Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1[C:9]([NH:10][C@H:11]([C:13]2[N:14]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[C:15](=[O:24])[C:16]3[C:21]([CH:22]=2)=[CH:20][CH:19]=[CH:18][C:17]=3Cl)[CH3:12])=[C:8]2[C:4]([NH:5][CH:6]=[N:7]2)=[N:3][CH:2]=1.[NH:31]1[CH:35]=[C:34](B(O)O)[CH:33]=[N:32]1.C([O-])([O-])=O.[Na+].[Na+].C12(P(C34CC5CC(CC(C5)C3)C4)CCCC)CC3CC(CC(C3)C1)C2>CN1C(=O)CCC1.CC([O-])=O.CC([O-])=O.[Pd+2]>[N:1]1[C:9]([NH:10][C@H:11]([C:13]2[N:14]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[C:15](=[O:24])[C:16]3[C:21]([CH:22]=2)=[CH:20][CH:19]=[CH:18][C:17]=3[C:35]2[CH:34]=[CH:33][NH:32][N:31]=2)[CH3:12])=[C:8]2[C:4]([NH:5][CH:6]=[N:7]2)=[N:3][CH:2]=1
Reactant: C[C@H](Nc1ncnc2[nH]cnc12)c1cc2cccc(Cl)c2c(=O)n1-c1ccccc1
Reactant: OB(O)c1cn[nH]c1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CCCCP(C12CC3CC(CC(C3)C1)C2)C12CC3CC(CC(C3)C1)C2
Solvent: CN1CCCC1=O
Product: C[C@H](Nc1ncnc2[nH]cnc12)c1cc2cccc(-c3cc[nH]n3)c2c(=O)n1-c1ccccc1
Temperature: 160 °C
Reaction time: 3 h

Procedure:
(S)-3-(1-((9H-purin-6-yl)amino)ethyl)-8-chloro-2-phenylisoquinolin-1(2H)-one (3) (200 mg, 0.48 mmol) and 1H-pyrazole-4-boronic acid (108 mg, 0.96 mmol) were dissolved in anhydrous NMP (8 mL) and the resulting solution was degassed and back-filled with argon (two cycles). To this mixture, Na2CO3 (152 mg, 1.44 mmol), Pd(OAc)2 (22 mg, 0.096 mmol) and di-(1-adamantyl)-n-butylphosphine (104 mg, 0.288 mmol) were added sequentially. The resulting mixture was degassed and back-filled with argon (two cycles) and then stirred at 160° C. under argon for 3 h. The reaction mixture was allowed to cool to RT and then partitioned between water and ethyl acetate. The organic layer was separated and the aqueous layer was extracted with ethyl acetate. The combined organic layers were washed with brine, dried over Na2SO4 and filtered. The filtrate was concentrated in vacuo and the residue was triturated with Et2O to afford the product, (S)-3-(1-((9H-purin-6-yl)amino)ethyl)-2-phenyl-8-(1H-pyrazol-3-yl)isoquinolin-1(2H)-one (6) as a yellowish solid. ESI-MS m/z: 449.2 [M+H]+.
Reaction SMILES: [H-].[Na+].[C:3]([NH:6][C:7]1[CH:12]=[CH:11][C:10]([SH:13])=[CH:9][CH:8]=1)(=[O:5])[CH3:4].Br[CH2:15][C:16]1[S:17][C:18]2[CH:24]=[CH:23][CH:22]=[CH:21][C:19]=2[N:20]=1>CN(C)C=O.C(OCC)(=O)C>[S:17]1[C:18]2[CH:24]=[CH:23][CH:22]=[CH:21][C:19]=2[N:20]=[C:16]1[CH2:15][S:13][C:10]1[CH:11]=[CH:12][C:7]([NH:6][C:3](=[O:5])[CH3:4])=[CH:8][CH:9]=1
Reactant: BrCc1nc2ccccc2s1
Reactant: CC(=O)Nc1ccc(S)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(=O)Nc1ccc(SCc2nc3ccccc3s2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 81.2 %

Procedure:
79.7 mg of sodium hydride (as a 60% w/w dispersion in mineral oil) were added to a solution of 303.1 mg of 4-acetamidothiophenol in 6 ml of dimethylformamide at room temperature, followed by the addition of a solution of 454.8 mg of 2-bromomethyl-benzothiazole in 1 ml of dimethylformamide. The resulting mixture was stirred at room temperature for 2 hours, after which the reaction mixture was diluted with ethyl acetate, washed with water and then dried over anhydrous sodium sulfate. The solvent was then removed by evaporation under reduced pressure and the resulting residue was purified by column chromatography through silica gel using a 1:2 by volume mixture of hexane and ethyl acetate as the eluent, to give 462.7 mg (yield 81%) of the title compound as a solid having a melting point of 147° to 149° C.
Reaction SMILES: [OH2:1].[Cl:2][C:3]1[C:4]2[CH:14]=[C:13]3[O:15][CH2:16][O:17][C:12]3=[CH:11][C:5]=2[S:6][C:7]=1[C:8](Cl)=[O:9]>O1CCOCC1>[Cl:2][C:3]1[C:4]2[CH:14]=[C:13]3[O:15][CH2:16][O:17][C:12]3=[CH:11][C:5]=2[S:6][C:7]=1[C:8]([OH:1])=[O:9]
Reactant: O
Reactant: O=C(Cl)c1sc2cc3c(cc2c1Cl)OCO3
Solvent: C1COCCO1
Product: O=C(O)c1sc2cc3c(cc2c1Cl)OCO3

Procedure:
40 ml of water are added to a solution of 70 mmol of the compound of Step A in 250 ml of dioxane. After 20 hours' reflux and then return to ambient temperature, a precipitate forms. After filtration and rinsing with water until neutral, the precipitate is dried over P2O5 under reduced pressure, allowing the expecting product to be isolated.
Reaction SMILES: [OH:1][C@H:2]([CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])[CH2:3][CH2:4][OH:5].N1C=CN=C1.[Si:22](Cl)([C:25]([CH3:28])([CH3:27])[CH3:26])([CH3:24])[CH3:23]>CN(C)C=O.C(OCC)(=O)C>[Si:22]([O:5][CH2:4][CH2:3][C@H:2]([OH:1])[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])([C:25]([CH3:28])([CH3:27])[CH3:26])([CH3:24])[CH3:23]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: CCCCCCCCCCC[C@@H](O)CCO
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCCCCCCCCCC[C@@H](O)CCO[Si](C)(C)C(C)(C)C
Reaction time: 2 h
Yield: 81.2 %

Procedure:
To a solution of diol compound 9 (2.28 g, 10 mmol) in N,N-dimethyl formamide (50 mL) at 0° C. was added sequentially imidazole (1.63 g, 24 mmol), and t-butyldimethylsilyl chloride (1.65 g, 11 mmol), and the reaction mixture was stirred for 2 h. After completion of the reaction (TLC). The mixture was diluted with ethyl acetate (200 mL), washed with water (2×50 mL), dried and concentrated to give a colorless oil, which after purification by flash chromatography, afforded the pure monosilyl compound 10 as an oil (Rf 0.71, silica, ethyl acetate and hexane, 1:10, 2.80 g, 84%).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[CH:5]=[C:4]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[N:3]=1.[C:15]([C:17]1[CH:18]=[C:19](B(O)O)[CH:20]=[CH:21][CH:22]=1)#[N:16]>>[Cl:1][C:2]1[N:7]=[C:6]([C:21]2[CH:20]=[CH:19][CH:18]=[C:17]([C:15]#[N:16])[CH:22]=2)[CH:5]=[C:4]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[N:3]=1
Reactant: N#Cc1cccc(B(O)O)c1
Reactant: Clc1cc(-c2ccccc2)nc(Cl)n1
Product: N#Cc1cccc(-c2cc(-c3ccccc3)nc(Cl)n2)c1

Procedure:
2-chloro-4-(3-cyanophenyl)-6-phenylpyrimidine was synthesized by the same method as in syntheses of 2,4-dichloro-6-phenylpyrimidine in the above (4-1-1), except that 2,4-dichloro-6-phenylpyrimidine was used in place of 2,4,6-trichloropyrimidine and that 3-cyanophenylboronic acid was used in place of phenylboronic acid.
Reaction SMILES: C[O:2][C:3](=[O:22])/[CH:4]=[CH:5]/[C:6]1[CH:15]=[CH:14][C:13]2[C:8](=[CH:9][C:10]([O:16][CH3:17])=[CH:11][CH:12]=2)[C:7]=1[CH2:18][CH2:19][CH2:20][CH3:21].[OH-].[Na+]>CO>[CH2:18]([C:7]1[C:8]2[C:13](=[CH:12][CH:11]=[C:10]([O:16][CH3:17])[CH:9]=2)[CH:14]=[CH:15][C:6]=1/[CH:5]=[CH:4]/[C:3]([OH:22])=[O:2])[CH2:19][CH2:20][CH3:21]
Reactant: CCCCc1c(/C=C/C(=O)OC)ccc2ccc(OC)cc12
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CCCCc1c(/C=C/C(=O)O)ccc2ccc(OC)cc12
Yield: 98.2 %

Procedure:
As in Example 112, (E)-3-(1-butyl-7-methoxy-2-naphthalenyl)-2-propenoic acid methyl ester (1.55 g) in methanol (20 mL) was treated with 2N sodium hydroxide solution (4 mL) at reflux for 2 hours and the normal isolation procedure afforded 1.45 g of (E)-3-(1-butyl-7-methoxy-2-naphthalenyl)-2-propenoic acid. Crystallization of a sample from diethyl ether gave the analytical specimen. Anal. Calcd for C18H20O3 : C, 76.03; H, 7.09 Found: C, 75.66; H, 7.13
Reaction SMILES: [CH3:1][N:2]1[C:6]([CH2:7][OH:8])=[C:5]([CH3:9])[N:4]=[CH:3]1.[H-].[Na+].[CH2:12]([C:16]1[N:20]([C:21]2[N:26]=[C:25]([C:27]3[S:28][CH:29]=[CH:30][CH:31]=3)[C:24]([CH3:32])=[CH:23][N:22]=2)[N:19]=[CH:18][C:17]=1[CH2:33]Cl)[CH2:13][CH2:14][CH3:15]>CN(C=O)C>[CH2:12]([C:16]1[N:20]([C:21]2[N:26]=[C:25]([C:27]3[S:28][CH:29]=[CH:30][CH:31]=3)[C:24]([CH3:32])=[CH:23][N:22]=2)[N:19]=[CH:18][C:17]=1[CH2:33][O:8][CH2:7][C:6]1[N:2]([CH3:1])[CH:3]=[N:4][C:5]=1[CH3:9])[CH2:13][CH2:14][CH3:15]
Reactant: CCCCc1c(CCl)cnn1-c1ncc(C)c(-c2cccs2)n1
Reactant: Cc1ncn(C)c1CO
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCCCc1c(COCc2c(C)ncn2C)cnn1-c1ncc(C)c(-c2cccs2)n1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 1.9 %

Procedure:
To a 20 mL vial was added (1,4-dimethyl-1H-imidazol-5-yl)methanol (32 mg, 0.26 mmol), NaH (10 mg, 60% in oil, 0.12 mmol) and 4 mL of DMF. The reaction mixture was stirred at room temperature for 30 minutes, at which time the reaction was cooled to 0° C., the crude intermediate 2-(5-butyl-4-(chloromethyl)-1H-pyrazol-1-yl)-5-methyl-4-(thiophen-2-yl)pyrimidine (60 mg, 0.17 mmol) was added, warmed to room temperature and stirred for an additional 2 hours. The crude reaction was partitioned between water and EtOAc, the organic layer was concentrated and was purified by reverse phase preparative HPLC to provide 1.4 mg of 24 as a clear film. 1H NMR (400 MHz, MeOD-d3) δ 0.851 (t, J=5.9 Hz, 3H), 1.35 (q, J=5.9 Hz, 2H), 1.57 (t, J=6.2 Hz, 2H), 2.38 (s, 3H), 2.67 (s, 3H), 3.35 (t, J=4.8 Hz, 2H), 3.91 (s, 3H), 4.61 (s, 2H), 4.67 (s, 2H) 7.31 (t, J=3.6 Hz, 1H), 7.76 (s, 1H), 7.78 (d, J=4.1 Hz, 1H), 7.96 (d, J=3.1 Hz, 1H), 8.71 (s, 1H), 8.81 (s, 1H). LCMS (ES+) m/z 437 (M+1).
Reaction SMILES: FC(F)(F)C([O-])=O.[F:8][C:9]1[CH:10]=[C:11]([CH2:16][C@H:17]([NH3+:54])[C:18](=[O:53])[NH:19][C@H:20]2[CH2:45][O:44][C:43](=[O:46])[C@H:42]3[N:38]([CH2:39][C@H:40]([CH3:47])[CH2:41]3)[C:37](=[O:48])[C@H:36]([CH3:49])[NH:35][C:34](=[O:50])[C@H:33]3[N:28]([CH2:29][CH2:30][CH2:31][CH2:32]3)[C:27](=[O:51])[C@H:26]3[N:22]([CH2:23][CH2:24][CH2:25]3)[C:21]2=[O:52])[CH:12]=[C:13]([F:15])[CH:14]=1.[C:55](O)(=[O:62])/[CH:56]=[CH:57]/[CH2:58][CH2:59][CH2:60][CH3:61].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(C(C)C)C(C)C)C>C(#N)C.O.CN(C)C=O>[F:15][C:13]1[CH:12]=[C:11]([CH2:16][C@H:17]([NH:54][C:55](=[O:62])/[CH:56]=[CH:57]/[CH2:58][CH2:59][CH2:60][CH3:61])[C:18](=[O:53])[NH:19][C@H:20]2[CH2:45][O:44][C:43](=[O:46])[C@H:42]3[N:38]([CH2:39][C@H:40]([CH3:47])[CH2:41]3)[C:37](=[O:48])[C@H:36]([CH3:49])[NH:35][C:34](=[O:50])[C@H:33]3[N:28]([CH2:29][CH2:30][CH2:31][CH2:32]3)[C:27](=[O:51])[C@H:26]3[N:22]([CH2:23][CH2:24][CH2:25]3)[C:21]2=[O:52])[CH:10]=[C:9]([F:8])[CH:14]=1
Reactant: CCCC/C=C/C(=O)O
Reactant: C[C@@H]1C[C@H]2C(=O)OC[C@H](NC(=O)[C@@H]([NH3+])Cc3cc(F)cc(F)c3)C(=O)N3CCC[C@H]3C(=O)N3CCCC[C@H]3C(=O)N[C@@H](C)C(=O)N2C1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: O=C([O-])C(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Solvent: O
Product: CCCC/C=C/C(=O)N[C@@H](Cc1cc(F)cc(F)c1)C(=O)N[C@H]1COC(=O)[C@@H]2C[C@@H](C)CN2C(=O)[C@H](C)NC(=O)[C@@H]2CCCCN2C(=O)[C@@H]2CCCN2C1=O
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
101.5 mg (0.13 mmol) of the compound from example 29A and 23.0 mg (0.17 mmol) of trans-2-heptenoic acid are introduced under argon into anhydrous dimethylformamide (2 ml) at 0° C. and then 65.0 mg (0.17 mmol) of HATU and 0.025 ml (0.14 mmol) of ethyldiisopropylamine are added. After 30 min, a further 0.05 ml (0.29 mmol) of ethyldiisopropylamine are added to the reaction mixture. The reaction mixture is stirred overnight with slow warming to RT. The reaction solution is subjected directly to an RP-HPLC using acetonitrile/water as eluent. In the course of this, 63 mg (62% of th.) of a colorless solid are obtained.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[NH:11][CH2:10][CH2:9][C:8]([C:12]([O:14][CH3:15])=[O:13])=[CH:7][C:6]=2[CH:16]=1.[CH3:17][O:18][C:19]1[CH:26]=[CH:25][CH:24]=[CH:23][C:20]=1[CH:21]=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].O>ClCCCl.C(OCC)(=O)C>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]([CH2:21][C:20]3[CH:23]=[CH:24][CH:25]=[CH:26][C:19]=3[O:18][CH3:17])[CH2:10][CH2:9][C:8]([C:12]([O:14][CH3:15])=[O:13])=[CH:7][C:6]=2[CH:16]=1
Reactant: COC(=O)C1=Cc2cc(Br)ccc2NCC1
Reactant: COc1ccccc1C=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: ClCCCl
Product: COC(=O)C1=Cc2cc(Br)ccc2N(Cc2ccccc2OC)CC1
Temperature: 25 °C
Reaction time: 24 h
Yield: 75.7 %

Procedure:
To a solution of methyl 7-bromo-2,3-dihydro-1-benzazepine-4-carboxylate (1.5 g) and 2-methoxybenzaldehyde (3.62 g) in 1,2-dichloroethane (50 ml) was added sodium triacetoxyborohydride (2.82 g), and the mixture was stirred under nitrogen atmosphere at room temperature for 1 day. Then, water was added to the mixture, and the mixture was extracted-with ethyl acetate. The organic layer was washed with saturated brine and dried with magnesium sulfate. The solvent was evaporated under reduced pressure, and the resulting residue was purified with silica gel column chromatography (hexane:ethyl acetate=5:1) to give methyl 7-bromo-1-(2-methoxybenzyl)-2,3-dihydro-1-benzazepine-4-carboxylate (1.62 g) as yellow oil.
Reaction SMILES: [NH2:1][CH2:2][C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:4].[C:11]1([CH3:21])[CH:16]=[CH:15][C:14]([S:17](Cl)(=[O:19])=[O:18])=[CH:13][CH:12]=1.O>N1C=CC=CC=1>[C:11]1([CH3:21])[CH:16]=[CH:15][C:14]([S:17]([NH:1][CH2:2][C:3]([C:5]2[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=2)=[O:4])(=[O:19])=[O:18])=[CH:13][CH:12]=1
Reactant: NCC(=O)c1ccccc1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: c1ccncc1
Solvent: O
Product: Cc1ccc(S(=O)(=O)NCC(=O)c2ccccc2)cc1
Temperature: 45 °C
Reaction time: 2 h
Yield: 52.5 %

Procedure:
To a solution of 2-aminoacetophenone (7.0 g, 0.05 mol) in 30 mL of pyridine was added p-toluenesulfonyl chloride (11.8 g, 120 mol %). The reaction mixture was refluxed with stirring for 2 h, cooled to 40-50° C. and poured in the cold water (150 mL). The mixture was stirred at rt for 1 h, filtered, washed with warm (~40° C.) water and then dried. Recrystallization from EtOH afforded 7.6 g (51%) of the title compound, mp 148.2-149.3° C. [lit 147-148° C. (Kemter, G.; Noack, H.; Russ, G. Z. Chem. 1963, 3, 352)]; 1H NMR (CDCl3) δ 11.48 (s, 1H, NH), 7.79 (dd, 1H, J=1.2, J=6.8), 7.72 (d, 1H, J=8.4), 7.67 (d, 1H, J=8.4), 7.44 (t, 1H, J=8), 7.21 (d, 1H, J=8), 7.02 (t, 1H, J=6), 2.55 (s, 3H), 2.36 (s, 3H); 13C NMR (CDCl3) δ 202.37, 143.83, 139.94, 136.47, 134.82, 131.87, 129.57, 127.16, 122.55, 122.18, 118.92, 28.04, 21.42; MS (EI, m/z) 289 (M+).
Reaction SMILES: C(O[C:4]([C:6]1([CH2:19][CH2:20]C=O)[CH2:11][CH2:10][N:9]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:8][CH2:7]1)=[O:5])C.[CH3:23][CH:24]1[CH2:28][CH2:27][CH2:26][N:25]1[CH:29]1[CH2:33][CH2:32][C@H:31]([C:34]2[CH:39]=[CH:38][C:37]([NH2:40])=[CH:36][CH:35]=2)[CH2:30]1>>[C:15]([O:14][C:12]([N:9]1[CH2:8][CH2:7][C:6]2([C:4](=[O:5])[N:40]([C:37]3[CH:38]=[CH:39][C:34]([CH:31]4[CH2:32][CH2:33][CH:29]([N:25]5[CH2:26][CH2:27][CH2:28][CH:24]5[CH3:23])[CH2:30]4)=[CH:35][CH:36]=3)[CH2:20][CH2:19]2)[CH2:11][CH2:10]1)=[O:13])([CH3:16])([CH3:17])[CH3:18]
Reactant: CC1CCCN1C1CC[C@H](c2ccc(N)cc2)C1
Reactant: CCOC(=O)C1(CCC=O)CCN(C(=O)OC(C)(C)C)CC1
Product: CC1CCCN1C1CCC(c2ccc(N3CCC4(CCN(C(=O)OC(C)(C)C)CC4)C3=O)cc2)C1

Procedure:
The title compound was synthesized in the manner essentially the same as the Example 1 by condensing 4-(3-oxo-propyl)-piperidine-1,4-dicarboxylic acid 1-tert-butyl ester 4-ethyl ester (Intermediate 4) with 4-[(S)-3-(2-methyl-pyrrolidin-1-yl)-cyclopentyl]-phenylamine (Intermediate 15), and subsequently cyclization.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1[CH:14]=[CH:13][C:12]([CH:15]([CH3:19])[C:16](O)=[O:17])=[CH:11][C:10]=1[OH:20].S(Cl)(Cl)=O.[NH3:25]>C1C=CC=CC=1>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1[CH:14]=[CH:13][C:12]([CH:15]([CH3:19])[C:16]([NH2:25])=[O:17])=[CH:11][C:10]=1[OH:20]
Reactant: CC(C(=O)O)c1ccc(-c2ccc(F)cc2F)c(O)c1
Reactant: N
Solvent: O=S(Cl)Cl
Solvent: c1ccccc1
Product: CC(C(N)=O)c1ccc(-c2ccc(F)cc2F)c(O)c1

Procedure:
A solution of 2-(2',4'-difluoro-2 -hydroxy-4-biphenylyl) propionic acid (1.75 g.) and thionyl chloride (1 ml.) in dry benzene (10 ml.) was refluxed for 1 hour and then cooled and added dropwise to stirred cold ammonia (d=0.880 g./ml; 20 ml.). The product was filtered and recrystallised first from aqueous industrial methylated spirits and then light petroleum (b.p. 62° - 68°C.) to give 2-(2',4'difluoro-2-hydroxy-4-biphenylyl)propionamide, m.p. 222° - 224°C.
Reaction SMILES: C([O:5][C:6]([C:8]1[CH:17]=[C:16]2[C:11]([CH2:12][CH:13]([CH2:19][C:20]([O:22][CH3:23])=[O:21])[C:14](=[O:18])[NH:15]2)=[CH:10][CH:9]=1)=[O:7])(C)(C)C.Cl>O1CCOCC1>[CH3:23][O:22][C:20]([CH2:19][CH:13]1[CH2:12][C:11]2[C:16](=[CH:17][C:8]([C:6]([OH:7])=[O:5])=[CH:9][CH:10]=2)[NH:15][C:14]1=[O:18])=[O:21]
Reactant: COC(=O)CC1Cc2ccc(C(=O)OC(C)(C)C)cc2NC1=O
Agent: Cl
Solvent: C1COCCO1
Product: COC(=O)CC1Cc2ccc(C(=O)O)cc2NC1=O
Temperature: 45 °C
Yield: 96.4 %

Procedure:
A suspension of 3-methoxycarbonylmethyl-2-oxo-1,2,3,4-tetrahydro-quinoline-7-carboxylic acid tert-butyl ester (3.5 g, 13.2 mmol) in dioxane (40 mL) was treated with 10 mL of 4N hydrochloric acid in dioxane and heated to 40-50° C. Evaporation of the volatiles in vacuo gave the title compound (3.35 g, 97%). NMR (dmso-d6, 200 MHz) : δ2.7-3.4 (m, 5H, CH2CHCH2), 3.6 (s, 3H, CH3), 7.2-7.5 (m, 3H, ArH), 10.3 (s, 1 H, NH).
Reaction SMILES: Cl[C:2]1[N:3]=[N:4][C:5]([C:8]2[CH:13]=[CH:12][C:11]([F:14])=[CH:10][CH:9]=2)=[CH:6][CH:7]=1.[C:15]([NH:18][NH2:19])(=O)[CH3:16]>C(O)CCC>[F:14][C:11]1[CH:12]=[CH:13][C:8]([C:5]2[CH:6]=[CH:7][C:2]3[N:3]([C:15]([CH3:16])=[N:18][N:19]=3)[N:4]=2)=[CH:9][CH:10]=1
Reactant: CC(=O)NN
Reactant: Fc1ccc(-c2ccc(Cl)nn2)cc1
Solvent: CCCCO
Product: Cc1nnc2ccc(-c3ccc(F)cc3)nn12

Procedure:
A mixture of 6.25 g. of 3-chloro-6-(p-fluorophenyl)pyridazine (prepared as in Example 8), 4.65 g. of acetylhydrazine and 50 ml. of butyl alcohol is refluxed until a clear solution results. The reaction mixture is cooled, filtered, and the solid precipitate washed with hexane and with water. The solid is recrystallized from 50 ml. of ethyl alcohol to give the product of the example as crystals, m.p. 227°-229° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4](=[O:25])[C:5]([C:21]([O:23]C)=[O:22])=[N:6][N:7]([C:9]2[C:19]([F:20])=[CH:18][C:12]3[O:13][C:14]([F:17])([F:16])[O:15][C:11]=3[CH:10]=2)[CH:8]=1.[OH-].[Na+].Cl>CO>[CH3:1][O:2][C:3]1[C:4](=[O:25])[C:5]([C:21]([OH:23])=[O:22])=[N:6][N:7]([C:9]2[C:19]([F:20])=[CH:18][C:12]3[O:13][C:14]([F:16])([F:17])[O:15][C:11]=3[CH:10]=2)[CH:8]=1
Reactant: COC(=O)c1nn(-c2cc3c(cc2F)OC(F)(F)O3)cc(OC)c1=O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: COc1cn(-c2cc3c(cc2F)OC(F)(F)O3)nc(C(=O)O)c1=O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 80.3 %

Procedure:
To a suspension of methyl 5-methoxy-4-oxo-1-(2,2,6-trifluoro-1,3-benzodioxol-5-yl)-1,4-dihydropyridazine-3-carboxylate (1.53 g, 4.27 mmol) in MeOH (17 mL) was added 1 M NaOH aqueous solution (8.5 mL) at 0° C. The mixture was stirred at room temperature for 30 min. To the mixture was added 1 M HCl aqueous solution (8.5 mL) at 0° C. The mixture was concentrated in vacuo. The precipitates were collected by filtration, washed with water and dried in vacuo at 60° C. to yield the title compound (1.18 g, 80% yield) as a pale yellow solid: 1H NMR (DMSO-d6, 300 MHz): δ ppm 3.86 (3H, s), 7.98 (1H, d, J=9.4 Hz), 8.03 (1H, d, J=6.4 Hz), 8.79 (1H, s), 14.77 (1H, brs).
Reaction SMILES: [N:1]([C:4]1[CH:14]=[CH:13][C:7]([C:8]([NH:10][CH2:11][CH3:12])=[O:9])=[CH:6][C:5]=1[OH:15])=[N+:2]=[N-:3].[CH2:16](Br)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.C(=O)([O-])[O-].[K+].[K+].O>CN(C=O)C>[N:1]([C:4]1[CH:14]=[CH:13][C:7]([C:8]([NH:10][CH2:11][CH3:12])=[O:9])=[CH:6][C:5]=1[O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[N+:2]=[N-:3]
Reactant: CCNC(=O)c1ccc(N=[N+]=[N-])c(O)c1
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCNC(=O)c1ccc(N=[N+]=[N-])c(OCc2ccccc2)c1
Temperature: 55 °C
Reaction time: 3.5 h
Yield: 97 %

Procedure:
To a solution of 4-azido-N-ethyl-3-hydroxybenzamide (3.44 g) obtained in Example 133b) in DMF (50 ml) were added benzyl bromide (2.4 ml) and potassium carbonate (2.76 g), and the reaction mixture was stirred at 55° C. for 3.5 hr. The reaction mixture was allowed to cool to room temperature, water was added and the resulting precipitate was collected by filtration and washed with water to give the title compound as a brown powder (4.81 g, 97%).
Reaction SMILES: [CH3:1][Si:2]([CH3:47])([CH3:46])[CH2:3][CH2:4][O:5][CH2:6][N:7]([CH2:38][O:39][CH2:40][CH2:41][Si:42]([CH3:45])([CH3:44])[CH3:43])[C:8]1[N:13]2[N:14]=[CH:15][C:16]([C:17]3[CH:18]=[N:19][C:20]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=4)=[CH:21][CH:22]=3)=[C:12]2[N:11]=[C:10]([CH:29]2[CH2:34][CH2:33][C:32]([CH2:36]O)([OH:35])[CH2:31][CH2:30]2)[CH:9]=1.CS(Cl)(=O)=O.[CH3:53][S:54]([NH2:57])(=[O:56])=[O:55].[H-].[Na+].[NH4+].[Cl-]>C(Cl)Cl.CN(C=O)C.CCOC(C)=O>[CH3:44][Si:42]([CH3:45])([CH3:43])[CH2:41][CH2:40][O:39][CH2:38][N:7]([CH2:6][O:5][CH2:4][CH2:3][Si:2]([CH3:46])([CH3:47])[CH3:1])[C:8]1[N:13]2[N:14]=[CH:15][C:16]([C:17]3[CH:18]=[N:19][C:20]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=4)=[CH:21][CH:22]=3)=[C:12]2[N:11]=[C:10]([CH:29]2[CH2:34][CH2:33][C:32]([CH2:36][NH:57][S:54]([CH3:53])(=[O:56])=[O:55])([OH:35])[CH2:31][CH2:30]2)[CH:9]=1
Reactant: CS(N)(=O)=O
Reactant: C[Si](C)(C)CCOCN(COCC[Si](C)(C)C)c1cc(C2CCC(O)(CO)CC2)nc2c(-c3ccc(-c4ccccc4)nc3)cnn12
Agent: CS(=O)(=O)Cl
Agent: [Cl-]
Agent: [H-]
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: C[Si](C)(C)CCOCN(COCC[Si](C)(C)C)c1cc(C2CCC(O)(CNS(C)(=O)=O)CC2)nc2c(-c3ccc(-c4ccccc4)nc3)cnn12
Temperature: 90 °C
Reaction time: 1 h

Procedure:
To a solution of 4-(7-(bis((2-(trimethylsilyl)ethoxy)methyl)amino)-3-(6-phenylpyridin-3-yl)pyrazolo[1,5-a]pyrimidin-5-yl)-1-(hydroxymethyl)cyclohexanol (820 mg, 1.21 mmol) in DCM (10 mL) was added TEA (0.337 mL, 2.42 mmol), followed by MsCl (0.104 mL, 1.33 mmol) at 0° C. and stirred for 1 h. The reaction mixture was concentrated, and then dissolved in EtOAc, washed with H2O and brine, dried over Na2SO4, and concentrated to afford a pale yellow oil. This oil was dissolved in DMF (10 mL). MeSO2NH2 (1.5 eq) was added, followed by NaH (4.0 eq). The resulting reaction mixture was heated at 90° C. for 2 d. The reaction mixture was diluted with EtOAc, neutralized with NH4Cl, washed with H2O and brine, dried over Na2SO4, and concentrated. The crude product was purified by a SiO2 column (0-10% MeOH/DCM, Rf=0.65 in 10% MeOH/DCM) to afford N-((4-(7-(bis((2-(trimethylsilyl)ethoxy)methyl)amino)-3-(6-phenylpyridin-3-yl)pyrazolo[1,5-a]pyrimidin-5-yl)-1-hydroxycyclohexyl)methyl)methanesulfonamide as a brownish oil (594 mg). HPLC-MS TR=2.86 min (UV 254 nm, 10 min method); mass calculated for formula C37H56N6O5SSi2 752.4, observed LCMS m/z 753.1 (M+H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:12]([O:16][CH:17]2[CH2:21][CH2:20][CH2:19][CH2:18]2)[C:13]([OH:15])=O)[CH:5]=[CH:6][C:7]=1[S:8]([CH3:11])(=[O:10])=[O:9].[NH2:22][C:23]1[S:24][CH:25]=[CH:26][N:27]=1.CN([P+](ON1N=NC2C=CC=CC1=2)(N(C)C)N(C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)CC)C>ClCCl.O>[Cl:1][C:2]1[CH:3]=[C:4]([CH:12]([O:16][CH:17]2[CH2:21][CH2:20][CH2:19][CH2:18]2)[C:13]([NH:22][C:23]2[S:24][CH:25]=[CH:26][N:27]=2)=[O:15])[CH:5]=[CH:6][C:7]=1[S:8]([CH3:11])(=[O:9])=[O:10]
Reactant: CS(=O)(=O)c1ccc(C(OC2CCCC2)C(=O)O)cc1Cl
Reactant: Nc1nccs1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: O
Solvent: CCN(CC)CC
Product: CS(=O)(=O)c1ccc(C(OC2CCCC2)C(=O)Nc2nccs2)cc1Cl
Temperature: 25 °C
Reaction time: 16 h
Yield: 70.7 %

Procedure:
To a stirred solution of rac-(3-chloro-4-methanesulfonyl-phenyl)-cyclopentyloxy-acetic acid (50 mg, 0.15 mmol) in dichloromethane (10 mL) at 25° C. was added 2-aminothiazole (23 mg, 0.23 mmol), BOP reagent (100 mg, 0.23 mmol) and triethylamine (0.06 mL, 0.45 mmol). The mixture was stirred at 25° C. for 16 h, then it was diluted with water (10 mL) and extracted with dichloromethane (3×20 mL). The combined organic layers were washed with water (1×10 mL), 1N sodium hydroxide (1×10 mL), 1N hydrochloric acid (1×10 mL) and brine ( 1×10 mL), then were dried over sodium sulfate, filtered and concentrated in vacuo. The product was purified by chromatography (Biotage Flash 40S column, 60/40 hexanes/ethyl acetate) to give rac-2-(3-chloro-4-methanesulfonyl-phenyl)-2-cyclopentyloxy-N-thiazol-2-yl-acetamide(44 mg, 71% yield) as a white solid: EI-HRMS m/e calculated for C17H19N2O4S2Cl (M+) 414.0475, found 414.0481.