Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CS(C)=O.C(Cl)(=O)C(Cl)=O.[F:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]([CH3:22])([CH3:21])[CH2:19][OH:20])=[CH:14][CH:13]=1.CCN(CC)CC>C(Cl)Cl>[F:11][C:12]1[CH:13]=[CH:14][C:15]([C:18]([CH3:22])([CH3:21])[CH:19]=[O:20])=[CH:16][CH:17]=1
Reactant: CC(C)(CO)c1ccc(F)cc1
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Product: CC(C)(C=O)c1ccc(F)cc1
Temperature: 0 °C
Reaction time: 0.08 h

Procedure:
A solution of DMSO (1.7 eq.) in DCM (0.5 M) was treated at −78° C. with a 2 M solution of oxalyl chloride in DCM (1.4 eq.). The reaction was stirred for 5 min, and a solution of 2-(4-fluorophenyl)-2-methylpropan-1-ol (1 eq.) in DCM (3 M) added to the reaction mixture. After stirring for 10 min, NEt3 (2.4 eq.) was added and the reaction mixture warmed to 0° C., stirred one hour, removed the cooling bath and stirred for one additional hour. The mixture was diluted with DCM, extracted with bleach/water, 1 M citric acid, water, dried (Na2SO4), concentrated.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:17](=[O:18])[C:16]2[C:11](=[N:12][C:13](S(C)=O)=[N:14][CH:15]=2)[N:10]2[CH:22]=[CH:23][N:24]=[C:9]12.[NH2:25][C:26]1[CH:31]=[CH:30][C:29]([CH:32]2[CH2:36][CH2:35][N:34](C(OC(C)(C)C)=O)[CH2:33]2)=[CH:28][CH:27]=1.[F:44][C:45]([F:50])([F:49])[C:46]([OH:48])=[O:47]>C(OCC)(=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:17](=[O:18])[C:16]2[CH:15]=[N:14][C:13]([NH:25][C:26]3[CH:27]=[CH:28][C:29]([CH:32]4[CH2:36][CH2:35][NH:34][CH2:33]4)=[CH:30][CH:31]=3)=[N:12][C:11]=2[N:10]2[CH:22]=[CH:23][N:24]=[C:9]12.[F:44][C:45]([F:50])([F:49])[C:46]([OH:48])=[O:47]
Reactant: CS(=O)c1ncc2c(=O)n(-c3ccccc3Cl)c3nccn3c2n1
Reactant: CC(C)(C)OC(=O)N1CCC(c2ccc(N)cc2)C1
Solvent: CCOC(C)=O
Solvent: O=C(O)C(F)(F)F
Product: O=c1c2cnc(Nc3ccc(C4CCNC4)cc3)nc2n2ccnc2n1-c1ccccc1Cl
Temperature: 35 °C
Reaction time: 5 h

Procedure:
A mixture of Example 1E (0.048 g, 0.133 mmol) and tert-butyl 3-(4-aminophenyl)pyrrolidine-1-carboxylate (0.056 g, 0.213 mmol) was heated in a capped vial at 90° C. for 1 hour. The reaction mixture was treated with ethyl acetate and washed with saturated aqueous NaHCO3. The organic layer was dried over MgSO4, filtered, and concentrated. The residue was dissolved in CH2Cl2 (2 mL) and treated with trifluoroacetic acid (0.103 ml, 1.334 mmol). The mixture was stirred at 35° C. for 5 hrs, concentrated, and purified by HPLC (see protocol in Example 1F) to provide the title compound as a trifluoroacetic acid salt. 1H NMR (500 MHz, CD3OD) δ 2.24-2.05 (m, 1H), 2.49 (dtd, J=10.2, 7.1, 3.1 Hz, 1H), 3.21 (dd, J=24.8, 13.8 Hz, 1H), 3.46-3.37 (m, 1H), 3.61-3.52 (m, 2H), 3.73 (dd, J=11.4, 7.9 Hz, 1H), 7.07 (d, J=1.8 Hz, 1H), 7.40-7.39 (m, 2H), 7.62-7.51 (m, 3H), 7.73-7.66 (m, 1H), 7.86-7.81 (m, 3H), 9.15 (s, 1H). MS (ESI+) m/z 458.2 (M+H)+.
Reaction SMILES: [C:1]([C:5]1[CH:30]=[CH:29][C:8]([C:9]([NH:11][C:12]2[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][C:13]=2[C:14]([NH:16][C:17]2[CH:22]=[CH:21][C:20]([F:23])=[CH:19][N:18]=2)=[O:15])=[O:10])=[C:7]([O:31][CH:32]2[CH2:37][CH2:36][N:35](C(OC(C)(C)C)=O)[CH2:34][CH2:33]2)[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].C1(OC)C=CC=CC=1.[C:53]([OH:59])([C:55]([F:58])([F:57])[F:56])=[O:54]>ClCCl>[F:56][C:55]([F:58])([F:57])[C:53]([OH:59])=[O:54].[C:1]([C:5]1[CH:30]=[CH:29][C:8]([C:9]([NH:11][C:12]2[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][C:13]=2[C:14]([NH:16][C:17]2[CH:22]=[CH:21][C:20]([F:23])=[CH:19][N:18]=2)=[O:15])=[O:10])=[C:7]([O:31][CH:32]2[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]2)[CH:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCC(Oc2cc(C(C)(C)C)ccc2C(=O)Nc2ccc(Cl)cc2C(=O)Nc2ccc(F)cn2)CC1
Solvent: COc1ccccc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(C)(C)c1ccc(C(=O)Nc2ccc(Cl)cc2C(=O)Nc2ccc(F)cn2)c(OC2CCNCC2)c1
Reaction time: 2 h
Yield: 90 %

Procedure:
To a stirring solution of 2-[4-(tert-butyl)-2-(1-Boc-piperidin-4-yloxy)benzoyl-amino]-5-chloro-N-(5-fluoropyridin-2-yl)benzamide (0.3 g, 0.48 mmol) and anisole (0.26 mL) in dichloromethane (10 mL) was added TFA (1 mL). After 2 h, the solvent was removed in vacuo and the residue was suspended in diethyl ether and concentrated in vacuo twice and then again suspended in diethyl ether with vigorous stirring. The solid was washed with diethyl ether, filtered and dried in vacuo to give 0.28 g (90%) of off-white solid,
Reaction SMILES: Cl[C:2]1[C:3](=[O:19])[NH:4][N:5]=[CH:6][C:7]=1[O:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[C:15]([F:18])([F:17])[F:16].[OH-].[Na+].[H][H]>[Pd].C(Cl)Cl.O>[F:17][C:15]([F:16])([F:18])[C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=1[O:8][C:7]1[CH:6]=[N:5][NH:4][C:3](=[O:19])[CH:2]=1
Reactant: [H][H]
Reactant: O=c1[nH]ncc(Oc2ccccc2C(F)(F)F)c1Cl
Agent: [Pd]
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: O
Product: O=c1cc(Oc2ccccc2C(F)(F)F)cn[nH]1
Reaction time: 96 h
Yield: 70.1 %

Procedure:
A pressure vial containing a mixture of 4-chloro-5-(2-trifluoromethyl-phenoxy)-2H-pyridazin-3-one (3.66 g, 12.59 mmol), water (70 mL), and a 2N aqueous sodium hydroxide solution (7 mL, 14 mmol) was treated with 10% palladium on carbon (0.37 mg, 10% weight of 4-chloro-5-(2-trifluoromethyl-phenoxy)-2H-pyridazin-3-one). The reaction was then pressurized with hydrogen (50 psi), where it shook for 4 d. The resulting reaction mixture was diluted with methylene chloride (100 mL) and water (100 mL) and filtered through a pad of diatomaceous earth. The filtrate was concentrated in vacuo. The aqueous residue was acidified with a 2N aqueous hydrochloric acid solution and was then extracted with a 90/10 methylene chloride/methanol solution. The combined organic layers were dried over sodium sulfate, filtered, and concentrated in vacuo. Silica gel column chromatography (ISCO, 120 g, 50%-70% ethyl acetate/hexanes) afforded 5-(2-trifluoromethyl-phenoxy)-2H-pyridazin-3-one (2.26 g, 70%) as a white solid. 1H NMR (300 MHz, DMSO-d6) δ ppm 5.79 (d, J=2.7 Hz, 1H), 7.52-7.60 (m, 2H), 7.82 (t, J=8.5 Hz, 1H), 7.89 (d, J=8.2 Hz, 1H), 8.00 (d, J=2.7 Hz, 1H), 13.04 (br. s., 1H).
Reaction SMILES: [Cl:1][SiH2:2][Cl:3].[CH2:4]=[CH:5][CH2:6][CH2:7][CH2:8][CH3:9]>[H+].[H+].Cl[Pt-2](Cl)(Cl)(Cl)(Cl)Cl>[CH2:4]([SiH:2]([Cl:3])[Cl:1])[CH2:5][CH2:6][CH2:7][CH2:8][CH3:9].[CH2:4]([Si:2]([CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH3:9])([Cl:3])[Cl:1])[CH2:5][CH2:6][CH2:7][CH2:8][CH3:9]
Reactant: Cl[SiH2]Cl
Reactant: C=CCCCC
Agent: Cl[Pt-2](Cl)(Cl)(Cl)(Cl)Cl
Agent: [H+]
Product: CCCCCC[SiH](Cl)Cl
Product: CCCCCC[Si](Cl)(Cl)CCCCCC

Procedure:
Dichlorosilane in an amount of 83.5 g (0.827 mol), 88.6 g of 1-hexene (1.08 mol) and 0.05 mol % of chloroplatinic acid (relative to dichlorosilane) were charged in a stainless steel reactor and sealed and subjected to reaction in a bath at a temperature of 50° C. for 5 hours. After reaction, the seal of the reactor was broken and the reacted liquid was discharged, and by vacuum distillation, n-hexyldichlorosilane was obtained with a yield of 18% and di-n-hexyldichlorosilane with a yield of 72%.
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[C:10]([N:12]2[CH2:17][CH2:16][N:15]([S:18]([CH3:21])(=[O:20])=[O:19])[CH2:14][CH2:13]2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.C[Si](C)(C)[N-][Si](C)(C)C.[Li+].[CH2:32]([O:34][P:35](Cl)([O:37][CH2:38][CH3:39])=[O:36])[CH3:33].C(O)(=O)C>C1COCC1.O>[CH2:32]([O:34][P:35]([CH2:21][S:18]([N:15]1[CH2:14][CH2:13][N:12]([C:10]2[C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[N:3]=[C:2]([CH3:1])[CH:11]=2)[CH2:17][CH2:16]1)(=[O:20])=[O:19])([O:37][CH2:38][CH3:39])=[O:36])[CH3:33]
Reactant: Cc1cc(N2CCN(S(C)(=O)=O)CC2)c2ccccc2n1
Reactant: CCOP(=O)(Cl)OCC
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: CC(=O)O
Solvent: O
Solvent: C1CCOC1
Product: CCOP(=O)(CS(=O)(=O)N1CCN(c2cc(C)nc3ccccc23)CC1)OCC
Temperature: -78 °C
Reaction time: 1 h
Yield: 97.5 %

Procedure:
2-Methyl-4-(4-methylsulfonylpiperazin-1-yl)quinoline (70 mg, 0.23 mmol) was placed in a Schlenk tube under an argon atmosphere, anhydrous THF (1.5 ml) was added and the solution cooled to −78° C. Lithium hexamethyldisilazid (50.6 mmol, 50.6 μl of a 1M solution in anhydrous THF) was added dropwise and the mixture stirred for one hour at −78° C. Diethylchlorophosphate (33.3 μl, 0.23 mmol) was added dropwise and stirring was continued for one hour. Acetic acid (100 μl) and water (1.5 ml) were added, the temperature raised slowly to room temperature and the mixture was extracted with diethylether (3×). The combined organic phases were washed with water and brine and evaporated to dryness under reduced pressure. 99 mg of an oily residue were obtained (0.22 mmol, 98%). MS (APCI) m/z=441.7 [M+1]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]=[C:7]([CH3:9])[N:6]=[C:5]([NH:10][C:11]([NH:13][S:14]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[C:23](OC)=[O:24])(=[O:16])=[O:15])=[O:12])[N:4]=1.C[Al](C)C.C.[NH2:32][C:33]1[N:37]=[CH:36][NH:35][N:34]=1.Cl>C(Cl)Cl.C1(C)C=CC=CC=1>[CH3:1][O:2][C:3]1[N:8]=[C:7]([CH3:9])[N:6]=[C:5]([NH:10][C:11]([NH:13][S:14]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[C:23]([NH:32][C:33]2[N:37]=[CH:36][NH:35][N:34]=2)=[O:24])(=[O:15])=[O:16])=[O:12])[N:4]=1
Reactant: COC(=O)c1ccccc1S(=O)(=O)NC(=O)Nc1nc(C)nc(OC)n1
Reactant: Nc1nc[nH]n1
Agent: C
Agent: C[Al](C)C
Agent: Cl
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: COc1nc(C)nc(NC(=O)NS(=O)(=O)c2ccccc2C(=O)Nc2nc[nH]n2)n1

Procedure:
To a slurry of 4.0 g of N-[(4-methoxy-6-methyl-1,3,5-triazin-2-yl)aminocarbonyl]-2-methoxycarbonylbenzenesulfonamide in 100 ml of methylene chloride was added by syringe 10 ml of a 2M solution of trimethylaluminum in toluene (1.44 g of Al(CH3)3). Evolution of methane gas was seen. 3-Amino-1,2,4-triazole (1.7 g) was then added and the mixture was heated at reflux for 18 hours. The reaction mixture was then treated with aqueous hydrochloric acid and the precipitated product was purified by trituration in methylene chloride, 0.63 g, m.p. 176°-179° C. NMR in TFA 2.9 ppm s, CH3 on triazine, 4.4 ppm s, OCH3 on triazine, 7.8-8.0 ppm and 8.2-8.5 ppm M, aromatic.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]([C:21]2[CH:26]=[CH:25][C:24]([C:27]([F:30])([F:29])[F:28])=[CH:23][CH:22]=2)[S:5][C:6]=1[CH2:7][NH:8][C:9]1[CH:14]=[CH:13][C:12]([C@@H:15]2[CH2:17][C@H:16]2[C:18]([OH:20])=O)=[CH:11][CH:10]=1.CN(C(ON1N=[N:46][C:41]2[CH:42]=CC=N[C:40]1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N)(C)C>ClCCl.CN(C=O)C>[CH:41]([NH:46][C:18]([CH:16]1[CH2:17][CH:15]1[C:12]1[CH:13]=[CH:14][C:9]([NH:8][CH2:7][C:6]2[S:5][C:4]([C:21]3[CH:22]=[CH:23][C:24]([C:27]([F:29])([F:30])[F:28])=[CH:25][CH:26]=3)=[N:3][C:2]=2[CH3:1])=[CH:10][CH:11]=1)=[O:20])([CH3:42])[CH3:40]
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Reactant: Cc1nc(-c2ccc(C(F)(F)F)cc2)sc1CNc1ccc([C@@H]2C[C@H]2C(=O)O)cc1
Agent: F[P-](F)(F)(F)(F)F
Solvent: CC(C)N
Solvent: ClCCl
Solvent: CN(C)C=O
Product: Cc1nc(-c2ccc(C(F)(F)F)cc2)sc1CNc1ccc(C2CC2C(=O)NC(C)C)cc1
Reaction time: 0.25 h
Yield: 60.3 %

Procedure:
To a mixture of (+)-(trans)-2-{4-[({4-methyl-2-[4-(trifluoromethyl)phenyl]-1,3-thiazol-5-yl}methyl)amino]phenyl}cyclopropanecarboxylic acid (III-3c) (0.12 g, 0.28 mmol) in dichloromethane (2 mL) and DMF (1 mL) was added HATU (0.16 g, 0.42 mmol). The mixture was stirred for 15 min followed by addition of isopropylamine (0.02 g, 0.33 mmol). The solution stirred for 6 h after which the dichloromethane was removed via rotavap. Sat. NaHCO3 and ethyl acetate were added and the organic layer separated and washed with H2O, dried over MgSO4, filtered and concentrated. The resulting oil was triterated with Et2O and formed a yellow ppt which was filtered and dried under high vacuum to give the title compound as a yellow powder (0.08 g, 61%). 1H NMR (400 MHz, CDCl3) δ 7.97 (d, J=8.3 Hz, 2H), 7.65 (d, J=8.2 Hz, 2H), 6.95 (d, J=8.4 Hz, 2H), 6.59 (d, J=8.4 Hz, 2H), 5.49 (d, J=7.9 Hz, 1H), 4.44 (s, 2H), 4.13-4.08 (m, 1H), 2.49 (s, 3H), 2.40-2.37 (m, 1H), 1.56-1.51 (m, 1H), 1.44-1.39 (m, 1H), 1.26-1.10 (m, 7H). ES-MS m/z 474.2 (MH+).
Reaction SMILES: CC1(C)C(C)(C)OB([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[NH:15][S:16]([CH3:19])(=[O:18])=[O:17])O1.Br[C:22]1[N:30]2[C:25]([CH:26]=[N:27][C:28]([S:31][CH3:32])=[N:29]2)=[CH:24][C:23]=1[CH3:33]>>[CH3:33][C:23]1[CH:24]=[C:25]2[N:30]([C:22]=1[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[NH:15][S:16]([CH3:19])(=[O:17])=[O:18])[N:29]=[C:28]([S:31][CH3:32])[N:27]=[CH:26]2
Reactant: CC1(C)OB(c2ccccc2NS(C)(=O)=O)OC1(C)C
Reactant: CSc1ncc2cc(C)c(Br)n2n1
Product: CSc1ncc2cc(C)c(-c3ccccc3NS(C)(=O)=O)n2n1

Procedure:
N-[2-(6-Methyl-2-methylsulfanyl-pyrrolo[2,1-f][1,2,4]triazin-7-yl)-phenyl]-methanesulfonamide was prepared in an analogous fashion to Example 47a after: replacing 2-methoxybenzeneboronic acid with N-[2-(4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)-phenyl]-methanesulfonamide, and replacing 7-Bromo-2-methylsulfanyl-pyrrolo[2,1-f][1,2,4]triazine with 7-Bromo-6-methyl-2-methylsulfanyl-pyrrolo[2,1-f][1,2,4]triazine, to give after purification via normal phase chromatography (EtOAc/hexane as eluant) N-[2-(6-Methyl-2-methylsulfanyl-pyrrolo[2,1-f][1,2,4]triazin-7-yl)-phenyl]-methanesulfonamide as a yellow solid (0.12 g, 44%). LC/MS (E/I+) 349.04 (M+H).
Reaction SMILES: [CH2:1]([C:8]1[CH:9]=[N:10][C:11]2[C:16]([C:17]=1[C:18]1[CH:19]=[C:20]([NH2:24])[CH:21]=[CH:22][CH:23]=1)=[CH:15][CH:14]=[CH:13][C:12]=2[C:25]([F:28])([F:27])[F:26])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:29][C:30]1[C:31]([F:38])=[C:32]([CH:35]=[CH:36][CH:37]=1)[CH:33]=O>>[CH2:1]([C:8]1[CH:9]=[N:10][C:11]2[C:16]([C:17]=1[C:18]1[CH:19]=[C:20]([NH:24][CH2:33][C:32]3[CH:35]=[CH:36][CH:37]=[C:30]([Cl:29])[C:31]=3[F:38])[CH:21]=[CH:22][CH:23]=1)=[CH:15][CH:14]=[CH:13][C:12]=2[C:25]([F:28])([F:26])[F:27])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Nc1cccc(-c2c(Cc3ccccc3)cnc3c(C(F)(F)F)cccc23)c1
Reactant: O=Cc1cccc(Cl)c1F
Product: Fc1c(Cl)cccc1CNc1cccc(-c2c(Cc3ccccc3)cnc3c(C(F)(F)F)cccc23)c1

Procedure:
The title compound was prepared from {3-[3-benzyl-8-(trifluoromethyl)quinolin-4-yl]phenyl}amine and 3-chloro-2-fluoro-benzaldehyde according to the procedure of Example 66. MS (ESI) m/z 521.
Reaction SMILES: [C:1]([NH:4][C:5](=[CH2:16])[C:6]([O:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)=[O:7])(=[O:3])[CH3:2].CCN(CC)CC.Br[C:25]1[CH:31]=[CH:30][C:28]([NH2:29])=[C:27]([CH2:32][CH3:33])[CH:26]=1>C(#N)C.CC([O-])=O.CC([O-])=O.[Pd+2]>[C:1]([NH:4]/[C:5](=[CH:16]/[C:25]1[CH:31]=[CH:30][C:28]([NH2:29])=[C:27]([CH2:32][CH3:33])[CH:26]=1)/[C:6]([O:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)=[O:7])(=[O:3])[CH3:2]
Reactant: CCc1cc(Br)ccc1N
Reactant: C=C(NC(C)=O)C(=O)OCc1ccccc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CCc1cc(/C=C(/NC(C)=O)C(=O)OCc2ccccc2)ccc1N
Yield: 25.7 %

Procedure:
To benzyl 2-(acetylamino)acrylate (80.0 mmol) in acetonitrile (200 mL) was added Pd(OAc)2 (488 mg, 2.18 mmol), (o-Tol)3P (1.32 g, 4.35 mmol), Et3N (20 mL) followed by addition of 4-bromo-2-ethylaniline (14.5 g, 72.5 mmol). The reaction mixture was heated to reflux overnight, concentrated under reduce pressure, taken up in ethyl acetate, washed with aqueous NaHCO3, dried (MgSO4), filtered and concentrated under reduced pressure. The residue was precipitated from ethyl acetate/hexane to provide the titled compound (6.3 g). The filtrate was precipitated a second time to provide and additional 5 g of the titled compound. MS (ESI(+)) m/e 339 (M+H)+; 1H NMR (300 MHz, DMSO-d6) δ 9.31 (s, 1H), 7.40-7.20 (m, 8H), 6.59 (d, 1H), 5.52 (s, 2H), 5.16 (s, 2H), 2.42 (q, 2H), 1.98 (s, 3H), 1.13 (t, 3H).
Reaction SMILES: [CH3:1][C:2]([C:4]1[CH:9]=[CH:8][C:7]([O:10]C)=[CH:6][CH:5]=1)=[O:3].C1(C)C(S([O-])(=O)=[O:19])=CC=CC=1.C([N+](CC)(CC)CC)C>[Pt].CO>[OH:10][C:7]1[CH:6]=[CH:5][C:4]([C:2]([CH:1]=[O:19])=[O:3])=[CH:9][CH:8]=1
Reactant: COc1ccc(C(C)=O)cc1
Reactant: Cc1ccccc1S(=O)(=O)[O-]
Agent: [Pt]
Agent: CC[N+](CC)(CC)CC
Solvent: CO
Product: O=CC(=O)c1ccc(O)cc1

Procedure:
In a standard undivided cell having a platinum anode and a glossy carbon cathode (33 cm2 each) there is charged 200 g methanol (65° C.), 11.3 g of 4-methoxyacetophenone (4-MAP), and 11.5 g tetraethylammonium toluene sulfonate. This electrolysis is conducted at a current density of about 30 mA/cm2 until a current passage of 50.9 Ah is charged (633% of theoretical value). According to an iodometrical determination, a current efficiency of 50% is obtained. About 150 g methanol is distilled off and the remaining solution is neutralized with aqueous NaHCO3 and extracted with ethyl acetate. The extract is dried and the solvent is removed by evaporation. The remaining oil is separated by column chromatography (silica gel, MTBE/cyclohexane=1/4). The acetal product is 6.4 g of 2,2-dimethoxy-1-[4'-methoxyphenyl]-ethanale (41% based on 4-MAP). Subsequent hydrolysis at 62° C. yields 4-hydroxyphenyl glyoxal (HPGO).
Reaction SMILES: [C:1]([CH:6]=[P: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)([O:3][CH2:4][CH3:5])=[O:2].C/C(/O[Si](C)(C)C)=N\[Si](C)(C)C.[C:38](Cl)(=[O:47])[C:39]1[CH:44]=[CH:43][C:42]([O:45][CH3:46])=[CH:41][CH:40]=1>C(Cl)Cl>[CH3:46][O:45][C:42]1[CH:43]=[CH:44][C:39]([C:38](=[O:47])[C:6](=[P:7]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)[C:1]([O:3][CH2:4][CH3:5])=[O:2])=[CH:40][CH:41]=1
Reactant: COc1ccc(C(=O)Cl)cc1
Reactant: CCOC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: C/C(=N\[Si](C)(C)C)O[Si](C)(C)C
Solvent: ClCCl
Product: CCOC(=O)C(C(=O)c1ccc(OC)cc1)=P(c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 0 °C
Reaction time: 8 h

Procedure:
To a stirred solution of (carbethoxymethylene)triphenylphosphorane (0.500 g, 1.44 mmol) in DCM (7 ml) under an N2 atmosphere was added N,O-bis(trimethylsilyl)acetamide (0.42 ml, 1.7 mmol). The solution was then cooled to 0° C. and p-anisoylchloride (0.250 g, 1.47 mmol) was added. The reaction mixture was then gradually warmed to room temperature and stirred overnight. The reaction was quenched by the addition of H2O (3 ml) and the aqueous phase was extracted with DCM. The combined organic phases were dried over MgSO4 and the solvent removed in vacuo to afford ethyl 3-(4-methoxyphenyl)-3-oxo-2-(triphenylphosphoranylidene)propionate. (0.637 g, 1.32 mmol, 92%) as an off white solid which was used without further purification. 1H NMR (CDCl3) δ 0.62 (3H, t), 3.69 (2H, q), 3.82 (3H, s), 6.86 (2H, d), 7.43-7.55 (9H, m), 7.71-7.80 (8H, m). LCMS (2) Rt: 3.65 min; m/z 483.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:25](=[CH:26][CH:27]=1)[CH2:24][C:6]1([C:14]3[C:9](=[N:10][CH:11]=[CH:12][CH:13]=3)[N:8](COCC[Si](C)(C)C)[C:7]1=[O:23])[CH2:5]2.Cl.C(N)CN.[OH-].[Na+]>CO.O>[NH2:1][C:2]1[CH:3]=[C:4]2[C:25](=[CH:26][CH:27]=1)[CH2:24][C:6]1([C:14]3[C:9](=[N:10][CH:11]=[CH:12][CH:13]=3)[NH:8][C:7]1=[O:23])[CH2:5]2
Reactant: C[Si](C)(C)CCOCN1C(=O)C2(Cc3ccc(N)cc3C2)c2cccnc21
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: NCCN
Solvent: CO
Solvent: O
Product: Nc1ccc2c(c1)CC1(C2)C(=O)Nc2ncccc21
Reaction time: 0.5 h

Procedure:
A solution of (−)-5-amino-1′-{[2-(trimethylsilyl)ethoxy]methyl}-1,3-dihydrospiro[indene-2,3′-pyrrolo [2,3-b]pyridin]-2′(1′H)-one from Step G (13.7 g, 35.9 mmol) in MeOH (300 mL) was saturated with HCl (g). The mixture was resaturated with HCl (g) every 30 min until the starting material was consumed, and then concentrated in vacuo. The residue was dissolved in MeOH (150 mL) and treated with ethylenediamine (2.40 mL, 35.9 mmol) and 10 N NaOH (7.20 mL, 72.0 mmol) to adjust the mixture to pH 10. After 30 min, the mixture was diluted with H2O (400 mL) and extracted with CHCl3 (2×1 L). The combined organic layers were dried over Na2SO4, filtered, and concentrated in vacuo. The crude material was triturated with MeOH (50 mL) to give the title compound. MS: m/z=252 (M+1).
Reaction SMILES: [C:1]([CH:4]([NH:13][C:14](=[O:21])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[CH2:5][CH2:6][CH2:7][CH2:8][C:9]([O:11][CH3:12])=[O:10])(=O)[CH3:2].P(Cl)(Cl)(Cl)=O.C(=O)([O-])O.[Na+]>C1(C)C=CC=CC=1>[CH3:2][C:1]1[O:21][C:14]([C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)=[N:13][C:4]=1[CH2:5][CH2:6][CH2:7][CH2:8][C:9]([O:11][CH3:12])=[O:10]
Reactant: COC(=O)CCCCC(NC(=O)c1ccccc1)C(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: O=P(Cl)(Cl)Cl
Product: COC(=O)CCCCc1nc(-c2ccccc2)oc1C
Yield: 83.3 %

Procedure:
Methyl 6-acetyl-6-benzoylaminohexanoate (4.35 g) was dissolved in 87 ml of toluene, and 2.9 ml of phosphorus oxychloride was added and heated to reflux for 50 minutes. The reaction solution was cooled, poured into ice-cold water, neutralized with aqueous sodium hydrogen carbonate solution, extracted with ethyl acetate and washed with brine. The resulting solution was dried over anhydrous magnesium sulfate and concentrated to provide 3.40 g of the objective compound as yellowish oil.
Reaction SMILES: [C:1]1([N:7]2[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][C:8]2=[O:14])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Li+].CC([N-]C(C)C)C.[CH2:23]([O:25]C=O)C.Cl[CH:29]1[CH:33]=[C:32]([CH3:34])[C:31](=[O:35])[O:30]1>O1CCCC1.C(OCC)(=O)C.O>[CH3:34][C:32]1[C:31](=[O:35])[O:30][CH:29]([O:25]/[CH:23]=[C:9]2/[C:8](=[O:14])[N:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[CH2:13][CH2:12][CH2:11][CH2:10]/2)[CH:33]=1
Reactant: CC1=CC(Cl)OC1=O
Reactant: CCOC=O
Reactant: O=C1CCCCCN1c1ccccc1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: O
Product: CC1=CC(O/C=C2\CCCCN(c3ccccc3)C2=O)OC1=O
Temperature: -78 °C
Reaction time: 0.17 h

Procedure:
1-Phenylazepan-2-one (0.500 g, as prepared in Organic Letters 2000, pages 1101-1104) was dissolved in tetrahydrofuran (30 mL) and cooled to −78° C. To the solution was added LDA (2.0 mol/L in THF/heptane/ethylbenzene, 2.6 mL) dropwise. After stirring for 10 min between −55 and −50° C., the reaction mixture was warmed up to −40° C., stirred for 5 min and ethylformate (0.657 mL, 0.605 g) was added slowly. The mixture was warmed up to 0° C. and stirred for another 30 min. 2-Chloro-4-methyl-2H-furan-5-one (0.420 g in 2 mL of THF) was added dropwise. The reaction mixture was warmed up to room temperature and stirred for 3 h. Water and ethyl acetate were added and the layers were separated. The aqueous layer was extracted with ethyl acetate, the organic layers were combined, washed with water and brine, dried over Na2SO4 and the solvent was evaporated to give a brown residue which was purified by flash chromatography (0-100% ethyl acetate in cyclohexane). (3E)-3-[(4-methyl-5-oxo-2H-furan-2-yl)oxymethylene]-1-phenyl-azepan-2-one Ic-13 (0.103 g, 11%) was obtained as a white solid; mp: 150-160° C.; LCMS (Method D): 0.91 min; ES+314 (M+H+).
Reaction SMILES: [C:1]([C:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[NH:5][N:4]=1)#[CH:2].[N:12]([C:15]1[CH:16]=[CH:17][C:18]([Cl:21])=[N:19][CH:20]=1)=[N+:13]=[N-:14]>O1CCOCC1.O.O.O.O.O.O.S([O-])([O-])(=O)=O.[Cu+2]>[Cl:21][C:18]1[N:19]=[CH:20][C:15]([N:12]2[CH:2]=[C:1]([C:3]3[C:11]4[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=4)[NH:5][N:4]=3)[N:14]=[N:13]2)=[CH:16][CH:17]=1
Reactant: C#Cc1n[nH]c2ccccc12
Reactant: [N-]=[N+]=Nc1ccc(Cl)nc1
Agent: [Cu+2]
Agent: O=S(=O)([O-])[O-]
Solvent: C1COCCO1
Solvent: O
Product: Clc1ccc(-n2cc(-c3n[nH]c4ccccc34)nn2)cn1
Temperature: 80 °C

Procedure:
3-Ethynyl-1H-indazole (249 mg; 1.75 mmol; 1.0 eq.) and 5-azido-2-chloropyridine (270 mg; 1.75 mmol; 1.0 eq.) were dissolved in 1,4-dioxane (11 mL). D-(−)-isoascorbic acid sodium salt (69 mg; 0.35 mmol; 0.2 eq.) was added followed by copper sulfate pentahydrate (17.5 mg; 0.07 mmol; 0.04 eq.) in water (3.7 mL) and the reaction mixture was heated at 80° C. for 2 days. The precipitate obtained was filtered, washed with water and EtOAc and dried under vacuum to afford the title compound as a beige powder. m.p.=272-280° C. 1H NMR (300 Mz, DMSO-d6) δ 13.40 (s, 1H), 9.44 (s, 1H), 9.16 (d, J=2.8 Hz, 1H), 8.56 (dd, J=2.9, 8.8 Hz, 1H), 8.33 (d, J=8.1 Hz, 1H), 7.83 (d, J=8.9 Hz, 1H), 7.61 (d, J=8.5 Hz, 1H), 7.44 (m, 1H), 7.26 (m, 1H). HPLC (Condition A): Rt 3.30 min (purity 100%).