Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][O:11][C:12]1[CH:16]=[C:15]([C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=2)[O:14][N:13]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:24](I)[CH3:25]>>[C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][O:11][C:12]1[C:16]([CH2:24][CH3:25])=[C:15]([C:17]2[CH:18]=[CH:19][C:20]([Cl:23])=[CH:21][CH:22]=2)[O:14][N:13]=1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)NCCOc1cc(-c2ccc(Cl)cc2)on1
Reactant: CCI
Product: CCc1c(OCCNC(=O)OC(C)(C)C)noc1-c1ccc(Cl)cc1
Yield: 61 %

Procedure:
3-(2-(N-tert-Butoxycarbonylamino)ethoxy)-5-(4-chlorophenyl)isoxazole (0.4 g) and ethyl iodide (0.11 ml) were subjected to reaction and post-treatment in a similar manner to that described in Example 14(a) to obtain the title compound (0.26 g, 61%) as a colorless oil.
Reaction SMILES: [CH3:1][N:2]1[CH2:15][CH2:14][C:5]2[NH:6][C:7]3[CH:8]=[CH:9][C:10]([CH3:13])=[CH:11][C:12]=3[C:4]=2[CH2:3]1.[CH:16]([C:18]1[CH:19]=[CH:20][C:21]([NH:24][C:25](=[O:27])[CH3:26])=[N:22][CH:23]=1)=[CH2:17].[OH-].[K+]>CN1C(=O)CCC1>[CH3:1][N:2]1[CH2:15][CH2:14][C:5]2[N:6]([CH2:17][CH2:16][C:18]3[CH:19]=[CH:20][C:21]([NH:24][C:25](=[O:27])[CH3:26])=[N:22][CH:23]=3)[C:7]3[CH:8]=[CH:9][C:10]([CH3:13])=[CH:11][C:12]=3[C:4]=2[CH2:3]1
Reactant: Cc1ccc2[nH]c3c(c2c1)CN(C)CC3
Reactant: C=Cc1ccc(NC(C)=O)nc1
Agent: [K+]
Agent: [OH-]
Solvent: CN1CCCC1=O
Product: CC(=O)Nc1ccc(CCn2c3c(c4cc(C)ccc42)CN(C)CC3)cn1

Procedure:
The title compound is prepared from a mixture of 2,3,4,5-tetrahydro-2,8-dimethyl-1H-pyrido[4,3-b]indole, N-(5-vinylpyridin-2-yl)acetamide and KOH (5-7 equiv) in NMP at a temperature ranging between 25 deg C. to 100 deg C. The product obtained is isolated by preparative HPLC.
Reaction SMILES: [Cl:1][C:2]([F:7])([F:6])[C:3]([O-:5])=[O:4].[Na+].Cl[Si:10]([O:17][CH2:18][CH3:19])([O:14][CH2:15][CH3:16])[O:11][CH2:12][CH3:13]>CCOCC>[Cl:1][C:2]([F:7])([F:6])[C:3]([O:5][Si:10]([O:17][CH2:18][CH3:19])([O:14][CH2:15][CH3:16])[O:11][CH2:12][CH3:13])=[O:4]
Reactant: O=C([O-])C(F)(F)Cl
Reactant: CCO[Si](Cl)(OCC)OCC
Agent: [Na+]
Solvent: CCOCC
Product: CCO[Si](OCC)(OCC)OC(=O)C(F)(F)Cl
Temperature: -70 °C

Procedure:
15.246 g (0.10 mol) sodium chlorodifluoroacetate, is dissolved to 100 mL Et2O and cooled to −70° C. 19.7 mL (0.10 mol, 19.872 g) chlorotriethoxysilane in Et2O (50 mL) was added dropwise to reaction solution. The solution was stirred for over night allowing it to warm up to room temperature. NaCl is removed by filtration and solution evaporated to dryness to result clear colourless liquid, chlorodifluoroacetic acid, triethoxysilyl ester.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N+:9]([O-:11])=[O:10])[CH:5]=[CH:6][C:7]=1F.O.[NH2:13][NH2:14]>C(O)C>[F:1][C:2]1[CH:3]=[C:4]([N+:9]([O-:11])=[O:10])[CH:5]=[CH:6][C:7]=1[NH:13][NH2:14]
Reactant: NN
Reactant: O=[N+]([O-])c1ccc(F)c(F)c1
Solvent: CCO
Solvent: O
Product: NNc1ccc([N+](=O)[O-])cc1F
Temperature: 25 °C
Yield: 92.2 %

Procedure:
690 μL 3,4-difluoronitrobenzene was added to 15 mL anhydrous ethanol, and then the blend was heated to reflux. Hydrazine hydrate (611.5 μL) was slowly dropped into the blend and the resultant mixture was refluxed for another 2 hours to complete reaction, after which the reaction mixture was cooled down to room temperature. The yellow solid precipitated upon cooling was filtered. The filter cake was washed with petroleum ether, and then was dried to get 884.5 mg of a yellow solid, with a yield of 92.2%.
Reaction SMILES: C([O:8][C:9]([C@H:11]1[CH2:15][CH2:14][CH2:13][N:12]1[CH2:16][C:17]1[S:21][C:20]([NH:22][C:23]([N:25]([CH:32]2[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]2)[CH:26]2[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]2)=[O:24])=[N:19][CH:18]=1)=[O:10])C1C=CC=CC=1>[Pd].CO>[CH:32]1([N:25]([CH:26]2[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]2)[C:23](=[O:24])[NH:22][C:20]2[S:21][C:17]([CH2:16][N:12]3[CH2:13][CH2:14][CH2:15][C@@H:11]3[C:9]([OH:10])=[O:8])=[CH:18][N:19]=2)[CH2:33][CH2:34][CH2:35][CH2:36][CH2:37]1
Reactant: O=C(OCc1ccccc1)[C@H]1CCCN1Cc1cnc(NC(=O)N(C2CCCCC2)C2CCCCC2)s1
Agent: [Pd]
Solvent: CO
Product: O=C(O)[C@H]1CCCN1Cc1cnc(NC(=O)N(C2CCCCC2)C2CCCCC2)s1
Yield: 84.8 %

Procedure:
1-[2-(3,3-Dicyclohexyl-ureido)-thiazol-5-ylmethyl]-pyrrolidine-2(R)-carboxylic acid benzyl ester (50 mg, 0.095 mmol) was combined with palladium on carbon (25 mg) in MeOH. Vacuum was applied to degas the mixture. The reaction was subjected to hydrogen and vigorous stirring until no ester could be detected (36 h). After filtering and concentration, 35 mg (84%) pure acid was obtained by trituration.
Reaction SMILES: [CH2:1]1[CH:5]2[CH2:6][CH:7]([NH2:8])[CH:3]([CH2:4]2)[CH2:2]1.FC(F)(F)S(O[C:15]1[C:16]2[CH2:37][N:36]([CH3:38])[CH2:35][CH2:34][C:17]=2[N:18]=[C:19]([NH:21][C:22]2[CH:27]=[CH:26][C:25]([N:28]3[CH:32]=[CH:31][N:30]=[C:29]3[CH3:33])=[CH:24][CH:23]=2)[N:20]=1)(=O)=O>C(Cl)Cl>[CH:3]12[CH2:4][CH:5]([CH2:1][CH2:2]1)[CH2:6][C@H:7]2[NH:8][C:15]1[C:16]2[CH2:37][N:36]([CH3:38])[CH2:35][CH2:34][C:17]=2[N:18]=[C:19]([NH:21][C:22]2[CH:23]=[CH:24][C:25]([N:28]3[CH:32]=[CH:31][N:30]=[C:29]3[CH3:33])=[CH:26][CH:27]=2)[N:20]=1
Reactant: Cc1nccn1-c1ccc(Nc2nc3c(c(OS(=O)(=O)C(F)(F)F)n2)CN(C)CC3)cc1
Reactant: NC1CC2CCC1C2
Solvent: ClCCl
Product: Cc1nccn1-c1ccc(Nc2nc3c(c(N[C@@H]4CC5CCC4C5)n2)CN(C)CC3)cc1
Temperature: 35 °C
Reaction time: 2 h
Yield: 54.8 %

Procedure:
exo-2-Aminonorbornane (20.24 μl, 0.17 mmol) was added to a solution of 6-methyl-2-(4-(2-methyl-1H-imidazol-1-yl)phenylamino)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-4-yl trifluoromethanesulfonate (80 mg, 0.17 mmol, Example 9a) in DCM (10 mL). The reaction was stirred at 35° C. for 2 h. Solvent was evaporated and the crude mixture dissolved in MeOH/DMSO and purified on preparative HPLC to give N4-((2R)-bicyclo[2.2.1]heptan-2-yl)-6-methyl-N2-(4-(2-methyl-1H-imidazol-1-yl)phenyl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidine-2,4-diamine (40.0 mg, 47.8%).
Reaction SMILES: [C:1]1([C:7]2[O:11][C:10]([C:12]3[C:13]([NH:24]C(=O)OC(C)(C)C)=[N:14][CH:15]=[C:16]([N:18]4[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]4)[N:17]=3)=[N:9][N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[C:1]1([C:7]2[O:11][C:10]([C:12]3[C:13]([NH2:24])=[N:14][CH:15]=[C:16]([N:18]4[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]4)[N:17]=3)=[N:9][N:8]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CC(C)(C)OC(=O)Nc1ncc(N2CCNCC2)nc1-c1nnc(-c2ccccc2)o1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Nc1ncc(N2CCNCC2)nc1-c1nnc(-c2ccccc2)o1
Temperature: 25 °C
Reaction time: 1 h
Yield: 82.3 %

Procedure:
Tert-butyl 3-(5-phenyl-1,3,4-oxadiazol-2-yl)-5-(piperazin-1-yl)pyrazin-2-ylcarbamate (2.29 g, 5.408 mmol) was dissolved in DCM (20 mL) and treated with TFA (5 mL, 64.90 mmol) was added. The reaction was allowed to stir for 1 hour at ambient temperature and then the solvent removed in vacuo. The mixture was treated with NaHCO3/brine and EtOAc and the 2 layers separated layers. The aqueous layer was extracted with EtOAc, followed by DCM and CHCl3. The mixture was dried over MgSO4, filtered and concentrated to give the product as an orange solid (1.44 g, 82% Yield). 1H NMR (400.0 MHz, DMSO) d 3.00 (4H, br m), 3.43 (4H, br m), 6.05 (2H, br s), 7.20 (1H, m), 7.34 (2H, m), 7.90 (1H, m), 8.13 (2H, m) ppm; (ES+) 324.03
Reaction SMILES: [C:1]([CH2:3][C@H:4]1[O:9][C:8]([CH3:11])([CH3:10])[O:7][C@@H:6]([CH2:12][C:13]([OH:15])=[O:14])[CH2:5]1)#[N:2].N.O.[H][H]>CO>[NH2:2][CH2:1][CH2:3][C@H:4]1[O:9][C:8]([CH3:11])([CH3:10])[O:7][C@@H:6]([CH2:12][C:13]([OH:15])=[O:14])[CH2:5]1
Reactant: CC1(C)O[C@H](CC#N)C[C@H](CC(=O)O)O1
Reactant: [H][H]
Agent: N
Solvent: O
Solvent: CO
Product: CC1(C)O[C@H](CCN)C[C@H](CC(=O)O)O1
Temperature: 45 °C
Yield: 52.8 %

Procedure:
A solution of 1.04 g (4.88 mmol) of (±)-cis-6-(cyanomethyl)-2,2-dimethyl-1,3-dioxane-4-acetic acid in 100 mL of methanol saturated with anhydrous ammonia is added to a Parr shaker bottle containing 0.53 g of water wet Raney nickel #30. The solution is heated at 45° C. and 50 psig hydrogen pressure for 17 hours. The suspension is cooled and filtered to remove the Raney nickel through filter aid and the precipitate washed with methanol. The filtrate is concentrated at reduced pressure. The residue is dissolved in methanol saturated with anhydrous ammonia treated with decolorizing charcoal, filtered through filter aid and evaporated to give 0.56 g of (±)-cis-6-(2-aminoethyl)-2,2-dimethyl-1,3-dioxane-4-acetic acid, mp 165° with decomposition at 169° C.
Reaction SMILES: [NH2:1][C:2]1[NH:6][N:5]=[C:4]([NH:7][C:8]2[CH:9]=[N:10][CH:11]=[CH:12][CH:13]=2)[C:3]=1[C:14]([NH2:16])=[O:15].[Cl:17][C:18]1[CH:25]=[CH:24][C:21]([CH:22]=O)=[CH:20][CH:19]=1.N1CCCCC1>C(O)C>[Cl:17][C:18]1[CH:25]=[CH:24][C:21]([CH:22]=[N:1][C:2]2[NH:6][N:5]=[C:4]([NH:7][C:8]3[CH:9]=[N:10][CH:11]=[CH:12][CH:13]=3)[C:3]=2[C:14]([NH2:16])=[O:15])=[CH:20][CH:19]=1
Reactant: NC(=O)c1c(Nc2cccnc2)n[nH]c1N
Reactant: O=Cc1ccc(Cl)cc1
Solvent: C1CCNCC1
Solvent: CCO
Product: NC(=O)c1c(Nc2cccnc2)n[nH]c1N=Cc1ccc(Cl)cc1
Yield: 55 %

Procedure:
5-amino-3-(pyridin-3-ylamino)-1H-pyrazole-4-carboxamide (1.0 g) was suspended in 10 mL of ethanol and 4-chlorobenzaldehyde (644 mg, 1.0 eq.) and piperidine (0.10 eq, 39 μL) was added. Stirred the reaction at reflux until starting material was absent and confirmed by HPLC. After reaction was complete (18 hrs) it was brought to room temperature and filtered to obtain 5-((4-chlorobenzylidene)amino)-3-(pyridin-3-ylamino)-1H-pyrazole-4-carboxamide as a yellow to orange powder. The product was washed with ethanol to remove any excess 4-chlorobenzaldehyde. Product was allowed to dry under vacuum for 1 hr (850 mg, 55% yield).
Reaction SMILES: B.O1CCCC1.[CH3:7][C:8]1[C:16]([OH:17])=[CH:15][CH:14]=[CH:13][C:9]=1[C:10](O)=[O:11].C(=O)([O-])O.[Na+]>C1COCC1>[OH:11][CH2:10][C:9]1[C:8]([CH3:7])=[C:16]([OH:17])[CH:15]=[CH:14][CH:13]=1
Reactant: Cc1c(O)cccc1C(=O)O
Agent: B
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Product: Cc1c(O)cccc1CO

Procedure:
Borane-tetrahydrofuran (1M in THF, 4.6 mL, 1.4 eq) was added to a solution of 2-methyl-3-hydroxybenzoic acid (0.50 g, 3.3 mmol) in THF (30 mL). The reaction mixture was stirred overnight at rt before addition of saturated sodium hydrogencarbonate. The aqueous phase was extracted with DCM. The combined organic phases were dried over sodium sulfate and concentrated in vacuo to afford 3-(hydroxymethyl)-2-methylphenol in a quantitative yield.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7](=S)[CH2:6][CH2:5]2.[C:13]([NH:16][NH2:17])(=O)[CH3:14]>C(O)CCC.O>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]1[C:13]([CH3:14])=[N:16][N:17]=[C:7]1[CH2:6][CH2:5]2
Reactant: S=C1CCc2cc(Br)ccc2N1
Reactant: CC(=O)NN
Solvent: O
Solvent: CCCCO
Product: Cc1nnc2n1-c1ccc(Br)cc1CC2
Temperature: 140 °C
Reaction time: 5 h

Procedure:
To a stirred solution of 6-bromo-3,4-dihydroquinoline-2(1H)-thione (74-4; 1.0 g, 0.004 mol) in n-butanol (20 mL) was added acetic hydrazide (1.19 g, 0.016 mol) at room temperature. Reaction mass was allowed to stir at 140° C. for 5 h. The reaction mixture was cooled to room temperature, diluted with water (50 mL) and extracted with ethyl acetate (3×25 mL). The combined organic layer was washed with saturated aqueous sodium chloride solution, dried over sodium sulphate and concentrated under vacuum to afford the crude compound. Crude compound was purified by silica gel column chromatography to obtain title compound. MS (M+2): 266.0.
Reaction SMILES: Cl.[NH2:2][CH2:3][CH:4]([C:6]1[CH:16]=[CH:15][C:9]([O:10][CH2:11][C:12]([OH:14])=[O:13])=[CH:8][CH:7]=1)[CH3:5].C(=O)([O-])[O-].[Na+].[Na+].[Cl:23][C:24]1[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][C:25]=1[S:31](Cl)(=[O:33])=[O:32]>O>[Cl:23][C:24]1[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][C:25]=1[S:31]([NH:2][CH2:3][CH:4]([C:6]1[CH:16]=[CH:15][C:9]([O:10][CH2:11][C:12]([OH:14])=[O:13])=[CH:8][CH:7]=1)[CH3:5])(=[O:33])=[O:32]
Reactant: O=S(=O)(Cl)c1cc(Cl)ccc1Cl
Reactant: CC(CN)c1ccc(OCC(=O)O)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Product: CC(CNS(=O)(=O)c1cc(Cl)ccc1Cl)c1ccc(OCC(=O)O)cc1
Temperature: 80 °C
Reaction time: 3 h

Procedure:
A mixture of 2.95 g of (±)-4-(2-amino-1-methylethyl)phenoxyacetic acid hydrochloride, 3.82 g of sodium carbonate, 30 ml of water and 3.1 g of 2,5-dichlorophenylsulfonyl chloride is stirred at 80° C. for 3 hours. The reaction mixture is treated in the same manner as described in Example 43, whereby (±)-4-[2-(2,5-dichlorophenyl)sulfonylamino-1-methylethyl)phenoxyacetic acid is obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[C:9](=O)[O:10][C:11](=[O:13])[CH:12]=2)[CH:5]=[CH:6][CH:7]=1.O.[NH2:16][NH2:17]>O.C(O)(=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:12]=[C:11]([OH:13])[N:17]=[N:16][C:9]=2[OH:10])[CH:5]=[CH:6][CH:7]=1
Reactant: O=C1C=C(c2cccc(Cl)c2)C(=O)O1
Reactant: NN
Solvent: O
Solvent: CC(=O)O
Product: Oc1cc(-c2cccc(Cl)c2)c(O)nn1
Reaction time: 1 h

Procedure:
To a 25 mL flask was added 3-(3-chlorophenyl)furan-2,5-dione (1.7 g, 8.15 mmol) from (1a) and hydrazine hydrate (0.476 mL, 9.78 mmol) in water (6 mL) and acetic acid (4 mL). The resulting mixture was refluxed for 18 hours. The solution was cooled and placed in the refrigerator for 1 hour. The resulting precipitate was filtered and dried, then purified by flash chromatography eluting with 5% methanol/dichloromethane to give 4-(3-chlorophenyl)pyridazine-3,6-diol.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]=[CH:10][CH2:11][O:12]C(=O)C)=[C:5]([N+:16]([O-])=O)[CH:4]=1>CO.[Pd].ClCCl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:6]([NH:9][CH2:10][C:11](=[O:12])[NH:16]2)=[CH:7][CH:8]=1
Reactant: COc1ccc(N=CCOC(C)=O)c([N+](=O)[O-])c1
Agent: [Pd]
Solvent: CO
Solvent: ClCCl
Product: COc1ccc2c(c1)NC(=O)CN2
Temperature: 25 °C
Reaction time: 3 h

Procedure:
The obtained [(4-methoxy-2-nitrophenyl)imino]ethyl-acetate crude product was dissolved in methanol (30 ml) and 10% palladium on carbon (50% wet, 1.20 g) was added thereto and the mixture was stirred at room temperature for 3 hours under a hydrogen gas atmosphere. The catalyst was removed by filtration using celite and the filtrate was concentrated under reduced pressure to yield 1.733 g of a crude product of 7-methoxy-3,4-dihydroquinoxalin-2(1H)-one. In dichloromethane (12 ml) was dissolved 518 mg of the obtained crude product of 7-methoxy-3,4-dihydroquinoxalin-2(1H)-one, and under a nitrogen gas atmosphere in an ice bath, N,N-diisopropylethylamine (0.604 ml, 3.47 mmol) and subsequently benzyl chloroformate (0.408 ml, 2.77 mmol) were added thereto. Then, the mixture was stirred at room temperature for 17 hours, a saturated sodium hydrogen carbonate aqueous solution was added thereto and the resultant was extracted with dichloromethane. The extract was combined, dried over anhydrous sodium sulfate and the solvent was removed under reduced pressure. The obtained residue was purified by silica gel column chromatography (n-hexane/ethyl acetate) to yield 291 mg (40%) of the title compound in the form of a light red solid.
Reaction SMILES: [Cl:1][C:2]1[C:11]([CH:12](Cl)[C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([C:19]([F:22])([F:21])[F:20])[CH:14]=2)=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[N:7]2.[NH:24]1[CH:28]=[N:27][CH:26]=[N:25]1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[Cl:1][C:2]1[C:11]([CH:12]([N:24]2[CH:28]=[N:27][CH:26]=[N:25]2)[C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([C:19]([F:22])([F:21])[F:20])[CH:14]=2)=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[N:7]2
Reactant: FC(F)(F)c1cccc(C(Cl)c2ccc3ncccc3c2Cl)c1
Reactant: c1nc[nH]n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: FC(F)(F)c1cccc(C(c2ccc3ncccc3c2Cl)n2cncn2)c1
Yield: 16.5 %

Procedure:
A mixture of intermediate 6 (8.4 g), 1,2,4-triazole (4.89 g) and potassium carbonate (9.78 g) in acetonitrile (300 ml) was stirred and refluxed for 12 hours. The solvent was evaporated and the residue was partitioned between CH2Cl2 and water. The separated organic layer was dried over MgSO4, filtered and the filtrate evaporated. The residue was purified by column chromatography over silica gel (eluent: CH2Cl2 /CH3OH/NH4OH 98.5/1.5/0.1). The pure fractions were collected and the solvent evaporated. The residue was crystallized from diisopropyl ether/petrol ether, yielding 1.51 g (32%) (±)-5-chloro-6-[1H-1,2,4-triazol-1-yl[3-(trifluoromethyl)phenyl]-methyl]quinoline (intermediate 7; mp. 144.5° C.). In a similar manner, there were prepared: (±)-8-methyl-6-[1H-1,2,4-triazol-1-yl[3-(trifluoromethyl)phenyl]methyl]quinoline (intermediate 8; mp. 108.9° C.) and (±)-8-fluoro-6-[1H-1,2,4-triazol-1-yl[3-(trifluoromethyl) phenyl]methyl]quinoline (intermediate 9; mp. 146.6° C.).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([CH:8]([CH3:10])[CH3:9])[CH:5]=[CH:4][C:3]=1[N:11]([CH2:21][CH3:22])[C:12]1[N:17]=[C:16]([CH2:18][OH:19])[CH:15]=[C:14]([CH3:20])[N:13]=1.C(N(CC)CC)C.[CH3:30][S:31](Cl)(=[O:33])=[O:32]>ClCCl>[Br:1][C:2]1[CH:7]=[C:6]([CH:8]([CH3:9])[CH3:10])[CH:5]=[CH:4][C:3]=1[N:11]([CH2:21][CH3:22])[C:12]1[N:17]=[C:16]([CH2:18][O:19][S:31]([CH3:30])(=[O:33])=[O:32])[CH:15]=[C:14]([CH3:20])[N:13]=1
Reactant: CCN(c1nc(C)cc(CO)n1)c1ccc(C(C)C)cc1Br
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCN(c1nc(C)cc(COS(C)(=O)=O)n1)c1ccc(C(C)C)cc1Br
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 84.1 %

Procedure:
To a mixture of N-(2-bromo-4-(1-methylethyl)phenyl)-N-ethyl-4-hydroxymethyl-6-methylpyrimidinamine (1.57 g, 4.3 mmol), triethylamine(2.5 mL, 17 mmol) and dichloromethane (15 mL) at 0° C. under a nitrogen atmosphere was added methanesulfonyl chloride (0.54 g, 4.7 mmol) dropwise and the reaction mixture was stirred at 0° C. for 1.5 h. It was then washed successively with an ice-cold 1N HCl solution, a saturated NaHCO3 solution and a saturated NaCl solution. Drying the methylene chloride solution over MgSO4, filtration and removal of solvent in vacuo gave N-(2-bromo-4-(1-methylethyl)phenyl)-N-ethyl-4-methanesulfonyloxymethyl-6-methylpyrimidinamine as a clear colorless oil (1.6 g): NMR (CDCl3, 300 MHz): 7.5 (d, 1H, J=1), 7.25-7.1 (m, 2H), 6.5 (s, 1H), 5.05-4.9 (br s, 2H), 4.3-4.1 (m, 1H), 3.8-3.6 (m, 1H), 3.0-2.85 (m, 1H), 2.8-2.6 (br s, 3H), 2.5-2.25 (br m, 3H), 1.3 (d, 6H, J=8), 1.2 (t, 3H, J=8); CI-MS, 442, 444 (M+H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[C:29](=[O:30])[N:28]([CH3:31])[C:12]2[N:13]([CH3:27])[C:14]3[C:19]([C:11]=2[CH:10]=1)=[CH:18][C:17]([C:20]1[N:21]=[C:22]([CH2:25]O)[S:23][CH:24]=1)=[CH:16][CH:15]=3.C(N(S(F)(F)[F:38])CC)C.O>C(Cl)Cl>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[C:29](=[O:30])[N:28]([CH3:31])[C:12]2[N:13]([CH3:27])[C:14]3[C:19]([C:11]=2[CH:10]=1)=[CH:18][C:17]([C:20]1[N:21]=[C:22]([CH2:25][F:38])[S:23][CH:24]=1)=[CH:16][CH:15]=3
Reactant: CCN(CC)S(F)(F)F
Reactant: Cn1c(=O)c(-c2ccc(Cl)cc2Cl)cc2c3cc(-c4csc(CO)n4)ccc3n(C)c21
Solvent: O
Solvent: ClCCl
Product: Cn1c(=O)c(-c2ccc(Cl)cc2Cl)cc2c3cc(-c4csc(CF)n4)ccc3n(C)c21
Temperature: 0 °C
Reaction time: 2 h

Procedure:
150 mg (0.319 mmol) of compound from Example 9, 3-(2,4-dichlorophenyl)-6-(2-hydroxymethylthiazol-4-yl)-1,9-dimethyl-1,9-dihydropyrido[2,3-b]indol-2-one, are dissolved in 3 ml of CH2Cl2. 51 μl of (diethylamino)sulphur trifluoride (DAST) are added at 0° C. The mixture is stirred at 0° C. for 2 hours. A further 100 μl of DAST are added (presence of starting product) and the mixture is left to stir at ambient temperature for a further 16 hours. H2O is added, the mixture is extracted with CH2Cl2, and the organic phase is dried over MgSO4, filtered and concentrated to dryness, adsorbing onto silica. Purification is carried out on a silica column, elution being carried out with EtOAc/40% cyclohexane and then with EtOAc/30% cyclohexane. The residue is taken up in MeOH and the precipitate is filtered off, and washed with MeOH and then with a minimum amount of Et2O.
Reaction SMILES: Cl.[CH:2]1([CH2:5][O:6][C:7]2[CH:12]=[C:11]([F:13])[CH:10]=[CH:9][C:8]=2[C:14]2[C:15]3[NH:22][C:21]([CH3:23])=[C:20]([C:24]([NH:26][C@H:27]4[C@H:31]([OH:32])[CH2:30][NH:29][CH2:28]4)=[O:25])[C:16]=3[N:17]=[CH:18][N:19]=2)[CH2:4][CH2:3]1.[CH3:33][O:34][CH2:35][C:36](Cl)=[O:37]>>[CH:2]1([CH2:5][O:6][C:7]2[CH:12]=[C:11]([F:13])[CH:10]=[CH:9][C:8]=2[C:14]2[C:15]3[NH:22][C:21]([CH3:23])=[C:20]([C:24]([NH:26][C@H:27]4[C@H:31]([OH:32])[CH2:30][N:29]([C:36](=[O:37])[CH2:35][O:34][CH3:33])[CH2:28]4)=[O:25])[C:16]=3[N:17]=[CH:18][N:19]=2)[CH2:4][CH2:3]1
Reactant: COCC(=O)Cl
Reactant: Cc1[nH]c2c(-c3ccc(F)cc3OCC3CC3)ncnc2c1C(=O)N[C@@H]1CNC[C@H]1O
Agent: Cl
Product: COCC(=O)N1C[C@@H](O)[C@H](NC(=O)c2c(C)[nH]c3c(-c4ccc(F)cc4OCC4CC4)ncnc23)C1

Procedure:
Starting from 4-[2-(cyclopropylmethoxy)-4-fluorophenyl]-N-[(3R*,4R*)-4-hydroxypyrrolidin-3-yl]-6-methyl-5H-pyrrolo[3,2-d]pyrimidine-7-carboxamide hydrochloride (example D.f10) and commercially available methoxy-acetyl chloride the title compound is obtained as colorless solid.
Reaction SMILES: C[O:2][C:3]([C:5]1[C:6]2[CH:7]=[CH:8][CH:9]=[N:10][C:11]=2[CH:12]=[CH:13][C:14]=1[OH:15])=O.[NH3:16]>>[OH:15][C:14]1[CH:13]=[CH:12][C:11]2[N:10]=[CH:9][CH:8]=[CH:7][C:6]=2[C:5]=1[C:3]([NH2:16])=[O:2]
Reactant: COC(=O)c1c(O)ccc2ncccc12
Reactant: N
Product: NC(=O)c1c(O)ccc2ncccc12

Procedure:
6-Hydroxy-5-quinolinecarboxylic acid methyl ester is reacted with excess ammonia in a steel bomb for 12-18 hr. The excess ammonia is allowed to evaporate and the residue is crystallized from a suitable solvent to give the title compound.
Reaction SMILES: CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[NH2:25][C:26]1[CH:31]=[CH:30][C:29]([N:32]2[CH:37]=[CH:36][C:35]([O:38][CH2:39][C:40]3[CH:45]=[CH:44][C:43]([Cl:46])=[CH:42][CH:41]=3)=[CH:34][C:33]2=[O:47])=[CH:28][C:27]=1[NH:48][CH3:49].C(N(CC)C(C)C)(C)C.[CH3:59][CH:60]1[CH2:62][CH:61]1[C:63](O)=O>CN(C=O)C>[Cl:46][C:43]1[CH:42]=[CH:41][C:40]([CH2:39][O:38][C:35]2[CH:36]=[CH:37][N:32]([C:29]3[CH:30]=[CH:31][C:26]4[N:25]=[C:63]([CH:61]5[CH2:62][CH:60]5[CH3:59])[N:48]([CH3:49])[C:27]=4[CH:28]=3)[C:33](=[O:47])[CH:34]=2)=[CH:45][CH:44]=1
Reactant: CNc1cc(-n2ccc(OCc3ccc(Cl)cc3)cc2=O)ccc1N
Reactant: CC1CC1C(=O)O
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
Product: CC1CC1c1nc2ccc(-n3ccc(OCc4ccc(Cl)cc4)cc3=O)cc2n1C
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A mixture of HATU (101 mg), 1-(4-amino-3-(methylamino)phenyl)-4-((4-chlorobenzyl)oxy)pyridin-2(1H)-one (90 mg), N,N-diisopropylethylamine (0.130 ml), 2-methylcyclopropanecarboxylic acid (0.049 ml) and DMF (2 ml) was stirred at room temperature for 1 h. The mixture was quenched with water and extracted with EtOAc. The organic layer was separated, washed with water and brine, dried over MgSO4 and concentrated in vacuo. The residue was dissolved in AcOH (2.00 ml), and the mixture was stirred at 90° C. for 2 h. After evaporation, the residue was purified by NH silica gel column chromatography (hexane/EtOAc). The resulting solid was recrystallized from EtOH to give the title compound (3 mg) as a diastereomeric mixture. The filtrate was concentrated in vacuo and the precipitate was recrystallized from THF to give the title compound (17 mg) as a diastereomeric mixture.