Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][CH2:2][C:3]([OH:5])=[O:4].[OH-].[Na+].[Cl:8][C:9]1[CH:10]=[C:11]([CH:15]=[CH:16][C:17]=1[Cl:18])[C:12](Cl)=[O:13].Cl>C(#N)C>[Cl:8][C:9]1[CH:10]=[C:11]([CH:15]=[CH:16][C:17]=1[Cl:18])[C:12]([NH:1][CH2:2][C:3]([OH:5])=[O:4])=[O:13]
Reactant: NCC(=O)O
Reactant: O=C(Cl)c1ccc(Cl)c(Cl)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CC#N
Product: O=C(O)CNC(=O)c1ccc(Cl)c(Cl)c1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 41.4 %

Procedure:
To glycine (3.6 g, 47.7 mmol) in acetonitrile (100 mL) at ambient temperature was added 2N aqueous sodium hydroxide (60 mL, 120 mmol). The reaction mixture was cooled to about 0° C. and 3,4-dichlorobenzoyl chloride (10 g, 47.7 mmol) in acetonitrile (20 mL) was added slowly over about 5 minutes. The reaction mixture was stirred for about 30 minutes at 0° C. then the pH of the reaction mixture was adjusted to 3 by addition of 3N aqueous hydrochloric acid. The organic solvent was removed in vacuo and the aqueous layer extracted with ethyl acetate. The combined organic layers were washed with brine (30 mL), dried over MgSO4 and concentrated in vacuo to afford a light yellow solid. The crude material was triturated with toluene (100 mL) and washed with cold toluene (3×100 mL). The resulting white solid was recrystallized from ethyl acetate to afford 2-(3,4-dichlorobenzamido)acetic acid (4.9 g, 42%) as a white solid. RP-HPLC (table 1, Method b) Rt 1.45 min; m/z: (M+H)+ 246.
Reaction SMILES: [CH:1]1[CH:6]=[C:5]2[C:7]([N-:9][C:10](=[O:11])[C:4]2=[CH:3][CH:2]=1)=[O:8].[K+].[N+:13]([C:16]1[CH:23]=[CH:22][CH:21]=[CH:20][C:17]=1[CH2:18]Cl)([O-:15])=[O:14]>CN(C)C=O>[N+:13]([C:16]1[CH:23]=[CH:22][CH:21]=[CH:20][C:17]=1[CH2:18][N:9]1[C:7](=[O:8])[C:5]2=[CH:6][CH:1]=[CH:2][CH:3]=[C:4]2[C:10]1=[O:11])([O-:15])=[O:14]
Reactant: O=C1[N-]C(=O)c2ccccc21
Reactant: O=[N+]([O-])c1ccccc1CCl
Agent: [K+]
Solvent: CN(C)C=O
Product: O=C1c2ccccc2C(=O)N1Cc1ccccc1[N+](=O)[O-]
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
The starting material is prepared as follows: The mixture of 54.0 of N-potassium phthalimide, 50.0 g of o-nitrobenzyl chloride and 120 ml of dimethylformamide is refluxed for 3 hours and poured into 900 ml of ice-water while stirring. After 30 minutes, it is filtered, and the residue washed with water, to yield the N-o-nitrobenzyl-phthalimide melting at 190-209°.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([C:16]([OH:18])=O)=[CH:8][C:9]=1[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)=[O:4].C(N(CC)CC)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C1C=CC2N(O)N=NC=2C=1.[C:60]([Si:64]([CH3:75])([CH3:74])[O:65][C:66]1[CH:67]=[C:68]([CH:71]=[CH:72][CH:73]=1)[CH2:69][NH2:70])([CH3:63])([CH3:62])[CH3:61]>CN(C=O)C>[CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([C:16](=[O:18])[NH:70][CH2:69][C:68]2[CH:71]=[CH:72][CH:73]=[C:66]([O:65][Si:64]([C:60]([CH3:63])([CH3:62])[CH3:61])([CH3:74])[CH3:75])[CH:67]=2)=[CH:8][C:9]=1[C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1)=[O:4]
Reactant: CC(C)(C)[Si](C)(C)Oc1cccc(CN)c1
Reactant: COC(=O)c1sc(C(=O)O)cc1-c1ccccc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COC(=O)c1sc(C(=O)NCc2cccc(O[Si](C)(C)C(C)(C)C)c2)cc1-c1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 39.1 %

Procedure:
To a solution of 3-Phenyl-thiophene-2,5-dicarboxylic acid 2-methyl ester (500 mg, 1.91 mmol) in anhydrous DMF (10 mL) was added triethylamine (0.53 mL, 3.82 mmol), HBTU (1.45 g, 3.82 mmol), HOBT (390 mg, 3.82 mmol), and 3-(tert-Butyl-dimethyl-silanyloxy)-benzylamine (540 mg, 2.29 mmol). The mixture was stirred at room temperature 1 h, then quenched by pouring into EtOAc. The organic layer was washed with brine, dried over Na2SO4 and concentrated under reduced pressure. The residue was purified by flash chromatography with 0-30% EtOAc in hexane to afford the desired product (0.36 g, 39% yield).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12](=[O:13])[NH:11][N:10]=[C:9]2[CH2:14][C@@H:15]2[CH2:19][CH2:18][N:17]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:16]2)=[CH:4][CH:3]=1.CC1(C)C(C)(C)OB([C:35]2[CH:36]=[CH:37][C:38]3[O:42][CH:41]=[CH:40][C:39]=3[CH:43]=2)O1.C(=O)(O)[O-].[Na+]>O1CCOCC1.O.C(OCC)(=O)C>[O:42]1[C:38]2[CH:37]=[CH:36][C:35]([C:2]3[CH:7]=[CH:6][C:5]([N:8]4[C:12](=[O:13])[NH:11][N:10]=[C:9]4[CH2:14][C@@H:15]4[CH2:19][CH2:18][N:17]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:16]4)=[CH:4][CH:3]=3)=[CH:43][C:39]=2[CH:40]=[CH:41]1
Reactant: CC1(C)OB(c2ccc3occc3c2)OC1(C)C
Reactant: CC(C)(C)OC(=O)N1CC[C@@H](Cc2n[nH]c(=O)n2-c2ccc(Br)cc2)C1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Solvent: O
Product: CC(C)(C)OC(=O)N1CC[C@@H](Cc2n[nH]c(=O)n2-c2ccc(-c3ccc4occc4c3)cc2)C1
Temperature: 100 °C
Reaction time: 24 h
Yield: 95.5 %

Procedure:
In a sealed pressure tube, a mixture of 1,1-dimethylethyl (3S)-3-{[4-(4-bromophenyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-3-yl]methyl}-1-pyrrolidinecarboxylate (2.5 g, 5.91 mmol), 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-benzofuran (1.514 g, 6.20 mmol), 1,1′-bis(diphenylphosphino)ferrocene-palladium(II)dichloride dichloromethane complex (0.241 g, 0.295 mmol), and sodium bicarbonate (1.488 g, 17.72 mmol) in 1,4-dioxane (30 mL) and water (15 mL) was stirred at 100° C. for 24 h. The reaction was cooled to room temperature. The reaction was diluted with ethyl acetate (300 mL) and water (100 mL), and the layers were separated. The aqueous layer was acidified to pH˜6 using a 1N aq HCl solution and then extracted with ethyl acetate (3×100 mL). The combined organic layers were dried over magnesium sulfate and concentrated in vacuo. Purification of the residue by silica gel chromatography (Analogix IF280, SF40-115g, Solvent A: ethyl acetate; Solvent B: 10% methanol/dichloromethane; Gradient: 100% A for 10 min, then 0-50% B/A over 20 min) provided the title compound as a tan solid (2.6 g, 96%). MS(ES)+ m/e 461.4 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[CH:23]=[CH:22][C:5]([C:6]([N:8]([CH3:21])[CH2:9][CH2:10][CH2:11][N:12]([CH3:20])[C:13](=[O:19])[O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:7])=[C:4]([Cl:24])[CH:3]=1.[C:25]1([C:53]2[CH:58]=[CH:57][CH:56]=[CH:55][CH:54]=2)[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[NH:31][C:32](=[O:52])[O:33][CH:34]1[CH2:39][CH2:38][N:37]([CH2:40][CH2:41][N:42]([CH3:51])[C:43](=[O:50])[CH2:44][CH2:45][CH2:46][CH2:47][CH:48]=O)[CH2:36][CH2:35]1>>[C:25]1([C:53]2[CH:54]=[CH:55][CH:56]=[CH:57][CH:58]=2)[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[NH:31][C:32](=[O:52])[O:33][CH:34]1[CH2:39][CH2:38][N:37]([CH2:40][CH2:41][N:42]([C:43](=[O:50])[CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][NH:1][C:2]2[CH:23]=[CH:22][C:5]([C:6](=[O:7])[N:8]([CH2:9][CH2:10][CH2:11][N:12]([C:13]([O:14][C:15]([CH3:18])([CH3:16])[CH3:17])=[O:19])[CH3:20])[CH3:21])=[C:4]([Cl:24])[CH:3]=2)[CH3:51])[CH2:36][CH2:35]1
Reactant: CN(CCCN(C)C(=O)c1ccc(N)cc1Cl)C(=O)OC(C)(C)C
Reactant: CN(CCN1CCC(OC(=O)Nc2ccccc2-c2ccccc2)CC1)C(=O)CCCCC=O
Product: CN(CCN1CCC(OC(=O)Nc2ccccc2-c2ccccc2)CC1)C(=O)CCCCCNc1ccc(C(=O)N(C)CCCN(C)C(=O)OC(C)(C)C)c(Cl)c1
Yield: 58.7 %

Procedure:
The compound (149 mg, 0.420 mmol) obtained in Example 85a and the compound (163 mg, 0.351 mmol) obtained in Example 4g were used to give the title compound (166 mg; yield, 59%) as a white solid according to the method described in Example 18b.
Reaction SMILES: [N:1]1([C:6]2[CH:26]=[CH:25][C:9]([CH2:10][C:11]3[C:12]([O:23][CH3:24])=[CH:13][C:14]([CH:21]=C)=[C:15]([CH:20]=3)[C:16]([O:18][CH3:19])=[O:17])=[CH:8][CH:7]=2)[CH:5]=[CH:4][CH:3]=[N:2]1.CC(C)=[O:29].C(#N)C.I([O-])(=O)(=O)=O.[Na+]>[Os]=O.O>[N:1]1([C:6]2[CH:7]=[CH:8][C:9]([CH2:10][C:11]3[C:12]([O:23][CH3:24])=[CH:13][C:14]([CH:21]=[O:29])=[C:15]([CH:20]=3)[C:16]([O:18][CH3:19])=[O:17])=[CH:25][CH:26]=2)[CH:5]=[CH:4][CH:3]=[N:2]1
Reactant: C=Cc1cc(OC)c(Cc2ccc(-n3cccn3)cc2)cc1C(=O)OC
Reactant: CC(C)=O
Agent: O=[Os]
Agent: [Na+]
Agent: [O-][I+3]([O-])([O-])[O-]
Solvent: O
Solvent: CC#N
Product: COC(=O)c1cc(Cc2ccc(-n3cccn3)cc2)c(OC)cc1C=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of methyl 5-(4-(1H-pyrazol-1-yl)benzyl)-4-methoxy-2-vinylbenzoate (0.16 g) in a mixed solvent of acetone (2.20 mL)-acetonitrile (2.20 mL)-water (2.20 mL) were added osmium oxide (fixed catalyst I) (0.06 g) and sodium periodate (0.48 g), and the mixture was stirred overnight at room temperature. The reaction mixture was filtered, and the filtrate was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure to give the title compound (0.16 g) as a crude product. This compound was used in the next step without an additional purification.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:9]2[C:13]([C:14]3[CH:19]=[C:18]([O:20][CH3:21])[CH:17]=[C:16]([F:22])[CH:15]=3)=[CH:12][C:11]([C:23]([OH:25])=O)=[N:10]2)[CH:5]=[CH:6][C:7]=1[F:8].ClC1C=C(N2C(C3C=C(OC)C=C(F)C=3)=CC(C([N:49]3[CH2:53][C:52](=[O:54])[NH:51][CH2:50]3)=O)=N2)C=CC=1>>[Cl:1][C:2]1[CH:3]=[C:4]([N:9]2[C:13]([C:14]3[CH:19]=[C:18]([O:20][CH3:21])[CH:17]=[C:16]([F:22])[CH:15]=3)=[CH:12][C:11]([C:23]([N:49]3[CH2:53][C:52](=[O:54])[NH:51][CH2:50]3)=[O:25])=[N:10]2)[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: COc1cc(F)cc(-c2cc(C(=O)N3CNC(=O)C3)nn2-c2cccc(Cl)c2)c1
Reactant: COc1cc(F)cc(-c2cc(C(=O)O)nn2-c2ccc(F)c(Cl)c2)c1
Product: COc1cc(F)cc(-c2cc(C(=O)N3CNC(=O)C3)nn2-c2ccc(F)c(Cl)c2)c1

Procedure:
The preparation of the title compound takes place starting from the compound of Example 92A in analogy to the synthesis of the compound of Example 21. 29 mg (24% of theory) of the title compound are obtained.
Reaction SMILES: [C:1]([NH:11][CH:12]([C:17]([OH:19])=O)[CH2:13][CH2:14][CH2:15]C)([O:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:2].S(Cl)(Cl)=O.[NH2:24][C:25]1[CH:39]=[CH:38][C:37]([N+:40]([O-:42])=[O:41])=[CH:36][C:26]=1[C:27]([C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=1[F:35])=[O:28]>O1CCCC1>[CH2:4]([O:3][C:1](=[O:2])[NH:11][CH:12]([C:17](=[O:19])[NH:24][C:25]1[CH:39]=[CH:38][C:37]([N+:40]([O-:42])=[O:41])=[CH:36][C:26]=1[C:27](=[O:28])[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=1[F:35])[CH2:13][CH2:14][CH3:15])[C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=1
Reactant: CCCCC(NC(=O)OCc1ccccc1)C(=O)O
Reactant: Nc1ccc([N+](=O)[O-])cc1C(=O)c1ccccc1F
Solvent: C1CCOC1
Solvent: O=S(Cl)Cl
Product: CCCC(NC(=O)OCc1ccccc1)C(=O)Nc1ccc([N+](=O)[O-])cc1C(=O)c1ccccc1F
Reaction time: 1 h

Procedure:
19.7 g of N-carbobenzoxy-DL-norleucine are dissolved in 200 ml of absolute tetrahydrofuran, the solution is treated dropwise while cooling with ice with 10 g of thionyl chloride and then stirred for 1 hour. To this solution there is rapidly added dropwise a solution of 17 g (0.065 M) of 2-amino-5-nitro-2'-fluorobenzophenone in 130 ml of absolute tetrahydrofuran and the mixture is then stirred at room temperature for 60 hours. The solution is concentrated and the residue is treated with ice and 10% sodium bicarbonate solution and extracted with methylene chloride. The organic solution is dried with sodium sulphate, filtered and concentrated. The residue is purified on a 450 g silica gel column using methylene chloride as the eluting agent and crystallised from ethanol. There is obtained benzyl-rac-{1-[[2-(o-fluorobenzoyl)-4-nitrophenyl]carbamoyl]butyl}carbamate which melts at 148°-150° C.
Reaction SMILES: [CH3:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[S:4][C:3]=1[CH2:11][C:12](Cl)=[O:13].C(N(CC)CC)C.[NH2:22][C:23]1[CH:44]=[CH:43][C:26]([C:27]([N:29]2[C:35]3[CH:36]=[CH:37][CH:38]=[CH:39][C:34]=3[CH2:33][N:32]3[CH:40]=[CH:41][CH:42]=[C:31]3[CH2:30]2)=[O:28])=[CH:25][CH:24]=1.CN(C1C=CC=CN=1)C>C(Cl)Cl>[CH:42]1[CH:41]=[CH:40][N:32]2[CH2:33][C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=3[N:29]([C:27]([C:26]3[CH:25]=[CH:24][C:23]([NH:22][C:12](=[O:13])[CH2:11][C:3]4[S:4][C:5]5[CH:6]=[CH:7][CH:8]=[CH:9][C:10]=5[C:2]=4[CH3:1])=[CH:44][CH:43]=3)=[O:28])[CH2:30][C:31]=12
Reactant: Cc1c(CC(=O)Cl)sc2ccccc12
Reactant: Nc1ccc(C(=O)N2Cc3cccn3Cc3ccccc32)cc1
Agent: CN(C)c1ccccn1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1c(CC(=O)Nc2ccc(C(=O)N3Cc4cccn4Cc4ccccc43)cc2)sc2ccccc12
Reaction time: 0.05 h
Yield: 39.5 %

Procedure:
To a stirred solution of 0.445 g of 3-methylbenzo[b]thiophene-2-acetyl chloride in 5 ml of methylene chloride is added 0.346 g of triethylamine at 0° C. After stirring for 3 minutes, 0.500 g of 10,11-dihydro-10-(4-aminobenzoyl)-5H-pyrrolo[2,1-c][1,4]benzodiazepine is added and stirring continued for 72 hours at room temperature. An additional 0.445 g of 3-methylbenzo[b]thiophene-2-acetyl chloride, 0.346 g of triethylamine and 30 mg of dimethylaminopyridine is added and stirring continued for an additional 18 hours. The reaction mixture is diluted with 45 ml of methylene chloride and washed with water, 2N citric acid, 1M NaHCO3, and brine. The reaction mixture is dried with Na2 SO4, filtered and evaporated in vacuo to give a solid which is purified by flash chromatography using 1:1 ethyl acetate-hexane to give 0.320 g of the desired product as a yellow foam.
Reaction SMILES: [CH:1]1([O:7][C:8]2[C:13](B(O)O)=[CH:12][CH:11]=[CH:10][N:9]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.Br[C:18]1[CH:23]=[CH:22][C:21]([C:24]2[N:25]=[CH:26][C:27]([NH2:30])=[N:28][CH:29]=2)=[C:20]([F:31])[CH:19]=1>>[CH:1]1([O:7][C:8]2[C:13]([C:18]3[CH:23]=[CH:22][C:21]([C:24]4[N:25]=[CH:26][C:27]([NH2:30])=[N:28][CH:29]=4)=[C:20]([F:31])[CH:19]=3)=[CH:12][CH:11]=[CH:10][N:9]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: Nc1cnc(-c2ccc(Br)cc2F)cn1
Reactant: OB(O)c1cccnc1OC1CCCCC1
Product: Nc1cnc(-c2ccc(-c3cccnc3OC3CCCCC3)cc2F)cn1

Procedure:
The title compound was prepared using methods analogous to those described in Example 369 using (2-(cyclohexyloxy)pyridin-3-yl)boronic acid and 5-(4-bromo-2-fluorophenyl)pyrazin-2-amine in Step B. MS (ESI): mass calcd. for C21H21FN4O, 364.17; m/z found, 365.2 [M+H]+. 1H NMR (400 MHz, CDCl3) δ 8.64-8.57 (m, 1H), 8.18-8.10 (m, 2H), 8.00-7.92 (m, 1H), 7.70-7.63 (m, 1H), 7.52-7.43 (m, 2H), 6.94 (dd, J=5.0, 7.4, 1H), 5.26-5.16 (m, 1H), 4.66 (s, 2H), 2.05-1.91 (m, 2H), 1.82-1.68 (m, 2H), 1.66-1.24 (m, 6H).
Reaction SMILES: [Cl:1][C:2]1[C:7]2[O:8][CH2:9][O:10][C:6]=2[CH:5]=[C:4]([CH2:11][C@H:12]([NH:20][C:21](=[O:27])[O:22][C:23]([CH3:26])([CH3:25])[CH3:24])[C:13](=[O:19])[C:14]2[S:15][CH:16]=[CH:17][N:18]=2)[CH:3]=1.[H-].C(O[Al](OC(C)(C)C)OC(C)(C)C)(C)(C)C.[Li+].C1COCC1>CCO>[Cl:1][C:2]1[C:7]2[O:8][CH2:9][O:10][C:6]=2[CH:5]=[C:4]([CH2:11][C@H:12]([NH:20][C:21](=[O:27])[O:22][C:23]([CH3:25])([CH3:24])[CH3:26])[C@H:13]([OH:19])[C:14]2[S:15][CH:16]=[CH:17][N:18]=2)[CH:3]=1
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1cc(Cl)c2c(c1)OCO2)C(=O)c1nccs1
Agent: CC(C)(C)O[Al](OC(C)(C)C)OC(C)(C)C
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CCO
Product: CC(C)(C)OC(=O)N[C@@H](Cc1cc(Cl)c2c(c1)OCO2)[C@H](O)c1nccs1
Reaction time: 2 h
Yield: 78.7 %

Procedure:
A cooled solution (0° C.) of (5)-tert-butyl 3-(7-chlorobenzo[d][1,3]dioxol-5-yl)-1-oxo-1-(thiazol-2-yl)propan-2-ylcarbamate (4.220 g, 10 mmol) in EtOH (60 mL) was added dropwise via cannula to a cooled solution (−78° C.) of lithium tri-tert-butoxyaluminum hydride 1M in THF (21 ml, 21 mmol) in EtOH (40 mL). After stirring for 2 hours, the reaction mixture was quenched with 1N HCl and diluted with EtOAc. The organic layer was washed with water, saturated NaHCO3 solution, and brine. The organic layer was dried over MgSO4 and concentrated under reduced pressure. The crude residue was crystallized from hot EtOH/water and the solid was collected yielding tert-butyl (1S,2S)-3-(7-chlorobenzo[d][1,3]dioxol-5-yl)-1-hydroxy-1-(thiazol-2-yl)propan-2-ylcarbamate (3.250 g, 77% yield) as a white solid.
Reaction SMILES: C(OC(=O)[C@@H]1CCCN1CCCSC(=O)[C@H](CC1C=CC=CC=1C(=O)C1C=CC=CC=1)N)(C)(C)C.C([O:40][C:41](=[O:71])[C@@H:42]1[CH2:46][CH2:45][CH2:44][N:43]1[C:47](=[O:70])[CH2:48][CH2:49][S:50][C:51](=[O:69])[C@H:52]([CH2:54][C:55]1[CH:60]=[CH:59][CH:58]=[CH:57][C:56]=1[C:61](=[O:68])[C:62]1[CH:67]=[CH:66][CH:65]=[CH:64][CH:63]=1)[NH2:53])(C)(C)C.FC(F)(F)C(O)=O>C1(OC)C=CC=CC=1>[C:61]([C:56]1[CH:57]=[CH:58][CH:59]=[CH:60][C:55]=1[CH2:54][C@@H:52]([C:51]([S:50][CH2:49][CH2:48][C:47]([N:43]1[CH2:44][CH2:45][CH2:46][C@H:42]1[C:41]([OH:71])=[O:40])=[O:70])=[O:69])[NH2:53])(=[O:68])[C:62]1[CH:67]=[CH:66][CH:65]=[CH:64][CH:63]=1
Reactant: CC(C)(C)OC(=O)[C@@H]1CCCN1C(=O)CCSC(=O)[C@@H](N)Cc1ccccc1C(=O)c1ccccc1
Agent: CC(C)(C)OC(=O)[C@@H]1CCCN1CCCSC(=O)[C@@H](N)Cc1ccccc1C(=O)c1ccccc1
Solvent: O=C(O)C(F)(F)F
Solvent: COc1ccccc1
Product: N[C@@H](Cc1ccccc1C(=O)c1ccccc1)C(=O)SCCC(=O)N1CCC[C@H]1C(=O)O
Reaction time: 3 h

Procedure:
The product of step (b), N-(2-benzoylphenylalanylthiopropanoyl)-L-proline-t-butyl ester, 1.25 g, was suspended in 4 ml anisole and reacted with 8 ml trifluoroacetic acid for 1 hour at room temperature with stirring. In view of the fact that some starting material was later recovered, the reaction time should be increased. Trifluoroacetic acid was removed with a rotary evaporator under high vacuum. The residue was dissolved in 1 ml THF and chromatographed on a 2.2 cm×99 cm column of Sephadex LH-20 eluted with THF. Fractions of about 5.3 ml were collected. The product was eluted in fractions 41-43. The combined fractions41-43 were evaporated to dryness, dissolved in a small amount of isopropanol and rechromatographed on a 1.2 cm×95 cm LH-20 column, eluted with isopropanol. Fractions of about 2.05 ml were collected. Fractions 48-50 contained 78 mg of the desired compound as an oil. Side fractions 46-47 and 51-53 were saved for rechromatography. The oil was dissolved in a small volume of THF in a vial, then the THF was evaporated under a stream of N2. The vial was then placed in a round bottom flask connected to a rotary evaporator. After 3 hours under high vacuum, a stable, dry foam was obtained.
Reaction SMILES: [H-].[Na+].[CH2:3]([O:5][C:6]1[C:10]([CH2:11][CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14])=[CH:9][NH:8][N:7]=1)[CH3:4].Cl[CH2:19][C:20]1[CH:21]=[N:22][CH:23]=[C:24]([O:26][CH2:27][C:28]2[N:29]=[C:30]([C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)[O:31][C:32]=2[CH3:33])[CH:25]=1.O>CN(C)C=O>[CH2:3]([O:5][C:6]1[C:10]([CH2:11][CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14])=[CH:9][N:8]([CH2:19][C:20]2[CH:21]=[N:22][CH:23]=[C:24]([O:26][CH2:27][C:28]3[N:29]=[C:30]([C:34]4[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=4)[O:31][C:32]=3[CH3:33])[CH:25]=2)[N:7]=1)[CH3:4]
Reactant: CCOC(=O)CCc1c[nH]nc1OCC
Reactant: Cc1oc(-c2ccccc2)nc1COc1cncc(CCl)c1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)CCc1cn(Cc2cncc(OCc3nc(-c4ccccc4)oc3C)c2)nc1OCC
Temperature: 25 °C
Reaction time: 1 h
Yield: 83.8 %

Procedure:
Sodium hydride (60%, oily, 60.0 mg) was added to a solution of ethyl 3-(3-ethoxy-1H-pyrazol-4-yl)propionate (318 mg) and 3-chloromethyl-5-(5-methyl-2-phenyl-4-oxazolylmethoxy)pyridine (472 mg) in N,N-dimethylformamide (10 ml) at 0° C., and the mixture was stirred at room temperature for 1 hour. The reaction mixture was poured into water, and extracted with ethyl acetate. The ethyl acetate layer was washed with saturated aqueous sodium chloride solution, dried (MgSO4), and concentrated. The residue was subjected to silica gel column chromatography to obtain ethyl 3-[3-ethoxy-1-[5-(5-methyl-2-phenyl-4-oxazolylmethoxy)-3-pyridylmethyl]-1H-pyrazol-4-yl]propionate (616 mg, yield: 84%) as a colorless oily substance from the fraction eluted with ethyl acetate.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1[CH:14]=[CH:13][C:12]([CH:15]=[O:16])=[C:11]([OH:17])[CH:10]=1.I[CH2:19][CH3:20].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[CH2:19]([O:17][C:11]1[CH:10]=[C:9]([C:3]2[CH:4]=[CH:5][C:6]([F:8])=[CH:7][C:2]=2[F:1])[CH:14]=[CH:13][C:12]=1[CH:15]=[O:16])[CH3:20]
Reactant: O=Cc1ccc(-c2ccc(F)cc2F)cc1O
Reactant: CCI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCOc1cc(-c2ccc(F)cc2F)ccc1C=O
Temperature: 60 °C
Reaction time: 3 h
Yield: 57.6 %

Procedure:
A mixture of 2′,4′-difluoro-3-hydroxybiphenyl-4-carbaldehyde (8.00 g), iodoethane (8.98 g) and potassium carbonate (6.19 g) in acetone (70 mL) was stirred at 60° C. for 3 hours. The mixture was filtered through celite. The filtrate was concentrated in vacuo. The residue was diluted with ethyl acetate and water. The organic layer was separated and concentrated in vacuo. The residue was refluxed for 30 minutes in methanol (30 mL), cooled to room temperature, and further stirred for 1 hour. The solid was collected by filtration, washed with methanol (10 mL) and dried at 70° C. to give the title compound (5.16 g).
Reaction SMILES: Br[C:2]1[CH:11]=[C:10]2[C:5]([N:6]=[CH:7][C:8]([C:12]3[CH:17]=[CH:16][N:15]=[CH:14][CH:13]=3)=[N:9]2)=[CH:4][CH:3]=1.[NH2:18][C:19]1[C:24]([S:25]([N:28]([CH3:30])[CH3:29])(=[O:27])=[O:26])=[CH:23][C:22](B2OC(C)(C)C(C)(C)O2)=[CH:21][N:20]=1.C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1>[NH2:18][C:19]1[C:24]([S:25]([N:28]([CH3:30])[CH3:29])(=[O:27])=[O:26])=[CH:23][C:22]([C:2]2[CH:11]=[C:10]3[C:5](=[CH:4][CH:3]=2)[N:6]=[CH:7][C:8]([C:12]2[CH:17]=[CH:16][N:15]=[CH:14][CH:13]=2)=[N:9]3)=[CH:21][N:20]=1
Reactant: Brc1ccc2ncc(-c3ccncc3)nc2c1
Reactant: CN(C)S(=O)(=O)c1cc(B2OC(C)(C)C(C)(C)O2)cnc1N
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Product: CN(C)S(=O)(=O)c1cc(-c2ccc3ncc(-c4ccncc4)nc3c2)cnc1N
Temperature: 100 °C
Yield: 47.2 %

Procedure:
A mixture of 7-bromo-2-(4-pyridinyl)quinoxaline (0.245 mmol), 2-amino-N,N-dimethyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3-pyridinesulfonamide (0.245 mmol), [1,1′-bis(diphenylphosphino)-ferrocene]dichloropalladium(II) dichloromethane complex (1:1) (0.0196 mmol), 2M aqueous potassium carbonate (2 mL) and anhydrous 1,4-dioxane (6 mL) was heated at 100° C. for 4 h in a sealed pressure vessel. After cooling to room temperature, the organic layer was separated and purified directly on silica gel, eluting with 0-10% methanol in ethyl acetate followed by a second purification by HPLC (eluting with acetonitrile: 0.1% TFA in H2O) to afford the title compound as a bright yellow solid (47 mg, 47% yield). MS(ES)+ m/e 407.2 [M+H]+.
Reaction SMILES: [C:1]1([C:7]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=2[CH3:25])=[CH:8][C:9]2[CH:14]=[CH:13][N:12]=[C:11]([NH:15][C:16]([NH2:18])=[O:17])[CH:10]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H][H]>CO.C(Cl)Cl.[Pd]>[C:1]1([CH:7]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=2[CH3:25])[CH2:8][C:9]2[CH:14]=[CH:13][N:12]=[C:11]([NH:15][C:16]([NH2:18])=[O:17])[CH:10]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: Cc1ccccc1C(=Cc1ccnc(NC(N)=O)c1)c1ccccc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Solvent: ClCCl
Product: Cc1ccccc1C(Cc1ccnc(NC(N)=O)c1)c1ccccc1
Yield: 14 %

Procedure:
[4-(2-Phenyl-2-o-tolyl-vinyl)-pyridin-2-yl]-urea (140 mg, 0.43 mmol) is dissolved in methanol (2 mL) and DCM (2 mL). Then 5% palladium on carbon (90 mg, 0.043 mmol) is added. The reaction is stirred for 16 hours under the hydrogen atmosphere. The palladium on carbon is filtered and the filtrate is concentrated to give the crude product. Purification by Gilson preparative HPLC affords 20 mg of the titled product.
Reaction SMILES: [C:1]([O:4][C:5]1[CH:10]=[C:9]([CH3:11])[C:8]([Br:12])=[C:7]([CH3:13])[CH:6]=1)(=[O:3])[CH3:2].[Br:14]N1C(=O)CCC1=O>C(Cl)(Cl)(Cl)Cl.N(C(C)(C)C#N)=NC(C)(C)C#N>[C:1]([O:4][C:5]1[CH:6]=[C:7]([CH3:13])[C:8]([Br:12])=[C:9]([CH2:11][Br:14])[CH:10]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)Oc1cc(C)c(Br)c(C)c1
Reactant: O=C1CCC(=O)N1Br
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Product: CC(=O)Oc1cc(C)c(Br)c(CBr)c1
Temperature: 75 °C
Reaction time: 5 h
Yield: 73 %

Procedure:
A suspension of 4-bromo-3,5-dimethylphenyl acetate (12.1 g, 49.8 mmol), N-bromosuccinimide (9.79 g, 55.0 mmol) and 2,2′-azobisisobutyronitrile (82.1 mg, 0.500 mmol) in carbon tetrachloride (100 mL) was stirred at 75° C. for 5 hr under nitrogen atmosphere. The reaction mixture was ice-cooled, and concentrated under reduced pressure. The residue was diluted with diethyl ether, the insoluble substance was filtered off, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate:hexane=0:100-25:75) to give the title compound (11.7 g, yield 73%) as colorless crystals.