Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[C:3](=[O:10])[C:4]([OH:9])=[CH:5][C:6](=[O:8])[CH:7]=1.C(C1C(=O)C2=C3C=CC=CC3=CN=NC2=CC=1)C=C(CCC=C(CCC=C(C)C)C)C.C1C(C(O)=O)=C[C@@H](O)[C@@H](O)[C@@H]1N.P(OC[C@@H](O)[C@@H](O)C=O)(O)(O)=O.C(C(C(O)=O)=O)[C@@H](O)[C@H](O)[C@H](O)COP(O)(O)=O.P(OC[C@@H](O)[C@@H](O)[C@H](N)CC(=O)C(O)=O)(O)(O)=O.C=C(OP(O)(O)=O)C(O)=O.NC1C=C(C=C(O)C=1)C(O)=O.NC1C(O)=C(C=C(O)C=1)C(O)=O>>[NH2:1][C:2]1[CH:7]=[C:6]([OH:8])[CH:5]=[C:4]([OH:9])[C:3]=1[OH:10]
Reactant: NC1=CC(=O)C=C(O)C1=O
Agent: C=C(OP(=O)(O)O)C(=O)O
Agent: CC(C)=CCCC(C)=CCCC(C)=CCc1ccc2nncc3ccccc3c-2c1=O
Agent: N[C@@H]1CC(C(=O)O)=C[C@@H](O)[C@H]1O
Product: Nc1cc(O)cc(O)c1O

Procedure:
Biosynthesis of the 2-amino-6-hydroxy-benzoquinone component of the farnesyl dibenzodiazepinone, requires components derived from the aminoshikimate pathway. FIG. 7 depicts the series of enzymatic reactions involved in the biosynthesis of this constituent. ORF 21 (ALDB) (SEQ ID NO: 42) resembles aldolases involved in the generation of precursors of D-erythrose-4-phosphate which is part of the aminoshikimate pathway used for the generation of 2-amino-6-hydroxy-[1,4]-benzoquinone. ORF 33 (DAHP) (SEQ ID NO: 67) catalyzes the initial step in the aminoshikimate pathway that corresponds to the formation of 3,4-dideoxy-4-amino-D-arabino-heptulosonic acid 7-phosphate (amino DAHP) from phosphoenolpyruvate (PEP) and erythrose 4-phosphate (E-4Ph). Subsequent reactions leading to 3-amino-5-hydroxy-benzoic acid are catalyzed by enzymes provided by primary metabolism biosynthetic pathways present in Micromonospora sp. strain 046-ECO11. ORF 25 (HOXV) (SEQ ID NO: 50) hydroxylates 3-amino-5-hydroxy-benzoic acid at position 2, generating 3-amino-2,5-dihydroxy-benzoic acid. This intermediate is further modified by ORF 32 (HOYH) (SEQ ID NO: 65) that catalyzes a decarboxylative oxidation reaction yielding 6-amino-benzene-1,2,4-triol. A final oxidation reaction is performed by ORF 16 (OXDS) (SEQ ID NO: 32) yielding 2-amino-6-hydroxy-[1,4]-benzoquinone (FIG. 7).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=2[CH2:11][N:10]([CH2:18][CH2:19][C@H:20]2[CH2:22][O:21]2)[S:9]1(=[O:24])=[O:23].C(O)C.[CH3:28][NH2:29]>>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=2[CH2:11][N:10]([CH2:18][CH2:19][C@H:20]([OH:21])[CH2:22][NH:29][CH3:28])[S:9]1(=[O:23])=[O:24]
Reactant: CN
Reactant: O=S1(=O)N(CC[C@H]2CO2)Cc2ccccc2N1c1ccccc1F
Solvent: CCO
Product: CNC[C@@H](O)CCN1Cc2ccccc2N(c2ccccc2F)S1(=O)=O
Temperature: 100 °C
Yield: 80 %

Procedure:
1-(2-fluorophenyl)-3-{2-[(2S)-oxiran-2-yl]ethyl}-3,4-dihydro-1H-2,1,3-benzothiadiazine 2,2-dioxide (0.12 g, 0.29 mmol) was dissolved in an 8 M solution of methylamine in ethanol (3 mL, 24 mmol) and was heated to 100° C. for 192 sec. in the microwave. The reaction mixture was evaporated and the residue purified by flash chromatography (SiO2, 0-5% 7 M NH3-methanol/dichloromethane). The purified free-base was dissolved in dichloromethane (3 mL) and treated with hydrogen chloride (1.0 mL of a 2 M solution in ethyl ether), resulting in a white precipitate that was evaporated and dried under vacuum to provide (2S)-4-[1-(2-fluorophenyl)-2,2-dioxido-1,4-dihydro-3H-2,1,3-benzothiadiazin-3-yl]-1-(methylamino)butan-2-ol (0.10 g, 80%) as a white solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([CH3:13])=[C:5]([CH:10]=[CH:11][CH:12]=1)[C:6]([NH:8][NH2:9])=[O:7].[O:14]1[CH2:19][CH2:18][C:17](=O)[CH2:16][CH2:15]1>CCOCC.C(O)(=O)C.C(Cl)Cl.CO>[O:14]1[CH2:19][CH2:18][C:17](=[N:9][NH:8][C:6](=[O:7])[C:5]2[CH:10]=[CH:11][CH:12]=[C:3]([O:2][CH3:1])[C:4]=2[CH3:13])[CH2:16][CH2:15]1
Reactant: COc1cccc(C(=O)NN)c1C
Reactant: O=C1CCOCC1
Solvent: ClCCl
Solvent: CC(=O)O
Solvent: CO
Product: COc1cccc(C(=O)NN=C2CCOCC2)c1C
Yield: 83.5 %

Procedure:
3-methoxy-2-methyl-benzoic acid hydrazide (4.14 g, 23 mmol) was suspended in a mixture of 80 mL of ether, 40 mL of CH2Cl2 and 2 drops of acetic acid. A solution of tetrahydro-pyran-4-one (2.3 g, 23 mmol) in 20 mL of CH2Cl2 and 2-3 mL of methanol were added, and the mixture was refluxed for 10 minutes. The reaction mixture was allowed to cool and was concentrated to about 80 mL. Pentane (100 mL) was added, resulting in the formation of a precipitate. The suspension was chilled in a freezer and filtered to yield 5.04 g of 3-methoxy-2-methyl-benzoic acid (tetrahydro-pyran-4-ylidene)-hydrazide as a tan, flocculent, semi-crystalline material. 1H NMR (300 MHz, CDCl3)δ(ppm): 7.2 (t, 1H), 6.98 (d, 1H), 6.95 (d, 1H), 3.9 (t, 2H), 3.86 (s, 3H), 3.8 (t, 2H), 2.65 (t, 2H), 2.42 (t, 2H), 2.35 (s, 3); Rf=0.15 (3:1 ethyl acetate:hexane).
Reaction SMILES: Cl.Cl.[NH2:3][C:4]1[CH:26]=[CH:25][C:7]([CH2:8][CH2:9][N:10]2[CH2:19][CH2:18][C:17]3[C:12](=[CH:13][C:14]([O:22][CH3:23])=[C:15]([O:20][CH3:21])[CH:16]=3)[CH:11]2[CH3:24])=[CH:6][CH:5]=1.C(N(CC)CC)C.[C:34]([Cl:37])(=[O:36])[CH3:35].CCOCC>C(Cl)(Cl)Cl>[ClH:37].[C:34]([NH:3][C:4]1[CH:5]=[CH:6][C:7]([CH2:8][CH2:9][N:10]2[CH2:19][CH2:18][C:17]3[C:12](=[CH:13][C:14]([O:22][CH3:23])=[C:15]([O:20][CH3:21])[CH:16]=3)[CH:11]2[CH3:24])=[CH:25][CH:26]=1)(=[O:36])[CH3:35]
Reactant: COc1cc2c(cc1OC)C(C)N(CCc1ccc(N)cc1)CC2
Reactant: CC(=O)Cl
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Solvent: CCOCC
Product: COc1cc2c(cc1OC)C(C)N(CCc1ccc(NC(C)=O)cc1)CC2
Reaction time: 1 h
Yield: 31.5 %

Procedure:
A stirred suspension of N-(4-aminophenethyl)-1,2,3,4-tetrahydro-6,7-dimethoxy-1-methylisoquinoline dihydrochloride (11.9 g, 0.03 m) in chloroform (300 ml) under nitrogen at 0° C. was treated with triethylamine (3.5 g, 0.035 m) and then after 5 minutes with acetyl chloride (2.75 g, 0.035 m). The mixture was stirred for 1 hour, retreated with 3.5 g triethylamine and 2.75 g acetyl chloride and stirred an additional hour at 0°. Chloroform (50 ml) and then ether (100 ml) were added and the white solid precipitate collected by filtration, 13.9 g. The solid was dissolved in chloroform (250 ml), filtered to remove insoluble salts and the filtrate washed with cold 10% NaOH (200 ml) and cold water (2×200 ml) and dried over MgSO4. The solvent was carefully evaporated under vacuum at 20°. The residue was dissolved in 200 ml CHCl3 /100 ml ether, cooled in an ice-salt bath and slowly acidified with HCl gas. The precipitated solid was collected by filtration and recrystallized as above, filtering under nitrogen to protect the solid product from moisture and vacuum dried at 85° to give 3.8 g of N-(4-acetamidophenethyl)-1,2,3,4-tetrahydro-6,7-dimethoxy-1-methylisoquinoline hydrochloride, m.p. 150°-154°.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[CH:4][N:5]([C:7]2[CH:14]=[CH:13][C:12]([O:15][C:16]([F:19])([F:18])[F:17])=[CH:11][C:8]=2[C:9]#[N:10])[CH:6]=1.[CH3:20][N+:21]([CH3:23])=[CH2:22].[I-]>CN(C=O)C>[CH3:20][N:21]([CH2:23][C:6]1[N:5]([C:7]2[CH:14]=[CH:13][C:12]([O:15][C:16]([F:19])([F:17])[F:18])=[CH:11][C:8]=2[C:9]#[N:10])[CH:4]=[N:3][C:2]=1[CH3:1])[CH3:22]
Reactant: Cc1cn(-c2ccc(OC(F)(F)F)cc2C#N)cn1
Reactant: C=[N+](C)C
Agent: [I-]
Solvent: CN(C)C=O
Product: Cc1ncn(-c2ccc(OC(F)(F)F)cc2C#N)c1CN(C)C
Yield: 38 %

Procedure:
As described for example 84b, 2-(4-methyl-imidazol-1-yl)-5-trifluoromethoxy benzonitrile (+regioisomer) was reacted with Eschenmoser's salt in DMF for 24 h at 90° C. Evaporation of the solvent, aqueous workup and chromatography afforded the title compound as a colorless oil that was sufficiently pure to be used in the next step (yield: 38%). 1H-NMR (300 MHz, DMSO): δ=1.93 (s, 6H), 2.17 (s, 3H), 3.21 (s, 2H), 7.80-7.95 (m, 3H), 8.22 (s, 1H).
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:10](=[O:19])[NH:11][C:12]([CH3:18])=[CH:13][C:14]=1[C:15]([OH:17])=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[SH:20][C:21]1[S:22][CH2:23][CH2:24][N:25]=1.C1(N=C=NC2CCCCC2)CCCCC1>C1COCC1.CN(C1C=CN=CC=1)C>[CH2:1]([O:8][C:9]1[C:10](=[O:19])[NH:11][C:12]([CH3:18])=[CH:13][C:14]=1[C:15]([N:25]1[CH2:24][CH2:23][S:22][C:21]1=[S:20])=[O:17])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cc1cc(C(=O)O)c(OCc2ccccc2)c(=O)[nH]1
Reactant: SC1=NCCS1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: C1CCOC1
Product: Cc1cc(C(=O)N2CCSC2=S)c(OCc2ccccc2)c(=O)[nH]1
Reaction time: 1 h
Yield: 49.7 %

Procedure:
3-benzyloxy-4-carboxy-6-methyl-2(1H)-pyridinone (5.39 g, 21.1 mmol) was dissolved in dry THF (200 ml). Then 2-mercaptothiazoline (2.71 g, 23.2 mmol) and DMAP (0.25 g, 2.0 mmol) were added and the solution stirred under an atmosphere of N2 for 1 h. Then dicyclohexylcarbodiimide (DCC, 5.12 g, 25.3 mmol) was added in small portions at intervals split over 3 hrs. The reaction was left to stir for 16h, and then left to stand at 0° C. for a further 24 h. The dicyclohexylurea (DCU) was removed by filtration, and the solvents removed. The remaining residue was dissolved in CH2Cl2, filtered and purified by a gradient flash silica column (2-6% CH3OH in CH2Cl2). The solvents were removed from the appropriate fractions by rotary evaporation, and the residue recrystallized from acetone, yielding yellow crystals (3.78 g, 56%). 1H NMR (CDCl3, 300 MHz): δ=7.32-7.47 (m, 5H, aromatic Bn), 5.98 (s, 1H, CH), 5.34 (s, 2H, Bn CH2), 4.34 (t, J=7.3 Hz, 2H, CH2) 2.92 (t, J=7.3 Hz, 2H, CH2), 2.34 (s, 3H, CH3) ppm. Anal. Calcd (Found) for C17H16N2O3S2: C, 56.65 (56.50); H, 4.47 (4.51); N, 7.77 (7.70). FAB-MS (+): m/z: 361[M+H]+.
Reaction SMILES: CS(Cl)(=O)=O.[C:6]([O:10][C:11]([NH:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[NH:20][C:21](=[O:46])[C:22]1[CH:27]=[CH:26][C:25]([CH2:28][N:29]([CH2:42][CH2:43][CH2:44]O)[C:30]([NH:32][C:33]2[CH:38]=[CH:37][C:36]([N:39]([CH3:41])[CH3:40])=[CH:35][CH:34]=2)=[O:31])=[CH:24][CH:23]=1)=[O:12])([CH3:9])([CH3:8])[CH3:7].[CH2:47]([N:49](CC)[CH2:50]C)[CH3:48].C(NC)C>ClCCl.O>[C:6]([O:10][C:11]([NH:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[NH:20][C:21](=[O:46])[C:22]1[CH:27]=[CH:26][C:25]([CH2:28][N:29]([CH2:42][CH2:43][CH2:44][N:49]([CH2:47][CH3:48])[CH3:50])[C:30]([NH:32][C:33]2[CH:34]=[CH:35][C:36]([N:39]([CH3:40])[CH3:41])=[CH:37][CH:38]=2)=[O:31])=[CH:24][CH:23]=1)=[O:12])([CH3:9])([CH3:8])[CH3:7]
Reactant: CCN(CC)CC
Reactant: CN(C)c1ccc(NC(=O)N(CCCO)Cc2ccc(C(=O)Nc3ccccc3NC(=O)OC(C)(C)C)cc2)cc1
Agent: CCNC
Agent: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: O
Product: CCN(C)CCCN(Cc1ccc(C(=O)Nc2ccccc2NC(=O)OC(C)(C)C)cc1)C(=O)Nc1ccc(N(C)C)cc1
Reaction time: 7 h
Yield: 4 %

Procedure:
Under ice cooling, methanesulfonyl chloride (0.30 mL, 3.9 mmol) was added to a solution of N-(2-t-butoxycarbonylaminophenyl)-4-[3-(4-dimethylamino phenyl)-1-(3-hydroxypropyl)ureidomethyl]benzamide (Reference Compound No. 13-79, 200 mg, 0.36 mmol) and triethylamine (0.68 mL, 4.9 mmol) in anhydrous dichloromethane (5.0 mL), and then the reaction mixture was stirred for 7 hours. Water (100 mL) was added thereto, the whole was extracted with ethyl acetate (100 mL), and then the organic layer was washed with brine (100 mL). The organic layer was dried over anhydrous sodium sulfate, and then the solvent was evaporated under reduced pressure. Anhydrous dichloromethane (1.0 mL) and ethylmethylamine (0.03 mL, 0.35 mmol) were added to the residue, and then the mixture was stirred at room temperature for 5 hours. Water (50 mL) was added thereto, the whole was extracted with ethyl acetate (50 mL) and then the organic layer was washed with brine (50 mL). After the organic layer was dried over anhydrous sodium sulfate, the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform-methanol) to give 9.0 mg of the title reference compound as colorless oil. (Yield 4%)
Reaction SMILES: C([O:3][C:4](=O)[CH2:5][C:6]1[CH:7]=[C:8]([O:25][C:26]([F:29])([F:28])[F:27])[CH:9]=[C:10]2[C:15]=1[O:14][CH:13]([C:16]([F:19])([F:18])[F:17])[C:12]([C:20]([O:22]CC)=[O:21])=[CH:11]2)C.C1COCC1.C(O)C.[BH4-].[Na+].Cl>[Cl-].[Na+].O.O>[OH:3][CH2:4][CH2:5][C:6]1[CH:7]=[C:8]([O:25][C:26]([F:29])([F:27])[F:28])[CH:9]=[C:10]2[C:15]=1[O:14][CH:13]([C:16]([F:19])([F:18])[F:17])[C:12]([C:20]([OH:22])=[O:21])=[CH:11]2
Reactant: CCOC(=O)Cc1cc(OC(F)(F)F)cc2c1OC(C(F)(F)F)C(C(=O)OCC)=C2
Agent: Cl
Agent: [BH4-]
Agent: [Cl-]
Solvent: C1CCOC1
Solvent: O
Solvent: CCO
Product: O=C(O)C1=Cc2cc(OC(F)(F)F)cc(CCO)c2OC1C(F)(F)F
Temperature: 25 °C
Yield: 23 %

Procedure:
To a solution of crude ethyl 8-(2-ethoxy-2-oxoethyl)-6-(trifluoromethoxy)-2-(trifluoromethyl)-2H-chromene-3-carboxylate prepared as in Example 621s, Step 2. (2.10 g) in 1:1 THF-ethanol (100 mL) was added NaBH4 (3.00 g, 79.3 mmole) and the mixture was stirred at room temperature for lh. Additional NaBH4 (3.00 g, 79.3 mmole) was then added and the mixture was stirred for 4 hrs. Additional NaBH4 (3.00 g, 79.3 mmole) was then added and the mixture was stirred for 3hrs. H2O (50 mL) was added and the mixture was stirred for 30 minutes. Brine (100 mL) was added; the mixture was acidified with 1N HCl and extracted with EtOAc (2×200 mL). The combined extracts were washed with brine (100 mL), dried over MgSO4, filtered and concentrated in vacuo. The crude product was purified by silica chromatography (25% EtOAc/1% HOAc in hexanes to 100% EtOAc/1% HOAc in hexanes) to give an off-white crystalline solid. Recrystallization from EtOAc-hexanes gave 427 mg (23% yield) of the product as an off-white crystalline solid: ESHRMS m/z 371.0334 (M−H, C14H9F6O5, Calc'd 371.0354); 1H NMR (dmso-d6/300 MHz) 13.40 (brs, 1H), 7.88 (s, 1H), 7.45 (d, 1H, J=2.2 Hz), 7.28 (d, 1H, J=2.4 Hz), 5.99 (q, 1H, J=7.3 Hz), 4.70 (s, 1H), 3.57 (s, 2H), 2.77-2.71 (m, 2H).
Reaction SMILES: [C:1]1([N:7]2[C:11]([NH2:12])=[CH:10][C:9]([C:13]3([C:16]([F:19])([F:18])[F:17])[CH2:15][CH2:14]3)=[N:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH-].[Na+].Cl.[C:23]1(C)C=CC(NN)=CC=1>CCO.O>[C:4]1([CH3:23])[CH:3]=[CH:2][C:1]([N:7]2[C:11]([NH2:12])=[CH:10][C:9]([C:13]3([C:16]([F:18])([F:19])[F:17])[CH2:15][CH2:14]3)=[N:8]2)=[CH:6][CH:5]=1
Reactant: Nc1cc(C2(C(F)(F)F)CC2)nn1-c1ccccc1
Reactant: Cc1ccc(NN)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: Cc1ccc(-n2nc(C3(C(F)(F)F)CC3)cc2N)cc1
Temperature: 80 °C
Yield: 57.4 %

Procedure:
To a solution of 3-oxo-3-(1-(trifluoromethyl)cyclopropyl)propanenitrile (500 mg, 2.8 mmol) (from Example 137A Step 2) in EtOH (10 mL) was added water (7.2 mL) and 1 M NaOH (2.8 mL) followed by p-tolylhydrazine hydrochloride (444 mg, 2.8 mmol) and the solution heated at 80° C. overnight. The solution was cooled to rt, diluted with water and extracted with 2 portions of EtOAc. The combined extracts were washed with brine, dried over magnesium sulfate, filtered, and concentrated. The crude solid was purified using silica gel chromatography using a gradient of 5-25% EtOAc/hexane to give 1-p-tolyl-3-(1-(trifluoromethyl)cyclopropyl)-1H-pyrazol-5-amine (452 mg, 57% yield). LC-MS (ESI) m/z 282 (M+H)+
Reaction SMILES: C(OC([N:11]1[C:15](=[O:16])[CH2:14][CH2:13][C@H:12]1[C:17]([N:19]([CH3:30])[C@H:20]([C:27]([OH:29])=O)[CH2:21][C:22]1[N:26]=[CH:25][NH:24][CH:23]=1)=[O:18])=O)C1C=CC=CC=1.[CH3:31][C@H:32]1[CH2:36][CH2:35][NH:34][C@@H:33]1[C:37]([NH2:39])=[O:38]>CN(C)C=O>[NH:11]1[C:15](=[O:16])[CH2:14][CH2:13][C@H:12]1[C:17]([N:19]([CH3:30])[C@H:20]([C:27]([N:34]1[CH2:35][CH2:36][C@H:32]([CH3:31])[C@H:33]1[C:37]([NH2:39])=[O:38])=[O:29])[CH2:21][C:22]1[N:26]=[CH:25][NH:24][CH:23]=1)=[O:18]
Reactant: CN(C(=O)[C@@H]1CCC(=O)N1C(=O)OCc1ccccc1)[C@@H](Cc1c[nH]cn1)C(=O)O
Reactant: C[C@H]1CCN[C@@H]1C(N)=O
Solvent: CN(C)C=O
Product: C[C@H]1CCN(C(=O)[C@H](Cc2c[nH]cn2)N(C)C(=O)[C@@H]2CCC(=O)N2)[C@@H]1C(N)=O
Yield: 46.1 %

Procedure:
This was prepared from benzyloxycarbonyl-L-pyroglutamyl-Nα -methyl-L-histidine (207 mg) and trans-3-methyl-L-prolineamide (77 mg) by the method of Example 2(vi) to yield a white hydroscopic solid (90 mg) RF 3A m.p. 135°-140° RF 3B 0.60 (Found C, 55.0; H, 7.0; N, 21.2; C18H23N6O4 requires C, 55.4; H, 6.7; N, 21.5%) [α]D22 - 23.9° (c = 1, dimethylformamide).
Reaction SMILES: C[O:2][C:3](=[O:40])[CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][C:13]2[CH:18]=[CH:17][C:16]([CH2:19][CH:20]([NH:32][C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])[C:21]([N:23]3[CH2:28][CH2:27][N:26]([C:29](=[O:31])[CH3:30])[CH2:25][CH2:24]3)=[O:22])=[CH:15][CH:14]=2)=[CH:8][CH:7]=1.[OH-].[Li+]>C1COCC1.O>[C:29]([N:26]1[CH2:27][CH2:28][N:23]([C:21](=[O:22])[CH:20]([NH:32][C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])[CH2:19][C:16]2[CH:17]=[CH:18][C:13]([O:12][C:9]3[CH:10]=[CH:11][C:6]([CH2:5][CH2:4][C:3]([OH:40])=[O:2])=[CH:7][CH:8]=3)=[CH:14][CH:15]=2)[CH2:24][CH2:25]1)(=[O:31])[CH3:30]
Reactant: COC(=O)CCc1ccc(Oc2ccc(CC(NC(=O)OC(C)(C)C)C(=O)N3CCN(C(C)=O)CC3)cc2)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CC(=O)N1CCN(C(=O)C(Cc2ccc(Oc3ccc(CCC(=O)O)cc3)cc2)NC(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 89.3 %

Procedure:
The amide compound 18 (2.3 g, 4.15 mmol) was dissolved in THF (20 mL) and diluted with water (20 mL). Lithium hydroxide (0.4 g, 17.0 mmol) was added and the reaction mixture was stirred at room temperature for about 2 h. The THF was evaporated and the resulting aqueous layer was acidified with 2.0 M HCl and extracted into EtOAc (2×30 mL). The organic layer was washed with water (1×40 mL) and brine (1×40 mL), dried and concentrated to yield the desired acid compound 19 (2.0 g, 89%). 1H NMR (400 MHz, DMSO-d6): 7.16 (overlapped d, J=8.4 Hz, 2H), 7.15 (overlapped d, J=8.8 Hz, 2H), 6.91 (d, J=8.0 Hz, 2H), 6.86 (d, J=8.0 Hz, 2H), 5.47 (dd, J=12.8 and 8.4 Hz, 1H), 4.81 (m, 1H), 4.81 (m, 1H), 3.32-3.57 (m, 6H), 2.92-3.00 (m, 6H), 2.66 (t, J=6.8 Hz, 2H), 2.08 (d, J=7.6 Hz, 3H), 1.43 (s, 9H).
Reaction SMILES: [CH3:1][C:2]1[C:10]2[CH2:9][O:8][C:7](=[O:11])[C:6]=2[C:5]([CH3:12])=[CH:4][C:3]=1[CH:13]=[CH2:14].C1C=C(Cl)C=C(C(OO)=[O:23])C=1>C(Cl)Cl>[CH3:1][C:2]1[C:10]2[CH2:9][O:8][C:7](=[O:11])[C:6]=2[C:5]([CH3:12])=[CH:4][C:3]=1[CH:13]1[CH2:14][O:23]1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: C=Cc1cc(C)c2c(c1C)COC2=O
Solvent: ClCCl
Product: Cc1cc(C2CO2)c(C)c2c1C(=O)OC2
Temperature: 25 °C
Reaction time: 48 h

Procedure:
To a solution of 4,7-dimethyl-5-vinyl-2-benzofuran-1(3H)-one (0.4 g, 2.1 mmol) in 60 mL of DCM was slowly added mCPBA (85%, 0.7 g, 4.2 mmol) at 0° C. After warming to room temperature, the mixture was stirred for 48 hours. The mixture was washed subsequently with saturated NaHCO3, aqueous Na2SO3, 5% NaOH and brine. The mixture was concentrated and the residue was purified by column chromatography to afford 4,7-dimethyl-5-oxiran-2-yl-2-benzofuran-1(3H)-one as white solid.
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH:6]12[O:12][CH:7]1[CH2:8][CH2:9][CH2:10][CH2:11]2>O>[N:1]1([C@H:6]2[CH2:11][CH2:10][CH2:9][CH2:8][C@@H:7]2[OH:12])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: C1CCNC1
Reactant: C1CCC2OC2C1
Solvent: O
Product: O[C@H]1CCCC[C@@H]1N1CCCC1
Yield: 87.4 %

Procedure:
Pyrrolidine (10.5 g, 148 mmol), cyclohexene oxide (15 mL, 148 mmol) and water (5 mL) were refluxed under nitrogen for 7h. The cooled, orange mixture was partitioned between saturated sodium hydroxide aq (150 mL) and diethyl ether (150 mL). The aqueous layer was back-washed with diethyl ether (75 ML) and the combined diethyl ether layers were dried over sodium sulfate. The diethyl ether was removed in vacuo the residual oil was vacuum distilled (bp 51° C. at full vacuum) to give (1R,2R)/(1S,2S)-2-(Pyrrolidinyl)cyclohexan-1-ol (21.9 g, 87%). 13C NMR (50 MHz, APT, CDCl3) δ 70.47 (−), 64.82 (−), 47.44 (+), 33.15 (+), 25.11 (+), 24.23 (+), 24.00 (+), 21.12 (+).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]1[CH2:17][C:16]([CH3:19])([CH3:18])[C:15]2[C:10](=[CH:11][CH:12]=[C:13]([C:20]#[N:21])[CH:14]=2)[NH:9]1.[CH3:22][CH:23]([S:25](Cl)(=[O:27])=[O:26])[CH3:24]>N1C=CC=CC=1.O>[C:20]([C:13]1[CH:14]=[C:15]2[C:10](=[CH:11][CH:12]=1)[NH:9][CH:8]([C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[NH:1][S:25]([CH:23]([CH3:24])[CH3:22])(=[O:27])=[O:26])[CH2:17][C:16]2([CH3:18])[CH3:19])#[N:21]
Reactant: CC(C)S(=O)(=O)Cl
Reactant: CC1(C)CC(c2ccccc2N)Nc2ccc(C#N)cc21
Solvent: c1ccncc1
Solvent: O
Product: CC(C)S(=O)(=O)Nc1ccccc1C1CC(C)(C)c2cc(C#N)ccc2N1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of 2-(2-aminophenyl)-4,4-dimethyl-1,2,3,4-tetrahydroquinoline-6-carbonitrile (500 mg, 1.8 mmol) in pyridine (3 mL) was added propane-2-sulfonyl chloride (201 μL, 1.8 mmol) at ice-bath under nitrogen. After addition, the resulting mixture was stirred at room temperature for 3 h. The reaction mixture was diluted with water, and extracted with ethyl acetate. The combined organic layer was dried over anhydrous sodium sulfate, concentrated. The residue was purified by HPLC to give propane-2-sulfonic acid [2-(6-cyano-4,4-dimethyl-1,2,3,4-tetrahydro-quinolin-2-yl)-phenyl]-amide LC/MS m/e obsd. (ESI+) [(M+H)+] 384.3.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6](I)[C:5]([F:9])=[C:4]([Cl:10])[C:3]=1[F:11].C([Mg]Cl)(C)C.[F:17][C:18]([F:25])([F:24])[C:19](OCC)=[O:20]>O1CCCC1.COC(C)(C)C>[Cl:10][C:4]1[C:5]([F:9])=[C:6]([C:19](=[O:20])[C:18]([F:25])([F:24])[F:17])[CH:7]=[C:2]([Cl:1])[C:3]=1[F:11]
Reactant: CCOC(=O)C(F)(F)F
Reactant: Fc1c(Cl)cc(I)c(F)c1Cl
Agent: CC(C)[Mg]Cl
Solvent: COC(C)(C)C
Solvent: C1CCOC1
Product: O=C(c1cc(Cl)c(F)c(Cl)c1F)C(F)(F)F
Temperature: 25 °C
Reaction time: 1 h
Yield: 69.2 %

Procedure:
1,3-Dichloro-2,4-difluoro-5-iodobenzene (4.0 g) was dissolved in tetrahydrofuran and cooled to −10 degree. A 2.0 M solution of isopropylmagnesium chloride in tetrahydrofuran (10 ml) was added dropwise via a dropping funnel. The reaction mixture was stirred for 1 hour at same temperature. A solution of ethyl trifluoroacetate (2.76 g) in tetrahydrofuran (6 ml) was added dropwise and the reaction mixture was allowed to warm to ambient temperature. The reaction mixture was diluted with t-butyl methyl ether and washed with 1 N NaOH and then brine. The combined extracts were dried over magnesium sulfate. After filtered off, the filtrate was concentrated in vacuo to give crude product which was purified with Kugel-Rohr to give 1-(3,5-dichloro-2,4-difluorophenyl)-2,2,2-trifluoroethanone (2.5 g).
Reaction SMILES: Br[CH:2]1[S:6][C:5](=[O:7])[NH:4][C:3]1=[O:8].[SH:9][C:10]1[O:11][C:12]2[CH:18]=[CH:17][CH:16]=[CH:15][C:13]=2[N:14]=1>>[O:11]1[C:12]2[CH:18]=[CH:17][CH:16]=[CH:15][C:13]=2[N:14]=[C:10]1[S:9][CH:2]1[S:6][C:5](=[O:7])[NH:4][C:3]1=[O:8]
Reactant: O=C1NC(=O)C(Br)S1
Reactant: Sc1nc2ccccc2o1
Product: O=C1NC(=O)C(Sc2nc3ccccc3o2)S1

Procedure:
This compound was prepared from 5-bromo-thiazolidine-2,4-dione and 2-mercaptobenzoxazole according to the procedure described in Example 5: mp 241-243 (dec).
Reaction SMILES: [Li].[C:2]([C:4]1[CH:11]=[CH:10][CH:9]=[CH:8][C:5]=1[CH:6]=O)#[N:3].[Br-].[O:13]1CCO[CH:14]1[CH2:18][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.O>CO.CN(C)C=O>[C:2]([C:4]1[CH:11]=[CH:10][CH:9]=[CH:8][C:5]=1/[CH:6]=[CH:18]/[CH:14]=[O:13])#[N:3]
Reactant: N#Cc1ccccc1C=O
Reactant: c1ccc([P+](CC2OCCO2)(c2ccccc2)c2ccccc2)cc1
Agent: [Br-]
Agent: [Li]
Solvent: CO
Solvent: O
Solvent: CN(C)C=O
Product: N#Cc1ccccc1/C=C/C=O
Temperature: 85 °C
Reaction time: 6 h
Yield: 45 %

Procedure:
A solution of lithium (77 mg) in methanol (30 ml) was added during 2 hours to a stirred suspension of 2-cyanobenzaldehyde and (1,3-dioxolan-2-yl-methyl)-triphenyl phosphonium bromide (4.71 g) in dimethylformamide (34 ml) at 85° C. The mixture was stirred at 85° C. for 6 hours, allowed to cool and poured into water (450 ml). The reaction mixture was extracted with diethyl ether (3×120 ml) and the combined ether extracts washed with saturated brine, dried (MgSO4) and evaporated. The residue was dissolved and stirred in tetrahydrofuran (30 ml) and 3M hydrochloric acid (30 ml) for 2 hours. The mixture was diluted with water (100 ml) and extracted with diethyl ether (300 ml). The ether was washed with saturated sodium hydrogen carbonate solution (2×50 ml) and saturated brine, dried (MgSO4) and evaporated. The residue was purified by flash column chromatography on silica, eluting with n-hexane-ethyl acetate (80:20:, by volume) to give as a pale yellow solid 2-cyano-(E)-cinnamaldehyde (504 mg, 45%) m.p. 107°-110° C.; NMR: 6.82 (1H,q), 7.69 (5H,m) and 9.81 (1H,d); m/e 157 (M+).