Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O[CH:2]([CH3:34])[CH2:3][N:4]([S:25]([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][N:29]=1)(=[O:27])=[O:26])[C:5]1[CH:22]=[C:21]([CH3:23])[C:20]([CH3:24])=[CH:19][C:6]=1[O:7][CH2:8][C:9]1[CH:18]=[CH:17][C:12]([C:13]([O:15][CH3:16])=[O:14])=[CH:11][CH:10]=1.C(N(S(F)(F)[F:41])CC)C.O>ClCCl>[F:41][CH:2]([CH3:34])[CH2:3][N:4]([S:25]([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][N:29]=1)(=[O:27])=[O:26])[C:5]1[CH:22]=[C:21]([CH3:23])[C:20]([CH3:24])=[CH:19][C:6]=1[O:7][CH2:8][C:9]1[CH:18]=[CH:17][C:12]([C:13]([O:15][CH3:16])=[O:14])=[CH:11][CH:10]=1
Reactant: CCN(CC)S(F)(F)F
Reactant: COC(=O)c1ccc(COc2cc(C)c(C)cc2N(CC(C)O)S(=O)(=O)c2ccccn2)cc1
Solvent: O
Solvent: ClCCl
Product: COC(=O)c1ccc(COc2cc(C)c(C)cc2N(CC(C)F)S(=O)(=O)c2ccccn2)cc1
Yield: 23.6 %

Procedure:
460 mg of methyl 4-({2-[(2-hydroxypropyl)(pyridin-2-ylsulfonyl)amino]-4,5-dimethylphenoxy}methyl)benzoate was dissolved in 4.00 mL of dichloromethane, and 161 mg of diethylaminosulfur trifluoride was added dropwise thereto under ice-cooling, followed by stirring under ice-cooling for 30 minutes. To the reaction liquid was added water, followed by extraction with ethyl acetate, and the organic layer was dried over anhydrous magnesium sulfate. The solvent was concentrated under reduced pressure and the obtained residue was purified by silica gel column chromatography (hexane:ethyl acetate=3:1 to 1:1) to obtain 109 mg of methyl 4-({2-[(2-fluoropropyl)(pyridin-2-ylsulfonyl)amino]-4,5-dimethylphenoxy}methyl)benzoate.
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]([OH:12])=O)=[CH:9][C:4]=2[N:3]=[CH:2]1.[CH2:13]([C:20]1[CH:33]=[CH:32][C:23]2[C@@H:24]3[C@H:29]([CH2:30][CH2:31][C:22]=2[CH:21]=1)[NH:28][CH2:27][CH2:26][CH2:25]3)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.C1(CC2C=CC3[C@@H]4[C@H](CCC=3C=2)NCCC4)CCCCC1>>[NH:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]([N:28]3[C@@H:29]4[C@@H:24]([C:23]5[CH:32]=[CH:33][C:20]([CH2:13][CH:14]6[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19]6)=[CH:21][C:22]=5[CH2:31][CH2:30]4)[CH2:25][CH2:26][CH2:27]3)=[O:12])=[CH:9][C:4]=2[N:3]=[CH:2]1
Reactant: O=C(O)c1ccc2[nH]cnc2c1
Reactant: c1ccc(Cc2ccc3c(c2)CC[C@@H]2NCCC[C@H]32)cc1
Agent: c1cc2c(cc1CC1CCCCC1)CC[C@@H]1NCCC[C@H]21
Product: O=C(c1ccc2[nH]cnc2c1)N1CCC[C@@H]2c3ccc(CC4CCCCC4)cc3CC[C@@H]21
Yield: 50 %

Procedure:
The title compound is prepared from 1H-benzoimidazole-5-carboxylic acid and a mixture of cis-8-benzyl-1,2,3,4,4a,5,6,10b-octahydro-benzo[f]quinoline and cis-8-cyclohexylmethyl-1,2,3,4,4a,5,6,10b-octahydro-benzo[f]quinoline (ca. 30:70) following a procedure analogous to that described in Example 1 and separated from the also formed Example 82 by HPLC on reversed phase (MeOH/H2O/NH4OH). Yield: 50% of theory; LC (method 1): tR=4.06 min; Mass spectrum (ESI+): m/z=428 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([C:12]3[N:17]=[CH:16][C:15]([N:18]([CH3:27])[C:19](=[O:26])/[CH:20]=[CH:21]/[CH2:22][N:23]([CH3:25])[CH3:24])=[CH:14][CH:13]=3)[N:9]=[C:10](I)[C:3]=12.[CH2:28]([Cl:30])Cl>COCCOC.O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([C:12]3[N:17]=[CH:16][C:15]([N:18]([CH3:27])[C:19](=[O:26])/[CH:20]=[CH:21]/[CH2:22][N:23]([CH3:25])[CH3:24])=[CH:14][CH:13]=3)[N:9]=[C:10]([C:14]3[CH:15]=[CH:16][C:28]([Cl:30])=[CH:12][CH:13]=3)[C:3]=12
Reactant: CN(C)C/C=C/C(=O)N(C)c1ccc(-n2nc(I)c3c(N)ncnc32)nc1
Reactant: ClCCl
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: c1ccc(P(c2ccccc2)[c-]2cccc2)cc1
Solvent: O
Solvent: COCCOC
Product: CN(C)C/C=C/C(=O)N(C)c1ccc(-n2nc(-c3ccc(Cl)cc3)c3c(N)ncnc32)nc1
Yield: 291.6 %

Procedure:
To a suspension of (E)-N-(6-(4-amino-3-iodo-1H-pyrazolo[3,4-d]pyrimidin-1-yl) pyridine-3-yl)-4-(dimethylamino)-N-methylbut-2-enamide (65) (100 mg, 0.21 mmol), arylboronic acid (0.27 mmol) and K3PO4.3H2O (168 mg, 0.63 mmol) in DME (8 mL) and water (2 mL) was added Pd(dppf)Cl2.DCM (9 mg, 0.02 mmol). The resulting mixture was purged with N2 (3×) before microwaved at 90° C. for 45 min. The solvents were evaporated and the residual was directly loaded to a silica gel column and pre-purified by column chromatography (0 to 10% MeOH in DCM) followed by preparative HPLC purification (RP C18, 10 to 95% acetonitrile in water (0.2% NH3)) to give (E)-N-(6-(4-amino-3-(4-chlorophenyl)-1H-pyrazolo[3,4-d]-pyrimidin-1-yl)pyridin-3-yl)-4-(dimethylamino)-N-methylbut-2-enamide (66) (27 mg, 28%) as a white solid. 1H NMR (400 MHz, DMSO) δ 9.82 (br, 2H), 8.57 (d, J=2.5 Hz, 1H), 8.40 (s, 1H), 8.33 (d, J=8.7 Hz, 1H), 8.08 (dd, J=8.7, 2.6 Hz, 1H), 7.75 (d, J=8.5 Hz, 2H), 7.64 (d, J=8.5 Hz, 2H), 6.73-6.65 (m, 1H), 6.34-6.19 (m, 1H), 3.80 (s, 2H), 3.34 (s, 3H), 2.69 (s, 6H). LC-MS (ESI): m/z (M/M+2) 463/465.
Reaction SMILES: C(OS([C:9]1[CH:14]=[CH:13][C:12]([CH3:15])=CC=1)(=O)=O)CC#C.[NH:16]1C[CH2:20][CH2:19][CH2:18][CH2:17]1.C(=O)([O-])[O-].[K+].[K+]>C(O)C.O>[CH2:17]([N:16]1[CH2:15][CH2:12][CH2:13][CH2:14][CH2:9]1)[CH2:18][C:19]#[CH:20]
Reactant: C1CCNCC1
Reactant: C#CCCOS(=O)(=O)c1ccc(C)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCO
Product: C#CCCN1CCCCC1
Temperature: 80 °C

Procedure:
A solution of toluene-4-sulfonic acid but-3-ynyl ester (45.0 g) and piperidine (40 mL) in ethanol (70 mL) was treated with a solution of potassium carbonate (27.8 g) in water (70 mL). The mixture was heated to 80° C. for 2 h, cooled to RT, and extracted with DCM (3×100 mL). The combined organic phases were dried (magnesium sulfate), and evaporated. Distillation of the residue (110° C., 30 mm Hg) gave the title compound as a colorless oil (17.3 g).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:25][CH:26]([F:28])[F:27])=[C:6]([C:8]2[C:13]([O:14][CH3:15])=[CH:12][N:11]([CH2:16][C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[C:10](=[O:24])[CH:9]=2)[CH:7]=1.FC(F)(F)S(O[CH2:35][C@@H:36]1[CH2:41][CH2:40][CH2:39][CH2:38][O:37]1)(=O)=O>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:25][CH:26]([F:28])[F:27])=[C:6]([C:8]2[C:13]([O:14][CH3:15])=[CH:12][N:11]([CH:16]([CH2:35][C@@H:36]3[CH2:41][CH2:40][CH2:39][CH2:38][O:37]3)[C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[C:10](=[O:24])[CH:9]=2)[CH:7]=1
Reactant: O=S(=O)(OC[C@@H]1CCCCO1)C(F)(F)F
Reactant: COc1cn(CC(=O)OC(C)(C)C)c(=O)cc1-c1cc(Cl)ccc1OC(F)F
Product: COc1cn(C(C[C@@H]2CCCCO2)C(=O)OC(C)(C)C)c(=O)cc1-c1cc(Cl)ccc1OC(F)F

Procedure:
237 mg (0.55 mmol) of tert-butyl {4-[5-chloro-2-(difluoromethoxy)phenyl]-5-methoxy-2-oxopyridin-1(2H)-yl}acetate in the presence of 0.72 ml (0.72 mmol, 1.3 eq.) of bis(trimethylsilyl)lithium amide (1M in THF) were reacted with 274 mg (1.11 mmol, 2.0 eq.) of (2S)-tetrahydro-2H-pyran-2-ylmethyl trifluoromethanesulphonate according to General Method 7B. Yield: 130 mg (45% of theory)
Reaction SMILES: N(C(OCC)=O)=NC(OCC)=O.[OH:13][CH2:14][CH2:15][CH2:16][N:17]1[CH:21]=[N:20][CH:19]=[N:18]1.[Cl:22][C:23]1[CH:42]=[CH:41][C:26]([NH:27][C:28]2[C:37]3[C:32](=[CH:33][C:34](O)=[C:35]([O:38][CH3:39])[CH:36]=3)[N:31]=[CH:30][N:29]=2)=[C:25]([F:43])[CH:24]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.Cl>C(Cl)Cl.C(Cl)Cl.CO>[ClH:22].[Cl:22][C:23]1[CH:42]=[CH:41][C:26]([NH:27][C:28]2[C:37]3[C:32](=[CH:33][C:34]([O:13][CH2:14][CH2:15][CH2:16][N:17]4[CH:21]=[N:20][CH:19]=[N:18]4)=[C:35]([O:38][CH3:39])[CH:36]=3)[N:31]=[CH:30][N:29]=2)=[C:25]([F:43])[CH:24]=1
Reactant: COc1cc2c(Nc3ccc(Cl)cc3F)ncnc2cc1O
Reactant: OCCCn1cncn1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CO
Solvent: ClCCl
Product: COc1cc2c(Nc3ccc(Cl)cc3F)ncnc2cc1OCCCn1cncn1
Temperature: 25 °C
Reaction time: 3 h
Yield: 83.9 %

Procedure:
Diethyl azodicarboxylate (295 μl, 1.8 mmol) was added dropwise to a solution of 1-(3-hydroxypropyl)-[1,2,4]-triazole (119 mg, 0.93 mmol), (EP0060696 A1), 4-(4-chloro-2-fluoroanilino)-7-hydroxy-6-methoxyquinazoline (200 mg, 0.62 mmol), (prepared as described for the starting material in Example 24), and triphenylphosphine (492 g, 1.8 mmol) in methylene chloride (4 ml) and the mixture stirred for 3 hours at ambient temperature. The mixture was purified by column chromatography eluting with methylene chloride/acetonitrile/methanol (60/32/8). The purified product was triturated with a mixture of pentane and ether, collected by filtration and dried under vacuum to give a white solid. This solid was dissolved in methylene chloride/methanol and ethereal hydrogen chloride (1 ml of a 5M solution) was added. The volatiles were removed by evaporation. The solid residue was suspended in ether, collected by filtration, washed with ether and dried under vacuum to give 4-(4-chloro-2-fluoroanilino)-6-methoxy-7-(3-(1,2,4-triazol-1-yl)propoxy)quinazoline hydrochloride (121 mg, 39%). 1H NMR Spectrum: (DMSOd6; CF3COOD) 2.44(t, 2H); 4.0(s, 3H); 4.3(t, 2H); 4.5(t, 2H); 7.32(s, 1H); 7.47(dd, 1H); 7.62(t, 1H); 7.70(dd, 1H); 8.08(s, 1H); 8.41(s, 1H); 887(s,1H); 9.10(s, 1H) MS-ESI: 429 [MH]+
Reaction SMILES: [C:1]([C:3]1[C:4](=[O:19])[NH:5][C:6]([C:9]2[CH:14]=[CH:13][C:12]([S:15][CH3:16])=[CH:11][C:10]=2[O:17][CH3:18])=[CH:7][CH:8]=1)#[N:2].ClC1C=CC=C(C(OO)=[O:28])C=1>ClCCl>[C:1]([C:3]1[C:4](=[O:19])[NH:5][C:6]([C:9]2[CH:14]=[CH:13][C:12]([S:15]([CH3:16])=[O:28])=[CH:11][C:10]=2[O:17][CH3:18])=[CH:7][CH:8]=1)#[N:2]
Reactant: COc1cc(SC)ccc1-c1ccc(C#N)c(=O)[nH]1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: COc1cc(S(C)=O)ccc1-c1ccc(C#N)c(=O)[nH]1

Procedure:
A solution of 3-cyano-6-(2-methoxy-4-methylthiophenyl)-2(1H)-pyridinone (1.24 g) in dichloromethane (500 ml) was treated with m-chloroperbenzoic acid (85%, 0.92 g). After 2 hours the solution was washed with sodium bicarbonate-solution and evaporated to give the crude product (1.27 g, m.p. 239-241° C.). Purification by chromatography (silica, dichloromethane) followed by recrystallization from aqueous ethanol yielded the pure title compound, 0.81 g, m.p. 243-245° C.
Reaction SMILES: C([Li])CCC.[CH2:6]1[CH2:14][O:13][C:12]2[C:8](=[CH:9][S:10][CH:11]=2)[O:7]1.[CH2:15]([Sn:19](Cl)([CH2:24][CH2:25][CH2:26][CH3:27])[CH2:20][CH2:21][CH2:22][CH3:23])[CH2:16][CH2:17][CH3:18]>C1COCC1>[CH2:24]([Sn:19]([CH2:15][CH2:16][CH2:17][CH3:18])([CH2:20][CH2:21][CH2:22][CH3:23])[C:9]1[S:10][CH:11]=[C:12]2[O:13][CH2:14][CH2:6][O:7][C:8]=12)[CH2:25][CH2:26][CH3:27]
Reactant: c1scc2c1OCCO2
Reactant: CCCC[Sn](Cl)(CCCC)CCCC
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CCCC[Sn](CCCC)(CCCC)c1scc2c1OCCO2
Temperature: -40 °C
Reaction time: 1 h
Yield: 98 %

Procedure:
n-Butyllithium (77 mL, 192.5 mmol, 2.5 M solution in hexane) was added dropwise at -78° C. to a solution of 3,4-(ethylenedioxy)thiophene (25 g, 175.9 mmol) in anhydrous THF (100 mL) under nitrogen. The solution was stirred for 1 h and warmed to -40° C. Tributylstannyl chloride (85.89 g, 263.9 mmol) was added and the entire solution was finally allowed to warm to room temperature. At room temperature the mixture was filtered using Celite and the solvent was stripped. The organo-tin compound was vacuum dried to give 2-(tributylstannyl)-3,4-(ethylenedioxy)thiophene, obtained as a dark yellow liquid, yield=98%. MS(EI) m/z (rel int): 375 [(M)+ --C4H8, 100%] and 319[(M)+ --C8H16, 18%].
Reaction SMILES: [OH-].[Na+].[CH3:3][C:4]1([CH3:13])[CH:9]([CH3:10])[CH2:8][CH2:7][CH:6]([CH3:11])[C:5]1=[O:12].[Cl-].[CH3:15][S+](C)C>CS(C)=O>[CH3:13][C:4]1([CH3:3])[CH:9]([CH3:10])[CH2:8][CH2:7][CH:6]([CH3:11])[C:5]21[O:12][CH2:15]2
Reactant: CC1CCC(C)C(C)(C)C1=O
Reactant: C[S+](C)C
Agent: [Cl-]
Agent: [Na+]
Agent: [OH-]
Solvent: CS(C)=O
Product: CC1CCC(C)C2(CO2)C1(C)C
Reaction time: 6 h

Procedure:
According to a preferred embodiment of the invention, NaOH is added to a mixture consisting of 2,2,3,6-tetramethyl-1-cyclohexanone and trimethylsulfonium chloride in dimethylsulfoxide. The reaction is slightly exothermic, hence the necessity to maintain an external cooling of the reaction mixture so as to keep the temperature at about 25°-30° C. Good stirring is also applied for about 6 hr. 4,4,5,8-Tetramethyl-1-oxaspiro[2.5]octane is then obtained by extraction of the resulting mixture with petrol ether, concentration of the organic extracts and fractional distillation
Reaction SMILES: C1(C)C=CC=CC=1.C(=O)([O-])[O-].[Na+].[Na+].[Si]([O:21][C@H:22]([CH2:35][CH2:36][C:37]1[CH:38]=[N:39][CH:40]=[CH:41][CH:42]=1)[C@H:23]([CH3:34])[O:24][C:25]1[CH:30]=[CH:29][C:28](B(O)O)=[CH:27][CH:26]=1)(C(C)(C)C)(C)C.[CH3:43][N:44]([C:46]1[CH:51]=[CH:50][CH:49]=[C:48](Br)[N:47]=1)[CH3:45]>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.C(O)C>[CH3:43][N:44]([CH3:45])[C:46]1[N:47]=[C:48]([C:28]2[CH:27]=[CH:26][C:25]([O:24][C@@H:23]([CH3:34])[C@H:22]([OH:21])[CH2:35][CH2:36][C:37]3[CH:38]=[N:39][CH:40]=[CH:41][CH:42]=3)=[CH:30][CH:29]=2)[CH:49]=[CH:50][CH:51]=1
Reactant: CN(C)c1cccc(Br)n1
Reactant: C[C@H](Oc1ccc(B(O)O)cc1)[C@@H](CCc1cccnc1)O[Si](C)(C)C(C)(C)C
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: CCO
Solvent: Cc1ccccc1
Product: C[C@H](Oc1ccc(-c2cccc(N(C)C)n2)cc1)[C@H](O)CCc1cccnc1
Temperature: 120 °C
Yield: 50.1 %

Procedure:
Prepared according to the method described in Example 15g) from toluene (4 ml), 2M aqueous sodium carbonate (0.5 ml), (1S,2R)-4-[2-(tert-butyldimethylsilanyloxy)-1-methyl-4-pyridin-3-yl-butoxy]benzeneboronic acid (0.200 g, Example 15f)), ethanol (1 ml), 6-bromo-2-N,N-dimethylaminopyridine (0.201 g, Example 18a)) and tetrakis(triphenylphosphine)palladium(0) (0.020 g) with heating at 120° C. for 4 hours. The product was purified by normal-phase HPLC eluting with a gradient of 0-25% ethanol in dichloromethane to give the title compound as an oil (0.091 g).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[NH:10][C:11]([C:21]3[CH:26]=[CH:25][N:24]=[CH:23][CH:22]=3)=[C:12]([C:14]3[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=3)[N:13]=2)=[CH:5][CH:4]=1)#[N:2].C([O-])([O-])=O.[K+].[K+].Cl.[NH2:34][OH:35]>CCO.O>[F:20][C:17]1[CH:18]=[CH:19][C:14]([C:12]2[N:13]=[C:9]([C:6]3[CH:5]=[CH:4][C:3]([C:1](=[N:34][OH:35])[NH2:2])=[CH:8][CH:7]=3)[NH:10][C:11]=2[C:21]2[CH:26]=[CH:25][N:24]=[CH:23][CH:22]=2)=[CH:15][CH:16]=1
Reactant: NO
Reactant: N#Cc1ccc(-c2nc(-c3ccc(F)cc3)c(-c3ccncc3)[nH]2)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Solvent: O
Product: NC(=NO)c1ccc(-c2nc(-c3ccc(F)cc3)c(-c3ccncc3)[nH]2)cc1
Yield: 92.4 %

Procedure:
To a mixture of 2-(4-cyanophenyl)-4-(4-fluorophenyl)-5-(4-pyridyl)-1H-imidazole (3.0 g, 8.7 mmol) [See Ex. 1 above] and K2CO3 (2.4 g, 17 mmol) in EtOH (120 mL) and H2O (6 mL) was added hydroxylamine hydrochloride (1.2 g, 17 mmol). After heating at reflux for 24 h, the reaction mixture was poured into H2O. The precipitate was collected, washed with H2O and air-dried. The crude product was dissolved in acetone, silica gel was added and the solvent was evaporated. The impregnated silica gel was added to the top of a flash column and the column was eluted with a solvent gradient of 2-10% MeOH/CHCl3 to afford the title compound as a white solid (3.0 g, 91%): ESMS (m/z): 374 (M+ +H).
Reaction SMILES: Br[C:2]1[CH:12]=[N:11][C:5]2[NH:6][CH2:7][CH2:8][CH2:9][O:10][C:4]=2[CH:3]=1.[C:13]([O:17][CH2:18][CH3:19])(=[O:16])[CH:14]=[CH2:15].C(N(C(C)C)CC)(C)C.CC1C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C>C(#N)CC.CC([O-])=O.CC([O-])=O.[Pd+2]>[CH2:18]([O:17][C:13](=[O:16])[C:14]([C:2]1[CH:12]=[N:11][C:5]2[NH:6][CH2:7][CH2:8][CH2:9][O:10][C:4]=2[CH:3]=1)=[CH2:15])[CH3:19]
Reactant: C=CC(=O)OCC
Reactant: Brc1cnc2c(c1)OCCCN2
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CCC#N
Solvent: CCN(C(C)C)C(C)C
Product: C=C(C(=O)OCC)c1cnc2c(c1)OCCCN2
Temperature: 100 °C
Reaction time: 8 h
Yield: 63.2 %

Procedure:
A solution of 3-bromo-6,7,8,9-tetrahydro-5-oxa-1,9-diaza-benzocycloheptene (1.1 g, 4.80 mmol), ethyl acrylate (1.5 mL, 14.4 mmol) and diisopropylethylamine (2.5 mL, 14.4 mmol) in propionitrile (100 mL) was purged with an Argon stream for 10 min. Pd(OAc)2 (108 mg, 048 mmol) and P(o-tol)3 (292 g, 0.96 mmol) were added and the Argon purge was repeated. The mixture was stirred at 100° C. for 8 h under Argon. Upon cooling, the resultant mixture was filtered through celite; the filtrate was evaporated. The crude product was purified by chromatography (silica, 0-2% MeOH CH2Cl2) to afford the title compound (0.753 g, 63%). 1H NMR (300 MHz, DMSO-d6, δ): 7.98 (d, J=1.9 Hz, 1H), 7.52 (d, J=1.9 Hz, 1H), 7.51 (d, J=16 Hz, 1H), 6.83 (s, br, 1H), 6.42 (d, J=16 Hz, 1H), 4.15 (m, 4H), 3.34 (m, 2H), 1.98 (m, 2H), 1.25 (t, J=2 Hz, 3H).
Reaction SMILES: [N+:1]([C:4]1[CH:18]=[CH:17][C:7]([O:8][C:9]2[N:14]=[CH:13][C:12]([CH2:15][OH:16])=[CH:11][CH:10]=2)=[CH:6][CH:5]=1)([O-:3])=[O:2].C(N(CC)CC)C.[CH3:26][S:27](Cl)(=[O:29])=[O:28]>ClCCl>[N+:1]([C:4]1[CH:18]=[CH:17][C:7]([O:8][C:9]2[N:14]=[CH:13][C:12]([CH2:15][O:16][S:27]([CH3:26])(=[O:29])=[O:28])=[CH:11][CH:10]=2)=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: CS(=O)(=O)Cl
Reactant: O=[N+]([O-])c1ccc(Oc2ccc(CO)cn2)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)OCc1ccc(Oc2ccc([N+](=O)[O-])cc2)nc1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
[6-(4-nitrophenoxy)pyridin-3-yl]methanol (6.1 g, 24.8 mmol) was dissolved in dichloromethane (150 mL), and to the resulting solution was added triethylamine (4.15 mL, 29.8 mmol) under ice cooling. To the resulting solution was added dropwise methanesulfonic acid chloride (2.11 mL, 27.3 mmol), and then stirred under a nitrogen atmosphere for 30 minutes at 0° C. The reaction solution was washed with a saturated sodium bicarbonate solution and brine. The organic layer was dried over anhydrous magnesium sulfate, and evaporated. To the residue was added a mixed solvent (50 mL) of n-hexane ethyl acetate=1:1. The precipitated crystals were removed by suction filtration, to thereby yield 7.9 g of the title compound.
Reaction SMILES: [Cl:1][C:2]1[C:15]([Cl:16])=[CH:14][C:5]2[NH:6][C:7]([CH2:9][C:10]([F:13])([F:12])[F:11])=[N:8][C:4]=2[CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[N+:23]([C:26]1[CH:33]=[CH:32][CH:31]=[CH:30][C:27]=1[CH2:28]Br)([O-:25])=[O:24]>CN(C=O)C>[Cl:16][C:15]1[C:2]([Cl:1])=[CH:3][C:4]2[N:8]([CH2:28][C:27]3[CH:30]=[CH:31][CH:32]=[CH:33][C:26]=3[N+:23]([O-:25])=[O:24])[C:7]([CH2:9][C:10]([F:12])([F:13])[F:11])=[N:6][C:5]=2[CH:14]=1
Reactant: O=[N+]([O-])c1ccccc1CBr
Reactant: FC(F)(F)Cc1nc2cc(Cl)c(Cl)cc2[nH]1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1ccccc1Cn1c(CC(F)(F)F)nc2cc(Cl)c(Cl)cc21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To 5,6-dichloro-2-(2,2,2-trifluoro-ethyl)-1H-benzimidazole (319 mg) in DMF (5 mL) was added potassium carbonate powder (491 mg) I) and 2-nitrobenzyl bromide (768 mg). The resulting mixture was stirred at room temperature overnight. The reaction mixture was quenched with water, extracted with EtOAc, and dried over Na2SO4. The crude product was purified by silica gel chromatography (5%-35% EtOAc/hexanes), followed by dissolution in CH2Cl2 and trituration with hexanes to yield the title compound as orange solid.
Reaction SMILES: [C:1]1([S:7][CH2:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.ClC1C=CC=C(C(OO)=[O:23])C=1.C([O-])(O)=O.[Na+]>C(Cl)Cl>[C:1]1([S:7]([CH2:8][C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=2)=[O:23])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: c1ccc(CSc2ccccc2)cc1
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: O=S(Cc1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 110.7 %

Procedure:
To a solution of benzyl phenyl sulfide (Aldrich; 1.068 g, 5.33 mmol) in 25 mL of CH2Cl2 at −78° C. was slowly added a solution of m-chloroperbenzoic acid (Aldrich, 50-60%; 760 mg, 2.64 mmol if 60%) in 10 mL of CH2CL2. After warming to room temperature and stirring overnight, the solution was added to 20 mL of a saturated NaHCO3 solution. The aqueous layer was separated and extracted with CH2Cl2 (2×10 mL). The pooled organic layers were then dried (MgSO4) and concentrated. The residue was subjected to flash column chromatography (silica gel, 10% acetone/hexane and 15% acetone/hexane) affording the sulfoxide (632 mg, 55%) as a white solid, mp 123-126° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:10]=[CH:11][C:12]=1[C:13]([F:16])([F:15])[F:14])[C:5]([N:7]=[C:8]=[O:9])=O.[Cl:17][C:18]1[CH:23]=[CH:22][C:21]([CH2:24][NH:25][C:26](=[O:31])[C:27]([CH3:30])([CH3:29])[CH3:28])=[CH:20][C:19]=1[NH:32][NH:33]C(OC(C)(C)C)=O.FC(F)(F)C(O)=O>C(Cl)Cl>[Cl:17][C:18]1[CH:23]=[CH:22][C:21]([CH2:24][NH:25][C:26](=[O:31])[C:27]([CH3:30])([CH3:29])[CH3:28])=[CH:20][C:19]=1[N:32]1[C:8](=[O:9])[NH:7][C:5]([C:4]2[CH:10]=[CH:11][C:12]([C:13]([F:16])([F:15])[F:14])=[C:2]([F:1])[CH:3]=2)=[N:33]1
Reactant: CC(C)(C)OC(=O)NNc1cc(CNC(=O)C(C)(C)C)ccc1Cl
Reactant: O=C=NC(=O)c1ccc(C(F)(F)F)c(F)c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(C)(C)C(=O)NCc1ccc(Cl)c(-n2nc(-c3ccc(C(F)(F)F)c(F)c3)[nH]c2=O)c1
Yield: 68 %

Procedure:
The title compound was prepared according to the procedure described in Example-83 by using 3-fluoro-4-(trifluoromethyl)benzoyl isocyanate (Intermediate-99, 2.0 g), tert-butyl 2-(2-chloro-5-{[(2,2-dimethylpropanoyl)amino]methyl}phenyl)hydrazinecarboxylate (Intermediate-94, 1.0 g), DCM (15 mL), and trifluoro acetic acid (3.0 mL) to afford 0.900 g of the desired product. 1H NMR (300 MHz, DMSO d6): δ 1.12 (s, 9H), 4.29 (d, J=5.4 Hz, 2H), 7.35 (d, J=8.4 Hz, 1H), 7.44 (s, 1H), 7.62 (d, J=8.7 Hz, 1H), 7.86-8.10 (m, 3H), 8.19 (m, 1H), 12.86 (s, 1H); MS (m/z): 471.35 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([N:12]2[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]2)[C:9]([OH:11])=O)=[CH:4][CH:3]=1.[CH3:18][NH:19][C@H:20]1[CH2:39][N:24]2[C:25]3[C:30]([C:31]([CH2:32][C:33]([O:35]CCC)=[O:34])=[C:23]2[CH2:22][CH2:21]1)=[CH:29][CH:28]=[CH:27][CH:26]=3>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]([N:12]2[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]2)[C:9]([N:19]([CH3:18])[C@H:20]2[CH2:39][N:24]3[C:25]4[C:30]([C:31]([CH2:32][C:33]([OH:35])=[O:34])=[C:23]3[CH2:22][CH2:21]2)=[CH:29][CH:28]=[CH:27][CH:26]=4)=[O:11])=[CH:6][CH:7]=1
Reactant: O=C(O)C(c1ccc(F)cc1)N1CCCCC1
Reactant: CCCOC(=O)Cc1c2n(c3ccccc13)C[C@H](NC)CC2
Product: CN(C(=O)C(c1ccc(F)cc1)N1CCCCC1)[C@@H]1CCc2c(CC(=O)O)c3ccccc3n2C1

Procedure:
The title compound was prepared using analogous procedures described in Example 1 (Method A) from (4-fluorophenyl)(piperidin-1-yl)acetic acid and propyl [(7R)-7-(methylamino)-6,7,8,9-tetrahydropyrido[1,2-a]indol-10-yl]acetate. MS (+ESI) m/z: 478.
Reaction SMILES: CN(C)[CH:3]=[O:4].[OH:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][C:27]1[C:32]([OH:33])=[C:31]([O:34][CH3:35])[C:30]([O:36][CH3:37])=[CH:29][C:28]=1C>O=O.C1C=C(C=NCCN=CC2C([O-])=CC=CC=2)C([O-])=CC=1.[Co+2]>[OH:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][C:27]1[C:32](=[O:33])[C:31]([O:34][CH3:35])=[C:30]([O:36][CH3:37])[C:3](=[O:4])[C:28]=1[CH3:29]
Reactant: COc1cc(C)c(CCCCCCCCCCCCCCCCCCCCO)c(O)c1OC
Reactant: CN(C)C=O
Agent: [Co+2]
Agent: O=O
Agent: [O-]c1ccccc1C=NCCN=Cc1ccccc1[O-]
Product: COC1=C(OC)C(=O)C(CCCCCCCCCCCCCCCCCCCCO)=C(C)C1=O

Procedure:
To a dimethylformamide solution (50 ml) of 6-(20-hydroxyeicosanyl)-2,3-dimethoxy-5-methylphenol (4.0 g) is added bis(salicylidene)ethylenediiminocobalt(II) (40 mg), and the mixture is stirred in oxygen streams at atmospheric temperature and pressure for 72 hours. The product is isolated as in Example 7 and recrystallized from ether. The above procedure yields 6-(20-hydroxyeicosyl)-2,3-dimethoxy-5-methyl-1,4-benzoquinone (3.28 g) as yellow needles melting at 85° C.