Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[Sn](C)C.C[Sn](C)C.[F:9][C:10]1[CH:11]=[CH:12][C:13](Br)=[N:14][CH:15]=1.Br[C:18]1[O:22][C:21]([C:23]2[CH:24]=[C:25]([CH:28]=[CH:29][CH:30]=2)[C:26]#[N:27])=[CH:20][CH:19]=1>ClCCl.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:9][C:10]1[CH:11]=[CH:12][C:13]([C:18]2[O:22][C:21]([C:23]3[CH:24]=[C:25]([CH:28]=[CH:29][CH:30]=3)[C:26]#[N:27])=[CH:20][CH:19]=2)=[N:14][CH:15]=1
Reactant: Fc1ccc(Br)nc1
Reactant: N#Cc1cccc(-c2ccc(Br)o2)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: C[Sn](C)C
Solvent: ClCCl
Product: N#Cc1cccc(-c2ccc(-c3ccc(F)cn3)o2)c1
Temperature: 80 °C
Reaction time: 15 h
Yield: 43.6 %

Procedure:
In a similar fashion, Pd(PPh3)4 (25 mg, 0.022 mmol) was added to a solution of hexamethylditin (163 mg, 0.50 mmol) and 5-fluoro-2-bromopyridine (87 mg, 0.49 mmol) in toulene (4 mL) under argon. The resulting solution was stirred at 80° C. for 15 h. After cooling to room temperature, a second portion of Pd(PPh3)4 (25 mg, 0.022 mmol) and 3-(5-bromofuran-2-yl)-benzonitrile (105 mg, 0.42 mmol) were added and the resulting solution was stirred at 110° C. for 48 h. After cooling to room temperature, the mixture was diluted with dichloromethane and passed through a 1 g silica gel SPE tube using dichloromethane to elute the product. Flash chromatography (silica gel, 50-100% dichloromethane in hexane) afforded 48.4 mg (43%) of 3-(5-(5-fluoro-2-pyridyl)-2-furyl)-benzonitrile (pure by GC/MS). 1H-NMR (CDCl3), δ (ppm): 8.48 (d, 1H), 8.03 (s, 1H), 7.95 (m, 1H), 7.81 (m, 1H), 7.51 (m, 3H), 7.11 (d, 1H), 6.87 (d, 1H).
Reaction SMILES: C(N(CC)CC)C.CC[S:10]([C:12]1[CH:24]=[CH:23][CH:22]=[CH:21][C:13]=1[C:14]([C:16]1[NH:17][CH:18]=[CH:19][CH:20]=1)=[O:15])=O.C1(C)C=CC=CC=1.C1N2C(SC3C=CC=CC=3C2=O)=CC=1>C(Cl)(Cl)Cl>[CH:20]1[CH:19]=[CH:18][N:17]2[C:16]=1[C:14](=[O:15])[C:13]1[CH:21]=[CH:22][CH:23]=[CH:24][C:12]=1[S:10]2
Reactant: CCS(=O)c1ccccc1C(=O)c1ccc[nH]1
Agent: O=c1c2ccccc2sc2cccn12
Solvent: Cc1ccccc1
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: O=c1c2ccccc2sn2cccc12
Reaction time: 24 h

Procedure:
Triethylamine (0.017 mL, 0.12 mmol, 0.1 eq), 2-(2-ethylsulfinyl) benzoyl pyrrole (0.3 g, 1.2 mmol), and toluene (15 mL) are combined and refluxed with stirring for 24 hours. After removal of volatiles in vacuo, a light brown oil is obtained which solidifies to a dark gold solid. Chromatography of the crude solid with a 1:1 ratio of CHCl3 to hexanes yields a product mix comprising 24 mg (0.12 mmol, 15 percent) of pyrrolo(2,1-b)-(1,3)benzothiazin-9-one, 114 mg (0.57 mmol, 69 percent) of pyrrolo(2,1-b)-(1,2)benzothiazin-10-one and 115 mg of light brown solid which proves by NMR to be a mixture of recovered starting material and 1H, 9H-(1)benzothiopyrano(3,2-b)pyrrol-9-one. By integration, the following approximate amounts for the above mixture are calculated: 93 mg (0.38 mmol) and 22 mg (0.11 mmol, 13 percent), respectively.
Reaction SMILES: [NH2:1][C@@:2]([C:6]1[N:15]=[CH:14][C:13]2[C:8](=[CH:9][CH:10]=[C:11]([O:16][CH3:17])[CH:12]=2)[N:7]=1)([CH3:5])[CH2:3][OH:4].C(Cl)Cl.C(N(CC)C(C)C)(C)C.Cl[C:31](Cl)([O:33]C(=O)OC(Cl)(Cl)Cl)Cl>>[CH3:17][O:16][C:11]1[CH:12]=[C:13]2[C:8](=[CH:9][CH:10]=1)[N:7]=[C:6]([C@:2]1([CH3:5])[CH2:3][O:4][C:31](=[O:33])[NH:1]1)[N:15]=[CH:14]2
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: COc1ccc2nc([C@@](C)(N)CO)ncc2c1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc2nc([C@]3(C)COC(=O)N3)ncc2c1
Temperature: -78 °C
Reaction time: 3 h

Procedure:
(R)-2-Amino-2-(6-methoxy-quinazolin-2-yl)-propan-1-ol (3.10 g, 13.3 mmol) was dissolved in methylene chloride (60 mL, 900 mmol), followed by N,N-diisopropylethylamine (6.94 mL, 39.9 mmol). The mixture was then cooled down to −78° C., and triphosgene (4.34 g, 14.6 mmol) was added in small portions over for 1 hour. The reaction mixture was then warmed up to 23° C. gradually and stirred for additional for 3 hours. Quenched with K2CO3 (sat), and organic layer was separated. The aqueous layer was extracted with DCM (2×20 mL) and combined organic layers were washed with water, brine and dried over Na2SO4. The crude product was then purified via chromatography (SiO2, 40 g, 0-10% MeOH/DCM) (1.78 g, 51%). 1H NMR (CHLOROFORM-d) δ: 9.29 (s, 1H), 7.90 (d, J=9.4 Hz, 1H), 7.58 (dd, J=9.1, 2.6 Hz, 1H), 7.16 (d, J=2.6 Hz, 1H), 6.29 (br. s., 1H), 5.18 (d, J=8.7 Hz, 1H), 4.49 (d, J=8.7 Hz, 1H), 3.97 (s, 3H), 1.76 (s, 3H). MS (M+1): 260.10.
Reaction SMILES: [C:1]12([C:11]([C:13]3[C:21]4[C:16](=[N:17][CH:18]=[C:19](Br)[N:20]=4)[NH:15][CH:14]=3)=[O:12])[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.[CH3:23][O:24][C:25]1[CH:26]=[C:27](B(O)O)[CH:28]=[C:29]([O:33][CH3:34])[C:30]=1[O:31][CH3:32]>>[C:1]12([C:11]([C:13]3[C:21]4[C:16](=[N:17][CH:18]=[C:19]([C:27]5[CH:28]=[C:29]([O:33][CH3:34])[C:30]([O:31][CH3:32])=[C:25]([O:24][CH3:23])[CH:26]=5)[N:20]=4)[NH:15][CH:14]=3)=[O:12])[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2
Reactant: O=C(c1c[nH]c2ncc(Br)nc12)C12CC3CC(CC(C3)C1)C2
Reactant: COc1cc(B(O)O)cc(OC)c1OC
Product: COc1cc(-c2cnc3[nH]cc(C(=O)C45CC6CC(CC(C6)C4)C5)c3n2)cc(OC)c1OC

Procedure:
Adamantan-1-yl-[2-(3,4,5-trimethoxy-phenyl)-5H-pyrrolo[2,3-b]pyrazin-7-yl]-methanone was prepared starting from adamantan-1-yl-(2-bromo-5H-pyrrolo[2,3-b]pyrazin-7-yl)-methanone and 3,4,5-trimethoxyphenylboronic acid following general procedures as described in these Examples. MP 267-268° C., M+H=448.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[NH:9][S:10]([CH:13]1[C:18]([C:19]([O:21][CH2:22][CH3:23])=[O:20])=[CH:17][C:16]([O:26][CH3:27])([O:24][CH3:25])[CH2:15][CH2:14]1)(=[O:12])=[O:11].C[Si](C)(C)[O:30][CH2:31][C:32](CO[Si](C)(C)C)(CO[Si](C)(C)C)[CH2:33][O:34][Si](C)(C)C.O>ClCCl.FC(F)(F)S(O[Si](C)(C)C)(=O)=O>[Cl:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[NH:9][S:10]([CH:13]1[CH2:14][CH2:15][C:16]2([O:24][CH2:25][C:32]([CH2:33][OH:34])([CH2:31][OH:30])[CH2:27][O:26]2)[CH:17]=[C:18]1[C:19]([O:21][CH2:22][CH3:23])=[O:20])(=[O:11])=[O:12]
Reactant: C[Si](C)(C)OCC(CO[Si](C)(C)C)(CO[Si](C)(C)C)CO[Si](C)(C)C
Reactant: CCOC(=O)C1=CC(OC)(OC)CCC1S(=O)(=O)Nc1ccc(F)cc1Cl
Agent: C[Si](C)(C)OS(=O)(=O)C(F)(F)F
Solvent: O
Solvent: ClCCl
Product: CCOC(=O)C1=CC2(CCC1S(=O)(=O)Nc1ccc(F)cc1Cl)OCC(CO)(CO)CO2
Yield: 86.8 %

Procedure:
500 mg (1.19 mmol) of ethyl 6-[N-(2-chloro-4-fluorophenyl)sulfamoyl]-3,3-dimethoxy-1-cyclohexene-1-carboxylate obtained in Example (16a) and 1.0 g (2.38 mmol) of 1,3-bis[(trimethylsilyl)oxy]-2,2-bis[(trimethylsilyl)oxy]methylpropane were dissolved in 10 ml dichloromethane and 10 μl (0.06 mmol) of trimethylsilyl trifluoromethanesulfonate was added thereto with stirring under ice-cooling, followed by stirring for 2 hours at the same temperature. Water was added to the reaction solution and the mixture was extracted with ethyl acetate. The organic layer was washed with water and dried over anhydrous magnesium sulfate, followed by concentration under reduced pressure. The residue was subjected to silica gel column chromatography (solvent; ethyl acetate alone) to give 510 mg of the title compound as an amorphous substance (yield: 87%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[CH:9][CH:8]=[CH:7]2.[I:12]N1C(=O)CCC1=O>C(O)(=O)C>[Br:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[CH:9][C:8]([I:12])=[CH:7]2
Reactant: Brc1cccc2cccnc12
Reactant: O=C1CCC(=O)N1I
Solvent: CC(=O)O
Product: Brc1cccc2cc(I)cnc12
Temperature: 70 °C
Reaction time: 18 h

Procedure:
To a solution of 8-bromoquinoline (commercially available, 1.0 g) in glacial acetic acid (6 mL) was added portionwise, N-iodosuccinimide (1.08 g). The resulting mixture was stirred at 70° C. for 18 hours. The reaction was cooled to room temperature and concentrated on a rotary evaporator. The residue was taken up in CH2Cl2 and washed with saturated aqueous NaHCO3 and brine. The organic layer was dried over anhydrous Na2SO4, filtered and concentrated on a rotary evaporator. The crude product was purified by flash chromatography on silica using hexane/ethyl acetate to give 0.74 g of the desired product as a white solid; MS (ES) m/z (relative intensity): 334 (M+H)+ (100).
Reaction SMILES: [CH2:1]([N:5]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([C:15]([O:17]C)=[O:16])[CH:13]=2)[N:8]([S:19]([CH3:22])(=[O:21])=[O:20])[CH2:7][CH2:6]1)[CH2:2][CH2:3][CH3:4].[OH-].[K+]>CO>[CH2:1]([N:5]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([C:15]([OH:17])=[O:16])[CH:13]=2)[N:8]([S:19]([CH3:22])(=[O:20])=[O:21])[CH2:7][CH2:6]1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCN1CCN(S(C)(=O)=O)c2ccc(C(=O)OC)cc21
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: CCCCN1CCN(S(C)(=O)=O)c2ccc(C(=O)O)cc21
Temperature: 25 °C
Reaction time: 48 h
Yield: 71.8 %

Procedure:
To a stirred solution of methyl 4-butyl-1-(methylsulfonyl)-1,2,3,4-tetrahydroquinoxaline-6-carboxylate (144 mg) in methanol (1.3 mL) was added 1 M potassium hydroxide (13 mL). The mixture was stirred at room temperature for 48 h and concentrated under reduced pressure. The residue was diluted with water and washed with ethyl acetate. The aqueous layer was acidified to pH 4 with 1 N hydrochloric acid and extracted with chlorform (4×100 mL). The combined organic extracts were dried (sodium sulfate), filtered, and concentrated under reduced pressure to give 99 mg of the title compound: 1NMR (300 MHz, CDCl3) δ 7.43, 7.39, 7.24, 3.77, 3.39, 3.32, 1.56, 1.33, 0.90.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH2:9][CH2:10][C:11](O)=[O:12].CO>C1COCC1>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH2:9][CH2:10][CH2:11][OH:12]
Reactant: COc1ccccc1CCC(=O)O
Solvent: C1CCOC1
Solvent: CO
Product: COc1ccccc1CCCO
Reaction time: 4 h
Yield: 102.5 %

Procedure:
3-(2-methoxyphenyl)propanoic acid (1.0 g, 5.55 mmol) was dissolved in THF (27.7 ml). A solution of borane tetrahydrofuran complex (12.21 ml, 12.21 mmol) was added slowly. The reaction was stirred for about 4 h. Methanol was added and the solvents removed. This process was repeated twice. The solution was passed through a short pad of silica gel with 1:1 ethyl acetate/heptane And then rotovapped to give 3-(2-methoxyphenyl)propan-1-ol (0.946 g, 5.69 mmol, 103% yield) as a colorless oil. 1H NMR (400 MHz, CDCl3) δ ppm 7.19 (dt, 1H), 7.15 (dd, 1H), 6.90 (dt, 1H), 6.86 (d, 1H), 3.84 (s, 3H), 3.60 (t, 2H), 2.73 (t, 2H), −1.92-1.79 (m, 2H), 1.76 (s, 1H),
Reaction SMILES: [Br:1][C:2]1[C:11]2[CH2:10][CH2:9][CH2:8][CH2:7][C:6]=2[C:5]([OH:12])=[CH:4][CH:3]=1.Cl.[CH3:14][N:15]([CH3:19])[CH2:16][CH2:17]Cl.C(=O)([O-])[O-].[K+].[K+].[Cl-]>C(#N)C>[Br:1][C:2]1[C:11]2[CH2:10][CH2:9][CH2:8][CH2:7][C:6]=2[C:5]([O:12][CH2:17][CH2:16][N:15]([CH3:19])[CH3:14])=[CH:4][CH:3]=1
Reactant: Oc1ccc(Br)c2c1CCCC2
Reactant: CN(C)CCCl
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cl-]
Solvent: CC#N
Product: CN(C)CCOc1ccc(Br)c2c1CCCC2
Yield: 65.2 %

Procedure:
To a 1 L round-bottomed flask equipped with condenser and N2 inlet were added 10.0 g (44 mmol) 4-bromo-5,6,7,8-tetrahydro-naphthalen-1-ol (Example 37A), 19 g (130 mmol) 2-dimethylaminoethyl chloride hydrochloride, 30.3 g (220 mmol) powdered potassium carbonate, and 600 mL acetonitrile. The reaction was refluxed 60 hours, followed by an additional portion of the chloride and continued refluxing for 24 hours. The reaction was cooled, filtered and concentrated. The residue was chromatographed on silica gel using methanol/methylene chloride as eluant to afford 8.55 g (65%) of a light brown oil.
Reaction SMILES: C(OC([N:8]1[CH2:16][C:15]2[C:10](=[CH:11][CH:12]=[C:13](I)[CH:14]=2)[CH2:9]1)=O)(C)(C)C.C1([As](C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH2:37]([O:39]C([Sn](CCCC)(CCCC)CCCC)=C)[CH3:38]>O1CCOCC1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH2:9]1[C:10]2[C:15](=[CH:14][C:13]([C:37](=[O:39])[CH3:38])=[CH:12][CH:11]=2)[CH2:16][NH:8]1
Reactant: CC(C)(C)OC(=O)N1Cc2ccc(I)cc2C1
Reactant: C=C(OCC)[Sn](CCCC)(CCCC)CCCC
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: c1ccc([As](c2ccccc2)c2ccccc2)cc1
Solvent: C1COCCO1
Product: CC(=O)c1ccc2c(c1)CNC2
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 95 %

Procedure:
To a stirred solution 0.72 mmol 5-iodo-1,3-dihydro-isoindole-2-carboxylic acid tert-butyl ester (Example A38(b)) in 3 ml dioxane were added 0.05 mmol palladium(II) acetate and 0.22 mmol triphenylarsine and the mixture was stirred at RT for 10 min. 1.01 mmol 1-ethoxyvinyltributylstannane was then added and the mixture was heated at 100° C. for 16 h. The reaction mixture was then cooled to room temperature, filtered, and the filtrate was concentrated in vacuo. The residue was resuspended in THF, 25% aqueous hydrochloric acid was added, and the mixture was stirred at RT for 3 h. The mixture was then partitioned between ethyl acetate and water and the phases were separated. The aqueous phase was made alkaline to pH 14 by addition of 30% aqueous NaOH solution and then extracted with ethyl acetate. The organic phase was then washed with brine, dried over sodium sulfate, and concentrated in vacuo to yield the title compound as a brown solid (95% yield). MS (m/e): 162.6 ([M+H]+, 100%).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[CH:18][C:17]([C:20](=[O:42])[NH:21][C:22]3[C:30]4[C:25](=[CH:26][C:27]([O:31][CH2:32][CH2:33][O:34][CH2:35][C:36]5[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=5)=[CH:28][CH:29]=4)[NH:24][N:23]=3)=[CH:16][CH:15]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.Cl>O1CCOCC1.CO>[CH2:35]([O:34][CH2:33][CH2:32][O:31][C:27]1[CH:26]=[C:25]2[C:30]([C:22]([NH:21][C:20](=[O:42])[C:17]3[CH:18]=[CH:19][C:14]([N:11]4[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]4)=[CH:15][CH:16]=3)=[N:23][NH:24]2)=[CH:29][CH:28]=1)[C:36]1[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=1
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc(C(=O)Nc3n[nH]c4cc(OCCOCc5ccccc5)ccc34)cc2)CC1
Agent: Cl
Solvent: CO
Solvent: C1COCCO1
Product: O=C(Nc1n[nH]c2cc(OCCOCc3ccccc3)ccc12)c1ccc(N2CCNCC2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 75.9 %

Procedure:
A solution of 4-{4-[6-(2-benzyloxy-ethoxy)-1H-indazol-3-ylcarbamoyl]-phenyl}-piperazine-1-carboxylic acid tert-butyl ester (180 mg, 0.31 mmol) in 1,4-dioxane (10 ml) and MeOH (5 ml) was treated with 4M hydrochloric acid in 1,4-dioxane (6 ml, 24 mmol). After stirring for 2 h at r.t. the reaction mixture was evaporated to dryness, diluted with water (50 ml) and brought to basic pH by addition of a saturated solution of NaHCO3. The precipitated solid was filtered, washed with water, dried and purified by chromatography (Biotage SP1 Flash Purification system) on a silica gel cartridge (Biotage SNAP 25 g) using DCM as eluant A and DCM/7N NH3 in MeOH 10:1 as eluant B. Elution with a gradient from A/B 100:0 to 0:100 over 15 CV, followed by an isocratic elution with eluant B (5 CV), gave a yellow solid that was triturated with diethyl ether (15 ml) affording 111 mg (yield: 75%) of the title compound as a white solid.
Reaction SMILES: CC(C)([O-])C.[K+].Cl[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.[NH:14]1[CH2:19][CH2:18][O:17][CH2:16][CH2:15]1>COCCOC>[C:8]1([N:14]2[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: Clc1ccccc1
Reactant: C1COCCN1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: COCCOC
Product: c1ccc(N2CCOCC2)cc1
Temperature: 50 °C

Procedure:
In air, potassium tert-butoxide (127 mg, 1.10 mmol) and complex Ih (6.8 mg, 0.01 mmol, 1.0 mol %) as defined in Example 1 were weighed into a vial with a stir bar and the vial was capped with a septum. The atmosphere was replaced with inert gas (Ar) and 1 mL of dry DME added and stirred until all the solids had dissolved. Chlorobenzene (102 μL, 112.56 mg, 1.0 mmol) and morpholine (96 μL, 96 mg, 1.10 mmol) were then added in quick succession with rapid stirring. The septum was then replaced with a Teflon® lined cap under inert gas (Ar) and the vial heated at 50° C. for 1 hour. After this time the reaction mixture was cooled and partitioned between water and ether, the organic phase was dried (anhydrous MgSO4), filtered, and the solvent removed. The resultant residue was purified by flash chromatography eluting with 9:1 pentane:ether. N-Phenylmorpholine was obtained as a white solid 155 mg, 95% yield.
Reaction SMILES: Cl[C:2]1[N:9]=[C:8]([NH:10][C:11]2[CH:15]=[C:14]([CH3:16])[NH:13][N:12]=2)[CH:7]=[C:6]([CH3:17])[C:3]=1[C:4]#[N:5].Cl.[Cl:19][C:20]1[CH:21]=[C:22]([CH:27]=[CH:28][C:29]=1[F:30])[O:23][CH2:24][CH2:25][NH2:26].C(=O)([O-])O.[Na+].CS(C)=O>O>[Cl:19][C:20]1[CH:21]=[C:22]([CH:27]=[CH:28][C:29]=1[F:30])[O:23][CH2:24][CH2:25][NH:26][C:2]1[N:9]=[C:8]([NH:10][C:11]2[CH:15]=[C:14]([CH3:16])[NH:13][N:12]=2)[CH:7]=[C:6]([CH3:17])[C:3]=1[C:4]#[N:5]
Reactant: Cc1cc(Nc2cc(C)c(C#N)c(Cl)n2)n[nH]1
Reactant: NCCOc1ccc(F)c(Cl)c1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: Cc1cc(Nc2cc(C)c(C#N)c(NCCOc3ccc(F)c(Cl)c3)n2)n[nH]1
Temperature: 100 °C
Reaction time: 27 h
Yield: 5.3 %

Procedure:
Compound A (300 mg, 1.22 mmol), 2-(3-chloro-4-fluorophenoxy)ethylamine hydrochloride (824 mg) and sodium hydrogencarbonate (1.02 g) were added to DMSO (10 ml), and the mixture was stirred at 100° C. for 27 hr. After stirring, the reaction mixture was added to cold water, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and concentrated, and the residue was washed by suspending in ethyl acetate to give the object compound of 2-(2-(3-chloro-4-fluorophenoxy)ethylamino)-6-(5-methyl-1H-pyrazol-3-ylamino)-4-methylnicotinonitrile (26 mg).
Reaction SMILES: [Br:1]Br.[CH3:3][C:4]1([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH2:9][CH2:8][CH2:7][CH2:6][C:5]1=[O:10]>C(Cl)(Cl)(Cl)Cl>[Br:1][CH:6]1[C:5](=[O:10])[C:4]([CH3:3])([C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH2:9][CH2:8][CH2:7]1
Reactant: BrBr
Reactant: CC1(c2ccccc2)CCCCC1=O
Solvent: ClC(Cl)(Cl)Cl
Product: CC1(c2ccccc2)CCCC(Br)C1=O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Step AAB (1): A solution of bromine (0.068 ml, 1.328 mmol) in CCl4 (2 mL) was added dropwise, over a period of 10 min, to a solution of 2-methyl-2-phenylcyclohexanone (250 mg, 1.328 mmol) in CCl4 (8 mL) at 0° C. The resulting solution was allowed to warm to rt and stir for 2 hr. The reaction mixture was concentrated in vacuo to afford 6-bromo-2-methyl-2-phenylcyclohexanone. The crude product was used for subsequent chemistry without purification or characterization.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:15]2[C:24]3[C:19](=[CH:20][CH:21]=[C:22](/[CH:25]=[C:26]4/[C:27](=[O:32])[N:28]=[C:29]([NH2:31])[S:30]/4)[CH:23]=3)[N:18]=[CH:17][C:16]=2[C:33]#[N:34])[CH2:10][CH2:9]1)=O)(C)(C)C.[ClH:35]>O1CCOCC1>[ClH:35].[NH2:31][C:29]1[S:30]/[C:26](=[CH:25]\[C:22]2[CH:23]=[C:24]3[C:19](=[CH:20][CH:21]=2)[N:18]=[CH:17][C:16]([C:33]#[N:34])=[C:15]3[O:14][CH:11]2[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]2)/[C:27](=[O:32])[N:28]=1
Reactant: CC(C)(C)OC(=O)N1CCC(Oc2c(C#N)cnc3ccc(/C=C4\SC(N)=NC4=O)cc23)CC1
Agent: Cl
Solvent: C1COCCO1
Product: N#Cc1cnc2ccc(/C=C3\SC(N)=NC3=O)cc2c1OC1CCNCC1
Reaction time: 0.5 h

Procedure:
To 4-{6-[2-amino-4-oxo-4H-thiazol-(5Z)-ylidenemethyl]-3-cyano-quinolin-4-yloxy}-piperidine-1-carboxylic acid tert-butyl ester (example 29, 34 mg, 0.071 mmol) was added 4N HCl in dioxane (3 mL). After stirring 30 min and removal of the solvent, ether was added. The solid was collected by filtration and washed with ether and dried to give 6-[2-amino-4-oxo-4H-thiazol-(5Z)-ylidenemethyl]-4-(piperidin-4-yloxy)-quinoline-3-carbonitrile hydrochloride. LC-MS m/e 480 (MH+).
Reaction SMILES: C(O)(C(F)(F)F)=O.[CH2:8]([O:50][CH:51]1[C@H:55]2[C@H:56](OC3CCCCO3)[N:57](C(OC(C)(C)C)=O)[C:58]3[CH:65]=[CH:64][C:63]([O:66][CH3:67])=[CH:62][C:59]=3[C:60](=[O:61])[N:54]2[CH2:53][CH2:52]1)[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][O:18][CH:19]1[C@H:23]2[C@H:24](OC3CCCCO3)[N:25](C(OC(C)(C)C)=O)[C:26]3[CH:33]=[CH:32][C:31]([O:34][CH3:35])=[CH:30][C:27]=3[C:28](=[O:29])[N:22]2[CH2:21][CH2:20]1.C([O-])(O)=O.[Na+]>CO.C(Cl)(Cl)Cl>[CH2:17]([O:18][CH:19]1[C@@H:23]2[CH:24]=[N:25][C:26]3[CH:33]=[CH:32][C:31]([O:34][CH3:35])=[CH:30][C:27]=3[C:28](=[O:29])[N:22]2[CH2:21][CH2:20]1)[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][O:50][CH:51]1[C@@H:55]2[CH:56]=[N:57][C:58]3[CH:65]=[CH:64][C:63]([O:66][CH3:67])=[CH:62][C:59]=3[C:60](=[O:61])[N:54]2[CH2:53][CH2:52]1
Reactant: COc1ccc2c(c1)C(=O)N1CCC(OCCCCCCCCCCOC3CCN4C(=O)c5cc(OC)ccc5N(C(=O)OC(C)(C)C)[C@@H](OC5CCCCO5)[C@H]34)[C@H]1[C@H](OC1CCCCO1)N2C(=O)OC(C)(C)C
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Solvent: ClC(Cl)Cl
Solvent: O=C(O)C(F)(F)F
Product: COc1ccc2c(c1)C(=O)N1CCC(OCCCCCCCCCCOC3CCN4C(=O)c5cc(OC)ccc5N=C[C@@H]34)[C@@H]1C=N2
Reaction time: 1 h
Yield: 94.1 %

Procedure:
95% TFA (3 mL) was added drop-wise to dimer compound 15h (180 mg, 0.17 mmol) at 0° C. This was then stirred for 1 hr and the mixture was poured into saturated NaHCO3 (30 mL) solution to naturalize the reaction mixture. The mixture was extracted with chloroform (3×20 mL). The organic layer was then washed water (20 mL), brine (20 mL) then dried (MgSO4) and filtrated. The excess solvent was removed under reduced pressure to give the crude product, which was subjected to flash column chromatography (SiO2, 2% methanol-chloroform). Removal of excess eluent under reduced pressure without heating afforded the final product 16h (103 mg, 0.16 mmol, 96%) as a solid: [α]20D=+500° (c=0.11, CHCl3); 1H NMR (CDCl3, 400 MHz): δ 1.26-1.50 (m, 12H, 14-H, 14′-H, 15-H, 15′-H, 16-H, 16′-H), 1.82-1.91 (m, 4H, 13-H, 13′-H), 1.98-2.09 (m, 4H, 2-H, 2′-H), 2.25-2.35 (m, 4H, 1-H, 1′-H), 3.54-3.61 (m, 2H, 3-H, 3′-H), 3.69-3.73 (m, 2H, 11a-H, 11a′-H), 3.78-3.83 (m, 2H, 3-H, 3′-H), 3.93 (s, 6H, 7-OMe, 7′-OMe), 3.98-4.14 (m, 4H, 12-H, 12′-H), 6.79 (s, 2H, 9-H, 9′-H), 7.50 (s, 2H, 6-H, 6′-H), 7.65 (d, 2H, J=4.4, 11-H, 11′-H); 13C NMR (CDCl3, 400 MHz): δ 24.1, 25.8, 28.8, 29.3, 29.4, 29.6, 46.6, 53.7, 56.1, 69.0. 110.4, 111.6, 120.0, 140.6, 147.8, 150.9, 162.3, 164.6; IR (neat): 2928, 1599, 1557, 1505, 1455, 1430, 1382, 1261, 1216, 1092, 1019 cm−1; MS (FAB) m/z (relative intensity) 695 ([M+2×MeOH]+., 8), 663 ([M+MeOH]+., 16), 631 (M+., 100).
Reaction SMILES: [H-].[Na+].[F:3][C:4]1[C:9]([F:10])=[CH:8][CH:7]=[CH:6][C:5]=1[CH2:11][C:12]#[N:13].Br[CH2:15][CH2:16][CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19].O>CN(C)C=O>[C:12]([CH:11]([C:5]1[CH:6]=[CH:7][CH:8]=[C:9]([F:10])[C:4]=1[F:3])[CH2:15][CH2:16][CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19])#[N:13]
Reactant: N#CCc1cccc(F)c1F
Reactant: CCOC(=O)CCCBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)CCCC(C#N)c1cccc(F)c1F
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Sodium hydride (60% dispersion in mineral oil; 2.9 g, 71.8 mmol) was slowly added to a solution of (2,3-difluorophenyl)acetonitrile (10.0 g, 65.3 mmol) and ethyl 4-bromobutanoate (12.7 g, 65.3 mmol) in N,N-dimethylformamide (100 mL) at 0° C. After 30 min, the reaction mixture was warmed to ambient temperature. After 3 h, water was added and the mixture was extracted with ethyl acetate (2×). The organic extracts were washed with saturated aqueous ammonium chloride, saturated brine, dried over magnesium sulfate, filtered and concentrated to give the title compound. MS 267.1 (M+1).