Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O[C:2]1[N:7]2[N:8]=[CH:9][CH:10]=[C:6]2[N:5]=[CH:4][C:3]=1[C:11]([O:13][CH2:14][CH3:15])=[O:12].[Cl:16][C:17]1[CH:23]=[CH:22][C:21]([F:24])=[CH:20][C:18]=1[NH2:19]>>[Cl:16][C:17]1[CH:23]=[CH:22][C:21]([F:24])=[CH:20][C:18]=1[NH:19][C:2]1[N:7]2[N:8]=[CH:9][CH:10]=[C:6]2[N:5]=[CH:4][C:3]=1[C:11]([O:13][CH2:14][CH3:15])=[O:12]
Reactant: CCOC(=O)c1cnc2ccnn2c1O
Reactant: Nc1cc(F)ccc1Cl
Product: CCOC(=O)c1cnc2ccnn2c1Nc1cc(F)ccc1Cl
Yield: 83.9 %

Procedure:
Using ethyl 7-hydroxypyrazolo[1,5-a]pyrimidine-6-carboxylate (3.5 g, 16.9 mmol) and 2-chloro-5-fluoroaniline (2.21 g, 15.2 mmol) instead of 4-fluoro-2-methylaniline, and in the same manner as in Example 1 step 1, the title compound (4.27 g, 75%) was obtained.
Reaction SMILES: Cl[C:2]1[CH:9]=[CH:8][C:7]([S:10]([CH3:13])(=[O:12])=[O:11])=[CH:6][C:3]=1[C:4]#[N:5].[Cl:14][C:15]1[CH:20]=[CH:19][C:18]([CH2:21][C:22]([OH:24])=[O:23])=[CH:17][C:16]=1[OH:25]>>[Cl:14][C:15]1[CH:20]=[CH:19][C:18]([CH2:21][C:22]([OH:24])=[O:23])=[CH:17][C:16]=1[O:25][C:2]1[CH:9]=[CH:8][C:7]([S:10]([CH3:13])(=[O:12])=[O:11])=[CH:6][C:3]=1[C:4]#[N:5]
Reactant: CS(=O)(=O)c1ccc(Cl)c(C#N)c1
Reactant: O=C(O)Cc1ccc(Cl)c(O)c1
Product: CS(=O)(=O)c1ccc(Oc2cc(CC(=O)O)ccc2Cl)c(C#N)c1

Procedure:
The title compound was prepared by the method of example 2 step (iii) using the product of step (i) and the product of example 1 step (iii).
Reaction SMILES: [CH2:1]([O:4][C:5]([N:7]1[CH2:12][CH2:11][O:10][CH2:9][C@H:8]1[C:13]([OH:15])=O)=[O:6])[CH:2]=[CH2:3].[CH3:16][C:17]1([CH3:25])[O:22][C:21](=[O:23])[CH2:20][C:19](=[O:24])[O:18]1.C1(N=C=NC2CCCCC2)CCCCC1>ClCCl.CN(C)C1C=CN=CC=1>[CH2:1]([O:4][C:5]([N:7]1[CH2:12][CH2:11][O:10][CH2:9][C@H:8]1[C:13]([CH:20]1[C:21](=[O:23])[O:22][C:17]([CH3:25])([CH3:16])[O:18][C:19]1=[O:24])=[O:15])=[O:6])[CH:2]=[CH2:3]
Reactant: C=CCOC(=O)N1CCOC[C@H]1C(=O)O
Reactant: CC1(C)OC(=O)CC(=O)O1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: C=CCOC(=O)N1CCOC[C@H]1C(=O)C1C(=O)OC(C)(C)OC1=O
Temperature: 25 °C
Yield: 100.8 %

Procedure:
To a mixture of (3S)-4-allyloxycarbonylmorpholine-3-carboxylic acid (5.20 g) and 2,2-dimethyl-1,3-dioxane-4,6-dione (3.5 g) in dichloromethane (50 ml) were added dicyclohexylcarbodiimide (5.00 g) and 4-dimethylaminopyridine (2.96 g), in turn, under ice-cooling. The mixture was stirred under ice-cooling for 2 hours and at ambient temperature for 18 hours. Insoluble material was filtered off. The filtrate was washed with 1N hydrochloric acid (50 ml×2) and, next, brine (50 ml), dried over magnesium sulfate, and concentrated under reduced pressure to give 5-[(3S)-4-allyloxycarbonylmorpholin-3-yl]carbonyl-2,2-dimethyl-1,3-dioxane-4,6-dione (8.31 g) as a syrup.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:20][C:21]([O:23]C)=[O:22])[CH:5]=[CH:6][C:7]=1[O:8][CH2:9][C:10]1[CH:19]=[CH:18][C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[N:11]=1.[OH-].[Na+].Cl>CO>[F:1][C:2]1[CH:3]=[C:4]([CH2:20][C:21]([OH:23])=[O:22])[CH:5]=[CH:6][C:7]=1[O:8][CH2:9][C:10]1[CH:19]=[CH:18][C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[N:11]=1
Reactant: COC(=O)Cc1ccc(OCc2ccc3ccccc3n2)c(F)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)Cc1ccc(OCc2ccc3ccccc3n2)c(F)c1
Reaction time: 3 h

Procedure:
25 g (0.077 mol) of the compound from Example XIV are dissolved in 300 ml of methanol and 125 ml of 1 molar sodium hydroxide solution are added. The mixture is stirred at the boiling point for 3 h, allowed to cool and neutralised with 1N hydrochloric acid. The whole is evaporated to dryness in vacuo, and covered with 50 ml of water and with 150 ml of dichloromethane. The dichloromethane phase is dried and the solvent is evaporated in vacuo. Colourless crystals remain.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([NH2:11])[C:5]2[CH:6]=[CH:7][NH:8][C:9]=2[CH:10]=1.[Cl:12][C:13]1[CH:20]=[CH:19][C:16]([CH2:17]Cl)=[CH:15][CH:14]=1.[OH-].[Na+]>>[Cl:12][C:13]1[CH:20]=[CH:19][C:16]([CH2:17][N:8]2[C:9]3[CH:10]=[C:2]([F:1])[CH:3]=[C:4]([NH2:11])[C:5]=3[CH:6]=[CH:7]2)=[CH:15][CH:14]=1
Reactant: ClCc1ccc(Cl)cc1
Reactant: Nc1cc(F)cc2[nH]ccc12
Agent: [Na+]
Agent: [OH-]
Product: Nc1cc(F)cc2c1ccn2Cc1ccc(Cl)cc1
Temperature: 60 °C

Procedure:
A mixture of 6-fluoro-1H-indol-4-amine (5 g, 0.033 mol), 4-chlorobenzyl chloride (5.55 g, 0.035 mol) and sodium hydroxide (1.32 g, 0.033 mol) was heated at 60° C. for 3 h. The solvent was evaporated and the residue was dissolved in EA (150 mL) and water (70 mL). The aqueous layer was extracted with EA and washed with brine (100 mL), dried over sodium sulfate and concentrated in vacuo. The residue was purified by silica gel flash chromatography (PE: EA=8:1) to afford the title compound. LC/MS m/z=275.1 [M+H]+.
Reaction SMILES: [CH3:1][NH:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.Cl[C:10]1[CH:15]=[C:14]([Cl:16])[N:13]=[C:12]([NH2:17])[N:11]=1.Cl>O1CCOCC1>[Cl:16][C:14]1[N:13]=[C:12]([NH2:17])[N:11]=[C:10]([N:2]([CH3:1])[C:3]2[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=2)[CH:15]=1
Reactant: CNc1ccccc1
Reactant: Nc1nc(Cl)cc(Cl)n1
Agent: Cl
Solvent: C1COCCO1
Product: CN(c1ccccc1)c1cc(Cl)nc(N)n1

Procedure:
A 20-mL screw-cap vial was charged with N-methylaniline (0.653 g, 6.1 mmol), 4,6-dichloro-2-pyrimidinamine (1 g, 6.1 mmol), 1,4-dioxane (5 mL), and HCl (0.152 mL, 0.61 mmol, 4M in 1,4-dioxane). The vial was capped and stirred at reflux overnight. At this time, LCMS analysis indicated good conversion to the desired product, so the reaction mixture was poured into 1:1 NaHCO3 (sat) and water (20 mL) and extracted with EtOAc (3×50 mL). The combined organics were dried (Na2SO4) and concentrated. The solid residue was triturated with CH2Cl2, to yield the title compound (644 mg) as an off-white solid. LC-MS (ES) m/z=235 [M+H]+.
Reaction SMILES: [CH2:1]([S:8][CH2:9][CH2:10][C@H:11]([NH:28]C(=O)OC(C)(C)C)[C:12]1[N:17]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:16](=[O:24])[C:15]2=[CH:25][CH:26]=[CH:27][N:14]2[N:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.O1CCOCC1>>[NH2:28][C@H:11]([C:12]1[N:17]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:16](=[O:24])[C:15]2=[CH:25][CH:26]=[CH:27][N:14]2[N:13]=1)[CH2:10][CH2:9][S:8][CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)N[C@@H](CCSCc1ccccc1)c1nn2cccc2c(=O)n1-c1ccccc1
Agent: Cl
Solvent: C1COCCO1
Product: N[C@@H](CCSCc1ccccc1)c1nn2cccc2c(=O)n1-c1ccccc1
Yield: 128 %

Procedure:
(S)-tert-Butyl (3-(benzylthio)-1-(4-oxo-3-phenyl-3,4-dihydropyrrolo[2,1-f][1,2,4]triazin-2-yl)propyl)carbamate (12 mg, 0.02 mmol) was treated with a solution of hydrochloric acid in dioxane (4M, 92 μl, 0.37 mmol) according to the method described in Preparation 1 to obtain 10 mg (96% yield) of the title compound as a yellow solid. Purity 100%.
Reaction SMILES: Cl[CH:2]([CH3:28])[CH2:3][CH2:4][CH2:5][CH:6]1[CH2:10][CH2:9][CH:8]([C:11]2[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=2)[N:7]1[S:18]([C:21]1[CH:26]=[CH:25][C:24]([CH3:27])=[CH:23][CH:22]=1)(=[O:20])=[O:19].[NH:29]1[CH:33]=[CH:32][N:31]=[CH:30]1>>[F:17][C:14]1[CH:13]=[CH:12][C:11]([CH:8]2[N:7]([S:18]([C:21]3[CH:22]=[CH:23][C:24]([CH3:27])=[CH:25][CH:26]=3)(=[O:19])=[O:20])[CH:6]([CH2:5][CH2:4][CH2:3][CH2:2][CH2:28][N:29]3[CH:33]=[CH:32][N:31]=[CH:30]3)[CH2:10][CH2:9]2)=[CH:16][CH:15]=1
Reactant: Cc1ccc(S(=O)(=O)N2C(CCCC(C)Cl)CCC2c2ccc(F)cc2)cc1
Reactant: c1c[nH]cn1
Product: Cc1ccc(S(=O)(=O)N2C(CCCCCn3ccnc3)CCC2c2ccc(F)cc2)cc1

Procedure:
The title compound, colorless oil, MS: m/e 456.5 (M+Ht), was prepared in accordance with the general method of example 82b from (2RS,5RS)-2-(4-chloro-pentyl)-5-(4-fluoro-phenyl)-1-(toluene-4-sulfonyl)-pyrrolidine and 1H-imidazole.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[CH2:7][CH2:6][CH2:5]2.Br[CH2:12][CH2:13][CH2:14][CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17].C(N(C(C)C)C(C)C)C>C(OCC)C>[CH2:7]1[C:8]2[C:4](=[CH:3][C:2]([NH:1][CH2:12][CH2:13][CH2:14][CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17])=[CH:10][CH:9]=2)[CH2:5][CH2:6]1
Reactant: Nc1ccc2c(c1)CCC2
Reactant: CCOC(=O)CCCCBr
Solvent: CCOCC
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)CCCCNc1ccc2c(c1)CCC2
Yield: 31.8 %

Procedure:
13.3 g of 5-aminoindane, 23.0 g of ethyl 5-bromovalerate and 14.2 g of ethyl diisopropylamine are stirred together for 12 hours at 50°. After addition of diethyl ether thereto, the resulting precipitate is filtered off, the solvent is removed, and all volatile components are distilled off from the residue at 50° under a pressure of 10-2 mm Hg. The residue (which is left) is recrystallized from petrol ether to obtain 8.3 g (55.7% of theory) of ethyl 5-(indan-5-ylamino)valerate, MP 61° to 63°.
Reaction SMILES: [NH2:1][CH2:2][C@@H:3]1[O:7][C:6](=[O:8])[N:5]([C:9]2[CH:14]=[CH:13][C:12]([CH:15]3[CH2:20][CH2:19][S:18](=[O:22])(=[O:21])[CH2:17][CH2:16]3)=[C:11]([F:23])[CH:10]=2)[CH2:4]1.C(N(C(C)C)CC)(C)C.[C:33](Cl)(=[O:40])[O:34][CH2:35][O:36][C:37](=[O:39])[CH3:38]>C(Cl)Cl>[C:37]([O:36][CH2:35][O:34][C:33]([NH:1][CH2:2][C@@H:3]1[O:7][C:6](=[O:8])[N:5]([C:9]2[CH:14]=[CH:13][C:12]([CH:15]3[CH2:20][CH2:19][S:18](=[O:21])(=[O:22])[CH2:17][CH2:16]3)=[C:11]([F:23])[CH:10]=2)[CH2:4]1)=[O:40])(=[O:39])[CH3:38]
Reactant: CC(=O)OCOC(=O)Cl
Reactant: NC[C@H]1CN(c2ccc(C3CCS(=O)(=O)CC3)c(F)c2)C(=O)O1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(=O)OCOC(=O)NC[C@H]1CN(c2ccc(C3CCS(=O)(=O)CC3)c(F)c2)C(=O)O1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 165.7 %

Procedure:
To a stirred suspension of the 4-{4-[(5S)-5-(aminomethyl)-2-oxo-1,3-oxazolidin-3-yl]-2-fluorophenyl}tetrahydro-1λ6-thiopyran-1,1(2H)-dione (4.68 g, 13.74 mmol) prepared according to the PCT international publication WO 97/09328 in CH2Cl2 (100 mL) cooled to 0° C. is added diisopropylethylamine (4.8 ml, 27.48 mmol) followed by a solution of 2.4 g (1.5 7 mmol) of the acid chloride (from Step 4) in CH2Cl2 (10 mL) with a 2 mL rinse. The reaction mixture is stirred at 0° C. fro 30 min then at RT for 3 h. The reaction mixture is partitioned between CH2Cl2 (300 mL) and H2O (200 mL). The phases are separated. The organics are washed with 1N HCl (100 mL), brine (100 mL), dried (MgSO4), filtered and concentrated. The residue is dissolved in CH2Cl2, absorbed onto silca gel and purified on a Biotage 40M with a SIM using 2% CH3OH in CH2Cl2 as the eluent to afford 5.32 g (11.6 mmol, 85%) of the desired carbamate as a white foam. 1H NMR (DMSO) δ 7.96 (t, J=6 Hz, 1H), 7.48 (dd, J=14, 2 Hz, 1H), 7.38 (t, J=9 Hz, 1H), 7.24 (dd, J=9, 2 Hz, 1H), 5.61(s, 2H), 4.74 (m, 1H), 4.12 (t, J=9 Hz, 1H), 3.76 (dd, J=9, 7 Hz, 1H), 3.38 (m, 4 H), 3.16 (m, 1H), 3.11 (m, 2H), 2.13 (m, 2H), 2.06 (m, 1H), 2.01 (s, 3H); 13C NMR (DMSO-d6) δ 169.3, 160.6, 158 (d, J=246 Hz), 154.8, 153.8, 138.3 (d, J=8 Hz), 128.1, 125.2 (d, J=11 Hz), 113.7, 105.2 (d, J=26 Hz), 79.3, 71.7, 54.8, 50.3, 46.8, 43.1, 33.3, 29.8, 20.4; IR (diffuse reflectance) 2415, 2351, 2328, 1921, 1916, 1753, 1744, 1515, 1411, 1292, 1247, 1223, 1121, 1010, 983 cm−1. % Water (KF titration): 1.08. [a]25D=−36° (c 0.91, DMSO). Anal. Calcd for C19H23FN2O8S plus 1.08% H2O: C, 49.24; H, 5.12; N, 6.04; S, 6.85. Found: C, 49.05; H, 5.21; N, 5.81; S, 6.85.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([O:8][C:9]2[C:14]([F:15])=[CH:13][C:12]([CH2:16][OH:17])=[CH:11][C:10]=2[F:18])[CH:5]=[CH:4][N:3]=1.Cl[C:20]1[CH:21]=[C:22]2[N:29]([CH3:30])[C:28]([CH3:32])([CH3:31])[CH2:27][N:23]2[C:24](=[O:26])[N:25]=1>>[Cl:1][C:2]1[CH:7]=[C:6]([O:8][C:9]2[C:14]([F:15])=[CH:13][C:12]([CH2:16][O:17][C:20]3[CH:21]=[C:22]4[N:29]([CH3:30])[C:28]([CH3:32])([CH3:31])[CH2:27][N:23]4[C:24](=[O:26])[N:25]=3)=[CH:11][C:10]=2[F:18])[CH:5]=[CH:4][N:3]=1
Reactant: OCc1cc(F)c(Oc2ccnc(Cl)c2)c(F)c1
Reactant: CN1c2cc(Cl)nc(=O)n2CC1(C)C
Product: CN1c2cc(OCc3cc(F)c(Oc4ccnc(Cl)c4)c(F)c3)nc(=O)n2CC1(C)C

Procedure:
The title compound was prepared by a procedure similar to that described for E9 starting from (4-((2-chloropyridin-4-yl)oxy)-3,5-difluorophenyl)methanol and 7-chloro-1,2,2-tri-methyl-2,3-dihydroimidazo[1,2-c]pyrimidin-5(1H)-one.
Reaction SMILES: C(O)(C)C.C([O-])=O.[NH4+].Cl[C:10]1[N:11]=[C:12]([N:25]2[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]2)[C:13]2[N:19]=[C:18]([C:20]([O:22][CH3:23])=[O:21])[CH:17]=[C:16](Cl)[C:14]=2[N:15]=1>O.[Pd]>[N:25]1([C:12]2[C:13]3[N:19]=[C:18]([C:20]([O:22][CH3:23])=[O:21])[CH:17]=[CH:16][C:14]=3[N:15]=[CH:10][N:11]=2)[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]1
Reactant: COC(=O)c1cc(Cl)c2nc(Cl)nc(N3CCCCC3)c2n1
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CC(C)O
Solvent: O
Product: COC(=O)c1ccc2ncnc(N3CCCCC3)c2n1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 80.1 %

Procedure:
To a round-bottom flask were added palladium (540 mg; 0.51 mmol; 0.05 eq.) isopropanol (90 mL). Ar was bubbled in this mixture. A degassed ammonium formate solution in water (2.56 g, 40.6 mmol, 4 eq., in 4 mL of water) was added, followed by methyl 2,8-dichloro-4-(1-piperidinyl)pyrido[3,2-d]pyrimidine-6-carboxylate (Intermediate 1.4) (3.46 g; 10.5 mmol; 1 eq.) and degassed isopropanol (10 mL). After 30 min, a second batch of ammonium formate was added as solution in water (2.56 g, 40.6 mmol, 4 eq., in 4 mL of water). Finally, after additional 30 min, another 8 equivalents of ammonium formate in water were (5.12 g, 81.2 mmol, 8 eq., in 8 mL of water). The mixture was then stirred at rt. overnight and filtered through celite. The filtrate was evaporated. The crude product was dissolved in DCM and washed with water and brine. Organic phase was dried over magnesium sulfate, filtered and evaporated to give methyl 4-(1-piperidinyl)pyrido[3,2-d]pyrimidine-6-carboxylate (2.29 g; 83%) (Intermediate 1.5), as a yellow solid in 92.9% HPLC purity. This product was used in the next step without further purification.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:13])[CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[OH:12].[Br:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19]Br.C(=O)([O-])[O-].[K+].[K+].C(#N)C>CCOCC>[CH3:1][O:2][C:3](=[O:13])[CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[O:12][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][Br:14]
Reactant: COC(=O)CCc1ccccc1O
Reactant: BrCCCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOCC
Solvent: CC#N
Product: COC(=O)CCc1ccccc1OCCCCCBr
Yield: 586.1 %

Procedure:
A mixture of 3.6 g (20 mmol) of 2-hydroxybenzenepropanoic acid methyl ester, 22 mL (160 mmol) of 1,5-dibromopentane, 8.73 g (63.3 mmol) of anhydrous granular potassium carbonate, and 145 mL of acetonitrile was stirred and refluxed for 24 hr. The resulting slurry was cooled and diluted with 300 mL of ether. The solids were removed by suction filtration and the filter cake was washed well with ether. The filtrate and washes were combined and concentrated in vacuo giving 38.59 g of a brown oil which was chromatographed on 200 g of silica gel, eluting with 49:1 and 19:1 hexane-ether. The fractions containing the desired product were combined and concentrated giving 5.86 g of an oil which was dissolved in 50 mL of methanol containing 0.2 g of p-toluenesulfonic acid monohydrate. The solution was stirred at room temperature for 17 hr and refluxed for 5 hr before being cooled and concentrated in vacuo. The residue was dissolved in ether and the solution was washed with saturated sodium bicarbonate solution and worked-up in the usual manner. The oily residue was chromatographed on 100 g of silica gel. Elution with 19:1 hexane-ether afforded 4.85 g (73.7%) of 2-[5-bromopentyl)oxy]benzenepropanoic acid methyl ester as a colorless oil.
Reaction SMILES: Cl.[F:2][CH:3]1[CH2:8][CH2:7][NH:6][CH2:5][CH2:4]1.Br[CH2:10][CH2:11][Cl:12]>>[Cl:12][CH2:11][CH2:10][N:6]1[CH2:7][CH2:8][CH:3]([F:2])[CH2:4][CH2:5]1
Reactant: ClCCBr
Reactant: FC1CCNCC1
Agent: Cl
Product: FC1CCN(CCCl)CC1
Yield: 21.1 %

Procedure:
The title compound has been prepared according to the similar manner described in 86-B (i) using 4-fluoropiperidine hydrochloride (1.00 g, 7.16 mmol) and 1-bromo-2-chloroethane (717 μL, 8.60 mmol). The crude product has been purified by silica gel column chromatography (EtOAc/hexane=10/90→40/60) to obtain pure title compound (250 mg, 21%) as a pale yellow oil.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[CH:5][C:6]2[O:11][C:10]([CH2:15][O:16][CH3:17])([CH2:12][O:13][CH3:14])[C@@H:9]([OH:18])[C@H:8]([NH:19][C:20]3[CH:25]=[CH:24][C:23](=[O:26])[NH:22][N:21]=3)[C:7]=2[CH:27]=1)#[N:2].[Cl:28][CH2:29][C:30]#[C:31][CH2:32]Cl.C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[C:1]([C:3]1[CH:4]=[CH:5][C:6]2[O:11][C:10]([CH2:12][O:13][CH3:14])([CH2:15][O:16][CH3:17])[C@@H:9]([OH:18])[C@H:8]([NH:19][C:20]3[CH:25]=[CH:24][C:23](=[O:26])[N:22]([CH2:32][C:31]#[C:30][CH2:29][Cl:28])[N:21]=3)[C:7]=2[CH:27]=1)#[N:2]
Reactant: COCC1(COC)Oc2ccc(C#N)cc2[C@@H](Nc2ccc(=O)[nH]n2)[C@@H]1O
Reactant: ClCC#CCCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COCC1(COC)Oc2ccc(C#N)cc2[C@@H](Nc2ccc(=O)n(CC#CCCl)n2)[C@@H]1O
Yield: 24.8 %

Procedure:
(-)-(3S,4R)-6-Cyano-3,4-dihydro-4-[(1,6-dihydro-6-oxo-3-pyridazinyl)amino]-2,2-bis(methoxymethyl)-2H-1-benzopyran-3-ol (556 mg, 1.5 mmol) obtained in Example 8 and 1,4-dichloro-2-butyne (2.9 ml, 30 mmol) were dissolved in dimethylformamide (10 ml). Potassium carbonate (413 mg) was added and the mixture was reacted at 120° C. overnight. Water was added to the reaction mixture and the mixture was extracted with chloroform. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was distilled away under reduced pressure. The residue obtained was purified by silica gel column chromatography (methanol:chloroform=1:30) to give 171 mg of crude (3S,4R)-6-cyano-4-[(1-(4-chloro-2-butyn-1-yl)-1,6-dihydro-6-oxo-3-pyridazinyl)amino]-3,4-dihydro-2,2-bis(methoxymethyl)-2H-1-benzopyran-3-ol. The compound was dissolved in dimethylformamide (3 ml), added with diethylamine and stirred at 70° C. for 2.5 hours. Water was added and the mixture was extracted with chloroform. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was distilled away under reduced pressure. The residue obtained was purified by silica gel column chromatography (chloroform:methanol=20:1) to give 71 mg of the title compound (38%).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[C:5]([C:9]([OH:11])=[O:10])=[C:4]([Cl:12])[N:3]=1.CCN(CC)CC.[NH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([CH3:27])[CH:22]=1.Cl>CN(C=O)C>[Cl:1][C:2]1[N:3]=[C:4]([Cl:12])[C:5]([C:9]([OH:11])=[O:10])=[C:6]([NH:20][C:21]2[CH:22]=[C:23]([CH3:27])[CH:24]=[CH:25][CH:26]=2)[N:7]=1
Reactant: O=C(O)c1c(Cl)nc(Cl)nc1Cl
Reactant: Cc1cccc(N)c1
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: Cc1cccc(Nc2nc(Cl)nc(Cl)c2C(=O)O)c1
Temperature: 25 °C
Reaction time: 12 h
Yield: 58.5 %

Procedure:
To a solution of 2,4,6-trichloropyrimidine-5-carboxylic acid (5.69 g, 25.02 mmol) in DMF (60 mL) was added Et3N (8 mL, 57.4 mmol) and m-toluidine (3.2 mL, 29.5 mmol) at 0° C. The mixture was stirred at RT for 12 h. To the mixture was added 1N HCl. The mixture was extracted with EtOAc. The organic layers were basified with saturated aq NaHCO3 and the aqueous layers were washed with EtOAc. The washed aqueous layer was acidified with 1N HCl and extracted with EtOAc. The combined organic layers were washed with 1N HCl, water, and brine, were dried over anhydrous Na2SO4, and then filtered. The filtrate was concentrated under reduced pressure, triturated with hexane, and filtered to give a first batch of the title compound (4.36 g). The filtrate was concentrated, triturated with hexane, and filtered to give a second batch (0.36 g) of the title compound (total 4.72 g, 63%). 1H NMR (500 MHz, DMSO-d6) δ ppm 2.30 (s, 3H), 7.00-7.02 (m, 1H), 7.25-7.28 (m, 2H), 7.33-7.35 (m, 2H), 10.13 (s, 1H), 1H not detected. [M+H] calc'd for C12H10Cl2N3O2, 298. found, 298.
Reaction SMILES: [N:1]1([C:10]2([C:15]([OH:17])=O)[CH2:14][CH2:13][CH2:12][CH2:11]2)[C:5]2=[N:6][CH:7]=[CH:8][CH:9]=[C:4]2[CH:3]=[CH:2]1.C(Cl)(=O)C([Cl:21])=O.CN(C)C=O>ClCCl>[N:1]1([C:10]2([C:15]([Cl:21])=[O:17])[CH2:14][CH2:13][CH2:12][CH2:11]2)[C:5]2=[N:6][CH:7]=[CH:8][CH:9]=[C:4]2[CH:3]=[CH:2]1
Reactant: O=C(Cl)C(=O)Cl
Reactant: O=C(O)C1(n2ccc3cccnc32)CCCC1
Solvent: CN(C)C=O
Solvent: ClCCl
Product: O=C(Cl)C1(n2ccc3cccnc32)CCCC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a stirred solution of 1-pyrrolo[2,3-b]pyridin-1-yl-cyclopentanecarboxylic acid (394) (1.2 g, 5.21 mmol) in dichloromethane (80 mL) was dropwise added oxalyl chloride (1 mL, 11.47 mmol) at 0° C., followed by dimethyl formamide (0.1 mL). The reaction mixture was stirred for 1 h at room temperature. After completion, the reaction mixture is concentrated under argon atmosphere tog et 1-pyrrolo[2,3-b]pyridin-1-yl-cyclopentanecarbonyl chloride (395) (1.3 g, 100%, crude) as a yellow solid which was directly used for the next step without analysis.
Reaction SMILES: [Cl:1][C:2]1[C:3](=[O:11])[N:4]([CH2:9][CH3:10])[N:5]=[CH:6][C:7]=1Cl.[CH3:12][O-:13].[Na+]>CO>[Cl:1][C:2]1[C:3](=[O:11])[N:4]([CH2:9][CH3:10])[N:5]=[CH:6][C:7]=1[O:13][CH3:12]
Reactant: CCn1ncc(Cl)c(Cl)c1=O
Reactant: C[O-]
Agent: [Na+]
Solvent: CO
Product: CCn1ncc(OC)c(Cl)c1=O

Procedure:
The title compound, white crystalline solid, was prepared in accordance with the general method of example 23e by treatment of 4,5-dichloro-2-ethyl-2H-pyridazin-3-one with sodium methoxide in methanol.
Reaction SMILES: [CH:1]1([OH:6])[CH2:5][CH2:4][CH2:3][CH2:2]1.[H-].[Na+].[Cl:9][C:10]1[N:11]=[C:12](Cl)[C:13]2[C:18]([I:19])=[CH:17][N:16]([CH2:20][O:21][CH2:22][CH2:23][Si:24]([CH3:27])([CH3:26])[CH3:25])[C:14]=2[N:15]=1>C1COCC1>[Cl:9][C:10]1[N:11]=[C:12]([O:6][CH:1]2[CH2:5][CH2:4][CH2:3][CH2:2]2)[C:13]2[C:18]([I:19])=[CH:17][N:16]([CH2:20][O:21][CH2:22][CH2:23][Si:24]([CH3:27])([CH3:26])[CH3:25])[C:14]=2[N:15]=1
Reactant: OC1CCCC1
Reactant: C[Si](C)(C)CCOCn1cc(I)c2c(Cl)nc(Cl)nc21
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: C[Si](C)(C)CCOCn1cc(I)c2c(OC3CCCC3)nc(Cl)nc21
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 46 %

Procedure:
To a solution of cyclopentanol (1 equiv) in anhydrous THF (0.22 M) was added sodium hydride (60% in mineral oil, 1.3 equiv) at 0° C. under nitrogen. After the resulting reaction mixture was stirred at room temperature for 30 min, 2,4-dichloro-5-iodo-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidine (0.67 equiv) was added. The reaction was stirred at room temperature for 4 h and quenched with saturated aqueous ammonium chloride solution. The aqueous layer was extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate and filtered. Concentration under vacuum gave the crude product, which was purified by silica gel column chromatography (5% ethyl acetate in petroleum ether) to afford the title compound (46% yield). MS (ESI) m/z 493.2. [M+1]+.
Reaction SMILES: C[O:2][C:3](=O)[CH:4]([CH:21]1[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]1)[C:5]([C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[CH:9][CH:8]=1)=O.[NH2:28][C:29]1[NH:33][N:32]=[C:31]([C:34]([NH2:36])=[O:35])[CH:30]=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[CH2:14]([O:13][C:10]1[CH:9]=[CH:8][C:7]([C:5]2[NH:28][C:29]3[N:33]([N:32]=[C:31]([C:34]([NH2:36])=[O:35])[CH:30]=3)[C:3](=[O:2])[C:4]=2[CH:21]2[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]2)=[CH:12][CH:11]=1)[C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: NC(=O)c1cc(N)[nH]n1
Reactant: COC(=O)C(C(=O)c1ccc(OCc2ccccc2)cc1)C1CCCCC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: O
Product: NC(=O)c1cc2[nH]c(-c3ccc(OCc4ccccc4)cc3)c(C3CCCCC3)c(=O)n2n1
Yield: 1.8 %

Procedure:
A mixture of 1.0 g (2.7 mmol) of 3-(4-benzyloxy-phenyl)-2-cyclohexyl-3-oxo-propionic acid methyl ester, 340 mg (2.7 mmol) of 5-amino-1H-pyrazole-3-carboxylic acid amide, 51 mg (10 mol %) of p-toluenesulfonic acid monohydrate (PTSA), and 15 mL of toluene was heated at reflux for 72 h. The reaction mixture was then concentrated to a residue which chromatographed on silica gel (Biotage; gradient elution 15% ethyl acetate in dichloromethane to 6% methanol in dichloromethane) to give a residue which was further purified via reverse-phase chromatography (Gilson) to afford (after lyophilization) 22 mg (2% yield) of desired 5-(4-benzyloxy-phenyl)-6-cyclohexyl-7-oxo-4,7-dihydro-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid amide as indicated by 1H-NMR; LC-MS calcd for C26H26N4O3 [M++H]+: 443.2, found: 443.2.