Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C@H:2]1[CH2:6][CH2:5][N:4]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:3]1.[H-].[Na+].Cl[C:17]1[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][C:25]=2[Cl:27])[CH:20]=[C:19]([C:28]#[N:29])[N:18]=1>C1COCC1>[Cl:27][C:25]1[CH:24]=[CH:23][CH:22]=[C:21]2[C:26]=1[C:17]([O:1][C@H:2]1[CH2:6][CH2:5][N:4]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:3]1)=[N:18][C:19]([C:28]#[N:29])=[CH:20]2
Reactant: N#Cc1cc2cccc(Cl)c2c(Cl)n1
Reactant: CC(C)(C)OC(=O)N1CC[C@H](O)C1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CC[C@H](Oc2nc(C#N)cc3cccc(Cl)c23)C1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 73.2 %

Procedure:
To a solution of (S)-tert-butyl 3-hydroxypyrrolidine-1-carboxylate (126 mg, 0.674 mmol) in THF (5 mL) was added NaH (26.8 mg, 0.677 mmol) at 0° C. The mixture was stirred for 30 minutes. Next, 1,8-dichloroisoquinoline-3-carbonitrile was added and the reaction mixture was warmed to RT for 4 hours. The reaction was quenched with H2O (2 mL) and the mixture was extracted with EtOAc (3×10 mL). The organic layers were combined and concentrated in vacuo. The crude product was purified by preparative TLC to give the title compound (120 mg, 73.2%).
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[N:10]([C:14](=[O:21])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[CH2:9][CH2:8]2)=[O:4].O[Li].O>C1COCC1.O>[C:14]([N:10]1[C:11]2[C:7](=[CH:6][C:5]([C:3]([OH:4])=[O:2])=[CH:13][CH:12]=2)[CH2:8][CH2:9]1)(=[O:21])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: COC(=O)c1ccc2c(c1)CCN2C(=O)c1ccccc1
Agent: [Li]O
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)c1ccc2c(c1)CCN2C(=O)c1ccccc1
Yield: 99 %

Procedure:
A solution of compound 55g (87 mg, 0.31 mmol), and LiOH.H2O (52 mg, 1.24 mmol) in THF/H2O (2/2 mL) was stirred at room temperature overnight. The resulting mixture was concentrated and diluted with water. The water layer was acidified with 1N aqueous HCl to pH ˜6 and extracted with CH2Cl2. The organic solution was dried over Na2SO4 and concentrated to give 55h (82 mg), which was used in the next reaction without further purification. MS m/z (M+H+) 268.0.
Reaction SMILES: C1(N2[C:12](=[O:13])[C:11]3[S:14][CH:15]=[C:16]([C:17]4[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=4)[C:10]=3[N:9]=[CH:8]2)C=CC=CC=1.NC1C(C2C=CC=CC=2)=CSC=1C(OC)=O.C(OCC)(OCC)OCC.[CH3:49][O:50][C:51]1[CH:52]=[C:53]([CH:55]=[C:56]([O:58][CH3:59])[CH:57]=1)[NH2:54]>C(O)(=O)C>[CH3:59][O:58][C:56]1[CH:55]=[C:53]([N:54]2[C:12](=[O:13])[C:11]3[S:14][CH:15]=[C:16]([C:17]4[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=4)[C:10]=3[N:9]=[CH:8]2)[CH:52]=[C:51]([O:50][CH3:49])[CH:57]=1
Reactant: COc1cc(N)cc(OC)c1
Reactant: O=c1c2scc(-c3ccccc3)c2ncn1-c1ccccc1
Agent: COC(=O)c1scc(-c2ccccc2)c1N
Solvent: CC(=O)O
Solvent: CCOC(OCC)OCC
Product: COc1cc(OC)cc(-n2cnc3c(-c4ccccc4)csc3c2=O)c1
Yield: 68 %

Procedure:
In the same manner as the synthesis of Compound 1, methyl 3-amino-4-phenylthiophene-2-carboxylate (72.3 mg, 0.31 mmol), triethyl orthoformate (0.62 ml), 3,5-dimethoxyaniline (88.8 mg, 0.58 mmol), and acetic acid (0.07 ml) were used to give 75.7 mg (0.21 mmol, 68% yield) of the title compound.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([F:8])[C:5]([N+:9]([O-:11])=[O:10])=[CH:4][C:3]=1[CH2:12][C:13]([OH:15])=[O:14].OS(O)(=O)=O.[CH3:21][CH2:22]O>>[Br:1][C:2]1[CH:7]=[C:6]([F:8])[C:5]([N+:9]([O-:11])=[O:10])=[CH:4][C:3]=1[CH2:12][C:13]([O:15][CH2:21][CH3:22])=[O:14]
Reactant: O=C(O)Cc1cc([N+](=O)[O-])c(F)cc1Br
Reactant: CCO
Agent: O=S(=O)(O)O
Product: CCOC(=O)Cc1cc([N+](=O)[O-])c(F)cc1Br
Temperature: 85 °C
Reaction time: 1.5 h
Yield: 87 %

Procedure:
2-(2-bromo-4-fluoro-5-nitrophenyl)acetic acid (6.04 g, 21.7 mmol) and cone. H2SO4 (1.2 mL) were combined in EtOH (100 mL) and stirred with heating at 85° C. After 1.5 h, the completed reaction was cooled to RT and concentrated as completely as possible. The residue was dissolved in MTBE (50 mL) and washed with H2O (2×), and brine (2×), dried (MgSO4), filtered and evaporated to afford a dark orange oil. The crude was purified by silica gel column chromatography to obtain ethyl 2-(2-bromo-4-fluoro-5-nitrophenyl)acetate (5.8 g, 87% yield).
Reaction SMILES: [NH2:1][C@H:2]([C:7]([OH:9])=[O:8])[C:3]([CH3:6])([CH3:5])[CH3:4].[OH-:10].[Na+].O1C[CH2:16][O:15][CH2:14]C1>>[CH3:14][O:15][C:16]([NH:1][C@H:2]([C:7]([OH:9])=[O:8])[C:3]([CH3:6])([CH3:5])[CH3:4])=[O:10]
Reactant: [OH-]
Reactant: CC(C)(C)[C@H](N)C(=O)O
Reactant: C1COCCO1
Agent: [Na+]
Product: COC(=O)N[C@H](C(=O)O)C(C)(C)C
Temperature: 60 °C

Procedure:
23.5 ml (305 mmol) of methyl chlorotormate are added, over a period of 20 min, to a solution of 20 g (152 mmol) of (L)-tert-leucine (=2(S)-amino-3,3-dimethylbutyric acid=(L)-α-tert-butylglycine; Fluka, Buchs, Switzerland) in a mixture of 252 ml (504 mmol) of a 2N aqueous solution of sodium hydroxide and 80 ml of dioxane, and the reaction solution is heated at 60° C. for 14 h. After the reaction solution has cooled down to room temperature, it is washed twice with methylene chloride. The aqueous phase is acidified to pH 2 with 4N aqueous hydrochloric acid and extracted three times with ethyl acetate. The organic extracts are combined, dried (Na2SO4) and concentrated by evaporation. During this procedure, the product begins to harden. Digestion of the hardened solid with hexane yields the title compound as a white powder. M.p. 106-108° C.
Reaction SMILES: C(O)(=O)C.[NH2:5][C:6]1[S:7][CH:8]=[C:9]([C:11](=[N:37][O:38][CH:39]([CH3:41])[CH3:40])[C:12]([NH:14][CH:15]2[C:35](=[O:36])[N:17]3[C:18]([C:22]([O:24]CC4C=CC([N+]([O-])=O)=CC=4)=[O:23])=[CH:19][CH2:20][S:21][C@H:16]23)=[O:13])[N:10]=1.Cl>[Pd].O.O1CCCC1>[NH2:5][C:6]1[S:7][CH:8]=[C:9]([C:11](=[N:37][O:38][CH:39]([CH3:41])[CH3:40])[C:12]([NH:14][CH:15]2[C:35](=[O:36])[N:17]3[C:18]([C:22]([OH:24])=[O:23])=[CH:19][CH2:20][S:21][C@H:16]23)=[O:13])[N:10]=1
Reactant: CC(C)ON=C(C(=O)NC1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=CCS[C@H]12)c1csc(N)n1
Agent: [Pd]
Agent: Cl
Solvent: CC(=O)O
Solvent: C1CCOC1
Solvent: O
Product: CC(C)ON=C(C(=O)NC1C(=O)N2C(C(=O)O)=CCS[C@H]12)c1csc(N)n1
Yield: 21.3 %

Procedure:
Acetic acid (1 ml.) and a suspension of 10% palladium on carbon (2.0 g.) in water (8 ml) were added to a solution of 4-nitrobenzyl 7-[2-(2-amino-4-thiazolyl)-2-isopropoxyiminoacetamido]-3-cephem-4-carboxylate (syn isomer, 5.0 g.) in tetrahydrofuran (150 ml.), and the suspension was subjected to catalytic reduction at room temperature under ordinary pressure. After removing the catalyst by filtration, the filtrate was concentrated under reduced pressure. Ethylacetate (80 ml.) was added to the residue, and adjusted to pH 7.5 with an aqueous solution of sodium bicarbonate. The organic layer was separated and extracted with an aqueous solution of sodium bicarbonate. The extract and the aqueous layer obtained above were combined, adjusted to pH 3.0 with conc. hydrochloric acid and extracted with tetrahydrofuran. The extract was washed with a saturated aqueous solution of sodium chloride, dried over magnesium sulfate and concentrated under reduced pressure. The precipitating crystalls were collected by filtration and dried to give 7-[2-(2-amino-4-thiazolyl)-2 -isopropoxyiminoacetamido]-3-cephem-4-carboxylic acid (syn isomer, 0.8 g.).
Reaction SMILES: [CH2:1]([C:5]1[NH:10][C:9](=[O:11])[C:8]([CH2:12][C:13](=[O:18])[C:14]([CH3:17])([CH3:16])[CH3:15])=[C:7]([CH3:19])[N:6]=1)[CH2:2][CH2:3][CH3:4].Br[CH2:21][C:22]1[CH:27]=[CH:26][C:25]([C:28]2[C:29]([C:34]#[N:35])=[CH:30][CH:31]=[CH:32][CH:33]=2)=[CH:24][CH:23]=1.C(=O)([O-])[O-].[K+].[K+].C(OCC)(=O)C>CN(C)C=O.O>[CH2:1]([C:5]1[N:10]([CH2:21][C:22]2[CH:23]=[CH:24][C:25]([C:28]3[C:29]([C:34]#[N:35])=[CH:30][CH:31]=[CH:32][CH:33]=3)=[CH:26][CH:27]=2)[C:9](=[O:11])[C:8]([CH2:12][C:13](=[O:18])[C:14]([CH3:17])([CH3:16])[CH3:15])=[C:7]([CH3:19])[N:6]=1)[CH2:2][CH2:3][CH3:4]
Reactant: N#Cc1ccccc1-c1ccc(CBr)cc1
Reactant: CCCCc1nc(C)c(CC(=O)C(C)(C)C)c(=O)[nH]1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCCCc1nc(C)c(CC(=O)C(C)(C)C)c(=O)n1Cc1ccc(-c2ccccc2C#N)cc1
Temperature: 80 °C
Reaction time: 24 h

Procedure:
To a solution of 2-butyl-5-(3,3-dimethyl-2-oxobutyl)-6-methylpyrimidin-4(3H)-one (0.48 g) and 4′-(bromomethyl)biphenyl-2-carbonitrile (0.99 g) in N,N-dimethylformamide (9 mL) was added potassium carbonate (0.75 g), and the mixture was stirred at 80° C. for 24 hr. The reaction mixture was allowed to cool to room temperature, ethyl acetate and water were added, and the aqueous layer was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was evaporated and the residue was purified by silica gel column chromatography to give the title compound as a pale-yellow viscous substance (0.33 g, 40%).
Reaction SMILES: [NH:1]1[CH:8]=[CH:7][C:5]([NH2:6])=[N:4][C:2]1=[S:3].Br[CH2:10][CH2:11][CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14].N12CCCCC1C=NCCC2.[F:29][C:30]([F:36])([F:35])[CH2:31][N:32]=[C:33]=[S:34].[N-]=C=S>C(#N)C>[F:29][C:30]([F:36])([F:35])[CH2:31][NH:32][C:33](=[S:34])[NH:6][C:5]1[CH:7]=[CH:8][N:1]=[C:2]([S:3][CH2:10][CH2:11][CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14])[N:4]=1
Reactant: FC(F)(F)CN=C=S
Reactant: CCOC(=O)CCCBr
Reactant: Nc1cc[nH]c(=S)n1
Agent: C1=NCCCN2CCCCC12
Agent: [N-]=C=S
Solvent: CC#N
Product: CCOC(=O)CCCSc1nccc(NC(=S)NCC(F)(F)F)n1
Reaction time: 4 h

Procedure:
A mixture of 2-thiocytosine (0.64 g.), ethyl 4-bromobutyrate (1.07 g.) and 1,5-diazabicyclo[5,4,0]undec-5-ene (0.84 g.) was stirred for 4 hours and then evaporated to dryness. The residue was treated with water and the mixture extracted with EtOAc, and the extract dried and evaporated to dryness to give a gum (1.9 g.). The gum was dissolved in acetonitrile (5 ml.) the solution treated with 2,2,2-trifluoroethyl isothiocyanate (1.1 g.) and the mixture heated at 70° for 72 hours with the addition of further portions of isothiocyanate (0.5 g.) at 24 and 48 hours. The mixture was cooled and the solid which crystallised was collected to give ethyl 4-[4-(3-[2,2,2-trifluoroethyl]thioureido)pyrimid-2-ylthio]butyrate, m.p. 104°-106°.
Reaction SMILES: [SH:1][CH2:2][C:3]([O:5][CH2:6][CH3:7])=[O:4].C(ON=O)CC(C)C.[Cl:16][C:17]1[CH:23]=[CH:22][C:20](N)=[C:19]([S:24][C:25]2[CH:30]=[CH:29][C:28]([S:31]([CH2:34][CH3:35])(=[O:33])=[O:32])=[CH:27][C:26]=2[Cl:36])[CH:18]=1>C(#N)C.O>[Cl:16][C:17]1[CH:23]=[CH:22][C:20]([S:1][CH2:2][C:3]([O:5][CH2:6][CH3:7])=[O:4])=[C:19]([S:24][C:25]2[CH:30]=[CH:29][C:28]([S:31]([CH2:34][CH3:35])(=[O:32])=[O:33])=[CH:27][C:26]=2[Cl:36])[CH:18]=1
Reactant: CCOC(=O)CS
Reactant: CCS(=O)(=O)c1ccc(Sc2cc(Cl)ccc2N)c(Cl)c1
Agent: CC(C)CCON=O
Solvent: O
Solvent: CC#N
Product: CCOC(=O)CSc1ccc(Cl)cc1Sc1ccc(S(=O)(=O)CC)cc1Cl
Temperature: 60 °C

Procedure:
Ethyl mercaptoacetate (0.11 ml) followed by isoamylnitrite (0.16 ml) were added to a solution of the product from step (iii) (0.35 g) in dry acetonitrile (20 ml) and heated at 60° C. for 10 h. The mixture was diluted with water, extracted with diethylether, the organics dried and evaporated under reduced pressure. The residue was purified by chromatography on silica eluting with isohexane/diethylether 1:1, yield 0.10 g.
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][N:5]=[C:6]2[CH:15]=[CH:14][C:13](=[CH:16][C:17]#[N:18])[CH2:12][C:7]32[CH2:11][S:10][CH2:9][C:8]=13.[CH3:19][N:20]1[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]1.C(N(CC)CC)C>CN(C)C=O>[C:17]([CH:16]=[C:13]1[CH2:12][C:7]23[CH2:11][S:10][CH2:9][C:8]2=[C:2]([N:23]2[CH2:24][CH2:25][N:20]([CH3:19])[CH2:21][CH2:22]2)[CH:3]=[CH:4][N:5]=[C:6]3[CH:15]=[CH:14]1)#[N:18]
Reactant: CN1CCNCC1
Reactant: N#CC=C1C=CC2=NC=CC(Cl)=C3CSCC23C1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CN1CCN(C2=C3CSCC34CC(=CC#N)C=CC4=NC=C2)CC1
Temperature: 100 °C
Reaction time: 2.5 h
Yield: 79.7 %

Procedure:
11.6 g (43 millimoles) of 4-chloro-10-cyanomethylenethieno[4,3-e]benzoazepine were dissolved in 70 ml of dimethylformamide, and 10 ml (90 millimoles) of N-methylpiperazine and 10 ml (75 millimoles) of triethylamine were added, a highly exothermic reaction taking place. The mixture was stirred for from 2 to 3 hours at 100° C. under nitrogen, the dark homogeneous reaction mixture was then cooled and poured onto ice water, the yellowish crude product 10-cyanomethylene-4-(4-methylpiperazin-1-yl)-thieno[4,3-e]benzoazepine, was filtered off under suction. The crude product was dried in a drying oven under reduced pressure and then recrystallized from ethanol with the addition of active carbon or purified by column chromatography (silica gel, mobile phase 95:5 methylene chloride/methanol). 11.6 g (81%) of yellowish 10-cyanomethylene4-(4-methylpiperazin-1-yl)-thieno[4,3-e]benzoazepine were obtained in the form of a cis/trans isomer mixture of melting point 90°-92° C.
Reaction SMILES: CN(C)[C:3]1[CH2:10][CH2:9][C:8]2[C:4]=1[CH:5]=[CH:6][CH:7]=2.[CH:12]1([Li])[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH:14]=[CH:13]1.O>O1CCCC1>[CH:12]1([C:3]2[CH2:10][CH2:9][C:8]3[C:4]=2[CH:5]=[CH:6][CH:7]=3)[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH:14]=[CH:13]1
Reactant: [Li]C1C=Cc2ccccc21
Reactant: CN(C)C1=C2C=CC=C2CC1
Solvent: O
Solvent: C1CCOC1
Product: C1=CC2=C(C3C=Cc4ccccc43)CCC2=C1
Temperature: 25 °C
Reaction time: 24 h
Yield: 74.9 %

Procedure:
A solution of 12.5 g (85 mmol) of 4-(dimethylamino)-5,6-dihydropentalene in 50 ml of tetrahydrofuran are admixed with a solution of 10.4 g (85 mmol) of indenyllithium in 20 ml of tetrahydrofuran. The reaction solution is stirred for 24 hours at room temperature and the reaction is stopped by addition of water. Extraction with diethyl ether, drying of the organic phases over MgSO4 and removal of the solvent under reduced pressure and subsequent recrystallization of the crude product from diethyl ether gives 13.9 g (75%) of 4-indenyl-5,6-dihydropentalene.
Reaction SMILES: B(F)(F)F.CCOCC.FC1C([Mg]Br)=C(F)C(F)=C(F)C=1F.[ClH:23].[CH3:24][N:25]([CH3:32])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>O.C(OCC)C>[Cl-:23].[CH3:24][NH+:25]([CH3:32])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: CN(C)c1ccccc1
Reactant: Cl
Agent: FB(F)F
Agent: Fc1c(F)c(F)c([Mg]Br)c(F)c1F
Solvent: CCOCC
Solvent: O
Product: C[NH+](C)c1ccccc1
Product: [Cl-]
Temperature: -10 °C

Procedure:
Boron trifluoride diethyl etherate (138.7 g, 0.98 mole) is added to a diethyl ether solution of pentafluorophenylmagnesium bromide (3326 g, 4.17 moles) formed as in Example 24. The addition is at a rate allowing the mixture to reach reflux temperature. The mixture is heated at reflux for 18 hours. This mixture is then cooled to −10° C. and N,N-dimethylanilinium chloride (1142 grams, 2.06 moles) previously formed from concentrated HCl, water, and N,N-dimethylaniline is slowly added while keeping the temperature at about 0° C. After the addition, the mixture is stirred for one hour at −5° C. to 0° C. Then the two phases are separated, and the organic phase is washed with water and dried over MgSO4. The N,N-dimethylanilinium tetrakis(pentafluorophenyl)borane is precipitated by addition of hexane with stirring, and recovered by filtration.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][C:5](=[S:8])[NH:6][CH:7]=1.[CH3:9][C:10](C)([O-:12])[CH3:11].[K+].C(C1OC1)I>CN(C=O)C>[O:12]1[CH2:11][CH:10]1[CH2:9][S:8][C:5]1[N:6]=[CH:7][C:2]([Cl:1])=[CH:3][N:4]=1
Reactant: CC(C)(C)[O-]
Reactant: S=c1ncc(Cl)c[nH]1
Agent: ICC1CO1
Agent: [K+]
Solvent: CN(C)C=O
Product: Clc1cnc(SCC2CO2)nc1
Yield: 29 %

Procedure:
A mixture of 5-chloropyrimidine-2-thione (6.9 mmol) and potassium tert-butoxide (6.9 mmol) was stirred together in anhydrous DMF (40 ml) for 5 min before epiiodohydrin (6.9 mmol) was added. The mixture was stirred at 80° C. for 7 h while small portions of potassium tert-butoxide were added from time to time to maintain a strong basic solution. The solvent was then removed at reduced pressure, the residue triturated with water (50 ml), the insoluble material extracted with chloroform and the dried (MgSO4) chloroform solution evaporated leaving the oily sulfide, yield 29%. This material was chromatographically homogenous and was identified by its spectroscopic properties. 1H NMR (CDCl3): δ2.6-3.4 (5H, m), 8.50 (H-4, H-6).
Reaction SMILES: [CH3:1][C:2]1[CH2:11][CH2:10][C:6](=[C:7]([CH3:9])[CH3:8])[C:4](=[O:5])[CH:3]=1.CC(C1C(OC)=C(C(C)(C)C)C=C(P(C2C=C(C(C)(C)C)C(OC)=C(C(C)(C)C)C=2)C2C=CC3OCOC=3C=2C2C3OCOC=3C=CC=2P(C2C=C(C(C)(C)C)C(OC)=C(C(C)(C)C)C=2)C2C=C(C(C)(C)C)C(OC)=C(C(C)(C)C)C=2)C=1)(C)C.[H][H]>C(OCC)(=O)C>[CH3:1][CH:2]1[CH2:3][CH:4]([OH:5])[C:6](=[C:7]([CH3:8])[CH3:9])[CH2:10][CH2:11]1
Reactant: CC1=CC(=O)C(=C(C)C)CC1
Reactant: [H][H]
Agent: COc1c(C(C)(C)C)cc(P(c2cc(C(C)(C)C)c(OC)c(C(C)(C)C)c2)c2ccc3c(c2-c2c(P(c4cc(C(C)(C)C)c(OC)c(C(C)(C)C)c4)c4cc(C(C)(C)C)c(OC)c(C(C)(C)C)c4)ccc4c2OCO4)OCO3)cc1C(C)(C)C
Solvent: CCOC(C)=O
Product: CC(C)=C1CCC(C)CC1O
Reaction time: 20 h
Yield: 88.7 %

Procedure:
A 500 ml capacity autoclave was charged with 150 g (1 mol) of piperitenone, 18.6 mg (0.04 mmol) of [Rh(cod)2]PF6, 47.2 mg (0.04 mmol) of (S)-DTBM-SEGPHOS, 14.8 mg (0.02 mmol) of BrPPh3(CH2)4PPh3Br and 7.5 ml of ethyl acetate, and the reaction was carried out at 50° C. for 20 hours under a hydrogen pressure of 3 Mpa. After completion of the reaction, hydrogen was purged, the reaction solution was concentrated and then distillation was carried out under a reduced pressure to obtain 136.8 g of pulegol. The yield was 90%.
Reaction SMILES: [NH2:1][C@@H:2]([CH2:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[C:14](=[O:22])[N:15]([CH3:21])[N:16]=[CH:17][C:18]=2[O:19][CH3:20])=[CH:9][CH:8]=1)[C:3]([OH:5])=[O:4].[CH3:23]OC(OC)(C)C.Cl>CO.O1CCOCC1>[CH3:23][O:4][C:3](=[O:5])[CH:2]([NH2:1])[CH2:6][C:7]1[CH:8]=[CH:9][C:10]([C:13]2[C:14](=[O:22])[N:15]([CH3:21])[N:16]=[CH:17][C:18]=2[O:19][CH3:20])=[CH:11][CH:12]=1
Reactant: COC(C)(C)OC
Reactant: COc1cnn(C)c(=O)c1-c1ccc(C[C@H](N)C(=O)O)cc1
Agent: Cl
Solvent: C1COCCO1
Solvent: CO
Product: COC(=O)C(N)Cc1ccc(-c2c(OC)cnn(C)c2=O)cc1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
2-(S)-Amino-3-[4-(5-methoxy-2-methyl-3-oxo-2,3-dihydro-pyridazin-4-yl)-phenyl]-propionic acid (0.40 g, 1.0 mmol) was dissolved in MeOH (2.6 mL). Dimethoxypropane (0.26 mL) and 1N HCl in dioxane (0.33 mL) were added and stirred at room temperature for 24 h. The mixture was concentrated in vacuo to give 2-Amino-3-[4-(5-methoxy-2-methyl-3-oxo-2,3-dihydro-pyridazin-4-yl)-phenyl]-propionic acid methyl ester. MS (ES+) 318.
Reaction SMILES: Cl[CH:2]([C:7]1[O:8][C:9]2[CH:17]=[CH:16][CH:15]=[CH:14][C:10]=2[C:11]=1[CH2:12][CH3:13])[CH2:3][CH:4]([CH3:6])[CH3:5].[NH2:18][C:19]1[CH:24]=[CH:23][C:22]([C:25]([N:27]([CH3:35])[CH2:28][CH2:29][C:30]([O:32]CC)=[O:31])=[O:26])=[CH:21][CH:20]=1>>[CH2:12]([C:11]1[C:10]2[CH:14]=[CH:15][CH:16]=[CH:17][C:9]=2[O:8][C:7]=1[CH:2]([NH:18][C:19]1[CH:20]=[CH:21][C:22]([C:25]([N:27]([CH3:35])[CH2:28][CH2:29][C:30]([OH:32])=[O:31])=[O:26])=[CH:23][CH:24]=1)[CH2:3][CH:4]([CH3:6])[CH3:5])[CH3:13]
Reactant: CCOC(=O)CCN(C)C(=O)c1ccc(N)cc1
Reactant: CCc1c(C(Cl)CC(C)C)oc2ccccc12
Product: CCc1c(C(CC(C)C)Nc2ccc(C(=O)N(C)CCC(=O)O)cc2)oc2ccccc12

Procedure:
Using 2-(1-chloro-3-methylbutyl)-3-ethyl-1-benzofuran (300 mg) synthesized above and ethyl 3-{[(4-aminophenyl)carbonyl](methyl)amino}propanoate (300 mg) synthesized in Example 2(2) and in the same manner as in Example A22(4), the title object compound (97.4 mg, 19%) was obtained as a yellow solid.
Reaction SMILES: C[O:2][C:3]1[CH:8]=[CH:7][C:6]([O:9]C)=[CH:5][C:4]=1[O:11]C.[Br:13]Br.[C:15]([O:18]CC)(=[O:17])[CH3:16]>C(Cl)(Cl)Cl.C(Cl)(Cl)(Cl)Cl>[BrH:13].[CH:7]1[C:6](=[O:9])[CH:5]=[C:4]([OH:11])[C:3]([OH:2])=[CH:8][C:16]=1[C:15]([OH:18])=[O:17]
Reactant: BrBr
Reactant: COc1ccc(OC)c(OC)c1
Reactant: CCOC(C)=O
Solvent: ClC(Cl)(Cl)Cl
Solvent: ClC(Cl)Cl
Product: Br
Product: O=C(O)c1cc(O)c(O)cc(=O)c1

Procedure:
Puberulic acid is also obtainable by direct chemical synthesis, as disclosed by Johns et al., Jour. Chem. Soc. 1954, 198. According to this method, a solution of 3,4,6-trimethoxycycloheptatriene-caboxylic acid (an intermediate obtained by reacting diazoacetic ester and 1,2,4-trimethoxybenzene) in chloroform is reacted with a solution of bromine in carbon tetrachloride; the obtained precipitate is then heated in ethyl acetate, cooled in ice and then hydrolyzed with hydrobromic acid, obtaining stipitatic acid. Said stipitatic acid is then reacted with bromine, in order to obtain monobromostipitatic acid which is in turn reacted with potassium hydroxide to obtain the desired puberulic acid.
Reaction SMILES: [H-].[Na+].Cl[CH2:4][CH2:5][NH:6][C:7]([NH:9][C:10]1[CH:15]=[CH:14][N:13]=[CH:12][CH:11]=1)=[O:8].O1CCCC1.CN(C=O)C>CO>[N:13]1[CH:14]=[CH:15][C:10]([N:9]2[CH2:4][CH2:5][NH:6][C:7]2=[O:8])=[CH:11][CH:12]=1
Reactant: O=C(NCCCl)Nc1ccncc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CO
Solvent: C1CCOC1
Product: O=C1NCCN1c1ccncc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 26.7 %

Procedure:
Sodium hydride (60% in oil, 2.4 g, 60 mmol) was added to a mixture of N-(2-chloroethyl)-N′-(4-pyridyl)urea (11.1 g, 55 mmol), tetrahydrofuran (40 ml) and DMF (40 ml) at 0° C., and the mixture was stirred at room temperature for 2 hrs. The reaction mixture was combined with methanol. The solvent was evaporated, and the residue was combined with water and extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over magnesium sulfate. The residue was recrystallized from tetrahydrofuran-hexane to give the titled compound (2.4 g, 27%) as white crystals.
Reaction SMILES: C[O:2][C:3](=[O:32])[CH2:4][N:5]1[C:13]2[C:8](=[CH:9][C:10]([F:14])=[CH:11][CH:12]=2)[C:7]([CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[S:22]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)(=[O:24])=[O:23])=[C:6]1[CH3:31].O1CCCC1.[OH-].[Na+].Cl>CO>[C:25]1([S:22]([C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=2[CH2:15][C:7]2[C:8]3[C:13](=[CH:12][CH:11]=[C:10]([F:14])[CH:9]=3)[N:5]([CH2:4][C:3]([OH:32])=[O:2])[C:6]=2[CH3:31])(=[O:24])=[O:23])[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1
Reactant: COC(=O)Cn1c(C)c(Cc2ccccc2S(=O)(=O)c2ccccc2)c2cc(F)ccc21
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: Cc1c(Cc2ccccc2S(=O)(=O)c2ccccc2)c2cc(F)ccc2n1CC(=O)O
Temperature: 25 °C
Reaction time: 2 h
Yield: 78.9 %

Procedure:
A mixture of [3-(2-benzenesulfonylbenzyl)-5-fluoro-2-methylindol-1-yl]acetic acid methyl ester (0.17 g), tetrahydrofuran (3.0 mL) and methanol (1.5 mL) was treated with 1.0 M aqueous sodium hydroxide solution (1.5 mL), and the resulting mixture was stirred at room temperature for 2 hours. The mixture was acidified by the addition of 1.0 M aqueous hydrochloric acid solution (1.5 mL) and concentrated under reduced pressure. The residue was dissolved in ethyl acetate, dried over magnesium sulfate and concentrated under reduced pressure to afford the title compound as a cream solid (0.13 g).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:16])[CH2:5][C:6]1[O:7][C:8]2[CH:14]=[CH:13][C:12]([CH3:15])=[CH:11][C:9]=2[CH:10]=1)[CH3:2].[H-].[Na+].Br[CH2:20][CH2:21][CH2:22][CH2:23]Br>CN(C=O)C.CCOC(C)=O>[CH2:1]([O:3][C:4]([C:5]1([C:6]2[O:7][C:8]3[CH:14]=[CH:13][C:12]([CH3:15])=[CH:11][C:9]=3[CH:10]=2)[CH2:23][CH2:22][CH2:21][CH2:20]1)=[O:16])[CH3:2]
Reactant: CCOC(=O)Cc1cc2cc(C)ccc2o1
Reactant: BrCCCCBr
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCOC(=O)C1(c2cc3cc(C)ccc3o2)CCCC1
Temperature: 80 °C
Reaction time: 0.25 h

Procedure:
To a solution of the product of Step 3, above (57) (1.85 mmol), in 2 ml DMF was added 60% sodium hydride in oil (3.6 mmol) at ambient temperature. The reaction mixture was stirred for 15 minutes and then 1,4-dibromobutane (1.85 mmol) was added. The reaction mixture was heated to 80° C. for 2 hours, cooled to ambient temperature, diluted with EtOAc and washed with saturated sodium bicarbonate and brine. The combined organics were then dried over MgSO4, filtered and concentrated to dryness. The crude material was chromatographed on silica gel using 10% EtOAc in hexanes as the eluant to obtain the title compound (58).