Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C1C=CC(C(O)[C:8]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[O:9])=CC=1.Cl.[OH2:18]>>[C:8]([OH:18])(=[O:9])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: O=C(c1ccccc1)C(O)c1ccccc1
Reactant: O
Agent: Cl
Product: O=C(O)c1ccccc1

Procedure:
An amount of 25 g of ground Siam benzoin resin was dispersed in 500 ml of a solution (pH of 3) prepared by adding hydrochloric acid to water and was extracted five times by using 20 v/v% of diethylether in a separatory funnel. The combined ether layer was evaporated to remove solvents until the volume thereof reached 5 ml. Benzoic acid with a concentration of 5 g/l was detected by HPLC analysis.
Reaction SMILES: [F:1][C:2]([F:21])([F:20])[C:3]([N:5]1[CH2:10][CH2:9][CH:8]([C:11]2[CH:19]=[CH:18][C:14]([C:15](Cl)=[O:16])=[CH:13][CH:12]=2)[CH2:7][CH2:6]1)=[O:4].CCN(C(C)C)C(C)C>CCOC(C)=O.[Pd]>[F:21][C:2]([F:1])([F:20])[C:3]([N:5]1[CH2:6][CH2:7][CH:8]([C:11]2[CH:12]=[CH:13][C:14]([CH:15]=[O:16])=[CH:18][CH:19]=2)[CH2:9][CH2:10]1)=[O:4]
Reactant: O=C(Cl)c1ccc(C2CCN(C(=O)C(F)(F)F)CC2)cc1
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: O=Cc1ccc(C2CCN(C(=O)C(F)(F)F)CC2)cc1
Reaction time: 0.5 h
Yield: 56.1 %

Procedure:
To a flask containing A1Cl3 (534 mg, 4.0 mmol) under an N2 atmosphere was added anhydrous CH2Cl2 (0.1 M), and the drop wise addition of oxalyl chloride (523 μL, 6.0 mmol) over a 20 min period at 15° C. Next, a solution of 2,2,2-trifluoro-1-(4-phenylpiperidin-1-yl)ethanone (17) (2.0 mmol) in anhydrous CH2Cl2 (0.1 M) was added drop-wise to the initial solution over a 45 min period at 15° C. When the reaction was complete as judged by TLC, ice was added to the solution in addition to CaCl2 (1.70 g). The product was extract into CH2Cl2, washed with brine and dried over anhydrous Na2SO4 before concentrating under reduced pressure to yield crude 4-(1-(2,2,2-trifluoroacetyl)piperidin-4-yl)benzoyl chloride (18). (b) To a stirred solution of 18 (2.0 mmol) and DIPEA (697 μL, 4.0 mmol) in EtOAc (0.1 M) was added 10% Pd/C. The flask was then evacuated and filled with H2 gas and allowed to stir for 30 min. After which time the reaction contents were filtered and concentrated under reduced pressure to give crude product which was purified by silica gel column chromatography (hexanes:EtOAc, 2:1) to furnish 19 (320 mg, 59% (yield over 2 steps)) δH (400 MHz, CDCl3) 1.69-1.81 (m, 2H, CH2), 1.98-2.06 (m, 2H, CH2), 2.83-2.97 (m, 2H, CH2), 3.27 (td, J=12.8 and 2.4 Hz, 1H, CH), 4.13-4.21 (m, 1H, CH), 4.70-4.76 (m, 1H, CH2), 7.37 (d, J=8.4 Hz, 2H, CH), 7.85 (d, J=8.4 Hz, 2H, CH), 9.99 (s, 1H, CHO); LRMS (ES+) calcd for [C14H14F3NO2+Na] 308.09 found 308.19 [M+Na].
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[NH:16][C:15](=[O:17])[O:14][C:8]3([CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]3)[C:6]=2[CH:7]=1.[Cl:18][C:19]1[CH:20]=[C:21](B(O)O)[CH:22]=[CH:23][CH:24]=1>>[Cl:18][C:19]1[CH:24]=[C:23]([C:2]2[CH:3]=[CH:4][C:5]3[NH:16][C:15](=[O:17])[O:14][C:8]4([CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]4)[C:6]=3[CH:7]=2)[CH:22]=[CH:21][CH:20]=1
Reactant: OB(O)c1cccc(Cl)c1
Reactant: O=C1Nc2ccc(Br)cc2C2(CCCCC2)O1
Product: O=C1Nc2ccc(-c3cccc(Cl)c3)cc2C2(CCCCC2)O1

Procedure:
Prepared according to Procedure A from 6-bromo-spiro[4H-3,1-benzoxazine-4,1′-cyclohexane]-2(1H)-one and 3-chlorophenyl boronic acid. Off-white solid: mp 165-168° C. 1H-NMR (DMSO-d6) δ10.25 (s, 1H), 7.74 (t, 1H, J=1.9 Hz), 7.50-7.67 (m, 3H), 7.42-7.49 (m 1H), 7.35-7.38 (m, 1H), 6.93-6.95 (d, 1H, J=4.2 Hz), 1.91-1.98 (m, 4H), 1.64-1.76 (m, 3H), 1.60 (m, 2H), 1.29-1.39 (m, 1H); MS (APCI) m/z 328 ([M+H]+, 80%)
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5](/[C:8](/[C:25]2[CH:30]=[CH:29][C:28]([C:31]#[C:32][CH2:33][N:34]3[CH2:39][CH2:38][N:37]([CH3:40])[CH2:36][CH2:35]3)=[CH:27][CH:26]=2)=[CH:9]/[CH2:10][O:11][C:12]2[CH:23]=[CH:22][C:15]([O:16][CH2:17][C:18]([O:20]C)=[O:19])=[C:14]([CH3:24])[CH:13]=2)=[CH:4][CH:3]=1.O.[OH-].[Li+]>C(O)C.O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5](/[C:8](/[C:25]2[CH:30]=[CH:29][C:28]([C:31]#[C:32][CH2:33][N:34]3[CH2:35][CH2:36][N:37]([CH3:40])[CH2:38][CH2:39]3)=[CH:27][CH:26]=2)=[CH:9]/[CH2:10][O:11][C:12]2[CH:23]=[CH:22][C:15]([O:16][CH2:17][C:18]([OH:20])=[O:19])=[C:14]([CH3:24])[CH:13]=2)=[CH:4][CH:3]=1
Reactant: COC(=O)COc1ccc(OC/C=C(/c2ccc(Cl)cc2)c2ccc(C#CCN3CCN(C)CC3)cc2)cc1C
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: Cc1cc(OC/C=C(/c2ccc(Cl)cc2)c2ccc(C#CCN3CCN(C)CC3)cc2)ccc1OCC(=O)O
Reaction time: 72 h

Procedure:
The above ester (0.36 g, 0.658 mmol) was dissolved in ethanol (30 mL), a solution of lithium hydroxide monohydrate (0.10 g, 2.38 mmol) in water (4 mL) was added and the mixture was left to stand for 72 h. The solvents were evaporated in vacuo; the residue was diluted with water (25 mL), acidified with acetic acid (0.25 mL) and extracted with chloroform (2×50 mL). The organic solution was dried with anhydrous potassium carbonate and subsequently evaporated in vacuo. The residue was triturated with hexanes (2×20 mL) yielding the title compound as amorphous solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:13]=[CH:12][C:11]([C:14]#[N:15])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.OO.[OH-].[Na+].C([OH:22])C>CC(C)=O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:13]=[CH:12][C:11]([C:14]([NH2:15])=[O:22])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1
Reactant: CCO
Reactant: N#Cc1ccc(-c2ccc(Cl)cc2)nc1
Agent: OO
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)=O
Product: NC(=O)c1ccc(-c2ccc(Cl)cc2)nc1
Reaction time: 1 h

Procedure:
6-(4-Chlorophenyl)-3-pyridinecarbonitrile (1.61 grams), 30% hydrogen peroxide (3.0 cc.), 6N sodium hydroxide (0.3 cc.), and about 6 ml ethanol were placed in a reaction vessel and cooled slightly. The reaction temperature rose to about 50° C. and the mixture was stirred for about 1 hour. After the reaction had cooled, a solid precipitate formed and was collected by filtration. As indicated by TLC, pure product was obtained by heating the solid in refluxing acetone, yield 0.4 gram, m.p. 245°-258° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([CH:7]=[C:8]([C:13]([OH:15])=O)[N:9]=[CH:10]2)=[CH:5][CH:4]=1.[NH:16]1[CH:20]=[CH:19][N:18]=[C:17]1[NH:21][C:22]([C:24]1[C:32]2[NH:31][C:30]([NH2:33])=[N:29][C:28]=2[CH:27]=[CH:26][CH:25]=1)=[O:23].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[NH:18]1[CH:19]=[CH:20][N:16]=[C:17]1[NH:21][C:22]([C:24]1[C:32]2[N:31]=[C:30]([NH:33][C:13]([C:8]3[N:9]=[CH:10][C:11]4[C:6]([CH:7]=3)=[CH:5][CH:4]=[C:3]([O:2][CH3:1])[CH:12]=4)=[O:15])[NH:29][C:28]=2[CH:27]=[CH:26][CH:25]=1)=[O:23]
Reactant: COc1ccc2cc(C(=O)O)ncc2c1
Reactant: Nc1nc2cccc(C(=O)Nc3ncc[nH]3)c2[nH]1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COc1ccc2cc(C(=O)Nc3nc4c(C(=O)Nc5ncc[nH]5)cccc4[nH]3)ncc2c1
Yield: 84 %

Procedure:
71.8 mg (84%) of 7-methoxy-isoquinoline-3-carboxylic acid [4-(1H-imidazol-2-ylcarbamoyl)-1H-benzoimidazol-2-yl]-amide was prepared according to General Procedure A using 41 mg (0.2 mmol) of 7-methoxy-isoquinoline-3-carboxylic acid, 48 mg (0.2 mmol) of intermediate B (2-amino-3H-benzoimidazole-4-carboxylic acid (1H-imidazol-2-yl)-amide), 100 mg (0.246 mmol) of HBTU, 0.07 mL (0.4 mmol) of DIEA and 2 mL of DMF stirring at 80° C. for 2 h. LCMS: 428 (M+1)+.
Reaction SMILES: Cl.[OH:2][CH:3]([CH:9]1[O:14][CH2:13][CH2:12][NH:11][CH2:10]1)[C:4]([O:6][CH2:7][CH3:8])=[O:5].[CH3:15][C:16]1[CH:24]=[CH:23][C:19]([C:20](Cl)=[O:21])=[CH:18][CH:17]=1.S(Cl)(C)(=O)=O>>[OH:2][CH:3]([CH:9]1[O:14][CH2:13][CH2:12][N:11]([C:20](=[O:21])[C:19]2[CH:23]=[CH:24][C:16]([CH3:15])=[CH:17][CH:18]=2)[CH2:10]1)[C:4]([O:6][CH2:7][CH3:8])=[O:5]
Reactant: CCOC(=O)C(O)C1CNCCO1
Reactant: Cc1ccc(C(=O)Cl)cc1
Agent: CS(=O)(=O)Cl
Agent: Cl
Product: CCOC(=O)C(O)C1CN(C(=O)c2ccc(C)cc2)CCO1
Yield: 31.2 %

Procedure:
According to the Step 28-1 in synthetic method for EXAMPLE 28, compound 115-3 (0.2 g) and 4-methylbenzoyl chloride (164 mg) were used instead of 26-5 and mesyl chloride to obtain compound 115-4 (85 mg) as a pale yellow amorphous solid.
Reaction SMILES: [CH3:1][N:2]1[C:6]2[CH:7]=[CH:8][C:9]([C:11]([NH:13][CH2:14][CH2:15][C:16](O)=[O:17])=[O:12])=[CH:10][C:5]=2[N:4]=[C:3]1[NH:19][C:20]1[S:21][C:22]2[CH:28]=[C:27]([O:29][C:30]([F:33])([F:32])[F:31])[CH:26]=[CH:25][C:23]=2[N:24]=1.[CH3:34][NH:35][CH3:36].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>>[CH3:34][N:35]([CH3:36])[C:16]([CH2:15][CH2:14][NH:13][C:11]([C:9]1[CH:8]=[CH:7][C:6]2[N:2]([CH3:1])[C:3]([NH:19][C:20]3[S:21][C:22]4[CH:28]=[C:27]([O:29][C:30]([F:32])([F:33])[F:31])[CH:26]=[CH:25][C:23]=4[N:24]=3)=[N:4][C:5]=2[CH:10]=1)=[O:12])=[O:17]
Reactant: CNC
Reactant: Cn1c(Nc2nc3ccc(OC(F)(F)F)cc3s2)nc2cc(C(=O)NCCC(=O)O)ccc21
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Product: CN(C)C(=O)CCNC(=O)c1ccc2c(c1)nc(Nc1nc3ccc(OC(F)(F)F)cc3s1)n2C

Procedure:
1-Methyl-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-1H-benzimidazole-5-carboxylic acid (2-dimethylcarbamoyl-ethyl)-amide (38 mg) was prepared by following General Procedure F using 3-{[1-methyl-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-1H-benzimidazole-5-carbonyl]-amino}-propionic acid (48 mg), dimethyl amine (0.3 ml, 1.0 M solution in THF), HBTU (38 mg), and DIEA (0.1 ml). LC/MS: m/z 508. 1H NMR (DMSO-d6, 400 MHz): δ 8.41 (t, 1H), 8.05 (s, 1H), 7.91 (s, 1H), 7.73 (m, 2H), 7.46 (m, 1H), 7.35 (d, 1H), 7.34 (m, 1H), 3.66 (s, 3H), 3.51-3.46 (q, 2H), 2.98 (s, 3H), 2.84 (s, 3H), and 2.62 (t, 2H).
Reaction SMILES: [N:1]1([C:5]2[C:10]([C:11]#[N:12])=[C:9]([C:13]3[CH:18]=[CH:17][C:16]([O:19][CH2:20][CH2:21][OH:22])=[CH:15][CH:14]=3)[C:8]([C:23]#[N:24])=[C:7]([S:25][CH2:26][C:27]3[N:28]=[C:29]([C:32]4[CH:37]=[CH:36][C:35]([Cl:38])=[CH:34][CH:33]=4)[S:30][CH:31]=3)[N:6]=2)[CH2:4][CH2:3][CH2:2]1.[C:39]([O:43][C:44]([NH:46][C@H:47]([C:49](O)=[O:50])[CH3:48])=[O:45])([CH3:42])([CH3:41])[CH3:40].C1COCC1.Cl.CN(C)CCCN=C=NCC>CN(C)C1C=CN=CC=1.CN(C=O)C>[C:39]([O:43][C:44]([NH:46][C@H:47]([C:49]([O:22][CH2:21][CH2:20][O:19][C:16]1[CH:17]=[CH:18][C:13]([C:9]2[C:8]([C:23]#[N:24])=[C:7]([S:25][CH2:26][C:27]3[N:28]=[C:29]([C:32]4[CH:37]=[CH:36][C:35]([Cl:38])=[CH:34][CH:33]=4)[S:30][CH:31]=3)[N:6]=[C:5]([N:1]3[CH2:2][CH2:3][CH2:4]3)[C:10]=2[C:11]#[N:12])=[CH:14][CH:15]=1)=[O:50])[CH3:48])=[O:45])([CH3:41])([CH3:42])[CH3:40]
Reactant: C[C@H](NC(=O)OC(C)(C)C)C(=O)O
Reactant: N#Cc1c(SCc2csc(-c3ccc(Cl)cc3)n2)nc(N2CCC2)c(C#N)c1-c1ccc(OCCO)cc1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: C[C@H](NC(=O)OC(C)(C)C)C(=O)OCCOc1ccc(-c2c(C#N)c(SCc3csc(-c4ccc(Cl)cc4)n3)nc(N3CCC3)c2C#N)cc1
Temperature: 40 °C
Reaction time: 8 h

Procedure:
350 mg (0.625 mmol) of 2-(azetidin-1-yl)-6-({(2-(4-chlorophenyl)-1,3-thiazol-4-yl)methyl}sulfanyl)-4-(4-(2-hydroxyethoxy)phenyl)pyridine-3,5-dicarbonitrile (Example 8), 354.7 mg (1.875 mmol) of N-(tert-butoxycarbonyl)-L-alanine and 38.17 mg (0.312 mmol) of 4-dimethylaminopyridine were initially charged in 3.3 ml of DMF. 3.3 ml of THF and 155.7 mg (0.812 mmol) of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride were added, and the reaction solution was then stirred at 40° C. overnight. After cooling, the reaction solution was purified by preparative HPLC (acetonitrile/water+0.1% TFA). This gave 377 mg (83% of theory) of the target compound.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([NH:16][C:17]2[N:22]=[C:21]([C:23]#[C:24][C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=3[CH2:31][C:32]([O:34][CH3:35])=[O:33])[C:20]([C:36]([F:39])([F:38])[F:37])=[CH:19][N:18]=2)=[CH:12][CH:11]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]>CN(C=O)C.CCN(CC)CC.[Pd]>[C:1]([O:5][C:6]([NH:8][CH2:9][C:10]1[CH:11]=[CH:12][C:13]([NH:16][C:17]2[N:22]=[C:21]([CH2:23][CH2:24][C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=3[CH2:31][C:32]([O:34][CH3:35])=[O:33])[C:20]([C:36]([F:38])([F:39])[F:37])=[CH:19][N:18]=2)=[CH:14][CH:15]=1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(=O)Cc1ccccc1C#Cc1nc(Nc2ccc(CNC(=O)OC(C)(C)C)cc2)ncc1C(F)(F)F
Agent: [Pd]
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COC(=O)Cc1ccccc1CCc1nc(Nc2ccc(CNC(=O)OC(C)(C)C)cc2)ncc1C(F)(F)F
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A suspension of 10% Pd/C (200 mg) and methyl 2-(2-((2-((4-(((tert-butoxycarbonyl)amino)methyl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)ethynyl)phenyl)acetate (A13) (412 mg, 0.762 mmol) in DMF (5 mL) and Et3N (1 mL) was stirred under a hydrogen atmosphere at room temperature for 16 h. The resulting mixture was filtered through Celite, washing with EtOAc (200 mL) then the combined filtrates were evaporated in vacuo to give the title compound A14 as a white solid (306 mg, 74%); 1H NMR (400 MHz, d6-DMSO) δ 10.19 (s, 1H), 8.68 (s, 1H), 7.68 (d, J=8.5 Hz, 2H), 7.34 (t, J=6.0 Hz, 1H), 7.27-7.16 (m, 6H), 4.09 (d, J=6.0 Hz, 2H), 3.76 (s, 2H), 3.59 (s, 3H), 3.11-2.95 (m, 4H), 1.40 (s, 9H). LCMS-A: rt 6.637 min; m/z 545 [M+H]+.
Reaction SMILES: Cl[CH2:2][C:3]1[N:4]=[C:5]([CH2:8][CH2:9][C:10]2[N:11]=[C:12]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[O:13][C:14]=2[CH3:15])[S:6][CH:7]=1.[OH:22][C:23]1[CH:24]=[C:25]([CH2:29][C:30]([O:32][CH3:33])=[O:31])[CH:26]=[CH:27][CH:28]=1.CN(C)C=O.[H-].[Na+]>O>[CH3:15][C:14]1[O:13][C:12]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[N:11][C:10]=1[CH2:9][CH2:8][C:5]1[S:6][CH:7]=[C:3]([CH2:2][O:22][C:23]2[CH:24]=[C:25]([CH2:29][C:30]([O:32][CH3:33])=[O:31])[CH:26]=[CH:27][CH:28]=2)[N:4]=1
Reactant: Cc1oc(-c2ccccc2)nc1CCc1nc(CCl)cs1
Reactant: COC(=O)Cc1cccc(O)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)Cc1cccc(OCc2csc(CCc3nc(-c4ccccc4)oc3C)n2)c1
Temperature: 25 °C
Reaction time: 15 h
Yield: 38.3 %

Procedure:
To a mixture of 4-[2-(4-chloromethyl-2-thiazolyl)ethyl]-5-methyl-2-phenyloxazole (0.64 g), methyl 2-(3-hydroxyphenyl)acetate (0.30 g) and N,N-dimethylformamide (20 mL) was added sodium hydride (60%, oil, 0.09 g) under ice-cooling, and the mixture was stirred at room temperature for 15 hrs. The reaction mixture was poured into water and extracted with ethyl acetate. The organic layer was washed successively with water, 2N aqueous sodium hydroxide solution and saturated brine, dried over anhydrous magnesium sulfate and concentrated. The obtained residue was subjected to silica gel column chromatography to give methyl 2-[3-[[2-[2-(5-methyl-2-phenyl-4-oxazolyl)ethyl]-4-thiazolyl]methoxy]phenyl]acetate as a colorless oil (0.31 g, 38%) from a fraction eluted with ethyl acetate-hexane (1:3, v/v).
Reaction SMILES: [C:1](O)([C:3](F)(F)F)=[O:2].[NH2:8][C:9]1[C:10]([C:26]([NH2:28])=[O:27])=[CH:11][C:12]2[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[N:14]([CH2:21][C@@H:22]([NH2:24])[CH3:23])[C:13]=2[N:25]=1>>[C:1]([NH:8][C:9]1[C:10]([C:26]([NH2:28])=[O:27])=[CH:11][C:12]2[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[N:14]([CH2:21][C@@H:22]([NH2:24])[CH3:23])[C:13]=2[N:25]=1)(=[O:2])[CH3:3]
Reactant: C[C@H](N)Cn1c2ccccc2c2cc(C(N)=O)c(N)nc21
Reactant: O=C(O)C(F)(F)F
Product: CC(=O)Nc1nc2c(cc1C(N)=O)c1ccccc1n2C[C@H](C)N
Yield: 63 %

Procedure:
xxxi-a (44 mg, 0.104 mmol) was deprotected using the TFA conditions detailed in the preparation of 30 to afford the title compound (66, 29 mg, 63%). NH4OAc standard conditions. DAD
Reaction SMILES: [CH2:1]([C:4]1[C:9]([Br:10])=[C:8]([F:11])[CH:7]=[CH:6][C:5]=1[OH:12])[CH:2]=C.S(=O)(=O)(O)O>C1(C)C=CC=CC=1>[Br:10][C:9]1[C:4]2[CH:1]=[CH:2][O:12][C:5]=2[CH:6]=[CH:7][C:8]=1[F:11]
Reactant: C=CCc1c(O)ccc(F)c1Br
Agent: O=S(=O)(O)O
Solvent: Cc1ccccc1
Product: Fc1ccc2occc2c1Br
Yield: 98 %

Procedure:
Beginning with 3 gm (13 mMol) 2-allyl-3-bromo-4-fluorophenol, the title compound was prepared in 98% yield essentially by the procedure described in Preparation XXVII with the exception that the cyclization/dehydration step was performed using sulfuric acid in toluene.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[CH:14]=[C:13]([C:15]([F:18])([F:17])[F:16])[N:12]3[N:19]=[CH:20][C:21]([C:22]#[CH:23])=[C:11]3[N:10]=2)[CH:5]=[CH:6][C:7]=1[Cl:8].Br[C:25]1[C:26]([F:36])=[CH:27][C:28]([F:35])=[C:29]([S:31]([NH2:34])(=[O:33])=[O:32])[CH:30]=1>>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[CH:14]=[C:13]([C:15]([F:16])([F:17])[F:18])[N:12]3[N:19]=[CH:20][C:21]([C:22]#[C:23][C:25]4[C:26]([F:36])=[CH:27][C:28]([F:35])=[C:29]([S:31]([NH2:34])(=[O:32])=[O:33])[CH:30]=4)=[C:11]3[N:10]=2)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: C#Cc1cnn2c(C(F)(F)F)cc(-c3ccc(Cl)c(Cl)c3)nc12
Reactant: NS(=O)(=O)c1cc(Br)c(F)cc1F
Product: NS(=O)(=O)c1cc(C#Cc2cnn3c(C(F)(F)F)cc(-c4ccc(Cl)c(Cl)c4)nc23)c(F)cc1F

Procedure:
The title compound was prepared from 5-(3,4-dichloro-phenyl)-3-ethynyl-7-trifluoromethyl-pyrazolo[1,5-a]pyrimidine (example C.9) (89 mg, 0.25 mmol) and 5-bromo-2,4-difluoro-benzenesulfonamide (68 mg, 0.25 mmol) according to general procedure II. Obtained as a yellow solid (10 mg, 7%). MS (ISP) 547.0 [(M+H)+]; mp 308-310° C.
Reaction SMILES: [CH3:1][N:2]([CH3:22])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:18]=[C:17]([C:19]([OH:21])=O)[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[N:10]=2)=[CH:5][CH:4]=1.Cl.[OH:24][C:25]1[C:34]([CH3:35])=[CH:33][CH:32]=[C:31]2[C:26]=1[CH2:27][CH2:28][NH:29][CH2:30]2>>[CH3:1][N:2]([CH3:22])[C:3]1[CH:4]=[CH:5][C:6]([C:9]2[N:18]=[C:17]([C:19]([N:29]3[CH2:28][CH2:27][C:26]4[C:31](=[CH:32][CH:33]=[C:34]([CH3:35])[C:25]=4[OH:24])[CH2:30]3)=[O:21])[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[N:10]=2)=[CH:7][CH:8]=1
Reactant: CN(C)c1ccc(-c2nc(C(=O)O)c3ccccc3n2)cc1
Reactant: Cc1ccc2c(c1O)CCNC2
Agent: Cl
Product: Cc1ccc2c(c1O)CCN(C(=O)c1nc(-c3ccc(N(C)C)cc3)nc3ccccc13)C2
Yield: 39 %

Procedure:
Reaction of 2-(4-(dimethylamino)phenyl)quinazoline-4-carboxylic acid with 5-hydroxy-6-methyl-1,2,3,4-tetrahydroisoquinoline hydrochloride gave compound 36 (39% yield) as a brown solid. 1H NMR (300 MHz, CDCl3) δ2.25 and 2.28 (2s, 3H), 2.81 and 3.03 (2t, 2H), 3.12 (s, 6H), 3.61 and 4.21 (2t, 2H), 4.50 and 5.08 (2s, 2H), 4.69 and 4.77 (2s, 1H), 6.36-7.09 (m, 4H), 7.48-7.56 (m, 1H), 7.88-7.98 (m, 2H), 8.20-8.23 (m, 1H), 8.56-8.61 (m, 2H); MS (ESI) m/z 439 ([M+H]+).
Reaction SMILES: CO[C:3]([CH3:5])=[CH2:4].[Br:6][CH2:7][C:8]([C:10]1[CH:15]=[CH:14][C:13]([OH:16])=[C:12]([CH2:17][OH:18])[CH:11]=1)=[O:9].C1(C)C=CC(S(O)(=O)=O)=CC=1>C(Cl)Cl>[Br:6][CH2:7][C:8]([C:10]1[CH:15]=[CH:14][C:13]2[O:16][C:3]([CH3:5])([CH3:4])[O:18][CH2:17][C:12]=2[CH:11]=1)=[O:9]
Reactant: C=C(C)OC
Reactant: O=C(CBr)c1ccc(O)c(CO)c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: ClCCl
Product: CC1(C)OCc2cc(C(=O)CBr)ccc2O1
Reaction time: 3 h
Yield: 82.5 %

Procedure:
2-Methoxypropene (10 g) was added over 15 min to a stirred solution of 2-bromo-1-[4-hydroxy-3-(hydroxymethyl)phenyl]ethanone (5 g) and toluene-4-sulphonic acid (0.5 g) in CH2Cl2 (100 ml) at 23°. The mixture was stirred for 3 h, filtered through a was of triethylamine-deactivated silica and evaporated to give an oil. Purification by [FCTS] (300 g) [E] afforded the title compound as an oil (4.8 g) which solidified on cooling. A small sample was crystallised from light petroleum (b.p. 60°-80°) to give white crystals m.p. 47°-48°.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[C:8]([OH:10])=O.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[F:35][C:36]([F:59])([F:58])[C:37]1[CH:42]=[CH:41][C:40]([CH:43]2[CH2:48][NH:47][CH2:46][CH:45]([NH:49][C:50](=[O:57])[C:51]3[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=3)[CH2:44]2)=[CH:39][CH:38]=1>CN(C)C1C=CN=CC=1.CN(C=O)C>[CH3:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[C:8]([N:47]1[CH2:48][CH:43]([C:40]2[CH:39]=[CH:38][C:37]([C:36]([F:59])([F:58])[F:35])=[CH:42][CH:41]=2)[CH2:44][CH:45]([NH:49][C:50]([C:51]2[CH:52]=[CH:53][CH:54]=[CH:55][CH:56]=2)=[O:57])[CH2:46]1)=[O:10]
Reactant: Cc1cnccc1C(=O)O
Reactant: O=C(NC1CNCC(c2ccc(C(F)(F)F)cc2)C1)c1ccccc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: CN(C)c1ccncc1
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Product: Cc1cnccc1C(=O)N1CC(NC(=O)c2ccccc2)CC(c2ccc(C(F)(F)F)cc2)C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
38 mg (0.28 mmol) of 3-methylpyridine-4-carboxylic acid together with 131 mg (0.34 mmol) of HATU and 56 mg (0.46 mmol) of 4-dimethylaminopyridine were initially charged in 2 ml of DMF, and 80 mg (0.23 mmol) of N-{5-[4-(trifluoromethyl)phenyl]piperidin-3-yl}benzamide were added. The reaction mixture was stirred overnight at RT and then purified by preparative HPLC (Reprosil C18, water/acetonitrile gradient). Yield: 65 mg (59% of theory)
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH2:9]/[C:10](/[C:13]2[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=2)=[N:11]\[OH:12])=[CH:4][CH:3]=1.[CH3:25][S:26]([C:29]1[CH:34]=[CH:33][C:32](B(O)O)=[CH:31][CH:30]=1)(=[O:28])=[O:27]>>[CH3:25][S:26]([C:29]1[CH:34]=[CH:33][C:32]([C:2]2[CH:7]=[CH:6][C:5]([CH:8]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[CH2:9]/[C:10](/[C:13]3[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=3)=[N:11]\[OH:12])=[CH:4][CH:3]=2)=[CH:31][CH:30]=1)(=[O:28])=[O:27]
Reactant: O/N=C(\CC(c1ccccc1)c1ccc(Br)cc1)c1ccncc1
Reactant: CS(=O)(=O)c1ccc(B(O)O)cc1
Product: CS(=O)(=O)c1ccc(-c2ccc(C(C/C(=N\O)c3ccncc3)c3ccccc3)cc2)cc1

Procedure:
In analogy to example 19, from (E)-3-(4-bromo-phenyl)-3-phenyl-1-pyridin-4-yl-propan-1-one oxime (example 5) and (4-methylsulfonylphenyl)boronic acid was prepared the title compound as a light yellow foam, MS (ESI+): m/z=457.2 ([M+H]+).
Reaction SMILES: [N+](C1C=CC([N:10]([C:14]2[CH:19]=[CH:18][C:17]([C:20]3[CH:25]=[CH:24][N:23]=[CH:22][CH:21]=3)=[CH:16][CH:15]=2)[C:11](=[O:13])[O-])=CC=1)([O-])=O.C(N(CC)C(C)C)(C)C.[NH2:35][C@@H:36]([C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1)[CH2:37][OH:38]>ClCCl>[OH:38][CH2:37][C@@H:36]([NH:35][C:11]([NH:10][C:14]1[CH:15]=[CH:16][C:17]([C:20]2[CH:21]=[CH:22][N:23]=[CH:24][CH:25]=2)=[CH:18][CH:19]=1)=[O:13])[C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1
Reactant: N[C@H](CO)c1ccccc1
Reactant: O=C([O-])N(c1ccc(-c2ccncc2)cc1)c1ccc([N+](=O)[O-])cc1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: O=C(Nc1ccc(-c2ccncc2)cc1)N[C@H](CO)c1ccccc1
Reaction time: 20 h
Yield: 81.6 %

Procedure:
To a solution of 4-nitrophenyl[4-(4-pyridinyl)phenyl]carbamate (7.50 g) and N,N-diisopropylethylamine (5.84 mL) in dichloromethane (150 mL) was added (2S)-2-amino-2-phenylethanol (4.60 g) at ambient temperature and the mixture was stirred at the same temperature for 20 hours. The resulting mixture was concentrated in vacuo and then water (45 mL) and ethyl acetate (45 mL) was added to the residue. The precipitated solid was collected by filtration and washed with water (30 mL×5) to obtain yellow crystals. The crystals were triturated with ethyl acetate (30 mL) to give 1-[(1S)-2-hydroxy-1-phenylethyl]-3-[4-(4-pyridinyl)phenyl]urea (6.1 g) as a slightly yellow crystals.
Reaction SMILES: [CH3:1][CH:2]([C:7]([O:9]C)=O)[C:3](OC)=[O:4].[NH2:11][C:12]1[NH:16][N:15]=[C:14]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:13]=1.C[O-].[Na+]>CO>[OH:9][C:7]1[N:16]2[N:15]=[C:14]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH:13]=[C:12]2[NH:11][C:3](=[O:4])[C:2]=1[CH3:1]
Reactant: COC(=O)C(C)C(=O)OC
Reactant: Nc1cc(-c2ccccc2)n[nH]1
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: Cc1c(O)n2nc(-c3ccccc3)cc2[nH]c1=O
Temperature: 75 °C
Yield: 126.3 %

Procedure:
To a solution of dimethyl methylmalonate (1.30 mL, 9.80 mmol) and 5-amino-3-phenylpyrazole (1.50 g, 9.42 mmol) in methanol (11 mL) is added 25% sodium methoxide in methanol (6.04 mL, 26.4 mmol). The reaction mixture is heated at 75° C. for 48 hr. The precipitate was collected in a Buchner funnel and washed with dichloromethane to provide 7-hydroxy-6-methyl-2-phenylpyrazolo[1,5-a]pyrimidin-5(4H)-one (2.87 g, yield 95%). LCMS: (AA) M+1 242; 1H NMR (400 MHz, DMSO) δ 10.39 (s, 1H), 7.92-7.86 (m, 2H), 7.41-7.33 (m, 2H), 7.32-7.26 (m, 1H), 5.92 (s, 1H), 1.75 (s, 3H).