Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6](OS(C(F)(F)F)(=O)=O)[CH:5]=[C:4]([C:16]2[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][CH:17]=2)[CH:3]=1.[N:26]1[CH:31]=[CH:30][C:29]([C:32]2[CH:33]=[C:34](B(O)O)[CH:35]=[CH:36][CH:37]=2)=[CH:28][CH:27]=1>>[CH3:1][C:2]1[CH:3]=[C:4]([C:16]2[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][CH:17]=2)[CH:5]=[C:6]([C:34]2[CH:35]=[CH:36][CH:37]=[C:32]([C:29]3[CH:28]=[CH:27][N:26]=[CH:31][CH:30]=3)[CH:33]=2)[N:7]=1
Reactant: Cc1cc(-c2ccc(C(F)(F)F)cc2)cc(OS(=O)(=O)C(F)(F)F)n1
Reactant: OB(O)c1cccc(-c2ccncc2)c1
Product: Cc1cc(-c2ccc(C(F)(F)F)cc2)cc(-c2cccc(-c3ccncc3)c2)n1

Procedure:
The title compound was prepared from trifluoro-methanesulfonic acid 6-methyl-4-(4-trifluoromethyl-phenyl)-pyridin-2-yl ester (example A.32) (0.250 g, 0.65 mmol) and 3-pyridin-4-yl-benzeneboronic acid [CAS-No. 337536-25-1] (0.143 g, 0.71 mmol) according to the general procedure VI. Obtained as a white solid (0.101 g, 40%). MS (ISP) 391.1 [(M+H)+]; mp 143-147° C.
Reaction SMILES: [NH2:1][C:2]1[C:3](=[O:14])[NH:4][C:5](=[S:13])[N:6]([CH2:9][CH:10]([CH3:12])[CH3:11])[C:7]=1[NH2:8].O.[CH:16](O)=[O:17]>>[NH2:8][C:7]1[N:6]([CH2:9][CH:10]([CH3:11])[CH3:12])[C:5](=[S:13])[NH:4][C:3](=[O:14])[C:2]=1[NH:1][CH:16]=[O:17]
Reactant: CC(C)Cn1c(N)c(N)c(=O)[nH]c1=S
Reactant: O=CO
Solvent: O
Product: CC(C)Cn1c(N)c(NC=O)c(=O)[nH]c1=S
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 86 %

Procedure:
5,6-Diamino-1-isobutyl-2-thioxo-2,3-dihydro-1H-pyrimidin-4-one (Example 6 (c), 0.25 g, 1.2 mmol) was dissolved in formic acid (1.5 mL) and stirred at ambient temperature for 0.5 h. A pink precipitate started to form after a few minutes. Water was added and the resulting mixture stirred for 10 minutes. The pink solid was collected by filtration, washed with water and dried to yield the title compound (0.25 g, 86%). This material was used without further purification. NMR showed that the product was obtained as a mixture of two tautomers: formamide (major) and imino (minor).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]2[CH2:9][O:8][B:7]([OH:10])[C:6]=2[CH:11]=1.N1C=CC=CC=1.Cl[S:19]([C:22]1[CH:27]=[CH:26][C:25]([NH:28][C:29](=[O:34])[C:30]([F:33])([F:32])[F:31])=[CH:24][C:23]=1[CH2:35][C:36]([O:38][CH2:39][CH3:40])=[O:37])(=[O:21])=[O:20]>C(Cl)Cl>[OH:10][B:7]1[C:6]2[CH:11]=[C:2]([NH:1][S:19]([C:22]3[CH:27]=[CH:26][C:25]([NH:28][C:29](=[O:34])[C:30]([F:31])([F:32])[F:33])=[CH:24][C:23]=3[CH2:35][C:36]([O:38][CH2:39][CH3:40])=[O:37])(=[O:20])=[O:21])[CH:3]=[CH:4][C:5]=2[CH2:9][O:8]1
Reactant: CCOC(=O)Cc1cc(NC(=O)C(F)(F)F)ccc1S(=O)(=O)Cl
Reactant: Nc1ccc2c(c1)B(O)OC2
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCOC(=O)Cc1cc(NC(=O)C(F)(F)F)ccc1S(=O)(=O)Nc1ccc2c(c1)B(O)OC2
Temperature: 25 °C
Reaction time: 2 h
Yield: 0.9 %

Procedure:
To a solution of 6-amino-3H-benzo[c][1,2]oxaborol-1-ol (0.7 g, 4.7 mmol), pyridine (1 mL, 12.4 mmol) in DCM (10 mL) was added ethyl 2-(2-(chlorosulfonyl)-5-(2,2,2-trifluoroacetamido)phenyl)acetate (1.5 g, 4 mmol). The reaction was stirred at r.t. for 2 hr and monitored by LC/MS. Purification: The solvent was removed and worked up with EtOAc and 1N HCl, brine, dried over Na2SO4. A portion of the crude material was purified by the preparative HPLC give the title product ethyl 2-(2-(N-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-6-yl)sulfamoyl)-5-(2,2,2-trifluoroacetamido)phenyl)acetate 18 mg as white powder 1H NMR (400 MHz, DMSO-d6) δ (ppm): 11.54 (s, 1H), 10.36 (s, 1H), 9.21 (bs, 1H), 7.85 (d, J=8 Hz, 1H), 7.71 (m, 2H), 7.44 (d, J=2 Hz, 1H), 7.25 (d, J=8.4 Hz, 1H), 7.12 (dd, J=8, 2 Hz, 1H), 4.87 (s, 2H), 4.06 (m, 4H), 1.17 (t, J=7.2 Hz, 3H); MS (ESI) m/z=485.1 (M−H, negative).
Reaction SMILES: Br[C:2]1[N:3]([C:13]2[CH:18]=[CH:17][C:16]([OH:19])=[CH:15][CH:14]=2)[C:4]2[C:9]([C:10]=1[C:11]#[N:12])=[CH:8][CH:7]=[CH:6][CH:5]=2.[NH:20]1[CH:24]=[CH:23][CH:22]=[CH:21]1.C(=O)([O-])[O-].[Cs+].[Cs+]>[Cu]I.CN(C=O)C>[OH:19][C:16]1[CH:17]=[CH:18][C:13]([N:3]2[C:4]3[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=3)[C:10]([C:11]#[N:12])=[C:2]2[N:20]2[CH:24]=[CH:23][CH:22]=[CH:21]2)=[CH:14][CH:15]=1
Reactant: N#Cc1c(Br)n(-c2ccc(O)cc2)c2ccccc12
Reactant: c1cc[nH]c1
Agent: [Cu]I
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: N#Cc1c(-n2cccc2)n(-c2ccc(O)cc2)c2ccccc12
Temperature: 120 °C
Reaction time: 48 h

Procedure:
2-Bromo-1-(4-hydroxy-phenyl)-1H-indole-3-carbonitrile (Example 1), 1.4 eq pyrrole, 2 eq cesium carbonate and 20 mol % copper(I) iodide was mixed in a oven-dried vial, DMF was added and the mixture was flushed with nitrogen. The vial was sealed and stirred at 120° C. for 48 hours. The reaction-mixture was cooled to rt, diluted with EtOAc and filtered through silica. The crude mixture was evaporated to dryness and subjected to reversed phase preparative HPLC. Appropriate fractions were combined and evaporated, and identified by 1H-NMR and LC/MS. Purity was determined by analytical HPLC. ES/MS m/z: 300.2 (M+H), 298.3 (M−H); 1H NMR (acetone-d6, 500 MHz): 7.74 (m, 1H), 7.41-7.35 (m, 2H), 7.27 (m, 2H), 7.23 (m, 1H), 6.98 (m, 2H), 6.95 (t, 2H, J=2.2 Hz) and 6.23 (t, 2H, J=2.2 Hz).
Reaction SMILES: [Cl:1][C:2]1[C:10]([C:11]([F:14])([F:13])[F:12])=[C:9]([F:15])[CH:8]=[CH:7][C:3]=1[C:4](O)=[O:5].[N:16]1([O-])C2C=CC=CC=2N=N1.[NH4+].Cl.CN(C)CCCN=C=NCC.C(N1CCOCC1)C.C(=O)([O-])O.[Na+]>ClCCl>[Cl:1][C:2]1[C:10]([C:11]([F:14])([F:13])[F:12])=[C:9]([F:15])[CH:8]=[CH:7][C:3]=1[C:4]([NH2:16])=[O:5]
Reactant: [O-]n1nnc2ccccc21
Reactant: O=C(O)c1ccc(F)c(C(F)(F)F)c1Cl
Agent: CCN1CCOCC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Product: NC(=O)c1ccc(F)c(C(F)(F)F)c1Cl
Reaction time: 0.25 h
Yield: 88.3 %

Procedure:
2-Chloro-4-fluoro-3-(trifluoromethyl)benzoic acid (0.560 g, 2.31 mmol), ammonium 1H-1,2,3-benzotriazol-1-olate (0.534 g, 3.47 mmol, prepared as described below), N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (0.643 g, 3.47 mmol), and N-ethyl morpholine (0.594 ml, 4.62 mmol) were stirred together in dichloromethane (30 ml) for a total of 3 hrs. Saturated aqueous sodium hydrogen carbonate (30 ml) was added and the mixture was stirred for 15 minutes. The organic layer was separated using a hydrophobic frit and then washed with 2N aqueous hydrogen chloride (2×50 ml). Separation of the organic layer, again using a hydrophobic frit, and evaporation in vacuo gave 2-chloro-4-fluoro-3-(trifluoromethyl)benzamide (0.493 g) as an off-white solid which was used without further purification in the subsequent step.
Reaction SMILES: I[C:2]1[C:3]([NH2:12])=[N:4][CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1.[NH:13]1[CH:17]=[N:16][CH:15]=[N:14]1.N1C2C(=CC=CC=2O)C=CC=1.C(=O)([O-])[O-].[K+].[K+]>C(OCC)(=O)C.[Cu]I.CS(C)=O>[N:13]1([C:2]2[C:3]([NH2:12])=[N:4][CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=2)[CH:17]=[N:16][CH:15]=[N:14]1
Reactant: c1nc[nH]n1
Reactant: Nc1ncc(C(F)(F)F)cc1I
Agent: [Cu]I
Agent: O=C([O-])[O-]
Agent: Oc1cccc2cccnc12
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: Nc1ncc(C(F)(F)F)cc1-n1cncn1
Temperature: 120 °C
Reaction time: 7 h
Yield: 60.3 %

Procedure:
A mixture of 3-iodo-5-(trifluoromethyl)pyridin-2-amine (5.0 g), 1,2,4-triazole (1.44 g), copper(I) iodide (0.496 g), 8-quinolinol (0.378 g), potassium carbonate (2.88 g) and DMSO (50 mL) was stirred at 120° C. for 7 hr under nitrogen gas atmosphere. The reaction solution was allowed to be cooled to room temperature, diluted with ethyl acetate, and filtered through basic silica gel column (ethyl acetate). The filtrate was washed successively with water and saturated brine, and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified successively by silica gel column chromatography (ethyl acetate/hexane) and silica gel column chromatography (NH, ethyl acetate/hexane) to give the title compound (2.4 g).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8](Cl)[CH3:9])=[CH:4][CH:3]=1.[SH:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][N+:13]=1[O-:18].[Na]>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([S:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][N+:13]=2[O-:18])[CH3:9])=[CH:4][CH:3]=1
Reactant: [O-][n+]1ccccc1S
Reactant: CC(Cl)c1ccc(Cl)cc1
Agent: [Na]
Product: CC(Sc1cccc[n+]1[O-])c1ccc(Cl)cc1
Yield: 78 %

Procedure:
The intermediate 2-(1-[4-chlorophenyl]ethylthio)-pyridine N-oxide is prepared from 1-(4-chlorophenyl)ethylchloride and 2-mercaptopyridine N-oxide, sodium salt by the procedure described in Example 2. Melting point 106° - 108° C. Structure confirmed by IR and NMR.
Reaction SMILES: [H-].[Na+].[CH3:3][C:4]1[C:5]([CH2:10][OH:11])=[N:6][CH:7]=[CH:8][CH:9]=1.Cl[C:13]1[C:14]([CH:28]2[CH2:31][CH2:30][CH2:29]2)=[CH:15][C:16]2[N:17]([C:19]([C:22]3[CH:23]=[N:24][CH:25]=[CH:26][CH:27]=3)=[N:20][N:21]=2)[N:18]=1>CN(C=O)C.O>[CH:28]1([C:14]2[C:13]([O:11][CH2:10][C:5]3[C:4]([CH3:3])=[CH:9][CH:8]=[CH:7][N:6]=3)=[N:18][N:17]3[C:19]([C:22]4[CH:23]=[N:24][CH:25]=[CH:26][CH:27]=4)=[N:20][N:21]=[C:16]3[CH:15]=2)[CH2:29][CH2:30][CH2:31]1
Reactant: Clc1nn2c(-c3cccnc3)nnc2cc1C1CCC1
Reactant: Cc1cccnc1CO
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1cccnc1COc1nn2c(-c3cccnc3)nnc2cc1C1CCC1
Reaction time: 18 h
Yield: 14.5 %

Procedure:
Sodium hydride (60% dispersion in oil, 13.4 mg, 0.34 mmol) was added to a solution of (3-methylpyridin-2-yl)methanol (38 mg, 0.31 mmol) in dry DMF (1 ml) at room temperature. After 1 h at room temperature a solution of 6-chloro-7-cyclobutyl-3-(pyridin-3-yl)-1,2,4-triazolo[4,3-b]pyridazine (80 mg, 0.28 mmol) was added and the reaction stirred for 18 h. The reaction mixture was diluted with water (10 ml) and stirred for 10 minutes after which time the mixture was filtered and the residue washed, first with water, then with diethyl ether. The residue was purified by chromatography on silica gel, eluting with 0-5% dichloromethane-methanol to afford the title pyridazine (15.1 mg, 14%). 1NMR (250 MHz, CDCl3) δ1.83-1.89 (1H, m), 1.96-2.23 (3H, m), 2.28-2.40 (2H, m), 2.43 (3H, s), 3.57-3.67 (1H, m), 5.59 (2H, s), 7.23 (1H, m), 7.45-7.50 (1H, m), 7.58-7.61 (1H, d, J=7.6 Hz), 7.85 (1H, d, J=1.5 Hz), 8.49 (1H, m), 8.66 (2H, m), 9.71 (1H, br s). MS (ES+) m/e 373 [MH]+.
Reaction SMILES: Br[CH2:2][CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.Cl.Cl.[O:12]=[C:13]1[CH2:18][NH:17][CH2:16][CH2:15][N:14]1[CH2:19][CH2:20][CH2:21][NH:22][C:23]([C:25]1[S:35][C:34]2[N:36]3[C:27](=[CH:28][N:29]=[C:30]3[CH:31]=[CH:32][CH:33]=2)[CH:26]=1)=[O:24].C(N(CC)CC)C.[I-].[Na+].N12CCCNC1CCCC=C2>C(#N)C>[C:4]1([CH2:3][CH2:2][N:17]2[CH2:16][CH2:15][N:14]([CH2:19][CH2:20][CH2:21][NH:22][C:23]([C:25]3[S:35][C:34]4[N:36]5[C:27](=[CH:28][N:29]=[C:30]5[CH:31]=[CH:32][CH:33]=4)[CH:26]=3)=[O:24])[C:13](=[O:12])[CH2:18]2)[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: BrCCc1ccccc1
Reactant: O=C(NCCCN1CCNCC1=O)C1=Cc2cnc3cccc(n23)S1
Agent: C1=CN2CCCNC2CCC1
Agent: Cl
Agent: [I-]
Solvent: CCN(CC)CC
Solvent: CC#N
Product: O=C(NCCCN1CCN(CCc2ccccc2)CC1=O)C1=Cc2cnc3cccc(n23)S1
Yield: 43.9 %

Procedure:
(2-Bromoethyl)benzene (312 mg, 1.68 mmol) was added to a stirred solution of N-[3-(2-oxopiperazin-1-yl)propan-1-yl]-5-thia-1,8b-diazaacenaphthylene-4-carboxamide dihydrochloride (610 mg, 1.42 mmol), triethylamine (722 mg, 7.13 mmol), sodium iodide (255 mg, 1.70 mmol) and 1,8-diazabicyclo[5.4.0]undecene (438 mg, 2.88 mmol) in acetonitrile (20 ml) at room temperature. After refluxing under nitrogen for 2 days, the reaction mixture was concentrated in vacuo. The residue was dissolved in water and extracted with chloroform. The extract was washed with brine, dried over MgSO4 and concentrated in vacuo. The residue was chromatographed on silica gel(20 g) with Ethyl acetate-Methanol (8:1) to give N-[3-[4-(2-phenylethan-1-yl)-2-oxopiperazin-1-yl]propan-1-yl]-5-thia-1,8b-diazaacenaphthylene-4-carboxamide as a purple amorphous powder (288 mg, 44%).
Reaction SMILES: [F:1][C:2]1[CH:20]=[CH:19][CH:18]=[C:17]([O:21][CH3:22])[C:3]=1[CH2:4][N:5]1[C:13]2[C:8](=[N:9][CH:10]=[CH:11][CH:12]=2)[C:7]([C:14](O)=[O:15])=[CH:6]1.[CH:23]1([CH2:26][NH2:27])[CH2:25][CH2:24]1.CCCP1(OP(CCC)(=O)OP(CCC)(=O)O1)=O>C(Cl)Cl>[CH:23]1([CH2:26][NH:27][C:14]([C:7]2[C:8]3=[N:9][CH:10]=[CH:11][CH:12]=[C:13]3[N:5]([CH2:4][C:3]3[C:17]([O:21][CH3:22])=[CH:18][CH:19]=[CH:20][C:2]=3[F:1])[CH:6]=2)=[O:15])[CH2:25][CH2:24]1
Reactant: NCC1CC1
Reactant: COc1cccc(F)c1Cn1cc(C(=O)O)c2ncccc21
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Solvent: ClCCl
Product: COc1cccc(F)c1Cn1cc(C(=O)NCC2CC2)c2ncccc21
Temperature: 25 °C
Reaction time: 0.83 h

Procedure:
See FIG. 24(c). In a 50 mL round-bottomed flask 1-(2-fluoro-6-methoxybenzyl)-1H-pyrrolo[3,2-b]pyridine-3-carboxylic acid (0.130 g, 0.43 mmol), cyclopropylmethanamine (0.040 g, 0.56 mmol) and TEA (0.181 mL, 1.30 mmol) was taken DCM (10 mL) under N2. To this 1-Propanephosphonic acid cyclic anhydride (0.317 g, 1.00 mmol) was added. The resulting reaction was stirred at RT for 50 min. LCMS analysis showed formation of required product. Reaction was diluted with DCM and water. DCM layer was extracted and washed with brine and dried over sodium sulphate and concentrated. Purification was done on Waters RP system to get product N-(cyclopropylmethyl)-1-(2-fluoro-6-methoxybenzyl)-1H-pyrrolo[3,2-b]pyridine-3-carboxamide (0.060 g, 39.2%). ES+MS m/z: 354 (M+1). 1H NMR (300 MHz, DMSO-d6) δ ppm 0.24 (q, J=4.90 Hz, 2 H ) 0.38-0.50 (m, 2 H ) 1.03 (t, J=7.06 Hz, 1H ) 3.25 (t, J=6.22 Hz, 2 H) 3.88 (s, 3 H ) 5.47 (s, 2 H ) 6.83-6.99 (m, 2 H ) 7.26-7.46 (m, 2 H ) 8.02 (s, 1H ) 8.07 (d, J=8.10 Hz, 1 H ) 8.49 (d, J=3.96 Hz, 1 H ) 8.75 (t, J=5.65 Hz, 1 H ).
Reaction SMILES: Br[C:2]1[CH:19]=[N:18][C:5]2[N:6]=[C:7]([NH:11][C:12](=[O:17])[C:13]([CH3:16])([CH3:15])[CH3:14])[N:8]=[C:9]([OH:10])[C:4]=2[CH:3]=1.[C:20]([C:22]1[CH:43]=[CH:42][C:25]([C:26]([NH:28][C@H:29]([C:37]([O:39][CH2:40][CH3:41])=[O:38])[CH2:30][CH2:31][C:32]([O:34][CH2:35][CH3:36])=[O:33])=[O:27])=[CH:24][CH:23]=1)#[CH:21].C(N(CC)CC)C.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C(#N)C.[Pd](Cl)Cl>[C:12]([NH:11][C:7]1[N:8]=[C:9]([OH:10])[C:4]2[CH:3]=[C:2]([C:21]#[C:20][C:22]3[CH:23]=[CH:24][C:25]([C:26]([NH:28][C@H:29]([C:37]([O:39][CH2:40][CH3:41])=[O:38])[CH2:30][CH2:31][C:32]([O:34][CH2:35][CH3:36])=[O:33])=[O:27])=[CH:42][CH:43]=3)[CH:19]=[N:18][C:5]=2[N:6]=1)(=[O:17])[C:13]([CH3:16])([CH3:15])[CH3:14]
Reactant: C#Cc1ccc(C(=O)N[C@@H](CCC(=O)OCC)C(=O)OCC)cc1
Reactant: CC(C)(C)C(=O)Nc1nc(O)c2cc(Br)cnc2n1
Agent: Cl[Pd]Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CCOC(=O)CC[C@H](NC(=O)c1ccc(C#Cc2cnc3nc(NC(=O)C(C)(C)C)nc(O)c3c2)cc1)C(=O)OCC
Temperature: 25 °C
Yield: 53.9 %

Procedure:
A mixture of 2.0 g of 6-bromo-2-pivaloylamino-4-hydroxypyrido[2,3-d]pyrimidine, 2.1 g of diethyl N-(4-ethynylbenzoyl)-L-glutamate, 2.57 ml of triethylamine, 0.11 g of palladium chloride, 0.32 g of triphenylphosphine, and 0.05 g of cuprous chloride in 150 ml of acetonitrile is heated at reflux under nitrogen for 2.5 hours. The solid which forms upon first cooling to room temperature is collected by filtration, and washed with cold acetonitrile to yield 1.91 g of diethyl N-[4-(2-pivaloylamino-4-hydroxypyrido[2,3-d]pyrimidin-6-ylethynyl)benzoyl]-L-glutamate which is sufficiently pure for further processing. Chromatography on silica gel with 5% methanol:methylene chloride showing the following physical properties. m.p. >250° C.; NMR (CDCl3, 300 MHz) delta 1.25 (t, 3H, J=7.20 Hz), 1.33 (t, 3H, J=7.20 Hz), 1.36 (s, 9H), 2.14-2.62 (m, 4H), 4.14 (q, 2H, J= 7.20 Hz), 4.27 (q, 2H, J=7.20 Hz) 4.79-4.86 (m, 1H), 7.30 (d, 1H, J=8.40 Hz), 7.63 (d, 2H, J=8.25 Hz), 7.86 (d, 2H, J=8.25 Hz), 8.51 (brs, 1H), 8.64 (d, 1H, J=2.40 Hz), 8.97 (d, 1H, J=2.40 Hz), 12.2 (brs, 1H); IR (KBr) 3330, 3290, 2970, 1730, 1655, 1590, 1530, 1440, 1370, 1260, 1140, 1020, 965, 925, 850, 810, and 760 cm-1 ; 13C-NMR (CDCl3, 75 MHz) delta 14.3, 27.1, 27.2, 30.7, 40.6, 52.7, 61.1, 62.0, 87.61, 92.71, 115.1, 117.3, 125.9, 127.4, 127.5, 132.0, 133.9, 138.7, 149.6, 157.8, 158.6, 160.5, 166.4 172.1, 173.5, 180.8.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([S:9][C:10]2[N:14]([CH3:15])[C:13]([CH2:16][OH:17])=[N:12][C:11]=2[CH:18]([CH3:20])[CH3:19])[CH:5]=[C:6]([Cl:8])[CH:7]=1.[CH2:21]([O:25][C:26]1(OCCCC)[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]1)[CH2:22][CH2:23][CH3:24]>>[CH2:21]([O:25][C:26]1([O:17][CH2:16][C:13]2[N:14]([CH3:15])[C:10]([S:9][C:4]3[CH:3]=[C:2]([Cl:1])[CH:7]=[C:6]([Cl:8])[CH:5]=3)=[C:11]([CH:18]([CH3:20])[CH3:19])[N:12]=2)[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]1)[CH2:22][CH2:23][CH3:24]
Reactant: CC(C)c1nc(CO)n(C)c1Sc1cc(Cl)cc(Cl)c1
Reactant: CCCCOC1(OCCCC)CCCCC1
Product: CCCCOC1(OCc2nc(C(C)C)c(Sc3cc(Cl)cc(Cl)c3)n2C)CCCCC1
Yield: 30.9 %

Procedure:
The compound 14 (3.1 mg, 0.1 mmol) was converted to the acetal with 1,1-dibutoxycyclohexane (228 mg, 1 mmol) in the same manner as the example 14 to give the compound 16 (15 mg, 30%) as oil. Rf 0.44 (Al2O3 60, Type E, toluene).
Reaction SMILES: [C:1]([C:3]1[N:8]=[C:7]([CH2:9][CH:10]2[CH2:17][CH2:16][C:13]3([CH2:15][CH2:14]3)[CH2:12][CH2:11]2)[C:6]([C:18]([OH:20])=O)=[CH:5][N:4]=1)#[N:2].[C:21]1([CH2:27][C@@H:28]([NH2:35])[CH2:29][N:30]2[CH2:34][CH2:33][CH2:32][CH2:31]2)[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.CCN=C=NCCCN(C)C.Cl.O.C1C=NC2N(O)N=NC=2C=1>CN(C=O)C>[C:21]1([CH2:27][C@@H:28]([NH:35][C:18]([C:6]2[C:7]([CH2:9][CH:10]3[CH2:11][CH2:12][C:13]4([CH2:14][CH2:15]4)[CH2:16][CH2:17]3)=[N:8][C:3]([C:1]#[N:2])=[N:4][CH:5]=2)=[O:20])[CH2:29][N:30]2[CH2:34][CH2:33][CH2:32][CH2:31]2)[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1
Reactant: N#Cc1ncc(C(=O)O)c(CC2CCC3(CC2)CC3)n1
Reactant: N[C@H](Cc1ccccc1)CN1CCCC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2cccnc21
Solvent: CN(C)C=O
Solvent: O
Product: N#Cc1ncc(C(=O)N[C@H](Cc2ccccc2)CN2CCCC2)c(CC2CCC3(CC2)CC3)n1
Reaction time: 24 h

Procedure:
To a solution of the crude 2-cyano-4-(spiro[2.5]oct-6-ylmethyl)pyrimidine-5-carboxylic acid (22 mg, step 74.5) in DMF (1.5 mL) are added (R)-2-phenyl-1-pyrrolidin-1-ylmethylethylamine (0.083 mmol), EDCl—H2O (0.11 mmol), and HOAt (0.11 mmol) at room temperature. The reaction mixture is stirred for 24 h and the reaction is quenched by the addition of H2O. The mixture is extracted with AcOEt, and the organic extracts are dried over Na2SO4, filtered, and concentrated in vacuo. The resulting residue is purified by RP-HPLC to give the title compound; MS (M+1)+: 474, Rf (solvent): 0.63 (CH2Cl2:MeOH=10:1).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[O:16][C:17]3[CH:22]=[C:21]([O:23][CH2:24][C@@H:25]([NH:27][C:28](=[O:30])[CH3:29])[CH3:26])[N:20]=[CH:19][C:18]=3[N:31]=2)=[C:11]([O:32][CH:33]([F:35])[F:34])[CH:10]=1)[C:2]1C=CC=[CH:4][CH:3]=1.BrCC1CC1>>[CH:2]1([CH2:1][O:8][C:9]2[CH:14]=[CH:13][C:12]([C:15]3[O:16][C:17]4[CH:22]=[C:21]([O:23][CH2:24][C@@H:25]([NH:27][C:28](=[O:30])[CH3:29])[CH3:26])[N:20]=[CH:19][C:18]=4[N:31]=3)=[C:11]([O:32][CH:33]([F:35])[F:34])[CH:10]=2)[CH2:3][CH2:4]1
Reactant: CC(=O)N[C@@H](C)COc1cc2oc(-c3ccc(OCc4ccccc4)cc3OC(F)F)nc2cn1
Agent: BrCC1CC1
Product: CC(=O)N[C@@H](C)COc1cc2oc(-c3ccc(OCC4CC4)cc3OC(F)F)nc2cn1

Procedure:
Using N-((2S)-1-((2-(4-(benzyloxy)-2-(difluoromethoxy)phenyl) [1,3]oxazolo[4,5-c]pyridin-6-yl)oxy)propan-2-yl)acetamide and (bromomethyl)cyclopropane, and in the same manner as in Step D of Example 68, the title compound was obtained.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([S:9]([CH2:12][CH2:13][CH2:14]S)(=[O:11])=[O:10])=[CH:5][CH:4]=1.C(N(CC)CC)C.C(OCC)(=[O:25])C>C(Cl)Cl.CS(C)=O>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([S:9]([CH2:12][CH2:13][CH:14]=[O:25])(=[O:11])=[O:10])=[CH:5][CH:4]=1
Reactant: COc1ccc(S(=O)(=O)CCCS)cc1
Reactant: CCOC(C)=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Product: COc1ccc(S(=O)(=O)CCC=O)cc1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
Part A: To a solution of 5.2 g (23 mmol) of 3-[(4-methoxyphenyl)sulfonyl]propan-1-ol from Example 13 and 12.6 mL (9.1 g, 90 mmole) of triethylamine in 25 mL of methylene chloride at zero° C., was added a solution of 14.4 g (90 mmol) of sulfur trioxide-pyridine complex in 25 mL of DMSO. After 1 hour, the reaction mixture was added to 200 mL of ice, ethyl acetate was added, the organic layer was separated and washed with water, 5% potassium hydrogen sulfate solution and brine, dried with magnesium sulfate, filtered and concentrated to afford 4.9 g of 3-[(4-methoxyphenyl)sulfonyl]propan-1-al suitable for the next reaction.
Reaction SMILES: [C:1]1([N:7]2[C:11]([C:12]3[S:13][CH:14]=[CH:15][CH:16]=3)=[CH:10][C:9]([CH2:17][CH2:18][CH:19]=O)=[N:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Cl:21][C:22]1[CH:27]=[CH:26][C:25]([N:28]2[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]2)=[CH:24][CH:23]=1.CCN(C(C)C)C(C)C.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>>[Cl:21][C:22]1[CH:23]=[CH:24][C:25]([N:28]2[CH2:33][CH2:32][N:31]([CH2:19][CH2:18][CH2:17][C:9]3[CH:10]=[C:11]([C:12]4[S:13][CH:14]=[CH:15][CH:16]=4)[N:7]([C:1]4[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=4)[N:8]=3)[CH2:30][CH2:29]2)=[CH:26][CH:27]=1
Reactant: Clc1ccc(N2CCNCC2)cc1
Reactant: O=CCCc1cc(-c2cccs2)n(-c2ccccc2)n1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Product: Clc1ccc(N2CCN(CCCc3cc(-c4cccs4)n(-c4ccccc4)n3)CC2)cc1

Procedure:
55 mg (78%) of target compound was obtained by using a method same as in Example 1 by using 3-(1-phenyl-5-(thiophene-2-yl)-1H-pyrazol-3-yl)-propanal (40 mg, 0.142 mmol), 1-(4-chlorophenyl)piperazine (38 mg, 0.142 mmol), DIPEA (0.040 mL, 0.213 mmol) and NaBH(OAc)3 (90 mg, 0.573 mmol).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([CH3:8])[N:5]=[C:4]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=2)[N:3]=1.[CH3:15][O:16][C:17]1[C:18]([NH2:23])=[CH:19][CH:20]=[CH:21][CH:22]=1>>[CH3:15][O:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[NH:23][C:2]1[CH:7]=[C:6]([CH3:8])[N:5]=[C:4]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=2)[N:3]=1
Reactant: Cc1cc(Cl)nc(-c2ccccn2)n1
Reactant: COc1ccccc1N
Product: COc1ccccc1Nc1cc(C)nc(-c2ccccn2)n1

Procedure:
The title compound was prepared from 4-chloro-6-methyl-2-(2-pyridinyl)pyrimidine (50 mg, 0.243 mmol) and o-anisidine (27 μl, 0.243 mmol) similar to Example 13 and isolated as a pale white solid (40 mg, 56%). 1H NMR (CDCl3): 8.82-8.80 (m, 1H), 8.46 (d, J=8.1 Hz, 1H), 7.90 (dd, J=1.4, 7.7 Hz, 1H), 7.84-7.78 (m, 1H), 7.36-7.32 (m, 1H), 7.28 (s, 1H), 7.18-6.98 (m, 2H), 6.92 (dd, J=1.8, 8.0 Hz, 1H), 6.63 (s, 1H), 3.85 (s, 3H), 2.50 (s, 3H).
Reaction SMILES: Cl[C:2]1[N:7]2[N:8]=[CH:9][CH:10]=[C:6]2[N:5]=[C:4]([CH2:11][CH3:12])[CH:3]=1.Cl.[NH2:14][CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17].C(=O)([O-])[O-].[Na+].[Na+]>C(O)C>[CH2:11]([C:4]1[CH:3]=[C:2]([NH:14][CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17])[N:7]2[N:8]=[CH:9][CH:10]=[C:6]2[N:5]=1)[CH3:12]
Reactant: CCOC(=O)CN
Reactant: CCc1cc(Cl)n2nccc2n1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Product: CCOC(=O)CNc1cc(CC)nc2ccnn12

Procedure:
1.8 g (9.9 mmol) 7-Chloro-5-ethylpyrazolo[1,5-a]pyrimidine (Example 1, Step B) and 1.4 g (10.0 mmol) ethyl 2-aminoacetate hydrochloride were dissolved in 50 ml dry ethanol. 500 mg (4.7 mmol) sodium carbonate were added, and the mixture was heated with reflux for 2 h. The inorganic material was filtered off, the residue treated with saturated aqueous sodium bicarbonate solution, and extracted with ethyl acetate. The organic layer was dried over sodium sulfate, and evaporated in vacuo to give the crude title compound as an oil, which was pure enough according to its 1H-NMR spectrum and was used for the reaction of the next step without further purification.