Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][NH2:9])=[C:4]([F:10])[C:3]=1[O:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.[Cl:18][C:19]1[N:20]=[C:21]([CH3:27])[NH:22][C:23]=1[C:24](O)=[O:25].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[Cl:18][C:19]1[N:20]=[C:21]([CH3:27])[NH:22][C:23]=1[C:24]([NH:9][CH2:8][C:5]1[CH:6]=[CH:7][C:2]([Cl:1])=[C:3]([O:11][C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)[C:4]=1[F:10])=[O:25]
Reactant: NCc1ccc(Cl)c(Oc2ccccc2)c1F
Reactant: Cc1nc(Cl)c(C(=O)O)[nH]1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1nc(Cl)c(C(=O)NCc2ccc(Cl)c(Oc3ccccc3)c2F)[nH]1
Temperature: 25 °C
Reaction time: 8 h
Yield: 23.5 %

Procedure:
A mixture of {[4-chloro-2-fluoro-3-(phenyloxy)phenyl]methyl}amine (0.021 g, 0.083 mmol), 4-chloro-2-methyl-1H-imidazole-5-carboxylic acid (0.013 g, 0.083 mmol), HATU (0.038 g, 0.100 mmol) and DIPEA (0.017 mL, 0.100 mmol) in DMF (1 mL) was stirred at room temperature overnight. The crude reaction mixture was purified by reverse phase HPLC (acetonitrile:water with 0.1% TFA). The fractions containing product were lyophilized to give 4-chloro-N-{[4-chloro-2-fluoro-3-(phenyloxy)phenyl]methyl}-2-methyl-1H-imidazole-5-carboxamide (0.0077 g, 18%) (trifluoroacetate salt) as a white solid. 1H NMR (400 MHz, DMSO-d6) d ppm 8.05-8.18 (m, 1H), 7.41-7.48 (m, 1H), 7.34 (t, 2H), 7.27 (t, 1H), 7.08 (t, 1H), 6.87 (d, 2 H), 4.49 (d, 2H), 2.24 (s, 3H). ES MS: m/z 394 (M+1).
Reaction SMILES: Br[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][C:9]=2[N+:11]([O-:13])=[O:12])[N:4]([CH2:14][C:15]2[S:16][C:17]([CH3:20])=[N:18][N:19]=2)[N:3]=1.[CH:21]1(B(O)O)[CH2:23][CH2:22]1.C(=O)([O-])[O-].[K+].[K+].C1(P(C2CCCCC2)C2C=CC=CC=2C2C(OC)=CC=C(S([O-])(=O)=O)C=2OC)CCCCC1.[Na+]>O.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.O1CCOCC1>[CH:21]1([C:2]2[C:10]3[C:5](=[CH:6][CH:7]=[CH:8][C:9]=3[N+:11]([O-:13])=[O:12])[N:4]([CH2:14][C:15]3[S:16][C:17]([CH3:20])=[N:18][N:19]=3)[N:3]=2)[CH2:23][CH2:22]1
Reactant: Cc1nnc(Cn2nc(Br)c3c([N+](=O)[O-])cccc32)s1
Reactant: OB(O)C1CC1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: COc1ccc(S(=O)(=O)[O-])c(OC)c1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Solvent: O
Solvent: C1COCCO1
Product: Cc1nnc(Cn2nc(C3CC3)c3c([N+](=O)[O-])cccc32)s1
Temperature: 25 °C
Reaction time: 16 h
Yield: 15.5 %

Procedure:
A 10 mL round bottom flask equipped with a reflux condenser and a nitrogen line was charged with 2-((3-bromo-4-nitro-1H-indazol-1-yl)methyl)-5-methyl-1,3,4-thiadiazole (195 mg, 0.551 mmol), cyclopropylboronic acid (104 mg, 1.21 mmol), palladium acetate (7 mg, 0.031 mmol), potassium carbonate (258 mg, 1.87 mmol), and sodium 2′-(dicyclohexylphosphino)-2,6-dimethoxybiphenyl-3-sulfonate (32 mg, 0.062 mmol). To the flask was added a 1,4-dioxane:water mixture (5:1; 2.4 mL) and the flask was evacuated and refilled with nitrogen three times. The reaction mixture was heated at reflux for 8 hours followed by stirring for 16 hours at ambient temperature. The cooled reaction mixture was diluted with excess water and extracted multiple times with DCM and EtOAc. The combined organic extracts were dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was subjected to preparative thin-layer chromatography (silica, 5% MeOH-DCM as eluent) to afford the desired product (27 mg) as a solid.
Reaction SMILES: O1CCOCC1.[CH2:7]([C:15]1[CH:27]=[CH:26][C:18]([C:19]([O:21]C(C)(C)C)=[O:20])=[C:17]([NH:28][C:29]2[CH:34]=[CH:33][CH:32]=[C:31]([N:35]3[CH:39]=[CH:38][CH:37]=[CH:36]3)[CH:30]=2)[CH:16]=1)[CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.[OH-].[Na+].Cl>C(OCC)(=O)C.CO>[CH2:7]([C:15]1[CH:27]=[CH:26][C:18]([C:19]([OH:21])=[O:20])=[C:17]([NH:28][C:29]2[CH:34]=[CH:33][CH:32]=[C:31]([N:35]3[CH:39]=[CH:38][CH:37]=[CH:36]3)[CH:30]=2)[CH:16]=1)[CH2:8][C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1
Reactant: CC(C)(C)OC(=O)c1ccc(CCc2ccccc2)cc1Nc1cccc(-n2cccc2)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: O=C(O)c1ccc(CCc2ccccc2)cc1Nc1cccc(-n2cccc2)c1
Temperature: 25 °C
Yield: 49.7 %

Procedure:
To dioxane 2.0 mL solution of tert-butyl 4-phenethyl-2-(3-(1H-pyrrol-1-yl)phenylamino)benzoate 83 mg were added methanol 2.0 mL and 2.0 mol/L sodium hydroxide aqueous solution 1.0 mL, and it was heated and refluxed for 3 hours. After the reaction mixture was cooled to room temperature, ethyl acetate and 1.0 mol/L hydrochloric acid were added to it. The organic layer was separated and collected,dried over anhydrous magnesium sulfate after washing with saturated sodium chloride aqueous solution, and the solvent was removed under reduced pressure. Diisopropyl ether was added to the obtained residue, and solid matter was filtrated to give 4-phenethyl-2-(3-(1H-pyrrol-1-yl)phenylamino)benzoic acid 36 mg of a white solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:21]=[CH:22][C:23]=1[O:24][CH3:25])[C:6]([C:8]1[N:12]([CH3:13])[C:11]([CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])=[CH:10][C:9]=1[CH3:20])=[O:7].Cl[C:27]1C=CC(C(C2N(C)C(CC(OCC)=O)=CC=2C)=O)=CC=1>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:21]=[CH:22][C:23]=1[O:24][CH3:25])[C:6]([C:8]1[N:12]([CH3:13])[C:11]([CH:14]([CH3:27])[C:15]([O:17][CH2:18][CH3:19])=[O:16])=[CH:10][C:9]=1[CH3:20])=[O:7]
Reactant: CCOC(=O)Cc1cc(C)c(C(=O)c2ccc(Cl)cc2)n1C
Reactant: CCOC(=O)Cc1cc(C)c(C(=O)c2ccc(OC)c(OC)c2)n1C
Product: CCOC(=O)C(C)c1cc(C)c(C(=O)c2ccc(OC)c(OC)c2)n1C

Procedure:
The methylation procedure of Example 77A is repeated, except that an equivalent quantity of ethyl 5-(3',4'-dimethoxybenzoyl)-1,4-dimethylpyrrole-2-acetate (from Example 90) is methylated instead of the ethyl 5-(p-chlorobenzoyl)-1,4-dimethylpyrrole-2-acetate used in Example 77A, to yield ethyl 5-(3',4'-dimethoxybenzoyl)-1,4,α-trimethylpyrrole-2-acetate.
Reaction SMILES: [NH2:1][C:2]1[CH:6]=[C:5]([C:7](=[N:18][OH:19])[NH:8][CH2:9][C:10]2[CH:15]=[C:14]([Cl:16])[CH:13]=[CH:12][C:11]=2[CH3:17])[O:4][N:3]=1.C1N=CN([C:25](N2C=NC=C2)=[O:26])C=1>C1COCC1>[NH2:1][C:2]1[CH:6]=[C:5]([C:7]2[N:8]([CH2:9][C:10]3[CH:15]=[C:14]([Cl:16])[CH:13]=[CH:12][C:11]=3[CH3:17])[C:25](=[O:26])[O:19][N:18]=2)[O:4][N:3]=1
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: Cc1ccc(Cl)cc1CNC(=NO)c1cc(N)no1
Solvent: C1CCOC1
Product: Cc1ccc(Cl)cc1Cn1c(-c2cc(N)no2)noc1=O
Temperature: 70 °C
Yield: 57.2 %

Procedure:
3-Amino-N-(5-chloro-2-methylbenzyl)-N′-hydroxyisoxazole-5-carboximidamide (0.320 g, 1.14 mmol) was dissolved in anhydrous THF (6 mL) followed by addition of N,N-carbonyldiimidazole (0.203 g, 1.25 mmol). The solution was heated at 70° C. for 1.5 h. and then concentrated and purified with silica gel chromatography (20% ethyl acetate/hexs) to give the desired product as a colorless oil (200 mg, 57%). LCMS calculated for C13H12ClN4O3(M+H)+: m/z=307.1.
Reaction SMILES: [C:1]([C:3]1[CH:15]=[C:14]2[C:6]([C:7]3[C:8](=[O:30])[C:9]4[CH:21]=[CH:20][C:19](OS(C(F)(F)F)(=O)=O)=[CH:18][C:10]=4[C:11]([CH3:17])([CH3:16])[C:12]=3[NH:13]2)=[CH:5][CH:4]=1)#[N:2].[SH:31][CH2:32][CH:33]([OH:36])[CH2:34][OH:35]>>[OH:36][CH:33]([CH2:34][OH:35])[CH2:32][S:31][C:19]1[CH:20]=[CH:21][C:9]2[C:8](=[O:30])[C:7]3[C:6]4[C:14](=[CH:15][C:3]([C:1]#[N:2])=[CH:4][CH:5]=4)[NH:13][C:12]=3[C:11]([CH3:16])([CH3:17])[C:10]=2[CH:18]=1
Reactant: OCC(O)CS
Reactant: CC1(C)c2cc(OS(=O)(=O)C(F)(F)F)ccc2C(=O)c2c1[nH]c1cc(C#N)ccc21
Product: CC1(C)c2cc(SCC(O)CO)ccc2C(=O)c2c1[nH]c1cc(C#N)ccc21

Procedure:
Under the same conditions as the method for synthesizing Compound B2-17, the title compound was prepared from Compound B1 and 3-mercaptopropane-1,2-diol.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:12]([C:13]2[CH:18]=[CH:17][C:16]([N+:19]([O-])=[O:20])=[CH:15][CH:14]=2)=[CH:11][CH:10]=[N:9]1.[F:22][C:23]([F:34])([F:33])[C:24]1[CH:29]=[CH:28][C:27]([CH2:30]C#N)=[CH:26][CH:25]=1>>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:12]([C:13]2[CH:18]=[CH:17][C:16]3=[N:19][O:20][C:30]([C:27]4[CH:26]=[CH:25][C:24]([C:23]([F:22])([F:33])[F:34])=[CH:29][CH:28]=4)=[C:15]3[CH:14]=2)=[CH:11][CH:10]=[N:9]1
Reactant: N#CCc1ccc(C(F)(F)F)cc1
Reactant: O=[N+]([O-])c1ccc(-c2ccnn2-c2ccccc2F)cc1
Product: Fc1ccccc1-n1nccc1-c1ccc2noc(-c3ccc(C(F)(F)F)cc3)c2c1

Procedure:
The title compound, light brown solid (88 mg, 59%), MS (ISP) m/z=424.2 [(M+H)+], mp 156° C., was prepared in accordance with the general method of example 1 from 1-(2-fluoro-phenyl)-5-(4-nitro-phenyl)-1H-pyrazole (intermediate B) (100 mg, 353 μmol) and commercially available 2-(4-trifluoromethyl-phenyl)-acetonitrile.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([N+]([O-])=O)[CH:5]=[CH:4][N+:3]=1[O-:11].C([Cl:15])(=O)C.C(=O)([O-])[O-].[Na+].[Na+]>>[Cl:15][C:6]1[CH:5]=[CH:4][N+:3]([O-:11])=[C:2]([CH3:1])[CH:7]=1
Reactant: Cc1cc([N+](=O)[O-])cc[n+]1[O-]
Reactant: CC(=O)Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Product: Cc1cc(Cl)cc[n+]1[O-]
Temperature: 0 °C
Yield: 32.7 %

Procedure:
15.4 g (0.1 mol) of 2-methyl-4-nitropyridine 1-oxide was added to 78.5 g (1 mol) of acetyl chloride at -10° C. The obtained mixture was stirred under cooling with ice for 0.5 hour. After the completion of the reaction, 300 ml of ice-water was added to the reaction mixture. The obtained mixture was neutralized with sodium carbonate and extracted with chloroform. The extract was dried over magnesium sulfate and filtered. The filtrate was concentrated under a reduced pressure and purified by silica gel column chromatography (ethyl acetate/n-hexane/methanol) to obtain 4.7 g of the title compound.
Reaction SMILES: FC1C=C(F)C=CC=1C1(CN2C=NC=N2)OC(COC2C=CC(N3CCN(C4C=CC(N5C(=O)N([C:40]6[CH:55]=[CH:54][CH:53]=[CH:52][C:41]=6[CH2:42][C@@H:43]([C:49]([OH:51])=[O:50])[NH:44][CH:45]([CH3:48])[CH2:46][CH3:47])N=C5)=CC=4)CC3)=CC=2)CO1.[C:62]([OH:69])(=[O:68])/[CH:63]=[CH:64]\[C:65]([OH:67])=[O:66]>CC(=O)C>[C:62]([OH:69])(=[O:68])/[CH:63]=[CH:64]\[C:65]([OH:67])=[O:66].[CH3:48][CH:45]([NH:44][C@H:43]([C:49]([OH:51])=[O:50])[CH2:42][C:41]1[CH:52]=[CH:53][CH:54]=[CH:55][CH:40]=1)[CH2:46][CH3:47]
Reactant: CCC(C)N[C@@H](Cc1ccccc1-n1ncn(-c2ccc(N3CCN(c4ccc(OCC5COC(Cn6cncn6)(c6ccc(F)cc6F)O5)cc4)CC3)cc2)c1=O)C(=O)O
Agent: O=C(O)/C=C\C(=O)O
Solvent: CC(C)=O
Product: CCC(C)N[C@@H](Cc1ccccc1)C(=O)O
Reaction time: 16 h

Procedure:
Compound 23 (0.00359 mol) was dissolved in 2-propanone (25 ml). A solution of (Z)-2-butenedioic acid (0.00359 mol) in 2-propanone (5 ml) was added. The mixture was stirred for 16 hours. The precipitate was filtered off, washed with 2-propanone (2.5 ml), and dried, yielding 3.12 g [2S-[2α,4α[(R*,R*)]]]-2-[4-[4-[4-[-difluorophenyl)-2-(1H-1,2,4-triazol-1-ylmethyl)-1,3-dioxolan-4-yl]methoxy]-phenyl]-1-piperazinyl]-phenyl]-4,5-dihydro-5-oxo-1H-1,2,4-triazol-1-yl]-1-methylpropyl L-phenylalanine (Z)-2-butenedioate (1:1) (compound 25).
Reaction SMILES: [CH3:1][N:2]1[C:7](=[O:8])[C:6]([NH:9][C:10]2[CH:15]=[CH:14][C:13]([N:16]3[CH2:21][CH2:20][N:19]([CH:22]4[CH2:25][O:24][CH2:23]4)[CH2:18][CH2:17]3)=[CH:12][N:11]=2)=[CH:5][C:4]([C:26]2[C:31]([CH:32]=[O:33])=[C:30]([N:34]3[CH:46]=[CH:45][N:37]4[C:38]5[CH2:39][CH2:40][CH2:41][CH2:42][C:43]=5[CH:44]=[C:36]4[C:35]3=[O:47])[N:29]=[CH:28][CH:27]=2)=[CH:3]1.[CH3:48]N1C=C(B2OC(C)(C)C(C)(C)O2)C=C(NC2C=CC(N3CCN(C4COC4)C[C@@H]3C)=CN=2)C1=O.C([O-])(=O)C.[Na+].C(#N)C>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].O>[CH3:1][N:2]1[C:7](=[O:8])[C:6]([NH:9][C:10]2[CH:15]=[CH:14][C:13]([N:16]3[CH2:21][CH2:20][N:19]([CH:22]4[CH2:25][O:24][CH2:23]4)[CH2:18][C@@H:17]3[CH3:48])=[CH:12][N:11]=2)=[CH:5][C:4]([C:26]2[C:31]([CH:32]=[O:33])=[C:30]([N:34]3[CH:46]=[CH:45][N:37]4[C:38]5[CH2:39][CH2:40][CH2:41][CH2:42][C:43]=5[CH:44]=[C:36]4[C:35]3=[O:47])[N:29]=[CH:28][CH:27]=2)=[CH:3]1
Reactant: C[C@H]1CN(C2COC2)CCN1c1ccc(Nc2cc(B3OC(C)(C)C(C)(C)O3)cn(C)c2=O)nc1
Reactant: Cn1cc(-c2ccnc(-n3ccn4c5c(cc4c3=O)CCCC5)c2C=O)cc(Nc2ccc(N3CCN(C4COC4)CC3)cn2)c1=O
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: CC(=O)[O-]
Solvent: CC#N
Solvent: O
Product: C[C@H]1CN(C2COC2)CCN1c1ccc(Nc2cc(-c3ccnc(-n4ccn5c6c(cc5c4=O)CCCC6)c3C=O)cn(C)c2=O)nc1
Temperature: 100 °C
Yield: 64.1 %

Procedure:
A round-bottomed flask was charged with 4-chloro-2-(1-oxo-6,7,8,9-tetrahydropyrazino[1,2-a]indol-2(1H)-yl)nicotinaldehyde 121a (180 mg, 0.55 mmol), (S)-1-methyl-3-(5-(2-methyl-4-(oxetan-3-yl)piperazin-1-yl)pyridin-2-ylamino)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2(1H)-one 191j (397 mg, 0.82 mmol), PdCl2(dppf) (45 mg, 0.06 mmol), K3PO4 trihydrate (286 mg, 1.10 mmol), sodium acetate (90 mg, 1.10 mmol), acetonitrile (15 mL), and water (1.5 mL). After three cycles of vacuum/argon flush, the mixture was heated at 100° C. for 3 h. It was then filtered and the filtrate was evaporated under reduced pressure. The residue was purified by silica-gel column chromatography eluting with 1:20 methanol/dichloromethane to afford 176a as a red solid (228 mg, 64%). MS-ESI: [M+H]+ 647.3
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([C:8]2[CH:13]=[CH:12][C:11]([N+:14]([O-])=O)=[C:10]([C:17]3[C:21]([CH3:22])=[CH:20][S:19][CH:18]=3)[CH:9]=2)[CH2:4][CH2:3]1>[Pd]>[CH3:1][N:2]1[CH2:7][CH2:6][N:5]([C:8]2[CH:13]=[CH:12][C:11]([NH2:14])=[C:10]([C:17]3[C:21]([CH3:22])=[CH:20][S:19][CH:18]=3)[CH:9]=2)[CH2:4][CH2:3]1
Reactant: Cc1cscc1-c1cc(N2CCN(C)CC2)ccc1[N+](=O)[O-]
Agent: [Pd]
Product: Cc1cscc1-c1cc(N2CCN(C)CC2)ccc1N
Yield: 89.2 %

Procedure:
Using a procedure similar to Example 4, step (d), 1-methyl-4-[3-(4-methyl-thiophen-3-yl)-4-nitro-phenyl]-piperazine (100 mg, 0.32 mmol) was stirred with 80 mg 5% Pd—C under H2 to afford 82 mg (89%) of the title compound as a dark oil, which was used immediately without further purification spectrum (ESI, m/z): Calcd. for C16H21N3S, 288.15 (M+H). found 288.1.
Reaction SMILES: [CH:1]([C@H:4]1[CH2:8][O:7][C:6](=[O:9])[N:5]1[C:10]1[CH:15]=[CH:14][N:13]=[C:12]([NH:16][C@H:17]([C:19]2[CH:26]=[CH:25][C:22]([CH:23]=O)=[CH:21][CH:20]=2)[CH3:18])[N:11]=1)([CH3:3])[CH3:2].[CH3:27][C:28]1([CH3:41])[CH2:33][NH:32][CH2:31][CH2:30][N:29]1[C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35].C(O)(=O)C>CO.O.CCOC(C)=O>[CH:1]([C@H:4]1[CH2:8][O:7][C:6](=[O:9])[N:5]1[C:10]1[CH:15]=[CH:14][N:13]=[C:12]([NH:16][C@H:17]([C:19]2[CH:26]=[CH:25][C:22]([CH2:23][N:32]3[CH2:31][CH2:30][N:29]([C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35])[C:28]([CH3:41])([CH3:27])[CH2:33]3)=[CH:21][CH:20]=2)[CH3:18])[N:11]=1)([CH3:2])[CH3:3]
Reactant: CC(C)[C@H]1COC(=O)N1c1ccnc(N[C@@H](C)c2ccc(C=O)cc2)n1
Reactant: CC(C)(C)OC(=O)N1CCNCC1(C)C
Solvent: O
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: CC(C)[C@H]1COC(=O)N1c1ccnc(N[C@@H](C)c2ccc(CN3CCN(C(=O)OC(C)(C)C)C(C)(C)C3)cc2)n1
Temperature: 50 °C
Reaction time: 4 h
Yield: 72.4 %

Procedure:
A solution of 4-((S)-1-(4-((S)-4-isopropyl-2-oxooxazolidin-3-yl)pyrimidin-2-ylamino)ethyl)benzaldehyde (71 mg, 0.2 mmol) and tert-butyl 2,2-dimethylpiperazine-1-carboxylate (47.1 mg, 0.22 mmol) in MeOH (4 mL) was added acetic acid (14.4 mg, 0.24 mmol) and 5-Ethyl-2-methylpyridine borane complex (27 mg, 0.2 mmol, sigma aldrich). The solution was stirred at 50° C. for 4 h then 5 drops of water was added. The solution was stirred at room temperature for another 2 h then diluted with EtOAc (10 mL) and washed with water (10 mL). After separation, the aqueous phase was extracted with EtOAc (3×10 mL). Combined organics were dried over Na2SO4, filtered and concentrated. The crude material was purified through Silica gel column chromatography (MeOH/EtOAc 0 to 10%) to give tert-butyl 4-(4-((S)-1-(4-((S)-4-isopropyl-2-oxooxazolidin-3-yl)pyrimidin-2-ylamino)ethyl)benzyl)-2,2-dimethylpiperazine-1-carboxylate as a white solid (80 mg, 72.4% yield).
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][CH2:12][CH2:13][CH2:14][CH2:15][C:16](=[O:31])[CH:17]([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[BH4-].[Na+].Cl>CO>[CH2:1]([O:8][C:9]([NH:11][CH2:12][CH2:13][CH2:14][CH2:15][CH:16]([OH:31])[CH:17]([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[C:18]([O:20][C:21]([CH3:22])([CH3:23])[CH3:24])=[O:19])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)C(C(=O)CCCCNC(=O)OCc1ccccc1)c1ccccc1
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CC(C)(C)OC(=O)C(c1ccccc1)C(O)CCCCNC(=O)OCc1ccccc1
Yield: 98 %

Procedure:
The same procedures as in Example 26 were performed except that 0.2 g (0.47 mmol) of t-butyl 7-(N-benzyloxycarbonylamino)-3-oxo-2-phenylheptanoate instead of ethyl 7-(N-benzyloxycarbonylamino)-3-oxo-2-phenylheptanoate was dissolved in 4 ml of methanol, 18 mg (0.47 mol) of sodium borohydride was added, and 4 ml of 4N hydrochloric acid was added to the reaction solution, to prepare the target compound as a pale yellow oil in an amount of 196 mg at a yield of 98%. The selectivity of the products in terms of the ratio of the syn-form to the anti-form was 7:3. The analytical results on the target compound are given below.
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:9]2[N:8]=[CH:7][C:6]3[N:12]([CH3:23])[C:13](=[O:22])[N:14]([C:15]4[C:16]([CH3:21])=[N:17][N:18]([CH3:20])[CH:19]=4)[C:5]=3[C:4]=2[CH:3]=1.[CH3:24][N:25]1[C:33]2[C:28](=[N:29][CH:30]=[C:31](B3OC(C)(C)C(C)(C)O3)[CH:32]=2)[N:27]([CH3:43])[C:26]1=[O:44]>>[CH3:24][N:25]1[C:33]2[C:28](=[N:29][CH:30]=[C:31]([C:2]3[CH:11]=[CH:10][C:9]4[N:8]=[CH:7][C:6]5[N:12]([CH3:23])[C:13](=[O:22])[N:14]([C:15]6[C:16]([CH3:21])=[N:17][N:18]([CH3:20])[CH:19]=6)[C:5]=5[C:4]=4[CH:3]=3)[CH:32]=2)[N:27]([CH3:43])[C:26]1=[O:44]
Reactant: Cn1c(=O)n(C)c2ncc(B3OC(C)(C)C(C)(C)O3)cc21
Reactant: Cc1nn(C)cc1-n1c(=O)n(C)c2cnc3ccc(Br)cc3c21
Product: Cc1nn(C)cc1-n1c(=O)n(C)c2cnc3ccc(-c4cnc5c(c4)n(C)c(=O)n5C)cc3c21

Procedure:
The title compound was synthesized in a similar manner as described for Example 1.1 using 8-bromo-1-(1,3-dimethyl-1H-pyrazol-4-yl)-3-methyl-1,3-dihydro-imidazo[4,5-c]quinolin-2-one (Intermediate A) and 1,3-dimethyl-6-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1,3-dihydro-imidazo[4,5-b]pyridin-2-one (Stage 67.1.1) to give the title compound as a white solid. (HPLC: tR 2.39 min (Method A); M+H=455 MS-ES; 1H-NMR (d6-DMSO, 400 MHz) 8.97 (s, 1H), 8.16-8.07 (m, 3H), 7.99-7.94 (m, 111, 7.58-7.53 (m, 2H), 3.91 (s, 3H), 3.57 (s, 3H), 3.41 (s, 3H), 3.35 (s, 3H), 1.97 (s, 3H))
Reaction SMILES: CO.[O:3]1[C:12]2[CH:11]=[C:10]([CH2:13][NH:14][CH:15]3[CH2:20][CH2:19][N:18]([CH2:21][CH2:22][N:23]4[C:32]5[C:27](=[CH:28][CH:29]=[C:30]([O:33][CH3:34])[CH:31]=5)[N:26]=[CH:25][C:24]4=[O:35])[CH:17]([C:36]([O:38]C)=O)[CH2:16]3)[N:9]=[CH:8][C:7]=2[O:6][CH2:5][CH2:4]1.[OH-].[Na+].Cl>C(OCC)C.CCCCCC.C(OCC)(=O)C.O>[O:3]1[C:12]2[CH:11]=[C:10]([CH2:13][N:14]3[C:36](=[O:38])[CH:17]4[CH2:16][CH:15]3[CH2:20][CH2:19][N:18]4[CH2:21][CH2:22][N:23]3[C:32]4[C:27](=[CH:28][CH:29]=[C:30]([O:33][CH3:34])[CH:31]=4)[N:26]=[CH:25][C:24]3=[O:35])[N:9]=[CH:8][C:7]=2[O:6][CH2:5][CH2:4]1
Reactant: COC(=O)C1CC(NCc2cc3c(cn2)OCCO3)CCN1CCn1c(=O)cnc2ccc(OC)cc21
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCCCCC
Solvent: CO
Solvent: CCOC(C)=O
Product: COc1ccc2ncc(=O)n(CCN3CCC4CC3C(=O)N4Cc3cc4c(cn3)OCCO4)c2c1
Reaction time: 0.17 h
Yield: 16 %

Procedure:
To 5 mL of a methanol solution containing 60 mg of methyl 4-((2,3-dihydro(1,4)dioxino(2,3-c)pyridin-7-ylmethyl)amino)-1-(2-(7-methoxy-2-oxoquinoxalin-1(2H)-yl)ethyl)piperidine-2-carboxylate, 0.2 mL of 20% aqueous sodium hydroxide solution was added at room temperature, and stirred for 1 hour and 10 min. Further, 0.5 mL of 20% aqueous sodium hydroxide solution was added at room temperature, and stirred at the sane temperature for 1 hour and 50 min. The reaction mixture was adjusted to pH 6.2 with 2 mol/L hydrochloric acid under water-cooling, the solvent was removed under reduced pressure, water, ethyl acetate and diethyl ether were added, and the resulting solid (A′) was filtered. Also, the solvent of the filtrate (B′) was removed under reduced pressure. To the residue thus obtained, water, ethyl acetate and diethyl ether were added, the organic layer was separated, and the solvent was removed under reduced pressure. To the residue thus obtained, hexane and diethyl ether were added, and the resulting solid (B) was filtered to give 9 mg of 1-(2-(6-(2,3-dihydro(1,4)dioxino(2,3-c)pyridin-7-ylmethyl)-7-oxo-2,6-diazabicyclo(3.2.1)oct-2-yl)ethyl)-7-methoxyquinoxalin-2(1H)-one as a pale yellow solid.
Reaction SMILES: CCOC(/N=N/C(OCC)=O)=O.[CH2:13]([N:20]1[C@@H:25]2[C@H:26]([C:28]3[NH:32][N:31]=[N:30][N:29]=3)[CH2:27][C@@:21]1([C:49]1[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=1)[C@H:22]([O:33][CH2:34][C:35]1[CH:40]=[C:39]([C:41]([F:44])([F:43])[F:42])[CH:38]=[C:37]([C:45]([F:48])([F:47])[F:46])[CH:36]=1)[CH2:23][CH2:24]2)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.[C:55]([O:59][C:60]([NH:62][CH2:63][CH2:64]O)=[O:61])([CH3:58])([CH3:57])[CH3:56].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>ClCCl>[CH2:13]([N:20]1[C@@H:25]2[C@H:26]([C:28]3[N:32]=[N:31][N:30]([CH2:64][CH2:63][NH:62][C:60]([O:59][C:55]([CH3:58])([CH3:57])[CH3:56])=[O:61])[N:29]=3)[CH2:27][C@@:21]1([C:49]1[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=1)[C@H:22]([O:33][CH2:34][C:35]1[CH:36]=[C:37]([C:45]([F:48])([F:47])[F:46])[CH:38]=[C:39]([C:41]([F:42])([F:43])[F:44])[CH:40]=1)[CH2:23][CH2:24]2)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: CC(C)(C)OC(=O)NCCO
Reactant: FC(F)(F)c1cc(CO[C@@H]2CC[C@H]3[C@H](c4nnn[nH]4)C[C@]2(c2ccccc2)N3Cc2ccccc2)cc(C(F)(F)F)c1
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NCCn1nnc([C@@H]2C[C@@]3(c4ccccc4)[C@H](OCc4cc(C(F)(F)F)cc(C(F)(F)F)c4)CC[C@@H]2N3Cc2ccccc2)n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 88 %

Procedure:
Diethylazodicarboxylate, 0.15 g, 0.86 mmol was added to a solution of (1R*,2 R*,5S*,6R*)-8-benzyl-2-{[3,5-bis(trifluoromethyl)phenyl]methoxyl 1-phenyl-6-(tetrazol-5-yl)-8-azabicyclo[3.2.1]octane (Example 138; 0.5 g, 0.85 mmol), [N-(t-butoxy-carbonyl)ethanolamine] (0.15 g, 0.93 mmol) and triphenylphosphine (0.23 g, 0.88 mmol) in dichloromethane (20 ml). The mixture was stirred at room temperature for 2 hours then concentrated in vacuo. The residue was chromatographed on silica gel eluting with 10, 20 and 30% ethyl acetate/iso-hexanes to yield the title compound (543 mg, 88%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([C:12]([N:14]3[CH2:18][CH2:17][C@H:16]([NH:19][C:20]4[CH:29]=[C:28]([CH3:30])[C:27]5[C:22](=[CH:23][CH:24]=[C:25]([O:31]C)[CH:26]=5)[N:21]=4)[CH2:15]3)=[O:13])[CH2:11][CH2:10][CH2:9]2)=[CH:4][CH:3]=1.B(Br)(Br)Br.C(=O)([O-])O.[Na+]>ClCCl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([C:12]([N:14]3[CH2:18][CH2:17][C@H:16]([NH:19][C:20]4[CH:29]=[C:28]([CH3:30])[C:27]5[C:22](=[CH:23][CH:24]=[C:25]([OH:31])[CH:26]=5)[N:21]=4)[CH2:15]3)=[O:13])[CH2:11][CH2:10][CH2:9]2)=[CH:4][CH:3]=1
Reactant: COc1ccc2nc(N[C@H]3CCN(C(=O)C4(c5ccc(Cl)cc5)CCC4)C3)cc(C)c2c1
Agent: BrB(Br)Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: Cc1cc(N[C@H]2CCN(C(=O)C3(c4ccc(Cl)cc4)CCC3)C2)nc2ccc(O)cc12
Temperature: 25 °C
Reaction time: 12 h
Yield: 47.8 %

Procedure:
A solution of (S)-(1-(4-chlorophenyl)cyclobutyl)-(3-(6-methoxy-4-methylquinolin-2-ylamino)pyrrolidin-1-yl)methanone (0.60 g) in dichloromethane (50 mL) was cooled to −78° C., followed by addition of a solution of 1 M boron tribromide in dichloromethane (7.3 mL), and the mixture was stirred for 12 h while slowly heating to room temperature. To the reaction mixture was added a saturated sodium hydrogencarbonate solution to make it basic, and the mixture was extracted with chloroform. The aqueous layer was reextracted with a mixed solution of ethyl acetate and n-butanol, then the organic layer was combined and concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (silica gel, chloroform/methanol, and NH silica gel, chloroform/methanol) and crystallized with ethyl acetate to obtain white solid (S)-(1-(4-chlorophenyl)cyclobutyl)-(3-(6-hydroxy-4-methylquinolin-2-ylamino)pyrrolidin-1-yl)methanone (0.278 g).