Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[C:5]([C:7]2[N:12]=[CH:11][C:10]([CH2:13][C:14]3[C:15]([CH3:26])=[CH:16][C:17]([CH:24]=C)=[C:18]([CH:23]=3)[C:19]([O:21][CH3:22])=[O:20])=[CH:9][CH:8]=2)[C:4]([CH3:27])=[N:3]1.CC(C)=[O:30].C(#N)C.I([O-])(=O)(=O)=O.[Na+]>[Os]=O.O>[CH3:1][N:2]1[CH:6]=[C:5]([C:7]2[N:12]=[CH:11][C:10]([CH2:13][C:14]3[C:15]([CH3:26])=[CH:16][C:17]([CH:24]=[O:30])=[C:18]([CH:23]=3)[C:19]([O:21][CH3:22])=[O:20])=[CH:9][CH:8]=2)[C:4]([CH3:27])=[N:3]1
Reactant: CC(C)=O
Reactant: C=Cc1cc(C)c(Cc2ccc(-c3cn(C)nc3C)nc2)cc1C(=O)OC
Agent: O=[Os]
Agent: [Na+]
Agent: [O-][I+3]([O-])([O-])[O-]
Solvent: CC#N
Solvent: O
Product: COC(=O)c1cc(Cc2ccc(-c3cn(C)nc3C)nc2)c(C)cc1C=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of methyl 5-((6-(1,3-dimethyl-1H-pyrazol-4-yl)pyridin-3-yl)methyl)-4-methyl-2-vinylbenzoate (0.18 g) in a mixed solvent of acetone (2.80 mL)-acetonitrile (2.80 mL)-water (2.80 mL) were added osmium oxide (fixed catalyst I) (0.06 g) and sodium periodate (0.53 g), and the mixture was stirred overnight at room temperature. The reaction mixture was filtered, and the filtrate was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure to give the title compound (0.18 g) as a crude product. This compound was used in the next step without an additional purification.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[C:9]1[CH:14]=[C:13]([NH:15][C:16]2[C:17]3[C:18](=[CH:22][N:23]([CH:25]4[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]4)[N:24]=3)[N:19]=[CH:20][CH:21]=2)[CH:12]=[CH:11][N:10]=1.C(N(CC)CC)C.[S:38](Cl)([CH3:41])(=[O:40])=[O:39]>ClCCl>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[C:9]1[CH:14]=[C:13]([NH:15][C:16]2[C:17]3[C:18](=[CH:22][N:23]([CH:25]4[CH2:26][CH2:27][N:28]([S:38]([CH3:41])(=[O:40])=[O:39])[CH2:29][CH2:30]4)[N:24]=3)[N:19]=[CH:20][CH:21]=2)[CH:12]=[CH:11][N:10]=1
Reactant: CS(=O)(=O)Cl
Reactant: Cc1ccc(F)c(-c2cc(Nc3ccnc4cn(C5CCNCC5)nc34)ccn2)c1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1ccc(F)c(-c2cc(Nc3ccnc4cn(C5CCN(S(C)(=O)=O)CC5)nc34)ccn2)c1
Temperature: 25 °C
Yield: 20.5 %

Procedure:
To a solution of N-(2-(2-fluoro-5-methylphenyl)pyridin-4-yl)-2-(piperidin-4-yl)-2H-pyrazolo[4,3-b]pyridin-7-amine (49 mg, 0.122 mmol) in dichloromethane (3 mL) at 0° C. was added triethylamine (0.051 ml, 0.365 mmol) and mesyl chloride (10.41 μl, 0.134 mmol). The reaction was removed from the ice bath and briefly stirred at room temperature. The reaction mixture was concentrated and subjected to silica column chromatography eluted with 0-5% methanol in dichloromethane using a step gradient (over 24 minutes) to give N-(2-(2-fluoro-5-methylphenyl)pyridin-4-yl)-2-(1-(methylsulfonyl)piperidin-4-yl)-2H-pyrazolo[4,3-b]pyridin-7-amine (12 mg, 21%). 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 2.31-2.49 (m, 7H) 2.83-2.95 (m, 3H) 2.95-3.10 (m, 2H) 4.03 (d, J=12.63 Hz, 2H) 4.42-4.66 (m, 1H) 7.03-7.24 (m, 4H) 7.34 (s, 1H) 7.75 (s, 1H) 7.83 (dd, J=7.58, 2.02 Hz, 1H) 8.18 (s, 1H) 8.44 (d, J=4.80 Hz, 1H) 8.65 (d, J=5.56 Hz, 1H). MS [M+H] found 481.4.
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:6]=[C:7]([NH:11][C:12]2[N:17]=[C:16]([NH:18][CH2:19][CH:20]3[CH2:25][CH2:24][CH2:23][N:22](C(OCC4C=CC=CC=4)=O)[CH2:21]3)[C:15]([C:36](=[O:38])[NH2:37])=[CH:14][N:13]=2)[CH:8]=[CH:9][CH:10]=1)(=[O:3])[CH3:2].Cl>CO.[Pd]>[C:1]([NH:4][C:5]1[CH:6]=[C:7]([NH:11][C:12]2[N:17]=[C:16]([NH:18][CH2:19][CH:20]3[CH2:25][CH2:24][CH2:23][NH:22][CH2:21]3)[C:15]([C:36]([NH2:37])=[O:38])=[CH:14][N:13]=2)[CH:8]=[CH:9][CH:10]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)Nc1cccc(Nc2ncc(C(N)=O)c(NCC3CCCN(C(=O)OCc4ccccc4)C3)n2)c1
Agent: [Pd]
Agent: Cl
Solvent: CO
Product: CC(=O)Nc1cccc(Nc2ncc(C(N)=O)c(NCC3CCCNC3)n2)c1
Reaction time: 18 h
Yield: 86.9 %

Procedure:
A mixture of benzyl 3-((2-(3-acetamidophenylamino)-5-carbamoylpyrimidin-4-ylamino)methyl)piperidine-1-carboxylate (340 mg, 0.657 mmol) and Pd—C (10%, 52 mg) in MeOH (10 mL) containing 5 drops of aq. 6N HCl was hydrogenated under balloon H2 for 18 h. It was then filtered through celite. The filtrate was concentrated in vacuo to give the titled compound (219 mg). MS 384.4 (M+H); UV 246.7 nm.
Reaction SMILES: Cl[CH2:2][CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([C:11](=[O:20])[CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[Cl:19])=[CH:7][CH:6]=1.[NH:21]1[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]1>CC(C)=O>[Cl:19][C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=1[CH2:12][C:11]([C:8]1[CH:9]=[CH:10][C:5]([O:4][CH2:3][CH2:2][N:21]2[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]2)=[CH:6][CH:7]=1)=[O:20]
Reactant: O=C(Cc1ccccc1Cl)c1ccc(OCCCl)cc1
Reactant: C1CCNCC1
Solvent: CC(C)=O
Product: O=C(Cc1ccccc1Cl)c1ccc(OCCN2CCCCC2)cc1

Procedure:
The mixture of 1-[4-(2-chloroethoxy)phenyl]-2-(2-chlorophenyl)ethanone (4 g, 13 mmol) and piperidine (5.8 g, 68 mmol) in 80% aqueous acetone (50 ml) is refluxed for 12 h. Additional portions of 0.3 g of piperidine are added three times in 4 h intervals to the mixture. The solvents are evaporated. Diethyl ether is added and the precipitated piperidine hydrochloride is filtered off. Diethyl ether is evaporated and the residual product is purified by flash chromatography (eluent toluene:triethylamine 9:1). The yield is 4.1 g, 89%.
Reaction SMILES: [CH2:1]([C@@H:4]1[N:7]([C:8](=[C:19]([CH3:21])[CH3:20])[C:9]([O:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[O:10])[C:6](=[O:22])[C@H:5]1[N:23]1C(=O)C2=CC=CC=C2C1=O)[CH:2]=[CH2:3].CN(C)CCCN>C(Cl)Cl.CO>[CH2:1]([C@@H:4]1[N:7]([C:8](=[C:19]([CH3:20])[CH3:21])[C:9]([O:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[O:10])[C:6](=[O:22])[CH:5]1[NH2:23])[CH:2]=[CH2:3]
Reactant: C=CC[C@H]1[C@H](N2C(=O)c3ccccc3C2=O)C(=O)N1C(C(=O)OCc1ccccc1)=C(C)C
Agent: CN(C)CCCN
Solvent: ClCCl
Solvent: CO
Product: C=CC[C@H]1C(N)C(=O)N1C(C(=O)OCc1ccccc1)=C(C)C
Temperature: 25 °C
Reaction time: 25 h
Yield: 64.5 %

Procedure:
To a solution of benzyl 2-[(3S,4S)-4-allyl-3-phthalimido-2-oxo-azetidin-1-yl]-3-methyl-2-butenoate (340 mg) in a mixture of methylene chloride (5 ml) and methanol (2.5 ml) was added N,N-dimethyl-1,3-propanediamine (0.21 ml) and the mixture was stirred at room temperature for 25 hours. After removal of the solvent by evaporation, the residue was dissolved in ethyl acetate and washed with water. Drying over magnesium sulfate and evaporation gave an oil, which was chromatographed on silica gel (3 g) eluting with a mixture of methylene chloride and acetone (6:1) to give benzyl 2-[(4S)-4-allyl-3-amino-2-oxoazetidin-1-yl]-3-methyl-2-butenoate (155 mg) as an oil.
Reaction SMILES: C(O[CH:6]([N:10]([CH3:12])[CH3:11])N(C)C)(C)(C)C.[Br:13][C:14]1[CH:19]=[CH:18][C:17]([C:20](=[O:22])[CH3:21])=[C:16]([OH:23])[CH:15]=1>C1(C)C=CC=CC=1>[Br:13][C:14]1[CH:19]=[CH:18][C:17]([C:20](=[O:22])/[CH:21]=[CH:6]/[N:10]([CH3:11])[CH3:12])=[C:16]([OH:23])[CH:15]=1
Reactant: CC(=O)c1ccc(Br)cc1O
Reactant: CN(C)C(OC(C)(C)C)N(C)C
Solvent: Cc1ccccc1
Product: CN(C)/C=C/C(=O)c1ccc(Br)cc1O
Yield: 82.8 %

Procedure:
A solution of 1-tert-Butoxy-N,N,N′,N′-tetramethylmethanediamine (19.2 mL, 93.0 mmol) and solution of 1-(4-bromo-2-hydroxyphenyl)ethanone (10 g, 46.5 mmol) in toluene (100 mL) was heated at 35° C. for 16 hours and at 80° C. for 1 hour. The solvent was removed under reduced pressure. The resulting solid was subjected to flash chromatography with eluant of dichloromethane. The product containing fractions were combined and the solvent was removed under reduced pressure to provide (E)-1-(4-bromo-2-hydroxyphenyl)-3-(dimethylamino)prop-2-en-1-one (10.4 g, 38.5 mmol, 82%).
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[N:12]=[C:11]([O:19][C@@H:20]2[CH2:24][C@@H:23]([C:25]([O:27][CH3:28])=[O:26])[NH2+:22][CH2:21]2)[C:10]=1[C:29]#[C:30][CH2:31][CH2:32][CH2:33][C@@H:34]1[CH2:36][C@H:35]1[O:37][C:38]([NH:40][C@H:41]([C:46](Cl)=[O:47])[C:42]([CH3:45])([CH3:44])[CH3:43])=[O:39])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C.CCOCC>[CH2:1]([O:8][C:9]1[C:18]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[N:12]=[C:11]2[O:19][C@H:20]3[CH2:21][N:22]([C:46](=[O:47])[C@H:41]([C:42]([CH3:44])([CH3:45])[CH3:43])[NH:40][C:38](=[O:39])[O:37][C@@H:35]4[CH2:36][C@H:34]4[CH2:33][CH2:32][CH2:31][C:30]#[C:29][C:10]=12)[C@H:23]([C:25]([O:27][CH3:28])=[O:26])[CH2:24]3)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COC(=O)[C@@H]1C[C@@H](Oc2nc3ccccc3c(OCc3ccccc3)c2C#CCCC[C@@H]2C[C@H]2OC(=O)N[C@H](C(=O)Cl)C(C)(C)C)C[NH2+]1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: CCOCC
Product: COC(=O)[C@@H]1C[C@@H]2CN1C(=O)[C@H](C(C)(C)C)NC(=O)O[C@@H]1C[C@H]1CCCC#Cc1c(nc3ccccc3c1OCc1ccccc1)O2
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of the product of step 3 in DMF (52 mL) at 0° C. was added DIPEA (3.1 mL) and HATU (1.64 g). The mixture was stirred at room temperature for 2 hours until disappearance of the starting material. The reaction mixture was diluted with Et2O and quenched with water and HCl (1N). The mixture was extracted (3×) with ether. The combined organic phases were washed with water then brine, dried over sodium sulfate, filtered and concentrated. Purification by flash chromatography (ISCO, 0 to 100% ethyl acetate in hexanes) afforded the desired product (1.3 g). LRMS (ES+) m/z 640.45 (M+H)+.
Reaction SMILES: [C:1]([O:9][CH2:10][CH3:11])(=[O:8])[CH2:2][C:3]([O:5][CH2:6][CH3:7])=[O:4].I[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>C(#N)C>[C:13]1([CH:2]([C:3]([O:5][CH2:6][CH3:7])=[O:4])[C:1]([O:9][CH2:10][CH3:11])=[O:8])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: CCOC(=O)CC(=O)OCC
Reactant: Ic1ccccc1
Solvent: CC#N
Product: CCOC(=O)C(C(=O)OCC)c1ccccc1

Procedure:
607 μl of diethyl malonate (3 mmoles), 224 μl of iodobenzene (2 mmoles), 1.2 ml of acetonitrile and 600 mg of ground and activated 3 Å molecular sieve were then added.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([C:8]2[C:17]3[C:12](=[CH:13][C:14]([O:20][CH3:21])=[C:15]([O:18][CH3:19])[CH:16]=3)[CH:11]=[C:10]([C:22](OC)=[O:23])[C:9]=2[C:26](OC)=[O:27])[CH:5]=[CH:4][N:3]=1.[BH4-].[Na+].CO>O1CCCC1>[Br:1][C:2]1[CH:7]=[C:6]([C:8]2[C:17]3[C:12](=[CH:13][C:14]([O:20][CH3:21])=[C:15]([O:18][CH3:19])[CH:16]=3)[CH:11]=[C:10]([CH2:22][OH:23])[C:9]=2[CH2:26][OH:27])[CH:5]=[CH:4][N:3]=1
Reactant: COC(=O)c1cc2cc(OC)c(OC)cc2c(-c2ccnc(Br)c2)c1C(=O)OC
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Product: COc1cc2cc(CO)c(CO)c(-c3ccnc(Br)c3)c2cc1OC
Yield: 90 %

Procedure:
To a suspension of 1-(2-bromo-4-pyridyl)-2,3-bis(methoxycarbonyl)-6,7-dimethoxynaphthalene (15.0 g) in tetrahydrofuran (150 ml) is added sodium borohydride (6.16 g), and the mixture is refluxed. To the mixture is added a mixture of methanol (60 ml) and tetrahydrofuran (60 ml) under reflux over a period of five hours. After the reaction is complete, the mixture is concentrated under reduced pressure to remove the solvent, and methyl chloride are an aqueous sodium hydrogen carbonate solution are added to the residue. The methylene chloride layer is separated, washed, dried and concentrated under reduced pressure to remove the solvent. The residue is crystallized from isopropyl ether to give 1-(2-bromo-4-pyridyl)-2,3-bis(hydroxymethyl)-6,7-dimethoxynaphthalene (11.86 g).
Reaction SMILES: [CH3:1][CH:2]([C:8](=[O:14])[CH2:9][CH:10]=[C:11]([CH3:13])[CH3:12])[CH2:3][C:4](OC)=[O:5].[H-].[Al+3].[Li+].[H-].[H-].[H-].C(=O)(O)[O-].[Na+].O>CCOCC.C(OCC)(=O)C>[CH3:1][CH:2]([CH:8]([OH:14])[CH2:9][CH:10]=[C:11]([CH3:13])[CH3:12])[CH2:3][CH2:4][OH:5]
Reactant: COC(=O)CC(C)C(=O)CC=C(C)C
Agent: O=C([O-])O
Agent: [Al+3]
Agent: [H-]
Solvent: O
Solvent: CCOCC
Solvent: CCOC(C)=O
Product: CC(C)=CCC(O)C(C)CCO
Temperature: 25 °C
Reaction time: 1 h
Yield: 863.9 %

Procedure:
Methyl 3,7-dimethyl-4-oxo-6-octenoate (68 g, 34 mmole) in ether (10 ml) is added to a mixture of lithium aluminum hydride (1.3 g, 34 mmole) and ether (150 ml) at 0°. After the addition is complete the mixture is allowed to warm to room temperature and stirred for 1 hour, after which it is cooled to 0° and carefully added to a 5% aqueous sodium bicarbonate solution (50 ml). The resulting mixture is treated with water (100 ml) and ethyl acetate (300 ml). The organic phase is separated, dried (Na2SO4) and the solvent is removed in vacuo to give a colorless oil (50.6 g, 94%). This material shows one spot on TLC (silica gel 50% ethyl acetate in hexane) and is not further purified.
Reaction SMILES: [C:1]([C:3]1[CH:9]=[CH:8][C:6]([NH2:7])=[CH:5][C:4]=1[Cl:10])#[N:2].[O:11]1[CH2:13][C@@H:12]1[CH2:14][N:15]1[C:23](=[O:24])[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[C:16]1=[O:25]>CC(O)C>[C:1]([C:3]1[CH:9]=[CH:8][C:6]([NH:7][CH2:13][C@@H:12]([OH:11])[CH2:14][N:15]2[C:16](=[O:25])[C:17]3[C:22](=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:23]2=[O:24])=[CH:5][C:4]=1[Cl:10])#[N:2]
Reactant: N#Cc1ccc(N)cc1Cl
Reactant: O=C1c2ccccc2C(=O)N1C[C@H]1CO1
Solvent: CC(C)O
Product: N#Cc1ccc(NC[C@@H](O)CN2C(=O)c3ccccc3C2=O)cc1Cl
Yield: 42.9 %

Procedure:
According to the same procedure as Preparation Example 1, 4-cyano-3-chloroaniline (VI-d) (3.00 g, 19.66 mmol) and 2-(((S)-oxiran-2-yl)methyl)isoindoline-1,3-dione (III) (4.66 g, 20.64 mmol) were stirred under reflux in 2-propylalcohol to obtain the title compound (VII-d) (3.00 g, 8.43 mmol, 43%) as yellow solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([CH:11]=C)[CH:10]=1)[N:7]([CH2:13][O:14][CH2:15][CH2:16][Si:17]([CH3:20])([CH3:19])[CH3:18])[CH:6]=[C:5]2[C:21]#[N:22].C[N+]1([O-])CC[O:27]CC1.C1COCC1.I([O-])(=O)(=O)=O.[Na+]>CC(C)=O.O.[Os](=O)(=O)(=O)=O>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([CH:11]=[O:27])[CH:10]=1)[N:7]([CH2:13][O:14][CH2:15][CH2:16][Si:17]([CH3:20])([CH3:19])[CH3:18])[CH:6]=[C:5]2[C:21]#[N:22]
Reactant: C=Cc1cc(Cl)cc2c(C#N)cn(COCC[Si](C)(C)C)c12
Reactant: C[N+]1([O-])CCOCC1
Agent: O=[Os](=O)(=O)=O
Agent: [Na+]
Agent: [O-][I+3]([O-])([O-])[O-]
Solvent: O
Solvent: C1CCOC1
Solvent: CC(C)=O
Product: C[Si](C)(C)CCOCn1cc(C#N)c2cc(Cl)cc(C=O)c21
Temperature: 25 °C
Reaction time: 2 h
Yield: 80 %

Procedure:
Osmium tetroxide (0.1 mL, 0.013 mmol) (4% in water) was added to a solution of 5-chloro-1-((2-(trimethylsilyl)ethoxy)methyl)-7-vinyl-1H-indole-3-carbonitrile (385 mg, 1.157 mmol) and NMO (271 mg, 2.313 mmol) in Acetone (20 mL) and Water (5 mL). The reaction was stirred at ambient temperature for 2 hours and then THF (10 mL) and sodium periodate (742 mg, 3.47 mmol) were added. The reaction was stirred for 1 hour, and precipitate formed. The solvent was evaporated and the residue was taken up in water (100 mL) and extracted with ethyl acetate (3×20 mL). The organic layers were dried with MgSO4 and evaporated. The residue was purified by chromatography on SiO2 with 10% to 15% ethyl acetate/hexanes to give 5-chloro-7-formyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indole-3-carbonitrile (310 mg, 0.926 mmol, 80% yield) as a white solid. 1H-NMR (CDCl3, 400 MHz) δ 10.22 (s, 1H), 8.0 (d, J=2.0 Hz, 1H), 7.84 (d, J=2.0 Hz, 1H), 7.79 (s, 1H), 5.80 (s, 2H), 3.43 (app T, J=8.2 Hz, 2H), 0.84 (app t, J=8.2 Hz, 2H), −0.07 (s, 9H). LC (HPLC method 4): tR=3.68 min.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[C:12]3=[N:13][CH:14]=[N:15][C:16]([NH:17][C:18](=[O:24])[O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[C:11]3[C:10]([I:25])=[N:9]2)=[N:6][CH:7]=1.C=O.[BH-](OC(C)=O)(OC(C)=O)O[C:30](C)=O.[Na+]>C1COCC1>[I:25][C:10]1[C:11]2[C:12](=[N:13][CH:14]=[N:15][C:16]=2[NH:17][C:18](=[O:24])[O:19][C:20]([CH3:21])([CH3:22])[CH3:23])[N:8]([C:5]2[CH:4]=[CH:3][C:2]([NH:1][CH3:30])=[CH:7][N:6]=2)[N:9]=1
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Reactant: CC(C)(C)OC(=O)Nc1ncnc2c1c(I)nn2-c1ccc(N)cn1
Agent: C=O
Agent: [Na+]
Solvent: C1CCOC1
Product: CNc1ccc(-n2nc(I)c3c(NC(=O)OC(C)(C)C)ncnc32)nc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 17.8 %

Procedure:
To a solution of tert-butyl 1-(5-aminopyridin-2-yl)-3-iodo-1H-pyrazolo[3,4-d]pyrimidin-4-ylcarbamate (63) (1.1 g, 2.4 mmol) in dry THF (15 mL) was added HCHO (38% aqueous, 3.4 g, 3.6 mmol). The mixture was stirred at room temperature overnight and NaBH(OAc)3 (612 mg, 2.88 mmol) was introduced in several portions. The reaction mixture was stirred at room temperature for 5 h and then quenched with water (10 mL). The solvent was removed in vacuo. The residue was purified by column chromatography (silica gel, 0 to 10% ethyl acetate in dichloromethane) to provide tert-butyl 3-iodo-1-(5-(methylamino)pyridin-2-yl)-1H-pyrazolo[3,4-d]pyrimidin-4-ylcarbamate (64) (200 mg, 18%) as a yellow solid. LC-MS (ESI): m/z (M+1) 468.
Reaction SMILES: [CH3:1][N:2]([CH3:21])[C:3]([N:5]1[C:9]([S:10][CH2:11][C:12]([O:14]CC)=[O:13])=[N:8][C:7]([C:17]([CH3:20])([CH3:19])[CH3:18])=[N:6]1)=[O:4]>C1COCC1>[CH3:1][N:2]([CH3:21])[C:3]([N:5]1[C:9]([S:10][CH2:11][C:12]([OH:14])=[O:13])=[N:8][C:7]([C:17]([CH3:19])([CH3:18])[CH3:20])=[N:6]1)=[O:4]
Reactant: CCOC(=O)CSc1nc(C(C)(C)C)nn1C(=O)N(C)C
Solvent: C1CCOC1
Product: CN(C)C(=O)n1nc(C(C)(C)C)nc1SCC(=O)O
Temperature: 20 °C
Reaction time: 48 h

Procedure:
To 1.2 g of 1-dimethylearbamoyl-3-t-butyl-5-carboethoxyrmthylthio-1H-1,2,4-triazole (the compound of Example 2) in 20 ml of THF was added 4 ml of 12 M HC1. After stirring for 48 h at 20° C. the reaction mixture was partitioned between ether and water, the ether layer was extracted with dilute NAOH and the resulting aqueous layer was acidified and extracted with fresh ether. The resulting ether layer was dried over magnesium sulfate, filtered and evaporated under vacuum to yield 1-dimethylcarbamyl-3-t-butyl-5-carboxymethylthio-1H-1,2,4-triazole as an oil.
Reaction SMILES: [N:1]1[N:2]([C:11]2[CH:16]=[CH:15][C:14]([N:17]3[CH2:21][CH2:20][O:19][C:18]3=[O:22])=[CH:13][CH:12]=2)[CH:3]=[C:4]2[CH2:10][CH2:9][NH:8][CH2:7][CH2:6][C:5]=12.[CH3:23][C:24]([CH3:26])=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCl.C(O)(=O)C.CO>[CH3:23][CH:24]([N:8]1[CH2:9][CH2:10][C:4]2=[CH:3][N:2]([C:11]3[CH:12]=[CH:13][C:14]([N:17]4[CH2:21][CH2:20][O:19][C:18]4=[O:22])=[CH:15][CH:16]=3)[N:1]=[C:5]2[CH2:6][CH2:7]1)[CH3:26]
Reactant: O=C1OCCN1c1ccc(-n2cc3c(n2)CCNCC3)cc1
Reactant: CC(C)=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Solvent: ClCCl
Product: CC(C)N1CCc2cn(-c3ccc(N4CCOC4=O)cc3)nc2CC1
Temperature: 25 °C

Procedure:
A solution of 3-[4-(5,6,7,8-tetrahydropyrazolo[3,4-d]azepin-2(4H)-yl)phenyl]-1,3-oxazolidin-2-one (25.0 mg, 0.08 mmol) (may be prepared as described in Description 27) in dichloromethane (3 ml) was treated with acetone (25.0 μl, 0.34 mmol) and acetic acid (1 drop) and stirred at room temperature. Sodium triacetoxyborohydride (72.0 mg, 0.34 mmol) was added and the mixture stirred for 3 hours and then overnight. The mixture was diluted with methanol and passed down a SCX cartridge eluting with methanol and then a 2M solution of ammonia in methanol. The basic fractions were combined and evaporated to afford the title compound (E9); MS (ES+) m/e 341 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[C:3]([N+:9]([O-])=O)=[C:4]([CH:6]=[CH:7][CH:8]=1)[NH2:5].Cl.C(O)C.O.O.[Sn](Cl)Cl.[OH-].[K+]>CCOC(C)=O>[Cl:1][C:2]1[CH:8]=[CH:7][CH:6]=[C:4]([NH2:5])[C:3]=1[NH2:9]
Reactant: Nc1cccc(Cl)c1[N+](=O)[O-]
Agent: Cl
Agent: Cl[Sn]Cl
Agent: [K+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CCO
Product: Nc1cccc(Cl)c1N
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To solution of 3-chloro-2-nitroaniline (10.00 g, 57.95 mmol), 3 N aq. HCl (96.58 mL, 289.7 mmol), and ethyl alcohol (148.6 mL, 57.95 mmol) was added Tin(II) chloride dihydrate (65.96 g, 289.7 mmol) and the mixture was heated under reflux with stirring. After 3 h, the mixture was cooled to room temperature and concentrated under reduced pressure to give a brown syrup. The mixture was cautiously treated with an excess of 10 M KOH (115.9 mL, 1159 mmol, 20 eqv.). The mixture was diluted with EtOAc (200 mL), filtered through Celite™ pad, and washed the pad well with EtOAc (100 mL×2). The filtrate was extracted with EtOAc (100 mL×2). The combined organic layers were washed with water (100 mL ×1), dried over MgSO4, filtered, and concentrated under reduced pressure to give 3-chlorobenzene-1,2-diamine as a red oil: 1H NMR (400 MHz, DMSO-d6) δ ppm 6.43-6.53 (2 H, m), 6.38 (1 H, t, J=7.8 Hz), 4.80 (2 H, s), 4.60 (2 H, s); LC-MS (ESI) m/z 142.9 [M+H]+. The crude product was carried on crude without purification for the next step.
Reaction SMILES: [Cl:1][C:2]1[C:3]([NH:23][C:24]2[CH:28]=[C:27]([CH3:29])[NH:26][N:25]=2)=[N:4][C:5]([NH:8][C:9]2[CH:14]=[C:13]([CH3:15])[C:12]([CH:16]3[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]3)=[CH:11][C:10]=2[F:22])=[N:6][CH:7]=1.Cl[CH2:31][C:32]1[O:36][N:35]=[C:34]([CH:37]([CH3:39])[CH3:38])[N:33]=1.CCN(C(C)C)C(C)C>CN(C=O)C.CCOC(C)=O>[Cl:1][C:2]1[C:3]([NH:23][C:24]2[CH:28]=[C:27]([CH3:29])[NH:26][N:25]=2)=[N:4][C:5]([NH:8][C:9]2[CH:14]=[C:13]([CH3:15])[C:12]([CH:16]3[CH2:17][CH2:18][N:19]([CH2:31][C:32]4[O:36][N:35]=[C:34]([CH:37]([CH3:39])[CH3:38])[N:33]=4)[CH2:20][CH2:21]3)=[CH:11][C:10]=2[F:22])=[N:6][CH:7]=1
Reactant: CC(C)c1noc(CCl)n1
Reactant: Cc1cc(Nc2nc(Nc3cc(C)c(C4CCNCC4)cc3F)ncc2Cl)n[nH]1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Product: Cc1cc(Nc2nc(Nc3cc(C)c(C4CCN(Cc5nc(C(C)C)no5)CC4)cc3F)ncc2Cl)n[nH]1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 5-chloro-N2-(2-fluoro-5-methyl-4-(piperidin-4-yl)phenyl)-N4-(5-methyl-1H-pyrazol-3-yl)pyrimidine-2,4-diamine (42 mg, 0.1 mmol), 5-(chloromethyl)-3-isopropyl-1,2,4-oxadiazole (17 mg, 0.10 mmol) and DIEA (86 μL, 0.5 mmol) in DMF (1 mL) was stirred at rt overnight. The reaction was diluted with EtOAc (50 mL) and washed with water (2×5 mL). The EtOAc layer was dried over Na2SO4 and concentrated in vacuo. The crude product was purified by silica chromatography (50-100% EtOAc in hexanes gradient) to give 5-Chloro-N2-(2-fluoro-4-(1-((3-isopropyl-1,2,4-oxadiazol-5-yl)methyl)piperidin-4-yl)-5-methylphenyl)-N4-(5-methyl-1H-pyrazol-3-yl)pyrimidine-2,4-diamine as a white solid; ESMS m/z 540.2 (M+H+).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]([C:8]([NH:10][C:11]2[CH:16]=[CH:15][C:14]([S:17](Cl)(=[O:19])=[O:18])=[CH:13][C:12]=2[CH3:21])=[O:9])[CH:3]=1.[CH3:22][NH:23][CH2:24][C:25]([O:27][CH3:28])=[O:26].C(NC(C)C)(C)C>C1COCC1>[Cl:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]([C:8]([NH:10][C:11]2[CH:16]=[CH:15][C:14]([S:17]([N:23]([CH2:24][C:25]([O:27][CH3:28])=[O:26])[CH3:22])(=[O:19])=[O:18])=[CH:13][C:12]=2[CH3:21])=[O:9])[CH:3]=1
Reactant: Cc1cc(S(=O)(=O)Cl)ccc1NC(=O)c1cc(Cl)ncn1
Reactant: CNCC(=O)OC
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: COC(=O)CN(C)S(=O)(=O)c1ccc(NC(=O)c2cc(Cl)ncn2)c(C)c1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A solution of 4-(6-chloropyrimidine-4-carboxamido)-3-methylbenzene-1-sulfonyl chloride (Intermediate 30, 1.2 g; 3.47 mmol) in THF (100 ml) was treated with methyl 2-(methylamino)acetate (666 mg; 4.77 mmol) and diisopropylamine (2 ml; 14.3 mmol). After stirring at RT for 18 hours the solvent was removed in vacuo and the residue redissolved in DCM and washed with water. The organic extracts were passed through a hydrophobic frit and the solvent removed in vacuo. The residue was purified by column chromatography (silica) eluting with petroleum ether containing increasing amounts of EtOAc. The title product was obtained as a white solid.