Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH:6]=[C:5]([CH:7]=O)[CH:4]=[C:3]([CH:9]=O)[CH:2]=1.NCCC[N:21]([CH2:26][CH:27]([CH3:29])[CH3:28])[CH2:22][CH2:23][CH2:24][NH2:25].[BH4-].[Na+].[OH-].[Na+]>CO>[C:1]1([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH:6]=[C:5]([CH2:7][NH:21][CH2:26][CH2:27][CH2:28][NH:25][CH2:24][CH2:23][CH2:22][NH:21][CH2:26][CH:27]([CH3:29])[CH3:28])[CH:4]=[C:3]([CH2:9][NH:25][CH2:24][CH2:23][CH2:22][NH:25][CH2:24][CH2:23][CH2:22][NH:21][CH2:26][CH:27]([CH3:28])[CH3:29])[CH:2]=1
Reactant: O=Cc1cc(C=O)cc(-c2ccccc2)c1
Reactant: CC(C)CN(CCCN)CCCN
Agent: [BH4-]
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CC(C)CNCCCNCCCNCc1cc(CNCCCNCCCNCC(C)C)cc(-c2ccccc2)c1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
[1,1′-Biphenyl]-3,5-dicarbaldehyde (3.03 g, 14.4 mmol) and MeOH (60 mL) were added to a round-bottom flask. To the solution was added N′-(3-aminopropyl)-N3-isobutylpropane-1,3-diamine (5.40 g, 28.8 mmol), and the reaction mixture was stirred at rt for 24 h. Sodium borohydride (0.55 g, 14.4 mmol) was added, and the reaction mixture was stirred for 2 h. The reaction mixture was concentrated under reduced pressure to afford a white solid. Aqueous NaOH (10%, 50 mL) was added, and the reaction mixture stirred for 30 min. The solution was extracted with CHCl3 (3×75 mL). The organic layers were combined, dried over Na2SO4, filtered, and concentrated under reduced pressure to afford a clear oil which was used without further purification.
Reaction SMILES: C1CCN(C(N=NC(N2CCCCC2)=O)=O)CC1.[CH3:19][O:20][C:21]1[N:26]=[C:25]([CH2:27][CH2:28]O)[CH:24]=[CH:23][CH:22]=1.[C:30]1(=[O:40])[NH:34][C:33](=[O:35])[C:32]2=[CH:36][CH:37]=[CH:38][CH:39]=[C:31]12.C(P(CCCC)CCCC)CCC>C(OCC)(=O)C.C1COCC1>[CH3:19][O:20][C:21]1[N:26]=[C:25]([CH2:27][CH2:28][N:34]2[C:30](=[O:40])[C:31]3[C:32](=[CH:36][CH:37]=[CH:38][CH:39]=3)[C:33]2=[O:35])[CH:24]=[CH:23][CH:22]=1
Reactant: COc1cccc(CCO)n1
Reactant: O=C1NC(=O)c2ccccc21
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COc1cccc(CCN2C(=O)c3ccccc3C2=O)n1
Temperature: 25 °C
Reaction time: 16 h
Yield: 69 %

Procedure:
ADDP (49.0 g, 194.09 mmol) was added to a mixture of 2-(6-methoxypyridin-2-yl)ethanol (22.87 g, 149.30 mmol), phthalimide (24.16 g, 164.23 mmol), tributylphosphine (48.5 mL, 194.09 mmol) and THF (340 mL) at 0° C. under argon atmosphere to give a solution. The solution was stirred at room temperature for 16 hr, to the reaction mixture was added ethyl acetate (about 500 mL), and the mixture was stirred at 0° C. for 20 min. The insoluble substance was removed by filtration with ethyl acetate, and washed with ethyl acetate. The filtrate was poured into water (1000 mL), and the mixture was extracted with ethyl acetate (×3). The organic layer was washed with water and brine, and dried over magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (solvent gradient; 5→20% ethyl acetate/hexane), and the precipitate was collected by filtration with hexane to give 2-(2-(6-methoxypyridin-2-yl)ethyl)isoindoline-1,3-dione (29.03 g, 103 mmol, 69%) as an off-white powder.
Reaction SMILES: [O:1]1[CH2:18][CH:2]1[CH2:3][O:4][C:5]1[CH:6]=[CH:7][C:8]2[CH:12]=[C:11]([S:13](=[O:16])(=[O:15])[NH2:14])[O:10][C:9]=2[CH:17]=1.[CH3:19][OH:20]>S(=O)(=O)(O)O>[CH3:19][O:20][CH2:18][CH:2]([OH:1])[CH2:3][O:4][C:5]1[CH:6]=[CH:7][C:8]2[CH:12]=[C:11]([S:13](=[O:15])(=[O:16])[NH2:14])[O:10][C:9]=2[CH:17]=1
Reactant: CO
Reactant: NS(=O)(=O)c1cc2ccc(OCC3CO3)cc2o1
Agent: O=S(=O)(O)O
Product: COCC(O)COc1ccc2cc(S(N)(=O)=O)oc2c1
Reaction time: 18 h

Procedure:
One drop of concentrated sulfuric acid is added to a solution of 6-[2,3-epoxypropoxy]-2-sulfamoylbenzo[b]furan (7.0 mmol) in methanol (25 ml). After 18 hours, the methanol is removed under vacuum. The residue is dissolved in ethyl acetate (200 ml), washed with water (2×25 ml), brine (2×25 ml) and dried (Na2SO4). The ethyl acetate is removed under vacuum. The white solid remaining is recrystallized from boiling ethyl acetate.
Reaction SMILES: COC1C=CC(C[N:10]2[C:14]3([C:25]4[CH:30]=[CH:29][N:28]=[CH:27][CH:26]=4)[CH2:15][N:16](C(OC(C)(C)C)=O)[CH2:17][CH:13]3[CH2:12][O:11]2)=CC=1.FC(F)(F)C(O)=O>ClCCl>[N:28]1[CH:27]=[CH:26][C:25]([C:14]23[CH2:15][NH:16][CH2:17][CH:13]2[CH2:12][O:11][NH:10]3)=[CH:30][CH:29]=1
Reactant: COc1ccc(CN2OCC3CN(C(=O)OC(C)(C)C)CC32c2ccncc2)cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: c1cc(C23CNCC2CON3)ccn1
Temperature: 25 °C
Reaction time: 1 h
Yield: 98 %

Procedure:
To a solution of tert-butyl 1-[(4-methoxyphenyl)methyl]-6a-(4-pyridyl)-3,3a,4,6-tetrahydropyrrolo[3,4-c]isoxazole-5-carboxylate (1.3 g, 3.16 mmol) in dichloromethane (30 mL) is added trifluoroacetic acid (7 mL, 94.77 mmol). The resulting solution is stirred at room temperature for 1 hour. The reaction is concentrated and the resulting residue is kept at room temperature overnight. This residue is then loaded onto an ion exchange column and the column is first eluted with methanol followed by 2 M ammonia/methanol solution. The desired basic fraction is collected and concentrated under reduced pressure to give the title compound (592 mg, 98%). ES/MS (m/e): 192 (M+1).
Reaction SMILES: [Cl:1][C:2]1[C:7]([O:8][CH2:9][CH:10]2[CH2:12][C:11]2([F:14])[F:13])=[CH:6][C:5]([N:15]=[C:16]=[S:17])=[C:4]([F:18])[CH:3]=1.[NH:19]1[CH2:24][CH2:23][CH2:22][CH2:21][CH:20]1[C:25](OCC)=[O:26]>CCCCCC>[Cl:1][C:2]1[C:7]([O:8][CH2:9][CH:10]2[CH2:12][C:11]2([F:14])[F:13])=[CH:6][C:5]([N:15]2[C:25](=[O:26])[CH:20]3[CH2:21][CH2:22][CH2:23][CH2:24][N:19]3[C:16]2=[S:17])=[C:4]([F:18])[CH:3]=1
Reactant: Fc1cc(Cl)c(OCC2CC2(F)F)cc1N=C=S
Reactant: CCOC(=O)C1CCCCN1
Solvent: CCCCCC
Product: O=C1C2CCCCN2C(=S)N1c1cc(OCC2CC2(F)F)c(Cl)cc1F

Procedure:
2.9 g 4-Chloro-5-(2,2-difluorocyclopropylmethoxy)-2-fluorophenyl isothiocyanate was dissolved in 20 ml hexane and added dropwise to a solution of 1.5 ml ethyl piperidine-2-carboxylate in 10 ml hexane. The mixture heated under reflux for 2 hours. The solvent was removed and the residue was chromatographed on silica gel using a mixture of 3 parts hexane and 1 part ethyl acetate.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[F:20])=[CH:10][C:9]=1[NH:21][C:22](=[O:38])[CH2:23][C:24](=O)[C:25]1[CH:30]=[CH:29][CH:28]=[C:27]([C:31]2[CH:36]=[N:35][CH:34]=[CH:33][N:32]=2)[CH:26]=1)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[F:20][C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=1[C:11]1[CH:12]=[CH:13][C:8]2[N:7]=[C:24]([C:25]3[CH:30]=[CH:29][CH:28]=[C:27]([C:31]4[CH:36]=[N:35][CH:34]=[CH:33][N:32]=4)[CH:26]=3)[CH2:23][C:22](=[O:38])[NH:21][C:9]=2[CH:10]=1
Reactant: CC(C)(C)OC(=O)Nc1ccc(-c2ccccc2F)cc1NC(=O)CC(=O)c1cccc(-c2cnccn2)c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C1CC(c2cccc(-c3cnccn3)c2)=Nc2ccc(-c3ccccc3F)cc2N1

Procedure:
The title compound was prepared from {2′-fluoro-3-[3-oxo-3-(3-pyrazin-2-yl-phenyl)-propionylamino]-biphenyl-4-yl}-carbamic acid tert-butyl ester (Example M84) (0.34 g, 0.65 mmol) by treatment with TFA in CH2Cl2 according to the general procedure N. Obtained as a light yellow solid (250 mg, 95%).
Reaction SMILES: [S:1](N)(N)(=[O:3])=[O:2].[CH3:6][NH:7][CH2:8][CH2:9][CH2:10][NH2:11]>N1C=CC=CC=1>[CH3:6][N:7]1[CH2:8][CH2:9][CH2:10][NH:11][S:1]1(=[O:3])=[O:2]
Reactant: NS(N)(=O)=O
Reactant: CNCCCN
Solvent: c1ccncc1
Product: CN1CCCNS1(=O)=O
Yield: 77.2 %

Procedure:
A mixture comprising 30 g (312 mmol) of sulfamide, 27.5 g (312 mmol) of N-methyl-1,3-propanediamine and 300 ml of dry pyridine was refluxed overnight at 130° C. The mixture was left to cool, and then pyridine was distilled off under reduced pressure. To the residue, 200 ml of chloroform was added and insoluble substance was filtered off. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (CHCl3) and then subjected to distillation under reduced pressure to obtain 36.2 g of 2-methyl-tetrahydro-1,2,6-thiadiazine-1,1-dioxide (boiling point: 130°-133° C./0.23 mmHg).
Reaction SMILES: [F:1][C:2]([F:31])([F:30])[C:3]1[CH:4]=[C:5]([NH:13][C:14](SC)=[C:15]([S:18]([C:21]2[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][CH:22]=2)(=[O:20])=[O:19])[C:16]#[N:17])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.[CH3:32][C@H:33]([NH2:38])[C:34]([CH3:37])([CH3:36])[CH3:35]>>[F:10][C:9]([F:12])([F:11])[C:7]1[CH:6]=[C:5]([NH:13][C:14]([NH:38][C@@H:33]([CH3:32])[C:34]([CH3:37])([CH3:36])[CH3:35])=[C:15]([S:18]([C:21]2[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][CH:22]=2)(=[O:19])=[O:20])[C:16]#[N:17])[CH:4]=[C:3]([C:2]([F:31])([F:1])[F:30])[CH:8]=1
Reactant: C[C@H](N)C(C)(C)C
Reactant: CSC(Nc1cc(C(F)(F)F)cc(C(F)(F)F)c1)=C(C#N)S(=O)(=O)c1ccc(Cl)cc1
Product: C[C@H](NC(Nc1cc(C(F)(F)F)cc(C(F)(F)F)c1)=C(C#N)S(=O)(=O)c1ccc(Cl)cc1)C(C)(C)C
Yield: 11 %

Procedure:
3-(3,5-Bis(trifluoromethyl)phenylamino)-2-(4-chlorophenylsulfonyl)-3-methylsulfanyl-2-propenenitrile (0.200 g, 0.4 mmol) was stirred in (S)-1,2,2-trimethylpropylamine (0.2 ml) at 80° C. in a sealed flask for 20 h. Work up as described in Example 1, 2) gave 25 mg (11%) of the title compound as white crystals. 1H NMR (300 MHz, CDCl3): d=0.95 (s, 9H), 1.15 (d, 3H), 3.0 (m, 1H), 7.40 (s, 2H), 7.50 (d, 2H), 7.70 (s, 1H), 7.82 (d, 2H).
Reaction SMILES: Cl[CH2:2][C:3]#[C:4][CH2:5][N:6]1[CH2:11][CH2:10][CH2:9][C@H:8]([O:12][CH2:13][C:14]2[CH:19]=[C:18]([C:20]([F:23])([F:22])[F:21])[CH:17]=[C:16]([C:24]3[N:28]([CH3:29])[N:27]=[N:26][CH:25]=3)[CH:15]=2)[C@@H:7]1[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1.[N-:36]=[N+:37]=[N-:38].[Na+].[Cl-].[NH4+].C(OCC)(=O)C>CS(C)=O>[N:36]([CH2:2][C:3]#[C:4][CH2:5][N:6]1[CH2:11][CH2:10][CH2:9][C@H:8]([O:12][CH2:13][C:14]2[CH:19]=[C:18]([C:20]([F:23])([F:22])[F:21])[CH:17]=[C:16]([C:24]3[N:28]([CH3:29])[N:27]=[N:26][CH:25]=3)[CH:15]=2)[C@@H:7]1[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)=[N+:37]=[N-:38]
Reactant: [N-]=[N+]=[N-]
Reactant: Cn1nncc1-c1cc(CO[C@H]2CCCN(CC#CCCl)[C@H]2c2ccccc2)cc(C(F)(F)F)c1
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: Cn1nncc1-c1cc(CO[C@H]2CCCN(CC#CCN=[N+]=[N-])[C@H]2c2ccccc2)cc(C(F)(F)F)c1
Yield: 83.4 %

Procedure:
To a solution of [2S,3S]-1-(4-chlorobut-2-yn-1-yl)-2-phenyl-3-[3-(1-methyl-1H-[1,2,3]triazol-5-yl)-5-(trifluoromethyl)phenylmethoxy]piperidine (142 mg) in dimethyl sulphoxide (3.0 ml) was added sodium azide (20.1 mg). The solution was stirred for 3 hours at room temperature at which time aqueous ammonium chloride and ethyl acetate were added. The organic phase was separated, washed with water (20 ml), saturated brine (20 ml) dried over MgSO4, filtered and the solvent removed under reduced pressure. Purification by MPLC (20% ethyl acetate/hexane) gave [2S,3S]-1-(4-azidobut-2-yn-1-yl)-2-phenyl-3-[3-(1-methyl-1H-[1,2,3]triazol5-yl)-5-(trifluoromethyl)phenylmethoxy]piperidine as a white solid (120 mg). 1H NMR (360 MHz,CDCl3) δ 1.20-1.60 (2H, m), 2.22 (2H, m), 2.67 (1H, m), 2.98 (1H, m), 3.27 (2H, m), 3.47 (1H, br s), 3.62 (1H, br s), 3.92 (2H, s), 3.98 (3H, s), 4.47 (1H, d, J=11.0 Hz), 4.81 (1H, d, J=11.0 Hz), 7.26-7.35 (4H, m), 7.44-7.47 (4H, m), 7.69 (1H, s).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:15]2[CH:20]=[CH:19][C:18]([N+:21]([O-])=O)=[CH:17][C:16]=2[C:24](=[O:26])[NH2:25])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]>CO.[Pd]>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:15]2[CH:20]=[CH:19][C:18]([NH2:21])=[CH:17][C:16]=2[C:24](=[O:26])[NH2:25])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCC(Oc2ccc([N+](=O)[O-])cc2C(N)=O)CC1
Agent: [Pd]
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCC(Oc2ccc(N)cc2C(N)=O)CC1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 91.7 %

Procedure:
To a solution of 4-(1-t-butoxycarbonylpiperidin-4-yloxy)-3-carbamoylnitrobenzene (5.7 g) in methanol (80 ml) was added palladium on carbon (0.6 g) and the mixture was stirred under a hydrogen atmosphere at room temperature for 2.5 hours. The reaction mixture was filtered. The filtrate was purified by chromatography on a silica gel column using dichloromethane/methanol=19/1 as an eluant to give the desired compound (4.8 g, yield 91%) as a pale yellow amorphous solid.
Reaction SMILES: [F:1][C:2]1[CH:35]=[CH:34][CH:33]=[CH:32][C:3]=1[O:4][C:5]1[C:19]([O:20][C:21]2[CH:22]=[N:23][C:24]([S:27]([CH2:30][CH3:31])(=[O:29])=[O:28])=[CH:25][CH:26]=2)=[CH:18][C:8]2[NH:9][C:10]([C:12]3[CH:17]=C[CH:15]=[CH:14][N:13]=3)=[N:11][C:7]=2[CH:6]=1.COC(C1C=NC=CN=1)=[NH:39]>>[F:1][C:2]1[CH:35]=[CH:34][CH:33]=[CH:32][C:3]=1[O:4][C:5]1[C:19]([O:20][C:21]2[CH:22]=[N:23][C:24]([S:27]([CH2:30][CH3:31])(=[O:28])=[O:29])=[CH:25][CH:26]=2)=[CH:18][C:8]2[NH:9][C:10]([C:12]3[CH:17]=[N:39][CH:15]=[CH:14][N:13]=3)=[N:11][C:7]=2[CH:6]=1
Reactant: CCS(=O)(=O)c1ccc(Oc2cc3[nH]c(-c4ccccn4)nc3cc2Oc2ccccc2F)cn1
Reactant: COC(=N)c1cnccn1
Product: CCS(=O)(=O)c1ccc(Oc2cc3[nH]c(-c4cnccn4)nc3cc2Oc2ccccc2F)cn1

Procedure:
The entitled compound was obtained as a brown solid in the same method as in Example 205 or in accordance with the method or by combining it with an ordinary method but using 4-(2-fluoro-phenoxy)-5-(6-ethanesulfonyl-pyridin-3-yloxy)-benzene-1,2-diamine obtained in Example 223 and methylpyrazin-2-imidate.
Reaction SMILES: [C:1]1([OH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N(CC)CC)C.[CH3:15][S:16](Cl)(=[O:18])=[O:17]>ClCCl>[CH3:15][S:16]([O:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)(=[O:18])=[O:17]
Reactant: CS(=O)(=O)Cl
Reactant: Oc1ccccc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CS(=O)(=O)Oc1ccccc1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 62.1 %

Procedure:
To a solution of 40.0 g (0.42 mol, 1 eq.) of phenol in 250 mL of dichloromethane at 0° C. was added 250 mL (1.8 mol, 4.2 eq.) of triethylamine. After 5 min, 49.3 mL (0.64 mol, 1.5 eq.) of methanesulfonyl chloride was added dropwise over 20 min. The resulting cloudy yellow solution was warmed to RT and stirred for 14 h. The reaction was partitioned between ether (250 mL) and water (100 mL) and the resulting organic layer was washed with cold 6N hydrochloric acid (2×200 mL). The combined aqueous layers were extracted with ether (2×50 mL) and the combined organic layers were washed with water (100 mL), saturated sodium bicarbonate (200 mL), brine (200 mL), dried (MgSO4) and concentrated. Recrystallization of the orange solid from isopropanol afforded 44.94 g (61%) of the title compound as light yellow crystals, mp 58.0°-58.5° C.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[OH:9].C(=O)([O-])[O-].[Cs+].[Cs+].FC(F)(F)S(O[CH2:22][C:23]([F:26])([F:25])[F:24])(=O)=O.O>CN1CCCC1=O>[Br:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[O:9][CH2:22][C:23]([F:26])([F:25])[F:24]
Reactant: O=S(=O)(OCC(F)(F)F)C(F)(F)F
Reactant: Oc1ccc(Cl)cc1Br
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN1CCCC1=O
Product: FC(F)(F)COc1ccc(Cl)cc1Br
Temperature: 25 °C
Reaction time: 14 h
Yield: 89 %

Procedure:
To a stirred solution of 2-bromo-4-chlorophenol (3.38 g, 16.3 mmol) in anhydrous 1-methyl-2-pyrrolidinone (25 ml) under an atmosphere of nitrogen, was added cesium carbonate (8.0 g, 24.4 mmol). The mixture was cooled to 0° C. before addition of 2,2,2-trifluoroethyl trifluoromethanesulfonate (3.78 g, 16.3 mmol) drop-wise over 2 minutes. The reaction was allowed to warm to room temperature and stirred for 14 hours. To encourage complete reaction the reaction mixture was warmed to 120° C. for 3 hours. The reaction mixture was cooled to room temperature then water (50 ml) was added. The layers were separated and the aqueous was extracted with heptane (3×50 ml). All organic extracts were combined then dried over anhydrous Na2SO4 (s), filtered and evaporated in vacuo to afford crude title compound as a yellow oil (4.20 g, 89%). Material was taken on without further purification.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:10](Cl)=[N:11][C:12]2[C:17]([C:18]=1[Cl:19])=[CH:16][C:15]([C:20]([C:32]1[N:36]([CH3:37])[CH:35]=[N:34][CH:33]=1)([C:22]1[CH:23]=[N:24][C:25]([C:28]([F:31])([F:30])[F:29])=[CH:26][CH:27]=1)[OH:21])=[CH:14][CH:13]=2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:39][O-:40].[Na+]>CO>[CH2:1]([O:8][C:9]1[C:10]([O:40][CH3:39])=[N:11][C:12]2[C:17]([C:18]=1[Cl:19])=[CH:16][C:15]([C:20]([C:32]1[N:36]([CH3:37])[CH:35]=[N:34][CH:33]=1)([C:22]1[CH:23]=[N:24][C:25]([C:28]([F:31])([F:29])[F:30])=[CH:26][CH:27]=1)[OH:21])=[CH:14][CH:13]=2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cn1cncc1C(O)(c1ccc(C(F)(F)F)nc1)c1ccc2nc(Cl)c(OCc3ccccc3)c(Cl)c2c1
Reactant: C[O-]
Agent: [Na+]
Solvent: CO
Product: COc1nc2ccc(C(O)(c3ccc(C(F)(F)F)nc3)c3cncn3C)cc2c(Cl)c1OCc1ccccc1
Temperature: 65 °C

Procedure:
To a mixture of (3-(benzyloxy)-2,4-dichloroquinolin-6-yl)(1-methyl-1H-imidazol-5-yl)(6-(trifluoromethyl)pyridin-3-yl)methanol (2.46 g, 4.4 mmol, Intermediate 11: step d) in methanol (24.6 mL) was added NaOMe (0.5 M in MeOH, 8.8 mL, 4.4 mmol) and the resulting suspension heated to 65° C. for 8 hours. The mixture was then cooled to room temperature and concentrated to dryness. Water was added and the mixture acidified with 2 N aqueous HCl to ˜pH 2. The aqueous was then extracted with EtOAc. The organics were combined and washed with water, saturated aqueous NaHCO3 and brine. The organics were then dried (MgSO4), filtered and concentrated to dryness to afford the title compound which was used without further purification.
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[CH:10][C:5]2[N:6]=[C:7]([NH2:9])[S:8][C:4]=2[CH:3]=1.[N:12]1([C:17](N2C=CN=C2)=[O:18])[CH:16]=[CH:15][N:14]=[CH:13]1>CN(C=O)C>[CH3:1][C:2]1[CH:11]=[CH:10][C:5]2[N:6]=[C:7]([NH:9][C:17]([N:12]3[CH:16]=[CH:15][N:14]=[CH:13]3)=[O:18])[S:8][C:4]=2[CH:3]=1
Reactant: Cc1ccc2nc(N)sc2c1
Reactant: O=C(n1ccnc1)n1ccnc1
Solvent: CN(C)C=O
Product: Cc1ccc2nc(NC(=O)n3ccnc3)sc2c1
Temperature: 25 °C
Yield: 99 %

Procedure:
To a solution of 6-methylbenzo[d]thiazol-2-amine (109, 328 mg, 2 mmol, Sigma-Aldrich) in DMF (5 mL) was added di(1H-imidazol-1-yl)methanone (110, 357 mg, 2.2 mmol, Sigma-Aldrich) at 0° C. Under vigorous stirring, the resulting reaction mixture was slowly allowed to warm to a temperature of about 25° C. over 14 h. A white precipitate formed. The precipitate was collected by filtration under reduced pressure, washed twice with EtOAc (10 mL for each wash), and dried under reduced pressure to provide 108 (yield >99%).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][CH:6]=[C:5]2[Cl:12].[Li]CCCC.CON(C)[C:21]([C:23]1[N:24]=[CH:25][S:26][CH:27]=1)=[O:22]>C1COCC1>[Cl:12][C:5]1[C:4]2[C:9](=[CH:10][CH:11]=[C:2]([C:21]([C:23]3[N:24]=[CH:25][S:26][CH:27]=3)=[O:22])[CH:3]=2)[N:8]=[CH:7][CH:6]=1
Reactant: CON(C)C(=O)c1cscn1
Reactant: Clc1ccnc2ccc(Br)cc12
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: O=C(c1ccc2nccc(Cl)c2c1)c1cscn1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 6-bromo-4-chloroquinoline (0.459 g, 1.89 mmol) in THF (8 mL) was added n-BuLi (1.12 mL, 1.80 mmol, 1.6M in hexane) at −78° C. under argon and the resulting mixture was stirred for 2 hr. A solution of N-methoxy-N-methylthiazole-4-carboxamide (0.39 g, 2.27 mmol) in THF (2 mL) was added and the resulting mixture was allowed to warm to room temperature and stirred at room temperature for 2 hr. The reaction mixture was quenched with ice and saturated NH4Cl. The aqueous layer was extracted with CH2Cl2. The combined organics were concentrated and purified by column chromatography (40-50% EtOAc/hexanes) to yield (4-chloroquinolin-6-yl)(thiazol-4-yl)methanone. (ES, m/z) [M+H]+ 275, 277.
Reaction SMILES: [CH3:1][C:2]1[C:7]2[NH:8][C:9](=[O:12])[CH2:10][O:11][C:6]=2[CH:5]=[CH:4][C:3]=1[N+:13]([O-:15])=[O:14].[CH3:16]C1C([N+]([O-])=O)=CC2NC(=O)COC=2C=1.C[Mg]Br>>[CH3:1][C:2]1[C:7]2[NH:8][C:9](=[O:12])[CH2:10][O:11][C:6]=2[CH:5]=[C:4]([CH3:16])[C:3]=1[N+:13]([O-:15])=[O:14]
Reactant: Cc1c([N+](=O)[O-])ccc2c1NC(=O)CO2
Reactant: Cc1cc2c(cc1[N+](=O)[O-])NC(=O)CO2
Agent: C[Mg]Br
Product: Cc1cc2c(c(C)c1[N+](=O)[O-])NC(=O)CO2

Procedure:
The title compound is synthesized from 5-methyl-6-nitro-3-oxo-3,4-dihydro-(2H)-1,4-benzoxazine or from 7-methyl-6-nitro-3-oxo-3,4-dihydro-(2H)-1,4-benzoxazine and methyl magnesium bromide using the method illustrated in Example 37.
Reaction SMILES: C(N(S(F)(F)[F:7])CC)C.[Br:10][C:11]1[N:12]=[C:13]([C:16]2(O)[CH2:21][CH2:20][N:19]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:18][CH2:17]2)[S:14][CH:15]=1>ClCCl>[Br:10][C:11]1[N:12]=[C:13]([C:16]2([F:7])[CH2:21][CH2:20][N:19]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:18][CH2:17]2)[S:14][CH:15]=1
Reactant: CCN(CC)S(F)(F)F
Reactant: CC(C)(C)OC(=O)N1CCC(O)(c2nc(Br)cs2)CC1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCC(F)(c2nc(Br)cs2)CC1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 78.3 %

Procedure:
Diethylaminosulfur trifluoride (DAST) (0.083 mL, 0.627 mmol) was added to a 0° C. of tert-butyl 4-(4-bromothiazol-2-yl)-4-hydroxypiperidine-1-carboxylate (0.207 g, 0.570 mmol) in dichloromethane (2.8 mL). After 5 minutes, the cooling bath was removed and the reaction mixture was allowed to stir at room temperature overnight. Saturated aqueous sodium bicarbonate solution was added, and the aqueous phase was separated and extracted with dichloromethane. The combined organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified via column chromatography on silica gel (Biotage 25 g column, gradient elution with 5-50% ethyl acetate-hexane) to afford tert-butyl 4-(4-bromothiazol-2-yl)-4-fluoropiperidine-1-carboxylate (0.163 g, 78%) as a colorless, waxy solid. MS (ESI, pos. ion) m/z 387, 389 [M+Na]+.
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[CH:9][C:8]2[NH:7][C:6]3[CH2:11][CH2:12][N:13]([C:15]4[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][CH:16]=4)[CH2:14][C:5]=3[C:4]=2[CH:3]=1.[CH3:22][C:23]1[CH:28]=[CH:27][C:26]([CH:29]=[CH2:30])=[CH:25][N:24]=1.[OH-].[K+]>CN1C(=O)CCC1>[CH3:1][C:2]1[CH:10]=[CH:9][C:8]2[N:7]([CH2:30][CH2:29][C:26]3[CH:25]=[N:24][C:23]([CH3:22])=[CH:28][CH:27]=3)[C:6]3[CH2:11][CH2:12][N:13]([C:15]4[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][CH:16]=4)[CH2:14][C:5]=3[C:4]=2[CH:3]=1
Reactant: C=Cc1ccc(C)nc1
Reactant: Cc1ccc(N2CCc3[nH]c4ccc(C)cc4c3C2)cc1
Agent: [K+]
Agent: [OH-]
Solvent: CN1CCCC1=O
Product: Cc1ccc(N2CCc3c(c4cc(C)ccc4n3CCc3ccc(C)nc3)C2)cc1

Procedure:
The title compound is prepared from a mixture of 2,3,4,5-tetrahydro-8-methyl-2-p-tolyl-1H-pyrido[4,3-b]indole, 2-methyl-5-vinylpyridine and KOH (5-7 equiv) in NMP at a temperature ranging between 25 deg C. to 100 deg C. The product obtained is isolated by preparative HPLC.
Reaction SMILES: [N+:1]([C:4]1[C:5]([CH:10](C(OCC)=O)[C:11]([O:13][CH2:14][CH3:15])=[O:12])=[N:6][CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2].O.[Cl-].[Li+]>CS(C)=O.[Cl-].[Na+].O>[N+:1]([C:4]1[C:5]([CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])=[N:6][CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2]
Reactant: CCOC(=O)C(C(=O)OCC)c1ncccc1[N+](=O)[O-]
Agent: [Cl-]
Agent: [Li+]
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: CCOC(=O)Cc1ncccc1[N+](=O)[O-]
Temperature: 100 °C
Yield: 92 %

Procedure:
Diethyl (3-nitropyridin-2-yl)-malonate (12.5 g, 0.044 mol) was dissolved in DMSO (150 mL) and water (0.79 mL, 0.044 mol) and lithium chloride (4.65 g, 0.11 mol) were added at room temperature under nitrogen. The reaction was warmed to 100° C. 12 h and more lithium chloride (1 g) was added to the reaction. The reaction was heated for another 5 hours and cooled to room temperature. Brine (150 mL) was added to the reaction before extracting with EtOAc (3×, 275 mL each). The organics were combined and dried over sodium sulfate, then concentrated in vacuo. The resulting residue was triturated with diethyl ether and collected by filtration (8.6 g, 92% yield).