Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:10]([CH3:22])[CH:11]=[CH:12][C:13]=2[C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=2)=[CH:5][CH:4]=1.C(N(C(C)C)C(C)C)C.[F:32][C:33](I)([F:35])[F:34]>>[CH3:21][O:20][C:17]1[CH:18]=[CH:19][C:14]([C:13]2[CH:12]=[C:11]([C:33]([F:35])([F:34])[F:32])[N:10]([CH3:22])[C:9]=2[C:6]2[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:8][CH:7]=2)=[CH:15][CH:16]=1
Reactant: COc1ccc(-c2ccn(C)c2-c2ccc(OC)cc2)cc1
Reactant: FC(F)(F)I
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc(-c2cc(C(F)(F)F)n(C)c2-c2ccc(OC)cc2)cc1

Procedure:
In a pressure reaction vessel was placed 2.9 g (0.01 mole) of 2,3-bis(4-methoxyphenyl)-1-methyl-1H-pyrrole and 1.3 g (0.01 mole) of ethyl diisopropylamine. The vessel was cooled and evacuated, and 2.0 g (0.01 mole) of trifluoromethyl iodide was added. The mixture was heated at 150° for approximately 18 hours. The vessel was cooled and vented, and the contents rinsed out with methylene chloride. The methylene chloride solution was washed with water three times then dried and concentrated to give the crude product. This was purified by chromatography on 400 g silica gel, eluting with toluene, to give after recrystallization from hexane, 1.0 g (28%) of product as a white solid, m.p. 125°-126°.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9](=O)[CH2:10][N:11]1[CH:15]=[N:14][CH:13]=[N:12]1.[OH:17][NH3+:18].O>C(O)C>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9](=[N:18][OH:17])[CH2:10][N:11]1[CH:15]=[N:14][CH:13]=[N:12]1
Reactant: [NH3+]O
Reactant: O=C(Cn1cncn1)c1ccc(Cl)cc1Cl
Solvent: CCO
Solvent: O
Product: ON=C(Cn1cncn1)c1ccc(Cl)cc1Cl
Yield: 42.8 %

Procedure:
106.8 g (0.44 mol) of 1-(2,4-dichlorophenyl)-2-(1,2,4-triazol-1-yl)-1-ethanone are dissolved in 780 ml of ethanol, 48 g of hydroxylammonium nydrochloride are added and the mixture is heated under reflux for five hours. Thereafter, 1000 ml of water are added and the reaction mixture is filtered. 51 g (45% of theory) of 1-(2,4-dichlorophenyl)-1-oximino-2-(1,2,4-triazol-1-yl)-ethane of melting point 165°-170° C. are obtained. ##STR15##
Reaction SMILES: [C:1]1([CH2:7][CH2:8][OH:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:10]=O.Cl>>[CH2:10]1[C:6]2[C:1](=[CH:2][CH:3]=[CH:4][CH:5]=2)[CH2:7][CH2:8][O:9]1
Reactant: C=O
Reactant: OCCc1ccccc1
Agent: Cl
Product: c1ccc2c(c1)CCOC2
Temperature: 25 °C
Reaction time: 2 h
Yield: 85.3 %

Procedure:
2-phenylethanol (48.8 g,) and paraformaldehyde (15 g,) were mixed and stirred on an ice bath while a stream of hydrogen chloride gas was passed vigorously through the suspension for 2 hr. The ice-bath was removed and the flow of hydrogen chloride was decreased. The mixture was stirred at room temperature for a further 4 hr. during which time the mixture cleared, after which the reaction mixture stood overnight at room temperature. Aqueous sodium hydroxide solution (100 g/100 ml) was added cautiously, with stirring to the reaction mixture over a period of 30 min. The mixture was heated at reflux for 2 hr., cooled and the oil extracted with ether (3×100 ml). The ether layer was dried (magnesium sulphate) and the solvent removed in vacuo. The residue was distilled under vacuum to give isochroman (45.7 g, b.pt 84.5°-85°/8 mmHg)
Reaction SMILES: [CH3:1][O:2][CH:3]([O:9][CH3:10])[CH2:4][CH2:5][N+:6]([O-])=O.[C:11](OC)(=[O:15])/[CH:12]=[CH:13]/[CH3:14]>>[O:9]1[CH2:10][CH2:1][O:2][CH:3]1[CH2:4][C@@H:5]1[NH:6][C:11](=[O:15])[CH2:12][C@H:13]1[CH3:14]
Reactant: C/C=C/C(=O)OC
Reactant: COC(CC[N+](=O)[O-])OC
Product: C[C@@H]1CC(=O)N[C@H]1CC1OCCO1

Procedure:
Example 300 A) cis and trans-5-[(1,3-dioxolan-2-yl)methyl]-4-(methyl)pyrrolidin-2-one was prepared in the manner described (R. Ohrlein, W. Schwab, R. Ehrler, V. Jager, Synthesis 1986, 535-538) starting with 1,1-dimethoxy-3-nitropropane and methyl crotonate.
Reaction SMILES: [OH-:1].[K+].[O:3]1[CH2:7][CH2:6][CH2:5][CH2:4]1.O>O>[CH:6]12[CH2:7][CH:4]([CH:4]=[CH:5]1)[CH2:5][CH:6]2[C:7]([OH:3])=[O:1]
Reactant: [OH-]
Reactant: C1CCOC1
Agent: [K+]
Solvent: O
Product: O=C(O)C1CC2C=CC1C2
Temperature: 25 °C
Reaction time: 24 h

Procedure:
27.5 g (110 mmol) of the Diels-Alder adduct obtained in the above step was dissolved in 420 ml of a mixture solvent of tetrahydrofuran-water (5:2), on ice cooling, 30.0 g (455 mmol) of potassium hydroxide (85%) in 120 ml of water was added, and the mixture was stirred at room temperature for 24 hours. After distilling off tetrahydrofuran, the residue was neutralized with 40 ml of concentrated hydrochloric acid, and the solution was extracted with a mixture solvent of hexane-methylene chloride (98:2) (150 ml×4). The extract was dried over anhydrous magnesium sulfate and filtered, the solvent was distilled off, and 15.7 g of crude 5-norbornene-2-carboxylic acid was obtained. Crude yield: 100%.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:10]([C:11]3[N:16]=[C:15]([NH:17][C@H:18]4[CH2:22][CH2:21][N:20](C(OC(C)(C)C)=O)[CH2:19]4)[C:14]([F:30])=[CH:13][N:12]=3)=[CH:9][N:8]([S:31]([C:34]3[CH:39]=[CH:38][C:37]([CH3:40])=[CH:36][CH:35]=3)(=[O:33])=[O:32])[C:5]2=[N:6][CH:7]=1.Cl>C1COCC1>[Cl:1][C:2]1[CH:3]=[C:4]2[C:10]([C:11]3[N:16]=[C:15]([NH:17][C@H:18]4[CH2:22][CH2:21][NH:20][CH2:19]4)[C:14]([F:30])=[CH:13][N:12]=3)=[CH:9][N:8]([S:31]([C:34]3[CH:39]=[CH:38][C:37]([CH3:40])=[CH:36][CH:35]=3)(=[O:33])=[O:32])[C:5]2=[N:6][CH:7]=1
Reactant: Cc1ccc(S(=O)(=O)n2cc(-c3ncc(F)c(N[C@H]4CCN(C(=O)OC(C)(C)C)C4)n3)c3cc(Cl)cnc32)cc1
Agent: Cl
Solvent: C1CCOC1
Product: Cc1ccc(S(=O)(=O)n2cc(-c3ncc(F)c(N[C@H]4CCNC4)n3)c3cc(Cl)cnc32)cc1
Temperature: 90 °C
Yield: 88 %

Procedure:
A solution of tert-butyl (3S)-3-[[2-[5-chloro-1-(p-tolylsulfonyl)pyrrolo[5,4-b]pyridin-3-yl]-5-fluoro-pyrimidin-4-yl]amino]pyrrolidine-1-carboxylate, 7b, (1.33 g, 2.27 mmol) in THF (25 mL) was treated with hydrogen chloride (12 mL of 4M solution in dioxane, 48.00 mmol) at room temperature. The reaction was then heated at 90° C. until LCMS showed reaction was complete. The mixture was concentrated to dryness then dried under vacuum to afford 1.04 g (88% yield) of 7c, as a tan solid.
Reaction SMILES: [CH3:1][C:2]1[N:7]2[C:8](=[O:15])[C:9]([C:12]([OH:14])=O)=[CH:10][N:11]=[C:6]2[CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.ClC(OC)=O.[F:28][C:29]1[CH:35]=[CH:34][C:32]([NH2:33])=[CH:31][CH:30]=1>C(Cl)(Cl)Cl>[F:28][C:29]1[CH:35]=[CH:34][C:32]([NH:33][C:12]([C:9]2[C:8](=[O:15])[N:7]3[C:2]([CH3:1])=[CH:3][CH:4]=[CH:5][C:6]3=[N:11][CH:10]=2)=[O:14])=[CH:31][CH:30]=1
Reactant: Cc1cccc2ncc(C(=O)O)c(=O)n12
Reactant: Nc1ccc(F)cc1
Agent: COC(=O)Cl
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: Cc1cccc2ncc(C(=O)Nc3ccc(F)cc3)c(=O)n12
Reaction time: 0.08 h
Yield: 76.9 %

Procedure:
A mixture containing 16.32 g (0.08 mol) of 6-methyl-4-oxo-4H-pyrido[1,2-a]pyrimidine-3-carboxylic acid and 12.4 ml (0.088 mol) of triethylamine in 480 ml of chloroform is cooled below -10° C. by ice-salt. A solution of 6.5 ml (0.08 mol) of methyl chloroformate in 40 ml of chloroform is dropped to the above mixture at a temperature between -12° C. and -17° C. during 25 minutes. After stirring for 5 minutes, 9.78 g (0.088 mol) of 4-fluoroaniline dissolved in 80 ml of chloroform are dropped to the above solution at -13° C. during 30 minutes. The reaction mixture is stirred below -10° C. for 1 hour, then allowed to stand overnight under cooling by ice. For working up, the reaction mixture is washed 3 times with 150 ml of 5% sodium hydrogen carbonate solution each and then 3 times with 150 ml of water each. The organic phase is dried over anhydrous sodium sulfate, filtered and evaporated to give 18.3 g (77%) of the named compound as yellow crystals after recrystallization from n-propanol, m.p.: 202°-204° C.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][CH2:10][N:11]2[CH:15]=[CH:14][N:13]=[CH:12]2)=[CH:4][CH:3]=1.Cl[CH2:17][C:18]1[N:19]=[C:20](/[CH:23]=[CH:24]/[C:25]2[S:26][CH:27]=[CH:28][CH:29]=2)[O:21][CH:22]=1>>[N:11]1([CH2:10][CH2:9][CH2:8][C:5]2[CH:6]=[CH:7][C:2]([O:1][CH2:17][C:18]3[N:19]=[C:20](/[CH:23]=[CH:24]/[C:25]4[S:26][CH:27]=[CH:28][CH:29]=4)[O:21][CH:22]=3)=[CH:3][CH:4]=2)[CH:15]=[CH:14][N:13]=[CH:12]1
Reactant: ClCc1coc(/C=C/c2cccs2)n1
Reactant: Oc1ccc(CCCn2ccnc2)cc1
Product: C(=C/c1cccs1)\c1nc(COc2ccc(CCCn3ccnc3)cc2)co1
Yield: 92 %

Procedure:
In substantially the same manner as in Working Example 72, 1-[3-(4-hydroxyphenyl)propyl]imidazole was allowed to react with 4-chloromethyl-2-[(E)-2-(2-thienyl)ethenyl]oxazole to give 4-[4-[3-(1-imidazolyl)propyl]phenoxymethyl]-2-[(E)-2-(2-thienyl)ethenyl]oxazole. The yield was 92%. Recrystallization from ethyl acetate-isopropyl ether gave colorless prisms, mp 131-132° C.
Reaction SMILES: [F:1][C:2]([F:18])([F:17])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[O:13][N:12]=[CH:11][C:10]=2[C:14]([OH:16])=O)=[CH:5][CH:4]=1.[CH3:19][O:20][CH2:21][C@H:22]1[CH2:26][CH2:25][CH2:24][NH:23]1>>[CH3:19][O:20][CH2:21][C@H:22]1[CH2:26][CH2:25][CH2:24][N:23]1[C:14]([C:10]1[CH:11]=[N:12][O:13][C:9]=1[C:6]1[CH:5]=[CH:4][C:3]([C:2]([F:1])([F:18])[F:17])=[CH:8][CH:7]=1)=[O:16]
Reactant: O=C(O)c1cnoc1-c1ccc(C(F)(F)F)cc1
Reactant: COC[C@H]1CCCN1
Product: COC[C@H]1CCCN1C(=O)c1cnoc1-c1ccc(C(F)(F)F)cc1

Procedure:
The title compound was prepared from 5-(4-trifluoromethylphenyl)isoxazole-4-carboxylic acid (12.9 mg, 0.050 mmol) and (R)-2-methoxymethyl-pyrrolidine (6.9 mg, 0.060 mmol) as described in synthetic method C and thereafter purified by preparative HPLC method B to give a solid (10.1 mg). Calcd for C17H17F3N2O3: 354.1191, found 354.1190.
Reaction SMILES: [ClH:1].[N:2]12[CH2:11][CH:6]3[CH2:7][CH:8]([CH2:10][CH:4]([C@H:5]3[NH2:12])[CH2:3]1)[CH2:9]2.[CH3:13][C:14]1[S:15][CH:16]=[C:17]([C:19]2[S:23][C:22]([C:24](O)=[O:25])=[CH:21][CH:20]=2)[N:18]=1.N>>[ClH:1].[N:2]12[CH2:11][CH:6]3[CH2:7][CH:8]([CH2:10][CH:4]([C@H:5]3[NH:12][C:24]([C:22]3[S:23][C:19]([C:17]4[N:18]=[C:14]([CH3:13])[S:15][CH:16]=4)=[CH:20][CH:21]=3)=[O:25])[CH2:3]1)[CH2:9]2
Reactant: Cc1nc(-c2ccc(C(=O)O)s2)cs1
Reactant: NC1C2CC3CC1CN(C3)C2
Agent: Cl
Agent: N
Product: Cc1nc(-c2ccc(C(=O)NC3C4CC5CC3CN(C5)C4)s2)cs1

Procedure:
Prepared from (4r)-1-azatricyclo[3.3.1.13,7]dec-4-ylamine hydrochloride and 5-(2-methylthiazol-4-yl)thiophene-2-carboxylic acid according to methods A and C. 1H NMR (300 MHz, methanol-d4) δ ppm 2.08-2.34 (m, 5H), 2.51 (s, 2H), 2.74 (s, 3H), 3.42-3.64 (m, 4H), 3.88 (d, J=12.5 Hz, 2H), 4.33 (s, 1H), 7.49 (d, J=4.1 Hz, 1H), 7.68 (s, 1 H), 7.79 (d, J=4.1 Hz, 1H). MS (DCI/NH3) m/z 360.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([C:19](=[O:21])[CH3:20])[CH:8]=[C:9]([N:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)[C:10]=1[O:11][CH3:12])([CH3:4])([CH3:3])[CH3:2].[Br:22]N1C(=O)CCC1=O.CCOCC>O1CCCC1.C(N(CC)CC)C>[Br:22][CH2:20][C:19]([C:7]1[CH:8]=[C:9]([N:13]2[CH2:14][CH2:15][O:16][CH2:17][CH2:18]2)[C:10]([O:11][CH3:12])=[C:5]([C:1]([CH3:4])([CH3:2])[CH3:3])[CH:6]=1)=[O:21]
Reactant: O=C1CCC(=O)N1Br
Reactant: COc1c(N2CCOCC2)cc(C(C)=O)cc1C(C)(C)C
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Solvent: CCOCC
Product: COc1c(N2CCOCC2)cc(C(=O)CBr)cc1C(C)(C)C
Reaction time: 0.5 h
Yield: 34.9 %

Procedure:
After dissolving the 1-[3-(tert-butyl)-4-methoxy-5-morpholinophenyl]-1-ethanone (76 g) in tetrahydrofuran (600 ml), triethylamine (110 ml) and tert-butyl dimethylsilyltrifluoromethanesulfonate (75 ml) was added dropwise while cooling on ice. The reaction mixture was stirred for 30 minutes while cooling on ice and then N-bromosuccinimide (70 g) was gradually added. After stirring the reaction mixture for 30 minutes, 2 l of ether was added and the mixture was washed twice with water. The organic layer was dried over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure and the residue was purified by silica gel column chromatography (solvent: n-hexane-ethyl acetate) to yield the title compound (33.7 g) as light yellow crystals.
Reaction SMILES: [NH2:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH2:11][CH2:12]/[CH:13]=[CH:14]/[P:15]([O:21]C(C)C)([O:17]C(C)C)=[O:16])=[C:4]([NH2:25])[N:3]=1.Br[Si](C)(C)C>ClCCl.CN(C)C=O>[NH2:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH2:11][CH2:12]/[CH:13]=[CH:14]/[P:15]([OH:21])([OH:17])=[O:16])=[C:4]([NH2:25])[N:3]=1
Reactant: CC(C)OP(=O)(/C=C/CCn1cnc2c(N)nc(N)nc21)OC(C)C
Agent: C[Si](C)(C)Br
Solvent: ClCCl
Solvent: CN(C)C=O
Product: Nc1nc(N)c2ncn(CC/C=C/P(=O)(O)O)c2n1
Temperature: 25 °C
Reaction time: 18 h
Yield: 27 %

Procedure:
To a solution of (E)-2,6-diamino-9-[4-(diisopropoxy-phosphoryl)but-3-enyl]purine (144mg, 391 μmol) in dichloromethane (10 ml) was added bromotrimethylsilane (1.20 g, 7.82 mmol) and the mixture stirred at room temperature under dry nitrogen for 18 hr. The resulting white suspension was evaporated to dryness and the residue azeotroped with methanol (×6). The residue was purified by column chromatography on reverse phase silica gel eluting with water to give a product which n.m.r. analysis showed to be the monoester. To a suspension of the monoester (approx. 306 μmol) in dry N,N-dimethylformamide (10 ml) was added bromotrimethylsilane (1.16 g, 7.58 mmol) and the resulting solution was stirred at room temperature under dry nitrogen for 18 hr. The solution was evaporated to dryness and the residue azeotroped with methanol (×3) then acetone-water (1:1) (×3). The residue was purified by column chromatography on reverse phase silica gel eluting with water to give (E)-2,6-diamino-9-(4-phosphonobut-3 -enyl)purine as a white solid (30 mg, 27%), m.p. >325° C.; λmax (MeOH) 256 (6,570) and 285 (6,490)nm; υmax (KBr) 3410, 1710, 1670, 1630, 1590, 1420, 1220 and 135 cm-1 ; δH [(CD3)2SO+one drop NH4OH solution] 2.50 (2H, m, CH2) 4.05 (2H, t, J 7 Hz, CH2N), 5.70 (1H, pseudo-t, J 17 Hz, PCH=CH), 5.81 (2H, s, NH2), 6.10 (1H, pseudo-tt, J 7 Hz and 20 Hz, PCH=CH), 6.69 (2H, s, NH2) , 7.76 (1H, s, H-8); FABMS thioglycerol) 285 (MH+).
Reaction SMILES: C[O:2][C:3](=[O:22])[CH:4]([C:11]1[CH:16]=[CH:15][C:14]([S:17]([CH3:20])(=[O:19])=[O:18])=[C:13]([Cl:21])[CH:12]=1)[CH2:5][CH:6]1[CH2:10][CH2:9][O:8][CH2:7]1.O.[OH-].[Li+]>CO.O>[Cl:21][C:13]1[CH:12]=[C:11]([CH:4]([CH2:5][CH:6]2[CH2:10][CH2:9][O:8][CH2:7]2)[C:3]([OH:22])=[O:2])[CH:16]=[CH:15][C:14]=1[S:17]([CH3:20])(=[O:19])=[O:18]
Reactant: COC(=O)C(CC1CCOC1)c1ccc(S(C)(=O)=O)c(Cl)c1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CS(=O)(=O)c1ccc(C(CC2CCOC2)C(=O)O)cc1Cl
Temperature: 25 °C
Reaction time: 2 h
Yield: 83.4 %

Procedure:
2-(3-Chloro-4-methanesulfonyl-phenyl)-3-(tetrahydro-furan-3-yl)-propionic acid methyl ester (0.85 g, 2.45 mmol) was dissolved in methanol (10 ml) and treated with a solution of lithium hydroxide monohydrate (0.51 g, 12.15 mmol) in water (1 ml) at 25° C. It was stirred at 25° C. for 2 h or until the starting material was all consumed by TLC. The reaction was then concentrated in vacuo to remove the methanol. The remaining aqueous layer was then diluted with water and acidified to pH=2 with an aqueous 1N hydrochloric acid solution. This was then extracted with methylene chloride (2×50 mL). The organic layers were combined and dried over magnesium sulfate, filtered and concentrated in vacuo to afford 2-(3-chloro-4-methanesulfonyl-phenyl)-3-(tetrahydro-furan-3-yl)-propionic acid (0.68 g, 84%) as a white solid: 1H NMR (300 MHz, DMSO-d6) δ ppm 1.41-1.56 (m, 1H, CH of CH2), 1.74-2.12 (m, 4H, CH and 3×CH of 2×CH2), 3.16-3.30 (m, 1H, OCH of OCH2), 3.37 (s, 3H, SO2CH3), 3.51-3.79 (m, 4H, ArCH and 3×OCH of 2×OCH2), 7.57 (2×dd, Jo=8.3 Hz, Jm=1.7 Hz, 1H, Ar), 7.71 (2×d, Jm=1.7 Hz, 1H, Ar), 8.00 (2×d, Jo=8.3 Hz, 1H, Ar), 12.76 (brs, 1H, CO2H).
Reaction SMILES: C(OC(=O)[NH:10][C:11]1([C:18]2[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=2)[CH2:16][CH2:15][CH:14]([OH:17])[CH2:13][CH2:12]1)C1C=CC=CC=1>CO.[Pd]>[NH2:10][C:11]1([C:18]2[CH:19]=[CH:20][C:21]([F:24])=[CH:22][CH:23]=2)[CH2:16][CH2:15][CH:14]([OH:17])[CH2:13][CH2:12]1
Reactant: O=C(NC1(c2ccc(F)cc2)CCC(O)CC1)OCc1ccccc1
Agent: [Pd]
Solvent: CO
Product: NC1(c2ccc(F)cc2)CCC(O)CC1
Yield: 95.2 %

Procedure:
0.5 g of [1-(4-Fluoro-phenyl)-4-hydroxy-cyclohexyl]-carbamic acid benzyl ester (78) were dissolved in 50 mL of methanol and 57 mg of palladium on charcoal (10%) were added. The mixture was stirred under a hydrogen atmosphere until conversion was complete. The catalyst was filtered off and the organic layer was evaporated to dryness to give 290 mg of the desired product. Rt=0.73 min (Method E). Detected mass: 175.2 (M+H—H2O—NH3+).
Reaction SMILES: [CH3:1][C:2]1[S:3][CH:4]=[C:5]([C:7]([N:9]2[CH2:27][CH2:26][C:13]3([CH2:18][CH2:17][N:16](C(OC(C)(C)C)=O)[CH2:15][CH2:14]3)[O:12][CH2:11][CH2:10]2)=[O:8])[N:6]=1.[F:28][C:29]([F:34])([F:33])[C:30]([OH:32])=[O:31].C1(C)C=CC=CC=1>C(Cl)Cl>[F:28][C:29]([F:34])([F:33])[C:30]([OH:32])=[O:31].[CH3:1][C:2]1[S:3][CH:4]=[C:5]([C:7]([N:9]2[CH2:27][CH2:26][C:13]3([CH2:18][CH2:17][NH:16][CH2:15][CH2:14]3)[O:12][CH2:11][CH2:10]2)=[O:8])[N:6]=1
Reactant: Cc1nc(C(=O)N2CCOC3(CCN(C(=O)OC(C)(C)C)CC3)CC2)cs1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Solvent: Cc1ccccc1
Product: Cc1nc(C(=O)N2CCOC3(CCNCC3)CC2)cs1
Reaction time: 0.42 h

Procedure:
A solution of tert-butyl 10-(2-methylthiazole-4-carbonyl)-7-oxa-3,10-diazaspiro[5.6]dodecane-3-carboxylate (example 89, step f) (0.21 g) in DCM (10 mL) was treated with trifluoroacetic acid (10 mL) and the solution allowed to stand at 20° C. for 25 minutes. Toluene (40 mL) was added and the solvents evaporated under reduced pressure. The residue was azeotroped with acetonitrile to afford the subtitled compound. Yield 0.21 g.
Reaction SMILES: Cl.[CH2:2]([NH:8][CH2:9][CH2:10][C:11]([O:13]C)=[O:12])[CH2:3][CH2:4][CH2:5][CH2:6][CH3:7]>Cl>[CH2:2]([NH:8][CH2:9][CH2:10][C:11]([OH:13])=[O:12])[CH2:3][CH2:4][CH2:5][CH2:6][CH3:7]
Reactant: CCCCCCNCCC(=O)OC
Agent: Cl
Product: CCCCCCNCCC(=O)O

Procedure:
Methyl 3-(1-hexylamino)propionate hydrochloride (see Example 2 for preparation) was hydrolyzed by refluxing in 2N HCl for 24 hours followed by evaporation to dryness; m.p.=95-97° C. (no lit. value).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[OH:9].C(=O)([O-])[O-].[Cs+].[Cs+].F[C:17]1[C:18]([O:35][C:36]2[CH:37]=[N:38][C:39]([S:42]([CH3:45])(=[O:44])=[O:43])=[CH:40][CH:41]=2)=[CH:19][C:20]([N+:32]([O-])=O)=[C:21]([NH:23][C:24]([C:26]2[CH:31]=[N:30][CH:29]=[CH:28][N:27]=2)=O)[CH:22]=1.O.O.[Sn](Cl)Cl.C(=O)(O)[O-].[Na+]>C(OCC)(=O)C.CN1CCCC1=O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[O:9][C:17]1[C:18]([O:35][C:36]2[CH:37]=[N:38][C:39]([S:42]([CH3:45])(=[O:44])=[O:43])=[CH:40][CH:41]=2)=[CH:19][C:20]2[NH:32][C:24]([C:26]3[CH:31]=[N:30][CH:29]=[CH:28][N:27]=3)=[N:23][C:21]=2[CH:22]=1
Reactant: CS(=O)(=O)c1ccc(Oc2cc([N+](=O)[O-])c(NC(=O)c3cnccn3)cc2F)cn1
Reactant: Oc1cc(F)ccc1F
Agent: Cl[Sn]Cl
Agent: O=C([O-])O
Agent: O=C([O-])[O-]
Solvent: CN1CCCC1=O
Solvent: O
Solvent: CCOC(C)=O
Product: CS(=O)(=O)c1ccc(Oc2cc3[nH]c(-c4cnccn4)nc3cc2Oc2cc(F)ccc2F)cn1
Temperature: 90 °C
Reaction time: 0.25 h

Procedure:
15 mg of 2,5-difluoro-phenol and 28 mg of cesium carbonate were added to an N-methylpyrrolidinone (0.5 ml) solution of 26 mg of pyrazine-2-carboxylic acid (5-fluoro-4-(6-methanesulfonyl-pyridin-3-yloxy)-2-nitro-phenyl)-amide obtained in (step 1), and the reaction liquid was stirred at 90° C. for 15 minutes, and 100 mg of tin(II) chloride dihydrate was added to the reaction liquid. The reaction liquid was stirred at 90° C. for 1 hour, and ethyl acetate and aqueous saturated sodium bicarbonate were added to it. The deposit was removed through filtration, the solvent was evaporated away under reduced pressure, and the residue was purified through reversed-phase middle-pressure liquid chromatography [ODS-AS-360-CC (by YMC), mobile phase: water-acetonitrile-0.1% trifluoroacetic acid]. The solvent of the resulting fraction was diluted with ethyl acetate, washed with aqueous saturated sodium bicarbonate, and dried with anhydrous sodium sulfate. The solvent was evaporated away under reduced pressure to obtain the entitled compound as a pale yellow solid.
Reaction SMILES: [CH3:1][C:2]1[C:6]2=[N:7][CH:8]=[C:9]([C:11]([F:14])([F:13])[F:12])[CH:10]=[C:5]2[S:4][C:3]=1[C:15](OCC)=[O:16].[Cl-].[Ca+2].[Cl-].[BH4-].[Na+].[Cl-].[NH4+]>O1CCCC1.[O-2].[O-2].[Mn+4].C(O)C>[CH3:1][C:2]1[C:6]2=[N:7][CH:8]=[C:9]([C:11]([F:14])([F:13])[F:12])[CH:10]=[C:5]2[S:4][C:3]=1[CH:15]=[O:16]
Reactant: CCOC(=O)c1sc2cc(C(F)(F)F)cnc2c1C
Agent: [Mn+4]
Agent: [BH4-]
Agent: [Ca+2]
Solvent: CCO
Solvent: C1CCOC1
Product: Cc1c(C=O)sc2cc(C(F)(F)F)cnc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 92.1 %

Procedure:
To a mixture of ethyl 3-methyl-6-(trifluoromethyl)thieno[3,2-b]pyridine-2-carboxylate (3.69 g) synthesized above, calcium chloride (2.84 g), ethanol (40 mL) and tetrahydrofuran (40 mL) was added sodium borohydride (1.94 g) at 0° C., and the mixture was stirred overnight at room temperature. Saturated aqueous ammonium chloride solution was added to quench the reaction, and the reaction mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure to give a white solid. To a solution (60 mL) of the obtained solid in tetrahydrofuran was added active manganese dioxide (16.3 g), and the mixture was stirred at 50° C. for 5 hr. Manganese dioxide was filtered off, and the filtrate was concentrated under reduced pressure to give the title object compound (2.88 g, 92%) as a white solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:21]=[CH:22][C:23]=1[O:24][CH2:25][C:26]1[N:27]=[C:28]([N:32]2[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]2)[S:29][C:30]=1[CH3:31])[CH2:6][O:7][C:8]1[C:12]([CH:13]=O)=[CH:11][N:10]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[N:9]=1.[CH2:38](P(=O)(OCC)OCC)[P:39](=[O:46])([O:43][CH2:44][CH3:45])[O:40][CH2:41][CH3:42].CN(C)C=O.[H-].[Na+]>O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:21]=[CH:22][C:23]=1[O:24][CH2:25][C:26]1[N:27]=[C:28]([N:32]2[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]2)[S:29][C:30]=1[CH3:31])[CH2:6][O:7][C:8]1[C:12](/[CH:13]=[CH:38]/[P:39](=[O:46])([O:43][CH2:44][CH3:45])[O:40][CH2:41][CH3:42])=[CH:11][N:10]([C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)[N:9]=1
Reactant: COc1cc(COc2nn(-c3ccccc3)cc2C=O)ccc1OCc1nc(N2CCCCC2)sc1C
Reactant: CCOP(=O)(CP(=O)(OCC)OCC)OCC
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOP(=O)(/C=C/c1cn(-c2ccccc2)nc1OCc1ccc(OCc2nc(N3CCCCC3)sc2C)c(OC)c1)OCC
Reaction time: 15 h
Yield: 58.3 %

Procedure:
To a mixture of 3-[(3-methoxy-4-{[5-methyl-2-(piperidin-1-yl)-1,3-thiazol-4-yl]methoxy}benzyl)oxy]-1-phenyl-1H-pyrazole-4-carbaldehyde (0.15 g), tetraethyl methylenediphosphonate (0.09 g) and N,N-dimethylformamide (5 mL) was added sodium hydride (60% in oil, 0.015 g) at room temperature, and the mixture was stirred at the same temperature for 15 hrs. Water was poured into the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated. The residue was subjected to silica gel column chromatography to give diethyl (E)-2-{3-[(3-methoxy-4-{[5-methyl-2-(piperidin-1-yl)-1,3-thiazol-4-yl]methoxy}benzyl)oxy]-1-phenyl-1H-pyrazol-4-yl}ethenylphosphonate as colorless crystals (0.11 g, yield 58%) from a fraction eluted with ethyl acetate-hexane (4:1, v/v). Recrystallization from ethyl acetate-hexane gave colorless prism crystals. melting point: 95-96° C.
Reaction SMILES: Br[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([Cl:12])[CH:10]=2)[C:5](=[O:13])[O:4][C:3]=1[CH:14]([OH:16])[CH3:15].[C:17]1(B(O)O)[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>>[Cl:12][C:9]1[CH:10]=[C:11]2[C:6](=[CH:7][CH:8]=1)[C:5](=[O:13])[O:4][C:3]([CH:14]([OH:16])[CH3:15])=[C:2]2[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: OB(O)c1ccccc1
Reactant: CC(O)c1oc(=O)c2ccc(Cl)cc2c1Br
Product: CC(O)c1oc(=O)c2ccc(Cl)cc2c1-c1ccccc1
Yield: 44.6 %

Procedure:
The title compound was made in a similar way of that of Intermediate B53 from 4-bromo-6-chloro-3-(1-hydroxyethyl)-1H-isochromen-1-one (intermediate A6, 0.973 g, 3.205 mmol) and phenylboronic acid (0.586 g, 4.808 mmol) to yield title compound as a white foam (0.430 g, 1.43 mmol, 45%).