Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][CH2:2][CH2:3][C:4](Cl)=[O:5].[N:7]1[C:12]2[NH:13][C:14]3[CH:22]=[CH:21][CH:20]=[CH:19][C:15]=3[C:16](=[O:18])[NH:17][C:11]=2[CH:10]=[CH:9][CH:8]=1>O1CCOCC1>[Cl:1][CH2:2][CH2:3][C:4]([N:13]1[C:14]2[CH:22]=[CH:21][CH:20]=[CH:19][C:15]=2[C:16](=[O:18])[NH:17][C:11]2[CH:10]=[CH:9][CH:8]=[N:7][C:12]1=2)=[O:5]
Reactant: O=C(Cl)CCCl
Reactant: O=C1Nc2cccnc2Nc2ccccc21
Solvent: C1COCCO1
Product: O=C1Nc2cccnc2N(C(=O)CCCl)c2ccccc21

Procedure:
Equimolar amounts of 3-chloropropionyl chloride and 5,11-dihydro-6H-pyrido-[2,3-b][1,4]-benzodiazepine-6-one in solution in dioxane were reacted to obtain 11-(3-chloropropionyl)-5,11-dihydro-6H-pyrido-[2,3-b][1,4]-benzodiazepine-6-one which melted at 216°-218° C. with decomposition.
Reaction SMILES: [NH2:1][C:2]1[N:6]([C:7]2[C:12]([Cl:13])=[CH:11][C:10]([C:14]([F:17])([F:16])[F:15])=[CH:9][C:8]=2[Cl:18])[N:5]=[C:4]([C:19]([F:22])([F:21])[F:20])[C:3]=1[C:23](O)=O.B.[OH-].[Na+]>O1CCCC1>[NH2:1][C:2]1[N:6]([C:7]2[C:8]([Cl:18])=[CH:9][C:10]([C:14]([F:15])([F:16])[F:17])=[CH:11][C:12]=2[Cl:13])[N:5]=[C:4]([C:19]([F:22])([F:21])[F:20])[C:3]=1[CH3:23]
Reactant: Nc1c(C(=O)O)c(C(F)(F)F)nn1-c1c(Cl)cc(C(F)(F)F)cc1Cl
Agent: B
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: Cc1c(C(F)(F)F)nn(-c2c(Cl)cc(C(F)(F)F)cc2Cl)c1N
Reaction time: 8 h

Procedure:
To a stirred solution of 5-amino-4-carboxy-1-(2,6-dichloro-4-trifluoromethylphenyl)-3-trifluoromethylpyrazole (15.0 g; hereinbefore described in Reference Example 24) in dry tetrahydrofuran (50 ml) was added, under nitrogen, a solution of boranetetrahydrofuran complex (1 Molar, 27.5 g) during 10 minutes keeping at −20° C. The solution was allowed to reach room temperature and stirred overnight. A further addition of the borane was made. (10 ml), and the solution heated under reflux overnight. After cooling, a further addition of the borane (20 ml) was made, and the solution again heated under reflux for 4 hours. After cooling, sodium hydroxide (6 N) solution was added to pH 11, and the solution extracted with dichloromethane. The organic phase was washed with water, dried over anhydrous magnesium sulphate, and evaporated in vacuo to give a brown oil. Purification by chromatography on silica (Merck, 40-230 mesh, 0.7 kg cm−2) eluting with hexane-ethyl acetate (2:1) gave 5-amino-1-(2,6-dichloro-4-trifluoromethylphenyl)-4-methyl-3-trifluoromethylpyrazole (2.0 g) from toluene-hexane, m.p. 97-100° C., in the form of white crystals.
Reaction SMILES: ClCCl.[OH:4][C:5]([CH3:14])([CH3:13])[C:6]#[C:7][C:8]([O:10][CH2:11][CH3:12])=[O:9].ClS([N:19]=[C:20]=[O:21])(=O)=O>O>[C:20]([O:4][C:5]([CH3:13])([CH3:14])[C:6]#[C:7][C:8]([O:10][CH2:11][CH3:12])=[O:9])(=[O:21])[NH2:19]
Reactant: CCOC(=O)C#CC(C)(C)O
Reactant: O=C=NS(=O)(=O)Cl
Solvent: O
Solvent: ClCCl
Product: CCOC(=O)C#CC(C)(C)OC(N)=O
Yield: 33.6 %

Procedure:
To 100 ml of a dichloromethane solution containing 4.9 g (31.4 millimoles) of ethyl 4-hydroxy-4-methyl-2-pentynoate, 3 ml (34.5 millimoles) of chlorosulfonyl isocyanate was added at a temperature of -10° C. The mixture was reacted for 30 minutes at -10° C. under stirring. The reaction mixture was returned to room temperature, and 20 ml of water was added thereto. The mixture was stirred for 15 minutes for hydrolysis treatment. The dichloromethane phase was separated by phase separation, washed with a 10% barium chloride solution and water successively, dried over sodium sulfate and then concentrated under reduced pressure, whereby 2.1 g (yield: 33%) of ethyl 4-carbamoyloxy-4-methyl-2-pentynoate in crystal form was obtained.
Reaction SMILES: CCO[Si:4]([O:11][CH2:12][CH3:13])([O:8][CH2:9][CH3:10])[O:5][CH2:6][CH3:7].[CH2:14]1[CH2:18]O[CH2:16][CH2:15]1.[Br-]>CCCCCC>[CH2:12]([O:11][Si:4]([O:5][CH2:6][CH3:7])([O:8][CH2:9][CH3:10])[C:14]1[CH:18]=[CH:18][C:14]([CH:15]=[CH2:16])=[CH:16][CH:15]=1)[CH3:13]
Reactant: CCO[Si](OCC)(OCC)OCC
Reactant: C1CCOC1
Agent: [Br-]
Solvent: CCCCCC
Product: C=Cc1ccc([Si](OCC)(OCC)OCC)cc1
Temperature: 25 °C
Reaction time: 15 h
Yield: 6 %

Procedure:
Firstly, dist. THF (1 mL) was added to Mg (2 g, 11 mmol) that has been activated under vacuum, and subsequently a small amount of I2 was added to the resultant mixture to obtain a mixed solution. Then, the activation of the Mg in the mixed solution was checked. Once such activation was confirmed, the mixed solution was added with dist. THF (16 mL). After that, at room temperature, a solution containing 4-bromostyrene (2 g, 11 mmol) and dist. THF (5 mL) was added dropwise to obtain a reaction solution. Then, the obtained reaction solution was stirred under a nitrogen atmosphere and a reflux condition (at 80° C.) for 20 hours to obtain 4-styrenemagnesium bromide. After that, TEOS (2.2 mL, 8.8 mmol)/dist. THF (10 mL) was added dropwise to the obtained 4-styrenemagnesium bromide under a nitrogen atmosphere at room temperature (25° C.) to obtain a reaction mixture. Subsequently, the obtained reaction mixture was stirred under a nitrogen atmosphere and a reflux condition (80° C.) for 15 hours, and then was left standing to cool to room temperature. The cooled reaction mixture was added with distilled hexane (dist. hexane: 50 mL) to make the excess Mg salt be precipitated. The salt thus formed was removed through a celite filtration process, and an organic layer was concentrated under reduced pressure to obtain a residue. Then, the obtained residue was purified through a reduced-pressure distillation process (0.01 mmHg, 80° C.) to obtain 4-(triethoxysilyl) styrene (176 mg, 6% yield).
Reaction SMILES: O=P(Cl)(Cl)Cl.[CH:6]([C:9]1[CH:18]=[C:17]2[C:13](=[C:14]([CH2:19][CH2:20][OH:21])[CH:15]=[CH:16]2)[CH:12]=[CH:11][CH:10]=1)([CH3:8])[CH3:7].[OH-].[Na+].CN([CH:27]=[O:28])C>>[CH:6]([C:9]1[CH:18]=[C:17]2[C:13](=[C:14]([CH2:19][CH2:20][OH:21])[CH:15]=[C:16]2[CH:27]=[O:28])[CH:12]=[CH:11][CH:10]=1)([CH3:8])[CH3:7]
Reactant: CC(C)c1cccc2c(CCO)ccc-2c1
Reactant: CN(C)C=O
Agent: [Na+]
Agent: [OH-]
Solvent: O=P(Cl)(Cl)Cl
Product: CC(C)c1cccc2c(CCO)cc(C=O)c-2c1
Reaction time: 0.17 h
Yield: 98.1 %

Procedure:
A POCl3 (0.4 ml ) was added to DMF (5.0 ml ) at 0° C. and stirred for 10 min. To this mixture, 0.5 g of 7-Isopropyl-[3-(2-hydroxyethyl)]-azulene in DMF (2.5 ml) was added and stirred at 0° C. for 30 min. The mixture was poured into icewater and basified with 10% NaOH solution. The solution was extracted with ethyl acetate. The ethyl acetate extracts were washed with H2O and brine, dried (MgSO4), then concentrated to dryness. Purification of the residue by silica gel column chromatography (elution with ether) gave 0.556 g of the desired compound (98.1%)
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:27])[CH:5]=[CH:6][C:7]1[CH:12]=[CH:11][C:10]([N:13]2[CH2:18][CH2:17][CH:16]([NH:19][C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:15][CH2:14]2)=[CH:9][CH:8]=1)[CH3:2].[H][H]>C(O)C.[Pd]>[CH2:1]([O:3][C:4](=[O:27])[CH2:5][CH2:6][C:7]1[CH:8]=[CH:9][C:10]([N:13]2[CH2:14][CH2:15][CH:16]([NH:19][C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:17][CH2:18]2)=[CH:11][CH:12]=1)[CH3:2]
Reactant: CCOC(=O)C=Cc1ccc(N2CCC(NC(=O)OC(C)(C)C)CC2)cc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: CCOC(=O)CCc1ccc(N2CCC(NC(=O)OC(C)(C)C)CC2)cc1

Procedure:
The 4-(4-tert-butoxycarbonylaminopiperidin-1-yl)-cinnamic acid ethyl ester (126 g, 0.33 mol) obtained in Example 8 (1) was dissolved in ethanol (1 L), and 10% Pd—C (48.5 g) was added, followed by stirring in a hydrogen atmosphere for 18 hours. The insoluble material was filtered with Celite, and the filtrate was evaporated under reduced pressure, thereby obtaining 4-(4-tert-butoxycarbonylaminopiperidin-1-yl)-dihydrocinnamic acid ethyl ester (107 g, 85%) as a white solid.
Reaction SMILES: [CH2:1]([N:8]1[C:17]2[C:12](=[CH:13][CH:14]=[C:15](Br)[CH:16]=2)[CH2:11][CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([Li])CCC.[Br:24][C:25]1[CH:26]=[CH:27][C:28]([CH:33]([CH3:35])[CH3:34])=[C:29]([CH:32]=1)[CH:30]=[O:31]>C1COCC1>[CH2:1]([N:8]1[C:17]2[C:12](=[CH:13][CH:14]=[C:15]([CH:30]([C:29]3[CH:32]=[C:25]([Br:24])[CH:26]=[CH:27][C:28]=3[CH:33]([CH3:35])[CH3:34])[OH:31])[CH:16]=2)[CH2:11][CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Brc1ccc2c(c1)N(Cc1ccccc1)CCC2
Reactant: CC(C)c1ccc(Br)cc1C=O
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC(C)c1ccc(Br)cc1C(O)c1ccc2c(c1)N(Cc1ccccc1)CCC2
Reaction time: 0.75 h
Yield: 70.9 %

Procedure:
To a solution of 1-benzyl-7-bromo-1,2,3,4-tetrahydro-quinoline (2.50 g, 8.27 mmol) in THF (20 mL) was added 1.6 M n-butyl lithium in hexanes (5.14 mL, 8.27 mmol) at −78° C. The mixture was stirred for 45 min. then transferred to a stirred solution of 5-bromo-2-isopropylbenzaldehyde (1.87 g, 8.27 mmol) in THF (15 mL) at −78° C. After stirring for 30 min, the reaction was quenched by the addition of saturated aqueous solution of ammonium chloride, and the resulting mixture was extracted with ethyl acetate (3×30 mL). The organic layers were combined and washed with water (25 mL) and brine (25 mL), then dried over sodium sulfate, concentrated and purified using neutral alumina column chromatography to furnish (1-benzyl-1,2,3,4-tetrahydro-quinolin-7-yl)-(5-bromo-2-isopropyl-phenyl)-methanol (2.64 g).
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[N:10]([CH2:12][CH2:13][O:14][C:15]1[CH:20]=[CH:19][C:18]([CH2:21][CH:22]([Cl:27])[C:23](OC)=[O:24])=[CH:17][CH:16]=1)[CH3:11].O1CCCC1.[NH3:33]>CO>[O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[N:10]([CH2:12][CH2:13][O:14][C:15]1[CH:20]=[CH:19][C:18]([CH2:21][CH:22]([Cl:27])[C:23]([NH2:33])=[O:24])=[CH:17][CH:16]=1)[CH3:11]
Reactant: N
Reactant: COC(=O)C(Cl)Cc1ccc(OCCN(C)c2nc3ccccc3o2)cc1
Solvent: C1CCOC1
Solvent: CO
Product: CN(CCOc1ccc(CC(Cl)C(N)=O)cc1)c1nc2ccccc2o1
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
A mixture of methyl 3-[4-[2-[N-(2-benzoxazolyl)-N-methylamino]ethoxy]phenyl]-2-chloropropanoate (2.36 g), tetrahydrofuran (40 mL), methanol (40 mL) and aqueous ammonia solution (specific gravity 0.88; 40 mL) was stirred at room temperature for 2.5 hrs. The organic solvents were evaporated in vacuo and the residue was diluted with water (1 L) and extracted with dichloromethane (3×400 mL). The combined dichloromethane layers were washed with dilute hydrochloric acid solution (2M; 400 mL), water (1 L), brine (1 L), dried (MgSO4) and evaporated. The residue was chromatographed on silica gel with 1.5% methanol in dichloromethane as eluent to afford the title compound, mp 149°-151° C. after recrystallisation from dichloromethane-hexane.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7][C:8]([O:10]C)=O.[NH2:12][C:13]1[CH:21]=[CH:20][C:16]([CH2:17][C:18]#[N:19])=[CH:15][CH:14]=1>C1(C)C(C)=CC=CC=1>[C:18]([CH2:17][C:16]1[CH:20]=[CH:21][C:13]([NH:12][C:8](=[O:10])[CH2:7][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=2)=[CH:14][CH:15]=1)#[N:19]
Reactant: COC(=O)Cc1ccccn1
Reactant: N#CCc1ccc(N)cc1
Solvent: Cc1ccccc1C
Product: N#CCc1ccc(NC(=O)Cc2ccccn2)cc1
Yield: 66.4 %

Procedure:
A reaction mixture of 5.12 g of methyl 2-pyridylacetate, 5.14 g of 4-aminobenzyl cyanide and 50 ml of xylene was heated to reflux for 24 hours. An appropriate amount of the solvent was evaporated, diethyl ether was added to the residue, and the resulting crystals were taken by filtration to give 5.65 g of 4′-cyanomethyl-2-(2-pyridyl)acetanilide.
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[C:3](=O)[CH2:4][C:5]([C:7]1[O:8][CH:9]=[CH:10][CH:11]=1)=O.Cl.Cl.Cl.[CH2:18]([NH:25][NH2:26])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.C([O-])(O)=O.[Na+]>C(O)C>[CH2:18]([N:25]1[C:5]([C:7]2[O:8][CH:9]=[CH:10][CH:11]=2)=[CH:4][C:3]([C:2]([F:14])([F:13])[F:1])=[N:26]1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: NNCc1ccccc1
Reactant: O=C(CC(=O)C(F)(F)F)c1ccco1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Product: FC(F)(F)c1cc(-c2ccco2)n(Cc2ccccc2)n1
Temperature: 25 °C
Yield: 105.1 %

Procedure:
To a solution of 50 g (0.240 mol) 4,4,4-trifluoro-1-(2-furyl)-1,3-butanedione in 24 ml (0.024 mol) 1M solution of hydrogen chloride in ethanol and further 520 ml EtOH was added. 50 g (0.248 mol) benzylhydrazine dihydrochloride in small portion at room temperature. The reaction mixture was then heated under reflux for 7 h. After cooling to room temperature the reaction mixture was neutralized with saturated NaHCO3, the EtOH was distilled off and the residual oil/water mixture was extracted with 300 ml dichloromethane. The organic phase was washed twice with 100 ml water and dried over Na2SO4 and concentrated in vacuo to give 73.7 g 1-benzyl-5-furan-2-yl-3-trifluoromethyl-1H-pyrazole as a brown oil which was used crude for the next reaction.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:11]2[N:15]([C:16]3[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=3)[C:14]([S:23][CH2:24][C:25]3[C:35]([F:36])=[CH:34][C:28]([O:29][CH2:30][CH2:31][CH2:32]O)=[CH:27][C:26]=3[F:37])=[N:13][CH:12]=2)([CH3:10])[CH3:9])=[CH:4][C:3]=1[O:38][CH3:39].[C:40]([O:44][C:45]([NH:47][C:48]([NH:50][C:51]([O:53][C:54]([CH3:57])([CH3:56])[CH3:55])=[O:52])=[NH:49])=[O:46])([CH3:43])([CH3:42])[CH3:41].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>C1COCC1>[C:54]([O:53][C:51](=[O:52])[N:50]=[C:48]([NH:47][C:45]([O:44][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:46])[NH:49][CH2:32][CH2:31][CH2:30][O:29][C:28]1[CH:34]=[C:35]([F:36])[C:25]([CH2:24][S:23][C:14]2[N:15]([C:16]3[CH:17]=[CH:18][C:19]([F:22])=[CH:20][CH:21]=3)[C:11]([C:8]([C:5]3[CH:6]=[CH:7][C:2]([Cl:1])=[C:3]([O:38][CH3:39])[CH:4]=3)([CH3:9])[CH3:10])=[CH:12][N:13]=2)=[C:26]([F:37])[CH:27]=1)([CH3:57])([CH3:56])[CH3:55]
Reactant: CC(C)(C)OC(=O)NC(=N)NC(=O)OC(C)(C)C
Reactant: COc1cc(C(C)(C)c2cnc(SCc3c(F)cc(OCCCO)cc3F)n2-c2ccc(F)cc2)ccc1Cl
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COc1cc(C(C)(C)c2cnc(SCc3c(F)cc(OCCCNC(=NC(=O)OC(C)(C)C)NC(=O)OC(C)(C)C)cc3F)n2-c2ccc(F)cc2)ccc1Cl

Procedure:
In a manner described previously, a mixture of 3-(4-((5-(2-(4-chloro-3-methoxyphenyl)propan-2-yl)-1-(4-fluorophenyl)-1H-imidazol-2-ylthio)methyl)-3,5-difluorophenoxy)propan-1-ol (330 mg, 0.57 mmol), 1,3-bis(tert-butoxycarbonyl)guanidine (266 mg, 1.02 mmol), PPh3 (225 mg, 0.85 mmol) and DIAD (177 μL, 0.85 mmol) was reacted in THF, processed and purified by flash chromatography (80% EtOAc/Hex) to give tert-butyl(tert-butoxycarbonylamino)(3-(4-((5-(2-(4-chloro-3-methoxyphenyl)propan-2-yl)-1-(4-fluorophenyl)-1H-imidazol-2-ylthio)methyl)-3,5-difluorophenoxy)propylamino)methylenecarbamate. MS (EI) m/z 818.6 (MH+).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][CH2:9][C:10]2[CH:11]=[CH:12][C:13]([O:18][C:19]3[CH:24]=[CH:23][C:22]([Cl:25])=[C:21]([C:26]([F:29])([F:28])[F:27])[CH:20]=3)=[C:14]([CH:17]=2)[C:15]#[N:16])[CH:5]=[CH:4][N:3]=1.C1N2CCN(CC2)C1.C(=O)([O-])[O-:39].[K+].[K+].O1CCOCC1>O>[Cl:25][C:22]1[CH:23]=[CH:24][C:19]([O:18][C:13]2[CH:12]=[CH:11][C:10]([CH2:9][NH:8][C:6]3[CH:5]=[CH:4][NH:3][C:2](=[O:39])[N:7]=3)=[CH:17][C:14]=2[C:15]#[N:16])=[CH:20][C:21]=1[C:26]([F:29])([F:28])[F:27]
Reactant: O=C([O-])[O-]
Reactant: N#Cc1cc(CNc2ccnc(Cl)n2)ccc1Oc1ccc(Cl)c(C(F)(F)F)c1
Agent: C1CN2CCN1CC2
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Product: N#Cc1cc(CNc2cc[nH]c(=O)n2)ccc1Oc1ccc(Cl)c(C(F)(F)F)c1
Temperature: 80 °C
Reaction time: 8 h
Yield: 78.3 %

Procedure:
A mixture of 5-{[(2-chloro-4-pyrimidinyl)amino]methyl}-2-{[4-chloro-3-(trifluoromethyl)phenyl]oxy}benzo-nitrile (200 mg, 0.455 mmol), DABCO (25.5 mg, 0.228 mmol) and potassium carbonate (252 mg, 1.821 mmol) in a mixed solvents of 1,4-Dioxane (5 mL) and water (5.00 mL) was stirred at 80° C. overnight. Purification via MDAP, afforded the title compound (150 mg) as a white solid. LC-MS (ESI): m/z 421 [M+H]+; 2.63 min (ret time).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:14])[CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([Cl:12])=[C:8]([NH2:13])[CH:7]=1.C([O:17][C:18](=O)[CH:19]([CH2:24][C:25]1[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=1)[C:20](=O)[CH2:21][CH3:22])C>O>[CH3:1][O:2][C:3](=[O:14])[CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([Cl:12])=[C:8]2[C:7]=1[CH:18]([OH:17])[C:19]([CH2:24][C:25]1[CH:26]=[CH:27][C:28]([F:31])=[CH:29][CH:30]=1)=[C:20]([CH2:21][CH3:22])[NH:13]2
Reactant: COC(=O)COc1ccc(Cl)c(N)c1
Reactant: CCOC(=O)C(Cc1ccc(F)cc1)C(=O)CC
Solvent: O
Product: CCC1=C(Cc2ccc(F)cc2)C(O)c2c(OCC(=O)OC)ccc(Cl)c2N1
Temperature: 130 °C

Procedure:
A mixture of (3-amino-4-chlorophenoxy)acetic acid methyl ester (1.0 g), 2-(4-fluorobenzyl)-3-oxopentanoic acid ethyl ester (2.1 g) and polyphosphoric acid (10 g) was heated at 130° C. for 4 hours. The mixture was cooled to room temperature, diluted with water and extracted with ethyl acetate. The combined extracts were dried over magnesium sulfate and the solvent removed under reduced pressure. The residue was purified by column chromatography on silica gel, eluting with a mixture of dichloromethane and methanol (1:0 to 19:1 by volume) to afford title compound, 0.25 g.
Reaction SMILES: [O:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4](=[O:11])[CH2:3][CH2:2]1.C(O[CH:15](OCC)[N:16]([CH3:18])[CH3:17])C>>[CH3:15][N:16]([CH:18]=[C:3]1[C:4](=[O:11])[C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[O:1][CH2:2]1)[CH3:17]
Reactant: O=C1CCOc2ccccc21
Reactant: CCOC(OCC)N(C)C
Product: CN(C)C=C1COc2ccccc2C1=O

Procedure:
The 3-(dimethylaminomethylene)-chroman-4-one starting material was prepared from 4-chromanone (5.0 g, 33.7 mmol) and N,N-dimethyl-formamide diethyl acetal (15 ml, 87.5 mmol) to give the desired product as orange crystals (4.3 g) m.p. 135.8°. MS (ES+) 204 (100%).
Reaction SMILES: [NH2:1][C:2]1[C:3]2[N:4]([C:8]([C@H:24]3[CH2:27][C@H:26]([CH2:28][O:29]S(C4C=CC(C)=CC=4)(=O)=O)[CH2:25]3)=[N:9][C:10]=2[C:11]2[CH:16]=[CH:15][C:14]([O:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[CH:13][CH:12]=2)[CH:5]=[CH:6][N:7]=1.[OH-].[K+].O.Cl>O1CCOCC1>[NH2:1][C:2]1[C:3]2[N:4]([C:8]([C@H:24]3[CH2:25][C@H:26]([CH2:28][OH:29])[CH2:27]3)=[N:9][C:10]=2[C:11]2[CH:12]=[CH:13][C:14]([O:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[CH:15][CH:16]=2)[CH:5]=[CH:6][N:7]=1
Reactant: Cc1ccc(S(=O)(=O)OC[C@H]2C[C@H](c3nc(-c4ccc(Oc5ccccc5)cc4)c4c(N)nccn43)C2)cc1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: Nc1nccn2c1c(-c1ccc(Oc3ccccc3)cc1)nc2[C@H]1C[C@H](CO)C1

Procedure:
A solution of trans-toluene-4-sulfonic acid 3-[8-amino-1-(4-phenoxy-phenyl)-imidazo[1,5-a]pyrazin-3-yl]-cyclobutylmethyl ester (10.0 mg, 0.0185 mmol), potassium hydroxide (10.4 mg, 0.185 mmol), H2O (1 mL) and 1,4-dioxane (1 mL) was heated to 60° C. overnight. The mixture was titrated to pH 2 with 2M HCl. The dioxane was removed in vacuo. DCM was added to extract the product. The organics were combined, dried (Na2SO4) and removed under reduced pressure to give a residue which was then purified by flash chromatography (5% MeOH in DCM). MS (ES+): m/z 386.94 (100) [MH+]. HPLC: tR=2.23 min (polar—5 min).
Reaction SMILES: [CH2:1]([C@H:3]1[C@@H:7]([C:8]2[N:12]3[C:13]4[CH:19]=[CH:18][NH:17][C:14]=4[N:15]=[CH:16][C:11]3=[N:10][N:9]=2)[CH2:6][C@@H:5]([CH2:20][C:21](OCC)=[O:22])[CH2:4]1)[CH3:2].O/[N:27]=[C:28](\[NH2:32])/[CH2:29][O:30][CH3:31].C([O-])([O-])=O.[K+].[K+]>C1(C)C=CC=CC=1.CO>[CH2:1]([C@H:3]1[C@@H:7]([C:8]2[N:12]3[C:13]4[CH:19]=[CH:18][NH:17][C:14]=4[N:15]=[CH:16][C:11]3=[N:10][N:9]=2)[CH2:6][C@@H:5]([CH2:20][C:21]2[O:22][N:32]=[C:28]([CH2:29][O:30][CH3:31])[N:27]=2)[CH2:4]1)[CH3:2]
Reactant: CCOC(=O)C[C@H]1C[C@@H](CC)[C@@H](c2nnc3cnc4[nH]ccc4n23)C1
Reactant: COC/C(N)=N/O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: CO
Product: CC[C@@H]1C[C@H](Cc2nc(COC)no2)C[C@@H]1c1nnc2cnc3[nH]ccc3n12
Temperature: 130 °C
Yield: 55.5 %

Procedure:
To a solution of ethyl 2-((1S,3R,4S)-3-ethyl-4-(6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)cyclopentyl)acetate (0.100 g, 0.293 mmol) in toluene (0.20 mL) and MeOH (0.20 mL) was added (Z)-N′-hydroxy-2-methoxyacetimidamide (0.300 g, 2.89 mmol, Tyger) and K2CO3 (0.100 g, 0.726 mmol). The solution was heated in a CEM microwave at about 130° C. for about 1 h (250 psi maximum pressure, 1 min ramp, 300 max watts). The solvent was removed under reduced pressure. The residue was diluted with DCM (3 mL) and a small amount of MeOH. The crude material was purified by flash chromatography on silica gel eluting with a gradient of 0-10% MeOH in DCM. The residue was dissolved in EtOAc and heptane was added. The solvent was concd. The solid was dried in a heated vacuum oven (about 70° C.) for about 20 h to afford 5-(((1S,3R,4S)-3-ethyl-4-(6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)cyclopentyl)methyl)-3-(methoxymethyl)-1,2,4-oxadiazole (0.062 g, 56%) as a white solid: LC/MS (Table 1, Method a) Rt=1.79 min; MS m/z: 382 (M+H)+.
Reaction SMILES: [C:1]1([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH:6]=[CH:5][CH:4]=[C:3]([C:7]2[O:8][C:9]([CH3:25])=[C:10]([CH2:12][CH2:13][O:14]S(C3C=CC(C)=CC=3)(=O)=O)[N:11]=2)[CH:2]=1.C([O:34][C:35](=[O:57])[C:36]([CH3:56])([O:45][C:46]1[CH:51]=[CH:50][C:49]([C:52]([CH3:55])([CH3:54])[CH3:53])=[CH:48][CH:47]=1)[CH2:37][C:38]1[CH:43]=[CH:42][C:41](O)=[CH:40][CH:39]=1)C>C(O)C>[C:1]1([C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=2)[CH:6]=[CH:5][CH:4]=[C:3]([C:7]2[O:8][C:9]([CH3:25])=[C:10]([CH2:12][CH2:13][O:14][C:41]3[CH:40]=[CH:39][C:38]([CH2:37][C:36]([CH3:56])([O:45][C:46]4[CH:51]=[CH:50][C:49]([C:52]([CH3:55])([CH3:54])[CH3:53])=[CH:48][CH:47]=4)[C:35]([OH:57])=[O:34])=[CH:43][CH:42]=3)[N:11]=2)[CH:2]=1
Reactant: Cc1ccc(S(=O)(=O)OCCc2nc(-c3cccc(-c4ccccc4)c3)oc2C)cc1
Reactant: CCOC(=O)C(C)(Cc1ccc(O)cc1)Oc1ccc(C(C)(C)C)cc1
Solvent: CCO
Product: Cc1oc(-c2cccc(-c3ccccc3)c2)nc1CCOc1ccc(CC(C)(Oc2ccc(C(C)(C)C)cc2)C(=O)O)cc1
Temperature: 55 °C
Yield: 45 %

Procedure:
Toluene-4-sulfonic acid 2-(2-biphenyl-3-yl-5-methyl-oxazol-4-yl)-ethyl ester (0.132 mmol) (see Ex. 2, Part F) was added to a one dram, screw-cap vial and diluted with ethanol (0.5 mL). To this solution are added 3-(4-hydroxyphenyl)-2-methyl-2-(4-tert-butylphenoxy)-propionic acid ethyl ester (0.5 mL of a 0.264 M solution in ethanol, 0.132 mmol) (see Ex. 15, Part B) and polystyrene bound 1,5,7-triazabicyclo[4.4.0]dec-5-ene (100–125 mg, 2.6 mmol/g) and the vial was tightly closed. The reaction vessel was heated in a block heater for 24–48 h at 55° C., or until TLC or MS analysis indicates the disappearance of starting materials. The suspension was filtered while warm and the residue washed with ethanol (1 mL). The solution was treated with aqueous NaOH (5N solution, 100 μl) and the vial resealed tightly. The solution was heated in a block heater at 55° C. for 3–16 h, or until MS analysis indicates the completion of the hydrolysis. The solvents are removed with a stream of nitrogen or under reduced pressure and the residue redissolved in 1 mL water. The solution was acidified with aqueous HCl (5N solution, 150 μl), often causing precipitation of product. The suspension was diluted with dichloromethane (3 mL) and the resultant biphasic solution was filtered through a Chrom-Elut column to remove water. The filtrate was concentrated in vacuo and the resultant residue was purified by preparative thin-layer silica chromatography eluting with 95:5 CH2Cl2:MeOH to produce a white solid (45%). MS [EI+] 590 (M+H)+, [EI−] 588 (M−H)+