Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([CH3:12])[CH:10]=2)[N:5]=[C:4]([N:13]2[CH2:19][C:18]3[CH:20]=[CH:21][CH:22]=[CH:23][C:17]=3[S:16](=[O:25])(=[O:24])[CH2:15][CH2:14]2)[CH:3]=1.[NH2:26][C:27]1([CH2:31][NH:32][C:33](=[O:39])OC(C)(C)C)[CH2:30][O:29][CH2:28]1.C1(P(C2C=CC=CC=2)C2C=CC3C(=CC=CC=3)C=2C2C3C(=CC=CC=3)C=CC=2P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Na]>C1(C)C=CC=CC=1.O.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[O:24]=[S:16]1(=[O:25])[C:17]2[CH:23]=[CH:22][CH:21]=[CH:20][C:18]=2[CH2:19][N:13]([C:4]2[CH:3]=[C:2]([N:26]3[C:33](=[O:39])[NH:32][CH2:31][C:27]43[CH2:30][O:29][CH2:28]4)[C:11]3[C:6](=[CH:7][CH:8]=[C:9]([CH3:12])[CH:10]=3)[N:5]=2)[CH2:14][CH2:15]1
Reactant: CC(C)(C)OC(=O)NCC1(N)COC1
Reactant: Cc1ccc2nc(N3CCS(=O)(=O)c4ccccc4C3)cc(Cl)c2c1
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Agent: [Na]
Solvent: Cc1ccccc1
Solvent: O
Product: Cc1ccc2nc(N3CCS(=O)(=O)c4ccccc4C3)cc(N3C(=O)NCC34COC4)c2c1
Temperature: 110 °C

Procedure:
A mixture of 4-(4-chloro-6-methylquinolin-2-yl)-2,3,4,5-tetrahydro-1,4-benzothiazepine 1,1-dioxide (372 mg, 1.0 mmol, prepared in analogy to the one in Example 17-1), tert-butyl [(3-aminooxetan-3-yl)methyl]carbamate (202 mg, 1.0 mmol), tris(dibenzylideneacetone)dipalladium(0) (91 mg, 0.10 mmol), 2,2′-bis(diphenylphosphino)-1,1′-binaphthyl (62 mg, 0.10 mmol) and sodium tert-buoxide (192 mg, 2.0 mmol) in toluene (10 mL) was heated at 110° C. overnight. The resulting mixture was diluted with water (20 mL), and extracted with dichloromethane (20 mL×3). The combined organic layers were washed with brine (50 mL), dried over sodium sulfate, and concentrated in vacuo. The residue was purified by preparative HPLC to afford 15 mg of the title compound. MS obsd. (ESI+) [(M+H)+] 465, 1H NMR (400 MHz, DMSO-d6) δ ppm 8.15 (s, 1 H), 7.98-7.96 (d, J=7.2 Hz, 1 H), 7.90-7.87 (m, 1 H), 7.68-7.64 (m, 1 H), 7.53-7.46 (m, 2 H), 7.37-7.34 (m, 2 H), 7.17 (s, 1 H), 5.14 (s, 2 H), 4.80-4.74 (m, 4 H), 4.44 (s, 2 H), 4.27 (s, 2 H), 3.66-3.64 (t, J=4.8, 4.4 Hz, 2 H), 2.36 (s, 3 H).
Reaction SMILES: [CH2:1]([Mg]Br)[CH2:2][CH3:3].Cl[C:7]1[N:15]=[C:14]([C:16]([F:19])([F:18])[F:17])[N:13]=[C:12]2[C:8]=1[NH:9][CH:10]=[N:11]2.C1COCC1.O>C(OCC)(=O)C.Cl[Ni]1(Cl)[P](C2C=CC=CC=2)(C2C=CC=CC=2)CCC[P]1(C1C=CC=CC=1)C1C=CC=CC=1>[CH2:1]([C:7]1[N:15]=[C:14]([C:16]([F:19])([F:18])[F:17])[N:13]=[C:12]2[C:8]=1[NH:9][CH:10]=[N:11]2)[CH2:2][CH3:3]
Reactant: CCC[Mg]Br
Reactant: FC(F)(F)c1nc(Cl)c2[nH]cnc2n1
Agent: Cl[Ni]1(Cl)[P](c2ccccc2)(c2ccccc2)CCC[P]1(c1ccccc1)c1ccccc1
Solvent: O
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCCc1nc(C(F)(F)F)nc2nc[nH]c12
Temperature: 50 °C
Reaction time: 12 h
Yield: 30 %

Procedure:
1-Propyl magnesium bromide (3.0 mmol) was added to a mixture of 6-chloro-2-trifluoromethylpurine 222 mg (1.0 mmol), [1,3-bis(diphenylphosphino)-propane]dichloronickel(II) (0.04 mmol) and THF 15 ml at 20° C. under nitrogen. The reaction mixture was allowed to stirred at 50° C. for 12 hours, then cooled to 20 ° C., and 0.2 ml of water was added to quench the reaction. The mixture was diluted with 20 ml ethyl acetate and filtered over celite. Evaporation under vacuo and chromatography (MeOH:EtOAc:hexane=2:50:50) gave the title compound with 30% yield. 1H NMR (300 MHz, CDCl3) δ 8.10 (s, 1H), 7.27 (t, J=8.37 Hz, 1H), 3.29 (t, J=7.5 Hz, 2H), 1.95 (m,2H), 1.02 (t, 7.5 Hz, 2H).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([O:9][CH3:10])=[CH:7][CH:6]=[CH:5][C:4]=1[OH:11].F[C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([F:19])[C:14]=1[N+:20]([O-:22])=[O:21].COC1C(OC)=CC=CC=1OC1C=CC=C(F)C=1N.NC1SC=CN=1>COC1C(OC)=CC=CC=1OC1C=CC=C(F)C=1NC(NC1SC=CN=1)=O>[CH3:1][O:2][C:3]1[C:8]([O:9][CH3:10])=[CH:7][CH:6]=[CH:5][C:4]=1[O:11][C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([F:19])[C:14]=1[N+:20]([O-:22])=[O:21]
Reactant: O=[N+]([O-])c1c(F)cccc1F
Reactant: COc1cccc(O)c1OC
Agent: COc1cccc(Oc2cccc(F)c2N)c1OC
Agent: COc1cccc(Oc2cccc(F)c2NC(=O)Nc2nccs2)c1OC
Agent: Nc1nccs1
Product: COc1cccc(Oc2cccc(F)c2[N+](=O)[O-])c1OC
Yield: 71.6 %

Procedure:
2-(2,3-Dimethoxyphenoxy)-6-fluoro-nitrobenzene (1.05 g, 72%) was prepared from 2,3-dimethoxyphenol (0.85 g, 5.5 mmol) and 2,6-difluoronitrobenzene (0.80 g, 5.0 mmol) following the general procedure A. This compound was reduced to 2-(2,3-dimethoxyphenoxy)-6-fluoroaniline (0.66 g, 70%) following the general procedure C N-[2-(2,3-Dimethoxyphenoxy)-6-fluorophenyl]-N′-(thiazol-2-yl)urea (136 mg, 70%) was prepared from 2-(2,3-dimethoxyphenoxy)-6-fluoroaniline (131 mg, 0.5 mmol) and 2-aminothiazole (60 mg, 0.6 mmol) following the general procedure D.
Reaction SMILES: [NH2:1][CH2:2][C@@H:3]1[C@H:8]([CH3:9])[CH2:7][CH2:6][CH2:5][N:4]1[C:10]([C:12]1[CH:17]=[C:16]([CH3:18])[CH:15]=[CH:14][C:13]=1[C:19]1[CH:20]=[N:21][N:22]([CH3:24])[CH:23]=1)=[O:11].Cl[C:26]1[O:27][C:28]2[CH:34]=[CH:33][CH:32]=[CH:31][C:29]=2[N:30]=1.C(N(C(C)C)CC)(C)C>CC#N>[O:27]1[C:28]2[CH:34]=[CH:33][CH:32]=[CH:31][C:29]=2[N:30]=[C:26]1[NH:1][CH2:2][C@@H:3]1[C@H:8]([CH3:9])[CH2:7][CH2:6][CH2:5][N:4]1[C:10]([C:12]1[CH:17]=[C:16]([CH3:18])[CH:15]=[CH:14][C:13]=1[C:19]1[CH:20]=[N:21][N:22]([CH3:24])[CH:23]=1)=[O:11]
Reactant: Clc1nc2ccccc2o1
Reactant: Cc1ccc(-c2cnn(C)c2)c(C(=O)N2CCC[C@@H](C)[C@H]2CN)c1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: Cc1ccc(-c2cnn(C)c2)c(C(=O)N2CCC[C@@H](C)[C@H]2CNc2nc3ccccc3o2)c1
Temperature: 25 °C

Procedure:
A mixture of ((2S,3R)-2-(aminomethyl)-3-methylpiperidin-1-yl)(5-methyl-2-(1-methyl-1H-pyrazol-4-yl)phenyl)methanone (40 mg, 122 μmol), 2-chlorobenzoxazole (38 mg, 245 μmol) and diisopropylethyl amine (DIPEA; 43 μL, 245 μmol) in CH3CN (2 mL) was heated at reflux overnight. The mixture was cooled to rt and the solvent was removed in vacuo. The crude was dissolved in EtOAc and washed with satd. NaHCO3, brine, and dried (MgSO4). The solvent was removed and the crude was purified by reverse-phase preparative HPLC to afford the title compound. MS (ESI) 442 (M+H).
Reaction SMILES: [CH:1]1[C:11]2[CH2:10][CH2:9][C:8]3[CH:12]=[CH:13][CH:14]=[CH:15][C:7]=3[CH:6]([CH:16]3[CH2:21][CH2:20][CH2:19][NH:18][CH2:17]3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.[OH-].[Na+].[CH3:24]CCCCC>C(O)=O.C=O>[CH:12]1[C:8]2[CH2:9][CH2:10][C:11]3[CH:1]=[CH:2][CH:3]=[CH:4][C:5]=3[CH:6]([CH:16]3[CH2:21][CH2:20][CH2:19][N:18]([CH3:24])[CH2:17]3)[C:7]=2[CH:15]=[CH:14][CH:13]=1
Reactant: CCCCCC
Reactant: c1ccc2c(c1)CCc1ccccc1C2C1CCCNC1
Agent: C=O
Agent: [Na+]
Agent: [OH-]
Solvent: O=CO
Product: CN1CCCC(C2c3ccccc3CCc3ccccc32)C1
Temperature: 25 °C
Yield: 76 %

Procedure:
Dissolved 3-(10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5-yl)-piperidine (0.75 g, 2.7 mmol) in 1.1 mL of formic acid and 1.5 mL of 37% aqueous formaldehyde. Heated in a 90°-95° C. oil bath for 20 hours. Cooled to room temperature, and made basic with 5% NaOH. Extracted with ether. Dried combined organic extracts with MgSO4, filtered, and evaporated. Crystallized product from hexane to give 0.60 g (76% yield) of 3-(10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5-yl)-1-methyl-piperidine as white solid. Dissolved the free base in ether, and added 19 weight % HCl-EtOH to precipitate the hydrochloride salt.
Reaction SMILES: [C:1]1([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH:6]=[CH:5][C:4]([C:7]2[NH:11][C:10]3[CH:12]=[CH:13][CH:14]=[C:15]([C:16](O)=[O:17])[C:9]=3[N:8]=2)=[CH:3][CH:2]=1.C[N:26]1CCOCC1.ClC(OCC(C)C)=O>C1COCC1>[C:1]1([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH:6]=[CH:5][C:4]([C:7]2[NH:11][C:10]3[CH:12]=[CH:13][CH:14]=[C:15]([C:16]([NH2:26])=[O:17])[C:9]=3[N:8]=2)=[CH:3][CH:2]=1
Reactant: O=C(O)c1cccc2[nH]c(-c3ccc(-c4ccccc4)cc3)nc12
Reactant: CN1CCOCC1
Agent: CC(C)COC(=O)Cl
Solvent: C1CCOC1
Product: NC(=O)c1cccc2[nH]c(-c3ccc(-c4ccccc4)cc3)nc12
Temperature: -50 °C
Reaction time: 2 h
Yield: 69.6 %

Procedure:
To the solution of 2-biphenyl-4-yl-1H-benzoimidazole-4-carboxylic acid (0.35 g, 1.1 mmol) in THF (20 mL) was added N-methyl morpholine (0.2 mL, 1.6 mmol) and the mixture was cooled to −50° C. Isobutyl chloroformate (0.22 mL, 1.6 mmol) was then added drop wise, the reaction mixture was warmed to −10° C. and stirred for 2 h. The reaction mixture was again cooled to −50° C. and purged with ammonia gas for 10 minutes. Reaction mixture warmed to room temperature and stirred for 1 hour. TLC showed completion of the reaction. The crude mixture was filtered and the filtrate concentrated. The resulting residue was stirred with hexane and the free solid formed filtered and dried to obtain title compound (0.24 g, 70%).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1.[CH2:8]([C:12]1[O:13][C:14]2[C:20]([C:21]#[N:22])=[CH:19][CH:18]=[CH:17][C:15]=2[N:16]=1)[CH2:9][C:10]#[CH:11]>>[N:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[C:11]#[C:10][CH2:9][CH2:8][C:12]1[O:13][C:14]2[C:20]([C:21]#[N:22])=[CH:19][CH:18]=[CH:17][C:15]=2[N:16]=1
Reactant: C#CCCc1nc2cccc(C#N)c2o1
Reactant: Brc1ccccn1
Product: N#Cc1cccc2nc(CCC#Cc3ccccn3)oc12
Yield: 17.6 %

Procedure:
The title compound was prepared in accordance with the general method of Example 1, from 2-bromopyridine (161 mg, 1.02 mmol) and 2-(but-3-ynyl)benzo[d]oxazole-7-carbonitrile (200 mg, 1.02 mmol). The crude residue was purified by flash chromatography (DCM/MeOH 99:1) to yield 48 mg (0.18 mmol, 17%) of 2-(4-(pyridin-2-yl)but-3-ynyl)benzo[d]oxazole-7-carbonitrile as a yellow solid (M.P.=126-126.5° C.).
Reaction SMILES: [F:1][CH:2]([F:10])[C:3](=O)[CH:4]=[CH:5]OCC.FC(F)C(=O)CC(OCC)OCC.[CH3:24][NH:25][NH2:26]>C(O)(=O)C>[F:1][CH:2]([F:10])[C:3]1[CH:4]=[CH:5][N:25]([CH3:24])[N:26]=1
Reactant: CNN
Reactant: CCOC=CC(=O)C(F)F
Agent: CCOC(CC(=O)C(F)F)OCC
Solvent: CC(=O)O
Product: Cn1ccc(C(F)F)n1
Temperature: 22 °C
Reaction time: 19 h
Yield: 75.5 %

Procedure:
At 22° C., a solution of 45 g of an 85.6% strength mixture comprising 1,1-difluoro-4-ethoxy-3-buten-2-one (0.164 mol) and 1,1-difluoro-4,4-diethoxy-2-butanone (0.071 mol) in a ratio of 2.3/1 in acetic acid (30 ml) was added dropwise over a period of 37 min to a solution of methylhydrazine (99% pure, 11.9 g, 0.258 mol) in acetic acid (460 ml). The resulting reaction solution was stirred at 22° C. for 19 h. The acetic acid was then removed under reduced pressure (43° C./30 mbar). The oily residue was taken up in methyl tert-butyl ether (MTBE, 300 ml) and washed with water (250 ml). The aqueous phase was extracted once with MTBE (150 ml). The collected organic solutions were dried over sodium sulfate, filtered and freed from the solvent under reduced pressure (40° C./400 to 30 mbar). The residue (23.5 g) was subjected to fractional distillation to isolate the product. The main fraction (21.5 g; transition temperature 52° C. at 22 mbar) contained 3-difluoro-N-methylpyrazole and 5-difluoro-N-methylpyrazole in a ratio of 2.6:1 (GC retention times: 5-isomer: 7.6 min; 3-isomer: 9.2 min). Taking into account the amounts of product found in the minor fractions and the cold traps, the yield is 75.5% (sum of both isomers).
Reaction SMILES: C([O:3][C:4](=[O:29])[CH:5]([NH:13][C:14](=[O:28])[C:15]1[CH:20]=[CH:19][C:18]([NH:21][C:22]2[N:27]=[CH:26][CH:25]=[CH:24][N:23]=2)=[CH:17][CH:16]=1)[CH2:6][CH2:7][C:8]([O:10]CC)=[O:9])C.CO.[OH-].[Na+]>C1COCC1>[N:23]1[CH:24]=[CH:25][CH:26]=[N:27][C:22]=1[NH:21][C:18]1[CH:17]=[CH:16][C:15]([C:14]([NH:13][C@H:5]([C:4]([OH:29])=[O:3])[CH2:6][CH2:7][C:8]([OH:10])=[O:9])=[O:28])=[CH:20][CH:19]=1
Reactant: CCOC(=O)CCC(NC(=O)c1ccc(Nc2ncccn2)cc1)C(=O)OCC
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: O=C(O)CC[C@H](NC(=O)c1ccc(Nc2ncccn2)cc1)C(=O)O
Temperature: 25 °C
Reaction time: 8 h
Yield: 56.2 %

Procedure:
A solution of 2-[4-(pyrimidin-2-ylamino)-benzoylamino]-pentanedioic acid diethyl ester (250 mg, 0.62 mmol) in THF (4 mL) was added to MeOH (4 mL), followed by the addition of 1N NaOH solution (5 mL, 5 mmol, 8 equiv.). The mixture was stirred at room temperature overnight. Reaction was complete as determined by HPLC. Solvents were removed by rotavap and a small amount of water (5 mL) was added to make a homogeneous solution. 1N HCl was added dropwise until the solution reached a pH of 4. The solid precipitate was collected by filtration, washed with EtOAc, and dried in vacuum oven. The product N-[4-(pyrimidin-2-ylamino)benzoyl]-L-glutamic acid (120 mg) was isolated in 45% yield. MS (ESI) m/z 343.
Reaction SMILES: Cl[C:2]1[N:26]=[CH:25][CH:24]=[CH:23][C:3]=1[C:4]([N:6]([C:10]1[CH:11]=[C:12]([CH:18]=[C:19]([O:21][CH3:22])[CH:20]=1)[C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH2:7][O:8][CH3:9])=[O:5].C(P(CCCC)CCCC)CCC.C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.ClCCl>[CH3:22][O:21][C:19]1[C:20]2[C:2]3[N:26]=[CH:25][CH:24]=[CH:23][C:3]=3[C:4](=[O:5])[N:6]([CH2:7][O:8][CH3:9])[C:10]=2[CH:11]=[C:12]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH:18]=1
Reactant: CCOC(=O)c1cc(OC)cc(N(COC)C(=O)c2cccnc2Cl)c1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CCCCP(CCCC)CCCC
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: O
Product: CCOC(=O)c1cc(OC)c2c3ncccc3c(=O)n(COC)c2c1
Temperature: 25 °C
Yield: 77.1 %

Procedure:
The compound (1.11 g, 2.94 mmol) prepared in step 5 was dissolved in N,N-dimethylformamide (10.0 ml), added with palladium(II) acetate (215 mg, 0.881 mmol), 1,3-bis(dephenylphosphino)propane (363 mg, 0.881 mmol), tributylphosphine (0.724 ml, 2.94 mmol), and potassium carbonate (812 mg, 5.87 mmol). The resulting mixture was refluxed for 3 hours and cooled to room temperature. Water and dichloromethane were added and the mixture was extracted. The organic layer was dried over anhydrous magnesium sulfate and concentrated to dryness. The residue was then purified by flash column chromatography (dichloromethane:ethyl acetate=4:1) to obtain the title compound (776.5 mg, yield: 77.3%, white solid).
Reaction SMILES: [C:1]1([OH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C1(C)C(S(O)(=O)=[O:15])=CC=CC=1>[Cu].CO>[C:1]1([OH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:4]1(=[O:15])[CH:5]=[CH:6][C:1](=[O:7])[CH:2]=[CH:3]1
Reactant: Cc1ccccc1S(=O)(=O)O
Agent: [Cu]
Solvent: CO
Solvent: Oc1ccccc1
Product: O=C1C=CC(=O)C=C1
Temperature: 100 °C
Reaction time: 0.5 h

Procedure:
Twenty milligrams of the inactive copper salt complex obtained from Example 1, 100 milligrams of phenol and 1 gram of methanol were dissolved in a 1/2 ounce bottle. Twenty micrograms of toluene sulfonic acid were added and solution was effected under steam heat at 100° C. One-half of the insoluble complex appeared to go into solution. One hundred microliters of the solution were charged into a micro reactor and reacted under the same conditions as described in Example 2. Samples were taken at 30 and 60 minutes. After 30 minutes of oxidation, a conversion of less than 1 percent phenol to benzoquinone was obtained. After 60 minutes reaction time, 4.74 percent conversion of phenol to benzoquinone was obtained.
Reaction SMILES: F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.[F:25][C:26]1[CH:34]=[CH:33][C:32]([CH2:35][C:36]2[C:45]3[C:40](=[CH:41][CH:42]=[CH:43][CH:44]=3)[C:39](=[O:46])[NH:38][N:37]=2)=[CH:31][C:27]=1[C:28](O)=[O:29].[CH3:47][O:48][CH:49]1[CH2:54][CH2:53][NH:52][CH2:51][CH2:50]1.C(N(CC)CC)C>CC(N(C)C)=O.O>[F:25][C:26]1[CH:34]=[CH:33][C:32]([CH2:35][C:36]2[C:45]3[C:40](=[CH:41][CH:42]=[CH:43][CH:44]=3)[C:39](=[O:46])[NH:38][N:37]=2)=[CH:31][C:27]=1[C:28]([N:52]1[CH2:53][CH2:54][CH:49]([O:48][CH3:47])[CH2:50][CH2:51]1)=[O:29]
Reactant: O=C(O)c1cc(Cc2n[nH]c(=O)c3ccccc23)ccc1F
Reactant: COC1CCNCC1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: O
Solvent: CC(=O)N(C)C
Product: COC1CCN(C(=O)c2cc(Cc3n[nH]c(=O)c4ccccc34)ccc2F)CC1
Temperature: 20 °C
Reaction time: 21 h
Yield: 61.6 %

Procedure:
O-Benzotriazol-1-yl-tetramethyluronium hexafluorophosphate (45.5 g, 119.86 mmol) was added portionwise to a solution of 2-fluoro-5-((4-oxo-3,4-dihydrophthalazin-1-yl)methyl)benzoic acid (1) (27.5 g, 92.20 mmol), 4-methoxypiperidine (11.68 g, 101.42 mmol) and triethylamine (30.8 mL, 221.28 mmol) in DMA (450 mL) at 20° C. under nitrogen. The resulting solution was stirred at 20° C. for 21 hours. The solution was poured into water (2.5 liters) and extracted with EtOAc (×3), the combined extracts washed with brine (×3), dried (MgSO4), filtered and evaporated to a gum. The crude product was purified by flash silica chromatography, elution gradient 0 to 100% EtOAc in isohexane. Pure fractions were evaporated to dryness and slurried with EtOAc to afford 4-(4-fluoro-3-(4-methoxypiperidine-1-carbonyl)benzyl)phthalazin-1(2H)-one (2b) (22.45 g, 61.6%) as a white solid after filtration and vacuum drying.
Reaction SMILES: Br[C:2]1[C:3]([O:12][CH3:13])=[CH:4][C:5]([O:10][CH3:11])=[C:6]([CH:9]=1)[CH:7]=[O:8].[S:14]1[CH:18]=[CH:17][CH:16]=[C:15]1B(O)O>C1COCC1>[CH3:11][O:10][C:5]1[CH:4]=[C:3]([O:12][CH3:13])[C:2]([C:15]2[S:14][CH:18]=[CH:17][CH:16]=2)=[CH:9][C:6]=1[CH:7]=[O:8]
Reactant: OB(O)c1cccs1
Reactant: COc1cc(OC)c(C=O)cc1Br
Solvent: C1CCOC1
Product: COc1cc(OC)c(-c2cccs2)cc1C=O
Temperature: 60 °C
Yield: 93.9 %

Procedure:
An alternative procedure: 5-bromo-2,4-dimethoxybenzaldehyde (20.3 g), thiophene-2-boronic acid (11.6 g) and THF (200 mL) were sequentially charged into a clean reaction vessel fitted with a reflux condenser, mechanical stirrer and nitrogen inlet adapter. Nitrogen was bubbled into the resulting solution for 20 min followed by the sequential addition of KF (10.1 g), and Pd(tBu3P)2 (0.424 g). The solution was immediately heated to 60° C. and aged for 1.5 h. The reaction was diluted with H2O (200 mL) and transferred to a separatory funnel containing EtOAc (200 mL) and H2O (200 mL). The layers were cut and the aqueous layer was extracted with EtOAc (100 mL). The combined organic cuts were filtered through a pre-washed pad of solka floe (5 g). The pad of solka floe and spent catalyst were washed with fresh EtOAc (200 mL) and this wash combined with the batch. The resultant filtrate was concentrated to dryness. The crude product was dissolved in THF (38 mL) and crystallized upon heptane (152 mL) addition. The product was filtered and then dried to a constant weight in the vacuum oven (38° C., 20 mHg) affording 19.32 g (94% yield) of desired 2,4-dimethoxy-5-thiophen-2-yl-benzaldehyde as a light off-white solid. 1H-NMR identical as above.
Reaction SMILES: [Mn]([O-])(=O)(=O)=O.[K+].[CH:7]1([O:12][C:13]2[C:18]([O:19][CH3:20])=[CH:17][N:16]=[C:15]([CH2:21][OH:22])[CH:14]=2)[CH2:11][CH2:10][CH2:9][CH2:8]1.[OH-].[K+].C([OH:28])(C)C>O>[CH:7]1([O:12][C:13]2[C:18]([O:19][CH3:20])=[CH:17][N:16]=[C:15]([C:21]([OH:28])=[O:22])[CH:14]=2)[CH2:8][CH2:9][CH2:10][CH2:11]1
Reactant: CC(C)O
Reactant: COc1cnc(CO)cc1OC1CCCC1
Agent: O=[Mn](=O)(=O)[O-]
Agent: [K+]
Agent: [OH-]
Solvent: O
Product: COc1cnc(C(=O)O)cc1OC1CCCC1
Temperature: 70 °C
Reaction time: 0.17 h

Procedure:
Solid potassium permanganate (5.87 g) is added portionwise during 30 minutes to a suspension of 4-cyclopentyloxy-2-hydroxymethyl-5-methoxypyridine (4.0 g) in water (100 mL) at 50±5° C. When the addition is complete the mixture is heated at 70±5° C. for 45 min and then cooled to room temperature. A solution of potassium hydroxide (1.95 g) in water (50 mL) is added followed by sufficient isopropanol to react with excess potassium permanganate. After stirring for 10 minutes the mixture is filtered through diatomaceous earth and the filtrate concentrated to ˜70 mL. The solution is acidified to pH 2 with concentrated aqueous hydrochloric acid and extracted with chloroform. After drying (MgSO4) the extracts are evaporated to give 4-cyclopentyloxy-5-methoxypyridine-2-carboxylic acid (2.5 g) as a white solid, m.p. 184–5° C. [1Hnmr in D6-DMSO shifts relative to Me4Si:—1.55–1.79, 6H, m; 1.95, 2H, m; 3.92, 3H, s; 5.00, 1H, m; 7.59, 1H, s; 8.24, 1H, s.].
Reaction SMILES: [CH2:1]([O:3][CH2:4][N:5]1[C:13]2[CH:12]=[CH:11][CH:10]=[C:9]([C:14]([O:16]C)=[O:15])[C:8]=2[CH:7]=[CH:6]1)[CH3:2].[OH-].[Na+]>CO>[CH2:1]([O:3][CH2:4][N:5]1[C:13]2[CH:12]=[CH:11][CH:10]=[C:9]([C:14]([OH:16])=[O:15])[C:8]=2[CH:7]=[CH:6]1)[CH3:2]
Reactant: CCOCn1ccc2c(C(=O)OC)cccc21
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CCOCn1ccc2c(C(=O)O)cccc21
Temperature: 50 °C
Reaction time: 3 h
Yield: 96.7 %

Procedure:
To a solution of methyl 1-(ethoxymethyl)-1H-indole-4-carboxylate (135 g, 0.58 mol) in methanol (2 L) is added aqueous sodium hydroxide (68 g, 1.74 mol in 340 mL of H2O). The reaction mixture is stirred at 50° C. for 3 h. The volatiles are removed in vacuo. The residue is acidified with HCl (2 M) until pH=3-4, then extracted with EA (2×700 mL). The combined extracts are washed with aqueous saturated sodium chloride (2×250 mL), dried over anhydrous Na2SO4, and concentrated to yield the title compound (123 g, 96%). MS (m/z): 220 (M+H)+.
Reaction SMILES: [CH:1]([N:4]1[CH2:8][CH2:7][N:6]=[C:5]1[CH3:9])([CH3:3])[CH3:2].N1CCN=C1>[Cr].[Cu].[Ni]>[CH:1]([N:4]1[CH:8]=[CH:7][N:6]=[C:5]1[CH3:9])([CH3:3])[CH3:2]
Reactant: CC1=NCCN1C(C)C
Agent: [Cr]
Agent: [Cu]
Agent: [Ni]
Product: Cc1nccn1C(C)C
Reaction time: 5 h
Yield: 98 %

Procedure:
A 100-ml three-necked flask equipped with a thermometer, condenser, magnetic stirrer, and nitrogen inlet was charged with 1-isopropyl-2-methylimidazoline (50 g, 0.4 mole) and nickel-copper-chromium catalyst (5.0 g) as described in U.S. Pat. No. 3,152,998. The reaction was carried out at 200° C. with stirring and under a nitrogen atmosphere for about 5 hours. GLC analysis showed that more than 99% of the starting imidazoline had been converted to give the corresponding imidazole with 98.5% selectivity. The product was fractionally distilled under reduced pressure (80° C. at 1.2 mm Hg) to give a clear, colorless liquid in about 98% yield.
Reaction SMILES: [CH3:1][CH2:2][O:3][C:4]([CH:6](P(OCC)(OCC)=O)[F:7])=[O:5].C([N-]C(C)C)(C)C.[Li+].[CH2:24]([O:27][C:28]1[C:29]([C:42](=O)[CH2:43][CH3:44])=[CH:30][C:31]2[C:32]([CH3:41])([CH3:40])[CH2:33][CH2:34][C:35]([CH3:39])([CH3:38])[C:36]=2[CH:37]=1)[CH2:25][CH3:26]>C1COCC1>[CH2:24]([O:27][C:28]1[C:29](/[C:42](/[CH2:43][CH3:44])=[C:6](/[F:7])\[C:4]([O:3][CH2:2][CH3:1])=[O:5])=[CH:30][C:31]2[C:32]([CH3:41])([CH3:40])[CH2:33][CH2:34][C:35]([CH3:39])([CH3:38])[C:36]=2[CH:37]=1)[CH2:25][CH3:26]
Reactant: CCCOc1cc2c(cc1C(=O)CC)C(C)(C)CCC2(C)C
Reactant: CCOC(=O)C(F)P(=O)(OCC)OCC
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CCCOc1cc2c(cc1/C(CC)=C(/F)C(=O)OCC)C(C)(C)CCC2(C)C
Temperature: -78 °C
Reaction time: 2 h

Procedure:
Triethyl 2-fluoro-2-phosphonoacetate (5.72 mL, 28.1 mmol, was added to a stirring solution of lithium diisopropylamide (28.1 mmol) in THF (54 mL) at −78° C. under argon. The dry ice bath was removed for about ten minutes, and then the solution was cooled again to −78° C. A solution of 1-(3-n-propoxy5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl)propan-1-one (Intermediate 7, 2.70 g, 9.36 mmol) and THF. (10 mL) was added, and the solution was stirred at 0° C. for 2 h. The reaction was quenched at −78° C. by adding saturated ammonium chloride. The solution was warmed to room temperature and the products were extracted three times with ether. The combined organic layers were washed with water, brine and dried over magnesium sulfate. The solvent was removed in vacuo to give the title compound.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([Li])CCC.[CH:13]([C:15]1[CH:27]=[CH:26][C:18]([C:19]([N:21]([CH2:24][CH3:25])[CH2:22][CH3:23])=[O:20])=[CH:17][CH:16]=1)=[O:14]>>[NH2:1][C:2]1[CH:7]=[C:6]([CH:5]=[CH:4][CH:3]=1)[CH:13]([C:15]1[CH:27]=[CH:26][C:18]([C:19]([N:21]([CH2:22][CH3:23])[CH2:24][CH3:25])=[O:20])=[CH:17][CH:16]=1)[OH:14]
Reactant: Nc1ccccc1
Reactant: CCN(CC)C(=O)c1ccc(C=O)cc1
Agent: [Li]CCCC
Product: CCN(CC)C(=O)c1ccc(C(O)c2cccc(N)c2)cc1
Yield: 25.2 %

Procedure:
The protected aniline (23.64 g. 0.101 mol) was treated with n-butyllithium (1.5M in hexane, 66 mL, 0.101 mol) and 4-formyl-N,N-diethylbenzamide (20.70 g, 0.101 mol) as in Example11. Chromatography of the crude product on silica gel (Waters Prep 500, dichloromethane:ethanol/100:1-3) gave 7.59 g (25%) of 4-(3-amino-α-hydroxybenzyl)-N,N-diethylbenzamide as a light yellow hygroscopic solid.