Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O.[OH:34][C:35]1[CH:42]=[CH:41][C:38]([C:39]#[N:40])=[CH:37][CH:36]=1.[CH3:43][C:44]([CH3:51])([CH2:49]O)[C:45]([O:47][CH3:48])=[O:46]>C1(C)C=CC=CC=1>[CH3:48][O:47][C:45](=[O:46])[C:44]([CH3:51])([CH3:49])[CH2:43][O:34][C:35]1[CH:42]=[CH:41][C:38]([C:39]#[N:40])=[CH:37][CH:36]=1
Reactant: COC(=O)C(C)(C)CO
Reactant: N#Cc1ccc(O)cc1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: COC(=O)C(C)(C)COc1ccc(C#N)cc1
Temperature: 80 °C
Reaction time: 0.5 h

Procedure:
A mixture of 2.65 g (10.1 mmol) of triphenylphosphine and 20 ml of toluene is prepared and 2 ml (10.2 mmol) of DIAD (diisopropyl azodicarboxylate) are added at 0° C. The solution obtained is added to a solution of 1 g (8.4 mmol) of 4-hydroxybenzonitrile and 1.30 ml (10.2 mmol) of methyl 2,2-dimethyl-3--hydroxy-propanoate in 10 ml of toluene at 0° C. The reaction mixture is subsequently stirred for 30 min at 80° C. and then concentrated under reduced pressure. The crude product is purified by chromatography on silica gel using toluene as the eluent to give the expected compound in the form of a colorless oil (yield=89%).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]2[C:10]3[CH2:16][N:15]([C:17]([N:19]4[CH2:24][C:23]([CH3:26])([CH3:25])[N:22]([CH3:27])[CH2:21][C@@H:20]4[CH3:28])=[O:18])[C:14]([CH3:30])([CH3:29])[C:11]=3[NH:12][N:13]=2)[C:5]([F:31])=[CH:4][N:3]=1.[CH2:32](B1OC(C)(C)C(C)(C)O1)[CH:33]=[CH2:34].C(=O)([O-])[O-].[Cs+].[Cs+].O>[Pd].C1COCC1>[F:31][C:5]1[C:6]([NH:8][C:9]2[C:10]3[CH2:16][N:15]([C:17]([N:19]4[CH2:24][C:23]([CH3:26])([CH3:25])[N:22]([CH3:27])[CH2:21][C@@H:20]4[CH3:28])=[O:18])[C:14]([CH3:30])([CH3:29])[C:11]=3[NH:12][N:13]=2)=[N:7][C:2]([CH2:32][CH2:33][CH3:34])=[N:3][CH:4]=1
Reactant: C=CCB1OC(C)(C)C(C)(C)O1
Reactant: C[C@H]1CN(C)C(C)(C)CN1C(=O)N1Cc2c(Nc3nc(Cl)ncc3F)n[nH]c2C1(C)C
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: C1CCOC1
Product: CCCc1ncc(F)c(Nc2n[nH]c3c2CN(C(=O)N2CC(C)(C)N(C)C[C@@H]2C)C3(C)C)n1
Temperature: 100 °C
Reaction time: 15 h

Procedure:
To a pressure vessel was added [3-(2-Chloro-5-fluoro-pyrimidin-4-ylamino)-6,6-dimethyl-4,6-dihydro-1H-pyrrolo[3,4-c]pyrazol-5-yl]-((S)-2,4,5,5-tetramethyl-piperazin-1-yl)-methanone (0.150 g, 0.330 mmol), 2-allyl-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (1.12 g, 6.66 mmol), cesium carbonate (0.543 g, 1.66 mmol), dichloro[1,1-bis(diphenylphosphino)ferrocene]palladium(II) dichloromethane adduct (0.0408 g, 0.0498 mmol), H2O (0.3 mL), and THF (3 mL). The suspension was purged with argon for 2 min, then stirred at 100° C. for 15 h. The cooled solution was filtered to remove undissolved solids and the volatiles removed in vacuo. The residue was redissolved in MeOH (5 mL) and 10% palladium on carbon (0.0400 g, 0.380 mmol) was added. The suspension was evacuated and backfilled with hydrogen for 3 times and allowed to stir for 15 h under hydrogen. The suspension was filtered through Celite, the filter cake washed with CH2Cl2, and the filtrate concentrated. Preparative HPLC provided the desired product I1 as a white solid (0.025 g, 14%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([O:8][C:9]2[CH:14]=[CH:13][N:12]=[C:11]([NH:15][C:16]([N:18]3[CH2:21][CH:20]([OH:22])[CH2:19]3)=[O:17])[CH:10]=2)[C:5]([F:23])=[CH:4][C:3]=1[NH:24][C:25]([C:27]1([C:30]([NH:32][C:33]2[CH:38]=[CH:37][C:36]([F:39])=[CH:35][CH:34]=2)=[O:31])[CH2:29][CH2:28]1)=[O:26].Cl.[CH3:41][N:42]([CH3:47])[CH2:43][C:44](O)=[O:45].C(N(CC)CC)C.CN([P+](ON1N=NC2C=CC=CC1=2)(N(C)C)N(C)C)C.F[P-](F)(F)(F)(F)F>CN(C)C=O>[F:1][C:2]1[CH:7]=[C:6]([O:8][C:9]2[CH:14]=[CH:13][N:12]=[C:11]([NH:15][C:16]([N:18]3[CH2:19][CH:20]([O:22][C:44](=[O:45])[CH2:43][N:42]([CH3:47])[CH3:41])[CH2:21]3)=[O:17])[CH:10]=2)[C:5]([F:23])=[CH:4][C:3]=1[NH:24][C:25]([C:27]1([C:30]([NH:32][C:33]2[CH:34]=[CH:35][C:36]([F:39])=[CH:37][CH:38]=2)=[O:31])[CH2:28][CH2:29]1)=[O:26]
Reactant: O=C(Nc1cc(Oc2cc(F)c(NC(=O)C3(C(=O)Nc4ccc(F)cc4)CC3)cc2F)ccn1)N1CC(O)C1
Reactant: CN(C)CC(=O)O
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CN(C)CC(=O)OC1CN(C(=O)Nc2cc(Oc3cc(F)c(NC(=O)C4(C(=O)Nc5ccc(F)cc5)CC4)cc3F)ccn2)C1
Reaction time: 8 h
Yield: 46.9 %

Procedure:
N-{2,5-Difluoro-4-[(2-{[(3-hydroxyazetidin-1-yl)carbonyl]amino}pyridin-4-yl)oxy]phenyl}-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide (38.9 mg) was dissolved in N,N-dimethylformamide (1.0 ml) under a nitrogen atmosphere, and N,N-dimethylglycine hydrochloride (20 mg), triethylamine (0.050 ml) and BOP reagent (63.5 mg) were added at room temperature, followed by stirring overnight. N,N-Dimethylglycine hydrochloride (20 mg), triethylamine (0.050 ml) and BOP reagent (63.5 mg) were added again at room temperature, and the reaction mixture was stirred for 5 hr. The reaction mixture was partitioned between ethyl acetate and water. The organic layer was separated, washed with a saturated aqueous solution of sodium hydrogencarbonate (twice) and brine, dried over anhydrous sodium sulfate. The solvent was concentrated under reduced pressure. The resultant residue was purified by silica gel column chromatography (Fuji Silysia NH, eluent; ethyl acetate), and fractions containing the target compound were concentrated under reduced pressure. To the resultant residue was added tert-butyl methyl ether (1 ml)—heptane (2 ml) to precipitate a solid. The solid was collected by filtration and dried under aeration to provide the titled compound as white powder (21.1 mg, 47%).
Reaction SMILES: [SH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.[H-].[Na+].[F:16][C:17](I)([F:25])[C:18]([F:24])([F:23])[C:19]([F:22])([F:21])[F:20]>CN(C=O)C>[F:23][C:18]([F:24])([C:19]([F:22])([F:21])[F:20])[C:17]([F:25])([F:16])[S:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: FC(F)(F)C(F)(F)C(F)(F)I
Reactant: Sc1ccccc1-c1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: FC(F)(F)C(F)(F)C(F)(F)Sc1ccccc1-c1ccccc1
Yield: 81.4 %

Procedure:
To a solution composed of 20 ml of DMF and 2.24 g (12 mmol) of 2-mercaptobiphenyl was added 481 mg (12 mmol) of sodium hydride (60% in oil) little by little under ice cooling and stirring. Then, 1.73 ml (12 mmol) of perfluoropropyl iodide was added dropwise. The temperature of the mixture was slowly elevated to room temperature, and the mixture was stirred for 2 days. The white precipitate formed in the reaction solution was removed by filtration. Water was addd to the filtrate, and the mixture was extracted with hexane. The organic layer was washed with water, dried over anhydrous magnesium sulfate, and filtered. The filtrate was concentrated under reduced pressure to give a brown oil. It was purified by silica gel column chromatography (ethyl acetate:hexane=1:30) to give 3.46 g (87.3%) of 2-(heptafluoropropylthio)biphenyl as a colorless oil. The properties of the product were as shown below.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:10]=[C:11]3[C:16]4=[C:17]([C@@H:19]5[CH2:24][NH:23][CH2:22][CH2:21][C@@H:20]5[N:15]4[CH2:14][CH2:13][CH2:12]3)[CH:18]=2)=[C:5]([C:25]([F:28])([F:27])[F:26])[CH:4]=1.[BH4-].[Na+].[C:31](O)(=O)[CH3:32]>>[CH2:31]([N:23]1[CH2:22][CH2:21][C@@H:20]2[N:15]3[C:16]4[C:11](=[CH:10][C:9]([C:6]5[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][C:5]=5[C:25]([F:28])([F:26])[F:27])=[CH:18][C:17]=4[C@@H:19]2[CH2:24]1)[CH2:12][CH2:13][CH2:14]3)[CH3:32]
Reactant: COc1ccc(-c2cc3c4c(c2)[C@@H]2CNCC[C@@H]2N4CCC3)c(C(F)(F)F)c1
Reactant: CC(=O)O
Agent: [BH4-]
Agent: [Na+]
Product: CCN1CC[C@H]2[C@@H](C1)c1cc(-c3ccc(OC)cc3C(F)(F)F)cc3c1N2CCC3
Temperature: 55 °C
Reaction time: 15 h
Yield: 81 %

Procedure:
To a solution of (7aS,11aR)-2-[4-methoxy-2-(trifluoromethyl)phenyl]-5,6,7a,8,9,10,11,11a-octahydro-4H-pyrido[3′,4′:4,5]pyrrolo[3,2,1-ij]quinoline (30 mg, 0.077 mmol) in acetic acid (0.28 mL) was added NaBH4 (30 mg, 0.80 mmol) in 2 portion in 10 min interval at 55° C. The reaction mixture was stirred for 15 h at 55° C. then quenched by addition of H2O. The aqueous solution was basified with 50% NaOH then extracted with CHCl3. The combined organic solution was dried over MgSO4, concentrated in vacuo. The residue was chromatographed (silica gel; CHCl3:MeOH 99:1-98:2) to give the title compound as a yellow oil (26 mg, 81%). 1H NMR (CDCl3, 300 MHz) δ1.21-1.35 (m, 3H), 2.05-2.30 (m, 5H), 2.53-2.78 (m, 6H), 2.98-3.07 (br, 1H), 3.08-3.18 (br, 1H), 3.27-3.42 (m, 2H), 3.43-3.57 (br, 1H), 3.88 (s, 3H), 6.83 (s, 1H), 6.86 (s, 1H), 7.04 (dd, J=8.8, 2.9 Hz, 1H), 7.20-7.26 (m, 2H) ppm. MS (CI, NH3): 417.1 (base, M+H).
Reaction SMILES: [N+:1]([C:4]1[C:9]([O:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[CH2:18][N:19]2C(=O)C3=CC=CC=C3C2=O)=[CH:8][CH:7]=[CH:6][N:5]=1)([O-:3])=[O:2].O.NN>C(O)C>[NH2:19][CH2:18][C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=1[CH2:11][O:10][C:9]1[C:4]([N+:1]([O-:3])=[O:2])=[N:5][CH:6]=[CH:7][CH:8]=1
Reactant: O=C1c2ccccc2C(=O)N1Cc1ccccc1COc1cccnc1[N+](=O)[O-]
Agent: NN
Solvent: CCO
Solvent: O
Product: NCc1ccccc1COc1cccnc1[N+](=O)[O-]
Yield: 97 %

Procedure:
A solution of 2-nitro-3-(2-phthalimidomethylbenzyloxy)pyridine (2.71 g) and hydrazine hydrate (1.05 g) in ethanol (54 ml) was refluxed for 1.5 hours. After cooling, precipitates were filtered off, and the filtrate was evaporated under reduced pressure. The resultant residue was dissolved in diethyl ether and insoluble materials were filtered off. The solvent was evaporated under reduced pressure to give 3-(2-aminomethylbenzyloxy)-2-nitropyridine (1.75 g).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH:4]([NH:6][C:7]1[CH:8]=[N:9][C:10]([Cl:13])=[CH:11][CH:12]=1)[CH3:5].CS[C:16](SC)=[CH:17][N+:18]([O-:20])=[O:19]>C(O)C>[N+:18]([CH:17]=[C:16]1[NH:1][CH2:2][CH2:3][CH:4]([CH3:5])[N:6]1[C:7]1[CH:8]=[N:9][C:10]([Cl:13])=[CH:11][CH:12]=1)([O-:20])=[O:19]
Reactant: CSC(=C[N+](=O)[O-])SC
Reactant: CC(CCN)Nc1ccc(Cl)nc1
Solvent: CCO
Product: CC1CCNC(=C[N+](=O)[O-])N1c1ccc(Cl)nc1
Temperature: 20 °C

Procedure:
A mixture of 1-amino-3-[N-(6-chloro-3-pyridyl)amino]butane (0.94 g, 0.0047 mol) (ex Example 6), 1,1-bis(methylthio)-2-nitroethene (0.78 g, 0.0047 mol) and ethanol (100 ml) was heated under reflux for 24 hours. The resulting mixture was cooled to ambient temperature (20° C.) and filtered to isolate the product 2-nitromethylene-1-(6-chloro-3-pyridyl)-6methylhexahydropyrimidine as a white solid in a yield of 0.3 g (25%), m.p. 184.5° C.
Reaction SMILES: [CH2:1]([C:3]1[S:11][C:6]2=[N:7][CH:8]=[CH:9][CH:10]=[C:5]2[CH:4]=1)[CH3:2].[Cl:12][S:13](O)(=[O:15])=[O:14].P(Cl)(Cl)(Cl)=O.P(Cl)(Cl)(Cl)(Cl)Cl>C(Cl)Cl>[CH2:1]([C:3]1[S:11][C:6]2=[N:7][CH:8]=[CH:9][CH:10]=[C:5]2[C:4]=1[S:13]([Cl:12])(=[O:15])=[O:14])[CH3:2]
Reactant: O=S(=O)(O)Cl
Reactant: CCc1cc2cccnc2s1
Agent: ClP(Cl)(Cl)(Cl)Cl
Solvent: O=P(Cl)(Cl)Cl
Solvent: ClCCl
Product: CCc1sc2ncccc2c1S(=O)(=O)Cl
Temperature: 25 °C
Reaction time: 20 h
Yield: 57.3 %

Procedure:
To a solution of 2-ethylthieno[2,3-b]pyridine (0.43 g, 2.6 mmoles) in CH2Cl2 (10 ml) at -78° C. was added chlorosulfonic acid (0.9 ml, 13 mmoles). The reaction was warmed to ambient temperature over a 1 hr. period, then stirred an additional 20 hrs., followed by the addition of phosphorus oxychloride (1.7 ml, 18 mmoles) and phosphorus pentachloride (0.82 g, 4.0 mmoles). One hour later the reaction mixture was added to ice (100 ml) and extracted with EtOAc (75 ml), then washed with sat. NaHCO3 (200 ml). The organic phase was dried (MgSO4), filtered and concentrated to collect a brown oil. Flash chromatography (10% EtOAc/hexanes) provided 0.39 g (56%) of the title compound as a light yellow oil.
Reaction SMILES: [CH3:1][CH:2](O)[C:3]#[CH:4].[O:6]([C:13]([NH:15][O:16][C:17]([O:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=[O:18])=[O:14])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CCOC(/N=N/C(OCC)=O)=O>C1COCC1>[O:6]([C:13]([N:15]([CH:3]([C:2]#[CH:1])[CH3:4])[O:16][C:17]([O:19][C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1)=[O:18])=[O:14])[C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1
Reactant: O=C(NOC(=O)Oc1ccccc1)Oc1ccccc1
Reactant: C#CC(C)O
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: C#CC(C)N(OC(=O)Oc1ccccc1)C(=O)Oc1ccccc1
Reaction time: 2 h
Yield: 88.1 %

Procedure:
To a 0° C. solution in THF (200 mL) of 3-butyn-2-ol (3.00 g, 42.9 mmol), N,O-bis(phenoxycarbonyl)hydroxylamine (11.7 g, 42.9 mmol), prepared according to the method of Stewart and Brooks, J. Org. Chem. 1992, 57, 5020, and triphenylphosphine (11.7 g, 42.9 mmol), was added dropwise diethylazodicarboxylate (7.40 g, 42.8 mmol). The reaction mixture was stirred for 2 hours at 0°-5° C. and then was concentrated almost to dryness. The residue was diluted with ethyl acetate, the solids were filtered off, and the filtrate was concentrated in vacuo. Chromatography on silica gel (5% ethyl acetate, pentane) provided N,O-bis(phenoxycarbonyl)-N-(3-butyn-2-yl)hydroxylamine (12.3 g, 88%).
Reaction SMILES: [CH2:1]([C:8]1[CH:9]=[N:10][C:11]2[C:16]([C:17]=1[C:18]1[CH:19]=[C:20]([NH2:24])[CH:21]=[CH:22][CH:23]=1)=[CH:15][CH:14]=[CH:13][C:12]=2[C:25]([F:28])([F:27])[F:26])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:29]([O:36][C:37]1[C:44]([O:45][CH3:46])=[CH:43][CH:42]=[CH:41][C:38]=1[CH:39]=O)[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1>>[CH2:29]([O:36][C:37]1[C:44]([O:45][CH3:46])=[CH:43][CH:42]=[CH:41][C:38]=1[CH2:39][NH:24][C:20]1[CH:21]=[CH:22][CH:23]=[C:18]([C:17]2[C:16]3[C:11](=[C:12]([C:25]([F:28])([F:26])[F:27])[CH:13]=[CH:14][CH:15]=3)[N:10]=[CH:9][C:8]=2[CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[CH:19]=1)[C:30]1[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=1
Reactant: Nc1cccc(-c2c(Cc3ccccc3)cnc3c(C(F)(F)F)cccc23)c1
Reactant: COc1cccc(C=O)c1OCc1ccccc1
Product: COc1cccc(CNc2cccc(-c3c(Cc4ccccc4)cnc4c(C(F)(F)F)cccc34)c2)c1OCc1ccccc1

Procedure:
The title compound was prepared from {3-[3-benzyl-8-(trifluoromethyl)quinolin-4-yl]phenyl}amine and 2-benzyloxy-3-methoxy-benzaldehyde according to the procedure of Example 66. MS (ESI) m/z 605.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([NH:11][CH:12]3[CH2:17][CH2:16][O:15][CH2:14][CH2:13]3)[CH:10]=1)[NH:7][C:6]([C:18]1[S:19][CH2:20][C@@H:21]([CH2:23][CH2:24][N:25]3[CH2:30][CH2:29][CH2:28][CH:27]([C:31](O)=[O:32])[CH2:26]3)[N:22]=1)=[CH:5]2.[CH3:34][NH:35][CH3:36].C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.C(=O)(O)[O-].[Na+]>CN(C)C=O>[CH3:34][N:35]([CH3:36])[C:31]([CH:27]1[CH2:28][CH2:29][CH2:30][N:25]([CH2:24][CH2:23][C@@H:21]2[CH2:20][S:19][C:18]([C:6]3[NH:7][C:8]4[C:4]([CH:5]=3)=[CH:3][C:2]([Cl:1])=[CH:10][C:9]=4[NH:11][CH:12]3[CH2:17][CH2:16][O:15][CH2:14][CH2:13]3)=[N:22]2)[CH2:26]1)=[O:32]
Reactant: O=C(O)C1CCCN(CC[C@@H]2CSC(c3cc4cc(Cl)cc(NC5CCOCC5)c4[nH]3)=N2)C1
Reactant: CNC
Agent: O=C([O-])O
Agent: On1nnc2ccccc21
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: ClCCCl
Product: CN(C)C(=O)C1CCCN(CC[C@@H]2CSC(c3cc4cc(Cl)cc(NC5CCOCC5)c4[nH]3)=N2)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 19.3 %

Procedure:
The compound (84 mg, 0.18 mmol) prepared in Example 112 was dissolved in N,N-dimethylformamide (4 ml). Dimethylamine (0.13 ml, 2M in THF, 0.27 mmol), EDC (58 mg, 0.30 mmol) and HOBT (48 mg, 0.35 mmol) were added thereto, and the mixture was stirred for 8 h at room temperature. After completion of the reaction, saturated sodium bicarbonate solution was added. The mixture was extracted with ethyl acetate, dried over anhydrous magnesium sulfate, and filtered. The filtrate was distilled under reduced pressure, and concentrated. The residue was purified by column chromatography to give the title compound (18 mg, Yield 20%).
Reaction SMILES: [CH:1]([NH2:4])([CH3:3])[CH3:2].CCN(C(C)C)C(C)C.[CH3:14][C:15]([C:19]1[N:23]([CH2:24][CH:25]2[CH2:30][CH2:29][O:28][CH2:27][CH2:26]2)[C:22]2[CH:31]=[CH:32][C:33]([S:35]([N:38]3[CH:42]=[C:41]([C:43](O)=[O:44])[CH:40]=[N:39]3)(=[O:37])=[O:36])=[CH:34][C:21]=2[N:20]=1)([CH3:18])[CH2:16][CH3:17].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[CH3:14][C:15]([C:19]1[N:23]([CH2:24][CH:25]2[CH2:30][CH2:29][O:28][CH2:27][CH2:26]2)[C:22]2[CH:31]=[CH:32][C:33]([S:35]([N:38]3[CH:42]=[C:41]([C:43]([NH:4][CH:1]([CH3:3])[CH3:2])=[O:44])[CH:40]=[N:39]3)(=[O:37])=[O:36])=[CH:34][C:21]=2[N:20]=1)([CH3:18])[CH2:16][CH3:17]
Reactant: CCC(C)(C)c1nc2cc(S(=O)(=O)n3cc(C(=O)O)cn3)ccc2n1CC1CCOCC1
Reactant: CC(C)N
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: CCC(C)(C)c1nc2cc(S(=O)(=O)n3cc(C(=O)NC(C)C)cn3)ccc2n1CC1CCOCC1
Yield: 74.2 %

Procedure:
Following the same procedure in Example 24, Step A, using isopropylamine (21 mg, 31 uL, 0.36 mmol), DIPEA (104 uL, 77 mg, 0.59 mmol), 1-{[2-(1,1-dimethylpropyl)-1-(tetrahydro-2H-pyran-4-ylmethyl)-1H-benzimidazol-5-yl]sulfonyl}-1H-pyrazole-4-carboxylic acid (0.18 mmol) and HATU (109 mg, 0.29 mmol) in DMF (3 mL). The crude product was purified by MPLC using Hex/EtOAc (1:2) on silica gel to give 67 mg (74%) of a white solid as the title compound. 1H NMR (400 MHz, METHANOL-D4) δ 0.79 (t, J=7.42 Hz, 3 H), 1.20 (d, J=6.64 Hz, 6 H), 1.42-1.58 (m, 4 H), 1.61 (s, 6 H), 1.97 (q, J=7.42 Hz, 2 H), 2.22-2.41 (m, 1 H), 3.26-3.37 (m, 2 H), 3.87-3.96 (m, 2 H), 4.06-4.19 (m, 1 H), 4.43 (d, J=7.62 Hz, 2 H), 7.95 (d, J=8.8 Hz, 1 H), 7.98-8.03 (dd, J=9.0, 2.0 Hz, 1 H), 8.07 (s, 1 H), 8.36 (d, J=1.76 Hz, 1 H), 8.79 (s, 1 H); MS (ESI) (M+H)+=502.0; Anal. Calcd for C25H35N5O4S+110 TFA+0.6H2O (626.48): C, 51.76; H, 5.99; N, 11.18. Found: C, 51.77; H, 5.96; N, 11.27.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][C:3]=1[C:10]1[CH:15]=[CH:14][C:13]([S:16]CC2C=CC(OC)=CC=2)=[CH:12][C:11]=1[CH2:26][C:27]([CH3:30])([CH3:29])[CH3:28].C1(OC)C=CC=CC=1.[OH-].[Na+]>FC(F)(F)C(O)=O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][C:3]=1[C:10]1[CH:15]=[CH:14][C:13]([SH:16])=[CH:12][C:11]=1[CH2:26][C:27]([CH3:30])([CH3:29])[CH3:28]
Reactant: COc1ccc(CSc2ccc(-c3cc(OC)ccc3F)c(CC(C)(C)C)c2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: COc1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: COc1ccc(F)c(-c2ccc(S)cc2CC(C)(C)C)c1
Temperature: 90 °C
Reaction time: 8 h
Yield: 76.2 %

Procedure:
To a solution of (2′-fluoro-5′-methoxy-2-neopentyl-[1,1′-biphenyl]-4-yl)(4-methoxybenzyl)sulfane (1.68 g) in trifluoroacetic acid (6.6 mL) was added anisole (2.15 mL) at room temperature, and the mixture was stirred at 90° C. for 8 hr. The reaction mixture was cooled to 0° C., neutralized with 8N aqueous sodium hydroxide solution, and extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography (NH, ethyl acetate/hexane) to give the title compound (918 mg) as a pale-yellow oil.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[C:17]([CH3:19])([CH3:18])[CH2:16][C:15]3[C:10](=[CH:11][CH:12]=[C:13]([C:20]([OH:22])=[O:21])[CH:14]=3)[NH:9]2)=[CH:4][CH:3]=1.[C:23]1([S:29](Cl)(=[O:31])=[O:30])[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>N1C=CC=CC=1>[CH3:19][C:17]1([CH3:18])[CH2:16][C:15]2[C:10](=[CH:11][CH:12]=[C:13]([C:20]([OH:22])=[O:21])[CH:14]=2)[NH:9][CH:8]1[C:5]1[CH:4]=[CH:3][C:2]([NH:1][S:29]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)(=[O:31])=[O:30])=[CH:7][CH:6]=1
Reactant: CC1(C)Cc2cc(C(=O)O)ccc2NC1c1ccc(N)cc1
Reactant: O=S(=O)(Cl)c1ccccc1
Solvent: c1ccncc1
Product: CC1(C)Cc2cc(C(=O)O)ccc2NC1c1ccc(NS(=O)(=O)c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 54.6 %

Procedure:
To a solution of 2-(4-aminophenyl)-3,3-dimethyl-1,2,3,4-tetrahydroquinoline-6-carboxylic acid (100 mg, 0.34 mmol) in pyridine (5 mL) was added benzenesulfonyl chloride (0.05 mL, 0.38 mmol) via syringe with ice cooling. Upon completion of the addition, the resultant mixture was allowed to warm back to room temperature and stir for 24 h. LC-MS showed the reaction was complete. Pyridine was removed in vacuo and the residue was purified by preparative thin layer chromatography to afford 81 mg of 3,3-dimethyl-2-(4-(phenylsulfonamido)phenyl)-1,2,3,4-tetrahydroquinoline-6-carboxylic acid as a white solid. Yield: 65%; MS (ESI+APCI) M+1=437.54.
Reaction SMILES: [F:1][C:2]1[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][CH:5]=[CH:4][C:3]=1[NH2:12].C(=O)(O)[O-].[Na+].[C:18](Cl)(Cl)=[S:19]>ClCCl.O>[F:1][C:2]1[C:7]([C:8]([F:10])([F:11])[F:9])=[CH:6][CH:5]=[CH:4][C:3]=1[N:12]=[C:18]=[S:19]
Reactant: S=C(Cl)Cl
Reactant: Nc1cccc(C(F)(F)F)c1F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Product: Fc1c(N=C=S)cccc1C(F)(F)F
Reaction time: 2 h
Yield: 89.1 %

Procedure:
To a two phase solution of 2-fluoro-3-trifluoromethyl-phenylamine (2 g, 11.17 mmole) in dichloromethane (40 ml) and sodium bicarbonate (6.57 g, 78.19 mmole) in water (30 ml) at 0° C. was added dropwise a solution of thiophosgene (1.28 g, 11.17 mmole) in dichloromethane (10 ml). After 2 hrs, the organic layer was separated, washed sequentially with 1M NaHCO3, brine and water. The organic layer was dried over Na2SO4, filtered and concentrated to yield 2.2 g (91%) of product as a viscous liquid. MS (ESI+) m/z 221 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[N:6]([CH2:7][O:8][CH2:9][CH2:10][Si:11]([CH3:14])([CH3:13])[CH3:12])[C:5]([N:15]2[CH2:20][CH2:19][N:18](S(CC)(=O)=O)[CH2:17][CH2:16]2)=[N:4][C:3]=1[C:26]1[CH:27]=[C:28]([O:33][CH3:34])[C:29]([NH2:32])=[N:30][CH:31]=1>C1COCC1.CN(C=O)C>[Br:1][C:2]1[N:6]([CH2:7][O:8][CH2:9][CH2:10][Si:11]([CH3:14])([CH3:13])[CH3:12])[C:5]([N:15]2[CH2:16][CH2:17][NH:18][CH2:19][CH2:20]2)=[N:4][C:3]=1[C:26]1[CH:27]=[C:28]([O:33][CH3:34])[C:29]([NH2:32])=[N:30][CH:31]=1
Reactant: CCS(=O)(=O)N1CCN(c2nc(-c3cnc(N)c(OC)c3)c(Br)n2COCC[Si](C)(C)C)CC1
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: COc1cc(-c2nc(N3CCNCC3)n(COCC[Si](C)(C)C)c2Br)cnc1N

Procedure:
Preparation of 5-(5-bromo-2-(4-(ethylsulfonyl)piperazin-1-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-4-yl)-3-methoxypyridin-2-amine: In a 10 mL round-bottomed flask was 5-(5-bromo-2-(piperazin-1-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-4-yl)-3-methoxypyridin-2-amine (22 mg, 0.046 mmol) in THF (1.2 ml) and DMF (0.2 mL) under Ar at 0° C. to give a colorless solution. Ethanesulfonyl chloride (8.62 μl, 0.091 mmol) and triethylamine (0.014 ml, 0.100 mmol) were added. The ice bath was removed and the mixture was stirred at ambient temperature for 30 min. The mixture was quenched with water (3 mL) and diluted with EtOAc (10 mL). The aq layer was extracted with EtOAc (2×10 mL). The combined org layers were washed with sat aq NaHCO3 solution (1×30 mL), brine (1×30 mL), dried over Na2SO4, filtered and conc in vacuo. The crude material was directly used in the next step without purification: LCMS (m/z): 577.2 (MH+), tR=0.82 min.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[N:12]1[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]1)[N:8]1[CH2:18][CH2:19][S:20][C:7]1=[C:6]([C:21]([OH:23])=[O:22])[C:5]2=[O:24].[CH:25]1[CH:30]=[C:29]([CH:31]=[O:32])[C:28]([CH:33]=[O:34])=[CH:27][CH:26]=1>CN(C)C=O>[F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[N:12]1[CH2:17][CH2:16][N:15]([CH:31]3[C:29]4[C:28](=[CH:27][CH:26]=[CH:25][CH:30]=4)[C:33](=[O:34])[O:32]3)[CH2:14][CH2:13]1)[N:8]1[CH2:18][CH2:19][S:20][C:7]1=[C:6]([C:21]([OH:23])=[O:22])[C:5]2=[O:24]
Reactant: O=C(O)c1c2n(c3cc(N4CCNCC4)c(F)cc3c1=O)CCS2
Reactant: O=Cc1ccccc1C=O
Solvent: CN(C)C=O
Product: O=C1OC(N2CCN(c3cc4c(cc3F)c(=O)c(C(=O)O)c3n4CCS3)CC2)c2ccccc21
Temperature: 120 °C
Reaction time: 7 h

Procedure:
A mixture of 300 mg (0.9 mmol) of 7-fluoro-8-(1-piperazinyl)-5-oxo-1,2-dihydro-5H-thiazolo(3,2-a)-quinoline-4-carboxylic acid and 13.5 mg (0.9 mmol) of o-phthal aldehyde acid was suspended in 4 ml of dimethyl formamide and the whole mixture was heated with stirring at 120° C. for seven hours in an oil bath. When the reaction was completed, the mixture was allowed to cool to room temperature and, by collecting the crystals separated out therefrom by filtration, the title compound was obtained as powder. Yield 207 mg (47.7 percent). Melting point 261° to 262° C. (decomposition). Elementary analysis calculated as C24H20FN3O5S: C 59.87, H 4.19, N 8.73; Found: C 60.09, H 4.32, N 8.64.