Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.C([NH:4][C:5]1[S:6][CH:7]=[C:8]([C:10](=[N:41][O:42][CH2:43][C:44]([O:46]C(C)(C)C)=[O:45])[C:11]([NH:13][C@@H:14]2[C:39](=[O:40])[N:16]3[C:17]([C:36]([O-:38])=[O:37])=[C:18]([CH2:21][N+:22]4([CH3:35])[CH2:27][CH2:26][N:25](C(OC(C)(C)C)=O)[CH2:24][CH2:23]4)[CH2:19][S:20][C@H:15]23)=[O:12])[N:9]=1)=O.Cl.C(OCC)(=O)C>CO>[NH2:4][C:5]1[S:6][CH:7]=[C:8]([C:10](=[N:41][O:42][CH2:43][C:44]([OH:46])=[O:45])[C:11]([NH:13][C@@H:14]2[C:39](=[O:40])[N:16]3[C:17]([C:36]([O-:38])=[O:37])=[C:18]([CH2:21][N+:22]4([CH3:35])[CH2:23][CH2:24][NH:25][CH2:26][CH2:27]4)[CH2:19][S:20][C@H:15]23)=[O:12])[N:9]=1
Reactant: CC(C)(C)OC(=O)CON=C(C(=O)N[C@@H]1C(=O)N2C(C(=O)[O-])=C(C[N+]3(C)CCN(C(=O)OC(C)(C)C)CC3)CS[C@H]12)c1csc(NC=O)n1
Agent: Cl
Solvent: CO
Solvent: CCOC(C)=O
Product: C[N+]1(CC2=C(C(=O)[O-])N3C(=O)[C@@H](NC(=O)C(=NOCC(=O)O)c4csc(N)n4)[C@H]3SC2)CCNCC1
Temperature: 25 °C
Reaction time: 4.5 h
Yield: 26.7 %

Procedure:
To a suspension of 7β-[2-(2-formamidothiazol-4-yl)-2-tert-butoxycarbonylmethoxyiminoacetamido]-3-(1-methyl-4-tert-butoxycarbonyl-1-piperazinio)methyl-3-cephem-4-carboxylate hydrochloride (syn isomer) (4.02 g) in methanol (12 ml) was added conc. hydrochloric acid (4.4 ml) at 10° C. The resulting solution was warmed to room temperature and stirred for 4.5 hours. The mixture was pulverized with ethyl acetate (800 ml) and the powder was collected by filtration, washed with ethyl acetate and dried in vacuo. The powder (3.68 g) was suspended in a mixture of dichloromethane (12 ml) and anisole (4 ml), and trifluoroacetic acid (8 ml) was added thereto. After being stirred at room temperature for 3.5 hours, the mixture was pulverized with diisopropyl ether (800 ml) and the powder was collected by filtration and washed with diisopropyl ether. The powder was suspended in a mixture of water (100 ml) and ethyl acetate (30 ml) and adjusted with a saturated aqueous solution of sodium bicarbonate. After removal of the insoluble materials, the aqueous layer was separated, adjusted to pH 4 with 1N hydrochloric acid and chromatographed on Diaion HP-20 (250 ml). The elution was carried out with 10% aqueous isopropyl alcohol. The eluate was lyophilized to give 7β-[2-(2-aminothiazol- 4-yl)-2-carboxymethoxyiminoacetamido]-3-(1-methyl-1-piperazinio)methyl-3-cephem-4-carboxylate (syn isomer) (763 mg).
Reaction SMILES: [CH3:1][CH:2]1[CH2:11][CH2:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[NH:3]1.[C:12](OC(=O)C)(=[O:14])[CH3:13]>>[C:12]([N:3]1[C:4]2[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=2)[CH2:10][CH2:11][CH:2]1[CH3:1])(=[O:14])[CH3:13]
Reactant: CC1CCc2ccccc2N1
Reactant: CC(=O)OC(C)=O
Product: CC(=O)N1c2ccccc2CCC1C
Reaction time: 8 h
Yield: 243.5 %

Procedure:
2-Methyl-1,2,3,4-tetrahydroquinoline (216 mg, 1.469 mmol, available from TCl), was measured into a reaction test tube and acetic anhydride (0.139 ml, 1.469 mmol) was added and left to stir overnight. LCMS analysis showed the reaction had gone to completion. The crude product was purified by MDAP to give the desired compound (677 mg)
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([OH:14])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:15][O:16][C:17]1[CH:22]=[C:21]([N+:23]([O-:25])=[O:24])[CH:20]=[CH:19][C:18]=1O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>ClCCl>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:18]2[CH:19]=[CH:20][C:21]([N+:23]([O-:25])=[O:24])=[CH:22][C:17]=2[O:16][CH3:15])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCC(O)CC1
Reactant: COc1cc([N+](=O)[O-])ccc1O
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: COc1cc([N+](=O)[O-])ccc1OC1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 20 h
Yield: 82.5 %

Procedure:
To a solution of 1-t-butoxycarbonyl-4-hydroxypiperidine (3.02 g), 2-methoxy-4-nitrophenol (2.54 g) and triphenylphosphine (10.20 g) in dichloromethane (60 ml) was added dropwise diethyl azodicarboxylate (3.1 ml) in an ice bath and the mixture was stirred at room temperature for 20 hours. The reaction mixture was concentrated in vacuo. The residue was purified by chromatography on a silica gel column using hexane/ethyl acetate=5/2 as an eluant to give the desired compound (4.36 g, yield 82%) as a pale yellow oil.
Reaction SMILES: [N+:1]([C:4]1[CH:18]=[CH:17][C:7]2[S:8][C:9]3([C:15](=[O:16])[C:6]=2[CH:5]=1)[CH2:13][CH2:12][O:11][C:10]3=[O:14])([O-])=O>C(O)(=O)C.[Pd]>[NH2:1][C:4]1[CH:18]=[CH:17][C:7]2[S:8][C:9]3([C:15](=[O:16])[C:6]=2[CH:5]=1)[CH2:13][CH2:12][O:11][C:10]3=[O:14]
Reactant: O=C1OCCC12Sc1ccc([N+](=O)[O-])cc1C2=O
Agent: [Pd]
Solvent: CC(=O)O
Product: Nc1ccc2c(c1)C(=O)C1(CCOC1=O)S2

Procedure:
5-Nitro-4',5'-dihydrospiro[benzo[b]thiophene-2(3H),3'(2'H)-furan]-3,2'-dione (1.0 g) was hydrogenated in the presence of 5% Pd-C (0.35 g) in acetic acid (100 ml) at room temperature under usual pressure of H2 gas with stirring. The catalyst was filtered off and the filtrate was evaporated in vacuo. The resulting residue was recrystallized from benzene to give 5-amino-4',5'-dihydrospiro[benzo[b]thiophene-2(3H),3'(2'H)-furan]-3,2'-dione as yellow needles, mp 187°-190° C. Anal. Calcd. for C11H9NO3S: C, 56.15; H, 3.86; N, 5.96. Found: C, 56.61; H, 3.73; N, 5.96.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[C:6]([OH:8])[CH:5]=[CH:4][C:3]=1[C:9]1[CH2:13][CH2:12][C:11](=O)[CH:10]=1.Cl.[NH2:16][OH:17].C(N(CC)CC)C>C(O)C>[OH:1][C:2]1[CH:7]=[C:6]([OH:8])[CH:5]=[CH:4][C:3]=1[C:9]1[CH2:13][CH2:12][C:11](=[N:16][OH:17])[CH:10]=1
Reactant: O=C1C=C(c2ccc(O)cc2O)CC1
Reactant: NO
Agent: Cl
Solvent: CCO
Solvent: CCN(CC)CC
Product: ON=C1C=C(c2ccc(O)cc2O)CC1

Procedure:
3-[2,4-Bis(methoxymethoxy)phenyl]-2-cyclopenten-1-one (20 mg) was heated at 50° C. in MeOH (4 ml) containing acidic ion exchange resin (100 mg) for 3 hr. The reaction mixture was filtered and the resin washed with ethyl acetate (20 ml). The filtrate was concentrated in vacuo and the residue purified by flash column chromatography (SiO2, ethyl acetate/petrol, 7:3 v/v) to furnish 3-(2,4-dihydroxyphenyl)-2-cyclopenten-1-one (11 mg, 79%). 3-(2,4-Dihydroxyphenyl)-2-cyclopenten-1-one (6 mg), hydroxylamine hydrochloride (3.3 mg) and triethylamine (6.6 μl) were heated in ethanol (3 ml) under reflux for 3 hr. The reaction mixture was partitioned between ethyl acetate (20 ml) and water (20 ml). The aqueous phase was extracted with ethyl acetate (10 ml), and the combined organic phases were washed with brine (10 ml), dried over magnesium sulfate, and concentrated in vacuo. The crude residue was purified by flash column chromatography (SiO2, ethyl acetate/petrol, 1:1 v/v) to furnish the title compound as a yellow solid and as one major isomer (4 mg, 62%). Data reported for the major isomer: δH (d4-MeOH) 2.74-2.77 (2H, m), 2.96-2.99 (2H, m), 6.34 (1H, dd), 6.38 (1H, d), 6.96 (1H, t), 7.22 (1H, d); m/z (ES−) 204 (M−H)−.
Reaction SMILES: [N+:1]([C:4]1[S:8][C:7]([S:9]([N:12]2[CH2:17][CH2:16][NH:15][C@@H:14]([CH2:18][N:19]([CH2:24][CH:25]([CH3:27])[CH3:26])[S:20]([CH3:23])(=[O:22])=[O:21])[CH2:13]2)(=[O:11])=[O:10])=[CH:6][CH:5]=1)([O-:3])=[O:2].Cl[C:29]1[N:34]=[CH:33][C:32]([C:35]([OH:44])([C:40]([F:43])([F:42])[F:41])[C:36]([F:39])([F:38])[F:37])=[CH:31][N:30]=1.CCN(C(C)C)C(C)C>O1CCOCC1>[N+:1]([C:4]1[S:8][C:7]([S:9]([N:12]2[CH2:17][CH2:16][N:15]([C:29]3[N:30]=[CH:31][C:32]([C:35]([OH:44])([C:36]([F:37])([F:38])[F:39])[C:40]([F:42])([F:43])[F:41])=[CH:33][N:34]=3)[C@@H:14]([CH2:18][N:19]([CH2:24][CH:25]([CH3:27])[CH3:26])[S:20]([CH3:23])(=[O:22])=[O:21])[CH2:13]2)(=[O:11])=[O:10])=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: CC(C)CN(C[C@H]1CN(S(=O)(=O)c2ccc([N+](=O)[O-])s2)CCN1)S(C)(=O)=O
Reactant: OC(c1cnc(Cl)nc1)(C(F)(F)F)C(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: C1COCCO1
Product: CC(C)CN(C[C@H]1CN(S(=O)(=O)c2ccc([N+](=O)[O-])s2)CCN1c1ncc(C(O)(C(F)(F)F)C(F)(F)F)cn1)S(C)(=O)=O
Temperature: 100 °C
Reaction time: 21 h
Yield: 17.2 %

Procedure:
A 5-mL vial was charged with N-(((2S)-4-((5-nitro-2-thiophenyl)sulfonyl)-2-piperazinyl)methyl)-N-(2-methylpropyl)methanesulfonamide (0.170 g, 0.386 mmol), 2-(2-chloropyrimidin-5-yl)-1,1,1,3,3,3-hexafluoropropan-2-ol (0.124 g, 0.442 mmol, Intermediate D), DIPEA (0.202 mL, 1.16 mmol), and 1,4-dioxane (2 mL). The vial was sealed and stirred at 100° C. for 21 h. The reaction mixture was allowed to cool to room temperature and partitioned between water (20 mL) and EtOAc (20 mL). The aqueous phase was extracted with EtOAc (20 mL) and the combined organic extracts were washed with saturated aqueous NaCl (40 mL), dried over sodium sulfate, filtered and concentrated in vacuo. The crude product was purified by column chromatography (25 g of silica gel, 40 to 100% EtOAc in hexanes followed by 0-10% (2M NH3 in MeOH) in CH2Cl2) to afford N-(((2S)-4-((5-nitro-2-thiophenyl)sulfonyl)-1-(5-(2,2,2-trifluoro-1-hydroxy-1-(trifluoromethyl)ethyl)-2-pyrimidinyl)-2-piperazinyl)methyl)-N-(2-methylpropyl)methanesulfonamide (0.0454 g) as a brown solid.
Reaction SMILES: C(=O)([O-])[O-].[Cs+].[Cs+].I[C:8]1[CH:9]=[CH:10][C:11]2[NH:15][C:14](=[O:16])[N:13]([CH3:17])[C:12]=2[CH:18]=1.[C:19]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1B(O)O)#[N:20]>>[CH3:17][N:13]1[C:12]2[CH:18]=[C:8]([C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=3[C:19]#[N:20])[CH:9]=[CH:10][C:11]=2[NH:15][C:14]1=[O:16]
Reactant: N#Cc1ccccc1B(O)O
Reactant: Cn1c(=O)[nH]c2ccc(I)cc21
Agent: O=C([O-])[O-]
Agent: [Cs+]
Product: Cn1c(=O)[nH]c2ccc(-c3ccccc3C#N)cc21
Reaction time: 0.25 h

Procedure:
A solution of Cesium carbonate (1100 mg, 3.38 mmol, 5.0 eq) was treated with a solution of 6-iodo-1-methyl-1,3-dihydro-2H-benzimidazol-2-one (6-3, 185 mg, 0.68 mmol) and 2-Cyanophenylboronic acid (198 mg, 1.35 mmol, 2.0 eq). The 1,1′-Bis(diphenylphosphino)ferrocene-palladium(II)dichloride dichloromethane complex (27.6 mg, 0.03 mmol, 0.05 eq) was introduced and the mixture was irradiated in a microwave at 140 deg C. for 15 min. The product was worked up by partitioning between EtOAc (2×85 ml) and saturated aqueous NaHCO3 (95 ml), and the combined organic layers were dried over Na2SO4 and concentrated. Afforded 2-(3-methyl-2-oxo-2,3-dihydro-1H-benzimidazol-5-yl)benzonitrile (6-4), as a maroon-orange solid.
Reaction SMILES: [NH2:1][C@@H:2]([CH3:18])[CH2:3][N:4]1[CH:8]=[CH:7][C:6]([C:9]2[CH:16]=[CH:15][C:12]([C:13]#[N:14])=[C:11]([Cl:17])[CH:10]=2)=[N:5]1.[C:19]([O:23][C:24]([N:26]1[CH2:31][CH2:30][CH:29]([C:32]2[S:33][CH:34]=[C:35]([C:37](O)=[O:38])[N:36]=2)[CH2:28][CH2:27]1)=[O:25])([CH3:22])([CH3:21])[CH3:20]>>[Cl:17][C:11]1[CH:10]=[C:9]([C:6]2[CH:7]=[CH:8][N:4]([CH2:3][C@@H:2]([NH:1][C:37]([C:35]3[N:36]=[C:32]([CH:29]4[CH2:28][CH2:27][N:26]([C:24]([O:23][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:25])[CH2:31][CH2:30]4)[S:33][CH:34]=3)=[O:38])[CH3:18])[N:5]=2)[CH:16]=[CH:15][C:12]=1[C:13]#[N:14]
Reactant: C[C@H](N)Cn1ccc(-c2ccc(C#N)c(Cl)c2)n1
Reactant: CC(C)(C)OC(=O)N1CCC(c2nc(C(=O)O)cs2)CC1
Product: C[C@@H](Cn1ccc(-c2ccc(C#N)c(Cl)c2)n1)NC(=O)c1csc(C2CCN(C(=O)OC(C)(C)C)CC2)n1
Yield: 33.9 %

Procedure:
(S)-tert-butyl 4-(4-(1-(3-(3-chloro-4-cyanophenyl)-1H-pyrazol-1-yl)propan-2-ylcarbamoyl)thiazol-2-yl)piperidine-1-carboxylate was prepared using the method of Example 34(d) starting from (S)-4-(1-(2-aminopropyl)-1H-pyrazol-3-yl)-2-chlorobenzonitrile (400 mg, 1.534 mmol) and 2-[1-(tert-butoxycarbonyl)piperidin-4-yl]-1,3-thiazole-4-carboxylic acid (479 mg, 1.534 mmol). The product was purified twice by Flash-chromatography. Yield 33.9%. 1H-NMR (400 MHz; DMSO-d6): δ 1.14 (d, 3H), 1.41 (s, 9H), 1.49-1.64 (m, 2H), 1.98-2.08 (m, 2H), 2.89 (bs, 2H), 3.15-3.27 (m, 1H), 3.96-4.09 (m, 2H), 4.29-4.52 (m, 3H), 6.96 (s, 1H), 7.84 (d, 1H), 7.92 (dd, 1H), 7.97 (dd, 1H), 8.06 (dd, 1H), 8.10 (s, 1H), 8.28 (d, 1H).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([C:12](=[O:14])[CH3:13])=[C:5]2[NH:15][C@H:16]1[CH2:21][CH2:20][C@H:19]([CH2:22][CH2:23][N:24]([CH3:26])[CH3:25])[CH2:18][CH2:17]1.[Cl:27][C:28]1[CH:33]=[C:32](B2OC(C)(C)C(C)(C)O2)[CH:31]=[C:30]([Cl:43])[C:29]=1[OH:44].Cl>CO>[ClH:27].[Cl:27][C:28]1[CH:33]=[C:32]([C:2]2[CH:3]=[C:4]3[C:9](=[CH:10][CH:11]=2)[N:8]=[CH:7][C:6]([C:12](=[O:14])[CH3:13])=[C:5]3[NH:15][C@H:16]2[CH2:21][CH2:20][C@H:19]([CH2:22][CH2:23][N:24]([CH3:26])[CH3:25])[CH2:18][CH2:17]2)[CH:31]=[C:30]([Cl:43])[C:29]=1[OH:44]
Reactant: CC(=O)c1cnc2ccc(Br)cc2c1N[C@H]1CC[C@H](CCN(C)C)CC1
Reactant: CC1(C)OB(c2cc(Cl)c(O)c(Cl)c2)OC1(C)C
Agent: Cl
Solvent: CO
Product: CC(=O)c1cnc2ccc(-c3cc(Cl)c(O)c(Cl)c3)cc2c1N[C@H]1CC[C@H](CCN(C)C)CC1

Procedure:
Following general procedure F, 1-(6-bromo-4-(trans-4-(2-(dimethylamino)ethyl)cyclohexyl amino)quinolin-3-yl)ethanone (4.8 g, 11.5 mmol) was reacted with 2,6-dichloro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol (3.8 g, 13.1 mmol) to obtain the free base. The purified product was suspended in methanol (100 mL) after which HCl (125 mL, 1.25 M in methanol) was added to form a solution. The solution was concentrated to ˜50 mL and the resultant solid was filtered, washed with methanol, and dried to obtain desired product (3.8 g, 58% over two steps) as a yellow solid: 1H NMR (300 MHz, CD3OD) δ 9.10 (s, 1H), 8.50 (s, 1H), 8.27 (dd, J=8.8, 1.8 Hz, 1H), 7.97 (d, J=8.8 Hz, 1H), 7.73 (s, 2H), 4.55-4.48 (m, 1H), 3.27-3.15 (m, 2H), 2.90 (s, 6H), 2.74 (s, 3H), 2.42 (br d, J=12.3 Hz, 2H), 2.04 (br d, J=12.9 Hz, 2H), 1.84-1.65 (m, 4H), 1.63-1.56 (m, 1H), 1.34 (q, J=12.3 Hz, 2H); ESI MS m/z 500 [C27H31Cl2N3O2+H]+; HPLC>99% (AUC), tR=6.87 min.
Reaction SMILES: [C:1]([O:5][C:6](=[O:25])[N:7]([CH2:9][C:10]1[CH:14]=[C:13](Br)[N:12]([S:16]([C:19]2[CH:20]=[N:21][CH:22]=[CH:23][CH:24]=2)(=[O:18])=[O:17])[CH:11]=1)[CH3:8])([CH3:4])([CH3:3])[CH3:2].[C:26]([C:28]1[CH:29]=[C:30](B(O)O)[CH:31]=[CH:32][CH:33]=1)#[N:27].C(=O)([O-])[O-].[Na+].[Na+]>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:1]([O:5][C:6](=[O:25])[N:7]([CH2:9][C:10]1[CH:14]=[C:13]([C:32]2[CH:31]=[CH:30][CH:29]=[C:28]([C:26]#[N:27])[CH:33]=2)[N:12]([S:16]([C:19]2[CH:20]=[N:21][CH:22]=[CH:23][CH:24]=2)(=[O:18])=[O:17])[CH:11]=1)[CH3:8])([CH3:4])([CH3:3])[CH3:2]
Reactant: CN(Cc1cc(Br)n(S(=O)(=O)c2cccnc2)c1)C(=O)OC(C)(C)C
Reactant: N#Cc1cccc(B(O)O)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Product: CN(Cc1cc(-c2cccc(C#N)c2)n(S(=O)(=O)c2cccnc2)c1)C(=O)OC(C)(C)C

Procedure:
By a similar operation as in Reference Example 79 and using tert-butyl{[5-bromo-1-(pyridin-3-ylsulfonyl)-1H-pyrrol-3-yl]methyl}methylcarbamate (300 mg), (3-cyanophenyl)boronic acid (205 mg), tetrakis(triphenylphosphine)palladium (40 mg) and sodium carbonate (222 mg), the title compound was obtained as a pale-yellow oil (yield 298 mg, 94%).
Reaction SMILES: [NH2:1][CH:2]([C:4]([OH:6])=[O:5])[CH3:3].O.C1(C)C=CC(S(O)(=O)=O)=CC=1.[C:19]1([C:25]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)=[N+]=[N-])[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.C(=O)(O)[O-].[Na+]>C(Cl)(Cl)Cl.O.CN(C)C=O>[NH2:1][CH:2]([C:4]([O:6][CH:25]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)=[O:5])[CH3:3]
Reactant: [N-]=[N+]=C(c1ccccc1)c1ccccc1
Reactant: CC(N)C(=O)O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: ClC(Cl)Cl
Solvent: O
Product: CC(N)C(=O)OC(c1ccccc1)c1ccccc1
Reaction time: 1 h

Procedure:
9.0 g. of D,L-alanine and 19.0 g. of p-toluenesulfonic acid monohydrate are dissolved in 50 ml. of dimethylformamide. 21.1 g. of diphenyldiazomethane in 100 ml. of dimethylformamide are added dropwise at 50°. This mixture is stirred for 1 hour at 50° and then the solvent is distilled off in vacuum. The oily residue solidifies upon treatment with ether. The D,L-alanine, diphenylmethyl ester p-toluenesulfonate salt is recrystallized from acetonitrile and is obtained as white crystals, yield 13.5 g.; m.p. 170°-172°. 30 g. of this salt are dissolved in 200 ml. of water, layered over with 200 ml. of chloroform and 10 g. of sodium bicarbonate are added with frequent agitation. The organic phase is washed with 50 ml. of water, dried over sodium sulfate and evaporated. 17 g. of white crystalline D,L-alanine, diphenylmethyl ester are obtained, m.p. 60°-62°.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH:12]2[CH2:14][CH:9]1[CH2:10][N:11]2[C:15]1[CH:20]=[C:19]([C:21]2[CH:26]=[CH:25][N:24]=[C:23]([NH:27][CH:28]([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)[CH3:29])[CH:22]=2)[CH:18]=[CH:17][N:16]=1)=O)(C)(C)C.Cl>O1CCOCC1.CO>[C@H:12]12[CH2:14][C@H:9]([NH:8][CH2:13]1)[CH2:10][N:11]2[C:15]1[CH:20]=[C:19]([C:21]2[CH:26]=[CH:25][N:24]=[C:23]([NH:27][C@H:28]([C:30]3[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=3)[CH3:29])[CH:22]=2)[CH:18]=[CH:17][N:16]=1
Reactant: CC(Nc1cc(-c2ccnc(N3CC4CC3CN4C(=O)OC(C)(C)C)c2)ccn1)c1ccccc1
Agent: Cl
Solvent: C1COCCO1
Solvent: CO
Product: C[C@H](Nc1cc(-c2ccnc(N3C[C@@H]4C[C@H]3CN4)c2)ccn1)c1ccccc1
Reaction time: 1 h

Procedure:
To 5-[2′-(1-phenyl-ethylamino)-[4,4′]bipyridinyl-2-yl]-2,5-diazabicyclo[2.2.1]-heptane-2-carboxylic acid tert-butyl ester (0.027 g, 0.058 mmol) were added 4N HCl (1 mL) in dioxane and a few drops of methanol. After 1 h, the reaction was concentrated in vacuo and the residue was taken up in water and extracted with ethyl acetate. The aqueous layer was neutralized with saturated sodium bicarbonate and extracted with chloroform (3×). The combined organic extract was dried (K2CO3), filtered, and concentrated in vacuo to give the title compound as a golden yellow solid. MS (ES+): 372.4 [M+H]+, 370.3 [M−H]−.
Reaction SMILES: [C:1]1([C:7]2[NH:8][CH:9]=[C:10]([CH:12]=[O:13])[N:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Na+].[CH3:16][O:17][C:18]1[CH:19]=[C:20]([S:24](Cl)(=[O:26])=[O:25])[CH:21]=[CH:22][CH:23]=1.O>O1CCCC1>[CH3:16][O:17][C:18]1[CH:19]=[C:20]([S:24]([N:8]2[CH:9]=[C:10]([CH:12]=[O:13])[N:11]=[C:7]2[C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)(=[O:26])=[O:25])[CH:21]=[CH:22][CH:23]=1
Reactant: O=Cc1c[nH]c(-c2ccccc2)n1
Reactant: COc1cccc(S(=O)(=O)Cl)c1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: COc1cccc(S(=O)(=O)n2cc(C=O)nc2-c2ccccc2)c1
Reaction time: 0.5 h
Yield: 86.5 %

Procedure:
To a solution of 2-phenyl-1H-imidazole-4-carbaldehyde (520 mg) in tetrahydrofuran (100 mL) was added sodium hydride (60% in oil, 182 mg) at room temperature, and the mixture was stirred for 30 min. 3-Methoxybenzenesulfonyl chloride (750 mg) was added to the reaction mixture, and the mixture was stirred for 1.5 hr. Water was added, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was crystallized from diethyl ether to give the title compound as colorless crystals (yield 894 mg, 87%).
Reaction SMILES: Br[CH2:2][CH2:3][C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([F:13])[CH:11]=2)[NH:6][CH:5]=1.[NH:14]1[CH:18]=[CH:17][CH:16]=[N:15]1.C(N(C(C)C)C(C)C)C>C(Cl)(Cl)Cl>[N:14]1([CH2:2][CH2:3][C:4]2[C:12]3[C:7](=[CH:8][CH:9]=[C:10]([F:13])[CH:11]=3)[NH:6][CH:5]=2)[CH:18]=[CH:17][CH:16]=[N:15]1
Reactant: Fc1ccc2[nH]cc(CCBr)c2c1
Reactant: c1cn[nH]c1
Solvent: ClC(Cl)Cl
Solvent: CCN(C(C)C)C(C)C
Product: Fc1ccc2[nH]cc(CCn3cccn3)c2c1

Procedure:
A solution of 3-(2-bromo-ethyl)-5-fluoro-1H-indole (7.26 g, 30 mmol), pyrazole (2.04 g, 30 mmol) and ethyl-diisopropylamine (5.1 ml, 30 mmol) in abs. chloroform (80 ml) was stirred at 90° C. for 12 h. The reaction solution was then washed twice with water, dried over Na2SO4 and concentrated i. vac. and the residue which remained was purified by flash chromatography with CHCl3/MeOH (20:1).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH2:9][C:10]3([CH2:13][C:14]=2[C:15]2[CH:20]=[CH:19][C:18]([S:21]([CH3:24])(=[O:23])=[O:22])=[CH:17][CH:16]=2)[CH2:12][CH2:11]3)=[CH:4][CH:3]=1.ClC1C=C(C=CC=1)C(OO)=O.ClC1C=C(C=CC=1)C(O)=O.C([O-])(=O)C.[Na+]>ClCCl.C(O)(=O)C.O>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:14]([C:15]3[CH:16]=[CH:17][C:18]([S:21]([CH3:24])(=[O:23])=[O:22])=[CH:19][CH:20]=3)=[CH:13][C:10]3([CH2:11][CH2:12]3)[CH:9]=2)=[CH:6][CH:7]=1
Reactant: CS(=O)(=O)c1ccc(C2=C(c3ccc(F)cc3)CC3(CC3)C2)cc1
Agent: CC(=O)[O-]
Agent: O=C(O)c1cccc(Cl)c1
Agent: O=C(OO)c1cccc(Cl)c1
Solvent: CC(=O)O
Solvent: ClCCl
Solvent: O
Product: CS(=O)(=O)c1ccc(C2=CC3(C=C2c2ccc(F)cc2)CC3)cc1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 63.8 %

Procedure:
A solution of 500 mg (1.46 mmol) of 5-(4-fluorophenyl)-6-[4-(methylsulfonyl)phenyl]spiro[2.4]hept-5-ene (from Step 11) in 7 mL of dichloromethane was treated with 480 mg (55% peroxyacid, 1.53 mmol) of m-chloroperoxybenzoic acid (MCPBA). The reaction was stirred at ambient temperature for 2.5 hours, washed with aqueous saturated sodium bisulfite, dried (MgSO4), and concentrated in vacuo to give a mixture of desired expoxide intermediate and m-chlorobenzoic acid; this crude mixture in 10 mL of acetic acid and 1 mL of water was subsequently treated with 500 mg (6.1 mmol) of sodium acetate and stirred at 80° C. for 10 hours. The reaction mixture was cooled to ambient temperature and concentrated in .vacuo. The residue was partitioned between water and ethyl acetate; the organic phase was washed with aqueous saturated sodium bicarbonate, water, brine, dried (MgSO4), and reconcentrated in vacuo. Purification by silica gel chromatography gave 317 mg (64%) of 5-(4-fluorophenyl)-6-[4-(methylsulfonyl)phenyl]spiro[2.4]hepta-4,6-diene as a colorless solid: mp 119°-128° C. (dec); NMR (CDCl3) δ 1.81 (s, 4H), 3.06 (s, 3H), 6.22 (d, J=2 Hz, 1H), 6.36 d, J=2 Hz, 1H), 6.95 (t, J=8 Hz, 2H), 7.02-7.18 (m, 2H), 7.33 (d, J=8 Hz, 2H), 7.80 (d, J=8 Hz, 2H). MS (FAB) m/e (rel intensity) 347 (100) (M+Li). HRMS. Calc'd for C20H17FO2S: 340.0933. Found: 340.0952. Anal. Calc'd for C20H17FO2S: C, 69.29; H, 4.97; F, 5.45. Found: C, 69.21; H, 5.23; F, 5.81.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([C:11]#[N:12])[CH:10]=1)[C:5](O)=[O:6].C(Cl)(=O)C([Cl:16])=O>CN(C)C=O>[Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([C:11]#[N:12])[CH:10]=1)[C:5]([Cl:16])=[O:6]
Reactant: N#Cc1cc(Cl)cc(C(=O)O)c1
Reactant: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Product: N#Cc1cc(Cl)cc(C(=O)Cl)c1
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
3-Chloro-5-cyanobenzoic acid (0.82 g, 4.97 mmol) was treated with a solution of oxalyl chloride (10 mL of 2.5 M in dichloromethane, 25 mmol) and a catalytic amount of N,N-dimethylformamide. The reaction was stirred at ambient temperature for 2.5 hours. The excess oxalyl chloride was removed in vacuo to afford 3-chloro-5-cyanobenzoyl chloride.
Reaction SMILES: [C:1]([OH:14])(=[O:13])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].O=C[C@@H]([C@H]([C@@H]([C@@H](CO)O)O)O)O.[OH-].[Na+]>>[CH3:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][C@@H:4]1[O:14][C:1](=[O:13])[CH2:2][CH2:3]1
Reactant: CCCCCCCCCCCC(=O)O
Agent: O=C[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO
Agent: [Na+]
Agent: [OH-]
Product: CCCCCCCC[C@H]1CCC(=O)O1
Reaction time: 55 h

Procedure:
Once the amount and the quality of mycelium have been attained, the substrate (lauric acid) is dispensed in mygliol. Glucose is continuously dispensed, in parallel, at the flow rate of 0.36 g/l/h for 55 h. The pH is regulated at 7 throughout the duration of the fermentation, with 5 N NaOH. The speed is increased to 900 rpm and aeration is carried out at the flow rate of 1 vvm, i.e. 12 m3/h. The conversion is pursued for 55 hours. A yield of 12 g/l of (S)-gamma-dodecalactone is obtained. By way of comparison, gamma-dodecalactones are prepared according to the teaching of patent U.S. Pat. No. 5,457,036 (Han), using the Mortierella strains described in U.S. Pat. No. 5,457,036.