Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:16]C1CCCCO1)[C:2]#[C:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH3:15].CC1C=CC(S(O)(=O)=O)=CC=1>CCOCC>[CH2:1]([OH:16])[C:2]#[C:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH3:15]
Reactant: CCCCCCCCCCCCC#CCOC1CCCCO1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCOCC
Product: CCCCCCCCCCCCC#CCO
Yield: 85.2 %

Procedure:
Cleavage of the THP ether from crude 2-(pentadec-2-ynyloxy)tetrahydro-2H-pyran (30 g) using PTSA as described above gave pentadec-2-yn-1-ol (18.6 g, 85%) as a colorless oil. TLC: 30% EtOAc/hexanes, Rf≈0.40; 1H NMR (CDCl3, 300 MHz) δ 4.25 (s, 2H), 2.17-2.23 (m, 2H), 1.70 (br s, 1H), 1.40-1.53 (m, 2H), 1.20-1.48 (m, 18H), 0.87 (t, 3H, J=7.3 Hz).
Reaction SMILES: [Br-].[CH2:2]([Zn+])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.C1COCC1.[O:15]1[C:19]2[CH:20]=[CH:21][C:22]([C:24]3([C:27]([NH:29][C:30]4[CH:35]=[CH:34][N:33]=[C:32](Cl)[CH:31]=4)=[O:28])[CH2:26][CH2:25]3)=[CH:23][C:18]=2[O:17][CH2:16]1>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]>[O:15]1[C:19]2[CH:20]=[CH:21][C:22]([C:24]3([C:27]([NH:29][C:30]4[CH:35]=[CH:34][N:33]=[C:32]([CH2:2][C:3]5[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=5)[CH:31]=4)=[O:28])[CH2:26][CH2:25]3)=[CH:23][C:18]=2[O:17][CH2:16]1
Reactant: [Zn+]Cc1ccccc1
Reactant: O=C(Nc1ccnc(Cl)c1)C1(c2ccc3c(c2)OCO3)CC1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: [Br-]
Solvent: C1CCOC1
Product: O=C(Nc1ccnc(Cc2ccccc2)c1)C1(c2ccc3c(c2)OCO3)CC1
Reaction time: 0.33 h
Yield: 48 %

Procedure:
To a 0.5 M solution of benzylzinc(II) bromide in THF (0.8 mL, 0.4 mmol) was added [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (8 mg, 0.01 mmol) and the reaction was stirred under nitrogen for 20 minutes. 1-(Benzo[d][1,3]dioxol-5-yl)-N-(2-chloropyridin-4-yl)cyclopropanecarboxamide (32 mg, 0.10 mmol) was added and the reaction was irradiated in the microwave for 10 minutes at 150° C. The reaction was quenched with a saturated ammonium chloride solution (2 mL) and a saturated ethylenediamine tetraacetic acid disodium salt solution (2 mL). The mixture was stirred for 30 minutes before it was extracted with dichloromethane (3×4 mL). The organics were dried over Na2SO4 and evaporated. The crude product was dissolved in DMSO (1 mL) and purified by reverse-phase preparative liquid chromatography utilizing a gradient of 0-99% acetonitrile in water containing 0.05% trifluoracetic acid to yield the pure product (18 mg, 0.048 mmol, 48%). ESI-MS m/z calc. 372.1, found 373.3 (M+1)+; retention time 2.44 minutes.
Reaction SMILES: C[O:2][C:3](=[O:24])[C:4]1[CH:9]=[CH:8][C:7]([CH2:10][N:11]([CH2:13][CH2:14][CH2:15][CH2:16][N:17]([CH2:21][CH2:22][CH3:23])[CH2:18][CH2:19][CH3:20])[CH3:12])=[CH:6][CH:5]=1.[OH-].[Na+].Cl>CO>[CH2:21]([N:17]([CH2:18][CH2:19][CH3:20])[CH2:16][CH2:15][CH2:14][CH2:13][N:11]([CH2:10][C:7]1[CH:6]=[CH:5][C:4]([C:3]([OH:24])=[O:2])=[CH:9][CH:8]=1)[CH3:12])[CH2:22][CH3:23]
Reactant: CCCN(CCC)CCCCN(C)Cc1ccc(C(=O)OC)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CCCN(CCC)CCCCN(C)Cc1ccc(C(=O)O)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 91 %

Procedure:
The compound (234 mg) obtained in Example 88-2 was dissolved in methanol (2.5 ml) and added with 1 mol/l sodium hydroxide aqueous solution (2.5 ml) and the whole was stirred at room temperature for 16 hours. After completion of the reaction, the solution was neutralized with a 1 mol/l hydrochloric acid and the solvent was distilled off under reduced pressure. The residue was suspended in ethanol and then a white precipitate was filtrated out. The organic layer was distilled off under reduced pressure and the residue was dried under vacuum, thereby obtaining the subject compound (204 mg) as a pale-yellow oily substance.
Reaction SMILES: Cl.[OH:2][C:3]1[C:4]([C:20]([OH:22])=O)=[C:5]([C:15](OCC)=[O:16])[CH:6]=[N:7][C:8]=1[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.O.[NH2:24][NH2:25]>C(O)C>[OH:2][C:3]1[C:4]2[C:20](=[O:22])[NH:25][NH:24][C:15](=[O:16])[C:5]=2[CH:6]=[N:7][C:8]=1[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: NN
Reactant: CCOC(=O)c1cnc(-c2ccccc2)c(O)c1C(=O)O
Agent: Cl
Solvent: O
Solvent: CCO
Product: O=c1[nH][nH]c(=O)c2c(O)c(-c3ccccc3)ncc12

Procedure:
A mixture of 2 g. ethyl 5-hydroxy-6-phenylpyridine3,4-dicarboxylate. hydrochloride, 40 ml ethanol and 4 ml hydrazine hydrate was refluxed for 4 hours. After cooling, the pale yellow crystals were recovered by filtration, suspended in 20 ml of water and made acid with dilute hydrochloric acid. The crystals were recovered by filtration, rinsed with water and dried. The procedure provided 1.2 g of 8-hydroxy-7-phenylpyrido[3,4-d]pyridazine-1,4-(2H,3H)-dione, melting point: more than 300° C.
Reaction SMILES: [N:1]#[C:2]Br.[F:4][C:5]([F:37])([F:36])[C:6]1[CH:7]=[C:8]([CH:29]=[C:30]([C:32]([F:35])([F:34])[F:33])[CH:31]=1)[CH2:9][NH:10][CH:11]1[CH2:17][CH2:16][CH2:15][N:14]([C:18]([O:20][CH:21]([CH3:23])[CH3:22])=[O:19])[C:13]2[CH:24]=[C:25]([Cl:28])[CH:26]=[CH:27][C:12]1=2>CCOCC>[F:37][C:5]([F:4])([F:36])[C:6]1[CH:7]=[C:8]([CH:29]=[C:30]([C:32]([F:33])([F:34])[F:35])[CH:31]=1)[CH2:9][N:10]([C:2]#[N:1])[CH:11]1[CH2:17][CH2:16][CH2:15][N:14]([C:18]([O:20][CH:21]([CH3:23])[CH3:22])=[O:19])[C:13]2[CH:24]=[C:25]([Cl:28])[CH:26]=[CH:27][C:12]1=2
Reactant: CC(C)OC(=O)N1CCCC(NCc2cc(C(F)(F)F)cc(C(F)(F)F)c2)c2ccc(Cl)cc21
Reactant: N#CBr
Solvent: CCOCC
Product: CC(C)OC(=O)N1CCCC(N(C#N)Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)c2ccc(Cl)cc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 60.7 %

Procedure:
Add a solution of cyanogen bromide (68 mg, 0.63 mmol) in ether (2.6 mL) to a solution of isopropyl 5-(3,5-bistrifluoromethyl-benzylamino)-8-chloro-2,3,4,5-tetrahydrobenzo[b]azepine-1-carboxylate (512 mg, 1.0 mmol) in ether (2.6 mL). Stir the mixture overnight at room temperature. Filter off the resulting solid and wash with ether. Wash the filtrate with water, dry over anhydrous sodium sulfate, filter and remove the solvent under reduced pressure. Purify the residue by flash chromatography, eluting with hexanes/ethyl acetate, to afford the title compound (204 mg, 38%): MS (ES+): 534 (M+H).
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:16]=[CH:15][C:14]([C:17](=[O:24])[CH2:18][CH2:19][C:20]([O:22]C)=[O:21])=[CH:13][CH:12]=2)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[OH-].[Na+]>C1COCC1.CO>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:16]=[CH:15][C:14]([C:17](=[O:24])[CH2:18][CH2:19][C:20]([OH:22])=[O:21])=[CH:13][CH:12]=2)=[CH:7][CH:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(=O)CCC(=O)c1ccc(-c2ccc(C(C)(C)C)cc2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: CC(C)(C)c1ccc(-c2ccc(C(=O)CCC(=O)O)cc2)cc1
Yield: 76.3 %

Procedure:
In a manner similar to Example 17, Step (b), 4-(4′-tert-butyl-biphenyl-4-yl)-4-oxo-butyric acid, methyl ester (0.43 g, 0.0013 mol) was allowed to react with 1.0 M aqueous sodium hydroxide (2.0 mL, 0.002 mol) in THF-methanol (5 mL each) to give 0.308 g of 4-(4′-tert-butyl-biphenyl-4-yl)-4-oxo-butyric acid as a white solid; mp 172.0-173.5° C.
Reaction SMILES: [CH2:1]([NH:3][C:4](=[O:41])[NH:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[N:20]=[C:19]3[C:15]([N:16]=[C:17]([C:22]4([OH:33])[CH2:25][N:24](C(OC(C)(C)C)=O)[CH2:23]4)[N:18]3[CH3:21])=[C:14]([N:34]3[CH2:39][CH2:38][O:37][CH2:36][C@@H:35]3[CH3:40])[N:13]=2)=[CH:8][CH:7]=1)[CH3:2].Cl.O1CCOCC1.FC(F)(F)C(O)=O>ClCCl.CO>[CH2:1]([NH:3][C:4]([NH:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[N:20]=[C:19]3[C:15]([N:16]=[C:17]([C:22]4([OH:33])[CH2:23][NH:24][CH2:25]4)[N:18]3[CH3:21])=[C:14]([N:34]3[CH2:39][CH2:38][O:37][CH2:36][C@@H:35]3[CH3:40])[N:13]=2)=[CH:8][CH:7]=1)=[O:41])[CH3:2]
Reactant: CCNC(=O)Nc1ccc(-c2nc(N3CCOC[C@@H]3C)c3nc(C4(O)CN(C(=O)OC(C)(C)C)C4)n(C)c3n2)cc1
Agent: Cl
Solvent: ClCCl
Solvent: C1COCCO1
Solvent: O=C(O)C(F)(F)F
Product: CCNC(=O)Nc1ccc(-c2nc(N3CCOC[C@@H]3C)c3nc(C4(O)CNC4)n(C)c3n2)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 20.9 %

Procedure:
To (S)-tert-butyl 3-(2-(4-(3-ethylureido)phenyl)-9-methyl-6-(3-methyl-morpholino)-9H-purin-8-yl)-3-hydroxyazetidine-1-carboxylate (45.2 mg, 0.08 mmol) in anhydrous dichloromethane (3.0 mL) and anhydrous methanol (3.0 mL) at 0° C. was added 4M hydrogen chloride in 1,4-dioxane (0.20 mL, 0.80 mmol, 10.0 eq.). The reaction mixture was stirred at RT under N2 for 16 h. Trifluoroacetic acid (0.20 mL) was added and the reaction mixture was stirred at 40° C. under N2 for 24 h. The reaction was then cooled to RT. The reaction mixture was concentrated in vacuo, and the residue was diluted with ethyl acetate. The organic layer was washed with saturated aqueous solution of sodium bicarbonate, water and brine, dried (Na2SO4), filtered and concentrated in vacuo. The crude was purified by reverse phase HPLC to give the title compound as a white solid (7.8 mg, 21%). 1H NMR (DMSO-d6, 400 MHz) δ ppm 8.70 (s, 1H), 8.27 (d, J=8.8 Hz, 2H), 7.95 (s, 1H), 7.48 (d, J=8.8 Hz, 2H), 6.44 (s, 1H), 6.22 (t, J=5.5 Hz, 1H), 5.48 (broad s, 1H), 5.15 (broad s, 1H), 4.14 (d, J=8.2 Hz, 1H), 4.08 (d, J=8.3 Hz, 1H), 4.01 (d, J=8.3 Hz, 1H), 3.84 to 3.67 (m, 7H), 3.61 to 3.52 (m, 1H), 3.50 to 3.39 (m, 1H), 3.17 to 3.07 (m, 2H), 1.34 (d, J=6.7 Hz, 3H), 1.06 (t, J=7.2 Hz, 3H); LC-MS m/z (method C)=467.2 [M+H]+, RT=3.21 min.
Reaction SMILES: CC(O[CH2:5][C:6]1[CH2:15][S:14][C@@H:9]2[C@H:10]([NH2:13])[C:11](=[O:12])[N:8]2[C:7]=1[C:16]([OH:18])=[O:17])=O.O.[SH:20][C:21]1[S:25][C:24]([S:26][CH2:27][C:28]([N:30]2[CH2:35][CH2:34][O:33][CH2:32][CH2:31]2)=[O:29])=[N:23][N:22]=1.P(Cl)(Cl)(OP(Cl)(Cl)=O)=O>C(#N)C>[NH2:13][CH:10]1[C:11](=[O:12])[N:8]2[C:7]([C:16]([OH:18])=[O:17])=[C:6]([CH2:5][S:20][C:21]3[S:25][C:24]([S:26][CH2:27][C:28]([N:30]4[CH2:31][CH2:32][O:33][CH2:34][CH2:35]4)=[O:29])=[N:23][N:22]=3)[CH2:15][S:14][C@H:9]12
Reactant: CC(=O)OCC1=C(C(=O)O)N2C(=O)[C@@H](N)[C@H]2SC1
Reactant: O=C(CSc1nnc(S)s1)N1CCOCC1
Agent: O=P(Cl)(Cl)OP(=O)(Cl)Cl
Solvent: O
Solvent: CC#N
Product: NC1C(=O)N2C(C(=O)O)=C(CSc3nnc(SCC(=O)N4CCOCC4)s3)CS[C@H]12
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 90 %

Procedure:
Mixed were 0.68 g of 7-ACA, 0.18 g of water and 0.90 g of 5-mercapto-2-morpholinocarbonylmethylthio-1,3,4-thiadiazole, and 4.0 ml of acetonitrile was added to the mixture, 2.52 g of diphosphoryl tetrachloride was added to the mixture under stirring in a dry ice/acetone bath at -20° to -40° C. over a period of about 10 minutes, and the cooling bath was removed. After the temperature was allowed to increase at 0° C., the reaction solution was stirred in a warm water bath at 40° C. for 20 minutes, cooled with ice and adjusted to pH 4.3 with aqueous concentrated ammonia following the addition of 5 ml of water. There was obtained 1.10 g (89.9% of yield) of 7-amino-3-(2-morpholinocarbonylmethylthio-1,3,4-thiadiazol-5-yl)thiomethyl-3-cephem-4-carboxylic acid thus produced.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][C:8]1[CH:19]=[CH:18][C:11]([CH2:12][CH2:13][C:14]([O:16][CH3:17])=[O:15])=[CH:10][CH:9]=1.[CH2:20]([NH:22][CH2:23][CH3:24])[CH3:21]>CO>[CH2:20]([N:22]([CH2:23][CH3:24])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][C:8]1[CH:19]=[CH:18][C:11]([CH2:12][CH2:13][C:14]([O:16][CH3:17])=[O:15])=[CH:10][CH:9]=1)[CH3:21]
Reactant: CCNCC
Reactant: COC(=O)CCc1ccc(CCCCCCBr)cc1
Solvent: CO
Product: CCN(CC)CCCCCCc1ccc(CCC(=O)OC)cc1
Yield: 84.4 %

Procedure:
To 10 ml of methanol was added 2.1 g of methyl p-(6-bromohexyl)dihydrocinnamate and 4.67 g of diethylamine, and the mixture was refluxed for 5 hours. The solvent was evaporated off under a reduced pressure, 50 ml of ethyl acetate was added to the residue, and the mixture was washed twice with 20 ml of water, dried over magnesium sulfate and evaporated under a reduced pressure, to obtain 1.73 g of methyl p-(6-diethylaminohexyl)dihydrocinnamate as a colorless oil. To 1.5 g of this oil was added 4.7 ml of 1N sodium hydroxide aqueous solution, the mixture was stirred with heating at 85° C. for 3 hours, and water was evaporated off under a reduced pressure to obtain a residue, which was then dried in the presence of phosphorus pentaoxide under a reduced pressure to obtain 1.5 g of sodium p-(6-diethylaminohexyl)dihydrocinnamate. To 20 ml of dimethylformamide were added 1.4 g of the above salt and 0.86 g of diethylaminoethylchloride, and the reaction mixture was stirred for 4 hours at 60° C. After adding 50 ml of a saturated sodium chloride aqueous solution, the reaction mixture was extracted three times with 20 ml of ethyl acetate, and the extract was washed three times with water, dried over magnesium sulfate and evaporated under a reduced pressure to obtain 1.43 g of 2-diethylaminoethyl p-(6-diethylaminohexyl)dihydrocinnamate as a residue. Next, 1 g of this compound and 6 ml of ethyl iodide were added to 7 ml of ethanol, and the mixture was refluxed for 8 hours and allowed to stand in a freezer. The resulting crystal was recovered by filtration, washed twice with 10 ml of ethanol, and dried in the presence of phosphorus pentaoxide under a reduced pressure to obtain 0.8 g of the title compound as a colorless crystal.
Reaction SMILES: Cl.C(OCC)(=O)C.C([O:12][C:13]1[C:14]([CH2:19][N:20]2[CH2:25][CH2:24][CH:23]([C:26](=[O:38])[CH2:27][C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=3[C:34]([F:37])([F:36])[F:35])[CH2:22][CH2:21]2)=[N:15][CH:16]=[CH:17][N:18]=1)(C)(C)C.[OH-].[Na+]>ClCCl>[F:37][C:34]([F:35])([F:36])[C:29]1[CH:30]=[CH:31][CH:32]=[CH:33][C:28]=1[CH2:27][C:26]([CH:23]1[CH2:22][CH2:21][N:20]([CH2:19][C:14]2[C:13](=[O:12])[NH:18][CH:17]=[CH:16][N:15]=2)[CH2:25][CH2:24]1)=[O:38]
Reactant: CC(C)(C)Oc1nccnc1CN1CCC(C(=O)Cc2ccccc2C(F)(F)F)CC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: O=C(Cc1ccccc1C(F)(F)F)C1CCN(Cc2ncc[nH]c2=O)CC1
Reaction time: 0.5 h
Yield: 71.5 %

Procedure:
After adding 3 ml of 4N hydrogen chloride/ethyl acetate to 249 mg of 1-[1-(3-tert-butoxy-2-pyrazinylmethyl)piperidin-4-yl]-2-[2-(trifluoromethyl)phenyl]ethanone while cooling on ice, the mixture was stirred for 30 minutes. A 2N sodium hydroxide solution was added to the reaction solution for neutralization, and extraction was performed with dichloromethane. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. Diethyl ether was added to the residue and the mixture was filtered to obtain the title compound (155 mg, 71% yield).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][N:3]=[C:2]1[NH:6][S:7]([C:10]1[CH:15]=[CH:14][C:13]([S:16](Cl)(=[O:18])=[O:17])=[CH:12][CH:11]=1)(=[O:9])=[O:8].[C:20]1([Mg]Br)[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>O1CCCC1>[C:20]1([S:16]([C:13]2[CH:14]=[CH:15][C:10]([S:7]([NH:6][C:2]3[S:1][CH:5]=[CH:4][N:3]=3)(=[O:9])=[O:8])=[CH:11][CH:12]=2)(=[O:18])=[O:17])[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: Br[Mg]c1ccccc1
Reactant: O=S(=O)(Cl)c1ccc(S(=O)(=O)Nc2nccs2)cc1
Solvent: C1CCOC1
Product: O=S(=O)(Nc1nccs1)c1ccc(S(=O)(=O)c2ccccc2)cc1
Temperature: -78 °C
Reaction time: 1 h
Yield: 4.1 %

Procedure:
4-(N-thiazol-2-ylsulfamoyl)benzene-1-sulfonyl chloride (0.339 g, 0.00100 mol) was mixed in tetrahydrofuran (15 mL) and cooled to −78° C. Phenylmagnesium bromide (0.363 g, 0.002 mol) solution in THF (1M) was added to the reaction in a dropwise manner. The reaction was allowed to stir 1 hour while warming to room temperature. A second portion of phenyl magnesium bromide solution (0.181 g, 0.001 mol) was added to the reaction mixture. The reaction mixture was then stirred for 18 hours then quenched with saturated ammonium chloride solution. The organic phase was separated and dried over magnesium sulfate. The organic phase was evaporated to a residue and purified by column chromatography (12 g silica gel ISCO column, hexanes to ethyl acetate gradient elution). Product fractions were combined and rotary evaporated to give 15.7 mg of product as white crystals. LCMS: Rt=1.30 min, MS m/z 380.6 [MH]+.
Reaction SMILES: [O:1]=[C:2]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[CH2:6][O:5][C:4]2[CH:13]=[CH:14][C:15]([CH2:17][C:18](OC)=[O:19])=[CH:16][C:3]1=2.[H-].[Al+3].[Li+].[H-].[H-].[H-]>CCOCC>[OH:1][CH:2]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[CH2:6][O:5][C:4]2[CH:13]=[CH:14][C:15]([CH2:17][CH2:18][OH:19])=[CH:16][C:3]1=2
Reactant: COC(=O)Cc1ccc2c(c1)C(=O)c1ccccc1CO2
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Product: OCCc1ccc2c(c1)C(O)c1ccccc1CO2
Temperature: 0 °C

Procedure:
A solution of 3.5 g. of methyl 6,11-dihydro-11oxodibenz[b,e]oxepin-2-acetate in 150 ml. of dry ether is added dropwise to suspension of 2.5 g. of lithium aluminum hydride in 50 ml. of dry ether. The mixture is refluxed for three hours, cooled to 0° C., and hydrolyzed. The mixture is extracted with ether, dried over sodium sulfate, and evaporated to a crude crystalline product. Recrystallization from acetonitrile provides colorless crystals, m.p. 135°-137° C. of 6,11-dihydro-11-hydroxydibenz-[b,e]oxepin-2-ethanol.
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[C:13]([O:17][CH2:18][CH3:19])(=[O:16])[CH2:14][CH3:15].[CH3:20][C:21]([S:24]([N:26]=[C:27]1[CH2:30][O:29][CH2:28]1)=[O:25])([CH3:23])[CH3:22]>C1COCC1>[C:21]([S:24]([NH:26][C:27]1([CH:14]([CH3:15])[C:13]([O:17][CH2:18][CH3:19])=[O:16])[CH2:30][O:29][CH2:28]1)=[O:25])([CH3:20])([CH3:22])[CH3:23]
Reactant: CCOC(=O)CC
Reactant: CC(C)(C)S(=O)N=C1COC1
Agent: [Li]CCCC
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: CCOC(=O)C(C)C1(NS(=O)C(C)(C)C)COC1
Temperature: -78 °C
Reaction time: 1 h

Procedure:
N,N-diisopropylamine (78 g, 770 mmol) was dissolved in anhydrous THF (200 mL) and cooled to −78° C. under nitrogen. Butyl lithium (2.5M solution in hexane, 297 mL, 743 mmol) was added drop-wise. The reaction was removed from the cooling bath for 30 minutes, then re-cooled to −78° C. A solution of ethyl propionate (72.8 g, 713 mmol) in anhydrous THF (200 mL) was added drop-wise and the reaction allowed to stir at room temperature for 1 hour. The reaction was cooled to −78° C. once again and a solution of 2-methyl-N-oxetan-3-ylidenepropane-2-sulfinamide (Preparation 39, 50 g, 285 mmol) in anhydrous THF (200 mL) was added drop-wise. The reaction was stirred at between −40° C. and −60° C. for 4 hours before being quenched with a saturated aqueous solution of ammonium chloride and extracted with ethyl acetate. The organic layer was dried over MgSO4 and concentrated in vacuo. Purification by silica gel column chromatography (ethyl acetate elution) was not successful. The title compound was obtained as a yellow oil (40 g, 51% yield) and used without further purification.
Reaction SMILES: [CH2:1]([N:3]([CH2:16][CH3:17])[C:4](=[O:15])[C:5]1[CH:10]=[CH:9][C:8](F)=[C:7]([N+:12]([O-:14])=[O:13])[CH:6]=1)[CH3:2].[C:18]1([CH2:24][CH2:25][NH2:26])[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>CCO>[CH2:1]([N:3]([CH2:16][CH3:17])[C:4](=[O:15])[C:5]1[CH:10]=[CH:9][C:8]([NH:26][CH2:25][CH2:24][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[C:7]([N+:12]([O-:14])=[O:13])[CH:6]=1)[CH3:2]
Reactant: CCN(CC)C(=O)c1ccc(F)c([N+](=O)[O-])c1
Reactant: NCCc1ccccc1
Solvent: CCO
Product: CCN(CC)C(=O)c1ccc(NCCc2ccccc2)c([N+](=O)[O-])c1
Temperature: 85 °C
Yield: 95.6 %

Procedure:
Following general procedure 2B: A mixture of N,N-diethyl-4-fluoro-3-nitrobenzamide (0.125 g, 0.521 mmol), 2-phenylethanamine (0.065 mL, 0.521 mmol) in 80% aq. EtOH (3 mL) was heated at 85° C. for 4 hours. Usual work-up provided the title compound (0.170 g, 96%) which was used without further purification. MS (ESI) (M+H)+=342.
Reaction SMILES: [O-]O.[C:3]([O:7][OH:8])([CH3:6])([CH3:5])[CH3:4]>C(OC)(C)(C)C>[C:3]([O:7][O:8][C:3]([CH3:6])([CH3:5])[CH3:4])([CH3:6])([CH3:5])[CH3:4]
Reactant: CC(C)(C)OO
Agent: [O-]O
Solvent: COC(C)(C)C
Product: CC(C)(C)OOC(C)(C)C

Procedure:
In similar manner, although optimal conditions may vary, hydrogen peroxide may be reacted with methyl t-amyl ether to provide t-amyl hydroperoxide or di-t-amyl peroxide; with methyl t-hexyl ether to provide t-hexyl hydroperoxide or di-t-hexyl peroxide; with ethyl t-butyl ether to provide t-butyl hydroperoxide or di-t-butyl peroxide; with ethyl t-amyl ether to provide t-amyl hydroperoxide or di-t-amyl peroxide; with ethyl t-hexyl ether to provide t-hexyl hydroperoxide or di-t-hexyl peroxide; with n-propyl t-butyl ether to provide t-butyl hydroperoxide or di-t-butyl peroxide; with n-propyl t-amyl ether to provide t-amyl hydroperoxide or di t-amyl peroxide; or with n-propyl t-hexyl ether to provide t-hexyl hydroperoxide or di-t-hexyl peroxide. Illustrative of reactions employing hydroperoxide reactants are the reaction of t-butyl hydroperoxide with methyl t-butyl ether to provide di-t-butyl peroxide; the reaction of t-hexyl hydroperoxide with methyl t-hexyl ether to provide di-t-hexyl peroxide; the reaction of t-butyl hydroperoxide with methyl t-amyl ether to provide t-butyl t-amyl peroxide; the reaction of t-butyl hydroperoxide with methyl t-hexyl ether to provide t-butyl t-hexyl peroxide; and the reaction of t-amyl hydroperoxide with ethyl t-hexyl ether to provide t-amyl t-hexyl peroxide.
Reaction SMILES: [CH3:1][CH:2]([O:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[N:11]1[CH2:16][CH2:15][N:14]([CH2:17][C:18]2[CH:19]=[C:20]([CH:23]=[CH:24][CH:25]=2)[CH2:21][NH2:22])[CH2:13][CH2:12]1)[CH3:3].[CH2:26]1[CH2:30][C:29]2([CH2:37][C:35](=O)[O:34][C:32](=[O:33])[CH2:31]2)[CH2:28][CH2:27]1.S(Cl)(Cl)=O>C1(C)C=CC=CC=1>[CH3:3][CH:2]([O:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[N:11]1[CH2:16][CH2:15][N:14]([CH2:17][C:18]2[CH:19]=[C:20]([CH2:21][N:22]3[C:35](=[O:34])[CH2:37][C:29]4([CH2:30][CH2:26][CH2:27][CH2:28]4)[CH2:31][C:32]3=[O:33])[CH:23]=[CH:24][CH:25]=2)[CH2:13][CH2:12]1)[CH3:1]
Reactant: CC(C)Oc1ccccc1N1CCN(Cc2cccc(CN)c2)CC1
Reactant: O=C1CC2(CCCC2)CC(=O)O1
Solvent: O=S(Cl)Cl
Solvent: Cc1ccccc1
Product: CC(C)Oc1ccccc1N1CCN(Cc2cccc(CN3C(=O)CC4(CCCC4)CC3=O)c2)CC1

Procedure:
A solution of 3-[[1-[2-(1-methylethoxy)phenyl]-4-piperazinyl]methyl]-benzyl amine (2.50 g, 7.37 mmol), prepared as described above, 3,3-tetramethyleneglutaric anhydride (1.12 g, 6.66 mmol), and toluene (30 mL) was heated to reflux, cooled slightly, and treated with thionyl chloride (9.72 mL, 13.32 mmol). The resulting slurry was refluxed for 30 min, cooled and the solid collected by filtration. This material was partitioned between CH2Cl2 /3N NAOH and the organic layer was separated, dried, filtered and evaporated giving 8-[[3-[[1-[2-(1-methylethoxy)phenyl]-4-piperazinyl]methyl]phenyl]methyl]-8-azaspiro[4.5]decane-7,9-dione as a crude oil. The oil was converted to the maleate salt in i-PrOH. The isolated residue was converted back to the free base which was obtained as an oil (2.10 g). Chromatography of this material on flash silica using EtOAc/hexane of varying proportions gave an oil which was dissolved in ether and added to ethereal HCl causing formation of a solid. Filtration afforded 8-[[3-[[1-[2-(1-methylethoxy)phenyl]-4-piperazinyl]methyl]phenyl]methyl]-8-azaspiro[4.5]decane-7,9-dione dihydrochloride (0.94 g, 25%), m.p. 212°-216° C. (dec). 1H NMR and mass spectral analysis supported the assigned structure.
Reaction SMILES: C[O:2][C:3]1[C:8]([C:9]([NH2:11])=[O:10])=[C:7]([NH:12][C:13]2[CH:14]=[N:15][C:16]([O:19][CH3:20])=[CH:17][CH:18]=2)[N:6]=[C:5]([S:21][CH3:22])[N:4]=1.Cl.[OH-].[Na+]>O>[CH3:20][O:19][C:16]1[N:15]=[CH:14][C:13]([NH:12][C:7]2[N:6]=[C:5]([S:21][CH3:22])[NH:4][C:3](=[O:2])[C:8]=2[C:9]([NH2:11])=[O:10])=[CH:18][CH:17]=1
Reactant: COc1ccc(Nc2nc(SC)nc(OC)c2C(N)=O)cn1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: COc1ccc(Nc2nc(SC)[nH]c(=O)c2C(N)=O)cn1
Temperature: 80 °C
Reaction time: 1.5 h
Yield: 101.6 %

Procedure:
To a mixture of 4-methoxy-6-[(6-methoxy-pyridin-3-yl)amino]-2-(methylsulfanyl)pyrimidine-5-carboxamide (Preparation Example 337) (0.35 g) and water (2.2 mL), concentrated hydrochloric acid (2.2 mL) was added and stirred at 80° C. for 1.5 hours. After the reaction liquid was cooled, 1M aqueous sodium hydroxide was added so that the reaction liquid became almost neutral, and then the resulting solid was collected by filtration to give 4-[(6-methoxy-pyridin-3-yl)amino]-2-(methylsulfanyl)-6-oxo-1,6-dihydropyrimidine-5-carboxamide (0.34 g).