Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([Cl:8])[N:5]=[CH:4][N:3]=1.CCN(C(C)C)C(C)C.[CH3:18][O:19][CH2:20][CH2:21][NH2:22].O>CC(O)C>[Cl:8][C:6]1[N:5]=[CH:4][N:3]=[C:2]([NH:22][CH2:21][CH2:20][O:19][CH3:18])[CH:7]=1
Reactant: COCCN
Reactant: Clc1cc(Cl)ncn1
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(C)O
Product: COCCNc1cc(Cl)ncn1
Temperature: 25 °C
Reaction time: 1 h
Yield: 74.2 %

Procedure:
To a solution of 4,6-dichloro-pyrimidine (2 g, 14 mmol) in iPrOH (70 mL) and DIPEA (1.94 g, 15 mmol) was added a solution of 2-methoxy-ethylamine (1.13 g, 15 mmol) at room temperature. The resulting mixture was stirred at room temperature for 1 hour. Water was added and the mixture was extracted with DCM. The combined extracts were washed with brine, dried over anhydrous Na2SO4, and concentrated to give the crude product, which was purified by flash chromatography on silica to obtain the title compound (1.95 g, yield: 82%). MS (ESI): 188 [M+H]+.
Reaction SMILES: [CH2:1]([N:3]1[C:7]2=[N:8][C:9]3[C:14]([C:15]([NH:16][CH2:17][CH:18]4[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]4)=[C:6]2[CH:5]=[N:4]1)=[CH:13][C:12]([O:24][CH2:25][CH:26]1[O:28][CH2:27]1)=[CH:11][CH:10]=3)[CH3:2].C(O)=[O:30]>>[CH2:1]([N:3]1[C:7]2=[N:8][C:9]3[C:14]([C:15]([NH:16][CH2:17][CH:18]4[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23]4)=[C:6]2[CH:5]=[N:4]1)=[CH:13][C:12]([O:24][CH2:25][CH:26]([OH:28])[CH2:27][OH:30])=[CH:11][CH:10]=3)[CH3:2]
Reactant: O=CO
Reactant: CCn1ncc2c(NCC3CCCCC3)c3cc(OCC4CO4)ccc3nc21
Product: CCn1ncc2c(NCC3CCCCC3)c3cc(OCC(O)CO)ccc3nc21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 1-ethyl-6-(2,3-epoxypropoxy)-N-(cyclohexylmethyl)-1H-pyrazolo[3,4-b]quinolin-4-amine (0.53 g) and formic acid (10 ml) were stirred at room temperature overnight. The excess formic acid was removed in vacuo and then methanol (75 ml) and triethylamine (10 ml) were added and the mixture was stirred for four hours. The reaction mixture was evaporated, ether was added and the product which crystallized was recrystallized from CH2Cl2 /Et2O and then purified by column chromatography on silca eluting with CH2Cl2 /THF (1/1) to afford 1-ethyl-6-(2,3-dihydroxypropoxy)-N-(cyclohexylmethyl)-1H-pyrazolo[3,4-b]quinolin-4-amine, m.p. 197°-199° C.
Reaction SMILES: [H-].[Na+].[CH3:3][N:4]1[C:8]2[CH:9]=[C:10]3[C:15](=[CH:16][C:7]=2[N:6]([CH3:23])[C:5]1=[O:24])[C:14](=[O:17])[CH:13]([C:18]([O:20][CH2:21][CH3:22])=[O:19])[CH2:12][CH2:11]3.Br[CH2:26][CH2:27][CH2:28][Cl:29].O>CN(C)C=O>[Cl:29][CH2:28][CH2:27][CH2:26][C:13]1([C:18]([O:20][CH2:21][CH3:22])=[O:19])[CH2:12][CH2:11][C:10]2[C:15](=[CH:16][C:7]3[N:6]([CH3:23])[C:5](=[O:24])[N:4]([CH3:3])[C:8]=3[CH:9]=2)[C:14]1=[O:17]
Reactant: CCOC(=O)C1CCc2cc3c(cc2C1=O)n(C)c(=O)n3C
Reactant: ClCCCBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)C1(CCCCl)CCc2cc3c(cc2C1=O)n(C)c(=O)n3C
Temperature: 60 °C
Reaction time: 1 h

Procedure:
60% Oily sodium hydride (832 mg) was added to a solution of ethyl (±)-1,3-dimethyl-2,5-dioxo-2,3,5,6,7,8-hexahydro-1H-naphtho[2,3-d]imidazole-6-carboxylate (5.0 g) obtained in Reference Example 138 in dimethylformamide, and the mixture was stirred at 60° C. for 1 hour. 1-Bromo-3-chloropropane was added thereto, and the mixture was stirred at 60° C. for 4 hours. The reaction mixture was allowed to cool, and water was added to decompose excessive sodium hydride. Then, the mixture was extracted with ethyl acetate, and washed with brine. The organic layer was dried over anhydrous magnesium sulfate, the solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography to give the title compound as a pale yellow oil.
Reaction SMILES: Cl[C:2]1[C:3]2[N:4]([C:12]([CH2:15][CH3:16])=[N:13][N:14]=2)[C:5]2[C:10]([N:11]=1)=[CH:9][CH:8]=[CH:7][CH:6]=2.[CH:17]1([NH2:20])[CH2:19][CH2:18]1.ClC1C2N(C(CCC)=NN=2)C2C(N=1)=CC=CC=2.C1(N)CCCC1>>[CH:17]1([NH:20][C:2]2[C:3]3[N:4]([C:12]([CH2:15][CH3:16])=[N:13][N:14]=3)[C:5]3[C:10]([N:11]=2)=[CH:9][CH:8]=[CH:7][CH:6]=3)[CH2:19][CH2:18]1
Reactant: NC1CC1
Reactant: CCc1nnc2c(Cl)nc3ccccc3n12
Agent: CCCc1nnc2c(Cl)nc3ccccc3n12
Agent: NC1CCCC1
Product: CCc1nnc2c(NC3CC3)nc3ccccc3n12

Procedure:
The title compound was prepared essentially as described in Example 4 substituting 4-chloro-1-ethyl[1,2,4]triazolo[4,3-a]quinoxaline and cyclopropyl amine for 4-chloro-1-n-propyl[1,2,4]triazolo[4,3-a]quinoxaline and cyclopentanamine respectively; mp 190°-192° C.
Reaction SMILES: N.C([O:5][C@@H:6]1[C@H:10]([O:11]C(=O)C)[C@@H:9]([CH2:15][O:16]C(=O)C)[O:8][C@H:7]1[N:20]1[C:36]2[N:35]=[CH:34][N:33]=[C:24]([NH:25][C@@H:26]3[CH2:30][C:29](=[O:31])[NH:28][C:27]3=[O:32])[C:23]=2[N:22]=[CH:21]1)(=O)C>>[O:32]=[C:27]1[C@H:26]([NH:25][C:24]2[C:23]3[N:22]=[CH:21][N:20]([C:36]=3[N:35]=[CH:34][N:33]=2)[C@@H:7]2[O:8][C@H:9]([CH2:15][OH:16])[C@@H:10]([OH:11])[C@H:6]2[OH:5])[CH2:30][C:29](=[O:31])[NH:28]1
Reactant: CC(=O)OC[C@H]1O[C@@H](n2cnc3c(N[C@@H]4CC(=O)NC4=O)ncnc32)[C@H](OC(C)=O)[C@@H]1OC(C)=O
Agent: N
Product: O=C1C[C@@H](Nc2ncnc3c2ncn3[C@@H]2O[C@H](CO)[C@@H](O)[C@H]2O)C(=O)N1
Yield: 30.8 %

Procedure:
Cold ammonia-saturated methanol (7 ml) was added to N6 -[(R)-2,5-dioxo-3-pyrrolidinyl]adenosine 2',3',5'-triacetate (300 mg) and the mixture was allowed to stand in a refrigerator overnight. Next morning it was concentrated under reduced pressure and the residue was subjected to high performance liquid chromatography on silica gel using chloroform-methanol-water (65:35:10) as the eluent to give a first fraction A and a second fraction B. The second fraction was concentrated under reduced pressure and the residue was freeze-dried to give N6 -[(R)-2,5-dioxo-3-pyrrolidinyl]adenosine as colorless powders (68.6 mg).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:9]=[C:10]([C:12]2[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][N:13]=2)[CH:11]=1)[C:5]([O:7][CH3:8])=[O:6].[CH:19]([B-](F)(F)F)=[CH2:20].[K+].C(N(CC)CC)C.O>C(O)C.C1C=CC([PH+]([C]2[CH][CH][CH][CH]2)C2C=CC=CC=2)=CC=1.C1C=CC([PH+]([C]2[CH][CH][CH][CH]2)C2C=CC=CC=2)=CC=1.C(Cl)Cl.Cl[Pd]Cl.[Fe]>[CH3:18][C:15]1[CH:16]=[CH:17][C:12]([C:10]2[CH:9]=[C:4]([CH:3]=[C:2]([CH:19]=[CH2:20])[CH:11]=2)[C:5]([O:7][CH3:8])=[O:6])=[N:13][CH:14]=1
Reactant: C=C[B-](F)(F)F
Reactant: COC(=O)c1cc(Br)cc(-c2ccc(C)cn2)c1
Agent: Cl[Pd]Cl
Agent: [Fe]
Agent: [CH]1[CH][CH][C]([PH+](c2ccccc2)c2ccccc2)[CH]1
Solvent: CCO
Solvent: O
Solvent: ClCCl
Product: C=Cc1cc(C(=O)OC)cc(-c2ccc(C)cn2)c1
Temperature: 25 °C
Yield: 91.3 %

Procedure:
To a solution of methyl 3-bromo-5-(5-methylpyridin-2-yl)benzoate (2.0 g, 6.53 mmol) in ethanol (13 mL) was added potassium vinyltrifluoroborate (1.31 g 9.80 mmol), triethylamine (1.37 mL, 9.80 mmol), and dichloro[1,1′-bis(diphenylphosphino)ferrocene]palladium(II) dichloromethane adduct (0.267 g, 0.327 mmol). The reaction mixture was stirred and microwaved at 140° C. for 10 min. The reaction mixture was cooled to ambient temperature. Water was added, and ethanol was concentrated. The mixture was extracted with dichloromethane (3×). The combined organic extracts were washed with brine, dried over magnesium sulfate, filtered and concentrated. Purification by silica gel chromatography (100% hexanes→50% hexanes/ethyl acetate) gave the title compound (1.51 g). MS 254.1 (M+1).
Reaction SMILES: [C:1]([O:5][C:6](=[O:23])[NH:7][C@@H:8]([C:17](=[O:22])N(OC)C)[CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[F:16])([CH3:4])([CH3:3])[CH3:2].[C:24]([NH:28][C:29](=[O:38])[C:30]1[CH:35]=[CH:34][C:33]([F:36])=[CH:32][C:31]=1[CH3:37])([CH3:27])([CH3:26])[CH3:25]>>[C:1]([O:5][C:6](=[O:23])[NH:7][C@H:8]([CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[F:16])[C:17](=[O:22])[CH2:37][C:31]1[CH:32]=[C:33]([F:36])[CH:34]=[CH:35][C:30]=1[C:29](=[O:38])[NH:28][C:24]([CH3:26])([CH3:25])[CH3:27])([CH3:2])([CH3:3])[CH3:4]
Reactant: Cc1cc(F)ccc1C(=O)NC(C)(C)C
Reactant: CON(C)C(=O)[C@@H](Cc1ccccc1F)NC(=O)OC(C)(C)C
Product: CC(C)(C)NC(=O)c1ccc(F)cc1CC(=O)[C@@H](Cc1ccccc1F)NC(=O)OC(C)(C)C

Procedure:
Using general procedure 2 with [(R)-2-(2-Fluoro-phenyl)-1-(methoxy-methyl-carbamoyl)-ethyl]-carbamic acid tert-butyl ester (1.6 g, 3.9 mmol) and N-tert-Butyl-4-fluoro-2-methyl-benzamide (3.0 g, 14 mmol) followed by purification by silica gel flash column chromatography gives the title compound.
Reaction SMILES: [OH-].[Na+].C(O)C.[C:6]1([N:12]2[C:16]3=[N:17][CH:18]=[CH:19][CH:20]=[C:15]3[C:14]([C:21]3[CH:33]=[CH:32][C:24]([O:25][CH2:26][C:27]([O:29]CC)=[O:28])=[CH:23][CH:22]=3)=[N:13]2)[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.Cl>O.O1CCOCC1>[C:6]1([N:12]2[C:16]3=[N:17][CH:18]=[CH:19][CH:20]=[C:15]3[C:14]([C:21]3[CH:22]=[CH:23][C:24]([O:25][CH2:26][C:27]([OH:29])=[O:28])=[CH:32][CH:33]=3)=[N:13]2)[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=1
Reactant: CCOC(=O)COc1ccc(-c2nn(-c3ccccc3)c3ncccc23)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Solvent: CCO
Product: O=C(O)COc1ccc(-c2nn(-c3ccccc3)c3ncccc23)cc1
Yield: 59.7 %

Procedure:
In 300 ml of water was dissolved 5.1 g of sodium hydroxide, and 800 ml of ethanol was added to the solution. While stirring, thereto was added a solution of 40 g of ethyl 4-(1-phenyl-1H-pyrazolo[3,4-b]pyridin-3-yl)phenoxyacetate dissolved in 200 ml of dioxane. After the mixture was stirred at room temperature for 4 hours, it was poured into about 3 l of cold water. The mixture was neutralized by the addition of dilute hydrochloric acid. The resulting crystals were collected by filtration and recrystallized from hydrous dioxane to give 22.1 g of 4-(1-phenyl-1H-pyrazolo[3,4-b]pyridin-3-yl)phenoxyacetic acid, m.p. 220°-222° C.
Reaction SMILES: [H-].[H-].[H-].[H-].[Li+].[Al+3].[CH3:7][CH:8]1[CH2:13][CH2:12][CH2:11][CH:10]([CH2:14][CH2:15][C:16](O)=[O:17])[CH2:9]1.S([O-])([O-])(=O)=O.[Na+].[Na+]>C(OCC)C>[CH3:7][CH:8]1[CH2:13][CH2:12][CH2:11][CH:10]([CH2:14][CH2:15][CH2:16][OH:17])[CH2:9]1
Reactant: CC1CCCC(CCC(=O)O)C1
Agent: O=S(=O)([O-])[O-]
Agent: [Al+3]
Agent: [H-]
Solvent: CCOCC
Product: CC1CCCC(CCCO)C1
Temperature: 0 °C
Reaction time: 3 h
Yield: 64 %

Procedure:
LiAlH4 (16 g, 0.42 mol, 1.2 eq) and diethyl ether (450 mL) were charged into a 2 L three-necked round-bottom flask equipped with a mechanical stirrer and a reflux condenser and cooled at 0° C. The crude 3-(3-methylcyclohexyl)propanoic acid (60 g, 0.35 mol) was dissolved in diethyl ether (400 mL) and added dropwise to the reaction flask. The reaction mixture was then stirred for 3 h at ambient temperature. The excess of lithium aluminium hydride was hydrolyzed with saturated aqueous sodium sulphate and the mixture filtered. THF (1 L) was added to the residue and the suspension was heated to 35° C. for 1 h. The suspension was filtered and the combined organic layers were dried over sodium sulphate and evaporated to yield the crude product as an oil. Chromatography on a silica gel column with 8% EtOAc in hexane as elution agent, followed by a bulb-to-bulb distillation (0.1 mBar, 140° C.) gave pure 3-(3-methylcyclohexyl)propan-1-ol (35 g, gc purity>98%; yield=61%).
Reaction SMILES: [F:1][C:2]1[CH:21]=[CH:20][C:5]([O:6][CH2:7][CH2:8][CH2:9][O:10][C:11]2[CH:12]=[C:13]([CH2:17][CH2:18]O)[CH:14]=[CH:15][CH:16]=2)=[CH:4][CH:3]=1.[Br-:22]>>[F:1][C:2]1[CH:21]=[CH:20][C:5]([O:6][CH2:7][CH2:8][CH2:9][O:10][C:11]2[CH:12]=[C:13]([CH2:17][CH2:18][Br:22])[CH:14]=[CH:15][CH:16]=2)=[CH:4][CH:3]=1
Reactant: [Br-]
Reactant: OCCc1cccc(OCCCOc2ccc(F)cc2)c1
Product: Fc1ccc(OCCCOc2cccc(CCBr)c2)cc1

Procedure:
By following the procedure of example 8 and using the product of Example 140 as starting material the title bromide was prepared.
Reaction SMILES: Br[CH2:2][C:3]1[C:4]([Cl:17])=[C:5]([CH:10]=[CH:11][C:12]=1[S:13]([CH3:16])(=[O:15])=[O:14])[C:6]([O:8][CH3:9])=[O:7].[CH3:18][O-:19].[Na+]>CO>[Cl:17][C:4]1[C:3]([CH2:2][O:19][CH3:18])=[C:12]([S:13]([CH3:16])(=[O:15])=[O:14])[CH:11]=[CH:10][C:5]=1[C:6]([O:8][CH3:9])=[O:7]
Reactant: COC(=O)c1ccc(S(C)(=O)=O)c(CBr)c1Cl
Reactant: C[O-]
Agent: [Na+]
Solvent: CO
Product: COCc1c(S(C)(=O)=O)ccc(C(=O)OC)c1Cl
Temperature: 25 °C
Reaction time: 8 h
Yield: 103.1 %

Procedure:
To a solution comprising 12.0 g of methyl 3-bromomethyl-2-chloro-4-methanesulfonylbenzoate prepared in Reference Example 3(1) and 100 ml of methanol, 50 ml of a methanol solution containing 1.7 g of sodium methoxide was added, and the mixture was stirred at room temperature overnight. The solvent was distilled off under reduced pressure. Then, dilute hydrochloric acid was added to the residue, and the mixture was extracted with chloroform. The extract was washed with water and dried over anhydrous sodium sulfate. Then, the solvent was distilled off to obtain 9.5 g of the desired product as a crude product. The crude product was purified by silica gel column chromatography (eluted with benzene) to obtain 7.5 g of a purified product as an oily substance.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[C:10]2[C:6]([C:7]([C:13]([OH:15])=O)=[CH:8][N:9]2[CH3:12])=[CH:5][CH:4]=1.C(Cl)(=O)C(Cl)=O.[CH3:22][NH2:23]>>[CH3:22][NH:23][C:13]([C:7]1[C:6]2[C:10](=[CH:11][C:3]([O:2][CH3:1])=[CH:4][CH:5]=2)[N:9]([CH3:12])[CH:8]=1)=[O:15]
Reactant: CN
Reactant: COc1ccc2c(C(=O)O)cn(C)c2c1
Agent: O=C(Cl)C(=O)Cl
Product: CNC(=O)c1cn(C)c2cc(OC)ccc12
Yield: 83.8 %

Procedure:
This material was prepared from 6-methoxy-1-methyl-indole-3-carboxylic acid 16b (515 mg, 2.5 mmole), oxalyl chloride (0.9 ml, 12.6 mmole) and methylamine (7.5 mmole) in a manner as previously described for example 16d to give 457 mg of a pale brown solid (83%). 1H NMR (CD3OD) δ7.83 (1H, d, J=8.7 Hz), 7.51 (1H, s), 6.81 (1H, d, J=2.3 Hz), 6.72 (1H, dd, J=2.3, 8.7 Hz), 3.75 (3H, s), 3.67 (3H, s), 2.80 (3H, s); ESIMS (MH+): 219.05.
Reaction SMILES: [CH:1]1(N(O)C(N)=O)[CH2:5][O:4][C:3]2[CH:6]=[CH:7][C:8]3[C:13]([C:2]1=2)=[CH:12][CH:11]=[CH:10][CH:9]=3.C[Si](N=C=[O:25])(C)C>C1COCC1>[C:1]1(=[O:25])[CH2:5][O:4][C:3]2[CH:6]=[CH:7][C:8]3[C:13]([C:2]1=2)=[CH:12][CH:11]=[CH:10][CH:9]=3
Reactant: NC(=O)N(O)C1COc2ccc3ccccc3c21
Reactant: C[Si](C)(C)N=C=O
Solvent: C1CCOC1
Product: O=C1COc2ccc3ccccc3c21
Temperature: 60 °C
Yield: 11 %

Procedure:
N-{1-(1,2-Dihydronaphtho[2,1-b]furyl}-N-hydroxyurea. To a solution of N-{1-(1,2-dihydronaphtho[2,1-b]furyl}-N-hydroxyamine (698 mg, 3.5 mmol) in THF (10 mL) was added trimethylsilylisocyanate (0.94 mL, 7.0 mmol). The resulting solution was heated at 60° C. for 1 h, then allowed to cool and concentrated under reduced pressure. The residue was dissolved in EtOAc and washed successively with H2O and saturated aqueous NaCl. The solvent was removed in vacuo. The residue was triturated with Et2O and recrystallized from MeOH/CH2Cl2 /hexanes to provide the title compound (93 mg, 11%). m.p. 194.5°-195.5° C.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([CH2:15]Cl)=[N:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:17][O-:18].[Na+].[Na]>CO.C(OCC)(=O)C>[CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([CH2:15][O:18][CH3:17])=[N:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: ClCc1ccc(OCc2ccccc2)cn1
Reactant: C[O-]
Agent: [Na+]
Agent: [Na]
Solvent: CO
Solvent: CCOC(C)=O
Product: COCc1ccc(OCc2ccccc2)cn1
Yield: 94 %

Procedure:
50 g (0.21 mol) of 5-benzyloxy-2-chloromethylpyridine (CAS 127590-90-3; D. I. Scopes, N. F. Norman, D. E. Bays, D. Belton, J. Brain et al., J. Med. Chem., 1992, 35, 490-501) in solution in 150 ml of methanol are added to the solution of sodium methoxide prepared by adding 6.4 g (0.28 mol) of sodium to 150 ml of methanol. After refluxing for 3 hours under nitrogen, the solution is concentrated to dryness. The oil obtained is taken up in ethyl acetate. The solution is washed with a saturated aqueous solution of sodium chloride, dried over anhydrous sodium sulphate and then concentrated to dryness. 46 g (94%) of a brown oil are obtained.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][C:6]([N:10]3[C:14]4=[N:15][C:16]([CH:19]=[CH2:20])=[CH:17][CH:18]=[C:13]4[N:12]=[CH:11]3)=[CH:7][CH:8]=2)[CH2:3][CH2:2]1.[Cl:21][CH2:22][S:23](Cl)(=[O:25])=[O:24].C(N(CC)C(C)C)(C)C>ClCCl>[Cl:21][CH2:22][S:23]([N:1]1[C:9]2[C:4](=[CH:5][C:6]([N:10]3[C:14]4=[N:15][C:16]([CH:19]=[CH2:20])=[CH:17][CH:18]=[C:13]4[N:12]=[CH:11]3)=[CH:7][CH:8]=2)[CH2:3][CH2:2]1)(=[O:25])=[O:24]
Reactant: C=Cc1ccc2ncn(-c3ccc4c(c3)CCN4)c2n1
Reactant: O=S(=O)(Cl)CCl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: C=Cc1ccc2ncn(-c3ccc4c(c3)CCN4S(=O)(=O)CCl)c2n1
Yield: 98.3 %

Procedure:
A solution of 3-(2,3-dihydro-1H-indol-5-yl)-5-vinyl-3H-imidazo[4,5-b]pyridine (2.57 g, 9.80 mmol) (Intermediate 10.1), chloromethanesulfonyl chloride (2.00 ml, 19.59 mmol), and N,N-diisopropylethylamine (11.98 ml, 68.58 mmol) in dichloromethane (100 ml) is stirred for 20 min at ambient temperature. The mixture is successively extracted with saturated aqueous ammonium chloride and saturated aqueous sodium bicarbonate. The organic layer is dried over sodium sulfate and concentrated in vacuo to give 3.61 g (98%) of the respective sulfonamide. HPLC (over 10 min 10-85% MeCN/100 mM aq. NaOAc): 92% purity, tR 8.05 min (tR(SM) 6.64 min). 1H-NMR (400 MHz, DMSO-d6) δ 9.03 (s, 1H), 8.22 (d, 1H), 7.85 (s, 1H), 7.79 (d, 1H), 7.56 (m, 2H), 6.93 (dd, 1H), 6.25 (d, 1H), 5.50 (d, 1H), 5.41 (s, 2H), 4.21 (t, 2H), 3.28 (t, 2H) ppm. MS (ESI) m/z (C17H15ClN4O2S) 375.0 (M+1, 100) Finnegan LCQ.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:10]([C:11]3[N:16]=[C:15]([NH:17][C@@H:18]4[CH2:23][CH2:22][CH2:21][C@H:20]([NH:24]C(=O)OC(C)(C)C)[CH2:19]4)[C:14]([F:32])=[CH:13][N:12]=3)=[CH:9][N:8]([S:33]([C:36]3[CH:41]=[CH:40][C:39]([CH3:42])=[CH:38][CH:37]=3)(=[O:35])=[O:34])[C:5]2=[N:6][CH:7]=1.ClC1C=C2C(C3N=C(N[C@H]4CCC[C@@H](NC(=O)OC(C)(C)C)C4)C(F)=CN=3)=CN(S(C3C=CC(C)=CC=3)(=O)=O)C2=NC=1.FC(F)(F)C(O)=O>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]2[C:10]([C:11]3[N:16]=[C:15]([NH:17][C@@H:18]4[CH2:23][CH2:22][CH2:21][C@H:20]([NH2:24])[CH2:19]4)[C:14]([F:32])=[CH:13][N:12]=3)=[CH:9][N:8]([S:33]([C:36]3[CH:37]=[CH:38][C:39]([CH3:42])=[CH:40][CH:41]=3)(=[O:35])=[O:34])[C:5]2=[N:6][CH:7]=1
Reactant: Cc1ccc(S(=O)(=O)n2cc(-c3ncc(F)c(N[C@@H]4CCC[C@H](NC(=O)OC(C)(C)C)C4)n3)c3cc(Cl)cnc32)cc1
Agent: Cc1ccc(S(=O)(=O)n2cc(-c3ncc(F)c(N[C@H]4CCC[C@@H](NC(=O)OC(C)(C)C)C4)n3)c3cc(Cl)cnc32)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)n2cc(-c3ncc(F)c(N[C@@H]4CCC[C@H](N)C4)n3)c3cc(Cl)cnc32)cc1
Reaction time: 2 h
Yield: 81 %

Procedure:
tert-Butyl N-[(1S,3R)-3-[[2-[5-chloro-1-(p-tolylsulfonyl)pyrrolo[2,3-b]pyridin-3-yl]-5-fluoro-pyrimidin-4-yl]amino]cyclohexyl]carbamate, 20b, (0.33 g, 0.53 mmol) was dissolved in CH2Cl2 (10 mL) and treated with trifluoroacetic acid (2 mL). After stirring for 2 hours, the solvent was evaporated under reduced pressure and the resulting residue was passed through a polymer supported carbonate column to provide the free base of (1R,3S)—N1-[2-[5-chloro-1-(p-tolylsulfonyl)pyrrolo[2,3-b]pyridin-3-yl]-5-fluoro-pyrimidin-4-yl]cyclohexane-1,3-diamine, 20c, (0.25 g, 0.43 mmol, 81%).
Reaction SMILES: [C:1]([N:8]1[CH2:13][CH2:12][CH2:11][CH2:10][C:9]1=O)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[Br:15][C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([NH:22][NH2:23])[N:17]=1>CO>[Br:15][C:16]1[N:17]=[C:18]([NH:22][N:23]=[C:11]2[CH2:12][CH2:13][N:8]([C:1]([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2])[CH2:9][CH2:10]2)[CH:19]=[CH:20][CH:21]=1
Reactant: NNc1cccc(Br)n1
Reactant: CC(C)(C)OC(=O)N1CCCCC1=O
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCC(=NNc2cccc(Br)n2)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 99.5 %

Procedure:
N-Boc piperidinone (13.8 g, 69.1 mmol) was added to a solution of 2-bromo-6-hydrazinylpyridine (13.0 g, 69.1 mmol) in MeOH (240 mL). The resulting solution was stirred at ambient temperature for 2 h. The solution was concentrated and dried to provide the title compound (25.4 g, 99%) as a white foam: 1H NMR (300 MHz, DMSO-d6) δ 9.97 (s, 1H), 7.49 (overlapping dd, J=7.8 Hz, 1H), 7.03 (d, J=8.4 Hz, 1H), 6.88 (d, J=7.5 Hz, 1H), 3.52-3.38 (m, 4H), 2.59-2.40 (m, 2H overlaps with solvent), 2.38 (t, J=5.7 Hz, 2H), 1.41 (s, 9H); ESI MS m/z 369 [M+H]+.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]([NH:9][CH2:10][CH2:11][CH2:12]OS(C)(=O)=O)=[O:8].[Br-:18].[Li+]>CC(C)=O>[Br:18][CH2:12][CH2:11][CH2:10][NH:9][C:7]([C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=1)=[O:8]
Reactant: [Br-]
Reactant: CS(=O)(=O)OCCCNC(=O)c1ccccn1
Agent: [Li+]
Solvent: CC(C)=O
Product: O=C(NCCCBr)c1ccccn1
Temperature: 25 °C
Yield: 81.3 %

Procedure:
A mixture of methanesulfonic acid 3-[(pyridine-2-carbonyl)-amino]-propyl ester (Example 57a) (1.96 g) and lithium bromide (3.29 g) in acetone (19 mL) was heated to reflux for 2 h. The reaction mixture was cooled to room temperature, concentrated in vacuo and the residue partitioned between EtOAc/H2O (60 mL, 1:1). The phases were separated and the aqueous phase further extracted with EtOAc (2×25 mL). The combined organics were dried (MgSO4) and concentrated in vacuo to a brown oil which solidified on standing. Purification by silica gel chromatography eluting with 0-100% EtOAc/cyclohexane gives the sub-titled compound (1.5 g) as a white solid.
Reaction SMILES: C(N(CC)CC)C.I[C:9]1[CH:18]=[CH:17][C:16]2[NH:15][C:14](=[O:19])[C:13]3[NH:20][CH:21]=[CH:22][C:12]=3[C:11]=2[CH:10]=1.[CH2:23]([C:25]([O-:27])=[O:26])[CH3:24].[CH3:28][N:29]([CH3:33])[CH2:30][C:31]#[CH:32]>O1CCOCC1.[Cu](I)I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH3:28][N:29]([CH3:33])[CH2:30][C:31]#[C:32][C:9]1[CH:18]=[CH:17][C:16]2[NH:15][C:14](=[O:19])[C:13]3[NH:20][CH:21]=[CH:22][C:12]=3[C:11]=2[CH:10]=1.[CH2:23]([C:25]([O-:27])=[O:26])[CH3:24]
Reactant: O=c1[nH]c2ccc(I)cc2c2cc[nH]c12
Reactant: C#CCN(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: I[Cu]I
Agent: CCC(=O)[O-]
Solvent: CCN(CC)CC
Solvent: C1COCCO1
Product: CN(C)CC#Cc1ccc2[nH]c(=O)c3[nH]ccc3c2c1
Temperature: 100 °C
Reaction time: 0.25 h
Yield: 36.4 %

Procedure:
50 mg (0.26 mmol) of copper iodide, 69 mg (0.68 mmol) of triethylamine and 37 mg (0.05 mmol) of dichlorobis(triphenylphosphine)-palladium (11) are added to a suspension of 200 mg (0.52 mmol) of 8-iodo-4-oxo-4,5-dihydro-3H-pyrrolo[2,3-c]quinoline-1-ethyl carboxylate in 5 ml of anhydrous dioxan, then this mixture is degassed under argon. After 15 minutes, 65 mg (0.78 mmol) of dimethyl-prop-2-ynyl-amine are added, then the mixture is heated at 100° C. for 6 hours. The raw reaction product is then filtered on celite, the filtrate is evaporated to dryness and the residue is purified by chromatography on silica (ethyl acetate/methanol/ammonia) to give 64 mg (36%) of 8-(3-dimethylamino-prop-1-ynyl)-4-oxo-4,5-dihydro-3H-pyrrolo[2,3-c]quinoline-1-ethyl carboxylate in the form of a white solid.
Reaction SMILES: FC(F)(F)C([NH:5][CH:6]([CH2:17][C:18](=[O:32])[N:19]1[CH2:24][CH2:23][N:22]2[C:25]([C:28]([F:31])([F:30])[F:29])=[N:26][N:27]=[C:21]2[CH2:20]1)[CH2:7][C:8]1[CH:13]=[C:12]([F:14])[C:11]([F:15])=[CH:10][C:9]=1[F:16])=O.O.[OH-].[Li+]>CO.O>[O:32]=[C:18]([N:19]1[CH2:24][CH2:23][N:22]2[C:25]([C:28]([F:31])([F:30])[F:29])=[N:26][N:27]=[C:21]2[CH2:20]1)[CH2:17][CH:6]([NH2:5])[CH2:7][C:8]1[CH:13]=[C:12]([F:14])[C:11]([F:15])=[CH:10][C:9]=1[F:16]
Reactant: O=C(CC(Cc1cc(F)c(F)cc1F)NC(=O)C(F)(F)F)N1CCn2c(nnc2C(F)(F)F)C1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: NC(CC(=O)N1CCn2c(nnc2C(F)(F)F)C1)Cc1cc(F)c(F)cc1F
Temperature: 27.5 °C
Reaction time: 24 h
Yield: 38.6 %

Procedure:
In a 25 mL three neck flask (2S) N-trifluoroacetyl-4-oxo-4-[3-(trifluoromethyl)-5,6-dihydro[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl]-1-(2,4,5-trifluorophenyl)butan-2-amine (wt.-0.250 g, % Purity by HPLC-96.5%) was dissolved in a mixture of MeOH (2.5 mL) and water (0.5 mL) at 25-30° C. To the reaction mixture lithium hydroxide monohydrate (21 mg) was added. It was stirred at 0 to 5° C. for 4 h and at 25 to 30° C. for 24 h. Distilled out solvent at reduced pressure on Buchi rotavapour. To the thick liquid water (2.5 mL) was added. It was transferred into a separating funnel. It was extracted twice with ethyl acetate. Both the extracts were combined and washed with water and brine solution. It was dried over anhydrous sodium sulfate. Distilled out solvent to obtain a 4-oxo-4-[3-(trifluoromethyl)-5,6-dihydro[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl]-1-(2,4,5-trifluorophenyl)butan-2-amine (Wt.-78 mg, % Purity by HPLC-83.1%).