Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(O[C:4]([NH:6]/[C:7](/[C:14]([F:17])([F:16])[F:15])=[CH:8]\[C:9]([O:11]CC)=O)=[O:5])C.[NH2:18][C:19]1[CH:20]=[CH:21][C:22]2[S:26][N:25]=[C:24]([C:27]3[CH:28]=[C:29]([CH3:35])[C:30]([O:33][CH3:34])=[CH:31][CH:32]=3)[C:23]=2[CH:36]=1.N12CCCN=C1CCCCC2>C1(C)C(C)=CC=CC=1>[CH3:34][O:33][C:30]1[C:29]([CH3:35])=[CH:28][C:27]([C:24]2[C:23]3[CH:36]=[C:19]([N:18]4[C:9](=[O:11])[CH:8]=[C:7]([C:14]([F:15])([F:16])[F:17])[NH:6][C:4]4=[O:5])[CH:20]=[CH:21][C:22]=3[S:26][N:25]=2)=[CH:32][CH:31]=1
Reactant: CCOC(=O)/C=C(\NC(=O)OCC)C(F)(F)F
Reactant: COc1ccc(-c2nsc3ccc(N)cc23)cc1C
Solvent: C1CCC2=NCCCN2CC1
Solvent: Cc1ccccc1C
Product: COc1ccc(-c2nsc3ccc(-n4c(=O)cc(C(F)(F)F)[nH]c4=O)cc23)cc1C
Yield: 72 %

Procedure:
A mixture of ethyl 3-[(ethoxycarbonyl)amino]-4,4,4-trifluorocrotonate, (Z)-(2.04 g, 8 mmol), 5-amino-3-(6-methoxy-m-tolyl)-1,2-benzisothiazole (2.59 g, 9.6 mmol) and 1,8-diazabicyclo[5,4,0]undec-7-ene (DBU, 1.46 g, 9.6 mmol) in xylene (15 mL) is heated at 110° C. for 6 hours, cooled, and quenched with ethyl acetate and water. The resultant mixture is extracted with ethyl acetate. The organic extracts are combined, washed with aqueous 2 N hydrochloric acid, dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo to obtain a foam. Flash chromatography of the foam using silica gel and a 3:7 ethyl acetate/hexanes solution gives the title product as a solid (2.5 g, 72% yield) which is identified by 1H and 19F NMR spectral analyses.
Reaction SMILES: [I:1]N1C(=O)CCC1=O.[CH3:9][C:10]([C@H:14]1[CH2:19][CH2:18][C@H:17]([O:20][C:21]2[CH:22]=[C:23]3[C:28](=[CH:29][CH:30]=2)[CH:27]=[C:26]([C@:31]2([CH3:37])[CH2:35][O:34][C:33](=[O:36])[NH:32]2)[CH:25]=[CH:24]3)[CH2:16][CH2:15]1)([CH3:13])[CH2:11][CH3:12]>C(Cl)Cl.[Cl-].[Cl-].[Cl-].[Cl-].[Zr+4]>[CH3:13][C:10]([C@H:14]1[CH2:19][CH2:18][C@H:17]([O:20][C:21]2[C:22]([I:1])=[C:23]3[C:28](=[CH:29][CH:30]=2)[CH:27]=[C:26]([C@:31]2([CH3:37])[CH2:35][O:34][C:33](=[O:36])[NH:32]2)[CH:25]=[CH:24]3)[CH2:16][CH2:15]1)([CH3:9])[CH2:11][CH3:12]
Reactant: O=C1CCC(=O)N1I
Reactant: CCC(C)(C)[C@H]1CC[C@H](Oc2ccc3cc([C@]4(C)COC(=O)N4)ccc3c2)CC1
Agent: [Zr+4]
Agent: [Cl-]
Solvent: ClCCl
Product: CCC(C)(C)[C@H]1CC[C@H](Oc2ccc3cc([C@]4(C)COC(=O)N4)ccc3c2I)CC1
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
A mixture of N-iodosuccinimide (204.77 mg, 0.91016 mmol), (R)-4-{6-[trans-4-(1,1-dimethyl-propyl)-cyclohexyloxy]-naphthalen-2-yl}-4-methyl-oxazolidin-2-one (300.00 mg, 0.75847 mmol) and zirconium tetrachloride (35.3 mg, 0.152 mmol) in methylene chloride (10.00 mL) was stirred RT for 2.5 hrs. LCMS showed the reaction was completed. The solution was purified with 4 g of silica gel column eluted with ethyl acetate in hexanes from 10 to 50% to give 100 mg of white precipitate, (R)-4-{6-[trans-4-(1,1-dimethylpropyl)-cyclohexyloxy]-5-iodo-naphthalen-2-yl}-4-methyl-oxazolidin-2-one. (20% yield). MS: m/z=522.20 M+H.
Reaction SMILES: [CH3:1][C@@H:2]1[CH2:7][CH2:6][CH2:5][NH:4][C@@H:3]1[CH2:8][N:9]1[C:17](=[O:18])[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10]1=[O:19].[CH3:20][C:21]1[CH:22]=[CH:23][C:24]([C:30]2[N:31]=[N:32][CH:33]=[CH:34][CH:35]=2)=[C:25]([CH:29]=1)[C:26](O)=[O:27].CCN(C(C)C)C(C)C.CCCP(=O)=O>C(Cl)Cl>[CH3:1][C@@H:2]1[CH2:7][CH2:6][CH2:5][N:4]([C:26](=[O:27])[C:25]2[CH:29]=[C:21]([CH3:20])[CH:22]=[CH:23][C:24]=2[C:30]2[N:31]=[N:32][CH:33]=[CH:34][CH:35]=2)[C@@H:3]1[CH2:8][N:9]1[C:17](=[O:18])[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10]1=[O:19]
Reactant: Cc1ccc(-c2cccnn2)c(C(=O)O)c1
Reactant: C[C@@H]1CCCN[C@@H]1CN1C(=O)c2ccccc2C1=O
Agent: CCCP(=O)=O
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccc(-c2cccnn2)c(C(=O)N2CCC[C@@H](C)[C@H]2CN2C(=O)c3ccccc3C2=O)c1
Temperature: 40 °C

Procedure:
To a mixture of 2-(((2S,3R)-3-methylpiperidin-2-yl)methyl)isoindoline-1,3-dione (1.09 g, 4.20 mmol), 5-methyl-2-(pyridazin-3-yl)benzoic acid (0.75 g, 3.5 mmol) and DIPEA (1.8 mL, 10.5 mmol) in DCM (20 mL) was added propylphosphonic anhydride (T3P) (50% in EtOAc, 4.2 mL, 7.0 mmol). The mixture was heated at 40° C. for 16 h. The mixture was cooled to rt and diluted with DCM. The mixture was washed with satd. aq. NaHCO3, brine, and dried (MgSO4). The solvent was removed in vacuo. The crude was purified by chromatography on silica gel (EtOAc/hexanes) to afford the title compound. ESI-MS (m/z): 455 [M+1]+.
Reaction SMILES: [C:1]([N:8]([CH3:40])[CH:9]1[CH2:14][CH2:13][CH:12]([N:15]([CH2:28][C:29]2[CH:30]=[C:31](B(O)O)[CH:32]=[CH:33][C:34]=2[O:35][CH3:36])[C:16]([C:18]2[S:22][C:21]3[CH:23]=[CH:24][CH:25]=[CH:26][C:20]=3[C:19]=2[Cl:27])=[O:17])[CH2:11][CH2:10]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].Br[C:42]1[CH:47]=[CH:46][C:45]([CH2:48][OH:49])=[CH:44][CH:43]=1>>[Cl:27][C:19]1[C:20]2[CH:26]=[CH:25][CH:24]=[CH:23][C:21]=2[S:22][C:18]=1[C:16]([N:15]([CH2:28][C:29]1[CH:30]=[C:31]([C:42]2[CH:47]=[CH:46][C:45]([CH2:48][OH:49])=[CH:44][CH:43]=2)[CH:32]=[CH:33][C:34]=1[O:35][CH3:36])[CH:12]1[CH2:11][CH2:10][CH:9]([N:8]([CH3:40])[C:1](=[O:2])[O:3][C:4]([CH3:7])([CH3:5])[CH3:6])[CH2:14][CH2:13]1)=[O:17]
Reactant: OCc1ccc(Br)cc1
Reactant: COc1ccc(B(O)O)cc1CN(C(=O)c1sc2ccccc2c1Cl)C1CCC(N(C)C(=O)OC(C)(C)C)CC1
Product: COc1ccc(-c2ccc(CO)cc2)cc1CN(C(=O)c1sc2ccccc2c1Cl)C1CCC(N(C)C(=O)OC(C)(C)C)CC1

Procedure:
Boronic acid 5 (210 mg, 0.36 mmol) is coupled to (4-bromophenyl)-methanol (80 mg, 0.43 mmol) using Method B to give the title compound.
Reaction SMILES: [NH2:1][C@@H:2]1[C:8](=[O:9])[N:7](CC2C=CC(OC)=CC=2)[C:6]2[CH:19]=[CH:20][CH:21]=[CH:22][C:5]=2[C:4]2[CH:23]=[CH:24][CH:25]=[CH:26][C:3]1=2.FC(F)(F)C(O)=O.FC(F)(F)S(O)(=O)=O>ClCCl>[NH2:1][C@@H:2]1[C:8](=[O:9])[NH:7][C:6]2[CH:19]=[CH:20][CH:21]=[CH:22][C:5]=2[C:4]2[CH:23]=[CH:24][CH:25]=[CH:26][C:3]1=2
Reactant: COc1ccc(CN2C(=O)[C@@H](N)c3ccccc3-c3ccccc32)cc1
Agent: O=S(=O)(O)C(F)(F)F
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: N[C@@H]1C(=O)Nc2ccccc2-c2ccccc21
Yield: 97.5 %

Procedure:
A solution of 0.55 g (1.6 mmol) (S)-7-amino-5-(4-methoxy-benzyl)-5H,7H-dibenzo[b,d]azepin-6-one, 3.74 ml (50 mmol) trifluoroacetic acid and 1.4 ml (16 mmol) trifluormethane sulfonic acid in 38 ml dichloromethane was stirred at room temperature for 4 hours. The solvent was distilled off and extraction with aqueous sodium bicarbonate solution/ethyl acetate followed by chromatography on silicagel with ethylacetate/methanol (100-95/0-5) yielded 0.35 g (96%) (S)-7-amino-5H,7H-dibenzo[b,d]azepin-6-one as orange solid; MS: m/e: 225.4 (M+H+).
Reaction SMILES: [Cl:1][C:2]1[CH:16]=[CH:15][C:5]([O:6][C:7]2[CH:14]=[CH:13][CH:12]=[CH:11][C:8]=2[CH2:9][NH2:10])=[CH:4][CH:3]=1.[C:17]([N:22]1[CH2:27][CH2:26][C:25](=O)[CH2:24][CH2:23]1)(=[O:21])[CH:18]([CH3:20])[CH3:19].[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].C(O)(=O)C>ClCCCl>[Cl:1][C:2]1[CH:16]=[CH:15][C:5]([O:6][C:7]2[CH:14]=[CH:13][CH:12]=[CH:11][C:8]=2[CH2:9][NH:10][CH:25]2[CH2:26][CH2:27][N:22]([C:17](=[O:21])[CH:18]([CH3:19])[CH3:20])[CH2:23][CH2:24]2)=[CH:4][CH:3]=1
Reactant: CC(C)C(=O)N1CCC(=O)CC1
Reactant: NCc1ccccc1Oc1ccc(Cl)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Solvent: CC(=O)O
Product: CC(C)C(=O)N1CCC(NCc2ccccc2Oc2ccc(Cl)cc2)CC1
Temperature: 25 °C
Yield: 77.9 %

Procedure:
A solution of 2-(4-chlorophenoxy)benzylamine (AMR01076, 100 mg, 0.428 mmol) and 1-isobutyrylpiperidin-4-one (78.4 mg, 0.428 mmol) in DCE (5 mL) was treated with NaBH(OAc)3 (127 mg, 0.60 mmol) and acetic acid (26 mg, 0.428 mmol). The mixture was stirred at room temperature under a N2 atmosphere until TLC showed that the reactants were consumed (30 min). Then, it was quenched with saturated NaHCO3 solution, the aqueous layer was washed with DCM (2×20 mL), and the combined organic layers were dried (MgSO4), filtered and evaporated to dryness. Column chromatography on silica gel of the crude product using DCM to DCM/MeOH 95:5 gradient as eluent gave 1-{4-[2-(4-chlorophenoxy)benzylamino]piperidin-1-yl}-2-methylpropan-1-one (129 mg, 78%) as a colorless oil. Rf: 0.4 (DCM/MeOH 9:1) LC/MS (APCI) tr=5.18 min, m/z 389.48 (36), 387.46 (M++H, 100). HPLC tr=3.65 min 97.72%) 1H NMR (270 MHz, CDCl3) δ 1.079 (3H, d, J=6.7 Hz, CH3), δ 1.082 (3H, d, J=6.7 Hz, CH3), 1.23 (2H, m, CH2), 1.45 (br s, NH), 1.83 (2H, m, CH2), 2.70 (2H, m, H2), 2.77 (1H, hept, J=6.7 Hz, CHMe2), 3.01 (1H, m, CHNH), 3.80 (2H, m, CH2), 3.83 (1H, m, ½CH2), 4.41 (1H, br d, J=13.4 Hz, ½CH2), 6.84 (2H, AA′BB′, ArH), 6.87 (1H, m, ArH), 7.12 (1H, td, ArH), 7.24 (1H, m, ArH), 7.25 (2H, AA′BB′, ArH) and 7.39 (1H, dd, J=7.4, 1.7 Hz, ArH). 13C NMR (270 MHz, CDCl3) δ 19.46, 19.65 (CH2), 30.13 (CH), 32.39, 33.30, 40.43, 43.95, 45.67 (CH2), 53.97 (CH), 118.94, 119.61, 124.54, 127.96, 128.72, 129.84, 130.58, 131.80, 154.35, 156.37 (ArC), and 175.30 (C═O).
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][C:8]([C:11]2[N:12]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[C:13]3[C:18]([CH:19]=2)=[CH:17][C:16]([CH2:20][N:21]2[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]2)=[CH:15][CH:14]=3)=[C:7]2[C:3]=1[CH2:4][NH:5][C:6]2=[O:34].C(N(CC)CC)C.[CH2:42]([C:44]1[CH:49]=[CH:48][C:47]([S:50](Cl)(=[O:52])=[O:51])=[CH:46][CH:45]=1)[CH3:43]>C(#N)C>[CH2:42]([C:44]1[CH:45]=[CH:46][C:47]([S:50]([O:1][C:2]2[CH:10]=[CH:9][C:8]([C:11]3[N:12]([C:27]([O:29][C:30]([CH3:31])([CH3:33])[CH3:32])=[O:28])[C:13]4[C:18]([CH:19]=3)=[CH:17][C:16]([CH2:20][N:21]3[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]3)=[CH:15][CH:14]=4)=[C:7]3[C:3]=2[CH2:4][NH:5][C:6]3=[O:34])(=[O:52])=[O:51])=[CH:48][CH:49]=1)[CH3:43]
Reactant: CC(C)(C)OC(=O)n1c(-c2ccc(O)c3c2C(=O)NC3)cc2cc(CN3CCCCC3)ccc21
Reactant: CCc1ccc(S(=O)(=O)Cl)cc1
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CCc1ccc(S(=O)(=O)Oc2ccc(-c3cc4cc(CN5CCCCC5)ccc4n3C(=O)OC(C)(C)C)c3c2CNC3=O)cc1
Yield: 51 %

Procedure:
In a similar manner to Step 1 of Example 233, 4-hydroxy-7-[1-(tert-butoxycarbonyl)-5-(piperidinomethyl)indol-2-yl]isoindolinone (0.0322 g, 0.0698 mmol) was dissolved in acetonitrile (0.650 mL), and the solution was treated with triethylamine (0.0580 mL, 0.419 mmol) and 4-ethylbenzene-1-sulfonyl chloride (0.0430 g, 0.209 mmol) to obtain 4-(4-ethylbenzenesulfonyloxy)-7-[1-(tert-butoxycarbonyl)-5-(piperidinomethyl)indol-2-yl]isoindolinone (0.0224 g, yield 51%).
Reaction SMILES: [CH2:1]([O:4]/[N:5]=[C:6](/[C:8]1[CH:13]=[C:12]([CH3:14])[C:11]([O:15]C)=[CH:10][C:9]=1[CH3:17])\[CH3:7])[CH2:2][CH3:3].B(Br)(Br)Br>ClCCl.O>[CH2:1]([O:4]/[N:5]=[C:6](/[C:8]1[CH:13]=[C:12]([CH3:14])[C:11]([OH:15])=[CH:10][C:9]=1[CH3:17])\[CH3:7])[CH2:2][CH3:3]
Reactant: CCCO/N=C(\C)c1cc(C)c(OC)cc1C
Agent: BrB(Br)Br
Solvent: O
Solvent: ClCCl
Product: CCCO/N=C(\C)c1cc(C)c(O)cc1C
Yield: 52 %

Procedure:
To a solution of 0.5 g (2.0 mmol) of (E)-1-(4-methoxy-2,5-dimethylphenyl)ethanone-propyloxime obtained in Step 4 in 15 mL of dichloromethane was added boron tribromide (BBr3) (0.28 mL, 2.9 mmol) and the reaction mixture was allowed to react at room temperature with stirring. After completion of the reaction, the residue was stirred in water (20 mL) and the aqueous layer was extracted twice with 20 mL of dichloromethane. The organic layer was dried over anhydrous magnesium sulfate and concentrated in a vacuum and the concentrate was purified by silica gel chromatography to afford 0.23 g of (E)-1-(4-hydroxy-2,5-dimethylphenyl)ethanone propyloxime as a white oil (yield: 49%).
Reaction SMILES: [NH2:1][C:2]1[N:6]([C:7]([CH3:10])([CH3:9])[CH3:8])[N:5]=[C:4]([C:11]2[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:13][CH:12]=2)[C:3]=1[C:21]#[N:22].[OH-:23].[Na+]>C(O)C>[NH2:1][C:2]1[N:6]([C:7]([CH3:9])([CH3:10])[CH3:8])[N:5]=[C:4]([C:11]2[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:13][CH:12]=2)[C:3]=1[C:21]([NH2:22])=[O:23]
Reactant: CC(C)(C)n1nc(-c2ccc(C(F)(F)F)cc2)c(C#N)c1N
Reactant: [OH-]
Agent: [Na+]
Solvent: CCO
Product: CC(C)(C)n1nc(-c2ccc(C(F)(F)F)cc2)c(C(N)=O)c1N

Procedure:
To a solution of 5-amino-1-tert-butyl-4-cyano-3-(4'-trifluoromethylphenyl)pyrazole (308 mg, 1.0 mmol) in ethanol (15 ml) was added 10M sodium hydroxide (3 ml) and the mixture heated at reflux for 72 h. On cooling, ethanol was removed under reduced pressure and water (50 ml) added. The resulting precipitate was collected by filtration, and washed with water (2×25 ml), to give the title compound (200 mg) as a colorless solid after recrystallisation from ethyl acetate m.p. 210-211°. δH (CDCl3) 1.67 (9H, s), 5.16 (2H, br s), 5.69 (2H, br s), and 7.71 (4H, s).
Reaction SMILES: CO[CH:3](OC)[C:4](=[N:7][OH:8])[C:5]#[N:6].[OH:11][CH2:12][CH2:13][NH:14][NH2:15].[ClH:16]>C(O)C>[ClH:16].[NH2:6][C:5]1[N:14]([CH2:13][CH2:12][OH:11])[N:15]=[CH:3][C:4]=1[N:7]=[O:8]
Reactant: COC(OC)C(C#N)=NO
Reactant: NNCCO
Agent: Cl
Solvent: CCO
Product: Nc1c(N=O)cnn1CCO
Temperature: 77.5 °C
Reaction time: 1 h
Yield: 71.1 %

Procedure:
To a flask having an inner volume of 100 ml and equipped with a stirring device, a thermometer and a reflux condenser were charged 8.43 g (55 mmol) of 3,3-dimethoxy-2-hydroxyiminopropionitrile with a purity of 94.0% by weight synthesized in the same manner as in Example 1, 4.01 g (50 mmol) of 2-hydroxyethylhydrazine with a purity of 95% by weight, 50 ml of ethanol and 7.60 g (75 mmol) of conc. hydrochloric acid, and the mixture was reacted under reflux (76 to 79° C.) for one hour. After completion of the reaction, the reaction mixture was concentrated under reduced pressure, 20 ml of toluene and 20 ml of isopropyl alcohol were added to the concentrate, and the mixture was stirred at room temperature for one hour. Then, the solution was filtered and the filtrate was dried at 40° C. under reduced pressure to obtain 6.85 g of 5-amino-1-(2-hydroxyethyl)-4-nitrosopyrazole hydrochloride (Isolation yield: 67.4%) as yellow solid with a purity of 94.8% by weight (absolute calibration curve method by high performance liquid chromatography).
Reaction SMILES: Cl.[F:2][C:3]1([F:9])[CH2:8][CH2:7][NH:6][CH2:5][CH2:4]1.C([O-])([O-])=O.[Cs+].[Cs+].[Cl:16][C:17]1[CH:22]=[N:21][CH:20]=[C:19](Cl)[N:18]=1>CN(C=O)C.CCOC(C)=O>[Cl:16][C:17]1[CH:22]=[N:21][CH:20]=[C:19]([N:6]2[CH2:7][CH2:8][C:3]([F:9])([F:2])[CH2:4][CH2:5]2)[N:18]=1
Reactant: FC1(F)CCNCC1
Reactant: Clc1cncc(Cl)n1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: FC1(F)CCN(c2cncc(Cl)n2)CC1
Temperature: 100 °C
Yield: 85 %

Procedure:
A mixture of 4,4-difluoropiperidine hydrochloride (598 mg, 3.79 mmol), Cs2CO3 (2471 mg, 7.58 mmol) and 2,6-dichloropyrazine (538 mg, 3.61 mmol) in DMF (5 mL) was heated in a microwave at 100° C. for 35 min. The mixture was diluted with EtOAc (50 mL) and washed with 2×5 mL of H2O. The organic layer was dried, filtered and concentrated. The residue was purified on a silica gel column (eluting with 25-35% EtOAc in Hex) to give 2-chloro-6-(4,4-difluoropiperidin-1-yl)pyrazine (717 mg, 85%) as a brown amorphous solid. MS (ESI, pos. ion) m/z 234.1 (M+1); 1H NMR (400 MHz, DMSO-d6) δ ppm 8.39 (s, 1H), 7.89 (s, 1H), 3.75 (t, J=5.7 Hz, 4H), 2.06 (m, 4H).
Reaction SMILES: [NH2:1][C:2]([N:8]1[CH2:12][CH2:11][CH2:10][CH2:9]1)=[C:3]([C:6]#[N:7])[C:4]#[N:5].C(N(CC)CC)C.[SH2:20]>N1C=CC=CC=1>[NH2:1][C:2]([N:8]1[CH2:12][CH2:11][CH2:10][CH2:9]1)=[C:3]([C:4]#[N:5])[C:6](=[S:20])[NH2:7]
Reactant: N#CC(C#N)=C(N)N1CCCC1
Reactant: S
Solvent: c1ccncc1
Solvent: CCN(CC)CC
Product: N#CC(C(N)=S)=C(N)N1CCCC1
Reaction time: 64 h

Procedure:
A mixture of 93.3 g of 3-amino-2-cyano-3-(1-pyrrolidinyl)propenenitrile, 58.2 g of triethylamine and 400 ml of pyridine was heated at 60°-65° and hydrogen sulfide passed in for 21/2 hours. While continuing the addition of hydrogen sulfide, the temperature of the mixture was increased to 80°, where it was maintained for two and a half hours. The mixture stood for 64 hours at ambient temperature, then was heated at 90° for 21/2 hours. The mixture was concentrated under reduced pressure. The tan solid residue was stirred with 750 ml of ice-water, the cold slurry was filtered and the solid was washed with cold water. The washed solid was recrystallized from 1200 ml of ethanol to give 87.4 g (three crops) of 3-amino-2-cyano-3-(1-pyrrolidinyl)propenethioamide, m.p. 164°. The nmr spectrum was consistent with the assigned structure.
Reaction SMILES: [C:1]([CH2:6][S:7][C:8]1[S:9][CH:10]=[CH:11][C:12]=1[CH:13]=O)([O:3][CH2:4][CH3:5])=[O:2].C1CCN2C(=NCCC2)CC1>CO>[S:7]1[C:8]2[S:9][CH:10]=[CH:11][C:12]=2[CH:13]=[C:6]1[C:1]([O:3][CH2:4][CH3:5])=[O:2]
Reactant: CCOC(=O)CSc1sccc1C=O
Solvent: C1CCC2=NCCCN2CC1
Solvent: CO
Product: CCOC(=O)c1cc2ccsc2s1
Temperature: 25 °C
Yield: 45 %

Procedure:
To a solution of 2-(carboethoxymethylthio)3-formylthiophene (from step c) in MeOH (200 mL) was added DBU (0.6 mL, 4.0 mmole) at 0° C. After 1 hr the mixture was warmed to RT and concentrated. The residue was taken up in EtOAc, washed with 10% HCl, H2O (3×), dried (MgSO4), and concentrated. Flash chromatography on silica gel (50% toluene/hexanes) gave the title compound (3.84 g, 45% over 4 steps) as an off-white solid: 1H NMR (400 MHz, CDCl3) δ 7.95 (s, 1 H), 7.40 (d, J=5.2 Hz, 1 H), 7.26 (d, J=5.2 Hz, 1 H), methyl ester 3.92 (s, 3 H), ethyl ester 4.38 (q, J=7.1 Hz, 2 H)) and 1.41 (t, J=2.4 Hz, 3 H).
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([C:13]2[O:17][C:16](=[O:18])[NH:15][N:14]=2)=[C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[N:6]=1.[C:19]1([CH2:25][C:26](Cl)=[O:27])[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>>[O:18]=[C:16]1[O:17][C:13]([C:4]2[S:3][C:2]([NH:1][C:26](=[O:27])[CH2:25][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)=[N:6][C:5]=2[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=2)=[N:14][NH:15]1
Reactant: O=C(Cl)Cc1ccccc1
Reactant: Nc1nc(-c2ccccc2)c(-c2n[nH]c(=O)o2)s1
Product: O=C(Cc1ccccc1)Nc1nc(-c2ccccc2)c(-c2n[nH]c(=O)o2)s1

Procedure:
Prepared from 5-(2-amino-4-phenyl-thiazol-5-yl)-3H-[1,3,4]oxadiazol-2-one and phenyl-acetyl chloride.
Reaction SMILES: [CH2:1](Cl)[CH:2]=[CH2:3].[C:5]([O:11][CH3:12])(=[O:10])[CH2:6][C:7]([CH3:9])=[O:8].C(Br)C=C>CCCCCCCC[N+](CCCCCCCC)(CCCCCCCC)C.[Cl-]>[C:5]([CH:6]([C:7](=[O:8])[CH3:9])[CH2:3][CH:2]=[CH2:1])([O:11][CH3:12])=[O:10]
Reactant: C=CCCl
Reactant: COC(=O)CC(C)=O
Agent: CCCCCCCC[N+](C)(CCCCCCCC)CCCCCCCC
Agent: [Cl-]
Solvent: C=CCBr
Product: C=CCC(C(C)=O)C(=O)OC
Yield: 30 %

Procedure:
In J. Org. Chem., Vol. 39, No. 22, 1974 at page 3271, an article by Durst & Liebeskind entitled, "Phase Transfer Catalysis. The Acetoacetic Ester Condensation" indicates that reaction of allyl chloride with methyl acetoacetate gives rise to a 30% yield of 4-carbomethoxy-1-hexen-5-one and reaction of methyl acetoacetate with allyl bromide in the presence of an Aliquat 336® catalyst gives rise to a 94.7% yield of 4-carbomethoxy-1-hexen-5-one. The reaction is carried out however in the presence of anhydrous benzene which gives rise to the danger of causing minute traces of benzene to exist in the final desired product which is to be used for its organoleptic properties in perfumery. The potential presence of such solvent is unacceptable in the perfumery field.
Reaction SMILES: Br[C:2]1[N:9]=[C:8]([CH:10]([CH3:12])[CH3:11])[CH:7]=[CH:6][C:3]=1[C:4]#[N:5].[NH3:13]>C(O)C>[NH2:13][C:2]1[N:9]=[C:8]([CH:10]([CH3:12])[CH3:11])[CH:7]=[CH:6][C:3]=1[C:4]#[N:5]
Reactant: CC(C)c1ccc(C#N)c(Br)n1
Reactant: N
Solvent: CCO
Product: CC(C)c1ccc(C#N)c(N)n1
Yield: 93 %

Procedure:
To a solution of the product of Example 36C (21 g, 0.093 mol) and liquid ammonia (250 mL) in 500 mL of ethanol were reacted in a sealed high-pressure vessel at 130° C. for 20 hours. The reaction mixture was concentrated under vacuum and the residue ground to a fine powder then washed with water (2×50 mL) and dried in a vacuum oven for 24 hours to provide the title compound as a beige solid (14 g, 93%).
Reaction SMILES: [CH3:1][C:2]([CH3:14])=[CH:3][CH2:4][CH2:5]/[C:6](/[CH3:13])=[CH:7]/[CH:8]=[CH:9]/[C:10]([CH3:12])=[O:11].S(=O)(=O)(O)O.O>C(Cl)Cl>[CH3:13][C:6]1[CH2:5][CH2:4][CH2:3][C:2]([CH3:14])([CH3:1])[C:7]=1/[CH:8]=[CH:9]/[C:10]([CH3:12])=[O:11]
Reactant: CC(=O)/C=C/C=C(\C)CCC=C(C)C
Agent: O=S(=O)(O)O
Solvent: ClCCl
Solvent: O
Product: CC(=O)/C=C/C1=C(C)CCCC1(C)C
Yield: 97 %

Procedure:
A solution of 600 g of a 96% pure pseudoionone in 1,200 ml of methylene chloride was introduced continuously in the course of 10 minutes, while stirring vigorously (800 rpm), through one of the two connections of the reactor, and 1,000 ml of a 96% strength sulfuric acid were fed in simultaneously through the other connection. The product, which was discharged at 42° C., was hydrolyzed in a downstream thin film reactor with 2,000 ml of water, the organic phase was separated off, washed neutral with 2% strength sodium carbonate solution and then with water and freed from solvent under reduced pressure, and the residue was then distilled under 0.2 mbar. 495 g of 97.0% pure β-ionone were obtained, corresponding to a yield of β-ionone of 83.3% of theory. In this case too, the residue produced was a resin which exhibited good flow.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[O:7][CH:8]([C:12]1[N:13]=[C:14]([NH:17][S:18]([CH3:21])(=[O:20])=[O:19])[S:15][CH:16]=1)[C:9]([OH:11])=O.CN(CC1C=CC=CC=1)C.ClC(OCCCC)=O.[CH3:40][N:41]1[C:45]([S:46][CH2:47][C:48]2[CH2:49][S:50][C@@H:51]3[CH:58]([NH2:59])[C:57](=[O:60])[N:52]3[C:53]=2[C:54]([OH:56])=[O:55])=[N:44][N:43]=[N:42]1>O1CCCC1.C(N(CC)CC)C>[CH3:40][N:41]1[C:45]([S:46][CH2:47][C:48]2[CH2:49][S:50][C@@H:51]3[CH:58]([NH:59][C:9](=[O:11])[CH:8]([O:7][CH:2]4[CH2:3][CH2:4][CH2:5][CH2:6][O:1]4)[C:12]4[N:13]=[C:14]([NH:17][S:18]([CH3:21])(=[O:20])=[O:19])[S:15][CH:16]=4)[C:57](=[O:60])[N:52]3[C:53]=2[C:54]([OH:56])=[O:55])=[N:44][N:43]=[N:42]1
Reactant: Cn1nnnc1SCC1=C(C(=O)O)N2C(=O)C(N)[C@H]2SC1
Reactant: CS(=O)(=O)Nc1nc(C(OC2CCCCO2)C(=O)O)cs1
Agent: CCCCOC(=O)Cl
Agent: CN(C)Cc1ccccc1
Agent: CS(=O)(=O)N=c1[nH]c(C(OC2CCCCO2)C(=O)O)cs1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: Cn1nnnc1SCC1=C(C(=O)O)N2C(=O)C(NC(=O)C(OC3CCCCO3)c3csc(NS(C)(=O)=O)n3)[C@H]2SC1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a mixture of 2-(2-tetrahydropyranyl)oxy-2-(2-mesylamino-1,3-thiazol-4-yl)acetic acid, which can be represented as 2-(2-tetrahydropyranyl)oxy-2-(2-mesylimino-2,3-dihydro-1,3-thiazol-4-yl)acetic acid, (350 mg.), triethylamine (96 mg.), N,N-dimethylbenzylamine (half drop) and tetrahydrofuran (7 ml.) was dropwise added a mixture of butyl chloroformate (130 mg.) and tetrahydrofuran (1 ml.) over 1 minute at -15° C., and then the mixture was stirred for 30 minutes at -15° to -10° C. To the mixture was added all at once a mixture of 3-(1-methyl-1H-tetrazol-5-yl)thiomethyl-7-amino-3-cephem-4-carboxylic acid (224 mg.), triethylamine (80 mg.) and 50% tetrahydrofuran aqueous solution (10 ml.) which was cooled at 0° C., and the mixture was stirred for 30 minutes under ice-cooling and further stirred for 2 hours at room temperature. After the reaction, the reaction mixture was concentrated. The residue was adjusted to pH 8 with 5% sodium bicarbonate aqueous solution and washed with ethyl acetate. Thus obtained aqueous layer was adjusted to pH 1 with 10% hydrochloric acid and extracted with ethyl acetate. After distillation of the solvent from the extract, the residue was pulverized in diethyl ether, collected by filtration and dried to give pale brown powder of 3-(1-methyl-1H-tetrazol-5-yl)thiomethyl-7-[2-(2-tetrahydropyranyl)oxy-2-(2-mesylamino-1,3-thiazol-4-yl)acetamido]-3-cephem-4-carboxylic acid, which can be represented as 3-(1-methyl-1H-tetrazol-5-yl)thiomethyl-7-[2-(2-tetrahydropyranyl)oxy-2-(2-mesylimino-2,3-dihydro-1,3-thiazol-4-yl)acetamido]-3-cephem-4-carboxylic acid, (270 mg.).
Reaction SMILES: [CH2:1]([C:4]1[CH:9]=[CH:8][C:7]([O:10][CH3:11])=[CH:6][CH:5]=1)[CH:2]=[CH2:3].ClC1C=C(C=CC=1)C(OO)=[O:17]>ClCCl>[CH3:11][O:10][C:7]1[CH:8]=[CH:9][C:4]([CH2:1][CH:2]2[CH2:3][O:17]2)=[CH:5][CH:6]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: C=CCc1ccc(OC)cc1
Solvent: ClCCl
Product: COc1ccc(CC2CO2)cc1

Procedure:
To a stirring solution of 4-allylanisole (3.1 g, 20.9 mmol) in 50 mL dichloromethane was added 3-chloroperoxybenzoic acid (80%, 6.7 g, 31.4 mmol) at room temperature. TLC (20:1 hexanes/ethyl acetate) showed no remaining allyl after 3 h. The precipitate was removed via filtration and washed with hexanes. The filtrate was purified on 40 g silica eluting with 0 to 10% ethyl acetate/hexanes to give the product. NMR CDCl3) d (1H, 2.55 ppm), m (2H, 2.7-2.8 ppm), dd (1H, 2.85 ppm), m (1H, 3.1 ppm), s (3H, 3.75 ppm), d (2H, 6.85 ppm), d (2H, 7.15 ppm).