Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:4][C:5](=O)C)(=O)[CH3:2].[F:8][CH:9]([F:18])[C:10](=[O:17])[CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13].C(OCC)(OCC)OCC>>[CH2:1]([O:4]/[CH:5]=[C:11](/[C:10](=[O:17])[CH:9]([F:18])[F:8])\[C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH3:2]
Reactant: CC(=O)OC(C)=O
Reactant: CCOC(=O)CC(=O)C(F)F
Solvent: CCOC(OCC)OCC
Product: CCO/C=C(\C(=O)OCC)C(=O)C(F)F
Temperature: 95 °C
Reaction time: 8.5 h
Yield: 85.5 %

Procedure:
Add acetic anhydride (166 kg, 1625 mol) to a mixture of ethyl 4,4-difluoroacetoacetate (33 kg, 199 mol) and triethyl orthoformate (60 kg, 407 mol) maintained at 90-100° C. Stir the mixture at 90-100° C. for 8.5 hours and remove ethyl acetate using a Dean-Stark apparatus. Concentrate the reaction mixture to give the title compound (37.8 kg, 86% yield, 97% GC purity). 1H NMR (500 MHz, CDCl3,) δ 7.88 (d, J=6 Hz, 1H), 6.3 (m, 1H), 4.3 (m, 4H), 1.4 (m, 3H), 1.32 (m, 3H).
Reaction SMILES: [OH:1][N:2]1[CH:6]=[CH:5][CH:4]=[N:3]1.[H-].[Na+].[CH3:9][C:10]([CH3:23])([O:12][C:13]1[CH:22]=[CH:21][C:16]([O:17][CH2:18][CH2:19]Br)=[CH:15][CH:14]=1)[CH3:11]>CN(C=O)C>[CH3:23][C:10]([CH3:9])([O:12][C:13]1[CH:22]=[CH:21][C:16]([O:17][CH2:18][CH2:19][O:1][N:2]2[CH:6]=[CH:5][CH:4]=[N:3]2)=[CH:15][CH:14]=1)[CH3:11]
Reactant: CC(C)(C)Oc1ccc(OCCBr)cc1
Reactant: On1cccn1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)Oc1ccc(OCCOn2cccn2)cc1
Temperature: 70 °C
Yield: 92.6 %

Procedure:
A solution of 12.7 g (0.15 mol) of N-hydroxypyrazole in 20 ml of DMF was added dropwise to a suspension of 4.95 g (1.1 eq.) of NaH (80% dispersion in mineral oil) in 40 ml of DMF at RT, and the mixture was heated at 70° C. for 1 h. A solution of 40.95 g (0.15 mol) of 2-[4-(1,1-dimethylethoxy)phenoxy]ethyl bromide in 100 ml of DMF was added and the mixture was then heated at 125° C. for 15 h. The solvent was then stripped off in a rotary evaporator, the residue was taken up in ethyl acetate, and the solution was washed twice each with 5% strength NaOH solution and water. Drying and removal of the solvent under reduced pressured resulted in 38.4 g (93%) of the required compound as a pale oil which was employed without further purification in the next stage.
Reaction SMILES: [Si]([O:8][C@H:9]([CH3:26])[C@:10]([C:18]1[CH:23]=[CH:22][C:21]([F:24])=[CH:20][C:19]=1[F:25])([OH:17])[CH2:11][N:12]1[CH:16]=[N:15][CH:14]=[N:13]1)(C(C)(C)C)(C)C.Cl.C1(C)C=CC=CC=1>CO>[F:25][C:19]1[CH:20]=[C:21]([F:24])[CH:22]=[CH:23][C:18]=1[C@:10]([OH:17])([C@H:9]([OH:8])[CH3:26])[CH2:11][N:12]1[CH:16]=[N:15][CH:14]=[N:13]1
Reactant: C[C@@H](O[Si](C)(C)C(C)(C)C)[C@](O)(Cn1cncn1)c1ccc(F)cc1F
Agent: Cl
Solvent: CO
Solvent: Cc1ccccc1
Product: C[C@@H](O)[C@](O)(Cn1cncn1)c1ccc(F)cc1F
Temperature: 50 °C
Reaction time: 4 h

Procedure:
The (2R, 3R)-3-(tert-butyldimethylsilyloxy)-2-(2,4-difluorophenyl)-1-(1H-1,2,4-triazol-1-yl)-2-butanol (12.2 g) synthesized in Example 12 was dissolved in methanol (41 mL). Hydrochloric acid (3 N, 21 g) was added to the solution and the mixture was stirred at 50° C. for four hours. Toluene (120 g) was added to the reaction mixture and was then stirred. Subsequently, an aqueous layer was separated. An aqueous solution (2 N, 41 g) of sodium hydroxide was added to the aqueous layer so that the pH of the mixture was controlled to be 9. The target compound was extracted with ethyl acetate (120 mL). The extracted organic layer was dried with anhydrous magnesium sulfate. The drying agent was filtered, and the filtrate was concentrated under reduced pressure. The resultant light yellow syrup was crystallized with toluene to recover-white crystals of the target compound (7.9 g, 92%). The values of the physical properties corresponded with those in Example 15. Diastereomeric excess: 99.5% de
Reaction SMILES: [H-].[Na+].C(O[CH:6]([O:10]CC)[N:7]([CH3:9])C)C.C(OC(OCC(C)(C)C)N(C)C)C(C)(C)C.[C:29]([CH:31]([C:35]1[CH2:40][CH2:39][CH2:38][C:37](=[O:41])[CH:36]=1)C(N)=O)#[N:30]>>[O:10]=[C:6]1[C:31]([C:29]#[N:30])=[C:35]2[C:36]([C:37](=[O:41])[CH2:38][CH2:39][CH2:40]2)=[CH:9][NH:7]1
Reactant: N#CC(C(N)=O)C1=CC(=O)CCC1
Reactant: CCOC(OCC)N(C)C
Agent: CN(C)C(OCC(C)(C)C)OCC(C)(C)C
Agent: [H-]
Agent: [Na+]
Product: N#Cc1c2c(c[nH]c1=O)C(=O)CCC2

Procedure:
The novel compounds of the present invention originate from a novel process which utilizes dihydroresorcinol as the starting material. That substance thus is allowed to react with a chlorinating reagent such as phosphorus trichloride to afford 3-chloro-2-cyclohexen-1-one. Reaction with cycnoacetamide and sodium hydride results in α-cyano-3-oxo-1-cyclohexen-1-acetamide, which is contacted with a dialkylformamide acetal, for example dimethylformamide diethyl acetal or dimethylformamide dineopentyl acetal, to produce 2,3,5,6,7,8-hexahydro-3,8-dioxo-4-isoquinolinecarbonitrile. Elimination of the cyano group is effected by heating with hydrobromic acid, thus affording 2,3,5,6,7,8-hexahydro-3,8-isoquinolinedione. Heating with an alkyl or cycloalkyl halide produces the corresponding 6-alkoxy and 6-cycloalkoxy 7-aza-1-tetralones together with the N-alkylated or N-cycloalkylated derivatives. Typically, 2,3,5,6,7,8-hexahydro-3,8-isoquinolinedione is heated in benzene at the reflux temperature with methyl iodide and silver carbonate to yield 7-aza-6-methoxy-1-tetralone together with 2-methyl-2,3,5,6,7,8-hexahydro-3,8-isoquinolinedione.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([S:8]([CH3:10])=[O:9])[N:5]=[C:4]([NH:11][C:12]2[NH:16][N:15]=[C:14]([CH3:17])[CH:13]=2)[CH:3]=1.[OH:18]OS([O-])=O.[K+]>CO.O>[Cl:1][C:2]1[N:7]=[C:6]([S:8]([CH3:10])(=[O:18])=[O:9])[N:5]=[C:4]([NH:11][C:12]2[NH:16][N:15]=[C:14]([CH3:17])[CH:13]=2)[CH:3]=1
Reactant: O=S([O-])OO
Reactant: Cc1cc(Nc2cc(Cl)nc(S(C)=O)n2)[nH]n1
Agent: [K+]
Solvent: O
Solvent: CO
Product: Cc1cc(Nc2cc(Cl)nc(S(C)(=O)=O)n2)[nH]n1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 88 %

Procedure:
To a stirred suspension of 6-chloro-N-(3-methyl-1H-pyrazol-5-yl)-2-(methylsulfinyl)pyrimidin-4-amine (8 g, 31.2 mmol) in methanol (200 ml) at 0° C. was added a suspension of Oxone (44 g, 71.7 mmol) in water (100 ml) portionwise over 10 minutes. The mixture was stirred for 30 minutes at 0° C. then warmed to ambient and stirred for an additional 2 hours. The reaction mixture was filtered and the resulting solid slurried in aqueous sodium bicarbonate. The mixture was filtered and the solid washed with water, then diethyl ether. The solid was slurried in ethyl acetate, filtered and dried. This gave the title product as an off-white solid (7.9 g, 88%); 1H NMR (d6-DMSO) δ 2.24 (3H, s), 3.35 (3H, s), 5.85 (0.5H, brs), 6.50 (0.5H, brs), 6.95 (0.5H, brs), 8.00 (0.5H, brs), 10.95 (1H, s), 12.28 (1H, s); MS ES+288.07, ES−286.25.
Reaction SMILES: [CH2:1]([O:3][N:4]=[C:5]([C:11](=O)[CH2:12]Cl)[C:6]([O:8][CH2:9][CH3:10])=[O:7])[CH3:2].[NH2:15][C:16]([NH2:18])=[S:17].C([O-])(=O)C.[Na+].C(=O)(O)[O-].[Na+]>O.CO>[NH2:18][C:16]1[S:17][CH:12]=[C:11]([C:5](=[N:4][O:3][CH2:1][CH3:2])[C:6]([O:8][CH2:9][CH3:10])=[O:7])[N:15]=1
Reactant: CCON=C(C(=O)CCl)C(=O)OCC
Reactant: NC(N)=S
Agent: CC(=O)[O-]
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Solvent: O
Product: CCON=C(C(=O)OCC)c1csc(N)n1
Temperature: 48 °C
Reaction time: 0.67 h
Yield: 34.8 %

Procedure:
A mixture of ethyl 2-ethoxyimino-3-oxo-4-chlorobutyrate (syn isomer 38.7 g.), thiourea (13.2 g.), sodium acetate (14.3 g.), methanol (95 ml.) and water (95 ml.) was stirred at 48° C. for 40 minutes. After the resultant solution was adjusted to pH 6.5 with an aqueous solution of sodium bicarbonate, the appeared precipitates were collected by filtration and washed with diisopropyl ether to give ethyl 2-(2-amino-4-thiazolyl)-2-ethoxyiminoacetate (syn isomer, 14.7 g.), mp 130° to 131° C.
Reaction SMILES: [CH2:1]([O:3][C:4]([NH:6][NH2:7])=[O:5])[CH3:2].C(N(CC)CC)C.[CH3:15][C:16]1[CH:21]=[C:20]([CH3:22])[CH:19]=[C:18]([CH3:23])[C:17]=1[CH2:24][C:25](Cl)=[O:26]>O1CCCC1>[CH2:1]([O:3][C:4]([NH:6][NH:7][C:25](=[O:26])[CH2:24][C:17]1[C:16]([CH3:15])=[CH:21][C:20]([CH3:22])=[CH:19][C:18]=1[CH3:23])=[O:5])[CH3:2]
Reactant: CCOC(=O)NN
Reactant: Cc1cc(C)c(CC(=O)Cl)c(C)c1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCOC(=O)NNC(=O)Cc1c(C)cc(C)cc1C
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of hydrazinecarboxylic acid ethyl ester (ethyl carbazate, 32.8 g, 314.9 mmol) and triethylamine (44.1 ml, 32.0 g, 316.4 mmol) in tetrahydrofuran (1000 ml) at 0° C. was added (2,4,6-trimethyl-phenyl)-acetyl chloride (62.0 g, 315.2 mmol) dropwise. The thick suspension was stirred at room temperature for one hour and the solvent evaporated. The residue was suspended in a mixture of t-butyl methyl ether (500 ml) and water (500 ml), stirred, filtered and the solid washed with small portions of water and t-butyl methyl ether. The solid was dried in vacuo over phosphorus pentoxide at 40° C. Yield: 78.4 g of N′-[2-(2,4,6-trimethyl-phenyl)-acetyl]-hydrazinecarboxylic acid ethyl ester as a white solid, mp 184-186° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([C:11]2([C:14]([NH:16][C:17]3[CH:22]=[CH:21][C:20]([O:23][C:24]4[C:33]5[C:28](=[CH:29][C:30]([OH:36])=[C:31]([O:34][CH3:35])[CH:32]=5)[N:27]=[CH:26][N:25]=4)=[C:19]([F:37])[CH:18]=3)=[O:15])[CH2:13][CH2:12]2)=[O:10])=[CH:4][CH:3]=1.[C:38]([O:42][C:43]([N:45]1[CH2:50][CH2:49][CH:48]([CH2:51]OS(C)(=O)=O)[CH2:47][CH2:46]1)=[O:44])([CH3:41])([CH3:40])[CH3:39].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.CCOC(C)=O>[C:38]([O:42][C:43]([N:45]1[CH2:50][CH2:49][CH:48]([CH2:51][O:36][C:30]2[CH:29]=[C:28]3[C:33]([C:24]([O:23][C:20]4[CH:21]=[CH:22][C:17]([NH:16][C:14]([C:11]5([C:9](=[O:10])[NH:8][C:5]6[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=6)[CH2:13][CH2:12]5)=[O:15])=[CH:18][C:19]=4[F:37])=[N:25][CH:26]=[N:27]3)=[CH:32][C:31]=2[O:34][CH3:35])[CH2:47][CH2:46]1)=[O:44])([CH3:41])([CH3:39])[CH3:40]
Reactant: COc1cc2c(Oc3ccc(NC(=O)C4(C(=O)Nc5ccc(F)cc5)CC4)cc3F)ncnc2cc1O
Reactant: CC(C)(C)OC(=O)N1CCC(COS(C)(=O)=O)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COc1cc2c(Oc3ccc(NC(=O)C4(C(=O)Nc5ccc(F)cc5)CC4)cc3F)ncnc2cc1OCC1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 80 °C
Yield: 60.6 %

Procedure:
Cyclopropane-1,1-dicarboxylic acid [3-fluoro-4-(7-hydroxy-6-methoxy-quinazolin-4-yloxy)-phenyl]-amide (4-fluoro-phenyl)-amide (325 mg, 0.64 mmol), 4-methanesulfonyloxymethyl-piperidine-1-carboxylic acid tert-butyl ester (193 mg, 0.66 mmol), K2CO3 (181 mg, 1.31 mmol) were combined in DMF (5 ml) and heated to 80° C. overnight. The reaction was not complete and more 4-methanesulfonyloxymethyl-piperidine-1-carboxylic acid tert-butyl ester (90 mg, 0.31 mmol) and K2CO3 (90 mg, 0.65 mmol) were added and heating at 80° C. continued for another night. The reaction mixture was allowed to cool to room temperature, then diluted with EtOAc and washed with H2O (3×), sat'd NaCl (1×), dried (Na2SO4) and concentrated in vacuo. The resulting crude material was purified by flash chromatography (1:1 hexanes:EtOAc, followed by 1:3 hexanes:EtOAc) to give 4-[4-(2-fluoro-4-{[1-(4-fluoro-phenylcarbamoyl)-cyclopropanecarbonyl]-amino}-phenoxy)-6-methoxy-quinazolin-7-yloxymethyl]-piperidine-1-carboxylic acid tert-butyl ester (273 mg, 60%). LC/S Calcd for [M+H]+ 704.3, found 704.4.
Reaction SMILES: [C:1]([N:5]1[CH:9]=[C:8]([C:10]2[CH:11]=[C:12]([OH:19])[C:13]3[N:14]([N:16]=[CH:17][CH:18]=3)[CH:15]=2)[CH:7]=[N:6]1)([CH3:4])([CH3:3])[CH3:2].[Br:20]N1C(=O)CCC1=O>C(#N)C.ClCCl>[Br:20][C:18]1[CH:17]=[N:16][N:14]2[CH:15]=[C:10]([C:8]3[CH:7]=[N:6][N:5]([C:1]([CH3:4])([CH3:2])[CH3:3])[CH:9]=3)[CH:11]=[C:12]([OH:19])[C:13]=12
Reactant: O=C1CCC(=O)N1Br
Reactant: CC(C)(C)n1cc(-c2cc(O)c3ccnn3c2)cn1
Solvent: ClCCl
Solvent: CC#N
Product: CC(C)(C)n1cc(-c2cc(O)c3c(Br)cnn3c2)cn1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 6-(1-tert-butyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridin-4-ol (138 mg, 0.538 mmol) in acetonitrile (6 mL) was added N-bromosuccinimide (105 mg, 0.590 mmol). The solution was stirred at room temperature for 1 h. The reaction was diluted with dichloromethane, washed with water and 2N NaOH. The combined aqueous layers were neutralized and extracted with ethyl acetate. The combined organic layers were washed with brine, dried, filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel to afford 3-bromo-6-(1-tert-butyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridin-4-ol.
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][CH:5]=[N:6][CH:7]=1.C([Mg]Cl)(C)C.[Br:13][C:14]1[CH:15]=[CH:16][C:17]([F:22])=[C:18]([CH:21]=1)[CH:19]=[O:20]>C1COCC1>[Br:13][C:14]1[CH:15]=[CH:16][C:17]([F:22])=[C:18]([CH:19]([C:2]2[CH:3]=[N:4][CH:5]=[N:6][CH:7]=2)[OH:20])[CH:21]=1
Reactant: Brc1cncnc1
Reactant: O=Cc1cc(Br)ccc1F
Agent: CC(C)[Mg]Cl
Solvent: C1CCOC1
Product: OC(c1cncnc1)c1cc(Br)ccc1F
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To an oven-dried flask was added anhydrous THF (40 mL) and 5-bromopyrimidine (6.36 g, 40 mmol). 2M isopropylmagnesium chloride in THF (22 mL) was then added dropwise over several minutes at 0° C. The mixture was stirred at 0° C. for 30 minutes, and then 5-bromo-2-fluorobenzaldehyde (2.4 mL, 20 mmol) was added. After warming to room temperature, the reaction was quenched with saturated aqueous NH4Cl. The aqueous layer was extracted with EtOAc, dried over MgSO4, and purified by column chromatography (gradient 0 to 60% EtOAc in hexanes) to afford the product. 1H NMR (400 MHz, CDCl3) δ 9.10 (s, 1H), 8.74 (s, 2H), 7.71 (dd, J=6.4, 2.5 Hz, 1H), 7.43 (ddd, J=8.7, 4.6, 2.6 Hz, 1H), 6.95 (dd, J=9.5, 8.9 Hz, 1H), 6.15 (s, 1H).
Reaction SMILES: [Br:1][C:2]1[C:3](=[O:9])[NH:4][C:5]([Cl:8])=[N:6][CH:7]=1.[CH3:10]N(C=O)C.[H-].[Li+].IC>COCCOC>[Br:1][C:2]1[C:3](=[O:9])[N:4]([CH3:10])[C:5]([Cl:8])=[N:6][CH:7]=1
Reactant: CN(C)C=O
Reactant: O=c1[nH]c(Cl)ncc1Br
Agent: [H-]
Agent: [Li+]
Solvent: CI
Solvent: COCCOC
Product: Cn1c(Cl)ncc(Br)c1=O
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 72 %

Procedure:
To a solution of 5-bromo-2-chloropyrimidin-4(3H)-one (1.00 g, 4.78 mmol) in DME (12 mL)/DMF (3 mL) under N2 at 0° C. was added LiH (0.044 g, 5.25 mmol), and the reaction mixture was stirred for 15 minutes at room temperature. Iodomethane (0.589 mL, 9.45 mmol) was then added and the reaction mixture was stirred at room temperature for 30 minutes and then at 60° C. for 1.5 hours. The reaction mixture was quenched with H2O and then partitioned between EtOAc and saturated aqueous NaCl. The phases were separated, and the aqueous phase was re-extracted with EtOAc (1×). The combined organic layers were dried (Na2SO4), filtered and concentrated to yield a crude yellow oil. The crude product was purified by flash column chromatography, eluting with 25:1 dichloromethane/EtOAc. The desired product (0.764 g, 72%) was obtained as a yellow crystalline solid. 1H NMR (400 MHz, DMSO-d6) δ 8.26 (s, 1H), 3.59 (s, 3H). LRMS (ESI pos) m/e 223, 225 (M+1, Br pattern).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([CH:10]=[CH:11][C:12]2[CH:17]=[CH:16][N:15]=[CH:14][CH:13]=2)=[CH:6][CH:5]=1)([O-])=O.[H][H]>[Pd].CCOC(C)=O>[N:15]1[CH:16]=[CH:17][C:12]([CH2:11][CH2:10][C:7]2[CH:6]=[CH:5][C:4]([NH2:1])=[CH:9][CH:8]=2)=[CH:13][CH:14]=1
Reactant: [H][H]
Reactant: O=[N+]([O-])c1ccc(C=Cc2ccncc2)cc1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: Nc1ccc(CCc2ccncc2)cc1
Yield: 99.5 %

Procedure:
To the EtOAc solution (30 mL) of 4-[2-(4-nitro-phenyl)-vinyl]-pyridine (160 mg, 0.71 mmol) was added palladium on carbon (0.1 g, 50% wet). The suspension was hydrogenated at 50 psi of hydrogen for 2 hours. The mixture was filtered over a celite pad. The filtrate was concentrate to give 4-(2-pyridin-4-yl-ethyl)-phenylamine as a yellow solid (140 mg, 100%).
Reaction SMILES: F[C:2](F)(F)C(O)=O.[OH:8][C:9]1[C:19]([CH:20]2[C:28]3[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=3)[N:22]([CH2:29][C@H:30]3[CH2:34][CH2:33][CH2:32][O:31]3)[C:21]2=[O:35])=[CH:18][C:12]2[N:13]([CH3:17])[CH2:14][CH2:15][O:16][C:11]=2[CH:10]=1.C1(C(C2C=CC=CC=2)N2C3C(=CC=CC=3)C(C3C=C(C)C(OC)=CC=3O)C2=O)C=CC=CC=1>>[CH3:17][N:13]1[C:12]2[CH:18]=[C:19]3[C:20]4([C:28]5[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=5)[N:22]([CH2:29][C@H:30]5[CH2:34][CH2:33][CH2:32][O:31]5)[C:21]4=[O:35])[CH2:2][O:8][C:9]3=[CH:10][C:11]=2[O:16][CH2:15][CH2:14]1
Reactant: O=C(O)C(F)(F)F
Reactant: CN1CCOc2cc(O)c(C3C(=O)N(C[C@H]4CCCO4)c4ccccc43)cc21
Agent: COc1cc(O)c(C2C(=O)N(C(c3ccccc3)c3ccccc3)c3ccccc32)cc1C
Product: CN1CCOc2cc3c(cc21)C1(CO3)C(=O)N(C[C@H]2CCCO2)c2ccccc21

Procedure:
Following the procedure as described in EXAMPLE 2 and making non-critical variations using 3-(7-hydroxy-4-methyl-3,4-dihydro-2H-1,4-benzoxazin-6-yl)-1-[(2R)-tetrahydrofuran-2-ylmethyl]-1,3-dihydro-2H-indol-2-one trifluoroacetate to replace 1-(diphenylmethyl)-3-(2-hydroxy-4-methoxy-5-methylphenyl)-1,3-dihydro-2H-indol-2-one, 1-methyl-1′-[(2R)-tetrahydrofuran-2-ylmethyl]-2,3-dihydro-1H-spiro[furo[3,2-g][1,4]benzoxazine-8,3′-indol]-2′(1′H)-one was obtained (72%) as a colorless solid. Following the procedure described in EXAMPLE 2.28 and making non-critical variations using 1-methyl-1′-[(2R)-tetrahydrofuran-2-ylmethyl]-2,3-dihydro-1H-spiro[furo-[3,2-g][1,4]benzoxazine-8,3′-indol]-2′(1′H)-one to replace 1-methyl-1′-{[5-(trifluoromethyl)furan-2-yl]methyl}-2,3-dihydro-1H-spiro[furo[3,2-g][1,4]benzoxazine-8,3′-indol]-2′(1′H)-one, 1-methyl-1′-[(2R)-tetrahydrofuran-2-ylmethyl]-2,3-dihydro-1H-spiro[furo-[3,2-g][1,4]benzoxazine-8,3′-indol]-2′(1′H)-one hydrochloride was obtained (83%) as a colorless solid: mp>135° C. (dec.) (hexanes); 1H NMR (300 MHz, DMSO-d6) (diastereomers) δ7.83 (br s, 1H), 7.36-7.29 (m, 1H), 7.22 (d, J=8.1 Hz, 1H), 7.15 (d, J=7.5 Hz, 1H), 7.07-7.00 (m, 1H), 6.51 (br s, 1H), 6.44, 6.40 (br s, 1H), 4.82-4.59 (m, 2H), 4.38-4.26 (m, 2H), 4.25-4.14 (m, 1H), 3.87-3.69 (m, 3H), 3.66-3.59 (m, 1H), 3.36-3.24 (m, 2H), 2.78, 2.75 (br s, 3H), 2.02-1.72 (m, 3H), 1.68-1.55 (m, 1H); 13C NMR (75 MHz, DMSO-d6) (diastereomers) δ 176.8, 158.2, 157.8, 148.3, 143.1, 142.9, 131.5, 131.2, 128.9, 128.8, 123.6, 123.5, 122.9, 122.3, 114.0, 113.3, 109.9, 109.8, 98.9, 79.9, 79.8, 75.7, 75.6, 67.3, 62.3, 57.0, 48.9, 43.9, 43.7, 42.3, 42.1, 28.7, 28.5, 25.2, 25.1; MS (ES+) m/z 393.1 (M+1).
Reaction SMILES: Cl[C:2]([O:4][CH2:5][C:6]([O:8][CH3:9])=[O:7])=[O:3].[NH2:10][C:11]1[CH:18]=[CH:17][CH:16]=[C:15]([CH3:19])[C:12]=1[CH2:13][OH:14].N1C=CC=CC=1>ClCCl>[OH:14][CH2:13][C:12]1[C:15]([CH3:19])=[CH:16][CH:17]=[CH:18][C:11]=1[NH:10][C:2](=[O:3])[O:4][CH2:5][C:6]([O:8][CH3:9])=[O:7]
Reactant: COC(=O)COC(=O)Cl
Reactant: Cc1cccc(N)c1CO
Solvent: c1ccncc1
Solvent: ClCCl
Product: COC(=O)COC(=O)Nc1cccc(C)c1CO
Yield: 35.1 %

Procedure:
Starting from methoxycarbonylmethyl chloroformate (11.7 g), 2-amino-6-methylbenzyl alcohol (10.5 g) and pyridine (6.2 ml) in dichloromethane (230 ml), 6.8 g (20%) of the title compound, m.p. 70-74° C., are obtained according to the procedure indicated in Example C1, after chromatography on silica gel (eluent: ethyl acetate/petroleum ether 50/70=1:1) and crystallization from diisopropyl ether.
Reaction SMILES: Br[C:2]1[N:3]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[C:4]2[N:5]=[C:6]([C:19]3[CH:24]=[CH:23][C:22]([C:25]([F:28])([F:27])[F:26])=[CH:21][CH:20]=3)[N:7]([C:12]3[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=3)[C:8](=[O:11])[C:9]=2[N:10]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:41]([NH:43][CH3:44])[CH3:42].C(#N)C>C(Cl)Cl>[Cl:18][C:15]1[CH:14]=[CH:13][C:12]([N:7]2[C:8](=[O:11])[C:9]3[N:10]=[C:2]([N:43]([CH2:41][CH3:42])[CH3:44])[N:3]([C:29]4[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=4)[C:4]=3[N:5]=[C:6]2[C:19]2[CH:24]=[CH:23][C:22]([C:25]([F:26])([F:27])[F:28])=[CH:21][CH:20]=2)=[CH:17][CH:16]=1
Reactant: CCNC
Reactant: O=c1c2nc(Br)n(-c3ccccc3)c2nc(-c2ccc(C(F)(F)F)cc2)n1-c1ccc(Cl)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: ClCCl
Product: CCN(C)c1nc2c(=O)n(-c3ccc(Cl)cc3)c(-c3ccc(C(F)(F)F)cc3)nc2n1-c1ccccc1
Temperature: 200 °C
Yield: 49.4 %

Procedure:
8-Bromo-1-(4-chloro-phenyl)-9-phenyl-2-(4-trifluoromethyl-phenyl)-1,9-dihydro-purin-6-one (19.0 mg, 0.0348 mmol), potassium carbonate (400 mg, 2.89 mmol), and ethyl-methyl-amine (172 mg, 2.91 mmol) are mixed in a microwave tube with 1 mL of dry acetonitrile. The tube is then capped and heated to 200° C. for 40 min in a microwave reactor. Then the reaction mixture is diluted with CH2Cl2 and filtered. The filtrate is evaporated and the crude product is purified by column chromatography, yielding 9 mg (49%) of the title compound. 1H NMR (CDCl3, 400 MHz) δ 7.54 (m, 4H), 7.47 (m, 1H), 7.42 (d, 2H), 7.30 (d, 4H), 7.08 (d, 2H), 3.17 (q, 2H), 2.90 (s, 3H), 1.03 (t, 3H). HPLC-MS calculated for C27H21ClF3N5O (M+H+) 524.1. Found: 524.1.
Reaction SMILES: C[O:2][C:3](=[O:38])[C:4]1[CH:9]=[C:8]([CH:10]=[CH:11][C:12](=[O:23])[N:13]([CH3:22])[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])[CH:7]=[C:6]([CH3:24])[C:5]=1[N:25]([S:27]([C:30]1[CH:35]=[CH:34][C:33]([O:36][CH3:37])=[CH:32][CH:31]=1)(=[O:29])=[O:28])[CH3:26]>CCCCCC.CCOC(C)=O>[CH3:37][O:36][C:33]1[CH:34]=[CH:35][C:30]([S:27]([N:25]([CH3:26])[C:5]2[C:6]([CH3:24])=[CH:7][C:8]([CH:10]=[CH:11][C:12](=[O:23])[N:13]([CH3:22])[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])=[CH:9][C:4]=2[C:3]([OH:38])=[O:2])(=[O:29])=[O:28])=[CH:31][CH:32]=1
Reactant: CCCCCCCCN(C)C(=O)C=Cc1cc(C)c(N(C)S(=O)(=O)c2ccc(OC)cc2)c(C(=O)OC)c1
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: CCCCCCCCN(C)C(=O)C=Cc1cc(C)c(N(C)S(=O)(=O)c2ccc(OC)cc2)c(C(=O)O)c1
Yield: 91.5 %

Procedure:
In the same manner as described in Example 18, 188 mg (0.35 mmol) of the product of Example 205 provided 170 mg (93%) of the desired carboxylic acid as a white solid after trituration with Hexane/EtOAc (2:1). Electrospray Mass Spec 575(M+HCOOH--H).
Reaction SMILES: [NH2:1][C:2]1[CH:15]=[C:14]2[O:16][CH2:17][O:18][C:13]2=[CH:12][C:3]=1[C:4]([NH:6][C:7]1[NH:11][N:10]=[N:9][N:8]=1)=[O:5].[CH2:19](OC(OCC)OCC)C>COCCO>[CH2:17]1[O:16][C:14]2[CH:15]=[C:2]3[C:3]([C:4](=[O:5])[N:6]([C:7]4[NH:8][N:9]=[N:10][N:11]=4)[CH:19]=[N:1]3)=[CH:12][C:13]=2[O:18]1
Reactant: CCOC(OCC)OCC
Reactant: Nc1cc2c(cc1C(=O)Nc1nnn[nH]1)OCO2
Solvent: COCCO
Product: O=c1c2cc3c(cc2ncn1-c1nnn[nH]1)OCO3

Procedure:
A slurry of 11.6 g of 2-amino-4,5-methylenedioxy-N-(1H-tetrazol-5-yl)benzamide and 25 g of triethoxymethane in 150 ml of 2-methoxyethanol was heated at reflux for 1 hour. A complete solution was not obtained at any time but the final mixture was filtered and the separated solid was air dried and recrystallized from a mixture of dimethylformamide and methanol to give 6,7-methylenedioxy-3-(1H-tetrazol-5-yl)-4(3H)-quinazolinone melting at about 280° C. (dec).
Reaction SMILES: [C:1]([O:5][CH2:6][CH2:7][CH2:8][CH3:9])(=[O:4])[CH:2]=[CH2:3].[C:10]([O-:15])(=[O:14])[C:11]([CH3:13])=[CH2:12].N(C(C)(CC)C#N)=NC(C)(CC)C#N.[C:30]([O:33][CH2:34][CH3:35])(=O)C>C1(C)C=CC=CC=1>[CH2:6]([O:5][C:1](=[O:4])[CH:2]=[CH2:3])[CH2:7][CH2:8][CH3:9].[C:10]([O:15][CH2:35][CH:34]1[O:33][CH2:30]1)(=[O:14])[C:11]([CH3:13])=[CH2:12]
Reactant: CCOC(C)=O
Reactant: C=C(C)C(=O)[O-]
Agent: C=CC(=O)OCCCC
Agent: CCC(C)(C#N)N=NC(C)(C#N)CC
Solvent: Cc1ccccc1
Product: C=C(C)C(=O)OCC1CO1
Temperature: 60 °C

Procedure:
The following were added to a 946 mL bottle: 72.0 g of butyl acrylate (Dow Chemical Co., Midland, Mich.), 48.0 g of glydicyl methacrylate (Sartomer Co. Inc., Easton, Pa.), 0.18 g of 2,2′-azobis(2-methylbutanenitrile) (DuPont, Wilmington, Del.), 140 g of ethyl acetate, and 140 g of toluene. The solution was purged with nitrogen for two minutes at a rate of one liter per minute. The bottle was sealed and placed in a water bath that was maintained at 60° C., for 24 hours. The reaction mixture was 29.5 wt % solids, had a measured inherent viscosity of 0.78 dL/g and a Brookfield viscosity of 0.7 Pascal-seconds.