Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]2[N:17]([C:18]3[CH:33]=[CH:32][C:21]([CH2:22][NH:23][C:24](=[O:31])[C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=4)=[CH:20][CH:19]=3)[C:11]3=[N:12][CH:13]=[C:14](Br)[CH:15]=[C:10]3[N:9]=2)=[CH:6][CH:5]=[CH:4][N:3]=1.[OH:34][CH2:35][C:36]1[CH:41]=[CH:40][C:39](B(O)O)=[CH:38][CH:37]=1>CN(C=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>[NH2:1][C:2]1[C:7]([C:8]2[N:17]([C:18]3[CH:33]=[CH:32][C:21]([CH2:22][NH:23][C:24](=[O:31])[C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=4)=[CH:20][CH:19]=3)[C:11]3=[N:12][CH:13]=[C:14]([C:39]4[CH:40]=[CH:41][C:36]([CH2:35][OH:34])=[CH:37][CH:38]=4)[CH:15]=[C:10]3[N:9]=2)=[CH:6][CH:5]=[CH:4][N:3]=1
Reactant: OCc1ccc(B(O)O)cc1
Reactant: Nc1ncccc1-c1nc2cc(Br)cnc2n1-c1ccc(CNC(=O)c2ccccc2)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Product: Nc1ncccc1-c1nc2cc(-c3ccc(CO)cc3)cnc2n1-c1ccc(CNC(=O)c2ccccc2)cc1
Temperature: 150 °C

Procedure:
N-(4-(2-(2-aminopyridin-3-yl)-6-bromo-3H-imidazo[4,5-b]pyridin-3-yl)benzyl)benzamide (62.4 mg, 0.125 mmol), CsCO3 (40.6 mg, 0.125 mmol), Pd(PPh3)4 (14.4 mg, 0.013 mmol) and 4-(hydroxymethyl)phenylboronic acid (33.5 mg, 0.25 mmol) were dissolved in DMF (3 mL). The reaction mixture was heated to 150° C. for 15 min and after cooling to room temperature filtered through a Bakerbond filtration column. The reaction mixture was directly purified by reversed phase HPLC to give the desired product as the mono-TFA salt (21 mg, 25% yield). Mp. 171-174° C.; 400 M Hz 1H NMR (DMSO-d6) δ: 9.15 (t, J=6 Hz, 1H), 8.68-8.64 (m, 1H), 8.5-8.47 (m, 1H), 8.08-8.03 (m, 1H), 7.96-7.9 (m, 3H), 7.77-7.72 (m, 3H), 7.6-7.42 (m, 8H), 4.63-4.53 (m, 4H); LCMS [M+H]: 527.
Reaction SMILES: [OH:1][C:2]1[C:10]2[C:5](=[N:6][CH:7]=[CH:8][CH:9]=2)[O:4][C:3]=1C(OCC)=O>Cl>[O:4]1[C:5]2=[N:6][CH:7]=[CH:8][CH:9]=[C:10]2[C:2](=[O:1])[CH2:3]1
Reactant: CCOC(=O)c1oc2ncccc2c1O
Agent: Cl
Product: O=C1COc2ncccc21

Procedure:
Ethyl 3-hydroxyfuro[2,3-b]pyridine-2-carboxylate (3.0 g, 11.23 mmol) was heated under reflux in 10% hydrochloric acid (50 mL) for 3 h. Evaporation of the hydrochloric acid solution gave furo[2,3-b]pyridin-3(2H)-one as the hydrochloride salt (1.73 g). A portion of the furo[2,3-b]pyridin-3(2H)-one hydrochloride was converted to its free base by treated with saturated sodium bicarbonate and extracted with chloroform in preparation for the following step.
Reaction SMILES: COC1C=CC([NH:9][C:10]2[C:15]([F:16])=[C:14]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=3)[N:13]=[C:12]([C:24]([O:26][CH3:27])=[O:25])[CH:11]=2)=CC=1.[Cl:28]N1C(C)(C)C(=O)N(Cl)C1=O.S(=O)(=O)(O)O.C(Cl)Cl>C(#N)C.O>[NH2:9][C:10]1[C:15]([F:16])=[C:14]([C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=2)[N:13]=[C:12]([C:24]([O:26][CH3:27])=[O:25])[C:11]=1[Cl:28]
Reactant: CC1(C)C(=O)N(Cl)C(=O)N1Cl
Reactant: COC(=O)c1cc(Nc2ccc(OC)cc2)c(F)c(-c2ccc(Cl)cc2)n1
Agent: O=S(=O)(O)O
Solvent: O
Solvent: CC#N
Solvent: ClCCl
Product: COC(=O)c1nc(-c2ccc(Cl)cc2)c(F)c(N)c1Cl

Procedure:
In a typical reaction accomplishing both chlorination and deprotection, methyl 4-(4-methoxyphenylamino)-5-fluoro-6-(4-chlorophenyl)picolinate is reacted with about two equivalents of 1,3-dichloro-5,5-dimethylimidazolidine-2,4-dione in the presence of a 1 M (molar) solution of sulfuric acid in a mixture of acetonitrile/water. The mixture is heated at reflux until the reaction is complete. The mixture is added to methylene chloride and the organic layer is separated, washed with brine and dried. The solvent is evaporated to provide crude methyl 4-amino-5-fluoro-3-chloro-6-(4-chlorophenyl)picolinate.
Reaction SMILES: [CH3:1][C:2]1[C:10]2[C:9]([CH3:12])([CH3:11])[CH2:8][CH2:7][S:6](=[O:14])(=[O:13])[C:5]=2[S:4][C:3]=1[C:15]([OH:17])=[O:16].C(Cl)(=O)C(Cl)=O.[CH2:24]([N:26]1[C:30](O)=[CH:29][CH:28]=[N:27]1)[CH3:25].C(N(CC)CC)C>CN(C)C=O.C(Cl)Cl>[CH3:1][C:2]1[C:10]2[C:9]([CH3:12])([CH3:11])[CH2:8][CH2:7][S:6](=[O:13])(=[O:14])[C:5]=2[S:4][C:3]=1[C:15]([O:17][C:30]1[N:26]([CH2:24][CH3:25])[N:27]=[CH:28][CH:29]=1)=[O:16]
Reactant: Cc1c(C(=O)O)sc2c1C(C)(C)CCS2(=O)=O
Reactant: CCn1nccc1O
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCn1nccc1OC(=O)c1sc2c(c1C)C(C)(C)CCS2(=O)=O
Temperature: 0 °C
Reaction time: 8 h
Yield: 58.4 %

Procedure:
2.0 g (0.0073 mol) of the title compound of Step D of Example 1 was added to 50 mL of methylene chloride. 1.27 mL (0.0146 mol) of oxalyl chloride (purchased from Janssen) was added followed by 2 drops of N,N-dimethylformamide. The mixture was refluxed under nitrogen for 2 h and was then evaporated to dryness. 50 mL of methylene chloride was added to the residue and evaporated to dryness. Another 50 mL of methylene chloride was added to the residue and the solution was cooled to about 0° C. 0.90 g (0.0080 mol) of 1-ethyl-1H-pyrazol-5-ol was added to the mixture followed by 2.8 mL (0.0020 mol) of triethylamine and the mixture was stirred overnight while warming to room temperature. The mixture was evaporated to dryness. The residue was stirred in 100 mL of water and the water was decanted. The residue was washed with hexane (2×100 mL) and then chromatographed on silica gel eluting with 4:6 ethyl acetate/hexane to yield 1.57 g of the title compound of Step A as a solid melting at 119°-120° C. 1H NMR (CDCl3): δ 1.4 (t, 3H), 1.5 (s, 6H), 2.5 (m, 2H), 2.8 (s, 3H), 3.4 (m, 2H), 4.1 (q, 2H), 6.2 (d, 1H), 7.5 (d, 1H).
Reaction SMILES: B(Cl)(Cl)Cl.C([O:8][C:9]1[CH:10]=[C:11]([C:15]2[C:23]3[C:22]([OH:24])=[C:21]([C:25]#[N:26])[C:20](=[O:27])[NH:19][C:18]=3[S:17][CH:16]=2)[CH:12]=[CH:13][CH:14]=1)C=C>ClCCl>[OH:24][C:22]1[C:23]2[C:15]([C:11]3[CH:12]=[CH:13][CH:14]=[C:9]([OH:8])[CH:10]=3)=[CH:16][S:17][C:18]=2[NH:19][C:20](=[O:27])[C:21]=1[C:25]#[N:26]
Reactant: C=CCOc1cccc(-c2csc3[nH]c(=O)c(C#N)c(O)c23)c1
Agent: ClB(Cl)Cl
Solvent: ClCCl
Product: N#Cc1c(O)c2c(-c3cccc(O)c3)csc2[nH]c1=O
Temperature: 25 °C
Reaction time: 16 h

Procedure:
Boron trichloride (1M in dichloromethane, 5 mL, 5 mmol) was added to a solution of 3-[3-(allyloxy)phenyl]-4-hydroxy-6-oxo-6,7-dihydrothieno[2,3-b]pyridine-5-carbonitrile (146B) (0.54 g, 1.65 mmol) in dichloromethane (30 mL) and the reaction was stirred at room temperature for 16 h. It was quenched with water (20 mL), filtered, concentrated and purified on a RP-HPLC system. The title compound was one of the three reaction products that were purified. MS (ESI) m/e 283.0 (M−H)+; 1H NMR (500 MHz, DMSO-d6): δ ppm 12.46 (br s, 1H), 9.36 (br s, 1H), 7.14 (t, 1H), 6.96 (s, 1H), 6.83–6.80 (m, 2H), 6.7–6.72 (m, 1H).
Reaction SMILES: [C:1]1([C:18]([OH:20])=[O:19])[C:14]2[C:5](=[CH:6][C:7]3[C:12]([C:13]=2[C:15]([OH:17])=O)=[CH:11][CH:10]=[CH:9][CH:8]=3)[CH:4]=[CH:3][CH:2]=1>C(OC(=O)C)(=O)C>[C:1]12[C:18](=[O:19])[O:20][C:15](=[O:17])[C:13]3=[C:14]1[C:5](=[CH:6][C:7]1[C:12]3=[CH:11][CH:10]=[CH:9][CH:8]=1)[CH:4]=[CH:3][CH:2]=2
Reactant: O=C(O)c1cccc2cc3ccccc3c(C(=O)O)c12
Solvent: CC(=O)OC(C)=O
Product: O=C1OC(=O)c2c3ccccc3cc3cccc1c23
Yield: 84.2 %

Procedure:
A suspension of 6.5 g of anthracene-1,9-dicarboxylic acid (E. D. Bergmann and R. Ikan, J. Org. Chem., 23, 907 (1958)) in 100 ml of acetic anhydride was heated at reflux for 3 hours. The mixture was cooled and the orange precipitate was collected by filtration, washed with ether and dried in air to give 5.1 g (68%) of the title compound. Recrystallization from dimethylsulfoxide or toluene gave orange plates with melting point 289°-290° C.
Reaction SMILES: [CH2:1]([N:5]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([C:15]([O:17]C)=[O:16])[CH:13]=2)[CH2:8][CH2:7][CH2:6]1)[CH2:2][CH2:3][CH3:4].[OH-].[K+]>CO.O>[CH2:1]([N:5]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([C:15]([OH:17])=[O:16])[CH:13]=2)[CH2:8][CH2:7][CH2:6]1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCN1CCCc2ccc(C(=O)OC)cc21
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CCCCN1CCCc2ccc(C(=O)O)cc21
Temperature: 25 °C
Reaction time: 48 h
Yield: 94.6 %

Procedure:
To a stirred solution of methyl 1-butyl-1,2,3,4-tetrahydroquinoline-7-carboxylate (156 mg, 0.63 mmol) in methanol (1.3 mL) was added potassium hydroxide (6.3 mL of a 1 M solution in water, 6.3 mmol). The reaction mixture was stirred at room temperature for 48 h and concentrated under reduced pressure. The residue was diluted with water and washed with ethyl acetate. The aqueous layer was acidified to pH 4 with 1 N hydrochloric acid and extracted with chloroform (4×100 mL). The combined organic extracts were dried (sodium sulfate), filtered, and concentrated under reduced pressure. Purification by flash column chromatography (silica, 1:9 methanol/chloroform) afforded 1-butyl-1,2,3,4-tetrahydroquinoline-7-carboxylic acid (139 mg): ESI MS m/z 234 [M+H]+.
Reaction SMILES: [CH2:1]([N:8]1[C:16]2[C:11](=[CH:12][C:13]([O:17][CH2:18][O:19][CH3:20])=[CH:14][CH:15]=2)[C:10]([CH:21]=O)=[C:9]1[CH:23]([CH3:25])[CH3:24])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:26][C:27]1[CH:28]=[C:29]([CH:32]=[C:33]([F:35])[CH:34]=1)[CH2:30][NH2:31].C([BH3-])#N.[Na+]>CO.C(O)(=O)C>[CH2:1]([N:8]1[C:16]2[C:11](=[CH:12][C:13]([O:17][CH2:18][O:19][CH3:20])=[CH:14][CH:15]=2)[C:10]([CH2:21][NH:31][CH2:30][C:29]2[CH:28]=[C:27]([F:26])[CH:34]=[C:33]([F:35])[CH:32]=2)=[C:9]1[CH:23]([CH3:25])[CH3:24])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COCOc1ccc2c(c1)c(C=O)c(C(C)C)n2Cc1ccccc1
Reactant: NCc1cc(F)cc(F)c1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: COCOc1ccc2c(c1)c(CNCc1cc(F)cc(F)c1)c(C(C)C)n2Cc1ccccc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 1-benzyl-2-isopropyl-5-(methoxymethoxy)-1H-indole-3-carboxaldehyde (Compound 4, 103 mg, 0.31 mmol) in methanol (5.0 ml) was added 3,5-difluorobenzylamine (49 μl, 0.40 mmol), and acetic acid (2 drops). After stirring at room temperature for 1 h, sodium cyanoborohydride (29 mg, 0.47 mmol) was added and the reaction was stirred for 5 h. More 3,5-difluorobenzylamine (50 μl, 0.40 mmol) was added, and the reaction was stirred for 64 h. The solvent was removed and the crude reaction mixture was purified by flash chromatography on silica gel eluting with 10-50% EtOAc-hexanes to yield 1-(1-benzyl-2-isopropyl-5-(methoxymethoxy)-1H-indol-3-yl)-N-(3,5-difluorobenzyl)methanamine (Compound 5) as a light greenish yellow oil.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:12]([F:15])([F:14])[F:13])=[C:6]([S:8](Cl)(=[O:10])=[O:9])[CH:7]=1.[NH:16]1[CH2:21][CH2:20][O:19][CH2:18][CH2:17]1>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:12]([F:15])([F:14])[F:13])=[C:6]([S:8]([N:16]2[CH2:21][CH2:20][O:19][CH2:18][CH2:17]2)(=[O:10])=[O:9])[CH:7]=1
Reactant: C1COCCN1
Reactant: O=S(=O)(Cl)c1cc(Cl)ccc1C(F)(F)F
Solvent: ClCCl
Product: O=S(=O)(c1cc(Cl)ccc1C(F)(F)F)N1CCOCC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
5-Chloro-2-trifluoromethyl-benzenesulfonyl chloride (0.17 g, 0.62 mmol) is added to a solution of morphline (0.114 ml, 1.3 mol) in DCM (5 ml) and the resulting white suspension is stirred at room temperature overnight. The reaction mixture is diluted with DCM (5 ml), and washed with 0.1M HCl, dried (MgSO4) and concentrated in vacuo to yield the title compound. [M+H]+ 330.
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1O)=[O:4].[CH2:14]([C@H:19]1[CH2:24][CH2:23][C@H:22]([CH2:25]Br)[CH2:21][CH2:20]1)[CH2:15][CH2:16][CH2:17][CH3:18].C([O-])([O-])=[O:28].[K+].[K+]>CN(C=O)C>[CH2:14]([C@H:19]1[CH2:24][CH2:23][C@H:22]([CH2:25][O:28][C:8]2[CH:9]=[CH:10][C:5]([C:3](=[O:4])[C:2]([F:13])([F:12])[F:1])=[CH:6][CH:7]=2)[CH2:21][CH2:20]1)[CH2:15][CH2:16][CH2:17][CH3:18]
Reactant: CCCCC[C@H]1CC[C@H](CBr)CC1
Reactant: O=C(c1ccccc1O)C(F)(F)F
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCCCC[C@H]1CC[C@H](COc2ccc(C(=O)C(F)(F)F)cc2)CC1
Temperature: 140 °C

Procedure:
A mixture of 0.1 mol of trifluoroacetylphenol, 0.11 mol of trans-4-pentylcyclohexylmethyl bromide, 0.3 mol of K2CO3 and 250 ml DMF is heated at 140° C. for 10 hours. Customary work-up and crystallization give 4-(trans-4-pentylcyclohexylmethoxy)-1-trifluoroacetylbenzene, mp. 60° C., Δε=13.7.
Reaction SMILES: C(OC([N:8]1[CH2:12][C:11](=[N:13][O:14][CH3:15])[CH2:10][C@H:9]1[C:16]([OH:18])=O)=O)(C)(C)C.[C:19]1([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[CH:24]=[CH:23][C:22]([S:25](Cl)(=[O:27])=[O:26])=[CH:21][CH:20]=1.[NH2:35][C@@H:36]1[CH2:41][CH2:40][CH2:39][CH2:38][C@H:37]1[CH2:42][OH:43]>>[C:19]1([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[CH:24]=[CH:23][C:22]([S:25]([N:8]2[CH2:12][C:11](=[N:13][O:14][CH3:15])[CH2:10][C@H:9]2[C:16]([NH:35][C@@H:36]2[CH2:41][CH2:40][CH2:39][CH2:38][C@H:37]2[CH2:42][OH:43])=[O:18])(=[O:27])=[O:26])=[CH:21][CH:20]=1
Reactant: CON=C1C[C@@H](C(=O)O)N(C(=O)OC(C)(C)C)C1
Reactant: N[C@@H]1CCCC[C@H]1CO
Reactant: O=S(=O)(Cl)c1ccc(-c2ccccc2)cc1
Product: CON=C1C[C@@H](C(=O)N[C@@H]2CCCC[C@H]2CO)N(S(=O)(=O)c2ccc(-c3ccccc3)cc2)C1

Procedure:
Following the general method as outlined in Example 22, starting from (2S,4EZ)-1-(tert-butoxycarbonyl)-4-(methoxyimino)-2-pyrrolidinecarboxylic acid, [1,1′-biphenyl]-4-sulfonyl chloride, and [(1R,2R)-2-aminocyclohexyl]methanol, the title compound was obtained in 40% purity by HPLC. MS(ESI+): m/z=486.
Reaction SMILES: [CH2:1]([C:5]1[N:6]=[C:7]([Cl:15])[C:8]2[NH:13][CH:12]=[C:11]([I:14])[C:9]=2[N:10]=1)[CH2:2][CH2:3][CH3:4].[CH2:16](C1N=C(Cl)C2NC(C)=CC=2N=1)CCC>>[CH2:1]([C:5]1[N:6]=[C:7]([Cl:15])[C:8]2[NH:13][C:12]([CH3:16])=[C:11]([I:14])[C:9]=2[N:10]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1nc(Cl)c2[nH]c(C)cc2n1
Reactant: CCCCc1nc(Cl)c2[nH]cc(I)c2n1
Product: CCCCc1nc(Cl)c2[nH]c(C)c(I)c2n1

Procedure:
Prepared similarly to Intermediate 4 from. 2-butyl-4-chloro-6-methyl-5H-pyrrolo[3,2-d]pyrimidine.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:25])[CH2:5][C@@H:6]([NH:13][C:14]1[C:19]([N+:20]([O-])=O)=[CH:18][CH:17]=[C:16]([C:23]#[N:24])[N:15]=1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[CH3:2]>CCO.[Pd]>[CH2:1]([O:3][C:4](=[O:25])[CH2:5][C@@H:6]([NH:13][C:14]1[C:19]([NH2:20])=[CH:18][CH:17]=[C:16]([C:23]#[N:24])[N:15]=1)[C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1)[CH3:2]
Reactant: CCOC(=O)C[C@@H](Nc1nc(C#N)ccc1[N+](=O)[O-])c1ccccc1
Agent: [Pd]
Solvent: CCO
Product: CCOC(=O)C[C@@H](Nc1nc(C#N)ccc1N)c1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 93.8 %

Procedure:
To a solution of (R)-3-(6-cyano-3-nitro-pyridin-2-ylamino)-3-phenyl-propionic acid ethyl ester (0.70 g, 2.06 mmol) in EtOH (20 mL) was added Pd/C (140 mg). The reaction mixture was de-gassed using house vacuum and saturated with H2. The reaction mixture was stirred at room temperature for 2 hours. The mixture was filtered through a pad of celite and the filtrate was concentrated to afford 0.60 g (94%) of the title compound, which was used for the next reaction without further purification.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([S:9][CH2:10][C:11]([OH:28])([CH3:27])[C:12]([NH:14][C:15]2[CH:20]=[CH:19][C:18]([C:21]#[N:22])=[C:17]([C:23]([F:26])([F:25])[F:24])[CH:16]=2)=[O:13])[CH:6]=[CH:7][CH:8]=1.OO.FC(F)(F)C(OC(=O)C(F)(F)F)=O.[OH2:44].[Cl-].[Na+].[OH2:47]>ClCCl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([S:9]([CH2:10][C:11]([OH:28])([CH3:27])[C:12]([NH:14][C:15]2[CH:20]=[CH:19][C:18]([C:21]#[N:22])=[C:17]([C:23]([F:24])([F:25])[F:26])[CH:16]=2)=[O:13])(=[O:47])=[O:44])[CH:6]=[CH:7][CH:8]=1
Reactant: COc1cccc(SCC(C)(O)C(=O)Nc2ccc(C#N)c(C(F)(F)F)c2)c1
Reactant: O
Agent: OO
Agent: [Cl-]
Agent: [Na+]
Solvent: ClCCl
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Product: COc1cccc(S(=O)(=O)CC(C)(O)C(=O)Nc2ccc(C#N)c(C(F)(F)F)c2)c1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 3-(3-methoxyphenylthio)-N-(4-Cyano-3-(trifluoromethyl)phenyl)-2-hydroxy-2-methylpropanamide (29 mg, 0.07 mmol) in dichloromethane (0.18 mL) at −78° C. was added 30% hydrogen peroxide (16 μL, 0.57 mmol) followed by the slow addition of trifluoroacetic anhydride (60 μL, 0.45 mmol). The reaction was stirred at room temperature for 16 h. The reaction was diluted with dichloromethane. Cold water and brine were added, and the reaction was stirred for 20 minutes. The organic layer was separated, dried over magnesium sulfate, filtered and evaporated. Purification by column chromatography (hexane:EtOAc 50:50) yielded 19 mg of desired product. Production of PLM5 was confirmed by 1-H NMR, 13-C NMR, and mass spectral analysis.
Reaction SMILES: Br[CH2:2][CH:3]1[O:8][C:7]2[CH:9]=[C:10]([S:14]([CH3:17])(=[O:16])=[O:15])[CH:11]=[C:12]([F:13])[C:6]=2[CH2:5][O:4]1.[CH2:18]([NH2:22])[CH2:19][CH2:20][CH3:21]>CCO>[F:13][C:12]1[C:6]2[CH2:5][O:4][CH:3]([CH2:2][NH:22][CH2:18][CH2:19][CH2:20][CH3:21])[O:8][C:7]=2[CH:9]=[C:10]([S:14]([CH3:17])(=[O:16])=[O:15])[CH:11]=1
Reactant: CS(=O)(=O)c1cc(F)c2c(c1)OC(CBr)OC2
Reactant: CCCCN
Solvent: CCO
Product: CCCCNCC1OCc2c(F)cc(S(C)(=O)=O)cc2O1

Procedure:
Preparation according to Example 34 using 2-(bromomethyl)-5-fluoro-7-(methylsulfonyl)-4H-1,3-benzodioxine (7 mg, 0.021 mmol), butane-1-amine (0.5 ml) and EtOH (3 ml). MS m/z (rel. intensity, 70 eV) 317 (M+, 0.3), 141 (11), 95 (11), 86 (bp), 72 (13), 57 (9).
Reaction SMILES: [F:1][C:2]1[CH:22]=[CH:21][C:5]([CH2:6][N:7]2[CH:16]=[CH:15][C:14]3[C:9](=[CH:10][CH:11]=[CH:12][C:13]=3[N+:17]([O-])=O)[C:8]2=[O:20])=[CH:4][CH:3]=1.O.O.[Sn](Cl)Cl.O1CCCC1>>[NH2:17][C:13]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:14]=1[CH:15]=[CH:16][N:7]([CH2:6][C:5]1[CH:4]=[CH:3][C:2]([F:1])=[CH:22][CH:21]=1)[C:8]2=[O:20]
Reactant: O=c1c2cccc([N+](=O)[O-])c2ccn1Cc1ccc(F)cc1
Agent: Cl[Sn]Cl
Solvent: C1CCOC1
Solvent: O
Product: Nc1cccc2c(=O)n(Cc3ccc(F)cc3)ccc12

Procedure:
2-(4-Fluorobenzyl)-5-nitroisoquinolin-1(2H)-one (0.66 g, 0.0022 mol) and tin dichloride dihydrate (2 g, 0.009 mol) were stirred in tetrahydrofuran (20 mL, 0.2 mol) at room temperature overnight. The volatiles were removed via rotovapor, and the residue was dissolved in MeOH, filter through a pad of basic alumina and concentrated to dryness to give the title compound as a brown oil. MS m/z (M+H) 268.8.
Reaction SMILES: Cl.Cl.[O:3]1[C:7]2[CH:8]=[CH:9][C:10]([C:12]3([CH2:18][CH2:19][N:20]4[CH:25]5[CH2:26][CH2:27][CH:21]4[CH2:22][CH:23]([N:28]4[C:32]6[CH:33]=[CH:34][CH:35]=[CH:36][C:31]=6[N:30]=[C:29]4[CH3:37])[CH2:24]5)[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]3)=[CH:11][C:6]=2[O:5][CH2:4]1.C(N(CC)CC)C.[C:45](O)(=[O:49])[CH:46]([CH3:48])[CH3:47].F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1>CN(C)C=O.O>[O:3]1[C:7]2[CH:8]=[CH:9][C:10]([C:12]3([CH2:18][CH2:19][N:20]4[C@H:25]5[CH2:26][CH2:27][C@@H:21]4[CH2:22][CH:23]([N:28]4[C:32]6[CH:33]=[CH:34][CH:35]=[CH:36][C:31]=6[N:30]=[C:29]4[CH3:37])[CH2:24]5)[CH2:13][CH2:14][N:15]([C:45](=[O:49])[CH:46]([CH3:48])[CH3:47])[CH2:16][CH2:17]3)=[CH:11][C:6]=2[O:5][CH2:4]1
Reactant: Cc1nc2ccccc2n1C1CC2CCC(C1)N2CCC1(c2ccc3c(c2)OCO3)CCNCC1
Reactant: CC(C)C(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: O
Product: Cc1nc2ccccc2n1C1C[C@H]2CC[C@@H](C1)N2CCC1(c2ccc3c(c2)OCO3)CCN(C(=O)C(C)C)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 70.9 %

Procedure:
A mixture of 1-(8-{2-[4-(1,3-benzodioxol-5-yl)piperidin-4-yl]ethyl}-8-azabicyclo[3.2.1]oct-3-yl)-2-methyl-1H-benzimidazole dihydrochloride (0.20 g, 0.39 mmol), triethylamine (0.17 mL, 1.25 mmol) and isobutyric acid (34 mg, 0.39 mmol) in dimethylformamide (1.25 mL) was treated with O-(7-azabenzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (163 mg, 0.43 mmol) and the resulting mixture was stirred for 1 h at rt. The mixture was diluted with water and the resulting precipitate was collected, washed with saturated sodium bicarbonate solution, with water and dried to give 1-((1R,5S)-8-{2-[4-(1,3-benzodioxol-5-yl)-1-isobutyrylpiperidin-4-yl]ethyl}-8-azabicyclo[3.2.1]oct-3-yl)-2-methyl-1H-benzimidazole as a solid (0.15 g, 72%). HRMS C33H42N4O3 m/z 543.3335 (M+H)Cal. 543.3322 (M+H)Obs..
Reaction SMILES: [CH3:1][N:2]1[C:14]2[C:13]3[CH:15]=[CH:16][CH:17]=[CH:18][C:12]=3[S:11][CH2:10][C:9]=2[C:8]2[C:3]1=[CH:4][CH:5]=[C:6]([OH:19])[CH:7]=2.[C:20](Cl)([C:22]([CH3:25])([CH3:24])[CH3:23])=[O:21]>>[CH3:1][N:2]1[C:14]2[C:13]3[CH:15]=[CH:16][CH:17]=[CH:18][C:12]=3[S:11][CH2:10][C:9]=2[C:8]2[C:3]1=[CH:4][CH:5]=[C:6]([O:19][C:20](=[O:21])[C:22]([CH3:25])([CH3:24])[CH3:23])[CH:7]=2
Reactant: CC(C)(C)C(=O)Cl
Reactant: Cn1c2c(c3cc(O)ccc31)CSc1ccccc1-2
Product: Cn1c2c(c3cc(OC(=O)C(C)(C)C)ccc31)CSc1ccccc1-2

Procedure:
Following the procedure in Example 80, using 11-methyl-6,11-dihydro-5-thia-11-aza-benzo[a]fluoren-8-ol (105 mg, 0.393 mmol) and PivCl (71 mg, 0.59 mmol) as the starting material, the title compound was prepared as a white solid.
Reaction SMILES: F[C:2]1[CH:10]=[C:9]([Br:11])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.S(Cl)(Cl)=O.[CH:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.[Cl-:22].[Cl-].[Cl-].[Al+3].Cl>CN(C=O)C>[Br:11][C:9]1[CH:8]=[CH:7][C:3]([C:4]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[O:6])=[C:2]([Cl:22])[CH:10]=1
Reactant: O=C(O)c1ccc(Br)cc1F
Reactant: c1ccccc1
Reactant: [Cl-]
Agent: Cl
Agent: [Al+3]
Solvent: O=S(Cl)Cl
Solvent: CN(C)C=O
Product: O=C(c1ccccc1)c1ccc(Br)cc1Cl
Temperature: 25 °C
Reaction time: 1 h

Procedure:
In an oven dried flask was added 2-fluoro-4-bromobenzoic acid (1.00 g, 4.25 mmol), thionyl chloride (0.77 mL, 0.010 mol) and a drop of DMF and the reaction was refluxed for 2 h. The excess thionyl chloride was then distilled off and the residual thionyl chloride was removed on the pump. Benzene (20 mL, 0.2 mol) and aluminum trichloride (0.676 g, 5.07 mmol) were added to the reaction mixture. The reaction mixture was stirred at room temp for 1 h. The crude reaction mixture was poured onto ice and conc. HCl (15 mL). The organic layer was separated and the aqueous layer extracted with EtOAc. The combined organic phases were washed with 5% aq NaOH solution, water and dried (Na2SO4). The organic phase was concentrated in vacuo to give a residue which was purified by silica gel chromatography, eluting with 2% EtOAc in hexane.
Reaction SMILES: [C:1]1([S:7][CH:8]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:9](O)=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH3:18]>C1C=CC=CC=1>[C:12]1([C:8]2[S:7][C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=3[C:9]=2[NH:18][C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: N
Reactant: O=C(O)C(Sc1ccccc1)c1ccccc1
Solvent: c1ccccc1
Product: c1ccc(Nc2c(-c3ccccc3)sc3ccccc23)cc1

Procedure:
3.0 g of anilide of phenylthio-phenyl acetic acid (colourless needles in a mixture of benzene and petroleum ether mp 142°-143°) in 130 g of polyphosphoric acid are heated to 100° for 19 hours. The cooled reaction mixture is poured onto water, made alkaline by concentrated ammonia and extracted with methylene chloride. By drying over sodium sulphate and evaporating the extracts of methylene chloride, 1.7 g (60.0% of theory) of yellow oil are obtained which are recrystallized in ethanol: 1.5 g (45% of theory) of yellow crystals, mp 150°-151° (ethanol).