Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3](=[O:26])[CH2:4][N:5]1[C:11]2[CH:12]=[CH:13][C:14]([Cl:16])=[CH:15][C:10]=2[C:9]([C:17]2[C:22]([F:23])=[CH:21][CH:20]=[CH:19][C:18]=2[F:24])=[N:8][CH2:7][C:6]1=O.P12(SP3(SP(SP(S3)(S1)=S)(=S)S2)=S)=[S:28].N1C=CC=CC=1>C(Cl)Cl.O>[CH3:1][O:2][C:3](=[O:26])[CH2:4][N:5]1[C:11]2[CH:12]=[CH:13][C:14]([Cl:16])=[CH:15][C:10]=2[C:9]([C:17]2[C:22]([F:23])=[CH:21][CH:20]=[CH:19][C:18]=2[F:24])=[N:8][CH2:7][C:6]1=[S:28]
Reactant: COC(=O)CN1C(=O)CN=C(c2c(F)cccc2F)c2cc(Cl)ccc21
Reactant: S=P12SP3(=S)SP(=S)(S1)SP(=S)(S2)S3
Solvent: O
Solvent: ClCCl
Solvent: c1ccncc1
Product: COC(=O)CN1C(=S)CN=C(c2c(F)cccc2F)c2cc(Cl)ccc21

Procedure:
A mixture of 0.01 mole of 7-chloro-5-(2,6-difluorophenyl)-2,3-dihydro-2-oxo-1H-1,4-benzodiazepin-1-acetic acid methyl ester, 0.0105 mole of phosphorus pentasulfide and 100 ml. of pyridine is heated under reflux for about 24 hours. The reaction mixture is evaporated and the residue thus obtained is dissolved in methylene chloride-water. The organic layer is separated, washed with saturated sodium bicarbonate solution, dried over anhydrous magnesium sulfate and evaporated to remove the solvent. The residue thus obtained is chromatographed on silica gel and eluted to give 7-chloro-5-(2,6-difluorophenyl)-2,3-dihydro-2-thioxo-1H-1,4-benzodiazepin-1-acetic acid methyl ester.
Reaction SMILES: [CH3:1][NH:2][NH2:3].[CH:4](=O)[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.[CH3:12][S:13][C:14](=[C:17]([C:20]#[N:21])[C:18]#[N:19])SC>COCCO>[CH3:1][N:2]([C:14]([S:13][CH3:12])=[C:17]([C:20]#[N:21])[C:18]#[N:19])[N:3]=[CH:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1
Reactant: O=Cc1ccccc1
Reactant: CNN
Reactant: CSC(SC)=C(C#N)C#N
Solvent: COCCO
Product: CSC(=C(C#N)C#N)N(C)N=Cc1ccccc1
Temperature: 0 °C

Procedure:
Methyl hydrazine (4.2 g) was added slowly to benzaldehyde (9.4 ml) in 2-methoxyethanol (15 ml) causing the solution to boil. The solution was heated under reflux for 20 minutes and was then added to a solution of bis(methylmercapto)methylenemalononitrile (15.6 g) in 2-methoxyethanol (75 ml). The solution was heated under reflux for 6 hours and was then cooled to 0° C. to precipitate benzaldehyde N-methyl-N-(2,2-dicyano-1-methylmercaptoethenyl) hydrazone (5.6 g), m.p. 159°-160° C.
Reaction SMILES: [CH3:1][C:2]1[C:7]([CH3:8])=[CH:6][C:5]([NH2:9])=[C:4]([NH2:10])[CH:3]=1.C([O:15][C:16](=O)[CH2:17][C:18](=O)[C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([C:25]2[CH:30]=[CH:29][N:28]=[CH:27][CH:26]=2)[CH:20]=1)(C)(C)C>C1(C)C(C)=CC=CC=1>[CH3:1][C:2]1[C:7]([CH3:8])=[CH:6][C:5]2[NH:9][C:16](=[O:15])[CH2:17][C:18]([C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([C:25]4[CH:26]=[CH:27][N:28]=[CH:29][CH:30]=4)[CH:20]=3)=[N:10][C:4]=2[CH:3]=1
Reactant: Cc1cc(N)c(N)cc1C
Reactant: CC(C)(C)OC(=O)CC(=O)c1cccc(-c2ccncc2)c1
Solvent: Cc1ccccc1C
Product: Cc1cc2c(cc1C)NC(=O)CC(c1cccc(-c3ccncc3)c1)=N2

Procedure:
The title compound was prepared from commercially available 4,5-dimethyl-1,2-phenylendiamine (136 mg, 1.0 mmol) and 3-oxo-3-(3-pyridin-4-yl-phenyl)-propionic acid tert-butyl ester (Example K2) (297 mg, 1.0 mmol) in xylene (20 ml) under reflux conditions for 2 h according to the general procedure M. Obtained as a light brown solid (294 mg, 86%).
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][C:7]([N:14]3[CH2:19][CH2:18][O:17][CH2:16][CH2:15]3)=[CH:8][C:9]=2[C:11]([OH:13])=O)[C:4]([CH:20]([CH3:22])[CH3:21])=[CH:3]1.[NH2:23][CH2:24][C:25]1[C:26](=[O:33])[NH:27][C:28]([CH3:32])=[CH:29][C:30]=1[CH3:31].Cl.ON1C2N=CC=CC=2N=N1.CN1CCOCC1.C(Cl)CCl>CS(C)=O>[CH3:31][C:30]1[CH:29]=[C:28]([CH3:32])[NH:27][C:26](=[O:33])[C:25]=1[CH2:24][NH:23][C:11]([C:9]1[CH:8]=[C:7]([N:14]2[CH2:15][CH2:16][O:17][CH2:18][CH2:19]2)[CH:6]=[C:5]2[C:10]=1[N:2]([CH3:1])[CH:3]=[C:4]2[CH:20]([CH3:21])[CH3:22])=[O:13]
Reactant: Cc1cc(C)c(CN)c(=O)[nH]1
Reactant: CC(C)c1cn(C)c2c(C(=O)O)cc(N3CCOCC3)cc12
Agent: Cl
Agent: On1nnc2cccnc21
Solvent: ClCCCl
Solvent: CN1CCOCC1
Solvent: CS(C)=O
Product: Cc1cc(C)c(CNC(=O)c2cc(N3CCOCC3)cc3c(C(C)C)cn(C)c23)c(=O)[nH]1
Temperature: 25 °C
Reaction time: 8 h
Yield: 26.1 %

Procedure:
1-Methyl-3-(1-methylethyl)-5-(4-morpholinyl)-1H-indole-7-carboxylic acid (62.5 mg, 0.21 mmol), 3-(aminomethyl)-4,6-dimethyl-2(1H)-pyridinone.HCl (58.5 mg, 0.31 mmol) and 1-hydroxy-7-azabenzotriazole (47.8 mg, 0.35 mmol) were stirred in 2 mL of DMSO for 10 min under nitrogen. N-methylmorpholine (0.095 mL, 0.87 mmol) was added along with EDC (67.4 mg, 0.35 mmol) and the mixture was stirred at rt overnight under nitrogen. Ice-water was added but no solid crashed out. The reaction mixture was concentrated until only DMSO was left and purified using a reversed-phase HPLC (30×100 Varian Polaris C18, 15-80% gradient of MeCN in water with 0.1% TFA over 12 minutes). Fractions containing the desired product were evaporated until a minimum of water remained and saturated solution of NaHCO3 was added. The light orange solids that crashed out were filtered off and dissolved in DMF. Water was added and the solids that crashed out were filtered, air-dried for 15 min and dried in vacuum-oven overnight to give N-[(4,6-dimethyl-2-oxo-1,2-dihydro-3-pyridinyl)methyl]-1-methyl-3-(1-methylethyl)-5-(4-morpholinyl)-1H-indole-7-carboxamide (24 mg, 26.1% yield). 1H NMR (400 MHz, DMSO-d6) δ ppm 11.49 (s, 1H) 8.33 (t, J=4.93 Hz, 1H) 7.04 (d, J=2.27 Hz, 1H) 6.96 (s, 1H) 6.80 (d, J=2.27 Hz, 1H) 5.87 (s, 1H) 4.33 (s, 1H) 4.31 (s, 1H) 3.72-3.78 (m, 4H) 3.60 (s, 3H) 3.06-3.12 (m, 1H) 3.00-3.06 (m, 4H) 2.22 (s, 3H) 2.11 (s, 3H) 1.26 (d, J=6.8 Hz, 6H). MS (ES) [M+H]+ 437.0.
Reaction SMILES: [H-].[Na+].[I-].[CH3:4][S+](C)(C)=O.[CH2:9]([O:16][C:17]([NH:19][C@@H:20]([CH2:23][CH:24]1[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]1)[CH:21]=[O:22])=[O:18])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>C1COCC1>[CH2:9]([O:16][C:17]([NH:19][C@H:20]([CH:21]1[CH2:4][O:22]1)[CH2:23][CH:24]1[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]1)=[O:18])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: O=C[C@H](CC1CCCCC1)NC(=O)OCc1ccccc1
Reactant: C[S+](C)(C)=O
Agent: [H-]
Agent: [I-]
Agent: [Na+]
Solvent: C1CCOC1
Product: O=C(N[C@@H](CC1CCCCC1)C1CO1)OCc1ccccc1
Temperature: 0 °C
Reaction time: 0.83 h

Procedure:
18.9 g of sodium hydride dispersion (55% in oil) are freed of oil in a dry reaction flask under argon by stirring three times in 50 ml of petroleum ether (b.p. 40°-60°) and subsequently decanting off the solvent each time. After drying under a high vacuum, a grey powder is obtained which is placed in 500 ml of THF; 55.6 g of trimethylsulphoxonium iodide are added thereto, the temperature increasing to approximately 40°. The grey suspension is boiled under reflux for 1 hour and then, within a period of 50 minutes at -70°, a solution of 108.6 g of 2(S)-benzyloxycarbonylamino-3-cyclohexylpropanal in 250 ml of THF is added. The yellow suspension is stirred at 0° for 2 hours. The yellowish turbid solution is poured onto 500 g of ice. The aqueous solution is extracted with 2.5 liters of ether, and the organic phase is washed with water and, after being dried over sodium sulphate, concentrated by evaporation. The oily residue is separated by means of flash chromatography (2.5 kg of silica gel 60, 40-63 μm, eluant C). The product-containing fractions are combined, concentrated by evaporation and dried under a high vacuum. The title compound (diastereoisomeric mixture, approximately 4:1) is obtained in the form of a slightly yellowish oil. Rf (K)=0.71; Rf (C)=0.16.
Reaction SMILES: [H-].[Na+].C([O:5][C:6](=[O:22])[C:7]1[CH:12]=[CH:11][C:10]([CH2:13]P(OCC)(OCC)=O)=[CH:9][CH:8]=1)C.[CH2:23]([O:25][CH2:26][C:27]1([CH3:40])[CH2:33][CH2:32][CH2:31][S:30][C:29]2[CH:34]=[C:35]([CH:38]=O)[CH:36]=[CH:37][C:28]1=2)[CH3:24]>CN(C=O)C>[CH2:23]([O:25][CH2:26][C:27]1([CH3:40])[CH2:33][CH2:32][CH2:31][S:30][C:29]2[CH:34]=[C:35](/[CH:38]=[CH:13]/[C:10]3[CH:9]=[CH:8][C:7]([C:6]([OH:5])=[O:22])=[CH:12][CH:11]=3)[CH:36]=[CH:37][C:28]1=2)[CH3:24]
Reactant: CCOC(=O)c1ccc(CP(=O)(OCC)OCC)cc1
Reactant: CCOCC1(C)CCCSc2cc(C=O)ccc21
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOCC1(C)CCCSc2cc(/C=C/c3ccc(C(=O)O)cc3)ccc21
Temperature: 0 °C
Reaction time: 1.5 h

Procedure:
85 mg of NaH (ca. 1.4 eq., 50% in mineral oil) was added to a solution of 534 mg (1.4 eq.) of 4-(diethoxyphosphorylmethyl)-benzoic acid ethyl ester in 1.9 ml of abs. DMF at 0° C. The mixture was stirred at 0° C. for 0.5 h and at room temperature for 1.5 h. After cooling to 0° C., 336 mg (1.27 mmol) of 5-ethoxymethyl-5-methyl-2,3,4,5-tetrahydrobenzo[b]thiepine-8-carbaldehyde, dissolved in 1 ml of DMF, was added and allowed to react for 2 h at room temperature. The mixture was then poured onto crushed ice, extracted twice with diethylether, the organic phase was washed with water, dried over magnesium sulfate, filtrated and evaporated to dryness. Purification of the residue by flash chromatography (silica gel, hexane/ethylacetate 95/5) afforded 409 mg of pure, colorless title compound.
Reaction SMILES: [NH2:1][C:2]1[N:7]([CH3:8])[C:6](=[O:9])[N:5]([CH2:10][CH2:11][CH3:12])[C:4](=[O:13])[C:3]=1[N:14]=O.[NH4+]=S.[CH:18]([C:20]1[CH:30]=[CH:29][C:23]([CH:24]=[CH:25][C:26]([OH:28])=[O:27])=[CH:22][CH:21]=1)=O>>[NH2:14][C:3]1[C:4](=[O:13])[N:5]([CH2:10][CH2:11][CH3:12])[C:6](=[O:9])[N:7]([CH3:8])[C:2]=1[NH2:1].[CH3:8][N:7]1[C:2]2[NH:1][C:18]([C:20]3[CH:30]=[CH:29][C:23](/[CH:24]=[CH:25]/[C:26]([OH:28])=[O:27])=[CH:22][CH:21]=3)=[N:14][C:3]=2[C:4](=[O:13])[N:5]([CH2:10][CH2:11][CH3:12])[C:6]1=[O:9]
Reactant: O=Cc1ccc(C=CC(=O)O)cc1
Reactant: CCCn1c(=O)c(N=O)c(N)n(C)c1=O
Product: CCCn1c(=O)c(N)c(N)n(C)c1=O
Product: CCCn1c(=O)c2nc(-c3ccc(/C=C/C(=O)O)cc3)[nH]c2n(C)c1=O

Procedure:
5,6-Diamino-1-methyl-3-propyl-2,4(1H,3H)pyrimidinedione was prepared freshly from 6-amino-1-methyl-5-nitroso-3-propyl-2,4-(1H,3H)pyrimidinedione by ammonium sulfide reduction using the method of V. Papesch, M. Grove, and E. F. Schroeder (U.S. Pat. No. 2,602,795). This diamine (2.00 g, 10.0 mmol) was condensed with 4-formylcinnamic acid (1.76 g, 10.0 mmol) by the procedure of Example 2 to give the title compound as an ivory powder, after crystallization from N,N-dimethylformamide-water; mp>300° C. Analysis for (C18H18N4O4.1/5 DMF): C,60.54; H,5.30; N,15.94. Found: C,60.52; H,5.22; N,16.03.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]2[C:15](=[O:16])[C:14]([C:17]([O:19]CC)=[O:18])=[CH:13][N:7]3[C@@H:8]([CH3:12])[CH2:9][O:10][C:11]=1[C:6]=23.C(O)(=O)C.Cl.O>C(O)C>[F:1][C:2]1[CH:3]=[CH:4][C:5]2[C:15](=[O:16])[C:14]([C:17]([OH:19])=[O:18])=[CH:13][N:7]3[C@@H:8]([CH3:12])[CH2:9][O:10][C:11]=1[C:6]=23
Reactant: CCOC(=O)c1cn2c3c(c(F)ccc3c1=O)OC[C@@H]2C
Agent: Cl
Solvent: CCO
Solvent: O
Solvent: CC(=O)O
Product: C[C@H]1COc2c(F)ccc3c(=O)c(C(=O)O)cn1c23
Temperature: 25 °C
Yield: 81.1 %

Procedure:
A mixture of ethyl 10-fluoro-2,3-dihydro-3-(S)-methyl-7-oxo-7H-pyrido[1,2,3-de][1,4]benzoxazine-6-carboxylate (5.60 g, 19.2 mmol), acetic acid (25 ml) and concentrated hydrochloric acid (25 ml) was heated under reflux for 4 hours. After cooling the reaction solution with ice, water (100 ml) was added thereto, and the precipitated crystals were filtered out and then washed with excess water, a small amount of cold ethanol and excess diethyl ether in that order. The crude crystals obtained were then suspended in ethanol (40 ml) and stirred under room temperature. The crystals were filtered out, washed with ethanol, and then dried under a reduced pressure at 80° C. for 17 hours. 4.10 g (81%) of the title compound was thereby obtained in the form of a white powder.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](O)=[O:7])=[C:4]([CH2:11][CH2:12][CH:13]([CH3:15])[CH3:14])[CH:3]=1.[CH3:16][S:17]([NH2:20])(=[O:19])=[O:18].Cl.C(N=C=NCCCN(C)C)C>CN(C)C=O.CN(C)C1C=CN=CC=1.C(OCC)(=O)C>[Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([NH:20][S:17]([CH3:16])(=[O:19])=[O:18])=[O:7])=[C:4]([CH2:11][CH2:12][CH:13]([CH3:15])[CH3:14])[CH:3]=1
Reactant: CS(N)(=O)=O
Reactant: CC(C)CCc1cc(Br)ccc1C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C)CCc1cc(Br)ccc1C(=O)NS(C)(=O)=O
Temperature: 30 °C
Reaction time: 16 h
Yield: 93.5 %

Procedure:
To a suspension of 4-bromo-2-(3-methylbutyl)benzoic acid (1.3 g) and methanesulfonamide (365 mg) in N,N-dimethylformamide (12 ml) was added 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (735 mg) and 4-dimethylaminopyridine (469 mg), and stirred at 30° C. for 16 hours. The mixture was diluted with ethyl acetate, washed with 1N aqueous hydrochloride solution, water and brine, dried over magnesium sulfate and evaporated under reduced pressure. The residue was purified by column chromatography on silica gel (hexane/ethyl acetate=2/1) to give 4-bromo-2-(3-methylbutyl)-N-(methylsulfonyl)benzamide (1.25 g).
Reaction SMILES: [CH3:1][C:2](=[N:4][OH:5])[CH3:3].[OH-].[Na+].[CH:8]1([N:14]=[C:15]=[N:16][CH:17]2[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]2)[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]1>C1COCC1.CCCCCC>[CH:17]1([NH:16][C:15](=[N:14][CH:8]2[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]2)[O:5][N:4]=[C:2]([CH3:3])[CH3:1])[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22]1
Reactant: CC(C)=NO
Reactant: C(=NC1CCCCC1)=NC1CCCCC1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CC(C)=NOC(=NC1CCCCC1)NC1CCCCC1
Temperature: 25 °C
Reaction time: 5 h
Yield: 98.8 %

Procedure:
To a solution of acetone oxime (3.65 g, 0.05 mol) in dry THF (35 ml) is added finely powdered NaOH (0.2 g) and dicyclohexylcarbodiimide (10.3 g, 0.05 mol). The mixture is then stirred 5 h at room temperature under argon. The turbid mixture is thereafter diluted with hexane (30 ml) filtered and evaporated under reduced pressure to afford 13.8 g of the title compound as a slightly yellow liquid.
Reaction SMILES: COCC[NH:5][C:6](=[O:35])[CH2:7][C@H:8]([OH:34])[CH2:9][C@H:10]([OH:33])[CH2:11][CH2:12][C@@H:13]1[C@@H:22]2[C:17](=[CH:18][C@H:19]([CH3:31])[CH2:20][C@@H:21]2[O:23][C:24](=[O:30])[C:25]([CH3:29])([CH3:28])[CH2:26][CH3:27])[CH:16]=[CH:15][C@@H:14]1[CH3:32].[OH-:36].[Na+].N>CO.O>[CH3:27][CH2:26][C:25]([C:24]([O:23][C@@H:21]1[C@@H:22]2[C@@H:13]([CH2:12][CH2:11][C@@H:10]([OH:33])[CH2:9][C@@H:8]([OH:34])[CH2:7][C:6]([O-:36])=[O:35])[C@@H:14]([CH3:32])[CH:15]=[CH:16][C:17]2=[CH:18][C@H:19]([CH3:31])[CH2:20]1)=[O:30])([CH3:28])[CH3:29].[NH4+:5]
Reactant: [OH-]
Reactant: CCC(C)(C)C(=O)O[C@H]1C[C@@H](C)C=C2C=C[C@H](C)[C@H](CC[C@@H](O)C[C@@H](O)CC(=O)NCCOC)[C@H]21
Agent: N
Agent: [Na+]
Solvent: CO
Solvent: O
Product: CCC(C)(C)C(=O)O[C@H]1C[C@@H](C)C=C2C=C[C@H](C)[C@H](CC[C@@H](O)C[C@@H](O)CC(=O)[O-])[C@H]21
Product: [NH4+]
Temperature: 75 °C
Reaction time: 1 h

Procedure:
To the concentrate obtained in step 2 is added methanol (840 ml), water (550 ml) and sodium hydroxide (45 gm) at 25° C. The contents are heated to 75° C. and maintained for 7 hours at about 75° C. Then the solvent is distilled off at reduced pressure, cooled to 20° C. and water (400 ml) is added. Then the pH of the reaction mass is adjusted to 5 with 2N hydrochloric acid at 25° C., ethyl acetate (400 ml) is added and the pH is again adjusted to 3.5 with 2N hydrochloric acid solution. The layers are separated and the aqueous layer is washed with ethyl acetate (200 ml). The combined organic layer is dried on sodium sulfate. Ammonia solution, prepared by mixing aqueous ammonia (20 ml) and methanol (20 ml), is added to the reaction mass for 15 minutes at about 25° C., stirred for 1 hour at 25° C. and again for 1 hour at 0° C.–5° C. Then the separated solid is filtered and washed with chilled ethyl acetate (50 ml) to give 28 gm of simvastatin ammonium salt (HPLC Purity 97.5%).
Reaction SMILES: Cl[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[CH:4][C:3]=1[N+:11]([O-:13])=[O:12].[F-:14].[K+].CN(C)C=O.O>C(Cl)Cl>[F:14][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[CH:4][C:3]=1[N+:11]([O-:13])=[O:12]
Reactant: O=[N+]([O-])c1cccc([N+](=O)[O-])c1Cl
Reactant: [F-]
Agent: [K+]
Solvent: O
Solvent: ClCCl
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1cccc([N+](=O)[O-])c1F

Procedure:
A mixture of 1-chloro-2,6-dinitrobenzene (30 grams), anhydrous potassium fluoride (35 grams), and dimethylformamide (50 ml.) is refluxed for 24 hours. The reaction mixture is poured into water (250 ml.) and extracted with ether (3 × 100 ml.). The combined ether extracts are dried with anhydrous sodium sulfate. Removal of the solvent leaves brown solid. Chromatography of the solid on silica gel with methylene chloride as the elutant gives a light yellow solid after recrystallization from pentane-methylene chloride. (20.30 grams, melting point 50°).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:13][C:14]1[CH2:18][CH2:17][CH2:16][CH:15]=1)[C:10]([OH:12])=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2]>CO.[Pd]>[C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:13][CH:14]1[CH2:15][CH2:16][CH2:17][CH2:18]1)[C:10]([OH:12])=[O:11])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N[C@@H](CC1=CCCC1)C(=O)O
Agent: [Pd]
Solvent: CO
Product: CC(C)(C)OC(=O)N[C@@H](CC1CCCC1)C(=O)O
Temperature: 25 °C
Reaction time: 8 h
Yield: 97.2 %

Procedure:
To a solution of (S)-2-((tert-butoxycarbonyl)amino)-3-(cyclopent-1-en-1-yl)propanoic acid (56 g, 0.22 mol) in methanol (500 mL) was added Pd/C (23 g, 0.022 mol, 10%). The mixture was stirred under a hydrogen atmosphere (1 atm) at ambient temperature overnight and then filtered through a pad of celite. The filtrate was concentrated under reduced pressure to afford (S)-2-((tert-butoxycarbonyl)amino)-3-cyclopentylpropanoic acid (55 g, 97% yield) as viscous oil, which was used in the next step without further purification.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[NH:15][C:14]([CH2:16][CH2:17][CH2:18][CH3:19])=[N:13][C:5]2=[N:6][C:7]=1[CH:8]([O:11][CH3:12])[O:9][CH3:10].[CH2:20]([O:22][CH:23]([N:25]1[C:29]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=2[C:36]2[CH:41]=[CH:40][C:39]([CH2:42]Br)=[CH:38][CH:37]=2)=[N:28][N:27]=[N:26]1)[CH3:24])[CH3:21].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.C(OCC)(=O)C>[Br:1][C:2]1[CH:3]=[C:4]2[N:15]=[C:14]([CH2:16][CH2:17][CH2:18][CH3:19])[N:13]([CH2:42][C:39]3[CH:38]=[CH:37][C:36]([C:31]4[CH:32]=[CH:33][CH:34]=[CH:35][C:30]=4[C:29]4[N:25]([CH:23]([O:22][CH2:20][CH3:21])[CH3:24])[N:26]=[N:27][N:28]=4)=[CH:41][CH:40]=3)[C:5]2=[N:6][C:7]=1[CH:8]([O:11][CH3:12])[O:9][CH3:10]
Reactant: CCCCc1nc2nc(C(OC)OC)c(Br)cc2[nH]1
Reactant: CCOC(C)n1nnnc1-c1ccccc1-c1ccc(CBr)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCCCc1nc2cc(Br)c(C(OC)OC)nc2n1Cc1ccc(-c2ccccc2-c2nnnn2C(C)OCC)cc1
Temperature: 25 °C
Reaction time: 5 h
Yield: 59.3 %

Procedure:
0.61 g (1.86 mmole) of the compound obtained in step 8 was dissolved in 3 ml of DMF and thereto were added 0.79 g (2.05 mmole) of 2'-[1-(1-ethoxyethyl)-1H-tetrazol-5-yl]-biphenyl-4-ylmethylbromide and 0.51 g (3.72 mmole) of K2CO3. The resulting solution was stirred at room temperature for 5 hours and diluted with 50 ml of ethyl acetate. The resultant was washed with water (25 ml×3) and dried over Na2SO4, and then concentrated under reduced pressure and purified with column chromatography (hexane:ethyl acetate=1:1) to obtain 0.7 g of the title compound (yield 59%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:12]=[CH:11][NH:10][N:9]=2)[S:5][C:6]=1[Br:7].[H-].[Na+].[CH:15](I)([CH3:17])[CH3:16].O>CN(C)C=O.CC(OC)(C)C>[Br:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:12]=[CH:11][N:10]([CH:15]([CH3:17])[CH3:16])[N:9]=2)[S:5][C:6]=1[Br:7].[Br:1][C:2]1[CH:3]=[C:4]([C:8]2[N:9]([CH:15]([CH3:17])[CH3:16])[N:10]=[CH:11][CH:12]=2)[S:5][C:6]=1[Br:7]
Reactant: CC(C)I
Reactant: Brc1cc(-c2cc[nH]n2)sc1Br
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Solvent: COC(C)(C)C
Product: CC(C)n1ccc(-c2cc(Br)c(Br)s2)n1
Product: CC(C)n1nccc1-c1cc(Br)c(Br)s1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 81 %
Yield: 7 %

Procedure:
3-(4,5-dibromo-2-thienyl)-1H-pyrazole (9.4 mmol) was dissolved in 20 mL dry N,N-dimethylformamide under argon atmosphere. Sodium hydride (11.3 mmol, 60% dispersion in mineral oil) was added in portions at room temperature. The reaction mixture was stirred at room temperature for 15 min. Isopropyl iodide (14.1 mmol) was added dropwise and the reaction mixture was stirred at room temperature for 14 h. Water and MTBE were added to the reaction mixture. The phases were separated and the aqueous phase was extracted with MTBE. The combined organic extracts were successively washed with water and brine, dried over MgSO4, filtered and concentrated. The residue was purified by chromatography on silica gel (toluene:ethyl acetate 100:0 to 0:100) to afford 2.67 g 3-(4,5-dibromo-2-thienyl)-1-isopropyl-1H-pyrazole (81% yield) and 238 mg of 5-(4,5-dibromo-2-thienyl)-1-isopropyl-1H-pyrazole (7% yield).
Reaction SMILES: C(ON=O)(C)(C)C.[CH2:8]([Br:11])[CH:9]=[CH2:10].Br[C:13]1[CH:19]=[CH:18][C:16](N)=[CH:15][CH:14]=1.NC1C=CC=CC=1>CC#N>[CH2:15]([C:14]1[CH:13]=[CH:19][C:8]([Br:11])=[CH:9][CH:10]=1)[CH:16]=[CH2:18]
Reactant: C=CCBr
Reactant: Nc1ccc(Br)cc1
Agent: CC(C)(C)ON=O
Solvent: Nc1ccccc1
Solvent: CC#N
Product: C=CCc1ccc(Br)cc1
Temperature: 32.5 °C
Reaction time: 1 h
Yield: 33.8 %

Procedure:
To a solution of t-butylnitrite (535 μl, 4.5 mmol) and allyl bromide (3.9 ml, 45.0 mmol) in CH3CN (3 ml), 4-bromoaniline (516 mg, 3.0 mmol) was added during 20 minutes, while maintaining the temperature of the reaction mixture at 30-35° C. At the end of the addition of the aniline, extra t-butylnitrite (180 μl, 1.5 mmol) was added to the reaction mixture which then was stirred at 30° C. for one hour. The volatile material in the reaction mixture was removed at reduced pressure. Column chromatography (pentane) gave 200 mg (34%) of 4-allylbromobenzene as a clear oil. 1H NMR (CDCl3, 400 MHz) δ 7.43, (m, 2H, J=8.3 Hz), 7.08, (m, 2H, J=8.3 Hz), 6.00-5.89, (m, 1H), 5.12-5.05, (m, 2H), 3.35, (d, 2H, J 6.7 Hz); 13C NMR (CDCl3, 100 MHz) δ 139.4, 137.2, 131.9, 130.8, 120.3, 116.7, 40.0; Anal HRMS Calcd. for C9H9Br (M): 195.9888. Found: 195.9887.
Reaction SMILES: [Na].C(OCC)(=O)[CH2:3][C:4](OCC)=[O:5].[CH3:13][C:14]1([CH3:31])[CH2:18][C:17]2[C:19]([CH3:30])=[C:20]([CH:25]=[CH:26][C:27](=[O:29])[CH3:28])[C:21]([CH3:24])=[C:22]([CH3:23])[C:16]=2[O:15]1.[OH-].[Na+]>CO>[CH3:13][C:14]1([CH3:31])[CH2:18][C:17]2[C:19]([CH3:30])=[C:20]([CH:25]3[CH2:3][C:4](=[O:5])[CH2:28][C:27](=[O:29])[CH2:26]3)[C:21]([CH3:24])=[C:22]([CH3:23])[C:16]=2[O:15]1
Reactant: CC(=O)C=Cc1c(C)c(C)c2c(c1C)CC(C)(C)O2
Reactant: CCOC(=O)CC(=O)OCC
Agent: [Na+]
Agent: [Na]
Agent: [OH-]
Solvent: CO
Product: Cc1c(C)c(C2CC(=O)CC(=O)C2)c(C)c2c1OC(C)(C)C2
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
To a solution of 0.86 g of sodium in 37 ml of absolute methanol was added 5.6 ml of diethyl malonate. After stirring for 20 minutes, the mixture was added 8 g of the 4-(2,3-dihydro-2,2,4,6,7-pentamethylbenzofuran-5- yl)-3-buten-2-one in 15 ml of absolute methanol, refluxed for 4 hours and then added 75 g of 6% aqueous solution of sodium hydroxide and refluxed for 4 hours. The reaction mixture was cooled to room temperature and washed three times with 50 ml of diethyl ether. 2N aqueous solution of hydrochloric acid was added drop wise into the aqueous layer until the bubble of carbon dioxide ceased. Solid was dissolved in ethyl acetate and washed with water. The combined organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure to afford 6.36 g of 5-(2,3-dihydro-2,2,4,6,7-pentamethylbenzofuran-5-yl)cyclohexane-1,3-dione as a yellow solid.