Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(C1C=C(NC2N=C(NC3C=CC=C(C(O)=O)C=3)C(F)=CN=2)C=CC=1)(O)=O.C[O:29][C:30]([C:32]1[CH:37]=[CH:36][C:35]([NH:38][C:39]2[N:44]=[C:43]([NH:45][C:46]3[CH:51]=[CH:50][C:49]([C:52]([O:54]C)=[O:53])=[CH:48][CH:47]=3)[C:42]([F:56])=[CH:41][N:40]=2)=[CH:34][CH:33]=1)=[O:31].[OH-].[Na+]>>[C:30]([C:32]1[CH:37]=[CH:36][C:35]([NH:38][C:39]2[N:44]=[C:43]([NH:45][C:46]3[CH:51]=[CH:50][C:49]([C:52]([OH:54])=[O:53])=[CH:48][CH:47]=3)[C:42]([F:56])=[CH:41][N:40]=2)=[CH:34][CH:33]=1)([OH:31])=[O:29]
Reactant: COC(=O)c1ccc(Nc2ncc(F)c(Nc3ccc(C(=O)OC)cc3)n2)cc1
Agent: O=C(O)c1cccc(Nc2ncc(F)c(Nc3cccc(C(=O)O)c3)n2)c1
Agent: [Na+]
Agent: [OH-]
Product: O=C(O)c1ccc(Nc2ncc(F)c(Nc3ccc(C(=O)O)cc3)n2)cc1
Yield: 59.7 %

Procedure:
In a manner analogous to the preparation of N2,N4-bis(3-carboxyphenyl)-5-fluoro-2,4-pyrimidinediamine, N2,N4-bis(4-methoxycarbonylphenyl)-5-fluoro-2,4-pyrimidinediamine (100 mg, 0.25 mmol) and NaOH (200 mg, 5 mmol) gave N2,N4-bis(4-carboxyphenyl)-5-fluoro-2,4-pyrimidinediamine (55 mg, 59%) as a white solid. 1H NMR (CD3OD): δ 7.77 (d, J=8.7 Hz, 2H), 7.92 (d, J=8.7 Hz, 2H), 7.94 (d, J=8.4 Hz, 2H), 8.02 (d, J=8.7 Hz, 2H), 8.07 (d, J=3.6 Hz, 1H); LCMS: ret. time: 16.34 min.; purity: 100%; MS (m/e): 368.87 (MH+).
Reaction SMILES: [C:1]([OH:16])(=[O:15])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH:9]=[CH:10][CH2:11][CH2:12][CH2:13][CH3:14].C(O)(=O)C=CCCCCCC.C(O)(=O)CC=CCCCCC.C(O)(=O)CCCCCCC=C.C(O)(=O)CC=CCCCC.C(O)(=O)C=CCCCCC>>[C:1]([OH:16])(=[O:15])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH:8]=[CH:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14]
Reactant: CCCCC=CCCCCCCCC(=O)O
Agent: C=CCCCCCCC(=O)O
Agent: CCCCC=CCC(=O)O
Agent: CCCCCC=CC(=O)O
Product: CCCCCC=CCCCCCCC(=O)O

Procedure:
9-tetradecenoic acid; 2-nonenoic acid; 3-nonenoic acid; 8-nonenoic acid; 2-octenoic acid 3-octenoic acid;
Reaction SMILES: [NH2:1][C:2]1[C:7]([NH:8][C:9]([C:11]2([C:14]3[CH:15]=[N+:16]([O-:20])[CH:17]=[CH:18][CH:19]=3)[CH2:13][CH2:12]2)=O)=[CH:6][CH:5]=[C:4]([N:21]2[CH2:26][CH2:25][CH2:24][C@@H:23]([C:27]([N:29]3[CH2:33][CH2:32][CH2:31][CH2:30]3)=[O:28])[CH2:22]2)[N:3]=1.C[O-].[Na+]>C(O)C(C)C.CO.C(OCC)(=O)C>[N:29]1([C:27]([C@@H:23]2[CH2:24][CH2:25][CH2:26][N:21]([C:4]3[N:3]=[C:2]4[NH:1][C:9]([C:11]5([C:14]6[CH:15]=[N+:16]([O-:20])[CH:17]=[CH:18][CH:19]=6)[CH2:13][CH2:12]5)=[N:8][C:7]4=[CH:6][CH:5]=3)[CH2:22]2)=[O:28])[CH2:33][CH2:32][CH2:31][CH2:30]1
Reactant: Nc1nc(N2CCC[C@@H](C(=O)N3CCCC3)C2)ccc1NC(=O)C1(c2ccc[n+]([O-])c2)CC1
Agent: C[O-]
Agent: [Na+]
Solvent: CC(C)CO
Solvent: CCOC(C)=O
Solvent: CO
Product: O=C([C@@H]1CCCN(c2ccc3nc(C4(c5ccc[n+]([O-])c5)CC4)[nH]c3n2)C1)N1CCCC1
Temperature: 110 °C
Yield: 29.4 %

Procedure:
To a solution of (R)-3-(1-(2-amino-6-(3-(pyrrolidine-1-carbonyl)piperidin-1-yl)pyridin-3-ylcarbamoyl)cyclopropyl)pyridine 1-oxide (0.25 g, 0.55 mmol) in isobutanol (5 mL) was added a solution of sodium methoxide (0.15 g, 2.77 mmol) in methanol (2 mL) at room temperature. The reaction mixture was heated to 110° C. for 16 h. The mixture was then cooled to room temperature, diluted with ethyl acetate, and washed with water. The organic layer was dried, filtered, and concentrated under reduced pressure. The resulting residue was purified first via flash chromatography (100-200 mesh silica gel, 0-10% methanol in dichloromethane) then via preparative HPLC to obtain the product which was further purified by chiral separation to afford (R)-3-(1-(5-(3-(pyrrolidine-1-carbonyl)piperidin-1-yl)-3H-imidazo[4,5-b]pyridin-2-yl)cyclopropyl)pyridine 1-oxide (70 mg). Chiral HPLC retention time: 13.808 min (Method: CHIRAL PAK IA, 4.6×250 mm 5 μm column, Mobile Phase: A: 0.1% DEA in n-hexane, Mobile Phase B: ethanol; isocratic; 70:30, 1 mL/min, Temperature 25 C) min MS (ES+APCI) (M+H) 433.1; LCMS retention time 4.698 min (Method B1). 1H NMR (400 MHz, CD3OD) δ 1.52-1.57 (m, 2H), 1.59-1.69 (m, 1H), 1.71-1.84 (m, 4H), 1.86-2.08 (m, 5H), 2.75 (t, 2H), 2.88-3.00 (m, 2H), 3.43 (t, 2H), 3.47-3.57 (m, 1H), 3.68 (br s, 1H), 4.27 (d, 1H), 4.52 (d, 1H), 6.78 (d, 1H), 7.50-7.56 (m, 1H), 7.58-7.72 (m, 2H), 8.26 (d, 1H), 8.31 (br s, 1H).
Reaction SMILES: [OH:1][C@H:2]([C:9]1[N:10]=[C:11]([C:14](=O)[CH3:15])[NH:12][CH:13]=1)[C@H:3]([OH:8])[C@H:4]([OH:7])[CH2:5][OH:6].O.[NH2:18][NH2:19]>CO.O.C(O)(=O)C.O1CCCC1>[N:18](=[C:14]([C:11]1[NH:12][CH:13]=[C:9]([C@@H:2]([OH:1])[C@H:3]([OH:8])[C@H:4]([OH:7])[CH2:5][OH:6])[N:10]=1)[CH3:15])[NH2:19]
Reactant: NN
Reactant: CC(=O)c1nc([C@@H](O)[C@H](O)[C@H](O)CO)c[nH]1
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: CC(=NN)c1nc([C@@H](O)[C@H](O)[C@H](O)CO)c[nH]1
Temperature: 50 °C
Reaction time: 6 h

Procedure:
1-[4-((1R,2S,3R)-1,2,3,4-Tetrahydroxy-butyl)-1H-imidazol-2-yl]-ethanone (THI, prepared according to Halweg, K. M. and Büchi, G., J. Org. Chem. 50:1134-1136 (1985)) (148 mg, 0.64 mmol) was suspended in methanol (3 ml) and water (1 ml). Hydrazine hydrate (35 mg, 0.7 mmol, 1.2 eq.) and acetic acid (one drop) were added, and the suspension was stirred at 50° C. for 6 hours. LCMS analysis indicated the formation of the product and the absence of starting material. The reaction mixture was cooled to room temperature and diluted with tetrahydrofuran. The resulting white precipitate was collected and washed with tetrahydrofuran to yield the product, a mixture of approximately 3:1 E:Z isomers, as a white solid: 90 mg (58%).
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([S:11]([NH:14][C:15]2[CH:16]=[C:17]([CH:21]=[C:22]([O:33][CH2:34][CH2:35][OH:36])[C:23]=2[O:24][C:25]2[CH:30]=[CH:29][CH:28]=[C:27]([O:31][CH3:32])[CH:26]=2)[C:18](O)=[O:19])(=[O:13])=[O:12])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH3:37][O:38][C:39](=[O:46])[C@H:40]([CH2:42][CH:43]([CH3:45])[CH3:44])[NH2:41]>>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([S:11]([NH:14][C:15]2[CH:16]=[C:17]([CH:21]=[C:22]([O:33][CH2:34][CH2:35][OH:36])[C:23]=2[O:24][C:25]2[CH:30]=[CH:29][CH:28]=[C:27]([O:31][CH3:32])[CH:26]=2)[C:18]([NH:41][CH:40]([CH2:42][CH:43]([CH3:45])[CH3:44])[C:39]([O:38][CH3:37])=[O:46])=[O:19])(=[O:12])=[O:13])=[CH:7][CH:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(=O)[C@@H](N)CC(C)C
Reactant: COc1cccc(Oc2c(NS(=O)(=O)c3ccc(C(C)(C)C)cc3)cc(C(=O)O)cc2OCCO)c1
Product: COC(=O)C(CC(C)C)NC(=O)c1cc(NS(=O)(=O)c2ccc(C(C)(C)C)cc2)c(Oc2cccc(OC)c2)c(OCCO)c1

Procedure:
Analogously to Example 74, by condensing 3-(4-tert-butyl-benzenesulphonylamino)-5-(2-hydroxy-ethoxy)-4-(3-methoxy-phenoxy)-benzoic acid with L-leucine methyl ester there was obtained methyl 2-[3-(4-tert-butyl-benzenesulphonylamino)-5-(2-hydroxy-ethoxy)-4-(3-methoxy-phenoxy)-benzoylamino]-4-methyl-pentanoate.
Reaction SMILES: Cl[C:2]1[C:7]2[N:8]=[C:9]([S:12][CH3:13])[N:10]=[CH:11][C:6]=2[CH:5]=[C:4]([CH3:14])[N:3]=1.[CH3:15][O:16][C:17]([CH3:21])([CH3:20])[CH2:18][NH2:19].C(N(CC)CC)C>CN1C(=O)CCC1.CCOC(C)=O>[CH3:15][O:16][C:17]([CH3:21])([CH3:20])[CH2:18][NH:19][C:2]1[C:7]2[N:8]=[C:9]([S:12][CH3:13])[N:10]=[CH:11][C:6]=2[CH:5]=[C:4]([CH3:14])[N:3]=1
Reactant: CSc1ncc2cc(C)nc(Cl)c2n1
Reactant: COC(C)(C)CN
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: CN1CCCC1=O
Product: COC(C)(C)CNc1nc(C)cc2cnc(SC)nc12
Temperature: 120 °C
Yield: 60.9 %

Procedure:
To a solution of 8-chloro-6-methyl-2-(methylthio)pyrido[3,4-d]pyrimidine (Preparation 52, 80 mg, 0.354 mmol) in NMP (7 mL) was added 2-methoxy-2-methylpropan-1-amine (0.086 ml, 0.709 mmol) and triethylamine (0.249 mL, 1.772 mmol). The reaction mixture was heated to 120° C. for 18 hours. The reaction mixture was diluted with EtOAc (30 mL), washed with water (30 mL), dried (MgSO4) and concentrated in vacuo. The residue was purified by silica gel column chromatography eluting with 0-50% EtOAc in cyclohexane to afford the title compound (63 mg, 61%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]([CH3:13])=[CH:11][NH:10][C:9]=2[C:14]([O:16][CH2:17][CH3:18])=[O:15])=[CH:4][CH:3]=1.[H-].[Na+].[CH2:21](Br)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.CCOC(C)=O>CN(C=O)C.[Cl-].[Na+].O>[CH2:21]([N:10]1[CH:11]=[C:12]([CH3:13])[C:8]([C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=2)=[C:9]1[C:14]([O:16][CH2:17][CH3:18])=[O:15])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: CCOC(=O)c1[nH]cc(C)c1-c1ccc(Cl)cc1
Reactant: BrCc1ccccc1
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: O
Product: CCOC(=O)c1c(-c2ccc(Cl)cc2)c(C)cn1Cc1ccccc1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 69.6 %

Procedure:
Ethyl 3-(4-chlorophenyl)-4-methyl-1H-pyrrole-2-carboxylate (9 g, 34.1 mmol) was dissolved in dry DMF (20 mL). At 0° C., 60% NaH in mineral oil (1.365 g, 34.1 mmol) was added. After 20 min gas evolution had ceased and benzyl bromide (4.08 mL, 34.1 mmol) was added. The reaction mixture was stirred at room temperature overnight. Brine (400 mL) was added, followed by EtOAc (400 mL). The organic layer was washed with H2O (2×400 mL), brine (400 mL), dried (Na2SO4) and evaporated under reduced pressure. The product was purified by column chromatography (silica, heptane/EtOAc, 9:1), to yield 8.40 g (70%) of the desired product.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[CH:10][C:6]([C:7]([OH:9])=O)=[CH:5][C:4]=1/[CH:12]=[CH:13]/[C:14]1[CH:19]=[CH:18][C:17]([O:20][C:21]([F:24])([F:23])[F:22])=[CH:16][CH:15]=1.[NH2:25][CH2:26][CH:27]([OH:30])[CH2:28][OH:29]>>[OH:30][CH:27]([CH2:28][OH:29])[CH2:26][NH:25][C:7](=[O:9])[C:6]1[CH:10]=[CH:11][C:3]([O:2][CH3:1])=[C:4](/[CH:12]=[CH:13]/[C:14]2[CH:15]=[CH:16][C:17]([O:20][C:21]([F:24])([F:23])[F:22])=[CH:18][CH:19]=2)[CH:5]=1
Reactant: COc1ccc(C(=O)O)cc1/C=C/c1ccc(OC(F)(F)F)cc1
Reactant: NCC(O)CO
Product: COc1ccc(C(=O)NCC(O)CO)cc1/C=C/c1ccc(OC(F)(F)F)cc1

Procedure:
The captioned compound was synthesized from 4-methoxy-3-[(E)-2-(4-trifluoromethoxyphenyl)vinyl]benzoic acid obtained in step B of Example 2-2-1 and 3-amino-1,2-propanediol in accordance with the same procedure as in the methods described in step C of Example 1-2-3.
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:14])[NH:10][CH2:11][C:12]#[CH:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:15]([O:19][C:20]([C:22]1[S:23][C:24](Br)=[CH:25][CH:26]=1)=[O:21])([CH3:18])([CH3:17])[CH3:16]>>[C:15]([O:19][C:20]([C:22]1[S:23][C:24]([C:13]#[C:12][CH2:11][NH:10][C:9]([O:8][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[O:14])=[CH:25][CH:26]=1)=[O:21])([CH3:18])([CH3:16])[CH3:17]
Reactant: CC(C)(C)OC(=O)c1ccc(Br)s1
Reactant: C#CCNC(=O)OCc1ccccc1
Product: CC(C)(C)OC(=O)c1ccc(C#CCNC(=O)OCc2ccccc2)s1

Procedure:
The title compound of Step B was prepared from prop-2-ynyl-carbamic acid benzyl ester and 5-bromo-thiophene-2-carboxylic acid tert-butyl ester in an analagous manner to Step A of Preparation 2.
Reaction SMILES: [C:1]([S:5]([NH:8][C:9]1[S:10][CH:11]=[CH:12][CH:13]=1)(=[O:7])=[O:6])([CH3:4])([CH3:3])[CH3:2].[Li]CCCC.I[CH2:20][CH2:21][CH2:22][CH2:23][CH3:24]>C1COCC1>[CH2:20]([C:11]1[S:10][C:9]([NH:8][S:5]([C:1]([CH3:4])([CH3:2])[CH3:3])(=[O:7])=[O:6])=[CH:13][CH:12]=1)[CH2:21][CH2:22][CH2:23][CH3:24]
Reactant: CCCCCI
Reactant: CC(C)(C)S(=O)(=O)Nc1cccs1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CCCCCc1ccc(NS(=O)(=O)C(C)(C)C)s1
Temperature: -20 °C
Reaction time: 8 h
Yield: 60 %

Procedure:
To a solution of 2-(t-butylsulfonamido)thiophene (3.42 g, 15.6 mmol) in anhydrous THF coole to -78° C. under N2 was added 2.5M n-BuLi (15.6 mL, 2.5 equiv). The reaction was warmed to -20° C. over 3.5 h. After stirring at -20° C. for an additional h, iodopentane (2.4 mL, 1.2 equiv) was added. The ice bath was removed and the reaction was stirred at rt overnight. The next day the reaction was quenched with sat'd NH4Cl solution and the THF was removed in vacuo. The residue was extracted with Et2O/EtOAc and washed with water and brine. The organic was dried over anhydrous MgSO4 and concentrated in vacuo. The product was purified by flash chromatography on a silica column eluting with Hex/EtOAc (15:1). Removal of the solvent afforded 2.72 g (60%) of the titled compound as a yellow oil. Rf=0.4 (6:1 Hex/EtOAc). 1H NMR (200 MHz, CDCl 3) δ0.91 (t, 3H), 1.28 (s, 9H), 1.33 (m, 4H), 1.68 (bt, 2H), 2.81 (t, 2H), 4.63 (s, 1H), 6.69 (d, 1H), 7.41 (d, 1H).
Reaction SMILES: [C:1]([N:4]1[CH2:9][CH2:8][NH:7][CH2:6][CH2:5]1)(=[O:3])[CH3:2].Br[C:11]1[CH:20]=[CH:19][C:14]([C:15]([O:17][CH3:18])=[O:16])=[CH:13][CH:12]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].C1(P(C2CCCCC2)C2C=CC=CC=2C2C(OC)=CC=CC=2OC)CCCCC1>C1(C)C=CC=CC=1>[C:1]([N:4]1[CH2:9][CH2:8][N:7]([C:11]2[CH:20]=[CH:19][C:14]([C:15]([O:17][CH3:18])=[O:16])=[CH:13][CH:12]=2)[CH2:6][CH2:5]1)(=[O:3])[CH3:2]
Reactant: CC(=O)N1CCNCC1
Reactant: COC(=O)c1ccc(Br)cc1
Agent: COc1cccc(OC)c1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Product: COC(=O)c1ccc(N2CCN(C(C)=O)CC2)cc1
Temperature: 100 °C
Reaction time: 24 h
Yield: 56.2 %

Procedure:
A deoxygenated suspension of 1-acetylpiperazine (0.308 g, 2.40 mmol), methyl 4-bromobenzoate (0.430 g, 2 mmol), tri-potassium orthophosphate (0.594 g, 2.80 mmol), 2-dicyclohexylphosphino-2′,6′-dimethoxy-1,1′-biphenyl (0.164 g, 0.40 mmol) and tris(dibenzylideneacetone)dipaladium(0) (0.092 g, 0.10 mmol) in toluene (10 mL) was stirred at 100° C., over a period of 24 h under nitrogen. The cooled reaction mixture was filtered and evaporated to give crude product. The crude product was purified by silica column chromatography, eluting with a gradient 0-5% MeOH in DCM. Pure fractions were evaporated to dryness to afford methyl 4-(4-acetylpiperazin-1-yl)benzoate (0.295 g, 56.2%) as a yellow solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]#[N:11])[CH:5]=[C:6]([Cl:8])[CH:7]=1.Cl.[OH-].[Na+]>C1COCC1.C(OCC)C>[Cl:1][C:2]1[CH:3]=[C:4]([CH2:9][CH2:10][NH2:11])[CH:5]=[C:6]([Cl:8])[CH:7]=1
Reactant: N#CCc1cc(Cl)cc(Cl)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCOCC
Solvent: C1CCOC1
Product: NCCc1cc(Cl)cc(Cl)c1
Temperature: 25 °C
Yield: 85.1 %

Procedure:
2-(3,5-dichlorophenyl)acetonitrile (155.5 mg, 0.836 mmol), 0.3 molar in THF, was heated to reflux and then treated with Borane-methyl sulfide complex (87.20 μL, 0.919 mmol). After 1 hour of refluxing, the reaction mixture was cooled to ambient temperature and then treated dropwise with 5.0 molar hydrochloric acid (601.8 μl, 3.009 mmol). The reaction mixture was heated to reflux for an additional 30 minutes. After 30 minutes the reaction mixture was cooled to 0° C. and treated with 1.0 molar sodium hydroxide (4597 μL, 4.597 mmol). The reaction mixture was diluted with diethyl ether and partitioned with deionized water. The organic layer was dried with potassium carbonate 98% powder, filtered, concentrated, and dried for one minute under high vacuum to provide the title compound (135.2 mg, 0.7113 mmol, 85.1% yield) as a light yellow oil.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N:15]2[CH2:19][C@H:18]([CH2:20][NH:21][C:22](=[O:24])[CH3:23])[O:17][C:16]2=[O:25])[CH:5]=[CH:6][C:7]=1[NH:8][CH:9]1[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]1.Cl[C:27]1[N:36]=[C:35]2[C:30]([C:31](=[O:43])[C:32]([C:40]([OH:42])=[O:41])=[CH:33][N:34]2[CH:37]2[CH2:39][CH2:38]2)=[CH:29][C:28]=1[F:44].C[Si](C)(C)Cl.C(N(CC)CC)C>CS(C)=O>[C:22]([NH:21][CH2:20][C@@H:18]1[O:17][C:16](=[O:25])[N:15]([C:4]2[CH:5]=[CH:6][C:7]([NH:8][CH:9]3[CH2:14][CH2:13][N:12]([C:27]4[N:36]=[C:35]5[C:30]([C:31](=[O:43])[C:32]([C:40]([OH:42])=[O:41])=[CH:33][N:34]5[CH:37]5[CH2:39][CH2:38]5)=[CH:29][C:28]=4[F:44])[CH2:11][CH2:10]3)=[C:2]([F:1])[CH:3]=2)[CH2:19]1)(=[O:24])[CH3:23]
Reactant: CC(=O)NC[C@H]1CN(c2ccc(NC3CCNCC3)c(F)c2)C(=O)O1
Reactant: O=C(O)c1cn(C2CC2)c2nc(Cl)c(F)cc2c1=O
Agent: C[Si](C)(C)Cl
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Product: CC(=O)NC[C@H]1CN(c2ccc(NC3CCN(c4nc5c(cc4F)c(=O)c(C(=O)O)cn5C4CC4)CC3)c(F)c2)C(=O)O1
Temperature: 150 °C
Reaction time: 0.12 h

Procedure:
A suspension of 100 mg N-{(5S)-3-[3-fluoro-4-(piperidin 4-ylamino)-phenyl]-2-oxo-oxazolidin-5-ylmethyl}acetamide (0.28 mmol), 80.66 mg 7-chloro-1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acid (0.28 mmol), 0.108 ml trimethylchlorosilane (0.84 mmol) and 0.16 ml triethylamine (1.12 mmol) in 2 ml DMSO was heated under stirring in a micro wave oven at 150° C. for 7 min. The DMSO was evaporated, the residue was purified by chromatography.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@H:12]1[CH2:17][CH2:16][C@H:15]([C:18]([N:20]2[CH2:28][C:27]3[C:22](=[CH:23][CH:24]=[C:25]([CH2:29][OH:30])[CH:26]=3)[CH2:21]2)=[O:19])[CH2:14][CH2:13]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>[O-2].[O-2].[Mn+4].C(Cl)(Cl)Cl>[CH2:1]([O:8][C:9]([NH:11][C@H:12]1[CH2:17][CH2:16][C@H:15]([C:18]([N:20]2[CH2:28][C:27]3[C:22](=[CH:23][CH:24]=[C:25]([CH:29]=[O:30])[CH:26]=3)[CH2:21]2)=[O:19])[CH2:14][CH2:13]1)=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(N[C@H]1CC[C@H](C(=O)N2Cc3ccc(CO)cc3C2)CC1)OCc1ccccc1
Agent: [Mn+4]
Agent: [O-2]
Solvent: ClC(Cl)Cl
Product: O=Cc1ccc2c(c1)CN(C(=O)[C@H]1CC[C@H](NC(=O)OCc3ccccc3)CC1)C2
Temperature: 25 °C
Reaction time: 4 h

Procedure:
20 g of manganese dioxide was added to 120 ml of a chloroform solution containing 4.0 g of N-benzyloxycarbonyl-trans-4-[(5-hydroxymethyl-2-isoindolinyl)carbonyl]cyclohexylamine, and the mixture was stirred at room temperature for 4 hours. Manganese dioxide was removed by filtration through Celite and the solvent was removed under reduced pressure. The residue was suspended in hexane-ethyl acetate and the crystals were collected by filtration to obtain N-benzyloxycarbonyl-trans-4-[(5-formyl-2-isoindolinyl)carbonyl]cyclohexylamine. (2) To an aqueous solution containing 3.35 g of silver nitrate were added 2.75 g of the compound obtained in the above (1) and 110 ml of ethanol under ice-cooling, and then, an aqueous solution containing 2.61 g of potassium hydroxide was added dropwise thereto. The mixture was stirred under ice-cooling for 1 hour and separated by filtration through Celite, and then, the solvent was removed under reduced pressure. To the residue was added 50 ml of an aqueous 1N hydrochloric acid solution and the mixture was extracted with chloroform. After the extract was dried over anhydrous sodium sulfate, the solvent was removed under reduced pressure. The residue was suspended in hexane-ether and the crystals were collected by filtration to obtain N-benzyloxycarbonyl-trans-4-[(5-carboxy-2-isoindolinyl)carbonyl]cyclohexylamine. (3) The compound obtained in the above (2) was used and condensed with a starting amine compound in the same manner as in Reference Example 11-1, and subsequently treated with palladium-carbon under hydrogen atmosphere to obtain trans-4-[(5-dimethylaminocarbonyl-2-isoindolinyl)carbonyl]cyclohexylamine (Reference 13-25 in Table 8).
Reaction SMILES: [C:1]([N:4]1[CH2:9][CH2:8][N:7]([CH2:10][C:11]2[CH:16]=[C:15]([O:17][CH3:18])[N:14]=[C:13]([NH:19][C:20](=O)OC(C)(C)C)[CH:12]=2)[CH2:6][CH2:5]1)(=[O:3])[CH3:2].[H-].[Na+].ClC1[S:31][C:32]([C:35]#[N:36])=[CH:33][N:34]=1>Cl.O1CCOCC1.O.C([O-])(O)=O.[Na+]>[C:1]([N:4]1[CH2:5][CH2:6][N:7]([CH2:10][C:11]2[CH:16]=[C:15]([O:17][CH3:18])[N:14]=[C:13]([NH:19][C:20]3[S:31][C:32]([C:35]#[N:36])=[CH:33][N:34]=3)[CH:12]=2)[CH2:8][CH2:9]1)(=[O:3])[CH3:2]
Reactant: N#Cc1cnc(Cl)s1
Reactant: COc1cc(CN2CCN(C(C)=O)CC2)cc(NC(=O)OC(C)(C)C)n1
Agent: Cl
Agent: O=C([O-])O
Agent: [H-]
Solvent: O
Solvent: C1COCCO1
Product: COc1cc(CN2CCN(C(C)=O)CC2)cc(Nc2ncc(C#N)s2)n1
Temperature: 25 °C

Procedure:
tert-Butyl 4-[(4-acetylpiperazin-1-yl)methyl]-6-methoxypyridin-2-ylcarbamate (15-4, 310 mg, 0.85 mmole) was taken up in 4 M HCl in dioxane (5 mL) at RT. After 4 hr the mixture was diluted with H2O and neutralized with solid NaHCO3. The resulting mixture was extracted with CH2Cl2 (3×). The combined organic layers were dried (MgSO4), filtered, and concentrated. The residue was taken up in dry THF (5 mL). To this was added NaH (90 mg, 60% dispersion in mineral oil, 2.13 mmole). After gas evolution had ceased 2-chloro-5-cyano-1,3-thiazole (185 mg, 1.28 mmole) was added and the mixture heated to reflux. After 2.5 hr the mixture was cooled to RT and quenched with saturated NH4Cl. The layers were separated and the aqueous layer extracted with CH2Cl2 (4×). The combined organic layers were dried (MgSO4), filtered, and concentrated. Flash column chromatography (gradient, 0-15% EtOH/EtOAc) gave the titled compound as a tan solid. 1H-NMR (500 MHz, d6-DMSO) δ 8.26 (s, 1 H), 6.70 (s, 1 H), 6.43 (s, 1 H), 4.04 (s, 3 H), 3.47 (s, 2 H), 3.43 (m, 4 H), 2.38 (m, 2 H), 2.31 (m, 2 H), 1.98 (s, 3 H); MS (ES) (M+H)+ 373.
Reaction SMILES: Cl.[CH:2]12[CH2:11][CH:6]3[CH2:7][CH:8]([CH2:10][CH:4]([CH2:5]3)[CH:3]1[NH2:12])[CH2:9]2.C(N(CC)CC)C.[CH3:20][O:21][C:22]1[CH:27]=[CH:26][C:25]([N:28]=[C:29]=[O:30])=[C:24]([CH3:31])[CH:23]=1>C(O)C>[CH:2]12[CH2:11][CH:6]3[CH2:7][CH:8]([CH2:10][CH:4]([CH2:5]3)[CH:3]1[NH:12][C:29]([NH:28][C:25]1[CH:26]=[CH:27][C:22]([O:21][CH3:20])=[CH:23][C:24]=1[CH3:31])=[O:30])[CH2:9]2
Reactant: COc1ccc(N=C=O)c(C)c1
Reactant: NC1C2CC3CC(C2)CC1C3
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CCO
Product: COc1ccc(NC(=O)NC2C3CC4CC(C3)CC2C4)c(C)c1
Temperature: 25 °C
Yield: 100.4 %

Procedure:
A mixture of 2.5 g (13.3 mmol) of 2-adamantylamine hydrochloride, 1.84 ml (13.3 mmol) of triethylamine in 50 ml of ethanol was heated under reflux. Then 1.94 ml (13.3 mmol) of 4-methoxy-2-methylphenylisocyanate was added and the mixture was stirred under reflux for 2 h. After cooling at room temperature the precipitate was filtered, washed with ethanol and dried under vacuum to give 4.2 g (61%) a white solid.
Reaction SMILES: [C:1]1([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:6]=[CH:5][C:4]([C:7]([NH:9][CH2:10][C:11]([OH:13])=O)=[O:8])=[CH:3][CH:2]=1.CCN(C(C)C)C(C)C.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl.Cl.[CH3:52][N:53]([CH:64]1[CH2:69][CH2:68][NH:67][CH2:66][CH2:65]1)[C:54]1[CH:59]=[CH:58][CH:57]=[CH:56][C:55]=1[C:60]([F:63])([F:62])[F:61]>CN(C=O)C.O>[CH3:52][N:53]([C:54]1[CH:59]=[CH:58][CH:57]=[CH:56][C:55]=1[C:60]([F:63])([F:61])[F:62])[CH:64]1[CH2:69][CH2:68][N:67]([C:11](=[O:13])[CH2:10][NH:9][C:7]([C:4]2[CH:3]=[CH:2][C:1]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)=[CH:6][CH:5]=2)=[O:8])[CH2:66][CH2:65]1
Reactant: O=C(O)CNC(=O)c1ccc(-c2ccccc2)cc1
Reactant: CN(c1ccccc1C(F)(F)F)C1CCNCC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: CN(c1ccccc1C(F)(F)F)C1CCN(C(=O)CNC(=O)c2ccc(-c3ccccc3)cc2)CC1
Reaction time: 8 h
Yield: 17.9 %

Procedure:
To a stirred solution of [(biphenyl-4-carbonyl)-amino]-acetic acid (0.075 g, 0.00029 mol) in DMF (3 mL), was added DIPEA (0.1519 g, 0.00117 mol), HOBt (0.03981 g, 0.00029 mol) and EDCI.HCl (0.06758 g, 0.00035 mol) at ambient temperature. After 2 minutes methyl-piperidin-4-yl-(2-trifluoromethyl-phenyl)-amine hydrochloride (0.06959 g, 0.00026 mol) was added and the resulting mixture was stirred at the same temperature overnight. The reaction mixture was diluted with cold water and the product was extracted with ethyl acetate. The ethyl acetate layer was washed aqueous sodium bicarbonate solution followed by brine solution, dried over sodium sulfate and concentrated under reduced pressure. The resulting residue was purified by preparative HPLC to afford 0.023 g (16%) of biphenyl-4-carboxylic acid (2-{4-[methyl-(2-trifluoromethyl-phenyl)-amino]-piperidin-1-yl}-2-oxo-ethyl)-amide. LCMS: 496.2 (M+1)+, 98.28%, 1H NMR (DMSO-d6): δ 8.6 (t, 1H), 7.56-7.3 (m, 4H), 7.8-7.6 (m, 7H), 7.98 (d, 2H), 4.4 (bs, 1H), 4.15 (d, 2H), 3.9 (bs, 1H), 3.2-2.9 (m, 2H), 1.7 (bs, 2H), 1.5-1.2 (m, 2H).