]1[CH:14]=[CH:15][C:10]([S:9][CH2:8][CH2:7][CH:2]=[CH:3][C:4](=[O:6])[CH3:5])=[CH:11][CH:12]=1
Reactant: CC(=O)CC(O)CCSc1ccc(C(F)(F)F)cc1
Agent: O=C(O)C(Cl)(Cl)Cl
Solvent: Cc1ccccc1
Product: CC(=O)C=CCCSc1ccc(C(F)(F)F)cc1

Procedure:
5.00 Grams of 4-hydroxy-6-(4-trifluoromethylphenylthio)-2-hexanone were dissolved in 50 ml of toluene, and 1.00 g of trichloroacetic acid was added thereto. The resulting mixture was refluxed for 2 hours with stirring. After having been cooled, the mixture was washed with a saturated aqueous sodium hydrogencarbonate solution and then with a saturated aqueous sodium chloride solution. Then the mixture was dried over anhydrous magnesium sulfate. Removing the solvent from the layer under reduced pressure gave 6-(4-trifluoromethylphenylthio)-3-hexen-2-one (trans : cis =8.1 : 1) having a purity of 72.4%. Percent recovery of the starting material was 4.3%.
Reaction SMILES: Cl.[NH2:2][C@H:3]1[CH2:8][CH2:7][C@H:6]([NH:9][C:10]([C:12]2[C:16]3[N:17]=[CH:18][N:19]=[C:20]([C:21]4[CH:26]=[C:25]([CH:27]([F:29])[F:28])[CH:24]=[CH:23][C:22]=4[O:30][CH2:31][CH:32]4[CH2:34][CH2:33]4)[C:15]=3[NH:14][C:13]=2[CH3:35])=[O:11])[CH2:5][CH2:4]1.[C:36](Cl)(=[O:39])[CH2:37][CH3:38]>>[CH:32]1([CH2:31][O:30][C:22]2[CH:23]=[CH:24][C:25]([CH:27]([F:29])[F:28])=[CH:26][C:21]=2[C:20]2[C:15]3[NH:14][C:13]([CH3:35])=[C:12]([C:10]([NH:9][C@H:6]4[CH2:7][CH2:8][C@H:3]([NH:2][C:36](=[O:39])[CH2:37][CH3:38])[CH2:4][CH2:5]4)=[O:11])[C:16]=3[N:17]=[CH:18][N:19]=2)[CH2:34][CH2:33]1
Reactant: CCC(=O)Cl
Reactant: Cc1[nH]c2c(-c3cc(C(F)F)ccc3OCC3CC3)ncnc2c1C(=O)N[C@H]1CC[C@H](N)CC1
Agent: Cl
Product: CCC(=O)N[C@H]1CC[C@H](NC(=O)c2c(C)[nH]c3c(-c4cc(C(F)F)ccc4OCC4CC4)ncnc23)CC1

Procedure:
Starting from N-(trans-4-aminocyclohexyl)-4-[2-(cyclopropylmethoxy)-5-(difluoromethyl)phenyl]-6-methyl-5H-pyrrolo[3,2-d]pyrimidine-7-carboxamide hydrochloride (example D.f61) and commercially available propionyl chloride the title compound is obtained as colorless solid.
Reaction SMILES: C[O:2][C:3]1[CH:8]=[CH:7][C:6]([N+:9]([O-:11])=[O:10])=[CH:5][C:4]=1[CH2:12][N:13]1[C:17](=[O:18])[C:16]2=[CH:19][CH:20]=[CH:21][CH:22]=[C:15]2[C:14]1=[O:23].B(Br)(Br)Br.O>C(Cl)Cl>[OH:2][C:3]1[CH:8]=[CH:7][C:6]([N+:9]([O-:11])=[O:10])=[CH:5][C:4]=1[CH2:12][N:13]1[C:17](=[O:18])[C:16]2=[CH:19][CH:20]=[CH:21][CH:22]=[C:15]2[C:14]1=[O:23]
Reactant: COc1ccc([N+](=O)[O-])cc1CN1C(=O)c2ccccc2C1=O
Agent: BrB(Br)Br
Solvent: ClCCl
Solvent: O
Product: O=C1c2ccccc2C(=O)N1Cc1cc([N+](=O)[O-])ccc1O
Temperature: -78 °C
Reaction time: 1 h
Yield: 83 %

Procedure:
To a solution of the compound (937 mg) obtained in Example 117 in anhydrous methylene chloride (30 ml), a solution of boron tribromide in methylene chloride (1.0 M, 9 ml) was added dropwise at −78° C. in a nitrogen atmosphere and the mixture was stirred at −78° C. for 1 h, then stirred at room temperature for 21 h. Water was added to the reaction mixture, which was extracted with chloroform. The organic layer was washed with a saturated aqueous sodium chloride solution, dried with anhydrous sodium sulfate and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent, n-hexane:ethyl acetate=1:1) to give 743 mg of the titled compound (yield, 83%).
Reaction SMILES: [Cl:1][C:2]1[C:7]([CH2:8][C:9](OCC)=[O:10])=[C:6]([NH:14]CC2C=CC(OC)=CC=2OC)[N:5]=[C:4]([S:26][CH2:27][C:28]2[CH:33]=[CH:32][CH:31]=[C:30]([F:34])[C:29]=2[F:35])[N:3]=1.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[Cl:1][C:2]1[C:7]2[CH2:8][C:9](=[O:10])[NH:14][C:6]=2[N:5]=[C:4]([S:26][CH2:27][C:28]2[CH:33]=[CH:32][CH:31]=[C:30]([F:34])[C:29]=2[F:35])[N:3]=1
Reactant: CCOC(=O)Cc1c(Cl)nc(SCc2cccc(F)c2F)nc1NCc1ccc(OC)cc1OC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: O=C1Cc2c(Cl)nc(SCc3cccc(F)c3F)nc2N1
Yield: 64 %

Procedure:
A solution of the product from example 1, step (d) (0.5 g) in dry toluene (50 ml) containing p-toluene sulphonic acid (25 mg) was heated under reflux for 4 hours. [Analysis of the reaction mixture by 1 c/ms indicated cyclisation was complete but with loss of the acid labile dimethoxybenzyl adduct.] The reaction mixture was evaporated to dryness and the residue purified by chromatography on silica eluting with ethyl acetate to afford the subtitle compound (0.20 g).