Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[NH2:2][C:3]1([C:8]([O:10][CH3:11])=[O:9])[CH2:7][CH2:6][CH2:5][CH2:4]1.[Br:12][C:13]1[S:17][C:16]([C:18](O)=[O:19])=[CH:15][CH:14]=1.S(Cl)(Cl)=O>ClCCl>[Br:12][C:13]1[S:17][C:16]([C:18]([NH:2][C:3]2([C:8]([O:10][CH3:11])=[O:9])[CH2:7][CH2:6][CH2:5][CH2:4]2)=[O:19])=[CH:15][CH:14]=1
Reactant: COC(=O)C1(N)CCCC1
Reactant: O=C(O)c1ccc(Br)s1
Agent: Cl
Solvent: ClCCl
Solvent: O=S(Cl)Cl
Product: COC(=O)C1(NC(=O)c2ccc(Br)s2)CCCC1

Procedure:
Prepared analogously to Example 37a from methyl 1-amino-cyclopentane-1-carboxylate hydrochloride and 5-bromo-thiophene-2-carboxylic acid with thionyl chloride in dichloromethane with TEA.
Reaction SMILES: [N+:1]([C:4]1[CH:19]=[CH:18][CH:17]=[CH:16][C:5]=1[CH2:6][N:7]([CH2:13][C:14]#[N:15])[C:8](=[O:12])[O:9][CH2:10][CH3:11])([O-])=O.CO.C(Cl)Cl>C(O)(=O)C.[Fe]>[CH2:10]([O:9][C:8]([N:7]1[CH2:6][C:5]2[CH:16]=[CH:17][CH:18]=[CH:19][C:4]=2[N:1]=[C:14]([NH2:15])[CH2:13]1)=[O:12])[CH3:11]
Reactant: CCOC(=O)N(CC#N)Cc1ccccc1[N+](=O)[O-]
Agent: [Fe]
Solvent: CO
Solvent: ClCCl
Solvent: CC(=O)O
Product: CCOC(=O)N1CC(N)=Nc2ccccc2C1
Temperature: 90 °C
Yield: 25.9 %

Procedure:
To a solution of ethyl-2-nitrobenzyl-(cyanomethyl)carbamate (2) (227 mg, 0.862 mmol) dissolved in acetic acid (5 mL) under a nitrogen atmosphere was added Fe (289 mg, 5.17 mmol). The reaction mixture was heated to 90° C. for 4 hours, then cooled to room temperature and concentrated under reduced pressure. The resulting brown oil was diluted with EtOAc (20 mL) and filtered over GF/F paper (rinsing with 10 mL of EtOAc). The organic phase was washed with saturated Na2CO3 (20 mL) and brine (20 mL), dried over Na2SO4, and concentrated. The resulting brown oil was purified by column chromatography (5% MeOH/CH2Cl2, then 20% MeOH/CH2Cl2) to provide 52 mg (0.223 mmol, 26% yield) of (E)-ethyl-2-amino-3H-benzo[e][1,4]diazepine-4(5H)-carboxylate (3) as a tan solid. 1H NMR (400 MHz, DMSO-d6) δ 1.17-1.25 (m, 3H), 3.81 (s, 2H), 4.02-4.12 (m, 2H), 4.23 (s, 2H), 6.79 (br s, 1H), 6.85-6.92 (m, 2H), 7.18-7.24 (m, 2H).
Reaction SMILES: C(O)(C(F)(F)F)=O.[CH:8]([C:10]1[C:15]([O:16]COC)=[CH:14][C:13]([C:20]([F:23])([F:22])[F:21])=[CH:12][C:11]=1[C:24]1[CH:25]=[CH:26][C:27]([C:30]([NH:32][CH2:33][CH2:34][C:35]([O:37][CH2:38][CH3:39])=[O:36])=[O:31])=[N:28][CH:29]=1)=[O:9]>C(Cl)Cl>[CH:8]([C:10]1[C:15]([OH:16])=[CH:14][C:13]([C:20]([F:21])([F:22])[F:23])=[CH:12][C:11]=1[C:24]1[CH:25]=[CH:26][C:27]([C:30]([NH:32][CH2:33][CH2:34][C:35]([O:37][CH2:38][CH3:39])=[O:36])=[O:31])=[N:28][CH:29]=1)=[O:9]
Reactant: CCOC(=O)CCNC(=O)c1ccc(-c2cc(C(F)(F)F)cc(OCOC)c2C=O)cn1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCOC(=O)CCNC(=O)c1ccc(-c2cc(C(F)(F)F)cc(O)c2C=O)cn1
Temperature: 25 °C

Procedure:
Neat TFA (1 mL) was added to a DCM solution (3 mL) of ethyl 3-(5-(2-formyl-3-(methoxymethoxy)-5-(trifluoromethyl)phenyl)picolinamido)propanoate (121 mg, 0.27 mmol) and the resulting mixture was stirred at room temperature. After 1 h the resulting mixture was concentrated to yield the title compound, which was used in the next step without further purification.
Reaction SMILES: [NH2:1][CH:2]1[C:34](=[O:35])[N:4]2[C:5]([C:18]([O:20][CH:21]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)=[O:19])=[C:6]([CH:9]=[CH:10][S:11][C:12]3[CH:17]=[CH:16][N:15]=[CH:14][CH:13]=3)[CH2:7][S:8][C@H:3]12.[C:36]([O:55]/[N:56]=[C:57](/[C:61]1[N:62]=[C:63]([NH:66][C:67]([C:80]2[CH:85]=[CH:84][CH:83]=[CH:82][CH:81]=2)([C:74]2[CH:79]=[CH:78][CH:77]=[CH:76][CH:75]=2)[C:68]2[CH:73]=[CH:72][CH:71]=[CH:70][CH:69]=2)[S:64][CH:65]=1)\[C:58](O)=[O:59])([C:49]1[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=1)([C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1)[C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1.C1(N=C=NC2CCCCC2)CCCCC1>C(Cl)Cl.CN(C)C=O>[C:36]([O:55][N:56]=[C:57]([C:61]1[N:62]=[C:63]([NH:66][C:67]([C:80]2[CH:85]=[CH:84][CH:83]=[CH:82][CH:81]=2)([C:74]2[CH:75]=[CH:76][CH:77]=[CH:78][CH:79]=2)[C:68]2[CH:69]=[CH:70][CH:71]=[CH:72][CH:73]=2)[S:64][CH:65]=1)[C:58]([NH:1][CH:2]1[C:34](=[O:35])[N:4]2[C:5]([C:18]([O:20][CH:21]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[C:28]3[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=3)=[O:19])=[C:6]([CH:9]=[CH:10][S:11][C:12]3[CH:17]=[CH:16][N:15]=[CH:14][CH:13]=3)[CH2:7][S:8][C@H:3]12)=[O:59])([C:49]1[CH:50]=[CH:51][CH:52]=[CH:53][CH:54]=1)([C:37]1[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=1)[C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1
Reactant: NC1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(C=CSc3ccncc3)CS[C@H]12
Reactant: O=C(O)/C(=N\OC(c1ccccc1)(c1ccccc1)c1ccccc1)c1csc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: CN(C)C=O
Solvent: ClCCl
Product: O=C(NC1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(C=CSc3ccncc3)CS[C@H]12)C(=NOC(c1ccccc1)(c1ccccc1)c1ccccc1)c1csc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1

Procedure:
To a solution of benzhydryl 7-amino-3-[2-(4-pyridyl)thiovinyl]-3-cephem-4-carboxylate (a mixture of cis- and trans-isomers) (1.0 g) in a mixture of methylene chloride (10 ml) and dimethylformamide (1.0 ml) were added (Z)-2-trityloxyimino-2-(2-tritylaminothiazol-4-yl)acetic acid (1.46 g) and DCC (dicyclohexylcarbodiimide) (450 mg) and the resultant mixture was stirred at room temperature for 2 hours. After completion of the reaction, the dicyclohexylurea was filtered off and the filtrate was diluted with ethyl acetate (50 ml), washed with saturated aqueous solution of sodium hydrogen carbonate and saturated aqueous solution of sodium chloride and dried over magnesium sulfate. The solvent was then distilled off under reduced pressure to give a crude product (2.65 g). This crude product was chromatographed on a column of silica gel and eluted with benzene-ethyl acetate to provide benzhydryl 7-[2-trityloxyimino-2-(2-tritylaminothiazol-4-yl)acetamido]-3-[2-(4-pyridyl)thiovinyl]-3-cephem-4-carboxylate (1.6 g).
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[CH:7][C:6]=1[N+:12]([O-:14])=[O:13])(=[O:3])[CH3:2].[CH2:15](Br)[CH2:16][CH2:17][CH3:18].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[C:1]([NH:4][C:5]1[CH:10]=[CH:9][C:8]([O:11][CH2:15][CH2:16][CH2:17][CH3:18])=[CH:7][C:6]=1[N+:12]([O-:14])=[O:13])(=[O:3])[CH3:2]
Reactant: CCCCBr
Reactant: CC(=O)Nc1ccc(O)cc1[N+](=O)[O-]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCCCOc1ccc(NC(C)=O)c([N+](=O)[O-])c1

Procedure:
2.94 G. of 1-acetamido-4-hydroxy-2-nitrobenzene, 4.0 g. n-butyl bromide, and 4.2 g. of anhydrous potassium carbonate in 100 ml. of acetone are refluxed overnight with stirring. The mixture is evaporated, diluted with water and extracted with ether to afford 1-acetamido-4-n-butoxy-2-nitrobenzene. This latter compound is treated in accordance with the second paragraph of Example XXXI to afford 1-amino-4-n-butoxy-2-nitrobenzene. This latter compound is treated in accordance with the first paragraph of Example VI to afford 4-n-butoxy-1-(3-methoxycarbonyl-2-thioureido)-2-nitrobenzene. This latter compound is treated in accordance with the iron reduction technique set forth in the third paragraph of Example XIX to afford 2-amino-4-n-butoxy-1-(3-methoxycarbonyl-2-thioureido)benzene. This latter compound is treated in accordance with the first paragraph of Example XVII to afford 4-n-butoxy-1-(3-methoxycarbonyl-2-thioureido)-2-succinamidobenzene.
Reaction SMILES: [Br:1][C:2]1[CH:14]=[C:13]2[C:5]([C:6]3[CH:7]=[CH:8][C:9]([CH:19]=O)=[CH:10][C:11]=3[C:12]2([CH2:17][CH3:18])[CH2:15][CH3:16])=[CH:4][CH:3]=1.Cl.[NH2:22]O>C(O)=O>[Br:1][C:2]1[CH:14]=[C:13]2[C:5]([C:6]3[CH:7]=[CH:8][C:9]([C:19]#[N:22])=[CH:10][C:11]=3[C:12]2([CH2:17][CH3:18])[CH2:15][CH3:16])=[CH:4][CH:3]=1
Reactant: CCC1(CC)c2cc(Br)ccc2-c2ccc(C=O)cc21
Reactant: NO
Agent: Cl
Solvent: O=CO
Product: CCC1(CC)c2cc(Br)ccc2-c2ccc(C#N)cc21

Procedure:
An alternate, but less satisfactory synthesis was conducted as follows: A mixture of 7-bromo-9,9-diethylfluorene-2-carboxaldehyde (3.29 g, 10.0 mmol), hydroxylamine hydrochloride (0.9 g, 10.0 mmol), and formic acid (15 mL), was held at reflux for 2 hours, cooled and filtered. The filtrate was worked up by extraction into toluene, washing the extract with water, and bicarbonate solution, drying and concentration. The residue was combined with the formic acid-insoluble solids, and chromatographed over silica gel. There were obtained, the desired nitrile product, 1.58 g (49%), m.p. 85-87° C., mass spectrum (m/z): 325, 327 (M+); the amide byproduct, 0.42 g (12%), m.p. 179-184° C., mass spectrum (m/z): 343, 345 (M+); and the oxime by-product, m.p. 104-107° C., 0.17 g (5%), mass spectrum (m/z): 343 (M+)
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][CH2:9][OH:10].[O:11]1[CH:16]=[CH:15][CH2:14][CH2:13][CH2:12]1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1.C(=O)([O-])O.[Na+]>C(Cl)(Cl)Cl>[Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][CH2:9][O:10][CH:12]1[CH2:13][CH2:14][CH2:15][CH2:16][O:11]1
Reactant: OCCc1ccccc1Br
Reactant: C1=COCCC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: ClC(Cl)Cl
Product: Brc1ccccc1CCOC1CCCCO1
Yield: 81.5 %

Procedure:
A solution of 2-(2-bromophenyl)ethanol (3.10 g, 15.4 mmol), 3,4-dihydro-2H-pyran (1.70 ml, 18.6 mmol) and p-toluenesulfonic acid monohydrate (10.0 mg, 5.35 mmol) in chloroform (30 ml) was stirred at room temperature for 1 hr. Saturated aqueous sodium hydrogen carbonate solution was added to the reaction mixture, and the mixture was extracted with chloroform. The organic layer was washed with saturated brine and dried over anhydrous sodium carbonate. After filtration, the solvent was evaporated under reduced pressure, and the residue was purified by silica gel chromatography (hexane:ethyl acetate=30:1-10:1) to give 2-[2-(2-bromophenyl)ethoxy]tetrahydropyran (3.58 g, yield 81.7%).
Reaction SMILES: Cl.[N+:2]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[NH:11]N)([O-:4])=[O:3].[C:13]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=1)(=O)[CH3:14]>>[N+:2]([C:5]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:6]=1[NH:11][C:13]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=1)=[CH:14]2)([O-:4])=[O:3]
Reactant: CC(=O)c1ccccn1
Reactant: NNc1ccccc1[N+](=O)[O-]
Agent: Cl
Product: O=[N+]([O-])c1cccc2cc(-c3ccccn3)[nH]c12
Yield: 16.1 %

Procedure:
2-Nitrophenylhydrazine hydrochloride (5 g, 26 mmol) and 2-acetylpyridine (2.5 ml, 26 mmol) were reacted according to the same procedures as Preparations 4 to 5 to give the title compound (1 g, Yield 16%).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:9]=[CH:10][CH:11]=1)[CH:7]=O)([O-:3])=[O:2].COC(OC)OC.[NH2:19][CH2:20][CH2:21][CH2:22][OH:23].[BH4-].[Na+]>CO>[N+:1]([C:4]1[CH:5]=[C:6]([CH:9]=[CH:10][CH:11]=1)[CH2:7][NH:19][CH2:20][CH2:21][CH2:22][OH:23])([O-:3])=[O:2]
Reactant: NCCCO
Reactant: O=Cc1cccc([N+](=O)[O-])c1
Agent: [BH4-]
Agent: [Na+]
Solvent: COC(OC)OC
Solvent: CO
Product: O=[N+]([O-])c1cccc(CNCCCO)c1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
To a solution of m-nitrobenzaldehyde (94.23 mmol) and trimethylorthoformate (15.5 mL, 141 mmol) in MeOH (300 mL) is added dropwise 3-amino-1-propanol (7.21 mL, 94.23 mmol) at room temperature. The reaction is allowed to stir at room temperature for 5 hours followed by cooling to 0° C. in an ice bath. Sodium borohydride (3.56 g, 94.23 mmol) is added in two portions and when the bubbling stops the solvent is evaporated. The resulting residue is partitioned between ethyl acetate (75 mL) and water (75 mL). The aqueous layer is extracted twice with ethyl acetate (75 mL). The ethyl acetate extracts are collected and washed twice with Brine (50 mL), dried over MgSO4, filtered, and concentrated. Drying will give the title compound.
Reaction SMILES: C([O:3][C:4]([C:6]1[NH:7][C:8]([CH:12]=[O:13])=[C:9]([CH3:11])[CH:10]=1)=[O:5])C.[OH-].[K+]>O.C(O)C>[CH:12]([C:8]1[NH:7][C:6]([C:4]([OH:5])=[O:3])=[CH:10][C:9]=1[CH3:11])=[O:13]
Reactant: CCOC(=O)c1cc(C)c(C=O)[nH]1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: Cc1cc(C(=O)O)[nH]c1C=O
Temperature: 100 °C
Yield: 99.4 %

Procedure:
To a solution of 0.8 g (4.4 mmol) of 5-formyl-4-methyl-1H-pyrrole-2-carboxylic acid ethyl ester in 35 mL of water and 15 mL of ethanol was added 0.5 gram (8.9 mmol) of potassium hydroxide. The reaction mixture was heated to 100° C. for 1 h, cooled to room temperature, and evaporated ethanol. The water layer was acidified to pH=3 using 2N hydrogen chloride solution. The precipitate was filtered and washed with water to afford 0.67 g (68%) of 5-formyl-4-methyl-1H-pyrrole-2-carboxylic acid as a tan solid.
Reaction SMILES: [H-].[Na+].[Br:3][C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[CH:10]=[C:9]([OH:14])[CH:8]=[CH:7]2.I[CH2:16][CH2:17][CH2:18][CH3:19].CN(C=O)C>C1COCC1.O>[Br:3][C:4]1[CH:13]=[CH:12][C:11]2[C:6](=[CH:7][CH:8]=[C:9]([O:14][CH2:16][CH2:17][CH2:18][CH3:19])[CH:10]=2)[CH:5]=1
Reactant: Oc1ccc2cc(Br)ccc2c1
Reactant: CCCCI
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Solvent: CN(C)C=O
Product: CCCCOc1ccc2cc(Br)ccc2c1
Yield: 92.2 %

Procedure:
An oil dispersion of 480 mg (50%, 10 mmol, Alfa) of sodium hydride was washed three times with petroleum ether then the residue covered with 5 ml of dry THF. To the resulting stirred slurry was added dropwise a solution of 2.00 g (8.97 mmol, Aldrich) of 6-bromo-2-naphthol, in 10 ml of THF over 10 minutes. The reaction mixture was stirred for 30 minutes then 1.70 g (9.23 mmol, Aldrich) of 1-iodobutane and 15 ml of sieve-dried DMF were added. The resulting solution was heated to 60° for two hours, then cooled, added to 100 ml of H2O and extracted with 50 ml of petroleum ether. The organic extract was washed with an additional 100 ml of H2O, dried (MgSO4) and concentrated in vacuo to give a solid. The crude material was purified by flash chromatography (15×5 cm, pet ether) to afford 2.31 g (92%) of title compound as a white solid, m.p. 48°-50°.
Reaction SMILES: [CH3:1][CH:2]([CH2:12][CH:13]=C)[CH2:3][O:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.I([O-])(=O)(=O)=[O:16].[K+]>CC(C)=O.O.[Os](=O)(=O)(=O)=O>[CH2:5]([O:4][CH2:3][C@H:2]([CH3:1])[CH2:12][CH:13]=[O:16])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: [O-][I+3]([O-])([O-])[O-]
Reactant: C=CCC(C)COCc1ccccc1
Agent: O=[Os](=O)(=O)=O
Agent: [K+]
Solvent: CC(C)=O
Solvent: O
Product: C[C@H](CC=O)COCc1ccccc1
Temperature: 25 °C
Reaction time: 6 h
Yield: 80.7 %

Procedure:
A 250 mL round-bottomed flask, equipped with a magnetic stirring bar and a thermometer was fitted with a septum and a nitrogen inlet. The apparatus was charged with benzyl 2-methyl-4-penten-1-yl ether (2.39 g, 12.5 mmol) in 75 mL of acetone and 25 mL of water. Osmium tetroxide (0.833 mL of an 0.15M aqueous solution, 0.125 mmol) was added in one portion, followed by potassium periodate (6.04 g, 26.2 mmol) in three equal portions. The resulting slurry was stirred for 6 hours at room temperature and decanted into a 500 mL separatory funnel. The aqueous layer was extracted with 3×200 mL of diethyl ether. Each washing was stirred over the solids for 5 minutes, washed with 150 mL of saturated aqueous sodium thiosulfate and 100 mL of saturated aqueous sodium chloride. The combined organic layers were dried over sodium sulfate, filtered, concentrated and chromatographed (4×20 cm column; 4:1 hexane:ethyl acetate) to afford 1.94 g (81%) of aldehyde 4 as a colorless oil. Rf =0.37 (4:1 hexane:ethyl acetate).
Reaction SMILES: [C:1]1([CH2:7][C:8]([NH2:10])=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(Cl)(=O)[C:12](Cl)=[O:13].[NH2:17][C:18]1[CH:36]=[CH:35][C:21]([O:22][C:23]2[CH:28]=[CH:27][N:26]=[C:25]([NH:29][C:30]([N:32]([CH3:34])[CH3:33])=[O:31])[CH:24]=2)=[C:20]([F:37])[CH:19]=1.C(OCC)(=O)C>ClCCCl.CN(C)C=O>[CH3:33][N:32]([CH3:34])[C:30]([NH:29][C:25]1[CH:24]=[C:23]([O:22][C:21]2[CH:35]=[CH:36][C:18]([NH:17][C:12]([NH:10][C:8](=[O:9])[CH2:7][C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)=[O:13])=[CH:19][C:20]=2[F:37])[CH:28]=[CH:27][N:26]=1)=[O:31]
Reactant: O=C(Cl)C(=O)Cl
Reactant: NC(=O)Cc1ccccc1
Reactant: CN(C)C(=O)Nc1cc(Oc2ccc(N)cc2F)ccn1
Solvent: CN(C)C=O
Solvent: ClCCCl
Solvent: CCOC(C)=O
Product: CN(C)C(=O)Nc1cc(Oc2ccc(NC(=O)NC(=O)Cc3ccccc3)cc2F)ccn1
Temperature: 110 °C
Reaction time: 8 h
Yield: 26 %

Procedure:
2-Phenylacetamide (126 mg) was dissolved in 1,2-dichloroethane (10 ml) under a nitrogen atmosphere, and then oxalyl chloride (0.101 ml) was added thereto, followed by stirring at 110° C. overnight. The reaction mixture was concentrated under a reduced pressure to give a residue, which was then dissolved in N,N-dimethylformamide (3 ml) under a nitrogen atmosphere. 4-(4-Amino-2-fluorophenoxy)-2-[(dimethylamino)carbonylamino]pyridine (90 mg) was then added thereto, followed by stirring for 20 min. The reaction mixture was partitioned between ethyl acetate and water. The organic layer was washed with a saturated aqueous solution of sodium hydrogencarbonate and brine in this order, and dried over anhydrous sodium sulfate. The solvent was evaporated to give a residue, which was then purified by silica gel column chromatography (FUJI Silysia NH, eluent; hexane:ethyl acetate=1:3). Fractions containing the target compound were concentrated to give a residue, to which ethyl acetate (1.5 ml) was added to precipitate crystals. The crystals were filtered off and dried under aeration to provide the titled compound (36.3 mg, 26%) as white crystals.
Reaction SMILES: [NH2:1][C@H:2]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[CH2:3][CH2:4][N:5]1[CH2:10][CH2:9][CH:8]([C:11]2[CH:12]=[C:13]([NH:17][C:18](=[O:22])[CH:19]([CH3:21])[CH3:20])[CH:14]=[CH:15][CH:16]=2)[CH2:7][CH2:6]1.[F:29][C:30]1[CH:35]=[CH:34][C:33]([CH2:36][C:37](Cl)=[O:38])=[CH:32][CH:31]=1>C1COCC1>[F:29][C:30]1[CH:35]=[CH:34][C:33]([CH2:36][C:37]([NH:1][C@H:2]([C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH2:3][CH2:4][N:5]2[CH2:10][CH2:9][CH:8]([C:11]3[CH:12]=[C:13]([NH:17][C:18](=[O:22])[CH:19]([CH3:21])[CH3:20])[CH:14]=[CH:15][CH:16]=3)[CH2:7][CH2:6]2)=[O:38])=[CH:32][CH:31]=1
Reactant: CC(C)C(=O)Nc1cccc(C2CCN(CC[C@H](N)c3ccccc3)CC2)c1
Reactant: O=C(Cl)Cc1ccc(F)cc1
Solvent: C1CCOC1
Product: CC(C)C(=O)Nc1cccc(C2CCN(CC[C@H](NC(=O)Cc3ccc(F)cc3)c3ccccc3)CC2)c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 90 %

Procedure:
A mixture of N-(3-{1-[(3S)-3-amino-3-phenylpropyl]-4-piperidinyl}phenyl)-2-methylpropanamide (11.0 mg, 0.0280 mmol) and (4-fluorophenyl)acetyl chloride (7.20 mg, 0.0420 mmol) in THF (5 mL) was stirred at room temperature for 4 h. The solvent was removed under reduced pressure and the residue was purified by preparative TLC using Hexane:EtOAc (2:1) to give the desired product (13 mg, 90% yield). 1H NMR (400 MHz, CDCl3) δ 7.89 (d, 1H, J=8.4 Hz), 7.59 (s, 1H), 7.31–6.93 (m, 13H), 5.13 (q, 1H, J=6.0 Hz), 3.56 (s, 2H), 3.07 (d, 1H, J=11.7 Hz), 2.91 (d, 1H, J=11.0 Hz), 2.62–2.42 (m, 2H), 2.40–2.30 (m, 1H), 2.12–1.54 (m, 9H), 1.24 (d, 6H, J=6.7 Hz); ESMS m/e: 515.3 (M+H)+.
Reaction SMILES: [Cl-].O[NH3+:3].[C:4](=[O:7])([O-])[OH:5].[Na+].CS(C)=O.[Si]([O:20][CH2:21][C:22]([CH3:55])([CH3:54])[CH:23]([OH:53])[CH2:24][N:25]1[C:30](=[O:31])[C:29]2[CH:32]=[C:33]([CH2:35][CH3:36])[S:34][C:28]=2[N:27]([CH2:37][C:38]2[CH:43]=[CH:42][C:41]([C:44]3[C:45]([C:50]#[N:51])=[CH:46][CH:47]=[CH:48][CH:49]=3)=[CH:40][CH:39]=2)[C:26]1=[O:52])(C(C)(C)C)(C)C>O.C(OCC)(=O)C>[OH:53][CH:23]([C:22]([CH3:55])([CH3:54])[CH2:21][OH:20])[CH2:24][N:25]1[C:30](=[O:31])[C:29]2[CH:32]=[C:33]([CH2:35][CH3:36])[S:34][C:28]=2[N:27]([CH2:37][C:38]2[CH:43]=[CH:42][C:41]([C:44]3[CH:49]=[CH:48][CH:47]=[CH:46][C:45]=3[C:50]3[NH:3][C:4](=[O:7])[O:5][N:51]=3)=[CH:40][CH:39]=2)[C:26]1=[O:52]
Reactant: O=C([O-])O
Reactant: [NH3+]O
Reactant: CCc1cc2c(=O)n(CC(O)C(C)(C)CO[Si](C)(C)C(C)(C)C)c(=O)n(Cc3ccc(-c4ccccc4C#N)cc3)c2s1
Agent: [Cl-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Solvent: CCOC(C)=O
Product: CCc1cc2c(=O)n(CC(O)C(C)(C)CO)c(=O)n(Cc3ccc(-c4ccccc4-c4noc(=O)[nH]4)cc3)c2s1
Temperature: 50 °C
Reaction time: 0.5 h
Yield: 18.6 %

Procedure:
A mixture of hydroxylammonium chloride (0.32 g), sodium hydrogencarbonate (0.49 g) and dimethyl sulfoxide (3 mL) was stirred at 50° C. for 30 min, 4′-{[3-(4-{[tert-butyl(dimethyl)silyl]oxy}-2-hydroxy-3,3-dimethylbutyl)-6-ethyl-2,4-dioxo-3,4-dihydrothieno[2,3-d]pyrimidin-1(2H)-yl]methyl}biphenyl-2-carbonitrile (0.36 g) was added, and the mixture was stirred at 90° C. for 20 hr. After allowing to cool to room temperature, ethyl acetate and water were added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed successively with water and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The, residue was purified by silica gel column chromatography and dissolved in tetrahydrofuran (8 mL). N,N′-Carbonyldiimidazole (0.097 g) and then 1,8-diazabicyclo[5.4.0]undec-7-ene (0.09 mL) were added, and the mixture was stirred at room temperature for 2 hr. The reaction mixture was diluted with ethyl acetate, washed successively with 1N hydrochloric acid and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The residue was dissolved in tetrahydrofuran (3 mL), tetrabutylammonium fluoride (0.2 g) was added, and the mixture was stirred at room temperature for 3 hr. To the reaction mixture were added ethyl acetate and water, and the mixture was extracted with ethyl acetate. The organic layer was washed successively with water and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography to give the title compound as a colorless amorphous solid (0.061 g, 19%).
Reaction SMILES: C([O:3][C:4]([C:6]1([NH:15][C:16]([C:18]2[CH:23]=[CH:22][N:21]=[CH:20][C:19]=2[N:24]2[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]2)=[O:17])[CH2:14][C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH2:7]1)=[O:5])C.O1CCOCC1.CO>O>[N:24]1([C:19]2[CH:20]=[N:21][CH:22]=[CH:23][C:18]=2[C:16]([NH:15][C:6]2([C:4]([OH:5])=[O:3])[CH2:7][C:8]3[C:13](=[CH:12][CH:11]=[CH:10][CH:9]=3)[CH2:14]2)=[O:17])[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]1
Reactant: CCOC(=O)C1(NC(=O)c2ccncc2N2CCCCC2)Cc2ccccc2C1
Solvent: C1COCCO1
Solvent: CO
Solvent: O
Product: O=C(NC1(C(=O)O)Cc2ccccc2C1)c1ccncc1N1CCCCC1
Reaction time: 68 h
Yield: 101.9 %

Procedure:
A 100 mL round bottom flask which contains 2-[(3,4,5,6-tetrahydro-2H-[1,3′]bipyridinyl-4′-carbonyl)-amino]-indan-2-carboxylic acid ethyl ester (355, 370 mg, 0.94 mmol) is charged with 1,4-dioxane (4 mL) and MeOH (4 mL). A stirring bar is added and stirring is initiated. After dissolution, water (2 mL) is added followed by the LiOH monohydrate (100 mg, 2.38 mmol). After 68 h, tlc analysis (silica, 50% EtOAc/Heptanes) indicates that the starting material is completely consumed. Amberlyst highly acidic exchange resin (0.5 g) is added to the reaction vial. The reaction is capped and allowed to stir at ambient temperature. After 20 h, the contents of the flask are filtered through a pad of Celite. The solvent is removed from the filtrate. The residue is reconstituted with iPrOH/toluene (20+20 mL) and the solvent is removed. This process is repeated 1 time. Pumping to constant weight provides white solid (0.35 g, 96%).