Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH2:7][CH2:6][C@@H:5]([C:8]([CH3:10])=[CH2:9])[CH2:4][CH:3]=1.B1([O-])OO1.[OH2:15].[OH2:16].O.O.[Na+].C(OC(=O)C)(=O)C>C1(C)C=CC=CC=1>[CH3:1][C:2]12[O:15][CH:7]1[CH2:6][CH:5]([C:8]1([CH3:10])[O:16][CH2:9]1)[CH2:4][CH2:3]2
Reactant: O
Reactant: C=C(C)[C@H]1CC=C(C)CC1
Agent: [Na+]
Agent: [O-]B1OO1
Solvent: CC(=O)OC(C)=O
Solvent: Cc1ccccc1
Product: CC1(C2CCC3(C)OC3C2)CO1
Temperature: 60 °C
Reaction time: 12 h
Yield: 96.9 %

Procedure:
Limonene (1.36 g, 10 mmol) was dissolved in toluene (25 ml), and a composition containing sodium perborate tetrahydrate (15.4 g, 100 mmol) and acetic anhydride (10.2 g, 100 mmol) was added thereto. The mixture was stirred at 60° C. After 12 hours, the reaction solution was washed with water to thereby completely remove acetic acid and sodium acetate, which were generated as by-products, and the remaining H2O2. Toluene was distilled off from the organic phase by distillation, and as a result, 1.63 g (97% yields) of limonene diepoxide with a GC purity of 98% was obtained.
Reaction SMILES: [NH2:1][C:2]1[C:11]2[N:12]=[C:13]([CH2:23][CH2:24][CH2:25][CH3:26])[N:14]([CH2:15][CH2:16][CH2:17][NH:18][CH2:19][CH2:20][CH2:21][OH:22])[C:10]=2[C:9]2[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=2[N:3]=1.Br[CH2:28][C:29]1[CH:30]=[C:31]([CH2:35][C:36]([O:38][CH3:39])=[O:37])[CH:32]=[CH:33][CH:34]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[NH2:1][C:2]1[C:11]2[N:12]=[C:13]([CH2:23][CH2:24][CH2:25][CH3:26])[N:14]([CH2:15][CH2:16][CH2:17][N:18]([CH2:28][C:29]3[CH:30]=[C:31]([CH2:35][C:36]([O:38][CH3:39])=[O:37])[CH:32]=[CH:33][CH:34]=3)[CH2:19][CH2:20][CH2:21][OH:22])[C:10]=2[C:9]2[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=2[N:3]=1
Reactant: CCCCc1nc2c(N)nc3ccccc3c2n1CCCNCCCO
Reactant: COC(=O)Cc1cccc(CBr)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCCCc1nc2c(N)nc3ccccc3c2n1CCCN(CCCO)Cc1cccc(CC(=O)OC)c1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
A mixture of the product from step (vii) (2 g), methyl 2-(3-(bromomethyl)phenyl)acetate (1.4 g) and potassium carbonate (2.1 g) in DMF (20 mL) was stirred at rt under nitrogen for 24 h. The mixture was partitioned between DCM/water, the organics separated, washed with water, dried, and evaporated under reduced pressure. The residue was purified by chromotography on silica eluting with DCM/MeOH/Et3N (1000/50/3). Yield 2.43 g of solid.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([S:11]([N:14]([CH2:24][C:25]([OH:27])=O)[C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[C:21](=[O:23])[NH2:22])(=[O:13])=[O:12])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH2:28]([NH:30][CH2:31][CH3:32])[CH3:29]>>[C:1]([C:5]1[CH:6]=[CH:7][C:8]([S:11]([N:14]([CH2:24][C:25](=[O:27])[N:30]([CH2:31][CH3:32])[CH2:28][CH3:29])[C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[C:21]([NH2:22])=[O:23])(=[O:13])=[O:12])=[CH:9][CH:10]=1)([CH3:2])([CH3:4])[CH3:3]
Reactant: CC(C)(C)c1ccc(S(=O)(=O)N(CC(=O)O)c2ccccc2C(N)=O)cc1
Reactant: CCNCC
Product: CCN(CC)C(=O)CN(c1ccccc1C(N)=O)S(=O)(=O)c1ccc(C(C)(C)C)cc1

Procedure:
prepared by reaction of [(4-tert-butyl-benzenesulfonyl)-(2-carbamoyl-phenyl)-amino]-acetic acid with diethylamine
Reaction SMILES: [CH3:1][O:2][C:3]1[C:24]2[O:23][C:10]3[C:11](=[O:22])[N:12]([C@@H:14]([CH2:18][CH:19]([CH3:21])[CH3:20])[C:15](O)=[O:16])[CH2:13][C:9]=3[CH2:8][C:7]=2[C:6]([O:25][CH3:26])=[CH:5][CH:4]=1.[CH3:27][O:28][C:29](=[O:37])[C:30]1[CH:35]=[CH:34][C:33]([NH2:36])=[N:32][CH:31]=1.ON1[C:43]2C=CC=[CH:47][C:42]=2N=N1>C(Cl)Cl.O>[CH3:27][O:28][C:29](=[O:37])[C:30]1[CH:35]=[CH:34][C:33]([NH:36][C:15](=[O:16])[C@@H:14]([N:12]2[CH2:13][C:9]3[CH2:8][C:7]4[C:6]([O:25][CH3:26])=[CH:5][CH:4]=[C:3]([O:2][CH3:1])[C:24]=4[O:23][C:10]=3[C:11]2=[O:22])[CH2:18][CH:19]2[CH2:20][CH2:47][CH2:42][CH2:43][CH2:21]2)=[N:32][CH:31]=1
Reactant: COc1ccc(OC)c2c1CC1=C(O2)C(=O)N([C@@H](CC(C)C)C(=O)O)C1
Reactant: On1nnc2ccccc21
Reactant: COC(=O)c1ccc(N)nc1
Solvent: ClCCl
Solvent: O
Product: COC(=O)c1ccc(NC(=O)[C@H](CC2CCCCC2)N2CC3=C(Oc4c(OC)ccc(OC)c4C3)C2=O)nc1
Yield: 36.5 %

Procedure:
A solution of (S)-2-(5,8-dimethoxy-3-oxo-3,9-dihydro-1H-chromeno[2,3-c]pyrrol-2-yl)-4-methyl-pentanoic acid (Example 13, step 2c) (100 mg, 0.21 mmol), commercially available 6-aminonicotinic acid methyl ester (45 mg, 0.30 mmol), N-ethyl-N-dimethyaminopropyl carbodiimide hydrochloride (EDCI. HCl) (52 mg, 0.27 mmol), and N-hydroxybenzotriazole (HOBt) (37 mg, 0.27 mmol) in methylene chloride (10 mL) was stirred for 16 hours at 25° C. The reaction mixture was diluted with water and extracted with ethyl acetate (3×). The combined organic layers were dried over anhydrous sodium sulfate and concentrated in vacuo. The resulting residue, upon silica gel flash chromatography using hexane-ethyl acetate gradient elution, afforded 6-[(S)-3-cyclohexyl-2-(5,8-dimethoxy-3-oxo-3,9-dihydro-1H-chromeno[2,3-c]pyrrol-2-yl)-propionylamino]-nicotinic acid methyl ester (41 mg, 30.8%), as a white solid. 1H NMR (DMSO-d6) δ: 11.31 (s, 1H), 8.87 (br. s., 1H), 8.28 (d, J=8.3 Hz, 1H), 8.14 (d, J=8.8 Hz, 1H), 6.91 (d, J=8.8 Hz, 1H), 6.67 (d, J=9.3 Hz, 1H), 5.10 (d, J=5.4 Hz, 1H), 4.38 (d, J=18.6 Hz, 1H), 4.03 (d, J=19.1 Hz, 1H), 3.86 (s, 3H), 3.76 (s, 6H), 3.55 (br. s., 2H), 1.41-1.90 (m, 7H), 0.78-1.31 (m, 6H).
Reaction SMILES: Cl[CH2:2][C:3]1[N:4]=[C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[S:6][CH:7]=1.[OH:14][C:15]1[CH:37]=[CH:36][C:18]([CH2:19][N:20]2[CH:24]=[C:23]([C:25]([O:27]CC)=[O:26])[C:22]([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)=[N:21]2)=[CH:17][CH:16]=1.C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[C:30]1([C:22]2[C:23]([C:25]([OH:27])=[O:26])=[CH:24][N:20]([CH2:19][C:18]3[CH:17]=[CH:16][C:15]([O:14][CH2:2][C:3]4[N:4]=[C:5]([C:8]5[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=5)[S:6][CH:7]=4)=[CH:37][CH:36]=3)[N:21]=2)[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=1
Reactant: CCOC(=O)c1cn(Cc2ccc(O)cc2)nc1-c1ccccc1
Reactant: ClCc1csc(-c2ccccc2)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: O=C(O)c1cn(Cc2ccc(OCc3csc(-c4ccccc4)n3)cc2)nc1-c1ccccc1
Temperature: 80 °C
Reaction time: 8 h
Yield: 76.1 %

Procedure:
A mixture of 4-chloromethyl-2-phenylthiazole (1.19 g), ethyl 1-(4-hydroxybenzyl)-3-phenyl-1H-pyrazol-4-carboxylate (1.65 g), potassium carbonate (1.18 g) and N,N-dimethylformamide (25 ml) was stirred overnight at 80° C. The reaction mixture was poured into water, which was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated aqueous sodium chloride solution, dried (MgSO4), then concentrated. A mixture of the residue, potassium hydroxide (0.93 g) and ethanol (50 ml) was refluxed for 5 hours. After the reaction solvent was removed under reduced pressure, water was added to the reaction mixture, then the mixture was acidified with 1N hydrochloric acid. The crystals obtained were collected by filtration to yield 3-phenyl-1-[4-(2-phenyl-4-thiazolylmethoxy)benzyl]-1H-pyrazol-4-carboxylic acid (1.82 g, yield: 76%). This was recrystallized from acetone-hexane. Melting point: 119–120° C.
Reaction SMILES: [C:1]([O:5][C@@H:6]([C:9]1[C:27]([CH3:28])=[CH:26][C:12]2[N:13]=[C:14]([C:16]3[CH:17]=[C:18]4[N:24]([CH3:25])[N:23]=[CH:22][C:19]4=[N:20][CH:21]=3)[S:15][C:11]=2[C:10]=1[C:29]1[CH:34]=[CH:33][C:32]([Cl:35])=[CH:31][CH:30]=1)[CH2:7][OH:8])([CH3:4])([CH3:3])[CH3:2].C(#N)C.[OH2:39]>>[C:1]([O:5][C@@H:6]([C:9]1[C:27]([CH3:28])=[CH:26][C:12]2[N:13]=[C:14]([C:16]3[CH:17]=[C:18]4[N:24]([CH3:25])[N:23]=[CH:22][C:19]4=[N:20][CH:21]=3)[S:15][C:11]=2[C:10]=1[C:29]1[CH:30]=[CH:31][C:32]([Cl:35])=[CH:33][CH:34]=1)[C:7]([OH:39])=[O:8])([CH3:4])([CH3:2])[CH3:3]
Reactant: Cc1cc2nc(-c3cnc4cnn(C)c4c3)sc2c(-c2ccc(Cl)cc2)c1[C@@H](CO)OC(C)(C)C
Reactant: O
Solvent: CC#N
Product: Cc1cc2nc(-c3cnc4cnn(C)c4c3)sc2c(-c2ccc(Cl)cc2)c1[C@H](OC(C)(C)C)C(=O)O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of (S)-2-tert-butoxy-2-(7-(4-chlorophenyl)-5-methyl-2-(1-methyl-1H-pyrazolo[4,3-b]pyridin-6-yl)benzo[d]thiazol-6-yl)ethanol (50 mg, 0.099 mmol) in acetonitrile/water (2 mL/0.5 mL) was added CrO3/H5IO6 (0.439M, 1.1 mL, 0.483 mmol) and CrO3 (20 mg, 0.198 mmol). The reaction solution was stirred at room temperature for 1 h and quenched with 5% Na2S2O3 solution. The mixture was extracted with ethyl acetate, washed with water and brine. The organic solution was dried and concentrated to give crude which was purified by reverse phase HPLC, eluting by 5-100% acetonitrile in H2O with 0.1% TFA to give the desired product. LCMS-ESI+: calc'd for C27H25ClN4O3S: 521.14 (M+H+); Found: 521.2 (M+H+), 1H NMR (400 MHz, CD3OD) δ 9.20 (d, J=8 Hz, 1H), 8.67 (s, 1H), 8.24 (s, 1H), 7.88 (s, 1H), 7.71-7.59 (m, 4H), 5.27 (s, 1H), 4.16 (s, 3H), 2.62 (s, 3H), 0.98 (s, 9H).
Reaction SMILES: Cl[C:2]1[C:3]2[C:10]([C:11]3[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=3)=[C:9]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[O:8][C:4]=2[N:5]=[CH:6][N:7]=1.[CH2:25]([O:27][CH:28]([O:33][CH2:34][CH3:35])[CH2:29][CH2:30][CH2:31][NH2:32])[CH3:26].CCN(C(C)C)C(C)C>CN(C=O)C>[CH2:34]([O:33][CH:28]([O:27][CH2:25][CH3:26])[CH2:29][CH2:30][CH2:31][NH:32][C:2]1[C:3]2[C:10]([C:11]3[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=3)=[C:9]([C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=3)[O:8][C:4]=2[N:5]=[CH:6][N:7]=1)[CH3:35]
Reactant: COc1ccc(-c2c(-c3ccccc3)oc3ncnc(Cl)c23)cc1
Reactant: CCOC(CCCN)OCC
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(CCCNc1ncnc2oc(-c3ccccc3)c(-c3ccc(OC)cc3)c12)OCC

Procedure:
Stir 600 mg (1.78 mmol) 4-chloro-5-(4-methoxyphenyl)-6-phenylfuro[2,3-d]pyrimidine, 344.7 mg (2.14 mmol) 4-aminobutyraldehyde-diethylacetal and 0.465 ml (2.67 mmol) DIEA in 5 ml DMF overnight at 80° C. After cooling, purify the mixture directly by preparative RP-HPLC (gradient acetonitrile/water). 746 mg (90.7% of theor.) of the target compound is obtained.
Reaction SMILES: S(Cl)([Cl:3])=O.Cl.[NH2:6][CH2:7][C@H:8]([NH:12][C:13]([O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:14])[C:9]([OH:11])=[O:10].[CH:23](OC(C)C)(C)C>CO>[ClH:3].[NH2:6][CH2:7][C@H:8]([NH:12][C:13]([O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:14])[C:9]([O:11][CH3:23])=[O:10]
Reactant: CC(C)OC(C)C
Reactant: O=S(Cl)Cl
Reactant: NC[C@H](NC(=O)OCc1ccccc1)C(=O)O
Agent: Cl
Solvent: CO
Product: COC(=O)[C@H](CN)NC(=O)OCc1ccccc1
Temperature: -15 °C
Reaction time: 20 h
Yield: 98 %

Procedure:
7.4 ml (100.8 mmol) of thionyl chloride are added dropwise, at −15° C., to 50 ml of absolute methanol. 12 g (50.4 mmol) of 3-amino-(2S)-benzyloxycarbonylamino propionic acid hydrochloride are added, followed by 40 ml of absolute methanol. After stirring at −15° C. for 45 min and at room temperature for 20 h, the reaction mixture is poured into diisopropyl ether and the precipitate is filtered off with suction and dried under high vacuum. 14.18 g (98%) of (3.7) are obtained as a colorless solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[CH:10][C:6]([C:7]([OH:9])=O)=[CH:5][C:4]=1/[CH:12]=[CH:13]/[C:14]1[CH:19]=[CH:18][C:17]([O:20][C:21]([F:24])([F:23])[F:22])=[CH:16][CH:15]=1.[CH3:25][O:26][CH2:27][CH2:28][NH2:29]>>[CH3:1][O:2][C:3]1[CH:11]=[CH:10][C:6]([C:7]([NH:29][CH2:28][CH2:27][O:26][CH3:25])=[O:9])=[CH:5][C:4]=1/[CH:12]=[CH:13]/[C:14]1[CH:15]=[CH:16][C:17]([O:20][C:21]([F:24])([F:23])[F:22])=[CH:18][CH:19]=1
Reactant: COCCN
Reactant: COc1ccc(C(=O)O)cc1/C=C/c1ccc(OC(F)(F)F)cc1
Product: COCCNC(=O)c1ccc(OC)c(/C=C/c2ccc(OC(F)(F)F)cc2)c1

Procedure:
The captioned compound was synthesized from 4-methoxy-3-[(E)-2-(4-trifluoromethoxyphenyl)vinyl]benzoic acid obtained in step B of Example 2-2-1 and 2-methoxyethylamine in accordance with the same procedure as in the methods described in step C of Example 1-2-3.
Reaction SMILES: [OH:1][CH:2]([CH2:18][CH2:19][S:20][CH3:21])[C:3]([O:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])=[O:4].[OH:22]O>CO>[OH:1][CH:2]([CH2:18][CH2:19][S:20]([CH3:21])=[O:22])[C:3]([O:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])=[O:4]
Reactant: OO
Reactant: CCCCCCCCCCCCOC(=O)C(O)CCSC
Solvent: CO
Product: CCCCCCCCCCCCOC(=O)C(O)CCS(C)=O
Temperature: 25 °C
Reaction time: 3 h
Yield: 98.1 %

Procedure:
To a solution of dodecyl 2-hydroxy-4-(methylthio)butanoate (20 g, 62.8 mmol) in methanol (100 mL) was added 30% hydrogen peroxide (20.0 mL, 176 mmol) at 0° C. The ice bath was removed and the reaction was stirred at room temperature for about 3 hrs. The reaction was mildly exothermic. Analysis indicated the reaction was completed within two hours. Water (400 mL) was added to the mixture. The mixture was extracted with EtOAc (2×100 mL). The extracts were combined and washed with a 10% sodium bisulfite solution (100 mL). The organic phase was dried with anhydrous magnesium sulfate and the solvent was evaporated with a rotary evaporator. A colorless viscous liquid was obtained which solidified upon standing to give a white solid (20.6 g, 98%). 1H NMR (500 MHz, DMSO-d6) δ ppm 0.86 (t, J=6.83 Hz, 3 H) 1.20-1.34 (m, 18 H) 1.53-1.62 (m, 2 H) 1.81-1.92 (m, 1 H) 1.98-2.07 (m, 1 H) 2.53 (d, J=4.13 Hz, 3 H) 2.60-2.90 (m, 2 H) 3.99-4.11 (m, 2 H) 4.12-4.19 (m, 1 H) 5.63 (dd, J=5.88, 2.38 Hz, 1 H). m/z 335 (MH+).
Reaction SMILES: [C:1]1([CH:7]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:8]([OH:11])[CH2:9]Br)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:18][NH:19][CH3:20]>C(O)C>[CH3:18][N:19]([CH3:20])[CH2:9][CH:8]([OH:11])[CH:7]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: OC(CBr)C(c1ccccc1)c1ccccc1
Reactant: CNC
Solvent: CCO
Product: CN(C)CC(O)C(c1ccccc1)c1ccccc1
Reaction time: 8 h
Yield: 75 %

Procedure:
1,1-Diphenyl-3-bromopropan-2-ol (500mg) prepared as described in Example 20 was treated with excess dimethylamine in ethanol and the solution allowed to stand overnight. Solvent was removed by evaporation and the residue dissolved in dilute hydrochloric acid and ether. Basification of the acid extract and isolation through ether in the usual manner gave 3-dimethylamino-1,1-diphenyl-propan-2-ol (330mg, 75%) m p 72° - 73°.
Reaction SMILES: [OH:1][C:2]1[CH:6]=[C:5]([CH2:7][CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])[N:4]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[N:3]=1.Cl[CH2:21][C:22]1[CH:41]=[CH:40][C:25]([O:26][CH2:27][C:28]2[N:29]=[C:30]([C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)[O:31][C:32]=2[CH3:33])=[CH:24][CH:23]=1.C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[CH3:33][C:32]1[O:31][C:30]([C:34]2[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=2)=[N:29][C:28]=1[CH2:27][O:26][C:25]1[CH:24]=[CH:23][C:22]([CH2:21][O:1][C:2]2[CH:6]=[C:5]([CH2:7][CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])[N:4]([C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=3)[N:3]=2)=[CH:41][CH:40]=1
Reactant: CCOC(=O)CCc1cc(O)nn1-c1ccccc1
Reactant: Cc1oc(-c2ccccc2)nc1COc1ccc(CCl)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)CCc1cc(OCc2ccc(OCc3nc(-c4ccccc4)oc3C)cc2)nn1-c1ccccc1
Temperature: 60 °C
Reaction time: 4 h
Yield: 95.3 %

Procedure:
A mixture of ethyl 3-(3-hydroxy-1-phenyl-1H-pyrazol-5-yl)propionate (500 mg), 4-(4-chloromethylphenoxymethyl)-5-methyl-2-phenyloxazole (600 mg), potassium carbonate (530 mg) and N,N-dimethylformamide (10 ml) was stirred at 60° C. for 4 hrs. The reaction mixture was poured into water and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried (MgSO4) and concentrated. The residue was subjected to silica gel column chromatography, and ethyl 3-[3-[4-(5-methyl-2-phenyl-4-oxazolylmethoxy)benzyloxy]-1-phenyl-1H-pyrazol-5-yl]propionate (980 mg, yield 95%) was obtained as a colorless oil from a fraction eluted with ethyl acetate-hexane (1:1, volume ratio).
Reaction SMILES: Cl.Cl.[C:3]1([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH:8]=[CH:7][CH:6]=[C:5]([N:9]2[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]2)[CH:4]=1.[F:21][C:22]([F:46])([F:45])[CH2:23][NH:24][C:25]([C:27]1([CH2:40][CH2:41][CH2:42][CH2:43]Br)[C:39]2[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=2[C:33]2[C:28]1=[CH:29][CH:30]=[CH:31][CH:32]=2)=[O:26].C(=O)([O-])[O-].[K+].[K+]>C(#N)C.O>[F:21][C:22]([F:45])([F:46])[CH2:23][NH:24][C:25]([C:27]1([CH2:40][CH2:41][CH2:42][CH2:43][N:12]2[CH2:11][CH2:10][N:9]([C:5]3[CH:4]=[C:3]([C:15]4[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=4)[CH:8]=[CH:7][CH:6]=3)[CH2:14][CH2:13]2)[C:39]2[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=2[C:33]2[C:28]1=[CH:29][CH:30]=[CH:31][CH:32]=2)=[O:26]
Reactant: O=C(NCC(F)(F)F)C1(CCCCBr)c2ccccc2-c2ccccc21
Reactant: c1ccc(-c2cccc(N3CCNCC3)c2)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: O
Product: O=C(NCC(F)(F)F)C1(CCCCN2CCN(c3cccc(-c4ccccc4)c3)CC2)c2ccccc2-c2ccccc21
Temperature: 60 °C
Reaction time: 24 h

Procedure:
A suspension of 0.2 g (0.643 mmol) of 1-biphenyl-3-yl-piperazine-dihydrochloride, 0.256 g (0.6 mmol) of 9-(4-bromo-butyl)-9H-fluorene-9-carboxylic acid-(2,2,2-trifluoroethyl)-amide and 0.1 g potassium carbonate in 20 ml of acetonitrile and 0.1 ml of water is stirred for 24 hours at 60° C. The reaction mixture is poured onto water, extracted with ethyl acetate and dried over sodium sulphate. Purification is by column chromatography on silica gel (eluant: dichloromethane/ethanol=30:1).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[CH:18][C:17]([NH2:20])=[C:16]([CH3:21])[N:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:22]([C:26]1[CH:27]=[C:28]([NH:38][C:39](=O)[O:40]CC(Cl)(Cl)Cl)[N:29]([C:31]2[CH:36]=[CH:35][C:34]([CH3:37])=[CH:33][CH:32]=2)[N:30]=1)([CH3:25])([CH3:24])[CH3:23].CCN(C(C)C)C(C)C.C(OCC)C>CS(C)=O>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[CH:18][C:17]([NH:20][C:39]([NH:38][C:28]3[N:29]([C:31]4[CH:36]=[CH:35][C:34]([CH3:37])=[CH:33][CH:32]=4)[N:30]=[C:26]([C:22]([CH3:25])([CH3:24])[CH3:23])[CH:27]=3)=[O:40])=[C:16]([CH3:21])[N:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: Cc1ccc(-n2nc(C(C)(C)C)cc2NC(=O)OCC(Cl)(Cl)Cl)cc1
Reactant: Cc1nc(N2CCN(C(=O)OC(C)(C)C)CC2)ccc1N
Solvent: CS(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOCC
Product: Cc1ccc(-n2nc(C(C)(C)C)cc2NC(=O)Nc2ccc(N3CCN(C(=O)OC(C)(C)C)CC3)nc2C)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 89 %

Procedure:
Heat a solution of 4-(5-amino-6-methyl-pyridin-2-yl)-piperazine-1-carboxylic acid tert-butyl ester (Preparation 3, 41.20 g, 140.9 mmol), (5-tert-butyl-2-p-tolyl-2H-pyrazol-3-yl)-carbamic acid, 2,2,2-trichloro-ethyl ester (Preparation 38, 57.03 g, 140.9 mmol), and DIEA (36.8 mL, 211.4 mmol) in DMSO (500 mL) at 60-65° C. for 2.5 hours. Add additional DMSO (100 mL) during the last 30 min to the thick slurry. Cool the slurry to room temperature and allow to stand overnight. Add diethyl ether (600 mL) and stir the slurry for 1 hour at room temperature. Filter and wash with diethyl ether (5×300 mL) then air-dry to afford a white solid (68.70 g, 89% yield uncorrected for DMSO—contains ca. 85 mol % of DMSO. LCMS(ES+): m/z=548 [M+H].
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4](F)[CH:3]=1.O.[NH2:10][NH2:11].[OH-].[Na+]>O>[Br:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([NH:10][NH2:11])[CH:3]=1
Reactant: Fc1cc(Br)ccn1
Reactant: NN
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: NNc1cc(Br)ccn1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A flask was charged with a stir bar, 4-bromo-2-fluoro-pyridine (2.00 g), and hydrazine hydrate (5.5 mL). The resulting mixture was vigorously stirred at room temperature overnight. Then, 4 M aqueous NaOH solution (5 mL) and water (10 mL) were added and the mixture was vigorously stirred for another 10 min. The precipitate was separated by filtration, washed with water, and dried at 50° C. The title compound was isolated as a colorless solid.
Reaction SMILES: Cl.[NH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:14]=[C:13]3[NH:15][N:16]=[C:17]([NH2:18])[C:12]3=[N:11][CH:10]=2)=[CH:5][CH:4]=1.[F:19][C:20]1[CH:25]=[CH:24][C:23]([CH3:26])=[CH:22][C:21]=1[S:27](Cl)(=[O:29])=[O:28]>C(Cl)Cl.N1C=CC=CC=1>[NH2:18][C:17]1[C:12]2[C:13](=[N:14][C:9]([C:6]3[CH:7]=[CH:8][C:3]([NH:2][S:27]([C:21]4[CH:22]=[C:23]([CH3:26])[CH:24]=[CH:25][C:20]=4[F:19])(=[O:28])=[O:29])=[CH:4][CH:5]=3)=[CH:10][N:11]=2)[NH:15][N:16]=1
Reactant: Cc1ccc(F)c(S(=O)(=O)Cl)c1
Reactant: Nc1ccc(-c2cnc3c(N)n[nH]c3n2)cc1
Agent: Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: Cc1ccc(F)c(S(=O)(=O)Nc2ccc(-c3cnc4c(N)n[nH]c4n3)cc2)c1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 500 mg of 6-(4-amino-phenyl)-1H-pyrazolo[3,4-b]pyrazin-3-ylamine hydrochloride and 397 mg of 2-fluoro-5-methyl-benzenesulfonyl chloride in 4 ml DCM, 0.16 ml pyridine were added and the reaction mixture was stirred for 16 h at RT. Then, the solvents were removed under reduced pressure and the crude product was purified by chromatography on silica gel eluting with a gradient of n-heptane/EtOAc. The fractions containing the product were combined and the solvent evaporated under reduced pressure. Yield: 220 mg.
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[C:11]1[C:19]2[C:14](=[N:15][CH:16]=[N:17][C:18]=2[NH2:20])[NH:13][N:12]=1.C([O-])([O-])=O.[K+].[K+].I[CH2:28][C:29]([NH2:31])=[O:30].O>CN(C=O)C>[NH2:20][C:18]1[N:17]=[CH:16][N:15]=[C:14]2[N:13]([CH2:28][C:29]([NH2:31])=[O:30])[N:12]=[C:11]([C:2]3[CH:3]=[CH:4][C:5]4[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=4)[CH:1]=3)[C:19]=12
Reactant: Nc1ncnc2[nH]nc(-c3ccc4ccccc4c3)c12
Reactant: NC(=O)CI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: NC(=O)Cn1nc(-c2ccc3ccccc3c2)c2c(N)ncnc21
Temperature: 60 °C

Procedure:
3-(naphthalen-2-yl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine (50 mg, 0.21 mmol) was dissolved in DMF (1.5 mL) and K2CO3 (110 mg, 0.8 mmol) and iodoacetamide (46 mg, 0.25 mmol) were added. The reaction was heated to 60° C. overnight, then cooled to RT and poured into water (30 mL). The precipitate was collected by filtration. ESI-MS (M+H)+ m/z calcd 319.1, found 319.2.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[C:9]([C:11]1[CH:12]=[N:13][CH:14]=[CH:15][CH:16]=1)=[O:10].[C:17]([C:21]1[CH:26]=[CH:25][C:24]([S:27](Cl)(=[O:29])=[O:28])=[CH:23][CH:22]=1)([CH3:20])([CH3:19])[CH3:18]>N1C=CC=CC=1.O>[C:17]([C:21]1[CH:26]=[CH:25][C:24]([S:27]([NH:1][C:2]2[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=2[C:9]([C:11]2[CH:12]=[N:13][CH:14]=[CH:15][CH:16]=2)=[O:10])(=[O:29])=[O:28])=[CH:23][CH:22]=1)([CH3:20])([CH3:18])[CH3:19]
Reactant: Nc1ccc(Cl)cc1C(=O)c1cccnc1
Reactant: CC(C)(C)c1ccc(S(=O)(=O)Cl)cc1
Solvent: O
Solvent: c1ccncc1
Product: CC(C)(C)c1ccc(S(=O)(=O)Nc2ccc(Cl)cc2C(=O)c2cccnc2)cc1
Temperature: 60 °C
Reaction time: 8 h

Procedure:
To (2-amino-5-chloro-phenyl)-pyridin-3-yl-methanone (150 mg, 0.64 mmol) dissolved in 750 uL pyridine was added 4-tert-butylbenzenesulfonyl chloride (225 mg, 0.97 mmol) and the mixture stirred at 60° C. overnight. The reaction mixture was diluted with 1.0 mL H2O and the precipitate formed was collected by vacuum filtration. The crude product was recrystallized from EtOAc/hexane yielding 190 mg of pure title compound. 1H NMR (CDCl3) δ 9.87 (s, 1H), 8.79 (d, J=4.8 Hz, 1H), 8.52 (s, 1H), 7.79 (d, J=8.8 Hz, 2H), 7.61 (d, J=8.8 Hz, 2H), 7.52 (dd, J=8.8 Hz, 2.4 Hz, 1H), 7.40 (dd, J=7.6 Hz, 4.8 Hz, 1H), 7.33-7.31 (m, 3H), 1.22 (s, 9H). MS: m/z=429.0 (M++1).
Reaction SMILES: [NH2:1][C@@H:2]([CH2:14][N:15]([CH3:17])[CH3:16])[CH2:3][C:4]([O:6][CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)=[O:5].[CH2:18]([C:28]1[CH:33]=[CH:32][C:31]([S:34](Cl)(=[O:36])=[O:35])=[CH:30][CH:29]=1)[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27]>>[CH2:18]([C:28]1[CH:29]=[CH:30][C:31]([S:34]([NH:1][C@@H:2]([CH2:14][N:15]([CH3:16])[CH3:17])[CH2:3][C:4]([O:6][CH2:7][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[O:5])(=[O:36])=[O:35])=[CH:32][CH:33]=1)[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27]
Reactant: CCCCCCCCCCc1ccc(S(=O)(=O)Cl)cc1
Reactant: CN(C)C[C@H](N)CC(=O)OCc1ccccc1
Product: CCCCCCCCCCc1ccc(S(=O)(=O)N[C@H](CC(=O)OCc2ccccc2)CN(C)C)cc1
Yield: 94 %

Procedure:
According to the method described in example S72a, (R)-benzyl 3-amino-4-(dimethylamino)butanoate (27 mg, 0.086 mmol) was reacted with 4-decylbenzene-1-sulfonyl chloride to yield the title compound as a white solid (50 mg, 94%). MS ESI 517.4 [M+H]+, calcd for [C29H44N2O4S+H]+ 517.3