Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:10]([C:28]([OH:30])=O)=[N:11][C:12]([I:27])=[C:13]2[C:18]=1[N:17]=[CH:16][C:15]([CH2:19][C:20]1[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=1)=[CH:14]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.ON1C2C=CC=CC=2N=N1.[CH3:41][O:42][CH2:43][CH2:44][NH2:45].Cl.C(N=C=NCCCN(C)C)C.Cl>ClCCl>[CH3:41][O:42][CH2:43][CH2:44][NH:45][C:28]([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]=[C:15]([CH2:19][C:20]3[CH:21]=[CH:22][C:23]([F:26])=[CH:24][CH:25]=3)[CH:16]=[N:17]2)=[C:12]([I:27])[N:11]=1)=[O:30]
Reactant: COCCN
Reactant: O=C(O)c1nc(I)c2cc(Cc3ccc(F)cc3)cnc2c1OCc1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Product: COCCNC(=O)c1nc(I)c2cc(Cc3ccc(F)cc3)cnc2c1OCc1ccccc1
Reaction time: 3 h
Yield: 81.2 %

Procedure:
To the above Compound 9 (7.0 g, 13.6 mmol), 1-hydroxybenzotriazole (208 mg, 1.36 mmol) was added dichloromethane (75 ml) to give suspension, and was added 2-methoxyethyl amine (1.42 ml, 16.3 mmol) in nitrogen gas flow under stirring on ice, followed by 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (3.13 g, 16.3 mmol). 30 minutes later, the solution was stirred at room temperature. After 3 hours, the reaction solution was subjected to distillation under reduced pressure, and to the residue (12 g) was added and solved ethyl acetate (150 ml) and water (100 ml), and followed by 2N hydrochloric acid aqueous solution (5.7 ml, 11.4 mmol). Then the solution was shaken for separation, washed once with water and with sodium chloride aqueous solution, dried over sodium sulfate and subjected to distillation under reduced pressure. The resultant residue (7.97 g) was solved in methanol (5 ml), and added with diisopropyl ether (35 ml) little by little under warming and left at room temperature. Then the product was collected by filtering and washed with diisopropyl ether, to give Compound 10 (6.31 g, 81.1%). The filtrate was subjected to silica gel silica gel chromatography, to give 8-benzyloxy-3-(4-fluorobenzyl)-5-iodo[1,6]naphthyridine-7-carboxylic acid (2-methoxyethyl)amide 10 (437 mg, 5.6%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[Cl:10])[CH2:5][NH2:6].Cl[C:12]1[C:13]2[CH:25]=[C:24]([Cl:26])[S:23][C:14]=2[N:15]=[C:16]([C:18]2[O:22][N:21]=[CH:20][CH:19]=2)[N:17]=1>>[O:22]1[C:18]([C:16]2[N:17]=[C:12]([NH:6][CH2:5][C:4]3[CH:7]=[CH:8][C:9]([Cl:10])=[C:2]([Cl:1])[CH:3]=3)[C:13]3[CH:25]=[C:24]([Cl:26])[S:23][C:14]=3[N:15]=2)=[CH:19][CH:20]=[N:21]1
Reactant: NCc1ccc(Cl)c(Cl)c1
Reactant: Clc1cc2c(Cl)nc(-c3ccno3)nc2s1
Product: Clc1cc2c(NCc3ccc(Cl)c(Cl)c3)nc(-c3ccno3)nc2s1

Procedure:
With the procedure of Example 1, the reaction of 3,4-dichlorobenzylamine with 4-chloro-2-(isoxazol-5-yl)-6-chloro-thieno-[2,3-d]-pyrimidine yields 2-(isoxazol-5-yl)-4-(3,4-dichlorobenzylamino)-6-chloro-thieno-[2,3-d]-pyrimidine.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:16][C:15]3[C:14](=[O:17])[N:13]([C:18]4[CH:23]=[CH:22][C:21]([OH:24])=[C:20]([O:25][CH3:26])[CH:19]=4)[CH:12]=[N:11][C:10]=3[CH:9]=2)=[CH:4][CH:3]=1.Cl[CH2:28][CH:29]1[CH2:34][CH2:33][CH2:32][N:31]([CH3:35])[CH2:30]1.C([O-])([O-])=O.[Cs+].[Cs+]>ClCCl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[S:16][C:15]3[C:14](=[O:17])[N:13]([C:18]4[CH:23]=[CH:22][C:21]([O:24][CH2:28][CH:29]5[CH2:34][CH2:33][CH2:32][N:31]([CH3:35])[CH2:30]5)=[C:20]([O:25][CH3:26])[CH:19]=4)[CH:12]=[N:11][C:10]=3[CH:9]=2)=[CH:6][CH:7]=1
Reactant: COc1cc(-n2cnc3cc(-c4ccc(Cl)cc4)sc3c2=O)ccc1O
Reactant: CN1CCCC(CCl)C1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: ClCCl
Product: COc1cc(-n2cnc3cc(-c4ccc(Cl)cc4)sc3c2=O)ccc1OCC1CCCN(C)C1
Temperature: 25 °C

Procedure:
A solution containing 6-(4-chlorophenyl)-3-(4-hydroxy-3-methoxyphenyl)thieno[3,2-d]pyrimidin-4(3H)-one (77 mg, 0.20 mmol, the preparation of which may be found in Example K1) and 3-(chloromethyl)-1-methylpiperidine (74 mg) was mixed with Cs2CO3 (261 mg, 0.80 mmol) and the resultant mixture was heated at 85° C. for 3 hours. The mixture was then cooled to room temperature, diluted with dichlormethane, washed with a saturated solution of NaHCO3 and brine, dried (MgSO4), and concentrated under reduced pressure. The resultant residue was purified by column chromatography to provide the title compound.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][C:2]1=[O:10].N1CCCC1.[NH:16]1[C:24]2[C:19](=[CH:20][CH:21]=[C:22]([C:25](=O)[CH3:26])[CH:23]=2)[CH:18]=[N:17]1>C1(C)C=CC=CC=1>[NH:16]1[C:24]2[C:19](=[CH:20][CH:21]=[C:22](/[C:25](=[C:3]3/[C:2](=[O:10])[NH:1][C:9]4[C:4]/3=[CH:5][CH:6]=[CH:7][CH:8]=4)/[CH3:26])[CH:23]=2)[CH:18]=[N:17]1
Reactant: O=C1Cc2ccccc2N1
Reactant: CC(=O)c1ccc2cn[nH]c2c1
Solvent: Cc1ccccc1
Solvent: C1CCNC1
Product: C/C(=C1\C(=O)Nc2ccccc21)c1ccc2cn[nH]c2c1
Temperature: 50 °C
Reaction time: 72 h
Yield: 15.1 %

Procedure:
A solution of oxindole (16 mg, 0.12 mmol), pyrrolidine (10 μL, 0.12 mmol) and 1-(1H-indazol-6-yl)ethanone (20 mg, 0.12 mmol) in toluene was refluxed in a Dean-Stark trap for 2 h. The solution was then stirred at 50° C. for 72 h. Two equivalents of pyrrolidine were added and the solution was heated to reflux for 48 h. The solution was concentrated and the red residue was purified by preparatory HPLC to give the title compound as an orange solid (5 mg, 16%). 1H NMR (400 MHz, CDCl3) δ 8.13 (s, 1H), 7.78 (s, 1H), 7.70 (d, 1H, J=8.5 Hz), 7.34 (d, 1H, J=8.5 Hz), 7.03 (t, 1H, J=7.6 Hz), 6.81 (d, 1H, J=7.7 Hz), 6.50 (t, 1H, J=7.6 Hz), 6.05 (d, 1H, J=7.7 Hz), 2.82 (s, 3H); MS ESI [M+H]+, calcd for [C17H13N3O+H]+ 276.1; found m/z 276.0.
Reaction SMILES: I[C:2]1[CH:3]=[C:4]([P:8](=[O:15])([O:12][CH2:13][CH3:14])[O:9][CH2:10][CH3:11])[CH:5]=[CH:6][CH:7]=1.[OH:16][CH2:17][C:18]1[CH:23]=[CH:22][C:21](B(O)O)=[CH:20][CH:19]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1(C)C=CC=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].O.CCOC(C)=O>[CH2:10]([O:9][P:8]([C:4]1[CH:3]=[C:2]([C:21]2[CH:22]=[CH:23][C:18]([CH2:17][OH:16])=[CH:19][CH:20]=2)[CH:7]=[CH:6][CH:5]=1)(=[O:15])[O:12][CH2:13][CH3:14])[CH3:11]
Reactant: OCc1ccc(B(O)O)cc1
Reactant: CCOP(=O)(OCC)c1cccc(I)c1
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOC(C)=O
Solvent: O
Solvent: Cc1ccccc1
Product: CCOP(=O)(OCC)c1cccc(-c2ccc(CO)cc2)c1
Reaction time: 18 h

Procedure:
To the product of Step 1 (680 mg, 2 mmol) in toluene (10 mL)—H2O (3 mL)—n Propanol (3 mL) were added 4-hydroxymethyl phenyl boronic acid (607 mg, 4 mmol), tris(dibenzylidene acetone)dipalladium (92 mg, 0.1 mmol), triphenylphosphine (209 mg, 0.8 mmol) and EtNH (175 mg, 2.4 mmol). After a period of 18 h at 90° C., the reaction mixture was partionned between EtOAc and H2O. The organic phase was separated, dried over NaSO4, filtered and evaporated under reduced pressure. The title compound was obtained after flash chromatography (446 mg, 69%).
Reaction SMILES: [CH2:1]([C:3]1[C:4]([CH3:10])=[N+:5]([O-:9])[CH:6]=[CH:7][CH:8]=1)[CH3:2].S(=O)(=O)(O)O.[N+:16]([O-])([OH:18])=[O:17]>>[CH2:1]([C:3]1[C:4]([CH3:10])=[N+:5]([O-:9])[CH:6]=[CH:7][C:8]=1[N+:16]([O-:18])=[O:17])[CH3:2]
Reactant: O=[N+]([O-])O
Reactant: CCc1ccc[n+]([O-])c1C
Agent: O=S(=O)(O)O
Product: CCc1c([N+](=O)[O-])cc[n+]([O-])c1C
Temperature: 80 °C
Reaction time: 8 h
Yield: 34.5 %

Procedure:
While cooling a mixture of 3-ethyl-2-methylpyridine 1-oxide (7.35 g, 53.6 mmol) and sulfuric acid (22.7 g, 231=mmol) in an ice bath, fuming nitric acid (3.64 ml, 87.9 mmol) was added dropwise, which was stirred at 80° C. for 8 hours. The reaction mixture was cooled to room temperature and then poured into ice. The obtained aqueous solution was extracted three times with chloroform. The organic layers were combined, dried over anhydrous magnesium sulfate, filtrated and concentrated to obtain the title compound (3.37 g, yield: 34.5%) as yellow solid.
Reaction SMILES: Cl[CH2:2][CH2:3][C:4]([NH:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([N:13]2[C:18]3[N:19]=[C:20]([NH:23][C:24]4[CH:29]=[CH:28][C:27]([N:30]5[CH2:35][CH2:34][N:33]([CH3:36])[CH2:32][CH2:31]5)=[CH:26][C:25]=4[O:37][CH3:38])[N:21]=[CH:22][C:17]=3[CH:16]=[CH:15][C:14]2=[O:39])[CH:8]=1)=[O:5].[CH3:40][NH:41][CH3:42]>>[CH3:40][N:41]([CH3:42])[CH2:2][CH2:3][C:4]([NH:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([N:13]2[C:18]3[N:19]=[C:20]([NH:23][C:24]4[CH:29]=[CH:28][C:27]([N:30]5[CH2:35][CH2:34][N:33]([CH3:36])[CH2:32][CH2:31]5)=[CH:26][C:25]=4[O:37][CH3:38])[N:21]=[CH:22][C:17]=3[CH:16]=[CH:15][C:14]2=[O:39])[CH:8]=1)=[O:5]
Reactant: CNC
Reactant: COc1cc(N2CCN(C)CC2)ccc1Nc1ncc2ccc(=O)n(-c3cccc(NC(=O)CCCl)c3)c2n1
Product: COc1cc(N2CCN(C)CC2)ccc1Nc1ncc2ccc(=O)n(-c3cccc(NC(=O)CCN(C)C)c3)c2n1
Temperature: 50 °C
Reaction time: 1.5 h
Yield: 76.7 %

Procedure:
3-Chloro-N-(3-(2-((2-methoxy-4-(4-methylpiperazin-1-yl)phenyl)amino)-7-oxopyrido[2,3-d]pyrimidin-8(7H)-yl)phenyl)propanamide (57 mg, 0.086 mmol) was treated with dimethylamine (2.0 M in THF, 2.00 mL, 4.00 mmol) and stirred at 50° C. for 90 min then stirred at RT for 72 h. The reaction mixture was then purified by chromatography on silica gel on an ISCO Combiflash RF (24 g Redisep HP (Gold), using a gradient of 0-20% 2M NH3/MeOH in DCM) affording 3-(dimethylamino)-N-(3-(2-((2-methoxy-4-(4-methylpiperazin-1-yl)phenyl)amino)-7-oxopyrido[2,3-d]pyrimidin-8(7H)-yl)phenyl)propanamide (44.6 mg, 0.066 mmol, 76% yield) as a yellow-orange amorphous foam. m/z (ESI, +ve ion) 557.0 (M+H)+. 1H NMR (400 MHz, MeOH-d4) δ ppm 8.71 (1H, s), 7.92 (1H, d, J=9.4 Hz), 7.57-7.61 (1H, m), 7.56 (1H, s), 7.44 (1H, d, J=7.8 Hz), 7.06 (1H, d, J=8.0 Hz), 6.58 (1H, d, J=2.5 Hz), 6.53 (1H, d, J=9.4 Hz): 6.12 (1H, br. s.), 3.88 (3H, s), 3.10-3.19 (4H, m), 2.77 (2H, q, J=6.7 Hz), 2.63-2.68 (4H, m), 2.57-2.62 (2H, m), 2.39 (3H, s), 2.33 (6H, s).
Reaction SMILES: [Si:1]([O:8][CH2:9][CH2:10][CH2:11][CH2:12][C:13]1[CH:18]=[CH:17][C:16]([CH2:19][OH:20])=[CH:15][CH:14]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[C:21]([N:25]1[C:30](=[O:31])[C:29]([Cl:32])=[C:28](Cl)[CH:27]=[N:26]1)([CH3:24])([CH3:23])[CH3:22].C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C)C=O>[C:21]([N:25]1[C:30](=[O:31])[C:29]([Cl:32])=[C:28]([O:20][CH2:19][C:16]2[CH:15]=[CH:14][C:13]([CH2:12][CH2:11][CH2:10][CH2:9][O:8][Si:1]([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2])=[CH:18][CH:17]=2)[CH:27]=[N:26]1)([CH3:24])([CH3:22])[CH3:23]
Reactant: CC(C)(C)[Si](C)(C)OCCCCc1ccc(CO)cc1
Reactant: CC(C)(C)n1ncc(Cl)c(Cl)c1=O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CC(C)(C)n1ncc(OCc2ccc(CCCCO[Si](C)(C)C(C)(C)C)cc2)c(Cl)c1=O
Reaction time: 12 h
Yield: 88.6 %

Procedure:
To a dry 25 mL round bottom flask, fitted with a reflux condenser, was added the product of Example 2D (0.41 g, 1.4 mmol), 2-tert-butyl-4,5-dichloro-2H-pyridazin-3-one (0.93 g, 4.2 mmol), cesium carbonate (1.37 g, 4.2 mmol), and anhydrous dimethylformamide (11 mL). The reaction flask was placed in a 68° C. oil bath and the reaction was stirred for 12 hours. The reaction flask was removed from the oil bath and allowed to cool. The mixture was diluted with ethyl acetate, transferred to a separatory funnel and washed with water (25 mL, 5×). The organic layer was dried with magnesium sulfate, filtered, and concentrated under reduced pressure to give 1.3 g of crude product. Column chromatography [silica gel; eluent hexanes-ethyl acetate (9:1)] provided the desired product (594 mg, 89%). 1H(CDCl3) δ(ppm): 0.05 (s, 6H); 0.90 (s, 9H); 1.64 (s, 9H); 2.65 (t, 2H); 3.64 (t, 2H); 5.23 (s, 2H); 7.23 (d, 2H); 7.33 (d, 2H); 7.74 (s, 1H). 13C (CDCl3) δ(ppm): 18.57, 26.19, 27.75, 28.09, 32.58, 35.61, 63.14, 66.57, 72.14, 118.46, 125.41, 127.44, 129.23, 132.38, 143.72, 154.02, 159.30.
Reaction SMILES: C[O:2][C:3](=[O:43])[CH2:4][C:5]1[CH:10]=[CH:9][C:8]([O:11][CH2:12][CH2:13][CH2:14][N:15]([CH2:30][C:31]2[CH:36]=[CH:35][CH:34]=[C:33]([C:37]([F:40])([F:39])[F:38])[C:32]=2[Cl:41])[CH2:16][CH:17]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[C:7]([Cl:42])[CH:6]=1.C1COCC1.[Li+].[OH-]>O>[ClH:41].[Cl:42][C:7]1[CH:6]=[C:5]([CH2:4][C:3]([OH:43])=[O:2])[CH:10]=[CH:9][C:8]=1[O:11][CH2:12][CH2:13][CH2:14][N:15]([CH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[C:33]([C:37]([F:40])([F:39])[F:38])[C:32]=1[Cl:41])[CH2:16][CH:17]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: COC(=O)Cc1ccc(OCCCN(Cc2cccc(C(F)(F)F)c2Cl)CC(c2ccccc2)c2ccccc2)c(Cl)c1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: Cl
Product: O=C(O)Cc1ccc(OCCCN(Cc2cccc(C(F)(F)F)c2Cl)CC(c2ccccc2)c2ccccc2)c(Cl)c1
Reaction time: 12 h
Yield: 175.2 %

Procedure:
To a solution of (3-chloro-4-{3-[(2-chloro-3-trifluoromethyl-benzyl)-2,2-diphenylethyl-amino]-propoxy}-phenyl)-acetic acid methyl ester (42.8 mg, 0.068 mmol) and THF (2.5 mL) and H2O (0.8 mL), LiOH (3.4 mg, 0.14 mmol) was added and the reaction mixture was stirred for 12 h. The mixture was concentrated and H2O was added. The mixture was acidified with 1N HCl, extracted several times with EtOAc, and concentrated. The resulting oil was diluted in Et2O and acidified with 1.0 M HCl/Et2O. The mixture was then concentrated to give the product as a white solid (38.9 mg, 88%). MS(ES) m/e 616.2 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:25][CH:26]([F:28])[F:27])=[C:6]([C:8]2[C:12]([NH:13][C:14]([C:16]3[CH:17]=[N:18][N:19]4[CH:24]=[CH:23][CH:22]=[N:21][C:20]=34)=[O:15])=[CH:11][NH:10][N:9]=2)[CH:7]=1.C([O-])([O-])=O.[Cs+].[Cs+].Cl[CH2:36][C@@H:37]([N:39]([CH2:41][C:42]1[CH:47]=[CH:46][C:45]([O:48][CH3:49])=[CH:44][CH:43]=1)[CH3:40])[CH3:38]>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:25][CH:26]([F:28])[F:27])=[C:6]([C:8]2[C:12]([NH:13][C:14]([C:16]3[CH:17]=[N:18][N:19]4[CH:24]=[CH:23][CH:22]=[N:21][C:20]=34)=[O:15])=[CH:11][N:10]([CH2:38][C@@H:37]([N:39]([CH2:41][C:42]3[CH:43]=[CH:44][C:45]([O:48][CH3:49])=[CH:46][CH:47]=3)[CH3:40])[CH3:36])[N:9]=2)[CH:7]=1.[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:25][CH:26]([F:28])[F:27])=[C:6]([C:8]2[N:9]([CH2:38][C@@H:37]([N:39]([CH2:41][C:42]3[CH:43]=[CH:44][C:45]([O:48][CH3:49])=[CH:46][CH:47]=3)[CH3:40])[CH3:36])[N:10]=[CH:11][C:12]=2[NH:13][C:14]([C:16]2[CH:17]=[N:18][N:19]3[CH:24]=[CH:23][CH:22]=[N:21][C:20]=23)=[O:15])[CH:7]=1
Reactant: COc1ccc(CN(C)[C@@H](C)CCl)cc1
Reactant: O=C(Nc1c[nH]nc1-c1cc(Cl)ccc1OC(F)F)c1cnn2cccnc12
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: COc1ccc(CN(C)[C@@H](C)Cn2cc(NC(=O)c3cnn4cccnc34)c(-c3cc(Cl)ccc3OC(F)F)n2)cc1
Product: COc1ccc(CN(C)[C@@H](C)Cn2ncc(NC(=O)c3cnn4cccnc34)c2-c2cc(Cl)ccc2OC(F)F)cc1

Procedure:
A 20-mL microwave vial was charged with N-[3-[5-chloro-2-(difluoromethoxy)phenyl]-1H-pyrazol-4-yl]pyrazolo[1,5-a]-pyrimidine-3-carboxamide (400 mg, 0.99 mmol), Cs2CO3 (652 mg, 2.00 mmol), DMF (10 mL) and [(2S)-1-chloropropan-2-yl][(4-methoxyphenyl)methyl]methylamine (454 mg, 1.99 mmol). The vessel was evacuated and refilled with nitrogen 3 times. The final reaction mixture was irradiated with microwave radiation for 30 min at 120° C. The reaction was then quenched by the addition of 50 mL of water. The resulting solution was extracted with dichloromethane (×2) and the organic layers combined and the organic layers were washed with brine, dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was purified by flash chromatography on silica gel eluting with dichloromethane/ethyl acetate (1:1). This resulted in 420 m of N-[3-[5-chloro-2-(difluoromethoxy)phenyl]-1-[(2S)-2-[[(4-methoxyphenyl)methyl](methyl)amino]propyl]-1H-pyrazol-4-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamide and N-[5-[5-chloro-2-(difluoromethoxy)phenyl]-1-[(2S)-2-[[(4-methoxyphenyl)methyl](methyl)amino]propyl]-1H-pyrazol-4-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamide mixture. LCMS (Method 25) [M+H]+=596.0, RT=0.81 min.
Reaction SMILES: [CH:1]1([N:6]2[C:10]3[N:11]=[C:12]([NH:15][C:16]4[S:17][CH:18]=[C:19]([C:21]([N:23]5[CH2:28][CH2:27][N:26](C(OC(C)(C)C)=O)[CH2:25][CH2:24]5)=[O:22])[N:20]=4)[N:13]=[CH:14][C:9]=3[C:8]3[CH:36]=[CH:37][N:38]=[CH:39][C:7]2=3)[CH2:5][CH2:4][CH2:3][CH2:2]1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH:1]1([N:6]2[C:10]3[N:11]=[C:12]([NH:15][C:16]4[S:17][CH:18]=[C:19]([C:21]([N:23]5[CH2:24][CH2:25][NH:26][CH2:27][CH2:28]5)=[O:22])[N:20]=4)[N:13]=[CH:14][C:9]=3[C:8]3[CH:36]=[CH:37][N:38]=[CH:39][C:7]2=3)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CC(C)(C)OC(=O)N1CCN(C(=O)c2csc(Nc3ncc4c5ccncc5n(C5CCCC5)c4n3)n2)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(c1csc(Nc2ncc3c4ccncc4n(C4CCCC4)c3n2)n1)N1CCNCC1

Procedure:
Compound 74 was dissolved in DCM (5 mL) and TFA (1.5 mL) and stirred at 20° C. for 2.5 hrs. The reaction was concentrated in vacuum and purified by preparative HPLC eluting with a gradient 10% MeCN/water/0.1% TFA -50% MeCN/water/0.1% TFA to provide compound 71 (23 mg) as a yellow solid. 1H NMR (500 MHz, CD3OD) δ 9.63 (1H, s), 9.32 (1H, s), 8.68 (1H, d, J=6.1 Hz), 8.63 (1H, d, J=6.4 Hz), 7.84 (1H, s), 5.56 (1H, p, J=8.1), 4.00-4.29 (4H, br s), 3.39 (4H, t, J=5.3 Hz), 2.63 (2H, m), 2.25 (4H, m), 1.98 (2H, m) ppm; LCMS-ESI (POS), M/Z, M+1: Found 449.2.
Reaction SMILES: CN(C)CCCOC1C=CC(C2SC(NC3C=CC=CC=3)=NC=2)=CC=1.[S:26]1[CH:30]=[CH:29][C:28]([C:31]2[S:35][C:34]([NH:36][C:37]3[CH:42]=[CH:41][C:40]([OH:43])=[CH:39][CH:38]=3)=[N:33][CH:32]=2)=[CH:27]1.Cl.Cl[CH2:46][CH2:47][N:48]1[CH2:52][CH2:51][CH2:50][CH2:49]1>C(Cl)Cl.CO>[N:48]1([CH2:47][CH2:46][O:43][C:40]2[CH:41]=[CH:42][C:37]([NH:36][C:34]3[S:35][C:31]([C:28]4[CH:29]=[CH:30][S:26][CH:27]=4)=[CH:32][N:33]=3)=[CH:38][CH:39]=2)[CH2:52][CH2:51][CH2:50][CH2:49]1
Reactant: ClCCN1CCCC1
Reactant: Oc1ccc(Nc2ncc(-c3ccsc3)s2)cc1
Agent: CN(C)CCCOc1ccc(-c2cnc(Nc3ccccc3)s2)cc1
Agent: Cl
Solvent: ClCCl
Solvent: CO
Product: c1cc(-c2cnc(Nc3ccc(OCCN4CCCC4)cc3)s2)cs1

Procedure:
The title compound is prepared as described in Example 8 for {5-[4-(3-dimethylamino-propoxy)-phenyl]-thiazol-2-yl}-phenyl-amine but starting from 4-(5-thiophen-3-yl-thiazol-2-yl-amino)-phenol (Example 12) and using 1-(2-chloroethyl)-pyrrolidine hydrochloride. Title compound: ES-MS: 372.0 [M+H]+; single peak at tR=6.07 min (System 1); Rf=0.30 (CH2Cl2/MeOH, 80/20).
Reaction SMILES: Cl.Cl.Cl.[NH:4]1[CH2:9][CH2:8][CH:7]([N:10]2[CH2:13][C:12]([CH2:36][C:37]#[N:38])([N:14]3[CH:18]=[C:17]([C:19]4[C:20]5[CH:27]=[CH:26][N:25]([CH2:28][O:29][CH2:30][CH2:31][Si:32]([CH3:35])([CH3:34])[CH3:33])[C:21]=5[N:22]=[CH:23][N:24]=4)[CH:16]=[N:15]3)[CH2:11]2)[CH2:6][CH2:5]1.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C.[OH:75][B:76]([OH:87])[C:77]1[CH:85]=[CH:84][C:80]([C:81](O)=[O:82])=[CH:79][C:78]=1[F:86]>C(Cl)Cl>[C:37]([CH2:36][C:12]1([N:14]2[CH:18]=[C:17]([C:19]3[C:20]4[CH:27]=[CH:26][N:25]([CH2:28][O:29][CH2:30][CH2:31][Si:32]([CH3:34])([CH3:33])[CH3:35])[C:21]=4[N:22]=[CH:23][N:24]=3)[CH:16]=[N:15]2)[CH2:11][N:10]([CH:7]2[CH2:8][CH2:9][N:4]([C:81]([C:80]3[CH:84]=[CH:85][C:77]([B:76]([OH:87])[OH:75])=[C:78]([F:86])[CH:79]=3)=[O:82])[CH2:5][CH2:6]2)[CH2:13]1)#[N:38]
Reactant: C[Si](C)(C)CCOCn1ccc2c(-c3cnn(C4(CC#N)CN(C5CCNCC5)C4)c3)ncnc21
Reactant: O=C(O)c1ccc(B(O)O)c(F)c1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: C[Si](C)(C)CCOCn1ccc2c(-c3cnn(C4(CC#N)CN(C5CCN(C(=O)c6ccc(B(O)O)c(F)c6)CC5)C4)c3)ncnc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 41 %

Procedure:
To a solution of {1-piperidin-4-yl-3-[4-(7-{[2-(trimethylsilyl)ethoxy]methyl}-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-3-yl}acetonitrile trihydrochloride (1.0 g, 2.0 mmol) in methylene chloride (DCM) (10 mL) were added benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate (1.2 g, 2.6 mmol), N,N-diisopropylethylamine (1.1 mL, 6.1 mmol), and 4-(dihydroxyboryl)-3-fluorobenzoic acid (0.37 g, 2.0 mmol). The mixture was stirred at room temperature overnight. Solvents were removed under reduced pressure and the residue was purified using HPLC to give 0.54 g (41%) of the corresponding product {4-[(4-{3-(cyanomethyl)-3-[4-(7-{[2-(trimethylsilyl)ethoxy]methyl}-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-1-yl}piperidin-1-yl)carbonyl]-2-fluorophenyl}boronic acid. LC-MS: 659.3 (M+H)+.
Reaction SMILES: C[O:2][C:3](=[O:40])[C:4]([CH3:39])([CH3:38])[CH2:5][CH2:6][CH2:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]([N:16]2[C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[C@H:19]([N:26]([C:34](=[O:36])[CH3:35])[C:27]3[CH:32]=[CH:31][C:30]([Cl:33])=[CH:29][CH:28]=3)[CH2:18][C@@H:17]2[CH3:37])=[O:15])=[CH:10][CH:9]=1.[OH-].[Na+]>CO.O1CCCC1.O>[C:34]([N:26]([C:27]1[CH:28]=[CH:29][C:30]([Cl:33])=[CH:31][CH:32]=1)[C@H:19]1[C:20]2[C:25](=[CH:24][CH:23]=[CH:22][CH:21]=2)[N:16]([C:14]([C:11]2[CH:12]=[CH:13][C:8]([CH2:7][CH2:6][CH2:5][C:4]([CH3:39])([CH3:38])[C:3]([OH:40])=[O:2])=[CH:9][CH:10]=2)=[O:15])[C@@H:17]([CH3:37])[CH2:18]1)(=[O:36])[CH3:35]
Reactant: COC(=O)C(C)(C)CCCc1ccc(C(=O)N2c3ccccc3[C@H](N(C(C)=O)c3ccc(Cl)cc3)C[C@@H]2C)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: CC(=O)N(c1ccc(Cl)cc1)[C@@H]1C[C@H](C)N(C(=O)c2ccc(CCCC(C)(C)C(=O)O)cc2)c2ccccc21
Temperature: 60 °C
Yield: 60 %

Procedure:
5-(4-{(2S,4R)-4-[acetyl(4-chloro-phenyl)-amino]-2-methyl-3,4-dihydro-2H-quinoline-1-carbonyl}-phenyl)-2,2-dimethyl-pentanoic acid methyl ester (500 mg, 0.89 mmol, 1 eq.) was dissolved in methanol/tetrahydrofuran (2/1) (4 ml). A solution of sodium hydroxide (71 mg, 1.8 mmol, 2 eq.) in water (1 ml) was added and reaction mixture heated to 60° C. for 20 h. The mixture was concentrated and the residue was acidified with a 1N HCl aqueous solution and extracted with ethyl acetate. The organic layer was washed with brine, dried over magnesium sulfate, filtered and concentrated to give the crude acid. Purification by silica gel chromatography gave pure 5-(4-{(2S,4R)-4-[acetyl(4-chloro-phenyl)-amino]-2-methyl-3,4-dihydro-2H-quinoline-1-carbonyl}-phenyl)-2,2-dimethyl-pentanoic acid (292 mg, 60%).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[N:6]=[C:7]([O:15]C(=O)C)[N:8](C(=O)C)[C:9]=1[CH2:10]Br)=[O:4].[SH:19][C:20]1[CH:25]=[CH:24][C:23]([OH:26])=[CH:22][CH:21]=1.C([O-])([O-])=O.[K+].[K+].Cl>CO.O>[CH3:1][O:2][C:3]([C:5]1[NH:6][C:7](=[O:15])[NH:8][C:9]=1[CH2:10][S:19][C:20]1[CH:25]=[CH:24][C:23]([OH:26])=[CH:22][CH:21]=1)=[O:4]
Reactant: Oc1ccc(S)cc1
Reactant: COC(=O)c1nc(OC(C)=O)n(C(C)=O)c1CBr
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CO
Product: COC(=O)c1[nH]c(=O)[nH]c1CSc1ccc(O)cc1
Temperature: 25 °C
Reaction time: 6 h
Yield: 78.5 %

Procedure:
To a solution of 4c (640 mg, 2 mmol) in 20 mL of MeOH was added 4-mercaptophenol (380 mg, 3.0 mmol) and K2CO3 (550 mg, 4.0 mmol). The solution was stirred at rt for 6 h. 20 mL of water was then added and 2 mL of 1N HCl was carefully added. This aqueous solution was extracted with Et2O. The aqueous solution was then concentrated and the residue was first dissolved in 5 mL of MeOH and the diluted with 50 mL of CH2Cl2. Filtration and concentration provided 5-(4-hydroxy-phenylsulfanyl methyl)-2-oxo-2,3-dihydro-1H-imidazole-4-carboxylic acid methyl ester 4d (440 mg, 80%). MS (ESI+) (M+AcN+1)=322.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([CH:10]=O)=[CH:9][C:4]=2[CH:3]=[CH:2]1.[NH:12]1[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>>[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([CH2:10][N:12]3[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]3)=[CH:9][C:4]=2[CH:3]=[CH:2]1
Reactant: O=Cc1ccc2occc2c1
Reactant: C1CCNCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Product: c1cc2cc(CN3CCCCC3)ccc2o1

Procedure:
1-Benzofuran-5-carbaldehyde was treated with piperidine and sodium triacetoxyborohydride under the standard reductive amination protocol to provide 1-(5-benzofuranylmethyl)piperidine.