Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Li]C(CC)C.CN(CCN(C)C)C.[CH3:14][O:15][C:16]1[CH:26]=[CH:25][C:19]2[CH2:20][C:21]([CH3:24])([CH3:23])[O:22][C:18]=2[CH:17]=1.[Li].[B:28](OC)([O:31]C)[O:29]C>C1COCC1>[CH3:14][O:15][C:16]1[CH:26]=[CH:25][C:19]2[CH2:20][C:21]([CH3:24])([CH3:23])[O:22][C:18]=2[C:17]=1[B:28]([OH:31])[OH:29]
Reactant: COB(OC)OC
Reactant: COc1ccc2c(c1)OC(C)(C)C2
Agent: CN(C)CCN(C)C
Agent: [Li]
Agent: [Li]C(C)CC
Solvent: C1CCOC1
Product: COc1ccc2c(c1B(O)O)OC(C)(C)C2
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 53 %

Procedure:
s-BuLi (35 mL, 1.3M in cyclohexane) was added to TMEDA (6.6 mL) at −78° C. drop wise within 30 min, 20 mL of THF was added to keep stirring. After 20 min, 6-methoxy-2,2-dimethyl-2,3-dihydrobenzofuran (5.4 g, 30.3 mmol) in THF (30 mL) was added into the lithium solution slowly. The solution was stirred at −78° C. for 1.5 h and trimethyl borate (18 mL) was added. The mixture was warmed to room temperature and stirred at room temperature overnight. The solution was acidified to pH=5-6 and extracted with ethyl acetate. The organic layer was concentrated and the resulted residue was purified on column chromatography (silica gel, dichloromethane/petroleum ether=3/1) to give the crude product, which was sonicated with petroleum ether. The white precipitate was filtered and dried to give 6-methoxy-2,2-dimethyl-2,3-dihydrobenzofuran-7-ylboronic acid (3.55 g, 53%) as a white solid.
Reaction SMILES: C([O:8][C:9]1[CH:14]=[CH:13][N:12]([CH2:15][CH2:16][CH:17]([CH3:19])[CH3:18])[C:11](=[O:20])[CH:10]=1)C1C=CC=CC=1.C([O-])=O.[NH4+]>O1CCCC1.[OH-].[OH-].[Pd+2]>[OH:8][C:9]1[CH:14]=[CH:13][N:12]([CH2:15][CH2:16][CH:17]([CH3:18])[CH3:19])[C:11](=[O:20])[CH:10]=1
Reactant: CC(C)CCn1ccc(OCc2ccccc2)cc1=O
Agent: [Pd+2]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CC(C)CCn1ccc(O)cc1=O
Yield: 99.1 %

Procedure:
The product of Example 457A (0.452 g, 1.67 mmol) in tetrahydrofuran (20 mL) was treated with ammonium formate (0.30 g, 5.01 mmol) and a catalytic amount of 20% palladium hydroxide on carbon at 60° C. for 2 hours. The reaction was filtered through diatomaceous earth and the filtrate concentrated under reduced pressure to provide the title compound (0.30 g, 100%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[CH2:16][CH2:15][C@@H:14]([CH2:17][C:18](=[O:39])[NH:19][C:20]3[CH:25]=[CH:24][C:23]([CH2:26][NH:27][C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])=[CH:22][C:21]=3[C:35]([O:37]C)=[O:36])[N:6]3[C:7](=[O:13])[C:8](=[O:12])[NH:9][C:10]([CH:11]=1)=[C:5]23.C1COCC1.CO>[OH-].[Na+]>[Br:1][C:2]1[CH:3]=[C:4]2[CH2:16][CH2:15][C@@H:14]([CH2:17][C:18](=[O:39])[NH:19][C:20]3[CH:25]=[CH:24][C:23]([CH2:26][NH:27][C:28]([O:30][C:31]([CH3:33])([CH3:34])[CH3:32])=[O:29])=[CH:22][C:21]=3[C:35]([OH:37])=[O:36])[N:6]3[C:7](=[O:13])[C:8](=[O:12])[NH:9][C:10]([CH:11]=1)=[C:5]23
Reactant: COC(=O)c1cc(CNC(=O)OC(C)(C)C)ccc1NC(=O)C[C@@H]1CCc2cc(Br)cc3[nH]c(=O)c(=O)n1c23
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: CC(C)(C)OC(=O)NCc1ccc(NC(=O)C[C@@H]2CCc3cc(Br)cc4[nH]c(=O)c(=O)n2c34)c(C(=O)O)c1
Temperature: 25 °C
Reaction time: 3.5 h
Yield: 97.6 %

Procedure:
A solution of (S)-9-bromo-5-[p-tert-butoxycarbonylaminomethyl-o-(methoxycarbonyl)phenylcarbamoylmethyl]-6,7-dihydro-1H, 5H-pyrido[1,2,3-de]quinoxaline-2,3-dione (680 mg, 1.06 mmol) in a mixture of 1N sodium hydroxide (6 mL), THF (6 mL), and methanol (6 mL) was stirred for 3.5 h at room temperature and the solvent was concentrated to ca. 6 mL. To the residue was added 5% potassium hydrogen sulfate and extracted with ethyl acetate. The organic layer was washed with water, dried over magnesium sulfate, and concentrated to give 608 mg of the title compound.
Reaction SMILES: [CH3:1][N:2]([CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH3:44])[CH2:3][CH:4]([OH:26])[CH2:5][O:6][C:7]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.[CH3:45][S:46](Cl)(=[O:48])=[O:47].O>C(OCC)C.ClCCl>[CH3:1][N:2]([CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH3:44])[CH2:3][CH:4]([O:26][S:46]([CH3:45])(=[O:48])=[O:47])[CH2:5][O:6][C:7]([C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1
Reactant: CCCCCCCCCCCCCCCCCCN(C)CC(O)COC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCOCC
Solvent: O
Product: CCCCCCCCCCCCCCCCCCN(C)CC(COC(c1ccccc1)(c1ccccc1)c1ccccc1)OS(C)(=O)=O
Yield: 82.1 %

Procedure:
18 g (30 mmol) of 2a was dissolved in 100 ml of dry diethyl ether and 50 ml of dichloromethane. 6.84 g (60 mmol) of methanesulphonyl chloride in 50 ml of dichloromethane was added under stirring, and the mixture was refluxed for 5 hours. Water was then added, and the organic phase was decanted, dried and evaporated. The crude product was chromatographed (eluent as in Step 2), yielding 16.7 g of 3a (80%).
Reaction SMILES: [BH4-].[Na+].[C:3]([N:6]1[C:14]2[C:9](=[CH:10][C:11]([C:15](=[O:21])[CH2:16][CH2:17][N:18]([CH3:20])[CH3:19])=[CH:12][CH:13]=2)[CH2:8][CH2:7]1)(=[O:5])[CH3:4].O>CO>[C:3]([N:6]1[C:14]2[C:9](=[CH:10][C:11]([CH:15]([OH:21])[CH2:16][CH2:17][N:18]([CH3:19])[CH3:20])=[CH:12][CH:13]=2)[CH2:8][CH2:7]1)(=[O:5])[CH3:4]
Reactant: CC(=O)N1CCc2cc(C(=O)CCN(C)C)ccc21
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: CC(=O)N1CCc2cc(C(O)CCN(C)C)ccc21
Temperature: 2.5 °C
Reaction time: 0.5 h
Yield: 76.2 %

Procedure:
Sodium borohydride (0.75 g) was added to a solution of 1-(1-acetyl-2,3-dihydro-1H-indol-5-yl)-3-(dimethylamino)-1-propanone (4.3 g) obtained in Reference Example 12 in methanol (40 ml) under cooling with ice-bath, and the mixture was stirred at 0 to 5° C. for 30 minutes. After iced water was added to the reaction solution, the solvent was distilled away under reduced pressure, and the residues were extracted with ethyl acetate. The extract was washed with a saturated saline solution and dried over anhydrous magnesium sulfate, and the solvent was distilled away under reduced pressure. The resultant residues were purified by alumina column chromatography (developing solvent; ethyl acetate), whereby 3-[1-acetyl-2,3-dihydro-1H-indol-5-yl]-3-hydroxy-N,N-dimethyl-1-propanamine (3.3 g) was obtained as colorless powder.
Reaction SMILES: [NH2:1][C@H:2]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[CH2:3][CH2:4][N:5]1[CH2:10][CH2:9][CH:8]([C:11]2[CH:12]=[C:13]([NH:17][C:18](=[O:22])[CH:19]([CH3:21])[CH3:20])[CH:14]=[CH:15][CH:16]=2)[CH2:7][CH2:6]1.[Cl:29][C:30]1[CH:31]=[C:32]([CH:36]=[C:37]([Cl:39])[CH:38]=1)[C:33](Cl)=[O:34]>>[Cl:29][C:30]1[CH:31]=[C:32]([CH:36]=[C:37]([Cl:39])[CH:38]=1)[C:33]([NH:1][C@H:2]([C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1)[CH2:3][CH2:4][N:5]1[CH2:10][CH2:9][CH:8]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([NH:17][C:18](=[O:22])[CH:19]([CH3:21])[CH3:20])[CH:12]=2)[CH2:7][CH2:6]1)=[O:34]
Reactant: O=C(Cl)c1cc(Cl)cc(Cl)c1
Reactant: CC(C)C(=O)Nc1cccc(C2CCN(CC[C@H](N)c3ccccc3)CC2)c1
Product: CC(C)C(=O)Nc1cccc(C2CCN(CC[C@H](NC(=O)c3cc(Cl)cc(Cl)c3)c3ccccc3)CC2)c1

Procedure:
Prepared by Procedure Q1 and Scheme AC using N-(3-{1-[(3S)-3-amino-3-phenylpropyl]-4-piperidinyl}phenyl)-2-methylpropanamide and 3,5-dichlorobenzoyl chloride: ESMS m/e: 552.3 (M+H)+.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][N:5]1[CH2:10][CH2:9][NH:8][CH2:7][CH2:6]1.Br[CH2:12][C:13]#[N:14]>>[CH3:1][O:2][CH2:3][CH2:4][N:5]1[CH2:10][CH2:9][N:8]([CH2:12][C:13]#[N:14])[CH2:7][CH2:6]1
Reactant: N#CCBr
Reactant: COCCN1CCNCC1
Product: COCCN1CCN(CC#N)CC1

Procedure:
The title compound is synthesized by coupling of 1-(2-Methoxy-ethyl)-piperazine and bromoacetonitrile analogously to the preparation of Intermediate 149.2 as a colorless oil; ES-MS: M+=184.2.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[C:6]([CH:17]=[CH:18][C:19]=1[O:20][CH2:21][C:22]1[CH:23]=[N:24][C:25]([O:28][CH3:29])=[CH:26][CH:27]=1)[CH2:7][NH:8][C:9]1[C:14]([NH2:15])=[CH:13][C:12]([I:16])=[CH:11][N:10]=1)[CH3:2].[CH:30](OCC)(OCC)OCC>C(O)C.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>[CH2:1]([O:3][C:4]1[CH:5]=[C:6]([CH:17]=[CH:18][C:19]=1[O:20][CH2:21][C:22]1[CH:23]=[N:24][C:25]([O:28][CH3:29])=[CH:26][CH:27]=1)[CH2:7][N:8]1[C:9]2=[N:10][CH:11]=[C:12]([I:16])[CH:13]=[C:14]2[N:15]=[CH:30]1)[CH3:2]
Reactant: CCOc1cc(CNc2ncc(I)cc2N)ccc1OCc1ccc(OC)nc1
Reactant: CCOC(OCC)OCC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCO
Solvent: O
Product: CCOc1cc(Cn2cnc3cc(I)cnc32)ccc1OCc1ccc(OC)nc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 61.4 %

Procedure:
To a stirred suspension of N2-(3-ethoxy-4-((6-methoxypyridin-3-yl)methoxy)benzyl)-5-iodopyridine-2,3-diamine (3.99 g, 7.88 mmol) in ethanol (50 mL) was added triethyl orthoformate (2.67 g, 18.02 mmol) and p-toluenesulfonic acid monohydrate (0.075 g, 0.39 mmol). As the mixture was heated to reflux, a brown solution was obtained. After 30 min, the mixture was allowed to cool to room temperature, resulting in the formation of a precipitate. The solids were isolated by filtration, washed with ethanol, and dried to provide 2.50 g (61%) of 3-(3-ethoxy-4-((6-methoxypyridin-3-yl)methoxy)benzyl)-6-iodo-3H-imidazo[4,5-b]pyridine as a tan solid.
Reaction SMILES: [C:1](N1C=CN=C1)(N1C=CN=C1)=[O:2].[Cl:13][C:14]1[C:23]([NH2:24])=[C:22]([NH:25][CH2:26][C:27]2[CH:32]=[CH:31][C:30]([O:33][CH3:34])=[CH:29][CH:28]=2)[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[N:15]=1.N1C=CC=CC=1.C(#N)C>C1COCC1>[Cl:13][C:14]1[C:23]2[N:24]=[C:1]([OH:2])[N:25]([CH2:26][C:27]3[CH:28]=[CH:29][C:30]([O:33][CH3:34])=[CH:31][CH:32]=3)[C:22]=2[C:21]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[N:15]=1
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: COc1ccc(CNc2c(N)c(Cl)nc3ccccc23)cc1
Solvent: CC#N
Solvent: C1CCOC1
Solvent: c1ccncc1
Product: COc1ccc(Cn2c(O)nc3c(Cl)nc4ccccc4c32)cc1
Temperature: 80 °C
Reaction time: 8 h
Yield: 41.8 %

Procedure:
1,1′-Carbonyldiimidazole (6.53 g, 40.3 mmol) was added to a solution of 2-chloro-N4-(4-methoxybenzyl)quinoline-3,4-diamine (11.49 g, 36.62 mmol) and pyridine (75 mL) in THF (75 mL), and the reaction was heated at 80° C. overnight. An analysis by LC/MS indicated the presence of starting material, and additional 1,1′-carbonyldiimidazole (1 equivalent) was added. The reaction was stirred overnight at 80° C., and additional 1,1′-carbonyldiimidazole (1 equivalent) was added. The reaction was stirred overnight at 80° C. and allowed to cool, and the solvent was removed under reduced pressure. The residue was dissolved in dichloromethane (500 mL), and the resulting solution was washed sequentially with brine and water, dried over magnesium sulfate, filtered, and concentrated under reduced pressure to provide a solid. The solid was mixed with acetonitrile and isolated by filtration to provide 5.2 g of 4-chloro-1-(4-methoxybenzyl)-1H-imidazo[4,5-c]quinolin-2-ol.
Reaction SMILES: [C:1]1([S:7](Cl)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH2:11][CH2:12][C:13]1[CH:14]=[C:15]2[C:19](=[CH:20][CH:21]=1)[NH:18][CH:17]=[C:16]2[CH2:22][CH2:23][N:24]1[C:32](=[O:33])[C:31]2[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=2)[C:25]1=[O:34]>N1C=CC=CC=1.O>[O:34]=[C:25]1[C:26]2[C:31](=[CH:30][CH:29]=[CH:28][CH:27]=2)[C:32](=[O:33])[N:24]1[CH2:23][CH2:22][C:16]1[C:15]2[C:19](=[CH:20][CH:21]=[C:13]([CH2:12][NH:11][S:7]([C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)(=[O:9])=[O:8])[CH:14]=2)[NH:18][CH:17]=1
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: NCc1ccc2[nH]cc(CCN3C(=O)c4ccccc4C3=O)c2c1
Solvent: c1ccncc1
Solvent: O
Product: O=C1c2ccccc2C(=O)N1CCc1c[nH]c2ccc(CNS(=O)(=O)c3ccccc3)cc12
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Benzenesulphonyl chloride (0.33 ml) was added to an ice-cooled, stirred solution of 2-[2-[5-(aminomethyl)-1H-indol-3-yl]ethyl]-1H-isoindole-1,3(2H)-dione, hemisulphate, hydrate (0.84 g) in dry pyridine (25 ml). After 2 h with ice cooling, the mixture was stirred at room temperature for 1 h. Water (5 ml) was added and the solution was stirred for 1 h. The mixture was diluted to 100 ml with water and the yellow solid (0.8 g) filtered off, m.p. 214°-6°.
Reaction SMILES: [O:1]1[C:6]2[CH:7]=[CH:8][C:9]([CH2:11][N:12]([CH:20]3[CH2:25][CH2:24][N:23]([CH2:26][CH2:27][N:28]4[C:37]5[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=5)[N:31]=[CH:30][C:29]4=[O:38])[CH2:22][CH2:21]3)C(=O)OC(C)(C)C)=[CH:10][C:5]=2[O:4][CH2:3][CH2:2]1.FC(F)(F)C(O)=O>ClCCl>[O:1]1[C:6]2[CH:7]=[CH:8][C:9]([CH2:11][NH:12][CH:20]3[CH2:25][CH2:24][N:23]([CH2:26][CH2:27][N:28]4[C:37]5[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=5)[N:31]=[CH:30][C:29]4=[O:38])[CH2:22][CH2:21]3)=[CH:10][C:5]=2[O:4][CH2:3][CH2:2]1
Reactant: CC(C)(C)OC(=O)N(Cc1ccc2c(c1)OCCO2)C1CCN(CCn2c(=O)cnc3ccccc32)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=c1cnc2ccccc2n1CCN1CCC(NCc2ccc3c(c2)OCCO3)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 94.3 %

Procedure:
To 3 mL of a dichloromethane solution containing 0.21 g of tert-butyl (2,3-dihydro-1,4-benzodioxin-6-ylmethyl)(1-(2-(2-oxoquinoxalin-1(2H)-yl)ethyl)piperidin-4-yl)carbamate, 3 mL of trifluoroacetic acid was added and stirred at room temperature for 1 hour. The solvent was removed under reduced pressure, chloroform and water were added, and adjusted to pH 13 with 20% aqueous sodium hydroxide solution. The organic layer was separated, and the aqueous layer was extracted with chloroform. The organic layer and extracts were combined, washed sequentially with water and aqueous saturated sodium chloride solution, dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure to give 0.16 g of 1-(2-(4-((2,3-dihydro-1,4-benzodioxin-6-ylmethyl)amino)piperidin-1-yl)ethyl)quinoxalin-2(1H)-one as a light brown oil.
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][C:5]([CH2:9][OH:10])=[CH:4][N:3]=1>C(Cl)Cl.[O-2].[Mn+2]>[Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][C:5]([CH:9]=[O:10])=[CH:4][N:3]=1
Reactant: OCc1cnc(Cl)c(Cl)c1
Agent: [Mn+2]
Agent: [O-2]
Solvent: ClCCl
Product: O=Cc1cnc(Cl)c(Cl)c1
Temperature: 25 °C
Reaction time: 48 h
Yield: 81.8 %

Procedure:
To a 500 mL round-bottom flask, manganese oxide (43.5 g, 0.50 mol) was added to a solution of 2,3-dichloro-5-hydroxylmethylpyridine (1, 8.10 g, 50.0 mMol) in anhydrous CH2Cl2 (150 mL). The resulting mixture was stirred at room temperature for 2 days, which was filtered through Celite and concentrated. The crude mixture was purified by a silica gel chromatography column eluting with a gradient of ethyl acetate (0-40%)/hexanes to give 7.2 g of the desired product 2 (90%). 1H NMR (400 MHz, CDCl3) δ 10.08 (1H, s), 8.77 (1H, d, J=1.97 Hz), 8.25 (1H, d, J=1.97 Hz). LC/MS (M+1): 176.
Reaction SMILES: [C:1]1([CH:7]([C:9]2[CH:10]=[N:11][CH:12]=[CH:13][CH:14]=2)O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:15][C:16]1[C:22]([CH3:23])=[C:21]([OH:24])[C:20]([CH3:25])=[CH:19][C:17]=1[OH:18].S(=O)(=O)(O)O.C(=O)([O-])O.[Na+]>ClCCl>[CH3:25][C:20]1[C:21](=[O:24])[C:22]([CH3:23])=[C:16]([CH3:15])[C:17](=[O:18])[C:19]=1[CH:7]([C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)[C:9]1[CH:10]=[N:11][CH:12]=[CH:13][CH:14]=1
Reactant: OC(c1ccccc1)c1cccnc1
Reactant: Cc1cc(O)c(C)c(C)c1O
Agent: O=C([O-])O
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: ClCCl
Product: CC1=C(C)C(=O)C(C(c2ccccc2)c2cccnc2)=C(C)C1=O
Yield: 72.9 %

Procedure:
To a solution of 1.0 g (5.4 mmol) of phenyl-(3-pyridyl)methanol and 823 mg (5.4 mmol) of 2,3,5-trimethylhydroquinone in 15 ml of dichloromethane, 0.5 ml (9.4 mmol) of concentrated sulfuric acid was added, and refluxed by heating for 2 hours. The reaction mixture was made weakly alkaline with a saturated aqueous solution of sodium hydrogen carbonate, from which the organic phase was separated while the aqueous phase was extracted with chloroform and the extract was combined with the organic phase. The organic phase was washed with water, dried, and oxidized with air, from which the solvent was evaporated off. The residue was purified with silica gel column chromatography (isopropyl ether-ethyl acetate (1:1)), to give 1.25 g (72.7%) of 3,5,6-trimethyl-2-[phenyl-(3-pyridyl)methyl]-1,4-benzoquinone. The physical data are shown in Table 1.
Reaction SMILES: [Na+].[CH3:2][S:3]([O-:5])=[O:4].F[C:7]1[CH:14]=[CH:13][C:10]([CH:11]=[O:12])=[CH:9][C:8]=1[C:15]([F:18])([F:17])[F:16]>CS(C)=O>[CH3:2][S:3]([C:7]1[CH:14]=[CH:13][C:10]([CH:11]=[O:12])=[CH:9][C:8]=1[C:15]([F:16])([F:18])[F:17])(=[O:5])=[O:4]
Reactant: O=Cc1ccc(F)c(C(F)(F)F)c1
Reactant: CS(=O)[O-]
Agent: [Na+]
Solvent: CS(C)=O
Product: CS(=O)(=O)c1ccc(C=O)cc1C(F)(F)F
Temperature: 75 °C
Reaction time: 2 h

Procedure:
Methane sulfinic acid sodium salt (6.65 g, 65.1 mmol) is added to a stirred solution of 4-Fluoro-3-trifluoromethyl-benzaldehyde (10.0 g, 52.1 mmol) in dry DMSO (200 ml) and the mixture is heated at 75° C. After 2 hours the reaction is allowed to cool and poured onto ice-water (300 ml). The precipitate is collected by filtration, washed with water and dissolved in dichloromethane (200 ml). The organic extract is washed with water (3×200 ml), dried over MgSO4, filtered, and the solvent is removed to give the title compound as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:16]([CH:17]([CH3:21])[C:18]([OH:20])=O)[C:11]3=[N:12][CH:13]=[CH:14][CH:15]=[C:10]3[N:9]=2)=[CH:4][CH:3]=1.C(N1C=CN=C1)(N1C=CN=C1)=O.[CH2:34]([NH:37][CH2:38][CH2:39][CH3:40])[CH2:35][CH3:36]>O1CCCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:16]([C@@H:17]([CH3:21])[C:18]([N:37]([CH2:38][CH2:39][CH3:40])[CH2:34][CH2:35][CH3:36])=[O:20])[C:11]3=[N:12][CH:13]=[CH:14][CH:15]=[C:10]3[N:9]=2)=[CH:6][CH:7]=1
Reactant: CCCNCCC
Reactant: CC(C(=O)O)n1c(-c2ccc(Cl)cc2)nc2cccnc21
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Product: CCCN(CCC)C(=O)[C@H](C)n1c(-c2ccc(Cl)cc2)nc2cccnc21
Temperature: 50 °C
Yield: 52.1 %

Procedure:
A solution of (S)-2-(4-chlorophenyl-α-methyl-3H-imidazo[4,5-b]pyridine-3-acetic acid (5.0 g, 0.0166 mole), 1,1'-carbonyldiimidazole (3.21 g, 0.0198 mole) and dry tetrahydrofuran (100 ml) was stirred at room temperature for 3 hours with nitrogen bubbling through it. A solution of dipropylamine (5.04 g, 0.050 mole) in tetrahydrofuran (7 ml) was added and the solution was heated at 50° C. overnight under nitrogen. The solvents were evaporated under reduced pressure and the resulting oil was partitioned between ethyl acetate (50 ml) and water (50 ml). The layers were separated and the aqueous layer was re-extracted with ethyl acetate (50 ml). The combined organic layers were washed once with water (50 ml) followed by two (50 ml) portions of 5% potassium hydroxide solution and then by water again (50 ml). The organic layer was dried over magnesium sulfate, charcoaled, filtered and evaporated to an oil which was crystallized from hot isopropyl ether. The solid was collected by filtration, and dried under high vacuum at room temperature to give 3.33 g (52%) of title compound, mp 96°-99° C.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]([F:11])[C:8]([N+:12]([O-])=O)=[CH:7][C:3]=1[C:4]([OH:6])=[O:5]>C(O)(=O)C.O.C(OCC)(=O)C.[Fe]>[Cl:1][C:2]1[CH:10]=[C:9]([F:11])[C:8]([NH2:12])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5]
Reactant: O=C(O)c1cc([N+](=O)[O-])c(F)cc1Cl
Agent: [Fe]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CC(=O)O
Product: Nc1cc(C(=O)O)c(Cl)cc1F
Temperature: 25 °C

Procedure:
A solution of 2-chloro-4-fluoro-5-nitrobenzoic acid (18.0 g, 0.0824 mol) in 75 ml of acetic acid was heated at reflux temperature. Iron powder (18.4 g, 0.328 mol) was added in several portions and the resulting suspension was cooled to room temperature and diluted with water and ethyl acetate. The mixture was filtered and the filtrate was saved. The organic layer was washed with brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure to afford the title compound as a tan solid. Yield: 9.00 g (58.1%); mp.: 153-155° C.; identified by NMR and mass spectral analysis.
Reaction SMILES: SC1C2C=CC=CC=2N=NN=1.CS(OCCCC(Br)(F)F)(=O)=O.C(=O)([O-])[O-].[K+].[K+].Br[C:31]([F:47])([F:46])[CH2:32][CH2:33][CH2:34][S:35][C:36]1[C:41]2[CH:42]=[CH:43][CH:44]=[CH:45][C:40]=2[N:39]=[N:38][N:37]=1>CC(C)=O.CCCCCC.C(OCC)(=O)C>[F:47][C:31]([F:46])=[CH:32][CH2:33][CH2:34][S:35][C:36]1[C:41]2[CH:42]=[CH:43][CH:44]=[CH:45][C:40]=2[N:39]=[N:38][N:37]=1
Reactant: FC(F)(Br)CCCSc1nnnc2ccccc12
Agent: CS(=O)(=O)OCCCC(F)(F)Br
Agent: O=C([O-])[O-]
Agent: Sc1nnnc2ccccc12
Solvent: CCCCCC
Solvent: CCOC(C)=O
Solvent: CC(C)=O
Product: FC(F)=CCCSc1nnnc2ccccc12

Procedure:
The product of Step 1 (1 g), 4-bromo-4,4-difluorobutyl methanesulfonate (1.65 g) and potassium carbonate (0.852 g) were stirred together in acetone (30 cm3) at ambient temperature for 36 hours. Inorganic solids were removed by filtration and the filtrate evaporated under reduced pressure to give a brown oil. Chromatography on silica gel using 1:4 ethyl acetate:hexane as eluant gave two yellow oils (ea 0.5 g). The first-eluted oil was identified as N-alkylated material and the second was the desired S-alkyated intermediate 4-(4-bromo-4,4-difluorobutylthio)-1,2,3-benzotriazine. 1H NMR: δ 2.18-2.31 (2H,m); 2.58-2.71 (2H,m); 3.63(2H,t); 7.95(1H,t); 8.09(2H,m); 8.40(1H,d).
Reaction SMILES: N[C:2]1[N:6]([C:7]2[C:12]([Cl:13])=[CH:11][C:10]([C:14]([F:17])([F:16])[F:15])=[CH:9][C:8]=2[Cl:18])[N:5]=[C:4]([C:19]#[N:20])[C:3]=1[C:21]1[CH:25]=[CH:24][O:23][C:22]=1[Cl:26].N(OC(C)(C)C)=O>O1CCCC1>[Cl:26][C:22]1[O:23][CH:24]=[CH:25][C:21]=1[C:3]1[C:4]([C:19]#[N:20])=[N:5][N:6]([C:7]2[C:12]([Cl:13])=[CH:11][C:10]([C:14]([F:17])([F:15])[F:16])=[CH:9][C:8]=2[Cl:18])[CH:2]=1
Reactant: N#Cc1nn(-c2c(Cl)cc(C(F)(F)F)cc2Cl)c(N)c1-c1ccoc1Cl
Agent: CC(C)(C)ON=O
Solvent: C1CCOC1
Product: N#Cc1nn(-c2c(Cl)cc(C(F)(F)F)cc2Cl)cc1-c1ccoc1Cl
Temperature: 65 °C

Procedure:
To a solution of 5-amino-4-(2-chlorofuran-3-yl)-3-cyano-1-(2,6-dichloro-4-trifluoromethylphenyl)pyrazole (0.204 g) in tetrahydrofuran (3 ml) was added t-butyl nitrite (171.8 μl). The mixture was heated to 65° C. for 1 hour, then cooled and evaporated. The residue was purified by column chromatography on silica gel (10 g) eluted with hexane containing increasing amounts of dichloromethane (up to 100%). Combination and evaporation of appropriate fraction gave the title compound as a white solid, m.p. 125° C.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[O:11][CH2:10][CH2:9][N:8]([C:12]([N:14]3[CH2:19][CH2:18][CH:17]([CH:20]([F:22])[F:21])[CH2:16][CH2:15]3)=[O:13])[CH2:7][C:6]=2[CH:23]=1.CC1(C)C(C)(C)OB([C:32]2[CH:37]=[CH:36][C:35]([C:38]3[NH:39][CH:40]=[CH:41][N:42]=3)=[CH:34][CH:33]=2)O1.C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCOCC1.O>[F:21][CH:20]([F:22])[CH:17]1[CH2:18][CH2:19][N:14]([C:12]([N:8]2[CH2:7][C:6]3[CH:23]=[C:2]([C:32]4[CH:37]=[CH:36][C:35]([C:38]5[NH:42][CH:41]=[CH:40][N:39]=5)=[CH:34][CH:33]=4)[CH:3]=[CH:4][C:5]=3[O:11][CH2:10][CH2:9]2)=[O:13])[CH2:15][CH2:16]1
Reactant: O=C(N1CCC(C(F)F)CC1)N1CCOc2ccc(Br)cc2C1
Reactant: CC1(C)OB(c2ccc(-c3ncc[nH]3)cc2)OC1(C)C
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1COCCO1
Solvent: O
Product: O=C(N1CCC(C(F)F)CC1)N1CCOc2ccc(-c3ccc(-c4ncc[nH]4)cc3)cc2C1
Temperature: 90 °C
Reaction time: 18 h
Yield: 4.4 %

Procedure:
A mixture of 7-bromo-4-{[4-(difluoromethyl)piperidine-1-yl]carbonyl]-2,3,4,5-tetrahydro-1,4-benzoxazepine (78 mg, 0.20 mmol) (example 2, step 3), 2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-1H-imidazole (0.20 mmol), cesium carbonate (325 mg, 1.00 mmol), and dichloro[1,1-bis(diphenylphosphino]ferrocenepalladium (II) dichloromethane adduct (16 mg, 0.02 mmol) in dioxane (5.0 mL) and water (0.5 mL) was degassed with nitrogen, and then stirred at 90° C. for 18 h. The reaction mixture was cooled to room temperature, diluted with ethyl acetate, and filtered through celite. The filtrate was washed with water (1×) and brine (1×), dried over sodium sulfate, filtered and concentrated. Purification by preparative reverse phase HPLC (0.1% aqueous trifluoroacetic acid-acetonitrile) provided the title compound (4 mg, 4% yield). 1H NMR (400 MHz, methanol-d4): 7.97 (d, 2H), 7.91 (d, 2H), 7.66 (s, 2H), 7.62 (d, 1H), 7.57 (dd, 1H), 7.08 (d, 1H), 5.72 (m, 1H), 4.53 (s, 2H), 4.24 (m, 2H), 3.72 (m, 4H), 2.84 (m, 2H), 2.00 (m, 1H), 1.76 (m, 2H), 1.49 (m, 2H); MS (EI) for C25H26F2N4O2: 453 (MH+).