Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:17]=[CH:18][CH:19]=1)[O:7][C:8]1[CH:13]=[CH:12][N:11]=[C:10](C(O)=O)[CH:9]=1)([O-:3])=[O:2].C1(P([N:34]=[N+]=[N-])(C2C=CC=CC=2)=O)C=CC=CC=1.C(N(CC)CC)C.CN(C)C=O>O>[N+:1]([C:4]1[CH:5]=[C:6]([CH:17]=[CH:18][CH:19]=1)[O:7][C:8]1[CH:13]=[CH:12][N:11]=[C:10]([NH2:34])[CH:9]=1)([O-:3])=[O:2]
Reactant: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Reactant: O=C(O)c1cc(Oc2cccc([N+](=O)[O-])c2)ccn1
Solvent: CCN(CC)CC
Solvent: O
Solvent: CN(C)C=O
Product: Nc1cc(Oc2cccc([N+](=O)[O-])c2)ccn1
Yield: 88.2 %

Procedure:
A mixture of 3-nitrophenol (3.65 g, 26.2 mmol), potassium tert-butoxide (3.23 g, 28.8 mmol) and N,N-dimethylformamide (20 mL) was stirred at room temperature for 30 min. After stirring, methyl 4-chloropyridine-2-carboxylate (3.00 g, 17.5 mmol) and potassium carbonate (10.9 g, 78.6 mmol) were added, and the mixture was stirred at 120° C. for 3 hr. The reaction mixture was diluted with water and extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous magnesium sulfate and filtrated. The filtrate was concentrated under reduced pressure, ethanol (20 mL) and 8N aqueous sodium hydroxide solution (3 mL) were added to the residue, and the mixture was stirred at room temperature for 2 hr. The reaction mixture was neutralized with 1N hydrochloric acid, and the precipitated solid was collected by filtration and washed with water to give 4-(3-nitrophenoxy)pyridine-2-carboxylic acid (345 mg, 8.0%) as a white solid. A mixture of 4-(3-nitrophenoxy)pyridine-2-carboxylic acid (339 mg, 1.24 mmol) thus-obtained, diphenylphosphoryl azide (333 μL, 1.55 mmol), triethylamine (215 μL, 1.55 mmol), N,N-dimethylformamide (5 mL) and water (5 mL) was stirred at 100° C. for 15 hr. The reaction mixture was diluted with water and extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous magnesium sulfate and filtrated. The filtrate was concentrated under reduced pressure. The residue was collected by filtration and washed with ethyl acetate-hexane to give the title compound (253 mg, 8.8%) as a white solid.
Reaction SMILES: C[O-].[Na+:3].[Na].[Cl:5][C:6]1[C:11]([Cl:12])=[CH:10][C:9]([S:13]([NH2:16])(=[O:15])=[O:14])=[CH:8][C:7]=1[S:17]([NH2:20])(=[O:19])=[O:18]>CO>[Na+:3].[Cl:5][C:6]1[C:11]([Cl:12])=[CH:10][C:9]([S:13]([NH-:16])(=[O:14])=[O:15])=[CH:8][C:7]=1[S:17]([NH2:20])(=[O:19])=[O:18]
Reactant: NS(=O)(=O)c1cc(Cl)c(Cl)c(S(N)(=O)=O)c1
Agent: C[O-]
Agent: [Na+]
Agent: [Na]
Solvent: CO
Product: [NH-]S(=O)(=O)c1cc(Cl)c(Cl)c(S(N)(=O)=O)c1
Temperature: 25 °C

Procedure:
To a solution of sodium methoxide (5.0 millimoles) in methanol (100 ml), freshly generated by the careful portionwise additions of sodium (1.15 g, 5.0 millimole) to methanol (100 ml.), is added 4,5-dichloro-m-benzenedisulfonamide (15.16 g, 5.0 millimole) with stirring at 25° C. The resulting mixture is stirred at 25° C. for 30 minutes to provide a colorless solution which is filtered. Evaporation of the clear, colorless filtrate at 40° C. in vacuo provides a solid residue which is dried in vacuo at 80° C. for 16 hours to provide analytically pure 4,5-dichloro-m-benzenedisulfonamide mono sodium salt as a colorless solid (14.0 g., 85%), m.p./252°-244° C.
Reaction SMILES: [CH3:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[C:6]([CH3:11])[N:5]=[C:4]([OH:12])[N:3]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:20][C:21]([O:23][CH2:24][CH3:25])=[O:22]>CC(C)=O>[CH3:11][C:6]1[C:7]([N+:8]([O-:10])=[O:9])=[C:2]([CH3:1])[N:3]=[C:4]([O:12][CH2:20][C:21]([O:23][CH2:24][CH3:25])=[O:22])[N:5]=1
Reactant: Cc1nc(O)nc(C)c1[N+](=O)[O-]
Reactant: CCOC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCOC(=O)COc1nc(C)c([N+](=O)[O-])c(C)n1
Temperature: 50 °C
Reaction time: 8 h
Yield: 45 %

Procedure:
Compound 1 (111.86 g) and potassium carbonate (274.21 g: 3 eq.) were suspended in acetone (2 L) and ethyl bromoacetate (165.67 g: 1.5 eq.) was added at room temperature (20 to 30° C.). The equipment used to add ethyl bromoacetate was thoroughly washed with acetone (237 mL) and stirred at 50° C. for 8 hours. Subsequently, the mixture was cooled to 35° C. and was concentrated under reduced pressure. To the resulting residue, toluene (1120 mL) was added and the mixture was stirred at room temperature overnight. The mixture was then suction-filtered and the filtered product was washed with toluene (560 mL). The filtered product was crushed and washed again with toluene (450 mL). The filtrate was evaporated under reduced pressure and the resulting crude product was purified by silica gel column chromatography (hexane:ethyl acetate=1:0 to 4:1) to give 75.98 g (45% yield) of the desired product as a yellow solid.
Reaction SMILES: [O:1]=[C:2]1[NH:7][C:6]([CH2:8][N:9]2C(=O)C3C(=CC=CC=3)C2=O)=[N:5][C:4]2[N:20]=[CH:21][CH:22]=[CH:23][C:3]1=2.O.NN.C(=O)([O-])[O-].[Na+].[Na+].O>C(O)C>[NH2:9][CH2:8][C:6]1[NH:7][C:2](=[O:1])[C:3]2[CH:23]=[CH:22][CH:21]=[N:20][C:4]=2[N:5]=1
Reactant: O=C1c2ccccc2C(=O)N1Cc1nc2ncccc2c(=O)[nH]1
Agent: NN
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: NCc1nc2ncccc2c(=O)[nH]1
Temperature: 50 °C
Reaction time: 3 h
Yield: 49.7 %

Procedure:
A suspension of 2-(4-oxo-3,4-dihydro-pyrido[2,3-d]pyrimidin-2-ylmethyl)-isoindole-1,3-dione (1.0 g, 3.26 mmol) and hydrazine monohydrate (0.48 ml, 9.79 mmol) in ethanol (90 ml) was stirred at 50° C. for 3 hours. The mixture was cooled to ambient temperature and sodium carbonate (0.38 g, 3.59 mmol) and water (1 ml) were added. The suspension was stirred overnight at ambient temperature. The solid residue was filtered off, triturated with CH2Cl2/MeOH (4/1) under reflux conditions. A white solid was filtered off and triturated with TBME to yield 2-aminomethyl-3H-pyrido[2,3-d]pyrimidin-4-one (0.285 g, 1.62 mmol; 50%), as white solid. MS (m/e): 176.8 [M+H+].
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([O:17][CH2:18][C:19]2[CH:24]=[CH:23][C:22]([F:25])=[C:21]([F:26])[CH:20]=2)=[C:6]([CH:16]=1)[C:7]([NH:9][C:10]1[CH:15]=[CH:14][N:13]=[N:12][CH:11]=1)=[O:8].[CH3:27][N:28]1[CH:32]=[C:31](B2OC(C)(C)C(C)(C)O2)[CH:30]=[N:29]1.C(=O)([O-])[O-].[Na+].[Na+]>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>[F:26][C:21]1[CH:20]=[C:19]([CH2:18][O:17][C:5]2[CH:4]=[CH:3][C:2]([C:31]3[CH:30]=[N:29][N:28]([CH3:27])[CH:32]=3)=[CH:16][C:6]=2[C:7]([NH:9][C:10]2[CH:15]=[CH:14][N:13]=[N:12][CH:11]=2)=[O:8])[CH:24]=[CH:23][C:22]=1[F:25]
Reactant: O=C(Nc1ccnnc1)c1cc(Br)ccc1OCc1ccc(F)c(F)c1
Reactant: Cn1cc(B2OC(C)(C)C(C)(C)O2)cn1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Product: Cn1cc(-c2ccc(OCc3ccc(F)c(F)c3)c(C(=O)Nc3ccnnc3)c2)cn1
Temperature: 120 °C

Procedure:
To a microwave vial was added 5-bromo-2-{[(3,4-difluorophenyl)methyl]oxy}-N-4-pyridazinylbenzamide (may be prepared by Example 78; 150 mg, 0.36 mmol), 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (75 mg, 0.36 mmol), 1,2-dimethoxyethane (2 nil), 1M sodium carbonate (0.71 ml, 0.71 mmol), and tetrakis(triphenylphosphine)palladium(0) (24.75 mg, 0.02 mmol). The vial was sealed and heated to 120° C. for 1 hour under microwave conditions. The mixture was evaporated under reduced pressure and water (5 ml) was added to the residue. The mixture was extracted with ethyl acetate (3×10 ml). The organics were combined and evaporated and the residue was purified using the MDAP to yield the title compound. 80 mg.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:12]=[CH:13][CH:14]=1)[O:7][CH2:8][C:9]([OH:11])=[O:10])([O-])=O>CO>[NH2:1][C:4]1[CH:5]=[C:6]([CH:12]=[CH:13][CH:14]=1)[O:7][CH2:8][C:9]([OH:11])=[O:10]
Reactant: O=C(O)COc1cccc([N+](=O)[O-])c1
Solvent: CO
Product: Nc1cccc(OCC(=O)O)c1
Reaction time: 3 h
Yield: 76.1 %

Procedure:
To a 2 L pressure vessel was added 3-nitrophenoxyacetic acid 1 (21.7 g, 110 mmol, 1.0 eq.) and methanol (600 mL). The resulting solution was purged with N2 for 5 min. 10% Pd/C (900 mg) was added to the solution and the vessel was placed on a Parr hydrogenator at 50 psi for 3 h. After removal from the Parr apparatus, the reaction mixture was gray in color, indicating the precipitation of product. DMF (400 mL) was added and was stirred until it was evident that the precipitated product had dissolved in the solvent phase. The Pd/C was removed by filtration and the filtrate was concentrated under high vacuum to yield a dark brown solid (14 g, 76%). LC/MSD (HP Series 1100 MSD) MS (ES+) m/z 168.0 (M+H)+1 1H-NMR, Varian 400 MHz (DMSO-d6) δ 7.93 (s, 1H), 6.86 (t, 1H), 6.14-5.99 (m, 3H), 4.50 (s, 2H) ppm.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:45]=[CH:44][CH:43]=[CH:42][C:4]=1[CH2:5][O:6][CH2:7][CH2:8][CH2:9][O:10][C:11]1[CH:16]=[CH:15][C:14]([C@H:17]2[CH2:22][CH2:21][N:20]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:19][C@@H:18]2[O:30][CH2:31][C:32]2[CH:33]=[CH:34][C:35]3[O:39][C:38](=[O:40])[NH:37][C:36]=3[CH:41]=2)=[CH:13][CH:12]=1.[H-].[Na+].Cl[CH2:49][CH2:50][CH2:51][O:52][CH3:53].[I-].[Na+]>CN(C)C=O>[CH3:1][O:2][C:3]1[CH:45]=[CH:44][CH:43]=[CH:42][C:4]=1[CH2:5][O:6][CH2:7][CH2:8][CH2:9][O:10][C:11]1[CH:16]=[CH:15][C:14]([CH:17]2[CH2:22][CH2:21][N:20]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:19][CH:18]2[O:30][CH2:31][C:32]2[CH:33]=[CH:34][C:35]3[O:39][C:38](=[O:40])[N:37]([CH2:49][CH2:50][CH2:51][O:52][CH3:53])[C:36]=3[CH:41]=2)=[CH:13][CH:12]=1
Reactant: COc1ccccc1COCCCOc1ccc([C@H]2CCN(C(=O)OC(C)(C)C)C[C@@H]2OCc2ccc3oc(=O)[nH]c3c2)cc1
Reactant: COCCCCl
Agent: [H-]
Agent: [I-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COCCCn1c(=O)oc2ccc(COC3CN(C(=O)OC(C)(C)C)CCC3c3ccc(OCCCOCc4ccccc4OC)cc3)cc21

Procedure:
The solution of 0.206 g of tert-butyl 4-{4-[3-(2-methoxybenzyloxy)propoxy]phenyl}-(3R,4R)-3-(2-oxo-2,3-dihydrobenzoxazol-5-ylmethoxy)piperidine-1-carboxylate in 2 ml of N,N-dimethylformamide is cooled to 0° C. with stirring and admixed with 12 mg of sodium hydride dispersion (60%). The mixture is stirred at 0° C. for 30 minutes and subsequently admixed with 0.048 ml of 1-chloro-3-methoxypropane and 5 mg of sodium iodide. The reaction mixture is stirred at 80° C. for 14 hours, cooled and poured onto water (40 ml). The mixture is extracted with ethyl acetate (2×40 ml). The organic phases are washed successively with water (2×40 ml) and brine (1×40 ml), dried over sodium sulphate and concentrated by evaporation. The title compound is obtained from the residue as a slightly yellowish oil by means of flash chromatography (SiO2 60F). Rf=0.25 (2:1 toluene-EtOAc); Rt=6.03.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[NH:9][N:8]=[C:7]2[OH:13])([O-:3])=[O:2].[CH3:14][N:15]1C(=O)O[C:18](=[O:19])[C:17]2=[CH:23][CH:24]=[CH:25][CH:26]=[C:16]12>>[CH3:14][NH:15][C:16]1[CH:26]=[CH:25][CH:24]=[CH:23][C:17]=1[C:18]([N:9]1[C:10]2[C:6](=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:12][CH:11]=2)[C:7]([OH:13])=[N:8]1)=[O:19]
Reactant: O=[N+]([O-])c1ccc2[nH]nc(O)c2c1
Reactant: Cn1c(=O)oc(=O)c2ccccc21
Product: CNc1ccccc1C(=O)n1nc(O)c2cc([N+](=O)[O-])ccc21
Yield: 47 %

Procedure:
5-Nitro-1H-indazol-3-ol was reacted with N-methylisatoic anhydride according to the general procedure A above and afforded the desired amine as an orange solid in 47.0% yield; m.p. >270° C.
Reaction SMILES: [H-].[Na+].[N:3]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[NH:5][CH:4]=1.[CH2:12]([S:14][C:15]1[N:20]=[C:19](Cl)[CH:18]=[C:17]([CH2:22][CH2:23][CH3:24])[N:16]=1)[CH3:13]>CN(C=O)C>[CH2:12]([S:14][C:15]1[N:20]=[C:19]([N:3]2[C:7]3[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=3[N:5]=[CH:4]2)[CH:18]=[C:17]([CH2:22][CH2:23][CH3:24])[N:16]=1)[CH3:13]
Reactant: CCCc1cc(Cl)nc(SCC)n1
Reactant: c1ccc2[nH]cnc2c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCCc1cc(-n2cnc3ccccc32)nc(SCC)n1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a suspension of NaH (76 mg) in DMF (2 mL) was added benzimidazole, and this was followed by addition of 2-ethylthio4-chloro-6-propylpyrimidine dissolved in DMF (3 mL). The reaction mixture was then placed in a 100° C. oil bath. After 1 h, the reaction was cooled to room temperature, quenched with 5 mL of water and extracted with ethyl acetate. The organic layer was washed with saturated NaCl and dried (anhydrous Na2SO4). Removal of solvent followed by purification on silica gel column (9% acetone/hexane) provided 390 mg of the title compound. Mass spectrum (CI) 298 (M+1). 1H NMR (500 MHz, CDCl3): δ 8.69 (s, 1H); 8.17 (d, J=7.6 Hz, 1H); 7.88 (d, J=7.8 Hz, 1H); 7.42 (m, 2H); 7.05 (s, 1H); 3.27 (q, J=7.4 Hz, 2H); 2.78 (t, J=7.5 Hz, 2H); 1.85 (m, 2H); 1.49 (t, J=7.3 Hz, 3H); 1.05 (t, J=7.3 Hz, 3H).
Reaction SMILES: [Cl:1][C:2]1[C:8]([OH:9])=[CH:7][C:5]([NH2:6])=[C:4]([F:10])[CH:3]=1.Cl[C:12]1[C:21]2[C:16](=[CH:17][C:18]([O:24][CH2:25][C:26]3[CH:31]=[CH:30][N:29]=[CH:28][CH:27]=3)=[C:19]([O:22][CH3:23])[CH:20]=2)[N:15]=[CH:14][N:13]=1.Cl>C(O)(C)C>[ClH:1].[Cl:1][C:2]1[C:8]([OH:9])=[CH:7][C:5]([NH:6][C:12]2[C:21]3[C:16](=[CH:17][C:18]([O:24][CH2:25][C:26]4[CH:31]=[CH:30][N:29]=[CH:28][CH:27]=4)=[C:19]([O:22][CH3:23])[CH:20]=3)[N:15]=[CH:14][N:13]=2)=[C:4]([F:10])[CH:3]=1
Reactant: Nc1cc(O)c(Cl)cc1F
Reactant: COc1cc2c(Cl)ncnc2cc1OCc1ccncc1
Agent: Cl
Solvent: CC(C)O
Product: COc1cc2c(Nc3cc(O)c(Cl)cc3F)ncnc2cc1OCc1ccncc1
Yield: 67.8 %

Procedure:
A mixture of 4-chloro-2-fluoro-3-hydroxyaniline (118 mg, 0.7 mmol), (EP 061741 A2), and 4-chloro-6-methoxy-7-((4-pyridyl)methoxy)quinazoline (200 mg, 0.7 mmol), (prepared as described for the starting material in Example 13), in isopropanol (10 ml) and ethereal hydrogen chloride (5 ml) was heated at 80° C. for 2 hours and the mixture was allowed to cool. The precipitated product was collected by filtration, washed with isopropanol and dried to give 4-(4-chloro-2-fluoro-5-hydroxyanilino)-6-methoxy-7-((4-pyridyl)methoxy)quinazoline hydrochloride (110 mg, 31%).
Reaction SMILES: C([O:8][C:9]1[CH:10]=[CH:11][C:12]2[C:13]3[N:21]=[C:20]([C:22]4[CH:27]=[CH:26][CH:25]=[C:24]([C:28]([F:31])([F:30])[F:29])[CH:23]=4)[CH:19]=[C:18]([C:32]([O:34][CH3:35])=[O:33])[C:14]=3[NH:15][C:16]=2[CH:17]=1)C1C=CC=CC=1>C(O)(C(F)(F)F)=O.O.C(Cl)Cl>[OH:8][C:9]1[CH:10]=[CH:11][C:12]2[C:13]3[N:21]=[C:20]([C:22]4[CH:27]=[CH:26][CH:25]=[C:24]([C:28]([F:31])([F:30])[F:29])[CH:23]=4)[CH:19]=[C:18]([C:32]([O:34][CH3:35])=[O:33])[C:14]=3[NH:15][C:16]=2[CH:17]=1
Reactant: COC(=O)c1cc(-c2cccc(C(F)(F)F)c2)nc2c1[nH]c1cc(OCc3ccccc3)ccc12
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Solvent: O
Product: COC(=O)c1cc(-c2cccc(C(F)(F)F)c2)nc2c1[nH]c1cc(O)ccc12
Yield: 110.9 %

Procedure:
A solution of methyl 7-(benzyloxy)-2-(3-(trifluoromethyl)phenyl)-5H-pyrido[3,2-b]indole-4-carboxylate (1.0 g, 2.1 mmol) in TFA (8.3 mL) and water (2.3 mL) was heated at 90° C. for 3 hrs. The solvent was removed to leave an orange solid. This was suspended in DCM:hexane=1:1 and then collected by filtration to give crude methyl 7-hydroxy-2-(3-(trifluoromethyl)phenyl)-5H-pyrido [3,2-b]indole-4-carboxylate (0.9 g) as a yellow solid that was used as such. MS (ESI) m/z 387.09 (M+H). 1H NMR (500 MHz, DMSO-d6) δ ppm 11.49 (1H, s), 8.53 (1H, s), 8.49 (1H, d, J=7.02 Hz), 8.30 (1H, s), 8.11 (1H, d, J=8.24 Hz), 7.75-7.80 (2H, m), 7.13 (1H, d, J=1.83 Hz), 6.81 (1H, dd, J=8.39, 1.98 Hz), 4.07 (3H, s).
Reaction SMILES: Cl[C:2]([O:4][CH3:5])=[O:3].[Br:6][C:7]1[CH:12]=[CH:11][C:10]([CH2:13][NH2:14])=[C:9]([F:15])[CH:8]=1.C(N(CC)CC)C>C(Cl)Cl>[Br:6][C:7]1[CH:12]=[CH:11][C:10]([CH2:13][NH:14][C:2](=[O:3])[O:4][CH3:5])=[C:9]([F:15])[CH:8]=1
Reactant: NCc1ccc(Br)cc1F
Reactant: COC(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)NCc1ccc(Br)cc1F
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
Methyl chloroformate (85.0 μL, 1.1 mmol) was added to a solution of 1-(4-bromo-2-fluorophenyl)methanamine (0.204 g, 1.0 mmol) and triethylamine (148.1 μL, 1.1 mmol) in methylene chloride (5 mL) at 0° C. After 10 min, the ice-water bath was removed. The mixture was stirred at RT for 1 h, washed with water, and brine. The organic layer was dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue (220 mg, 83.9%) was directly used in next step without further purification. LCMS: (M+H)=263.9/261.8.
Reaction SMILES: [CH2:1]([N:7]1[CH2:12][CH2:11][C:10]([CH3:28])([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([C:19]3[N:20]=[N:21][NH:22][C:23]=3[Si](C)(C)C)[CH:14]=2)[CH:9]([CH3:29])[CH2:8]1)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].C(=O)([O-])O.[Na+]>Cl.CO>[CH2:1]([N:7]1[CH2:12][CH2:11][C:10]([CH3:28])([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([C:19]3[N:20]=[N:21][NH:22][CH:23]=3)[CH:14]=2)[CH:9]([CH3:29])[CH2:8]1)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: CCCCCCN1CCC(C)(c2cccc(-c3nn[nH]c3[Si](C)(C)C)c2)C(C)C1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Product: CCCCCCN1CCC(C)(c2cccc(-c3c[nH]nn3)c2)C(C)C1
Yield: 93.2 %

Procedure:
A solution of 1-hexyl-3,4-dimethyl-4-(3-(5-(trimethylsilyl)-1H-1,2,3-triazol-4-yl)phenyl)piperidine (Example 3, assume 0.64 mmol) in 2 N hydrochloric acid/methanol (1:1, 40 mL) was heated at 90° C. overnight. After allowing to cool, the reaction mixture was adjusted to pH 9 using solid sodium hydrogencarbonate. The aqueous mixture was extracted with ethyl acetate (3×20 mL) and the extracts were dried over MgSO4, filtered and concentrated in vacuo to provide the title compound as a white solid (203 mg, 92%).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][NH:5][C:4](=[O:8])[CH:3]=1.[CH:9]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH:12]=[CH:11][C:10]=1[C:19](Cl)=[O:20]>>[CH:9]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH:12]=[CH:11][C:10]=1[C:19]([O:1][C:2]1[CH:7]=[CH:6][NH:5][C:4](=[O:8])[CH:3]=1)=[O:20]
Reactant: O=c1cc(O)cc[nH]1
Reactant: O=C(Cl)c1ccc2ccccc2c1
Product: O=C(Oc1cc[nH]c(=O)c1)c1ccc2ccccc2c1
Yield: 69.1 %

Procedure:
Using 1.00 g of 4-hydroxy-2-pyridone and 2.57 g of β-naphthoyl chloride and following the general procedure of Example 18, 1.65 g of the title compound was produced in a yield of 69%.
Reaction SMILES: [CH:1]1([NH:4][CH3:5])[CH2:3][CH2:2]1.FC(F)(F)S([O-])(=O)=O.[N:14]1([S:19](N2C=C[NH+](C)C2)(=[O:21])=[O:20])[CH:18]=[CH:17][N:16]=[CH:15]1>>[CH:1]1([N:4]([CH3:5])[S:19]([N:14]2[CH:18]=[CH:17][N:16]=[CH:15]2)(=[O:21])=[O:20])[CH2:3][CH2:2]1
Reactant: CNC1CC1
Reactant: C[NH+]1C=CN(S(=O)(=O)n2ccnc2)C1
Agent: O=S(=O)([O-])C(F)(F)F
Product: CN(C1CC1)S(=O)(=O)n1ccnc1

Procedure:
Imidazole-1-sulfonic acid cyclopropyl-methyl-amide was prepared in accordance with step A of the general method described in example 76 from cyclopropyl-methylamine and 3-(1H-imidazol-1-ylsulfonyl)-1-methyl-1H-imidazolium trifluoromethanesulfonate; MS: m/e=202.5 (M+H+).
Reaction SMILES: [OH:1][C:2]1[N:3]=[CH:4][C:5]([N:8]2[C:15]3[C@@H:14]4[CH2:16][C@@H:13]4[CH2:12][C:11]=3[C:10]([C:17](O)=[O:18])=[N:9]2)=[N:6][CH:7]=1.[NH2:20][C:21]([CH3:25])([CH3:24])[CH2:22][OH:23]>>[OH:23][CH2:22][C:21]([NH:20][C:17]([C:10]1[C:11]2[CH2:12][C@H:13]3[CH2:16][C@H:14]3[C:15]=2[N:8]([C:5]2[CH:4]=[N:3][C:2]([OH:1])=[CH:7][N:6]=2)[N:9]=1)=[O:18])([CH3:25])[CH3:24]
Reactant: O=C(O)c1nn(-c2cnc(O)cn2)c2c1C[C@H]1C[C@@H]21
Reactant: CC(C)(N)CO
Product: CC(C)(CO)NC(=O)c1nn(-c2cnc(O)cn2)c2c1C[C@H]1C[C@@H]21

Procedure:
The title compound was prepared in a manner similar to that described in Method RR using (1aR,5aR)-2-(5-hydroxypyrazin-2-yl)-1a,2,5,5a-tetrahydro-1H-2,3-diaza-cyclopropa[a]pentalene-4-carboxylic acid and 2-amino-2-methylpropan-1-ol. LCMS m/z=330.4 [M+H]+; 1H NMR (400 MHz, DMSO-d6) δ ppm 0.36 (td, J=4.5 and 3.3 Hz, 1H), 1.17-1.23 (m, 1H), 1.30 (s, 3H), 1.31 (s, 3H), 2.23-2.28 (m, 1H), 2.54-2.58 (m, 1H), 2.74 (d, J=16.5 Hz, 1H), 2.85 (dd, J=16.3 and 6.3 Hz, 1H), 3.43 (s, 2H), 7.20 (s, 1H), 8.01 (d, J=1.3 Hz, 1H), 8.38 (bs, 1H).
Reaction SMILES: [CH3:1][NH:2][CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:17][CH2:18][CH2:19][CH2:20][CH3:21]>CC(C)=O>[CH3:1][N:2]([CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)[CH2:17][CH2:18][CH2:19][CH2:20][CH3:21]
Reactant: CNCc1ccccc1
Reactant: CCCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCCCCN(C)Cc1ccccc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 98.2 %

Procedure:
N-methylbenzylamine 100 gms (0.82 moles), acetone (200 ml) and potassium carbonate 114 gms (0.82 moles) were mixed at room temperature and to the slurry obtained, 1-bromopentane 211.4 gms (1.4 moles) was added dropwise at room temperature. Reaction mixture was stirred at room temperature for 18 hours. The reaction mixture was filtered, washed with acetone and concentrated under vacuum to an oily residue. The residue was dissolved in MDC (200 ml) and washed with water (3×100 ml). Organic layer was dried over sodium sulphate and concentrated under vacuum to get 154 gms of the title compound as an oil.
Reaction SMILES: O[CH2:2][C:3]1[CH:8]=[CH:7][N:6]=[C:5]([NH:9][C:10]2[S:11][C:12]([C:15]#[N:16])=[CH:13][N:14]=2)[C:4]=1[CH3:17].CN(C)C=O.P(Cl)(Cl)(Cl)=O.ClCC1C=CN=C(NC2SC(C#N)=CN=2)C=1C.[Cl-].[CH3:46][NH:47][C:48]([N:50]1[CH2:55][CH2:54][NH2+:53][CH2:52][CH2:51]1)=[O:49].C(N(C(C)C)CC)(C)C>ClCCl.CS(C)=O>[CH3:46][NH:47][C:48]([N:50]1[CH2:55][CH2:54][N:53]([CH2:2][C:3]2[CH:8]=[CH:7][N:6]=[C:5]([NH:9][C:10]3[S:11][C:12]([C:15]#[N:16])=[CH:13][N:14]=3)[C:4]=2[CH3:17])[CH2:52][CH2:51]1)=[O:49]
Reactant: CNC(=O)N1CC[NH2+]CC1
Reactant: Cc1c(CO)ccnc1Nc1ncc(C#N)s1
Agent: Cc1c(CCl)ccnc1Nc1ncc(C#N)s1
Agent: [Cl-]
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: CS(C)=O
Product: CNC(=O)N1CCN(Cc2ccnc(Nc3ncc(C#N)s3)c2C)CC1
Reaction time: 5 h

Procedure:
2-(4-Hydroxymethyl-3-methyl-pyridin-2-ylamino)-thiazole-5-carbonitrile (10-4, 0.620 g, 2.52 mmol) was stirred in 5 mL of anhydrous dichloromethane. Anhydrous N,N-dimethylformamide (0.195 mL, 2.52 mmol) was added followed by phosphorous oxychloride (0.235 mL, 2.52 mmol). After 2 hours the reaction was quenched with half-saturated NaHCO3 (aq). The aqueous phase was extracted 3× with DCM. The combined organic extracts were dried over Na2SO4, filtered and concentrated to afford an orange-brown solid. 1H NMR indicated that this solid was composed of impure 2-(4-chloromethyl-3-methyl-pyridin-2-ylamino)thiazole-5-carbonitrile (10-5), containing BINAP dioxide impurity. This material and 4-methylcarbamoyl-piperazin-1-ium chloride (4-3, 0.445 g, 2.48 mmol) were dissolved in 3 mL DMSO. Diisopropylethylamine (0.863 mL, 4.96 mmol) was added and the reaction was stirred for 5 hours. The reaction mixture was then directly loaded onto a reverse phase purification system, which afforded titled compound, 10-6, as the TFA salt. 1H NMR (DMSO-d6) δ 11.60 (s, 1H), 9.77 (bs, 1H), 8.36 (s overlapping with d, 2H), 7.23 (d, 1H, J=5.2 Hz), 6.69 (s, 1H), 4.44 (s, 2H), 4.03 (s, 2H), 3.36 (s, 2H), 3.06 (s, 4H), 2.59 (s, 3H), 2.42 (s, 3H). MS [M+H]+=372.2. (2,6-Dichloro-pyridin-4-yl)-methanol (11-2)
Reaction SMILES: [ClH:1].[CH3:2][C:3]1[CH:8]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:6]=[CH:5][C:4]=1[C:13]1[CH:14]=[C:15]([CH:20]=[CH:21][N:22]=1)[C:16]([O:18][CH3:19])=[O:17]>CO.[Pt](=O)=O>[ClH:1].[CH3:2][C:3]1[CH:8]=[C:7]([C:9]([F:10])([F:11])[F:12])[CH:6]=[CH:5][C:4]=1[CH:13]1[CH2:14][CH:15]([C:16]([O:18][CH3:19])=[O:17])[CH2:20][CH2:21][NH:22]1
Reactant: COC(=O)c1ccnc(-c2ccc(C(F)(F)F)cc2C)c1
Agent: O=[Pt]=O
Agent: Cl
Solvent: CO
Product: COC(=O)C1CCNC(c2ccc(C(F)(F)F)cc2C)C1
Reaction time: 5 h
Yield: 87.3 %

Procedure:
Methyl 2-(2-methyl-4-(trifluoromethyl)phenyl)isonicotinate hydrochloride (9 g, 27.13 mmol) was dissolved in MeOH (50 mL), platinum(IV) oxide (0.185 g, 0.81 mmol) was added and the resulting mixture hydrogenated in a Büchi hydrogenator at 5 bar for 5 h. The catalyst was filtered off and the filtrate evaporated to give methyl 2-(2-methyl-4-(trifluoromethyl)phenyl)-piperidine-4-carboxylate hydrochloride (8 g, 87%) as a yellowish solid. MS m/z 302 (M+H)+