Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[C:3]([O:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[N:4][C:5]([CH3:22])=[C:6]([CH3:21])[C:7]=1[NH:8][CH2:9][CH2:10][CH2:11][CH2:12][NH:13][C:14](=[O:20])[O:15][C:16]([CH3:19])([CH3:18])[CH3:17].[C:30](OC)(OC)(OC)[CH2:31][CH2:32][CH3:33]>>[CH3:22][C:5]1[N:4]=[C:3]([O:23][C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=2)[C:2]2[N:1]=[C:30]([CH2:31][CH2:32][CH3:33])[N:8]([CH2:9][CH2:10][CH2:11][CH2:12][NH:13][C:14](=[O:20])[O:15][C:16]([CH3:19])([CH3:18])[CH3:17])[C:7]=2[C:6]=1[CH3:21]
Reactant: Cc1nc(Oc2ccccc2)c(N)c(NCCCCNC(=O)OC(C)(C)C)c1C
Reactant: CCCC(OC)(OC)OC
Product: CCCc1nc2c(Oc3ccccc3)nc(C)c(C)c2n1CCCCNC(=O)OC(C)(C)C
Yield: 83.1 %

Procedure:
Using the general method of Example 15 Part E, tert-butyl 4-[(3-amino-5,6-dimethyl-2-phenoxypyridin-4-yl)amino]butylcarbamate (3.41 g, 8.51 mmol) was reacted with trimethyl orthobutyrate (1.50 mL, 9.37 mmol) to provide 3.2 g of crude tert-butyl 4-(6,7-dimethyl-4-phenoxy-2-propyl-1H-imidazo[4,5-c]pyridin-1-yl)butylcarbamate as purplish semisolid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[N:13]2[N:14]=[C:15]([O:17]S(C3C=CC(C)=CC=3)(=O)=O)[CH:16]=[C:12]2[CH:11]=[N:10][N:9]=1.[OH-].[Na+]>O1CCOCC1.O>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[N:13]2[N:14]=[C:15]([OH:17])[CH:16]=[C:12]2[CH:11]=[N:10][N:9]=1
Reactant: Cc1ccc(S(=O)(=O)Oc2cc3cnnc(-c4ccccc4F)n3n2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: Oc1cc2cnnc(-c3ccccc3F)n2n1
Temperature: 60 °C
Yield: 83 %

Procedure:
To a stirred solution of toluene-4-sulfonic acid 7-(2-fluorophenyl)pyrazolo[1,5-d][1,2,4]triazin-2-yl ester (82.0 mg, 0.213 mmol) in 1,4-dioxane (4 ml) and water (0.8 ml) was added aqueous 4 N NaOH solution (0.270 ml, 1.08 mmol). The solution was heated at 60° C. for 3 h, then the solvents were removed in vacuo. The residue was dissolved in water (10 ml) and washed with ethyl acetate (10 ml). The aqueous layer was acidified to pH<3 and extracted with dichloromethane (6×25 ml). The combined organic extracts were dried (Na2SO4) and evaporated in vacuo to leave 40.7 mg (83%) of the title compound; 1H NMR (360 MHz, d6-DMSO) δ 6.34 (1H, s), 7.42-7.48 (2H, m), 7.71 (1H, m), 7.79 (1H, td, J 7.2 and 1.7 Hz), 9.40 (1H, s), 11.74 (1H, s).
Reaction SMILES: [I:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.Cl[C:10]1[CH:18]=[CH:17][C:13]([C:14]([NH2:16])=[O:15])=[CH:12][N:11]=1.C(=O)([O-])[O-].[K+].[K+].CC(N(C)C)=O>O>[I:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:10]2[CH:18]=[CH:17][C:13]([C:14]([NH2:16])=[O:15])=[CH:12][N:11]=2)=[CH:4][CH:3]=1
Reactant: NC(=O)c1ccc(Cl)nc1
Reactant: Oc1ccc(I)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC(=O)N(C)C
Product: NC(=O)c1ccc(Oc2ccc(I)cc2)nc1
Temperature: 200 °C
Yield: 84.7 %

Procedure:
Combine 4-iodophenol (6.31 g, 28.7 mmol), 6-chloro-nicotinamide (4.51 g, 28.8 mmol), potassium carbonate (10.0 g, 72.4 mmol), and dimethylacetamide (145 mL), stir and heat at 200° C. After 3 h. cool to ambient temperature and dilute with water (600 mL), filter, and dry in vacuo to provide 8.27 g (85%) of the title compound as a white/brown solid: mass spectrum (electrospray): m/z=341.0 (M+1); 1H NMR (methanol-d4): 8.67 (d, 1H, J=2.4 Hz), 8.31 (dd, 1H, J=2.4, 8.3 Hz), 7.82-7.79 (m, 2H), 7.09 (d, 1H, J=8.8 Hz), 7.03-6.99 (m, 2H).
Reaction SMILES: [Cl-].O[NH3+:3].[C:4](=[O:7])([O-])[OH:5].[Na+].CS(C)=O.[OH:13][C:14]1[CH:19]=[CH:18][C:17]([N:20]2[C:25](=[O:26])[C:24]([CH2:27][C:28]3[CH:33]=[CH:32][C:31]([C:34]4[C:35]([C:40]#[N:41])=[CH:36][CH:37]=[CH:38][CH:39]=4)=[CH:30][CH:29]=3)=[C:23]([CH2:42][CH2:43][CH3:44])[N:22]=[C:21]2[CH3:45])=[CH:16][CH:15]=1>O.C(OCC)(=O)C>[OH:13][C:14]1[CH:15]=[CH:16][C:17]([N:20]2[C:25](=[O:26])[C:24]([CH2:27][C:28]3[CH:33]=[CH:32][C:31]([C:34]4[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=4[C:40]4[NH:3][C:4](=[O:7])[O:5][N:41]=4)=[CH:30][CH:29]=3)=[C:23]([CH2:42][CH2:43][CH3:44])[N:22]=[C:21]2[CH3:45])=[CH:18][CH:19]=1
Reactant: O=C([O-])O
Reactant: [NH3+]O
Reactant: CCCc1nc(C)n(-c2ccc(O)cc2)c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Agent: [Cl-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CS(C)=O
Product: CCCc1nc(C)n(-c2ccc(O)cc2)c(=O)c1Cc1ccc(-c2ccccc2-c2noc(=O)[nH]2)cc1
Temperature: 40 °C
Reaction time: 0.5 h
Yield: 48.6 %

Procedure:
A mixture of hydroxylammonium chloride (1.40 g), sodium hydrogen carbonate (2.00 g) and dimethyl sulfoxide (10 mL) was stirred at 40° C. for 30 min, 4′-{[1-(4-hydroxyphenyl)-2-methyl-6-oxo-4-propyl-1,6-dihydropyrimidin-5-yl]methyl}biphenyl-2-carbonitrile (0.87 g) was added, and the mixture was stirred at 90° C. for 18 hr. The reaction mixture was allowed to cool to room temperature, ethyl acetate and water were added, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was evaporated and the residue was dissolved in tetrahydrofuran (10 mL). N,N′-carbonyldiimidazole (0.39 g) and then 1,8-diazabicyclo[5.4.0]undec-7-ene (0.36 mL) were added, and the mixture was stirred at room temperature for 3 hr. The reaction mixture was diluted with ethyl acetate, washed with 1 M hydrochloric acid and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography to give the title compound as colorless crystals (0.48 g, 49%).
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([C:7]([O:9][CH3:10])=[O:8])=[CH:4][C:3]=1[C:11]1[N:15]([CH3:16])[N:14]=[CH:13][CH:12]=1.[Br:17]N1C(=O)CCC1=O>O1CCCC1>[Br:17][C:12]1[CH:13]=[N:14][N:15]([CH3:16])[C:11]=1[C:3]1[CH:4]=[C:5]([C:7]([O:9][CH3:10])=[O:8])[O:6][C:2]=1[CH3:1]
Reactant: COC(=O)c1cc(-c2ccnn2C)c(C)o1
Reactant: O=C1CCC(=O)N1Br
Solvent: C1CCOC1
Product: COC(=O)c1cc(-c2c(Br)cnn2C)c(C)o1
Yield: 15.1 %

Procedure:
A solution of methyl 5-methyl-4-(1-methyl-1H-pyrazol-5-yl)-2-furancarboxylate (600 mg, 2.72 mmol) [prepared in Example 116] and N-bromosuccinimide (485 mg, 2.72 mmol) in tetrahydrofuran (13 ml) was stirred in a sealed tube for 1 h at 70° C. The reaction mixture was divided and half of the solution was partitioned between H2O-DCM and the aqueous phase was washed several times with DCM. The combined organic fractions were dried over Na2SO4, concentrated and purified by column chromatography (5-15% EtOAc in hexanes yielding methyl 4-(4-bromo-1-methyl-1H-pyrazol-5-yl)-5-methyl-2-furancarboxylate (130 mg, 0.41 mmol, 15% yield) as an orange oil: LCMS (ES) m/e 299, 301 (M, M+2)+.
Reaction SMILES: [Br:1][C:2]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][C:3]=1[CH:4]=[O:5].Br[CH2:12][CH:13]1[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1>>[Br:1][C:2]1[CH:9]=[CH:8][C:7]([O:10][CH2:12][CH:13]2[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]2)=[CH:6][C:3]=1[CH:4]=[O:5]
Reactant: O=Cc1cc(O)ccc1Br
Reactant: BrCC1CCCCC1
Product: O=Cc1cc(OCC2CCCCC2)ccc1Br

Procedure:
Alkylation of 2-bromo-5-hydroxybenzaldehyde using (bromomethyl)cyclohexane following the method used in Example 1 gave 2-bromo-5-(cyclohexylmethoxy)benzaldehyde. The crude aldehyde was used in the subsequent reaction.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[C:5]([N+:9]([O-:11])=[O:10])=[CH:4][N:3]=1.C([N:15](CC)[CH:16]([CH3:18])[CH3:17])(C)C.C1(N)CC1>C1COCC1>[Cl:1][C:2]1[N:7]=[C:6]([NH:15][CH:16]2[CH2:18][CH2:17]2)[C:5]([N+:9]([O-:11])=[O:10])=[CH:4][N:3]=1
Reactant: O=[N+]([O-])c1cnc(Cl)nc1Cl
Reactant: CCN(C(C)C)C(C)C
Agent: NC1CC1
Solvent: C1CCOC1
Product: O=[N+]([O-])c1cnc(Cl)nc1NC1CC1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 15.3 %

Procedure:
To 10.0 g (53 mmol, 1.0 eq.) of 2,4-dichloro-5-nitropyrimidine in 40 mL of THF at −78° C. was added 22 mL (120 mmol, 2.2 eq.) of N,N-diisopropylethylamine and 3.7 mL (53 mmol, 1.0 eq.) of cyclopropylamine. The reaction mixture was stirred at −78° C. for 30 min and then allowed to warm to room temperature and stirred for an additional 1 h. The solvent was removed in vacuo to afford a yellow solid. The product was purified by flash chromatography (15% EtOAc/hexanes) to provide 8.8 g (8.1 mmol, 77%) of 2-chloro-N-cyclopropyl-5-nitropyrimidin-4-amine (I-1) as a yellow solid.
Reaction SMILES: [O:1]1[C:5]2([CH2:10][CH2:9][CH:8]([N:11]3[CH2:15][CH2:14][CH2:13][C:12]3=[O:16])[CH2:7][CH2:6]2)[O:4][CH2:3][CH2:2]1.[Li+].CC([N-]C(C)C)C.Br[CH2:26][C:27]1[C:32]([Cl:33])=[CH:31][C:30]([O:34][CH3:35])=[CH:29][C:28]=1[Cl:36]>O1CCCC1>[Cl:33][C:32]1[CH:31]=[C:30]([O:34][CH3:35])[CH:29]=[C:28]([Cl:36])[C:27]=1[CH2:26][CH:13]1[CH2:14][CH2:15][N:11]([CH:8]2[CH2:7][CH2:6][C:5]3([O:4][CH2:3][CH2:2][O:1]3)[CH2:10][CH2:9]2)[C:12]1=[O:16]
Reactant: COc1cc(Cl)c(CBr)c(Cl)c1
Reactant: O=C1CCCN1C1CCC2(CC1)OCCO2
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: COc1cc(Cl)c(CC2CCN(C3CCC4(CC3)OCCO4)C2=O)c(Cl)c1
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
Cool a solution of 1-(1,4-Dioxa-spiro[4.5]dec-8-yl)-pyrrolidin-2-one (5 g, 22.2 mmol) in tetrahydrofuran (100 mL) to −78° C. under nitrogen purge. Add LDA (2.0 M, 15 mL, 30 mmol) at a rate such that the internal reaction temperature did not reach above −67° C. Stir 30 min at −78° C., add a solution of 2-bromomethyl-1,3-dichloro-5-methoxy-benzene, 6.6 g, 24.4 mmol) in THF (20 mL) over a 1-2 minute period, remove the cold bath and allow reaction to warm over 3 hr. Quench the reaction with saturated aqueous ammonium chloride (100 mL), extract with ethyl acetate (3×100 mL), combine the extracts and dry over anhydrous sodium sulfate. Purify on silica column eluting with 8:2 hexanes:ethyl acetate to 1:1 hexanes:ethyl acetate to afford the product as a ivory solid, 6.5 g, 71%. 1H NMR (CDCl3) δ 6.86 (s, 2H), 4.06-4.12 (m, 1H), 3.94 (s, 4H), 3.77 (s, 3H), 3.32-3.41 (m, 2H), 3.15-3.21 (m, 1H), 2.83-2.97 (m, 2H), 1.68-2.04 (m, 8H). LCMS m+1 414.
Reaction SMILES: Br.[CH:2]1([C:5]2[CH:6]=[CH:7][C:8](/[C:13](/[C:21]3[CH:26]=[CH:25][C:24]([S:27][CH3:28])=[CH:23][CH:22]=3)=[CH:14]/[CH2:15][CH2:16][NH:17][C:18](=[O:20])[CH3:19])=[N:9][C:10]=2[O:11]C)[CH2:4][CH2:3]1.O>O1CCOCC1>[CH:2]1([C:5]2[C:10](=[O:11])[NH:9][C:8](/[C:13](/[C:21]3[CH:26]=[CH:25][C:24]([S:27][CH3:28])=[CH:23][CH:22]=3)=[CH:14]/[CH2:15][CH2:16][NH:17][C:18](=[O:20])[CH3:19])=[CH:7][CH:6]=2)[CH2:3][CH2:4]1
Reactant: COc1nc(/C(=C/CCNC(C)=O)c2ccc(SC)cc2)ccc1C1CC1
Agent: Br
Solvent: O
Solvent: C1COCCO1
Product: CSc1ccc(/C(=C\CCNC(C)=O)c2ccc(C3CC3)c(=O)[nH]2)cc1
Temperature: 80 °C
Reaction time: 1 h
Yield: 64.4 %

Procedure:
48% hydrobromic acid (2 mL) was added to a solution of N-{(3E)-4-(5-cyclopropyl-6-methoxypyridin-2-yl)-4-[4-(methylsulfanyl)phenyl]but-3-en-1-yl}acetamide (87 mg) in 1,4-dioxane (2 mL), and the mixture was stirred at 80° C. for one hour. The reaction solution was poured into water, followed by extraction with ethyl acetate. The organic layer was washed with brine, dried over anhydrous magnesium sulfate and filtered. The solvent was then evaporated under reduced pressure. The residue was recrystallized from a mixed solvent of chloroform-ethyl acetate-hexane. Filtration gave the title compound as a colorless solid (54 mg, 64%).
Reaction SMILES: [CH2:1]([C:3]1[C:24]([N:25]2[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]2)=[CH:23][C:6]2[C:7]([CH3:22])([CH3:21])[C:8]3[NH:9][C:10]4[C:15]([C:16]=3[C:17](=[O:18])[C:5]=2[CH:4]=1)=[CH:14][CH:13]=[C:12]([C:19]#[N:20])[CH:11]=4)[CH3:2].[C:31]1(=O)[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]1.C[Si]([C:42]#[N:43])(C)C>C(Cl)(Cl)Cl.C(OCC)(=O)C.[I-].[Zn+2].[I-]>[C:42]([C:31]1([N:28]2[CH2:29][CH2:30][N:25]([C:24]3[C:3]([CH2:1][CH3:2])=[CH:4][C:5]4[C:17](=[O:18])[C:16]5[C:15]6[C:10](=[CH:11][C:12]([C:19]#[N:20])=[CH:13][CH:14]=6)[NH:9][C:8]=5[C:7]([CH3:22])([CH3:21])[C:6]=4[CH:23]=3)[CH2:26][CH2:27]2)[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]1)#[N:43]
Reactant: CCc1cc2c(cc1N1CCNCC1)C(C)(C)c1[nH]c3cc(C#N)ccc3c1C2=O
Reactant: C[Si](C)(C)C#N
Reactant: O=C1CCCCC1
Agent: [I-]
Agent: [Zn+2]
Solvent: ClC(Cl)Cl
Solvent: CCOC(C)=O
Product: CCc1cc2c(cc1N1CCN(C3(C#N)CCCCC3)CC1)C(C)(C)c1[nH]c3cc(C#N)ccc3c1C2=O
Temperature: 60 °C
Reaction time: 17 h
Yield: 21 %

Procedure:
9-Ethyl-6,6-dimethyl-11-oxo-8-piperazin-1-yl-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile (45 mg) and cyclohexanone (25 mg) were suspended in chloroform (2 ml), added with trimethylsilyl cyanide (30 mg) and zinc iodide (5 mg), and the mixture was stirred at 60° C. for 17 hrs. The reaction mixture was diluted with ethyl acetate (20 ml) and the organic layer was washed with 10% brine solution and concentrated under reduced pressure. The resulting residues were purified by silica gel column (dichloromethane/methanol (=99/1)) to obtain the title compound (12 mg, yield 30%).
Reaction SMILES: C1(CC2CCCC[N:9]2[CH2:14][CH:15]([C:17]2C=CC=C(Br)C=2)[CH3:16])CCCCC1.[CH2:24]([Li])[CH2:25][CH2:26][CH3:27]>C(OCC)C>[CH3:27][C:26]1[CH:16]=[C:15]([CH:17]=[CH:24][CH:25]=1)[C:14]#[N:9]
Reactant: [Li]CCCC
Reactant: CC(CN1CCCCC1CC1CCCCC1)c1cccc(Br)c1
Solvent: CCOCC
Product: Cc1cccc(C#N)c1
Yield: 212 %

Procedure:
Following a procedure similar to that described in Example 7, 18.9 g. (0.05 mole) of 2-cyclohexylmethyl-1-[2-(3-bromophenyl)propyl]piperidine was reacted with 0.095 mole of n-butyl lithium in diethyl ether and the resulting lithio derivative reacted directly with 12.4 g. (0.106 mole) of 3-methylbenzonitrile to give 10.7 g. of 2-cyclohexylmethyl-1-{2-[3-(3-methylbenzoyl)phenyl]propyl}piperidine as a yellow oil.
Reaction SMILES: [CH2:1]([C@@H:8]([NH:25][CH3:26])[CH2:9][N:10]1[CH2:15][CH2:14][C:13]([C:16]2[CH:21]=[C:20]([F:22])[CH:19]=[CH:18][C:17]=2[O:23][CH3:24])=[CH:12][CH2:11]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH:34]1([N:40]=[C:41]=[O:42])[CH2:39][CH2:38][CH2:37][CH2:36][CH2:35]1>ClCCl>[CH2:1]([C@@H:8]([N:25]([CH3:26])[C:41]([NH:40][CH:34]1[CH2:39][CH2:38][CH2:37][CH2:36][CH2:35]1)=[O:42])[CH2:9][N:10]1[CH2:15][CH2:14][CH:13]([C:16]2[CH:21]=[C:20]([F:22])[CH:19]=[CH:18][C:17]=2[O:23][CH3:24])[CH2:12][CH2:11]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C=NC1CCCCC1
Reactant: CN[C@H](Cc1ccccc1)CN1CC=C(c2cc(F)ccc2OC)CC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1ccc(F)cc1C1CCN(C[C@@H](Cc2ccccc2)N(C)C(=O)NC2CCCCC2)CC1
Reaction time: 8 h
Yield: 82.2 %

Procedure:
Under a N2 atmosphere, a solution of {(1R)-1-benzyl-2-[4-(5-fluoro-2-methoxy-phenyl)-1,2,3,6-tetrahydropyridin-1-yl]-ethyl}-methyl-amine (0.17 g, 0.48 mmole, described as intermediate 12 above) and triethylamine (0.15 mL, 1.0 mmole) in dichloromethane (10 mL) was cooled to 0° C. and a solution of cyclohexyl isocyanate (0.070 mL, 0.51 mmole) was added dropwise. The resulting mixture was stirred at 0° C. to room temperature (ice melt) overnight. The solvent was evaporated and the residue dissolved in EtOAc (25 mL) and water (25 mL). The layers were separated and the organics washed with water (25 mL), brine (30 mL) and dried over Na2SO4. Filtration and concentration gave the crude product which was purified by flash chromatography (elution with EtOAc) to yield 0.19 g (83% yield) of 1-{(1R)-1-benzyl-2-[4-(5-fluoro-2-methoxy-phenyl)-1,2,5,6-tetrahydro-4H-pyridin-1-yl]-ethyl}-3-cyclohexyl-1-methyl-urea. An ethanolic solution of the product was heated to gentle reflux and 1 equivalent of fumaric acid in hot ethyl alcohol solution was added to afford the fumarate salt of the titled compound as a white solid.
Reaction SMILES: Cl[C:2]1[N:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[C:9]([CH3:12])[CH:8]=[CH:7]2.[NH2:13][C:14]1[N:15]=[C:16]([CH3:19])[S:17][CH:18]=1>>[CH3:12][C:9]1[CH:8]=[CH:7][C:6]2[C:11](=[C:2]([NH:13][C:14]3[N:15]=[C:16]([CH3:19])[S:17][CH:18]=3)[N:3]=[CH:4][CH:5]=2)[N:10]=1
Reactant: Cc1nc(N)cs1
Reactant: Cc1ccc2ccnc(Cl)c2n1
Product: Cc1ccc2ccnc(Nc3csc(C)n3)c2n1

Procedure:
The title compound, MS: m/e=257.2 (M+H+), was prepared in accordance with the general method of example 1 from 8-chloro-2-methyl-[1,7]naphthyridine (Example E) and 4-amino-2-methylthiazole (Example F).
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([NH2:8])[N:5]2[N:9]=[C:10]([C:12]3[O:13][CH:14]=[CH:15][CH:16]=3)[N:11]=[C:4]2[CH:3]=1.[C:17]1([OH:27])[C:26]2[CH2:25][CH2:24][CH2:23][CH2:22][C:21]=2[CH:20]=[CH:19][CH:18]=1>CN1CCCC1=O>[O:13]1[CH:14]=[CH:15][CH:16]=[C:12]1[C:10]1[N:11]=[C:4]2[CH:3]=[C:2]([O:27][C:17]3[C:26]4[CH2:25][CH2:24][CH2:23][CH2:22][C:21]=4[CH:20]=[CH:19][CH:18]=3)[CH:7]=[C:6]([NH2:8])[N:5]2[N:9]=1
Reactant: Nc1cc(Br)cc2nc(-c3ccco3)nn12
Reactant: Oc1cccc2c1CCCC2
Solvent: CN1CCCC1=O
Product: Nc1cc(Oc2cccc3c2CCCC3)cc2nc(-c3ccco3)nn12

Procedure:
A mixture of 1 eq. 7-bromo-2-furan-2-yl-[1,2,4]triazolo[1,5-a]pyridin-5-ylamine, 5 eq. 5,6,7,8-tetrahydro-naphthalen-1-ol and a catalytic amount of CS2CO3 in 200 μl N-methyl-pyrrolidon was heated for 2 h to 160°. The mixture was, after filtration, purified with reversed phase column chromatography eluting with an acetonitrile/water gradient yielding the title compound, MS m/e (%): 346 M+H+ (100%).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][OH:9])=[CH:4][C:3]=1[CH2:10][C:11]([F:14])([F:13])[F:12].C1C=C[NH+]=CC=1.[O-][Cr](Cl)(=O)=O>ClCCl>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]=[O:9])=[CH:4][C:3]=1[CH2:10][C:11]([F:12])([F:13])[F:14]
Reactant: OCc1ccc(Br)c(CC(F)(F)F)c1
Agent: O=[Cr](=O)([O-])Cl
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Product: O=Cc1ccc(Br)c(CC(F)(F)F)c1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Into a 100-mL round-bottom flask, was placed a solution of [4-bromo-3-(2,2,2-trifluoroethyl)phenyl]methanol (800 mg, 2.97 mmol, 1.00 equiv) in dichloromethane (20 mL), PCC (1.3 g, 6.03 mmol, 2.00 equiv). The resulting solution was stirred for 3 h at 25° C. The resulting mixture was concentrated under vacuum. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (1:30-1:10). This resulted in 700 mg (88%) of 4-bromo-3-(2,2,2-trifluoroethyl)benzaldehyde as yellow oil.
Reaction SMILES: [Cl:1][C:2]1[CH:12]=[CH:11][C:5]([CH:6]=[CH:7][C:8]([OH:10])=O)=[CH:4][CH:3]=1.O=S(Cl)Cl.Cl.[NH2:18][N:19]1[CH2:25][C:23](=[O:24])[NH:22][C:20]1=[O:21].Cl>N1C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH:6]=[CH:7][C:8]([NH:18][N:19]2[CH2:25][C:23](=[O:24])[NH:22][C:20]2=[O:21])=[O:10])=[CH:11][CH:12]=1
Reactant: O=C(O)C=Cc1ccc(Cl)cc1
Reactant: NN1CC(=O)NC1=O
Agent: Cl
Solvent: O=S(Cl)Cl
Solvent: c1ccncc1
Product: O=C(C=Cc1ccc(Cl)cc1)NN1CC(=O)NC1=O
Temperature: 0 °C
Reaction time: 8 h

Procedure:
To 4-chlorocinnamic acid (46 g, 0.25 mole) was added dropwise SOCl2 (140 ml). The mixture was heated under reflux for 45 minutes after the addition was complete. After stirring at room temperature for 1 hour the SOCl2 was removed in vacuo. Dry benzene was added and then removed in vacuo. The acid chloride residue was treated with 1-aminohydantoin hydrochloride (42 g, 0.275 mole) in 350 ml of pyridine, then heated under reflux for 2 hrs. After cooling slightly, the reaction mixture was poured into a mixture of 200 ml of con HCl and 1500 ml of ice. After standing overnight the product was removed by filtration and washed with H2O. Recrystallization from NaOH/dimethylformamide (H2O) provided analytical material which melted at 230°-235° (25 g, 36%).
Reaction SMILES: [CH3:1]C(C)([O-])C.[K+].[C:7]([N:10]1[C:23]2[C:18](=[CH:19][C:20]([OH:28])=[C:21]3[CH:27]=[CH:26][CH:25]=[CH:24][C:22]3=2)[S:17][C:16]2[C:11]1=[CH:12][CH:13]=[CH:14][CH:15]=2)(=[O:9])[CH3:8].CI.O>CN(C=O)C>[C:7]([N:10]1[C:23]2[C:18](=[CH:19][C:20]([O:28][CH3:1])=[C:21]3[CH:27]=[CH:26][CH:25]=[CH:24][C:22]3=2)[S:17][C:16]2[C:11]1=[CH:12][CH:13]=[CH:14][CH:15]=2)(=[O:9])[CH3:8]
Reactant: CC(=O)N1c2ccccc2Sc2cc(O)c3ccccc3c21
Reactant: CC(C)(C)[O-]
Agent: [K+]
Solvent: O
Solvent: CI
Solvent: CN(C)C=O
Product: COc1cc2c(c3ccccc13)N(C(C)=O)c1ccccc1S2
Reaction time: 0.25 h

Procedure:
Potassium tert-butoxide (800 mg) was added to a solution of 12-acetyl-5-hydroxy-12H-benzo[a]phenothiazine (950 mg) (from Example 3) and methyl iodide (1.5 ml) in DMF (10 ml) and stirred for 15 minutes. Water (80 ml) was added to the reaction mixture and the precipitate was filtered to afford the title compound.
Reaction SMILES: [F:1][C:2]([F:28])([F:27])[C:3]1[CH:4]=[C:5]([CH:20]=[C:21]([C:23]([F:26])([F:25])[F:24])[CH:22]=1)[CH2:6][O:7][CH:8]1[O:13][CH2:12][CH2:11][NH:10][CH:9]1[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.C(N(CC)C(C)C)(C)C.Br[CH2:39][C:40]([O:42][CH3:43])=[O:41]>C(#N)C>[F:28][C:2]([F:1])([F:27])[C:3]1[CH:4]=[C:5]([CH:20]=[C:21]([C:23]([F:24])([F:25])[F:26])[CH:22]=1)[CH2:6][O:7][CH:8]1[O:13][CH2:12][CH2:11][N:10]([CH2:39][C:40]([O:42][CH3:43])=[O:41])[CH:9]1[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: COC(=O)CBr
Reactant: FC(F)(F)c1cc(COC2OCCNC2c2ccccc2)cc(C(F)(F)F)c1
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)CN1CCOC(OCc2cc(C(F)(F)F)cc(C(F)(F)F)c2)C1c1ccccc1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
A solution of 150 mg (0.37 mmol) of the trans-isomer of (±)-2-(3,5-bis(trifluoromethyl)benzyloxy)-3-phenyl morpholine (Example 4) and 0.18 mL (1.00 mmol) of N,N-diisopropyl-ethyl- amine in 2 mL of acetonitrile was treated with 0.095 mL (1.00 mmol) of methyl bromoacetate and the resulting solution was stirred at rt for 20 h. The solution was concentrated in vacuo and the residue was partitioned between 20 mL of ethyl acetate and 5 mL of 0.5N aqueous potassium hydrogen sulfate solution. The layers were separated; the organic layer was washed with 10 mL of saturated aqueous sodium chloride solution, dried over magnesium sulfate and concentrated in vacuo. Flash chromatography on 10 g of silica gel using 4:1 v/v hexanes/ether as the eluant afforded 164 mg (93%) of the trans-isomer of the title compound as an oil: 1H NMR 2.79 (dr, 1 H, J=3.2, 11.2), 2.93 (dt, 1 H, J=11.2, 1.6), 3.52 (d, 1 H, J=7.2), 3.63 (s, 3 H), 3.92 (dt, 1 H, J=2.8, 11.6), 4.04 (ddd, 1 H, J=11.6, 3.2, 1.6), 4.45 and 4.84 (AB q, 2 H, J=13.2), 4.46 (d, 1 H, J=7.2), 7.31-7.38 (m, 6 H), 7.68 (s, 1 H);
Reaction SMILES: C1(N[C:8]([C:10]2[C:11]([NH:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=3[Cl:28])=[N:12][C:13]3[C:18]([CH:19]=2)=[CH:17][CH:16]=[C:15]([OH:20])[CH:14]=3)=[O:9])C=CC=CC=1.[O:29]1CCOCC1>Cl>[Cl:28][C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=1[NH:21][C:11]1[C:10]([C:8]([OH:29])=[O:9])=[CH:19][C:18]2[C:13](=[CH:14][C:15]([OH:20])=[CH:16][CH:17]=2)[N:12]=1
Reactant: O=C(Nc1ccccc1)c1cc2ccc(O)cc2nc1Nc1ccccc1Cl
Reactant: C1COCCO1
Agent: Cl
Product: O=C(O)c1cc2ccc(O)cc2nc1Nc1ccccc1Cl

Procedure:
A suspension of 2-(2-Chloro-phenylamino)-7-hydroxy-quinoline-3-carboxylic acid phenylamide (17 mg, 0.04 mmol) in 16N aqueous HCl (0.1 ml) and 1,4-Dioxane (0.1 ml) was heated at reflux for 5 days. After evaporating the solvent, the residue was recrystallized from methanol to give 2-(2-Chloro-phenylamino)-7-hydroxy-quinoline-3-carboxylic acid as the white crystal; 13 mg (99%). 1H NMR (400 MHz, DMSO-d6) ppm 6.96 (dd, 1H, J=2.3, 8.6 Hz), 6.99 (d, 1H. J=2.3 Hz), 7.04 (ddd, 1H, J=1.5, 7.8, 8.8 Hz), 7.40 (ddd, 1H, J=1.5, 7.8, 8.8 Hz), 7.52 (dd, 1H, J=1.5, 7.8 Hz), 7.83 (d, 1H, J=8.8 Hz), 8.84 (s, 1H), 9.10 (d, 1H, J=11.2 Hz), 10.48 (s, 1H), 11.05 (s, 1H). LC/MS: m/z 315 (M+1)+, 313 (M−1)−.
Reaction SMILES: [F:1][C:2]1[C:34]([F:35])=[CH:33][CH:32]=[CH:31][C:3]=1[CH2:4][S:5][C:6]1[N:11]=[C:10]([NH:12][S:13]([N:16]2[CH2:20][CH2:19][C@@H:18]([NH:21]C(=O)OC(C)(C)C)[CH2:17]2)(=[O:15])=[O:14])[CH:9]=[C:8]([O:29][CH3:30])[N:7]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH2:21][C@@H:18]1[CH2:19][CH2:20][N:16]([S:13]([NH:12][C:10]2[CH:9]=[C:8]([O:29][CH3:30])[N:7]=[C:6]([S:5][CH2:4][C:3]3[CH:31]=[CH:32][CH:33]=[C:34]([F:35])[C:2]=3[F:1])[N:11]=2)(=[O:14])=[O:15])[CH2:17]1
Reactant: COc1cc(NS(=O)(=O)N2CC[C@@H](NC(=O)OC(C)(C)C)C2)nc(SCc2cccc(F)c2F)n1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COc1cc(NS(=O)(=O)N2CC[C@@H](N)C2)nc(SCc2cccc(F)c2F)n1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of tert-butyl {(3R)-1-[({2-[(2,3-difluorobenzyl)thio]-6-methoxypyrimidin-4-yl}amino)sulfonyl]pyrrolidin-3-yl}carbamate (0.75 g) in DCM (10 ml) was added TFA (10 ml) slowly. The reaction then stirred at room temperature for 18 h. The reaction was reduced in vacuo and the residue purified by prep HPLC to give the subtitle compound as a white solid.