Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1([F:16])[CH2:5][CH:4]([C:6]([O:8]CC2C=CC=CC=2)=O)[CH2:3]1.[CH3:17][C:18]1([CH3:26])[O:25][C:23](=[O:24])[CH2:22][C:20](=[O:21])[O:19]1.CCN=C=NCCCN(C)C.O>CO.CN(C1C=CN=CC=1)C.[Pd]>[F:16][C:2]1([F:1])[CH2:3][CH:4]([C:6]([CH:22]2[C:23](=[O:24])[O:25][C:18]([CH3:26])([CH3:17])[O:19][C:20]2=[O:21])=[O:8])[CH2:5]1
Reactant: CC1(C)OC(=O)CC(=O)O1
Reactant: O=C(OCc1ccccc1)C1CC(F)(F)C1
Agent: [Pd]
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Solvent: O
Solvent: CO
Product: CC1(C)OC(=O)C(C(=O)C2CC(F)(F)C2)C(=O)O1
Temperature: 0 °C
Reaction time: 2 h
Yield: 76.3 %

Procedure:
A mixture of benzyl 3,3-difluorocyclobutanecarboxylate (28 g, 0.12 mol) and Pd/C (5 g) in methanol (150 mL) was hydrogenated for 2 h at ambient temperature. Pd/C was filtered off and the filtrate was concentrated. The residue was dissolved in dichloromethane (200 mL) and cooled to 0° C. DMAP (30.8 g, 0.250 mol), Meldrum's acid (19.6 g, 0.140 mol) and EDCI (26.9 g, 0.140 mol) were added successively. The reaction mixture was stirred overnight at ambient temperature. Water (200 mL) was added and the resulting mixture was extracted with dichloromethane (300 mL×3). The organic extracts were combined, dried over anhydrous sodium sulfate, and concentrated. The residue was purified by flash column chromatography on silica gel (dichloromethane/methanol=100:1 to 20:1) to afford 5-(3,3-difluorocyclobutanecarbonyl)-2,2-dimethyl-1,3-dioxane-4,6-dione (24 g, 74% yield).
Reaction SMILES: [C:1]([C:3]1[C:4]([C:20]([F:23])([F:22])[F:21])=[C:5]2[C:9](=[CH:10][CH:11]=1)[N:8]([CH2:12][C:13](=[NH:16])[NH:14][OH:15])[C:7]([CH2:17][CH2:18][CH3:19])=[CH:6]2)#[N:2].[CH3:24][S:25][C:26]1[CH:34]=[CH:33][CH:32]=[CH:31][C:27]=1[C:28](O)=O.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)CC)C>CN(C=O)C>[CH3:24][S:25][C:26]1[CH:34]=[CH:33][CH:32]=[CH:31][C:27]=1[C:28]1[O:15][N:14]=[C:13]([CH2:12][N:8]2[C:9]3[C:5](=[C:4]([C:20]([F:22])([F:23])[F:21])[C:3]([C:1]#[N:2])=[CH:11][CH:10]=3)[CH:6]=[C:7]2[CH2:17][CH2:18][CH3:19])[N:16]=1
Reactant: CCCc1cc2c(C(F)(F)F)c(C#N)ccc2n1CC(=N)NO
Reactant: CSc1ccccc1C(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCCc1cc2c(C(F)(F)F)c(C#N)ccc2n1Cc1noc(-c2ccccc2SC)n1
Temperature: 150 °C
Yield: 29.9 %

Procedure:
A solution was prepared using 2-[5-cyano-2-propyl-4-(trifluoromethyl)-1H-indol-1-yl]-N-hydroxyethanimidamide (Example 275A) (0.100 g, 0.308 mmol), 2-(methylthio)benzoic acid (0.076 g, 0.463 mmol), HATU (0.176 g, 0.463 mmol), triethylamine (1.0 mL, 13.6 mmol) and anhydrous DMF (10 mL). The mixture was then heated in a microwave at 150° C. for 30 min. Upon cooling, the mixture was poured onto a biotage prepak column and the mixture was purified by flash chromatography (0-25% EtOAc-hexanes gradient) to give 0.042 g (30% yield) of pure product: MS (ES) m/z 456 (M+).
Reaction SMILES: COC1C=C(OC)C=CC=1C[N:6]([C:32]1[CH:37]=[CH:36][N:35]=[CH:34][N:33]=1)[S:7]([C:10]1[C:15]([F:16])=[CH:14][C:13]([O:17][C@H:18]2[CH2:23][CH2:22][CH2:21][CH2:20][C@@H:19]2[C:24]2[N:28]([CH2:29][CH3:30])[N:27]=[CH:26][CH:25]=2)=[CH:12][C:11]=1[F:31])(=[O:9])=[O:8].C([SiH](CC)CC)C.FC(F)(F)C(O)=O>ClCCl>[CH2:29]([N:28]1[C:24]([C@H:19]2[CH2:20][CH2:21][CH2:22][CH2:23][C@@H:18]2[O:17][C:13]2[CH:12]=[C:11]([F:31])[C:10]([S:7]([NH:6][C:32]3[CH:37]=[CH:36][N:35]=[CH:34][N:33]=3)(=[O:8])=[O:9])=[C:15]([F:16])[CH:14]=2)=[CH:25][CH:26]=[N:27]1)[CH3:30]
Reactant: CCn1nccc1[C@H]1CCCC[C@@H]1Oc1cc(F)c(S(=O)(=O)N(Cc2ccc(OC)cc2OC)c2ccncn2)c(F)c1
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCn1nccc1[C@H]1CCCC[C@@H]1Oc1cc(F)c(S(=O)(=O)Nc2ccncn2)c(F)c1
Yield: 41.5 %

Procedure:
The reaction and aftertreatment were conducted in the same manner as in Example 1b by using the N-(2,4-dimethoxybenzyl)-4-{[(1S*,2R*)-2-(1-ethyl-1H-pyrazol-5-yl)cyclohexyl]oxy}-2,6-difluoro-N-(pyrimidin-4-yl)benzenesulfonamide (0.080 g, 0.13 mmol) prepared in Example 59a, triethylsilane (0.10 mL), trifluoroacetic acid (1.0 mL) and dichloromethane (1.0 mL), to yield the title compound (25 mg, 42%) as a colorless solid.
Reaction SMILES: [CH2:1]([N:8]1[CH2:12][CH2:11][CH:10]([CH2:13][OH:14])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[CH:16]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>C1(C)C(C)=CC=CC=1.C(OCC)(=O)C>[CH2:1]([N:8]1[CH2:12][CH2:11][CH:10]([CH2:13][O:14][CH:16]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: OCC1CCN(Cc2ccccc2)C1
Reactant: BrC(c1ccccc1)c1ccccc1
Solvent: Cc1ccccc1C
Solvent: CCOC(C)=O
Product: c1ccc(CN2CCC(COC(c3ccccc3)c3ccccc3)C2)cc1
Temperature: 25 °C
Yield: 48.8 %

Procedure:
A mixture of 1-benzylpyrrolidine-3-methanol (1.72 g) (J. Org. Chem., 1961, 26, 1521) and bromodiphenylmethane (4.94 g) in xylene (150 ml) was heated under reflux for 3 hours, allowed to cool to room temperature, diluted with ethyl acetate, washed with 10% aqueous sodium carbonate solution, dried over magnesium sulphate and evaporated. The residue was purified by chromatography on silica using dichloromethane plus 20% ethyl acetate plus 0-10% methanol as eluant. Appropriate fractions were combined and evaporated to give the title compound (1.57 g) as a pale brown oil which was charcterised by its 1H-NMR spectrum.
Reaction SMILES: COC([CH:5]1[CH2:9][CH2:8][C:7]2([CH2:14][CH2:13][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:11][CH2:10]2)[C:6]1=[O:22])=O.[OH-].[Li+]>C(O)C.O1CCCC1.O>[O:22]=[C:6]1[C:7]2([CH2:10][CH2:11][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:13][CH2:14]2)[CH2:8][CH2:9][CH2:5]1
Reactant: COC(=O)C1CCC2(CCN(C(=O)OC(C)(C)C)CC2)C1=O
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CCO
Product: CC(C)(C)OC(=O)N1CCC2(CCCC2=O)CC1
Temperature: 90 °C
Yield: 67.5 %

Procedure:
To a solution of tert-butyl 2-(methoxycarbonyl)-1-oxo-8-azaspiro[4.5]decane-8-carboxylate (17.2 g, 0.055 mol) from Step F in a 2:2:1 mixture of ethanol/tetrahydrofuran/water (555 mL) was added pulverized lithium hydroxide (26 g, 1.10 mol). The reaction mixture was heated to 90° C. for 60 h. The reaction mixture was allowed to cool and was then concentrated, dissolved in water and dichloromethane, and extracted three times with dichloromethane. The organic layers were combined, washed with brine, dried over sodium sulfate, filtered, and concentrated to afford 11.4 g. The residue was purified by flash chromatography eluting with 20–30% ethyl acetate in hexanes to give the title compound (9.41 g).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][CH:16]([O:22]S(C)(=O)=O)[C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:27][C:28]1[CH:33]=[CH:32][C:31](O)=[CH:30][CH:29]=1.C(=O)([O-])[O-].[K+].[K+]>>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][CH:16]([O:22][C:31]2[CH:32]=[CH:33][C:28]([Cl:27])=[CH:29][CH:30]=2)[C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)C(Cc1ccc(OCc2ccccc2)cc1)OS(C)(=O)=O
Reactant: Oc1ccc(Cl)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CCOC(=O)C(Cc1ccc(OCc2ccccc2)cc1)Oc1ccc(Cl)cc1
Yield: 62.6 %

Procedure:
In a similar manner to that described in Reference example 35(b), a reaction was carried out using ethyl 3-(4-benzyloxyphenyl)-2-methanesulfonyloxypropionate (8.82 g), which is the product of Reference example 35(a), 4-chlorophenol (3.00 g) and potassium carbonate (6.44 g) and the reaction mixture was treated to afford the desired compound (5.99 g) as colorless crystals.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([NH:11][C:12]([N:14]2[CH2:19][CH2:18][N:17]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[O:26][CH3:27])[CH2:16][CH2:15]2)=[O:13])[C:5]([O:9][CH3:10])=[N:6][C:7]=1[CH3:8].[H-].[Na+].[CH2:30](Br)[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1>CN(C)C=O>[CH2:30]([N:11]([C:4]1[C:5]([O:9][CH3:10])=[N:6][C:7]([CH3:8])=[C:2]([CH3:1])[CH:3]=1)[C:12]([N:14]1[CH2:15][CH2:16][N:17]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=2[O:26][CH3:27])[CH2:18][CH2:19]1)=[O:13])[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1
Reactant: BrCc1ccccc1
Reactant: COc1ccccc1N1CCN(C(=O)Nc2cc(C)c(C)nc2OC)CC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1ccccc1N1CCN(C(=O)N(Cc2ccccc2)c2cc(C)c(C)nc2OC)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 93 %

Procedure:
1-[(5,6-Dimethyl-2-methoxypyridin-3-yl)aminocarbonyl]-4-(2-methoxyphenyl)piperazine(100 mg, 0.27 mmol) was dissolved in dimethylformamide(15 ml) and thereto sodium hydride(6.5 mg, 0.27 mmol) was added, followed by stirring at room temperature for 1 hr, and successively benzyl bromide(46.2 mg, 0.27 mmol) was added. The resulting mixture was stirred at room temperature for 16 hrs, concentrated under the reduced pressure and purified by column chromatography(ethylacetate:hexane=1:2) to obtain the titled compound.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][C:10]=1[F:11])[C:7](=[CH:12][C:13]1[CH:18]=[CH:17][C:16]([S:19][CH3:20])=[CH:15][CH:14]=1)[C:6]([CH3:21])=[C:5]2[CH2:22][C:23]([OH:25])=[O:24].CO.I([O-])(=O)(=O)=[O:29].[Na+]>CC(C)=O.O>[F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][C:10]=1[F:11])[C:7](=[CH:12][C:13]1[CH:18]=[CH:17][C:16]([S:19]([CH3:20])=[O:29])=[CH:15][CH:14]=1)[C:6]([CH3:21])=[C:5]2[CH2:22][C:23]([OH:25])=[O:24]
Reactant: CSc1ccc(C=C2C(C)=C(CC(=O)O)c3cc(F)c(F)cc32)cc1
Reactant: [O-][I+3]([O-])([O-])[O-]
Agent: [Na+]
Solvent: CC(C)=O
Solvent: CO
Solvent: O
Product: CC1=C(CC(=O)O)c2cc(F)c(F)cc2C1=Cc1ccc(S(C)=O)cc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 0.358 g (1.0 mmol) of 5,6-difluoro-2-methyl-1-(p-methylthiobenzylidene)-indene-3-acetic acid in acetone (10 ml) is added 10-15 ml MeOH. With magnetic stirring 0.32 g (1.5 mmol) of sodium meta periodate is added in 5 ml of water. The proportions of acetone, methanol and water are adjusted if necessary in order to preserve homogeneity. After several minutes, a precipitation of sodium iodate appears. The suspension is stirred at room temperature for 16 h, and is then poured into approximately 50 ml of water and 100 ml methylene chloride. The two phases are separated and extracted twice with methylene chloride. The organic layer is washed with water and dried (MgSO4). The residue after evaporation is dissolved in the minimum amount of boiling ethyl acetate and is allowed to stand for 12 h in the freezer compartment. The deep orange crystals are filtered. The filtrate is reduced to 1/2 volume and allowed to stand in the cold for several hours to give a large second crop. In this way, 5,6-difluoro-2-methyl-1-(p-methylsulfinylbenzylidene)-3-indenylacetic acid is isolated, m.p. 200°-210° C.
Reaction SMILES: [C:1]1([CH:7]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[N:8]2[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Br[CH2:21][C:22]([C:24]1[CH:29]=[CH:28][C:27]([Cl:30])=[C:26]([N+:31]([O-:33])=[O:32])[CH:25]=1)=[O:23]>CC(=O)C>[ClH:30].[ClH:30].[Cl:30][C:27]1[CH:28]=[CH:29][C:24]([C:22](=[O:23])[CH2:21][N:11]2[CH2:10][CH2:9][N:8]([CH:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[CH2:13][CH2:12]2)=[CH:25][C:26]=1[N+:31]([O-:33])=[O:32]
Reactant: c1ccc(C(c2ccccc2)N2CCNCC2)cc1
Reactant: O=C(CBr)c1ccc(Cl)c([N+](=O)[O-])c1
Solvent: CC(C)=O
Product: Cl
Product: O=C(CN1CCN(C(c2ccccc2)c2ccccc2)CC1)c1ccc(Cl)c([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A mixture of 13.9 parts of 1-(diphenylmethyl)piperazine, 8.35 parts of 2-bromo-1-(4-chloro-3-nitrophenyl)ethanone and 40 parts of 2-propanone is stirred for 30 minutes at room temperature. The formed precipitate is filtered off and 210 parts of 2,2'-oxybispropane are added to the filtrate. The whole is treated with activated charcoal. The latter is filtered off and an excess of 2-propanol, previously saturated with gaseous hydrogen chloride, is added to the filtrate. The formed hydrochloride salt is filtered off, stirred in 80 parts of 2-propanol, filtered off again and crystallized from ethanol. The product is filtered off and recrystallized from 2-methoxyethanol, yielding 6.4 parts of 1-(4-chloro-3-nitrophenyl)-2-[4-(diphenylmethyl)-1-piperazinyl]ethanone dihydrochloride; mp. 165° C.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][N:6]=[C:5]([N:9]2[C:16]3[C@@H:15]4[CH2:17][C@@H:14]4[CH2:13][C:12]=3[C:11]([C:18](O)=[O:19])=[N:10]2)[CH:4]=1)#[N:2].[NH2:21][C:22]([CH3:27])([CH2:25][OH:26])[CH2:23][OH:24].C(N(CC)CC)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[OH:24][CH2:23][C:22]([NH:21][C:18]([C:11]1[C:12]2[CH2:13][C@H:14]3[CH2:17][C@H:15]3[C:16]=2[N:9]([C:5]2[CH:4]=[C:3]([C:1]#[N:2])[CH:8]=[CH:7][N:6]=2)[N:10]=1)=[O:19])([CH2:25][OH:26])[CH3:27]
Reactant: N#Cc1ccnc(-n2nc(C(=O)O)c3c2[C@@H]2C[C@@H]2C3)c1
Reactant: CC(N)(CO)CO
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(CO)(CO)NC(=O)c1nn(-c2cc(C#N)ccn2)c2c1C[C@H]1C[C@@H]21
Temperature: 23 °C
Reaction time: 0.5 h
Yield: 94.1 %

Procedure:
To a solution of (1aR,5aR)-2-(4-cyano-pyridin-2-yl)-1a,2,5,5a-tetrahydro-1H-2,3-diaza-cyclopropa[a]pentalene-4-carboxylic acid (100 mg, 0.376 mmol), 2-amino-2-methylpropane-1,3-diol (39.5 mg, 0.376 mmol), and triethylamine (0.105 mL, 0.751 mmol) in DMF (2 mL) was added HATU (157 mg, 0.413 mmol). The reaction was stirred at 23° C., for 30 min then concentrated. The residue was purified by silica gel flash column chromatography to give the title compound (125 mg) as a white solid. LCMS m/z=354.3 [M+H]+; 1H NMR (400 MHz, CDCl3) δ 0.46 (td, J=4.7, 3.3 Hz, 1H), 1.27 (td, J=8.0, 4.9 Hz, 1H), 1.36 (s, 3H), 2.27-2.33 (m, 1H), 2.78-2.89 (m, 2H), 3.00 (dd, J=16.8, 6.4 Hz, 1H), 3.72-3.77 (m, 4H), 3.87-3.94 (m, 2H), 7.23 (m, 1H), 7.42 (dd, J=5.1, 1.0 Hz, 1H), 8.16-8.17 (m, 1H), 8.62 (d, J=5.1 Hz, 1H).
Reaction SMILES: [O:1]=[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][C:10]=2[C:12]([F:15])([F:14])[F:13])[NH:5][CH:4]=[C:3]1[C:16]([OH:18])=O.[CH:19]12[N:25]([C:26]3[CH:32]=[CH:31][C:29]([NH2:30])=[C:28]([C:33]#[C:34][CH2:35][N:36]([CH3:38])[CH3:37])[CH:27]=3)[CH:22]([CH2:23][CH2:24]1)[CH2:21][CH2:20]2.C(P1(=O)OP(CCC)(=O)OP(CCC)(=O)O1)CC.N1C=CC=CC=1>CC1CCCO1.CCOC(C)=O>[CH:19]12[N:25]([C:26]3[CH:32]=[CH:31][C:29]([NH:30][C:16]([C:3]4[C:2](=[O:1])[C:11]5[C:6](=[CH:7][CH:8]=[CH:9][C:10]=5[C:12]([F:13])([F:14])[F:15])[NH:5][CH:4]=4)=[O:18])=[C:28]([C:33]#[C:34][CH2:35][N:36]([CH3:38])[CH3:37])[CH:27]=3)[CH:22]([CH2:23][CH2:24]1)[CH2:21][CH2:20]2
Reactant: CN(C)CC#Cc1cc(N2C3CCC2CC3)ccc1N
Reactant: O=C(O)c1c[nH]c2cccc(C(F)(F)F)c2c1=O
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Solvent: CC1CCCO1
Product: CN(C)CC#Cc1cc(N2C3CCC2CC3)ccc1NC(=O)c1c[nH]c2cccc(C(F)(F)F)c2c1=O
Temperature: 100 °C
Yield: 22.5 %

Procedure:
To a solution of 4-oxo-5-(trifluoromethyl)-1H-quinoline-3-carboxylic acid 17 (19 mg, 0.07 mmol) and 4-(7-azabicyclo[2.2.1]heptan-7-yl)-2-(3-dimethylaminoprop-1-ynyl)aniline 27 (20 mg, 0.07 mmol) in 2-methyltetrahydrofuran (190.9 μL) was added T3P (118 mg, 0.19 mmol) and pyridine (12 mg, 12 μL, 0.15 mmol). The reaction was heated at 100° C. for 30 min under microwave irradiation. The reaction was diluted with EtOAc and quenched with saturated aqueous NaHCO3 (50 mL). The layers were separated, and the aqueous layer was extracted twice with EtOAc. The combined organics were washed once with water, dried over Na2SO4, filtered and concentrated. The residue was purified by reverse phase HPLC (0-99% CH3CN/0.05% TFA) to give N-[4-(7-azabicyclo[2.2.1]heptan-7-yl)-2-(3-dimethylaminoprop-1-ynyl)phenyl]-4-oxo-5-(trifluoromethyl)-1H-quinoline-3-carboxamide (8 mg, 17% yield). LC/MS m/z 509.7 [M+H]+, retention time 1.06 min (RP—C18, 10-99% CH3CN/0.05% TFA over 3 min). 1H NMR (400.0 MHz, DMSO-d6) δ 13.23 (d, J=6.8 Hz, 1H), 12.40 (s, 1H), 10.31 (s, 1H), 8.96 (d, J=6.6 Hz, 1H), 8.40 (d, J=9.0 Hz, 1H), 8.08-8.06 (m, H), 8.07 (dd, J=1.5 Hz, 8.1 Hz, 1H), 8.00-7.95 (m, 2H), 7.15-7.09 (m, 2H), 4.49 (s, 2H), 4.29 (s, 2H), 2.94 (s, 6H), 1.67 (d, J=7.2 Hz, 4H), 1.44 (d, J=7.0 Hz, 4H).
Reaction SMILES: [C:1]([OH:10])(=[O:9])[CH:2]([CH:4]([C:6]([OH:8])=[O:7])[OH:5])[OH:3].NC1C2C(C3C=CC(NC(NC4C=CC=C(F)C=4)=O)=CC=3)=CSC=2C(C2C=NN(CCO)C=2)=CN=1>C1COCC1.O>[C:1]([OH:10])(=[O:9])[C@@H:2]([C@H:4]([C:6]([OH:8])=[O:7])[OH:5])[OH:3]
Reactant: O=C(O)C(O)C(O)C(=O)O
Agent: Nc1ncc(-c2cnn(CCO)c2)c2scc(-c3ccc(NC(=O)Nc4cccc(F)c4)cc3)c12
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)[C@H](O)[C@@H](O)C(=O)O
Reaction time: 8 h

Procedure:
A saturated solution of l-tartaric acid was prepared at 25 C by dissolving tartaric acid in a 85/15 v/v THF/water mixture. This solution (2 mL) was heated 2 to 65 C. Approximately 200 mg of N-(4-{4-amino-7-[1-(2-hydroxyethyl)-1H-pyrazol-4-yl]thieno[3,2-c]pyridin-3-yl}phenyl)-N′-(3-fluorophenyl)urea free base solid was then added, which readily dissolved. N-(4-{4-amino-7-[1-(2-hydroxyethyl)-1H-pyrazol-4-yl]thieno[3,2-c]pyridin-3-yl}phenyl)-N′-(3-fluorophenyl)urea L-bitartrate crystallized within 30 minutes from this clear solution. The slurry was then diluted with the saturated solution (at 25° C.) of l-tartaric acid and cooled to ambient temperatures. The slurry was continue to be stirred overnight and the solids were isolated via filtration. The filtered solids were washed with 85/15 v/v mixture of THF/water to remove excess l-tartaric acid and then dried in the oven at 45° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH2:11][CH2:12][N:13]([CH:17]([CH3:19])[CH3:18])[CH:14]([CH3:16])[CH3:15])[C:9]#[N:10])=[CH:4][CH:3]=1.Cl[CH2:21][CH2:22][N:23]([CH3:25])[CH3:24].C(N(C(C)C)CCC(C1C=CC=CC=1)C#N)(C)C.ClCCN(C(C)C)C(C)C>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([CH2:11][CH2:12][N:13]([CH:17]([CH3:19])[CH3:18])[CH:14]([CH3:15])[CH3:16])([CH2:21][CH2:22][N:23]([CH3:25])[CH3:24])[C:9]#[N:10])=[CH:6][CH:7]=1
Reactant: CC(C)N(CCC(C#N)c1ccc(F)cc1)C(C)C
Reactant: CN(C)CCCl
Agent: CC(C)N(CCC(C#N)c1ccccc1)C(C)C
Agent: CC(C)N(CCCl)C(C)C
Product: CC(C)N(CCC(C#N)(CCN(C)C)c1ccc(F)cc1)C(C)C

Procedure:
Substitution of equivalent quantities of α-(p-fluorophenyl)-α-[2-(diisopropylamino)ethyl]acetonitrile and 2-chloro-N,N-dimethylethylamine for α-[2-(diisopropylamino)ethyl]-α-phenylacetonitrile and 2-chloro-N,N-diisopropylethylamine called for respectively in the procedure of Example 2, Method B, there is obtained α-(p-fluorophenyl)-α-[2-(diisopropylamino)ethyl]-α-[2-(dimethylamino)ethyl]acetonitrile, as an oil.
Reaction SMILES: [NH2:1][C:2]1[CH:14]=[CH:13][C:5]([O:6][C:7]([CH3:12])([CH3:11])[C:8]([OH:10])=[O:9])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:21](Br)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>C(O)C>[CH2:21]([NH:1][C:2]1[CH:3]=[CH:4][C:5]([O:6][C:7]([CH3:12])([CH3:11])[C:8]([OH:10])=[O:9])=[CH:13][CH:14]=1)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: BrCc1ccccc1
Reactant: CC(C)(Oc1ccc(N)cc1)C(=O)O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: CC(C)(Oc1ccc(NCc2ccccc2)cc1)C(=O)O

Procedure:
A mixture of 1.95 g (0.01 mole) of 4-aminophenoxyisobutyric acid, 25 ml of ethanol, 1.76 g (0.02 mole) of potassium carbonate and 1.2 ml (0.01 mole) of benzyl bromide was stirred and refluxed for 24 hours. Most of the ethanol was evaporated. The residue was dissolved in water, charcoaled, filtered, and acidified water acetic acid to give an oily material which by cooling turned into a solid with a melting point of 194-196° C. The structure (shown below as Formula EX1) was confirmed by NMR spectroscopy.
Reaction SMILES: [CH3:1][C:2]1[N:6]2[N:7]=[C:8]([C:11]3[CH:16]=[CH:15][CH:14]=[C:13]([NH2:17])[CH:12]=3)[CH:9]=[CH:10][C:5]2=[N:4][N:3]=1.C(N(CC)C(C)C)(C)C.[CH:27]1([C:30](Cl)=[O:31])[CH2:29][CH2:28]1>ClCCl>[CH3:1][C:2]1[N:6]2[N:7]=[C:8]([C:11]3[CH:12]=[C:13]([NH:17][C:30]([CH:27]4[CH2:29][CH2:28]4)=[O:31])[CH:14]=[CH:15][CH:16]=3)[CH:9]=[CH:10][C:5]2=[N:4][N:3]=1
Reactant: O=C(Cl)C1CC1
Reactant: Cc1nnc2ccc(-c3cccc(N)c3)nn12
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: Cc1nnc2ccc(-c3cccc(NC(=O)C4CC4)c3)nn12
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of 7.6 g of 3-methyl-6-(3-aminophenyl)-1,2,4-triazolo[4,3-b]pyridazine in 1.5 liters of dichloromethane was added 6 ml of N,N-diisopropylethylamine and 3.1 ml of cyclopropane carboxylic acid chloride. The solution was stirred at room temperature for 4 hours, washed with 200 ml of saturated sodium bicarbonate solution, dried and the solvent removed in vacuo. The residue was crystallized from dichloromethane-hexane to give 2.24 g of tan crystals, mp 255°-258° C. A sample recrystallized from dichloromethane-hexane gave white crystals, mp 259°-262° C.
Reaction SMILES: [NH:1]1[CH2:9][CH2:8][CH:4]([C:5]([NH2:7])=[O:6])[CH2:3][CH2:2]1.I[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].C(=O)([O-])[O-].[K+].[K+]>>[CH2:11]([N:1]1[CH2:9][CH2:8][CH:4]([C:5]([NH2:7])=[O:6])[CH2:3][CH2:2]1)[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18]
Reactant: NC(=O)C1CCNCC1
Reactant: CCCCCCCCI
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CCCCCCCCN1CCC(C(N)=O)CC1
Yield: 110.9 %

Procedure:
Prepared from isonipecotamide (2.7 g, 21.0 mmol), 1-iodooctane (5.05 g, 21.0 mmol) and potassium carbonate (2.9 g, 21.0 mmol) of according to procedure used for Example 8 (Step A) to give 5.6 g of the title compound as a white solid.
Reaction SMILES: [F:1][C:2]([F:9])([F:8])[C@H:3]([OH:7])[CH2:4][CH2:5]I.[N-:10]=[N+:11]=[N-:12].[Na+]>CS(C)=O.O>[N:10]([CH2:5][CH2:4][C@@H:3]([OH:7])[C:2]([F:9])([F:8])[F:1])=[N+:11]=[N-:12]
Reactant: O[C@H](CCI)C(F)(F)F
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: [N-]=[N+]=NCC[C@@H](O)C(F)(F)F
Temperature: 50 °C
Yield: 100.1 %

Procedure:
A solution of (R)-1,1,1-trifluoro-4-iodo-2-butanol (3.30 g, 13.0 mmol) in DMSO (22 mL) was treated with sodium azide (0.930 g, 14.3 mmol) at ambient temperature, followed by heating at 50° C. for 20 h. The mixture was diluted with cold water (250 mL) and extracted with diethyl ether. The combined organic extracts were washed (brine), dried, and evaporated without heat to give the product as a pale yellow oil (2.20 g, 100%).
Reaction SMILES: C[Mg]Cl.[CH3:4][N:5]1[C:13]2[N:12]=[CH:11][N:10]([CH2:14][CH2:15][CH3:16])[C:9]=2[C:8](=[O:17])[N:7]([CH2:18][CH2:19][CH2:20][CH2:21][C:22](=[O:24])[CH3:23])[C:6]1=[O:25].[CH3:26]COCC.[Cl-].[NH4+]>O1CCCC1>[OH:24][C:22]([CH3:26])([CH3:23])[CH2:21][CH2:20][CH2:19][CH2:18][N:7]1[C:8](=[O:17])[C:9]2[N:10]([CH2:14][CH2:15][CH3:16])[CH:11]=[N:12][C:13]=2[N:5]([CH3:4])[C:6]1=[O:25]
Reactant: CCOCC
Reactant: CCCn1cnc2c1c(=O)n(CCCCC(C)=O)c(=O)n2C
Agent: C[Mg]Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CCCn1cnc2c1c(=O)n(CCCCC(C)(C)O)c(=O)n2C

Procedure:
22.4 g (0.3 mol) of methylmagnesium chloride in the form of a 20% strength solution in tetrahydrofuran are added dropwise with vigorous stirring at room temperature to a suspension of 61.3 g (0.2 mol) of 3-methyl-1-(5-oxohexyl)-7-propylxanthine in 2 1 of anhydrous ether, the internal temperature rising to approximately 30° C. The mixture is then warmed with stirring and under reflux for 2 hours, treated with saturated aqueous ammonium chloride solution to decompose the alkoxide formed, and the organic phase is separated off and washed twice with 500 ml of water each time. The collected water phases are extracted thoroughly with dichloromethane again. The dichloromethane extract is combined with the ethereal phase, dried over sodium sulfate, filtered and evaporated under reduced pressure, 59.0 g of crude product (91.5% of theory) being obtained, which is purified by recrystallization from diisopropyl ether.