Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC([N:8]1[C:17]2[C:12](=[CH:13][C:14]([C:18]3[CH:19]=[N:20][CH:21]=[CH:22][C:23]=3[O:24][CH3:25])=[CH:15][N:16]=2)[CH2:11][CH2:10][CH2:9]1)=O)(C)(C)C>FC(F)(F)C(O)=O.C(Cl)Cl>[CH3:25][O:24][C:23]1[CH:22]=[CH:21][N:20]=[CH:19][C:18]=1[C:14]1[CH:13]=[C:12]2[C:17](=[N:16][CH:15]=1)[NH:8][CH2:9][CH2:10][CH2:11]2
Reactant: COc1ccncc1-c1cnc2c(c1)CCCN2C(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COc1ccncc1-c1cnc2c(c1)CCCN2
Temperature: 25 °C
Reaction time: 16 h
Yield: 100.2 %

Procedure:
6-(4-Methoxy-pyridin-3-yl)-3,4-dihydro-2H-[1,8]naphthyridine-1-carboxylic acid tert-butyl ester (420 mg, 1.2 mmol) is dissolved in 20% trifluoroacetic acid in DCM (20 mL). The solution is stirred at room temperature for 16 hrs and then the solvent is removed. The residue is dissolved in DCM and saturated aqueous NaHCO3 solution is used to adjust the pH to 9˜10. The organic layer is separated, dried over Na2SO4, filtered and concentrated to give 290 mg of 6-(4-methoxy-pyridin-3-yl)-1,2,3,4-tetrahydro-[1,8]naphthyridine (290 mg crude) which is converted to 38 mg of the titled product according to the procedure of Urea Formation Method I.
Reaction SMILES: Br[C:2]1[N:6]([CH3:7])[C:5]([CH3:8])=[N:4][CH:3]=1.[CH3:9][O:10][C:11]1[CH:17]=[C:16](B2OC(C)(C)C(C)(C)O2)[CH:15]=[CH:14][C:12]=1[NH2:13].[F-].[Cs+]>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.COCCOC.CO>[CH3:7][N:6]1[C:2]([C:16]2[CH:15]=[CH:14][C:12]([NH2:13])=[C:11]([O:10][CH3:9])[CH:17]=2)=[CH:3][N:4]=[C:5]1[CH3:8]
Reactant: COc1cc(B2OC(C)(C)C(C)(C)O2)ccc1N
Reactant: Cc1ncc(Br)n1C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cs+]
Agent: [F-]
Solvent: COCCOC
Solvent: CO
Product: COc1cc(-c2cnc(C)n2C)ccc1N
Temperature: 150 °C
Yield: 42.2 %

Procedure:
To a microwave vial was added 5-bromo-1,2-dimethyl-1H-imidazole (230 mg, 1.31 mmol), 2-methoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (393 mg, 1.58 mmol), Pd(PPh3)4 (152 mg, 0.13 mmol), CsF (599 mg, 3.94 mmol) and DME/MeOH 3/1 (4 mL). The mixture was heated in a microwave at 150° C. for 1 hour. The reaction mixture was then filtered and concentrated onto silica gel and purified by Biotage silica gel column chromatography eluting with (EtOAc/MeOH 100/0 to 96/4) to give the title product as a light brown oil (120 mg, 42%). 1H NMR (500 MHz, CDCl3): δ 2.43 (s, 3H), 3.48 (s, 3H), 3.87 (s, 3H), 6.73-6.78 (m, 3H), 6.87 (s, 1H). LC (Method A)-MS (ESI, m/z) tR 0.49 min, 218 [(M+H+), 100%].
Reaction SMILES: C([O:3][C:4]([CH:6]1[CH2:11][CH2:10][N:9]([C:12]2[CH:17]=[CH:16][C:15]([C:18]([CH3:21])([CH3:20])[CH3:19])=[CH:14][CH:13]=2)[CH2:8][CH2:7]1)=[O:5])C.[OH-].[Na+]>CO>[C:18]([C:15]1[CH:14]=[CH:13][C:12]([N:9]2[CH2:10][CH2:11][CH:6]([C:4]([OH:5])=[O:3])[CH2:7][CH2:8]2)=[CH:17][CH:16]=1)([CH3:21])([CH3:19])[CH3:20]
Reactant: CCOC(=O)C1CCN(c2ccc(C(C)(C)C)cc2)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CC(C)(C)c1ccc(N2CCC(C(=O)O)CC2)cc1
Temperature: 90 °C

Procedure:
1-(4-Tert-butyl-phenyl)-piperidine-4-carboxylic acid ethyl ester (120 mg, 0.41 mmol, prepared in accordance with Example 48) was diluted in methanol (4 mL). An aqueous solution of sodium hydroxide (2 mL, 4M, 8.00 mmol) was then added. The resulting mixture was heated to 90° C., and then maintained at that temperature for 3 hr. After cooling to room temperature, the mixture was filtered. The filtrate was diluted with water (10 mL), and the aqueous phase was washed with ethyl acetate (10 mL). The aqueous phase was then acidified to a pH of 4 with 1 M HCl and then extracted with ethyl acetate (2×10 mL). The organic layer was collected, dried over magnesium sulfate, filtered, and concentrated under vacuum. The desired product was isolated as a solid (28 mg, 26% yield).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([S:8]([CH3:11])(=[O:10])=[O:9])[C:3]=1[NH2:12].[Cl:13][C:14]1[N:19]=[C:18](Cl)[C:17]([Cl:21])=[CH:16][N:15]=1>>[Cl:13][C:14]1[N:19]=[C:18]([NH:12][C:3]2[C:4]([S:8]([CH3:11])(=[O:10])=[O:9])=[CH:5][CH:6]=[CH:7][C:2]=2[F:1])[C:17]([Cl:21])=[CH:16][N:15]=1
Reactant: CS(=O)(=O)c1cccc(F)c1N
Reactant: Clc1ncc(Cl)c(Cl)n1
Product: CS(=O)(=O)c1cccc(F)c1Nc1nc(Cl)ncc1Cl

Procedure:
(2,5-Dichloro-pyrimidin-4-yl)-(2-fluoro-6-methanesulfonyl-phenyl)-amine was prepared from 2-Fluoro-6-methanesulfonyl-phenylamine and 2,4,5-trichloropyrimidine in an analogous manner to Example 1251d to afford an orange solid (1.38 g, 62%). MP 212-215, HPLC purity 95%, LCMS 338 (M+H), 1H-NMR (CDCl3, 400 MHz) δ 8.33 (s, 1H), 8.23 (s, 1H), 7.88 (d, J=2.7 Hz, 1H), 7.90-7.87 (m, 2H), 3.01 (s, 3H).
Reaction SMILES: N1[CH:2]=[CH:3]N2C(N)=CC=CC=12.[NH2:11][C:12]1[N:17]=[C:16]([NH2:18])[CH:15]=[CH:14][N:13]=1>>[N:11]1[CH:2]=[CH:3][N:13]2[CH:14]=[CH:15][C:16]([NH2:18])=[N:17][C:12]=12
Reactant: Nc1ccnc(N)n1
Reactant: Nc1cccc2nccn12
Product: Nc1ccn2ccnc2n1

Procedure:
Intermediate 7 was prepared using methods analogous to those described for Intermediate 6 except 2,4-diaminopyrimidine was the starting material. MS (ESI+): calcd for C6H6N4 m/z 134.06. found 135.1 (M+H)+. 1H NMR (d4-methanol): 8.27 (d, J=7.2, 1H), 7.31 (d, J=1.8, 1H), 7.18 (d, J=1.8, 1H), 6.35 (d, J=7.2, 1H).
Reaction SMILES: CCOCC.[CH2:6]([Mg]Cl)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[Cl:15][C:16]1[CH:17]=[CH:18][C:19]([OH:30])=[C:20]([CH:29]=1)[C:21]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)=[O:22].[Cl-].[NH4+]>C1C=CC=CC=1>[Cl:15][C:16]1[CH:17]=[CH:18][C:19]([OH:30])=[C:20]([C:21]([CH2:6][C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[OH:22])[CH:29]=1
Reactant: Cl[Mg]Cc1ccccc1
Reactant: O=C(c1ccccc1)c1cc(Cl)ccc1O
Agent: [Cl-]
Agent: [NH4+]
Solvent: c1ccccc1
Solvent: CCOCC
Product: Oc1ccc(Cl)cc1C(O)(Cc1ccccc1)c1ccccc1
Temperature: 20 °C
Reaction time: 1 h

Procedure:
322 ml of an ether solution titrating 1.12 M/liter of benzyl magnesium chloride were added over one hour to a solution of 34 g of 5-chloro-2-hydroxy-benzophenone in 150 ml of benzene and the mixture was allowed to stand for one hour and was then stirred at 20° C. for 16 hours. The mixture was poured into one liter of aqueous saturated ammonium chloride solution and the mixture was washed with water and was extracted 3 times with 400 ml of ether. The ether phase was dried over magnesium sulfate and was evaporated to dryness under reduced pressure. The residue was taken up in 100 ml of cyclohexane and the mixture stood for 16 hours at 20° C. and was iced and vacuum filtered to obtain 42.9 g of 5-chloro-2-hydroxy-α-benzyl-α-phenyl-benzene methanol melting at 128° C.
Reaction SMILES: CON(C)[C:4](=[O:17])[C:5]1[CH:10]=[CH:9][C:8]([O:11][CH2:12][C:13]([F:16])([F:15])[F:14])=[N:7][CH:6]=1.[CH2:19]([Mg]Br)[CH3:20]>>[F:16][C:13]([F:14])([F:15])[CH2:12][O:11][C:8]1[N:7]=[CH:6][C:5]([C:4](=[O:17])[CH2:19][CH3:20])=[CH:10][CH:9]=1
Reactant: CC[Mg]Br
Reactant: CON(C)C(=O)c1ccc(OCC(F)(F)F)nc1
Product: CCC(=O)c1ccc(OCC(F)(F)F)nc1
Yield: 87 %

Procedure:
The title compound is prepared in 87% yield (0.53 g, colorless oil) from N-methoxy-N-methyl-6-(2,2,2-trifluoroethoxy)nicotinamide (0.70 g, 2.65 mmol, Step-2 of Amine-1) and ethyl magnesium bromide instead of methyl magnesium bromide by the similar manner in Step-3 of Amine-1.
Reaction SMILES: [OH:1][CH2:2][CH2:3][NH:4][C:5](=[O:19])[C@@H:6]([NH:11]C(=O)OC(C)(C)C)[C:7]([CH3:10])([CH3:9])[CH3:8].FC(F)(F)C(O)=O>C(Cl)Cl>[NH2:11][C@@H:6]([C:7]([CH3:10])([CH3:9])[CH3:8])[C:5]([NH:4][CH2:3][CH2:2][OH:1])=[O:19]
Reactant: CC(C)(C)OC(=O)N[C@H](C(=O)NCCO)C(C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(C)(C)[C@H](N)C(=O)NCCO

Procedure:
(S)-tert-Butyl 1-(2-hydroxyethylamino)-3,3-dimethyl-1-oxobutan-2-ylcarbamate was treated overnight with trifluoroacetic acid in methylene chloride. The solution was concentrated to give the title compound without further purification.
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][C:3]=1B1OC(C)(C)C(C)(C)O1.I[C:22]1[NH:26][N:25]=[CH:24][CH:23]=1.C(Cl)Cl>O1CCOCC1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[CH3:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][C:3]=1[C:22]1[NH:26][N:25]=[CH:24][CH:23]=1
Reactant: Ic1ccn[nH]1
Reactant: COC(=O)c1ccc(C)c(B2OC(C)(C)C(C)(C)O2)c1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: c1ccc(P(c2ccccc2)[c-]2cccc2)cc1
Solvent: ClCCl
Solvent: C1COCCO1
Product: COC(=O)c1ccc(C)c(-c2ccn[nH]2)c1
Temperature: 90 °C
Reaction time: 0.17 h
Yield: 41.1 %

Procedure:
To methyl 4-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate (compound 5.4, 800 mg, 2.9 mmol) in dioxane (30 mL) was added 5-iodo-1H-pyrazole (674 mg, 3.5 mmol), and Pd(dppf)Cl2.DCM (237 mg, 0.29 mmol). The mixture was degassed with argon and stirred for 10 minutes then an aqueous potassium carbonate solution (2 M, 8 mL) was added. The mixture was heated at 90° C. for 18 h, then cooled and diluted with EtOAc and filtered through Celite®. The filtrate was washed with brine, dried (MgSO4), filtered, and concentrated under reduced pressure. The residue was purified by flash chromatography (SiO2; 0-30% EtOAc in hexanes) to yield 258 mg (41%) of the title compound as a solid. m/z (ES+) 217 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5](OS(C(F)(F)F)(=O)=O)=[C:4]([N+:16]([O-:18])=[O:17])[CH:3]=1.[SH:19][C:20]1[CH:25]=[CH:24][C:23]([OH:26])=[CH:22][CH:21]=1.C([O-])([O-])=O.[Na+].[Na+]>CCO>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:19][C:20]2[CH:25]=[CH:24][C:23]([OH:26])=[CH:22][CH:21]=2)=[C:4]([N+:16]([O-:18])=[O:17])[CH:3]=1
Reactant: Cc1ccc(OS(=O)(=O)C(F)(F)F)c([N+](=O)[O-])c1
Reactant: Oc1ccc(S)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Product: Cc1ccc(Sc2ccc(O)cc2)c([N+](=O)[O-])c1
Temperature: 25 °C

Procedure:
The product from Example 9a (11.22 g, 39.3 mmol) and 4-mercaptophenol (4.96 g, 39.3 mmol) in 100 mL of EtOH was treated with Na2CO3 and heated overnight under efflux. Cooled to room temperature and quenched with water. Extracted with EtOAc. Dried over MgSO4, filtered and concentrated under vacuum giving the title compound, which was purified by silica gel column chromatography eluting with 25% EtOAc/hexane giving a red oil (8.65 g, 85%).
Reaction SMILES: [CH2:1]([CH2:3][NH2:4])[OH:2].Br[CH2:6][CH2:7][CH2:8][C:9]#[N:10]>C(O)C>[OH:2][CH2:1][CH2:3][NH:4][CH:8]([CH2:7][CH3:6])[C:9]#[N:10]
Reactant: NCCO
Reactant: N#CCCCBr
Solvent: CCO
Product: CCC(C#N)NCCO

Procedure:
Dissolve ethanolamine (11.3 g, 0.185 mol) and 4-bromobutyronitrile (32.6 g, 0.22 mol) in ethanol (700 mL) and heat at reflux for 18 hours. Evaporate the solvent in vacuo and purify by distillation to give the title compound.
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:12]=[CH:11][C:10]([B:13]3[O:17][C:16]([CH3:19])([CH3:18])[C:15]([CH3:21])([CH3:20])[O:14]3)=[CH:9][CH:8]=2)=[N:4][C:3]=1[CH2:22][CH2:23]O.BrC1C=CC(C2OC(C)=C(CC[N:39]3[CH2:43][CH2:42][CH2:41][CH2:40]3)N=2)=CC=1>>[CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:8]=[CH:9][C:10]([B:13]3[O:17][C:16]([CH3:18])([CH3:19])[C:15]([CH3:20])([CH3:21])[O:14]3)=[CH:11][CH:12]=2)=[N:4][C:3]=1[CH2:22][CH2:23][N:39]1[CH2:43][CH2:42][CH2:41][CH2:40]1
Reactant: Cc1oc(-c2ccc(B3OC(C)(C)C(C)(C)O3)cc2)nc1CCO
Reactant: Cc1oc(-c2ccc(Br)cc2)nc1CCN1CCCC1
Product: Cc1oc(-c2ccc(B3OC(C)(C)C(C)(C)O3)cc2)nc1CCN1CCCC1

Procedure:
The titled compound is prepared substantially in accordance with the procedure of 2-{5-Methyl-2-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)phenyl]-oxazol-4-yl}-ethanol (see Intermediate 3) using 2-(4-Bromo-phenyl)-5-methyl-4-(2-pyrrolidin-1-yl-ethyl)-oxazole (See Example 8). MS (m/e) 383.3 (M+1)
Reaction SMILES: [CH:1]1([NH2:4])[CH2:3][CH2:2]1.[C:5]([NH:9][C:10]([C:12]1[C:16]([C:17]([O:19][CH3:20])=[O:18])=[C:15]([C:21](OC)=[O:22])[O:14][N:13]=1)=[O:11])([CH3:8])([CH3:7])[CH3:6]>CO.C(OC)(C)(C)C>[C:5]([NH:9][C:10]([C:12]1[C:16]([C:17]([O:19][CH3:20])=[O:18])=[C:15]([C:21]([NH:4][CH:1]2[CH2:3][CH2:2]2)=[O:22])[O:14][N:13]=1)=[O:11])([CH3:8])([CH3:6])[CH3:7]
Reactant: COC(=O)c1onc(C(=O)NC(C)(C)C)c1C(=O)OC
Reactant: NC1CC1
Solvent: CO
Solvent: COC(C)(C)C
Product: COC(=O)c1c(C(=O)NC(C)(C)C)noc1C(=O)NC1CC1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
0.75 g (I3.1 mmol) of cyclopropylamine was added dropwise at 20° C., with cooling, to a solution of 2.5 g (8.8 mmol) of dimethyl 3-tert-butylaminocarbonylisoxazole-4,5-dicarboxylate in 50 ml of dry methanol, and the mixture was stirred at room temperature for 20 hours. The solvents were stripped off under reduced pressure, and the residue was taken up in methyl tert-butyl ether and extracted with dilute HCl and once with water. The organic phase was then dried over magnesium sulfate, and the solution was evaporated. The resulting methyl3-tert-butylaminocarbonyl-5-cyclopropylaminocarbonylisoxazole-4-carboxylate was purified by column chromatography (SiO2 ; cyclohexane/ethyl acetate 4:1).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]([F:11])[C:8]2[NH:7][C:6]3[CH2:12][CH2:13][N:14]([CH3:16])[CH2:15][C:5]=3[C:4]=2[CH:3]=1.[OH-].[K+].[F:19][C:20]([F:30])([F:29])[C:21]1[CH:26]=[CH:25][C:24]([CH:27]=[CH2:28])=[CH:23][N:22]=1.O>CN1C(=O)CCC1>[Cl:1][C:2]1[CH:10]=[C:9]([F:11])[C:8]2[N:7]([CH2:28][CH2:27][C:24]3[CH:23]=[N:22][C:21]([C:20]([F:30])([F:19])[F:29])=[CH:26][CH:25]=3)[C:6]3[CH2:12][CH2:13][N:14]([CH3:16])[CH2:15][C:5]=3[C:4]=2[CH:3]=1
Reactant: CN1CCc2[nH]c3c(F)cc(Cl)cc3c2C1
Reactant: C=Cc1ccc(C(F)(F)F)nc1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CN1CCCC1=O
Product: CN1CCc2c(c3cc(Cl)cc(F)c3n2CCc2ccc(C(F)(F)F)nc2)C1
Reaction time: 0.17 h
Yield: 2.9 %

Procedure:
To a solution of 8-chloro-6-fluoro-2,3,4,5-tetrahydro-2-methyl-1H-pyrido[4,3-b]indole (300 mg, 1.26 mmol) in NMP (3.0 ml), powdered KOH (705 mg, 12.57 mmol) was added and stirred for 10 min at 25 deg C. After which 2-(trifluoromethyl)-5-vinylpyridine (435 mg, 2.5 mmol) was added slowly to the above solution and stirred for 24 h at 25 deg C. After completion of the reaction (monitored by LCMS), DM water was added to the crude and extracted with the ethylacetate. The organic layer was separated, dried and concentrated. The resulting crude was purified by reverse-phase chromatography (C-18, 500 mm×50 mm, Mobile Phase A=0.05% TFA in water, B=0.05% TFA in acetonitrile, Gradient: 10% B to 80% B in 30 min, injection vol. 5 mL) to obtain 15 mg of 8-chloro-6-fluoro-5-(2-(6-(trifluoromethyl)pyridin-3-yl)ethyl)-2,3,4,5-tetrahydro-2-methyl-1H-pyrido[4,3-b]indole as TFA salt.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[S:12][C:11]([CH:13]([CH3:15])[CH3:14])=[N:10][C:9]=2[C:16]2[CH:17]=[CH:18][C:19]([F:34])=[C:20]([NH:22][S:23]([C:26]3[C:31]([F:32])=[CH:30][CH:29]=[CH:28][C:27]=3[F:33])(=[O:25])=[O:24])[CH:21]=2)[CH:5]=[CH:4][N:3]=1.[NH2:35][CH2:36][CH2:37][S:38]([CH3:41])(=[O:40])=[O:39]>>[F:33][C:27]1[CH:28]=[CH:29][CH:30]=[C:31]([F:32])[C:26]=1[S:23]([NH:22][C:20]1[CH:21]=[C:16]([C:9]2[N:10]=[C:11]([CH:13]([CH3:15])[CH3:14])[S:12][C:8]=2[C:6]2[CH:5]=[CH:4][N:3]=[C:2]([NH:35][CH2:36][CH2:37][S:38]([CH3:41])(=[O:40])=[O:39])[N:7]=2)[CH:17]=[CH:18][C:19]=1[F:34])(=[O:25])=[O:24]
Reactant: CS(=O)(=O)CCN
Reactant: CC(C)c1nc(-c2ccc(F)c(NS(=O)(=O)c3c(F)cccc3F)c2)c(-c2ccnc(Cl)n2)s1
Product: CC(C)c1nc(-c2ccc(F)c(NS(=O)(=O)c3c(F)cccc3F)c2)c(-c2ccnc(NCCS(C)(=O)=O)n2)s1

Procedure:
Following a procedure analogous to the procedure described in Example 1 using N-{5-[5-(2-chloro-4-pyrimidinyl)-2-(1-methylethyl)-1,3-thiazol-4-yl]-2-fluorophenyl}-2,6-difluorobenzenesulfonamide (3.0 g, 5.71 mmol) and 2-aminoethyl-methyl-sulfone (2.82 g, 22.86 mmol), the title compound was obtained as a white solid (1.9 g, 53% yield). 1H NMR (400 MHz, DMSO-d6) δ ppm 10.93 (s, 1H), 8.14 (d, J=5.0 Hz, 1H), 7.67-7.77 (m, 1H), 7.48 (t, J=5.5 Hz, 1H), 7.38-7.46 (m, 2H), 7.28 (q, J=9.2 Hz, 3H), 6.22-6.31 (m, 1H), 3.62-3.73 (m, 2H), 3.34-3.40 (m, 2H), 3.25-3.30 (m, 1H), 3.02 (s, 3H), 1.36 (d, J=6.9 Hz, 6H). MS (ESI): 612.2 [M+H]+.
Reaction SMILES: C([O:3][CH:4](OCC)[CH2:5][N:6]1[CH:10]=[CH:9][C:8]([C:11]2[CH:16]=[CH:15][C:14]([F:17])=[CH:13][N:12]=2)=[N:7]1)C.C(O)(C(F)(F)F)=O.C([O-])(O)=O.[Na+]>C(Cl)(Cl)Cl>[F:17][C:14]1[CH:15]=[CH:16][C:11]([C:8]2[CH:9]=[CH:10][N:6]([CH2:5][CH:4]=[O:3])[N:7]=2)=[N:12][CH:13]=1
Reactant: CCOC(Cn1ccc(-c2ccc(F)cn2)n1)OCC
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: ClC(Cl)Cl
Product: O=CCn1ccc(-c2ccc(F)cn2)n1
Temperature: 35 °C
Reaction time: 6 h

Procedure:
To a solution of 2-[1-(2,2-diethoxyethyl)-1H-pyrazol-3-yl]-5-fluoropyridine obtained in Reference Example 12 (4.0 g, 14.3 mmol) in CHCl3 (72 mL), TFA (6.4 mL, 85.9 mmol) was added, and the resulting mixture was stirred for 6 hours at 35° C. TFA (6.4 mL, 85.9 mmol) was further added thereto, and the mixture was stirred for 3 hours at 35° C. The reaction mixture was allowed to cool to room temperature, then an aqueous solution of NaHCO3 was added to the reaction mixture, followed by extraction with CHCl3. The organic layer was washed with a saturated aqueous solution of sodium chloride, dried over MgSO4, and then the drying agent was filtered off. The solvent was distilled off under reduced pressure to obtain [3-(5-fluoropyridin-2-yl)-1H-pyrazol-1-yl]acetaldehyde (colorless oil). To a solution of [3-(5-fluoropyridin-2-yl)-1H-pyrazol-1-yl]acetaldehyde in CHCl3 (36 mL), activated molecular sieve 4 A (29 g) and 2-aminoethanol (1.1 mL, 14.3 mmol) were added, and the resulting mixture was stirred for 48 hours at room temperature. The molecular sieve 4 A was filtered off through Celite®, and then the solvent was distilled off under reduced pressure to obtain a colorless oil. To a solution of the obtained colorless oil (0.10 g, 0.40 mmol) and 2-(2H-1,2,3-triazol-2-yl)benzoic acid (76 mg, 0.40 mmol) in DMF (0.4 mL), DIPEA (0.21 mL, 1.2 mmol) and HATU (0.16 g, 0.48 mmol) were added, and the resulting mixture was stirred for 48 hours at room temperature. The reaction mixture was purified by HPLC to obtain the title compound (40.8 mg) (colorless solid).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([OH:14])[CH2:10][CH2:9]1)=O)(C)(C)C.[Br:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21]Br.[ClH:23]>>[ClH:23].[Br:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][O:14][CH:11]1[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]1
Reactant: CC(C)(C)OC(=O)N1CCC(O)CC1
Reactant: BrCCCCCCBr
Agent: Cl
Product: BrCCCCCCOC1CCNCC1

Procedure:
In analogy to example 1.2a and 1.3, reaction of 4-Hydroxy-piperidine-1-carboxylic-acid tert-butyl ester and 1,6-dibromohexane followed by treatment with 4N HCl yielded 4-(6-Bromo-hexyloxy)-piperidine hydrochloride, MS: 264 (MH+, 1Br).
Reaction SMILES: F[C:2]1[C:7]([C:8]2[N:13]=[C:12]([CH3:14])[N:11]=[C:10]([NH2:15])[N:9]=2)=[CH:6][C:5]([O:16][CH2:17][CH2:18][O:19][CH3:20])=[CH:4][N:3]=1.[NH2:21][C:22]1[CH:23]=[C:24]([NH:29][S:30]([CH3:33])(=[O:32])=[O:31])[C:25]([CH3:28])=[N:26][CH:27]=1.C[Si]([N-][Si](C)(C)C)(C)C.[Na+].C1COCC1>CN(C=O)C>[NH2:15][C:10]1[N:11]=[C:12]([CH3:14])[N:13]=[C:8]([C:7]2[C:2]([NH:21][C:22]3[CH:23]=[C:24]([NH:29][S:30]([CH3:33])(=[O:32])=[O:31])[C:25]([CH3:28])=[N:26][CH:27]=3)=[N:3][CH:4]=[C:5]([O:16][CH2:17][CH2:18][O:19][CH3:20])[CH:6]=2)[N:9]=1
Reactant: Cc1ncc(N)cc1NS(C)(=O)=O
Reactant: COCCOc1cnc(F)c(-c2nc(C)nc(N)n2)c1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: COCCOc1cnc(Nc2cnc(C)c(NS(C)(=O)=O)c2)c(-c2nc(C)nc(N)n2)c1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 30.3 %

Procedure:
To a 15 mL round-bottom flask was added 4-(2-fluoro-5-(2-methoxyethoxy)pyridin-3-yl)-6-methyl-1,3,5-triazin-2-amine (Example 335 Step 3) (0.050 g, 0.179 mmol), N-(5-amino-2-methylpyridin-3-yl)methanesulfonamide (0.043 g, 0.215 mmol), and DMF (2.0 mL). The mixture was cooled to 0° C. under N2. Sodium bis(trimethylsilyl)amide, 1.0 m in THF (Aldrich) (0.145 mL, 0.716 mmol) was then added to the solution in one portion. The now dark burgundy color mixture was stirred at 0° C. for 10 min then warmed up to rt and stirred for 1 h. The reaction mixture was partitioned between sat. NH4Cl and CHCl3. The aqueous layer was extracted with more CHCl3 (2×10 mL). The combined organic layers were dried over MgSO4 and concentrated. The crude product was purified by column chromatography (16 g, 5% to 10% MeOH in DCM) to afford the desired product as a yellow solid (25 mg). MS (ESI pos. ion) m/z: 461.0. 1H NMR (300 MHz, DMSO-d6) δ ppm 2.45 (d, J=2.63 Hz, 6H) 2.52 (s, 3H) 3.06 (s, 3H) 3.61-3.73 (m, 2H) 4.09-4.23 (m, 2H) 7.77 (br. s., 1H) 7.89 (br. s., 1H) 8.17 (d, J=2.92 Hz, 1H) 8.33 (d, J=1.75 Hz, 1H) 8.42 (d, J=3.07 Hz, 1H) 8.65 (s, 1H) 9.29 (br. s., 1H) 11.76 (s, 1H).
Reaction SMILES: [N+:1]([O-:4])([O-])=[O:2].[K+].[Cl:6][C:7]1[C:14]([Cl:15])=[CH:13][CH:12]=[CH:11][C:8]=1[CH:9]=[O:10]>S(=O)(=O)(O)O>[Cl:6][C:7]1[C:14]([Cl:15])=[CH:13][CH:12]=[C:11]([N+:1]([O-:4])=[O:2])[C:8]=1[CH:9]=[O:10]
Reactant: O=Cc1cccc(Cl)c1Cl
Reactant: O=[N+]([O-])[O-]
Agent: O=S(=O)(O)O
Agent: [K+]
Product: O=Cc1c([N+](=O)[O-])ccc(Cl)c1Cl
Temperature: 25 °C
Reaction time: 240 h
Yield: 34.5 %

Procedure:
Potassium nitrate (578 mg, 5.71 mmol) was dissolved in concentrated sulfuric acid (4.5 mL) and added dropwise to a stirred solution of 2,3-dichlorobenzaldehyde (1.0 g, 5.71 mmol) at room temperature. The mixture was left without stirring for 10 days at room temperature. Material that had crystallized out of the reaction mixture was collected by filtration to afford 2,3-dichloro-6-nitrobenzaldehyde (196MBT36, 433 mg, 34%) as yellow needles. Regioselectivity was confirmed by the Bayer-Drewson indigo synthesis.
Reaction SMILES: [CH3:1][C:2]1([CH3:21])[O:6][CH:5]([CH2:7][C:8]2[CH:17]=[C:16]3[C:11]([CH2:12][CH2:13][C:14](=[O:18])[NH:15]3)=[CH:10][C:9]=2[O:19][CH3:20])[CH2:4][O:3]1.[H-].[Na+].I[CH3:25]>CN(C)C=O.C(OCC)(=O)C>[CH3:1][C:2]1([CH3:21])[O:6][CH:5]([CH2:7][C:8]2[CH:17]=[C:16]3[C:11]([CH2:12][CH2:13][C:14](=[O:18])[N:15]3[CH3:25])=[CH:10][C:9]=2[O:19][CH3:20])[CH2:4][O:3]1
Reactant: CI
Reactant: COc1cc2c(cc1CC1COC(C)(C)O1)NC(=O)CC2
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COc1cc2c(cc1CC1COC(C)(C)O1)N(C)C(=O)CC2
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 98.6 %

Procedure:
300 mg of 7-((2,2-dimethyl-[1,3]dioxolan-4-yl)methyl)-6-methoxy-1,2,3,4-tetrahydroquinolin-2-one was dissolved in 6 ml of N,N-dimethylformamide. While cooling on ice, 49 mg of 60% sodium hydride was added to the reaction solution, and the obtained mixture was then stirred at room temperature for 30 minutes. Thereafter, 0.29 g of iodomethane was added to the reaction solution while cooling on ice. The obtained mixture was stirred at room temperature for 2 hours. The reaction solution was diluted with ethyl acetate and then washed with a saturated ammonium chloride aqueous solution and a saturated sodium chloride aqueous solution. The organic layer was dried over magnesium sulfate and then concentrated under a reduced pressure. The residue was purified by NH silica gel column chromatography (hexane-ethyl acetate), so as to obtain 310 mg of the subject compound.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([S:7][CH2:8][CH2:9][CH2:10][CH2:11][N:12]2[C:21](=[O:22])[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[NH:14][C:13]2=[O:23])=[CH:3][CH:2]=1.Cl[CH2:25][S:26][C:27]1[CH:32]=[CH:31][N:30]=[CH:29][CH:28]=1.O>CN(C)C=O>[N:30]1[CH:31]=[CH:32][C:27]([S:26][CH2:25][N:14]2[C:15]3[C:20](=[CH:19][CH:18]=[CH:17][CH:16]=3)[C:21](=[O:22])[N:12]([CH2:11][CH2:10][CH2:9][CH2:8][S:7][C:4]3[CH:5]=[CH:6][N:1]=[CH:2][CH:3]=3)[C:13]2=[O:23])=[CH:28][CH:29]=1
Reactant: O=c1[nH]c2ccccc2c(=O)n1CCCCSc1ccncc1
Reactant: ClCSc1ccncc1
Solvent: CN(C)C=O
Solvent: O
Product: O=c1c2ccccc2n(CSc2ccncc2)c(=O)n1CCCCSc1ccncc1
Temperature: 80 °C
Reaction time: 16 h
Yield: 46.6 %

Procedure:
To a solution of 491 mg (1.5 mmol) of 3-[4-(4-pyridylthio)butyl]quinazoline-2,4(1H,3H)-dione and 287 mg (1.8 mmol) of 4-chloromethylthiopyridine in 15 ml of dimethylformamide, 0.27 ml (1.8 mmol) of 1,8-diazabicyclo-[5.4.0]-7-undecene was added, and the mixture was stirred at 80° C. for 16 hours. After cooling, water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was dried and the solvent was distilled off. The residue was purified by flash column chromatography (eluent: ethyl acetate/hexane=2:1 to 4:1 to ethyl acetate) to give 0.315 g of the desired product (46.7% yield, colorless oil).