Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:3][C:4](=S)[NH:5][C:6]1[CH:11]=[C:10]([S:12]([CH3:15])(=[O:14])=[O:13])[CH:9]=[C:8]([NH:16][C:17]2[N:26]=[CH:25][C:24]3[N:23]([CH3:27])[C:22](=[O:28])[CH2:21][N:20]([CH:29]([CH3:31])[CH3:30])[C:19]=3[N:18]=2)[CH:7]=1)C.[C:33]([O:37][C:38](=[O:47])[NH:39][C@H:40]1[CH2:45][CH2:44][C@@H:43]([NH2:46])[CH2:42][CH2:41]1)([CH3:36])([CH3:35])[CH3:34]>CN(C=O)C.O>[C:33]([O:37][C:38](=[O:47])[NH:39][CH:40]1[CH2:41][CH2:42][CH:43]([NH:46][C:4]([NH:5][C:6]2[CH:11]=[C:10]([S:12]([CH3:15])(=[O:14])=[O:13])[CH:9]=[C:8]([NH:16][C:17]3[N:26]=[CH:25][C:24]4[N:23]([CH3:27])[C:22](=[O:28])[CH2:21][N:20]([CH:29]([CH3:31])[CH3:30])[C:19]=4[N:18]=3)[CH:7]=2)=[O:3])[CH2:44][CH2:45]1)([CH3:36])([CH3:34])[CH3:35]
Reactant: CC(C)(C)OC(=O)N[C@H]1CC[C@@H](N)CC1
Reactant: CCOC(=S)Nc1cc(Nc2ncc3c(n2)N(C(C)C)CC(=O)N3C)cc(S(C)(=O)=O)c1
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)N1CC(=O)N(C)c2cnc(Nc3cc(NC(=O)NC4CCC(NC(=O)OC(C)(C)C)CC4)cc(S(C)(=O)=O)c3)nc21
Temperature: 70 °C
Reaction time: 8 h
Yield: 99 %

Procedure:
[3-(8-Isopropyl-5-methyl-6-oxo-5,6,7,8-tetrahydro-pteridin-2-ylamino)-5-(methylsulfonyl)-phenyl]-thiocarbamic acid ethyl ester (150 mg; 0.313 mmol) was dissolved in 1 ml of dry DMF, tert-butyl-cis-4-aminocyclohexylcarbamate (201 mg; 0.940 mmol) was added. The reaction mixture was stirred at 70° C., overnight, then, it was diluted with water. The precipitated formed was filtered, washed with water and dried in vacuo. 196 mg (0.311 mmol; 99% yield) of the desired compound to were obtained.
Reaction SMILES: [OH:1][C:2]1[C:7]2[O:8][CH:9]([CH2:12][OH:13])[CH2:10][O:11][C:6]=2[CH:5]=[CH:4][CH:3]=1.[OH-].[Na+].[CH3:16]I>O>[CH3:16][O:1][C:2]1[C:7]2[O:8][CH:9]([CH2:12][OH:13])[CH2:10][O:11][C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: CI
Reactant: OCC1COc2cccc(O)c2O1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: COc1cccc2c1OC(CO)CO2
Temperature: 0 °C
Reaction time: 4 h

Procedure:
A mixture of 8-hydroxy-1,4-benzodioxan-2-ylmethanol (10 g--prepared in a similar manner to that described in U.S. Pat. No. 3,101,354), sodium hydroxide (2.2 g) and water (150 ml) was stirred for 30 minutes, then cooled to 0° C. Methyl iodide (3.42 ml) was added dropwise, then the mixture was heated to 80° C. and stirred for 4 hours. The mixture was cooled to ambient temperature and stirred for 16 hours. The product was extracted into ethyl acetate (2×200 ml), and the combined extracts were washed with saturated sodium thiosulphate solution (2×200 ml), dried over magnesium sulphate, and the solvent removed in vacuo to yield 1-(8-methoxy-1,4-benzodioxan-2-yl)methanol as a solid (6.89 g)
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[C:3]1[CH:13]=[C:6]2[C:7]([CH2:11][OH:12])=[CH:8][CH:9]=[CH:10][N:5]2[N:4]=1.N1C=CN=C1.[Si:21](Cl)([C:24]([CH3:27])([CH3:26])[CH3:25])([CH3:23])[CH3:22].O>CN(C=O)C>[Si:21]([O:12][CH2:11][C:7]1[C:6]2[N:5]([N:4]=[C:3]([C:2]([F:1])([F:14])[F:15])[CH:13]=2)[CH:10]=[CH:9][CH:8]=1)([C:24]([CH3:27])([CH3:26])[CH3:25])([CH3:23])[CH3:22]
Reactant: OCc1cccn2nc(C(F)(F)F)cc12
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)[Si](C)(C)OCc1cccn2nc(C(F)(F)F)cc12
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 43.3 %

Procedure:
The compound of Example 64 (5.17 g, crude product) was dissolved in DMF (100 mL). To this solution, imidazole (4.89 g) and t-butyldimethylsilyl chloride (4.33 g) were added and the mixture was stirred at room temperature for 1.5 hours. Subsequently, water was added and the mixture was extracted with ethyl acetate. The organic layer was washed sequentially with water and saturated brine and dried over anhydrous sodium sulfate. Evaporation of the solvent and subsequent purification by silica gel column chromatography (hexane:ethyl acetate=9:1) afforded the title compound as a yellow oil (3.42 g).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:13])[CH2:5][C:6]1[CH:7]=[N:8][C:9](Cl)=[CH:10][CH:11]=1)[CH3:2].P([O-])([O-])([O-])=O.[K+].[K+].[K+].[CH3:22][C:23]1[CH:24]=[C:25]([C:39]([C:44]2[CH:49]=[CH:48][C:47](/[CH:50]=[CH:51]/[C:52]([CH2:56][CH3:57])([OH:55])[CH2:53][CH3:54])=[C:46]([CH3:58])[CH:45]=2)([CH2:42][CH3:43])[CH2:40][CH3:41])[CH:26]=[C:27]([CH3:38])[C:28]=1B1OC(C)(C)C(C)(C)O1.C(OCC)(=O)C>CN(C)C=O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH2:1]([O:3][C:4](=[O:13])[CH2:5][C:6]1[CH:7]=[N:8][C:9]([C:28]2[C:27]([CH3:38])=[CH:26][C:25]([C:39]([CH2:40][CH3:41])([C:44]3[CH:49]=[CH:48][C:47](/[CH:50]=[CH:51]/[C:52]([CH2:56][CH3:57])([OH:55])[CH2:53][CH3:54])=[C:46]([CH3:58])[CH:45]=3)[CH2:42][CH3:43])=[CH:24][C:23]=2[CH3:22])=[CH:10][CH:11]=1)[CH3:2]
Reactant: CCOC(=O)Cc1ccc(Cl)nc1
Reactant: CCC(O)(/C=C/c1ccc(C(CC)(CC)c2cc(C)c(B3OC(C)(C)C(C)(C)O3)c(C)c2)cc1C)CC
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCOC(=O)Cc1ccc(-c2c(C)cc(C(CC)(CC)c3ccc(/C=C/C(O)(CC)CC)c(C)c3)cc2C)nc1
Temperature: 140 °C
Yield: 21.6 %

Procedure:
(6-Chloro-pyridin-3-yl)-acetic acid ethyl ester (30 mg, 0.149 mmol), tetrakis(triphenylphosphine)palladium (0) (16 mg, 0.014 mmol) and potassium phosphate (32 mg, 0.149 mmol) were added to a solution of (E)-1-(4-{1-[3,5-dimethyl-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-1-ethyl-propyl}-2-methyl-phenyl)-3-ethyl-1-penten-3-ol (Example 38-(6); 50 mg, 0.099 mmol) in N,N-dimethylformamide (0.5 mL). After replacement with nitrogen, the mixture was stirred with microwave heating at 140° C. for 10 minutes. Then, ethyl acetate was added to the reaction mixture, which was washed with water and brine. The organic layer was dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The resulting residue was purified by silica gel chromatography (hexane:ethyl acetate=4:1) to give the target compound as a colorless oil (11.6 mg, 22%).
Reaction SMILES: [Cl:1][C:2]1[C:7]([OH:8])=[CH:6][C:5]([N:9]2[C:14](=[O:15])[C:13]([CH3:16])=[C:12]([C:17]([F:20])([F:19])[F:18])[CH:11]=[N:10]2)=[C:4]([F:21])[CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:28](Br)[CH:29]=[CH2:30].O>CN(C)C=O>[Cl:1][C:2]1[C:7]([O:8][CH2:30][CH:29]=[CH2:28])=[CH:6][C:5]([N:9]2[C:14](=[O:15])[C:13]([CH3:16])=[C:12]([C:17]([F:18])([F:20])[F:19])[CH:11]=[N:10]2)=[C:4]([F:21])[CH:3]=1
Reactant: Cc1c(C(F)(F)F)cnn(-c2cc(O)c(Cl)cc2F)c1=O
Reactant: C=CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: C=CCOc1cc(-n2ncc(C(F)(F)F)c(C)c2=O)c(F)cc1Cl
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 91.7 %

Procedure:
First, 400 mg (1.2 mmol) of 2-(4-chloro-2-fluoro-5-hydroxyphenyl)-4-methyl-5-trifluoromethyl-3-oxo-2,3-dihydropyridazine (intermediate 1) was dissolved in 2.0 ml of N,N-dimethylformamide, to which 257 mg (1.86 mmol) of potassium carbonate and 165 mg (1.36 mmol) of allyl bromide were added, and the mixture was stirred at room temperature for 30 minutes. The reaction mixture was poured into water, and extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and then concentrated. The residue was subjected to silica gel column chromatography, which afforded 405 mg (1.1 mmol) of 2-{4-chloro-2-fluoro-5-(2-propenyloxy)phenyl}-4-methyl-5-trifluoromethyl-3-oxo-2,3-dihydropyridazine (hereinafter referred to as intermediate 2), m.p. 79.8° C.
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:12]([OH:14])=[O:13])=[N:4][C:5]([Cl:11])=[C:6](Cl)[C:7]=1NN.[OH-].[Na+].C(Cl)Cl.Cl>O>[Cl:1][C:2]1[C:3]([C:12]([OH:14])=[O:13])=[N:4][C:5]([Cl:11])=[CH:6][CH:7]=1
Reactant: NNc1c(Cl)c(Cl)nc(C(=O)O)c1Cl
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: O
Product: O=C(O)c1nc(Cl)ccc1Cl
Temperature: 25 °C
Yield: 62 %

Procedure:
To a reaction flask containing 400 milliliters of water was added 30 grams (0.11 mole) of 3,5,6-trichloro-4-hydrazinopicolinic acid and 4.5 grams (0.11 mole) of sodium hydroxide dissolved in 25 milliliters of water. The reaction was heated to reflux and maintained under reflux while an additional 4.5 grams of sodium hydroxide dissolved in 25 milliliters of water was added dropwise over 50 minutes. The resulting solution was thereafter heated an additional 45 minutes under reflux and cooled to room temperature. The reaction mixture was mixed with 100 milliliters of methylene chloride and the solution acidified with 35 milliliters of concentrated hydrochloric acid. The two phases which formed were separated and the aqueous layer extracted twice with methylene chloride. The extracts were combined and dried over magnesium sulfate and the solvent evaporated to give 13.1 grams (62 percent of theoretical) of 3,6-dichloropicolinic acid.
Reaction SMILES: [NH2:1][C:2]1[NH:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[C:9]([N+:13]([O-:15])=[O:14])[CH:8]=2)[C:3]=1[C:16]#[N:17].C(O[CH:26](OCC1C=CC=CC=1)[N:27]([CH3:29])[CH3:28])C1C=CC=CC=1>C1(C)C=CC=CC=1>[N+:13]([C:9]1[CH:8]=[C:7]([C:4]2[C:3]([C:16]#[N:17])=[C:2]([N:1]=[CH:26][N:27]([CH3:29])[CH3:28])[NH:6][N:5]=2)[CH:12]=[CH:11][CH:10]=1)([O-:15])=[O:14]
Reactant: CN(C)C(OCc1ccccc1)OCc1ccccc1
Reactant: N#Cc1c(-c2cccc([N+](=O)[O-])c2)n[nH]c1N
Solvent: Cc1ccccc1
Product: CN(C)C=Nc1[nH]nc(-c2cccc([N+](=O)[O-])c2)c1C#N

Procedure:
In 8 ml of toluene, 229 mg (1.00 mmol) of 5-amino-3-(3-nitro-phenyl)-1H-pyrazole-4-carbonitrile and 317 μl of N,N-dimethylformamide dibenzylacetal are boiled overnight. Cooling, filtering the suspension and washing with hexane yield N'-[3-(3-nitrophenyl)-4-cyano-1H-pyrazol-5-yl]-N,N-dimethylformamidine; m.p. 221-225° C.; TRet (Grad22-100)=8.7.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:7])[CH2:5][NH2:6])[CH3:2].Cl.CCN(CC)CC.[CH2:16]([N:20]=[C:21]=[O:22])[CH2:17][CH2:18][CH3:19]>C(Cl)Cl>[CH2:16]([NH:20][C:21]([NH:6][CH2:5][C:4]([O:3][CH2:1][CH3:2])=[O:7])=[O:22])[CH2:17][CH2:18][CH3:19]
Reactant: CCCCN=C=O
Reactant: CCOC(=O)CN
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCCNC(=O)NCC(=O)OCC
Temperature: 25 °C
Reaction time: 8 h
Yield: 94.4 %

Procedure:
Glycine ethyl ester·HCl (5.58 g, 40 mmol) was suspended in distilled CH2Cl2 (20 ml). After cooling in an ice bath, distilled Et3N (6.13 ml, 44 mmol) was added. Distilled n-butyl isocyanate (4.95 ml, 44 mmol) was added. The cooling bath was removed and the mixture was left stirring overnight at room temperature. Additional Et3N (3.05 ml) was added and the mixture was stirred 3 more hours. After diluting with more CH2Cl2, the solution was washed with water (50 ml), lN HCl (50 ml), saturated NaHCO3 solution (50 ml) and water (50 ml). After drying (MgSO4), the solvent was removed in vacuo leaving the title compound (7.641 g, 94%) which slowly crystallized. This was used without further purification.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:17]3[C:12](=[CH:13][C:14]([F:20])=[C:15](F)[C:16]=3[F:18])[C:11](=[O:21])[C:10]([C:22]([OH:24])=[O:23])=[CH:9]2)=[CH:4][CH:3]=1.[Br:25][C:26]1[CH:34]=[CH:33][CH:32]=[C:31]2[C:27]=1[CH2:28][NH:29][CH2:30]2>CN(C=O)C>[Br:25][C:26]1[CH:34]=[CH:33][CH:32]=[C:31]2[C:27]=1[CH2:28][N:29]([C:15]1[C:16]([F:18])=[C:17]3[C:12]([C:11](=[O:21])[C:10]([C:22]([OH:24])=[O:23])=[CH:9][N:8]3[C:5]3[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=3)=[CH:13][C:14]=1[F:20])[CH2:30]2
Reactant: Brc1cccc2c1CNC2
Reactant: O=C(O)c1cn(-c2ccc(F)cc2)c2c(F)c(F)c(F)cc2c1=O
Solvent: CN(C)C=O
Product: O=C(O)c1cn(-c2ccc(F)cc2)c2c(F)c(N3Cc4cccc(Br)c4C3)c(F)cc2c1=O
Yield: 62.4 %

Procedure:
170 mg of 1-(4-fluorophenyl)-6,7,8-trifluoro-1,4- dihydro-4-oxoquinoline-3-carboxylic acid, 300 mg of 4-bromoisoindoline, and 1.5 ml of anhydrous DMF were processed in the same manner as in Example 20 to produce 162 mg of the target compound.
Reaction SMILES: O=S(Cl)[Cl:3].[CH3:5][C:6]1[O:10][C:9]([C:11]([OH:13])=O)=[CH:8][CH:7]=1>C1C=CC=CC=1>[CH3:5][C:6]1[O:10][C:9]([C:11]([Cl:3])=[O:13])=[CH:8][CH:7]=1
Reactant: O=S(Cl)Cl
Reactant: Cc1ccc(C(=O)O)o1
Solvent: c1ccccc1
Product: Cc1ccc(C(=O)Cl)o1
Temperature: 80 °C
Reaction time: 1 h

Procedure:
A solution of 0.31 g of SOCl2 in 2 ml of benzene was added dropwise at 0° C. under nitrogen atmosphere to a solution of 0.22 g of 5-methylfuran-2-carboxylic acid, prepared following the method described by Robert et al., Eur. J. Med. Chem. 30, 915-924 (1995), in 5 ml of benzene. The mixture was stirred at 80° C. for 1 hour and the excess SOCl2 was then distilled off. The residue (0.24 g, 97% of theory) was utilized for the next step without further purification.
Reaction SMILES: F[C:2]1[C:7]([C:8]([OH:10])=O)=[CH:6][CH:5]=[C:4]([F:11])[N:3]=1.Cl.[F:13][C:14]1[CH:15]=[C:16]([CH2:20][CH2:21][O:22][CH2:23][C:24]([NH2:26])=[NH:25])[CH:17]=[CH:18][CH:19]=1>>[F:11][C:4]1[CH:5]=[CH:6][C:7]2[C:8](=[O:10])[NH:26][C:24]([CH2:23][O:22][CH2:21][CH2:20][C:16]3[CH:17]=[CH:18][CH:19]=[C:14]([F:13])[CH:15]=3)=[N:25][C:2]=2[N:3]=1
Reactant: O=C(O)c1ccc(F)nc1F
Reactant: N=C(N)COCCc1cccc(F)c1
Agent: Cl
Product: O=c1[nH]c(COCCc2cccc(F)c2)nc2nc(F)ccc12

Procedure:
The title compound was prepared in analogy to example 85 from 2,6-difluoropyridine-3-carboxylic acid and 2-[2-(3-fluoro-phenyl)-ethoxy]-acetamidine hydrochloride. Light brown solid. MS: m/e=318.1 [M+H+].
Reaction SMILES: [CH2:1]([NH2:5])[CH2:2][CH2:3][CH3:4].[C:6](Cl)(=[O:10])[C:7]([CH3:9])=[CH2:8]>C1COCC1>[CH2:1]([NH:5][C:6](=[O:10])[C:7]([CH3:9])=[CH2:8])[CH2:2][CH2:3][CH3:4]
Reactant: C=C(C)C(=O)Cl
Reactant: CCCCN
Solvent: C1CCOC1
Product: C=C(C)C(=O)NCCCC
Temperature: 5 °C

Procedure:
In a 1 liter 3-necked flask were combined 400 ml dry THF and 40 ml distilled n-butylamine (0.405 mol). After cooling to 5° C. in an ice bath, 20 ml (0.205 mol) methacryloyl chloride was added slowly so as to keep the temperature below 10° C. The precipitate was removed by filtration, and the filtrate concentrated on a rotary evaporator. 1 g DNPD was added and the oil distilled at 76°-78° C. and 20 m torr. Yield 24.3 g (84%).
Reaction SMILES: [CH:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[O:13][N:12]=[C:11]([C:14]3[CH:29]=[C:28]([CH3:30])[C:17]([O:18][CH2:19][CH:20]([OH:27])[CH2:21][NH:22][C:23](=[O:26])[CH2:24][OH:25])=[C:16]([CH3:31])[CH:15]=3)[N:10]=2)=[CH:5][CH:4]=1)=O.[CH3:32][NH:33][CH3:34]>>[CH3:32][N:33]([CH2:1][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[O:13][N:12]=[C:11]([C:14]3[CH:29]=[C:28]([CH3:30])[C:17]([O:18][CH2:19][CH:20]([OH:27])[CH2:21][NH:22][C:23](=[O:26])[CH2:24][OH:25])=[C:16]([CH3:31])[CH:15]=3)[N:10]=2)=[CH:5][CH:4]=1)[CH3:34]
Reactant: CNC
Reactant: Cc1cc(-c2noc(-c3ccc(C=O)cc3)n2)cc(C)c1OCC(O)CNC(=O)CO
Product: Cc1cc(-c2noc(-c3ccc(CN(C)C)cc3)n2)cc(C)c1OCC(O)CNC(=O)CO

Procedure:
The title compound was prepared starting from rac-N-(3-{4-[5-(4-formyl-phenyl)-[1,2,4]oxadiazol-3-yl]-2,6-dimethyl-phenoxy}-2-hydroxy-propyl)-2-hydroxy-acetamide and dimethyl amine according to Method B. LC-MS*: tR=0.78 min; [M+1]+=455.38, 1H NMR (CDCl3): δ2.30 (s, 6H), 2.38 (s, 6H), 3.47-3.53 (m, 1H), 3.54 (s, 2H), 3.75-3.93 (m, 3H), 4.16-4.25 (m, 3H), 7.00 (br s, 1H), 7.53 (d, J=7.8 Hz, 2H), 7.86 (s, 2H), 8.19 (d, J=7.3 Hz, 2H).
Reaction SMILES: Cl.[O:2]=[C:3]1[C:9]2[S:10][CH:11]=[CH:12][C:8]=2[CH:7]([NH2:13])[CH2:6][CH2:5][CH2:4]1.[CH3:14][N:15]=[C:16]=[O:17].C(N(CC)CC)C>C(Cl)Cl>[CH3:14][NH:15][C:16]([NH:13][CH:7]1[C:8]2[CH:12]=[CH:11][S:10][C:9]=2[C:3](=[O:2])[CH2:4][CH2:5][CH2:6]1)=[O:17]
Reactant: CN=C=O
Reactant: NC1CCCC(=O)c2sccc21
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CNC(=O)NC1CCCC(=O)c2sccc21

Procedure:
Stoichiometric quantities of 5,6,7,8-tetrahydro-8-oxo-4H-cyclohepta[b]thiophen-4-amine hydrochloride, methyl isocyanate, and triethylamine are allowed to react in dry methylene chloride to afford the title compound.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:34])[CH2:4][C@H:5]1[C:9]2[CH:10]=[CH:11][C:12]([O:14][C@H:15]3[C:23]4[C:18](=[C:19](B5OC(C)(C)C(C)(C)O5)[CH:20]=[CH:21][C:22]=4[F:24])[CH2:17][CH2:16]3)=[CH:13][C:8]=2[O:7][CH2:6]1.Br[C:36]1[C:41]([CH3:42])=[CH:40][C:39]([C:43]2[CH:48]=[N:47][C:46]([CH3:49])=[CH:45][N:44]=2)=[CH:38][C:37]=1[CH3:50].BrC1C=CC(F)=C2C=1CC[C@H]2OC1C=CC2[C@H](CC(OC)=O)COC=2C=1>>[CH3:1][O:2][C:3](=[O:34])[CH2:4][C@H:5]1[C:9]2[CH:10]=[CH:11][C:12]([O:14][C@H:15]3[C:23]4[C:18](=[C:19]([C:36]5[C:37]([CH3:50])=[CH:38][C:39]([C:43]6[CH:48]=[N:47][C:46]([CH3:49])=[CH:45][N:44]=6)=[CH:40][C:41]=5[CH3:42])[CH:20]=[CH:21][C:22]=4[F:24])[CH2:17][CH2:16]3)=[CH:13][C:8]=2[O:7][CH2:6]1
Reactant: Cc1cnc(-c2cc(C)c(Br)c(C)c2)cn1
Reactant: COC(=O)C[C@@H]1COc2cc(O[C@@H]3CCc4c(B5OC(C)(C)C(C)(C)O5)ccc(F)c43)ccc21
Agent: COC(=O)C[C@@H]1COc2cc(O[C@@H]3CCc4c(Br)ccc(F)c43)ccc21
Product: COC(=O)C[C@@H]1COc2cc(O[C@@H]3CCc4c(-c5c(C)cc(-c6cnc(C)cn6)cc5C)ccc(F)c43)ccc21

Procedure:
The title compound is prepared from {(S)-6-[(R)-7-fluoro-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-indan-1-yloxy]-2,3-dihydro-benzofuran-3-yl}-acetic acid methyl ester and 2-(4-bromo-3,5-dimethyl-phenyl)-5-methyl-pyrazine following a procedure analogous to that described in Step 5 of Intermediate 1.
Reaction SMILES: C[N:2](C)C=O.[CH3:6][O:7][C:8]([C:10]1[CH:15]=[CH:14][C:13]([C:16](=O)[CH2:17][C:18]([C:20]2[CH:25]=[CH:24][C:23]([O:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31])=[CH:22][CH:21]=2)=[O:19])=[CH:12][CH:11]=1)=[O:9].C([O-])=O.[NH4+].C(OCC)(=O)C>O>[NH2:2][C:16]([C:13]1[CH:14]=[CH:15][C:10]([C:8]([O:7][CH3:6])=[O:9])=[CH:11][CH:12]=1)=[CH:17][C:18](=[O:19])[C:20]1[CH:25]=[CH:24][C:23]([O:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31])=[CH:22][CH:21]=1
Reactant: CCCCCOc1ccc(C(=O)CC(=O)c2ccc(C(=O)OC)cc2)cc1
Reactant: CN(C)C=O
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CCOC(C)=O
Solvent: O
Product: CCCCCOc1ccc(C(=O)C=C(N)c2ccc(C(=O)OC)cc2)cc1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
Dimethylformamide (123 l), 1-(4-methoxycarbonylphenyl)-3-(4-pentyloxyphenyl)propane-1,3-dione (24.5 kg) and ammonium formate (21.0 kg) were charged in 2000-liter reactor at room temperature and heated, and a reaction was carried out at the inner temperature of 100 to 105° C. for 5 hours. After completion of the reaction, the mixture was cooled down to room temperature, ethyl acetate (613 l) and water (613 l) were added, the mixture was stirred, and an ethyl acetate layer was separated, and then washed with 10% sodium chloride solution (613 l) and with 20% sodium chloride solution (613 l). The ethyl acetate layer was concentrated in vacuo to 125 l and then diluted with n-heptane (625 l) at the inner temperature of 40 to 45° C. to separate crystals of 1-amino-1-(4-methoxycarbonylphenyl)-3-oxo-3-(4-pentyloxyphenyl)-1-propene. The cyrstals were filtered at room temperature and washed with a mixture of n-heptane (104 l) and ethyl acetate (21 l). The crystals were dried overnight in vacuo and purified by suspending in a 70% aqueous acetone (158 l) to give 1-amino-1-(4-methoxycarbonylphenyl)-3-oxo-3-(4-pentyloxyphenyl)-1-propene (14.3 kg).
Reaction SMILES: [NH:1]([C:6]([O:8][CH2:9][CH:10]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[C:16]2[C:11]1=[CH:12][CH:13]=[CH:14][CH:15]=2)=[O:7])[CH2:2][C:3](O)=[O:4].CN(C)CCCN=C=NCC.ON1C2C=CC=CC=2N=N1.C(N(CC)CC)C.Cl.[CH3:52][O:53][C:54](=[O:74])[CH:55]([NH2:73])[CH:56]([C:61]1[CH:66]=[CH:65][C:64]([C:67]2[CH:72]=[CH:71][CH:70]=[CH:69][CH:68]=2)=[CH:63][CH:62]=1)[C:57]([O:59][CH3:60])=[O:58]>CN(C)C=O>[CH3:60][O:59][C:57](=[O:58])[CH:56]([C:61]1[CH:62]=[CH:63][C:64]([C:67]2[CH:68]=[CH:69][CH:70]=[CH:71][CH:72]=2)=[CH:65][CH:66]=1)[CH:55]([NH:73][C:3](=[O:4])[CH2:2][NH:1][C:6]([O:8][CH2:9][CH:10]1[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:16]=2[C:17]2[C:22]1=[CH:21][CH:20]=[CH:19][CH:18]=2)=[O:7])[C:54]([O:53][CH3:52])=[O:74]
Reactant: O=C(O)CNC(=O)OCC1c2ccccc2-c2ccccc21
Reactant: COC(=O)C(N)C(C(=O)OC)c1ccc(-c2ccccc2)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COC(=O)C(NC(=O)CNC(=O)OCC1c2ccccc2-c2ccccc21)C(C(=O)OC)c1ccc(-c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 14 h
Yield: 54 %

Procedure:
A solution of Fmoc-Gly-OH (from Bachem) (1.66 g., 5.6 mmol), N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide (from Aldrich, 39391) (1.1 g., 5.7 mmol), 1-hydroxybenzotriazole (from Aldrich, 54804) (0.76 g., 5.6 mmol) and triethylamine (0.4 mL, 2.8 mmol) in dimethylformamide (50 mL) was stirred at room temperature for 1 hour. A solution of 2-amino-3-biphenyl-4-yl-succinic acid dimethyl ester hydrochloride (0.98 g., 2.8 mmol) in dimethylformamide (10 mL) was added and the reaction mixture was stirred at room temperature for a further 14 hours. The solvent was removed in vacuo and the residue partitioned between ethylacetate (100 mL) and sodium bicarbonate (100 mL, saturated solution in water). The aqueous layer was washed with ethylacetate (2×100 mL), the organics combined, dried over magnesium sulphate and concentrated in vacuo to afford a crude residue. The crude product was purified using flash chromatography (SiO2) eluting with ethylacetate/isohexane (3:1) to afford 2-biphenyl-4-yl-3-[2-(9H-fluoren-9-ylmethoxycarbonylamino)-acetylamino]-succinic acid dimethyl ester as a white crystalline solid (0.89 g., 54% yield). 1HNMR (CDCl3) δH(ppm); 3.71-3.73 (m, 7H), 3.81 0.2H (d, CH J=5.6 Hz), 3.86, 0.3H (d, CH J=5.8 Hz), 3.9, 0.3H (d, CH J=5.3 Hz), 3.94, 0.2H (d, CH J=5.8 Hz), 4.13-4.24 (m, 1H), 4.28-4.44 (m, 2.5H), 4.5 (d, 0.5H J=4.4 Hz), 5.1-5.4 (m, 2H), 6.4 (d, NH J=8.5 Hz), 7.19 (d, NH J=9.4 Hz), 7.23-7.34, 5H (m, Ar—H), 7.35-7.42, 4H (m, Ar—H), 7.47-7.60, 6H (m, Ar—H), 7.74, 2H (d, Ar—H J=7.6 Hz); LCMS analysis (solvent MeCN/H2O/0.1% HCO2H, 5-95% gradient/H2O 2.5 min, 95% 4 min., Phenomenex C18 reverse phase, flow rate 1 mL/min.) HPLC retention times 5.33 and 5.47 min. (diastereoisomers).; mass found 593 (M+H).
Reaction SMILES: CO[C:3](=[O:69])[C@H:4]([CH2:60][O:61][CH2:62][C:63]1[CH:68]=[CH:67][CH:66]=[CH:65][CH:64]=1)[NH:5][C:6](=[O:59])[C@H:7]([CH2:44][C:45]1[CH:50]=[CH:49][C:48]([O:51][CH2:52][C:53]2[CH:58]=[CH:57][CH:56]=[CH:55][CH:54]=2)=[CH:47][CH:46]=1)[NH:8][C:9](=[O:43])[C@@H:10]1[CH2:14][CH2:13][CH2:12][N:11]1[C:15](=[O:42])[C@@H:16]1[CH2:20][CH2:19][CH2:18][N:17]1[C:21](=[O:41])[C@H:22]([CH2:31][C:32]1[C:40]2[C:35](=[CH:36][CH:37]=[CH:38][CH:39]=2)[NH:34][CH:33]=1)[NH:23][C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25].[NH3:70]>CO>[C:27]([O:26][C:24]([NH:23][C@H:22]([C:21]([N:17]1[CH2:18][CH2:19][CH2:20][C@H:16]1[C:15]([N:11]1[CH2:12][CH2:13][CH2:14][C@H:10]1[C:9]([NH:8][C@H:7]([C:6]([NH:5][C@H:4]([C:3]([NH2:70])=[O:69])[CH2:60][O:61][CH2:62][C:63]1[CH:64]=[CH:65][CH:66]=[CH:67][CH:68]=1)=[O:59])[CH2:44][C:45]1[CH:50]=[CH:49][C:48]([O:51][CH2:52][C:53]2[CH:58]=[CH:57][CH:56]=[CH:55][CH:54]=2)=[CH:47][CH:46]=1)=[O:43])=[O:42])=[O:41])[CH2:31][C:32]1[C:40]2[C:35](=[CH:36][CH:37]=[CH:38][CH:39]=2)[NH:34][CH:33]=1)=[O:25])([CH3:29])([CH3:30])[CH3:28]
Reactant: COC(=O)[C@H](COCc1ccccc1)NC(=O)[C@H](Cc1ccc(OCc2ccccc2)cc1)NC(=O)[C@@H]1CCCN1C(=O)[C@@H]1CCCN1C(=O)[C@H](Cc1c[nH]c2ccccc12)NC(=O)OC(C)(C)C
Reactant: N
Solvent: CO
Product: CC(C)(C)OC(=O)N[C@@H](Cc1c[nH]c2ccccc12)C(=O)N1CCC[C@H]1C(=O)N1CCC[C@H]1C(=O)N[C@@H](Cc1ccc(OCc2ccccc2)cc1)C(=O)N[C@@H](COCc1ccccc1)C(N)=O
Reaction time: 72 h

Procedure:
Nα -t-Butoxycarbonyl-L-tryptophyl-L-prolyl-L-prolyl-O-benzyl-L-tyrosyl-O-benzyl-L-serine methyl ester (0.5 g.) is dissolved in methanol, 25 ml., and the solution saturated with gaseous ammonia. The reaction is let stand for three days at room temperature, and the solvent then removed by evaporation.