Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[N:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[C:11]1(C)C=CC=CC=1.C[Si](C=[N+]=[N-])(C)C>CO>[CH3:11][O:5][C:4](=[O:6])[C:3]1[CH:7]=[CH:8][N:9]=[CH:10][C:2]=1[NH2:1]
Reactant: Nc1cnccc1C(=O)O
Reactant: Cc1ccccc1
Agent: C[Si](C)(C)C=[N+]=[N-]
Solvent: CO
Product: COC(=O)c1ccncc1N
Temperature: 25 °C
Reaction time: 2 h

Procedure:
3-Aminoisonicotinic acid (400 mg) was suspended in methanol (6 mL) and toluene (18 mL) was added. A solution of (trimethylsilyl)diazomethane (2.0 M in diethyl ether, 1.88 mL) was added slowly to the suspension. Within 5 to 10 minutes after addition, the suspension turned into a solution. After 2 hours stirring at room temperature, the reaction mixture was quenched with water and extracted 3× with ethyl acetate. The combined organic layer was washed with 2N hydrochloric acid, saturated bicarbonate solution and brine, dried over MgSO4 and concentrated in vacuum. The residue was purified by column chromatography (silica gel 60, hexane/ethyl acetate=1:2, Rf=0.40) to afford 340 mg of the title compound of the formula
Reaction SMILES: [N+:1]([C:4]1[C:5]([CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])=[N:6][CH:7]=[CH:8][CH:9]=1)([O-])=O>C(O)C.[Pd]>[NH2:1][C:4]1[C:5]([CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])=[N:6][CH:7]=[CH:8][CH:9]=1
Reactant: CCOC(=O)Cc1ncccc1[N+](=O)[O-]
Agent: [Pd]
Solvent: CCO
Product: CCOC(=O)Cc1ncccc1N
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 9.4 %

Procedure:
Under an atmosphere of nitrogen, Pd/C (10%, 1.36 g) was charged to a round bottom flask. Ethyl 2-(3-nitro-pyridin-2-yl)-acetate (8.6 g, 0.41 mol) was dissolved in ethanol (200 mL) and added to the reaction vessel. The reaction was placed under an atmosphere of hydrogen and stirred at room temperature for 30 min. The reaction was filtered through celite and the filtrate was concentrated in vacuo to afford the product as a tan solid (6.94 g, 94% yield).
Reaction SMILES: [Cl:1][C:2]1[CH:12]=[CH:11][CH:10]=[CH:9][C:3]=1[C:4]([N:6]=[C:7]=[O:8])=[O:5].[F:13][C:14]([F:32])([F:31])[O:15][C:16]1[CH:21]=[CH:20][C:19]([NH:22][S:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=2[CH3:30])=[CH:18][CH:17]=1>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:12]=[CH:11][CH:10]=[CH:9][C:3]=1[C:4]([NH:6][C:7]([N:22]([C:19]1[CH:20]=[CH:21][C:16]([O:15][C:14]([F:13])([F:31])[F:32])=[CH:17][CH:18]=1)[S:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[CH3:30])=[O:8])=[O:5]
Reactant: Cc1ccccc1SNc1ccc(OC(F)(F)F)cc1
Reactant: O=C=NC(=O)c1ccccc1Cl
Solvent: Cc1ccccc1
Product: Cc1ccccc1SN(C(=O)NC(=O)c1ccccc1Cl)c1ccc(OC(F)(F)F)cc1
Temperature: -5 °C

Procedure:
A solution of 2.0 g of 2-chlorobenzoyl isocyanate in 5 ml of dry toluene was added to a stirred suspension of 3.0 g of N-[4-(trifluoromethoxy)phenyl]-2-methyl-benzenesulphenamide in 40 ml of dry light petroleum at room temperature. After a few minutes, the reaction mixture became clear and subsequently the product came out of solution as an oil which eventually crystallized. After 24 hours the reaction mixture was cooled to -5° C. and filtered, and the pale purple product was washed with cold light petroluem. Recrystallization from ether/light petroleum gave 4, as colorless crystals, m.p.: 79°-80° C.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[NH:9][C:8](=[O:11])[CH2:7]2.CCN(C(C)C)C(C)C.[N:21]([CH:24]([CH3:26])[CH3:25])=[C:22]=[O:23]>C1COCC1>[CH:24]([NH:21][C:22]([NH:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[NH:9][C:8](=[O:11])[CH2:7]2)=[O:23])([CH3:26])[CH3:25]
Reactant: Nc1cccc2c1NC(=O)C2
Reactant: CC(C)N=C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CC(C)NC(=O)Nc1cccc2c1NC(=O)C2
Temperature: 25 °C
Reaction time: 8 h
Yield: 59.9 %

Procedure:
To a suspension of 7-aminoindolin-2-one (60 mg, 0.41 mmol) in THF (3 mL) was added DIPEA (0.28 mL, 1.62 mmol), and 2-isocyanatopropane (0.05 mL, 0.49 mmol). The mixture was stirred at rt overnight then filtered. The filter cake was washed with diethyl ether to give the title compound as a pale solid (57.3 mg, 61%). 1H NMR (400 MHz, CD3OD) δ 7.09-7.04 (m, 2H), 6.99-6.95 (m, 1H), 3.57 (s, 2H), 2.64 (m, 1H), 1.20 (d, 6H, J=6.4 Hz). MS ESI [M+H]+, calcd for [C12H15N3O2+H]+ 234.12; found m/z 234.0.
Reaction SMILES: [CH2:1]([C:3]1[CH:12]=[CH:11][CH:10]=[CH:9][C:4]=1[C:5]([O:7][CH3:8])=[O:6])[CH3:2].[Br:13]N1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(Cl)(Cl)(Cl)Cl>[Br:13][CH:1]([C:3]1[CH:12]=[CH:11][CH:10]=[CH:9][C:4]=1[C:5]([O:7][CH3:8])=[O:6])[CH3:2]
Reactant: CCc1ccccc1C(=O)OC
Reactant: O=C1CCC(=O)N1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: COC(=O)c1ccccc1C(C)Br
Reaction time: 2 h

Procedure:
A mixture of 10.7 g. (0.065 mole) of methyl 2-ethylbenzoate, 12.5 g. (0.07 mole) of N-bromosuccinimide, 50 mg. of benzoyl peroxide, and 125 ml. of carbon tetrachloride is stirred at reflux until the reaction is complete in 2 hours. The precipitated succinimide is filtered from the cooled mixture and the filtrate is evaporated to dryness under reduced pressure leaving methyl 2-(1-bromoethyl)benzoate as the residual yellow oil in quantitative yield.
Reaction SMILES: Cl[C:2]1[N:11]=[C:10]2[C:5]([C:6](=[O:18])[C:7]([C:15]([OH:17])=[O:16])=[CH:8][N:9]2[CH:12]2[CH2:14][CH2:13]2)=[CH:4][C:3]=1[F:19].CC([N:24]([CH2:28][C:29]1[CH:34]=[CH:33][C:32]([CH:35]2[CH2:39][CH2:38][NH:37][CH2:36]2)=[CH:31][CH:30]=1)C(=O)[O-])(C)C>>[NH2:24][CH2:28][C:29]1[CH:30]=[CH:31][C:32]([CH:35]2[CH2:39][CH2:38][N:37]([C:2]3[N:11]=[C:10]4[C:5]([C:6](=[O:18])[C:7]([C:15]([OH:17])=[O:16])=[CH:8][N:9]4[CH:12]4[CH2:14][CH2:13]4)=[CH:4][C:3]=3[F:19])[CH2:36]2)=[CH:33][CH:34]=1
Reactant: O=C(O)c1cn(C2CC2)c2nc(Cl)c(F)cc2c1=O
Reactant: CC(C)(C)N(Cc1ccc(C2CCNC2)cc1)C(=O)[O-]
Product: NCc1ccc(C2CCN(c3nc4c(cc3F)c(=O)c(C(=O)O)cn4C3CC3)C2)cc1

Procedure:
Starting from 7-chloro-1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acid (0.94 g, 3.3 mmol) and 1,1-dimethylethyl[[4-(3-pyrrolidinyl)phenyl]methyl]carbamate, a procedure analogous to that given in Example 6 provided the title compound (1.30 g) as an off-white solid, mp 268°-272° C.
Reaction SMILES: [CH2:1]([Li])CCC.[CH2:6]([O:13][C:14]([N:16]1[CH2:20][CH:19]([CH:21]=O)[C@H:18]([NH:23][C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:17]1)=[O:15])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>[Br-].C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.O1CCCC1.C(OCC)(=O)C>[CH2:6]([O:13][C:14]([N:16]1[CH2:20][CH:19]([CH:21]=[CH2:1])[C@H:18]([NH:23][C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:17]1)=[O:15])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: CC(C)(C)OC(=O)N[C@@H]1CN(C(=O)OCc2ccccc2)CC1C=O
Reactant: [Li]CCCC
Agent: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [Br-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: C=CC1CN(C(=O)OCc2ccccc2)C[C@H]1NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
Butyl lithium (3.56 mL, 1.58 M, toluene solution) was added dropwise under cooling with ice to a suspension of methyltriphenylphosphonium bromide (2.15 g, 6.03 mmol) in tetrahydrofuran (20 mL), followed by stirring at room temperature for 20 minutes, and further at 40° C. for 5 minutes. Subsequently, a solution of (3S)-1-benzyloxycarbonyl-3-(tert-butoxycarbonyl)amino-4-formylpyrrolidine [an isomer mixture of (4S)-form: (4R)-form (1:3)] (700 mg, 2.01 mmol) in tetrahydrofuran (7.0 mL) was added under cooling with ice to the resultant mixture, followed by stirring at room temperature for 10 hours. The reaction mixture was poured to a 10% aqueous citric acid solution (20 mL), and the resultant mixture was diluted with ethyl acetate (100 mL). The obtained aqueous layer was extracted with ethyl acetate (100 mL×2). The combined organic layer was washed sequentially by saturated sodium hydrogencarbonate (100 mL) and saturated brine (100 mL), and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The obtained residue was purified through silica gel column chromatography (ethyl acetate:n-hexane=1:4), to thereby yield the title compound (an isomer mixture of (4S)-form and (4R)-form (1:4)) as a colorless oily substance (250 mg, 36%).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[C:5]([F:9])=[CH:4][N:3]=1.[CH3:10][C:11]1[CH:17]=[CH:16][C:14]([NH2:15])=[CH:13][C:12]=1[C:18]([F:21])([F:20])[F:19]>>[Cl:1][C:2]1[N:7]=[C:6]([NH:15][C:14]2[CH:16]=[CH:17][C:11]([CH3:10])=[C:12]([C:18]([F:19])([F:20])[F:21])[CH:13]=2)[C:5]([F:9])=[CH:4][N:3]=1
Reactant: Fc1cnc(Cl)nc1Cl
Reactant: Cc1ccc(N)cc1C(F)(F)F
Product: Cc1ccc(Nc2nc(Cl)ncc2F)cc1C(F)(F)F

Procedure:
In a like manner to the preparation of 2-chloro-N4-(3,4-ethylenedioxyphenyl)-5-fluoro-4-pyrimidineamine, 2,4-dichloro-5-fluoropyrimidine and 4-methyl-3-trifluoromethylaniline were reacted to provide 2-chloro-5-fluoro-N4-(4-methyl-3-trifluoromethylphenyl)-4-pyrimidineamine. 1H NMR (CDCl3): δ 8.10 (d, 1H, J=3.0 Hz), 7.85-7.78 (m, 2H), 7.33 (d, 1H, J=9.3 Hz), 6.96 (bs, 1H), 2.48 (d, 3H, J=1.2 Hz); 19F NMR (282 MHz, CDCl3): −17641, −44541; LCMS: purity: 97%; MS (m/e): 306 (MH+).
Reaction SMILES: [O:1]=[C:2]([C:18]1[CH:19]=[C:20]2[C:25](=[CH:26][CH:27]=1)[NH:24][C:23](=[O:28])[CH2:22][CH2:21]2)[CH2:3][CH2:4][CH2:5][N:6]1[CH2:11][CH2:10][N:9]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH2:8][CH2:7]1.[H][H]>O.[Pd]>[OH:1][CH:2]([C:18]1[CH:19]=[C:20]2[C:25](=[CH:26][CH:27]=1)[NH:24][C:23](=[O:28])[CH2:22][CH2:21]2)[CH2:3][CH2:4][CH2:5][N:6]1[CH2:7][CH2:8][N:9]([C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH2:10][CH2:11]1
Reactant: [H][H]
Reactant: O=C1CCc2cc(C(=O)CCCN3CCN(c4ccccc4)CC3)ccc2N1
Agent: [Pd]
Solvent: O
Product: O=C1CCc2cc(C(O)CCCN3CCN(c4ccccc4)CC3)ccc2N1

Procedure:
2.0 Grams of 6-[1-oxo-4-(4-phenylpiperazinyl)-butyl]-3,4-dihydrocarbostyril and 0.5 g of palladium black were dispersed in 80 ml of water and stirred at a room temperature under 2 atmospheric pressure of hydrogen gas for 5 hours. The reaction mixture was filtered for removing the palladium black and the mother liquor was concentrated under a reduced pressure and the residue thus obtained was crystallized from acetone and a small amount of ethanol. The crude crystals thus obtained were collected by filtration and recrystallized from isopropanol to obtained 1.5 g of 6-[1-hydroxy-4-(4-phenyl-1-piperazinyl)butyl]-3,4-dihydrocarbostyril in colorless needle like crystals.
Reaction SMILES: [H-].[Na+].[C:3]([O:7][C:8]([N:10]1[CH2:14][C@H:13]([OH:15])[C@@H:12]([N:16]=[N+:17]=[N-:18])[CH2:11]1)=[O:9])([CH3:6])([CH3:5])[CH3:4].Br[CH2:20][C:21]([O:23][CH2:24][CH3:25])=[O:22]>CN(C=O)C.CCOC(C)=O>[C:3]([O:7][C:8]([N:10]1[CH2:14][C@H:13]([O:15][CH2:20][C:21]([O:23][CH2:24][CH3:25])=[O:22])[C@@H:12]([N:16]=[N+:17]=[N-:18])[CH2:11]1)=[O:9])([CH3:6])([CH3:4])[CH3:5]
Reactant: CC(C)(C)OC(=O)N1C[C@H](N=[N+]=[N-])[C@@H](O)C1
Reactant: CCOC(=O)CBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCOC(=O)CO[C@H]1CN(C(=O)OC(C)(C)C)C[C@@H]1N=[N+]=[N-]
Temperature: 0 °C
Reaction time: 1.5 h

Procedure:
96.1 A suspension of 210 mg NaH (55% in mineral oil) in 3 ml DMF was treated at 0° C. with 1.0 g (3S,4S)-3-azido-4-hydroxy-pyrrolidine-1-carboxylic acid tert-butyl ester in 6 ml DMF. The reaction mixture was stirred at 0° C. for 90 min, then it was cooled to 0° C. A solution of 0.53 ml ethyl bromoacetate was added dropwise. The reaction mixture was slowly warmed to r.t., stirred overnight, then heated for 1 hr at 50° C. After cooling to r.t. the mixture was taken up in EtOAc and washed with H2O. The combined organics were dried over MgSO4, filtrated and concentrated. The crude product was purified by column chromatography (silica gel; cyclohexane->cyclohexane/EtOAc 3:2) to give 584 mg (3S,4S)-3-azido-4-ethoxycarbonylmethoxy-pyrrolidine-1-carboxylic acid tert-butyl ester as yellow liquid. MS 315.2 ([M+H]+)
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][OH:9].[C:10]([O-:13])([O-])=[O:11].[K+].[K+]>C(Cl)Cl>[OH:9][N:8]([C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[CH3:1])[C:10](=[O:11])[O:13][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cc1ccccc1NO
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Product: Cc1ccccc1N(O)C(=O)Oc1ccccc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of 2.5 g (20 mmol) of N-(2-methylphenyl)-hydroxylamine (crude product, obtained according to Bamberger et al., Anm. Chem. 316 (1901), 278), 3.5 g (25 mmol) of K2CO3 and 3.5 g (22 mmol) of phenyl Chlorooformate in 20 ml of CH2Cl2 is stirred for 2 hours at room temperature. The reaction mixture is then extracted with water, dried over MgSO4 and evaporated down. The residue is purified by column chromatography with mixtures of cyclohexane and ethyl acetate. There is obtained 2.0 g (8.2 mmol=42%) of the title compound as a colorless solid (mp=98° C.).
Reaction SMILES: [CH:1]12[NH:8][CH:5]([CH2:6][CH2:7]1)[CH2:4][N:3]([C:9]([C:11]1[CH:12]=[CH:13][C:14]([NH:17][C:18]3[N:19]=[CH:20][C:21]4[CH:26]=[C:25]([C:27]([N:29]([CH3:31])[CH3:30])=[O:28])[N:24]([CH:32]5[CH2:36][CH2:35][CH2:34][CH2:33]5)[C:22]=4[N:23]=3)=[N:15][CH:16]=1)=[O:10])[CH2:2]2.[CH3:37][C:38]([CH3:40])=O>C(Cl)Cl>[CH:32]1([N:24]2[C:22]3[N:23]=[C:18]([NH:17][C:14]4[CH:13]=[CH:12][C:11]([C:9]([N:3]5[CH2:4][CH:5]6[N:8]([CH:38]([CH3:40])[CH3:37])[CH:1]([CH2:7][CH2:6]6)[CH2:2]5)=[O:10])=[CH:16][N:15]=4)[N:19]=[CH:20][C:21]=3[CH:26]=[C:25]2[C:27]([N:29]([CH3:31])[CH3:30])=[O:28])[CH2:33][CH2:34][CH2:35][CH2:36]1
Reactant: CN(C)C(=O)c1cc2cnc(Nc3ccc(C(=O)N4CC5CCC(C4)N5)cn3)nc2n1C1CCCC1
Reactant: CC(C)=O
Solvent: ClCCl
Product: CC(C)N1C2CCC1CN(C(=O)c1ccc(Nc3ncc4cc(C(=O)N(C)C)n(C5CCCC5)c4n3)nc1)C2
Temperature: 25 °C
Yield: 88 %

Procedure:
To a solution of 2-(5-(3,8-diazabicyclo[3.2.1]octane-3-carbonyl)pyridin-2-ylamino)-7-cyclopentyl-N,N-dimethyl-7H-pyrrolo[2,3-d]pyrimidine-6-carboxamide (42 mg, 0.086 mmol) in 6 ml of DCM, acetone (0.6 ml) was added and the resulting reaction mixture was stirred for 1H at room temperature. Na(AcO)3BH (55 mg, 0.26 mmol) was added and the resulting reaction mixture was stirred at room temperature overnight. When LCMS showed the reaction was complete the reaction mixture was diluted with DCM, washed with sat NaHCO3 (2×), brine. The combined aqueous layers were backextracted with DCM and the combined organic layers were dried over Na2SO4, filtered and purified by column chromatography (0-20% MeOH/CHCl2) which gave 7-cyclopentyl-2-(5-(8-isopropyl-3,8-diazabicyclo[3.2.1]octane-3-carbonyl)pyridin-2-ylamino)-N,N-dimethyl-7H-pyrrolo[2,3-d]pyrimidine-6-carboxamide (64 mg, 88% yield).
Reaction SMILES: [Cl:1][C:2]1[C:3](Cl)=[N:4][CH:5]=[C:6]([CH:32]=1)[C:7]([NH:9][C@H:10]([CH:29]([CH3:31])[CH3:30])[C:11]([N:13]1[CH2:18][CH2:17][C@@:16]([C:20]2[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][CH:21]=2)([OH:19])[C:15]([CH3:28])([CH3:27])[CH2:14]1)=[O:12])=[O:8].[C:34]1([O-:40])[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1.[Na+]>CN(C=O)C>[Cl:1][C:2]1[C:3]([O:40][C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)=[N:4][CH:5]=[C:6]([CH:32]=1)[C:7]([NH:9][C@H:10]([CH:29]([CH3:30])[CH3:31])[C:11]([N:13]1[CH2:18][CH2:17][C@@:16]([C:20]2[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][CH:21]=2)([OH:19])[C:15]([CH3:28])([CH3:27])[CH2:14]1)=[O:12])=[O:8]
Reactant: CC(C)[C@@H](NC(=O)c1cnc(Cl)c(Cl)c1)C(=O)N1CC[C@](O)(c2ccc(Cl)cc2)C(C)(C)C1
Reactant: [O-]c1ccccc1
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)[C@@H](NC(=O)c1cnc(Oc2ccccc2)c(Cl)c1)C(=O)N1CC[C@](O)(c2ccc(Cl)cc2)C(C)(C)C1
Yield: 35.2 %

Procedure:
5,6-Dichloro-N—((R)-1-((S)-4-(4-chlorophenyl)-4-hydroxy-3,3-dimethylpiperidin-1-yl)-3-methyl-1-oxobutan-2-yl)nicotinamide (35 mg, 0.068 mmol), 0.5 mL DMF, and sodium phenolate (9.51 mg, 0.08 mmol) was heated for 1 hr at 120° C. Example 624 was isolated as a white solid by preparative reverse phase HPLC (13.7 mg, 35.2% yield), M+H=570.07.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][NH2:12])=[S:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+].[N:15]#[C:16]Br>CO>[NH2:15][C:16]1[S:10][C:9]([O:8][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[N:11][N:12]=1
Reactant: NNC(=S)OCc1ccccc1
Reactant: N#CBr
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: Nc1nnc(OCc2ccccc2)s1
Temperature: 0 °C
Yield: 58.5 %

Procedure:
In a 250 ml round-bottom flask equipped with a mechanical stirrer were mixed (benzyloxythiocarbonyl)hydrazine and 2N sodium hydroxide (90 ml). This mixture was stirred vigorously and cooled to 0° C. A solution of cyanogen bromide (14.5 g, 0.137 mol) in methanol (60 ml) was added dropwise at a rate that kept the reaction temperature between about 0°-5° C. A precipitate formed. When the addition was complete, the reaction mixture was filtered and the residue was rinsed well with water and dried in vacuo. The product was recrystallized from methanol/water to give a white solid of 16.6 g, 58.5% yield with a m.p. of 173°-175° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[CH:10]=[N:9][NH:8][C:5]2=[N:6][CH:7]=1.[O:11]1[CH:16]=[CH:15][CH2:14][CH2:13][CH2:12]1.C12(CS(O)(=O)=O)C(C)(C)C(CC1)CC2=O>O1CCCC1.C(OCC)(=O)C>[Br:1][C:2]1[CH:3]=[C:4]2[CH:10]=[N:9][N:8]([CH:12]3[CH2:13][CH2:14][CH2:15][CH2:16][O:11]3)[C:5]2=[N:6][CH:7]=1
Reactant: C1=COCCC1
Reactant: Brc1cnc2[nH]ncc2c1
Agent: CC1(C)C2CCC1(CS(=O)(=O)O)C(=O)C2
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: Brc1cnc2c(cnn2C2CCCCO2)c1
Temperature: 65 °C
Reaction time: 16 h
Yield: 88.6 %

Procedure:
To a solution of 5-bromo-1H-pyrazolo[3,4-b]pyridine (1.4 g, 7.2 mmol) and dihydropyran (3.3 mL, 36.0 mmol) in tetrahydrofuran (20 mL) was added (±)-camphorsulfonic acid (250 mg) and the reaction mixture was stirred at 65° C. for 16 hours. After cooling to room temperature it was diluted with ethyl acetate (250 mL), washed with saturated aqueous sodium bicarbonate (2×100 mL) and brine (100 mL), dried over sodium sulfate, filtered and concentrated. Gradient column chromatography (10% to 30% ethyl acetate in hexane) provided 5-bromo-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4-b]pyridine (1.8 g, 90%). MS (EI) for C11H12BrN3O: 283 (MH+).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C:16]2[C:11](=[CH:12][C:13]([N+:17]([O-])=O)=[CH:14][CH:15]=2)[CH:10]=[CH:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]>CO.CCOC(C)=O.[OH-].[OH-].[Pd+2]>[C:1]([O:5][C:6]([N:8]1[C:16]2[C:11](=[CH:12][C:13]([NH2:17])=[CH:14][CH:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)n1ccc2cc([N+](=O)[O-])ccc21
Agent: [Pd+2]
Agent: [OH-]
Solvent: CO
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CCc2cc(N)ccc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 98.5 %

Procedure:
A solution of 5-nitro-indole-1-carboxylic acid tert-butyl ester (0.50 g) and catalytic amount of Pd(OH)2 in a mixture of MeOH-EtOAc was stirred at room temperature under hydrogen for 1 h. The reaction mixture was filtered through celite and the filtrate was concentrated to provide 5-amino-2,3-dihydro-indole-1-carboxylic acid tert-butyl ester (0.44 g, 98%).
Reaction SMILES: [Br:1][CH2:2][CH:3]([OH:16])[CH2:4][N:5]1[C:13](=[O:14])[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6]1=[O:15].N1C=CN=C1.[C:22]([Si:26](Cl)([CH3:28])[CH3:27])([CH3:25])([CH3:24])[CH3:23]>CN(C=O)C.CN(C1C=CN=CC=1)C.CCOC(C)=O>[Br:1][CH2:2][CH:3]([O:16][Si:26]([C:22]([CH3:25])([CH3:24])[CH3:23])([CH3:28])[CH3:27])[CH2:4][N:5]1[C:6](=[O:15])[C:7]2[C:12](=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:13]1=[O:14]
Reactant: O=C1c2ccccc2C(=O)N1CC(O)CBr
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: CN(C)c1ccncc1
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C)(C)[Si](C)(C)OC(CBr)CN1C(=O)c2ccccc2C1=O
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A solution of 2-(3-bromo-2-hydroxypropyl)isoindoline-1,3-dione (100 mg, 0.352 mmol) in DMF (0.5 mL) was added dropwise to a mixture of DMAP (43.0 mg, 0.352 mmol), imidazole (47.9 mg, 0.704 mmol) and tertbutyldimethylsilyl chloride (74.3 mg, 0.493 mmol) in DMF (1 mL). The mixture was stirred at room temperature for 18 hours. The mixture was diluted with EtOAc (20 ml) and washed with saturated NaHCO3(aq) (20 ml) and brine (3×10 ml). The organic phase was dried over magnesium sulfate and evaporated under vacuum. Purification by chromatography on silica, eluting with 0-100% EtOAc/hexane, afforded the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4]([O:10][C@@H:11]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH2:12][CH2:13][CH2:14]I)[CH:3]=1.[C:22]([OH:27])(=[O:26])[C:23]([OH:25])=[O:24].[CH3:28][NH2:29]>O1CCCC1.CO>[C:22]([OH:27])(=[O:26])[C:23]([OH:25])=[O:24].[Cl:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4]([O:10][C@@H:11]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH2:12][CH2:13][CH2:14][NH:29][CH3:28])[CH:3]=1
Reactant: CN
Reactant: N#Cc1ccc(Cl)cc1O[C@H](CCCI)c1ccccc1
Agent: O=C(O)C(=O)O
Solvent: C1CCOC1
Solvent: CO
Product: CNCCC[C@@H](Oc1cc(Cl)ccc1C#N)c1ccccc1

Procedure:
A solution of the product from step (c) (286 mg) in 40% aqueous methylamine (1 ml) and tetrahydrofuran (10 ml) was stirred for 6 h. The solvent was removed in vacuo and the residue dissolved in water and extracted with ethyl acetate (three times). The combined organic extracts were washed with water, dried (magnesium sulphate) and evaporated to give an oil. To a solution of this amine in methanol (10 ml) was added a solution of oxalic acid (57 mg) in methanol. The solvent was removed in vacuo and the residue triturated with ethyl acetate. The solid was collected and dried to afford the title compound as a white solid (110 mg). M.p. 167-169° C.
Reaction SMILES: [OH:1][N:2]=[C:3]([C:9](=[O:11])[CH3:10])[C:4]([O:6][CH2:7][CH3:8])=[O:5].C(=O)([O-])[O-].[K+].[K+].[CH:18]1(Br)[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]1>CN(C)C=O>[CH:18]1([O:1][N:2]=[C:3]([C:9](=[O:11])[CH3:10])[C:4]([O:6][CH2:7][CH3:8])=[O:5])[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]1
Reactant: CCOC(=O)C(=NO)C(C)=O
Reactant: BrC1CCCCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)C(=NOC1CCCCC1)C(C)=O
Yield: 91.9 %

Procedure:
Ethyl 2-hydroxyimino-3-oxobutyrate (syn isomer, 30 g.), N,N-dimethylformamide (100 ml.), potassium carbonate (39.5 g.) and cyclohexyl bromide (31.1 g.) were treated in a similar manner to that of Example F-(1) to give ethyl 2-cyclohexyloxyimino-3-oxobutyrate (syn isomer, 41.8 g.), oil.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:8]2[C:12]([C:13]3[CH:18]=[CH:17][N:16]=[C:15]([NH2:19])[N:14]=3)=[CH:11][N:10]([CH2:20][C:21]3[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][CH:22]=3)[N:9]=2)[CH:5]=[CH:6][CH:7]=1.[F:29][C:30]1[CH:35]=[CH:34][C:33]([F:36])=[CH:32][C:31]=1[S:37](Cl)(=[O:39])=[O:38].[Na]>N1C=CC=CC=1>[NH2:19][C:15]1[N:14]=[C:13]([C:12]2[C:8]([C:4]3[CH:3]=[C:2]([NH:1][S:37]([C:31]4[CH:32]=[C:33]([F:36])[CH:34]=[CH:35][C:30]=4[F:29])(=[O:39])=[O:38])[CH:7]=[CH:6][CH:5]=3)=[N:9][N:10]([CH2:20][C:21]3[CH:22]=[CH:23][C:24]([O:27][CH3:28])=[CH:25][CH:26]=3)[CH:11]=2)[CH:18]=[CH:17][N:16]=1
Reactant: COc1ccc(Cn2cc(-c3ccnc(N)n3)c(-c3cccc(N)c3)n2)cc1
Reactant: O=S(=O)(Cl)c1cc(F)ccc1F
Agent: [Na]
Solvent: c1ccncc1
Product: COc1ccc(Cn2cc(-c3ccnc(N)n3)c(-c3cccc(NS(=O)(=O)c4cc(F)ccc4F)c3)n2)cc1
Temperature: 25 °C
Yield: 31 %

Procedure:
175 mg (0.47 mmol) of 4-[3-(3-aminophenyl)-1-(4-methoxybenzyl)-1H-pyrazol-4-yl]-pyrimidin-2-amine were dissolved with 10 ml of dry pyridine and 63 μl of 2,5-difluorobenzensulfonylchloride were added under stirring. The solution was maintained at room temperature overnight. The reaction mixture was then poured into aqueous sodium hydrogenocarbonate and extracted with dichloromethane. The organic layer was dried over sodium sulphate and evaporated to dryness. The residue was purified by flash-chromatography on a silica gel column (CH2Cl2-CH3COCH3; from 9/1 to 8/2), giving 80 mg (31%) of the title compound.