Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[N:7]([CH2:8][C:9]([O:11][CH3:12])=[O:10])[C:6](=[O:13])[C:5]([N+:14]([O-:16])=[O:15])=[C:4](OS(C(F)(F)F)(=O)=O)[CH:3]=1.[C:25]([C:27]1[CH:32]=[CH:31][C:30]([CH2:33]Br)=[CH:29][CH:28]=1)#[N:26]>>[C:25]([C:27]1[CH:32]=[CH:31][C:30]([CH2:33][C:4]2[CH:3]=[C:2]([CH3:1])[N:7]([CH2:8][C:9]([O:11][CH3:12])=[O:10])[C:6](=[O:13])[C:5]=2[N+:14]([O-:16])=[O:15])=[CH:29][CH:28]=1)#[N:26]
Reactant: COC(=O)Cn1c(C)cc(OS(=O)(=O)C(F)(F)F)c([N+](=O)[O-])c1=O
Reactant: N#Cc1ccc(CBr)cc1
Product: COC(=O)Cn1c(C)cc(Cc2ccc(C#N)cc2)c([N+](=O)[O-])c1=O

Procedure:
This compound is prepared from 15.3 g (40.9 mmol) of methyl 6-methyl-3-nitro-2-oxo-4-[[(trifluoromethyl)sulphonyl]oxy]-1,2-dihydropyridine-1-acetate and 10 g (51 mmol) of (4-cyanophenyl)methyl bromide according to the method described in Example 1.5.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][C:9]2[CH:18]=[C:17]([C:19]([O:21][CH2:22][CH3:23])=[O:20])[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[N:10]=2)=[CH:4][CH:3]=1.[Cl:24][C:25]1[CH:30]=[CH:29][C:28]([N:31]=[C:32]=[S:33])=[CH:27][C:26]=1[C:34]([F:37])([F:36])[F:35]>>[CH2:22]([O:21][C:19]([C:17]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[N:10]=[C:9]([S:8][C:5]2[CH:6]=[CH:7][C:2]([NH:1][C:32]([NH:31][C:28]3[CH:29]=[CH:30][C:25]([Cl:24])=[C:26]([C:34]([F:37])([F:35])[F:36])[CH:27]=3)=[S:33])=[CH:3][CH:4]=2)[CH:18]=1)=[O:20])[CH3:23]
Reactant: FC(F)(F)c1cc(N=C=S)ccc1Cl
Reactant: CCOC(=O)c1cc(Sc2ccc(N)cc2)nc2ccccc12
Product: CCOC(=O)c1cc(Sc2ccc(NC(=S)Nc3ccc(Cl)c(C(F)(F)F)c3)cc2)nc2ccccc12
Yield: 89 %

Procedure:
2-(4-aminophenylthio)-4-ethoxycarbonylquinoline (6.0 moles, 2.0 g) and 4-chloro-3-trifluoromethylphenylisothiocyanate (6.0 mmoles, 1.4 g) were reacted according to procedure C to yield 3.0 g, 89% of the title compound. Mass Spec (FD) 561. Calculated for C26H19ClF3N3O2S2 : C, 55.56; H, 3.41; N, 7.48. Found: C, 55.38 H, 3.38; N, 7.36.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7]([CH3:18])=[C:8]2[C:13](Cl)=[C:12]([C:15]#[N:16])[CH:11]=[N:10][N:9]2[CH:17]=1)=[O:5])[CH3:2].C([O-])([O-])=O.[K+].[K+].[O:25]([C:32]1[CH:38]=[CH:37][C:35]([NH2:36])=[CH:34][CH:33]=1)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>CN(C=O)C.ClCCl>[CH2:1]([O:3][C:4]([C:6]1[C:7]([CH3:18])=[C:8]2[C:13]([NH:36][C:35]3[CH:34]=[CH:33][C:32]([O:25][C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=4)=[CH:38][CH:37]=3)=[C:12]([C:15]#[N:16])[CH:11]=[N:10][N:9]2[CH:17]=1)=[O:5])[CH3:2]
Reactant: Nc1ccc(Oc2ccccc2)cc1
Reactant: CCOC(=O)c1cn2ncc(C#N)c(Cl)c2c1C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CCOC(=O)c1cn2ncc(C#N)c(Nc3ccc(Oc4ccccc4)cc3)c2c1C
Reaction time: 12 h
Yield: 75.2 %

Procedure:
To a solution of compound 1D (26 mg, 0.10 mmol) in DMF (2 mL) were added K2CO3 (138 mg, 1.00 mmol) and p-phenoxyaniline (20 mg, 0.11 mmol) at 25° C. The reaction mixture was stirred for 12 h and then diluted with dichloromethane (15 mL) and washed with water (10 mL) and brine (10 mL). The organic phase was dried over Na2SO4 and concentrated and the resulting residue was triturated with methanol to afford 31 mg (76% yield) of the desired compound as a yellow solid. HPLC: 100% at 4.62 min (retention time) (YMC S5 ODS column, 4.6×50 mm, eluting with 10-90% aqueous methanol over 4 min containing 0.2% phosphoric acid, 4 mL/min, monitoring at 220 nm). MS (ES): m/z 413.12 [M+H]+.
Reaction SMILES: [F:1][C:2]([F:11])([F:10])[CH2:3][CH2:4][CH:5]([C:8]#[N:9])[C:6]#[N:7].C(=O)([O-])[O-].[K+].[K+].[Br:18][C:19]1[N:24]=[C:23]([CH2:25]Br)[CH:22]=[CH:21][CH:20]=1>CN(C)C=O>[Br:18][C:19]1[N:24]=[C:23]([CH2:25][C:5]([CH2:4][CH2:3][C:2]([F:10])([F:11])[F:1])([C:8]#[N:9])[C:6]#[N:7])[CH:22]=[CH:21][CH:20]=1
Reactant: N#CC(C#N)CCC(F)(F)F
Reactant: BrCc1cccc(Br)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: N#CC(C#N)(CCC(F)(F)F)Cc1cccc(Br)n1
Yield: 69.3 %

Procedure:
By using (3,3,3-trifluoropropyl)malononitrile (540 mg), N,N-dimethylformamide (4 ml), potassium carbonate (400 mg) and 6-bromo-2-(bromomethyl)pyridine (590 mg) according to the similar method described in Production Example 4 was obtained 541 mg of 2-((6-bromo-2-pyridyl)methyl)-2-(3,3,3-trifluoropropyl)malononitrile represented by the following formula (hereinafter referred to as the present invention compound (14)).
Reaction SMILES: [C:1]1([CH2:7][C:8]([NH:10][NH2:11])=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl[C:13]1[N:14]=[N:15][C:16]([C:19]2[S:20][CH:21]=[CH:22][CH:23]=2)=[CH:17][CH:18]=1>>[CH2:7]([C:8]1[N:14]2[N:15]=[C:16]([C:19]3[S:20][CH:21]=[CH:22][CH:23]=3)[CH:17]=[CH:18][C:13]2=[N:11][N:10]=1)[C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: Clc1ccc(-c2cccs2)nn1
Reactant: NNC(=O)Cc1ccccc1
Product: c1ccc(Cc2nnc3ccc(-c4cccs4)nn23)cc1

Procedure:
The title compound was prepared as described in Example 17 from phenylacetic acid hydrazide (0.67 mmol) and 3-chloro-6-thiophen-2-yl-pyridazine (0.21 mmol). 1H NMR (400 MHz, CDCl3) δ 8.05 (1H, d, J=9.8 Hz), 7.66 (1H, dd, J=3.8 Hz, 1.3 Hz), 7.55 (1H, dd, J=5.0 Hz, 1.0 Hz), 7.53 (2H, m), 7.46 (1H, d, J=9.9 Hz), 7.31 (2H, m), 7.24 (1H, t, J=7.5 Hz), 7.17 (1H, dd, J=5.0 Hz, 3.8 Hz), 4.60 (2H, s). ESI-MS (m/z): Calcd for C16H12N4S: 292.1; found 293.2 (M+H).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[CH:4][C:3]=1[N+:8]([O-:10])=[O:9].B([C:14]1[CH:15]=[C:16]([CH:20]=[CH:21][CH:22]=1)[C:17]([OH:19])=[O:18])(O)O.C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1>[N+:8]([C:3]1[CH:4]=[N:5][CH:6]=[CH:7][C:2]=1[C:14]1[CH:15]=[C:16]([CH:20]=[CH:21][CH:22]=1)[C:17]([OH:19])=[O:18])([O-:10])=[O:9]
Reactant: O=[N+]([O-])c1cnccc1Cl
Reactant: O=C(O)c1cccc(B(O)O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Product: O=C(O)c1cccc(-c2ccncc2[N+](=O)[O-])c1
Temperature: 100 °C
Reaction time: 15 h

Procedure:
To a degassed mixture containing 4-chloro-3-nitropyridine (3.0 g, 18.9 mmol), 3-boronobenzoic acid (3.7 g, 22.7 mmol), potassium carbonate (5.2 g, 37.8 mmol) and dioxane (189 mL) was added tetrakis(tiphenylphosphine)palladium(0) (0.30 g, 0.28 mmol) in one portion under a nitrogen atmosphere. The mixture was heated with fast stirring at 100° C. for 15 h, cooled to room temperature, filtered and concentrated to afford 3-(3-nitropyridin-4-yl)benzoic acid as a tan residue which was used without further purification. LCMS: retention time: 1.375 min. LC data was recorded on a Shimadzu LC-10AS liquid chromatograph equipped with a Waters-Sunfire, 5 u, C18, 4.6×50 mm column using a SPD-10AV UV-Vis detector at a detector wave length of 220 nM. The elution conditions employed a flow rate of 4 mL/min, a gradient of 100% solvent A/0% solvent B to 0% solvent A/100% solvent B, a gradient time of 3 min, a hold time of 1 min, and an analysis time of 4 min where solvent A was 10% CH3CN/90% H2O/10 mM TFA and solvent B was 10% H2O/90% CH3CN/10 mM TFA. MS data was determined using a Micromass Platform for LC in electrospray mode. m/z 245 (MH+).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:6]=[CH:7][C:8]([OH:11])=[CH:9][CH:10]=1)=[O:4].[CH:12]1(Br)[CH2:16][CH2:15][CH2:14][CH2:13]1.[H-].[Na+]>>[CH:12]1([O:11][C:8]2[CH:9]=[CH:10][C:5]([C:3]([O:2][CH3:1])=[O:4])=[CH:6][CH:7]=2)[CH2:16][CH2:15][CH2:14][CH2:13]1
Reactant: COC(=O)c1ccc(O)cc1
Reactant: BrC1CCCC1
Agent: [H-]
Agent: [Na+]
Product: COC(=O)c1ccc(OC2CCCC2)cc1
Temperature: 0 °C
Yield: 99.5 %

Procedure:
To 50 g of methyl p-hydroxybenzoate were added 82 g of cyclopentyl bromide. The mixture was cooled to 0° C. and 24 g of sodium hydride (in a 50% mineral oil suspension) were added in small portions. Ice bath cooling was continued until the resulting effervescence terminated. The reaction mixture then was heated to 75° C. for four hours, cooled, and 25 mL of ethanol was added dropwise. The resulting mixture was evaporated to dryness, and the residue was dissolved in a mixture of water and ether. The ether layer was separated and washed with cold 5% aqueous sodium hydroxide and then with water. The ether layer then was dried over magnesium sulfate and evaporated to dryness to give about 72 g of crude methyl p-cyclopentyloxybenzoate. The crude ester was added to 400 mL of ethylene glycol containing 100 g of potassium hydroxide. The mixture was refluxed for several hours and then was transferred to a 4 L beaker. A mixture of ice and water was added. The resulting mixture then was placed in a separatory funnel and was washed with ether. The aqueous layer was acidified by addition of concentrated hydrochloric acid. The resulting precipitate was collected by filtration, washed with water, and recrystallized from methanol to obtain 44.1 g of p-cyclopentyloxybenzoic acid. A solution of 8.7 g (0.024 mole) of p-cyclopentyloxybenzoic acid in 250 mL of anhydrous ether was prepared. The solution was cooled to 5° C.-10° C. and 8.85 g of thionyl chloride followed by two drops of pyridine were added. The mixture was allowed to warm to room temperature and was stirred overnight. The mixture then was evaporated to dryness, and the oily residue of p-cyclopentyloxybenzoyl chloride was dissolved in 150 mL of 1,2-dichloroethane for use as described in Example 10 below.
Reaction SMILES: [CH3:1][S-:2].[Na+].[Cl:4][C:5]1[CH:10]=[C:9]([S:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2F)(=[O:13])=[O:12])[CH:8]=[CH:7][C:6]=1[NH:21][C:22](=[O:30])[C@:23]([OH:29])([CH3:28])[C:24]([F:27])([F:26])[F:25].[Cl-].[NH4+]>CN1C(=O)CCC1>[Cl:4][C:5]1[CH:10]=[C:9]([S:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[S:2][CH3:1])(=[O:13])=[O:12])[CH:8]=[CH:7][C:6]=1[NH:21][C:22](=[O:30])[C@:23]([OH:29])([CH3:28])[C:24]([F:27])([F:26])[F:25]
Reactant: C[S-]
Reactant: C[C@@](O)(C(=O)Nc1ccc(S(=O)(=O)c2ccccc2F)cc1Cl)C(F)(F)F
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CN1CCCC1=O
Product: CSc1ccccc1S(=O)(=O)c1ccc(NC(=O)[C@@](C)(O)C(F)(F)F)c(Cl)c1
Temperature: 120 °C
Yield: 62.5 %

Procedure:
Sodium methanethiolate (49.5 mg) was added to a solution of (R)-N-[2-chloro-4-(2-fluorophenylsulphonyl)phenyl]-2-hydroxy-2-methyl-3,3,3-trifluoropropanamide (Method 63) (0.15 g) in NMP (1.5 ml) and the mixture was heated at 120° C. for 18 hours then cooled. Saturated aqueous ammonium chloride solution (15 ml) was added and the mixture was extracted with ethyl acetate (2×50 ml). The organic extracts were combined, washed with brine and dried. Volatile material was removed by evaporation and the residue was purified by chromatography on a silica gel Mega Bond Elut column eluting with 0-20% ethyl acetate/hexane to give the title compound (0.10 g) as a solid. NMR: (CDCl3): 1.75 (s, 3H), 2.4 (s, 3H), 3.6 (brs, 1H), 7.3 (t, 1H), 7.35 (t, 1H), 7.55 (m, 1H), 7.9 (dd, 1H), 8.05 (d, 1H) 8.25 (dd, 1H), 8.6 (d, 1H), 9.25 (brs, 1H); MS (ESP−): 452.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=1.[CH3:11][O:12][CH2:13][CH2:14][CH2:15][NH2:16]>>[N+:8]([C:5]1[CH:6]=[CH:7][C:2]([NH:16][CH2:15][CH2:14][CH2:13][O:12][CH3:11])=[CH:3][CH:4]=1)([O-:10])=[O:9]
Reactant: COCCCN
Reactant: O=[N+]([O-])c1ccc(F)cc1
Product: COCCCNc1ccc([N+](=O)[O-])cc1
Temperature: 0 °C

Procedure:
One heats to reflux for 5 hours 0.2 mole (28.2 g) of parafluoronitrobenzene in 102 ml of γ-methoxypropylamine. One then pours the cooled reaction mixture into 200 g of crushed ice. The intended product precipitates first in the form of an oil which crystallizes rapidly. After recrystallization in methanol and vacuum drying the product melts at 56° C. Analysis gives the following results:
Reaction SMILES: [CH3:1][C:2]1([CH3:20])[C:10]2[C:5](=[CH:6][CH:7]=[C:8](OS(C(F)(F)F)(=O)=O)[CH:9]=2)[C:4](=[O:19])[CH2:3]1.[CH3:21][N:22]1[CH:26]=[CH:25][CH:24]=[C:23]1[C:27]#[N:28]>>[CH3:1][C:2]1([CH3:20])[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([C:26]3[N:22]([CH3:21])[C:23]([C:27]#[N:28])=[CH:24][CH:25]=3)[CH:9]=2)[C:4](=[O:19])[CH2:3]1
Reactant: CC1(C)CC(=O)c2ccc(OS(=O)(=O)C(F)(F)F)cc21
Reactant: Cn1cccc1C#N
Product: Cn1c(C#N)ccc1-c1ccc2c(c1)C(C)(C)CC2=O

Procedure:
5-(3,3-Dimethyl-1-oxo-2,3-dihydro-1H-inden-5-yl)-1-methyl-1H-pyrrole-2-carbonitrile was prepared from trifluoro-methanesulfonic acid 3,3-dimethyl-1-oxo-indan-5-yl ester and 1-methyl-2-cyanopyrrole according to the same coupling procedure as described in example 2. MS (ES) m/z 265.1. HRMS: calcd for C17H16N2O+H+, 265.13354; found (ESI, [M+H]+), 265.1332.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3([C:13]([NH:15][C:16]4[CH:17]=[C:18]([C:23]5[CH:28]=[CH:27][C:26]([CH2:29]O)=[CH:25][CH:24]=5)[C:19]([CH3:22])=[CH:20][CH:21]=4)=[O:14])[CH2:12][CH2:11]3)=[CH:9][C:4]=2[O:3][CH2:2]1.CS(Cl)(=O)=O.[CH:36]([N:39](CC)C(C)C)(C)C.CN.C1COCC1>ClCCl>[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3([C:13]([NH:15][C:16]4[CH:17]=[C:18]([C:23]5[CH:28]=[CH:27][C:26]([CH2:29][NH:39][CH3:36])=[CH:25][CH:24]=5)[C:19]([CH3:22])=[CH:20][CH:21]=4)=[O:14])[CH2:12][CH2:11]3)=[CH:9][C:4]=2[O:3][CH2:2]1
Reactant: Cc1ccc(NC(=O)C2(c3ccc4c(c3)OCO4)CC2)cc1-c1ccc(CO)cc1
Reactant: CCN(C(C)C)C(C)C
Agent: CN
Agent: CS(=O)(=O)Cl
Solvent: C1CCOC1
Solvent: ClCCl
Product: CNCc1ccc(-c2cc(NC(=O)C3(c4ccc5c(c4)OCO5)CC3)ccc2C)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 60.2 %

Procedure:
1-(Benzo[d][1,3]dioxol-5-yl)-N-(4′-(hydroxymethyl)-6-methylbiphenyl-3-yl)cyclopropanecarboxamide (610 mg, 1.52 mmol), methanesulfonyl chloride (0.13 mL, 1.7 mmol), and N,N-diisopropylethylamine (0.79 mL, 4.6 mmol) were dissolved in dichloromethane (10 mL) at 25° C. The reaction was stirred for 10 minutes before a 2.0 M solution of MeNH2 in THF (15 mL, 30 mmol) was added. The mixture was stirred for 30 minutes at ambient temperature before it was extracted with 1N HCl (20 mL×2) and saturated NaHCO3 (20 mL×2). The organic extracts were dried over Na2SO4 and evaporated. The crude product was purified by chromatography on silica gel (eluting with 0-20% methanol in dichloromethane) to afford 1-(Benzo[d][1,3]dioxol-5-yl)-N-(6-methyl-4′-((methylamino)methyl)biphenyl-3-yl)cyclopropanecarboxamide (379 mg, 60%). ESI-MS m/z calc. 414.5, found 415.5 (M+1)+; retention time 2.44 minutes.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][C:5]([NH:6][CH3:7])=[CH:4][CH:3]=1.[CH2:10]=[C:11]1[O:15][C:13](=[O:14])[CH2:12]1>ClCCCl>[Cl:1][C:2]1[CH:9]=[CH:8][C:5]([N:6]([CH3:7])[C:13](=[O:14])[CH2:12][C:11]([CH3:10])=[O:15])=[CH:4][CH:3]=1
Reactant: C=C1CC(=O)O1
Reactant: CNc1ccc(Cl)cc1
Solvent: ClCCCl
Product: CC(=O)CC(=O)N(C)c1ccc(Cl)cc1

Procedure:
An appropriately fitted reaction flask was charged with 26.5 g (0.187 mole) of 4-chloro-N-methylaniline [prepared as described by Kadin in The Journal of Organic Chemistry, vol. 38, p. 1348 (1973)] and 90 ml of 1,2-dichloroethane. Dropwise addition of 16.7 g (0.2 mole) of diketene produced an exothermic response. The reaction solution was refluxed for four hours. Additional 1,2-dichloroethane was added and the organic phase was extracted with: (a) dilute hydrochloric acid, (b) water and (c) saturated aqueous sodium chloride. After drying the 1,2-dichloroethane solution over sodium sulfate, the solvent was evaporated under an efficient source of vacuum. The residual oil (38.9 g, 92%) was used in the following reaction without further purification. N.M.R. (CDCl3) ∂1.8 (CH3, enol), 2.2 (CH3, keto), 3.2 (NCH3), 3.7 (CH2), 4.8 (CH), 7.2-7.4 (aromatic).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([NH:28][C:29]([C:31]2[C:32](=[O:44])[N:33]([C:37]3[CH:42]=[CH:41][C:40]([F:43])=[CH:39][CH:38]=3)[CH:34]=[CH:35][CH:36]=2)=[O:30])[CH:5]=[CH:6][C:7]=1[O:8][C:9]1[CH:14]=[CH:13][N:12]=[C:11]2[N:15](CC3C=CC(OC)=CC=3)[N:16]=[C:17]([CH3:18])[C:10]=12.C(O)(C(F)(F)F)=O>>[F:1][C:2]1[CH:3]=[C:4]([NH:28][C:29]([C:31]2[C:32](=[O:44])[N:33]([C:37]3[CH:38]=[CH:39][C:40]([F:43])=[CH:41][CH:42]=3)[CH:34]=[CH:35][CH:36]=2)=[O:30])[CH:5]=[CH:6][C:7]=1[O:8][C:9]1[CH:14]=[CH:13][N:12]=[C:11]2[NH:15][N:16]=[C:17]([CH3:18])[C:10]=12
Reactant: COc1ccc(Cn2nc(C)c3c(Oc4ccc(NC(=O)c5cccn(-c6ccc(F)cc6)c5=O)cc4F)ccnc32)cc1
Solvent: O=C(O)C(F)(F)F
Product: Cc1n[nH]c2nccc(Oc3ccc(NC(=O)c4cccn(-c5ccc(F)cc5)c4=O)cc3F)c12
Temperature: 50 °C
Yield: 73.8 %

Procedure:
A mixture of N-(3-fluoro-4-(1-(4-methoxybenzyl)-3-methyl-1H-pyrazolo[3,4-b]pyridin-4-yloxy)phenyl)-1-(4-fluorophenyl)-2-oxo-1,2-dihydropyridine-3-carboxamide (0.045 g, 0.0758 mmol) and TFA (0.58 mL, 7.58 mmol) was placed in a vial and heated at 50° C. for 4 hours. The reaction mixture was concentrated under reduced pressure using toluene to azeotrope. The crude was treated with THF and Et3N and purified by silica gel flash column chromatography (2% MeOH in CH2Cl2) to afford 26.5 mg (74%) of the desired product. LRMS (ESI pos) m/e 474.2 (M+1). 1H-NMR (400 MHz, CD3OD/CDCl3) δ 8.72 (dd, 1H), 8.24 (d, 1H), 7.99 (dd, 1H), 7.92 (dd, 1H), 7.51 (m, 2H), 7.42 (m, 1H), 7.32 (t, 3H), 6.75 (t, 1H), 6.26 (d, 1H), 2.73 (s, 3H); 19F NMR (376 MHz, CD3OD/CDCl3) δ −113.2, −128.8.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1([C:12]([C:14]2[CH:15]=[CH:16][C:17]([S:20][CH3:21])=[N:18][CH:19]=2)=[CH2:13])[CH2:11][O:10]1.C(=O)([O-])[O-].[K+].[K+].[NH:28]1[CH:32]=[N:31][CH:30]=[N:29]1.C(OCC)(=O)C>CN(C=O)C>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]([OH:10])([C:12]([C:14]1[CH:15]=[CH:16][C:17]([S:20][CH3:21])=[N:18][CH:19]=1)=[CH2:13])[CH2:11][N:28]1[CH:32]=[N:31][CH:30]=[N:29]1
Reactant: C=C(c1ccc(SC)nc1)C1(c2ccc(F)cc2F)CO1
Reactant: c1nc[nH]n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: C=C(c1ccc(SC)nc1)C(O)(Cn1cncn1)c1ccc(F)cc1F
Temperature: 50 °C
Reaction time: 20 h
Yield: 71.9 %

Procedure:
A solution of the product of part (vi) (3.6 g, 13 mmol) in DMF (30 ml) was added to potassium carbonate (2.0 g, 15 mmol) and 1H-1,2,4-triazole (1.0 g, 15 mmol). The mixture was stirred at 50° C. for 20 hours then poured into ethyl acetate (200 ml) and washed with water (2×100 ml). The organic phase was dried (MgSO4) and evaporated under reduced pressure. Flash chromatography of the residue on silica by elution with ethyl acetate gave the title compound as an oil, (3.5 g).
Reaction SMILES: [CH:1]1([N:7]2[C:16]3[C:11](=[CH:12][C:13]([F:19])=[C:14](F)[C:15]=3[F:17])[C:10](=[O:20])[C:9]([C:21]([OH:23])=[O:22])=[CH:8]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH2:24]([NH:26][CH2:27][CH:28]1[CH2:32][CH2:31][NH:30][CH2:29]1)[CH3:25]>C(#N)C>[CH:1]1([N:7]2[C:16]3[C:11](=[CH:12][C:13]([F:19])=[C:14]([N:30]4[CH2:31][CH2:32][CH:28]([CH2:27][NH:26][CH2:24][CH3:25])[CH2:29]4)[C:15]=3[F:17])[C:10](=[O:20])[C:9]([C:21]([OH:23])=[O:22])=[CH:8]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CCNCC1CCNC1
Reactant: O=C(O)c1cn(C2CCCCC2)c2c(F)c(F)c(F)cc2c1=O
Solvent: CC#N
Product: CCNCC1CCN(c2c(F)cc3c(=O)c(C(=O)O)cn(C4CCCCC4)c3c2F)C1
Yield: 80.6 %

Procedure:
To 0.80 g (2.46 mmol) of 1-cyclohexyl-6,7,8-trifluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid in 15 ml of acetonitrile was added 0.37 g 2.46 mmol) of 1,8-diazobicyclo[5.4.0]undec-7-ene and 0.33 g (2.58 mmol) of 3-[(ethylamino)methyl]pyrrolidine. The mixture was refluxed for one hour, cooled, filtered, and the solids washed with ether to give 0.86 g of 1-cyclohexyl-7-[3-[(ethylamino)methyl]-1-pyrrolidinyl]-6,8-difluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid, mp 194°-196° C.
Reaction SMILES: [S:1]=[C:2]1[C@@:7]([O:13][C:14]2[CH:19]=[C:18]([F:20])[C:17]([F:21])=[C:16]([F:22])[CH:15]=2)([C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH2:6][CH2:5][CH2:4][NH:3]1.[CH3:23]I>C(#N)C>[CH3:23][S:1][C:2]1[C@@:7]([O:13][C:14]2[CH:15]=[C:16]([F:22])[C:17]([F:21])=[C:18]([F:20])[CH:19]=2)([C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH2:6][CH2:5][CH2:4][N:3]=1
Reactant: CI
Reactant: CCOC(=O)[C@@]1(Oc2cc(F)c(F)c(F)c2)CCCNC1=S
Solvent: CC#N
Product: CCOC(=O)[C@@]1(Oc2cc(F)c(F)c(F)c2)CCCN=C1SC
Temperature: 50 °C
Reaction time: 1 h

Procedure:
Lawesson's reagent (4.46 g) was added to a mixture of ethyl (3R)-2-oxo-3-(3,4,5-trifluorophenoxy)piperidine-3-carboxylate (5.00 g) in toluene (50 mL) at room temperature, and the mixture was stirred with heating at 100° C. for 1 hr. After cooling to room temperature, the reaction mixture was purified by silica gel column chromatography (NH, ethyl acetate/hexane) to give ethyl (3S)-2-thioxo-3-(3,4,5-trifluorophenoxy)piperidine-3-carboxylate (5.25 g). To a mixture of ethyl (3S)-2-thioxo-3-(3,4,5-trifluorophenoxy)piperidine-3-carboxylate (5.25 g) in acetonitrile (25 mL) was added methyl iodide (2.94 mL) at room temperature, and the mixture was stirred under a nitrogen atmosphere at 50° C. for 1 hr. The reaction mixture was concentrated under reduced pressure, to the residue was added 10% aqueous potassium carbonate solution, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous sodium sulfate, and purified by silica gel column chromatography (NH, ethyl acetate) to give the title compound (5.65 g).
Reaction SMILES: [F:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][CH:8]=[N:9]2)=[CH:4][C:3]=1[CH2:12][C:13]1[N:17]2[N:18]=[C:19]([C:22]3[CH:23]=[N:24][NH:25][CH:26]=3)[CH:20]=[CH:21][C:16]2=[N:15][CH:14]=1.Cl.Cl[CH2:29][CH2:30][N:31]1[CH2:35][CH2:34][CH2:33][CH2:32]1.C([O-])([O-])=O.[Cs+].[Cs+]>CN(C=O)C.CCOC(C)=O>[F:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][CH:8]=[N:9]2)=[CH:4][C:3]=1[CH2:12][C:13]1[N:17]2[N:18]=[C:19]([C:22]3[CH:23]=[N:24][N:25]([CH2:29][CH2:30][N:31]4[CH2:35][CH2:34][CH2:33][CH2:32]4)[CH:26]=3)[CH:20]=[CH:21][C:16]2=[N:15][CH:14]=1
Reactant: ClCCN1CCCC1
Reactant: Fc1cc2ncccc2cc1Cc1cnc2ccc(-c3cn[nH]c3)nn12
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Fc1cc2ncccc2cc1Cc1cnc2ccc(-c3cnn(CCN4CCCC4)c3)nn12
Temperature: 95 °C
Reaction time: 18 h

Procedure:
A mixture of 7-fluoro-6-[6-(1H-pyrazol-4-yl)-imidazo[1,2-b]pyridazin-3-ylmethyl]-quinoline (Example 251, 50 mg, 0.145 mmol), 1-(2-chlorethyl)pyrrolidine hydrochloride (25 mg, 0.145 mmol) and Cs2CO3 (99 mg, 0.305 mmol) in DMF (1 mL) was stirred at 95° C. for 18 h. The mixture was diluted with EtOAc and washed with NaHCO3 and brine. The organic layer was dried over Na2SO4, filtered and concentrated. The residue was purified by flash chromatography (CombiFlash® Companion System®, with a 4 g RediSep® silica gel column, DCM/(DCM/MeOH 19:1)=100:0→0:100) to afford the title compound as a foam (tR 3.06 min (conditions 3), MH+=442.2, 1H-NMR in DMSO-d6: 8.84 (m, 1H); 8.44 (s, 1H); 8.34 (d, 1H); 8.08 (m, 2H); 8.03 (d, 1H); 7.76 (d, 1H); 7.61 (s, 1H); 7.52 (d, 1H); 7.46 (dd, 1H); 4.54 (s, 2H); 4.26 (t, 2H); 2.83 (m, 2H); 2.44 (m, 4H); 1.62 (m, 4H)).
Reaction SMILES: [C:1](Cl)(=[O:5])[C:2]([Cl:4])=[O:3].OC1OC[N:10]([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([O:19][C:20]([F:23])([F:22])[F:21])[CH:14]=2)[C:9]1=O>C(Cl)Cl.CN(C=O)C>[Cl:4][CH:2]1[O:3][CH2:9][N:10]([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([O:19][C:20]([F:21])([F:22])[F:23])[CH:14]=2)[C:1]1=[O:5]
Reactant: O=C(Cl)C(=O)Cl
Reactant: O=C1C(O)OCN1c1cccc(OC(F)(F)F)c1
Solvent: ClCCl
Solvent: CN(C)C=O
Product: O=C1C(Cl)OCN1c1cccc(OC(F)(F)F)c1
Temperature: 25 °C

Procedure:
Oxalyl chloride (2.7 ml) was added dropwise over 1 min to a stirred solution of 5-hydroxy-3-(3-trifluoromethoxyphenyl)oxazolidin-4-one (8.17 g) in DCM (60 ml) containing DMF (1 drop) at 0° C. The mixture was allowed to warm to room temperature and once gas evolution had stopped the solvent was removed in vacuo to give the sub-title compound (8.5 g) which was used directly in the next step.