Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([CH:8]2[N:12]([C:13]3[CH:18]=[CH:17][C:16]([F:19])=[CH:15][C:14]=3[F:20])[N:11]=[C:10]([C:21]([F:27])([F:26])[C:22]([F:25])([F:24])[F:23])[CH2:9]2)[CH:5]=[CH:4][N:3]=1.[C:28]([N:35]1[CH2:40][CH2:39][NH:38][CH2:37][CH2:36]1)([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29].C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1.CC(C)([O-])C.[Na+]>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].C1(C)C=CC=CC=1>[C:28]([N:35]1[CH2:36][CH2:37][N:38]([C:2]2[CH:7]=[C:6]([CH:8]3[N:12]([C:13]4[CH:18]=[CH:17][C:16]([F:19])=[CH:15][C:14]=4[F:20])[N:11]=[C:10]([C:21]([F:27])([F:26])[C:22]([F:25])([F:23])[F:24])[CH2:9]3)[CH:5]=[CH:4][N:3]=2)[CH2:39][CH2:40]1)([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29]
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: Fc1ccc(N2N=C(C(F)(F)C(F)(F)F)CC2c2ccnc(Br)c2)c(F)c1
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)N1CCN(c2cc(C3CC(C(F)(F)C(F)(F)F)=NN3c3ccc(F)cc3F)ccn2)CC1
Temperature: 100 °C
Reaction time: 12 h
Yield: 86.3 %

Procedure:
5-(2-Bromo-pyridin-4-yl)-1-(2,4-difluoro-phenyl)-3-pentafluoroethyl-4,5-dihydro-1H-pyrazole (300.0 mg, 0.66 mmol) prepared in Step 4 of Preparation 12, 1-BOC-piperazine (184.0 mg, 0.99 mmol), Pd2(dba)3 (30.2 mg, cat.), BINAP (41.1 mg, cat.) and sodium t-butoxide (114.0 mg, 1.19 mmol) were added to toluene (10.0 mL). The reaction mixture was stirred at 100° C. for 12 hours and then filtered through celite pad. A saturated solution of ammonium chloride was added to the filtrate, which was then extracted with ethyl acetate three times. The combined extract was washed with brine, dried on anhydrous magnesium sulfate, and then concentrated under reduced pressure to give a yellow liquid residue. The resulting residue was purified by silica gel column chromatography (eluent: ethyl acetate/n-hexane=1/3) to give 320.0 mg of the titled compound as a yellow liquid.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([O:8][C:9]2[S:10][CH:11]=[C:12]([C:14]([F:17])([F:16])[F:15])[N:13]=2)[CH:5]=[C:4]([CH3:18])[C:3]=1[NH:19][C:20]([NH:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[S:21].I[CH3:28]>C(O)C>[CH3:1][C:2]1[CH:7]=[C:6]([O:8][C:9]2[S:10][CH:11]=[C:12]([C:14]([F:16])([F:17])[F:15])[N:13]=2)[CH:5]=[C:4]([CH3:18])[C:3]=1[NH:19][C:20](=[N:22][C:23]([CH3:26])([CH3:25])[CH3:24])[S:21][CH3:28]
Reactant: CI
Reactant: Cc1cc(Oc2nc(C(F)(F)F)cs2)cc(C)c1NC(=S)NC(C)(C)C
Solvent: CCO
Product: CSC(=NC(C)(C)C)Nc1c(C)cc(Oc2nc(C(F)(F)F)cs2)cc1C

Procedure:
5 g of N-[2,6-dimethyl-4-(4-trifluoromethylthiazol-2-yloxy)phenyl]-N'-tert-butylthiourea are heated in 30 ml of ethanol and 2.1 g of iodomethane for 5 hours to 50° C. The alcohol is subsequently removed by evaporation and the residue is taken up in methylene chloride. The methylene chloride solution is washed twice with dilute sodium carbonate solution and dried over sodium sulfate. The solvent is removed by evaporation and the residue is recrystallised from hexane, affording the title compound of formula ##STR35## with a melting point of 88°-90° C. (compound 4.01).
Reaction SMILES: [Br:1][C:2]1[N:9]=[CH:8][C:7]([CH:10]=[O:11])=[CH:6][C:3]=1[C:4]#[N:5]>[N+]([O-])([O-])=O.[Ag+]>[Br:1][C:2]1[N:9]=[CH:8][C:7]([CH2:10][OH:11])=[CH:6][C:3]=1[C:4]#[N:5]
Reactant: N#Cc1cc(C=O)cnc1Br
Agent: [Ag+]
Agent: O=[N+]([O-])[O-]
Product: N#Cc1cc(CO)cnc1Br

Procedure:
Compound 23 is prepared from 10 in a manner similar to the preparation of 13 except a slight excess over one equivalent of AgNO3 is used.
Reaction SMILES: [NH2:1][CH:2]1[CH2:7][CH2:6][N:5]([CH3:8])[CH2:4][CH2:3]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[N+:33]([C:36]1[C:41]2[O:42][CH2:43][O:44][C:40]=2[C:39]([C:45](O)=[O:46])=[CH:38][CH:37]=1)([O-:35])=[O:34].C(N(C(C)C)CC)(C)C>CN(C=O)C>[CH3:8][N:5]1[CH2:6][CH2:7][CH:2]([NH:1][C:45]([C:39]2[C:40]3[O:44][CH2:43][O:42][C:41]=3[C:36]([N+:33]([O-:35])=[O:34])=[CH:37][CH:38]=2)=[O:46])[CH2:3][CH2:4]1
Reactant: CN1CCC(N)CC1
Reactant: O=C(O)c1ccc([N+](=O)[O-])c2c1OCO2
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CN1CCC(NC(=O)c2ccc([N+](=O)[O-])c3c2OCO3)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 50.8 %

Procedure:
4-Amino-1-methylpiperidine (Fluorochem; 325 mg, 2.84 mmol), HATU (1.09 g, 2.84 mmol) and 7-nitrobenzo[1,3]dioxole-4-carboxylic acid (WO 2003082827; 400 mg, 1.89 mmol) were stirred in DMF (5 mL) and diisopropylethylamine (0.99 ml, 5.68 mmol) added. The mixture was stirred for 2 hours at room temperature. The reaction mixture was loaded on to an SCX column, which was subsequently washed with methanol and eluted with ammonia in methanol. Product containing fractions were concentrated and the solid suspended in methanol and filtered off to yield the title compound as a yellow solid (295 mg, 51%).
Reaction SMILES: [CH:1]([C:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[NH:5][C:4]=1[CH2:12][C:13]([O:15]CC)=[O:14])=[O:2].[OH-].[Na+].O>O1CCOCC1>[CH:1]([C:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[NH:5][C:4]=1[CH2:12][C:13]([OH:15])=[O:14])=[O:2]
Reactant: CCOC(=O)Cc1[nH]c2ccccc2c1C=O
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: O=Cc1c(CC(=O)O)[nH]c2ccccc12
Temperature: 25 °C
Reaction time: 96 h
Yield: 73.7 %

Procedure:
Ethyl (3-formylindolyl)acetate (15.9 g) was dissolved in 1,4-dioxane (100 ml) and added 36% aq. NaOH (10 ml). The resulting mixture was stirred at room temperature for 4 days. Water (500 ml) was added and the mixture was washed with diethyl ether (150 ml). The aqueous phase was made acidic with 5N HCl and extracted with ethyl acetate (250+150 ml). The combined organic extracts were dried (MgSO4) and evaporated in vacuo to afford 10.3 g (73% over two steps) of (3-formylindolyl)acetic acid.
Reaction SMILES: [CH3:1][C:2]1([CH3:23])[C:11]2[CH:10]=[C:9]3[NH:12][C:13]([C:15]4[CH:20]=[CH:19][N:18]=[CH:17][CH:16]=4)=[N:14][C:8]3=[CH:7][C:6]=2[C:5](=[O:21])[NH:4][C:3]1=[O:22].O1CCOCC1.CO.[BH4-].[Na+]>O>[CH3:1][C:2]1([CH3:23])[C:11]2[CH:10]=[C:9]3[NH:12][C:13]([C:15]4[CH:20]=[CH:19][N:18]=[CH:17][CH:16]=4)=[N:14][C:8]3=[CH:7][C:6]=2[C:5](=[O:21])[NH:4][CH:3]1[OH:22]
Reactant: CC1(C)C(=O)NC(=O)c2cc3nc(-c4ccncc4)[nH]c3cc21
Agent: [BH4-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: CO
Solvent: O
Product: CC1(C)c2cc3[nH]c(-c4ccncc4)nc3cc2C(=O)NC1O

Procedure:
5 g. (17 mmole) of the compound obtained in Example 8 were suspended in 250 ml. dioxan, 250 ml. methanol and 25 ml. water. While cooling with water, sodium borohydride was added thereto in 0.5 g. portions. After each addition, the course of the reaction is monitored chromatographically. When the substance had just gone into solution (conversion 70% of theory), the reaction is discontinued. The product is precipitated by the addition of 1 liter of water and evaporated to give 3.8 g. (76% of theory) of the title compound; m.p. 260°-268° C.
Reaction SMILES: [C:1]([O:5][C:6](=[O:33])[NH:7][CH:8]([C:28]1[NH:29][CH:30]=[CH:31][N:32]=1)[CH2:9][C:10]1[CH:18]=[C:17]([CH3:19])[C:16]2[C:12](=[CH:13][N:14]([CH2:20][O:21][CH2:22][CH2:23][Si:24]([CH3:27])([CH3:26])[CH3:25])[N:15]=2)[CH:11]=1)([CH3:4])([CH3:3])[CH3:2].[Cl:34][C:35]1[CH:40]=[C:39]([CH2:41]Cl)[CH:38]=[C:37]([CH3:43])[N:36]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C)C=O>[Cl:34][C:35]1[CH:40]=[C:39]([CH2:41][N:32]2[CH:31]=[CH:30][N:29]=[C:28]2[CH:8]([NH:7][C:6](=[O:33])[O:5][C:1]([CH3:4])([CH3:2])[CH3:3])[CH2:9][C:10]2[CH:18]=[C:17]([CH3:19])[C:16]3[C:12](=[CH:13][N:14]([CH2:20][O:21][CH2:22][CH2:23][Si:24]([CH3:25])([CH3:27])[CH3:26])[N:15]=3)[CH:11]=2)[CH:38]=[C:37]([CH3:43])[N:36]=1
Reactant: Cc1cc(CCl)cc(Cl)n1
Reactant: Cc1cc(CC(NC(=O)OC(C)(C)C)c2ncc[nH]2)cc2cn(COCC[Si](C)(C)C)nc12
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: Cc1cc(Cn2ccnc2C(Cc2cc(C)c3nn(COCC[Si](C)(C)C)cc3c2)NC(=O)OC(C)(C)C)cc(Cl)n1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
tert-Butyl-1-(1H-imidazol-2-yl)-2-(7-methyl-2-[{2-[trimethylsilyl]ethoxy}methyl]-2H-indazol-5-yl)ethylcarbamate (0.1 g, 0.212 mmol), 2-chloro-4-(chloromethyl)-6-methylpyridine (39.0 mg, 0.222 mmol, 1.05 equiv), and cesium carbonate (0.21 g, 0.64 mmol) were combined in dimethylformamide (2.0 mL). After stirring at room temperature for 16 h, the solvents were removed and the residue purified by column chromatography to afford 0.1 g (77%). Mass spec.: 611.21 (MH)+.
Reaction SMILES: Cl.[OH:2][CH2:3][C@@H:4]1[CH2:9][CH2:8][CH2:7][CH2:6][C@H:5]1[NH2:10].[F:11][C:12]1[CH:13]=[N:14][C:15]([O:21][C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([S:28][CH3:29])[CH:23]=2)=[C:16]([CH:20]=1)[C:17](O)=[O:18].Cl.CN(C)CCCN=C=NCC.ON1C2C=CC=CC=2N=N1>CN(C)C=O.C(N(CC)CC)C>[F:11][C:12]1[CH:13]=[N:14][C:15]([O:21][C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([S:28][CH3:29])[CH:23]=2)=[C:16]([CH:20]=1)[C:17]([NH:10][C@@H:5]1[CH2:6][CH2:7][CH2:8][CH2:9][C@H:4]1[CH2:3][OH:2])=[O:18]
Reactant: CSc1cccc(Oc2ncc(F)cc2C(=O)O)c1
Reactant: N[C@@H]1CCCC[C@H]1CO
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CSc1cccc(Oc2ncc(F)cc2C(=O)N[C@@H]2CCCC[C@H]2CO)c1
Temperature: 25 °C
Reaction time: 48 h
Yield: 70.9 %

Procedure:
A solution of trans-2-hydroxymethyl-1-cyclohexylamine hydrochloride (130 mg, 0.78 mmol) and triethylamine (300 μl) in dimethylformamide (5 ml) was added to a solution of 5-fluoro-2-(3-methylsulfanyl-phenoxy)-nicotinic acid (218 mg, 0.78 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (165 mg, 0.86 mmol) and 1-hydroxybenzotriazole (116 mg, 0.86 mmol) in dimethylformamide (4 ml) and the reaction was stirred under nitrogen at room temperature for 48 h. The reaction mixture was concentrated under reduced pressure, and the residue was partitioned between ethyl acetate (25 ml) and water (25 ml). The organic phase was removed and washed with sat. sodium bicarbonate solution (25 ml) followed by 1M citric acid (25 ml) and brine (25 ml). The organic layer was dried over MgSO4 and the solvent was removed by reduced pressure. The residue was purified by flash column chromatography on silica gel eluting with a solvent gradient of ethyl acetate:pentane (20:80 changing to 30:70 then 50:50, by volume) to give 5-fluoro-N-[trans-2-hydroxymethyl-cyclohexyl)-2-(3-methylsulfanyl-phenoxy)-nicotinamide (216 mg) as a colourless oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][CH3:10])[CH:6]=[C:5]([O:11][CH3:12])[CH:4]=1.[Cl:13][S:14](O)(=[O:16])=[O:15]>ClCCl>[CH3:12][O:11][C:5]1[CH:4]=[C:3]([O:2][CH3:1])[CH:8]=[C:7]([O:9][CH3:10])[C:6]=1[S:14]([Cl:13])(=[O:16])=[O:15]
Reactant: O=S(=O)(O)Cl
Reactant: COc1cc(OC)cc(OC)c1
Solvent: ClCCl
Product: COc1cc(OC)c(S(=O)(=O)Cl)c(OC)c1

Procedure:
In 500 ml of dichloromethane is dissolved 5.05 g of 1,3,5-trimethoxybenzene and the solution was cooled to -5°~-10° C. A solution of 6 ml of chlorosulfonic acid in 400 ml of dichloromethane was added dropwise, and the mixture was allowed to stand at room temperature. The reaction mixture was then treated as in Reference Example 1. The resulting product was crystallized from carbon tetrachloride and filtered. Yield 610 mg (6.3%), m.p. 126°-129° C.
Reaction SMILES: [CH3:1][C:2]1([CH3:21])[CH2:7][N:6]([C:8]2[CH:9]=[C:10]([NH2:20])[C:11]([N:14]3[CH2:19][CH2:18][O:17][CH2:16][CH2:15]3)=[N:12][CH:13]=2)[CH2:5][CH2:4][O:3]1.Cl[C:23]1[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][C:31]=2[F:33])[N:26]=[C:25]([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][N:35]=2)[C:24]=1[CH3:40].Cl.O1CCOCC1.CN1C(=O)CCC1>>[CH3:1][C:2]1([CH3:21])[O:3][CH2:4][CH2:5][N:6]([C:8]2[CH:9]=[C:10]([NH:20][C:23]3[C:32]4[C:27](=[CH:28][CH:29]=[CH:30][C:31]=4[F:33])[N:26]=[C:25]([C:34]4[CH:39]=[CH:38][CH:37]=[CH:36][N:35]=4)[C:24]=3[CH3:40])[C:11]([N:14]3[CH2:15][CH2:16][O:17][CH2:18][CH2:19]3)=[N:12][CH:13]=2)[CH2:7]1
Reactant: CC1(C)CN(c2cnc(N3CCOCC3)c(N)c2)CCO1
Reactant: Cc1c(-c2ccccn2)nc2cccc(F)c2c1Cl
Agent: Cl
Solvent: C1COCCO1
Solvent: CN1CCCC1=O
Product: Cc1c(-c2ccccn2)nc2cccc(F)c2c1Nc1cc(N2CCOC(C)(C)C2)cnc1N1CCOCC1
Temperature: 160 °C

Procedure:
Prepared according to Procedure K, method 2 using 5-(2,2-dimethylmorpholino)-2-morpholinopyridin-3-amine (62 mg, 0.213 mmol; described herein), 4-chloro-5-fluoro-3-methyl-2-(pyridin-2-yl)quinoline (58 mg, 0.213 mmol; described herein), 4.0M hydrochloric acid in 1,4-dioxane (50 μL, 0.21 mmol), and NMP (310 μL, 3.2 mmol), and heating in a microwave for 3 h at 160° C. Purification afforded N-(5-(2,2-dimethyl-4-morpholinyl)-2-(4-morpholinyl)-3-pyridinyl)-5-fluoro-3-methyl-2-(2-pyridinyl)-4-quinolinamine as a yellow solid. 1H NMR (400 MHz, chloroform-d) δ ppm 8.70 (1H, d, J=4.7 Hz), 7.86-8.04 (4H, m), 7.54-7.66 (2H, m), 7.38 (1H, ddd, J=6.7, 4.7, 2.0 Hz), 7.19 (1H, dd, J=13.7, 7.8 Hz), 6.45 (1H, d, J=2.3 Hz), 3.93 (4H, t, J=4.3 Hz), 3.78-3.87 (2H, m), 3.02-3.31 (6H, m), 2.88 (2H, s), 2.21 (3H, s) 1.24-1.34 (6H, m). Mass Spectrum (ESI) m/e=529.2 (M+1).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:6]=[C:7]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([NH:17][CH2:18][CH2:19][N:20]([CH2:28][C@@H:29]([C:38]3[CH:43]=[CH:42][CH:41]=[C:40]([Cl:44])[CH:39]=3)[O:30][Si](C(C)(C)C)(C)C)C(OC(C)(C)C)=O)[CH:12]=2)[CH:8]=[CH:9][CH:10]=1)=[O:4].C(OCC)C>Cl.O1CCOCC1>[ClH:44].[ClH:44].[CH3:1][O:2][C:3]([C:5]1[CH:6]=[C:7]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([NH:17][CH2:18][CH2:19][NH:20][CH2:28][C@@H:29]([C:38]3[CH:43]=[CH:42][CH:41]=[C:40]([Cl:44])[CH:39]=3)[OH:30])[CH:12]=2)[CH:8]=[CH:9][CH:10]=1)=[O:4]
Reactant: COC(=O)c1cccc(-c2cccc(NCCN(C[C@H](O[Si](C)(C)C(C)(C)C)c3cccc(Cl)c3)C(=O)OC(C)(C)C)c2)c1
Agent: Cl
Solvent: CCOCC
Solvent: C1COCCO1
Product: COC(=O)c1cccc(-c2cccc(NCCNC[C@H](O)c3cccc(Cl)c3)c2)c1
Reaction time: 0.33 h

Procedure:
A solution of (R)-3′-[[2-[[2-(3-chlorophenyl)-2-[[(tert-butyl)dimethylsilyl]oxy]ethyl][(tert-butoxy)carbonyl]amino]ethyl]amino]-[1,1′-biphenyl]-3-carboxylic acid methyl ester (275 mg) in 4 N hydrochloric acid in dioxane (10 mL) was stirred for 3 days. Diethyl ether was added and the reaction was stirred for 20 minutes. The title compound was collected by suction filtration as a white solid (210 mg);
Reaction SMILES: Br[C:2]1[N:7]=[C:6]([N:8]2[C:16]3[CH:15]=[C:14]([C:17]4[CH:22]=[N:21][CH:20]=[C:19]([CH3:23])[N:18]=4)[N:13]=[CH:12][C:11]=3[CH:10]=[N:9]2)[CH:5]=[CH:4][CH:3]=1.[O:24]=[C:25]1[CH2:30][CH2:29][N:28]([C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[CH2:27][CH2:26]1.CC(C)([O-])C.[Na+].O1CCCC1.C(P(C(C)(C)C)C(C)(C)C)(C)(C)C>C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH3:23][C:19]1[N:18]=[C:17]([C:14]2[N:13]=[CH:12][C:11]3[CH:10]=[N:9][N:8]([C:6]4[N:7]=[C:2]([CH:30]5[C:25](=[O:24])[CH2:26][CH2:27][N:28]([C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[CH2:29]5)[CH:3]=[CH:4][CH:5]=4)[C:16]=3[CH:15]=2)[CH:22]=[N:21][CH:20]=1
Reactant: Cc1cncc(-c2cc3c(cn2)cnn3-c2cccc(Br)n2)n1
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)(C)P(C(C)(C)C)C(C)(C)C
Solvent: C1CCOC1
Product: Cc1cncc(-c2cc3c(cn2)cnn3-c2cccc(C3CN(C(=O)OC(C)(C)C)CCC3=O)n2)n1
Temperature: 48 °C
Yield: 60.6 %

Procedure:
To a solution of 1-(6-bromo-2-pyridyl)-6-(6-methylpyrazin-2-yl)pyrazolo[4,3-c]pyridine (125 mg, 0.340 mmol), tert-butyl 4-oxopiperidine-1-carboxylate (100 mg, 0.51 mmol), palladium acetate (8.0 mg, 0.034 mmol) and sodium tert-butoxide (74 mg, 0.75 mmol) in tetrahydrofuran (8.0 ml, 99 mmol) was added tri-t-butylphosphine (0.020 mL, 0.068 mmol). The mixture was degassed and heat at 48° C. 2 h. The reaction was quenched with water then extract with EtOAc. The organic layers was dried with sodium sulfate, filtered, and concentrated in vacuum. The crude product was purified by flash chromatography (EtOAc/Heptane eluted @75% EtOAc) to give the desired product 100 mg 60% yield. MS (ESI) m/z: 486.1.
Reaction SMILES: Br[CH2:2][C:3]([CH3:5])=[CH2:4].CN(C=O)C.[CH3:11][C:12]1[C:17]([CH3:18])=[CH:16][C:15]([CH3:19])=[CH:14][C:13]=1[OH:20].C(=O)([O-])[O-].[K+].[K+]>O.C(OCC)(=O)C>[CH3:18][C:17]1[CH:16]=[C:15]([CH3:19])[CH:14]=[C:13]([O:20][CH2:4][C:3]([CH3:5])=[CH2:2])[C:12]=1[CH3:11]
Reactant: C=C(C)CBr
Reactant: Cc1cc(C)c(C)c(O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: O
Product: C=C(C)COc1cc(C)cc(C)c1C
Temperature: 80 °C
Reaction time: 15 h
Yield: 96 %

Procedure:
3-bromo-2-methylpropene (29.8 g, 221 mmol) was added to a mixture of DMF (130 mL) containing 2,3,5-trimethylphenol (25.0 g, 184 mmol) and potassium carbonate (50.9 g, 368 mmol), and the resulting mixture was stirred at 80° C. for 15 hours. After cooled to room temperature, the reaction solution was distributed using ethyl acetate and water. The organic layer was washed with saturated saline, and then dried using anhydrous magnesium sulfate. The solvent was removed under reduced pressure, and the obtained residue was purified by silica gel column chromatography (hexane-ethyl acetate 50:1 to 9:1) to give 33.6 g of the title compound (yield: 96%) as an oily product.
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[S:3]([O:6]S(C(F)(F)F)(=O)=O)(=[O:5])=[O:4].[CH3:16][O:17][C:18]1[C:26]2[O:25][CH2:24][C:23](=O)[C:22]=2[CH:21]=[CH:20][CH:19]=1.C(N(CC)CC)C.C([O-])(O)=O.[Na+]>ClCCl>[F:1][C:2]([F:15])([F:14])[S:3]([O:6][C:23]1[C:22]2[CH:21]=[CH:20][CH:19]=[C:18]([O:17][CH3:16])[C:26]=2[O:25][CH:24]=1)(=[O:5])=[O:4]
Reactant: COc1cccc2c1OCC2=O
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1cccc2c(OS(=O)(=O)C(F)(F)F)coc12
Temperature: -20 °C
Reaction time: 2 h
Yield: 71.2 %

Procedure:
Trifluoromethanesulfonic anhydride (4.6 g, 16.3 mmol) was added dropwise to a solution of 7-methoxybenzofuran-3(2H)-one (1.8 g, 10.9 mmol), triethylamine (2.2 g, 21.8 mmol), and dichloromethane (40 mL) at −20° C. The resulting mixture was stirred at −20° C. for 2 h. The reaction mixture was neutralized with saturated aqueous NaHCO3 (22 mL). The organic layer was separated, washed with water (40 mL) and brine (40 mL), dried over Na2SO4, and concentrated in vacuo. The residue was purified on a silica gel column using petroleum ether to afford the title compound as yellow oil (2.3 g, yield 71%). 1H NMR (DMSO-d6, 400 MHz): δ 8.67 (s, 1H), 7.36 (t, 1H), 7.21 (d, 1H), 7.20 (d, 1H), 3.96 (s, 3H).
Reaction SMILES: [H-].[Na+].[CH2:3]([O:10][C:11]([NH:13][CH:14]1[N:20]=[C:19]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=2[F:27])[C:18]2[CH:28]=[CH:29][CH:30]=[CH:31][C:17]=2[NH:16][C:15]1=[O:32])=[O:12])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.Br[CH2:34][C:35]([O:37][CH3:38])=[O:36].C(O)(=O)C>CN(C)C=O.O>[CH2:3]([O:10][C:11]([NH:13][CH:14]1[N:20]=[C:19]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=2[F:27])[C:18]2[CH:28]=[CH:29][CH:30]=[CH:31][C:17]=2[N:16]([CH2:34][C:35]([O:37][CH3:38])=[O:36])[C:15]1=[O:32])=[O:12])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: O=C(NC1N=C(c2ccccc2F)c2ccccc2NC1=O)OCc1ccccc1
Reactant: COC(=O)CBr
Agent: [H-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)CN1C(=O)C(NC(=O)OCc2ccccc2)N=C(c2ccccc2F)c2ccccc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 106.8 %

Procedure:
To a suspension of sodium hydride (0.294g of a 60 % dispersion in mineral oil (7.36 mmol) in N,N-dimethylformamide (20 ml) was added slowly (3RS)-3-benzyloxycarbonylamino-2,3-dihydro-5-(2-fluorophenyl)-1H-1,4-benzodiazepin-2-one (2.70 g) under cooling in an ice-bath. The mixture was stirred at the same temperature for 0.5 hour and at ambient temperature for 1 hour. To the mixture was added dropwise a solution of methyl bromoacetate (1.13 g) in N,N-dimethylformamido (5 ml) under cooling in an ice-bath. The mixture was stirred at ambient temperature overnight. To the reaction mixture was added acetic acid (1 ml) and stirred for 0.5 hour. The resultant was poured into water (100 ml) and extracted with ethyl acetate. The organic layer was dried over sodium sulfate, filtered and concentrated in vacuo to afford (3RS)-3-benzyloxycarbonylamino-2,3-dihydro-5-(2-fluoro-phenyl)-1-(methoxycarbonylmethyl)-1H-1,4-benzodiazepin-2-one (3.4 g).
Reaction SMILES: [CH3:1][O:2][C:3]1([O:18][CH3:19])[CH2:8][CH2:7][C:6]([C:14](OC)=[O:15])([C:9](OCC)=[O:10])[CH2:5][CH2:4]1.[H-].[H-].[H-].[H-].[Li+].[Al+3]>CCOCC.C1COCC1>[CH3:19][O:18][C:3]1([O:2][CH3:1])[CH2:4][CH2:5][C:6]([CH2:9][OH:10])([CH2:14][OH:15])[CH2:7][CH2:8]1
Reactant: CCOC(=O)C1(C(=O)OC)CCC(OC)(OC)CC1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Solvent: C1CCOC1
Product: COC1(OC)CCC(CO)(CO)CC1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 102.9 %

Procedure:
To a solution of 1-ethyl 1-methyl 4,4-dimethoxycyclohexane-1,1-dicarboxylate (4.7 g, 17.13 mmol) in dry Et2O (250 mL) at 0° C. was added LiAlH4 (17.1 mL of a 2 M solution in THF; 34.3 mmol) dropwise over 15 min. The reaction mixture was stirred at 0° C. for 15 min, then warmed to rt and stirred for 1 h. It was then cooled to 0° C. and carefully quenched with aqueous NaOH (7.3 mL of a 1N solution; 7.3 mmol). The mixture was filtered and the filtrate was concentrated in vacuo to afford the title compound (3.6 g, 100% yield) as a semisolid. 1H NMR (500 MHz, CDCl3) δ 3.65 (d, J=4.4 Hz, 4H), 3.20 (s, 6H), 2.42 (t, J=4.6 Hz, 2H), 1.67 (dd, J=7.3, 4.9 Hz, 4H), 1.53-1.41 (m, 4H).
Reaction SMILES: [F:1][C:2]1[C:29]([O:30][CH3:31])=[CH:28][C:5]2[N:6]=[C:7]([S:9][CH2:10][C:11]3[CH:12]=[CH:13][CH:14]=[C:15]4[C:20]=3[N:19]([CH2:21][CH3:22])[CH2:18][CH2:17][CH:16]4[CH2:23][O:24]C(=O)C)[NH:8][C:4]=2[CH:3]=1.C(=O)([O-])[O-].[K+].[K+]>CO>[F:1][C:2]1[C:29]([O:30][CH3:31])=[CH:28][C:5]2[N:6]=[C:7]([S:9][CH2:10][C:11]3[CH:12]=[CH:13][CH:14]=[C:15]4[C:20]=3[N:19]([CH2:21][CH3:22])[CH2:18][CH2:17][CH:16]4[CH2:23][OH:24])[NH:8][C:4]=2[CH:3]=1
Reactant: CCN1CCC(COC(C)=O)c2cccc(CSc3nc4cc(OC)c(F)cc4[nH]3)c21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: CCN1CCC(CO)c2cccc(CSc3nc4cc(OC)c(F)cc4[nH]3)c21
Temperature: 25 °C
Reaction time: 1 h
Yield: 75.4 %

Procedure:
To a solution of 8-(5-fluoro-6-methoxy-2-benzimidazolyl)thiomethyl-1-ethyl-4-acetyloxymethyl-1,2,3,4-tetrahydroquinoline (2.55 g) in methanol (20 ml) was added a saturated aqueous solution of potassium carbonate (10 ml) and the mixture was stirred for 1 hour at room temperature. The reaction mixture was extracted with dichloromethane and dried. The solvent was distilled off to give 8-(5-fluoro-6-methoxy-2-benzimidazolyl)thiomethyl-1-ethyl-4-hydroxymethyl-1,2,3,4-tetrahydroquinoline (1.74 g).
Reaction SMILES: [F:1][C:2]([F:23])([F:22])[C:3]1[CH:4]=[C:5]([CH:19]=[CH:20][CH:21]=1)[C:6]([NH:8][C:9]1[CH:10]=[C:11]([CH:16]=[CH:17][CH:18]=1)[C:12]([NH:14][NH2:15])=[O:13])=[O:7].[Cl:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[N:31]=[C:32]=[S:33]>O1CCCC1>[Cl:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[NH:31][C:32](=[S:33])[NH:15][NH:14][C:12](=[O:13])[C:11]1[CH:16]=[CH:17][CH:18]=[C:9]([NH:8][C:6](=[O:7])[C:5]2[CH:19]=[CH:20][CH:21]=[C:3]([C:2]([F:22])([F:23])[F:1])[CH:4]=2)[CH:10]=1
Reactant: NNC(=O)c1cccc(NC(=O)c2cccc(C(F)(F)F)c2)c1
Reactant: S=C=Nc1ccccc1Cl
Solvent: C1CCOC1
Product: O=C(NNC(=S)Nc1ccccc1Cl)c1cccc(NC(=O)c2cccc(C(F)(F)F)c2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 71 %

Procedure:
To 200 mg (0.62 mmol) of 3-(3-trifluoromethylbenzamido)benzhydrazide in 2.5 mL of tetrahydrofuran was added 157 mg (121 μL, 0.93 mmol) of 2-chlorophenyl isothiocyanate. The reaction was stirred at room temperature overnight. After concentration by rotoevaporation, the residue was purified by preparative HPLC to give 219 mg (0.44 mmol, 72% yield) of 4-(2-chlorophenyl)-1-[3-(3-trifluoromethylbenzamido)-benzoyl]thiosemicarbazide. 1H NMR (CDCl3): δ7.28 (d of t, 1H), 7.36 (d of t, 1H), 7.49 (d of d, 1H), 7.55 (t, 1H), 7.69 (d, 2H), 7.74 (t, 1H), 7.94 (d of t, 2H), 8.21 (d, 1H), 8.27 (s, 1H), 8.36 (s, 1H), and 9.09 ppm (s, 1H). MS m/z: 493.0 (M+H).