Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O:2][C:3](=O)[N:4]([CH2:18][C:19]1[CH:24]=[CH:23][C:22]([C:25]#[N:26])=[CH:21][CH:20]=1)[C:5]1[CH:10]=[N:9][C:8]([CH3:11])=[C:7]2[O:12]C(C)(C)[O:14][CH2:15][C:6]=12.C(O)=O>C(O)C>[OH:12][C:7]1[C:6]2[CH2:15][O:14][C:3](=[O:2])[N:4]([CH2:18][C:19]3[CH:24]=[CH:23][C:22]([C:25]#[N:26])=[CH:21][CH:20]=3)[C:5]=2[CH:10]=[N:9][C:8]=1[CH3:11]
Reactant: COC(=O)N(Cc1ccc(C#N)cc1)c1cnc(C)c2c1COC(C)(C)O2
Solvent: O=CO
Solvent: CCO
Product: Cc1ncc2c(c1O)COC(=O)N2Cc1ccc(C#N)cc1
Yield: 68.2 %

Procedure:
The hydrolysis of (4-cyano-benzyl)-(2,2,8-trimethyl-4H-[1,3]dioxino[4,5-c]pyridin-5-yl)-carbamic acid methyl ester (81) (5.1 g, 13.9 mmol) and subsequent cyclization was achieved by heating 81 in a 1:1 mixture of aqueous formic acid (20%) and ethyl alcohol at 80° C. for 2 hours. The evaporation of solvent, followed by the addition of water precipitated the product 4-(5-hydroxy-6-methyl-2-oxo-4H-pyrido[3,4-d][1,3]oxazin-1-ylmethyl)-benzonitrile (82) (2.8 g, 74% yield).
Reaction SMILES: I([O-])(=O)(=O)=[O:2].[Na+].[CH3:7][C:8]([CH3:41])([CH2:39][CH3:40])[CH2:9][C:10]1[N:11]=[C:12]([C:21]([OH:38])([CH3:37])[CH2:22][C:23]2[CH:28]=[CH:27][C:26]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=3[S:35][CH3:36])=[CH:25][CH:24]=2)[N:13]([S:15]([N:18]([CH3:20])[CH3:19])(=[O:17])=[O:16])[CH:14]=1>C(O)C.O>[CH3:7][C:8]([CH3:41])([CH2:39][CH3:40])[CH2:9][C:10]1[N:11]=[C:12]([C:21]([OH:38])([CH3:37])[CH2:22][C:23]2[CH:24]=[CH:25][C:26]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=3[S:35]([CH3:36])=[O:2])=[CH:27][CH:28]=2)[N:13]([S:15]([N:18]([CH3:19])[CH3:20])(=[O:16])=[O:17])[CH:14]=1
Reactant: CCC(C)(C)Cc1cn(S(=O)(=O)N(C)C)c(C(C)(O)Cc2ccc(-c3ccccc3SC)cc2)n1
Reactant: [O-][I+3]([O-])([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: CCC(C)(C)Cc1cn(S(=O)(=O)N(C)C)c(C(C)(O)Cc2ccc(-c3ccccc3S(C)=O)cc2)n1
Temperature: 25 °C

Procedure:
Sodium periodate (40 mg, 0.19 mmol) was added to an ambient temperature solution of 4-(2,2-dimethylbutyl)-2-{1-hydroxy-1-methyl-2-[2′-(methylthio)biphenyl-4-yl]ethyl}-N,N-dimethyl-1H-imidazole-1-sulfonamide (65 mg, 0.13 mmol) in ethanol/water (1:1) (5 mL). After stirring at ambient temperature until no further reaction (LCMS), the reaction mixture was quenched with saturated aqueous sodium thiosulfate and extracted with methylene chloride. Combined extracts were dried (magnesium sulfate) and concentrated in vacuo. Chromatography over silica eluting with 0-30% acetone/methylene chloride afforded 4-(2,2-dimethylbutyl)-2-{1-hydroxy-1-methyl-2-[2′-(methylsulfinyl)biphenyl-4-yl]ethyl}-N,N-dimethyl-1H-imidazole-1-sulfonamide.
Reaction SMILES: [NH:1]=[C:2]1[CH2:7][CH2:6][CH2:5][CH2:4][N:3]1[CH3:8].[Cl:9][C:10]1[CH:15]=[CH:14][C:13]([N:16]=[C:17]=[O:18])=[CH:12][CH:11]=1>C1C=CC=CC=1>[Cl:9][C:10]1[CH:15]=[CH:14][C:13]([NH:16][C:17]([N:1]=[C:2]2[CH2:7][CH2:6][CH2:5][CH2:4][N:3]2[CH3:8])=[O:18])=[CH:12][CH:11]=1
Reactant: CN1CCCCC1=N
Reactant: O=C=Nc1ccc(Cl)cc1
Solvent: c1ccccc1
Product: CN1CCCCC1=NC(=O)Nc1ccc(Cl)cc1
Reaction time: 6 h

Procedure:
The hydrochloride salt of 2-imino-1-methylpiperidine (7.43 g.; 0.05 mole) is converted to the free base in benzene in the usual manner. After drying over K 2 CO 3 and filtering, a benzene solution of 0.05 mole of p-chlorophenylisocvanate is added dropwise with stirring. After addition is complete, further stirring is continued for about 6 hours at room temperature. The benzene is evaporated in vacuo and the solid residue is recrystallized from methanol to give the product, 1-(4-chlorophenyl)- 3-(1-methyl-2-piperidylidene)urea.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([N:18]2[CH2:23][CH2:22][O:21][CH2:20][CH2:19]2)[C:5]2[S:10][C:9]([C:11]3[CH:12]=[C:13]([NH2:17])[CH:14]=[CH:15][CH:16]=3)=[CH:8][C:6]=2[N:7]=1.[C:24]([NH:31][CH2:32][C:33](O)=[O:34])([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25]>>[C:27]([O:26][C:24](=[O:25])[NH:31][CH2:32][C:33](=[O:34])[NH:17][C:13]1[CH:14]=[CH:15][CH:16]=[C:11]([C:9]2[S:10][C:5]3[C:4]([N:18]4[CH2:23][CH2:22][O:21][CH2:20][CH2:19]4)=[N:3][C:2]([Cl:1])=[N:7][C:6]=3[CH:8]=2)[CH:12]=1)([CH3:30])([CH3:28])[CH3:29]
Reactant: Nc1cccc(-c2cc3nc(Cl)nc(N4CCOCC4)c3s2)c1
Reactant: CC(C)(C)OC(=O)NCC(=O)O
Product: CC(C)(C)OC(=O)NCC(=O)Nc1cccc(-c2cc3nc(Cl)nc(N4CCOCC4)c3s2)c1

Procedure:
3-(2-Chloro-4-morpholinothieno[3,2-d]pyrimidin-6-yl)benzenamine (50 mg) was reacted with Boc-glycine via General Procedure I to give tert-butyl(3-(2-chloro-4-morpholinothieno[3,2-d]pyrimidin-6-yl)phenylcarbamoyl)methylcarbamate. 70 mg of the crude tert-butyl (3-(2-chloro-4-morpholinothieno[3,2-d]pyrimidin-6-yl)phenylcarbamoyl)methylcarbamate was coupled to 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indazole 7 via General Procedure A to yield tert-butyl(3-(2-(1H-indazol-4-yl)-4-morpholinothieno[3,2-d]pyrimidin-6-yl)phenylcarbamoyl)methylcarbamate.
Reaction SMILES: [C:1]([CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(O)CO.[C:19]1(C)[CH:24]=[CH:23]C=[CH:21][CH:20]=1>>[O:8]=[C:1]([CH:2]1[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1)[CH2:9][C:10]([O:12][CH2:13][C:14]1[CH:23]=[CH:24][CH:19]=[CH:20][CH:21]=1)=[O:11]
Reactant: CCOC(=O)CC(=O)c1ccccc1
Reactant: Cc1ccccc1
Solvent: OCCO
Product: O=C(CC(=O)C1CCCCC1)OCc1ccccc1
Reaction time: 24 h
Yield: 45 %

Procedure:
To prepare compound 79u, a transesterification reaction shown schematically in FIG. 10 was used. Ethyl benzoylacetate (1.92 g, 10 mmol) and ethylene glycol (0.621 g, 10 mmol) in toluene (10 mL) were heated with stirring for 24 h. The solvent was removed, and the residue was chromatographed (silica 60, petroleum ether-ethyl acetate (3:1)) to give 0.946 g of the desired product, yield: 45%. The 1HNMR data are set forth below.
Reaction SMILES: [C:1]1([C:7]2[C:11]3[C:12](=[O:16])[CH2:13][CH2:14][CH2:15][C:10]=3[O:9][N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C([N-]C(C)C)(C)C.[Li+].Br[CH2:26][C:27]([O:29][CH2:30][CH3:31])=[O:28].O>O1CCCC1.CCOCC>[CH2:30]([O:29][C:27](=[O:28])[CH2:26][CH:13]1[C:12](=[O:16])[C:11]2[C:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)=[N:8][O:9][C:10]=2[CH2:15][CH2:14]1)[CH3:31]
Reactant: CCOC(=O)CBr
Reactant: O=C1CCCc2onc(-c3ccccc3)c21
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CCOCC
Solvent: O
Product: CCOC(=O)CC1CCc2onc(-c3ccccc3)c2C1=O
Temperature: -78 °C

Procedure:
In 115 ml anhydrous tetrahydrofuran was dissolved 2.44 g of 6,7-dihydro-3-phenyl-1,2-benzisoxazol-4(5H)-one under nitrogen. The solution was cooled to -78° C. and 11.5 ml lithium diisopropylamide was added dropwise. The resultant solution was sniffed for 15 minutes at -78° C. and ethyl bromoacetate (2.6 ml) was added. Upon warming to room temperature, the reaction mixture was poured into water and ether. The layers were separated and the aqueous phase was extracted three times with dichloromethane and once with ether. The combined organic layers were washed with brine and dried (MgSO4). Flash column chromatography (30% ethyl acetate/hexane) gave 2.94 g of 4,5,6,7-tetrahydro-4-oxo-3-phenyl-1,2-benzisoxazol-5-acetic acid ethyl ester
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:10]=[CH:9][C:6]([CH2:7]Cl)=[CH:5][CH:4]=1.[F:11][C:12]1[CH:13]=[C:14]2[C:19](=[CH:20][CH:21]=1)[C:18](=[O:22])[NH:17][CH:16]=[CH:15]2.C([O-])([O-])=O.[Cs+].[Cs+]>CN(C=O)C>[F:11][C:12]1[CH:13]=[C:14]2[C:19](=[CH:20][CH:21]=1)[C:18](=[O:22])[N:17]([CH2:7][C:6]1[CH:9]=[CH:10][C:3]([O:2][CH3:1])=[CH:4][CH:5]=1)[CH:16]=[CH:15]2
Reactant: O=c1[nH]ccc2cc(F)ccc12
Reactant: COc1ccc(CCl)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: COc1ccc(Cn2ccc3cc(F)ccc3c2=O)cc1
Reaction time: 2 h
Yield: 93.7 %

Procedure:
169 μL of p-methoxybenzylchloride (1.24 mmol, 1.1 eq) were added to a suspension of 200 mg of 6-fluoro-isoquinolinone (13) (1.13 mmol) and 368 mg of Cs2CO3 (1.36 mmol, 1.2 eq) in 3 mL of DMF. The mixture was stirred for 2 h and then poured on ice. The precipitate was filtered, washed with water and dried to yield 300 mg of the title compound. LCMS Method B, retention time 1.76 min, detected mass 284.14 [M+H]+
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[CH2:13][CH2:12][O:11][C:10]2=[O:14])=[CH:5][CH:4]=1>[Rh].C(O)C>[CH3:1][O:2][CH:3]1[CH2:4][CH2:5][CH:6]([CH:9]2[CH2:13][CH2:12][O:11][C:10]2=[O:14])[CH2:7][CH2:8]1
Reactant: COc1ccc(C2CCOC2=O)cc1
Agent: [Rh]
Solvent: CCO
Product: COC1CCC(C2CCOC2=O)CC1
Yield: 91 %

Procedure:
Stir a mixture of 3-(4-methoxyphenyl)-dihydro-furan-2-one (0.98 g), rhodium on carbone (5%, 0.98 g) and ethanol (50 mL) on a hydrogenation parr shaker at 60 psi, 60° C. for 18 hours. Remove the reaction from the parr shaker and filter the mixture through celite, concentrate the filtrate to afford 0.92 g (90%) of the title compound.
Reaction SMILES: OC(C(F)(F)F)=O.[NH:8]1[CH2:11][CH:10]([NH:12][C:13](=[O:34])[CH2:14][NH:15][C:16]2[C:24]3[C:19](=[CH:20][CH:21]=[C:22]([C:25]([F:32])([O:30][CH3:31])[C:26]([F:29])([F:28])[F:27])[CH:23]=3)[N:18]([CH3:33])[N:17]=2)[CH2:9]1.[OH:35][C:36]1([C:43]2[CH:44]=[N:45][C:46]([CH3:49])=[CH:47][CH:48]=2)[CH2:41][CH2:40][C:39](=O)[CH2:38][CH2:37]1>>[OH:35][C:36]1([C:43]2[CH:44]=[N:45][C:46]([CH3:49])=[CH:47][CH:48]=2)[CH2:37][CH2:38][CH:39]([N:8]2[CH2:9][CH:10]([NH:12][C:13](=[O:34])[CH2:14][NH:15][C:16]3[C:24]4[C:19](=[CH:20][CH:21]=[C:22]([C:25]([F:32])([O:30][CH3:31])[C:26]([F:29])([F:27])[F:28])[CH:23]=4)[N:18]([CH3:33])[N:17]=3)[CH2:11]2)[CH2:40][CH2:41]1
Reactant: COC(F)(c1ccc2c(c1)c(NCC(=O)NC1CNC1)nn2C)C(F)(F)F
Reactant: Cc1ccc(C2(O)CCC(=O)CC2)cn1
Solvent: O=C(O)C(F)(F)F
Product: COC(F)(c1ccc2c(c1)c(NCC(=O)NC1CN(C3CCC(O)(c4ccc(C)nc4)CC3)C1)nn2C)C(F)(F)F

Procedure:
The title compound was prepared as a white solid from reaction of a N-azetidin-3-yl-2-[1-methyl-5-(1,2,2,2-tetrafluoro-1-methoxy-ethyl)-1H-indazol-3-ylamino]-acetamide TFA salt and 4-hydroxy-4-(6-methyl-pyridin-3-yl)-cyclohexanone using the procedure described in Step E of Example 1.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][CH2:12][CH2:13][C@H:14]([OH:18])[C:15]([OH:17])=[O:16])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.N1C=CC=CC=1.[C:25](Cl)(=[O:32])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>C1COCC1.CN(C1C=CN=CC=1)C>[C:25]([O:18][C@@H:14]([CH2:13][CH2:12][NH:11][C:9]([O:8][CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)=[O:10])[C:15]([OH:17])=[O:16])(=[O:32])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: O=C(NCC[C@H](O)C(=O)O)OCc1ccccc1
Reactant: O=C(Cl)c1ccccc1
Agent: CN(C)c1ccncc1
Solvent: C1CCOC1
Solvent: c1ccncc1
Product: O=C(NCC[C@H](OC(=O)c1ccccc1)C(=O)O)OCc1ccccc1
Reaction time: 0.33 h
Yield: 51 %

Procedure:
To a stirring solution of (S)-4-(benzyloxycarbonylamino)-2-hydroxybutanoic acid (1, 612 g, 2.41 mol) in THF (6 L) at 0° C. was added DMAP (2.4 g) and pyridine (196 mL, 2.41 mol). After stirring for 20 minutes, benzoyl chloride (280 mL) was added slowly and the reaction was allowed to stir overnight at room temperature. The resulting precipitate was filtered and the filtrate was acidified with 1 M citric acid (1 L). The organic solvent was removed by rotary evaporation and the desired product was extracted with EtOAc (2×2 L). The combined organic layers were washed with 1 M citric acid (1 L), brine (1 L) and then dried over MgSO4. Solvent removal under vacuum resulted in a viscous oil, which was purified on a 6-inch reverse-phase HPLC column to yield (S)-2-(benzoyloxy)-4-(benzyloxycarbonylamino)butanoic acid (2) as a non-flowing viscous oil (439 g, 51% yield).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:12]2[CH2:17][CH:16]([C:18]([O:20]C)=[O:19])[CH2:15][CH2:14][N:13]2[C:22]([O:24][CH3:25])=[O:23])[CH:5]=[CH:6][C:7]=1[C:8]([F:11])([F:10])[F:9].[Br-].[Li+].C(N(CC)CC)C.CC(OC)(C)C>C(#N)C.O>[F:1][C:2]1[CH:3]=[C:4]([CH:12]2[CH2:17][CH:16]([C:18]([OH:20])=[O:19])[CH2:15][CH2:14][N:13]2[C:22]([O:24][CH3:25])=[O:23])[CH:5]=[CH:6][C:7]=1[C:8]([F:10])([F:9])[F:11]
Reactant: COC(=O)C1CCN(C(=O)OC)C(c2ccc(C(F)(F)F)c(F)c2)C1
Agent: [Br-]
Agent: [Li+]
Solvent: CCN(CC)CC
Solvent: O
Solvent: COC(C)(C)C
Product: COC(=O)N1CCC(C(=O)O)CC1c1ccc(C(F)(F)F)c(F)c1
Yield: 99.8 %

Procedure:
Dimethyl 2-(3-fluoro-4-(trifluoromethyl)phenyl)piperidine-1,4-dicarboxylate (3.2 g, 8.81 mmol) was dissolved in acetonitrile (40 mL) and water (0.800 mL), then lithium bromide (6.12 g, 70.46 mmol) was added. Triethylamine (4.88 mL, 35.23 mmol) was added and the resulting solution was heated under reflux for 5 h. MTBE (110 mL) and water (60 mL) were added, the phases separated and the organic layer was extracted with water. The combined aqueous layers were acidified to pH 1 with 3.8 M HCl and extracted with MTBE. The combined organic layers were dried with Na2SO4 and evaporated to yield 2-(3-fluoro-4-(trifluoromethyl)phenyl)-1-(methoxycarbonyl)piperidine-4-carboxylic acid (3.07 g, quant.). MS m/z 348 (M−H)−
Reaction SMILES: [CH:1]1([CH2:7][O:8][C:9]2[N:17]=[C:16]3[C:12]([N:13]=[CH:14][N:15]3[CH:18]3[CH2:23][CH2:22][CH2:21][CH2:20][O:19]3)=[C:11]([NH2:24])[N:10]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[Br:25]N1C(=O)CCC1=O.O>C(Cl)(Cl)Cl>[Br:25][C:14]1[N:15]([CH:18]2[CH2:23][CH2:22][CH2:21][CH2:20][O:19]2)[C:16]2[C:12]([N:13]=1)=[C:11]([NH2:24])[N:10]=[C:9]([O:8][CH2:7][CH:1]1[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1)[N:17]=2
Reactant: Nc1nc(OCC2CCCCC2)nc2c1ncn2C1CCCCO1
Reactant: O=C1CCC(=O)N1Br
Solvent: O
Solvent: ClC(Cl)Cl
Product: Nc1nc(OCC2CCCCC2)nc2c1nc(Br)n2C1CCCCO1
Temperature: 2 °C
Reaction time: 0.25 h
Yield: 63.9 %

Procedure:
2-[(Cyclohexylmethyl)oxy]-9-(tetrahydro-2H-pyran-2-yl)-9H-purin-6-amine (1.0364 g) was dissolved in chloroform (20 mL) and cooled to 0° C. before N-bromosuccinimide (0.5852 g) was added gradually (the reaction temperature not exceeding 1.9° C. during the addition of N-bromosuccinimide). The reaction mixture was stirred at ˜2° C. for 15 minutes before being warmed to room temperature at which it was stirred for 6 hours (under nitrogen). Water (100 mL) was added to the reaction mixture and stirred rapidly before the organic layer was separated using a hydrophobic frit. The organic phase was evaporated under reduced pressure to give dark brown oil. This material was purified by silica chromatography eluting with 0-50% ethyl acetate; cyclohexane to give the title compound as a pale yellow solid (0.8200 g).
Reaction SMILES: Cl[CH2:2][CH2:3][O:4][C:5]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:8]([NH:15][C:16](=[O:30])[C:17]2[CH:22]=[C:21]([N:23]3[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]3)[CH:20]=[C:19]([F:29])[CH:18]=2)=[CH:7][CH:6]=1.[CH2:31]([O:33][C:34]([CH:36]1[CH2:41][CH2:40][NH:39][CH2:38][CH2:37]1)=[O:35])[CH3:32]>>[CH2:31]([O:33][C:34]([CH:36]1[CH2:41][CH2:40][N:39]([CH2:2][CH2:3][O:4][C:5]2[C:14]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[C:8]([NH:15][C:16](=[O:30])[C:17]3[CH:22]=[C:21]([N:23]4[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]4)[CH:20]=[C:19]([F:29])[CH:18]=3)=[CH:7][CH:6]=2)[CH2:38][CH2:37]1)=[O:35])[CH3:32]
Reactant: O=C(Nc1ccc(OCCCl)c2ccccc12)c1cc(F)cc(N2CCCCC2)c1
Reactant: CCOC(=O)C1CCNCC1
Product: CCOC(=O)C1CCN(CCOc2ccc(NC(=O)c3cc(F)cc(N4CCCCC4)c3)c3ccccc23)CC1

Procedure:
Compound is prepared from N-[4-(2-chloroethoxy)-naphthalen-1-yl]-3-fluoro-5-piperidin-1-yl-benzamide and piperidine-4-carboxylic acid ethyl ester according to conditions described in general procedure N. 1H NMR 300 MHz (CDCl3) 8.31 (dd, 1H, J=1.2 and 8.4 Hz), 7.88 (s, 1H), 7.83 (d, 1H, J=7.5 Hz), 7.73 (d, 1H, J=8.1Hz), 7.54 (m, 2H), 7.31 (s, 1H), 6.98 (d, 1H, J=7.8 Hz), 6.84 (d, 1H, J=8.4 Hz), 6.76 (d, 1H, J=11.7 Hz), 4.31 (t, 2H, J=5.7 Hz), 4.14 (q, 2H, J=6.9 Hz), 3.28 (m, 4H), 3.05 (m, 2H), 2.97 (t, 2H, J=5.7 Hz), 2.24-2.32 (m, 3H), 1.64-1.97 (m, 10H), 1.25 (t, 3H, J=7.5 Hz).
Reaction SMILES: [C:1]([OH:6])(=[O:5])[C:2]([CH3:4])=[CH2:3].[OH2:7]>>[C:1]([OH:6])(=[O:5])[C:2]([CH3:4])=[CH2:3].[OH:7][C:2]([CH3:4])([CH3:3])[C:1]([OH:6])=[O:5]
Reactant: O
Agent: C=C(C)C(=O)O
Product: CC(C)(O)C(=O)O

Procedure:
Finally, several other processes have become known (Stanford Research Institute Report, 11: 30) for oxidizing isobutene with nitric acid or a mixture of nitric acid and nitrogen dioxide, or mixtures thereof with acetic acid, to obtain α-hydroxyisobutyric acid, a precursor of methacrylic acid. By splitting off water, methacrylic acid is obtained from α-hydroxyisobutyric acid (German Pat. No. 1,568,948=British Pat. No. 1,080,473 and Canadian Pat. No. 771,714; DOS No. 1,768,253=British Pat. No. 1,179,987).
Reaction SMILES: I[C:2]1[CH:12]=[CH:11][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:4][CH:3]=1.[CH:13]1([CH:17]=[O:18])[CH2:16][CH2:15][CH2:14]1>>[CH:13]1([C:17]([C:2]2[CH:12]=[CH:11][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:4][CH:3]=2)=[O:18])[CH2:16][CH2:15][CH2:14]1
Reactant: CCOC(=O)c1ccc(I)cc1
Reactant: O=CC1CCC1
Product: CCOC(=O)c1ccc(C(=O)C2CCC2)cc1

Procedure:
The title compound was prepared by a method analogous to that described for Intermediate (16), using ethyl 4-iodobenzoate and cyclobutanecarbaldehyde. 1H NMR (400 MHz, CDCl3, δ): 7.93 (d, J=8.0 Hz, 2H), 7.31 (d, J=8.0 Hz, 2H), 4.58 (d, J=8.0 Hz, 1H), 4.29 (q, J=6.8 Hz, 2H), 2.50-2.58 (m, 1H), 1.70-2.02 (m, 6H), 1.34 (t, J=7.2 Hz, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:12](=[O:13])[C:11]3[CH:14]=[C:15]([CH:18]([S:23]([N:26]([CH3:28])[CH3:27])(=[O:25])=[O:24])C(OC)=O)[CH:16]=[CH:17][C:10]=3[CH:9]=[CH:8][C:5]2=[N:6][CH:7]=1.C(=O)([O-])O.[Na+]>CC(O)=O.Cl>[Cl:1][C:2]1[CH:3]=[C:4]2[C:12](=[O:13])[C:11]3[CH:14]=[C:15]([CH2:18][S:23]([N:26]([CH3:28])[CH3:27])(=[O:24])=[O:25])[CH:16]=[CH:17][C:10]=3[CH:9]=[CH:8][C:5]2=[N:6][CH:7]=1
Reactant: COC(=O)C(c1ccc2ccc3ncc(Cl)cc3c(=O)c2c1)S(=O)(=O)N(C)C
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Product: CN(C)S(=O)(=O)Cc1ccc2ccc3ncc(Cl)cc3c(=O)c2c1
Temperature: 100 °C

Procedure:
Methyl (3-chloro-5-oxo-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-7-yl)[(dimethylamino)sulfonyl]acetate (2.04 g, 4.85 mmol) was dissolved in a mixture of AcOH (24.24 ml) and 6M HCl (24.24 ml) and heated to 100° C. for 3 h. The solution was then cooled to room temperature, basified with saturated aqueous sodium hydrogen carbonate and extracted with dichloromethane (3×50 mL). The combined organics were dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (EtOAc/Hexanes gradient) to afford the title compound as a yellow solid. 1H NMR (600 MHz, DMSO-D6) δ 8.99 (d, 1H); 8.48 (d, 1H); 8.21 (s, 1H); 7.84 (m, 2H); 7.49 (d, 1H); 7.33 (d, 1H); 4.63 (s, 2H); 2.74 (s, 6H). LRMS (APCI) calculated for C17H16ClN2O3S [M+H]+, 363.1. found 363.1.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8]([NH:12][C:13](=[O:20])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[N:7][CH:6]=[CH:5]2.C(N(CC)CC)C.N1C=CC=CC=1.[CH3:34][N:35]([CH3:39])[C:36](Cl)=[S:37]>O1CCCC1.CCCCCCC.C(OCC)(=O)C>[C:13]([NH:12][C:8]1[C:9]2[C:4](=[CH:3][C:2]([O:1][C:36](=[S:37])[N:35]([CH3:39])[CH3:34])=[CH:11][CH:10]=2)[CH:5]=[CH:6][N:7]=1)(=[O:20])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: O=C(Nc1nccc2cc(O)ccc12)c1ccccc1
Reactant: CN(C)C(=S)Cl
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CN(C)C(=S)Oc1ccc2c(NC(=O)c3ccccc3)nccc2c1
Temperature: 65 °C
Reaction time: 48 h
Yield: 52.6 %

Procedure:
To a solution of N-(6-hydroxyisoquinolin-1-yl)benzamide (100 mg, 0.379 mmol), triethylamine (105 mL, 0.758 mmol) and pyridine (306 mL, 3.79 mmol) in anhydrous tetrahydrofuran (2 ml) was added N,N-dimethylthiocarbamoyl chloride (70 mg, 0.568 mmol) at 0° C., under nitrogen. The mixture was heated to 65° C. and stirred for 48 h. The organics were removed under reduced pressure and excess pyridine was removed by azeotroping with toluene (x 2). Saturated aqueous NaHCO3 was added and the mixture was extracted with dichloromethane (x 2), dried (magnesium sulphate) and concentrated in vacuo to give a residue. Flash chromatography of the residue (eluent: 5-50% ethyl acetate in heptane) gave dimethylthiocarbamic acid O-(1-benzoylaminoisoquinolin-6-yl)ester (70 mg), EIMS: m/z=352.7 [M+H]+.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11]/[C:12](=[CH:17]\[C:18]1[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH:21]=[CH:20][CH:19]=1)/[C:13]([O:15][CH3:16])=[O:14])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([O-])(=O)C=C.[SH:33][CH2:34][CH2:35][NH:36][C:37](=[O:43])[O:38][C:39]([CH3:42])([CH3:41])[CH3:40]>>[CH2:1]([O:8][C:9]([NH:11][C@H:12]([C:13]([O:15][CH3:16])=[O:14])[CH:17]([C:18]1[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH:21]=[CH:20][CH:19]=1)[S:33][CH2:34][CH2:35][NH:36][C:37]([O:38][C:39]([CH3:42])([CH3:41])[CH3:40])=[O:43])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)/C(=C/c1cccc2ccccc12)NC(=O)OCc1ccccc1
Reactant: CC(C)(C)OC(=O)NCCS
Agent: C=CC(=O)[O-]
Product: COC(=O)[C@@H](NC(=O)OCc1ccccc1)C(SCCNC(=O)OC(C)(C)C)c1cccc2ccccc12

Procedure:
Using a procedure similar to that described in Example 10 part b, substituting methyl (2Z)-2-{[(benzyloxy)carbonyl]amino}-3-(1-naphthyl)acrylate (5a) (2.8 g, 7.75 mmol) as the acrylate component and tert-butyl (2-mercaptoethyl)carbamate (5.3 g, 29.9 mmol) as the thio component (stirred 5 days), the title compound (25b) was obtained (3.3 g, 79%) as a semi-solid.
Reaction SMILES: [C:1]([N:12]1[CH2:17][CH2:16][CH:15]([OH:18])[CH2:14][CH2:13]1)(=[O:11])/[CH:2]=[CH:3]/[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10].[H-].[Na+].[CH3:21]I.O>C1COCC1>[C:1]([N:12]1[CH2:13][CH2:14][CH:15]([O:18][CH3:21])[CH2:16][CH2:17]1)(=[O:11])/[CH:2]=[CH:3]/[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10]
Reactant: CCCCCCC/C=C/C(=O)N1CCC(O)CC1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CCCCCCC/C=C/C(=O)N1CCC(OC)CC1
Temperature: 25 °C
Reaction time: 20 h
Yield: 65.4 %

Procedure:
Compound 8 (0.62 g, 2.4 mmol) was dissolved in THF (10 mL), and sodium hydride (60% in mineral oil) (0.10 g, 2.6 mmol) was added thereto under ice-cooling. After mixing for 15 minutes under ice-cooling, methyl iodide (0.16 mL, 2.6 mmol) was added thereto, and stirred at room temperature for 20 hours. Water was added to the liquid reaction mixture, the mixture was extracted with ethyl acetate, an organic layer was washed with water and saturated sodium chloride solution, and the washed extract was then dried over anhydrous sodium sulfate. The residue was purified with silica gel column chromatography (developing solvent: hexane:ethyl acetate=3:2), to give an intended compound (0.42 g, 65%) in the form of a pale yellow oily substance.
Reaction SMILES: [C:1]([NH:4][CH2:5][CH:6]([NH:14][C:15]([C:17]1([NH:32]C(=O)OC(C)(C)C)[CH2:22][CH2:21][N:20]([C:23]2[C:24]3[CH:31]=[CH:30][NH:29][C:25]=3[N:26]=[CH:27][N:28]=2)[CH2:19][CH2:18]1)=[O:16])[C:7]1[CH:12]=[CH:11][C:10]([Cl:13])=[CH:9][CH:8]=1)(=[O:3])[CH3:2].FC(F)(F)C(O)=O>>[C:1]([NH:4][CH2:5][CH:6]([NH:14][C:15]([C:17]1([NH2:32])[CH2:18][CH2:19][N:20]([C:23]2[C:24]3[CH:31]=[CH:30][NH:29][C:25]=3[N:26]=[CH:27][N:28]=2)[CH2:21][CH2:22]1)=[O:16])[C:7]1[CH:12]=[CH:11][C:10]([Cl:13])=[CH:9][CH:8]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)NCC(NC(=O)C1(NC(=O)OC(C)(C)C)CCN(c2ncnc3[nH]ccc23)CC1)c1ccc(Cl)cc1
Solvent: O=C(O)C(F)(F)F
Product: CC(=O)NCC(NC(=O)C1(N)CCN(c2ncnc3[nH]ccc23)CC1)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 103.2 %

Procedure:
Tert-butyl 4-(2-acetamido-1-(4-chlorophenyl)ethylcarbamoyl)-1-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperidin-4-ylcarbamate (Intermediate 84) (97 mg, 0.17 mmol) was treated with trifluoroacetic acid (2 mL). The solution was stirred for 1 hours at room temperature. The mixture was concentrated under reduced pressure. The crude product was purified by ion exchange chromatography, using an SCX column. The residue was loaded onto the column in methanol and washed with methanol. The desired product was eluted from the column using 2M ammonia in methanol and pure fractions were evaporated to dryness to afford N-(2-acetamido-1-(4-chlorophenyl)ethyl)-4-amino-1-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperidine-4-carboxamide (80 mg, quant.) as a cream dry film.