Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[C:7]([OH:8])=[CH:6][CH:5]=[CH:4][N:3]=1.C(=O)([O-])[O-].[Na+].[Na+].[I:15]I.Cl>O.C(OCC)(=O)C>[Br:1][C:2]1[C:7]([OH:8])=[CH:6][CH:5]=[C:4]([I:15])[N:3]=1
Reactant: Oc1cccnc1Br
Reactant: II
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Product: Oc1ccc(I)nc1Br
Temperature: 25 °C
Reaction time: 2 h
Yield: 52.4 %

Procedure:
2-Bromo-pyridin-3-ol (5 g) is dissolved in water (150 ml) and thereto are added sodium carbonate (6.15 g) and iodine (7.65 g) and the mixture is stirred at room temperature for 2 hours. Thereto are added a 1N-hydrochloric acid and ethyl acetate, and the mixture is separated, and the organic layer is washed with a saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The residue is purified by silica gel column chromatography (hexane:ethyl acetate=9:1→3:1) to give 2-bromo-6-iodo-pyridin-3-ol (4.52 g). MS (m/z): 300/302 [M+H]+
Reaction SMILES: [CH3:1][S:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]2[C:13]3[CH:14]=[C:15]([C:18]([NH:20][NH2:21])=[O:19])[CH:16]=[CH:17][C:12]=3[N:11]=[CH:10]2)=[CH:5][CH:4]=1.[C:22](Cl)(=[O:24])[CH3:23].C(OCC)(=O)C>CN(C)C(=O)C>[C:22]([NH:21][NH:20][C:18]([C:15]1[CH:16]=[CH:17][C:12]2[N:11]=[CH:10][N:9]([C:6]3[CH:7]=[CH:8][C:3]([S:2][CH3:1])=[CH:4][CH:5]=3)[C:13]=2[CH:14]=1)=[O:19])(=[O:24])[CH3:23]
Reactant: CSc1ccc(-n2cnc3ccc(C(=O)NN)cc32)cc1
Reactant: CC(=O)Cl
Solvent: CC(=O)N(C)C
Solvent: CCOC(C)=O
Product: CSc1ccc(-n2cnc3ccc(C(=O)NNC(C)=O)cc32)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 100 %

Procedure:
To a solution of 1-[4-(methylthio)phenyl]-1H-benzimidazole-6-carbohydrazide (1.0 g, 3.35 mmol) in N,N-dimethylacetamide (5 mL) was added acetyl chloride (262 μL, 3.69 mmol) at 0° C., and the resulting mixture was stirred at room temperature for 1 hr. Ethyl acetate was added to the reaction mixture, the precipitate was collected by filtration and washed with ethyl acetate to give the title compound (1.14 g, yield 100%) as colorless crystals.
Reaction SMILES: I(C1C=CC=CC=1C(O)=O)(=O)=O.[F:13][C:14]([F:30])([F:29])[O:15][C:16]1[CH:21]=[CH:20][C:19]([C:22]2[S:23][CH:24]=[C:25]([CH2:27][OH:28])[N:26]=2)=[CH:18][CH:17]=1.O>CS(C)=O>[F:30][C:14]([F:13])([F:29])[O:15][C:16]1[CH:21]=[CH:20][C:19]([C:22]2[S:23][CH:24]=[C:25]([CH:27]=[O:28])[N:26]=2)=[CH:18][CH:17]=1
Reactant: OCc1csc(-c2ccc(OC(F)(F)F)cc2)n1
Agent: O=C(O)c1ccccc1I(=O)=O
Solvent: O
Solvent: CS(C)=O
Product: O=Cc1csc(-c2ccc(OC(F)(F)F)cc2)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 99.9 %

Procedure:
A solution of 2-iodoxybenzoic acid (441 mg) in dimethylsulfoxide (5 mL) was added to a solution of {2-[4-(trifluoromethoxy)phenyl]-1,3-thiazol-4-yl}methanol (361 mg) in dimethylsulfoxide (10 mL) and the resulting mixture was stirred at room temperature overnight. After water was added, the mixture was filtered through Celite and then extracted with ethyl acetate. The solvent was distilled off under reduced pressure to afford the title compound (358 mg) as the residue.
Reaction SMILES: C[O-].[Na+].[C:4](OC)(=O)[CH2:5][C:6]([O:8][CH3:9])=[O:7].[CH2:13]([C:18]1C(=O)[CH2:20][CH2:21][C:22]=1[O:23]C)[CH2:14][CH2:15][CH2:16][CH3:17].Cl>CO>[CH3:9][O:8][C:6](=[O:7])[CH2:5][C:4]1[CH2:20][CH2:21][C:22](=[O:23])[C:18]=1[CH2:13][CH2:14][CH2:15][CH2:16][CH3:17]
Reactant: CCCCCC1=C(OC)CCC1=O
Reactant: COC(=O)CC(=O)OC
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: CCCCCC1=C(CC(=O)OC)CCC1=O
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
The air in a reactor (a volume of 0.3 L) was preliminarily replaced with nitrogen at ordinary pressure. The reactor was charged with 13.5 g (70 mmol) of a 28% methanol solution of sodium methoxide and 140 ml of absolute methanol. Thereto was added 6.6 g (50 mmol) of dimethyl malonate, and the mixture was stirred for 30 minutes at 25° C. Thereto was added 6.6 g (36 mmol) of 2-pentyl-3-methoxy-2-cyclopentenone, and the mixture was heated under reflux for 24 hours in a nitrogen atmosphere. The resulting mixture was ice-cooled and neutralized by gradually adding 6.1 ml of concentrated hydrochloric acid, and methanol was distilled off. Thereto were added 50 ml of water and 100 ml of toluene, and then the mixture was stirred sufficiently and allowed to stand to separate the organic phase. The toluene in the organic phase was distilled off in vacuo followed by vacuum distillation, yielding methyl(2-pentyl-3-keto-1-cyclopentenyl-)acetate (a compound in which R22 represents an n-pentyl group, and R23 represents a methyl group in the above formula (15)). Gas chromatographic analysis showed that the yield of methyl(2-pentyl-3-keto-1-cyclopentenyl-)acetate relative to 2-pentyl-3-methoxy-2-cyclopentenone was 90%.
Reaction SMILES: [CH2:1]([O:4][CH2:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[CH:17]=[CH:16][C:15]([CH2:18][N:19]3[CH2:23][C:22]4([CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]4)[O:21][C:20]3=[O:29])=[CH:14][CH:13]=2)=[CH:8][CH:7]=1)[CH:2]=C.NC(N)=S.C(Cl)Cl.C[OH:38]>C(=O)=O.CC(C)=O>[O:29]=[C:20]1[N:19]([CH2:18][C:15]2[CH:14]=[CH:13][C:12]([C:9]3[CH:8]=[CH:7][C:6]([CH2:5][O:4][CH2:1][CH:2]=[O:38])=[CH:11][CH:10]=3)=[CH:17][CH:16]=2)[CH2:23][C:22]2([CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]2)[O:21]1
Reactant: CO
Reactant: C=CCOCc1ccc(-c2ccc(CN3CC4(CCCCC4)OC3=O)cc2)cc1
Agent: NC(N)=S
Agent: O=C=O
Solvent: CC(C)=O
Solvent: ClCCl
Product: O=CCOCc1ccc(-c2ccc(CN3CC4(CCCCC4)OC3=O)cc2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 41 %

Procedure:
3-(4′-Allyloxymethyl-biphenyl-4-ylmethyl)-1-oxa-3-aza-spiro[4.5]decan-2-one (200 mg, 0.51 mmol) was dissolved in DCM/methanol (4:1, 7.5 mL) and was cooled to −78° C. in dry ice-acetone bath. O3 was bubbled through the solution for 15 min. Thin layer chromatography (TLC) confirmed the completion of the reaction at this stage. Thiourea was added to the reaction mixture and stirred at low temperature for 0.5 hr. The cooling bath was removed and the reaction mixture was allowed to warm to room temperature, and stirred overnight. The reaction mixture was concentrated, and the residue was purified on silica gel eluting with 5˜20% ethyl acetate in hexane to give the product as a white solid (80 mg, 41%). 1H NMR (300 MHz, CDCl3): δ (ppm) 9.76 (s, 1H), 7.63 (m, 4H), 7.44 (d, 2H), 7.35 (d, 2H), 4.7 (s, 2H), 4.47 (s, 2H), 4.16 (s, 2H), 3.14 (s, 2H), 1.78 (m, 4H), 1.45 (m, 6H).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([CH3:8])[N:5]=[C:4]([N:9]([CH2:19][C:20]2[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=2)[CH2:10][C:11]2[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=2)[CH:3]=1.[C:28]([O:32][C:33]([N:35]1[CH2:40][CH2:39][N:38]([CH2:41][C:42]2[CH:43]=[C:44](B(O)O)[C:45]([F:48])=[N:46][CH:47]=2)[CH2:37][CH2:36]1)=[O:34])([CH3:31])([CH3:30])[CH3:29].C([O-])(=O)C.[K+]>C(O)C.O>[CH3:18][O:17][C:14]1[CH:15]=[CH:16][C:11]([CH2:10][N:9]([CH2:19][C:20]2[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=2)[C:4]2[N:5]=[C:6]([CH3:8])[N:7]=[C:2]([C:44]3[CH:43]=[C:42]([CH2:41][N:38]4[CH2:39][CH2:40][N:35]([C:33]([O:32][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:34])[CH2:36][CH2:37]4)[CH:47]=[N:46][C:45]=3[F:48])[CH:3]=2)=[CH:12][CH:13]=1
Reactant: COc1ccc(CN(Cc2ccc(OC)cc2)c2cc(Cl)nc(C)n2)cc1
Reactant: CC(C)(C)OC(=O)N1CCN(Cc2cnc(F)c(B(O)O)c2)CC1
Agent: CC(=O)[O-]
Agent: [K+]
Solvent: CCO
Solvent: O
Product: COc1ccc(CN(Cc2ccc(OC)cc2)c2cc(-c3cc(CN4CCN(C(=O)OC(C)(C)C)CC4)cnc3F)nc(C)n2)cc1
Temperature: 100 °C
Yield: 42.4 %

Procedure:
6-Chloro-N,N-bis(4-methoxybenzyl)-2-methylpyrimidin-4-amine (214.0 mg, 0.557 mmol), 5-((4-(tert-butoxycarbonyl)piperazin-1-yl)methyl)-2-fluoropyridin-3-ylboronic acid (Example 34, Step 3)(189 mg, 0.557 mmol), PdCl2 (AmPhos)2 (Aldrich, St. Louis, Mo.) (19.74 mg, 0.028 mmol), and potassium acetate (164 mg, 1.672 mmol) in a mixture of ethanol (3.0 mL) and water (0.300 mL) was sparged with argon and then heated (microwave) at 100° C. in a 20 mL microwave vial for 20 min. The reaction mixture was then concentrated onto silica gel and chromatographically purified (ISCO, 24 g, 0 to 100% EtOAc/Hexanes) to provide tert-butyl 4-((5-(6-(bis(4-methoxybenzyl)amino)-2-methylpyrimidin-4-yl)-6-fluoropyridin-3-yl)methyl)piperazine-1-carboxylate (152.0 mg, 0.236 mmol, 42.4% yield) as a colorless oil. 1H NMR (400 MHz, CDCl3) δ 8.44 (dd, J=9.39, 2.15 Hz, 1H); 8.14 (s, 1H); 7.17 (d, J=7.82 Hz, 4H); 6.86 (d, J=8.61 Hz, 5H); 4.74 (br. s., 4H); 3.79 (s, 6H); 3.55 (s, 2H); 3.42 (t, J=4.69 Hz, 4H); 2.62 (s, 3H); 2.37-2.43 (m, 4H); 1.45 (s, 9H). 19F NMR (377 MHz, CDCl3) 6-71.01 (d, J=9.16 Hz, 1F). m/z (ESI, +ve ion) 643.2 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[C:19]3[C:14](=[CH:15][C:16]([O:21][CH3:22])=[C:17]([OH:20])[CH:18]=3)[N:13]=[CH:12][N:11]=2)[CH:5]=[CH:6][C:7]=1[F:8].O[C@@H:24]1[CH2:28][CH2:27][O:26][CH2:25]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>C(#N)C>[Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[C:19]3[C:14](=[CH:15][C:16]([O:21][CH3:22])=[C:17]([O:20][C@H:24]4[CH2:28][CH2:27][O:26][CH2:25]4)[CH:18]=3)[N:13]=[CH:12][N:11]=2)[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: COc1cc2ncnc(Nc3ccc(F)c(Cl)c3)c2cc1O
Reactant: O[C@@H]1CCOC1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CC#N
Product: COc1cc2ncnc(Nc3ccc(F)c(Cl)c3)c2cc1O[C@H]1CCOC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
300 mg of 4-[(3-chloro-4-fluoro-phenyl)amino]-6-hydroxy-7-methoxy-quinazoline in 6 ml acetonitrile are combined with 114 μl (R)-3-hydroxy-tetrahydrofuran and 370 mg triphenylphosphine. Then 234 μl diethyl azodicarboxylate are added and the reaction mixture is stirred overnight at ambient temperature. For working up the reaction mixture is filtered and the filtrate evaporated down in vacuo. The crude product is purified by chromatography over a silica gel column with ethyl acetate/methanol (95:5) as eluant.
Reaction SMILES: [C:1]([C:5]1[CH:22]=[CH:21][CH:20]=[CH:19][C:6]=1[O:7][CH:8]1[CH2:13][CH2:12][N:11]([C:14](=[O:18])[C:15](O)=[O:16])[CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].C(Cl)(=O)C(Cl)=O.[NH:29]1[C:33]([NH2:34])=[N:32][N:31]=[N:30]1.C(N(CC)CC)C>C1(C)C=CC=CC=1>[C:1]([C:5]1[CH:22]=[CH:21][CH:20]=[CH:19][C:6]=1[O:7][CH:8]1[CH2:13][CH2:12][N:11]([C:14](=[O:18])[C:15]([NH:34][C:33]2[NH:32][N:31]=[N:30][N:29]=2)=[O:16])[CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: Nc1nnn[nH]1
Reactant: CC(C)(C)c1ccccc1OC1CCN(C(=O)C(=O)O)CC1
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: CC(C)(C)c1ccccc1OC1CCN(C(=O)C(=O)Nc2nnn[nH]2)CC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 86.9 %

Procedure:
A solution of [4-(2-tert-butylphenoxy)piperidin-1-yl](oxo)acetic acid (300 mg, 0.98 mmol) obtained in Example 52 and oxalyl chloride (126 μL, 1.47 mmol) in toluene (5 ml) was stirred at room temperature for 3 hr. The reaction mixture was concentrated, and DMF (1 mL) was added to the residue. The mixture was added to a solution of 1H-tetrazole-5-amine (255 mg, 3.0 mmol) and triethylamine (205 μL, 1.47 mmol) in toluene (10 ml) under ice-cooling, and the mixture was stirred at room temperature for 16 hr. The reaction mixture was partitioned between ethyl acetate-1N hydrochloric acid, and the ethyl acetate layer was washed with saturated brine, dried over anhydrous magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure to give the title compound (317 mg, 87%) as a white solid.
Reaction SMILES: [C:1]1([C:7]2[CH:12]=[CH:11][CH:10]=[C:9]([C:13]3[N:14]=[N:15]NN=3)[N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:18](Cl)(=[O:25])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.O.[OH-].[Na+]>N1C=CC=CC=1>[C:19]1([C:18]2[O:25][C:13]([C:9]3[N:8]=[C:7]([C:1]4[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=4)[CH:12]=[CH:11][CH:10]=3)=[N:14][N:15]=2)[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: c1ccc(-c2cccc(-c3nn[nH]n3)n2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: c1ccncc1
Product: c1ccc(-c2cccc(-c3nnc(-c4ccccc4)o3)n2)cc1
Temperature: 50 °C
Reaction time: 2 h
Yield: 91 %

Procedure:
5.0 g of 2-phenyl-6-(2H-tetrazol-5-yl)pyridine was dissolved in 125 ml of dehydrated pyridine. Temperature was elevated to 120° C., and 75 ml was dehydrated by azeotropy. After cooling to 50° C., 3.17 g of benzoyl chloride was added. Temperature was elevated to 100° C., and stirring was conducted for 2 hours under flux. After cooling to room temperature, the reaction solution was poured into 300 ml water, and after adjusting pH to 12 with 20% sodium hydroxide aqueous solution, stirring was conducted for 1 hour. A precipitated yellow solid was taken out by suction filtration, and washed with water. The solid obtained was vacuum dried at 70° C. for 20 hours, and purified with adsorption purification (carrier: NH silica gel, eluting solution: chloroform) to obtain 6.11 g (yield 91%) of PhpyOXDPh. The product was identified with NMR analysis. The result of NMR analysis (CDCl3) was as follows. 8.23-8.26 ppm (3H), 8.14-8.17 ppm (2H), 7.90-7.99 ppm (2H), 7.48-7.58 ppm (6H).
Reaction SMILES: [CH3:1][O:2][C:3]1[NH:4][CH:5]=[CH:6][C:7](=[O:9])[N:8]=1.C1C(=O)N([I:17])C(=O)C1>CN(C=O)C.O>[I:17][C:6]1[C:7](=[O:9])[N:8]=[C:3]([O:2][CH3:1])[NH:4][CH:5]=1
Reactant: COc1nc(=O)cc[nH]1
Reactant: O=C1CCC(=O)N1I
Solvent: O
Solvent: CN(C)C=O
Product: COc1nc(=O)c(I)c[nH]1
Temperature: 70 °C
Reaction time: 2.5 h

Procedure:
2-Methoxypyrimidin-4(1H)-one (1.00 g, 7.93 mmol) and n-iodosuccinimide (3.57 g, 15.86 mmol) were mixed in DMF (8 mL) under a nitrogen atmosphere. The reaction mixture was stirred at 70° C. for 2.5 h. The reaction mixture was cooled to room temperature, diluted with water, and extracted with EtOAc (3×). The combined organic layers were washed with sat. sodium chloride, dried over magnesium sulfate, filtered, and concentrated. The resulting solid was suspended in DCM, filtered, and washed with DCM to give 5-iodo-2-methoxypyrimidin-4(1H)-one. [M+1]=252.9.
Reaction SMILES: [C:1]([C:4]1[CH:9]=[C:8]([C@@H:10]([NH:13][C:14]([C:16]2[C:17]3[CH:24]=[N:23][N:22]([C:25]4[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=4)[C:18]=3[CH:19]=[N:20][CH:21]=2)=[O:15])[CH2:11][CH3:12])[CH:7]=[CH:6][N:5]=1)(=[O:3])[CH3:2].[CH3:32][Li]>C1COCC1.C(OCC)C>[OH:3][C:1]([C:4]1[CH:9]=[C:8]([C@@H:10]([NH:13][C:14]([C:16]2[C:17]3[CH:24]=[N:23][N:22]([C:25]4[CH:26]=[CH:27][C:28]([F:31])=[CH:29][CH:30]=4)[C:18]=3[CH:19]=[N:20][CH:21]=2)=[O:15])[CH2:11][CH3:12])[CH:7]=[CH:6][N:5]=1)([CH3:32])[CH3:2]
Reactant: CC[C@H](NC(=O)c1cncc2c1cnn2-c1ccc(F)cc1)c1ccnc(C(C)=O)c1
Reactant: [Li]C
Solvent: CCOCC
Solvent: C1CCOC1
Product: CC[C@H](NC(=O)c1cncc2c1cnn2-c1ccc(F)cc1)c1ccnc(C(C)(C)O)c1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a chilled (−78°) solution of 1-(4-fluorophenyl)-1H-pyrazolo[3,4-c]pyridine-4-carboxylic acid [(S)-1-(2-acetyl-pyridin-4-yl)-propyl]-amide (32 mg, 0.08 mmol) in anhydrous THF (2 mL) was added a solution of 1.6 N methyl lithium (0.29 mL, 0.46 mmol) in diethyl ether. The reaction mixture was slowly warmed to room temperature. After 18 hours, the mixture was cooled to −78° C., quenched with saturated aqueous ammonium chloride and extracted with EtOAc (4×60 mL). The combined organic layers were washed with brine, dried over sodium sulfate, and concentrated. The residue was purified by reversed-phase HPLC (Sunfire PrepC18 OBD 5 μM 30×150 mm column) using a gradient of 15-65% acetonitrile in water with 0.1% TFA. Fractions from the chromatography were concentrated, made basic by saturated aqueous NaHCO3 solution and extracted with EtOAc. The organic layer was washed with brine, dried over Na2SO4, filtered, and concentrated. The solid was triturated with EtOAc-hexanes to afford the title.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][C:3]([C:6]([O:8][CH3:9])=[O:7])=[CH:2]1.[C:10]1([CH3:18])[CH:15]=[CH:14][C:13]([S:16]Cl)=[CH:12][CH:11]=1>C(Cl)Cl>[CH3:18][C:10]1[CH:15]=[CH:14][C:13]([S:16][C:5]2[NH:1][CH:2]=[C:3]([C:6]([O:8][CH3:9])=[O:7])[CH:4]=2)=[CH:12][CH:11]=1
Reactant: COC(=O)c1cc[nH]c1
Reactant: Cc1ccc(SCl)cc1
Solvent: ClCCl
Product: COC(=O)c1c[nH]c(Sc2ccc(C)cc2)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 28.5 %

Procedure:
Methyl pyrrole-3-carboxylate (2.5 g., 20 mmoles) was dissolved in 50 ml. of methylene chloride. To the stirred solution there was added dropwise p-toluenesulfenyl chloride (2.92 g., 20 mmoles), with the temperature maintained below 30° C. by occasional cooling with an ice-water bath. The reaction was stirred for 60 minutes at room temperature. The reaction mixture was concentrated in vacuo to an oil. The residue was taken up in a mixture of isopropyl alcohol and hexane, a small amount of gum removed by filtration and the filtrate reevaporated in vacuo to an oil (5.0 g.). The latter was chromatographed on 150 g. of silica gel, with 100 ml. fractions of the benzene eluant collected. Fractions 10 to 19 were combined to yield the desired product (1.41 g.) contaminated with an impurity showing a mass spectral peak at 281. The latter was removed by recrystallization from methylene chloride/hexane to yield purified methyl 5-(4-methylphenylthio)pyrrole-3-carboxylate (1.14 g., m.p. 118°-121° C., m/e 247).
Reaction SMILES: [C:1]([C:3]1[N:4](C(OC(C)(C)C)=O)[C:5]2[C:10]([CH:11]=1)=[CH:9][C:8]([CH2:12]Br)=[CH:7][CH:6]=2)#[N:2].[NH:21]1[CH2:26][CH2:25][CH:24]([NH:27][C:28]2[C:29]3[CH:36]=[C:35]([CH2:37][C:38]([F:41])([F:40])[F:39])[S:34][C:30]=3[N:31]=[CH:32][N:33]=2)[CH2:23][CH2:22]1.CCN(C(C)C)C(C)C.Cl[Sn](Cl)(Cl)Cl>C(Cl)Cl>[F:40][C:38]([F:39])([F:41])[CH2:37][C:35]1[S:34][C:30]2[N:31]=[CH:32][N:33]=[C:28]([NH:27][CH:24]3[CH2:23][CH2:22][N:21]([CH2:12][C:8]4[CH:9]=[C:10]5[C:5](=[CH:6][CH:7]=4)[NH:4][C:3]([C:1]#[N:2])=[CH:11]5)[CH2:26][CH2:25]3)[C:29]=2[CH:36]=1
Reactant: FC(F)(F)Cc1cc2c(NC3CCNCC3)ncnc2s1
Reactant: CC(C)(C)OC(=O)n1c(C#N)cc2cc(CBr)ccc21
Agent: Cl[Sn](Cl)(Cl)Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: N#Cc1cc2cc(CN3CCC(Nc4ncnc5sc(CC(F)(F)F)cc45)CC3)ccc2[nH]1
Yield: 68 %

Procedure:
16.7 mg of tert-butyl 2-cyano-5-bromomethyl-1H-indole-1-carboxylate (0.05 mmol) and 15.8 mg of N-(piperidin-4-yl)-6-(2,2,2-trifluoroethyl)thieno[2,3-d]pyrimidin-4-amine (0.05 mmol) were dissolved in 0.6 mL of DCM. 12.9 mg of DIPEA (0.1 mmol) was added to that solution and reaction mixture was stirred for 18 hs. Then reaction mixture was directly loaded on silica gel column and the product was eluted with DCM-MeOH 30:1. After evaporation of solvent boc-protected intermediate was dissolved in 0.5 mL of ACN and 0.06 mL of SnCl4 (0.5 mmol) was added. The homogenous reaction mixture was stirred for 1 h and then all volatiles were removed in vacuo. The residue was quenched ammonia and extracted with ethyl acetate. Combined organic fractions were dried over MgSO4 and concentrated. The residue was purified on silica gel column using hexane-ethyl acetate-MeOH 1:1:0.1 to produce 16 mg of 5((4-((6-(2,2,2-trifluoroethyl)thieno[2,3-d]pyrimidin-4-yl)amino)piperidin-1-yl)methyl)-1H-indole-2-carbonitrile (Compound 175). Its monohydrochloride salt was obtained by adding 1 equivalent of 1N HCl solution in diethyl ether to a solution of compound in ethanol. The hydrochloride salt was recrystallized from methanol. 1H NMR (600 MHz, DMSO-d6): δ 12.62 (s, 1H), 10.74 (br, 1H), 8.33 (s, 1H), 8.07 (d, 1H, J=7 Hz), 7.93, s, 1H), 7.70 (s, 1H), 7.62 (d, 1H, J=12 Hz), 7.56 (d, 1H, J=12 Hz), 7.45 (s, 1H), 4.36 (s, 1H), 4.30 (m, 1H), 4.03 (q, 2H, J=11 Hz), 3.41 (m, 2H), 3.11 (m, 2H), 2.12 (m, 2H), 1.98 (m, 2H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][C:10]([C:15]2[N:16]([CH3:31])[C:17]3[C:22]([N:23]=2)=[C:21]([N:24]2[CH2:29][CH2:28][O:27][CH2:26][CH2:25]2)[N:20]=[C:19]([Cl:30])[N:18]=3)([OH:14])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].I[CH3:35]>C1COCC1.C1OCCOCCOCCOCCOC1>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][C:10]([C:15]2[N:16]([CH3:31])[C:17]3[C:22]([N:23]=2)=[C:21]([N:24]2[CH2:29][CH2:28][O:27][CH2:26][CH2:25]2)[N:20]=[C:19]([Cl:30])[N:18]=3)([O:14][CH3:35])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: Cn1c(C2(O)CCCN(C(=O)OC(C)(C)C)C2)nc2c(N3CCOCC3)nc(Cl)nc21
Reactant: CI
Agent: C1COCCOCCOCCOCCO1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COC1(c2nc3c(N4CCOCC4)nc(Cl)nc3n2C)CCCN(C(=O)OC(C)(C)C)C1
Reaction time: 2.5 h
Yield: 91.9 %

Procedure:
To a solution of 3-(2-chloro-9-methyl-6-morpholin-4-yl-9H-purin-8-yl)-3-hydroxypiperidine-1-carboxylic acid tert-butyl ester (4.54 g, 10.02 mmol) in THF (100 mL) was added NaH (481 mg, 12.02 mmol, 60% dispersion in mineral oil) and the mixture allowed to stir for 5 min before the addition of iodomethane (750 μL, 12.02 mmol) and 15-Crown-5 (10 drops). The resulting mixture was allowed to stir for 2.5 h then concentrated in vacuo. The resulting residue was partitioned between EtOAc and H2O and the aqueous layer further extracted with 2-methyl THF. The combined organic phases were dried (Na2SO4) and concentrated in vacuo affording 3-(2-Chloro-9-methyl-6-morpholin-4-yl-9H-purin-8-yl)-3-methoxypiperidine-1-carboxylic acid tert-butyl ester (4.30 g, 92%). LCMS (method A): RT 4.05 min, [M+H]+ 467.2
Reaction SMILES: ClC1C=C(Cl)C=C(Cl)C=1[O:10][C:11](=O)[CH2:12][C:13](OC1C(Cl)=CC(Cl)=CC=1Cl)=[O:14].[NH2:26]/[C:27](/[CH3:34])=[CH:28]\[C:29]([O:31][CH2:32][CH3:33])=[O:30]>BrC1C=CC=CC=1.CCOC(C)=O>[CH2:32]([O:31][C:29](=[O:30])[C:28]1[C:11]([OH:10])=[CH:12][C:13]([OH:14])=[N:26][C:27]=1[CH3:34])[CH3:33]
Reactant: O=C(CC(=O)Oc1c(Cl)cc(Cl)cc1Cl)Oc1c(Cl)cc(Cl)cc1Cl
Reactant: CCOC(=O)/C=C(/C)N
Solvent: Brc1ccccc1
Solvent: CCOC(C)=O
Product: CCOC(=O)c1c(O)cc(O)nc1C
Temperature: 50 °C
Yield: 85.6 %

Procedure:
A mixture of malonic acid (20 g, 192 mmol), 2,4,6-trichlorophenol (72 g, 365 mmol), and phosphorus oxychloride (38 mL, 403.2 mmol) was stirred at reflux for 12 h. The reaction mixture was cooled to 70° C. and poured into ice water. The solid was collected by filtration, washed with water, and air-dried to give malonic acid bis-(2,4,6-trichloro-phenyl)ester (85 g, 95%). A solution of malonic acid bis-(2,4,6-trichloro-phenyl)ester (85 g, 183.6 mmol) and ethyl 3-aminocrotonate (26.1 g, 202 mmol) in bromobenzene (100 mL) was stirred at reflux for 50 min. The reaction mixture was cooled to 50° C. and diluted with EtOAc (260 mL). The solid was collected by filtration, washed with water, and air-dried, to give 4,6-dihydroxy-2-methyl nicotinic acid ethyl ester (31 g, 86%).
Reaction SMILES: [H-].[Na+].[OH:3][C@@H:4]([CH2:9][O:10][CH:11]([CH3:13])[CH3:12])[C:5]([O:7][CH3:8])=[O:6].Cl[C:15]1[N:20]=[CH:19][N:18]=[C:17]2[N:21]([C:24]3[C:29]([CH3:30])=[CH:28][CH:27]=[CH:26][N:25]=3)[N:22]=[CH:23][C:16]=12.Cl>C1COCC1>[CH:11]([O:10][CH2:9][C@H:4]([O:3][C:15]1[N:20]=[CH:19][N:18]=[C:17]2[N:21]([C:24]3[C:29]([CH3:30])=[CH:28][CH:27]=[CH:26][N:25]=3)[N:22]=[CH:23][C:16]=12)[C:5]([O:7][CH3:8])=[O:6])([CH3:13])[CH3:12]
Reactant: COC(=O)[C@@H](O)COC(C)C
Reactant: Cc1cccnc1-n1ncc2c(Cl)ncnc21
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COC(=O)[C@H](COC(C)C)Oc1ncnc2c1cnn2-c1ncccc1C
Temperature: 5 °C
Reaction time: 0.17 h
Yield: 79.2 %

Procedure:
60% Sodium hydride (0.720 g, 18.00 mmol) was added to a solution of (S)-methyl 2-hydroxy-3-isopropoxypropanoate (2.353 g, 12.00 mmol) in anhydrous THF (100 mL) at 5° C., under nitrogen. The resulting suspension was stirred at 5° C. for 10 minutes and then a solution of 4-chloro-1-(3-methylpyridin-2-yl)-1H-pyrazolo[3,4-d]pyrimidine (Intermediate J4) (2.95 g, 12 mmol) in dry THF (50 mL) was added dropwise maintaining a temperature below 5° C. The reaction mixture was stirred at 5° C. for 10 mins and then allowed to warm to room temperature. The reaction was stirred at room temperature for 1 hour. The reaction mixture was neutralised with HCl (1M, aq). The majority of the THF was evaporated in vacuo and then EtOAc (75 mL) and water (50 mL) were added. The organic layer was separated and the aqueous layer re-extracted with EtOAc (2×50 mL). The combined organics were washed with saturated brine (50 mL), dried (MgSO4), filtered and concentrated in vacuo. The crude product was purified by flash silica chromatography (120 g), elution gradient 30 to 80% EtOAc in isohexane to afford (2S)-methyl 3-isopropoxy-2-(1-(3-methylpyridin-2-yl)-1H-pyrazolo[3,4-d]pyrimidin-4-yloxy)propanoate (3.53 g, 79%). 1H NMR (400 MHz, DMSO-d6) δ 1.11-1.14 (6H, m), 2.11 (3H, s), 3.68-3.74 (4H, m), 3.95-4.03 (2H, m), 5.79-5.81 (1H, m), 7.56-7.59 (1H, dd), 7.98-8.00 (1H, d), 8.49 (1H, m), 8.57 (2H, d). m/z (ESI+) (M+H)+=372; HPLC tR=1.99 min.