Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:10]([CH2:20][CH:21]([C:23]2[CH:28]=[CH:27][CH:26]=[C:25]([C:29]3[S:30][C:31]([CH3:34])=[CH:32][CH:33]=3)[CH:24]=2)[NH2:22])=[CH:11][C:12]([Cl:19])=[C:13]2[C:18]=1[N:17]=[CH:16][CH:15]=[CH:14]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:35]([O:42][CH2:43][C:44](Cl)=[O:45])[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1.C(N(CC)CC)C.[Si](I)(C)(C)C>C(OCC)(=O)C>[CH2:35]([O:42][CH2:43][C:44]([NH:22][CH:21]([C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([C:29]2[S:30][C:31]([CH3:34])=[CH:32][CH:33]=2)[CH:24]=1)[CH2:20][C:10]1[C:9]([O:8][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[C:18]2[C:13]([CH:14]=[CH:15][CH:16]=[N:17]2)=[C:12]([Cl:19])[CH:11]=1)=[O:45])[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1.[CH2:35]([O:42][CH2:43][C:44]([NH:22][CH:21]([C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([C:29]2[S:30][C:31]([CH3:34])=[CH:32][CH:33]=2)[CH:24]=1)[CH2:20][C:10]1[C:9]([OH:8])=[C:18]2[C:13]([CH:14]=[CH:15][CH:16]=[N:17]2)=[C:12]([Cl:19])[CH:11]=1)=[O:45])[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1
Reactant: O=C(Cl)COCc1ccccc1
Reactant: Cc1ccc(-c2cccc(C(N)Cc3cc(Cl)c4cccnc4c3OCc3ccccc3)c2)s1
Agent: C[Si](C)(C)I
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: Cc1ccc(-c2cccc(C(Cc3cc(Cl)c4cccnc4c3O)NC(=O)COCc3ccccc3)c2)s1
Product: Cc1ccc(-c2cccc(C(Cc3cc(Cl)c4cccnc4c3OCc3ccccc3)NC(=O)COCc3ccccc3)c2)s1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 57.4 %

Procedure:
2-Benzyloxy-N-{2-(8-benzyloxy-5-chloro-quinolin-7-yl)-1-[3-(5-methyl-thiophen-2-yl)-phenyl]-ethyl}-acetamide was prepared from 2-[8-(benzyloxy)-5-chloroquinolin-7-yl]-1-[3-(5-methyl-2-thienyl)phenyl]ethanamine (0.411 mmol) and benzyloxyacetyl chloride (0.452 mmol, 1.1 eq.) according to the general procedure described above (Alternate General Procedure for N-Acylations). After stirring 15 min at room temperature, additional benzyloxyacetyl chloride (0.206 mmol, 0.5 eq.) and triethylamine (0.206 mmol, 0.5 eq.) was added. Stirring was continued for 2 min at room temperature and the reaction was worked up as described in the general procedure. Ethyl acetate was used in place of dichloromethane in the workup procedure. Crude product obtained was a white foam that was subjected to the conditions described above for TMSI-mediated O-benzyl deprotection. Crude product obtained was a brown solid that was purified by column chromatography using 10% acetone/dichloromethane to give the title compound as a tan solid (0.118 mmol, 29% for 2 steps). MS (ESI) m/z 543.4.
Reaction SMILES: [Cl:1][S:2]([OH:5])(=O)=[O:3].[CH3:6][N:7]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[N:10]([CH3:17])[C:9](=[O:18])[C:8]1=[O:19]>>[CH3:17][N:10]1[C:11]2[C:16](=[CH:15][C:14]([S:2]([Cl:1])(=[O:5])=[O:3])=[CH:13][CH:12]=2)[N:7]([CH3:6])[C:8](=[O:19])[C:9]1=[O:18]
Reactant: O=S(=O)(O)Cl
Reactant: Cn1c(=O)c(=O)n(C)c2ccccc21
Product: Cn1c(=O)c(=O)n(C)c2cc(S(=O)(=O)Cl)ccc21
Temperature: 25 °C
Reaction time: 4 h

Procedure:
Chlorosulfonic acid (3 mL) was heated to 65° C. and 1,4-dimethylquinoxaline-2,3 (1H,4H)-dione (example 6-3b, 1 g, 5.5 mmol) was added in portions over 0.5 hour. The reaction mixture was stirred for 4 hours then cooled to ambient temperature and poured slowly onto ice. The resulting precipitate was filtered and washed with water to give 1,4-dimethyl-2,3-dioxo-1,2,3,4-tetrahydroquinoxaline-6-sulfonyl chloride as a white solid. 1H NMR (400 MHz, DMSO-d6): δ, ppm: 3.50(s, 6H), 7.25(m, 2H), 7.38(m, 4H).
Reaction SMILES: S(Cl)(Cl)=O.[F:5][C:6]1[C:14]([F:15])=[CH:13][C:12]([C:16]([F:19])([F:18])[F:17])=[CH:11][C:7]=1[C:8]([NH2:10])=O.CN(C)C=O.C(=O)([O-])[O-].[K+].[K+]>CCCCC>[F:5][C:6]1[C:14]([F:15])=[CH:13][C:12]([C:16]([F:19])([F:17])[F:18])=[CH:11][C:7]=1[C:8]#[N:10]
Reactant: NC(=O)c1cc(C(F)(F)F)cc(F)c1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCCCC
Solvent: O=S(Cl)Cl
Product: N#Cc1cc(C(F)(F)F)cc(F)c1F
Reaction time: 1 h
Yield: 56 %

Procedure:
Thionyl chloride, 6.0 g (50 mmol) was added to a slurry of 4.0 g (18 mmol) 2,3-difluoro-5-(trifluoromethyl)benzamide and 15 mL dimethylformamide at 0° C. After stirring for 1 hour, the reaction mixture was diluted with 25 mL pentane and neutralized by dropwise addition of a saturated potassium carbonate solution and filtered. The pentane solution was dried and distilled to yield 2,3-difluoro-5-(trifluoromethyl) benzonitrile in 56% yield, bp 65°-70° C./20 mm Hg.
Reaction SMILES: [O:1]=[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[O:5][CH:4]([C:12](O)=[O:13])[CH2:3]1.B.CSC.Cl>C1COCC1>[OH:13][CH2:12][CH:4]1[CH2:3][C:2](=[O:1])[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[O:5]1
Reactant: O=C1CC(C(=O)O)Oc2ccccc21
Agent: B
Agent: Cl
Solvent: C1CCOC1
Solvent: CSC
Product: O=C1CC(CO)Oc2ccccc21
Temperature: 0 °C
Reaction time: 2 h
Yield: 93.5 %

Procedure:
The 3 g of 4-oxo-chromane-2-carboxylic acid in THF (65 mL) was stirred was cooled to 0° C. and borane-methyl sulfide complex (2.5 mL of M solution, 25 mmoles) was added dropwise for about 15 minutes. The solution was warmed to room temperature and then heated at reflux for 4 hours. The solution was cooled to room temperature and 10% aqueous hydrochloric acid (20 mL) was added over 15 minutes and the solution was stirred at room temperature for 2 hours. The mixture was concentrated to approximately 25 mL. The solution was poured into ethyl acetate (50 mL) and washed with water (2×30 mL), saturated sodium bicarbonate (2×30 mL) and saturated ammonium chloride (2×30 mL). The organic layer was separated dried over anhydrous MgSO4, and then concentrated in vacuo to yield about 2.6 g of 2-(hydroxymethyl)-chroman-4-one (86.7% yield)
Reaction SMILES: [CH:1](O)=[O:2].C(OC(=O)C)(=O)C.[CH2:11]([O:18][NH:19][CH2:20][C:21]1([C:26]([OH:28])=[O:27])[CH2:25][CH2:24][CH2:23][CH2:22]1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>ClCCl>[CH2:11]([O:18][N:19]([CH2:20][C:21]1([C:26]([OH:28])=[O:27])[CH2:25][CH2:24][CH2:23][CH2:22]1)[CH:1]=[O:2])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: O=C(O)C1(CNOCc2ccccc2)CCCC1
Reactant: O=CO
Solvent: CC(=O)OC(C)=O
Solvent: ClCCl
Product: O=CN(CC1(C(=O)O)CCCC1)OCc1ccccc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a cold solution of formic acid (10.3 mL, 0.27 mol) in dichloromethane (40 mL) at 0° C. under a nitrogen atmosphere was added acetic anhydride (4.2 mL, 44.1 mmol). After 1 h, a solution of 1-(benzyloxyamino-methyl)-cyclopentanecarboxylic acid (1.1 g, 4.41 mmol) in dichloromethane (20 mL) was added. The mixture was stirred at room temperature for 18 h and was concentrated in vacuo. Water (100 mL) was added and the mixture was extracted with dichloromethane (100 mL×2). The combined organic extracts were dried (MgSO4) and were evaporated in vacuo to yield the title compound as a pale, yellow oil (1.05 g, 86%). MH+278.
Reaction SMILES: [NH2:1][C:2]1[CH:23]=[CH:22][C:5]([C:6]([NH:8][C@H:9]([C:17]([O:19][CH2:20][CH3:21])=[O:18])[CH2:10][CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])=[O:7])=[CH:4][C:3]=1[O:24][CH3:25].[C:26]([NH:29][C:30]1[NH:31][C:32](=[O:47])[C:33]([CH2:43][CH2:44][CH:45]=O)=[C:34]([N:36]([C:40](=[O:42])[CH3:41])[C:37](=[O:39])[CH3:38])[N:35]=1)(=[O:28])[CH3:27].C(O)(=O)C.C([BH3-])#N.[Na+]>C(O)C.CO>[C:26]([NH:29][C:30]1[NH:31][C:32](=[O:47])[C:33]([CH2:43][CH2:44][CH2:45][NH:1][C:2]2[CH:23]=[CH:22][C:5]([C:6]([NH:8][C@H:9]([C:17]([O:19][CH2:20][CH3:21])=[O:18])[CH2:10][CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])=[O:7])=[CH:4][C:3]=2[O:24][CH3:25])=[C:34]([N:36]([C:37](=[O:39])[CH3:38])[C:40](=[O:42])[CH3:41])[N:35]=1)(=[O:28])[CH3:27]
Reactant: CC(=O)Nc1nc(N(C(C)=O)C(C)=O)c(CCC=O)c(=O)[nH]1
Reactant: CCOC(=O)CC[C@H](NC(=O)c1ccc(N)c(OC)c1)C(=O)OCC
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CCO
Solvent: CC(=O)O
Product: CCOC(=O)CC[C@H](NC(=O)c1ccc(NCCCc2c(N(C(C)=O)C(C)=O)nc(NC(C)=O)[nH]c2=O)c(OC)c1)C(=O)OCC
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Both diethyl N-(4-amino-3-methoxybenzoyl)-(L)-glutamate (3.52 g, 9.99 mmoles) and 3-(2-acetylamino-4-diacetylamino-1,6-dihydro-6-oxo-5-pyrimidinyl)propionaldehyde (3.08 g, 9.99 mmoles) were stirred in absolute ethanol (100 mL) under nitrogen while glacial acetic acid (6 mL) was added dropwise during 1 minute. After solution was achieved (0.5 hour), activated 3 Å molecular sieves (20 mL) were added and stirring was continued 2 hours. The reaction mixture was chilled (ice bath) and sodium cyanoborohydride (628 mg, 9.99 mmoles) added in one portion. After stirring cold 0.5 hour, the bath was removed and the reaction mixture allowed to warm to ambient temperature. The reaction mixture was filtered after 16 hours and the solids were rinsed with ethanol (100 mL). The filtrate was spin evaporated and dried to a cream foam that was dissolved in ethyl acetate (100 mL). The organic phase was washed (2×100 mL 1:1 brine/water) and poured onto a silica gel column (175 g, pre-wet with ethyl acetate). The column was rinsed with ethyl acetate (400 mL) and then the product eluted with 5% added methanol. Like fractions were combined by spin evaporation and dried to give a white solid; yield, 2.07 g (32%); mp 73°-84° C. (eff.); 1H-NMR (DMSO-d6) δ 1.15 and 1.17 (2t overlapped, 6H), 1.65 (br m, 2H) 1.9-2.3 (br m, 4H), 2.12 (s, 3H), 2.20 (s, 6H), 2.40 (t, 2H), 3.10 (br m, 2H), 3.80 (s, 3H), 4.0-4.2 (2 q overlapped, 4H), 4.39 (m, 1H), 5.46 (br t, 1H), 6.47 (d, Jo=8 Hz, 1H), 7.29 (d, Jm=2 Hz, 1H), 7.42 (dxd, Jo=8 Hz, Jm=2 hz, 1H), 8.28 (d, 1H), 11.9 (v br s, 2H); uv (MeOH) 306 nm max (25800), 258 min (3940), 227 sh (17800), 205 max (32400), mass spec (FAB) m/e 645.6 (62%), 442.5 (81), 400.1 (100).
Reaction SMILES: [C:1]([O:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[C:12](=O)[C:13]([NH2:15])=[O:14])(=[O:3])[CH3:2].Cl.[NH2:18][OH:19].C([O-])(=O)C.[K+].CO>O>[C:1]([O:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[C:12](=[N:18][OH:19])[C:13]([NH2:15])=[O:14])(=[O:3])[CH3:2]
Reactant: NO
Reactant: CC(=O)OCc1ccccc1C(=O)C(N)=O
Agent: CC(=O)[O-]
Agent: Cl
Agent: [K+]
Solvent: CO
Solvent: O
Product: CC(=O)OCc1ccccc1C(=NO)C(N)=O
Reaction time: 18 h
Yield: 70.8 %

Procedure:
A mixture of 2-(2-acetoxymethylphenyl)-2-oxoacetamide (1.56 g), 95% hydroxylamine hydrochloride (0.62 g), potassium acetate (1.34 g) and methanol (14 ml) was heated under reflux with stirring for 18 hours. After the mixture was cooled by allowing it to stand, water (about 150 ml) was added to the reaction mixture, and the mixture was extracted with ethyl acetate three times. The combined ethyl acetate layer was washed with saturated brine and dried over anhydrous sodium sulfate. Evaporation of the solvent under reduced pressure gave the crude product (1.55 g). The crude product was purified by column chromatography on silica gel (ethyl acetate:hexane=2:1) to give the title compound (1.18 g, yield: 70.9%) as a mixture of the E- and Z-isomers (E:Z=65:35 determined by 1H-NMR analysis).
Reaction SMILES: [CH3:1][N:2]([CH2:4][CH2:5][CH:6]([OH:12])[C:7]1[S:8][CH:9]=[CH:10][CH:11]=1)[CH3:3].[OH-].[K+].F[C:16]1[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH:19]=[CH:18][CH:17]=1.[C:26]([OH:35])(=[O:34])[C@H:27]([C@@H:29]([C:31]([OH:33])=[O:32])[OH:30])[OH:28]>CS(C)=O.O>[CH3:1][N:2]([CH2:4][CH2:5][CH:6]([O:12][C:24]1[C:25]2[C:20](=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH:21]=[CH:22][CH:23]=1)[C:7]1[S:8][CH:9]=[CH:10][CH:11]=1)[CH3:3].[C:31]([C@H:29]([C@@H:27]([C:26]([O-:35])=[O:34])[OH:28])[OH:30])([O-:33])=[O:32]
Reactant: CN(C)CCC(O)c1cccs1
Reactant: Fc1cccc2ccccc12
Reactant: O=C(O)[C@@H](O)[C@H](O)C(=O)O
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CS(C)=O
Product: CN(C)CCC(Oc1cccc2ccccc12)c1cccs1
Product: O=C([O-])[C@@H](O)[C@H](O)C(=O)[O-]
Temperature: 110 °C
Reaction time: 2 h

Procedure:
A mixture of N,N-dimethyl-3-hydroxy-3-(2-thienyl)propylamine (185 g, 1 mole), potassium hydroxide (112 g, 2 moles) and 1-fluoronaphthalene (146 g, 1 mole) in dimethylsulfoxide (1000 ml) is stirred at 110° C. for 2 hours. After cooling down to 20° C., the mixture is filtered, diluted with water (3 l), D-tartaric acid (75 g, 0.5 mole) is added and the mixture is stirred at 80° C. for 0.5 hour. After cooling down, the precipitated product is sucked off, washed with water and dried. Yield: 313 g (81%).
Reaction SMILES: Cl.[CH3:2][O:3][CH2:4][C:5](=[NH:7])[NH2:6].C[O-].[Na+].[C:11]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[C:19]1[CH:24]=[CH:23][C:22]([CH2:25][CH:26]([C:31](=O)[CH2:32][CH2:33][CH2:34][CH3:35])[C:27](OC)=[O:28])=[CH:21][CH:20]=1)#[N:12]>CO.O1CCOCC1>[CH2:32]([C:31]1[N:7]=[C:5]([CH2:4][O:3][CH3:2])[NH:6][C:27](=[O:28])[C:26]=1[CH2:25][C:22]1[CH:21]=[CH:20][C:19]([C:14]2[C:13]([C:11]#[N:12])=[CH:18][CH:17]=[CH:16][CH:15]=2)=[CH:24][CH:23]=1)[CH2:33][CH2:34][CH3:35]
Reactant: COCC(=N)N
Reactant: CCCCC(=O)C(Cc1ccc(-c2ccccc2C#N)cc1)C(=O)OC
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Solvent: C1COCCO1
Product: CCCCc1nc(COC)[nH]c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Yield: 66.1 %

Procedure:
A solution of 2-methoxyethanimidamide hydrochloride (10 g), 28% sodium methoxide (24 mL) and methyl 2-[(2′-cyanobiphenyl-4-yl)methyl]-3-oxoheptanoate (15 g) in methanol (150 mL) and 1,4-dioxane (50 mL) was stirred overnight. The solvent was evaporated under reduced pressure, and water and acetic acid were added. The precipitated solid was collected by filtration, and washed with water and diethyl ether to give the title compound (11 g, 71%) as a pale-yellow solid.
Reaction SMILES: [CH3:1][CH:2]([N:4]1[C:12]2[CH:11]=[C:10]([C:13]([F:16])([F:15])[F:14])[CH:9]=[C:8]([C:17](O)=[O:18])[C:7]=2[CH:6]=[CH:5]1)[CH3:3].[NH2:20][CH2:21][C:22]1[C:23](=[O:30])[NH:24][C:25]([CH3:29])=[CH:26][C:27]=1[CH3:28].CN1CCOCC1.ON1C2N=CC=CC=2N=N1.C(Cl)CCl>CS(C)=O>[CH3:28][C:27]1[CH:26]=[C:25]([CH3:29])[NH:24][C:23](=[O:30])[C:22]=1[CH2:21][NH:20][C:17]([C:8]1[C:7]2[CH:6]=[CH:5][N:4]([CH:2]([CH3:3])[CH3:1])[C:12]=2[CH:11]=[C:10]([C:13]([F:15])([F:16])[F:14])[CH:9]=1)=[O:18]
Reactant: CC(C)n1ccc2c(C(=O)O)cc(C(F)(F)F)cc21
Reactant: Cc1cc(C)c(CN)c(=O)[nH]1
Agent: On1nnc2cccnc21
Solvent: ClCCCl
Solvent: CS(C)=O
Solvent: CN1CCOCC1
Product: Cc1cc(C)c(CNC(=O)c2cc(C(F)(F)F)cc3c2ccn3C(C)C)c(=O)[nH]1
Reaction time: 8 h
Yield: 65.4 %

Procedure:
To a solution of 1-(1-methylethyl)-6-(trifluoromethyl)-1H-indole-4-carboxylic acid (40 mg, 0.147 mmol) in dimethyl sulfoxide (1 mL) were added 3-(aminomethyl)-4,6-dimethyl-2(1H)-pyridinone (41.7 mg, 0.221 mmol), N-methylmorpholine (0.065 mL, 0.590 mmol), 1-hydroxy-7-azabenzotriazole (40.1 mg, 0.295 mmol) and EDC (56.5 mg, 0.295 mmol), and the mixture was stirred overnight. The mixture was quenched with water (5 mL) and stirred for 10 min. The precipitate was collected by filtration and dried under high vacuum to give the title compound (39 mg, 63%) as an off-white solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.47 (m, 6H), 2.13 (s, 3H), 2.23 (s, 3H), 4.36 (d, J=5.05 Hz, 2H), 4.99 (dt, J=13.20, 6.66 Hz, 1H), 5.89 (s, 1H), 6.98 (d, J=3.03 Hz, 1H), 7.68 (s, 1H), 7.86 (d, J=3.28 Hz, 1H), 8.08 (s, 1H), 8.45 (t, J=4.93 Hz, 1H), 11.56 (s, 1H). MS: (M+H)+=406.1.
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].C(OC([N:15]1[CH2:20][CH2:19][CH:18]([N:21]2[C:25]3=[N:26][CH:27]=[N:28][C:29]([O:30][C:31]4[CH:36]=[CH:35][C:34]([S:37]([CH3:40])(=[O:39])=[O:38])=[CH:33][CH:32]=4)=[C:24]3[CH:23]=[N:22]2)[CH2:17][CH2:16]1)=O)(C)(C)C>ClCCl>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[CH3:40][S:37]([C:34]1[CH:33]=[CH:32][C:31]([O:30][C:29]2[N:28]=[CH:27][N:26]=[C:25]3[N:21]([CH:18]4[CH2:17][CH2:16][NH:15][CH2:20][CH2:19]4)[N:22]=[CH:23][C:24]=23)=[CH:36][CH:35]=1)(=[O:39])=[O:38]
Reactant: CC(C)(C)OC(=O)N1CCC(n2ncc3c(Oc4ccc(S(C)(=O)=O)cc4)ncnc32)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CS(=O)(=O)c1ccc(Oc2ncnc3c2cnn3C2CCNCC2)cc1
Reaction time: 3 h
Yield: 96.9 %

Procedure:
Trifluoroacetic acid (38.0 mL, 512 mmol) was added to a cooled solution of 4-[4-(4-methanesulfonyl-phenoxy)-pyrazolo[3,4-d]pyrimidin-1-yl]-piperidine-1-carboxylic acid tert-butyl ester (Example 59; 12.0 g, 25.4 mmol) in dichloromethane (70 mL) at about 0° C. The reaction mixture was stirred for 3 h. The solvent was evaporated under reduced pressure, and the residue was coevaporated three times with toluene to give 4-(4-methanesulfonyl-phenoxy)-1-piperidin-4-yl-1H-pyrazolo[3,4-d]pyrimidine trifluoroacetate salt (12.0 g, 97%) as an off-white solid which was used in the next step without further purification. 1H NMR (300 MHz, DMSO-d6) δ 2.14-2.17 (m, 2H), 2.32-2.41 (m, 2H), 3.22-3.30 (m, 2H), 3.30 (methyl sulfonyl peak and water peak), 3.45-3.50 (m, 2H), 5.15-5.21 (m, 1H), 7.62-7.64 (m, 2H), 8.06-8.08 (m, 2H), 8.44 (s, 1H), 8.50-8.58 (br s, 1H), 8.59 (s, 1H), 8.76-8.83 (br s, 1H). Mass spectrum (ES) MH+=374.
Reaction SMILES: [CH:1]([C@H:4]1[CH2:8][O:7][C:6](=[O:9])[N:5]1[C:10]1[CH:15]=[CH:14][N:13]2[N:16]=[CH:17][C:18]([C:19]3[CH:24]=[CH:23][C:22]([C:25]4[N:29]=[CH:28][N:27](COCC[Si](C)(C)C)[N:26]=4)=[CH:21][CH:20]=3)=[C:12]2[N:11]=1)([CH3:3])[CH3:2].C([C@H]1COC(=O)N1C1C=CN2N=CC(C3C=CC(C4N(COCC[Si](C)(C)C)N=CN=4)=CC=3)=C2N=1)(C)C.FC(F)(F)C(O)=O>ClCCl>[NH:27]1[CH:28]=[N:29][C:25]([C:22]2[CH:21]=[CH:20][C:19]([C:18]3[CH:17]=[N:16][N:13]4[CH:14]=[CH:15][C:10]([N:5]5[C@@H:4]([CH:1]([CH3:2])[CH3:3])[CH2:8][O:7][C:6]5=[O:9])=[N:11][C:12]=34)=[CH:24][CH:23]=2)=[N:26]1
Reactant: CC(C)[C@H]1COC(=O)N1c1ccn2ncc(-c3ccc(-c4ncn(COCC[Si](C)(C)C)n4)cc3)c2n1
Agent: CC(C)[C@H]1COC(=O)N1c1ccn2ncc(-c3ccc(-c4ncnn4COCC[Si](C)(C)C)cc3)c2n1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(C)[C@H]1COC(=O)N1c1ccn2ncc(-c3ccc(-c4nc[nH]n4)cc3)c2n1
Temperature: 25 °C
Reaction time: 6 h
Yield: 78 %

Procedure:
A mixture of (S)-4-isopropyl-3-(3-(4-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-1,2,4-triazol-3-yl)phenyl)pyrazolo[1,5-a]pyrimidin-5-yl)oxazolidin-2-one and (S)-4-isopropyl-3-(3-(4-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-1,2,4-triazol-5-yl)phenyl)pyrazolo[1,5-a]pyrimidin-5-yl)oxazolidin-2-one (2.37 g, 4.25 mmol) was dissolved in dichloromethane (12 mL) and trifluoroacetic acid (22.5 mL) was added and the mixture allowed to stir at ambient temperature for 6 hours. The reaction mixture was concentrated and the residue partitioned between saturated aqueous NaHCO3 (100 mL) and EtOAc (100 mL). The aqueous layer was washed with EtOAc (2×100 mL). The combined organic extracts were washed with brine, dried (Na2SO4), filtered and concentrated to give a golden yellow solid. Purification of the crude material by column chromatography, eluting with a gradient of Hexanes to 50% EtOAc/Hexanes to 0-2% (9:1 MeOH/NH4OH)/EtOAc provided (S)-3-(3-(4-(1H-1,2,4-triazol-3-yl)phenyl)pyrazolo[1,5-a]pyrimidin-5-yl)-4-isopropyloxazolidin-2-one (1.30 g, 78%) as a yellow crystalline solid. LCMS (APCI+) m/z 390 [M+H]+; 1H NMR (400 MHz, DMSO-d6) δ 9.11 (d, J=7.8 Hz, 1H), 8.77 (s, 1H), 8.37 (bs, 1H), 8.22 (d, J=8.6 Hz, 2H), 8.05 (d, J=8.6 Hz, 2H), 7.89 (d, J=7.4 Hz, 1H), 4.95-4.99 (m, 1H), 4.52 (d, J=6.2 Hz, 2H), 2.74-2.82 (m, 1H), 1.07 (d, J=7.0 Hz, 3H), 0.87 (d, J=6.6 Hz, 3H).
Reaction SMILES: [CH:1]1[C:10]2[CH2:9][CH2:8][CH2:7][CH2:6][C:5]=2[CH:4]=[CH:3][C:2]=1[C:11]1[N:15]([CH2:16][O:17][CH2:18][CH2:19][Si:20]([CH3:23])([CH3:22])[CH3:21])[CH:14]=[N:13][CH:12]=1.[Li]CCCC.CN([CH:32]=[O:33])C>>[CH:1]1[C:10]2[CH2:9][CH2:8][CH2:7][CH2:6][C:5]=2[CH:4]=[CH:3][C:2]=1[C:11]1[N:15]([CH2:16][O:17][CH2:18][CH2:19][Si:20]([CH3:23])([CH3:22])[CH3:21])[C:14]([CH:32]=[O:33])=[N:13][CH:12]=1
Reactant: C[Si](C)(C)CCOCn1cncc1-c1ccc2c(c1)CCCC2
Reactant: CN(C)C=O
Agent: [Li]CCCC
Product: C[Si](C)(C)CCOCn1c(-c2ccc3c(c2)CCCC3)cnc1C=O
Yield: 56.8 %

Procedure:
Reaction of 5-(5,6,7,8-tetrahydro-naphthalen-2-yl)-1-(2-trimethylsilanyl ethoxymethyl)-1H-imidazole (268 mg, 0.82 mmol), 2.5 M n-BuLi (424 uL, 1.06 mmol), and DMF (253 uL, 3.27 mmol) for 2 h at −40° C. followed by column chromatography on silica gel (EtOAc/hexane 9:1) gave the title compound (166 mg, 57%) as a yellow oil. 1H NMR (300 MHz, CDCl3) δ 0.00 (s, 9H), 0.94 (t, 2H, J=7.5 Hz), 1.80-1.85 (m, 4H), 2.80-2.83 (m, 4H), 3.60 (t, 2H, J=9.0 Hz), 5.81 (s, 2H), 7.13 (d, 1H, J=6.0 Hz), 7.51 (d, 1H, J=6.0 Hz), 7.57 (s, 1H), 7.60 (s, 1H). 9.88 (s, 1H).
Reaction SMILES: [CH2:1](Br)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].[OH:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]2[CH:25]=[CH:24][C:20](C(O)=O)=[CH:19][CH:18]=2)=[CH:13][CH:12]=1.[OH-].[Na+]>>[CH2:1]([O:10][C:11]1[CH:12]=[CH:13][C:14]([C:17]2[CH:25]=[CH:24][CH:20]=[CH:19][CH:18]=2)=[CH:15][CH:16]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8]
Reactant: CCCCCCCCBr
Reactant: O=C(O)c1ccc(-c2ccc(O)cc2)cc1
Agent: [Na+]
Agent: [OH-]
Product: CCCCCCCCOc1ccc(-c2ccccc2)cc1
Temperature: 70 °C
Reaction time: 18 h

Procedure:
n-Octyl bromide (0.102 mol) is added to a solution of 4-(4-hydroxyphenyl)benzoic acid (0.102 mol) and 2.5N sodium hydroxide (0.102 mol) and the mixture stirred at 70° C. for a period of 18 hours. The reaction mixture is allowed to cool and then acidified to pH 3 and partitioned between ethyl acetate and water. The organic phase is washed with water and brine and the solvent then removed to obtain the 4'-n-octyloxy 1,1'-biphenyl!-4-ylcarboxylic acid, C21H23O3, M.W. 326.4.
Reaction SMILES: [F:1][C:2]1[CH:3]=[N:4][C:5]2[C:10]([C:11]=1[C:12](=[CH2:17])[C:13]([O:15][CH3:16])=[O:14])=[N:9][C:8]([O:18][CH3:19])=[CH:7][CH:6]=2.CC([N:24]([CH2:28][C@@H:29]1[O:34][CH2:33][CH2:32][NH:31][CH2:30]1)[C:25](=[O:27])[O-:26])(C)C>>[CH3:2][C:11]([O:26][C:25]([NH:24][CH2:28][C@@H:29]1[O:34][CH2:33][CH2:32][N:31]([CH2:17][CH:12]([C:11]2[C:10]3[C:5](=[CH:6][CH:7]=[C:8]([O:18][CH3:19])[N:9]=3)[N:4]=[CH:3][C:2]=2[F:1])[C:13]([O:15][CH3:16])=[O:14])[CH2:30]1)=[O:27])([CH3:12])[CH3:10]
Reactant: C=C(C(=O)OC)c1c(F)cnc2ccc(OC)nc12
Reactant: CC(C)(C)N(C[C@H]1CNCCO1)C(=O)[O-]
Product: COC(=O)C(CN1CCO[C@@H](CNC(=O)OC(C)(C)C)C1)c1c(F)cnc2ccc(OC)nc12
Yield: 100 %

Procedure:
This compound was prepared from methyl 2-[3-fluoro-6-(methyloxy)-1,5-naphthyridin-4-yl]-2-propenoate and 1,1-dimethylethyl[(2R)-2-morpholinylmethyl]carbamate according to the general method of Example 2(d), in 100% yield.
Reaction SMILES: Cl.[Cl:2][CH2:3][CH2:4][NH:5][CH:6]1[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]1.[P:12]([OH:15])([OH:14])[OH:13].Cl.[CH2:17]=O>O>[CH:6]1([N:5]([CH2:17][P:12](=[O:15])([OH:14])[OH:13])[CH2:4][CH2:3][Cl:2])[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]1
Reactant: ClCCNC1CCCCC1
Reactant: C=O
Reactant: OP(O)O
Agent: Cl
Solvent: O
Product: O=P(O)(O)CN(CCCl)C1CCCCC1

Procedure:
A total of 101 parts of N-(2-chloroethyl)cyclohexylamine hydrochloride, 41.5 parts phosphorous acid in 101 parts water, 75 parts of 37% aqueous hydrochloric acid, and 104 parts of 37% aqueous formaldehyde were used to prepare Reagent E-2.
Reaction SMILES: C([O:5][C:6](=[O:14])[C:7]1[CH:12]=[CH:11][CH:10]=[C:9](I)[CH:8]=1)(C)(C)C.C1([Mg]Cl)CCCCC1.[NH2:23][C:24]1[N:28]([C:29]2[CH:30]=[C:31]([CH:38]=[CH:39][C:40]=2[CH3:41])[C:32]([NH:34][CH:35]2[CH2:37][CH2:36]2)=[O:33])[CH:27]=[N:26][C:25]=1[C:42]#N.Cl.C([O-])([O-])=[O:46].[K+].[K+]>C1COCC1>[NH2:23][C:24]1[N:28]([C:29]2[CH:30]=[C:31]([C:32](=[O:33])[NH:34][CH:35]3[CH2:37][CH2:36]3)[CH:38]=[CH:39][C:40]=2[CH3:41])[CH:27]=[N:26][C:25]=1[C:42]([C:9]1[CH:8]=[C:7]([CH:12]=[CH:11][CH:10]=1)[C:6]([OH:5])=[O:14])=[O:46]
Reactant: CC(C)(C)OC(=O)c1cccc(I)c1
Reactant: O=C([O-])[O-]
Reactant: Cc1ccc(C(=O)NC2CC2)cc1-n1cnc(C#N)c1N
Agent: Cl
Agent: Cl[Mg]C1CCCCC1
Agent: [K+]
Solvent: C1CCOC1
Product: Cc1ccc(C(=O)NC2CC2)cc1-n1cnc(C(=O)c2cccc(C(=O)O)c2)c1N
Temperature: 42.5 °C
Reaction time: 0.33 h

Procedure:
To a solution of 3-iodobenzoic acid tert-butyl ester (4.6g) in THF (20 mL) at −40° C. under N2 was added cyclohexylmagnesium chloride (2M in THF, 8.5 mL). The solution was kept at −40° C. to 0° C. for 20 min., when 3-(5-amino-4-cyano-imidazol-1-yl)-N-cyclopropyl-4-methyl-benzamide was added and the reaction was kept at rt for 1 h. Then HCl (4 M, 10 mL) was added and the mixuture was heated at 40 to 45° C. overnight. The mixture was neutralized with K2CO3 solution and extracted with EtOAc (2×100 mL) and the combined organics dried over Na2SO4, and concentrated. Purification of the crude product by column chromatography (EtOAc: MeOH=6:1) gave the desired product (0.46 g).