Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.C[O:3][C:4](=O)[CH2:5][NH2:6].[OH-].[Na+].[C:10](=[NH:17])(OC)[CH2:11][CH2:12][CH2:13][CH3:14].CO[CH:20](OC)[N:21]([CH3:23])[CH3:22]>CO>[CH2:11]([C:10]1[NH:17][C:4](=[O:3])[C:5](=[CH:20][N:21]([CH3:23])[CH3:22])[N:6]=1)[CH2:12][CH2:13][CH3:14]
Reactant: COC(OC)N(C)C
Reactant: COC(=O)CN
Reactant: CCCCC(=N)OC
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CCCCC1=NC(=CN(C)C)C(=O)N1
Reaction time: 0.25 h
Yield: 87 %

Procedure:
5.00 g (39.42 mmol) of glycine methyl ester hydrochloride was added in a single portion to a solution of 1.59 g (39.42 mmol) of sodium hydroxide in 13 ml of methanol at 0° C. The temperature dropped to -10° C. The mixture was then stirred for 15 minutes and during this time the temperature rose again to 0° C. 4.73 g (39.42 mmol) of methyl pentanimidate was added, and the mixture was stirred at room temperature for 3 hours. Then, during the course of 5 minutes, 5.62 g (43.39 mmol) of N,N-dimethylformamide dimethyl acetal was added, and the reaction mixture was stirred for a further 3 hours. Thereafter, solvent was removed on a Rotavapor, and the residue was treated with 40 ml of CH2Cl2 and 15 ml of water. After phase separation, the organic phase was washed with 10 ml of water, and then the combined H2O phases were washed twice, each time with 20 ml of CH2Cl2. Then, the combined organic phases were dried (MgSO4), filtered, concentrated on the Rotavapor and dried in a high vacuum. 6.70 g of 2-butyl-4-dimethylaminomethylene-2-imidazolin-5-one was obtained, having a content of about 90 percent, according to 1H-NMR. This corresponds to a yield of about 78 percent, based on the methyl pentanimidate.
Reaction SMILES: [N:1]1[NH:2][CH:3]=[C:4]2[CH2:8][N:7]([C@H:9]3[CH2:14][S:13](=[O:15])[CH:12]([C:16]4[CH:21]=[C:20]([F:22])[CH:19]=[C:18]([F:23])[C:17]=4[F:24])[C@@H:11]([NH:25]C(=O)OC(C)(C)C)[CH2:10]3)[CH2:6][C:5]=12.[C:33]([OH:39])([C:35]([F:38])([F:37])[F:36])=[O:34]>C(Cl)Cl>[F:36][C:35]([F:38])([F:37])[C:33]([OH:39])=[O:34].[N:1]1[NH:2][CH:3]=[C:4]2[CH2:8][N:7]([C@H:9]3[CH2:14][S:13](=[O:15])[CH:12]([C:16]4[CH:21]=[C:20]([F:22])[CH:19]=[C:18]([F:23])[C:17]=4[F:24])[C@@H:11]([NH2:25])[CH2:10]3)[CH2:6][C:5]=12
Reactant: CC(C)(C)OC(=O)N[C@H]1C[C@@H](N2Cc3c[nH]nc3C2)CS(=O)C1c1cc(F)cc(F)c1F
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: N[C@H]1C[C@@H](N2Cc3c[nH]nc3C2)CS(=O)C1c1cc(F)cc(F)c1F
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
tert-Butyl N-[(3S,5R)-5-(4,6-dihydro-2H-pyrrolo[3,4-c]pyrazol-5-yl)-1-oxo-2-(2,3,5-trifluorophenyl)thian-3-yl]carbamate was dissolved in a mixture of TFA (0.02 mL) and methylene chloride (0.2 mL). After stirring at RT for 30 min, additional TFA (0.02 mL) was added and the mixture was stirred an additional 60 min at room temperature. The solvents were evaporated and the residue was freeze-dried from a mixture of benzene and ethanol to give the title compound as a white solid.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][C:11]=1[CH:12]1[CH2:15][CH2:14][CH2:13]1)[C:5]([O:7]C)=[O:6].[OH-].[Na+].CO>O>[NH2:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][C:11]=1[CH:12]1[CH2:13][CH2:14][CH2:15]1)[C:5]([OH:7])=[O:6]
Reactant: COC(=O)c1ccc(C2CCC2)c(N)c1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: Nc1cc(C(=O)O)ccc1C1CCC1
Temperature: 20 °C
Reaction time: 8 h
Yield: 53.7 %

Procedure:
Into around-bottom flask, was placed a solution of methyl 3-amino-4-cyclobutylbenzoate (1.00 g, 4.87 mmol, 1.00 equiv) and sodium hydroxide (compound 443.2, 800 mg, 20.0 mmol, 4.00 equiv) in a solvent mixture of methanol and H2O (20/10 mL). The resulting solution was stirred for 8 h at 20° C. After cooling to ambient temperature, the organic solvent was removed under reduced pressure. The pH of the remaining aqueous layer was adjusted to ˜4-5 with HCl (aqueous, 1 M). The resulting precipitate was then collected by filtration and dried to furnish 500 mg (54%) of the title compound as a white solid.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:18]=[C:17]2[C:12]([C:13](Cl)=[CH:14][CH:15]=[N:16]2)=[CH:11][C:10]=1[O:20][CH3:21])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:22][C:23]1[CH:28]=[C:27]([N+:29]([O-:31])=[O:30])[CH:26]=[CH:25][C:24]=1[OH:32].ClC1C=CC=CC=1>C(=O)([O-])[O-].[Na+].[Na+]>[CH2:1]([O:8][C:9]1[CH:18]=[C:17]2[C:12]([C:13]([O:32][C:24]3[CH:25]=[CH:26][C:27]([N+:29]([O-:31])=[O:30])=[CH:28][C:23]=3[F:22])=[CH:14][CH:15]=[N:16]2)=[CH:11][C:10]=1[O:20][CH3:21])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COc1cc2c(Cl)ccnc2cc1OCc1ccccc1
Reactant: O=[N+]([O-])c1ccc(O)c(F)c1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Clc1ccccc1
Product: COc1cc2c(Oc3ccc([N+](=O)[O-])cc3F)ccnc2cc1OCc1ccccc1
Yield: 38.8 %

Procedure:
A mixture of 7-benzyloxy-4-chloro-6-methoxy-quinoline (2.04 g, 6.8 mmol), 2-fluoro-4-nitrophenol (2.34 g 14.9 mmol) and chlorobenzene (40 ml) was stirred at reflux temperature for 2 days. The reaction mixture was cooled, diluted with saturated sodium carbonate solution (30 ml) and stirred for 3 hours. The precipitate was filtered and the filtrate was separated. The aqueous layer was extracted with chloroform (3×30 ml). The organic layers were combined, washed with water and dried over sodium sulfate. The solvent was removed by evaporation under the reduced pressure. The residue was purified by column chromatography. The pure product was solidified under diisopropyl ether to give 1.11 g of product [F]. Yield: 39%.
Reaction SMILES: [CH2:1]([N:8]1[CH2:18][CH2:17][C:11]2[N:12]=[CH:13][NH:14][C:15](=O)[C:10]=2[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O=P(Cl)(Cl)[Cl:21]>>[CH2:1]([N:8]1[CH2:18][CH2:17][C:11]2[N:12]=[CH:13][N:14]=[C:15]([Cl:21])[C:10]=2[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=c1[nH]cnc2c1CN(Cc1ccccc1)CC2
Reactant: O=P(Cl)(Cl)Cl
Product: Clc1ncnc2c1CN(Cc1ccccc1)CC2

Procedure:
Various N-substituted 2-(4-amino-7,8-dihydropyrido[4,3-d]pyrimidin-6(5H)-yl)benzonitriles are prepared using a general procedure shown above (Scheme 2). 6-Benzyl-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-4(3H)-one is treated with POCl3 to give 6-benzyl-4-chloro-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidine which is treated with sodium methoxide to give 6-benzyl-4-methoxy-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidine. Debenzylation and reacting the product with an appropriate 2-halo-benzonitrile under SNAR or Buchwald coupling reaction conditions give the 2-(4-methoxy-7,8-dihydropyrido[4,3-d]pyrimidin-6(5H)-yl)benzonitrile which is reacted with POCl3 or POBr3. Displacement of the resultant 4-chloro or 4-bromo group using appropriately substituted amines via SNAR displacement affords various N-substituted 2-(4-amino-7,8-dihydropyrido[4,3-d]pyrimidin-6(5H)-yl)benzonitriles.
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:10]=[N:9][C:8]([CH2:11][O:12][C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([O:19][C:20]([F:23])([F:22])[F:21])[CH:14]=2)=[CH:7][N:6]=1)=[O:4].[Li+].[OH-]>C1COCC1.CO.O>[F:23][C:20]([F:21])([F:22])[O:19][C:15]1[CH:14]=[C:13]([CH:18]=[CH:17][CH:16]=1)[O:12][CH2:11][C:8]1[N:9]=[CH:10][C:5]([C:3]([OH:4])=[O:2])=[N:6][CH:7]=1
Reactant: COC(=O)c1cnc(COc2cccc(OC(F)(F)F)c2)cn1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: O=C(O)c1cnc(COc2cccc(OC(F)(F)F)c2)cn1
Yield: 81.4 %

Procedure:
A solution of 5-(3-trifluoromethoxy-phenoxymethyl)-pyrazine-2-carboxylic acid methyl ester (0.234 g, 0.712 mmol) in THF:MeOH (4:1, 5 mL) was treated with LiOH (0.150 g, 3.564 mmol) in 1.5 mL of water by the general procedure C to give 0.182 g of 5-(3-trifluoromethoxy-phenoxymethyl)-pyrazine-2-carboxylic acid. LCMS: 316 (M+2)+
Reaction SMILES: [Cl:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[C:4]([Cl:11])[C:3]=1[CH2:12][C:13]([OH:15])=O.[NH2:16][C:17]1[CH:24]=[CH:23][CH:22]=[CH:21][C:18]=1[CH:19]=[O:20]>S(Cl)(Cl)=O.ClCCl.CCOC(C)=O>[Cl:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[C:4]([Cl:11])[C:3]=1[CH2:12][C:13]([NH:16][C:17]1[CH:24]=[CH:23][CH:22]=[CH:21][C:18]=1[CH:19]=[O:20])=[O:15]
Reactant: O=C(O)Cc1c(Cl)ccc([N+](=O)[O-])c1Cl
Reactant: Nc1ccccc1C=O
Solvent: CCOC(C)=O
Solvent: O=S(Cl)Cl
Solvent: ClCCl
Product: O=Cc1ccccc1NC(=O)Cc1c(Cl)ccc([N+](=O)[O-])c1Cl
Temperature: 25 °C
Reaction time: 2 h
Yield: 88.1 %

Procedure:
A solution of (2,6-dichloro-3-nitro-phenyl)-acetic acid (0.90 g, 3.35 mmol) in thionyl chloride (15 mL) is refluxed for one hour. The solvent is removed by concentration and dry toluene is added to thoroughly remove thionyl chloride. To the solution of acid chloride in dry dichloromethane (30 mL) is added (drop-wise) a solution of 2-aminobenzaldehyde (0.365 g, 3.02 mmol) in dichloromethane (5.0 mL). The mixture is stirred at room temperature for 2 hours. The reaction mixture is diluted with EtOAc and washed with saturated K2CO3 and brine. The organic layer is dried, filtered and concentrated to give crude product (0.94 g, 88.6%).
Reaction SMILES: [C:1]([N:5]1[C:9]([C:10]2[S:11][CH:12]=[CH:13][CH:14]=2)=[CH:8][C:7]([CH2:15][CH2:16][CH:17]=O)=[N:6]1)([CH3:4])([CH3:3])[CH3:2].[Cl:19][C:20]1[CH:25]=[CH:24][C:23]([N:26]2[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]2)=[CH:22][CH:21]=1.CCN(C(C)C)C(C)C.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>>[C:1]([N:5]1[C:9]([C:10]2[S:11][CH:12]=[CH:13][CH:14]=2)=[CH:8][C:7]([CH2:15][CH2:16][CH2:17][N:29]2[CH2:28][CH2:27][N:26]([C:23]3[CH:22]=[CH:21][C:20]([Cl:19])=[CH:25][CH:24]=3)[CH2:31][CH2:30]2)=[N:6]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)n1nc(CCC=O)cc1-c1cccs1
Reactant: Clc1ccc(N2CCNCC2)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)n1nc(CCCN2CCN(c3ccc(Cl)cc3)CC2)cc1-c1cccs1

Procedure:
77 mg (73%) of target compound was obtained by using a method same as in Example 1 by using 3-(1-tert-butyl-5-(thiophene-2-yl)-1H-pyrazol-3-yl)propanal (50 mg, 0.191 mmol), 1-(4-chlorophenyl)piperazine (34 mg, 0.191 mmol), DIPEA (0.050 mL, 0.287 mmol) and NaBH(OAc)3 (121 mg, 0.573 mmol).
Reaction SMILES: [CH3:1][C:2]([C:6]1[CH:11]=[CH:10][C:9]([C:12]([F:15])([F:14])[F:13])=[CH:8][C:7]=1[N+:16]([O-])=O)([CH3:5])[CH2:3]N.C=O.[C:21](O)(=O)C.[C:25]([BH3-])#[N:26].[Na+]>CO.O.ClCCl>[CH3:21][N:26]([CH3:25])[CH2:1][C:2]([C:6]1[CH:11]=[CH:10][C:9]([C:12]([F:15])([F:14])[F:13])=[CH:8][C:7]=1[NH2:16])([CH3:5])[CH3:3]
Reactant: CC(=O)O
Reactant: [BH3-]C#N
Reactant: CC(C)(CN)c1ccc(C(F)(F)F)cc1[N+](=O)[O-]
Agent: C=O
Agent: [Na+]
Solvent: ClCCl
Solvent: CO
Solvent: O
Product: CN(C)CC(C)(C)c1ccc(C(F)(F)F)cc1N
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 2-Methyl-2-(2-nitro-4-trifluoromethyl-phenyl)-propylamine (0.76 g, 2.9 mmol) in methanol (29 mL) at 0 degrees C. was added formaldehyde (0.60 mL of a 37 wt solution in water, excess), acetic acid (0.83 mL, 14.5 mmol), and sodium cyanoborohydride (0.36 g, 5.8 mmol). The homogeneous yellow solution was allowed to warm to room temperature and was stirred overnight. After approximately 12 h, the reaction was quenched by the addition of saturated aqueous sodium bicarbonate until basic. The mixture was concentrated in vacuo, and the resulting material was partitioned between ethyl acetate and saturated aqueous sodium bicarbonate. The organic layer was washed once with brine, dried over sodium sulfate, filtered, and concentrated in vacuo to give a yellow oil which contained solid material. The oil was dissolved in dichloromethane and filtered through a plug of cotton. Purification by flash chromatography provided the title compound as a yellow oil. MS m/z 291=[M+H]+. Calc'd for C13H17F3N2O2: 290.29.
Reaction SMILES: [F:1][S:2]([F:14])([F:13])([F:12])([F:11])[C:3]1[CH:10]=[CH:9][C:6]([CH:7]=O)=[CH:5][CH:4]=1.C(O)(=O)[CH2:16][C:17]([OH:19])=[O:18].N1CCCCC1.C(=O)=O.Cl>N1C=CC=CC=1>[F:1][S:2]([F:14])([F:13])([F:12])([F:11])[C:3]1[CH:10]=[CH:9][C:6]([CH:7]=[CH:16][C:17]([OH:19])=[O:18])=[CH:5][CH:4]=1
Reactant: O=Cc1ccc(S(F)(F)(F)(F)F)cc1
Reactant: O=C(O)CC(=O)O
Agent: Cl
Agent: O=C=O
Solvent: c1ccncc1
Solvent: C1CCNCC1
Product: O=C(O)C=Cc1ccc(S(F)(F)(F)(F)F)cc1
Temperature: 0 °C

Procedure:
A mixture of 5.40 g (23.3 mmol) 4-pentafluorosulfanyl-benzaldehyde, 2.42 g (23.3 mmol) malonic acid, 0.20 g (2.3 mmol) piperidine and 10.0 ml pyridine was kept at reflux temperature until carbon dioxide development ceased (4 h). The reaction mixture was poured into a solution of 100 ml ice and 60 ml 6N HCl. The precipitate was isolated, washed with water, then with n-heptane and dried in vacuum at 40° C. Yield: 5.73 g (90%) 3-(4-pentafluorosulfanyl-phenyl)-acrylic acid.
Reaction SMILES: [C:1]1([Mg][Br:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(OCC)C.[C:14]1([S:20]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=O)[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.Br>C1C=CC=CC=1.CCCCCCC>[Br-:8].[C:1]1([S+:20]([C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=S(c1ccccc1)c1ccccc1
Reactant: Br[Mg]c1ccccc1
Agent: Br
Solvent: c1ccccc1
Solvent: CCCCCCC
Solvent: CCOCC
Product: [Br-]
Product: c1ccc([S+](c2ccccc2)c2ccccc2)cc1
Temperature: 25 °C
Yield: 60 %

Procedure:
A 3.0 M solution of phenylmagnesium bromide in diethyl ether (50 ml, 0.15 mole) was distilled under vacuum with slow heating from 20° to 80° C. Benzene (40 ml) was added, followed by n-heptane (300 ml). The resulting mixture was stirred and a solution of diphenylsulfoxide 10.1 g, (0.050 mol), in benzene (60 ml) was added during 1 hour at 80° C. The mixture was stirred for 3 hours and cooled to room temperature. An 25% aqueous hydrobromic acid solution (180 ml) was slowly added to the reaction mixture (exotherm-). The layers were separated and the organic layer was extracted twice with 5% aqueous hydrobromic acid (2 x 30 ml). The combined aqueous extracts were extracted three times with dichloromethane (3×250 ml). The dichloromethane extracts were dried over magnesium sulfate, filtered and the organic solvent evaporated to leave triphenylsulfonium bromide (10.2 g, 60%), which was crystallized from dichloromethane/diethyl ether. M.p. 285-7 ° C.
Reaction SMILES: [Cl:1][C:2]1[CH:22]=[C:21]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH:20]=[CH:19][C:3]=1[CH2:4][C:5]1[C:13]2[C:8](=[CH:9][CH:10]=[C:11]([C:14]([O:16]C)=[O:15])[CH:12]=2)[NH:7][C:6]=1[CH3:18].C(O)C.[OH-].[Na+].Cl>O>[C:14]([C:11]1[CH:12]=[C:13]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]([CH3:18])=[C:5]2[CH2:4][C:3]1[CH:19]=[CH:20][C:21]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[CH:22][C:2]=1[Cl:1])([OH:16])=[O:15]
Reactant: COC(=O)c1ccc2[nH]c(C)c(Cc3ccc(-c4ccccc4)cc3Cl)c2c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: Cc1[nH]c2ccc(C(=O)O)cc2c1Cc1ccc(-c2ccccc2)cc1Cl
Yield: 76.5 %

Procedure:
To 3-(2-chloro-4-phenylbenzyl)-5-methoxycarbonyl-2-methylindole (0.95 g), added are ethanol (5 ml), water (5 ml) and aqueous sodium hydroxide (0.29 g), and refluxed for 3 hours. The reaction mixture is cooled, and neutralized with HCl. This is extracted with ethyl acetate and water, and the organic layer is dried and concentrated. The resulting residue is crystallized from a small amount of a mixed solution of chloroform and ether. The crystal is taken out through filtration and dried to obtain 5-carboxy-3-(2-chloro-4-phenylbenzyl)-2-methylindole (145) (0.701 g).
Reaction SMILES: Cl.[NH2:2][C:3]([NH2:5])=[NH:4].[Cl:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[CH:13]1[C:18]([C:19]([O:21][CH3:22])=[O:20])=[C:17]([CH3:23])[NH:16][C:15]([CH2:24][O:25][CH2:26][C:27](=O)[CH2:28][C:29](OCC)=[O:30])=[C:14]1[C:35]([O:37][CH2:38][CH3:39])=[O:36].N12CCCC1=NCCC2>C(O)C>[NH2:4][C:3]1[NH:5][C:29](=[O:30])[CH:28]=[C:27]([CH2:26][O:25][CH2:24][C:15]2[NH:16][C:17]([CH3:23])=[C:18]([C:19]([O:21][CH3:22])=[O:20])[CH:13]([C:8]3[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=3[Cl:6])[C:14]=2[C:35]([O:37][CH2:38][CH3:39])=[O:36])[N:2]=1
Reactant: N=C(N)N
Reactant: CCOC(=O)CC(=O)COCC1=C(C(=O)OCC)C(c2ccccc2Cl)C(C(=O)OC)=C(C)N1
Agent: C1CN=C2CCCN2C1
Agent: Cl
Solvent: CCO
Product: CCOC(=O)C1=C(COCc2cc(=O)[nH]c(N)n2)NC(C)=C(C(=O)OC)C1c1ccccc1Cl
Yield: 23.5 %

Procedure:
A solution of guanidine hydrochloride (0.20 g), ethyl 4-{[4-(2-chlorophenyl)-3-ethoxycarbonyl-5-methoxycarbonyl-6-methyl-1,4-dihydropyridin-2-yl]methoxy}acetoacetate (0.99 g), and 1,5-diazabicyclo[4.3.0]non-5-ene (0.30 g) in ethanol (50 ml) was stirred at room temperature for 5 days and then evaporated. The residue was dissolved in chloroform and washed with 2M hydrochloric acid, 10% aqueous sodium carbonate, and water, dried (MgSO4), and evaporated. The residual solid was recrystallised from ethyl acetate to give the title compound (0.23 g), m.p. 185°-187° C. Found: C,56.08; H,5.14; N,11.33. C23H25ClN4O6 requires C,56.50; H,5.15; N,11.46%.
Reaction SMILES: [CH:1]1([C:7]2[C:15]3[C:10](=[CH:11][C:12](C(OC)=O)=[CH:13][CH:14]=3)[NH:9][C:8]=2[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[OH-].[K+].C(N[C:32](=NC(C)C)[O:33][C:34]([CH3:37])([CH3:36])[CH3:35])(C)C.C(=N)([O-:44])N>C1COCC1.O>[CH:1]1([C:7]2[C:15]3[C:10](=[CH:11][C:12]([C:32]([O:33][C:34]([CH3:35])([CH3:36])[CH3:37])=[O:44])=[CH:13][CH:14]=3)[NH:9][C:8]=2[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: N=C(N)[O-]
Reactant: CC(C)N=C(NC(C)C)OC(C)(C)C
Reactant: COC(=O)c1ccc2c(C3CCCCC3)c(-c3ccccc3)[nH]c2c1
Agent: [K+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)OC(=O)c1ccc2c(C3CCCCC3)c(-c3ccccc3)[nH]c2c1
Temperature: 80 °C
Reaction time: 8 h

Procedure:
Methyl 3-cyclohexyl-2-phenyl-1H-indole-6-carboxylate (from Step 4) was dissolved in THF (0.2 M) and treated with aqueous KOH (2 eq., 1 M solution). The resulting mixture was heated to 80° C. for 4 h and then cooled to RT. The mixture was diluted with water and extracted with EtOAc (2×). The aqueous phase was acidified to pH 2 using hydrochloric acid (1 M) and then extracted with DCM and EtOAc. Drying over Na2SO4 and evaporation left a grey powder, which was dissolved in DCM (0.3 M). tert-Butyl N,N′-diisopropylimidocarbamate (2 eq.) was added in one portion, and the mixture stirred overnight. Another 2 eq. of the imidocarbamate were added at this point, and the heterogeneous mixture was stirred for another 24 h. Evaporation gave a white powder, which was loaded onto a column containing silica gel. Elution with PE/EtOAc (10:1) gave the title compound as an off-white solid. 1H NMR (400 MHz, CDCl3, 300K) δ 1.30-1.47 (m, 3H), 1.62 (s, 9H), 1.74-1.96 (m, 5H), 1.99-2.16 (m, 2H), 2.95 (t, J 12.4, 1H), 7.40-7.48 (m, 1H), 7.49-7.61 (m, 4H), 7.74 (d, J 8.6, 1H), 7.84 (d, J 8.6, 1H), 8.05 (s, 1H), 8.11 (bs, 1H). MS (ES+) m/z 376 (M+H)+.
Reaction SMILES: [CH2:1]=[CH:2][CH:3]=[CH:4][CH2:5][CH3:6].[CH:7](C=C)=[O:8].[C:11]1(C=CC(O)=C[CH:13]=1)O>>[CH2:2]([C@H:3]1[CH:13]=[CH:11][CH2:6][CH2:5][C@H:4]1[CH:7]=[O:8])[CH3:1]
Reactant: Oc1ccc(O)cc1
Reactant: C=CC=O
Reactant: C=CC=CCC
Product: CC[C@H]1C=CCC[C@H]1C=O

Procedure:
A mixture of 1,3-hexadiene (cis/trans mixture, 20 g., 0.24 mole), acrolein (18 ml., 0.27 mole) and hydroquinone (50 mg.) was heated at 70°-75° C. for 22 hours. Distillation in vacuo gave purified title product (21.7 g.; b.p. 90° C./12-15 mm.; 78% cis, 22% trans by pnmr assay).
Reaction SMILES: [CH3:1][O:2][CH:3]=[CH:4][C:5]1[CH:14]=[CH:13][C:8]([C:9]([O:11][CH3:12])=[O:10])=[CH:7][CH:6]=1.[OH2:15].[C:16]1(C)C=CC(S(O)(=O)=O)=CC=1>CO>[CH3:16][O:15][CH:3]([O:2][CH3:1])[CH2:4][C:5]1[CH:14]=[CH:13][C:8]([C:9]([O:11][CH3:12])=[O:10])=[CH:7][CH:6]=1
Reactant: O
Reactant: COC=Cc1ccc(C(=O)OC)cc1
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CO
Product: COC(=O)c1ccc(CC(OC)OC)cc1

Procedure:
To a solution of methyl 4-(2-methoxyvinyl)benzoate (1.36 g, 7.08 mmol) in methanol (30 mL) was added para-toluenesulfonic acid monohydrate (pTSA) (0.135 g, 0.71 mmol) and the reaction mixture heated under reflux for 18 hours. The solvent was evaporated at reduced pressure. The residue was partitioned between DCM and 10% aqueous potassium carbonate. The organic phase was poured through a hydrophobic fit and the solvent evaporated at reduced pressure. The crude material was used in the next step without further purification.
Reaction SMILES: [Cl:1][CH2:2][C:3](Cl)=[O:4].[NH2:6][C:7]1[S:8][C:9]([C:12]2[CH2:19][S:18][CH:17]3[N:14]([C:15](=[O:28])[CH:16]3[NH:20][C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[C:13]=2[C:29]([O:31][CH:32]([C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)[C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)=[O:30])=[CH:10][N:11]=1.C(N(CC)CC)C>O1CCCC1.C(=O)(O)[O-].[Na+]>[CH:32]([O:31][C:29]([C:13]1[N:14]2[CH:17]([S:18][CH2:19][C:12]=1[C:9]1[S:8][C:7]([NH:6][C:3](=[O:4])[CH2:2][Cl:1])=[N:11][CH:10]=1)[CH:16]([NH:20][C:21]([O:23][C:24]([CH3:26])([CH3:25])[CH3:27])=[O:22])[C:15]2=[O:28])=[O:30])([C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)[C:39]1[CH:40]=[CH:41][CH:42]=[CH:43][CH:44]=1
Reactant: CC(C)(C)OC(=O)NC1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(c3cnc(N)s3)CSC12
Reactant: O=C(Cl)CCl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)NC1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(c3cnc(NC(=O)CCl)s3)CSC12
Temperature: 0 °C
Reaction time: 1 h
Yield: 54.9 %

Procedure:
Chloroacetyl chloride (12.37 g) is added to a solution of 3-(2-amino-thiazol-5-yl)-2-benzhydryloxycarbonyl-7-t-butoxycarbonylamino-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene (60 g) in tetrahydrofuran (350 cc) cooled to 0° C., and triethylamine (16.3 cc) is then added in 6 minutes. After 1 hour at 0° C., the reaction mixture is diluted with a half-saturated sodium bicarbonate solution (800 cc) and extracted with ethyl acetate (3×200 cc). The combined organic phases are washed with a saturated sodium chloride solution (250 cc) and dried, after which they are concentrated to dryness under reduced pressure (30 mm Hg; 4 kPa) at 40° C. to give an orange froth (78 g) which is recrystallised from acetonitrile (300 cc) to give cream crystals (37.4 g) of 2-benzhydryloxycarbonyl-7-t-butoxycarbonylamino-3-(2-chloroacetamido-thiazol-5-yl)-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene
Reaction SMILES: [CH:1]1([O:6][C:7]2[N:12]=[C:11]([CH2:13][C:14]3[CH:19]=[CH:18][C:17]([CH2:20][C:21]([O:23]C)=[O:22])=[CH:16][CH:15]=3)[CH:10]=[C:9]([C:25]([F:28])([F:27])[F:26])[N:8]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.O1CCOCC1.O.[OH-].[Li+].Cl>C(OCC)(=O)C.O>[CH:1]1([O:6][C:7]2[N:12]=[C:11]([CH2:13][C:14]3[CH:19]=[CH:18][C:17]([CH2:20][C:21]([OH:23])=[O:22])=[CH:16][CH:15]=3)[CH:10]=[C:9]([C:25]([F:27])([F:28])[F:26])[N:8]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: COC(=O)Cc1ccc(Cc2cc(C(F)(F)F)nc(OC3CCCC3)n2)cc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: O
Solvent: C1COCCO1
Product: O=C(O)Cc1ccc(Cc2cc(C(F)(F)F)nc(OC3CCCC3)n2)cc1
Temperature: 50 °C
Reaction time: 1.5 h
Yield: 53.6 %

Procedure:
An 100-mL round bottom flask was charged with methyl 2-(4-((2-(cyclopentyloxy)-6-(trifluoromethyl)pyrimidin-4-yl)methyl)phenyl)acetate (0.100 g, 0.25 mmol), dioxane (6 ml) and water (3 ml). To this solution was then added lithium hydroxide monohydrate (0.053 g, 1.26 mmol). The resulting mixture was stirred at 50° C. for 1.5 h. The cooled reaction mixture was treated with 2N aqueous HCl until pH˜5, then diluted with ethyl acetate (75 mL). The organic layer was washed with saturated sodium chloride (5 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by chromatography on silica using hexane/ethyl acetate (10:0 to 0:10) as the eluent, followed by preparative HPLC (water/acetonitrile with 0.05% TFA) to afford the title compound (0.051 g, 53%) as an off-white solid. MW=380.36. M.p. 97-99° C. 1H NMR (DMSO-d6, 500 MHz) δ 12.28 (br s, 1H), 7.52 (s, 1H), 7.28 (d, J=8.0 Hz, 2H), 7.20 (d, J=8.0 Hz, 2H), 5.35 (septet, J=3.0 Hz, 1H), 4.11 (s, 2H), 3.52 (s, 2H), 2.00-1.89 (m, 2H), 1.77-1.65 (m, 4H), 1.65-1.55 (m, 2H); APCI MS m/z 381 [M+H]+.