Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]#[C:12][Si](C)(C)C)=[CH:7][CH:6]=1)[CH:2]([CH3:4])[CH3:3].FC(F)(F)S(O[C:23]1[CH:32]=[C:31]2[C:26]([CH:27]=[C:28]([CH:33]=[O:34])[CH2:29][O:30]2)=[C:25]([F:35])[CH:24]=1)(=O)=O>CN(C=O)C.[Cu](Cl)Cl.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>[F:35][C:25]1[CH:24]=[C:23]([C:12]#[C:11][C:8]2[CH:9]=[CH:10][C:5]([CH2:1][CH:2]([CH3:4])[CH3:3])=[CH:6][CH:7]=2)[CH:32]=[C:31]2[C:26]=1[CH:27]=[C:28]([CH:33]=[O:34])[CH2:29][O:30]2
Reactant: CC(C)Cc1ccc(C#C[Si](C)(C)C)cc1
Reactant: O=CC1=Cc2c(F)cc(OS(=O)(=O)C(F)(F)F)cc2OC1
Agent: Cl[Cu]Cl
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Product: CC(C)Cc1ccc(C#Cc2cc(F)c3c(c2)OCC(C=O)=C3)cc1
Temperature: 80 °C
Reaction time: 12 h
Yield: 23.8 %

Procedure:
To a solution of copper chloride (10 mg) and Pd(PPh3)4 (60 mg) in DMF (2 mL) were added [(4-isobutylphenyl)ethynyl](trimethyl)silane (288 mg) and 5-fluoro-3-formyl-2H-chromen-7-yl trifluoromethanesulfonate (340 mg) at room temperature, followed by stirring at 80° C. for 12 hours. The reaction liquid was concentrated and the residue was purified by silica gel column chromatography (CHCl3) to obtain 5-fluoro-7-[(4-isobutylphenyl)ethynyl]-2H-chromene-3-carbaldehyde (83 mg) as a yellow solid.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][C@H:11]([OH:13])[CH2:10][C@H:9]1[C:14]([OH:16])=[O:15])=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl[C:18]1[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[C:21]([O:28][CH3:29])=[CH:20][N:19]=1.CC([O-])(C)C.[K+]>CS(C)=O>[C:1]([O:5][C:6]([N:8]1[CH2:12][C@H:11]([O:13][C:18]2[C:27]3[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=3)[C:21]([O:28][CH3:29])=[CH:20][N:19]=2)[CH2:10][C@H:9]1[C:14]([OH:16])=[O:15])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1C[C@H](O)C[C@H]1C(=O)O
Reactant: COc1cnc(Cl)c2ccccc12
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: COc1cnc(O[C@@H]2C[C@@H](C(=O)O)N(C(=O)OC(C)(C)C)C2)c2ccccc12
Temperature: 25 °C
Reaction time: 2 h
Yield: 71.8 %

Procedure:
To a solution of (2S,4R)-1-(tert-butoxycarbonyl)-4-hydroxypyrrolidine-2-carboxylic acid (2.0 g, 8.6 mmole) and 1-chloro-4-methoxyisoquinoline (2.0 g, 10.3 mmole) in DMSO (15 mL) was added t-BuOK (1 M solution in THF, 25.9 mL) at room temperature under nitrogen atmosphere. The reaction mixture was stirred at room temperature for 2 h. The reaction mass was quenched with aqueous citric acid solution and extracted with ethyl acetate (50 mL×3). The combined organics were washed with water, brine solution, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to get crude compound. The crude compound was purified by silica gel chromatography (55% ethyl acetate in pet-ether) to get 2.4 g (71.4%) of (2S,4R)-1-(tert-butoxycarbonyl)-4-((4-methoxyisoquinolin-1-yl)oxy)pyrrolidine-2-carboxylic acid as gummy liquid. 1H NMR (400 MHz, CD3OD): δ ppm 8.13-8.12 (m, 2H), 7.76-7.72 (m, 1H), 7.60-7.64 (m, 1H), 7.53 (s, 1H), 5.70 (sb, 1H), 4.50-4.52 (m, 1H), 4.08 (s, 3H), 3.80-3.90 (m, 2H), 2.71-2.68 (m, 1H), 2.46-2.40 (m, 1H), 1.48 (s, 9H); MS: MS m/z 389.8 (M++1).
Reaction SMILES: O=P(Cl)(Cl)[Cl:3].[S:6]1[C:14]2[C:9](=[N:10][CH:11]=[CH:12][C:13]=2O)[CH:8]=[CH:7]1.[NH4+].[OH-]>>[Cl:3][C:13]1[CH:12]=[CH:11][N:10]=[C:9]2[CH:8]=[CH:7][S:6][C:14]=12
Reactant: O=P(Cl)(Cl)Cl
Reactant: Oc1ccnc2ccsc12
Agent: [NH4+]
Agent: [OH-]
Product: Clc1ccnc2ccsc12
Temperature: 100 °C
Reaction time: 0.25 h
Yield: 95.7 %

Procedure:
To neat POCl3 (200 mL, 2146 mmol) at 60° C. in a 500 mL round-bottom flask was added thieno[3,2-b]pyridin-7-ol (1 eq., 200 g, 1323 mmol) in small portions over 1.5 h. The reaction mixture was heated at 60° C. for 1 h and at 100° C. for an additional hour. After cooling down to 0° C., the reaction mixture was poured onto crushed ice (1 L) over a period of 30 min. After 15 min, NH4OH (1.5 L) was added to the mixture to form a grey precipitate that was collected by filtration, washed with water (50 mL) and air dried. The dry solid was suspended in EtOAc (1 L). The slurry was stirred at r.t. for 15 min, filtered and the filter was washed with EA (2×100 mL). The organic phase was collected, dried over MgSO4 and concentrated. The residue was passed through a short silica gel pad (300 g, eluent—a gradient hexane/EtOAc, 8/2 to 5/5) and dried in the vacuum oven (35° C.) for 2 h to afford 6 as a off-white solid (214.8 g, 1266 mmol, 96% yield). MS (m/z): 170.0 (M+H). 1H NMR (400 MHz, DMSO-d6) δ (ppm): 8.64 (d, J=5.1 Hz, 1H), 8.25 (d, J=5.5 Hz, 1H), 7.66 (d, J=5.5 Hz, 1H), 7.54 (d, J=5.1 Hz, 1H).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([NH:9][CH:10]2[CH2:15][CH2:14][CH:13]([O:16][CH2:17][C:18]([N:20]3[CH2:25][CH2:24][N:23]([C:26]4[CH:35]=[CH:34][C:33]5[C:28](=[CH:29][CH:30]=[C:31]([C:36]([F:39])([F:38])[F:37])[CH:32]=5)[N:27]=4)[CH2:22][CH2:21]3)=[O:19])[CH2:12][CH2:11]2)=[CH:5][C:4]=1[C:40]([F:43])([F:42])[F:41])#[N:2].[H-].[Na+].I[CH3:47]>C1COCC1.O>[CH3:47][N:9]([C:6]1[CH:7]=[CH:8][C:3]([C:1]#[N:2])=[C:4]([C:40]([F:42])([F:43])[F:41])[CH:5]=1)[CH:10]1[CH2:15][CH2:14][CH:13]([O:16][CH2:17][C:18]([N:20]2[CH2:21][CH2:22][N:23]([C:26]3[CH:35]=[CH:34][C:33]4[C:28](=[CH:29][CH:30]=[C:31]([C:36]([F:37])([F:38])[F:39])[CH:32]=4)[N:27]=3)[CH2:24][CH2:25]2)=[O:19])[CH2:12][CH2:11]1
Reactant: N#Cc1ccc(NC2CCC(OCC(=O)N3CCN(c4ccc5cc(C(F)(F)F)ccc5n4)CC3)CC2)cc1C(F)(F)F
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CN(c1ccc(C#N)c(C(F)(F)F)c1)C1CCC(OCC(=O)N2CCN(c3ccc4cc(C(F)(F)F)ccc4n3)CC2)CC1
Reaction time: 0.5 h
Yield: 100.9 %

Procedure:
To a solution of 2-[(4-[[4-cyano-3-(trifluoromethyl)phenyl]amino]-cyclohexyl)oxy]-1-[4-[6-(trifluoromethyl)quinolin-2-yl]piperazin-1-yl]ethan-1-one (100 mg, 0.16 mmol) in THF (3 ml) was added sodium hydride (25 mg, 0.63 mmol, 3.9 eq.) and the mixture was stirred for 30 minutes. The mixture was then treated with iodomethane (100 mg, 0.7 mmol, 4 eq.) and stirred for 5 days. The resulting mixture was diluted with water (30 ml), and extracted with ethyl acetate (30 mL). The organic layer was separated, washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum to give a residue from which the product was purified by silica gel column flash chromatography eluting with ethyl acetate/heptanes to afford 2-[(4-[methyl[4-cyano-3-(trifluoromethyl)phenyl]-amino]-cyclohexyl)oxy]-1-[4-[6-(trifluoromethyl)quinolin-2-yl)piperazin-1-yl]ethan-1-one as a yellow solid (100 mg, 98%). (CI, m/z): [M+H]+ 620; 1H NMR (400 MHz, DMSO-d6): δ 8.24 (d, J=9.3 Hz, 1H), 8.17 (s, 1H), 7.76 (d, J=8.7 Hz, 2H), 7.70 (d, J=8.7 Hz, 1H), 7.40 (d, J=9.3 Hz, 1H), 7.13-7.07 (m, 2H), 4.23 (s, 2H), 3.94-3.76 (m, 5H), 3.63-3.57 (m, 4H), 3.41-3.32 (m, 1H), 2.85 (s, 3H), 2.14-2.05 (m, 2H), 1.69-1.57 (m, 4H), 1.50-1.38 (m, 2H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[O:10][CH3:11])[CH2:5][NH2:6].[CH3:12][O:13][C:14](=[O:32])[C:15]1[CH:20]=[CH:19][C:18]([C:21]2[N:22]=[C:23](Cl)[C:24]3[CH:29]=[C:28]([CH3:30])[S:27][C:25]=3[N:26]=2)=[CH:17][CH:16]=1>>[CH3:12][O:13][C:14](=[O:32])[C:15]1[CH:16]=[CH:17][C:18]([C:21]2[N:22]=[C:23]([NH:6][CH2:5][C:4]3[CH:7]=[CH:8][C:9]([O:10][CH3:11])=[C:2]([Cl:1])[CH:3]=3)[C:24]3[CH:29]=[C:28]([CH3:30])[S:27][C:25]=3[N:26]=2)=[CH:19][CH:20]=1
Reactant: COC(=O)c1ccc(-c2nc(Cl)c3cc(C)sc3n2)cc1
Reactant: COc1ccc(CN)cc1Cl
Product: COC(=O)c1ccc(-c2nc(NCc3ccc(OC)c(Cl)c3)c3cc(C)sc3n2)cc1

Procedure:
The reaction of 3-chloro-4-methoxy-benzylamine with 4-(4-chloro-6-methyl-thieno-[2,3-d]-pyrimidin-2-yl)-benzoic acid methylester yields 4-[4-(3-chloro-4-methoxybenzylamino)-6-methyl-thieno-[2,3-d]-pyrimidin-2-yl]-benzoic acid methylester.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:15]=[C:16](I)[C:17]=1[O:18][CH3:19])[CH2:6][C:7]1[C:8]([NH2:14])=[N:9][C:10]([NH2:13])=[N:11][CH:12]=1.[CH3:21][N:22]([CH3:33])[C:23]1[CH:28]=[CH:27][C:26](OB(O)O)=[CH:25][CH:24]=1.C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1>[CH3:21][N:22]([CH3:33])[C:23]1[CH:28]=[CH:27][C:26]([C:16]2[C:17]([O:18][CH3:19])=[C:3]([O:2][CH3:1])[CH:4]=[C:5]([CH2:6][C:7]3[C:8]([NH2:14])=[N:9][C:10]([NH2:13])=[N:11][CH:12]=3)[CH:15]=2)=[CH:25][CH:24]=1
Reactant: COc1cc(Cc2cnc(N)nc2N)cc(I)c1OC
Reactant: CN(C)c1ccc(OB(O)O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Product: COc1cc(Cc2cnc(N)nc2N)cc(-c2ccc(N(C)C)cc2)c1OC
Temperature: 0 °C
Yield: 88.5 %

Procedure:
376 mg of 5-(3,4-dimethoxy-5-iodo-benzyl)-pyrimidine-2,4-diamine and 400 mg of 4-dimethylamino-phenylboric acid (Example 3a)) are treated with 40 ml of dioxan and 2.4 ml of a 2M potassium carbonate solution and 24 mg of tetrakis-tri-phenylphosphine-palladium. The mixture is heated at reflux under argon for 14 hrs. Subsequently, it is poured on to ice-water, extracted with methylene chloride, dried over magnesium sulphate and chromatographed on silica gel with methylenechloride/methanol 98:2. 327 mg (91%) of 5-(4'-dimethylamino-5,6-dimethoxy-biphenyl-3-ylmethyl)-pyrimidine-2,4-diamine are isolated as a yellowish solid. M.p. 230°.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5](=[O:12])[NH:4][N:3]=1.[SH:13][C:14]1[CH:19]=[CH:18][C:17]([NH:20][C:21](=[O:27])[O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[CH:16][CH:15]=1>>[O:12]=[C:5]1[C:6]2[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=2)[C:2]([S:13][C:14]2[CH:15]=[CH:16][C:17]([NH:20][C:21](=[O:27])[O:22][C:23]([CH3:25])([CH3:24])[CH3:26])=[CH:18][CH:19]=2)=[N:3][NH:4]1
Reactant: CC(C)(C)OC(=O)Nc1ccc(S)cc1
Reactant: O=c1[nH]nc(Cl)c2ccccc12
Product: CC(C)(C)OC(=O)Nc1ccc(Sc2n[nH]c(=O)c3ccccc23)cc1

Procedure:
4-chlorophthalazin-1(2H)-one and tert-butyl 4-mercaptophenylcarbamate were processed using a method similar to that described in Example 57A to afford the title compound. MS (APCI+) M/Z 370 (M+H)+.
Reaction SMILES: C([O:3][C:4](=[O:46])[C:5]([CH3:45])([O:38][C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1)[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][CH2:15][CH:16]2[CH2:20][N:19]([CH2:21][C:22]3[CH:27]=[C:26]([C:28]([F:31])([F:30])[F:29])[CH:25]=[C:24]([C:32]([F:35])([F:34])[F:33])[CH:23]=3)[C:18](=[O:36])[N:17]2[CH3:37])=[CH:9][CH:8]=1)C.[OH-].[Na+].Cl>C(O)C>[F:35][C:32]([F:33])([F:34])[C:24]1[CH:23]=[C:22]([CH:27]=[C:26]([C:28]([F:29])([F:30])[F:31])[CH:25]=1)[CH2:21][N:19]1[CH2:20][CH:16]([CH2:15][CH2:14][O:13][C:10]2[CH:11]=[CH:12][C:7]([CH2:6][C:5]([CH3:45])([O:38][C:39]3[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=3)[C:4]([OH:46])=[O:3])=[CH:8][CH:9]=2)[N:17]([CH3:37])[C:18]1=[O:36]
Reactant: CCOC(=O)C(C)(Cc1ccc(OCCC2CN(Cc3cc(C(F)(F)F)cc(C(F)(F)F)c3)C(=O)N2C)cc1)Oc1ccccc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CN1C(=O)N(Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)CC1CCOc1ccc(CC(C)(Oc2ccccc2)C(=O)O)cc1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
To a solution of the esters obtained from Step A (378 mg) in absolute ethanol (4 ml) is added 5N NaOH (1.5 ml, 7.5 mmol), and the mixture stirred for 20 hours at ambient temperature. The mixture is poured into 1N HCl, then extracted with ethyl acetate (2×20 ml). The combined ethyl acetate extracts were washed with water, brine, dried (Na2SO4), and concentrated to an oil which is purified is purified by flash chromatography on a Biotage silica cartridge (gradient elution, 3:1 hexanes:ethyl acetate to 1:2 hexanes:ethyl acetate to yield a foam (266 mg.)
Reaction SMILES: CC1(C)CCCC(C)(C)N1.C([Li])CCC.[Cl:16][C:17]1[CH:25]=[CH:24][CH:23]=[C:22]2[C:18]=1[C:19]([CH2:26][C:27]#[N:28])=[CH:20][NH:21]2.[CH3:29][N:30]=[C:31]=[O:32]>O1CCCC1>[CH3:29][NH:30][C:31]([N:21]1[C:22]2[C:18](=[C:17]([Cl:16])[CH:25]=[CH:24][CH:23]=2)[C:19]([CH2:26][C:27]#[N:28])=[CH:20]1)=[O:32]
Reactant: CN=C=O
Reactant: N#CCc1c[nH]c2cccc(Cl)c12
Agent: CC1(C)CCCC(C)(C)N1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CNC(=O)n1cc(CC#N)c2c(Cl)cccc21
Temperature: -78 °C
Reaction time: 0.08 h
Yield: 20.8 %

Procedure:
To a solution of 2,2,6,6-tetramethyl piperidine (0.18 ml, 1.05 mmol) dissolved in anhydrous tetrahydrofuran (5 ml) was added butyllithium (2.5M in hexanes; 0.42 ml, 1.05 mmol). The reaction was cooled to −78° C. and a solution of (4-chloro-1H-indol-3-yl)-acetonitrile (200 mg, 1.05 mmol) in anhydrous tetrahydrofuran (5 ml) was added, maintaining the temperature between −78° C. and −72° C. After 5 minutes, methyl isocyanate (0.06 ml, 1.05 mmol) was added. The dry ice bath was removed after 15 minutes and the reaction was allowed to stir overnight. After the solvent was removed under reduced pressure, the residue was partitioned between dichloromethane(100 ml) and saturated sodium chloride solution (5 ml). The organic extract was dried (anhydrous magnesium sulfate), filtered and concentrated under reduced pressure. Purification by flash column chromatography over silica gel eluting with 30% ethyl acetate in hexane to give 4-chloro-3-cyanomethyl-indole-1-carboxylic acid methylamide as a white solid (54 mg, 21%). 1H NMR (CDCl3) δ: 3.07 (d, 3H, J=4.7 Hz), 4.17 (s, 2H), 7.24 (m, 2H), 7.50 (s, 1H), 8.14 (m, 1H) M+247.
Reaction SMILES: [CH2:1]([C:5]1[CH:10]=[CH:9][C:8]([Cl:11])=[CH:7][CH:6]=1)[CH2:2][CH:3]=[CH2:4].[CH3:12][SiH:13]([CH2:15][Si:16]([CH3:19])([CH3:18])[CH3:17])[CH3:14]>>[Cl:11][C:8]1[CH:7]=[CH:6][C:5]([CH2:1][CH2:2][CH2:3][CH2:4][Si:13]([CH3:14])([CH3:12])[CH2:15][Si:16]([CH3:19])([CH3:18])[CH3:17])=[CH:10][CH:9]=1
Reactant: C[SiH](C)C[Si](C)(C)C
Reactant: C=CCCc1ccc(Cl)cc1
Product: C[Si](C)(C)C[Si](C)(C)CCCCc1ccc(Cl)cc1
Yield: 70.8 %

Procedure:
About 33.3 g (0.2 mol) of 4-(3-butenyl)-1-chlorobenzene prepared in accordance with Example 1 (b) were silylated with 2,4,4-trimethyl-2,4-disilapentane (compare Example 1 (d) with Pt as catalyst to give 1-chloro-4-(5,5,7,7-tetramethyl-5,7disilaoctyl)benzene. The boiling point was 115° C. under 0.05 hPa, and the yield was 70.8% of theory.
Reaction SMILES: Cl[CH:2]1[C:8]2[CH:9]=[C:10]([F:13])[CH:11]=[CH:12][C:7]=2[S:6][C:5]2[CH:14]=[C:15]([C:18]([F:21])([F:20])[F:19])[CH:16]=[CH:17][C:4]=2[CH2:3]1.[N:22]1([CH2:28][CH2:29][N:30]2[CH2:34][CH2:33][O:32][C:31]2=[O:35])[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]1.[OH-].[Na+]>>[F:13][C:10]1[CH:11]=[CH:12][C:7]2[S:6][C:5]3[CH:14]=[C:15]([C:18]([F:21])([F:20])[F:19])[CH:16]=[CH:17][C:4]=3[CH2:3][CH:2]([N:25]3[CH2:26][CH2:27][N:22]([CH2:28][CH2:29][N:30]4[CH2:34][CH2:33][O:32][C:31]4=[O:35])[CH2:23][CH2:24]3)[C:8]=2[CH:9]=1
Reactant: Fc1ccc2c(c1)C(Cl)Cc1ccc(C(F)(F)F)cc1S2
Reactant: O=C1OCCN1CCN1CCNCC1
Agent: [Na+]
Agent: [OH-]
Product: O=C1OCCN1CCN1CCN(C2Cc3ccc(C(F)(F)F)cc3Sc3ccc(F)cc32)CC1

Procedure:
11.6 G. of 10-chloro-8-fluoro-10,11-dihydro-3-trifluoromethyl-dibenzo[b,f]thiepin are treated with 27.8 g. of 3-[2-(1-piperazinyl)-ethyl]-2-oxazolidinone and stirred at 115°-120° C. for 10 minutes. The mixture is cooled and treated with 2N sodium hydroxide. The product separating as an oil is extracted with ether. The organic solution is washed to neutrality with water and shaken out with a dilute, aqueous methanesulfonic acid solution. The aqueous solution is made alkaline with sodium hydroxide and extracted with ether. The ether solution is washed with water, dried over magnesium sulfate and concentrated, whereby there is obtained 3-{2-[4-(8-fluoro-10,11-dihydro-3-trifluoromethyl-dibenzo[b,f]thiepin-10-yl)-1-piperazinyl]-ethyl}-2-oxazolidinone as a yellow oil which is converted into the dimethanesulfonate (melting point 149°-151° C.) by the addition of methansulfonic acid.
Reaction SMILES: [F:1][C:2]1[CH:24]=[C:23]([N+:25]([O-])=O)[CH:22]=[CH:21][C:3]=1[O:4][C:5]1[CH:6]=[CH:7][C:8]2[N:9]([C:11]([CH3:20])=[C:12]([NH:14][C:15]([CH:17]3[CH2:19][CH2:18]3)=[O:16])[N:13]=2)[CH:10]=1.[Cl-].[NH4+].O>C(O)C.C(OCC)(=O)C>[NH2:25][C:23]1[CH:22]=[CH:21][C:3]([O:4][C:5]2[CH:6]=[CH:7][C:8]3[N:9]([C:11]([CH3:20])=[C:12]([NH:14][C:15]([CH:17]4[CH2:19][CH2:18]4)=[O:16])[N:13]=3)[CH:10]=2)=[C:2]([F:1])[CH:24]=1
Reactant: Cc1c(NC(=O)C2CC2)nc2ccc(Oc3ccc([N+](=O)[O-])cc3F)cn12
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CCO
Product: Cc1c(NC(=O)C2CC2)nc2ccc(Oc3ccc(N)cc3F)cn12
Yield: 81.6 %

Procedure:
A mixed solution of N-[6-(2-fluoro-4-nitrophenoxy)-3-methylimidazo[1,2-a]pyridin-2-yl]cyclopropanecarboxamide (80 mg, 0.216 mmol), reduced iron (64 mg, 1.08 mmol) and ammonium chloride (116 mg, 2.16 mmol) in ethanol (2 mL)/water (0.5 mL) was stirred at 80° C. for 3 hr. The reaction mixture was diluted with ethyl acetate and filtered through celite. Water was added to the filtrate, and the mixture was extracted 3 times with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and filtered. The solvent was evaporated under reduced pressure to give the title compound (60 mg, 82%) as a slightly yellow solid.
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][C:5]1[CH:6]=[C:7]([CH:11]=[C:12]([O:16][CH3:17])[C:13]=1[O:14][CH3:15])[C:8]([OH:10])=[O:9].[CH2:18](Br)[CH3:19]>>[CH2:18]([O:1][CH2:2][CH2:3][CH2:4][C:5]1[CH:6]=[C:7]([CH:11]=[C:12]([O:16][CH3:17])[C:13]=1[O:14][CH3:15])[C:8]([OH:10])=[O:9])[CH3:19]
Reactant: CCBr
Reactant: COc1cc(C(=O)O)cc(CCCO)c1OC
Product: CCOCCCc1cc(C(=O)O)cc(OC)c1OC
Yield: 72 %

Procedure:
3-(3-Ethoxypropyl)-4,5-dimethoxybenzoic acid was prepared from 3-(3-hydroxypropyl)-4,5-Dimethoxybenzoic acid (Example 10, Step 1) and ethyl bromide by following Method I in 72% yield. The product was used without further purification.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([F:12])=[CH:9][CH:10]=2)[N:5]=[C:4]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=2)[C:3]=1[CH3:19].[NH2:20][C:21]1[C:22]([C:33]#[N:34])=[N:23][CH:24]=[C:25]([N:27]2[CH2:32][CH2:31][O:30][CH2:29][CH2:28]2)[CH:26]=1.Cl.O1CCOCC1>CN1C(=O)CCC1>[F:12][C:8]1[CH:7]=[C:6]2[C:11]([C:2]([NH:20][C:21]3[C:22]([C:33]#[N:34])=[N:23][CH:24]=[C:25]([N:27]4[CH2:28][CH2:29][O:30][CH2:31][CH2:32]4)[CH:26]=3)=[C:3]([CH3:19])[C:4]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=3)=[N:5]2)=[CH:10][CH:9]=1
Reactant: N#Cc1ncc(N2CCOCC2)cc1N
Reactant: Cc1c(-c2ccccn2)nc2cc(F)ccc2c1Cl
Agent: Cl
Solvent: C1COCCO1
Solvent: CN1CCCC1=O
Product: Cc1c(-c2ccccn2)nc2cc(F)ccc2c1Nc1cc(N2CCOCC2)cnc1C#N

Procedure:
Prepared according to general Procedure K using 4-chloro-7-fluoro-3-methyl-2-(pyridin-2-yl)quinoline (93 mg, 0.34 mmol), 3-amino-5-morpholinopicolinonitrile (70 mg, 0.34 mmol) and a 4.0M solution of HCl in dioxane (0.08 mL, 0.34 mmol) in NMP (1.0 mL) and heating in the microwave for 2 h at 150° C. After purification 3-((7-fluoro-3-methyl-2-(2-pyridinyl)-4-quinolinyl)amino)-5-(4-morpholinyl)-2-pyridinecarbonitrile was obtained. 1H NMR (400 MHz, chloroform-d) δ ppm 8.74 (1H, dt, J=3.1, 1.6 Hz), 7.76-8.00 (5H, m), 7.31-7.49 (2H, m), 6.46 (1H, s), 5.92 (1H, d, J=2.3 Hz), 3.68-3.84 (4H, m), 3.00-3.19 (4H, m), 2.42 (3H, s). Mass Spectrum (ESI) m/e=441.0 (M+1).
Reaction SMILES: [CH3:1][CH:2]([O:9][C:10]([C:12]1[CH:17]=[CH:16][C:15]([C:18]2[CH:23]=[CH:22][C:21]([O:24]CC3C=CC=CC=3)=[CH:20][CH:19]=2)=[CH:14][CH:13]=1)=[O:11])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8]>C(O)C.[Pd]>[OH:24][C:21]1[CH:20]=[CH:19][C:18]([C:15]2[CH:16]=[CH:17][C:12]([C:10]([O:9][CH:2]([CH3:1])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8])=[O:11])=[CH:13][CH:14]=2)=[CH:23][CH:22]=1
Reactant: CCCCCCC(C)OC(=O)c1ccc(-c2ccc(OCc3ccccc3)cc2)cc1
Agent: [Pd]
Solvent: CCO
Product: CCCCCCC(C)OC(=O)c1ccc(-c2ccc(O)cc2)cc1
Yield: 80.1 %

Procedure:
Next, S(+)-2-octanol (50 g, 0.38 mol) was dissolved in dry pyridine (150 ml), and to the solution was dropwise added under cooling, a solution of 4'-benzyloxybiphenyl-4-carboxylic chloride (112 g, 0.35 mol) dissolved in dry toluene (150 ml), followed by agitating the mixture at about 50°-60° C. for 2 hours, thereafter adding water (300 ml) and toluene (300 ml), agitating the mixture, washing the separated toluene layer with 6N-HCl, then with 2N-NaOH aqueous solution and further with water until the washing water became neutral, drying the toluene layer with anhydrous sodium sulfate and distilling off toluene to obtain 4'-benzyloxybiphenyl-4-carboxylic acid 1-methylheptyl ester (53 g), dissolving this ester (53 g, 0.13 mol) in ethanol (500 ml) and reducing it in the presence of palladium/carbon (Pd/C) 5 g) to obtain 4'-hydroxy-4-(1-methyl-heptyloxycarbonyl)biphenyl (34 g). (ii) Preparation of 4-octyloxycarbonyloxybenzoic chloride
Reaction SMILES: N(OC(C)(C)C)=O.[Cl:8][C:9]1[CH:15]=[CH:14][C:12](N)=[C:11]([CH3:16])[CH:10]=1.[CH3:17][S:18]SC>C(Cl)(Cl)Cl>[Cl:8][C:9]1[CH:15]=[CH:14][C:12]([S:18][CH3:17])=[C:11]([CH3:16])[CH:10]=1
Reactant: Cc1cc(Cl)ccc1N
Reactant: CSSC
Agent: CC(C)(C)ON=O
Solvent: ClC(Cl)Cl
Product: CSc1ccc(Cl)cc1C
Temperature: 70 °C
Reaction time: 2 h
Yield: 908.2 %

Procedure:
t-Butyl nitrite (1.52 g) was added to a mixture of 4-chloro-2-methylaniline (2.0 g) and dimethyl disulphide (14.49 g) in chloroform The mixture was heated to 70° C. to initiate the reaction. A solution of 4-chloro-2-methylaniline (9.0 g) in chloroform and t-butyl nitrite (7.25 g) were added simultaneously while maintaining the temperature in the range 60°-70° C. Further dimethyl disulphide (11.83 g) was added followed by the simultaneous addition of a solution of 4-chloro-2-methylaniline (9.0 g) in chloroform and t-butyl nitrite (7.25 g) while maintaining the temperature in the range 50°-55° C. The mixture was stirred at room temperature for 2 hours. It was washed thoroughly with water, 2M hydrochloric acid, water, dried (MgSO4) and filtered. The filtrate was evaporated to dryness to give 5-chloro-2-(methylsulphenyl)toluene (22.15 g) as a red oil which was not further characterized.
Reaction SMILES: [F:1][C:2]([F:36])([F:35])[C:3]([N:5]1[CH:10]2[CH2:11][CH2:12][CH:6]1[CH2:7][C:8](=[C:13]1[C:26]3[CH:25]=[CH:24][CH:23]=[C:22](OS(C(F)(F)F)(=O)=O)[C:21]=3[O:20][C:19]3[C:14]1=[CH:15][CH:16]=[CH:17][CH:18]=3)[CH2:9]2)=[O:4].[NH2:37][C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1.CC(C)([O-])C.[Na+]>C1(C)C=CC=CC=1.[Pd].C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.[Fe+2]>[F:35][C:2]([F:36])([F:1])[C:3]([N:5]1[CH:6]2[CH2:12][CH2:11][CH:10]1[CH2:9][C:8](=[C:13]1[C:26]3[CH:25]=[CH:24][CH:23]=[C:22]([NH:37][C:38]4[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=4)[C:21]=3[O:20][C:19]3[C:14]1=[CH:15][CH:16]=[CH:17][CH:18]=3)[CH2:7]2)=[O:4]
Reactant: O=C(N1C2CCC1CC(=C1c3ccccc3Oc3c(OS(=O)(=O)C(F)(F)F)cccc31)C2)C(F)(F)F
Reactant: Nc1ccccc1
Agent: [Fe+2]
Agent: [Pd]
Agent: CC(C)(C)[O-]
Solvent: Cc1ccccc1
Product: O=C(N1C2CCC1CC(=C1c3ccccc3Oc3c(Nc4ccccc4)cccc31)C2)C(F)(F)F
Temperature: 80 °C

Procedure:
A solution of trifluoromethanesulfonic acid 9-[8-(2,2,2-trifluoroacetyl)-8-aza-bicyclo[3.2.1]oct-3-ylidene]-9H-xanthen-4-yl ester in toluene (0.1 to 2 M solution) may be treated with a catalytic amount of a palladium catalyst such as Pd2(dba)3 (0.01 to 0.1 equiv), DPPF (0.1 to 0.3 equiv), aniline (2 to 5 equiv), sodium tert-butoxide (1.2 to 2 equiv) under an argon atmosphere. The mixture may be heated to 80° C. for a period of 1 to 10 hr. After filtration and removal of the solvent via evaporation, the residue may be taken up in a halogenated solvent such as methylene chloride, and the solution may be washed with water, dried over a suitable drying agent such as magnesium sulfate, filtered, and concentrated. The residue may be purified via column chromatography to yield Compound 1d.
Reaction SMILES: [Cl:1][C:2]1[CH:16]=[CH:15][C:5]2[N:6]=[C:7]([N:9]3[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]3)[S:8][C:4]=2[CH:3]=1.[N:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[S:23]([NH:26][C:27]1[CH:35]=[CH:34][C:30]([C:31](O)=[O:32])=[CH:29][CH:28]=1)(=[O:25])=[O:24]>>[Cl:1][C:2]1[CH:16]=[CH:15][C:5]2[N:6]=[C:7]([N:9]3[CH2:14][CH2:13][N:12]([C:31]([C:30]4[CH:29]=[CH:28][C:27]([NH:26][S:23]([C:18]5[CH:19]=[CH:20][CH:21]=[CH:22][N:17]=5)(=[O:25])=[O:24])=[CH:35][CH:34]=4)=[O:32])[CH2:11][CH2:10]3)[S:8][C:4]=2[CH:3]=1
Reactant: O=C(O)c1ccc(NS(=O)(=O)c2ccccn2)cc1
Reactant: Clc1ccc2nc(N3CCNCC3)sc2c1
Product: O=C(c1ccc(NS(=O)(=O)c2ccccn2)cc1)N1CCN(c2nc3ccc(Cl)cc3s2)CC1

Procedure:
Compound 15 is prepared using synthesis method 2 using intermediates 3g and 5c (yield: 80%).