Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([N:8]2[CH2:20][CH2:19][C:11]3([CH2:15][NH:14][C@H:13]([C:16]([OH:18])=[O:17])[CH2:12]3)[CH2:10][CH2:9]2)[CH:5]=[C:4]([O:21][C@H:22]([C:27]2[CH:32]=[CH:31][C:30](Cl)=[CH:29][C:28]=2[N:34]2[CH:38]=[CH:37][C:36]([CH3:39])=[N:35]2)[C:23]([F:26])([F:25])[F:24])[N:3]=1.[Br:40]C1C=CC([C@@H](O)C(F)(F)F)=C(C2C=CC=CC=2)C=1>>[NH2:1][C:2]1[N:7]=[C:6]([N:8]2[CH2:20][CH2:19][C:11]3([CH2:15][NH:14][C@H:13]([C:16]([OH:18])=[O:17])[CH2:12]3)[CH2:10][CH2:9]2)[CH:5]=[C:4]([O:21][C@H:22]([C:27]2[CH:32]=[CH:31][C:30]([Br:40])=[CH:29][C:28]=2[N:34]2[CH:38]=[CH:37][C:36]([CH3:39])=[N:35]2)[C:23]([F:26])([F:25])[F:24])[N:3]=1
Reactant: Cc1ccn(-c2cc(Cl)ccc2[C@@H](Oc2cc(N3CCC4(CC3)CN[C@H](C(=O)O)C4)nc(N)n2)C(F)(F)F)n1
Reactant: O[C@H](c1ccc(Br)cc1-c1ccccc1)C(F)(F)F
Product: Cc1ccn(-c2cc(Br)ccc2[C@@H](Oc2cc(N3CCC4(CC3)CN[C@H](C(=O)O)C4)nc(N)n2)C(F)(F)F)n1

Procedure:
The title compound was prepared as described for (S)-8-(2-amino-6-((R)-1-(4-chloro-2-(3-methyl-1H-pyrazol-1-yl)phenyl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylic acid (Example 10d) starting with (R)-1-(5-bromo-[1,1′-biphenyl]-2-yl)-2,2,2-trifluoroethanol (Intermediate 38).
Reaction SMILES: [CH2:1]([N:3]1[CH:7]=[C:6]([C:8]2[S:16][C:15]3[C:10](=[N:11][CH:12]=[CH:13][C:14]=3[O:17][C:18]3[CH:23]=[CH:22][C:21]([NH2:24])=[CH:20][C:19]=3[F:25])[CH:9]=2)[N:5]=[CH:4]1)[CH3:2].[C:26]1([CH2:32][C:33]([N:35]=[C:36]=[O:37])=[O:34])[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>>[CH2:1]([N:3]1[CH:7]=[C:6]([C:8]2[S:16][C:15]3[C:10](=[N:11][CH:12]=[CH:13][C:14]=3[O:17][C:18]3[CH:23]=[CH:22][C:21]([NH:24][C:36]([NH:35][C:33](=[O:34])[CH2:32][C:26]4[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=4)=[O:37])=[CH:20][C:19]=3[F:25])[CH:9]=2)[N:5]=[CH:4]1)[CH3:2]
Reactant: CCn1cnc(-c2cc3nccc(Oc4ccc(N)cc4F)c3s2)c1
Reactant: O=C=NC(=O)Cc1ccccc1
Product: CCn1cnc(-c2cc3nccc(Oc4ccc(NC(=O)NC(=O)Cc5ccccc5)cc4F)c3s2)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 45 %

Procedure:
A mixture of 308 (300 mg, 0.85 mmol) and 2-phenylacetyl isocyanate (164 mg, 1.02 mmoL) [Arthur J. Hill, et al. JACS, 62: 1940; 1595] was stirred for 1 h at room temperature, loaded directly onto a flash chromatography column and gradient eluted with EtOAc, to MeOH/EtOAc (20:80) to afford the title compound 309a (45% yield) as a white solid. 1H NMR (d-DMSO) δ (ppm): 11.07(s, 1H), 10.63(s, 1H), 8.41(d, 1H, J=5.5 Hz), 7.94(d, 1H, J=1.4 Hz), 7.80(dd, 1H, J1=13.1 Hz, J2=2.4 Hz), 7.77(d, 1H, J=1.1 Hz), 7.65(s, 1H), 7.46-7.39(m, 2H), 7.35-7.19(m, 4H), 7.28-7.24(m, 1H), 6.54(dd, 1H, J1=5.5 Hz, J2=0.8 Hz), 4.03(q, 2H), 3.73(s, 2H), 1.38(t, 3H). MS (m/z): 516.1(M+H) (found).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([CH2:8][CH2:9][O:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:13][CH:12]=2)[CH:5]=[CH:4][C:3]=1[CH:21]1OCCO1.Cl.[N:27]1([C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]1.C([O-])(O)=O.[Na+]>C(Cl)Cl.C1COCC1>[F:1][C:2]1[CH:7]=[C:6]([CH2:8][CH2:9][O:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]([F:18])([F:19])[F:20])=[CH:13][CH:12]=2)[CH:5]=[CH:4][C:3]=1[CH2:21][N:30]1[CH2:31][CH2:32][N:27]([C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])[CH2:28][CH2:29]1
Reactant: Fc1cc(CCOc2ccc(C(F)(F)F)cc2)ccc1C1OCCO1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCN(Cc2ccc(CCOc3ccc(C(F)(F)F)cc3)cc2F)CC1
Yield: 68.4 %

Procedure:
To a THF (10 mL) solution of 2-(2-fluoro-4-{2-[4-(trifluoromethyl)phenoxy]-ethyl}phenyl)-1,3-dioxolane (0.552 g) was added 6 M HCl (0.775 mL) at 0° C., then the resultant mixture was room temperature for 5 hours. The reaction mixture was evaporated to afford a pale yellow oil. To a CH2Cl2 (15 mL) solution of that pale yellow oil and tert-Butyl 1-piperazinecarboxylate (0.375 g) were added NaB(OAc)3 (0.657 g) at 0° C. The resultant mixture was stirred at room temperature for 3 days. To the reaction mixture was added saturated aqueous NaHCO3, and extracted with CH2Cl2. The organic layer was washed with saturated aqueous NaCl, dried over anhydrous MgSO4, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (n-hexane/AcOEt=9/1 to 4/1) to afford tert-butyl 4-(2-fluoro-4-{2-[4-(trifluoromethyl)phenoxy]ethyl}benzyl)piperazine-1-carboxylate as a colorless oil (0.511 g).
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]2[CH:10]=[C:9]([O:11][C:12]3[CH:13]=[C:14]([NH:19][C:20](=[O:32])[C:21]4[CH:26]=[CH:25][CH:24]=[C:23]([C:27]5([C:30]#[N:31])[CH2:29][CH2:28]5)[CH:22]=4)[CH:15]=[CH:16][C:17]=3[CH3:18])[CH:8]=[CH:7][C:5]=2[N:6]=1.[CH:33]1([C:36](Cl)=[O:37])[CH2:35][CH2:34]1>CN(C)C1C=CN=CC=1>[C:30]([C:27]1([C:23]2[CH:22]=[C:21]([CH:26]=[CH:25][CH:24]=2)[C:20]([NH:19][C:14]2[CH:15]=[CH:16][C:17]([CH3:18])=[C:12]([O:11][C:9]3[CH:8]=[CH:7][C:5]4[N:6]=[C:2]([NH:1][C:36]([CH:33]5[CH2:35][CH2:34]5)=[O:37])[S:3][C:4]=4[CH:10]=3)[CH:13]=2)=[O:32])[CH2:29][CH2:28]1)#[N:31]
Reactant: Cc1ccc(NC(=O)c2cccc(C3(C#N)CC3)c2)cc1Oc1ccc2nc(N)sc2c1
Reactant: O=C(Cl)C1CC1
Agent: CN(C)c1ccncc1
Product: Cc1ccc(NC(=O)c2cccc(C3(C#N)CC3)c2)cc1Oc1ccc2nc(NC(=O)C3CC3)sc2c1
Yield: 33 %

Procedure:
Using N-{3-[(2-amino-1,3-benzothiazol-6-yl)oxy]-4-methylphenyl}-3-(1-cyanocyclopropyl)benzamide (0.11 g, 0.25 mmol), cyclopropanecarbonyl chloride (0.21 g, 2.0 mmol), and N,N-dimethylpyridine-4-amine (0.24 g, 2.0 mmol), and in the same manner as in Example A29(vi), the title compound (42 mg, 33%) was obtained as a pale-yellow powder.
Reaction SMILES: [CH2:1]([C:12]1[NH:13][C:14]2[C:19]([CH:20]=1)=[CH:18][CH:17]=[C:16]([C:21]([OH:23])=[O:22])[CH:15]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11].Cl.[CH2:25](O)[CH3:26]>>[CH2:1]([C:12]1[NH:13][C:14]2[C:19]([CH:20]=1)=[CH:18][CH:17]=[C:16]([C:21]([O:23][CH2:25][CH3:26])=[O:22])[CH:15]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11]
Reactant: CCCCCCCCCCCc1cc2ccc(C(=O)O)cc2[nH]1
Reactant: CCO
Agent: Cl
Product: CCCCCCCCCCCc1cc2ccc(C(=O)OCC)cc2[nH]1

Procedure:
A solution of 2-(n-undecyl)indole-6-carboxylic acid (11.9 g) in ethanol (50 ml) containing a solution of hydrogen chloride gas in ethanol (75 ml, of strength 39% w/v) was refluxed for 4.5 hours. The solution was cooled and a solid was collected which was dissolved in diethyl ether, and the ethereal solution was washed with water (2×100 ml) and dried over magnesium sulphate. The solvent was removed in vacuo to give a residue which was recrystallised from methanol to give ethyl 2-(n-undecyl)indole-6-carboxylate (6.2 g), in the form of very pale yellow needles, m.p. 84°-86° C.
Reaction SMILES: [CH3:1][N:2]([CH2:4][C:5]1[NH:6][CH:7]=[CH:8][CH:9]=1)[CH3:3].[NH:10]1C=CN=[CH:11]1>C1(C)C(C)=CC=CC=1>[N:2]1([CH2:4][C:5]2[NH:6][CH:7]=[CH:8][CH:9]=2)[CH:3]=[CH:11][N:10]=[CH:1]1
Reactant: CN(C)Cc1ccc[nH]1
Reactant: c1c[nH]cn1
Solvent: Cc1ccccc1C
Product: c1c[nH]c(Cn2ccnc2)c1
Yield: 52.1 %

Procedure:
A solution of 2-(dimethylaminomethyl)pyrrole (24.8 g) and imidazole (13.6 g) in xylene (120 ml) are heated under reflux for 3 hours. The solution was cooled and the solid was filtered off and crystallised from ether to give 2-(imidazol-1-ylmethyl) pyrrole (15.3 g), m.p. 89°-90°, raised to 91°-92° on further crystallisation from water.
Reaction SMILES: [F:1][C:2]1[CH:24]=[CH:23][CH:22]=[C:21]([F:25])[C:3]=1[C:4]([NH:6][CH:7]([C:11]1[CH:16]=[CH:15][C:14]([C:17]([CH3:20])([CH3:19])[CH3:18])=[CH:13][CH:12]=1)[CH2:8][CH2:9]O)=O.P12(SP3(SP(SP(S3)(S1)=S)(=S)S2)=S)=[S:27].[OH-].[Na+]>C1(C)C=CC=CC=1>[F:1][C:2]1[CH:24]=[CH:23][CH:22]=[C:21]([F:25])[C:3]=1[C:4]1[S:27][CH2:9][CH2:8][CH:7]([C:11]2[CH:16]=[CH:15][C:14]([C:17]([CH3:20])([CH3:19])[CH3:18])=[CH:13][CH:12]=2)[N:6]=1
Reactant: CC(C)(C)c1ccc(C(CCO)NC(=O)c2c(F)cccc2F)cc1
Reactant: S=P12SP3(=S)SP(=S)(S1)SP(=S)(S2)S3
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1
Product: CC(C)(C)c1ccc(C2CCSC(c3c(F)cccc3F)=N2)cc1
Yield: 54.3 %

Procedure:
A mixture of 5.0 g (14.4 mmol) of N-(2,6-difluorobenzoyl)-3-amino-3-(4-tert-butylphenyl)-1-propanol, 3.2 g (14.4 mmol) of phosphorus pentasulfide and 30 ml of toluene is heated under reflux for 6 hours. The mixture is allowed to cool, 10 ml of 20% strength aqueous sodium hydroxide solution are added and the mixture is heated under reflux for 30 minutes. After customary working up, the crude product is purified by column chromatography on silica gel (mobile phase n-hexane/ethyl acetate 8/2). 2.7 g (54.3%) of 2-(2,6-difluorophenyl)-4-(4-tert-butylphenyl)-5,6-dihydro-(4H)1,3-thiazine of melting point 91.0-91.5° C. are obtained.
Reaction SMILES: [CH3:1][CH:2]([CH3:4])[O-:3].[CH3:5][CH:6]([CH3:8])[O-:7].[CH3:9][CH:10]([CH3:12])[O-:11].[Ti+3:13].[NH2:14]CCCCCCO>>[CH3:1][CH:2]([CH3:4])[O-:3].[CH3:5][CH:6]([CH3:8])[O-:7].[CH3:9][CH:10]([CH3:12])[O-:11].[NH2:14][Ti+3:13][CH2:1][CH2:2][CH2:4][CH2:5][CH2:6][CH3:8]
Reactant: NCCCCCCO
Reactant: [Ti+3]
Agent: CC(C)[O-]
Product: CCCCCC[Ti+3]N
Temperature: 25 °C
Reaction time: 0.02 h
Yield: 200 %

Procedure:
0.1 moles of titanium-tri-isopropoxide (Tyzor TPT Dupont, Wilmington, Del.) and 0.1 moles of 6-amino-1-hexanol were added to a 50 ml beaker and stirred at room temperature for 1 minute to form 0.1 mole of amino-hexyl-titanium-tri-isopropoxide. The reaction mixture was heated to 70° C. for 10 minutes to evaporate the isopropyl alcohol formed during the reaction.
Reaction SMILES: [CH2:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:15]=[CH:14][C:13](B(O)O)=[C:12]([F:19])[CH:11]=2)=[CH:6][CH:5]=1)[CH2:2][CH3:3].Br[C:21]1[S:25][C:24]([CH:26]=[O:27])=[CH:23][CH:22]=1>>[F:19][C:12]1[CH:11]=[C:10]([C:7]2[CH:8]=[CH:9][C:4]([CH2:1][CH2:2][CH3:3])=[CH:5][CH:6]=2)[CH:15]=[CH:14][C:13]=1[C:21]1[S:25][C:24]([CH:26]=[O:27])=[CH:23][CH:22]=1
Reactant: CCCc1ccc(-c2ccc(B(O)O)c(F)c2)cc1
Reactant: O=Cc1ccc(Br)s1
Product: CCCc1ccc(-c2ccc(-c3ccc(C=O)s3)c(F)c2)cc1

Procedure:
5-(3-Fluoro-4′-propylbiphenyl-4-yl)thiophene-2-carbaldehyde is prepared analogously to Example 3 by Suzuki coupling of 4′-propyl-3-fluoro-4-biphenylboronic acid to 5-bromothiophene-2-carbaldehyde.
Reaction SMILES: C(C1C=C(C2ON=C(C3C=C(C)C(OCC(O)CNC(=O)CO)=C(C)C=3)N=2)C=CC=1)=O.[CH:32]([C:34]1[CH:42]=[CH:41][C:37]([C:38]([OH:40])=O)=[CH:36][C:35]=1[CH3:43])=[O:33].[CH2:44]([C:46]1[CH:61]=[C:60]([C:62](=[NH:65])[NH:63]O)[CH:59]=[C:58]([CH3:66])[C:47]=1[O:48][CH2:49][C@@H:50]([OH:57])[CH2:51][NH:52][C:53](=[O:56])[CH2:54][OH:55])[CH3:45]>>[CH2:44]([C:46]1[CH:61]=[C:60]([C:62]2[N:65]=[C:38]([C:37]3[CH:41]=[CH:42][C:34]([CH:32]=[O:33])=[C:35]([CH3:43])[CH:36]=3)[O:40][N:63]=2)[CH:59]=[C:58]([CH3:66])[C:47]=1[O:48][CH2:49][C@@H:50]([OH:57])[CH2:51][NH:52][C:53](=[O:56])[CH2:54][OH:55])[CH3:45]
Reactant: CCc1cc(C(=N)NO)cc(C)c1OC[C@@H](O)CNC(=O)CO
Reactant: Cc1cc(C(=O)O)ccc1C=O
Agent: Cc1cc(-c2noc(-c3cccc(C=O)c3)n2)cc(C)c1OCC(O)CNC(=O)CO
Product: CCc1cc(-c2noc(-c3ccc(C=O)c(C)c3)n2)cc(C)c1OC[C@@H](O)CNC(=O)CO

Procedure:
The title compound was prepared in analogy to rac-N-(3-{4-[5-(3-formyl-phenyl)-[1,2,4]oxadiazol-3-yl]-2,6-dimethyl-phenoxy}-2-hydroxy-propyl)-2-hydroxy-acetamide, starting from 4-formyl-3-methyl benzoic acid and N—((S)-3-[2-ethyl-4-(N-hydroxycarbamimidoyl)-6-methyl-phenoxy]-2-hydroxy-propyl)-2-hydroxy-acetamide. LC-MS: tR=0.68 min; [M+1]+=454.26; 1H NMR (D6-DMSO): δ 1.24 (t, J=7.5 Hz, 3H), 2.36 (s, 3H), 2.78 (s, 3H), 3.23-3.30 (m, 1H), 3.41-3.48 (m, 1H), 3.72-3.81 (m, 2H), 3.84 (d, J=5.3 Hz, 2H), 3.94-4.01 (m, 1H), 5.32 (d, J=5.3 Hz, 1H), 5.56 (t, J=5.8 Hz, 1H), 7.71 (t, J=5.5 Hz, 1H), 7.82 (s, 2H), 8.08 (d, J=8.0 Hz, 1H), 8.19-8.24 (m, 2H), 10.37 (s, 1H).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]2[N:8]([CH2:11][C:12]3[CH:17]=[CH:16][CH:15]=[C:14]([C:18]([F:21])([F:20])[F:19])[C:13]=3[CH3:22])[CH:9]=[N:10][C:5]2=[C:4]([O:23]C)[CH:3]=1.[NH:25]1[CH2:30][CH2:29][O:28][CH2:27][CH2:26]1>>[CH3:22][C:13]1[C:14]([C:18]([F:21])([F:20])[F:19])=[CH:15][CH:16]=[CH:17][C:12]=1[CH2:11][N:8]1[C:6]2=[N:7][C:2]([N:25]3[CH2:30][CH2:29][O:28][CH2:27][CH2:26]3)=[CH:3][C:4]([OH:23])=[C:5]2[N:10]=[CH:9]1
Reactant: COc1cc(Cl)nc2c1ncn2Cc1cccc(C(F)(F)F)c1C
Reactant: C1COCCN1
Product: Cc1c(Cn2cnc3c(O)cc(N4CCOCC4)nc32)cccc1C(F)(F)F
Reaction time: 3 h

Procedure:
5-chloro-7-(methyloxy)-3-{[2-methyl-3-(trifluoromethyl)phenyl]methyl}-3H-imidazo[4,5-b]pyridine (45 mg, 0.126 mmol) was suspended in 1.5 mL of morpholine in a microwave vial and the mixture was irradiated in a microwave oven at 130° C. for 45 min, then for additional 3 h, another 3 h and then additional 12 h. Product is slowly forming (as observed by LC/MS) going through the formation of the 7-hydroxy derivative first. The mixture was then irradiated for 3 h at 200° C., to provide complete conversion to the desired product. An additional aliquot of 5-chloro-7-(methyloxy)-3-{[2-methyl-3-(trifluoromethyl)phenyl]methyl}-3H-imidazo[4,5-b]pyridine (60 mg, 0.169 mmol) was suspended in morpholine (1.5 mL) and irradiated in a microwave oven at 200° C. for 3 h. The reaction was not completed, so it was irradiated again in the microwave at 200° C. for 150 min. The two reaction mixtures were combined and diluted with water and 1 N HCl was added to pH 4-5. The precipitate formed was collected by filtration, washed with water and dried. The solid was dissolved in DMSO and purified by Reverse phase-HPLC (25 to 80% AcCN in water plus 0.1% TFA). Two peaks closely eluted on the HPLC and were isolated for the product. The slower retention time peak presented 2% impurity so it was kept separated. The collected fractions were neutralized by the addition of NaHCO3 sat sol and the solvent volume was reduced to ½-⅓ of the original. The precipitates were collected washed with water and dried in a vacuum oven at 45° C. for 5 h to give 3-{[2-methyl-3-(trifluoromethyl)phenyl]methyl}-5-(4-morpholinyl)-3H-imidazo[4,5-b]pyridin-7-ol (21 mg, 0.052 mmol, 17.77% yield) which was submitted for testing, and the less pure sample of 3-{[2-methyl-3-(trifluoromethyl)phenyl]methyl}-5-(4-morpholinyl)-3H-imidazo[4,5-b]pyridin-7-ol (18 mg, 0.046 mmol, 15.54% yield), which was stored as is. MS (ES+) m/e 393 (MH+); 1H NMR (400 MHz, DMSO-d6) δ ppm 10.85 (br. s., 1H), 7.99 (s, 1H), 7.62 (d, J=8.08 Hz, 1H), 7.34 (t, J=7.83 Hz, 1H), 7.26 (d, J=7.58 Hz, 1H), 6.07 (s, 1H), 5.41 (s, 2H), 3.57-3.76 (m, 4H), 3.24-3.40 (m, 4H), (CH3 peak under DMSO peak).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([C:11]([OH:13])=O)[CH:10]=1)[NH:7][CH:6]=[CH:5]2.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C(N(CC)C(C)C)(C)C.[C:45]([C:49]1[CH:66]=[CH:65][C:52]([CH2:53][NH:54][CH2:55][CH2:56][C:57]2[CH:62]=[CH:61][C:60]([F:63])=[C:59]([Cl:64])[CH:58]=2)=[CH:51][CH:50]=1)([CH3:48])([CH3:47])[CH3:46]>CN(C=O)C.O>[C:45]([C:49]1[CH:66]=[CH:65][C:52]([CH2:53][N:54]([CH2:55][CH2:56][C:57]2[CH:62]=[CH:61][C:60]([F:63])=[C:59]([Cl:64])[CH:58]=2)[C:11]([C:9]2[CH:10]=[C:2]([Cl:1])[CH:3]=[C:4]3[C:8]=2[NH:7][CH:6]=[CH:5]3)=[O:13])=[CH:51][CH:50]=1)([CH3:48])([CH3:46])[CH3:47]
Reactant: O=C(O)c1cc(Cl)cc2cc[nH]c12
Reactant: CC(C)(C)c1ccc(CNCCc2ccc(F)c(Cl)c2)cc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: CC(C)(C)c1ccc(CN(CCc2ccc(F)c(Cl)c2)C(=O)c2cc(Cl)cc3cc[nH]c23)cc1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 73.7 %

Procedure:
To a solution of 59 mg (0.3 mmol) of 5-chloro-1H-indole-7-carboxylic acid and 96 mg of TBTU (0.3 mmol) in 3 ml DMF, were added 0.26 ml (1.5 mmol) of N,N-diisopropylethyl amine. After stirring for 5 min at rt, 96 mg (0.3 mmol) (4-tert-butyl-benzyl)-[2-(3-chloro-4-fluoro-phenyl)-ethyl]-amine in 2 ml DMF was added. After 3.5 h stirring at rt, the reaction mixture was diluted with 50 ml water and extracted with 2×50 ml EtOAc. The combined organic phases were washed with water and brine, dried with magnesium sulfate, filtered and concentrated in vacuo. The residue was purified by column chromatography (8 g silica gel; EtOAc/heptane 1:9) to give to give 110 mg light yellow solid (68%). MS (EI) 496.1 (M)+.
Reaction SMILES: [N:1]1([C@H:6]2[CH2:11][CH2:10][CH2:9][CH2:8][C@H:7]2[NH2:12])[CH2:5][CH2:4][CH2:3][CH2:2]1.N1C=CC=CC=1.[Cl:19][C:20]1[CH:21]=[C:22]([CH2:27][C:28](O)=O)[CH:23]=[CH:24][C:25]=1[Cl:26].C1(N=C=NC2CCCCC2)CCCCC1>C(Cl)(Cl)Cl>[Cl:19][C:20]1[CH:21]=[C:22]([CH2:27][CH2:28][NH:12][C@@H:7]2[CH2:8][CH2:9][CH2:10][CH2:11][C@@H:6]2[N:1]2[CH2:2][CH2:3][CH2:4][CH2:5]2)[CH:23]=[CH:24][C:25]=1[Cl:26]
Reactant: N[C@@H]1CCCC[C@@H]1N1CCCC1
Reactant: O=C(O)Cc1ccc(Cl)c(Cl)c1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: ClC(Cl)Cl
Solvent: c1ccncc1
Product: Clc1ccc(CCN[C@@H]2CCCC[C@@H]2N2CCCC2)cc1Cl
Temperature: 25 °C
Reaction time: 12 h

Procedure:
(±)-cis-2-(1-pyrrolidinyl)cyclohexylamine (5 gm) was combined with pyridine (1.2 gm), chloroform (200 ml), 3,4-dichlorophenylacetic acid (9.15 gm), and dicyclohexylcarbodiimide (12.3 gm) and the mixture was stirred for 12 hr at room temperature. The mixture was filtered, the precipitate was washed with ether (100 ml) and the filtrate and ether wash were combined. The organic solution was diluted with ether (200 ml) and extracted with 10% citric acid in water (300 ml). The acid layer was washed with ether (2×200 ml), then treated with excess concentrated aqueous ammonia until basic. The resulting mixture was extracted with methylene chloride (2×200 ml) and the combined organic extracts were washed with water (2×50 ml) and concentrated on a rotary evaporator. The resulting white solid was combined with tetrahydrofuran (25 ml) and added dropwise to a solution of AlH3 in tetrahydrofuran (76.2 ml of a 0.665M solution) at room temperature. After the addition, the mixture was poured into 15% NaOH and the resulting mixture was extracted with ether (3×100 ml). The ether was removed on a rotary evaporator and the residue was dissolved in ethanol (100 ml). The ethanol was removed on a rotary evaporator and the residue was converted to the hydrogen bromide salt which was recrystallized from ethanol. Analytical data are reported in Table I.
Reaction SMILES: [CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:20])=[C:11]([N:14]4[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]4)[CH:12]=3)[C:7](=[O:21])[C:6]([C:22]([OH:24])=[O:23])=[CH:5]2)[CH2:3][CH2:2]1.[C:25]([O:29][C:30](=O)[O:31]C(C)(C)C)([CH3:28])([CH3:27])[CH3:26]>CO.C(Cl)(Cl)Cl>[CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:20])=[C:11]([N:14]4[CH2:19][CH2:18][N:17]([C:30]([O:29][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:31])[CH2:16][CH2:15]4)[CH:12]=3)[C:7](=[O:21])[C:6]([C:22]([OH:24])=[O:23])=[CH:5]2)[CH2:2][CH2:3]1
Reactant: CC(C)(C)OC(=O)OC(C)(C)C
Reactant: O=C(O)c1cn(C2CC2)c2cc(N3CCNCC3)c(F)cc2c1=O
Solvent: ClC(Cl)Cl
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCN(c2cc3c(cc2F)c(=O)c(C(=O)O)cn3C2CC2)CC1
Temperature: 50 °C
Reaction time: 5 h
Yield: 97.4 %

Procedure:
3.31 g of 1-cyclopropyl-6-fluoro-7-(piperazin-1-yl)-1,4-dihydro-4-oxoquinoline-3-carboxylic acid was dissolved in a mixture of 30 ml of methanol and 20 ml of chloroform, and the resulting solution was stirred at 50° C. for 5 hours after addition of 2.29 g of di-t-butylcarbonate thereto. The solvent was removed under reduced pressure to obtain 4.2 g of the object compound
Reaction SMILES: [F:1][CH:2]([F:19])[C@H:3]1[CH2:8][C@@H:7]([C:9]2[O:13][NH:12][C:11](=[O:14])[CH:10]=2)[CH2:6][CH2:5][N:4]1C(OC)=O.Br>>[F:19][CH:2]([F:1])[C@H:3]1[CH2:8][C@@H:7]([C:9]2[O:13][NH:12][C:11](=[O:14])[CH:10]=2)[CH2:6][CH2:5][NH:4]1
Reactant: COC(=O)N1CC[C@H](c2cc(=O)[nH]o2)C[C@@H]1C(F)F
Agent: Br
Product: O=c1cc([C@H]2CCN[C@@H](C(F)F)C2)o[nH]1
Temperature: 25 °C
Reaction time: 16 h
Yield: 101.6 %

Procedure:
(2R,4S)-Methyl 2-(difluoromethyl)-4-(3-oxo-2,3-dihydroisoxazol-5-yl)piperidine-1-carboxylate (278 mg, 1.01 mmol) was dissolved in hydrogen bromide (33% in acetic acid, 7.93 mL, 45.29 mmol) and stirred at room temperature for 16 h. The solvent was removed in vacuo and the compound was purified by preparative HPLC on a XBridge C18 column (10 μm 250×19 ID mm) using a gradient of 0-10% Acetonitrile in H2O/MeCN/NH3 95/5/0.2 buffer over 20 minutes with a flow of 19 mL/min. 5-((2R,4S)-2-(Difluoromethyl)piperidin-4-yl)isoxazol-3(2H)-one (224 mg) was isolated. 1H NMR (400 MHz, cd3od) δ 1.66-1.77 (m, 1H), 1.77-1.89 (m, 1H), 2.24-2.31 (m, 1H), 2.36-2.43 (m, 1H), 3.12-3.27 (m, 2H), 3.51-3.58 (m, 1H), 3.73-3.86 (m, 1H), 5.84 (s, 1H), 6.14 (dt, 1H). HRMS Calcd for [C9H12F2N2O2+H]+: 219.0945. Found: 219.0950.
Reaction SMILES: [CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:17])=[C:11](F)[C:12]=3[O:14][CH3:15])[C:7](=[O:18])[C:6]([C:19]([OH:21])=[O:20])=[CH:5]2)[CH2:3][CH2:2]1.[C:22]([O:26][C:27]([NH:29][C@H:30]1[C@H:34]([CH3:35])[CH2:33][NH:32][CH2:31]1)=[O:28])([CH3:25])([CH3:24])[CH3:23].C1CCN2C(=NCCC2)CC1>C(#N)C>[C:22]([O:26][C:27]([NH:29][C@H:30]1[C@H:34]([CH3:35])[CH2:33][N:32]([C:11]2[C:12]([O:14][CH3:15])=[C:13]3[C:8]([C:7](=[O:18])[C:6]([C:19]([OH:21])=[O:20])=[CH:5][N:4]3[CH:1]3[CH2:3][CH2:2]3)=[CH:9][C:10]=2[F:17])[CH2:31]1)=[O:28])([CH3:25])([CH3:23])[CH3:24]
Reactant: COc1c(F)c(F)cc2c(=O)c(C(=O)O)cn(C3CC3)c12
Reactant: C[C@@H]1CNC[C@H]1NC(=O)OC(C)(C)C
Solvent: CC#N
Solvent: C1CCC2=NCCCN2CC1
Product: COc1c(N2C[C@@H](C)[C@H](NC(=O)OC(C)(C)C)C2)c(F)cc2c(=O)c(C(=O)O)cn(C3CC3)c12

Procedure:
A mixture of 1-cyclopropyl-6,7-difluoro-1,4-dihydro-8-methoxy-4-oxo-3-quinolinecarboxylic acid (0.40 g), trans-3-t-butoxycarbonylamino-4-methylpyrrolidine (0.41 g), DBU (0.21 g) and anhydrous acetonitrile (5 ml) was refluxed for 2.5 hours and then the reaction mixture was concentrated under reduced pressure. The residue was dissolved in chloroform (40 ml) and washed with 10% aqueous citric acid solution (20 ml) and with saturated saline (20 ml) successively. The organic layer was dried over anhydrous sodium sulfate and then concentrated under reduced pressure. The residue was crystallized from ethanol to give 7-(trans-3-t-butoxycarbonylamino-4-methyl-1-pyrrolidinyl)-1-cyclopropyl-6-fluoro-1,4-dihydro-8-methoxy-4-oxo-3-quinolinecarboxylic acid. To a suspension of these crystals in methanol (5 ml) was added concentrated hydrochloric acid (5 ml) dropwise. After stirring for 1.5 hours at room temperature, the reaction mixture was neutralized with concentrated aqueous ammonia, the resulting crystals were collected by filtration and washed with water sufficiently to give the title compound (0.29 g) as colorless powder, mp 214°-215° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])[C:6]([O:26][CH3:27])=[CH:5][C:4]=1[N+:28]([O-])=O.[H][H]>C(O)C.[Ni]>[CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])[C:6]([O:26][CH3:27])=[CH:5][C:4]=1[NH2:28]
Reactant: CCCCCCCCCCCCCCCCOc1cc(OC)c([N+](=O)[O-])cc1OC
Reactant: [H][H]
Agent: [Ni]
Solvent: CCO
Product: CCCCCCCCCCCCCCCCOc1cc(OC)c(N)cc1OC

Procedure:
In an autoclave 49.5 g (0.117 mole) of 2,5-dimethoxy-4-hexadecyloxy nitrobenzene dissolved in 120 ml of ethanol were hydrogenated using 2.5 ml of Raney-nickel, a hydrogen pressure between 750 and 1500 psi and a temperature of 70° C. After 3 h of agitation the catalyst was filtered off and the filtrate was cooled in ice. The residue formed was filtered off, stirred in ethanol and dried. Yield: 39.5 g (86%). Melting point: 61° C.
Reaction SMILES: [O:1]=[CH:2][C:3]1[CH:11]=[CH:10][C:7]([O:8][CH3:9])=[C:5]([OH:6])[CH:4]=1.[CH2:12](Br)[CH:13]=[CH2:14]>C(=O)([O-])[O-].[K+].[K+].CC(C)=O>[CH2:14]([O:6][C:5]1[CH:4]=[C:3]([CH:11]=[CH:10][C:7]=1[O:8][CH3:9])[CH:2]=[O:1])[CH:13]=[CH2:12]
Reactant: COc1ccc(C=O)cc1O
Reactant: C=CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: C=CCOc1cc(C=O)ccc1OC
Yield: 88.5 %

Procedure:
Isovanillin (76 g) was dissolved in a stirred mixture of potassium carbonate (104 g) and acetone (450 mls) followed by the dropwise addition of allyl bromide (67 g) over ca. 20 mins. The mixture was refluxed for 5 hours, cooled and filtered. The solvent was removed from the filtrate under reduced pressure and the residue was distilled under vacuum to yield 3-allyloxy-4-methoxybenzaldehyde (85 g), b.p. 1.37-150° C. at 1.5 mbar.