Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][CH2:2][CH2:3][C:4]1[N:5]=[C:6]([S:9][C:10]([CH3:15])([CH3:14])[C:11]([OH:13])=[O:12])[S:7][CH:8]=1.C1C=C2N=NN(O)C2=CC=1.O.C(N=C=NC(C)C)(C)C.[CH3:36][CH:37]([CH3:47])[CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][C:44](O)=[O:45]>CN(C)C=O>[CH3:14][C:10]([S:9][C:6]1[S:7][CH:8]=[C:4]([CH2:3][CH2:2][NH:1][C:44](=[O:45])[CH2:43][CH2:42][CH2:41][CH2:40][CH2:39][CH2:38][CH:37]([CH3:36])[CH3:47])[N:5]=1)([CH3:15])[C:11]([OH:13])=[O:12]
Reactant: CC(C)(Sc1nc(CCN)cs1)C(=O)O
Reactant: CC(C)CCCCCCC(=O)O
Agent: CC(C)N=C=NC(C)C
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)CCCCCCC(=O)NCCc1csc(SC(C)(C)C(=O)O)n1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a suspension of 2-{[4-(2-aminoethyl)-1,3-thiazol-2-yl]thio}-2-methylpropionic acid resin (0.30 g) synthesized in Example 483-3 in dimethylformamide (4.0 mL) were added HOBT monohydrate (0.092 g), diisopropylcarbodiimide (0.10 mL) and 8-methylnonanoic acid (0.10 g), and the mixture was stirred at room temperature overnight. The resin was collected by filtration from the reaction mixture, washed three times each with dimethylformamide, tetrahydrofuran and methanol, and vacuum dried to give 2-methyl-2-[(4-{2-[(8-methylnonanoyl)amino]ethyl}-1,3-thiazol-2-yl)thio]propionic acid resin.
Reaction SMILES: [OH:1][C:2]1[C:9](I)=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=[O:5].[CH3:11][O:12][C:13]1[CH:14]=[C:15]([C:19]#[CH:20])[CH:16]=[CH:17][CH:18]=1.N1C=CC=CC=1>C(OCC)(=O)C>[CH3:11][O:12][C:13]1[CH:14]=[C:15]([C:19]2[O:1][C:2]3[C:3]([CH:4]=[O:5])=[CH:6][CH:7]=[CH:8][C:9]=3[CH:20]=2)[CH:16]=[CH:17][CH:18]=1
Reactant: O=Cc1cccc(I)c1O
Reactant: C#Cc1cccc(OC)c1
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Product: COc1cccc(-c2cc3cccc(C=O)c3o2)c1
Yield: 143 %

Procedure:
A mixture of 11 g of 2-hydroxy-3-iodo benzaldehyde, 8.6 g of (3-methoxy-phenyl) acetylene and 150 ml of pyridine was refluxed for 45 minutes and then allowed to return to ambient temperature. Ethyl acetate was added, and washing was carried out with an acid solution, followed by drying and concentrating to obtain 16 g of product which was chromatographed on silica (eluant: hexane-isopropyl ether (7-3)) to obtain 9 g of the desired product melting at 55° C. to 60° C.
Reaction SMILES: [C:1]1([CH3:11])[CH:6]=[CH:5][C:4]([S:7](Cl)(=[O:9])=[O:8])=[CH:3][CH:2]=1.[N+:12]([C:15]1[CH:16]=[C:17]([CH:25]([OH:27])[CH3:26])[CH:18]=[C:19]([C:21]([F:24])([F:23])[F:22])[CH:20]=1)([O-:14])=[O:13].C(N(CC)CC)C>ClCCl>[CH3:11][C:1]1[CH:6]=[CH:5][C:4]([S:7]([O:27][CH:25]([C:17]2[CH:18]=[C:19]([C:21]([F:24])([F:23])[F:22])[CH:20]=[C:15]([N+:12]([O-:14])=[O:13])[CH:16]=2)[CH3:26])(=[O:9])=[O:8])=[CH:3][CH:2]=1
Reactant: CC(O)c1cc([N+](=O)[O-])cc(C(F)(F)F)c1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)OC(C)c2cc([N+](=O)[O-])cc(C(F)(F)F)c2)cc1
Temperature: 25 °C
Reaction time: 12 h
Yield: 80.6 %

Procedure:
Add p-toluenesulfonyl chloride (1.7 g, 8.9 mmol) dropwise at 0° C. to the mixture of 1-(3-nitro-5-(trifluoromethyl)phenyl)ethanol (520 mg, 2.23 mmol) and triethylamine (1.4 g, 13.4 mmol) in dichloromethane (20 mL), stir the resulting mixture for 12 hrs at ambient temperature. Concentrate the mixture under reduced pressure to get a residue, purify the residue by chromatography (silica gel, EtOAc:PE=1:10) to afford the title compound (700 mg, 80.6%).
Reaction SMILES: [CH3:1][N:2]([CH2:26][CH:27]=[CH2:28])[S:3]([C:6]1[CH:11]=[C:10]([N:12]2[C:17](=[O:18])[CH:16]=[C:15]([C:19]([F:22])([F:21])[F:20])[N:14]([CH3:23])[C:13]2=[O:24])[CH:9]=[CH:8][C:7]=1[Cl:25])(=[O:5])=[O:4].IC.[H][H]>[Pd].C(OCC)(=O)C>[CH3:1][N:2]([CH2:26][CH2:27][CH3:28])[S:3]([C:6]1[CH:11]=[C:10]([N:12]2[C:17](=[O:18])[CH:16]=[C:15]([C:19]([F:21])([F:22])[F:20])[N:14]([CH3:23])[C:13]2=[O:24])[CH:9]=[CH:8][C:7]=1[Cl:25])(=[O:4])=[O:5]
Reactant: [H][H]
Reactant: C=CCN(C)S(=O)(=O)c1cc(-n2c(=O)cc(C(F)(F)F)n(C)c2=O)ccc1Cl
Agent: [Pd]
Solvent: CI
Solvent: CCOC(C)=O
Product: CCCN(C)S(=O)(=O)c1cc(-n2c(=O)cc(C(F)(F)F)n(C)c2=O)ccc1Cl
Reaction time: 0.5 h
Yield: 87.1 %

Procedure:
A mixture of 1.6 g of N-methyl-N-(2-propenyl)-2-chloro-5-(3,6-dihydro-3-methyl-4-trifluoromethyl-2,6-dioxo-1(2H)-pyrimidinyl)benzenesulfonamide (Compound #29), prepared byprocess C from Compound #28 and iodomethane, 100 ml of ethyl acetate and 200 mg of 5% palladium/carbon catalyst was hydrogenated in a Paar® apparatus at 28 psi of hydrogen. After 30 minutes, the catalyst was filtered and solvent removed from the filtrate by rotary evaporation. The glassy residue was treated with ethanol to give 1.4 g of the title compound as a light gray powder, m.p. 143.5°-145° C.
Reaction SMILES: Cl.Cl.[NH:3]1[CH2:6][CH:5]([C:7]2[C:8]([O:28][CH3:29])=[C:9]([CH:15]([N:17]3[C:21]4=[N:22][CH:23]=[N:24][C:25]([NH2:26])=[C:20]4[C:19]([CH3:27])=[N:18]3)[CH3:16])[CH:10]=[C:11]([Cl:14])[C:12]=2[CH3:13])[CH2:4]1.[O:30]1[CH2:33][C:32](=O)[CH2:31]1.C(N(CC)CC)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(Cl)Cl>[Cl:14][C:11]1[C:12]([CH3:13])=[C:7]([CH:5]2[CH2:4][N:3]([CH:32]3[CH2:33][O:30][CH2:31]3)[CH2:6]2)[C:8]([O:28][CH3:29])=[C:9]([CH:15]([N:17]2[C:21]3=[N:22][CH:23]=[N:24][C:25]([NH2:26])=[C:20]3[C:19]([CH3:27])=[N:18]2)[CH3:16])[CH:10]=1
Reactant: O=C1COC1
Reactant: COc1c(C(C)n2nc(C)c3c(N)ncnc32)cc(Cl)c(C)c1C1CNC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1c(C(C)n2nc(C)c3c(N)ncnc32)cc(Cl)c(C)c1C1CN(C2COC2)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 9.8 %

Procedure:
To a mixture of 1-[1-(3-azetidin-3-yl-5-chloro-2-methoxy-4-methylphenyl)ethyl]-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-amine dihydrochloride (21 mg, 0.046 mmol, racemic intermediate from Example 2, Step 1), oxetan-3-one (from Synthonix, 3.6 mg, 0.050 mmol), and triethylamine (20 μL, 0.14 mmol) in methylene chloride (0.32 mL) was added resin of sodium triacetoxyborohydride (40 mg, 0.091 mmol). The resulting mixture was stirred overnight at room temperature. The mixture was filtered and concentrated and then purified by RP-HPLC (XBridge C18 column, eluting with a gradient of acetonitrile/water containing 0.1% ammonium hydroxide, at flow rate of 30 mL/min) to give the desired product (2 mg, 9.9%). The product was isolated as a racemic mixture. LCMS calculated for C22H28ClN6O2 (M+H)+: m/z=443.2; Found: 443.1.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([OH:9])=[CH:5][CH:4]=1.[H-].[Na+].CC1C=CC(S(O[CH2:23][C@@H:24]2[CH2:28][CH2:27][CH2:26][N:25]2[S:29]([C:32]2[CH:40]=[CH:39][C:38]3[N:37]4[CH2:41][C:42]([CH3:46])([CH3:45])[CH2:43][N:44]=[C:36]4[C:35]4(OCCC[O:47]4)[C:34]=3[CH:33]=2)(=[O:31])=[O:30])(=O)=O)=CC=1.CN(C=O)C>C1COCC1>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([O:9][CH2:23][C@@H:24]2[CH2:28][CH2:27][CH2:26][N:25]2[S:29]([C:32]2[CH:40]=[CH:39][C:38]3[N:37]4[CH2:41][C:42]([CH3:46])([CH3:45])[CH2:43][N:44]=[C:36]4[C:35](=[O:47])[C:34]=3[CH:33]=2)(=[O:31])=[O:30])=[CH:5][CH:4]=1
Reactant: COc1ccc(O)cc1
Reactant: Cc1ccc(S(=O)(=O)OC[C@@H]2CCCN2S(=O)(=O)c2ccc3c(c2)C2(OCCCO2)C2=NCC(C)(C)CN23)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: COc1ccc(OC[C@@H]2CCCN2S(=O)(=O)c2ccc3c(c2)C(=O)C2=NCC(C)(C)CN23)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 30.5 %

Procedure:
To a solution of 4-methoxy-phenol (0.420 mmol) in THF (3 mL) was added NaH (60% dispersion in mineral oil) (0.015 g, 0.063 mmol) and the reaction was stirred at rt for 1 hr. {(2S)-1-[(3′,3′-Dimethyl-3′,4′-dihydro-2′H-spiro[1,3-dioxane-2,10′-pyrimido[1,2-a]indol]-8′-yl)sulfonyl]pyrrolidin-2-yl}methyl 4-methylbenzenesulfonate (0.12 g, 0.21 mmol) in THF (2 mL)/DMF (2 mL) was then added and the reaction heated overnight at 100° C. The reaction was quenched with water and extracted with EtOAc (3×). The combined organic extracts were dried over Na2SO4, filtered, concentrated and purified on Biotage Si 12+M cartridge silica gel eluting with acetone/hexane (30/70). The resulting product was dissolved in CH2Cl2 (3 mL) and methanesulfonic acid (2 mL) was added and the solution was stirred at 50° C. overnight. The reaction mixture was poured onto ice, basified to pH 11 with ammonium hydroxide and extracted with EtOAc (3×). The combined organic extracts were dried over Na2SO4, filtered, concentrated and purified on Biotage Si 12+M cartridge silica gel eluting with acetone/hexane (30/70) to give the title compound as a light yellow foam (0.031 g, 38%). NMR (400 Mz, DMSO-d6): consistent. MS: (ESI+) m/z 484.1 [M+H].
Reaction SMILES: [OH-].[Na+].[Cl:3][C:4]1(Cl)[CH2:9][CH2:8][CH2:7][C:6]([Cl:11])([F:10])[CH:5]1O.CC[O:16]CC>O>[Cl:3][C:4]12[O:16][CH:9]1[CH2:8][CH2:7][C:6]([Cl:11])([F:10])[CH2:5]2
Reactant: OC1C(F)(Cl)CCCC1(Cl)Cl
Reactant: CCOCC
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: FC1(Cl)CCC2OC2(Cl)C1
Reaction time: 0.25 h

Procedure:
0.85 g (21.3 mmol) of sodium hydroxide pellets were added in three portions to 1.6 g (7.22 mmol) of pure alcohol 1f in suspension in 22 cm3 of distilled water at 15°-20° C. The reaction mixture was kept at room temperature for 1 h 15 min, 10 cm3 of ether were then added, stirring was continued for 5 min and then the aqueous phase was separated off and extracted with ether (5×25 cm3). The ether phases were combined, dried over magnesium sulfate and filtered, and the solvent was evaporated off. 1.28 g of a liquid, the epoxide 2e, were obtained; the crude yield was 96% (macrobore GC purity>98%).
Reaction SMILES: I[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([OH:12])=[CH:5]2.[Cl-].[C:14]([O:18][C:19](=[O:22])[CH2:20][Zn+])([CH3:17])([CH3:16])[CH3:15]>C1COCC1.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>[OH:12][C:6]1[CH:7]=[N:8][C:9]2[C:4]([CH:5]=1)=[CH:3][C:2]([CH2:20][C:19]([O:18][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:22])=[CH:11][CH:10]=2
Reactant: CC(C)(C)OC(=O)C[Zn+]
Reactant: Oc1cnc2ccc(I)cc2c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cl-]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)Cc1ccc2ncc(O)cc2c1
Temperature: 75 °C
Reaction time: 3 h

Procedure:
A stirred solution of 6-iodoquinolin-3-ol (1.76 g, 6 mmol) in THF (10 mL) was treated with 2-tert-butoxy-2-oxoethylzinc chloride (39 ml, 19 mmol) followed by tetrakis(triphenylphosphine)palladium(0) (0.8 g, 0.6 mmol). After the addition, it was heated to reflux (75° C.) under N2. After 3 h, TLC 89368-3-1 showed no sign of starting material. Reaction was stop. The reaction was cooled to rt. Solvent was removed. The residue was stirred in EtOAc/10% EDTA (50 mL/50 mL) solution mixture. After 1 h, the organic layer was separated. The aqueous layer was extracted with more EtOAc (2×25 mL). The combined organic layers were washed with water, brine, dried over MgSO4, and removed solvent. The crude product was purified using SiO2 chromatography (Teledyne Isco RediSep®, P/N 68-2203-026, 12 g SiO2, hex:acetone=80%:20%, Flow=30 mL/min). to afford the desired product as brownish liquid. MS m/z: 260.3 (M+H). Calc'd. for C15H17NO3—259.2.
Reaction SMILES: [C:1]([C:3]1[C:23]([N+:24]([O-:26])=[O:25])=[CH:22][CH:21]=[CH:20][C:4]=1[O:5][CH2:6][CH:7]1[CH2:12][CH2:11][CH2:10][CH2:9][N:8]1C(OC(C)(C)C)=O)#[N:2].[ClH:27]>CCO>[ClH:27].[N+:24]([C:23]1[CH:22]=[CH:21][CH:20]=[C:4]([O:5][CH2:6][CH:7]2[CH2:12][CH2:11][CH2:10][CH2:9][NH:8]2)[C:3]=1[C:1]#[N:2])([O-:26])=[O:25]
Reactant: CC(C)(C)OC(=O)N1CCCCC1COc1cccc([N+](=O)[O-])c1C#N
Agent: Cl
Solvent: CCO
Product: N#Cc1c(OCC2CCCCN2)cccc1[N+](=O)[O-]
Temperature: 80 °C
Reaction time: 1 h
Yield: 116 %

Procedure:
To a solution of tert-butyl 2-((2-cyano-3-nitrophenoxy)methyl)piperidine-1-carboxylate (Example 26e, 1.02 g, 2.83 mmol) in EtOH (20 mL) was added HCl 1.25N in EtOH (11.3 mL, 14.13 mmol) and the reaction mixture was stirred at 80° C. under nitrogen for 1 hour. After cooling to room temperature, the reaction mixture was concentrated in vacuum. The oily residue was washed with Hexane:DCM (1:4) and the solvent concentrated in vacuum to give 2-nitro-6-(piperidin-2-ylmethoxy)benzonitrile hydrochloride (0.982 g, 116%). MS 262 (MH).
Reaction SMILES: FC(F)(F)S(O[C:7]1[C:16]([O:17][CH3:18])=[CH:15][C:14]2[N:13]=[CH:12][C:11]3[N:19]([CH3:32])[C:20](=[O:31])[N:21]([C:22]4[CH:27]=[CH:26][C:25]([C:28]#[N:29])=[CH:24][C:23]=4[F:30])[C:10]=3[C:9]=2[CH:8]=1)(=O)=O.CC1(C)C(C)(C)OB([C:43]2[CH:44]=[N:45][C:46]3[C:51]([CH:52]=2)=[CH:50][CH:49]=[CH:48][CH:47]=3)O1.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>O=O>[F:30][C:23]1[CH:24]=[C:25]([CH:26]=[CH:27][C:22]=1[N:21]1[C:10]2[C:9]3[CH:8]=[C:7]([C:43]4[CH:44]=[N:45][C:46]5[C:51]([CH:52]=4)=[CH:50][CH:49]=[CH:48][CH:47]=5)[C:16]([O:17][CH3:18])=[CH:15][C:14]=3[N:13]=[CH:12][C:11]=2[N:19]([CH3:32])[C:20]1=[O:31])[C:28]#[N:29]
Reactant: CC1(C)OB(c2cnc3ccccc3c2)OC1(C)C
Reactant: COc1cc2ncc3c(c2cc1OS(=O)(=O)C(F)(F)F)n(-c1ccc(C#N)cc1F)c(=O)n3C
Agent: O=O
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Product: COc1cc2ncc3c(c2cc1-c1cnc2ccccc2c1)n(-c1ccc(C#N)cc1F)c(=O)n3C
Temperature: 130 °C
Reaction time: 0.5 h
Yield: 54.1 %

Procedure:
1-(4-Cyano-2-fluorophenyl)-7-methoxy-3-methyl-2-oxo-2,3-dihydro-1H-imidazo[4,5-c]quinolin-8-yl trifluoromethanesulfonate (79 mg, 159 μmol), 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)quinoline (325 mg, 1.27 mmol), tripotassium phosphate (70 mg, 319 μmol) and trans-bis(tricyclohexylphosphine)palladium(II) dichloride (35 mg, 48 μmol) were dissolved in oxygen-free N,N-dimethylformamide (4.7 ml). The reaction mixture was subsequently heated at 130° C. for 90 min (microwave). The mixture was then decanted off into water (50 ml) and stirred for a further 30 min. The precipitate formed was filtered off with suction and rinsed with water. The filter cake was subsequently suspended in a little cold dimethyl sulfoxide, filtered off and rinsed with 2-propanol, giving 3-fluoro-4-(7-methoxy-3-methyl-2-oxo-8-quinolin-3-yl-2,3-dihydroimidazo[4,5-c]quinolin-1-yl)benzonitrile (41 mg, 86 μmol) as colourless solid after drying in a high vacuum. MS: 476.1 (M+H+), TLC (HPTLC): Rf=0.24 (ethyl acetate/ethanol 5:1, parts by volume).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[NH:10][CH2:11][CH3:12])[C:5]#[N:6].[CH2:13]([N:20]=[C:21]=[S:22])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>C1COCC1>[CH2:13]([NH:20][C:21]([NH:1][C:2]1[CH:3]=[C:4]([C:5]#[N:6])[CH:7]=[CH:8][C:9]=1[NH:10][CH2:11][CH3:12])=[S:22])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: S=C=NCc1ccccc1
Reactant: CCNc1ccc(C#N)cc1N
Solvent: C1CCOC1
Product: CCNc1ccc(C#N)cc1NC(=S)NCc1ccccc1
Temperature: 50 °C
Reaction time: 6 h
Yield: 92.5 %

Procedure:
To a solution of 3-amino-4-ethylamino-benzonitrile (1.0 g, 6.2 mmol) in THF (50 mL, anhyd) was added benzylisothiocyanate (0.92 g, 6.2 mmol). The reaction mixture was heated at 50° C. with stirring. After 6 h, the reaction mixture was cooled, concentrated under reduced pressure, and chromatographed (silica gel, 1:1 EtOAc/Hex) to yield 1-benzyl-3-(5-cyano-2-ethylaminophenyl)thiourea (1.78 g, 93%). 1H-NMR (CDCl3): δ 7.48 (1H, dd), 7.37 (1H, d), 7.31 (3H, m), 7.24 (1H, s), 7.18 (1H, br), 6.67 (1H, d), 5.95 (1H, br), 4.81 (2H, d), 4.68 (1H, br), 3.19 (2H, m), 1.23 (3H, t).
Reaction SMILES: [C:1]([N:4]1[CH2:9][CH2:8][N:7]([CH2:10][CH2:11][CH2:12][O:13][C:14]2[CH:19]=[CH:18][C:17]([CH:20]3[CH2:25][CH2:24][N:23]([C:26]4[CH:27]=[CH:28][C:29]5[N:30]([C:32]([C:35]([F:38])([F:37])[F:36])=[N:33][N:34]=5)[N:31]=4)[CH2:22][CH2:21]3)=[CH:16][CH:15]=2)[CH2:6][CH2:5]1)(=[O:3])[CH3:2].C([O-])=O.[NH4+]>[Pd].C(O)C.C(Cl)Cl>[C:1]([N:4]1[CH2:5][CH2:6][N:7]([CH2:10][CH2:11][CH2:12][O:13][C:14]2[CH:15]=[CH:16][C:17]([CH:20]3[CH2:21][CH2:22][N:23]([C:26]4[CH2:27][CH2:28][C:29]5[N:30]([C:32]([C:35]([F:36])([F:37])[F:38])=[N:33][N:34]=5)[N:31]=4)[CH2:24][CH2:25]3)=[CH:18][CH:19]=2)[CH2:8][CH2:9]1)(=[O:3])[CH3:2]
Reactant: CC(=O)N1CCN(CCCOc2ccc(C3CCN(c4ccc5nnc(C(F)(F)F)n5n4)CC3)cc2)CC1
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CCO
Solvent: ClCCl
Product: CC(=O)N1CCN(CCCOc2ccc(C3CCN(C4=Nn5c(nnc5C(F)(F)F)CC4)CC3)cc2)CC1
Temperature: 76 °C
Reaction time: 32 h
Yield: 71.5 %

Procedure:
10% Palladium on carbon (0.276 g, 0.26 mmol) was added to 6-[4-[4-[3-(4-acetylpiperazin-1-yl)propoxy]phenyl]piperidin-1-yl]-3-(trifluoromethyl)[1,2,4]triazolo[4,3-b]pyridazine (13.80 g, 25.96 mmol) and ammonium formate (16.37 g, 259.61 mmol) in ethanol (300 mL) at 20° C. The resulting slurry was stirred at 76° C. for 32 hours, regularly adding more ammonium formate and catalyst to force the reaction to completion. The cooled reaction mixture was filtered through diatomaceous earth and the filtrate was concentrated under vacuum to give a colourless gum which was dissolved in DCM (1 L) and the solution washed with water (1 L). The organic layer was washed with brine, dried (Na2SO4), filtered and evaporated to dryness. The crude product was purified by flash silica chromatography, elution gradient 0 to 8% MeOH in DCM. Pure fractions were evaporated to dryness and the resulting oil was triturated with ether to give 6-[4-[4-[3-(4-acetylpiperazin-1-yl)propoxy]phenyl]piperidin-1-yl]-3-(trifluoromethyl)-7,8-dihydro[1,2,4]triazolo[4,3-b]pyridazine (9.90 g, 71.4%) as a white solid.
Reaction SMILES: [CH2:1]([N:8]([CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[CH:9]1[CH2:13][CH:12]([C:14](O)=[O:15])[CH:11]([CH3:17])[CH2:10]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(Cl)(=O)C([Cl:28])=O.CN(C=O)C>C(Cl)Cl>[CH2:1]([N:8]([CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[CH:9]1[CH2:13][CH:12]([C:14]([Cl:28])=[O:15])[CH:11]([CH3:17])[CH2:10]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(Cl)C(=O)Cl
Reactant: CC1CC(N(Cc2ccccc2)Cc2ccccc2)CC1C(=O)O
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CC1CC(N(Cc2ccccc2)Cc2ccccc2)CC1C(=O)Cl
Temperature: 25 °C
Reaction time: 14 h

Procedure:
To a solution of 4-(dibenzylamino)-2-methylcyclopentanecarboxylic acid (7.34 g, 22.7 mmol, Preparation #TT.1) in DCM (100 mL), oxalyl chloride (4.37 mL, 49.9 mmol) was slowly added followed by a dropwise addition of DMF (0.26 mL, 3.4 mmol). The mixture was stirred at ambient temperature for about 14 h and the solvent was removed under reduced pressure to yield 4-(dibenzylamino)-2-methylcyclopentanecarbonyl chloride as a beige solid. The solid was dissolved in THF and MeCN (1:1, 100 mL) and added to a solution of trimethylsilyldiazomethane (2 M in Et2O, 39.7 mL, 79.4 mmol) in 1:1 mixture of THF and MeCN (100 mL) at about 0° C. The resulting mixture was stirred at about 0° C. for about 3 h and then was quenched by dropwise addition of 48% aqueous HBr (25 mL, 221 mmol). The resulting mixture was neutralized by dropwise addition of saturated aqueous NaHCO3 (300 mL) and the layers were separated. The organic layer was dried over anhydrous MgSO4, filtered, and concd under reduced pressure. The residue was purified by silica gel flash chromatography eluting with a gradient of 5-45% EtOAc in heptane to yield 2-bromo-1-(4-(dibenzylamino)-2-methylcyclopentyl)ethanone (6.3 g, 69%) as a yellow oil: LC/MS (Table 1, Method a) Rt=2.90 min; MS m/z 400, 402 (1:1) (M+H)+.
Reaction SMILES: [CH3:1][C:2]([NH:22]C(=O)OC(C)(C)C)([CH3:21])[C:3]([NH:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([O:19][CH3:20])[CH:14]=2)=[CH:8][CH:7]=1)=[O:4].C(O)(C(F)(F)F)=O>ClCCl>[CH3:21][C:2]([C:3]([NH:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([O:19][CH3:20])[CH:14]=2)=[CH:8][CH:7]=1)=[O:4])([CH3:1])[NH2:22]
Reactant: COc1cccc(Oc2ccc(NC(=O)C(C)(C)NC(=O)OC(C)(C)C)cc2)c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COc1cccc(Oc2ccc(NC(=O)C(C)(C)N)cc2)c1
Reaction time: 2 h
Yield: 94.5 %

Procedure:
To a solution of 1,1-dimethylethyl {1,1-dimethyl-2-[(4-{[3-(methyloxy)phenyl]oxy}phenyl)amino]-2-oxoethyl}carbamate (Intermediate 71, 1.89 g) in dry dichloromethane (60 mL) at 0° C. TFA (20 mL, 260 mmol) was added dropwise and the reaction mixture was stirred for 2 hours at the same temperature. The solvent and the excess of TFA were evaporated and the residue was purified by SCX cartridge (50 g) to afford the title compound as a light brown oil (1.34 g).
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][CH:5]=[CH:4][C:3]=1[C:12]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=O.F[C:21]1[C:26](C(F)(F)F)=[CH:25][CH:24]=[CH:23][C:22]=1[C:31]([C:33]1C=CC=[CH:35][CH:34]=1)=[O:32]>>[CH3:35][C:34]1[C:33]([C:31]([C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:21]=2)=[O:32])=[C:12]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:3]2[C:2](=[C:7]([C:8]([F:11])([F:10])[F:9])[CH:6]=[CH:5][CH:4]=2)[N:1]=1
Reactant: O=C(c1ccccc1)c1cccc(C(F)(F)F)c1F
Reactant: Nc1c(C(=O)c2ccccc2)cccc1C(F)(F)F
Product: Cc1nc2c(C(F)(F)F)cccc2c(-c2ccccc2)c1C(=O)c1ccccc1

Procedure:
[2-amino-3-(trifluoromethyl)phenyl](phenyl)methanone: The title compound was prepared from (2-Fluoro-3-trifluoromethyl-phenyl)-phenyl-methanone following the procedure of Example 457, Step 3: MS (ESI) m/z 266; HRMS: calcd for C14H10F3NO+H+, 266.07872; found (ESI, [M+H]+), 266.0771
Reaction SMILES: [F:1][C:2]1[CH:17]=[CH:16][CH:15]=[C:14]([C:18]([F:21])([F:20])[F:19])[C:3]=1[CH2:4][N:5]1[C:10]([CH3:11])=[CH:9][C:8](=[O:12])[NH:7][C:6]1=[O:13].[I:22]Cl>CO>[F:1][C:2]1[CH:17]=[CH:16][CH:15]=[C:14]([C:18]([F:21])([F:19])[F:20])[C:3]=1[CH2:4][N:5]1[C:10]([CH3:11])=[C:9]([I:22])[C:8](=[O:12])[NH:7][C:6]1=[O:13]
Reactant: Cc1cc(=O)[nH]c(=O)n1Cc1c(F)cccc1C(F)(F)F
Reactant: ClI
Solvent: CO
Product: Cc1c(I)c(=O)[nH]c(=O)n1Cc1c(F)cccc1C(F)(F)F
Temperature: 50 °C
Yield: 91.8 %

Procedure:
To a 250 mL three-neck round bottom flask was charged 1-(2-fluoro-6-trifluoromethyl-benzyl)-6-methyl-1H-pyrimidine-2,4-dione 1a (25.0 g) and methanol (250 mL). Iodine monochloride (30.9 g) was charged over 2.5 min. The mixture was heated at 50° C. for 3 hours. After cooling to ambient temperature, the mixture was filtered. The cake was re-slurried in methanol (250 mL) and heated to 50° C. for 3 hours. After cooling to ambient temperature, the mixture was filtered and the filter cake was washed with methanol (50 mL). The off-white solid was dried in a vacuum oven at 50° C. to provide 1-(2-fluoro-6-trifluoromethyl-benzyl)-5-iodo-6-methyl-1H-pyrimidine-2,4-dione 1b (32.5 g, 90% yield). LCMS (ESI) m/z 429.3 (MH+). The material may be re-slurried in MeOH as needed.
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([F:13])=[CH:9][C:10]=2[F:12])[N:5]=[C:4]([N:14]2[CH2:19][CH2:18][NH:17][C:16](=[O:20])[CH2:15]2)[C:3]=1[CH3:21].[H-].[Na+].I[CH3:25]>C1COCC1.O>[Cl:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([F:13])=[CH:9][C:10]=2[F:12])[N:5]=[C:4]([N:14]2[CH2:19][CH2:18][N:17]([CH3:25])[C:16](=[O:20])[CH2:15]2)[C:3]=1[CH3:21]
Reactant: CI
Reactant: Cc1c(N2CCNC(=O)C2)nc2cc(F)cc(F)c2c1Cl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: Cc1c(N2CCN(C)C(=O)C2)nc2cc(F)cc(F)c2c1Cl
Reaction time: 1.5 h

Procedure:
The 4-(4-chloro-5,7-difluoro-3-methylquinolin-2-yl)piperazin-2-one (30 mg, 0.096 mmol) was dissolved in THF (1.0 mL) and sodium hydride (10.0 mg, 0.42 mmol) (60% suspension) was added followed by addition of iodomethane (17.0 μL, 0.27 mmol). The mixture was stirred for 1.5 h, then diluted with water. The mixture was extracted with EtOAc (2×15 mL). The combined organic layers were dried over magnesium sulfate. The filtrate was concentrated to give the desired product. Mass Spectrum (ESI) m/e=326.0 (M+1).