Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[CH:2]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[Cl:12])[C:3]([OH:5])=[O:4].S(=O)(=O)(O)O.[S:18]1[CH:22]=[CH:21][CH:20]=[C:19]1[CH2:23][CH2:24][NH2:25].[CH3:26]O>>[S:18]1[CH:22]=[CH:21][CH:20]=[C:19]1[CH2:23][CH2:24][NH:25][CH:2]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[Cl:12])[C:3]([O:5][CH3:26])=[O:4]
Reactant: CO
Reactant: O=C(O)C(Br)c1ccccc1Cl
Reactant: NCCc1cccs1
Agent: O=S(=O)(O)O
Product: COC(=O)C(NCCc1cccs1)c1ccccc1Cl
Temperature: 30 °C

Procedure:
543 g of alpha-bromo(2-chlorophenyl)acetic acid and 30 g of concentrated sulphuric acid are introduced into 300 ml methanol. The mixture is refluxed for 3 hours and, after it has cooled to about 30° C., 230 g of KHCO3 and 265 g of 2-(2-thienyl)ethylamine are added progressively. The mixture is refluxed for 1 hour 30 min and the solvent is then evaporated off under vacuum. 1 l of water and 1 l of ethyl acetate are poured onto the residue and the organic phase is separated off after stirring and phase separation. 300 ml of ice and 180 ml of concentrated hydrochloric acid are then introduced into it. The precipitated product is filtered off and dried. 641 g of the hydrochloride of the required product, which melts at 175° C., are thus obtained.
Reaction SMILES: [CH:1]1([C:4]2[C:9]([C:10](OC)=[O:11])=[CH:8][N:7]=[C:6]([N:14]3[CH2:19][CH2:18][N:17]4[C:20]5[CH:26]=[C:25]([S:27]([CH3:30])(=[O:29])=[O:28])[C:24]([C:31](OC)=[O:32])=[CH:23][C:21]=5[N:22]=[C:16]4[C@H:15]3[CH:35]([CH3:37])[CH3:36])[N:5]=2)[CH2:3][CH2:2]1.CC(C[AlH]CC(C)C)C.[NH4+].[Cl-]>C(Cl)Cl.C1(C)C=CC=CC=1>[CH:1]1([C:4]2[C:9]([CH2:10][OH:11])=[CH:8][N:7]=[C:6]([N:14]3[CH2:19][CH2:18][N:17]4[C:20]5[CH:26]=[C:25]([S:27]([CH3:30])(=[O:29])=[O:28])[C:24]([CH2:31][OH:32])=[CH:23][C:21]=5[N:22]=[C:16]4[C@H:15]3[CH:35]([CH3:37])[CH3:36])[N:5]=2)[CH2:2][CH2:3]1.[CH:1]1([C:4]2[C:9]([CH2:10][OH:11])=[CH:8][N:7]=[C:6]([N:14]3[CH2:19][CH2:18][N:17]4[C:20]5[CH:26]=[C:25]([S:27]([CH3:30])(=[O:29])=[O:28])[C:24]([CH2:31][OH:32])=[CH:23][C:21]=5[N:22]=[C:16]4[C@@H:15]3[CH:35]([CH3:37])[CH3:36])[N:5]=2)[CH2:2][CH2:3]1
Reactant: COC(=O)c1cc2nc3n(c2cc1S(C)(=O)=O)CCN(c1ncc(C(=O)OC)c(C2CC2)n1)[C@@H]3C(C)C
Agent: CC(C)C[AlH]CC(C)C
Agent: [Cl-]
Agent: [NH4+]
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: CC(C)[C@@H]1c2nc3cc(CO)c(S(C)(=O)=O)cc3n2CCN1c1ncc(CO)c(C2CC2)n1
Product: CC(C)[C@H]1c2nc3cc(CO)c(S(C)(=O)=O)cc3n2CCN1c1ncc(CO)c(C2CC2)n1
Temperature: -78 °C
Reaction time: 1 h
Yield: 24.5 %
Yield: 15.1 %

Procedure:
To a solution of (R)-methyl 2-(4-cyclopropyl-5-(methoxycarbonyl)pyrimidin-2-yl)-1-isopropyl-7-(methylsulfonyl)-1,2,3,4-tetrahydrobenzo[4,5]imidazo[1,2-a]pyrazine-8-carboxylate (50 mg, 0.1 mmol) in CH2Cl2 (2 mL) was added DIBAL H (1M in toluene, 1 mL, 1 mmol) at −78° C. The mixture was stirred at −78° C. for 1 h and then rt for 1 h. Sat. NH4Cl solution (5 mL) was added slowly at 0° C. and the mixture was filtered. The aqueous layer was extracted with EtOAc (3×5 mL). The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered and concentrated under vacuum. The residue was purified by preparative TLC and then SFC separation to afford (R)-(4-cyclopropyl-2-(8-(hydroxymethyl)-1-isopropyl-7-(methylsulfonyl)-3,4-dihydrobenzo[4,5]imidazo[1,2-a]pyrazin-2(1H)-yl)pyrimidin-5-yl)methanol (11.50 mg, 24.5% yield, isomer 1) as a colorless oil and (S)-(4-cyclopropyl-2-(8-(hydroxymethyl)-1-isopropyl-7-(methylsulfonyl)-3,4-dihydrobenzo[4,5]imidazo[1,2-a]pyrazin-2(1H)-yl)pyrimidin-5-yl)methanol (7.10 mg, 15.1% yield, isomer 2) as a colorless oil.
Reaction SMILES: [CH3:1][C:2]1([CH3:52])[S:7](=[O:9])(=[O:8])[C@@H:6]2[CH2:10][C@H:11]([CH3:35])[O:12][C:13]3[CH:18]=[CH:17][C:16]([NH:19][C:20]([C:22]4[CH:27]=[CH:26][C:25]([O:28][CH2:29][C:30]5[O:31][CH:32]=[CH:33][N:34]=5)=[CH:24][N:23]=4)=[O:21])=[CH:15][C:14]=3[C@@:5]2([CH3:36])[N:4]=[C:3]1[N:37](C(OC(C)(C)C)=O)C(=O)OC(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl.C(=O)(O)[O-].[Na+]>[NH2:37][C:3]1[C:2]([CH3:1])([CH3:52])[S:7](=[O:9])(=[O:8])[C@@H:6]2[CH2:10][C@H:11]([CH3:35])[O:12][C:13]3[CH:18]=[CH:17][C:16]([NH:19][C:20](=[O:21])[C:22]4[CH:27]=[CH:26][C:25]([O:28][CH2:29][C:30]5[O:31][CH:32]=[CH:33][N:34]=5)=[CH:24][N:23]=4)=[CH:15][C:14]=3[C@@:5]2([CH3:36])[N:4]=1
Reactant: C[C@H]1C[C@@H]2[C@](C)(N=C(N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)C(C)(C)S2(=O)=O)c2cc(NC(=O)c3ccc(OCc4ncco4)cn3)ccc2O1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: C[C@H]1C[C@@H]2[C@](C)(N=C(N)C(C)(C)S2(=O)=O)c2cc(NC(=O)c3ccc(OCc4ncco4)cn3)ccc2O1
Temperature: 25 °C
Reaction time: 2 h
Yield: 84.6 %

Procedure:
To a solution tert-butyl N-[(4aR,6S,11bR)-3,3,6,11b-tetramethyl-10-[[5-(oxazol-2-ylmethoxy)pyridine-2-carbonyl]amino]-4,4-dioxo-5,6-dihydro-4aH-[1]benzoxepino[4,5-b][1,4]thiazin-2-yl]-N-tert-butoxycarbonyl-carbamate (19 mg, 0.026 mmol) in DCM (2 mL) was added TFA (0.049 mL, 0.642 mmol). The reaction was stirred at ambient temperature for 2 h. The reaction mixture was diluted with DCM and neutralized with saturated aqueous sodium bicarbonate. The crude product was purified by column chromatography, eluting with 20-100% (3:1 ethyl acetate/ethanol) in heptane, to provide N-((4aR,6S,11bR)-2-amino-3,3,6,11b-tetramethyl-4,4-dioxido-4a,5,6,11b-tetrahydro-3H-benzo[6,7]oxepino[4,5-b][1,4]thiazin-10-yl)-5-(oxazol-2-ylmethoxy)picolinamide (12 mg, 0.022 mmol, 87% yield) as a white powder. MS m/z=540.0 (M+H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:14]2[CH:15]=[C:16]([CH2:18][CH3:19])[S:17][C:13]=2[N:12]2[CH:20]=[N:21][N:22]=[C:11]2[CH2:10][N:9]=1.[Br:23]Br>ClC(Cl)C>[Br:23][C:20]1[N:12]2[C:13]3[S:17][C:16]([CH2:18][CH3:19])=[CH:15][C:14]=3[C:8]([C:3]3[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=3[Cl:1])=[N:9][CH2:10][C:11]2=[N:22][N:21]=1
Reactant: CCc1cc2c(s1)-n1cnnc1CN=C2c1ccccc1Cl
Reactant: BrBr
Solvent: CC(Cl)Cl
Product: CCc1cc2c(s1)-n1c(Br)nnc1CN=C2c1ccccc1Cl
Temperature: 25 °C
Reaction time: 8 h

Procedure:
4-(2-Chlorophenyl)-2-ethyl-6H-thieno[3,2-f] [1,2,4]triazolo[4,3-a] [1,4]diazepine (10 g) was dissolved in dichloroethane (100 ml), and bromine (1.7 ml) was added under ice-cooling. The mixture was heated to room temperature, and allowed to stand overnight. The solvent was evaporated, and chloroform was added. The mixture was washed with an aqueous sodium thiosulfate solution, a saturated aqueous sodium hydrogencarbonate solution and brine, and dried over magnesium sulfate. The solvent was evaporated, and the residue was purified by silica gel column chromatography (developing solvent:ethyl acetate-hexane) and crystallized from ethyl acetate to give 3.4 g of 9-bromo-4-(2-chlorophenyl)-2-ethyl-6H-thieno[3,2-f] [1,2,4]triazolo[4,3-a] [1,4]diazepine.
Reaction SMILES: [Br:1][C:2]1[N:7]=[C:6]2[NH:8][CH:9]=[CH:10][C:5]2=[CH:4][CH:3]=1.[H-].[Na+].[CH3:13]I>CN(C=O)C>[Br:1][C:2]1[N:7]=[C:6]2[N:8]([CH3:13])[CH:9]=[CH:10][C:5]2=[CH:4][CH:3]=1
Reactant: CI
Reactant: Brc1ccc2cc[nH]c2n1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cn1ccc2ccc(Br)nc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 37.2 %

Procedure:
To a solution of 6-bromo-1H-pyrrolo[2,3-b]pyridine (500 mg, 2.55 mmol) in DMF (10 mL) was added NaH (306 mg, 7.65 mmol, m %/60%). The mixture was stirred at room temperature for 1 h and then MeI (398 mg, 2.8 mmol) was added. The reaction mixture was then stirred at room temperature for 4 h after which, TLC showed the completion of the reaction. The reaction mixture was quenched by addition of water and then extracted with EtOAc. Combined organic layers were concentrated and the residue was purified by Prep-TLC (PE:EA=5:1) to give the desired product (200 mg) which was used directly in the next step.
Reaction SMILES: [CH:1]1([Si:7]([CH3:19])([CH3:18])[O:8][C:9]2[CH2:10][C:11]3[C:16]([CH:17]=2)=[CH:15][CH:14]=[CH:13][CH:12]=3)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[Li][CH2:21][CH2:22][CH2:23][CH3:24].Br[CH:26](Br)[CH3:27]>C1COCC1>[CH:1]1([Si:7]([CH3:19])([CH3:18])[O:8][C:9]2[CH:10]([CH:23]([CH:22]3[C:21]4[C:16](=[CH:15][CH:14]=[CH:13][CH:12]=4)[CH:17]=[C:9]3[O:8][Si:7]([CH3:1])([CH3:18])[CH:26]3[CH2:27][CH2:2][CH2:3][CH2:4][CH2:5]3)[CH3:24])[C:11]3[C:16]([CH:17]=2)=[CH:15][CH:14]=[CH:13][CH:12]=3)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: [Li]CCCC
Reactant: C[Si](C)(OC1=Cc2ccccc2C1)C1CCCCC1
Reactant: CC(Br)Br
Solvent: C1CCOC1
Product: CC(C1C(O[Si](C)(C)C2CCCCC2)=Cc2ccccc21)C1C(O[Si](C)(C)C2CCCCC2)=Cc2ccccc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 28.2 %

Procedure:
To an ice-cooled solution of 2-(cyclohexyldimethylsiloxy)indene (13.62 g, 50.0 mmol) in THF (50 mL) was added dropwise n-BuLi (20.0 mL of a 2.5 M solution in hexanes, 50.0 mmol) and the reaction mixture was stirred overnight at room temperature. The resulting solution was then cooled to −80° C. and treated dropwise with a solution of dibromoethane (4.70 g, 25.0 mmol) in THF (30 mL). The reaction mixture was gradually warmed to room temperature, stirred overnight and washed with saturated ammonium chloride solution (150 mL). The organic phase was dried over sodium sulfate. Solvents were evaporated and the remaining oil was dissolved in Et2O (100 mL). Repeated crystallizations gave a total yield 4.03 g (28.2%) of the title compound as off-white crystals. The first crystalline fraction was used for spectral characterization. EIMS (calcd/found): m/e 570.3349/570.3342. 1H NMR (CDCl3, δ): 7.19-7.07 (m, 6H); 6.99 (td, 3J=7.3 Hz, 4J=1.3 Hz, 2H), 5.65 (s, 2H); 3.17 (m, 2H); 1.84-1.79 (m, AA′, 2H); 1.73 (m, 10H); 1.59-1.54 (m, BB′, 2H); 1.20 (m, 10H); 0.84 (m, 2H); 0.22 (s, 6H); 0.22 (s, 6H). 13C NMR (CDCl3, δ): 164.98; 144.47; 140.65; 126.51; 122.52; 122.33; 118.72; 104.64; 49.09; 27.72; 26.80; 26.48; 26.37; 24.29; −3.60.
Reaction SMILES: O/N=[C:3](/[C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([O:26][CH3:27])[CH:21]=1)\[CH2:4][O:5][C:6]1[CH:19]=[CH:18][C:9]([CH2:10][CH:11]2[S:15][C:14](=[O:16])[NH:13][C:12]2=[O:17])=[CH:8][CH:7]=1.[OH-:28].[Na+].CO.C(Cl)Cl>C1COCC1.Cl>[CH3:27][O:26][C:22]1[CH:21]=[C:20]([C:3](=[O:28])[CH2:4][O:5][C:6]2[CH:19]=[CH:18][C:9]([CH2:10][CH:11]3[S:15][C:14](=[O:16])[NH:13][C:12]3=[O:17])=[CH:8][CH:7]=2)[CH:25]=[CH:24][CH:23]=1
Reactant: COc1cccc(/C(COc2ccc(CC3SC(=O)NC3=O)cc2)=N/O)c1
Reactant: [OH-]
Agent: Cl
Agent: [Na+]
Solvent: ClCCl
Solvent: CO
Solvent: C1CCOC1
Product: COc1cccc(C(=O)COc2ccc(CC3SC(=O)NC3=O)cc2)c1

Procedure:
A stirring solution of 5-(4-{[(2Z)-2-(hydroxyimino)-2-(3-methoxyphenyl)ethyl]oxy}benzyl)-1,3-thiazolidine-2,4-dione (0.76 g, 2.0 mmol; Supplier=Kalexsyn; Lot=1003-TTP-124) in THF (5 ml) and 6M HCl (5 ml) was heated to reflux. Little reaction after 4 hours at reflux. Left to reflux overnight. Reaction is complete. 2N NaOH was added until the reaction mixture was ca. pH 8-9. The reaction mixture was extracted with EtOAc (2×25 ml). The combined extracts were washed with brine, dried (Na2SO4), filtered and evaporated in vacuo to give a light yellow oily solid. This material was treated with 5% MeOH/DCM (10 ml) and the resulting white solids were collected by suction filtration and dried to afford 495 mg of final product. 1H-NMR (DMSO-d6): δ 12.03(s, 1H), 7.62(d, J=7.7 Hz, 1H), 7.49((m, 2H), 7.27(dd, J=8.2, 2.6 Hz, 1H), 7.15(d, J=8.7 Hz, 2H), 6.91(d, J=8.5 Hz, 2H), 5.55(s, 2H), 4.88(dd, J=9.1, 4.3 Hz, 1H), 3.83(s, 3H), 3.31(m, 1H), 3.31(m, 1H), 3.05(dd, J=14.1, 9.3 Hz, 1H). HPLC: 3.782 min., 93 area % @ 210 nm; 3.785 min. 100 area % @ 254 nm. MS (ESI−) for C19H17NO5S m/z 370.1 (M−H)−.
Reaction SMILES: [CH:1](=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)(O)O.[NH2:13][C:14]([NH2:16])=[NH:15].[C:17]([CH2:19][C:20](OCC)=[O:21])#[N:18].C([O-])(=O)C.[Na+]>N1C=CC=CC=1>[NH2:15][C:14]1[NH:16][C:20](=[O:21])[C:19]([C:17]#[N:18])=[C:1]([C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[N:13]=1
Reactant: O=Cc1ccccc1
Reactant: N=C(N)N
Reactant: CCOC(=O)CC#N
Agent: CC(=O)[O-]
Agent: O=C(O)O
Agent: [Na+]
Solvent: c1ccncc1
Product: N#Cc1c(-c2ccccc2)nc(N)[nH]c1=O
Temperature: 25 °C

Procedure:
Benzaldehyde (15 g, 141.3 mmol, 1 eq), guanidine carbonate (25.47 g, 141.3 mmol, 1 eq), ethyl cyanoacetate (15.99 g, 141.3 mmol, 1 eq) and anhydrous sodium acetate (11.59 g, 141.3 mmol, 1 eq) were added to 300 ml anhydrous pyridine and refluxed for 4 hours. The reaction was then cooled to room temperature and the solvent was removed under reduced pressure. The brown residue was triturated with 400 ml aqueous acetic acid (30%) and filtered off. The yellow solid was then triturated with 300 ml diethyl ether and filtered off to yield 2-amino-6-oxo-4-phenyl-1,6-dihydro-pyrimidine-5-carbonitrile as an off-white solid.
Reaction SMILES: [O:1]1[CH2:6][CH:5]=[C:4]([C:7]2[CH:12]=[C:11]([CH3:13])[CH:10]=[C:9]([CH3:14])[C:8]=2[OH:15])[CH2:3][CH2:2]1>CO.[C].[Pd]>[CH3:14][C:9]1[CH:10]=[C:11]([CH3:13])[CH:12]=[C:7]([CH:4]2[CH2:5][CH2:6][O:1][CH2:2][CH2:3]2)[C:8]=1[OH:15]
Reactant: Cc1cc(C)c(O)c(C2=CCOCC2)c1
Agent: [Pd]
Solvent: CO
Product: Cc1cc(C)c(O)c(C2CCOCC2)c1
Reaction time: 24 h
Yield: 66.3 %

Procedure:
2-(3,6-dihydro-2H-pyran-4-yl)-4,6-dimethylphenol (Compound 6-17) (234 mg, 1.14 mmol) was dissolved in methanol. Palladium carbon (92 mg, 40 wt %) was added thereto, followed by stirring under hydrogen balloon for 24 hours. After the completion of the reaction, the reaction mixture was filtered through Celite. The filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (silica gel; hexane/ethyl acetate, 9/1) to obtain 2,4-dimethyl-6-(tetrahydro-2H-pyran-4-yl)phenol (156 mg, 66%) as a white solid.
Reaction SMILES: [CH:1]([N:3]([CH2:12][C@@H:13]([CH2:34][CH2:35][CH2:36][CH2:37][CH3:38])[C:14]([N:16]1[C@H:20]([C:21]([OH:23])=O)[CH2:19][CH2:18][N:17]1[C:24]([O:26][CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)=[O:25])=[O:15])[O:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[O:2].CN1CCOCC1.F[B-](F)(F)F.COC1N=C(OC)N=C([N+]2(C)CCOCC2)N=1.[F:68][C:69]1[CH:70]=[CH:71][C:72]([NH2:75])=[N:73][CH:74]=1>C(#N)C>[F:68][C:69]1[CH:70]=[CH:71][C:72]([NH:75][C:21]([C@@H:20]2[CH2:19][CH2:18][N:17]([C:24]([O:26][CH2:27][C:28]3[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=3)=[O:25])[N:16]2[C:14](=[O:15])[C@@H:13]([CH2:12][N:3]([CH:1]=[O:2])[O:4][CH2:5][C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=2)[CH2:34][CH2:35][CH2:36][CH2:37][CH3:38])=[O:23])=[N:73][CH:74]=1
Reactant: Nc1ccc(F)cn1
Reactant: CCCCC[C@H](CN(C=O)OCc1ccccc1)C(=O)N1[C@H](C(=O)O)CCN1C(=O)OCc1ccccc1
Agent: COc1nc(OC)nc([N+]2(C)CCOCC2)n1
Agent: F[B-](F)(F)F
Solvent: CN1CCOCC1
Solvent: CC#N
Product: CCCCC[C@H](CN(C=O)OCc1ccccc1)C(=O)N1[C@H](C(=O)Nc2ccc(F)cn2)CCN1C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 69.4 %

Procedure:
To a solution of (3S)-2-[(2R)-2-({formyl[(phenylmethyl)oxy]amino}methyl)heptanoyl]-1-{[(phenylmethyl)oxy]carbonyl}-3-pyrazolidinecarboxylic acid (1.015 g, 1.931 mmol) in acetonitrile (30 mL) at 0° C. was added 4-methylmorpholine (0.467 mL, 4.25 mmol), followed by 4-[4,6-bis(methyloxy)-1,3,5-triazin-2-yl]-4-methylmorpholin-4-ium tetrafluoroborate (DMTMM) (0.559 g, 2.317 mmol). The solution was stirred for 15 min, then 5-fluoro-2-pyridinamine (0.260 g, 2.317 mmol) was added. The reaction mixture was warmed up to room temperature and stirred overnight. The solvent was evaporated, and the residue was dissolved in DCM. The solution was washed with 5% aq. NaHSO4 followed by water, and the organic phase was dried over anhydrous Na2SO4, filtered, and concentrated in vacuo to afford a crude oil which was purified by RP-HPLC to yield phenylmethyl (3S)-3-{[(5-fluoro-2-pyridinyl)amino]carbonyl}-2-[(2R)-2-({formyl[(phenylmethyl)oxy]amino}methyl)heptanoyl]-1-pyrazolidinecarboxylate as a colorless gum (830 mg, 69%). LCMS: (M+H)+: 620.2.
Reaction SMILES: O[CH:2]([CH2:7][CH2:8][S:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][C:17]([F:22])([F:21])[CH:18]([F:20])[F:19])=[CH:12][CH:11]=1)[CH2:3][C:4](=[O:6])[CH3:5].C(O)(=O)C(O)=O>C1(C)C=CC=CC=1>[F:22][C:17]([F:21])([O:16][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)[CH:18]([F:20])[F:19]
Reactant: CC(=O)CC(O)CCSc1ccc(OC(F)(F)C(F)F)cc1
Agent: O=C(O)C(=O)O
Solvent: Cc1ccccc1
Product: CC(=O)C=CCCSc1ccc(OC(F)(F)C(F)F)cc1
Yield: 96.8 %

Procedure:
12.48 Grams of 4-hydroxy-6-[4-(1,1,2,2-tetrafluoroethoxy)phenylthio]-2-hexanone were dissolved in 150 ml of toluene, and 1.50 g of oxalic acid were added thereto. The resulting mixture was refluxed for 2 hours with stirring, allowed to cool and then treated in the same manner as in Production example 34. Thus, 11.76 g of 6-[4-(1,1,2,2-tetrafluoroethoxy)phenylthio]-3-hexen-2-one (trans : cis =4.6 : 1) were obtained (purity: 98.0%). Further, the product was column chromatographed to obtain a purified product having a refractive index (nD23) of 1.5202. The yield was 96.8%.
Reaction SMILES: [I:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6]Cl)=[CH:4][CH:3]=1.[C:10]1(=[O:20])[NH:14][C:13](=[O:15])[C:12]2=[CH:16][CH:17]=[CH:18][CH:19]=[C:11]12.[K]>CN(C=O)C>[I:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][N:14]2[C:13](=[O:15])[C:12]3=[CH:16][CH:17]=[CH:18][CH:19]=[C:11]3[C:10]2=[O:20])=[CH:4][CH:3]=1
Reactant: O=C1NC(=O)c2ccccc21
Reactant: ClCc1ccc(I)cc1
Agent: [K]
Solvent: CN(C)C=O
Product: O=C1c2ccccc2C(=O)N1Cc1ccc(I)cc1
Temperature: 55 °C
Yield: 75.6 %

Procedure:
(Brown, Stephen; Grigg, Ronald; Hinsley, Joanne; Korn, Stewart; Sridharan, Visuvanathar; Uttley, Michael; Tetrahedron (2001), 57(52), 10347-10355.) A mixture of 4-iodobenzylchloride (40.0 g, 134.7 mmol), potassium phthalimide (26.20 g, 141.5 mmol) and dry DMF (150 mL) was heated overnight at 55° C. under Ar, and then the solvent was removed at reduced pressure. The solid residue was triturated with CHCl3 (200 mL), filtered, and washed with CHCl3 (3×200 mL). The combined organic extracts were successively washed with aqueous 0.2 M NaOH (200 mL) and H2O (400 mL), and then dried (MgSO4). The solvent was removed at reduced pressure to afford a crude solid, which was triturated with Et2O to obtain a white solid (37.00 g, 75%): Rf=0.75 (1/1 EtOAc/hexanes); mp 138-139° C.; 1H NMR (CDCl3) □4.77 (s, CH2), 7.17 (d, J=8.6 Hz, 2 ArH), 7.63 (d, J=8.6 Hz, 2 ArH), 7.78 (dd, J=3.0, 5.7 Hz, 2 PhtH), 7.83 (dd, J=3.0, 5.7 Hz, 2 PhtH); 13C NMR (CDCl3) δ 41.0 (CH2), 93.5 (Cl), 123.4, 130.6, 131.9, 134.1, 135.9, 137.7 (6 Ar), 167.2 (2 C(O)); HRMS (ESI) 363.9831 [M+H+] (calcd for C17H13NO2H+ 363.9835).
Reaction SMILES: [NH2:1][CH:2]([C:6]1[N:11]([CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[C:10](=[O:19])[C:9]([CH3:20])=[C:8]([CH3:21])[N:7]=1)[CH:3]([CH3:5])[CH3:4].Br[CH2:23][C:24](=[O:38])[CH2:25][CH2:26][N:27]1[C:35](=[O:36])[C:34]2[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=2)[C:28]1=[O:37].C(N(CC)C(C)C)(C)C>CN(C=O)C>[CH2:12]([N:11]1[C:10](=[O:19])[C:9]([CH3:20])=[C:8]([CH3:21])[N:7]=[C:6]1[CH:2]([NH:1][CH2:23][C:24](=[O:38])[CH2:25][CH2:26][N:27]1[C:35](=[O:36])[C:34]2[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=2)[C:28]1=[O:37])[CH:3]([CH3:4])[CH3:5])[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: O=C(CBr)CCN1C(=O)c2ccccc2C1=O
Reactant: Cc1nc(C(N)C(C)C)n(Cc2ccccc2)c(=O)c1C
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1nc(C(NCC(=O)CCN2C(=O)c3ccccc3C2=O)C(C)C)n(Cc2ccccc2)c(=O)c1C
Temperature: 25 °C
Reaction time: 16 h
Yield: 89.2 %

Procedure:
To 2-(1-Amino-2-methyl-propyl)-3-benzyl-5,6-dimethyl-3H-pyrimidin-4-one (0.66 g, 2.33 mmol) in DMF (15 mL) was added 2-(4-bromo-3-oxo-butyl)-isoindole-1,3-dione (0.69 g, 2.33 mmol, prepared as described in WO 89/10360) and N,N-diisopropylethylamine (0.301 g, 2.33 mmol). The reaction was stirred for 16 h at room temperature, concentrated under vacuum, dissolved in EtOAc/H2O, washed with water, dried (Na2SO4), and evaporated to give the title compound as a white foam (1.04 g, 89%). MS(ES+) m/e 501 [M+H]+.
Reaction SMILES: [F:1][C:2]1[C:3]([NH2:9])=[N:4][CH:5]=[C:6]([F:8])[CH:7]=1.Br[CH2:11][C:12](=O)[CH2:13][CH2:14][C:15]#[C:16][Si:17]([CH3:20])([CH3:19])[CH3:18]>>[F:8][C:6]1[CH:7]=[C:2]([F:1])[C:3]2[N:4]([CH:11]=[C:12]([CH2:13][CH2:14][C:15]#[C:16][Si:17]([CH3:20])([CH3:19])[CH3:18])[N:9]=2)[CH:5]=1
Reactant: Nc1ncc(F)cc1F
Reactant: C[Si](C)(C)C#CCCC(=O)CBr
Product: C[Si](C)(C)C#CCCc1cn2cc(F)cc(F)c2n1
Yield: 49.1 %

Procedure:
The title compound was prepared in accordance with the general method of Example 223(D), from 3,5-difluoropyridin-2-amine (492 mg, 3.78 mmol) and 1-bromo-6-(trimethylsilyl)hex-5-yn-2-one (compound 223(C), 1.87 mg, 7.56 mmol). The crude residue was purified over silicagel chromatography (prepacked 25 g silicagel column, from DCM/Cyclohexane:70/30 to DCM/MeOH: 95/5 as eluent) to afford 517 mg of 6,8-difluoro-2-(4-(trimethylsilyl)but-3-ynyl)-imidazo[1,2-a]pyridine (Yield: 49%) as a brown oil.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][CH2:5][C:6]1[CH:7]=[C:8]([CH2:12][OH:13])[CH:9]=[CH:10][CH:11]=1.CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O>C(Cl)Cl>[CH3:1][O:2][CH2:3][CH2:4][CH2:5][C:6]1[CH:7]=[C:8]([CH:9]=[CH:10][CH:11]=1)[CH:12]=[O:13]
Reactant: COCCCc1cccc(CO)c1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: ClCCl
Product: COCCCc1cccc(C=O)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a CH2Cl2 solution (0.3 M) of [3-(3-methoxypropyl)phenyl]methanol from the previous step (1 eq.) was added Dess-Martin periodinane (1.2 eq.). The resulting suspension was stirred at RT for 2 h. The reaction was quenched with sat. aq. NaHCO3 and 2 N aq. Na2S2O3. The biphasic mixture was allowed to stir at RT for 20 min, poured into sat. aq. NaHCO3 and extracted with CH2Cl2. The combined organic extracts were washed with brine, dried over MgSO4 and filtered. Concentration of the filtrate in vacuo afforded a cloudy oil. Purification of the crude product thus obtained by way of flash chromatography (SiO2, Hex→7:3 (v/v) Hex:EtOAc) afforded the title compound as a colorless oil.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:24]=[CH:25][CH:26]=1)[CH2:5][NH:6][C:7]([C:9]1S[CH:11]=[CH:12][C:13]=1[NH:14][C:15]1[C:16]2[CH:23]=[CH:22][NH:21][C:17]=2[N:18]=[CH:19][N:20]=1)=[O:8].C[O:28]C(C1OC=CC=1NC1C2C=CNC=2N=CN=1)=O>>[Cl:1][C:2]1[CH:3]=[C:4]([CH:24]=[CH:25][CH:26]=1)[CH2:5][NH:6][C:7]([C:9]1[O:28][CH:11]=[CH:12][C:13]=1[NH:14][C:15]1[C:16]2[CH:23]=[CH:22][NH:21][C:17]=2[N:18]=[CH:19][N:20]=1)=[O:8]
Reactant: O=C(NCc1cccc(Cl)c1)c1sccc1Nc1ncnc2[nH]ccc12
Reactant: COC(=O)c1occc1Nc1ncnc2[nH]ccc12
Product: O=C(NCc1cccc(Cl)c1)c1occc1Nc1ncnc2[nH]ccc12
Yield: 9 %

Procedure:
The title compound was prepared in an analogous manner as 3-(7H-pyrrolo[2,3-d]pyrimidin-4-ylamino)-thiophene-2-carboxylic acid 3-chloro-benzylamide using 3-(7H-pyrrolo[2,3-d]pyrimidin-4-ylamino)-furan-2-carboxylic acid methyl ester instead of 3-(7H-pyrrolo[2,3-d]pyrimidin-4-ylamino)-thiophene-2-carboxylic acid methyl ester and obtained in 9% yield. 1H NMR (DMSO-d6) 11.97 (br s, 1H), 9.67 (s, 1H), 9.01 (t, J=6.2 Hz, 1H), 8.38 (s, 1H), 7.83 (d, J=1.8 Hz, 1H), 7.73 (d, J=1.8 Hz, 1H), 7.41-7.30 (m, 5H), 6.45 (d, J=2.2 Hz, 1H), 4.49 (d, J=5.9 Hz, 2H); MS (m/z) 368 [M+H]+ (35Cl).