Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6](Cl)[N:5]=[C:4]([S:9][CH3:10])[N:3]=1.[CH2:11]([Mg]Br)[CH2:12][CH:13]=[CH2:14]>C1COCC1>[CH2:14]([C:6]1[CH:7]=[C:2]([Cl:1])[N:3]=[C:4]([S:9][CH3:10])[N:5]=1)[CH2:13][CH:12]=[CH2:11]
Reactant: CSc1nc(Cl)cc(Cl)n1
Reactant: C=CCC[Mg]Br
Solvent: C1CCOC1
Product: C=CCCc1cc(Cl)nc(SC)n1
Reaction time: 8 h

Procedure:
To a mixture of 4,6-dichloro-2-(methylthio)pyrimidine (5.20 g, 26.66 mmol) and tris(acetylacetonate)iron (III) (0.47 g, 1.33 mmol) in THF (130 mL) and DMP (13 mL) at 0° C. was added slowly 3-butenylmagnesium bromide (0.5M in THF, 56 mL, 28.0 mmol). The reaction mixture was stirred overnight. After the reaction was completed, THF was removed by evaporation in vacuo. The residue was dissolved in dichloromethane (100 mL), and washed with water (50 mL×2), dried over MgSO4, filtered and evaporated in vacuo to provide the title compound. MH+215.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][CH2:9][C:10]([SH:13])([CH3:12])[CH3:11].[CH3:14][CH:15]([CH3:18])[CH:16]=O>>[SH:13][C:10]([CH3:11])([CH3:12])[CH2:9][NH:8][C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[NH:1][CH2:14][C:15]([S:13][CH:10]([CH3:11])[CH3:9])([CH3:18])[CH3:16]
Reactant: CC(C)C=O
Reactant: CC(C)(S)CNc1ccccc1N
Product: CC(C)SC(C)(C)CNc1ccccc1NCC(C)(C)S
Yield: 28 %

Procedure:
2-Amino-1-(2-mercapto-2-methylpropylamino)benzene (0.515 g, 2.65×10-3 mol) and 0.786 g (5.31×10-3 mol, 200 M%) 2-(1-methylethylthio)-2-methylethylthio)-2-methypropanal were reacted by the method of Example 2 to give 2-(2-mercapto-2-methylpropylamino)-1-[2-(1-methylethylthio)-2-methylpropylamino]benzene 0.244 g (28% yield) as a colorless oil after purification by radial chromatography on a 2 mm silica gel plate eluting with 100 ml 100% petroleum ether and 200 ml 5% diethyl ether/petroleum ether.
Reaction SMILES: [CH3:1][O-:2].[Na+].[NH2:4][CH:5]1[N:10]=[C:9]([Cl:11])[N:8]=[C:7](F)[N:6]1[O:13][CH:14]([F:16])[F:15]>CO>[NH2:4][CH:5]1[N:10]=[C:9]([Cl:11])[N:8]=[C:7]([O:2][CH3:1])[N:6]1[O:13][CH:14]([F:16])[F:15]
Reactant: C[O-]
Reactant: NC1N=C(Cl)N=C(F)N1OC(F)F
Agent: [Na+]
Solvent: CO
Product: COC1=NC(Cl)=NC(N)N1OC(F)F
Temperature: 0 °C
Reaction time: 1 h

Procedure:
8.4 g (0.0466 mol) of 30% strength sodium methylate were added over the course of 15 minutes to a stirred mixture of 10 g (0.0466 mol) of 2-amino-4-chlorodifluoromethoxy-6-fluoro-1,3,5-triazine and 100 ml of methanol at 0° C. The mixture was stirred at 0° C. for one hour and then concentrated under reduced pressure, taken up in methylene chloride and extracted with water. Drying and concentration yielded 10.4 g (98.5% of theory) of the title compound of melting point 109°-111° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:26]2([F:39])[CH2:31][CH2:30][N:29](C(OC(C)(C)C)=O)[CH2:28][CH2:27]2)[CH:5]=[C:6]([F:25])[C:7]=1[O:8][CH:9]1[CH2:14][CH2:13][N:12]([CH2:15][C:16]2[O:20][N:19]=[C:18]([C:21]([F:24])([F:23])[F:22])[N:17]=2)[CH2:11][CH2:10]1.Cl>ClCCl.O1CCOCC1>[F:1][C:2]1[CH:3]=[C:4]([C:26]2([F:39])[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]2)[CH:5]=[C:6]([F:25])[C:7]=1[O:8][CH:9]1[CH2:14][CH2:13][N:12]([CH2:15][C:16]2[O:20][N:19]=[C:18]([C:21]([F:24])([F:22])[F:23])[N:17]=2)[CH2:11][CH2:10]1
Reactant: CC(C)(C)OC(=O)N1CCC(F)(c2cc(F)c(OC3CCN(Cc4nc(C(F)(F)F)no4)CC3)c(F)c2)CC1
Agent: Cl
Solvent: ClCCl
Solvent: C1COCCO1
Product: Fc1cc(C2(F)CCNCC2)cc(F)c1OC1CCN(Cc2nc(C(F)(F)F)no2)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of tert-butyl 4-(3,5-difluoro-4-((1-((3-(trifluoromethyl)-1,2,4-oxadiazol-5-yl)methyl)piperidin-4-yl)oxy)phenyl)-4-fluoropiperidine-1-carboxylate D1i in dichloromethane (5 mL) is treated with hydrogen chloride in dioxane (4 M solution; 0.1 mL, 0.4 mL). The mixture is stirred at room temperature for 1 hour and concentrated to yield 5-((4-(2,6-difluoro-4-(4-fluoropiperidin-4-yl)phenoxy)piperidin-1-yl)methyl)-3-(trifluoromethyl)-1,2,4-oxadiazole D1j (hydrochloride salt) as an oil. LCMS calcd. for C20H23F6N4O2+ ([M+H]+): 465.2, found: 465.2.
Reaction SMILES: CC1(C)COB([C:8]2[CH:9]=[CH:10][C:11](=[O:22])[N:12]([C:14]3[C:19]([C:20]#[N:21])=[CH:18][CH:17]=[CH:16][N:15]=3)[CH:13]=2)OC1.Br[C:25]1[N:29]2[N:30]=[CH:31][C:32]([C:34]([OH:37])([CH3:36])[CH3:35])=[N:33][C:28]2=[N:27][CH:26]=1.O1CCOCC1.C(=O)([O-])[O-].[Na+].[Na+]>C(OCC)(=O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[OH:37][C:34]([C:32]1[CH:31]=[N:30][N:29]2[C:25]([C:8]3[CH:9]=[CH:10][C:11](=[O:22])[N:12]([C:14]4[C:19]([C:20]#[N:21])=[CH:18][CH:17]=[CH:16][N:15]=4)[CH:13]=3)=[CH:26][N:27]=[C:28]2[N:33]=1)([CH3:36])[CH3:35]
Reactant: CC(C)(O)c1cnn2c(Br)cnc2n1
Reactant: CC1(C)COB(c2ccc(=O)n(-c3ncccc3C#N)c2)OC1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: CC(C)(O)c1cnn2c(-c3ccc(=O)n(-c4ncccc4C#N)c3)cnc2n1
Temperature: 95 °C

Procedure:
To a degassed mixture of 5-(5,5-dimethyl-[1,3,2]dioxaborinan-2-yl)-2-oxo-2H-[1,2′]bipyridinyl-3′-cabonitrile (from step f), 2-(7-bromo-imidazo[1,2-b][1,2,4]triazin-3-yl)propan-2-ol (from step d) (0.23 g), dry 1,4-dioxane (5 ml), and 2 M aqueous sodium carbonate (3 ml), was added tetrakis(triphenylphosphine)palladium(0) (0.12 g). The mixture was heated at 95° C. under a nitrogen atmosphere for 24 h. After cooling to 25° C., the reaction was diluted with ethyl acetate, and the organic phase separated. The solvent was evaporated at reduced pressure and the residue purified by chromatography (silica gel, 5% MeOH/CH2Cl2) to give the title compound, crystallised from hot isopropanol as a yellow solid: 1H NMR (400 MHz, DMSO-d6) δ 8.98 (1H, s), 8.97 (1H, d, J 2.0), 8.62–8.68 (2H, m), 8.40 (1H, s), 8.32 (1H, dd, J 2.7, 9.8), 7.85 (1H, dd, J 5.1, 7.8), 6.83 (1H, d, J 9.8), 5.75 (1H, s), 1.54 (6H, s); MS (ES+) m/z 374 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:9]2[CH:19]=[CH:18][S:17][C:10]=2[N:11]=[C:12]([NH:15][NH2:16])[CH2:13][N:14]=1.C(=O)(O)[O-].[Na+].[C:25](Cl)(=O)[CH3:26]>C(Cl)Cl>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:9]2[CH:19]=[CH:18][S:17][C:10]=2[N:11]2[C:25]([CH3:26])=[N:16][N:15]=[C:12]2[CH2:13][N:14]=1
Reactant: NNC1=Nc2sccc2C(c2ccccc2Cl)=NC1
Reactant: CC(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: Cc1nnc2n1-c1sccc1C(c1ccccc1Cl)=NC2
Temperature: 0 °C
Reaction time: 0.75 h

Procedure:
2 g (0.0069 mol) of 5-(o-chlorophenyl)-2-hydrazino-3H-thieno[2,3-e]-1,4-diazepine are suspended in 200 ml of dry methylene chloride and treated with 10 g of sodium bicarbonate. The solution is cooled to 0° C. and treated with stirring with 0.8 ml of acetyl chloride. After 45 minutes, the solid material is filtered off from the solution which is then shaken out twice with 100 ml of water each time. After drying over sodium sulphate, the organic phase is evaporated and treated with 100 ml of butanol, whereupon 20 ml thereof are evaporated off under reduced pressure. The solution is refluxed for 8 hours and evaporated under vacuum. After trituration of the oily residue with ethanol, the resulting crystals are refluxed with a small amount of ethanol, left to crystallize in a refrigerator, filtered under a vacuum and dried to yield 4-(o-chlorophenyl)-9-methyl-6H-thieno[3,2-f]-s-triazolo[4,3-a][1,4]diazepine, melting point 221°-223° C.
Reaction SMILES: Br[C:2]1[C:3]2[N:4]([N:8]=[C:9]([Cl:11])[N:10]=2)[CH:5]=[CH:6][CH:7]=1.[CH3:12][S:13]([C:16]1[CH:23]=[CH:22][CH:21]=[CH:20][C:17]=1[CH2:18][NH2:19])(=[O:15])=[O:14].Cl>>[Cl:11][C:9]1[N:10]=[C:3]2[C:2]([NH:19][CH2:18][C:17]3[CH:20]=[CH:21][CH:22]=[CH:23][C:16]=3[S:13]([CH3:12])(=[O:15])=[O:14])=[CH:7][CH:6]=[CH:5][N:4]2[N:8]=1
Reactant: CS(=O)(=O)c1ccccc1CN
Reactant: Clc1nc2c(Br)cccn2n1
Agent: Cl
Product: CS(=O)(=O)c1ccccc1CNc1cccn2nc(Cl)nc12

Procedure:
(2-Chloro-[1,2,4]triazolo[1,5-a]pyridin-8-yl)-(2-methanesulfonyl-benzyl)-amine was prepared from 8-bromo-2-chloro-[1,2,4]triazolo[1,5-a]pyridine (470.0 mg, 2.022 mmol) and 2-methanesulfonyl-benzylamine; hydrochloride (500.0 mg, 2.255 mmol) in a manner analogous to Example 2d. Product isolated as a yellow solid (0.45 g, 66%). MP=161-163° C. 1H NMR (400 MHz, CDCl3, δ, ppm): 8.11 (d, J=7.6 Hz, 1H), 7.92 (d, J=6.6 Hz, 1H), 7.64-7.60 (m, 2H), 7.56-7.51 (m, 1H), 6.88 (t, J=7.5 Hz, 1H), 6.53 (d, J=7.8 Hz, 1H), 5.43 (t, J=5.9 Hz, 1H), 4.98 (d, J=6.1 Hz, 2H), 3.15 (s, 3H). MS=337, 339 (MH)+. 138b) N(8)-(2-Methanesulfonyl-benzyl)-N(2)-[4-(4-methyl-piperazin-1-yl)-phenyl]-[1,2,4]triazolo[1,5-a]pyridine-2,8-diamine was prepared from (2-chloro-[1,2,4]triazolo[1,5-a]pyridin-8-yl)-(2-methanesulfonyl-benzyl)-amine (75.0 mg, 0.223 mmol) and 4-(4-methyl-piperazin-1-yl)-phenylamine (47.0 mg, 0.246 mmol) with 2,2′-bis-dicyclohexylphosphanyl-biphenyl (25.0 mg, 0.0457 mmol) as the ligand in a manner analogous to Example 2d. Product isolated as a tan foam (0.035 g, 32%). 1H NMR (400 MHz, CDCl3, δ, ppm): 8.11 (d, J=7.9 Hz, 1H), 7.84 (d, J=6.5 Hz, 1H), 7.67-7.59 (m, 2H), 7.55-7.50 (m, 1H), 7.47 (d, J=8.8 Hz, 2H), 6.96 (d, J=8.9 Hz, 2H), 6.68 (t, J=7.3 Hz, 1H), 6.55 (s, 1H), 6.41 (d, J=7.7 Hz, 1H), 5.19 9t, J=6.1 Hz, 1H), 4.96 (d, J=6.1 Hz, 2H), 3.20-3.14 (m, 7H), 2.69-2.58 (m, 4H), 2.39 (s, 3H). MS=492 (MH)+.
Reaction SMILES: I[C:2]1[N:3]=[C:4]([CH3:13])[N:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[CH:6]=1.C([Mg]Cl)(C)C.[CH2:19]([Sn:23](Cl)([CH2:28][CH2:29][CH2:30][CH3:31])[CH2:24][CH2:25][CH2:26][CH3:27])[CH2:20][CH2:21][CH3:22].[NH4+].[Cl-]>C1COCC1.C(OCC)(=O)C>[CH3:13][C:4]1[N:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[CH:6]=[C:2]([Sn:23]([CH2:24][CH2:25][CH2:26][CH3:27])([CH2:28][CH2:29][CH2:30][CH3:31])[CH2:19][CH2:20][CH2:21][CH3:22])[N:3]=1
Reactant: CCCC[Sn](Cl)(CCCC)CCCC
Reactant: Cc1nc(I)cn1-c1ccccc1
Agent: CC(C)[Mg]Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCCC[Sn](CCCC)(CCCC)c1cn(-c2ccccc2)c(C)n1
Temperature: 25 °C
Yield: 23.1 %

Procedure:
4-Iodo-2-methyl-1-phenyl-1H-imidazole (0.55 g, 1.94 mmol) was dissolved in 9 mL of anhydrous THF and isopropylmagnesium chloride (2 M THF solution, 1.2 mL, 2.4 mmol) was added dropwise. The reaction was stirred for more than 1 h at room temperature. Tributylstannyl chloride (0.55 mL, 2.03 mmol) was slowly added. After the reaction was judged to be complete by TLC, NH4Cl solution and ethyl acetate were added. The layers were separated and the aqueous layer was extracted twice more with ethyl acetate. The combined organic layers were washed with brine, dried over sodium sulfate and concentrated. The residue was purified by silica gel chromatography (triethylamine/ethyl acetate/hexanes) to give 0.2 g (23%) of 2-methyl-1-phenyl-4-tributylstannanyl-1H-imidazole.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[NH:13][C:12](=[O:14])[CH:11]=[C:10]([C:15]3[CH:20]=[CH:19][C:18]([OH:21])=[C:17]([CH3:22])[CH:16]=3)[CH:9]=2)=[C:4]([CH3:23])[CH:3]=1.ClCCCl.C([N:35]1[CH2:40][CH2:39][CH:38]([CH:41]=O)[CH2:37][CH2:36]1)(OC(C)(C)C)=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(O)(=O)C>[OH:21][C:18]1[CH:19]=[CH:20][C:15]([C:10]2[CH:9]=[C:8]([C:5]3[CH:6]=[CH:7][C:2]([NH:1][CH2:41][CH:38]4[CH2:39][CH2:40][NH:35][CH2:36][CH2:37]4)=[CH:3][C:4]=3[CH3:23])[NH:13][C:12](=[O:14])[CH:11]=2)=[CH:16][C:17]=1[CH3:22]
Reactant: CC(C)(C)OC(=O)N1CCC(C=O)CC1
Reactant: Cc1cc(-c2cc(-c3ccc(N)cc3C)[nH]c(=O)c2)ccc1O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Solvent: CC(=O)O
Product: Cc1cc(-c2cc(-c3ccc(NCC4CCNCC4)cc3C)[nH]c(=O)c2)ccc1O
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
In a round bottom flask was added 6-(4-amino-2-methylphenyl)-4-(4-hydroxy-3-methylphenyl)pyridin-2(1H)-one (76 mg, 0.25 mmol), 1,2 Dichloroethane (5.0 mL), acetic acid (0.1 mL), and N-Boc-4-Formyl piperidine (0.65 mg, 0.30 mmol). The reaction was stirred at room temperature for 15 minutes before adding sodium triacetoxy borohydride (85 mg, 0.40 mmol). Stirring was continued at room temperature for 10 min. The reaction was then concentrated down under reduced pressure. The resulting oil was then dissolved in 4N HCl/dioxane (5.0 mL) and stirred at 45° C. for 1 h. The resulting slurry was cooled down to room temperature and the precipitate was filtered off. The resulting solid was then dissolved in MeOH and purified by preparatory HPLC (15-40% gradient of NH4OAc/ACN) to give 4-(4-hydroxy-3-methylphenyl)-6-{2-methyl-4-[(piperidin-4-ylmethyl)amino]phenyl}pyridin-2(1H)-one as the acetate salt (16 mg, 14% yield over 2 steps). 1H NMR (400 MHz, d6-DMSO) δ 7.47 (s, 1H), 7.39 (dd, 1H), 7.06 (d, 1H), 6.85 (d, 1H), 6.45 (m, 2H), 6.36 (s, 1H), 6.27 (s, 1H), 5.95 (t, 1H), 2.98 (m, 2H), 2.91 (t, 1H), 2.48 (m, 2H), 2.22 (s, 3H), 2.16 (s, 3H), 1.72 (m, 4H), 1.09 (m, 1H); MS (EI) for C25H29N3O2: 404 (MH+).
Reaction SMILES: Cl[C:2]1([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[O:19][CH3:20])[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([Cl:11])[CH:9]=2)[NH:4][C:3]1=[O:12].[F:21][CH:22]1[CH2:26][NH:25][C@H:24]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH2:23]1>>[Cl:11][C:8]1[CH:9]=[C:10]2[C:5](=[CH:6][CH:7]=1)[NH:4][C:3](=[O:12])[C:2]2([N:25]1[CH2:26][CH:22]([F:21])[CH2:23][C@H:24]1[C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[O:19][CH3:20]
Reactant: COc1ccccc1C1(Cl)C(=O)Nc2ccc(Cl)cc21
Reactant: CC(C)(C)OC(=O)[C@@H]1CC(F)CN1
Product: COc1ccccc1C1(N2CC(F)C[C@H]2C(=O)OC(C)(C)C)C(=O)Nc2ccc(Cl)cc21

Procedure:
With 1.06 g of 3,5-dichloro-3-(2-methoxyphenyl)-1,3-dihydro-2H-indol-2-one and 685 mg of the compound obtained in Step 12-2 as starting materials, respectively 678 mg (Isomer A: colorless solid) and 839 mg (Isomer B: colorless amorphous) of two species of diastereoisomers of the title compound were obtained by a similar method to Step 4-2.
Reaction SMILES: [S:1]1[C:5]([CH2:6][O:7][C:8]([NH:10][C@@H:11]([CH2:33][C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[CH2:12][NH:13][CH2:14][C@@H:15]([NH:23][C:24]([O:26][CH2:27][C:28]2[S:32][CH:31]=[N:30][CH:29]=2)=[O:25])[CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[O:9])=[CH:4][N:3]=[CH:2]1.[C:40](=O)([O:51][CH2:52][C:53]1[S:57][CH:56]=[N:55][CH:54]=1)[O:41]C1C=CC([N+]([O-])=O)=CC=1.C(N(CC)CC)C>C(OCC)(=O)C>[S:57]1[C:53]([CH2:52][O:51][C:40]([N:13]([CH2:14][C@@H:15]([NH:23][C:24]([O:26][CH2:27][C:28]2[S:32][CH:31]=[N:30][CH:29]=2)=[O:25])[CH2:16][C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH2:12][C@@H:11]([NH:10][C:8]([O:7][CH2:6][C:5]2[S:1][CH:2]=[N:3][CH:4]=2)=[O:9])[CH2:33][C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)=[O:41])=[CH:54][N:55]=[CH:56]1
Reactant: O=C(N[C@H](CNC[C@H](Cc1ccccc1)NC(=O)OCc1cncs1)Cc1ccccc1)OCc1cncs1
Reactant: O=C(OCc1cncs1)Oc1ccc([N+](=O)[O-])cc1
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: O=C(N[C@@H](Cc1ccccc1)CN(C[C@H](Cc1ccccc1)NC(=O)OCc1cncs1)C(=O)OCc1cncs1)OCc1cncs1
Reaction time: 18 h
Yield: 35.8 %

Procedure:
The product from Example 35 (30 mg, 0.053 mmol) in ethyl acetate (2 mL) was treated with a solution of 4-nitrophenyl 1,3-thiazol-5-ylmethyl carbonate [prepared from 4-nitrophenyl 1,3-thiazol-5-ylmethyl carbonate hydrochloride salt (18 mg, 0.058 mmol) by extraction with aqueous NaHCO3], triethylamine (15 μl, 0.106 mmol), and N,N-dimethylaminopyridine (6 mg, 0.053 mmol) at ambient temperature. After stirring for 18 hours, the mixture was washed with aqueous 10% K2CO3 (5×2 mL), brine (2 mL), dried over sodium sulfate, filtered, and the filtrate was concentrated. The residue was purify on a silica gel cartridge eluting with (chloroform:methanol, 99:1) to provide the title compound (13.4 mg, 36%). 1H NMR (CDCl3) δ 8.80-8.68 (m, 3H), 7.81 (m, 3H), 7.31-6.96 (m, 10H), 5.27-5.05 (m, 6H), 4.04-3.25 (m, 5H), 3.11-2.98 (m, 2H), 2.89-2.56 (m, 5H); MS (ESI+) m/z 707 (M+H)+.
Reaction SMILES: C[O:2][C:3]1[CH:18]=[CH:17][C:6]2[O:7][CH2:8][C:9]3[CH:16]=[CH:15][CH:14]=[CH:13][C:10]=3[C:11](=[O:12])[C:5]=2[CH:4]=1.Cl.N1C=CC=CC=1>O>[OH:2][C:3]1[CH:18]=[CH:17][C:6]2[O:7][CH2:8][C:9]3[CH:16]=[CH:15][CH:14]=[CH:13][C:10]=3[C:11](=[O:12])[C:5]=2[CH:4]=1
Reactant: COc1ccc2c(c1)C(=O)c1ccccc1CO2
Agent: Cl
Solvent: O
Solvent: c1ccncc1
Product: O=C1c2ccccc2COc2ccc(O)cc21
Temperature: 180 °C
Yield: 79.7 %

Procedure:
A mixture of 20 g of 2-methoxy-6,11-dihydrodibenz[b,e]oxepin-11-one and 150 g of pyridine hydrochloride is stirred with heating at 180° C for 2 hours. The solution is poured into 2 liter of water with stirring to give 15 g of 2-hydroxy-6,11-dihydrodibenz[b,e]oxepin-11-one. Mass spectrum m/z: 226(M+), melting point: 165°-166° C. (recrystallized from ethanol).
Reaction SMILES: Cl[C:2]1[C:3]2[CH:14]=[C:13]([Cl:15])[CH:12]=[CH:11][C:4]=2[N:5]([CH3:10])[C:6](=[O:9])[CH2:7][N:8]=1.COCCOC.C([O-])([O-])=O.[Na+].[Na+].[CH3:28][O:29][C:30]1[CH:35]=[CH:34][C:33](B(O)O)=[CH:32][CH:31]=1>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CCOC(C)=O>[Cl:15][C:13]1[CH:12]=[CH:11][C:4]2[N:5]([CH3:10])[C:6](=[O:9])[CH2:7][N:8]=[C:2]([C:33]3[CH:34]=[CH:35][C:30]([O:29][CH3:28])=[CH:31][CH:32]=3)[C:3]=2[CH:14]=1
Reactant: COc1ccc(B(O)O)cc1
Reactant: CN1C(=O)CN=C(Cl)c2cc(Cl)ccc21
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: COCCOC
Product: COc1ccc(C2=NCC(=O)N(C)c3ccc(Cl)cc32)cc1
Temperature: 85 °C
Reaction time: 2 h
Yield: 109.4 %

Procedure:
In a 1 L 3-neck RBF equipped with magnetic stir bar, condenser, thermocouple, and N2 inlet, crude D1 (30 g, 0.124 mol) was dissolved into 300 mL of ethylene glycol dimethyl ether (DME). To this was added a solution of Na2CO3 (21 g, 0.2 mol in 200 mL of H2O) followed by addition of 4-methoxyphenyl boronic acid (22 g, 0.145 mol) and Pd(PPh3)4 (1.2 g, 8.3 mmol). The reaction mixture was heated in a 85° C. oil bath, under N2, for 2 h and then cool to room temp. To this was added 200 mL of EtOAc and the mixture stirred for 5 min. The organic layer was separated and washed with H2O (200 mL) and brine (200 mL). The organic layer was dried over MgSO4 and then concentrated to dryness to give 53 g of crude product. This material was subjected to silica gel chromatography using 210 g of silica gel and EtOAc/hepatene (12:88 to 30:70 to 50:50 to 70:30; total of 8 L mobile phase). Fractions containing pure product were combined and concentrated to dryness to give 42.7 g of pure product in approximately quantitative yield. 1H NMR (300 MHz, CDCl3) δ 3.38 (s, 3H), 3.73 (d, 1H), 3.85 (s, 3H), 4.75 (d, 1H), 6.9 (m, 2H), 7.31 (m, 2H), 7.48-7.58 (m, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([S:8]([CH:11]2[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]2)(=[O:10])=[O:9])[CH:5]=[CH:6][CH:7]=1.Cl[C:18]1[C:23]([N+:24]([O-:26])=[O:25])=[CH:22][CH:21]=[CH:20][N:19]=1.CCN(C(C)C)C(C)C>O1CCOCC1>[Cl:1][C:2]1[CH:3]=[C:4]([S:8]([CH:11]2[CH2:16][CH2:15][N:14]([C:18]3[C:23]([N+:24]([O-:26])=[O:25])=[CH:22][CH:21]=[CH:20][N:19]=3)[CH2:13][CH2:12]2)(=[O:10])=[O:9])[CH:5]=[CH:6][CH:7]=1
Reactant: O=S(=O)(c1cccc(Cl)c1)C1CCNCC1
Reactant: O=[N+]([O-])c1cccnc1Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: C1COCCO1
Product: O=[N+]([O-])c1cccnc1N1CCC(S(=O)(=O)c2cccc(Cl)c2)CC1
Yield: 81.3 %

Procedure:
Using the procedure from Example 7A, 4-[(3-chlorophenyl)sulfonyl]piperidine (100 mg, 0.38 mmol) was reacted with 2-chloro-3-nitropyridine (122 mg, 0.76 mmol), DIEA (0.2 ml, 1.14) and 1,4-dioxane (0.3 ml) to afford the title compound (118 mg), a yellow solid, in 81% yield.
Reaction SMILES: C1(OC2C=CC=CC=2)C=CC=CC=1.[C:14]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[C:23]1[CH:32]=[C:31](C(O)=O)[C:30]2[C:25](=[CH:26][CH:27]=[C:28]([CH3:36])[CH:29]=2)[N:24]=1)([OH:16])=[O:15].C1(C)C=CC(S(O)(=O)=O)=CC=1.[OH-].[Na+]>O>[CH3:36][C:28]1[CH:29]=[C:30]2[C:25](=[CH:26][CH:27]=1)[N:24]=[C:23]([C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=1[C:14]([OH:16])=[O:15])[CH:32]=[CH:31]2
Reactant: Cc1ccc2nc(-c3ccccc3C(=O)O)cc(C(=O)O)c2c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: c1ccc(Oc2ccccc2)cc1
Product: Cc1ccc2nc(-c3ccccc3C(=O)O)ccc2c1
Temperature: 160 °C
Yield: 46.7 %

Procedure:
To 1 ml of diphenyl ether were added 0.2 g of the 2-(2-carboxyphenyl)-6-methyl-4-quinolinecarboxylic acid obtained in Example 2. After adding 123 mg of p-toluenesulfonic acid, the mixture was heated at 160° C. for 1 hour. Then the reaction mixture was poured into water, made alkaline by adding sodium hydroxide and washed with ethyl acetate. The aqueous layer was neutralized with 3M hydrochloric acid until a precipitate was formed. After extracting with ethyl acetate, 80 mg of 2-(6-methylquinolin-2-yl)benzoic acid were obtained. NMR (270 MHz, CD3OD): δ 7.58-8.32 (m,9H); 2.58 (s,3H).
Reaction SMILES: FC(F)(F)C(O)=O.[Cl:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH2:20][CH2:19][N:18]([C@H:21]3[CH2:26][CH2:25][CH2:24][N:23](C(OC(C)(C)C)=O)[CH2:22]3)[CH2:17][CH:16]=2)=[CH:11][C:10]=1[NH:34][C@@H:35]([C:37]1[CH:42]=[CH:41][C:40]([Cl:43])=[CH:39][C:38]=1[Cl:44])[CH3:36]>ClCCl>[Cl:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH2:20][CH2:19][N:18]([C@H:21]3[CH2:26][CH2:25][CH2:24][NH:23][CH2:22]3)[CH2:17][CH:16]=2)=[CH:11][C:10]=1[NH:34][C@@H:35]([C:37]1[CH:42]=[CH:41][C:40]([Cl:43])=[CH:39][C:38]=1[Cl:44])[CH3:36]
Reactant: C[C@@H](Nc1cc(C2=CCN([C@H]3CCCN(C(=O)OC(C)(C)C)C3)CC2)ccc1Cl)c1ccc(Cl)cc1Cl
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: C[C@@H](Nc1cc(C2=CCN([C@H]3CCCNC3)CC2)ccc1Cl)c1ccc(Cl)cc1Cl
Reaction time: 1 h

Procedure:
Trifluoroacetic acid (1.5 mL) was added to a solution of (S)-t-butyl 3-(4-(4-chloro-3-((R)-1-(2,4-dichlorophenyl)ethylamino)phenyl)-5,6-dihydropyridin-1(2H)-yl)piperidine-1-carboxylate (0.83 g, 1.5 mmol) in dichloromethane (3 mL) at room temperature, and the solution was stirred for 1 h. Excess solvent was removed in vacuo, and the residue was diluted with dichloromethane. The organic layer was neutralized with aqueous saturated sodium bicarbonate solution, and the aqueous layer was further extracted with dichloromethane. The combined organic layers were dried (Na2SO4), filtered, and concentrated in vacuo. The crude product was used without further purification (0.65 g, 1.4 mmol, 96%). MS: (ES) m/z calculated for C24H29ClN3 [M+H]+ 464.1. found 464.
Reaction SMILES: Br[CH2:2][CH2:3][C:4]([O:6]CC)=[O:5].[NH:9]1[C:13]([C:14]2[CH:15]=[CH:16][C:17]3[C:18](=[O:30])[C:19]4[C:24]([S:25](=[O:29])(=[O:28])[C:26]=3[CH:27]=2)=[CH:23][CH:22]=[CH:21][CH:20]=4)=[N:12][N:11]=[N:10]1.[OH-].[Na+]>CC(C)=O.O>[C:4]([CH2:3][CH2:2][N:9]1[C:13]([C:14]2[CH:15]=[CH:16][C:17]3[C:18](=[O:30])[C:19]4[C:24]([S:25](=[O:28])(=[O:29])[C:26]=3[CH:27]=2)=[CH:23][CH:22]=[CH:21][CH:20]=4)=[N:12][N:11]=[N:10]1)([OH:6])=[O:5]
Reactant: CCOC(=O)CCBr
Reactant: O=C1c2ccccc2S(=O)(=O)c2cc(-c3nnn[nH]3)ccc21
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC(C)=O
Product: O=C(O)CCn1nnnc1-c1ccc2c(c1)S(=O)(=O)c1ccccc1C2=O

Procedure:
Ethyl 3-bromopropionate (9.05 g) in acetone (70 ml) was added to 3-(5-tetrazolyl)thioxanthone-10,10-dioxide (15.6 g) and sodium hydroxide (2.0 g) in water (15 ml). The mixture was boiled under reflux for 8 hr. On cooling the ester product crystallised out and was filtered off, washed with dilute sodium bicarbonate solution, and recrystallised from ethanol, m.p. 143°-145° C. The ester (4.5 g) was boiled with a mixture of concentrated hydrochloric acid (40 ml) and acetic acid (120 ml) for 3 hr. On cooling, 3-((2-carboxyethyl)-5-tetrazolyl)thioxanthone-10,10-dioxide crystallised out and was filtered off and washed with water, m.p. 206°-207° C.