Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][C:7](B(O)O)=[CH:6][CH:5]=1)(=[O:3])[CH3:2].I[C:14]1[C:22]2[C:17](=[N:18][CH:19]=[N:20][C:21]=2[NH2:23])[N:16]([CH:24]([CH3:26])[CH3:25])[N:15]=1.C([O-])([O-])=O.[Na+].[Na+]>CCO.COCCOC.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[NH2:23][C:21]1[N:20]=[CH:19][N:18]=[C:17]2[N:16]([CH:24]([CH3:26])[CH3:25])[N:15]=[C:14]([C:7]3[CH:8]=[CH:9][C:4]([C:1](=[O:3])[CH3:2])=[CH:5][CH:6]=3)[C:22]=12
Reactant: CC(=O)c1ccc(B(O)O)cc1
Reactant: CC(C)n1nc(I)c2c(N)ncnc21
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: CCO
Product: CC(=O)c1ccc(-c2nn(C(C)C)c3ncnc(N)c23)cc1
Temperature: 80 °C
Yield: 62.4 %

Procedure:
A solution of 4-Acetylphenylboronic acid (12.7 mg, 0.08 mmol) in EtOH (3.3 mL) was added to a solution of 3-iodo-1-isopropyl-1H-pyrazolo[3,4-d]pyrimidin-4-amine (20 mg, 0.07 mmol) in DME (12 mL). Pd(PPh3)4 (16 mg, 0.014 mmol) and saturated Na2CO3 (1.9 mL) were added and the reaction was heated to 80° C. under an argon atmosphere overnight. After cooling, the reaction was extracted with saturated NaCl and CH2Cl2. Organic phases were combined, concentrated in vacuo and purified by RP-HPLC (MeCN:H2O:0.1% TFA) to yield BA31 (12.9 mg, 62% yield).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[NH:7][C:8](=[S:12])SCC.[NH2:13][CH2:14][CH2:15][CH2:16][CH2:17][NH:18][C:19](=[O:25])[O:20][C:21]([CH3:24])([CH3:23])[CH3:22]>>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[NH:7][C:8]([NH:13][CH2:14][CH2:15][CH2:16][CH2:17][NH:18][C:19](=[O:25])[O:20][C:21]([CH3:23])([CH3:22])[CH3:24])=[S:12]
Reactant: CCSC(=S)Nc1ccccn1
Reactant: CC(C)(C)OC(=O)NCCCCN
Product: CC(C)(C)OC(=O)NCCCCNC(=S)Nc1ccccn1
Yield: 340.3 %

Procedure:
Ethyl 2-pyridyldithiocarbamate (500 mg) and t-butyl 4-aminobutylcarbamate (474 mg) were reacted in a similar manner to in Reference Example 58, and crystallized from n-hexane-diethyl ether to give the title compound (2.78 g).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:13](=[O:14])[C:12]3[CH:15]=[N:16][N:17]([C:18]4[CH:26]=[CH:25][C:21]([C:22](O)=[O:23])=[CH:20][CH:19]=4)[C:11]=3[N:10]=[C:9]2[C:27]2[CH:32]=[CH:31][C:30]([Cl:33])=[CH:29][C:28]=2[Cl:34])=[CH:4][CH:3]=1.C(OC(Cl)=O)C(C)C.[BH4-].[Na+]>C1COCC1.O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:13](=[O:14])[C:12]3[CH:15]=[N:16][N:17]([C:18]4[CH:19]=[CH:20][C:21]([CH2:22][OH:23])=[CH:25][CH:26]=4)[C:11]=3[N:10]=[C:9]2[C:27]2[CH:32]=[CH:31][C:30]([Cl:33])=[CH:29][C:28]=2[Cl:34])=[CH:4][CH:3]=1
Reactant: O=C(O)c1ccc(-n2ncc3c(=O)n(-c4ccc(Cl)cc4)c(-c4ccc(Cl)cc4Cl)nc32)cc1
Agent: CC(C)COC(=O)Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: O=c1c2cnn(-c3ccc(CO)cc3)c2nc(-c2ccc(Cl)cc2Cl)n1-c1ccc(Cl)cc1
Reaction time: 1.5 h

Procedure:
4-[5-(4-Chloro-phenyl)-6-(2,4-dichloro-phenyl)-4-oxo-4,5-dihydro-pyrazolo[3,4-d]pyrimidin-1-yl]-benzoic acid (115 mg, 0.225 mmol) is dissolved in 6 mL of THF. To the solution TEA (68.0 mg, 0.674 mmol) and isobutylchloroformate (46.0 mg, 0.337 mmol) are added and the mixture is stirred for 1.5 h. The resulting mixture is added to a solution of sodium borohydride (33.3 mg, 0.898 mmol) in 3 mL of water and then stirred for 3 h, concentrated, and extracted with water/ethyl acetate and purified by column chromatography. 1H NMR (dioxane, 400 MHz) δ 8.33 (s, 1H), 8.00 (d, 2H), 7.45 (s, 1H), 7.39 (d, 2H), 7.16 (d, 1H), 7.29-7.19 (m, 5H), 7.03 (m, 1H), 4.53 (d, 2H), 3.71 (t, 1H). HPLC-MS calculated for C24H15Cl3N4O2 (M+H+) 497.0, Found 497.0.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][C:3]([C:6]([OH:8])=O)=[CH:2]1.C(N(CC)CC)C.[I-].ClC1C=CC=C[N+]=1C.[NH:25]1[C:29]2[CH:30]=[CH:31][CH:32]=[CH:33][C:28]=2[N:27]=[C:26]1[NH:34][CH:35]1[CH2:40][CH2:39][N:38]([CH2:41][C:42]#[N:43])[CH2:37][CH2:36]1>ClCCl>[O:1]1[CH:5]=[CH:4][C:3]([C:6]([N:25]2[C:29]3[CH:30]=[CH:31][CH:32]=[CH:33][C:28]=3[N:27]=[C:26]2[NH:34][CH:35]2[CH2:36][CH2:37][N:38]([CH2:41][C:42]#[N:43])[CH2:39][CH2:40]2)=[O:8])=[CH:2]1
Reactant: N#CCN1CCC(Nc2nc3ccccc3[nH]2)CC1
Reactant: O=C(O)c1ccoc1
Agent: C[n+]1ccccc1Cl
Agent: [I-]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: N#CCN1CCC(Nc2nc3ccccc3n2C(=O)c2ccoc2)CC1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 74 %

Procedure:
To a stirred mixture of 3.14 parts of 3-furancarboxylic acid, 6 parts of N,N-diethylethanamine and 390 parts of dichloromethane were added 7.2 parts of 2-chloro-1-methylpyridinium iodide. After stirring for 10 minutes at room temperature, 7 parts of 4-[(1H-benzimidazol-2-yl)amino]-1-piperidineacetonitrile were added and the whole was stirred for 1 hour at room temperature. The reaction mixture was washed with water. The organic phase was dried, filtered and evaporated. The residue was crystallized from acetonitrile, yielding 7 parts (74%) of 4-[[1-(3-furanylcarbonyl)-1H-benzimidazol-2-yl]amino]-1-piperidineacetonitrile (129).
Reaction SMILES: [C:1]1([C:7]2[C:12]([C:13]([O:15]CC)=[O:14])=[CH:11][N:10]=[C:9]([NH:18][CH2:19][C:20]3[S:21][CH:22]=[CH:23][CH:24]=3)[N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH-].[K+]>C(O)C.O>[C:1]1([C:7]2[C:12]([C:13]([OH:15])=[O:14])=[CH:11][N:10]=[C:9]([NH:18][CH2:19][C:20]3[S:21][CH:22]=[CH:23][CH:24]=3)[N:8]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CCOC(=O)c1cnc(NCc2cccs2)nc1-c1ccccc1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: O=C(O)c1cnc(NCc2cccs2)nc1-c1ccccc1
Yield: 97.6 %

Procedure:
Ethyl 4-phenyl-2-[(thiophen-2-ylmethyl)amino]pyrimidine-5-carboxylate (1.70 g, 5 mmol) was dissolved in ethanol (10 ml). To the solution potassium hydroxide (0.56 g, 10 mmol) dissolved in 10 ml of water was added and the mixture was refluxed for 3 hours. The solvent was distilled off in vacuum, the residue was dissolved in water (35 ml), acidified to pH=3 with 10% hydrochloric acid. The precipitated white crystals were filtered off, washed with water (2×20 ml) and dried. 1.52 g (92%) of the title acid was obtained, m.p.: 212-213° C.; [M+H]+ 312.
Reaction SMILES: [Si:1]([O:18][CH2:19][C@@H:20]([CH3:23])[CH:21]=[CH2:22])([C:14]([CH3:17])([CH3:16])[CH3:15])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1C=C(Cl)C=C(C(OO)=[O:32])C=1>ClCCl>[Si:1]([O:18][CH2:19][C@H:20]([CH3:23])[CH:21]1[O:32][CH2:22]1)([C:14]([CH3:15])([CH3:16])[CH3:17])([C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C=C[C@H](C)CO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: C[C@@H](CO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C)C1CO1
Reaction time: 0.25 h

Procedure:
Under argon atmosphere, (S)-4-(t-butyldiphenylsilyloxy)-3-methyl-1-butene (50) (1.0 g, 3.1 mmol) was dissolved in 25 ml of dry dichloromethane, mCPBA (1.4 g, 7.4 mmol) was added to the resultant solution at 0° C., and the mixture was stirred for 15 min. Then, the mixture was further stirred overnight after the temperature was returned to room temperature. The reaction mixture was extracted with ethyl acetate after the addition of water. The ethyl acetate layer was washed with brine, dried over magnesium sulfate and evaporated. The obtained crude product was purified by column chromatography (30 g, 2% Et2O-hexane) to obtain a colorless oily product (51). (1.1 g, quant.).
Reaction SMILES: [CH2:1]([NH:13][C:14]([C:16]1[CH:17]=[C:18]([C:27]2[CH:32]=[CH:31][CH:30]=[C:29]([C:33]([F:36])([F:35])[F:34])[CH:28]=2)[C:19]([O:23][CH2:24][CH2:25][NH2:26])=[C:20]([Br:22])[CH:21]=1)=[O:15])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].C(N(CC)CC)C.Cl[C:45]([O:47][CH3:48])=[O:46]>C1COCC1>[CH3:48][O:47][C:45](=[O:46])[NH:26][CH2:25][CH2:24][O:23][C:19]1[C:20]([Br:22])=[CH:21][C:16]([C:14](=[O:15])[NH:13][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12])=[CH:17][C:18]=1[C:27]1[CH:32]=[CH:31][CH:30]=[C:29]([C:33]([F:36])([F:34])[F:35])[CH:28]=1
Reactant: COC(=O)Cl
Reactant: CCCCCCCCCCCCNC(=O)c1cc(Br)c(OCCN)c(-c2cccc(C(F)(F)F)c2)c1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCCCCCCCCCCCNC(=O)c1cc(Br)c(OCCNC(=O)OC)c(-c2cccc(C(F)(F)F)c2)c1
Reaction time: 0.25 h
Yield: 861.4 %

Procedure:
To a solution of 6-(amino-ethoxy)-5-bromo-3′-trifluoromethyl-biphenyl-3 carboxylic acid dodecylamide (0.273 g, 0.48 mmol, 1 eq) in THF (6 mL) at 0° C. was added triethylamine (0.150 mL, 1.08 mmol, 2.25 eq) followed by methyl chloroformate (0.040 mL, 0.052 mmol, 1.11 eq). The reaction was stirred for 15 min, then poured into pH 7 buffer and extracted with Et2O. The combined organics were dried over MgSO4 and concentrated in vacuo. The residue was purified by flash chromatography (30% EtOAc:hexane ) to afford the title compound (0.282 g, 93%) as a white solid. mp 79.6-80.5° C. 1H NMR (DMSO-d6) δ 8.56 (bt, 1H); 8.12 (d, 1H); 7.88 (m, 3H); 7.79 (d, 1H); 7.70 (t, 1H); 7.02 (t, 1H); 3.54 (dd, 2H); 3.44 (s, 3H); 3.24 (dd, 2H); 3.08 (ddd, 2H); 1.48 (dd, 2H); 1.23 (m, 18H); 0.83 (t, 3H); IR (KBr) 3330, 2950, 2840, 1695, 1640, 1540, 1340, 1180, 1110, 920, 805 cm−1; mass spectrum [(+)MAT900], rm/z 629/631 (M+H)+; Anal. Calcd. for C30H40BrF3N2O4: C, 57.23; H, 6.40; N, 4.45, Found: C, 56.12; H, 6.29; N, 4.29.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[C:12]([CH3:14])[C:11]([Cl:15])=[CH:10][C:9]=1[NH:16][C:17](=[O:41])[CH2:18][C:19](=O)[C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([C:26]2[CH:31]=[CH:30][N:29]=[C:28]([CH2:32][O:33]C3CCCCO3)[CH:27]=2)[CH:21]=1)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[Cl:15][C:11]1[C:12]([CH3:14])=[CH:13][C:8]2[N:7]=[C:19]([C:20]3[CH:25]=[CH:24][CH:23]=[C:22]([C:26]4[CH:31]=[CH:30][N:29]=[C:28]([CH2:32][OH:33])[CH:27]=4)[CH:21]=3)[CH2:18][C:17](=[O:41])[NH:16][C:9]=2[CH:10]=1
Reactant: Cc1cc(NC(=O)OC(C)(C)C)c(NC(=O)CC(=O)c2cccc(-c3ccnc(COC4CCCCO4)c3)c2)cc1Cl
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1cc2c(cc1Cl)NC(=O)CC(c1cccc(-c3ccnc(CO)c3)c1)=N2

Procedure:
The title compound was prepared from (RS)-[4-chloro-5-methyl-2-(3-oxo-3-{3-[2-(tetrahydro-pyran-2-yloxymethyl)-pyridin-4-yl]-phenyl}-propionylamino)-phenyl]-carbamic acid tert-butyl ester (Example M259) (0.50 g, 0.84 mmol) by treatment with TFA in CH2Cl2 according to the general procedure N. Obtained as an off-white solid (182 mg, 55%).
Reaction SMILES: [F:1][C:2]1[C:10]2[NH:9][C:8](=[O:11])[N:7]([CH:12]3[CH2:17][CH2:16][N:15](C(OC(C)(C)C)=O)[CH2:14][CH2:13]3)[C:6]=2[CH:5]=[C:4]([CH3:25])[C:3]=1[F:26].[ClH:27]>ClCCl.O1CCOCC1>[ClH:27].[F:1][C:2]1[C:10]2[NH:9][C:8](=[O:11])[N:7]([CH:12]3[CH2:13][CH2:14][NH:15][CH2:16][CH2:17]3)[C:6]=2[CH:5]=[C:4]([CH3:25])[C:3]=1[F:26]
Reactant: Cc1cc2c([nH]c(=O)n2C2CCN(C(=O)OC(C)(C)C)CC2)c(F)c1F
Agent: Cl
Solvent: C1COCCO1
Solvent: ClCCl
Product: Cc1cc2c([nH]c(=O)n2C2CCNCC2)c(F)c1F

Procedure:
1,1-Dimethylethyl 4-(4,5-difluoro-6-methyl-2-oxo-2,3-dihydro-1H-benzimidazol-1-yl)-1-piperidinecarboxylate D22 (150 mg, 0.4 mmol) was dissolved in dichloromethane (5 ml) and treated with HCl in 1,4-dioxane (1 ml×4M) at room temperature for 4 h. Solvent was then evaporated to afford the title compound, 120 mg. M++H=268.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([CH2:13][OH:14])[CH2:12][CH2:11][CH2:10][CH2:9]2)=[CH:4][CH:3]=1.C1(C2(C[O:27][S:28]([CH3:31])(=O)=[O:29])CCCC2)C=CC=CC=1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2([CH2:13][O:14][S:28]([CH3:31])(=[O:29])=[O:27])[CH2:12][CH2:11][CH2:10][CH2:9]2)=[CH:6][CH:7]=1
Reactant: OCC1(c2ccc(Cl)cc2)CCCC1
Reactant: CS(=O)(=O)OCC1(c2ccccc2)CCCC1
Product: CS(=O)(=O)OCC1(c2ccc(Cl)cc2)CCCC1
Yield: 93.08 %

Procedure:
Methanesulfonic acid 1-(4-chlorophenyl)-cyclopentylmethyl ester (24-02) (32 g, 93.08%) was synthesized from [1-(4-chlorophenyl)-cyclopentyl]-methanol (23-02) (25 g, 119.04 mmol) as a crude product as a yellow liquid following the procedure as described for methanesulfonic acid 1-phenyl-cyclopentylmethyl ester (24-01).
Reaction SMILES: [CH2:1]([O:4][CH2:5][C:6]([CH2:15][O:16][CH2:17][CH:18]=[CH2:19])([CH2:13][CH3:14])[CH2:7][O:8][Si:9]([CH3:12])([CH3:11])[CH3:10])[CH:2]=[CH2:3].[CH2:20]([O:22][SiH:23]([O:27][CH2:28][CH3:29])[O:24][CH2:25][CH3:26])[CH3:21]>>[CH2:20]([O:22][Si:23]([O:27][CH2:28][CH3:29])([O:24][CH2:25][CH3:26])[CH2:3][CH2:2][CH2:1][O:4][CH2:5][C:6]([CH2:15][O:16][CH2:17][CH2:18][CH2:19][Si:23]([O:27][CH2:28][CH3:29])([O:24][CH2:25][CH3:26])[O:22][CH2:20][CH3:21])([CH2:13][CH3:14])[CH2:7][O:8][Si:9]([CH3:12])([CH3:11])[CH3:10])[CH3:21]
Reactant: CCO[SiH](OCC)OCC
Reactant: C=CCOCC(CC)(COCC=C)CO[Si](C)(C)C
Product: CCO[Si](CCCOCC(CC)(COCCC[Si](OCC)(OCC)OCC)CO[Si](C)(C)C)(OCC)OCC
Temperature: 80 °C

Procedure:
A 1-liter, 3-neck flask equipped with magnetic stirrer, pot thermometer, addition funnel and condenser was charged with 143.2 g of 2,2-Bis(allyloxymethyl)-1-trimethylsiloxybutane. After heating to ˜80° C., 35 g of triethoxysilane was added followed by 1 ml of Karstedt catalyst containing 2% Pt. Once initiation was observed, the balance of triethoxysilane (133.4 g) was added at a rate to maintain temperature at 80-110° C. When the addition was complete, an additional 0.5 ml of Karstedt catalyst was added and temperature of 90° C. was maintained for 2 hours. A GC indicated the reaction was not complete. Two additional portions 43 g of triethoxysilane and 0.5 g of Karstedt were added, maintaining the temperature at 95-105° C. The product was purified by means of a wiped-film evaporator, removing volatiles on a first pass and then distilling crude product on a second pass. A short-path distillation produced purified product: b.p.: 200-205° C. at 0.8 mm; density: 0.980; 1HNMR(C6D6): 0.13(s, 9H), 0.77(m, 4H), 1.00(m, 3H), 1.14(t, 18H), 1.18(m, 2H), 1.85(m, 4H) 3.38(dd, 8H), 3.76(s, 2H), 3.81(q, 12H). The FTIR showed a strong absorption at 1105.1 cm−1, which is characteristic of Si—O.
Reaction SMILES: [C:1]1(=[O:7])[O:6][C:4](=[O:5])[CH2:3][CH2:2]1.O.[NH2:9][CH2:10][C:11]1[CH:16]=[CH:15][C:14]([NH:17][C:18]2[C:26]3[C:21](=[N:22][CH:23]=[N:24][C:25]=3[NH:27][C:28]3[CH:33]=[CH:32][CH:31]=[C:30]([Cl:34])[CH:29]=3)[NH:20][N:19]=2)=[CH:13][CH:12]=1>C1COCC1>[C:1]([CH2:2][CH2:3][C:4]([CH:10]([NH2:9])[C:11]1[CH:16]=[CH:15][C:14]([NH:17][C:18]2[C:26]3[C:21](=[N:22][CH:23]=[N:24][C:25]=3[NH:27][C:28]3[CH:33]=[CH:32][CH:31]=[C:30]([Cl:34])[CH:29]=3)[NH:20][N:19]=2)=[CH:13][CH:12]=1)=[O:5])([OH:6])=[O:7]
Reactant: NCc1ccc(Nc2n[nH]c3ncnc(Nc4cccc(Cl)c4)c23)cc1
Reactant: O=C1CCC(=O)O1
Solvent: O
Solvent: C1CCOC1
Product: NC(C(=O)CCC(=O)O)c1ccc(Nc2n[nH]c3ncnc(Nc4cccc(Cl)c4)c23)cc1
Temperature: 25 °C

Procedure:
A solution of 57.4 mg (0.573 mmol) of succinic anhydride in 0.5 ml of THF is added dropwise, with stirring, to a suspension, cooled to 0° C., of 200 mg (0.521 mmol) of 3-(4-aminomethyl-phenylamino)-4-(3-chloro-phenylamino)-1H-pyrazolo[3,4-d]pyrimidine hydrate (see Step 77.5) in 3 ml of THF. The reaction mixture is stirred at RT for 4 hours and then a further solution of 57.4 mg (0.573 mmol) of succinic anhydride in 0.5 ml of THF is added. The mixture is stirred for a further 3 hours at 40° C., then allowed to cool to RT and filtered, and the filter residue is washed with diethyl ether. 3-[4-({3-Carboxy-propionyl}-aminomethyl)-phenylamino]-4-(3-chlorophenylamino)-1H-pyrazolo[3,4-d]pyrimidine having a water content of 2.45% is obtained; m.p. 205-207° C.; ESI-MS: (M−H)−=464.
Reaction SMILES: [C:1]1([C:7]([NH:9][CH:10]2[CH2:15][CH:14]([C:16]3[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][CH:17]=3)[CH2:13][N:12]([C:26]([O:28]C3C=CC([N+]([O-])=O)=CC=3)=O)[CH2:11]2)=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH:38]1[CH2:43][CH2:42][S:41][CH2:40][CH2:39]1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[N:38]1([C:26]([N:12]2[CH2:13][CH:14]([C:16]3[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:23])[F:24])=[CH:18][CH:17]=3)[CH2:15][CH:10]([NH:9][C:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)=[O:8])[CH2:11]2)=[O:28])[CH2:43][CH2:42][S:41][CH2:40][CH2:39]1
Reactant: C1CSCCN1
Reactant: O=C(NC1CC(c2ccc(C(F)(F)F)cc2)CN(C(=O)Oc2ccc([N+](=O)[O-])cc2)C1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=C(NC1CC(c2ccc(C(F)(F)F)cc2)CN(C(=O)N2CCSCC2)C1)c1ccccc1

Procedure:
80 mg (0.16 mmol) of 4-nitrophenyl 3-[(phenylcarbonyl)amino]-5-[4-(trifluoromethyl)phenyl]piperidine-1-carboxylate were initially charged in 1.7 ml of DMF, and 48 mg (0.47 mmol) of thiomorpholine and 22 mg (0.16 mmol) of potassium carbonate were added. The mixture was reacted in a microwave (Emrys Optimizer) at 150° C. for 15 min. The crude product was then purified by preparative HPLC (Reprosil C18, water/acetonitrile gradient). Yield: 45 mg (60% of theory)
Reaction SMILES: Br[C:2]1[CH:40]=[CH:39][C:5]([CH2:6][N:7]2[C:11]3[CH:12]=[CH:13][C:14]([O:16][CH2:17][C:18]4[CH:27]=[CH:26][C:25]5[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=5)[N:19]=4)=[CH:15][C:10]=3[N:9]=[C:8]2[CH2:28][C:29]2([C:34]([O:36]CC)=[O:35])[CH2:33][CH2:32][CH2:31][CH2:30]2)=[CH:4][CH:3]=1.[NH:41]1[CH:45]=[C:44](B2OC(C)(C)C(C)(C)O2)[CH:43]=[N:42]1>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[NH:42]1[CH:43]=[C:44]([C:2]2[CH:40]=[CH:39][C:5]([CH2:6][N:7]3[C:11]4[CH:12]=[CH:13][C:14]([O:16][CH2:17][C:18]5[CH:27]=[CH:26][C:25]6[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=6)[N:19]=5)=[CH:15][C:10]=4[N:9]=[C:8]3[CH2:28][C:29]3([C:34]([OH:36])=[O:35])[CH2:33][CH2:32][CH2:31][CH2:30]3)=[CH:4][CH:3]=2)[CH:45]=[N:41]1
Reactant: CC1(C)OB(c2cn[nH]c2)OC1(C)C
Reactant: CCOC(=O)C1(Cc2nc3cc(OCc4ccc5ccccc5n4)ccc3n2Cc2ccc(Br)cc2)CCCC1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Product: O=C(O)C1(Cc2nc3cc(OCc4ccc5ccccc5n4)ccc3n2Cc2ccc(-c3cn[nH]c3)cc2)CCCC1

Procedure:
The title compound was prepared using similar methods to those in Example 110 using ethyl 1-((1-(4-bromobenzyl)-5-(quinolin-2-ylmethoxy)-1H-benzo[d]imidazol-2-yl)methyl)cyclopentanecarboxylate, 4.5 equivalents 4-pyrazoleboronic acid pinacol ester and 0.2 equivalents Pd(PPh3)4 in Step A. MS (ESI): mass calcd. for C34H31N5O3, 557.24; m/z found, 558.2 [M+H]+. 1H NMR (500 MHz, CDCl3) δ 8.21 (d, J=8.5, 1H), 8.10 (d, J=8.4, 1H), 7.84 (d, J=7.6, 1H), 7.78 (s, 2H), 7.77-7.73 (m, 1H), 7.71 (d, J=8.5, 1H), 7.59-7.54 (m, 1H), 7.43 (d, J=8.2, 2H), 7.36-7.34 (m, 1H), 7.18 (d, J=8.9, 1H), 7.07-7.04 (m, 1H), 7.02 (d, J=8.1, 2H), 5.42 (s, 2H), 5.34 (s, 2H), 3.43-3.41 (m, 1H), 3.13 (s, 2H), 1.74-1.66 (m, 2H), 1.58-1.50 (m, 4H), 1.30-1.24 (m, 1H).
Reaction SMILES: [CH3:1][C:2]1([CH3:10])[O:6][C@H:5]([C@H:7]([OH:9])[CH3:8])[CH2:4][O:3]1.[Cl:11][C:12]1[CH:17]=[C:16](Cl)[N:15]=[C:14]([S:19][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[C:23]([F:27])[C:22]=2[F:28])[N:13]=1>C1COCC1.[H-].[Na+]>[Cl:11][C:12]1[CH:17]=[C:16]([O:9][C@@H:7]([C@@H:5]2[CH2:4][O:3][C:2]([CH3:10])([CH3:1])[O:6]2)[CH3:8])[N:15]=[C:14]([S:19][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[C:23]([F:27])[C:22]=2[F:28])[N:13]=1
Reactant: Fc1cccc(CSc2nc(Cl)cc(Cl)n2)c1F
Reactant: C[C@@H](O)[C@@H]1COC(C)(C)O1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: C[C@@H](Oc1cc(Cl)nc(SCc2cccc(F)c2F)n1)[C@@H]1COC(C)(C)O1

Procedure:
The subtitle compound was prepared according to the procedure outlined in example 1 step (iii) using (1R)-1-[(4S)-2,2-dimethyl-1,3-dioxolan-4-yl]ethanol (prepared according to Liebigs Ann. Chem. 1987, 7-14) (0.25 g) and 4,6-Dichloro-2-[(2,3-difluorobenzyl)thio]pyrimidine (the product of example 1 step ii) (0.53 g) in THF (20 mL) and 60% sodium hydride (80 mg). Crude material was purified by column chromatography on silica gel using EtOAc/isohexane (1:3) as eluent to give the subtitle compound as a clear, colourless oil. Yield: 0.37 g.
Reaction SMILES: [O:1]=[C:2]1[C:10](=[C:11]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[CH:13]([CH2:20][C:21]([OH:23])=[O:22])[O:12]2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[NH:3]1.[Li]CCCC.C(Cl)(=O)C(Cl)=O.O[CH2:36][CH2:37][N:38]1[CH2:43][CH2:42][O:41][CH2:40][CH2:39]1>C1COCC1.CCCCCC>[N:38]1([CH2:37][CH2:36][O:22][C:21](=[O:23])[CH2:20][CH:13]2[C:14]3[C:19](=[CH:18][CH:17]=[CH:16][CH:15]=3)[C:11](=[C:10]3[C:9]4[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=4)[NH:3][C:2]3=[O:1])[O:12]2)[CH2:43][CH2:42][O:41][CH2:40][CH2:39]1
Reactant: OCCN1CCOCC1
Reactant: O=C(O)CC1OC(=C2C(=O)Nc3ccccc32)c2ccccc21
Agent: O=C(Cl)C(=O)Cl
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: O=C(CC1OC(=C2C(=O)Nc3ccccc32)c2ccccc21)OCCN1CCOCC1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 32 %

Procedure:
To a slurry of [3-(2-oxo-1,2-dihydro-indol-3-ylidene)-1,3-dihydro-isobenzofuran-1-yl]-acetic acid (100 mg, 0.32 mmol) in THF (4.0 ml) at room temperature was added 2.5M n-BuLi in hexane (13611), and the reaction was stirred for 10 minutes. After the reaction was cooled to 0° C., oxalyl chloride (163 μl, 0.32 mmol) was added. After stirring for 20 minutes, 4-(2-hydroxyethyl)morpholine (118 μl, 0.976 mmol) was added. The reaction was stirred for 5 minutes at 0° C., and then at room temperature for 20 minutes. The reaction was partitioned between EtOAc and saturated NaHCO3. The EtOAc layer was washed with brine, dried with anhydrous Na2SO4 and rotary evaporated to afford an orange oil. The orange oil was chromatographed through silica gel column, eluted with CHCl3, to give [3-(2-oxo-1,2-dihydro-indol-3-ylidene)-1,3-dihydro-isobenzofuran-1-yl]-acetic acid 2-morpholin-4-yl-ethyl ester as a yellow foam (43 mg, 32%).
Reaction SMILES: CC1(C)C(C)(C)OB([C:9]2[CH:42]=[CH:41][C:12]([CH2:13][O:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[C:21]3[N:26]=[C:25]([N:27]4[C:31]([C:32]([F:35])([F:34])[F:33])=[C:30]([C:36]([O:38][CH2:39][CH3:40])=[O:37])[CH:29]=[N:28]4)[CH:24]=[CH:23][CH:22]=3)=[CH:11][CH:10]=2)O1.Br[C:45]1[CH:46]=[N:47][C:48]([C:51]([F:54])([F:53])[F:52])=[CH:49][CH:50]=1.C(=O)([O-])[O-].[Na+].[Na+]>C(#N)C>[F:34][C:32]([F:33])([F:35])[C:31]1[N:27]([C:25]2[CH:24]=[CH:23][CH:22]=[C:21]([C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=3[O:14][CH2:13][C:12]3[CH:11]=[CH:10][C:9]([C:45]4[CH:46]=[N:47][C:48]([C:51]([F:54])([F:53])[F:52])=[CH:49][CH:50]=4)=[CH:42][CH:41]=3)[N:26]=2)[N:28]=[CH:29][C:30]=1[C:36]([O:38][CH2:39][CH3:40])=[O:37]
Reactant: CCOC(=O)c1cnn(-c2cccc(-c3ccccc3OCc3ccc(B4OC(C)(C)C(C)(C)O4)cc3)n2)c1C(F)(F)F
Reactant: FC(F)(F)c1ccc(Br)cn1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC#N
Product: CCOC(=O)c1cnn(-c2cccc(-c3ccccc3OCc3ccc(-c4ccc(C(F)(F)F)nc4)cc3)n2)c1C(F)(F)F
Temperature: 25 °C
Reaction time: 6 h

Procedure:
To a vial containing the title compound from Example 14 Step A (14.0 mg, 0.024 mmol) were added 3-bromo-6-trifluoromethylpyridine (6.4 mg, 0.028 mmol) and trans-dichlorobis(triphenylphosphine) palladium (II) (1.7 mg, 0.0024 mmol). Acetonitrile (0.500 mL) and sodium carbonate (0.059 mL, 1.0 M in water, 0.059 mmol) were added, and the resulting mixture was degassed by a nitrogen sparge. The reaction vial was capped and placed in a pre-heated oil bath (70° C.). After 6 h, the reaction mixture was allowed to cool to room temperature, then was purified by flash chromatography on silica gel: LCMS m/z 613.2 [M+H]+.