Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].[C:3](#[N:7])[CH2:4][C:5]#[N:6].Br[C:9]([C:15]1[N:16]=[C:17]([CH3:20])[O:18][CH:19]=1)([CH3:14])[C:10]([O:12][CH3:13])=[O:11]>CN(C=O)C>[C:5]([CH:4]([C:3]#[N:7])[C:9]([CH3:14])([C:15]1[N:16]=[C:17]([CH3:20])[O:18][CH:19]=1)[C:10]([O:12][CH3:13])=[O:11])#[N:6]
Reactant: N#CCC#N
Reactant: COC(=O)C(C)(Br)c1coc(C)n1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)C(C)(c1coc(C)n1)C(C#N)C#N
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To NaH (60%, 0.293 g, 7.32 mmol) in 10 mL of DMF at room temperature was added dropwise malononitrile (0.483 g, 7.32 mmol) in 5 mL of DMF. After stirring at room temperature for 15 minutes, the intermediate from Step C (1.82 g, 7.32 mmol) in 10 mL of DMF was added. The resulting mixture was stirred for 2 hours and then quenched with water. The mixture was extracted with EtOAc, dried with MgSO4, and concentrated. The residue was purified by silica gel chromatography using a hexanes/EtOAc gradient to give the indicated compound (a pale yellow oil). 1H NMR (CDCl3, 500 MHz) δ 7.66 (1H, s), 4.88 (1H, s), 3.87 (3H, s), 2.49 (3H, s), 1.92 (3H, s). m/z=234 (M+H).
Reaction SMILES: [F:1][C:2](I)([F:19])[C:3]([F:18])([F:17])[C:4]([F:16])([F:15])[C:5]([F:14])([F:13])[C:6]([F:12])([F:11])[C:7]([F:10])([F:9])[F:8].[H][H]>[Ni]>[CH:2]([F:19])([F:1])[C:3]([F:17])([F:18])[C:4]([F:15])([F:16])[C:5]([F:13])([F:14])[C:6]([F:12])([F:11])[C:7]([F:10])([F:9])[F:8]
Reactant: FC(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)I
Reactant: [H][H]
Agent: [Ni]
Product: FC(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F
Temperature: -80 °C
Yield: 81.1 %

Procedure:
A 225-mL Hastelloy™ nickel alloy tube was charged with 134.0 g (0.30 mol) of perfluorohexyl iodide, cooled to −80° C. and evacuated, then warmed to 22° C. and pressured to 380 psi (2.72 mPa) with hydrogen (0.17 mol). Heating to 300° C. was accompanied by at least three temperature spikes, the first beginning at 240° C. The pressure at 300° C. began at 990 psi (6.93 mPa) and dropped to 860 psi (6.03 mPa) within 2 hours. When cooled to 25° C., the reactor showed zero pressure on the gauge. Distillation of the liquid product afforded 77.9 g (81%) of pure 1H-perfluorohexane (Boiling Point 70.6-71.2° C.), confirmed by GC and NMR.
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][CH2:3][C:2]1=[O:6].C([Li])CCC.[C:12]([C:16]1[CH:21]=[CH:20][C:19]([S:22](Cl)(=[O:24])=[O:23])=[CH:18][CH:17]=1)([CH3:15])([CH3:14])[CH3:13]>O1CCCC1.CCCCCC>[C:12]([C:16]1[CH:21]=[CH:20][C:19]([S:22]([N:1]2[CH2:5][CH2:4][CH2:3][C:2]2=[O:6])(=[O:24])=[O:23])=[CH:18][CH:17]=1)([CH3:15])([CH3:13])[CH3:14]
Reactant: CC(C)(C)c1ccc(S(=O)(=O)Cl)cc1
Reactant: O=C1CCCN1
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CC(C)(C)c1ccc(S(=O)(=O)N2CCCC2=O)cc1
Temperature: -20 °C
Reaction time: 0.42 h
Yield: 50.5 %

Procedure:
1.65 g of 2-pyrrolidinone in solution in 75 cm3 of tetrahydrofuran is cooled to -5° C., and 12.1 cm3 of a 1.6M solution of n-butyllithium in hexane is added, maintaining the temperature between -5° C. and 0° C. Agitation is carried out for 25 minutes at -5° C.; the mixture is cooled to -20° C. and 4.5 g of 4-tert-butyl-phenylsulphonyl chloride is added [Recueil Trav. Chim. Pays-Bas, 53, 1101 (1934)]. After allowing to return to ambient temperature, the tetrahydrofuran is evaporated off under reduced pressure, the residue is taken up with water, filtered and crystallized from ethanol. 2.75 g of expected product is obtained.
Reaction SMILES: CC1(C)C(C)(C)OB([C:9]2[CH:21]=[CH:20][C:12]([O:13][C:14]3[C:15](=[O:19])[CH2:16][CH2:17][CH:18]=3)=[CH:11][CH:10]=2)O1.[F-].[Cs+].[C:25]([O:28][C@H:29]1[C@H:35]([O:36][C:37](=[O:39])[CH3:38])[C@@H:34]([O:40][C:41](=[O:43])[CH3:42])[C@:33]2([C:45]3[CH:50]=[CH:49][C:48]([Cl:51])=[C:47]([CH2:52]Br)[CH:46]=3)[O:44][C@@:30]1([CH2:54][O:55][C:56](=[O:58])[CH3:57])[CH2:31][O:32]2)(=[O:27])[CH3:26]>O1CCOCC1.C(OC(=O)C)C>[C:25]([O:28][C@H:29]1[C@H:35]([O:36][C:37](=[O:39])[CH3:38])[C@@H:34]([O:40][C:41](=[O:43])[CH3:42])[C@:33]2([C:45]3[CH:50]=[CH:49][C:48]([Cl:51])=[C:47]([CH2:52][C:9]4[CH:10]=[CH:11][C:12]([O:13][C:14]5[C:15](=[O:19])[CH2:16][CH2:17][CH:18]=5)=[CH:20][CH:21]=4)[CH:46]=3)[O:44][C@@:30]1([CH2:54][O:55][C:56](=[O:58])[CH3:57])[CH2:31][O:32]2)(=[O:27])[CH3:26]
Reactant: CC(=O)OC[C@@]12CO[C@@](c3ccc(Cl)c(CBr)c3)(O1)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]2OC(C)=O
Reactant: CC1(C)OB(c2ccc(OC3=CCCC3=O)cc2)OC1(C)C
Agent: [Cs+]
Agent: [F-]
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: CC(=O)OC[C@@]12CO[C@@](c3ccc(Cl)c(Cc4ccc(OC5=CCCC5=O)cc4)c3)(O1)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]2OC(C)=O
Temperature: 110 °C
Yield: 35.1 %

Procedure:
To a solution of 2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy)cyclopent-2-enone (295 mg, 0.989 mmol), CsF (296 mg, 1.95 mmol) in dioxane (3.1 mL), (1R,2S,3S,4R,5S)-1-(acetoxymethyl)-5-(3-(bromomethyl)-4-chlorophenyl)-6,8-dioxabicyclo[3.2.1]octane-2,3,4-triyl triacetate (369.4 mg, 0.65 mmol, Intermediate 2) and Pd(PPh3) (60 mg, 0.05 mmol) were added under N2 atmosphere. The reaction mixture was heated to 110° C. for 1 h. After completion of the reaction as confirmed by TLC, the reaction mixture was diluted with ethylacetate (100 mL), washed with water (20 mL) and brine (20 mL) successively. The organic layer was dried over Na2SO4 and the volatiles were evaporated in vacuo. The residue obtained was purified by column chromatography (silica gel, 2:8 Acetone:hexane) to provide title compound (150 mg, 35%) as off-white solid.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([S:11]([C:14]1[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][C:15]=1[Br:22])(=[O:13])=[O:12])[CH:6]=[C:5]2[CH2:23]Cl.[NH:25]1[CH2:31][CH2:30][CH2:29][NH:28][CH2:27][CH2:26]1>>[Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([S:11]([C:14]1[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][C:15]=1[Br:22])(=[O:13])=[O:12])[CH:6]=[C:5]2[CH2:23][N:25]1[CH2:31][CH2:30][CH2:29][NH:28][CH2:27][CH2:26]1
Reactant: COc1ccc(S(=O)(=O)n2cc(CCl)c3cc(Br)ccc32)c(Br)c1
Reactant: C1CNCCNC1
Product: COc1ccc(S(=O)(=O)n2cc(CN3CCCNCC3)c3cc(Br)ccc32)c(Br)c1

Procedure:
Using essentially the same procedure as described in example 127, 5-Bromo-1-(2-Bromo-4-methoxybenzenesulfonyl)-3-chloromethyl-1H-indole was reacted with homopiperazine to obtain the above derivative.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH:9]=[CH:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])=[C:5]([O:16][CH2:17][C@H:18]2[CH2:22][CH2:21][CH2:20][N:19]2C(OC(C)(C)C)=O)[CH:4]=1)#[N:2].[H][H].[ClH:32]>C(O)C.O1CCOCC1.[Pd]>[ClH:32].[C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])=[C:5]([O:16][CH2:17][C@H:18]2[CH2:22][CH2:21][CH2:20][NH:19]2)[CH:4]=1)#[N:2]
Reactant: CCOC(=O)C=Cc1ccc(C#N)cc1OC[C@H]1CCCN1C(=O)OC(C)(C)C
Reactant: [H][H]
Agent: [Pd]
Agent: Cl
Solvent: CCO
Solvent: C1COCCO1
Product: CCOC(=O)CCc1ccc(C#N)cc1OC[C@H]1CCCN1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
3.0 g (7.5 mmol) of ethyl 3-[4-cyano-(2R)-2-(1-t-butoxycarbonylpyrrolidine-2-ylmethoxy)phenyl]acrylate was dissolved in 20 ml of ethanol. 600 mg of 10% palladium/carbon (50% aqueous) was added to the obtained solution, and they were stirred in the presence of hydrogen overnight. The reaction solution was filtered through Celite, and the solvent was evaporated. The obtained crude product was dissolved in 10 ml of 4 N solution of hydrogen chloride in dioxane, and the obtained solution was stirred at room temperature for 3 hours. The solvent was evaporated to obtain hydrochloride of the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH:9]([OH:11])[CH3:10])=[CH:4][CH:3]=1.[N+:12]([C:15]1[CH:22]=[CH:21][C:18]([CH:19]=O)=[CH:17][CH:16]=1)([O-:14])=[O:13].Cl>C1C=CC=CC=1.O.[Cl-].[Zn+2].[Cl-]>[Cl:1][C:2]1[CH:3]=[C:4]2[C:5]([CH2:8][CH:9]([CH3:10])[O:11][CH:19]2[C:18]2[CH:21]=[CH:22][C:15]([N+:12]([O-:14])=[O:13])=[CH:16][CH:17]=2)=[CH:6][CH:7]=1
Reactant: O=Cc1ccc([N+](=O)[O-])cc1
Reactant: CC(O)Cc1ccc(Cl)cc1
Agent: Cl
Agent: [Cl-]
Agent: [Zn+2]
Solvent: c1ccccc1
Solvent: O
Product: CC1Cc2ccc(Cl)cc2C(c2ccc([N+](=O)[O-])cc2)O1

Procedure:
11.94 g (70 mM) of 1-(4-chlorophenyl)-2-propanol [J. Med. Chem. 21, 454 (1978)] and 10.57 g (70 mM) of 4-nitrobenzaldehyde were dissolved in 70 ml of anhydrous benzene, then 9.56 g (70 mM) of freshly prepared anhydrous zinc chloride were added and dry hydrochloric acid gas was led into the mixture for 3 hours. Then the mixture was refluxed for 1.5 hours, cooled, diluted with water and the layers were separated. The organic layer was first washed with water then with a solution of sodium hydrogen carbonate, dried and evaporated. The resulting crude product was recrystallized from ethanol.
Reaction SMILES: [NH:1]([C:8]1[S:9][CH:10]=[C:11]([CH:13]([CH3:19])[C:14]([O:16][CH2:17][CH3:18])=[O:15])[N:12]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CI.[C:22](=O)([O-])[O-].[K+].[K+]>C(O)C>[C:2]1([N:1]=[C:8]2[N:12]([CH3:22])[C:11]([CH:13]([CH3:19])[C:14]([O:16][CH2:17][CH3:18])=[O:15])=[CH:10][S:9]2)[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C([O-])[O-]
Reactant: CCOC(=O)C(C)c1csc(Nc2ccccc2)n1
Agent: [K+]
Solvent: CCO
Solvent: CI
Product: CCOC(=O)C(C)c1csc(=Nc2ccccc2)n1C
Temperature: 100 °C

Procedure:
A mixture of ethyl 2-(2-anilinothiazol-4-yl)-propionate (6.15 g), methyl iodide (17 ml) and ethanol (17 ml) is heated at 100° C for 11.5 hours in a sealed tube. The resultant mixture is treated with potassium carbonate in the same manner as in Example 1 (2) to give ethyl 2-(2-phenylimino-3-methyl-4-thiazolin-4-yl)propionate (1.6 g) melting at 80°-81° C (recrystallized from ether/hexane).
Reaction SMILES: Cl[C:2]1[C:11]([CH3:12])=[C:10]([Cl:13])[C:9]2[C:4](=[CH:5][C:6]([F:15])=[CH:7][C:8]=2[F:14])[N:3]=1.O.[CH3:17][N:18]([C:20]1[CH:25]=[CH:24][C:23](B(O)O)=[CH:22][N:21]=1)[CH3:19].C(=O)([O-])[O-].[K+].[K+]>C1(C)C=CC=CC=1>[Cl:13][C:10]1[C:9]2[C:4](=[CH:5][C:6]([F:15])=[CH:7][C:8]=2[F:14])[N:3]=[C:2]([C:23]2[CH:24]=[CH:25][C:20]([N:18]([CH3:19])[CH3:17])=[N:21][CH:22]=2)[C:11]=1[CH3:12]
Reactant: Cc1c(Cl)nc2cc(F)cc(F)c2c1Cl
Reactant: CN(C)c1ccc(B(O)O)cn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: Cc1ccccc1
Product: Cc1c(-c2ccc(N(C)C)nc2)nc2cc(F)cc(F)c2c1Cl

Procedure:
The Suzuki coupled product was prepared according to Procedure F using 2,4-dichloro-5,7-difluoro-3-methylquinoline (0.50 g, 2.02 mmol), 2-(N,N-dimethylamino)pyridine-5-boronic acid hydrate (0.335 g, 2.02 mmol), palladium tetrakistriphenylphosphine (0.23 g, 0.20 mmol), potassium carbonate (0.56 g, 4.03 mmol) in toluene (4 mL) at 100° C. for 1.3 h to give 5-(4-chloro-5,7-difluoro-3-methylquinolin-2-yl)-N,N-dimethylpyridin-2-amine as a yellow solid. Mass Spectrum (ESI) m/e=344.1 (M+1).
Reaction SMILES: [CH3:1][N:2]([CH3:18])[C:3]([CH:5]1[C:17]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[C:11]2[C:6]1=[CH:7][CH:8]=[CH:9][CH:10]=2)=[O:4].[C:19](#[N:22])[CH:20]=[CH2:21]>O1CCCC1>[C:19]([CH2:20][CH2:21][C:5]1([C:3](=[O:4])[N:2]([CH3:18])[CH3:1])[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:11]=2[C:12]2[C:17]1=[CH:16][CH:15]=[CH:14][CH:13]=2)#[N:22]
Reactant: CN(C)C(=O)C1c2ccccc2-c2ccccc21
Reactant: C=CC#N
Solvent: C1CCOC1
Product: CN(C)C(=O)C1(CCC#N)c2ccccc2-c2ccccc21
Reaction time: 0.25 h

Procedure:
A 28 g. of portion of 9-(N,N-dimethylcarbamoyl)fluorene was added to a 3-liter flask, and 1 liter of tetrahydrofuran was added. The mixture was heated to 45°, and 10 ml. of Triton B was added. The mixture was stirred at constant temperature for 15 minutes, and then 8 g. of acrylonitrile was added in one portion. The mixture was then stirred at reflux temperature for 3 hours, and was cooled and concentrated under vacuum to obtain 51.8 g. of oil. The product was isolated as described in Example 1 and was recrystallized from hexane to obtain 15 g. of first-crop purified product, m.p. 109°-110°. Infrared analysis showed a characteristic carbonyl band at 1610 cm-1, and a characteristic nitrile band at 2220 cm-1.
Reaction SMILES: [CH3:1][N:2](N=O)[C:3]([NH:5][N+:6]([O-:8])=[O:7])=[NH:4].[Cl:11][C:12]1[CH:13]=C([CH:16]=[C:17]([Cl:20])[C:18]=1[Cl:19])N.[OH-].[Na+]>C(O)C>[N+:6]([NH:5][C:3]([NH:2][C:1]1[CH:13]=[C:12]([Cl:11])[C:18]([Cl:19])=[C:17]([Cl:20])[CH:16]=1)=[NH:4])([O-:8])=[O:7]
Reactant: CN(N=O)C(=N)N[N+](=O)[O-]
Reactant: Nc1cc(Cl)c(Cl)c(Cl)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: N=C(Nc1cc(Cl)c(Cl)c(Cl)c1)N[N+](=O)[O-]
Temperature: 40 °C
Yield: 25.1 %

Procedure:
To a slurry of N-methyl-N-nitroso-N'-nitroguanidine 3.3 g (0.0225 mol) in 200 ml of a 50% aqueous ethanol mixture is added 5.0 g (0.025 mol) of 3,4,5-trichloroaniline. This mixture is heated to 40° C. for 72 hours and then treated with one equivalent of NaOH to decompose excess N-methyl-N-nitroso-N'-nitroguanidine. The mixture is then filtered and acidified with concentrated HCl to give 1.6 g of a yellow solid which, when recrystallized, gives 1.4 g of the desired product. The melting point of the product is 209.5° C. dec.
Reaction SMILES: [C:1]([C:9](=[CH:28]N(C)C)[CH2:10][C:11]([O:13][CH2:14][CH2:15][N:16]1[CH2:21][CH2:20][N:19]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH2:18][CH2:17]1)=[O:12])(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:32]1([NH:38][NH2:39])[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1>>[C:32]1([N:38]2[C:1]([C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)=[C:9]([CH2:10][C:11]([O:13][CH2:14][CH2:15][N:16]3[CH2:21][CH2:20][N:19]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)[CH2:18][CH2:17]3)=[O:12])[CH:28]=[N:39]2)[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1
Reactant: CN(C)C=C(CC(=O)OCCN1CCN(c2ccccc2)CC1)C(=O)c1ccccc1
Reactant: NNc1ccccc1
Product: O=C(Cc1cnn(-c2ccccc2)c1-c1ccccc1)OCCN1CCN(c2ccccc2)CC1

Procedure:
2-(4-phenylpiperazino)-ethyl 3-benzoyl-4-dimethylamino-3-butenoate respectively, with phenylhydrazine.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[N:6][NH:7][CH:8]=1)([O-:3])=[O:2].Br[C:10]([CH3:17])([CH3:16])[C:11]([O:13][CH2:14][CH3:15])=[O:12].O>CN(C)C=O>[CH3:16][C:10]([N:6]1[CH:5]=[C:4]([N+:1]([O-:3])=[O:2])[CH:8]=[N:7]1)([CH3:17])[C:11]([O:13][CH2:14][CH3:15])=[O:12]
Reactant: O=[N+]([O-])c1cn[nH]c1
Reactant: CCOC(=O)C(C)(C)Br
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)C(C)(C)n1cc([N+](=O)[O-])cn1
Temperature: 80 °C
Reaction time: 2 h

Procedure:
To a solution of 4-nitro-1H-pyrazole (25 g) in N,N-dimethylformamide (100 mL) was added ethyl 2-bromo-2-methylpropanoate (39 mL), and the mixture was stirred at 80° C. for 2 hr. To the reaction mixture was added water, and the mixture was extracted with ethyl acetate. The obtained organic layer was washed with saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate) to give the title compound (50 g).
Reaction SMILES: [SH:1][C:2]1[S:3][CH:4]=[C:5]([CH2:7][C:8]([OH:10])=[O:9])[N:6]=1.[CH3:11][O:12][C:13]([CH:15]1[CH2:20][CH2:19][CH2:18][CH2:17][CH:16]1Br)=[O:14].C[O-].[Na+]>CO>[CH3:11][O:12][C:13]([C:15]1([S:1][C:2]2[S:3][CH:4]=[C:5]([CH2:7][C:8]([OH:10])=[O:9])[N:6]=2)[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1)=[O:14]
Reactant: COC(=O)C1CCCCC1Br
Reactant: O=C(O)Cc1csc(S)n1
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: COC(=O)C1(Sc2nc(CC(=O)O)cs2)CCCCC1
Yield: 10.5 %

Procedure:
(2-Mercapto-1,3-thiazol-4-yl)acetic acid (3.50 g) synthesized in Reference Example 51 and 2-bromocyclohexanecarboxylic acid methyl ester (4.42 g) were dissolved in methanol (180 mL), sodium methoxide (2.38 g) was added and the mixture was heated under reflux for 22 hr. The solvent was evaporated, and diethyl ether (50 mL) and water (50 mL) were added to the residue. After stirring, the aqueous layer was obtained by partitioning and adjusted to about pH 4 with 1 mol/L hydrochloric acid. The mixture was extracted with ethyl acetate (100 mL), and the organic layer was washed with saturated sodium chloride aqueous solution, and dried over anhydrous sodium sulfate. The solvent was evaporated and the residue was purified by silica gel column chromatography (elution solvent; hexane:ethyl acetate=3:2 to 0:1) and the obtained solid was washed by suspending in hexane-ethyl acetate to give the title compound (663 mg).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([NH2:20])[CH:5]=[C:6]2[C:11]=1[N:10]([CH2:12][CH2:13][CH:14]1[CH2:18][CH2:17][CH2:16][N:15]1[CH3:19])[CH2:9][CH2:8][CH2:7]2.I.[S:22]1[CH:26]=[CH:25][CH:24]=[C:23]1[C:27](SC)=[NH:28]>C(O)C>[F:1][C:2]1[CH:3]=[C:4]([NH:20][C:27]([C:23]2[S:22][CH:26]=[CH:25][CH:24]=2)=[NH:28])[CH:5]=[C:6]2[C:11]=1[N:10]([CH2:12][CH2:13][CH:14]1[CH2:18][CH2:17][CH2:16][N:15]1[CH3:19])[CH2:9][CH2:8][CH2:7]2
Reactant: CSC(=N)c1cccs1
Reactant: CN1CCCC1CCN1CCCc2cc(N)cc(F)c21
Agent: I
Solvent: CCO
Product: CN1CCCC1CCN1CCCc2cc(NC(=N)c3cccs3)cc(F)c21
Temperature: 25 °C
Reaction time: 8 h
Yield: 60 %

Procedure:
To a stirred solution of 8-fluoro-1-(2-(1-methylpyrrolidin-2-yl)ethyl)-1,2,3,4-tetrahydroquinolin-6-amine (580 mg, 2.091 mmol) in ethanol (15 ml) was added methyl thiophene-2-carbimidothioate hydroiodide (1193 mg, 4.18 mmol) as a solid. The resulting suspension was stirred overnight at room temperature under argon. The reaction mixture was then quenched with water and sodium carbonate (sat) and extracted with dichloromethane (3×). The combined organics were dried, filtered and concentrated. The residue was then chromatographed in ethyl acetate, followed by 0-10% (2M NH3 in methanol) in dichloromethane, giving the desired N-(8-fluoro-1-(2-(1-methylpyrrolidin-2-yl)ethyl)-1,2,3,4-tetrahydroquinolin-6-yl)thiophene-2-carboximidamide (485 mg, 1.255 mmol, 60.0% yield). 1H NMR (DMSO-d6) δ 7.71 (d, J=3 Hz, 1H), 7.57 (d, J=4.5 Hz, 1H), 7.07 (dd, J=4.8, 3.9 Hz, 1H), 6.44 (brs, 2H), 6.39-6.34 (m, 2H), 3.07-3.02 (m, 4H), 2.95-2.89 (m, 1H), 2.69-2.65 (m, 2H), 2.21 (s, 3H), 2.03-1.99 (m, 2H), 1.94-1.87 (m, 2H), 1.76-1.74 (m, 2H), 1.63-1.59 (m, 2H), 1.46-1.40 (m, 2H).
Reaction SMILES: P(Cl)(Cl)(Cl)=O.[F:6][C:7]1[C:36]([F:37])=[CH:35][CH:34]=[CH:33][C:8]=1[CH2:9][N:10]1[C:14]2=[N:15][CH:16]=[CH:17][CH:18]=[C:13]2[C:12]([C:19]2[N:20]=[N:21][C:22]([C:26]([CH3:32])([CH3:31])[C:27]([O:29]C)=O)=[C:23](O)[N:24]=2)=[N:11]1.[NH3:38]>C(#N)C>[F:6][C:7]1[C:36]([F:37])=[CH:35][CH:34]=[CH:33][C:8]=1[CH2:9][N:10]1[C:14]2=[N:15][CH:16]=[CH:17][CH:18]=[C:13]2[C:12]([C:19]2[N:20]=[N:21][C:22]3[C:26]([CH3:32])([CH3:31])[C:27](=[O:29])[NH:38][C:23]=3[N:24]=2)=[N:11]1
Reactant: COC(=O)C(C)(C)c1nnc(-c2nn(Cc3cccc(F)c3F)c3ncccc23)nc1O
Reactant: N
Solvent: O=P(Cl)(Cl)Cl
Solvent: CC#N
Product: CC1(C)C(=O)Nc2nc(-c3nn(Cc4cccc(F)c4F)c4ncccc34)nnc21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
8 ml of phosphoryl chloride were added to 0.75 g (1.703 mmol) of the compound from Example 75A, and the mixture was stirred at RT overnight. The reaction mixture was then taken up in 120 ml of acetonitrile and, with ice cooling, stirred into 72 ml of concentrated ammonia solution (33% in water). The reaction mixture was stirred at room temperature for 3 days and then concentrated on a rotary evaporator. The residue was stirred with water and ethyl acetate and the aqueous phase was extracted twice with ethyl acetate. The combined organic phases were washed with saturated aqueous sodium chloride solution and then dried over sodium sulphate, filtered and concentrated on a rotary evaporator. The residue was purified by preparative HPLC (acetonitrile/water/water+1% TFA—40:55:5). This gave 134 mg of the title compound (19% of theory).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:15]=[CH:14][C:13]([CH:16]([CH3:25])[CH2:17][NH:18][S:19]([CH:22]([CH3:24])[CH3:23])(=[O:21])=[O:20])=[CH:12][CH:11]=2)=[CH:6][CH:5]=1.[F:26][C:27]1[CH:28]=[C:29]([CH:33]=[CH:34][CH:35]=1)[C:30](Cl)=[O:31]>>[F:26][C:27]1[CH:28]=[C:29]([CH:33]=[CH:34][CH:35]=1)[C:30]([NH:1][CH2:2][CH2:3][C:4]1[CH:5]=[CH:6][C:7]([C:10]2[CH:15]=[CH:14][C:13]([CH:16]([CH3:25])[CH2:17][NH:18][S:19]([CH:22]([CH3:24])[CH3:23])(=[O:21])=[O:20])=[CH:12][CH:11]=2)=[CH:8][CH:9]=1)=[O:31]
Reactant: CC(CNS(=O)(=O)C(C)C)c1ccc(-c2ccc(CCN)cc2)cc1
Reactant: O=C(Cl)c1cccc(F)c1
Product: CC(CNS(=O)(=O)C(C)C)c1ccc(-c2ccc(CCNC(=O)c3cccc(F)c3)cc2)cc1

Procedure:
The title compound was prepared following the method of Example 147 and using 1 mL of a stock solution of 0.6 g (1.8 mmol) of material from Example 50 and 13 μL (0.11 mmol) 3-fluorobenzoyl chloride. NMR was consistent with the proposed compound.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:15][CH2:16][CH3:17])=[C:9]([O:12][CH2:13][CH3:14])[CH:10]=2)[N:5]=[CH:4][C:3]=1[C:18]#[N:19].[CH3:20][O:21][C:22]1[CH:23]=[C:24]([CH:27]=[CH:28][C:29]=1[O:30][CH3:31])[CH2:25][NH2:26]>>[CH3:20][O:21][C:22]1[CH:23]=[C:24]([CH2:25][NH:26][C:2]2[C:11]3[C:6](=[CH:7][C:8]([O:15][CH2:16][CH3:17])=[C:9]([O:12][CH2:13][CH3:14])[CH:10]=3)[N:5]=[CH:4][C:3]=2[C:18]#[N:19])[CH:27]=[CH:28][C:29]=1[O:30][CH3:31]
Reactant: CCOc1cc2ncc(C#N)c(Cl)c2cc1OCC
Reactant: COc1ccc(CN)cc1OC
Product: CCOc1cc2ncc(C#N)c(NCc3ccc(OC)c(OC)c3)c2cc1OCC

Procedure:
In the manner of Example 61 reaction of 4-chloro-6,7-diethoxy-3-quinolinecarbonitrile with 3,4-dimethoxybenzylamine gave the title compound as a tan solid, mp 200-204° C.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:7][N:8]([CH3:39])[C:9]1[CH:10]=[C:11]([CH:36]=[CH:37][CH:38]=1)[C:12]([NH:14][C:15]1[CH:16]=[CH:17][C:18]([CH3:35])=[C:19]([NH:21][C:22](=[O:34])[C:23]2[CH:28]=[CH:27][CH:26]=[C:25]([O:29][CH2:30][CH:31]3[O:33][CH2:32]3)[CH:24]=2)[CH:20]=1)=[O:13]>C(Cl)Cl.CO>[CH3:39][N:8]([CH3:7])[C:9]1[CH:10]=[C:11]([CH:36]=[CH:37][CH:38]=1)[C:12]([NH:14][C:15]1[CH:16]=[CH:17][C:18]([CH3:35])=[C:19]([NH:21][C:22](=[O:34])[C:23]2[CH:28]=[CH:27][CH:26]=[C:25]([O:29][CH2:30][CH:31]([OH:33])[CH2:32][N:1]3[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]3)[CH:24]=2)[CH:20]=1)=[O:13]
Reactant: C1CCNCC1
Reactant: Cc1ccc(NC(=O)c2cccc(N(C)C)c2)cc1NC(=O)c1cccc(OCC2CO2)c1
Solvent: ClCCl
Solvent: CO
Product: Cc1ccc(NC(=O)c2cccc(N(C)C)c2)cc1NC(=O)c1cccc(OCC(O)CN2CCCCC2)c1
Yield: 84 %

Procedure:
Piperidine (3 g) was added to a stirred solution of N-[5-(3-dimethylaminobenzamido)-2-methylphenyl]-3-(2,3-epoxypropoxy)benzamide (0.19 g) in a mixture of methylene chloride (3 ml) and methanol (3 ml). The resultant solution was stirred at ambient temperature for 18 hours. The mixture was evaporated and the residue was purified by column chromatography on silica using increasingly polar mixtures of methylene chloride and methanol as eluent. There was thus obtained the title compound (0.19 g); NMR Spectrum: (DMSOd6) 1.6 (m, 6H), 2.18 (s, 3H), 2.92 (m, 12H), 4.02 (m, 2H), 4.22 (m, 1H), 6.9 (m, 1H), 7.2 (m, 4H), 7.29 (t, 1H), 7.43 (t, 1H), 7.57 (m, 3H), 7.8 (d, 1H), 9.92 (br s, 1H), 10.12 (br s, 1H); Mass Spectrum: M+H+ 531.
Reaction SMILES: [OH:1][CH:2]1[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.C(N(CC)CC)C.[C:15](Cl)(=[O:17])[CH3:16]>C1COCC1>[OH:1][CH:2]1[CH2:7][CH2:6][N:5]([C:15](=[O:17])[CH3:16])[CH2:4][CH2:3]1
Reactant: CC(=O)Cl
Reactant: OC1CCNCC1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(=O)N1CCC(O)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 4-hydroxypiperidine (5.00 g, 49.4 mmol) in anhydrous THF (30 mL) and triethylamine (10 mL, 75 mmol) was added acetyl chloride (3.52 mL, 49.4 mmol). After the addition, the mixture was stirred for another 2 hours at room temperature. The solid formed was filtered and the mother liquid was concentrated to yield 5.0 g of crude product, which was purified by column chromatography on silica gel (230-400 mesh), using 5% methanol in dichloromethane as eluent, to give 1-(4-hydroxy-piperidin-1-yl)-ethanone. Yield: 2.40 g (34%).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][CH:11]=1)[C:5]([O:7][CH3:8])=[O:6].C(=O)([O-])[O-].[K+].[K+].[Cl:18][CH2:19][CH2:20]OS(C1C=CC(C)=CC=1)(=O)=O.O>CN(C=O)C>[Cl:18][CH2:19][CH2:20][O:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][CH:11]=1)[C:5]([O:7][CH3:8])=[O:6]
Reactant: Cc1ccc(S(=O)(=O)OCCCl)cc1
Reactant: COC(=O)c1cccc(O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)c1cccc(OCCCl)c1
Temperature: 60 °C
Reaction time: 8 h

Procedure:
To a solution of methyl 3-hydroxybenzoate (10.0 g, 65.7 mmol) in DMF (100 mL) was added potassium carbonate (18.17 g, 131.4 mmol) and 2-chloroethyl-p-toluenesulfonate (15.7 g, 67.0 mmol). After stirring at 60° C. overnight the reaction mixture was poured into H2O, extracted with ethyl acetate (three times), dried over MgSO4 and concentrated under vacuum. Purification by silica gel chromatography (10% EtOAc/hexanes) afforded the desired product.