Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: F[C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][C:3]=1[C:10]([F:13])([F:12])[F:11].[NH:14]1[CH2:19][CH2:18][O:17][CH2:16][CH2:15]1.C(=O)([O-])[O-].[K+].[K+]>CS(C)=O>[O:17]1[CH2:18][CH2:19][N:14]([C:2]2[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][C:3]=2[C:10]([F:13])([F:12])[F:11])[CH2:15][CH2:16]1
Reactant: C1COCCN1
Reactant: N#Cc1ccc(F)c(C(F)(F)F)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: N#Cc1ccc(N2CCOCC2)c(C(F)(F)F)c1
Temperature: 90 °C
Yield: 85.2 %

Procedure:
To a solution of 4-fluoro-3-(trifluoromethyl)benzonitrile (15 g, 79 mmol) in dimethylsulfoxide (160 mL) was added morpholine (13.8 mL, 159 mmol) and potassium carbonate (16.4 g, 119 mmol). The mixture was heated at about 90° C. for 18 hours. The mixture was cooled to ambient temperature and the solid was removed by filtration. The fitrate was partitioned between ethyl acetate (1.8 L) and water (1.5 L). The organic layer was washed with water (1.0 L) and brine (1.0 L) and dried over anhydrous magnesium sulphate. The solvent was removed in vacuo to give 4-morpholino-3-(trifluoromethyl)benzonitrile (17.25 g, 85%). 1H NMR (DMSO-d6, 400 MHz) δ 8.18 (d, J=2.05 Hz, 1H), 8.09 (dd, J=8.51, 2.06 Hz, 1H), 7.60 (d, J=8.52 Hz, 1H), 3.69-3.75 (m, 4H), 2.97-3.04 (m, 4H).
Reaction SMILES: CC(OC(/N=N/C(OC(C)C)=O)=O)C.[Cl:15][C:16]1[C:17]([OH:26])=[C:18]([C:23](=[O:25])[CH3:24])[CH:19]=[CH:20][C:21]=1[OH:22].O[CH2:28][C:29]1[CH:34]=[CH:33][C:32]([CH:35]([O:44][CH:45]2[CH2:50][CH2:49][CH2:48][CH2:47][O:46]2)[C:36]2[CH:37]=[C:38]([CH:41]=[CH:42][CH:43]=2)[C:39]#[N:40])=[CH:31][CH:30]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>O1CCCC1>[C:23]([C:18]1[CH:19]=[CH:20][C:21]([O:22][CH2:28][C:29]2[CH:30]=[CH:31][C:32]([CH:35]([O:44][CH:45]3[CH2:50][CH2:49][CH2:48][CH2:47][O:46]3)[C:36]3[CH:37]=[C:38]([CH:41]=[CH:42][CH:43]=3)[C:39]#[N:40])=[CH:33][CH:34]=2)=[C:16]([Cl:15])[C:17]=1[OH:26])(=[O:25])[CH3:24]
Reactant: CC(=O)c1ccc(O)c(Cl)c1O
Reactant: N#Cc1cccc(C(OC2CCCCO2)c2ccc(CO)cc2)c1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(=O)c1ccc(OCc2ccc(C(OC3CCCCO3)c3cccc(C#N)c3)cc2)c(Cl)c1O
Temperature: 25 °C
Reaction time: 2 h
Yield: 98.6 %

Procedure:
Add diisopropylazodicarboxylate (DIAD, 5.418 g, 26.80 mmol) to a solution of 1-(3-chloro-2,4-dihydroxy-phenyl)ethanone (5.000 g, 26.80 mmol), 3-[(4-hydroxymethyl-phenyl)-(tetrahydro-pyran-2-yloxy)-methyl]-benzonitrile (8.666 g, 26.80 mmol), and triphenylphosphine (7.028 g, 26.80 mmol) in tetrahydrofuran (0.200M) at 0° C. Stir for 2 hours while warming to room temperature. Add silica gel and evaporate solvent. Chromatograph with Biotage Flash 75, eluting with 50-90% ethyl acetate/hexanes to afford the title compound as a white solid (13.00 g, 26.42 mmol, 98%): MS (m/z): 490 (M−H).
Reaction SMILES: C([Li])CCC.[Cl:6][C:7]1[CH:8]=[C:9]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH:10]=[CH:11][C:12]=1[C:13]#[CH:14].[C:21](=[O:23])=[O:22]>C1COCC1>[Cl:6][C:7]1[CH:8]=[C:9]([C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH:10]=[CH:11][C:12]=1[C:13]#[C:14][C:21]([OH:23])=[O:22]
Reactant: C#Cc1ccc(-c2ccccc2)cc1Cl
Reactant: O=C=O
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: O=C(O)C#Cc1ccc(-c2ccccc2)cc1Cl
Temperature: -60 °C

Procedure:
13.8 mL (22.1 mmol) of butyllithium solution (1.6M in hexane) are added dropwise to a solution of 4.7 g (22.1 mmol) of 3-chloro-4-ethynylbiphenyl in 100 mL of absolute THF at −10° C. to −20° C. and after five minutes cooled to −60° C. At this temperature dry ice is added batchwise to the reaction mixture and it is slowly allowed to come up to ambient temperature. Then the solvent is evaporated down and the residue is extracted between ethyl acetate and 1M hydrochloric acid. The organic phase is dried, the desiccant filtered off, and the solvent concentrated by evaporation. The residue is stirred with petroleum ether, suction filtered, and dried at 80° C. in the circulating air dryer. Yield: 4.8 g (85% of theory); C15H9ClO2 (M=256.68); calc.: molecular ion peak (M+H)+: 257/259 (Cl); found: molecular ion peak (M+H)+: 257/259 (Cl); Rf value: 0.2 (silica gel, dichloromethane/methanol/glacial acetic acid (90:10:0.1)).
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[C:12]([CH3:14])[C:11]([CH2:15][NH:16][C:17]([C:19]2[O:20][C:21]([CH2:24][C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)=[N:22][N:23]=2)=[O:18])=[C:10]([CH3:31])[N:9]=1)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH2:7][C:8]1[N:9]=[C:10]([CH3:31])[C:11]([CH2:15][NH:16][C:17]([C:19]2[O:20][C:21]([CH2:24][C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)=[N:22][N:23]=2)=[O:18])=[C:12]([CH3:14])[CH:13]=1
Reactant: Cc1cc(NC(=O)OC(C)(C)C)nc(C)c1CNC(=O)c1nnc(Cc2ccccc2)o1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1cc(N)nc(C)c1CNC(=O)c1nnc(Cc2ccccc2)o1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of (5-{[(5-Benzyl-[1,3,4]oxadiazole-2-carbonyl)-amino]-methyl}-4,6-dimethyl-pyridin-2-yl)-carbamic acid tert-butyl ester (412 mg, 0.94 mmol), 4 mL TFA and 8 mL DCM was stirred of room temperature for 2 h. The mixture was evaporated in vacuo and the residue was purified by preparative HPLC (Macherey-Nagel Nucleosil 250×40 mm, 5 to 100% ACN and 0.1% TFA, flow 40ml/min). The product containing fractions were lyophilised, then dissolved in 1 mL MeOH and the resulting mixture was filtered over a MeOH flushed PL-HCO3 MP-resin column. The column was washed with MeOH, the solvent was removed and the crude product was dissolved in water/ACN and lyophilised to yield the title compound. 1H-NMR (DMSO-d6, 400 MHz) 9.33 (t, 1H), 7.29-7.39 (m, 5H), 6.11 (s, 1H), 5.71 (bs, 2H), 4.34-4.36 (m, 4H), 2.30 (s, 3 H), 2.17 (s, 3H); LCMS (method A) RtA=0.814 min; [M+H]+=338.0.
Reaction SMILES: [CH3:1][C:2]([CH:4]1[CH2:6][CH2:5]1)=[O:3].[Br:7][C:8]1[CH:17]=[CH:16][C:11]([C:12](OC)=[O:13])=[C:10]([CH2:18][S:19][CH3:20])[CH:9]=1.[H-].[Na+].C(=O)(O)[O-].[Na+]>O1CCCC1>[Br:7][C:8]1[CH:17]=[CH:16][C:11]([C:12](=[O:13])[CH2:1][C:2]([CH:4]2[CH2:6][CH2:5]2)=[O:3])=[C:10]([CH2:18][S:19][CH3:20])[CH:9]=1
Reactant: COC(=O)c1ccc(Br)cc1CSC
Reactant: CC(=O)C1CC1
Agent: O=C([O-])O
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CSCc1cc(Br)ccc1C(=O)CC(=O)C1CC1
Temperature: 0 °C
Yield: 52.1 %

Procedure:
A solution of cyclopropyl methyl ketone (1.1 g) and methyl 4-bromo-2-(methylsulphenylmethyl)benzoate (3.6 g ) in tetrahydrofuran was added to a refluxing suspension of sodium hydride (80%, 0.9 g) in tetrahydrofuran. After the addition was complete, the mixture was maintained at reflux temperature for 30 minutes. It was then cooled and poured onto 100 g of ice and 50 ml of saturated aqueous sodium bicarbonate. The mixture was extracted with hexane, the organic solution dried (anhydrous sodium sulphate) and the solvent evaporated to give 1-[4-bromo-2-(methylsulphenylmethyl)phenyl]-3-cyclopropylpropan-1,3-dione as an orange oil (2.23 g), NMR (CDCl3): 1.00(2H, m), 1.20(2H, m), 1.75(1H, m), 2.03(3H, s), 3.92(2H, s), 6.00(1H, s), 7.35(1H, m), 7.45(1H, m), 7.58(1H, m) 14.74(1H, s).
Reaction SMILES: [Cl:1][C:2]1[CH:12]=[CH:11][C:10]([CH2:13][NH:14][C:15](=[O:20])[C:16]([F:19])([F:18])[F:17])=[CH:9][C:3]=1[C:4]([N:6]=[C:7]=[O:8])=[O:5].[CH3:21][O:22][C:23]1[CH:24]=[C:25]([NH:32][NH:33][C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35])[CH:26]=[CH:27][C:28]=1[N+:29]([O-:31])=[O:30]>C(Cl)Cl>[Cl:1][C:2]1[CH:12]=[CH:11][C:10]([CH2:13][NH:14][C:15](=[O:20])[C:16]([F:18])([F:19])[F:17])=[CH:9][C:3]=1[C:4]([NH:6][C:7]([N:32]([C:25]1[CH:26]=[CH:27][C:28]([N+:29]([O-:31])=[O:30])=[C:23]([O:22][CH3:21])[CH:24]=1)[NH:33][C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35])=[O:8])=[O:5]
Reactant: COc1cc(NNC(=O)OC(C)(C)C)ccc1[N+](=O)[O-]
Reactant: O=C=NC(=O)c1cc(CNC(=O)C(F)(F)F)ccc1Cl
Solvent: ClCCl
Product: COc1cc(N(NC(=O)OC(C)(C)C)C(=O)NC(=O)c2cc(CNC(=O)C(F)(F)F)ccc2Cl)ccc1[N+](=O)[O-]
Yield: 74.2 %

Procedure:
The title compound was prepared according to the procedure described in step-1 of Intermediate-9 by using 2-chloro-5-((2,2,2-trifluoroacetamido)methyl)benzoyl isocyanate (step-3 of Intermediate-26, 1.400 g, 4.57 mmol), tert-butyl 2-(3-methoxy-4-nitrophenyl)hydrazinecarboxylate (step-3 of Intermediate-32, 1.30 g, 4.57 mmol) and DCM 30 mL) to afford 2.0 g of the desired product. 1H NMR (300 MHz, DMSO d6): δ 1.33-1.46 (m, 9H), 3.87 (s, 3H), 4.40 (s, 2H), 7.06 (d, J=8.4 Hz, 1H), 7.32-7.36 (m, 3H), 7.45-7.52 (m, 1H), 7.96 (d, J=8.7 Hz, 1H), 9.92 (s, 1H), 10.07 (br s, 1H), 11.13 (br s, 1H); MS (m/z): 589.69 (M)+.
Reaction SMILES: [OH:1]O.[CH3:3][O:4][C:5]1[CH:10]=[CH:9][C:8](B(O)O)=[C:7]([CH3:14])[N:6]=1.O>ClCCl>[CH3:3][O:4][C:5]1[N:6]=[C:7]([CH3:14])[C:8]([OH:1])=[CH:9][CH:10]=1
Reactant: OO
Reactant: COc1ccc(B(O)O)c(C)n1
Solvent: ClCCl
Solvent: O
Product: COc1ccc(O)c(C)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 62.3 %

Procedure:
Add hydrogen peroxide (7.69 mL, 89.8 mmol) to a stirred mixture of 2-methoxy-6-methyl-5-pyridylboronic acid (5.0 g, 30 mmol) in dichloromethane (100 mL) kept under nitrogen at room temperature. Stir overnight at ambient temperature, add water and extract the mixture with dichloromethane. Combine the organic phases, dry (MgSO4), filter and concentrate to afford 2.6 g (62%) of the title compound. MS (m/z)=140 [M+1]
Reaction SMILES: [Cl:1][C:2]1[CH:24]=[C:23]([CH3:25])[C:5]([O:6][C:7]2[C:12]([O:13]C)=[C:11]([C:15](=[O:21])[CH:16]([CH2:19][CH3:20])[CH2:17][CH3:18])[CH:10]=[C:9]([CH3:22])[N:8]=2)=[C:4]([CH3:26])[CH:3]=1.B(Br)(Br)Br.B(Cl)(Cl)Cl>C1COCC1.C(Cl)Cl>[Cl:1][C:2]1[CH:24]=[C:23]([CH3:25])[C:5]([O:6][C:7]2[C:12]([OH:13])=[C:11]([C:15](=[O:21])[CH:16]([CH2:17][CH3:18])[CH2:19][CH3:20])[CH:10]=[C:9]([CH3:22])[N:8]=2)=[C:4]([CH3:26])[CH:3]=1
Reactant: CCC(CC)C(=O)c1cc(C)nc(Oc2c(C)cc(Cl)cc2C)c1OC
Agent: BrB(Br)Br
Agent: ClB(Cl)Cl
Solvent: ClCCl
Solvent: C1CCOC1
Product: CCC(CC)C(=O)c1cc(C)nc(Oc2c(C)cc(Cl)cc2C)c1O

Procedure:
The title compound was prepared by reacting 1-[2-(4-Chloro-2,6-dimethyl-phenoxy)-3-methoxy-6-methyl-pyridin-4-yl]-2-ethyl-butan-1-one with BBr3 or BCl3 in THF or methylene chloride. 1H NMR (CDCl3) d 7.04(s,2H), 7.01(s,1H), 3.26(m,1H), 2.24(s,3H), 2.08(s,6H), 1.80(m,2H), 1.63(m,2H), 0.91(t,6H) ppm.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([CH3:8])[N:5]=[C:4]([C:9](Cl)=[O:10])[CH:3]=1.[OH2:12]>>[Cl:1][C:2]1[N:7]=[C:6]([CH3:8])[N:5]=[C:4]([C:9]([OH:10])=[O:12])[CH:3]=1
Reactant: Cc1nc(Cl)cc(C(=O)Cl)n1
Reactant: O
Product: Cc1nc(Cl)cc(C(=O)O)n1
Reaction time: 0.5 h

Procedure:
16 g of 6-chloro-2-methylpyrimidine-4-carbonyl chloride are added dropwise at 10°-15° C. to 150 ml of water. The mixture is then stirred for 1/2 h, the solid is filtered off with suction, and the filter residue is then washed well with water and dried in vacuo at 50° C. 11.5 g of 6-chloro-2-methylpyrimidine-4-carboxylic acid of melting point 132° C. (dec.) are obtained in this way.
Reaction SMILES: Cl[C:2]1[C:3](=[O:19])[NH:4][N:5]=[CH:6][C:7]=1[CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[C:15]([F:18])([F:17])[F:16].[OH-].[Na+].[H][H]>[Pd].C(O)C>[F:18][C:15]([F:16])([F:17])[C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=1[CH2:8][C:7]1[CH:6]=[N:5][NH:4][C:3](=[O:19])[CH:2]=1
Reactant: O=c1[nH]ncc(Cc2ccccc2C(F)(F)F)c1Cl
Reactant: [H][H]
Agent: [Pd]
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=c1cc(Cc2ccccc2C(F)(F)F)cn[nH]1
Reaction time: 20 h
Yield: 79.7 %

Procedure:
A pressure vial containing a mixture of 4-chloro-5-(2-trifluoromethyl-benzyl)-2H-pyridazin-3-one (328.1 mg, 1.1 mmol), ethanol (12.1 mL), and a 2N aqueous sodium hydroxide solution (0.61 mL) was treated with 10% palladium on carbon (121 mg). The reaction was then pressurized with hydrogen (50 psi), where it shook for 20 h. The resulting reaction mixture was removed from the hydrogenator and then filtered through a pad of diatomaceous earth, washing with ethanol. The filtrate was concentrated in vacuo to remove organics. The resulting residue was taken up in 90/10 methylene chloride/methanol (75 mL) and water (40 mL). The aqueous layer was acidified with a 2N aqueous hydrochloric acid solution to pH=1, and the layers were separated. The aqueous layer was then back extracted with a 90/10 methylene chloride/methanol solution (2×75 mL). The combined organic layers were dried over sodium sulfate, filtered, and concentrated in vacuo to afford 5-(2-trifluoromethyl-benzyl)-2H-pyridazin-3-one (223 mg, 77%) as a yellow solid; ES+-HRMS m/e calcd for C12H9N2OF3 [M+H+] 255.0740, found 255.0740. 1H NMR (300 MHz, DMSO-d6) δ ppm 4.05 (s, 2H), 6.28 (s, 1H), 7.49 (d, J=7.8 Hz, 1H), 7.54 (d, J=7.8 Hz, 1H), 7.69 (t, J=7.8 Hz, 1H), 7.75 (d, J=2.1 Hz, 1H), 7.78 (d, J=7.8 Hz, 1H), 12.96 (br. s., 1H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([O:16][CH2:17][CH2:18][CH2:19][N:20]([CH3:22])[CH3:21])=[C:6]([C:8]2[CH:13]=[C:12](Cl)[N:11]=[C:10]([NH2:15])[N:9]=2)[CH:7]=1.[Cl:23][C:24]1[CH:29]=[CH:28][C:27]([NH2:30])=[CH:26][CH:25]=1>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([O:16][CH2:17][CH2:18][CH2:19][N:20]([CH3:22])[CH3:21])=[C:6]([C:8]2[N:9]=[C:10]([NH2:15])[N:11]=[C:12]([NH:30][C:27]3[CH:28]=[CH:29][C:24]([Cl:23])=[CH:25][CH:26]=3)[CH:13]=2)[CH:7]=1
Reactant: CN(C)CCCOc1ccc(Br)cc1-c1cc(Cl)nc(N)n1
Reactant: Nc1ccc(Cl)cc1
Product: CN(C)CCCOc1ccc(Br)cc1-c1cc(Nc2ccc(Cl)cc2)nc(N)n1
Yield: 55 %

Procedure:
Following the method described in Example 4, 4-[5-bromo-2-(3-dimethylamino-propoxy)-phenyl]-6-chloro-pyrimidin-2-ylamine and 4-chloro-phenylamine provided the title compound (55% yield) as its hydrochloride salt. 1H NMR (CD3OD) δ 2.28-2.32 (m, 2H, CH2), 2.92 (s, 6H, CH3), 3.28-3.36 (m, 2H, CH2), 4.25 (m, 2H, CH2), 6.51 (s, 1H, Ar), 7.20-7.22 (m, 1H, Ar), 7.41-7.43 (m, 2H, Ar), 7.73-7.76 (m, 2H, Ar), 7.85-7.86 (m, 2H, Ar).
Reaction SMILES: [F:1][C:2]1[CH:56]=[CH:55][CH:54]=[CH:53][C:3]=1[CH2:4][N:5]1[CH:10]2[CH2:11][CH2:12][CH:6]1[CH:7]([C:13]1[O:14][C:15]([C:18]3[CH:19]=[C:20]4[C:24](=[CH:25][CH:26]=3)[N:23](C(C3C=CC=CC=3)(C3C=CC=CC=3)C3C=CC=CC=3)[N:22]=[C:21]4[C:46]3[CH:51]=[CH:50][N:49]=[C:48]([CH3:52])[CH:47]=3)=[N:16][N:17]=1)[CH2:8][CH2:9]2.C([SiH](CC)CC)C>>[F:1][C:2]1[CH:56]=[CH:55][CH:54]=[CH:53][C:3]=1[CH2:4][N:5]1[CH:10]2[CH2:11][CH2:12][CH:6]1[CH:7]([C:13]1[O:14][C:15]([C:18]3[CH:19]=[C:20]4[C:24](=[CH:25][CH:26]=3)[NH:23][N:22]=[C:21]4[C:46]3[CH:51]=[CH:50][N:49]=[C:48]([CH3:52])[CH:47]=3)=[N:16][N:17]=1)[CH2:8][CH2:9]2
Reactant: Cc1cc(-c2nn(C(c3ccccc3)(c3ccccc3)c3ccccc3)c3ccc(-c4nnc(C5CCC6CCC5N6Cc5ccccc5F)o4)cc23)ccn1
Agent: CC[SiH](CC)CC
Product: Cc1cc(-c2n[nH]c3ccc(-c4nnc(C5CCC6CCC5N6Cc5ccccc5F)o4)cc23)ccn1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To 2-(8-(2-Fluorobenzyl)-8-azabicyclo[3.2.1]octan-2-yl)-5-(3-(2-methylpyridin-4-yl)-1-trityl-1H-indazol-5-yl)-1,3,4-oxadiazole (40 mg, 0.054 mmol) 95% trifluoroacetic acid (3 mL) was added. The reaction was stirred at room temperature for 30 minutes. After reaction completion, triethylsilane (0.1 mL) was added. The reaction was concentrated and submitted for prep LC/MS. A total of 6 mg of purified compound was retrieved.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]([OH:16])=O)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH3:48][N:49]1[CH2:54][CH2:53][NH:52][CH2:51][CH2:50]1>CN(C)C=O>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][CH:11]([C:14]([N:52]2[CH2:53][CH2:54][N:49]([CH3:48])[CH2:50][CH2:51]2)=[O:16])[CH2:12][CH2:13]1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CN1CCNCC1
Reactant: CC(C)(C)OC(=O)N1CCC(C(=O)O)CC1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CN1CCN(C(=O)C2CCN(C(=O)OC(C)(C)C)CC2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 86.8 %

Procedure:
The solution of 1-(tert-butoxycarbonyl)-4-piperidinecarboxylic acid (Aldrich) (21.88 g, 95.4 mmol), triethylamine (13.3 mL, 95.4 mmol) and HBTU [O-benzotriazol-1-yl-N,N,N′,N′-tetramethyluronium hexafluorophosphate (Advanced Chem. Tech.)] (38.36 g, 101.0 mmol) in dry dimethylformamide (100 mL) was stirred at room temperature for five minutes before N-methyl-piperazine (10.6 mL, 95.5 mmol) was added. The pH of the reaction mixture was adjusted to 8 by the addition of triethylamine, the so obtained mixture was stirred at room temperature overnight, then concentrated in vacuo. The residue was treated with saturated sodium hydrogencarbonate solution (350 mL), extracted with ethyl acetate (3×250 mL), the combined organic layers were washed with saturated sodium hydrogencarbonate solution, water and brine, dried over sodium sulfate, filtered and concentrated. The residue was submitted to column chromatography using Kieselgel 60 (0.040-0.063 mm) (Merck) as adsorbent, and chloroform:methanol=9:1 as eluent to yield 25.8 g (87%) of the title compound as an oil.
Reaction SMILES: [CH3:1][N:2]([C:16]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=[O:17])[CH:3]1[CH2:8][CH2:7][N:6](C(OC(C)(C)C)=O)[CH2:5][CH2:4]1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH3:1][N:2]([CH:3]1[CH2:8][CH2:7][NH:6][CH2:5][CH2:4]1)[C:16](=[O:17])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: CN(C(=O)c1ccccc1)C1CCN(C(=O)OC(C)(C)C)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CN(C(=O)c1ccccc1)C1CCNCC1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
1,1-dimethylethyl 4-[methyl(phenylcarbonyl)amino]-1-piperidinecarboxylate D14 (1.66 g) was dissolved in DCM (5 mL) then TFA (4.02 mL, 52.1 mmol) was slowly added. The reaction was stirred at room temperature for 30 minutes. TFA and DCM were removed in vacuo. The crude mixture was poured on a top of an Isolute Si—SCX-2 cartridge, eluting with DCM then MeOH then a 2M NH3 in MeOH solution. Fractions containing desired compound were evaporated in vacuo to give title compound D15 in 1.18 g. LCMS [M+H]+219.01@0.45 min (2 min run)
Reaction SMILES: [Cl-].[CH3:2][O:3][CH2:4][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C([Li])CCC.[Cl:29][C:30]1[N:34]([CH3:35])[N:33]=[C:32]([C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][N:37]=2)[C:31]=1[C:42]([C:44]1[CH:49]=[CH:48][C:47]([Cl:50])=[CH:46][C:45]=1[CH3:51])=O.[NH4+].[Cl-]>C1COCC1>[Cl:29][C:30]1[N:34]([CH3:35])[N:33]=[C:32]([C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][N:37]=2)[C:31]=1[C:42]([C:44]1[CH:49]=[CH:48][C:47]([Cl:50])=[CH:46][C:45]=1[CH3:51])=[CH:2][O:3][CH3:4]
Reactant: Cc1cc(Cl)ccc1C(=O)c1c(-c2ccccn2)nn(C)c1Cl
Reactant: COC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Product: COC=C(c1ccc(Cl)cc1C)c1c(-c2ccccn2)nn(C)c1Cl
Temperature: -10 °C
Reaction time: 1 h
Yield: 68.9 %

Procedure:
To a solution of (methoxymethyl)triphenylphosphonium chloride (91 g, 265 mmol) in THF (330 mL) at about −10° C. was added 1.6 M butyllithium in hexanes (161 mL, 258 mmol) dropwise. The mixture was stirred at about −10° C. for about 1 h. A solution of (5-chloro-1-methyl-3-(pyridin-2-yl)-1H-pyrazol-4-yl)(4-chloro-2-methylphenyl)methanone (22.35 g, 64.6 mmol) in THF (220 mL) was added to the mixture in a dropwise manner. The mixture was stirred at about −10° C. for about 16 h then treated with a saturated aqueous NH4Cl solution (1000 mL). The mixture was extracted with EtOAc (2×700 mL). The combined organic layers were washed with brine (500 mL), dried with Na2SO4, filtered and concentrated in vacuo. The residue was purified by column chromatography (SiO2, 0-25% EtOAc/heptanes) to give 2-(5-chloro-4-(1-(4-chloro-2-methylphenyl)-2-methoxyvinyl)-1-methyl-1H-pyrazol-3-yl)pyridine (16.65 g, 69%): LC-MS (Table 1, Method g) Rt=2.56 min, m/z 374/376 (M+H)+; 1H-NMR (CDCl3, Bruker 400 MHz) δ 8.44-8.39 (m, 1H), 7.70-7.58 (m, 2H), 7.21-6.93 (m, 4H), 6.39 (s, 1H), 3.90 (s, 3H), 3.64 (s, 3H), 2.28 (2s, 3H) major; 1H-NMR (CDCl3, Bruker 400 MHz) δ 8.44-8.39 (m, 1H), 7.70-7.58 (m, 2H), 7.21-6.93 (m, 4H), 6.38 (s, 1H), 3.88 (s, 3H), 3.52 (s, 3H), 2.20 (s, 3H) minor.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[C:7]3[N:15]=[C:14]([N:16]4[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]4)[CH:13]=[C:12]([C:22]([O:24]C)=O)[C:8]=3[NH:9][C:10]=2[CH:11]=1.[NH3:26]>CO>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[C:7]3[N:15]=[C:14]([N:16]4[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21]4)[CH:13]=[C:12]([C:22]([NH2:26])=[O:24])[C:8]=3[NH:9][C:10]=2[CH:11]=1
Reactant: COC(=O)c1cc(N2CCCCC2)nc2c1[nH]c1cc(OC)ccc12
Reactant: N
Solvent: CO
Product: COc1ccc2c(c1)[nH]c1c(C(N)=O)cc(N3CCCCC3)nc12
Temperature: 75 °C
Yield: 87 %

Procedure:
A mixture of methyl 7-methoxy-2-(piperidin-1-yl)-5H-pyrido[3,2-b]indole-4-carboxylate (15 mg, 0.044 mmol) and 7 N NH3 in MeOH (1.5 mL) in a sealed microwave tube was heated at 75° C. for 40 h. Removal of solvent to afford 7-methoxy-2-(piperidin-1-yl)-5H-pyrido[3,2-b]indole-4-carboxamide (14 mg, 0.038 mmol, 87% yield) as a solid. MS (ESI) m/z 325.1 (M+H). 1H NMR (500 MHz, MeOD) δ ppm 8.04 (1H, d, J=8.85 Hz), 7.21 (1H, s), 7.06 (1H, d, J=2.14 Hz), 6.82 (1H, dd, J=8.70, 2.29 Hz), 3.91 (3H, s), 3.49-3.62 (4H, m), 1.74-1.82 (4H, m), 1.66-1.73 (2H, m).
Reaction SMILES: C(N(CC)CC)C.ClC(OCC)=O.[CH:14]1([C:19]([OH:21])=O)[CH2:18][CH2:17][CH2:16][CH2:15]1.Cl.Cl.[NH2:24][C:25]1[CH:57]=[CH:56][C:28]([O:29][C:30]2[CH:31]=[CH:32][C:33]3[N:37]=[C:36]([CH2:38][O:39][C:40]4[CH:53]=[CH:52][C:43]([CH2:44][CH:45]5[S:49][C:48](=[O:50])[NH:47][C:46]5=[O:51])=[CH:42][CH:41]=4)[N:35]([CH3:54])[C:34]=3[CH:55]=2)=[CH:27][CH:26]=1>CN(C)C=O>[O:50]=[C:48]1[NH:47][C:46](=[O:51])[CH:45]([CH2:44][C:43]2[CH:42]=[CH:41][C:40]([O:39][CH2:38][C:36]3[N:35]([CH3:54])[C:34]4[CH:55]=[C:30]([O:29][C:28]5[CH:56]=[CH:57][C:25]([NH:24][C:19]([CH:14]6[CH2:15][CH2:16][CH2:17][CH2:18]6)=[O:21])=[CH:26][CH:27]=5)[CH:31]=[CH:32][C:33]=4[N:37]=3)=[CH:53][CH:52]=2)[S:49]1
Reactant: O=C(O)C1CCCC1
Reactant: Cn1c(COc2ccc(CC3SC(=O)NC3=O)cc2)nc2ccc(Oc3ccc(N)cc3)cc21
Agent: CCOC(=O)Cl
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: Cn1c(COc2ccc(CC3SC(=O)NC3=O)cc2)nc2ccc(Oc3ccc(NC(=O)C4CCCC4)cc3)cc21

Procedure:
A reaction was conducted by a similar procedure to that described in Example 58 using triethylamine (0.32 ml), ethyl chloroformate (0.08 ml), cyclopentanecarboxylic acid (0.09 ml), anhydrous N,N-dimethylformamide (8 ml) and 5-[4-[6-(4-aminophenoxy)-1-methyl-1H-benzimidazol-2-ylmethoxy]benzyl]thiazolidine-2,4-dione dihydrochloride (400 mg). The reaction mixture was concentrated under reduced pressure. The residue was partitioned between ethyl acetate and water. The extract was washed with saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate and concentrated. To the residue was added water and ethyl acetate and the insoluble material was isolated by filtration to afford the title compound (236 mg, white powder, mp 227-228° C.).
Reaction SMILES: [NH2:1][C:2]1[C:10]([F:11])=[CH:9][C:8]([F:12])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].Cl[C:14](Cl)([O:16]C(=O)OC(Cl)(Cl)Cl)Cl>O1CCCC1>[F:12][C:8]1[CH:9]=[C:10]([F:11])[C:2]2[NH:1][C:14](=[O:16])[O:5][C:4](=[O:6])[C:3]=2[CH:7]=1
Reactant: Nc1c(F)cc(F)cc1C(=O)O
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Solvent: C1CCOC1
Product: O=c1[nH]c2c(F)cc(F)cc2c(=O)o1
Temperature: 25 °C
Reaction time: 4 h
Yield: 94 %

Procedure:
2-Amino-3,5-difluoro-benzoic acid (2.44 g, 0.0141 mol) was dissolved in Tetrahydrofuran (100 mL). Triphosgene (4.18 g, 0.0141 mol) was dissolved in Tetrahydrofuran (10 mL) and added. The resulting solution was stirred for 4 h at rt. The reaction mixture was concentrated, and the resulting residue was sonicated in H20. The peach ppt was filtered, taken up in acetone, and was concentrated under reduced pressure. It was then azeotroped in toluene to give 6,8-Difluoro-1H-3,1-benzoxazine-2,4-dione as tan solids (2.64 g, 94%). 1H-NMR (DMSO): 12.00 (s, 1H), 7.85 (m, 1H), 7.60 (m, 1H); 19F-NMR (DMSO): −116, −125.