Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([CH2:7][CH:8]2[CH2:13][CH2:12][CH2:11][CH2:10][N:9]2[CH2:14][CH2:15][C:16]2[C:24]3[C:19](=[CH:20][CH:21]=[C:22]([O:25][CH3:26])[CH:23]=3)[NH:18][C:17]=2[CH3:27])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[H-].[Na+].[Na].[Br:31][C:32]1[CH:33]=[C:34]([CH:38]=[CH:39][C:40]=1[F:41])[C:35](Cl)=[O:36]>CN(C=O)C>[Br:31][C:32]1[CH:33]=[C:34]([CH:38]=[CH:39][C:40]=1[F:41])[C:35]([N:18]1[C:19]2[C:24](=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=2)[C:16]([CH2:15][CH2:14][N:9]2[CH2:10][CH2:11][CH2:12][CH2:13][CH:8]2[CH2:7][CH:1]2[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]2)=[C:17]1[CH3:27])=[O:36]
Reactant: O=C(Cl)c1ccc(F)c(Br)c1
Reactant: COc1ccc2[nH]c(C)c(CCN3CCCCC3CC3CCCCC3)c2c1
Agent: [H-]
Agent: [Na+]
Agent: [Na]
Solvent: CN(C)C=O
Product: COc1ccc2c(c1)c(CCN1CCCCC1CC1CCCCC1)c(C)n2C(=O)c1ccc(F)c(Br)c1

Procedure:
1-(3-Bromo-4-fluorobenzoyl)-3-[2-(2-cyclohexylmethylpiperidino)-ethyl]-5-methoxy-2-methylindole is prepared by reaction of 3-[2-(2-cyclohexylmethylpiperidino)ethyl]-5-methoxy-2-methylindole with sodium hydride in DMF and reaction of the resulting sodium salt with 3-bromo-4-fluorobenzoyl chloride following the procedure described above in Example 1.
Reaction SMILES: [F:1][C:2]([F:21])([F:20])[C:3]1[C:11]2[CH2:10][CH2:9][CH2:8][CH2:7][C:6]=2[N:5]([CH2:12][C:13]2[CH:19]=[CH:18][C:16]([NH2:17])=[CH:15][CH:14]=2)[N:4]=1.C(N(C(C)C)CC)(C)C.Cl[CH2:32][CH2:33][CH2:34][C:35](Cl)=[O:36].[H-].[Na+]>ClCCl>[F:21][C:2]([F:1])([F:20])[C:3]1[C:11]2[CH2:10][CH2:9][CH2:8][CH2:7][C:6]=2[N:5]([CH2:12][C:13]2[CH:14]=[CH:15][C:16]([N:17]3[CH2:32][CH2:33][CH2:34][C:35]3=[O:36])=[CH:18][CH:19]=2)[N:4]=1
Reactant: Nc1ccc(Cn2nc(C(F)(F)F)c3c2CCCC3)cc1
Reactant: O=C(Cl)CCCCl
Agent: [H-]
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: O=C1CCCN1c1ccc(Cn2nc(C(F)(F)F)c3c2CCCC3)cc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 93.4 %

Procedure:
A solution of 4-{[3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazol-1-yl]methyl}aniline (166 mg, 0.56 mmol) in dichloromethane (4 ml) was treated with diisopropylethylamine (1.12 mmol, 146 mg) followed by 4-chlorobutyryl chloride (80 mg, 0.56 mmol). After stirring at room temperature for 15 minutes a solid suspension of sodium hydride (60% in mineral oil) (22 mg, 0.55 mmol) was added and stirring continued for 30 minutes. The dichloromethane was removed by blowing with air and dimethylformamide added (3 ml) and stirring continued for 30 minutes. The reaction mix was partitioned between dichloromethane and water (2×5 ml). The organic layer was dried over sodium sulphate and evaporated under reduced pressure to give a yellow oil (190 mg) which was purified by mass directed auto prep to give the title compound as a yellow oil (39 mg, 19%).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7](O)=[CH:6][CH:5]=1)([O-:3])=[O:2].[OH-].[Na+].C(=O)([O-])[O-].[K+].[K+].Cl.CN(CCCl)C>C1(C)C(C)=CC=CC=1.O>[N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: O=[N+]([O-])c1ccc(O)cc1
Agent: CN(C)CCCl
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: Cc1ccccc1C
Solvent: O
Product: O=[N+]([O-])c1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A suspension of 5 g (36 mmol) of 4-nitrophenol in 250 ml of xylene was treated with a solution of 1.63 g (41 mmol) of sodium hydroxide in 20 ml of water and the mixture was stirred at room temperature for 30 minutes. The mixture was then treated with 7.5 g (54 mmol) of potassium carbonate and 5.11 g (36 mmol) of dimethylaminoethyl chloride hydrochloride. The mixture was heated at reflux for 2 hours and then for a further 24 hours with azeotropic removal of water. The mixture was filtered while hot and the solid was washed with hot xylene. The combined filtrate and washings were evaporated and the residue was distilled under a high vacuum to give 1.28 g (20%) of 4-[2-dimethylamino)ethoxy]nitrobenzene as an orange colored liquid.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:14]2[CH:15]=[C:16]([C:18](=O)[CH2:19]Br)[O:17][C:13]=2[CH:12]=[C:11]([O:22][CH3:23])[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:24][C@H:25]([C:27]1[S:31][C:30]([NH2:32])=[N:29][N:28]=1)[CH3:26].CC(O)C>C(Cl)Cl.C(#N)C>[CH2:1]([O:8][C:9]1[C:14]2[CH:15]=[C:16]([C:18]3[N:32]=[C:30]4[N:29]([CH:19]=3)[N:28]=[C:27]([C@@H:25]([F:24])[CH3:26])[S:31]4)[O:17][C:13]=2[CH:12]=[C:11]([O:22][CH3:23])[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COc1cc(OCc2ccccc2)c2cc(C(=O)CBr)oc2c1
Reactant: C[C@H](F)c1nnc(N)s1
Solvent: CC(C)O
Solvent: CC#N
Solvent: ClCCl
Product: COc1cc(OCc2ccccc2)c2cc(-c3cn4nc([C@H](C)F)sc4n3)oc2c1
Temperature: 80 °C
Reaction time: 0.08 h

Procedure:
In a 20 mL vial, 1-(4-(benzyloxy)-6-methoxybenzofuran-2-yl)-2-bromoethanone (Example 1E, 407 mg, 1.085 mmol) and (S)-5-(1-fluoroethyl)-1,3,4-thiadiazol-2-amine (Example 40A, 202 mg, 1.373 mmol) were suspended in 2-propanol (10 ml, 130 mmol) and heated at 80° C. for 18 h. After 5 min. the solution became homogeneous. A precipitate was present after overnight stirring. The cooled mixtures were transferred into 20 mL microwaves vials and then heated 30 min at 150° C. The mixtures were combined, diluted in CH2Cl2 (200 mL) and washed once with sat. NaHCO3, once with brine, dried over anh. Na2SO4 and concentrated. The residue was purified on ISCO using a REDISEP® Gold 40 g column (CH2Cl2/EtOAc). The crude product was adsorbed on SiO2. Fractions were collected and the orange solid obtained was tritured twice in ACN to give the title material a light yellow solid. LC (Method B): 2.403 min. MS (ESI) calcd. for C22H19FN3O3S [M+H]+ m/z: 424.1126. found: 424.1146. 1H NMR (400 MHz, DMSO-d6) d ppm 8.61 (s, 1H) 7.51 (d, J=7.4 Hz, 2H) 7.42 (t, J=7.6 Hz, 2H) 7.35 (t, J=7.0 Hz, 1H) 7.08 (s, 1H) 6.83-6.85 (m, 1H) 6.54 (d, J=1.2 Hz, 1H) 6.16 (dq, J=47.1, 6.4 Hz, 1H) 5.26 (s, 2H) 3.80 (s, 3H) 1.79 (dd, J=24.5, 6.8 Hz, 3H).
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([CH3:9])[C:4]=1[S:10]([NH:13][C:14]1[CH:19]=[CH:18][C:17]([F:20])=[C:16]([NH:21][C:22]2[C:27]([C:28]3[N:36]=[CH:35][N:34]=[C:33]4[C:29]=3[N:30]=[CH:31][N:32]4C3CCCCO3)=[CH:26][CH:25]=[CH:24][N:23]=2)[C:15]=1[F:43])(=[O:12])=[O:11]>>[N:36]1[C:28]([C:27]2[C:22]([NH:21][C:16]3[C:15]([F:43])=[C:14]([NH:13][S:10]([C:4]4[C:5]([CH3:9])=[CH:6][CH:7]=[CH:8][C:3]=4[Cl:2])(=[O:12])=[O:11])[CH:19]=[CH:18][C:17]=3[F:20])=[N:23][CH:24]=[CH:25][CH:26]=2)=[C:29]2[C:33]([NH:32][CH:31]=[N:30]2)=[N:34][CH:35]=1
Reactant: Cc1cccc(Cl)c1S(=O)(=O)Nc1ccc(F)c(Nc2ncccc2-c2ncnc3c2ncn3C2CCCCO2)c1F
Agent: Cl
Product: Cc1cccc(Cl)c1S(=O)(=O)Nc1ccc(F)c(Nc2ncccc2-c2ncnc3[nH]cnc23)c1F
Reaction time: 2 h

Procedure:
1M aqueous hydrochloric acid solution was added into the 2-chloro-N-(2,4-difluoro-3-(3-(9-(tetrahydro-2H-pyran-2-yl)-9H-purin-6-yl)pyridin-2-ylamino)phenyl)-6-methylbenzenesulfonamide (20 mg, 0.033 mmol) prepared at Step 10 and stirred for 2 hours. After the reaction, the reactant was washed with an aqueous solution of sodium hydrogen carbonate and salt water. After extraction with ethylacetate, the organic layer was dried with sulfuric anhydride magnesium and vacuum concentrated, and then refined by means of column chromatography, so that the target compound was obtained.
Reaction SMILES: [C:1]([C:5]1[S:6][CH:7]=[C:8]([N+:10]([O-:12])=[O:11])[CH:9]=1)(=[O:4])[CH2:2][CH3:3].[Br:13]Br>C(Cl)Cl>[Br:13][CH:2]([CH3:3])[C:1]([C:5]1[S:6][CH:7]=[C:8]([N+:10]([O-:12])=[O:11])[CH:9]=1)=[O:4]
Reactant: CCC(=O)c1cc([N+](=O)[O-])cs1
Reactant: BrBr
Solvent: ClCCl
Product: CC(Br)C(=O)c1cc([N+](=O)[O-])cs1

Procedure:
Following the procedure of Example 12B, using 9.26 g. of 2-propionyl-4-nitrothiophene and 7.99 g. of bromine in 100 ml. of methylene chloride, there is obtained 13.0 g. of product m.p. 79°-82° C. which is recrystallized from ethanol affording 2-(2-bromopropionyl)-4-nitrothiophene m.p. 82.5°-83° C.
Reaction SMILES: [CH:1]1([N:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[NH2:8])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(=O)(O)[O-].[Na+].[S:20]([C:24]1[CH:25]=[C:26]([CH:30]=[CH:31][C:32]=1[Cl:33])[C:27](Cl)=[O:28])(=[O:23])(=[O:22])[NH2:21].O>C(O)(C)C>[CH:9]1([N:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[NH:8][C:27](=[O:28])[C:26]2[CH:30]=[CH:31][C:32]([Cl:33])=[C:24]([S:20](=[O:22])(=[O:23])[NH2:21])[CH:25]=2)[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]1
Reactant: NS(=O)(=O)c1cc(C(=O)Cl)ccc1Cl
Reactant: NN(c1ccccc1)C1CCCCC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(C)O
Solvent: O
Product: NS(=O)(=O)c1cc(C(=O)NN(c2ccccc2)C2CCCCC2)ccc1Cl

Procedure:
A mixture of 8.5 g (0.045 mol) 1-cyclohexyl-1-phenyl hydrazine in 50 ml isopropanol and 4.7 g (0.045 mol) sodium bicarbonate was stirred and chilled. Addition of 11.36 g (0.045 mol) 3-sulfamoyl-4-chlorobenzoyl chloride was made in several portions. The mixture was stirred for 2 hours at room temperature and for 2.5 hours at 40°-50° C. Dilution of the reaction mixture with water yielded a solid material which was recrystallized from aqueous ethanol. M.P. 216°-217° C.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[N:7][NH:8]2)=[C:4]([N+:11]([O-:13])=[O:12])[CH:3]=1.[O:14]1[CH:19]=[CH:18][CH2:17][CH2:16][CH2:15]1.CC1C=CC(S(O)(=O)=O)=CC=1.N1C=CC=CC=1.C(=O)(O)[O-].[Na+]>ClCCl>[Br:1][C:2]1[CH:3]=[C:4]([N+:11]([O-:13])=[O:12])[C:5]2[C:9]([CH:10]=1)=[N:8][N:7]([CH:15]1[CH2:16][CH2:17][CH2:18][CH2:19][O:14]1)[CH:6]=2
Reactant: C1=COCCC1
Reactant: O=[N+]([O-])c1cc(Br)cc2[nH]ncc12
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: c1ccncc1
Solvent: ClCCl
Product: O=[N+]([O-])c1cc(Br)cc2nn(C3CCCCO3)cc12
Temperature: 25 °C
Yield: 96.5 %

Procedure:
A mixture of 6-bromo-4-nitro-1H-indazole (available from Sinova, 10 g, 0.041 mol), 3,4-dihydro-2H-pyran (7.85 g, 8.52 ml, 0.093 mol) and pyridine 4-methylbenzenesulfonate (0.125 g, 0.496 mol) in dichloromethane (150 ml) was heated at reflux for 4.5 hours. The reaction was allowed to cool to room temperature and was poured onto saturated aqueous sodium bicarbonate (200 ml). The layers were separated and the aqueous layer extracted with dichloromethane (2×100 ml). The combined organic layers were washed with 5% aqueous citric acid (w/v, 100 ml) and brine (100 ml) and dried over magnesium sulphate. Solvent was removed in vacuo to give the title compound (12.9 g) as a dark orange solid.
Reaction SMILES: CC(O[CH2:6][C:7]1[C:11]([C:12]([O:14][CH3:15])=[O:13])=[C:10]([CH:16]([CH3:18])[CH3:17])[O:9][N:8]=1)(C)C.FC(F)(F)C(O)=O.OCC1C(C(OC)=O)=C(C(C)C)ON=1.C(Br)(Br)(Br)[Br:41].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>ClCCl.CCCCCC>[Br:41][CH2:6][C:7]1[C:11]([C:12]([O:14][CH3:15])=[O:13])=[C:10]([CH:16]([CH3:18])[CH3:17])[O:9][N:8]=1
Reactant: COC(=O)c1c(COC(C)(C)C)noc1C(C)C
Reactant: BrC(Br)(Br)Br
Agent: COC(=O)c1c(CO)noc1C(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Solvent: CCCCCC
Product: COC(=O)c1c(CBr)noc1C(C)C
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 56.1 %

Procedure:
A solution of methyl 3-{[(1,1-dimethylethyl)oxy]methyl}-5-(1-methylethyl)-4-isoxazolecarboxylate (2.00 g, 7.83 mmol) in dichloromethane (32.5 mL) was stirred at 0° C. as trifluoroacetic acid (32.5 mL, 0.42 mol) was added dropwise. The resulting solution was allowed to stir at 0° C. for 5 minutes then at room temperature for 30 minutes. The solution was concentrated and the residue was partitioned between ethyl acetate and saturated aqueous NaHCO3. The organic layer was dried with MgSO4, filtered and concentrated. The residue was purified by chromatography (silica gel, hexane to 2:3 ethyl acetate:hexanes). Fractions containing methyl 3-(hydroxymethyl) -5-(1-methylethyl)-4-isoxazolecarboxylate were combined and concentrated. A solution of methyl 3-(hydroxymethyl)-5-(1-methylethyl)-4-isoxazolecarboxylate (1.042 g, 5.23 mmol) in dichloromethane (24.3 mL) was stirred as carbon tetrabromide (1.85 g, 5.5 mmol) was added. The solution was cooled in ice bath before the addition of triphenyl phosphine (1.44 g, 5.5 mmol) in three portions. The solution was allowed to stir at 0° C. for 30 minutes then at room temperature for 1.5 hours. Hexane (67 mL) was added before the mixture was filtered through Celite® and concentrated. The residue was purified by chromatography (silica gel, hexane to 1:4 ethyl acetate:hexanes). Fractions containing the product were combined and concentrated to yield methyl 3-(bromomethyl)-5-(1-methylethyl)-4-isoxazolecarboxylate (0.809 g, 57% as 0.10 ethyl acetate). 1H NMR (400 MHz, DMSO-d6): δ 4.70 (s, 2H), 3.82 (s, 3H), 3.69 (septet, J=7 Hz, 1H), 1.26 (d, J=7 Hz, 6H). ESI-LCMS m/z 262 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:27])[C:4](O)([C:22]([F:25])([F:24])[F:23])[C:5]1[C:9](=[O:10])[N:8]([C:11]2[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:13][CH:12]=2)[NH:7][C:6]=1[CH3:21].S(Cl)(Cl)=O>C1(C)C=CC=CC=1>[CH3:1][O:2][C:3](=[O:27])[C:4](=[C:5]1[C:9](=[O:10])[N:8]([C:11]2[CH:16]=[CH:15][C:14]([C:17]([F:19])([F:20])[F:18])=[CH:13][CH:12]=2)[N:7]=[C:6]1[CH3:21])[C:22]([F:25])([F:24])[F:23]
Reactant: COC(=O)C(O)(c1c(C)[nH]n(-c2ccc(C(F)(F)F)cc2)c1=O)C(F)(F)F
Solvent: Cc1ccccc1
Solvent: O=S(Cl)Cl
Product: COC(=O)C(=C1C(=O)N(c2ccc(C(F)(F)F)cc2)N=C1C)C(F)(F)F

Procedure:
To a toluene solution (5 ml) of 2,5-dihydro-α-hydroxy-3-methyl-5-oxo-α-trifluoromethyl-1-(4-trifluoromethylphenyl)-1H-pyrazole-4-acetic acid methyl ester (180 mg, 0.5 mmol), thionyl chloride (0.365 ml, 5.0 mmol) was added and the mixture was stirred under reflux for 3 hours. After concentrating the liquid reaction mixture under reduced pressure, the title compound was obtained as a reddish brown solid (171 mg).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][N:5]=[CH:4][C:3]=1[N:8]([CH3:25])[C:9](=[O:24])[C:10]1[CH:15]=[C:14]([C:16]([F:19])([F:18])[F:17])[CH:13]=[C:12]([C:20]([F:23])([F:22])[F:21])[CH:11]=1.[CH3:26][C:27]1[S:28][C:29](B2OC(C)(C)C(C)(C)O2)=[C:30]([CH3:32])[N:31]=1.C([O-])([O-])=O.[K+].[K+].COC1C=CC=C(OC)C=1C1C=CC=CC=1P(C1CCCCC1)C1CCCCC1>CN(C=O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:26][C:27]1[S:28][C:29]([C:2]2[CH:7]=[CH:6][N:5]=[CH:4][C:3]=2[N:8]([CH3:25])[C:9](=[O:24])[C:10]2[CH:15]=[C:14]([C:16]([F:19])([F:18])[F:17])[CH:13]=[C:12]([C:20]([F:23])([F:22])[F:21])[CH:11]=2)=[C:30]([CH3:32])[N:31]=1
Reactant: Cc1nc(C)c(B2OC(C)(C)C(C)(C)O2)s1
Reactant: CN(C(=O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1cnccc1Br
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: COc1cccc(OC)c1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Agent: O=C([O-])[O-]
Solvent: CN(C)C=O
Product: Cc1nc(C)c(-c2ccncc2N(C)C(=O)c2cc(C(F)(F)F)cc(C(F)(F)F)c2)s1
Temperature: 80 °C
Yield: 7 %

Procedure:
A mixture of N-(4-bromo-pyridin-3-yl)-N-methyl-3,5-bis-trifluoromethyl-benzamide (200 mg, 0.468 mmol, example 25, intermediate a), 2,4-dimethyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3-thiazole (107.4 mg, 0.7 mmol, CAS RN 859833-13-9) and K2CO3 (193.75 mg, 1.4 mmol) in DMF (6 mL), taken in a sealed tube, was degassed well for 30 min with argon. To this mixture was added S-PHOS (50.1 mg, 0.25 mmol, CAS RN 657408-07-6) and Pd(PPh3)4 (54 mg, 0.05 mmol), and degassed again for 15 min. The reaction mixture was heated to 80° C. for 30 min irradiated with microwave. After the completion of reaction, it was cooled to room temperature, filtered through a bed of celite and the residue washed with EtOAc (50 mL). Volatilities were removed in vacuo and the resultant residue was diluted with water (30 mL) and extracted with EtOAc (2×50 mL). The combined organic layers were washed with brine (30 mL), dried over anhydrous Na2SO4, filtered, and evaporated. The crude residue was purified by column chromatography over silica gel (30-40% EtOAc in n-hexane) to afford the title compound as a pale yellow solid (15 mg, 7%). MS (ESI): m/z=460.1 [M+H]+.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:19])[CH2:5][O:6][C:7]1[CH:12]=[C:11]([CH3:13])[C:10]([O:14][CH3:15])=[CH:9][C:8]=1[CH:16]([CH3:18])[CH3:17])[CH3:2].[H-].[Na+].[CH:22]([O:24][CH2:25]C)=O.IC>COCCOC>[CH2:1]([O:3][C:4](=[O:19])[C:5]([O:6][C:7]1[CH:12]=[C:11]([CH3:13])[C:10]([O:14][CH3:15])=[CH:9][C:8]=1[CH:16]([CH3:18])[CH3:17])=[CH:22][O:24][CH3:25])[CH3:2]
Reactant: CCOC(=O)COc1cc(C)c(OC)cc1C(C)C
Reactant: CCOC=O
Agent: [H-]
Agent: [Na+]
Solvent: CI
Solvent: COCCOC
Product: CCOC(=O)C(=COC)Oc1cc(C)c(OC)cc1C(C)C
Temperature: 85 °C
Reaction time: 0.08 h
Yield: 23.2 %

Procedure:
To a solution of (2-isopropyl-4-methoxy-5-methyl-phenoxy)-acetic acid ethyl ester (4.42 g, 16.6 mmol) in anhydrous 1,2-dimethoxy ethane (60 ml) was added sodium hydride (60% in mineral oil, 3.5 g, 87.5 mmol) at room temperature. After 5 minutes of stirring, ethyl formate (40 ml, 495 mmol) was added. The mixture was heated at 85° C. for 7 hours. After cooling to room temperature, iodomethane was added and stirring was continued overnight. Solvent was concentrated under reduced pressure and the residue was partitioned between ethyl acetate and water. The organic phase was washed with brine and dried over anhydrous sodium sulfate. After removal of drying agent, the organic solution was concentrated under reduced pressure. The residue was purified with silica gel chromatography (10% to 30% ethyl acetate in hexane) to yield 2-(2-isopropyl-4-methoxy-5-methyl-phenoxy)-3-methoxy-acrylic acid ethyl ester as a pale yellow oil (1.19 g, 23%).
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:4]=[C:5]([NH:9][C:10](=[O:16])[O:11][C:12]([CH3:15])([CH3:14])[CH3:13])[CH:6]=[CH:7][CH:8]=1.C(N(CC)CC)C.[N+:24]([C:27]1[CH:28]=[C:29]([S:33](Cl)(=[O:35])=[O:34])[CH:30]=[CH:31][CH:32]=1)([O-:26])=[O:25].C([O-])([O-])=O.[Na+].[Na+]>O1CCCC1>[N+:24]([C:27]1[CH:28]=[C:29]([S:33]([NH:1][CH2:2][C:3]2[CH:4]=[C:5]([NH:9][C:10](=[O:16])[O:11][C:12]([CH3:13])([CH3:15])[CH3:14])[CH:6]=[CH:7][CH:8]=2)(=[O:35])=[O:34])[CH:30]=[CH:31][CH:32]=1)([O-:26])=[O:25]
Reactant: O=[N+]([O-])c1cccc(S(=O)(=O)Cl)c1
Reactant: CC(C)(C)OC(=O)Nc1cccc(CN)c1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)Nc1cccc(CNS(=O)(=O)c2cccc([N+](=O)[O-])c2)c1
Temperature: 25 °C
Yield: 109.1 %

Procedure:
To a stirring solution of tert-butyl [3-(aminomethyl)phenyl]carbamate (2.00 g, 9.0 mmol) and triethylamine (1.32 mL, 9.45 mmol) in dry tetrahydrofuran (25.5 mL) at 0° C. was slowly added a solution of m-nitrobenzenesulfonyl chloride (2.09 g, 9.45 mmol) in tetrahydrofuran (7.3 mL). The resulting mixture was slowly warmed up to rt and stirred for one additional hour at rt. The reaction mixture was treated with Na2CO3 (aq) and layers separated. The aqueous layer was extracted with EtOAc three times. The combined organic layers were dried, filtered and concentrated to give the desired product as an off-white powder (4.0 g, 100%). LCMS for C18H21N3O6S (M-Boc+H)+: m/z=308.0. 1H NMR (400 MHz, CD3OD): δ 8.43 (t, J=2.0 Hz, 1H), 8.31 (ddd, J=8.0, 2.0, 1.2 Hz, 1H), 8.04 (dt, J=8.0, 2.8 Hz, 1H), 7.64 (t, J=8.0 Hz, 1H), 7.19 (br, 1H), 7.04 (m, 2H), 6.77 (dt, J=7.2, 1.2 Hz, 1H), 4.13 (s, 2H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[N:14]=[C:13]([NH:15][CH:16]([CH3:26])[CH2:17][NH:18]C(=O)OC(C)(C)C)[N:12]2[CH:27]=[CH:28][N:29]=[C:11]2[CH:10]=1.[F:30][C:31]([F:36])([F:35])[C:32]([OH:34])=[O:33]>ClCCl>[F:30][C:31]([F:36])([F:35])[C:32]([OH:34])=[O:33].[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[N:14]=[C:13]([NH:15][CH:16]([CH3:26])[CH2:17][NH2:18])[N:12]2[CH:27]=[CH:28][N:29]=[C:11]2[CH:10]=1
Reactant: CC(CNC(=O)OC(C)(C)C)Nc1nc(-c2ccc(Cl)cc2Cl)cc2nccn12
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(CN)Nc1nc(-c2ccc(Cl)cc2Cl)cc2nccn12
Temperature: 25 °C
Reaction time: 1 h
Yield: 138.8 %

Procedure:
tert-Butyl (2-{[7-(2,4-dichlorophenyl)imidazo[1,2-c]pyrimidin-5-yl]amino}propyl)carbamate (Example 36A) (700 mg, 1.6 mmol) is dissolved in dichloromethane (20 ml), and trifluoroacetic acid (2.5 ml, 32 mmol) is added. The resulting solution is stirred at RT for 1 h, concentrated in a rotary evaporator and dried on the vacuum line. 1 g of the product is obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9](=O)[C:10](=[C:15]([NH:17]C)[CH3:16])[C:11]([O:13][CH3:14])=[O:12].[CH3:20][NH:21]N>C(OCC)C>[Cl:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1[N:21]([CH3:20])[N:17]=[C:15]([CH3:16])[C:10]=1[C:11]([O:13][CH3:14])=[O:12]
Reactant: CNC(C)=C(C(=O)OC)C(=O)c1ccc(F)cc1Cl
Reactant: CNN
Solvent: CCOCC
Product: COC(=O)c1c(C)nn(C)c1-c1ccc(F)cc1Cl
Temperature: 25 °C
Reaction time: 48 h

Procedure:
A mixture of methyl 2-chloro-4-fluoro-α-[1-(methylamino)ethylidene]-β-oxobenzenepropanoate (i.e. the product of Step B) (15.91 g, 55.82 mmol) and methylhydrazine (3 mL, 56 mmol) in diethyl ether (150 mL) was stirred at room temperature for 48 h. The reaction mixture was concentrated under reduced pressure to provide the title compound as a colorless oil (15 g).
Reaction SMILES: C(O)C(N)(CO)CO.Cl.[Mg+2].[Cl-].[Cl-].C(S)[C@@H](O)[C@H](O)CS.[CH:21]1[N:25]([C@@H:26]2[O:30][C@@H:29]3[CH2:31][O:32]P(O)([O:35][C@H:28]3[C@H:27]2[OH:37])=O)[C:24]2[NH:38][C:39]([NH2:43])=[N:40][C:41](=[O:42])[C:23]=2[N:22]=1.C(N(CC(O)=O)CC(O)=O)COCCOCCN(CC(O)=O)CC(O)=O>CS(C)=O.O>[C@@H:26]1([N:25]2[C:24]3[NH:38][C:39]([NH2:43])=[N:40][C:41](=[O:42])[C:23]=3[N:22]=[CH:21]2)[O:30][C@H:29]([CH2:31][OH:32])[C@@H:28]([OH:35])[C@H:27]1[OH:37]
Reactant: Nc1nc(=O)c2ncn([C@@H]3O[C@@H]4COP(=O)(O)O[C@H]4[C@H]3O)c2[nH]1
Agent: Cl
Agent: NC(CO)(CO)CO
Agent: O=C(O)CN(CCOCCOCCN(CC(=O)O)CC(=O)O)CC(=O)O
Solvent: CS(C)=O
Solvent: O
Product: Nc1nc(=O)c2ncn([C@@H]3O[C@H](CO)[C@@H](O)[C@H]3O)c2[nH]1
Reaction time: 0.17 h

Procedure:
To 100 μL of a buffer D (40 mmol/L Tris-HCl, pH: 7.4, 10 mmol/L MgCl2, 1 mM DTT, 2 μM cGMP) solution containing [3H]-cGMP (0.5 pa/mL), 10 μL of a compound solution for evaluation (a solution in which a compound was dissolved in DMSO and diluted so that the DMSO concentration became 5%) and 90 μL of a solution prepared by diluting the PDE9 enzyme solution prepared in the above with a buffer E (40 mmol/L Tris-HCl, pH: 7.4, 10 mmol/L MgCl2, 1 mM DTT, 1 mmol/L EGTA) were added under ice cooling. The resultant mixed solution was incubated at 30° C. for 10 min, and thereafter heated for 2 min in boiled water to stop the enzyme reaction of the PDE9. Then, the resultant was returned to room temperature; 50 μL of 5′-Nucleotidase (Biomol GmbH, 10 units/mL) was added thereto; and the resultant was incubated at 30° C. for 10 min to thereby convert [3H]-5′-GMP formed in the previous reaction to [3H]-guanosine. 500 μL of an anion exchange resin (Bio-Rad AG1-X2 resin, mesh size: 200-400, H2O:resin=2:1) was added to the resultant reaction liquid, and allowed to stand for 10 min, and thereafter centrifuged (2,000 rpm, 10 min); and a supernatant in which the [3H]-guanosine was present was transferred to a LumaPlate (PerkinElmer, Inc.), and the radioactivity was measured by a TopCount NXT microplate scintillation and luminescence counter (PerkinElmer, Inc.).