Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CC1(C)C(C)(C)OB([C:9]2[CH:14]=[CH:13][C:12]([NH:15][C:16](=[O:22])[O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[CH:11][CH:10]=2)O1.I[C:25]1[C:33]2[C:28](=[N:29][CH:30]=[N:31][C:32]=2[NH2:34])[N:27]([C@H:35]2[CH2:40][CH2:39][C@@H:38]([N:41]3[CH2:46][CH2:45][N:44]([CH3:47])[CH2:43][CH2:42]3)[CH2:37][CH2:36]2)[N:26]=1.O.C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.O>[NH2:34][C:32]1[N:31]=[CH:30][N:29]=[C:28]2[N:27]([C@H:35]3[CH2:40][CH2:39][C@@H:38]([N:41]4[CH2:42][CH2:43][N:44]([CH3:47])[CH2:45][CH2:46]4)[CH2:37][CH2:36]3)[N:26]=[C:25]([C:9]3[CH:10]=[CH:11][C:12]([NH:15][C:16](=[O:22])[O:17][C:18]([CH3:19])([CH3:20])[CH3:21])=[CH:13][CH:14]=3)[C:33]=12
Reactant: CC(C)(C)OC(=O)Nc1ccc(B2OC(C)(C)C(C)(C)O2)cc1
Reactant: CN1CCN([C@H]2CC[C@@H](n3nc(I)c4c(N)ncnc43)CC2)CC1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Product: CN1CCN([C@H]2CC[C@@H](n3nc(-c4ccc(NC(=O)OC(C)(C)C)cc4)c4c(N)ncnc43)CC2)CC1
Temperature: 25 °C
Yield: 80.2 %

Procedure:
A mixture of tert-butyl N-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]carbamate (3.71 g, 0.0116 mol), cis-3-iodo-1-[4-(4-methylpiperazino)-cyclohexyl]-1H-pyrazolo[3,4-d]pyrimidin-4-amine (4.46 g, 0.0101 mol), tetrakis-(triphenylphosphine)palladium (0.700 g, 0.00061 mol) and sodium carbonate monohydrate (3.13 g, 0.0253 mol) was heated in a mixture of ethylene glycol dimethyl ether (140 mL) and water (70 mL) at 80° C. for sixteen hours under an atmosphere of nitrogen. The mixture was allowed to cool to ambient temperature and solvents were removed under the reduced pressure. The residue was partitioned between saturated aqueous sodium bicarbonate solution (300 mL) and ethyl acetate (300 mL), the organic layer separated and the aqueous layer further extracted with ethyl acetate twice (150 mL each). The combined organic extracts were dried over magnesium sulfate. The solvents were evaporated under reduced pressure to leave a tan solid which was purified by flash column chromatography on silica using dichloromethane/triethylamine/methanol (95:4:1) as a mobile phase to give cis-tert-butyl N-(4-{4-amino-1-[4-(4-methylpiperazino)cyclohexyl]-1H-pyrazolo[3,4-d]pyrimidin-3-yl}phenyl)carbamate (4.1 g, 0.0081 mol) as a white solid.
Reaction SMILES: [CH3:1][C:2]1([CH3:10])[CH2:7][CH2:6][CH2:5][C:4]([CH3:9])([CH3:8])[NH:3]1.[Li:11]CCCC.C1(N=CC2C=CC(OC)=CC=2C)CCCCC1.CN(OC)C(C1CC1)=O.[NH4+].[Cl-]>C1COCC1>[Li:11][N:3]1[C:4]([CH3:9])([CH3:8])[CH2:5][CH2:6][CH2:7][C:2]1([CH3:10])[CH3:1]
Reactant: CC1(C)CCCC(C)(C)N1
Reactant: [Li]CCCC
Agent: CON(C)C(=O)C1CC1
Agent: COc1ccc(C=NC2CCCCC2)c(C)c1
Agent: [Cl-]
Solvent: C1CCOC1
Product: [Li]N1C(C)(C)CCCC1(C)C
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
Lithium tetramethylpiperidide was prepared by the treatment of 2,2,6,6-tetramethylpiperidine (1.0 g; 7.0 mmol) in THF (17 mL) with n-BuLi (1.6 M in hexanes; 8.0 mmol) dropwise at −15° C. After 15 min at −15° C., a solution of cyclohexyl(4-methoxy-2-methylbenzylidene)amine (660 mg; 2.86 mmol) in THF (3 mL) was added dropwise to give a purple solution. The reaction mixture was allowed to warm to 0° C. over a 20-min period then a solution of N-methyl-N-methoxycyclopropanecarboxamide (630 mg: 4.4 mmol) in THF (2 mL) was added in one portion while at 0° C. The reaction mixture was kept at room temperature for 30 min and then added to saturated aq. NH4Cl. The solution was extracted with diethyl ether and the organic phase was washed with saturated aq. NaCl, dried and concentrated in vacuo.
Reaction SMILES: C(OC(N1CCC([C:12]2[C:20]3[C:15](=[N:16][CH:17]=[CH:18][CH:19]=3)[N:14]([CH2:21][CH2:22][O:23][CH2:24][CH3:25])[CH:13]=2)CC1)=O)C.[OH-].[K+]>C(O)(C)C>[CH2:24]([O:23][CH2:22][CH2:21][N:14]1[C:15]2=[N:16][CH:17]=[CH:18][CH:19]=[C:20]2[C:12]([N:16]2[CH2:17][CH2:18][CH2:19][CH2:20][CH2:15]2)=[CH:13]1)[CH3:25]
Reactant: CCOCCn1cc(C2CCN(C(=O)OCC)CC2)c2cccnc21
Agent: [K+]
Agent: [OH-]
Solvent: CC(C)O
Product: CCOCCn1cc(N2CCCCC2)c2cccnc21
Yield: 149.5 %

Procedure:
1.1 g (3.18 mmol) of 4-[1-(2-ethoxyethyl)-1H-pyrrolo[2,3-b]pyridin-3-yl]-piperidine-1-carboxylic acid ethyl ester were added to a solution of 2.1 g (31.8 mmol) of potassium hydroxide in 30 ml of isopropanol. The mixture was refluxed for 20 hours. The solvent was distilled off and cold water was added. This solution was acidified with concentrated hydrochloric acid and then basified with 8 N aqueous sodium hydroxide solution. This aqueous solution was extracted twice with ethyl acetate. The organic phase was washed with water and brine, dried over magnesium sulphate, filtered and evaporated under reduced pressure affording 0.65 g (75% of yield) of 1-(2-ethoxyethyl)-3-piperidinyl-1H-pyrrolo[2,3-b]pyridine obtained as an oil.
Reaction SMILES: CC1C=C(N2CCN(CCOC3C=CC=CC=3)C2=O)SC=1C(O)=O.[F:25][C:26]1[CH:47]=[CH:46][C:29]([CH2:30][N:31]2[CH2:35][CH2:34][N:33]([C:36]3[S:40][C:39]([C:41](O)=[O:42])=[C:38]([CH3:44])[CH:37]=3)[C:32]2=[O:45])=[CH:28][CH:27]=1.Cl.[NH2:49][CH2:50][C:51]1[O:55][C:54]([C:56]([O:58][CH2:59][CH3:60])=[O:57])=[CH:53][CH:52]=1>>[F:25][C:26]1[CH:27]=[CH:28][C:29]([CH2:30][N:31]2[CH2:35][CH2:34][N:33]([C:36]3[S:40][C:39]([C:41]([NH:49][CH2:50][C:51]4[O:55][C:54]([C:56]([O:58][CH2:59][CH3:60])=[O:57])=[CH:53][CH:52]=4)=[O:42])=[C:38]([CH3:44])[CH:37]=3)[C:32]2=[O:45])=[CH:46][CH:47]=1
Reactant: Cc1cc(N2CCN(Cc3ccc(F)cc3)C2=O)sc1C(=O)O
Reactant: CCOC(=O)c1ccc(CN)o1
Agent: Cc1cc(N2CCN(CCOc3ccccc3)C2=O)sc1C(=O)O
Agent: Cl
Product: CCOC(=O)c1ccc(CNC(=O)c2sc(N3CCN(Cc4ccc(F)cc4)C3=O)cc2C)o1
Yield: 59 %

Procedure:
Following the procedures as described in Example 55, making variations as required to replace 3-methyl-5-(2-oxo-3-(2-phenoxyethyl)imidazolidin-1-yl)thiophene-2-carboxylic acid with 5-(3-(4-fluorobenzyl)-2-oxoimidazolidin-1-yl)-3-methylthiophene-2-carboxylic acid to react with ethyl 5-(aminomethyl)furan-2-carboxylate hydrochloride, the title compound was obtained as a colorless solid in 59% yield: 1H NMR (300 MHz, CDCl3) δ 7.30-7.23 (m, 2H), 7.11 (d, J=3.4 Hz, 1H), 7.07-6.99 (m, 2H), 6.41 (d, J=3.4 Hz, 1H), 6.10 (br s, 2H), 4.62 (d, J=5.7 Hz, 2H), 4.43 (s, 2H), 4.36 (q, J=7.1 Hz, 2H), 3.83-3.75 (m, 2H), 3.47-3.40 (m, 2H), 2.48 (s, 3H), 1.38 (t, J=7.1 Hz, 3H); MS (ES+) m/z 508.15 (M+23).
Reaction SMILES: [F:1][C:2]([F:35])([F:34])[C:3]1[CH:4]=[C:5]([C:13]2([C:30]([F:33])([F:32])[F:31])[O:17][N:16]=[C:15]([C:18]3[N:23]4[CH:24]=[CH:25][N:26]=[C:22]4[C:21]([C:27](O)=[O:28])=[CH:20][CH:19]=3)[CH2:14]2)[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.[CH3:36][S:37][CH2:38][CH2:39][NH2:40]>>[CH3:36][S:37][CH2:38][CH2:39][NH:40][C:27]([C:21]1[C:22]2[N:23]([CH:24]=[CH:25][N:26]=2)[C:18]([C:15]2[CH2:14][C:13]([C:5]3[CH:6]=[C:7]([C:9]([F:10])([F:11])[F:12])[CH:8]=[C:3]([C:2]([F:35])([F:1])[F:34])[CH:4]=3)([C:30]([F:32])([F:33])[F:31])[O:17][N:16]=2)=[CH:19][CH:20]=1)=[O:28]
Reactant: O=C(O)c1ccc(C2=NOC(c3cc(C(F)(F)F)cc(C(F)(F)F)c3)(C(F)(F)F)C2)n2ccnc12
Reactant: CSCCN
Product: CSCCNC(=O)c1ccc(C2=NOC(c3cc(C(F)(F)F)cc(C(F)(F)F)c3)(C(F)(F)F)C2)n2ccnc12

Procedure:
Using a procedure similar to that described in Example 1, except using 5-[5-(3,5-bistrifluoromethylphenyl)-5-trifluoromethyl-4,5-dihydroisoxazol-3-yl]-imidazo[1,2-a]pyridine-8-carboxylic acid (45 mg) and 2-methylthioethylamine (0.016 mL), the title compound was isolated as an orange-reddish solid (11.9 mg, 23%). MS (ES): M/Z [M+H]=585. 1H NMR (400 MHz, CHLOROFORM-d): 2.22 (s, 3H), 2.85 (t, J=6.8 Hz, 2H), 3.82 (q, J=6.6 Hz, 2H), 4.01 (d, J=17.0 Hz, 1H), 4.44 (d, J=16.8 Hz, 1H), 7.21 (d, J=7.6 Hz, 1H), 7.85 (s, 1H), 8.02 (s, 1H), 8.12 (s, 2H), 8.28 (d, J=7.6 Hz, 1H), 8.90 (d, J=1.0 Hz, 1H), 10.67 (br. s., 1H). 19F NMR (376 MHz, CHLOROFORM-d): −80.0 (s, 3F), −63.3 (s, 6F).
Reaction SMILES: COC[N:4]1[C:12]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[C:10]([CH3:11])[C:8](=[O:9])[NH:7][C:5]1=[S:6]>Cl>[C:13]1([C:12]2[NH:4][C:5](=[S:6])[NH:7][C:8](=[O:9])[C:10]=2[CH3:11])[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: COCn1c(-c2ccccc2)c(C)c(=O)[nH]c1=S
Agent: Cl
Product: Cc1c(-c2ccccc2)[nH]c(=S)[nH]c1=O
Yield: 28.1 %

Procedure:
To 100 ml of concentrated hydrochloric acid, 17.2 g (62 mmole) of 1-(methoxymethyl)-6-phenylthiothymine was added and allowed to react for 2 hours at 80° C. The reaction mixture was concentrated under reduced pressure and crystallized from ethanol to obtain 3.8 g of the target compound (Yield: 26%).
Reaction SMILES: [Se:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[CH:11]=[CH:10][C:9]([OH:12])=[CH:8][CH:7]=1.C(N(CC)CC)C.[CH:20]([Si:23]([CH:28]([CH3:30])[CH3:29])([CH:25]([CH3:27])[CH3:26])Cl)([CH3:22])[CH3:21].O>CN(C1C=CN=CC=1)C.ClCCl>[CH:20]([Si:23]([CH:28]([CH3:30])[CH3:29])([CH:25]([CH3:27])[CH3:26])[O:12][C:9]1[CH:10]=[CH:11][C:6]([C:2]2[Se:1][CH:5]=[CH:4][CH:3]=2)=[CH:7][CH:8]=1)([CH3:22])[CH3:21]
Reactant: CC(C)[Si](Cl)(C(C)C)C(C)C
Reactant: Oc1ccc(-c2ccc[se]2)cc1
Agent: CN(C)c1ccncc1
Solvent: O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)[Si](Oc1ccc(-c2ccc[se]2)cc1)(C(C)C)C(C)C

Procedure:
8.0 g (35.9 mmol) of 4-selenophen-2-ylphenol are initially introduced together with 50 ml (0.36 mol) of triethylamine and 0.44 g (3.6 mmol) of DMAP in 100 ml of dichloromethane, and 20 ml (93.5 mmol) of triisopropylchlorosilane are added. When the addition is complete, the mixture is warmed under reflux for 3 h. After cooling, the reaction mixture is added to water, and the organic phase is separated off. The aqueous phase is extracted with dichloromethane, and the combined organic phase is washed with sat. sodium chloride soln. The solution is dried using sodium sulfate and concentrated to dryness. The residue is purified by column chromatography (SiO2, n-heptane:MTBE=4:1). Further purification is carried out by further column chromatography (SiO2, n-heptane:toluene=4:1); triisopropyl-(4-selenophen-2-ylphenoxy)silane is obtained as a yellow oil.
Reaction SMILES: [CH2:1]([O:9][C:10]1[CH:18]=[CH:17][C:13]([C:14]([OH:16])=[O:15])=[CH:12][CH:11]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].C(Cl)(=O)C(Cl)=O.O[C:26]1[CH:61]=[CH:60][C:29]([CH2:30][N:31]([CH2:52][C:53]([O:55]C(C)(C)C)=[O:54])[C:32](=[O:51])[C:33]2[CH:38]=[CH:37][C:36]([NH:39][C:40](=[O:50])[CH2:41][C:42]3[CH:47]=[CH:46][C:45]([O:48][CH3:49])=[CH:44][CH:43]=3)=[CH:35][CH:34]=2)=[CH:28][CH:27]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl.CN(C=O)C>[CH3:49][O:48][C:45]1[CH:44]=[CH:43][C:42]([CH2:41][C:40]([NH:39][C:36]2[CH:35]=[CH:34][C:33]([C:32]([N:31]([CH2:52][C:53]([OH:55])=[O:54])[CH2:30][C:29]3[CH:28]=[CH:27][C:26]([O:15][C:14](=[O:16])[C:13]4[CH:12]=[CH:11][C:10]([O:9][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8])=[CH:18][CH:17]=4)=[CH:61][CH:60]=3)=[O:51])=[CH:38][CH:37]=2)=[O:50])=[CH:47][CH:46]=1
Reactant: COc1ccc(CC(=O)Nc2ccc(C(=O)N(CC(=O)OC(C)(C)C)Cc3ccc(O)cc3)cc2)cc1
Reactant: CCCCCCCCOc1ccc(C(=O)O)cc1
Agent: O=C(Cl)C(=O)Cl
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CCCCCCCCOc1ccc(C(=O)Oc2ccc(CN(CC(=O)O)C(=O)c3ccc(NC(=O)Cc4ccc(OC)cc4)cc3)cc2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 14 %

Procedure:
Prepared using General Procedures 2 and 8: To a stirring solution of 4-(octyloxy)benzoic acid (30 mg, 0.119 mmol) in DCM (0.5 mL) were added DMF (1 drop) and oxalyl chloride (0.011 mL, 0.127 mmol). The reaction mixture was stirred at room temperature for 30 min. To this mixture was added a solution of tert-butyl 2-(N-(4-hydroxybenzyl)-4-(2-(4-methoxyphenyl)acetamido)benzamido)acetate INT-7 (40 mg, 0.079 mmol) and TEA (0.022 mL, 0.159 mmol) in DCM (1 mL). The reaction was stirred at room temperature for 2 h then TFA (1 mL) was added. After stirring for 2 h, the solvent was concentrated and the product was purified by preparative HPLC to afford 7.6 mg (14%) of 2-(4-(2-(4-methoxyphenyl)acetamido)-N-(4-((4-(octyloxy)benzoyl)oxy)benzyl)benzamido)acetic acid 17. LCMS-ESI (m/z) calculated for C40H44N2O8: 680; found 679 [M−H]−, tR=9.96 min (Method 4).
Reaction SMILES: [Cl:1][C:2]1[C:3]2[NH:10][CH:9]=[CH:8][C:4]=2[N:5]=[CH:6][N:7]=1.C(=O)([O-])[O-].[Cs+].[Cs+].Br[CH2:18][CH2:19][F:20]>CN(C)C=O.O>[Cl:1][C:2]1[C:3]2[N:10]([CH2:18][CH2:19][F:20])[CH:9]=[CH:8][C:4]=2[N:5]=[CH:6][N:7]=1
Reactant: Clc1ncnc2cc[nH]c12
Reactant: FCCBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: FCCn1ccc2ncnc(Cl)c21
Temperature: 25 °C
Yield: 84.6 %

Procedure:
To a suspension of 4-chloro-5H-pyrrolo[3,2-d]pyrimidine (100 mg) in N,N-dimethylformamide (0.6 mL) was added cesium carbonate (281 mg) under ice-cooling, and the mixture was stirred while warming to room temperature for 15 min. To the reaction mixture was added 1-bromo-2-fluoroethane (124 mg), and the mixture was stirred at room temperature for 5 hrs. The reaction mixture was diluted with water (20 mL) and extracted with ethyl acetate (20 mL×3). The organic layer washed with saturated brine (20 mL×3) and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the obtained residue was subjected to silica gel column chromatography (silica gel, eluent:hexane/ethyl acetate=90/10→40/10). The object fraction was concentrated under reduced pressure and dried to give the title compound (110 mg) as a colorless transparent oil.
Reaction SMILES: [CH3:1][N:2]1[C:7]([CH3:8])=[CH:6][C:5]([OH:9])=[C:4]([C:10]([O:12]CC)=O)[C:3]1=[O:15].[NH2:16][C:17]1[S:18][C:19]([CH2:22][CH3:23])=[N:20][N:21]=1.BrC1C=CC=CC=1>>[CH2:22]([C:19]1[S:18][C:17]([NH:16][C:10]([C:4]2[C:3](=[O:15])[N:2]([CH3:1])[C:7]([CH3:8])=[CH:6][C:5]=2[OH:9])=[O:12])=[N:21][N:20]=1)[CH3:23]
Reactant: CCc1nnc(N)s1
Reactant: CCOC(=O)c1c(O)cc(C)n(C)c1=O
Solvent: Brc1ccccc1
Product: CCc1nnc(NC(=O)c2c(O)cc(C)n(C)c2=O)s1
Temperature: 25 °C
Reaction time: 5 h
Yield: 75 %

Procedure:
212 mg of ethyl 1,6-dimethyl-4-hydroxy-2-oxo-1,2-dihydropyridine-3-carboxylate and 117 mg of 2-amino-5-ethyl-1,3,4-thiadiazole were added to 2.5 ml of bromobenzene, then, the mixture was stirred for 5 hours under heat refluxing condition. The reaction mixture was cooled to room temperature. The resulting solid was collected by filtration, and washed with a mixed solvent of t-butyl methyl ether and hexane and dried to obtain 200 mg of N-(5-ethyl-1,3,4-thiadiazol-2-yl)-1,6-dimethyl-4-hydroxy-2-oxo-1,2-dihydropyridine-3-carboxamide (hereinafter, referred to as present compound 17) represented by the formula:
Reaction SMILES: [Cl:1][C:2]1[C:10]([OH:11])=[CH:9][C:8]([I:12])=[C:7]2[C:3]=1[CH2:4][NH:5][C:6]2=[O:13].C(=O)([O-])[O-].[K+].[K+].[C:20]([Si:24]([O:27][CH2:28][CH2:29][CH2:30]Br)([CH3:26])[CH3:25])([CH3:23])([CH3:22])[CH3:21]>CN(C=O)C.[I-].C([N+](CCCC)(CCCC)CCCC)CCC>[Cl:1][C:2]1[C:10]([O:11][CH2:30][CH2:29][CH2:28][O:27][Si:24]([C:20]([CH3:21])([CH3:23])[CH3:22])([CH3:25])[CH3:26])=[CH:9][C:8]([I:12])=[C:7]2[C:3]=1[CH2:4][NH:5][C:6]2=[O:13]
Reactant: O=C1NCc2c(Cl)c(O)cc(I)c21
Reactant: CC(C)(C)[Si](C)(C)OCCCBr
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=C([O-])[O-]
Agent: [I-]
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](C)(C)OCCCOc1cc(I)c2c(c1Cl)CNC2=O
Yield: 79.7 %

Procedure:
In a similar manner to Step 1 of Example 429, 4-chloro-5-hydroxy-7-iodoisoindolinone (100 mg, 0.323 mmol) was dissolved in DMF (3.0 mL), and the solution was treated with potassium carbonate (134 mg, 0.969 mmol), tetrabutylammonium iodide (11.8 mg, 0.032 mmol) and tert-butyl(3-bromopropoxy)dimethylsilane (0.112 mL, 0.485 mmol), followed by purification by flash column chromatography (chloroform/methanol=99/1, 19/1) to obtain 4-chloro-5-[3-(tert-butyldimethylsiloxy)propoxy]-7-iodoisoindolinone (124 mg, yield 79%).
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([O:11][CH3:12])=[CH:7][CH:6]=1)=O.[CH3:13][O:14][C:15]([C:17]1[C:18]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=2[N+:32]([O-:34])=[O:33])=[CH:19][CH:20]=[C:21]([C:23](=[S:25])[NH2:24])[CH:22]=1)=[O:16]>O1CCOCC1>[CH3:13][O:14][C:15]([C:17]1[C:18]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=2[N+:32]([O-:34])=[O:33])=[CH:19][CH:20]=[C:21]([C:23]2[S:25][CH:2]=[C:3]([C:5]3[CH:10]=[CH:9][C:8]([O:11][CH3:12])=[CH:7][CH:6]=3)[N:24]=2)[CH:22]=1)=[O:16]
Reactant: COc1ccc(C(=O)CBr)cc1
Reactant: COC(=O)c1cc(C(N)=S)ccc1-c1ccccc1[N+](=O)[O-]
Solvent: C1COCCO1
Product: COC(=O)c1cc(-c2nc(-c3ccc(OC)cc3)cs2)ccc1-c1ccccc1[N+](=O)[O-]
Temperature: 40 °C
Reaction time: 16 h

Procedure:
2-Bromo-4′-methoxyacetophenone (available from Oakwood Products, Inc.; 144.3 mg, 0.63 mmol) was added to a suspension of 2′-nitro-4-thiocarbamoyl-biphenyl-2-carboxylic acid methyl ester (which may be prepared as described for Intermediate 4; 200 mg, 0.63 mmol) in dioxane (4 mL), and the resulting mixture was stirred at 40° C. for 16 h. The precipitate was collected by filtration (187 mg) and used directly in the next step without purification.
Reaction SMILES: C(N(CC)CC)C.C(O)=O.CC1C=CC(C(C)C)=CC=1.[F:21][C:22]([F:32])([F:31])[C:23](=[O:30])[CH2:24][C:25]([O:27][CH2:28][CH3:29])=[O:26]>O1CCCC1>[F:21][C:22]([F:31])([F:32])[CH:23]([OH:30])[CH2:24][C:25]([O:27][CH2:28][CH3:29])=[O:26]
Reactant: CCOC(=O)CC(=O)C(F)(F)F
Solvent: O=CO
Solvent: C1CCOC1
Solvent: Cc1ccc(C(C)C)cc1
Product: CCOC(=O)CC(O)C(F)(F)F
Temperature: 35 °C
Reaction time: 0.5 h
Yield: 88.6 %

Procedure:
A solution of 50 mL of a mixture of formic acid-triethylamine (5:2 in molar ratio) and 70.1 mg of RuCl[(1R,2R)-p-TsNHCH(C6H5)CH(C6H5)NH2] (p-cymene) dissolved in 25 mL of tetrahydrofuran was stirred at 35° C., and a solution of 10.0 g of ethyl 4,4,4-trifluoro-3-oxobutanoate dissolved in 25 mL of tetrahydrofuran was added thereto over a period of 30 minutes. The reaction mixture was stirred at the same temperature for 21 hours and the conversion into the hydroxy compound was found to be 100%. After the reaction mixture was concentrated under reduced pressure using an evaporator, 20 mL of water and 40 mL of ethyl acetate were added to the resulting concentrate and then a saturated sodium carbonate aqueous solution was added thereto under stirring until the pH became 7 or higher. After the separation of the ethyl acetate layer, the water layer was further extracted with 25 mL of ethyl acetate. Then, the ethyl acetate layer was combined with the previous ethyl acetate layer and the combined layer was concentrated. The resulting concentrate was distilled under reduced pressure (88-89° C./2660 Pa) to obtain 8.96 g of optically active ethyl 4,4,4-trifluoro-3-hydroxybutanoate (yield 88.6%). Upon the measurement under the above conditions, the optical purity of the resulting optically active ethyl 4,4,4-trifluoro-3-hydroxybutanoate was found to be 94.2% e.e.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:21])[CH2:5][CH:6]1[O:10][B:9]([OH:11])[C:8]2[CH:12]=[C:13]([OH:20])[CH:14]=[C:15]([CH2:16][N:17]=[N+:18]=[N-:19])[C:7]1=2)[CH3:2].Cl[C:23]1[CH:28]=[N:27][CH:26]=[CH:25][N:24]=1.C([O-])([O-])=O.[Cs+].[Cs+].Cl>CN(C=O)C>[CH2:1]([O:3][C:4](=[O:21])[CH2:5][CH:6]1[O:10][B:9]([OH:11])[C:8]2[CH:12]=[C:13]([O:20][C:23]3[CH:28]=[N:27][CH:26]=[CH:25][N:24]=3)[CH:14]=[C:15]([CH2:16][N:17]=[N+:18]=[N-:19])[C:7]1=2)[CH3:2]
Reactant: CCOC(=O)CC1OB(O)c2cc(O)cc(CN=[N+]=[N-])c21
Reactant: Clc1cnccn1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CCOC(=O)CC1OB(O)c2cc(Oc3cnccn3)cc(CN=[N+]=[N-])c21
Temperature: 80 °C
Yield: 28.7 %

Procedure:
To a mixture of (4-azidomethyl-1,6-dihydroxy-1,3-dihydro-benzo[c][1,2]oxaborol-3-yl)-acetic acid ethyl ester (550 mg, 1.89 mmol), 2-chloropyrazine (350 mg, 3.05 mmol), Cs2CO3 (1.34 g, 4.11 mmol) in 5 mL of DMF was heated to 80° C. for 3.5 h. The reaction mixture was adjusted to pH 3 by 1N HCl. The crude product was purified by HPLC to yield 200 mg of the title compound.
Reaction SMILES: [CH:1]1([C:4]2[O:5][C:6]3[C:7](=[C:9]([C:24]#[N:25])[C:10]([CH3:23])=[C:11]([CH:21]=[O:22])[C:12]=3[N:13]3[CH2:17][CH2:16][C@H:15]([N:18]([CH3:20])[CH3:19])[CH2:14]3)[N:8]=2)[CH2:3][CH2:2]1.[BH4-].[Na+].C(=O)([O-])O.[Na+]>CO.ClCCl>[CH:1]1([C:4]2[O:5][C:6]3[C:7](=[C:9]([C:24]#[N:25])[C:10]([CH3:23])=[C:11]([CH2:21][OH:22])[C:12]=3[N:13]3[CH2:17][CH2:16][C@H:15]([N:18]([CH3:20])[CH3:19])[CH2:14]3)[N:8]=2)[CH2:2][CH2:3]1
Reactant: Cc1c(C=O)c(N2CC[C@H](N(C)C)C2)c2oc(C3CC3)nc2c1C#N
Agent: O=C([O-])O
Agent: [BH4-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CO
Product: Cc1c(CO)c(N2CC[C@H](N(C)C)C2)c2oc(C3CC3)nc2c1C#N
Reaction time: 1 h
Yield: 76.4 %

Procedure:
2-Cyclopropyl-7-[(3S)-3-(dimethylamino)pyrrolidin-1-yl]-6-formyl-5-methyl-1,3-benzoxazole-4-carbonitrile (free form of #88) (120 mg, 0.35 mmol) was dissolved in methanol (2.4 ml) and dichloromethane (0.8 ml), then at 0° C., sodium borohydride (18 mg, 0.43 mmol) was added, followed by stirring at the same temperature for 1 hour. Next, at the same temperature, sodium borohydride (9 mg, 0.22 mmol) was further added, followed by stirring at the same temperature for 1 hour. An aqueous saturated sodium hydrogencarbonate solution was added, followed by farmer stirring for 5 minutes. The solution was extracted three times with chloroform. The organic layers were combined, washed with saturated brine, and dried over anhydrous sodium sulfate. The insoluble matter was separated by filtration, the solvent was evaporated away, and the resulting residue was purified by preparative TLC (eluent, chloroform:methanol=9:1) to obtain the entitled compound (91 mg) as a roughly-purified product. This was washed with isopropyl ether to obtain the entitled compound (85 mg, 70%) as a white solid.
Reaction SMILES: [CH2:1]([O:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[CH:2]1[O:4][CH2:3]1.[NH2:12][CH2:13][CH2:14][NH:15][C:16]1[C:17](=[O:26])[N:18]([CH3:25])[C:19](=[O:24])[N:20]([CH3:23])[C:21]=1[CH3:22]>>[O:5]([CH2:1][CH:2]([OH:4])[CH2:3][NH:12][CH2:13][CH2:14][NH:15][C:16]1[C:17](=[O:26])[N:18]([CH3:25])[C:19](=[O:24])[N:20]([CH3:23])[C:21]=1[CH3:22])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: c1ccc(OCC2CO2)cc1
Reactant: Cc1c(NCCN)c(=O)n(C)c(=O)n1C
Product: Cc1c(NCCNCC(O)COc2ccccc2)c(=O)n(C)c(=O)n1C
Reaction time: 24 h

Procedure:
2.43 g. Phenyl glycidyl ether and 5.15 g. 5-(2-aminoethylamino)-1,3,6-trimethylpyrimidine-2,4(1H,3H)-dione are left to stand for 24 hours at ambient temperature, whereupon the reaction mixture is separated with silica gel using, as elution agent, methylene chloride-ammoniacal methanol (95:5 v/v). The yellowish oil obtained by evaporation of the pure fractions is triturated with ethyl acetate. After subsequent recrystallization from ethyl acetate, there are obtained 2.55 g. (43% of theory) of the desired product in the form of colorless crystals; m.p. 92°-94° C.
Reaction SMILES: [C:1]([C:3]([C:6]1[CH:7]=[C:8]([CH:21]=[CH:22][CH:23]=1)[C:9]([NH:11][C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([N+:18]([O-])=O)[CH:13]=1)=[O:10])([CH3:5])[CH3:4])#[N:2].O1CCCC1>C(O)C.[C].[Pd]>[NH2:18][C:14]1[CH:13]=[C:12]([NH:11][C:9](=[O:10])[C:8]2[CH:21]=[CH:22][CH:23]=[C:6]([C:3]([C:1]#[N:2])([CH3:5])[CH3:4])[CH:7]=2)[CH:17]=[CH:16][CH:15]=1
Reactant: CC(C)(C#N)c1cccc(C(=O)Nc2cccc([N+](=O)[O-])c2)c1
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CCO
Product: CC(C)(C#N)c1cccc(C(=O)Nc2cccc(N)c2)c1
Temperature: 25 °C
Reaction time: 14 h

Procedure:
To a solution of 3-(1-cyano-1-methylethyl)-N-(3-nitrophenyl)benzamide (495 mg, 1.60 mmol) in ethanol (12 mL)/tetrahydrofuran (4 mL) was added 10% palladium-carbon (85 mg), and the mixture was stirred at room temperature under a hydrogen atmosphere (1 atm) for 14 hr. The insoluble material was filtered off, and the filtrate was concentrated under reduced pressure to give N-(3-aminophenyl)-3-(1-cyano-1-methylethyl)benzamide as a pale-brown oil. The obtained compound was used for the next reaction without further purification.
Reaction SMILES: C(OC([NH:11][C@H:12]([C:17]([NH:19][C@H:20]([C:28]([OH:30])=[O:29])[CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=[O:18])[CH2:13][C:14](=[O:16])[OH:15])=O)C1C=CC=CC=1>C1(C)C=CC=CC=1>[NH2:11][C@H:12]([C:17]([NH:19][C@H:20]([C:28]([OH:30])=[O:29])[CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=[O:18])[CH2:13][C:14](=[O:15])[OH:16]
Reactant: O=C(O)C[C@H](NC(=O)OCc1ccccc1)C(=O)N[C@@H](Cc1ccccc1)C(=O)O
Solvent: Cc1ccccc1
Product: N[C@@H](CC(=O)O)C(=O)N[C@@H](Cc1ccccc1)C(=O)O

Procedure:
The lower alkyl ester of N-benzyloxycarbonyl-α-L-aspartyl-L-phenylalanine as the starting compound is dissolved in toluene and, as the reaction of elimination proceeds, the lower alkyl ester of α-L-aspartyl-L-phenylalanine as the product formed in the organic phase is transferred into the aqueous phase.