Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([C:14]([NH:16][CH2:17][C:18]2[C:19](=[O:26])[NH:20][C:21]([CH3:25])=[CH:22][C:23]=2[CH3:24])=[O:15])[C:5]2[CH:10]=[N:9][N:8]([CH:11]([CH3:13])[CH3:12])[C:6]=2[N:7]=1.[CH3:27][N:28]1[CH2:33][CH2:32][N:31]([C:34]2[CH:39]=[CH:38][C:37](B3OC(C)(C)C(C)(C)O3)=[CH:36][N:35]=2)[CH2:30][CH2:29]1.C(=O)([O-])[O-].[Na+].[Na+]>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.CS(C)=O>[CH3:24][C:23]1[CH:22]=[C:21]([CH3:25])[NH:20][C:19](=[O:26])[C:18]=1[CH2:17][NH:16][C:14]([C:4]1[C:5]2[CH:10]=[N:9][N:8]([CH:11]([CH3:13])[CH3:12])[C:6]=2[N:7]=[C:2]([C:37]2[CH:36]=[N:35][C:34]([N:31]3[CH2:30][CH2:29][N:28]([CH3:27])[CH2:33][CH2:32]3)=[CH:39][CH:38]=2)[CH:3]=1)=[O:15]
Reactant: CN1CCN(c2ccc(B3OC(C)(C)C(C)(C)O3)cn2)CC1
Reactant: Cc1cc(C)c(CNC(=O)c2cc(Cl)nc3c2cnn3C(C)C)c(=O)[nH]1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CS(C)=O
Product: Cc1cc(C)c(CNC(=O)c2cc(-c3ccc(N4CCN(C)CC4)nc3)nc3c2cnn3C(C)C)c(=O)[nH]1

Procedure:
The title compound was prepared in the same manner as described in example 74 using 6-chloro-N-[(4,6-dimethyl-2-oxo-1,2-dihydro-3-pyridinyl)methyl]-1-(1-methylethyl)-1H-pyrazolo[3,4-b]pyridine-4-carboxamide (70 mg, 0.187 mmol), 1-methyl-4-[5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-pyridinyl]piperazine (73.8 mg, 0.243 mmol), DMSO (2 mL), sodium carbonate (0.281 mL, 0.562 mmol), and bis(triphenylphosphine)palladium(II) chloride (10.51 mg, 0.015 mmol). The final product was collected as 12 mg (13%). LCMS E-S (M+H)=515.1 1H NMR (400 MHz, DMSO-d6) δ ppm 1.53 (d, J=6.4 Hz, 6H), 2.13 (s, 3H), 2.23 (m, 6H), 2.37-2.46 (m, 4H), 3.56-3.69 (m, 4H), 4.40 (d, J=4.6 Hz, 2H), 5.30 (quin, J=6.7 Hz, 1H), 5.91 (s, 1H), 6.99 (d, J=9.1 Hz, 1H), 8.10 (s, 1H), 8.32 (s, 1H), 8.38 (dd, J=9.1, 2.5 Hz, 1H), 8.91 (br. s., 1H), 9.03 (d, J=2.3 Hz, 1H).
Reaction SMILES: [I:1][C:2]1[N:7]=[CH:6][C:5]([C:8]([OH:10])=[O:9])=[CH:4][CH:3]=1.[C:11]1(C)C=CC(S(O)(=O)=O)=CC=1>CO>[I:1][C:2]1[N:7]=[CH:6][C:5]([C:8]([O:10][CH3:11])=[O:9])=[CH:4][CH:3]=1
Reactant: O=C(O)c1ccc(I)nc1
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CO
Product: COC(=O)c1ccc(I)nc1
Yield: 43 %

Procedure:
A solution of 6-iodo-pyridine-3-carboxylic acid (J. Am. Chem. Soc. 72, 1032, (1950)), 1.2 g of trimethyl o-formate and 0.2 g of p-toluenesulphonic acid in 75 ml of methanol is held at reflux for 2 hrs. The reaction mixture is concentrated and the residue is taken up in 50 ml of diethyl ether. The ether phase is washed twice with 50 ml of 2N aqueous sodium hydroxide solution each time and twice with 50 ml of saturated, aqueous sodium chloride solution each time, dried over magnesium sulphate and concentrated. The residue is recrystallized from 30 ml of hot methanol. 1.15 g (43%) of methyl 6-iodo-pyridine-3-carboxylate are isolated as a colourless solid. M.p. 134°-135°.
Reaction SMILES: [Cl:1][C:2]1[S:6][C:5]([C:7]([N:9](C=O)[CH2:10][C@@H:11]2[O:15][C:14](=[O:16])[N:13]([C:17]3[CH:22]=[CH:21][C:20]([N:23]4[CH2:28][CH2:27][O:26][CH2:25][C:24]4=[O:29])=[CH:19][CH:18]=3)[CH2:12]2)=[O:8])=[CH:4][CH:3]=1.C(O)(=O)C.Cl>CO>[CH:19]1[C:20]([N:23]2[C:24](=[O:29])[CH2:25][O:26][CH2:27][CH2:28]2)=[CH:21][CH:22]=[C:17]([N:13]2[C:14](=[O:16])[O:15][C@@H:11]([CH2:10][NH:9][C:7]([C:5]3[S:6][C:2]([Cl:1])=[CH:3][CH:4]=3)=[O:8])[CH2:12]2)[CH:18]=1
Reactant: O=CN(C[C@H]1CN(c2ccc(N3CCOCC3=O)cc2)C(=O)O1)C(=O)c1ccc(Cl)s1
Agent: Cl
Solvent: CO
Solvent: CC(=O)O
Product: O=C(NC[C@H]1CN(c2ccc(N3CCOCC3=O)cc2)C(=O)O1)c1ccc(Cl)s1
Temperature: 75 °C

Procedure:
5-chloro-N-formyl-N-({(5 S)-2-oxo-3-[4-(3-oxomorpholin-4-yl)phenyl]-1,3-oxazolidin-5-yl}methyl)thiophene-2-carboxamide (1.0 g) taken in mixture of acetic acid (5 ml) and conc hydrochloric acid (0.25 ml). Obtained reaction mixture is heated to 70 to 80° C. for 3 to 4 h. After completion of reaction, cooled reaction mixture 25 to 30° C. and added methanol (5 ml). The precipitated solid is filtered off and washed by methanol (3 ml).
Reaction SMILES: [CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:15])=[C:11](F)[CH:12]=3)[C:7](=[O:16])[C:6]([C:17]([OH:19])=[O:18])=[CH:5]2)[CH2:3][CH2:2]1.[NH:20]1[CH2:24][CH2:23][CH:22]([C:25]2[CH:30]=[CH:29][N:28]=[CH:27][CH:26]=2)[CH2:21]1>>[CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:15])=[C:11]([N:20]4[CH2:24][CH2:23][CH:22]([C:25]5[CH:26]=[CH:27][N:28]=[CH:29][CH:30]=5)[CH2:21]4)[CH:12]=3)[C:7](=[O:16])[C:6]([C:17]([OH:19])=[O:18])=[CH:5]2)[CH2:3][CH2:2]1
Reactant: c1cc(C2CCNC2)ccn1
Reactant: O=C(O)c1cn(C2CC2)c2cc(F)c(F)cc2c1=O
Product: O=C(O)c1cn(C2CC2)c2cc(N3CCC(c4ccncc4)C3)c(F)cc2c1=O
Yield: 52 %

Procedure:
Starting from 1-cyclopropyl-6,7-difluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid (1.13 g, 4.3 mmol) and 4-(3-pyrrolidinyl)pyridine, a procedure analogous to that given in Example 1 provided the title compound (0.87 g, 52%) as an off-white solid, mp 260°-261° C.
Reaction SMILES: [F:1][CH:2]([F:17])[O:3][N:4]=[C:5]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[CH3:16])[C:6]([O:8][CH3:9])=[O:7].C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1.[Br:36]N1C(=O)CCC1=O>C(Cl)(Cl)(Cl)Cl>[F:1][CH:2]([F:17])[O:3][N:4]=[C:5]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[CH2:16][Br:36])[C:6]([O:8][CH3:9])=[O:7]
Reactant: COC(=O)C(=NOC(F)F)c1ccccc1C
Reactant: O=C1CCC(=O)N1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: COC(=O)C(=NOC(F)F)c1ccccc1CBr
Temperature: 20 °C

Procedure:
A solution of 5.1 g of o-tolylglyoxalic acid methyl ester O-difluoromethyl oxime, 0.16 g of dibenzoyl peroxide and 40 ml of carbon tetrachloride is heated to reflux. With radiation from a lamp, 3.55 g of N-bromosuccinimide are added thereto in several small portions, the mixture is left to react under reflux for 30 minutes and is then cooled to 20° C. and the succinimide which precipitates is removed by filtration. The filtrate is concentrated by evaporation; after chromatography on silica gel with hexane/ethyl acetate (6:1) pure 2-(bromomethyl)-phenylglyoxalic acid methyl ester O-difluoromethyl oxime is obtained in the form of a pale yellow oil.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8](O)[C:9]2[C:10]([C:28]([O:30][CH2:31][CH3:32])=[O:29])=[N:11][N:12]([C:18]3[C:19]([O:26][CH3:27])=[N:20][C:21]([O:24][CH3:25])=[N:22][CH:23]=3)[C:13]=2[C:14]([F:17])([F:16])[F:15])=[CH:4][CH:3]=1.[NH2:34][C:35]1[CH:36]=[C:37]([Cl:43])[C:38](=[O:42])[N:39]([CH3:41])[CH:40]=1>>[Cl:43][C:37]1[C:38](=[O:42])[N:39]([CH3:41])[CH:40]=[C:35]([NH:34][CH:8]([C:5]2[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=2)[C:9]2[C:10]([C:28]([O:30][CH2:31][CH3:32])=[O:29])=[N:11][N:12]([C:18]3[C:19]([O:26][CH3:27])=[N:20][C:21]([O:24][CH3:25])=[N:22][CH:23]=3)[C:13]=2[C:14]([F:15])([F:16])[F:17])[CH:36]=1
Reactant: Cn1cc(N)cc(Cl)c1=O
Reactant: CCOC(=O)c1nn(-c2cnc(OC)nc2OC)c(C(F)(F)F)c1C(O)c1ccc(Cl)cc1
Product: CCOC(=O)c1nn(-c2cnc(OC)nc2OC)c(C(F)(F)F)c1C(Nc1cc(Cl)c(=O)n(C)c1)c1ccc(Cl)cc1

Procedure:
The title compound was prepared in analogy to the procedure described in Step 40.3 using ethyl 4-((4-chlorophenyl)(hydroxy)methyl)-1-(2,4-dimethoxypyrimidin-5-yl)-5-(trifluoromethyl)-1H-pyrazole-3-carboxylate (Step 47.2) and 5-amino-3-chloro-1-methylpyridin-2(1H)-one (Step 5.2). The crude product was purified by silica gel chromatography (50% EtOAc/CH2Cl2). tR: 1.21 min (LC-MS 2); ESI-MS: 627 [M+H]+ (LC-MS 2); Rf=0.20 (50% EtOAc/CH2Cl2).
Reaction SMILES: CC(=[N:4][OH:5])C.CC(C)([O-])C.[K+].Cl[C:13]1[C:18]([C:19]([C:21]2[CH:26]=[CH:25][CH:24]=[C:23]([O:27][CH3:28])[CH:22]=2)=O)=[CH:17][CH:16]=[CH:15][N:14]=1>CN(C)C=O>[CH3:28][O:27][C:23]1[CH:22]=[C:21]([C:19]2[C:18]3[C:13](=[N:14][CH:15]=[CH:16][CH:17]=3)[O:5][N:4]=2)[CH:26]=[CH:25][CH:24]=1
Reactant: CC(C)=NO
Reactant: COc1cccc(C(=O)c2cccnc2Cl)c1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1cccc(-c2noc3ncccc23)c1
Reaction time: 1 h
Yield: 67.7 %

Procedure:
Combine acetone oxime (3.1 g, 42.4 mmol) in dimethylformamide (15 mL) and add potassium t-butoxide (4.76 g, 42.4 mmol) and stir for 1 hour. Add (2-chloro-pyridin-3-yl)-(3-methoxy-phenyl)-methanone (8.40 g, 34 mmol) dissolved in dimethylformamide (10 mL) and stir at room temperature, overnight. Separate the product between water and ether and evaporate. Purify by column (silica) chromatography (10% ethyl acetate/dichloromethane) and then reflux in a mixture of 1:1 ethanol:5% aqueous hydrochloric acid. Work-up with 5% aqueous sodium hydroxide and ether and purify by flash chromatography (5% ethyl acetate in dichloromethane) to give the title compound (5.21 g, 68% Yield).
Reaction SMILES: [CH3:1][C:2]1([CH3:23])[O:6][C@@H:5]2[C@@H:7]([CH2:20][NH:21][CH3:22])[O:8][C@@H:9]([N:10]3[CH:18]=[N:17][C:16]4[C:11]3=[N:12][CH:13]=[N:14][C:15]=4[NH2:19])[C@@H:4]2[O:3]1.O=[C:25]1[CH2:28][CH:27]([NH:29][C:30](=[O:39])[O:31][CH2:32][C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[CH2:26]1.[BH3-]C#N.[Na+]>CO>[NH2:19][C:15]1[N:14]=[CH:13][N:12]=[C:11]2[C:16]=1[N:17]=[CH:18][N:10]2[C@H:9]1[C@@H:4]2[O:3][C:2]([CH3:1])([CH3:23])[O:6][C@@H:5]2[C@@H:7]([CH2:20][N:21]([CH3:22])[CH:25]2[CH2:28][CH:27]([NH:29][C:30](=[O:39])[O:31][CH2:32][C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)[CH2:26]2)[O:8]1
Reactant: O=C1CC(NC(=O)OCc2ccccc2)C1
Reactant: CNC[C@H]1O[C@@H](n2cnc3c(N)ncnc32)[C@@H]2OC(C)(C)O[C@@H]21
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Product: CN(C[C@H]1O[C@@H](n2cnc3c(N)ncnc32)[C@@H]2OC(C)(C)O[C@@H]21)C1CC(NC(=O)OCc2ccccc2)C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 29.1 %

Procedure:
To a solution of 9-((3aR,4R,6R,6aR)-2,2-dimethyl-6-((methylamino)methyl)tetrahydrofuro[3,4-d][1,3]dioxol-4-yl)-9H-purin-6-amine (190 mg, 0.59 mmol) and benzyl (3-oxocyclobutyl)carbamate (240 mg, 1.37 mmol) in MeOH (5 mL) was added Ti[OCH(CH3)2]4 (216 mg, 0.59 mmol). The mixture was stirred at rt for 1 h. Then NaCNBH3 (95 mg, 1.52 mmol) was added, the reaction was stirred at rt overnight. The reaction was filtered and evaporated, the residue was purified by prep-TLC (DCM:MeOH=20:1) to obtain the desired compound (90 mg, yield 29%).
Reaction SMILES: [O:1]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[O:4][CH2:3][CH2:2]1.[Br:11]N1C(=O)CCC1=O>CN(C)C=O>[Br:11][C:9]1[CH:8]=[CH:7][C:6]2[O:1][CH2:2][CH2:3][O:4][C:5]=2[CH:10]=1
Reactant: c1ccc2c(c1)OCCO2
Reactant: O=C1CCC(=O)N1Br
Solvent: CN(C)C=O
Product: Brc1ccc2c(c1)OCCO2
Reaction time: 24 h

Procedure:
35 g of 1,4-benzodioxane and 200 ml of anhydrous dimethylformamide are placed under argon at 0° C. 54.9 g of N-bromosuccinimide are then added in portions. After it has returned gradually to room temperature, the reaction mixture is stirred for 24 hours. The solvents are evaporated off under reduced pressure and the white solid obtained is washed with dichloromethane. The filtrate is treated with 50 ml of saturated aqueous sodium sulfate solution, washed with 50 ml of saturated aqueous sodium chloride solution and dried over magnesium sulfate. After evaporation of the solvents under reduced pressure, a yellow oil is obtained (quantitative yield).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][N:15]([CH2:23][C:24]2[CH:32]=[CH:31][C:27]([C:28]([OH:30])=[O:29])=[CH:26][CH:25]=2)[C:16](=[O:22])[C:17]([O:19][CH2:20][CH3:21])=[O:18])[CH2:10][CH2:9]1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH2:20]([O:19][C:17](=[O:18])[C:16]([N:15]([CH2:23][C:24]1[CH:32]=[CH:31][C:27]([C:28]([OH:30])=[O:29])=[CH:26][CH:25]=1)[CH2:14][CH:11]1[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]1)=[O:22])[CH3:21]
Reactant: CCOC(=O)C(=O)N(Cc1ccc(C(=O)O)cc1)CC1CCN(C(=O)OC(C)(C)C)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCOC(=O)C(=O)N(Cc1ccc(C(=O)O)cc1)CC1CCNCC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 176 %

Procedure:
To a solution of 4-({{[1-(tert-butoxycarbonyl)piperidin-4-yl]methyl}[ethoxy(oxo)acetyl]-amino}methyl)benzoic acid (5.80 g, 12.93 mmol) in DCM (150 mL) was added TFA (9.90 mL) and the resulting reaction mixture was stirred at rt for 3 h, evaporated under vacuum to give the title compound as a pink oil (7.93 g, 99.9%). 1H NMR (DMSO-d6, 300 MHz) δ 8.7 (m, 1H), 8.39 (m, 1H), 7.96 (d, 1H, J=8.3 Hz), 7.94 (d, 1H, J=8.3 Hz), 7.39 (d, 1H, J=8.3 Hz), 7.37 (d, 1H, J=8.3 Hz), 4.64 (s, 1H), 4.58 (s, 1H), 4.33 (q, 0.9H, J=7.2 Hz), 4.23 (q, 1.1H, J=7.2 Hz), 3.33-3.22 (m, 2H), 3.18 (d, 1H, J=7.6 Hz), 3.10 (d, 1H, J=7.2 Hz), 2.90-2.69 (m, 2H), 1.98 (m, 1H), 1.40-1.21 (m, 3H), 1.16 (t, 2H, J=7.1 Hz). HPLC (Condition A), Rt: 1.87 min (HPLC purity 98.9%).
Reaction SMILES: [NH2:1][C:2]([NH2:4])=[O:3].N[C:6]1[CH:7]=[C:8]([CH3:13])[CH:9]=[CH:10][C:11]=1N>C(O)CCCC>[CH3:13][C:8]1[CH:7]=[CH:6][C:11]2=[N:1][C:2](=[O:3])[N:4]=[C:10]2[CH:9]=1
Reactant: NC(N)=O
Reactant: Cc1ccc(N)c(N)c1
Solvent: CCCCCO
Product: Cc1ccc2c(c1)=NC(=O)N=2
Temperature: 25 °C
Reaction time: 2 h
Yield: 56 %

Procedure:
A solution of urea (6.00 g, 0.1000 mol) and 3,4-diaminotoluene (1) (12.20 g, 0.0999 mol) in pentan-1-ol (40 mL) was vigorously stirred and heated to reflux under a nitrogen atmosphere. After 2 hours the heating was discontinued and on cooling to room temperature a pink solid settled out. This was filtered off and recrystallised from boiling ethanol (17.98 g. in 400 mL) to give 2 crops of 5-methylbenzimidazol-2-one (2) as a pink powder. The total mass was recovered was 8.21 g (56% yield);
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([C:14](=[O:30])[CH2:15][CH:16]([CH2:22][CH2:23][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[C:17]([O:19]CC)=[O:18])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.Cl[C:32]1[O:33][C:34]2[CH:40]=[CH:39][CH:38]=[CH:37][C:35]=2[N:36]=1.[OH-].[Na+]>C1(C)C=CC=CC=1>[O:33]1[C:34]2[CH:40]=[CH:39][CH:38]=[CH:37][C:35]=2[N:36]=[C:32]1[NH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[CH:10][C:11]([C:14](=[O:30])[CH2:15][CH:16]([CH2:22][CH2:23][C:24]3[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=3)[C:17]([OH:19])=[O:18])=[CH:12][CH:13]=2)=[CH:4][CH:3]=1
Reactant: CCOC(=O)C(CCc1ccccc1)CC(=O)c1ccc(-c2ccc(N)cc2)cc1
Reactant: Clc1nc2ccccc2o1
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1
Product: O=C(CC(CCc1ccccc1)C(=O)O)c1ccc(-c2ccc(Nc3nc4ccccc4o3)cc2)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 32.6 %

Procedure:
A solution of ethyl 4-(4′-amino-1,1′-biphenyl-4-yl)-4-oxo-2-(2-phenylethyl)butanoate (100 mg, 0.25 mmol) and 2-chlorobenzoxazole (38.3 mg, 0.25 mmol) in toluene (1.0 mL) was heated at reflux for 16 h. Solvent was removed under reduced pressure, and the residue was dissolved in dichloromethane. The solution was washed with water, solvent was again removed under reduced pressure, and the residue was dissolved in methanol (1 mL) and tetrahydrofuran (1 mL). A 1 N aqueous solution of sodium hydroxide (0.77 mL, 0.77 mmol) was added, and the mixture was stirred at rt for 16 h and then concentrated under reduced pressure. The residue was purified by preparative reverse-phase HPLC (water/acetonitrile gradient, containing 0.1% TFA) to afford 4-[4′-(1,3-benzoxazol-2-ylamino)-1,1′-biphenyl-4-yl]-4-oxo-2-(2-phenylethyl)butanoic acid (40 mg, 33% yield). LC-MS ret. time 4.14 min, m/z 519.5 (MH+); 1H NMR (300 MHz, DMSO-d6) δ 1.82-1.90 (m, 2H), 2.68 (m, 2H), 2.80-2.85 (m, 1H), 3.16 (dd, 1H), 3.41 (m, 1H), 7.10-7.30 (m, 8H), 7.48 (t, 2H), 7.78-7.86 (m, 4H), 7.89 (d, 2H), 8.02 (d, 2H), 10.83 (br s, 1H).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([O:10][CH3:11])=[O:9])=[N:6][CH:7]=1.[H-].[Na+].Br[C:15]1[C:19]2[CH:20]=[CH:21][C:22]([O:24][CH3:25])=[CH:23][C:18]=2[S:17](=[O:26])[C:16]=1[C:27]1[CH:32]=[CH:31][C:30]([O:33][CH3:34])=[CH:29][CH:28]=1>CN(C=O)C>[CH3:25][O:24][C:22]1[CH:21]=[CH:20][C:19]2[C:15]([O:1][C:2]3[CH:3]=[CH:4][C:5]([C:8]([O:10][CH3:11])=[O:9])=[N:6][CH:7]=3)=[C:16]([C:27]3[CH:32]=[CH:31][C:30]([O:33][CH3:34])=[CH:29][CH:28]=3)[S:17](=[O:26])[C:18]=2[CH:23]=1
Reactant: COC(=O)c1ccc(O)cn1
Reactant: COc1ccc(C2=C(Br)c3ccc(OC)cc3S2=O)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(OC2=C(c3ccc(OC)cc3)S(=O)c3cc(OC)ccc32)cn1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 52.6 %

Procedure:
To a solution of methyl 5-hydroxypyridine-2-carboxylate (0.273 g, 1.78 mmol) in DMF (6.84 mL) at room temperature was added sodium hydride (60% suspension in oil, 0.043 g, 1.78 mmol) and the resulting mixture was stirred at room temperature for 30 mins. After 30 min at room temperature 3-bromo-6-methoxy-2-(4-methoxyphenyl)benzothiophene 1-oxide (0.5 g, 1.37 mmol) was added and the reaction was heated to 80° C. for 18 h. Upon completion the reaction was cooled to room temperature, quenched with water and extracted with DCM. The organic layers were combined, passed through a phase separator and concentrated in vacuo to give the crude product, which was purified by column chromatography (SiO2, 0-75% EtOAc/heptane) to afford methyl 5-((6-methoxy-2-(4-methoxyphenyl)-1-oxidobenzo[b]thiophen-3-yl)oxy)picolinate (314 mg, 0.72 mmol, 52% yield). 1H NMR (400 MHz, CDCl3) δ ppm=3.73 (s, 3H), 3.84 (s, 3H), 3.90-3.92 (m, 3H), 6.79-6.86 (m, 2H), 6.91 (dd, J=8.59, 2.53 Hz, 1H), 7.03 (d, J=8.59 Hz, 1H), 7.30 (dd, J=8.59, 3.03 Hz, 1H), 7.48 (d, J=2.53 Hz, 1H), 7.55-7.60 (m, 2H), 7.95 (d, J=8.59 Hz, 1H), 8.55 (d, J=2.02 Hz, 1H). LC/MS (m/z, MH+): 438.2.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([Cl:10])[C:3]=1[CH:4]=O.[CH3:11][O:12][C:13]1[CH:22]=[CH:21][CH:20]=[C:19]2[C:14]=1[CH2:15][O:16][C:17]2=[O:18].C[O-].[Na+]>C(OCC)(=O)C.CO>[CH3:11][O:12][C:13]1[CH:22]=[CH:21][CH:20]=[C:19]2[C:14]=1[C:15](=[O:16])[CH:4]([C:3]1[C:2]([Cl:1])=[CH:9][CH:8]=[CH:7][C:6]=1[Cl:10])[C:17]2=[O:18]
Reactant: COc1cccc2c1COC2=O
Reactant: O=Cc1c(Cl)cccc1Cl
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Solvent: CCOC(C)=O
Product: COc1cccc2c1C(=O)C(c1c(Cl)cccc1Cl)C2=O
Yield: 82.4 %

Procedure:
A solution of 2,6-dichlorobenzaldehyde (5.98 grams, 0.034 mole) and 4-methoxyphthalide (5.6 grams, 0.34 mole) in 20.5 milliliters of ethyl acetate was added to a solution of sodium methoxide in methanol (prepared from 2.36 grams of sodium metal and 34 milliliters of methanol). The mixture was then heated under reflux for 1 hour. The bulk of the ethyl acetate and methanol was removed under reduced pressure. The residue was dissolved in water and the solution filtered from insoluble material. Acidification of the filtered alkaline solution afforded 9.0 grams of a yellow solid which was recrystallized from ethanol to give 6.5 grams (59.3%) of the title compound, melting point 163°-165°C. Calc'd: C, 59.83, H, 3.14; Found: C, 59.55, H, 3.19.
Reaction SMILES: [C:1]([CH2:4][CH2:5][C:6]([C:8]1[CH:13]=[CH:12][C:11]([C:14]([C:16]2([OH:22])[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]2)=[O:15])=[CH:10][CH:9]=1)=[O:7])(O)=[O:2].S(Cl)([Cl:25])=O>C(OCC)C>[Cl:25][C:1]([CH2:4][CH2:5][C:6]([C:8]1[CH:13]=[CH:12][C:11]([C:14]([C:16]2([OH:22])[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]2)=[O:15])=[CH:10][CH:9]=1)=[O:7])=[O:2]
Reactant: O=S(Cl)Cl
Reactant: O=C(O)CCC(=O)c1ccc(C(=O)C2(O)CCCCC2)cc1
Solvent: CCOCC
Product: O=C(Cl)CCC(=O)c1ccc(C(=O)C2(O)CCCCC2)cc1
Temperature: 30 °C
Reaction time: 0.5 h
Yield: 93.7 %

Procedure:
A 250-ml round-bottomed flask fitted with a condenser was charged with 12.0 g of 1-hydroxycyclohexyl 4-(2-carboxyethyl)carbonylphenyl ketone (0.04 mole), 5.95 g (0.05 mole) of thionyl chloride (Aldrich Chemical Co., Milwaukee, Wis.), and 50 ml of diethyl ether. The resulting reaction mixture was stirred at 30° C. for 30 minutes, after which time the solvent was removed under reduced pressure. The residue, a white solid, was maintained at 0.01 Torr for 30 minutes to remove residual solvent and excess thionyl chloride, leaving 12.1 g (94 percent) of 1-hydroxycyclohexyl 4-(2-chloroformylethyl)carbonylphenyl ketone.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][N:7]1[C:15]2[N:14]=[C:13]([CH3:16])[NH:12][C:11]=2[C:10](=[O:17])[NH:9][C:8]1=[O:18].[H-].[Na+].[C:21]([O:27][CH2:28]Cl)(=[O:26])[C:22]([CH3:25])([CH3:24])[CH3:23]>CS(C)=O>[O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][N:7]1[C:15]2[N:14]=[C:13]([CH3:16])[N:12]([CH2:28][O:27][C:21](=[O:26])[C:22]([CH3:25])([CH3:24])[CH3:23])[C:11]=2[C:10](=[O:17])[NH:9][C:8]1=[O:18]
Reactant: Cc1nc2c([nH]1)c(=O)[nH]c(=O)n2Cc1ccco1
Reactant: CC(C)(C)C(=O)OCCl
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Product: Cc1nc2c(c(=O)[nH]c(=O)n2Cc2ccco2)n1COC(=O)C(C)(C)C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 68.9 %

Procedure:
To a stirring solution of 3-(2-furylmethyl)-8-methylxanthine (1.35 g, 5.48 mmol) in dimethyl sulfoxide (20 ml) was added sodium hydride (132 mg, 5.48 mmol) in one portion. After 30 minutes, chloromethyl pivalate (0.83 ml, 5.76 mmol) was added neat. The reaction was allowed to stir at ambient temperature for 24 h. The reaction was quenched by slow addition of water (75 ml). After stirring for 3 hours, the solid was filtered and rinsed with water (4×50 ml) and ethanol (50 ml). The product was recrystallized from ethanol/ethyl acetate/hexane to give 3-(2-Furylmethyl)-7-pivaloyloxymethyl-8-methylxanthine (1.36 g, 69%) as an off-white solid.
Reaction SMILES: [CH2:1]([O:8][N:9]1[CH2:15][CH:14]=[CH:13][CH2:12][C@@H:11]([NH:16][S:17]([C:20]2[S:21][C:22](Br)=[CH:23][CH:24]=2)(=[O:19])=[O:18])[C:10]1=[O:26])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:27][O:28][C:29]1[CH:34]=[CH:33][C:32](B(O)O)=[CH:31][CH:30]=1.C(=O)([O-])[O-].[K+].[K+]>C1COCC1.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>[CH2:1]([O:8][N:9]1[CH2:15][CH:14]=[CH:13][CH2:12][C@@H:11]([NH:16][S:17]([C:20]2[S:21][C:22]([C:32]3[CH:33]=[CH:34][C:29]([O:28][CH3:27])=[CH:30][CH:31]=3)=[CH:23][CH:24]=2)(=[O:19])=[O:18])[C:10]1=[O:26])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C1[C@H](NS(=O)(=O)c2ccc(Br)s2)CC=CCN1OCc1ccccc1
Reactant: COc1ccc(B(O)O)cc1
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: [K+]
Solvent: C1CCOC1
Product: COc1ccc(-c2ccc(S(=O)(=O)N[C@@H]3CC=CCN(OCc4ccccc4)C3=O)s2)cc1
Yield: 51.6 %

Procedure:
(R)-5-Bromo-thiophene-2-sulfonic acid (1-benzyloxy-2-oxo-2,3,4,7-tetrahydro-1H-azepin-3-yl)-amide (100 mg, 0.28 mmol) from example 16 was dissolved in THF (3 mL). (4-Methoxyphenyl) boronic acid (64 mg, 0.42 mmol), potassium carbonate (80 mg, 0.56 mmol) and tetrakis(triphenylphosphine)palladium (16 mg, 0.014 mmol) were added at room temperature. The mixture in a sealed vessel was irradiated in microwave oven at 150° C. for 20 min. The resulting reaction mixture was filtered. The solids were washed with water and 1:1 Ether-hexane, then dried under vacuum to give the desired product (70 mg, 51% yield). MS: 485, 487 (M+H).
Reaction SMILES: [CH2:1]([O:5][CH2:6][CH2:7][CH2:8][N:9]1[CH2:14][CH2:13][C:12](=O)[CH2:11][CH2:10]1)[CH2:2][CH2:3][CH3:4].Cl.[NH2:17][OH:18]>>[CH2:1]([O:5][CH2:6][CH2:7][CH2:8][N:9]1[CH2:14][CH2:13][C:12](=[N:17][OH:18])[CH2:11][CH2:10]1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCOCCCN1CCC(=O)CC1
Reactant: NO
Agent: Cl
Product: CCCCOCCCN1CCC(=NO)CC1

Procedure:
1-(3-Butoxypropyl)-4-piperidone oxime is prepared from 1-(3-butoxypropyl)-4-piperidone and hydroxylamine hydrochloride essentially as described above in Example 38, Scheme C, step b.
Reaction SMILES: [Br:1][C:2]1[S:6][C:5]([CH2:7][NH:8][C:9]([NH:11][C:12]([S:14][CH3:15])=[NH:13])=[O:10])=[CH:4][CH:3]=1.[CH:16](OCC)(OCC)OCC>>[Br:1][C:2]1[S:6][C:5]([CH2:7][N:8]2[CH:16]=[N:13][C:12]([S:14][CH3:15])=[N:11][C:9]2=[O:10])=[CH:4][CH:3]=1
Reactant: CCOC(OCC)OCC
Reactant: CSC(=N)NC(=O)NCc1ccc(Br)s1
Product: CSc1ncn(Cc2ccc(Br)s2)c(=O)n1
Yield: 76 %

Procedure:
Methyl N-({[(5-bromothiophen-2-yl)methyl]amino}carbonyl)-carbamimidothioate (700 mg, 2.27 mmol) synthesized in Reference Synthesis Example 295 and triethyl orthoformate were used to obtain the title compound (547 mg, yield 76%) by synthesis in a similar manner to Reference Synthesis Example 292.