Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CO[C:3]([C:5]1[CH:6]([C:17]2[C:22]([F:23])=[CH:21][CH:20]=[CH:19][C:18]=2[Cl:24])[N:7]([CH:11]2[CH2:16][CH2:15][CH2:14][CH2:13][O:12]2)[O:8][C:9]=1[CH3:10])=[O:4].[OH-].[Na+].Cl.[NH2:28][C:29]1[CH:30]=[C:31]([CH2:35][C:36]([NH:38][C:39]2[CH:44]=[C:43]([O:45][CH3:46])[C:42]([O:47][CH3:48])=[C:41]([O:49][CH3:50])[CH:40]=2)=[O:37])[CH:32]=[CH:33][CH:34]=1.CCN=C=NCCCN(C)C.C1C=NC2N(O)N=NC=2C=1>ClCCl.CN(C1C=CN=CC=1)C.C1COCC1.CO>[CH3:46][O:45][C:43]1[CH:44]=[C:39]([NH:38][C:36](=[O:37])[CH2:35][C:31]2[CH:32]=[CH:33][CH:34]=[C:29]([NH:28][C:3]([C:5]3[CH:6]([C:17]4[C:22]([F:23])=[CH:21][CH:20]=[CH:19][C:18]=4[Cl:24])[N:7]([CH:11]4[CH2:16][CH2:15][CH2:14][CH2:13][O:12]4)[O:8][C:9]=3[CH3:10])=[O:4])[CH:30]=2)[CH:40]=[C:41]([O:49][CH3:50])[C:42]=1[O:47][CH3:48]
Reactant: COc1cc(NC(=O)Cc2cccc(N)c2)cc(OC)c1OC
Reactant: COC(=O)C1=C(C)ON(C2CCCCO2)C1c1c(F)cccc1Cl
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: C1CCOC1
Solvent: CO
Solvent: ClCCl
Product: COc1cc(NC(=O)Cc2cccc(NC(=O)C3=C(C)ON(C4CCCCO4)C3c3c(F)cccc3Cl)c2)cc(OC)c1OC
Temperature: 55 °C
Reaction time: 8 h
Yield: 51.1 %

Procedure:
A mixture of 4-methoxycarbonyl-5-methyl(tetrahydropyran-2-yl)-3-(2-chloro-6-fluoro-phenyl)isoxazole (2.95 g, 7.98 mmol), 2N NaOH (8.0 ml, 16.0 mmol), MeOH (20 ml), and THF (10 ml) was heated to 55° C. for 4 h. After cooling to 0° C., HCl (1N) was added until pH 3. The mixture was extracted with ethyl acetate (3×), and the combined extracts were washed (brine), dried (MgSO4), filtered, and concentrated to give the crude acid. The crude acid was dissolved in dichloromethane (50 ml) along with 2-(3-aminophenyl)-N-(3,4,5-trimethoxyphenyl)acetamide (3.80 g, 12.0 mmol), EDCI (3.33 g, 17.4 mmol), HOAt (2.72 g, 20.00 mmol), and DMAP (0.10 g, 0.80 mmol) and stirred at room temperature overnight. The mixture was applied to a silica gel column and eluted with dichloromethane/acetone (gradient) to give the title compound (2.61 g, 41%).
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[CH2:11][CH2:10][CH:9]([C:12]2[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[NH:14][CH:13]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2].[Cl:21][C:22]1[S:23][C:24]([CH2:27]Cl)=[CH:25][CH:26]=1>>[CH2:1]([O:3][C:4]([N:6]1[CH2:11][CH2:10][CH:9]([C:12]2[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[N:14]([CH2:27][C:24]3[S:23][C:22]([Cl:21])=[CH:26][CH:25]=3)[CH:13]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)N1CCC(c2c[nH]c3ccccc23)CC1
Reactant: ClCc1ccc(Cl)s1
Product: CCOC(=O)N1CCC(c2cn(Cc3ccc(Cl)s3)c3ccccc23)CC1
Reaction time: 15 h

Procedure:
This compound was prepared following the procedure described in example 13 (part B) at room temperature for 15 hours, starting with 3.5 g (13 mmol) of 4-(1H-indol-3-yl)-piperidine-1-carboxylic acid ethyl ester and 1.9 mL (16 mmol) of 2-chloro-5-chloromethyl-thiophene. After standard work-up, 5.2 g (99% of yield) of the expected product was obtained.
Reaction SMILES: [C:1](Cl)([Cl:3])=[O:2].[OH:5][CH2:6][C:7]([O:9][CH2:10][C:11]1[CH:16]=[CH:15][C:14]([N+:17]([O-:19])=[O:18])=[CH:13][CH:12]=1)=[O:8].C1(C2CCCCCCCCCC=2)CCCCCCCCNN=1>C1C=CC=CC=1>[Cl:3][C:1]([O:5][CH2:6][C:7]([O:9][CH2:10][C:11]1[CH:16]=[CH:15][C:14]([N+:17]([O-:19])=[O:18])=[CH:13][CH:12]=1)=[O:8])=[O:2]
Reactant: O=C(CO)OCc1ccc([N+](=O)[O-])cc1
Reactant: O=C(Cl)Cl
Agent: C1=C(C2=NNCCCCCCCC2)CCCCCCCCC1
Solvent: c1ccccc1
Product: O=C(Cl)OCC(=O)OCc1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
17.8 g of phosgene are introduced into 60 cm3 of benzene then a suspension of 7.1 g 4-nitrobenzyl hydroxyacetate (Izv. Akad. Nauk. SSSR. Khim 1964 (4) 685-692, Chem. Abst 61, 4469g) in 150 cm3 of benzene. The mixture is agitated for 2 hours at ambient temperature, brought to 7°/8° C. and 5.16 cm3 of diazabicycloundecene is added. After maintaining for one hour at this temperature, the mixture is decanted and the supernatant phase is partially concentrated under reduced pressure at 30°/35° C. until about 30 cm3 is obtained and the product is used as it is for the following stage.
Reaction SMILES: [Cl:1][C:2]1[CH:13]=[CH:12][C:5]2[O:6][CH:7]([CH2:10]Cl)[CH2:8][O:9][C:4]=2[CH:3]=1.[CH3:14][NH2:15]>>[Cl:1][C:2]1[CH:13]=[CH:12][C:5]2[O:6][CH:7]([CH2:10][NH:15][CH3:14])[CH2:8][O:9][C:4]=2[CH:3]=1
Reactant: ClCC1COc2cc(Cl)ccc2O1
Reactant: CN
Product: CNCC1COc2cc(Cl)ccc2O1

Procedure:
14.8 g (0.0675 mol) of 6-chloro-2-chloromethylbenzo-1,4-dioxane and 31.0 g of methylamine are heated in a pressure tube for 24 hours at 120°. Evaporating off the excess methylamine and distilling under reduced pressure yield 6-chloro-2-methylaminomethylbenzo-1,4-dioxane having a boiling point of 70°-73° (at 0.001 mbar).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8]Br)=[CH:4][C:3]=1[Cl:10].[OH:11][C:12]1[CH:13]=[C:14]([CH2:18][CH2:19][C:20]([O:22][CH3:23])=[O:21])[CH:15]=[CH:16][CH:17]=1>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][O:11][C:12]2[CH:13]=[C:14]([CH2:18][CH2:19][C:20]([O:22][CH3:23])=[O:21])[CH:15]=[CH:16][CH:17]=2)=[CH:4][C:3]=1[Cl:10]
Reactant: COC(=O)CCc1cccc(O)c1
Reactant: Clc1cc(CBr)ccc1Br
Product: COC(=O)CCc1cccc(OCc2ccc(Br)c(Cl)c2)c1

Procedure:
Compound 39.3 was synthesized using the procedure described above for preparing 1.1 using 1-bromo-4-(bromomethyl)-2-chlorobenzene 39.1 (available from Metina AB) and methyl 3-(3-hydroxyphenyl)propanoate 39.2 (available from Aagile Labs Division of Tyger Scientific). 1H NMR (400 MHz, CDCl3) δ ppm 7.63 (1H, d, J=8.2 Hz), 7.55 (1H, d, J=2.0 Hz), 7.17-7.24 (2H, m), 6.78-6.85 (3H, m), 4.99 (2H, s), 3.68 (3H, s) 2.94 (2H, t, J=7.8 Hz), 2.64 (2H, t, J=7.8 Hz).
Reaction SMILES: Br[C:2]1[C:3]2[C:4]3[CH:18]=[CH:17][S:16][C:5]=3[C:6](=[O:15])[NH:7][C:8]=2[C:9]([CH3:14])=[CH:10][C:11]=1[O:12][CH3:13].[CH3:19][CH:20]([CH3:46])[CH:21]([C:31]1[CH:36]=[CH:35][C:34](B2OC(C)(C)C(C)(C)O2)=[CH:33][CH:32]=1)[CH2:22][NH:23][C:24](=[O:30])[O:25][C:26]([CH3:29])([CH3:28])[CH3:27]>>[CH3:13][O:12][C:11]1[CH:10]=[C:9]([CH3:14])[C:8]2[NH:7][C:6](=[O:15])[C:5]3[S:16][CH:17]=[CH:18][C:4]=3[C:3]=2[C:2]=1[C:34]1[CH:33]=[CH:32][C:31]([CH:21]([CH:20]([CH3:46])[CH3:19])[CH2:22][NH:23][C:24](=[O:30])[O:25][C:26]([CH3:27])([CH3:28])[CH3:29])=[CH:36][CH:35]=1
Reactant: COc1cc(C)c2[nH]c(=O)c3sccc3c2c1Br
Reactant: CC(C)C(CNC(=O)OC(C)(C)C)c1ccc(B2OC(C)(C)C(C)(C)O2)cc1
Product: COc1cc(C)c2[nH]c(=O)c3sccc3c2c1-c1ccc(C(CNC(=O)OC(C)(C)C)C(C)C)cc1
Yield: 15 %

Procedure:
Following General Procedure B, 9-bromo-8-methoxy-6-methylthieno[2,3-c]quinolin-4(5H)-one) (500 mg, 1.54 mmol) was reacted with tert-butyl 3-methyl-2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)butylcarbamate (590 mg, 1.9 mmol) to afford the desired product (120 mg, 15%) as a yellow solid: ESI MS m/z 507 [C29H34N2O4S+H]+.
Reaction SMILES: [C:1]([O:5][C:6](=[O:28])[NH:7][C:8]1[C:13]([NH2:14])=[CH:12][C:11]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[F:21])=[C:10]([O:22][CH2:23][C:24]([F:27])([F:26])[F:25])[CH:9]=1)([CH3:4])([CH3:3])[CH3:2].C([O:33][C:34](=O)[CH2:35][C:36]([C:38]1[CH:43]=[CH:42][CH:41]=[C:40]([C:44]2[O:48][N:47]=[C:46]([CH3:49])[CH:45]=2)[CH:39]=1)=[O:37])(C)(C)C>>[C:1]([O:5][C:6](=[O:28])[NH:7][C:8]1[C:13]([NH:14][C:34](=[O:33])[CH2:35][C:36]([C:38]2[CH:43]=[CH:42][CH:41]=[C:40]([C:44]3[O:48][N:47]=[C:46]([CH3:49])[CH:45]=3)[CH:39]=2)=[O:37])=[CH:12][C:11]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[F:21])=[C:10]([O:22][CH2:23][C:24]([F:25])([F:26])[F:27])[CH:9]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: Cc1cc(-c2cccc(C(=O)CC(=O)OC(C)(C)C)c2)on1
Reactant: CC(C)(C)OC(=O)Nc1cc(OCC(F)(F)F)c(-c2ccccc2F)cc1N
Product: Cc1cc(-c2cccc(C(=O)CC(=O)Nc3cc(-c4ccccc4F)c(OCC(F)(F)F)cc3NC(=O)OC(C)(C)C)c2)on1

Procedure:
The title compound was prepared from [5-amino-2′-fluoro-2-(2,2,2-trifluoro-ethoxy)-biphenyl-4-yl]-carbamic acid tert.-butyl ester (Example J5) (200 mg, 0.5 mmol) and 3-[3-(3-methyl-isoxazol-5-yl)-phenyl]-3-oxo-propionic acid tert.-butyl ester (Example K4) (160 mg, 0.53 mmol) according to the general procedure M. Obtained as a white solid (40 mg).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7]([CH2:12][CH2:13][CH3:14])=[C:6]2[CH:15]=O.[C:17]([C:20]1[CH:25]=[CH:24][N:23]=[CH:22][CH:21]=1)(=[O:19])[CH3:18].N1CCCCC1>CO>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7]([CH2:12][CH2:13][CH3:14])=[C:6]2/[CH:15]=[CH:18]/[C:17]([C:20]1[CH:25]=[CH:24][N:23]=[CH:22][CH:21]=1)=[O:19]
Reactant: CC(=O)c1ccncc1
Reactant: CCCc1[nH]c2ccc(OC)cc2c1C=O
Solvent: CO
Solvent: C1CCNCC1
Product: CCCc1[nH]c2ccc(OC)cc2c1/C=C/C(=O)c1ccncc1
Temperature: 40 °C
Yield: 85.8 %

Procedure:
5-Methoxy-2-propylindole-3-carboxaldehyde (200 mg, 0.92 mmol) was dissolved in anhydrous methanol (7.5 mL) under an atmosphere of Argon (g). 4-Acetylpyridine (167.17 mg, 1.38 mmol) and piperidine (117.5 mg, 1.38 mmol) were added to the reaction mixture and the solution was refluxed for 24 hours. A precipitate slowly formed which was collected, washed with cold MeOH (30 mL) and dried overnight in an oil driven vacuum pump equipped to a vacuum desiccator heated to 40° C. to yield a bright yellow powder (253 mg, 85%): TLC Rf 0.43 in 4:1 ethyl acetate/hexanes. Melting point=221-224° C. 1H NMR (600 MHz, d6-DMSO) δ 11.87 (s, 1H), 8.82-8.82 (m, 2H), 8.10-8.07 (d, 1H, J=15.24 Hz), 7.94-7.93 (m, 2H), 7.46-7.45 (d, 1H, J=2.34), 7.40-7.37 (d, 1H, J=15.24 Hz), 7.34-7.32 (d, 1H, J=8.7 Hz), 6.87-6.86 (dd, 1H, J1=2.4 Hz, J2=8.7 Hz), 3.87 (s, 3H), 2.92-2.89 (t, 2H, J=7.44 Hz) 1.74-1.70 (m, 2H) 0.95-0.92 (t, 3H, J=14.7 Hz); 13C NMR (150 MHz, d6-DMSO) δ 188.0, 155.1, 150.5, 149.7, 145.0, 139.4, 131.1, 126.2, 121.3, 112.8, 112.3, 111.0, 109.0, 103.7, 55.5, 27.6, 22.8, 13.5. Elemental analysis calculated for C20H20N2O2: C, 74.98; H, 6.29; N, 8.74. Found: C, 75.05; H, 6.32; N, 8.70.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([CH3:10])=[C:6]([N:11]2[C:20](=[O:21])[C:19]3[CH:18]=[CH:17][N:16]=[CH:15][C:14]=3[C:12]2=[O:13])[CH:5]=1)([O-])=O.[H][H]>[Ni].C(OCC)(=O)C>[NH2:1][C:4]1[CH:9]=[CH:8][C:7]([CH3:10])=[C:6]([N:11]2[C:20](=[O:21])[C:19]3[CH:18]=[CH:17][N:16]=[CH:15][C:14]=3[C:12]2=[O:13])[CH:5]=1
Reactant: [H][H]
Reactant: Cc1ccc([N+](=O)[O-])cc1N1C(=O)c2ccncc2C1=O
Agent: [Ni]
Solvent: CCOC(C)=O
Product: Cc1ccc(N)cc1N1C(=O)c2ccncc2C1=O

Procedure:
The mixture of 2.5 g of N-(4-nitro-o-tolyl)-pyridine-3,4- dicarboximide, 1.2 g of Raney nickel and 575 ml of ethyl acetate is hydrogenated at 3.4 atm. and room temperature until the hydrogen uptake ceases. It is filtered, evaporated and the residue thoroughly leached with hot benzene. The filtrate is evaporated, the residue chromatographed on silica gel and eluted with ethyl acetate, to yield the N-(4-amino-o-tolyl)-pyridine-3,4-dicarboximide as an oil, the mass spectrum of which shows the expected molecular ion of 253.
Reaction SMILES: [Br:1]Br.[CH:3]1([NH:9][C:10]([NH:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[CH3:19])=[NH:11])[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]1.S(=O)(O)[O-].[Na+]>C(O)(=O)C>[CH:3]1([NH:9][C:10]([NH:12][C:13]2[CH:18]=[CH:17][C:16]([Br:1])=[CH:15][C:14]=2[CH3:19])=[NH:11])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8]1
Reactant: BrBr
Reactant: Cc1ccccc1NC(=N)NC1CCCCC1
Agent: O=S([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Product: Cc1cc(Br)ccc1NC(=N)NC1CCCCC1
Temperature: 70 °C
Yield: 153.1 %

Procedure:
A solution of bromine (0.336 g, 2.1 mmol) in glacial acetic acid (1 ml) was added dropwise to a stirred solution of N-cyclohexyl-N'-(2-methylphenyl)guanidine (0.231 g, 1 mmol) in glacial acetic acid (2 ml) at room temperature. After the addition, the addition funnel was replaced by a reflux condenser and the red reaction solution was heated on a warm water bath at 70° C. for about an hour. The reaction mixture was allowed to cool to room temperature and then poured in cold ice water (30 ml) containing a 200 mg of sodium bisulfite. The mixture was then extracted with dichloromethane (3×15 ml) and the combined organic layers were dried over sodium sulfate, filtered and concentrated to give a colorless liquid (0.475 g). This liquid was purified on a flash silica gel column to give a bright foamy product (0.25 g), mp 89°-91° C.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[O:14][CH2:13][CH2:12][C:11]3[CH:10]=[C:9]([C:15]4[N:19]([C:20]5[CH:25]=[CH:24][C:23]([F:26])=[CH:22][C:21]=5[Cl:27])[CH:18]=[N:17][N:16]=4)[S:8][C:7]=3[C:6]=2[CH:28]=1.[CH2:29]([N:33]1C=CN=C1)CCC>[C-]#N.[C-]#N.[C-]#N.[C-]#N.[C-]#N.[C-]#N.[K+].[K+].[K+].[K+].[Fe+2].[Cu]I.C1(C)C=CC=CC=1>[Cl:27][C:21]1[CH:22]=[C:23]([F:26])[CH:24]=[CH:25][C:20]=1[N:19]1[CH:18]=[N:17][N:16]=[C:15]1[C:9]1[S:8][C:7]2[C:6]3[CH:28]=[C:2]([C:29]#[N:33])[CH:3]=[CH:4][C:5]=3[O:14][CH2:13][CH2:12][C:11]=2[CH:10]=1
Reactant: CCCCn1ccnc1
Reactant: Fc1ccc(-n2cnnc2-c2cc3c(s2)-c2cc(Br)ccc2OCC3)c(Cl)c1
Agent: [Cu]I
Agent: [Fe+2]
Agent: [C-]#N
Solvent: Cc1ccccc1
Product: N#Cc1ccc2c(c1)-c1sc(-c3nncn3-c3ccc(F)cc3Cl)cc1CCO2
Temperature: 160 °C
Yield: 30.3 %

Procedure:
A microwave tube was charged with 3-(9-bromo-4,5-dihydro-6-oxa-1-thia-benzo[e]azulen-2-yl)-4-(2-chloro-4-fluoro-phenyl)-4H-[1,2,4]triazole (0.57 g; 1.2 mmol), K4[Fe(CN)6](101 mg; 0.24 mmol), CuI (23 mg; 0.12 mmol), 1-butylimidazole (0.32 ml; 2.4 mmol) and toluene (5 ml). The mixture was flushed with argon and heated in a microwave at 160° C. for 4 h. LCMS shows approx. 40% conversion so the same amount of K4[Fe(CN)6], CuI and 1-butylimidazole was added again and reaction mixture heated in a microwave at 170° C. for a further 4 h. The reaction mixture was partitioned between CH2Cl2 and water, the organic layer was dried (Na2SO4) and purified by ISCO then prep. LCMS to give 355 as a white solid (154 mg; 30%). δH (400 MHz, CDCl3) 3.19 (t, J=5.2, 2H), 4.36 (t, J=5.2, 2H), 7.08-7.11 (m, 2H), 7.23-7.32 (m, 1H), 7.43-7.52 (m, 3H), 7.81 (d, J=2.0, 1H), 8.23 (s, 1H). [M+H]+: 423
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[C:5]([NH:7][C:8]2[N:13]=[C:12]3[NH:14][N:15]=[CH:16][C:11]3=[CH:10][N:9]=2)[CH:4]=[N:3]1.Br[C:18]1[CH:23]=[CH:22][C:21]([N:24]([CH3:29])[S:25]([CH3:28])(=[O:27])=[O:26])=[CH:20][CH:19]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].N[C@@H]1CCCC[C@H]1N>O1CCOCC1.CCOC(C)=O.[Cu](I)I>[CH3:29][N:24]([C:21]1[CH:22]=[CH:23][C:18]([N:14]2[C:12]3=[N:13][C:8]([NH:7][C:5]4[CH:4]=[N:3][N:2]([CH3:1])[CH:6]=4)=[N:9][CH:10]=[C:11]3[CH:16]=[N:15]2)=[CH:19][CH:20]=1)[S:25]([CH3:28])(=[O:26])=[O:27]
Reactant: CN(c1ccc(Br)cc1)S(C)(=O)=O
Reactant: Cn1cc(Nc2ncc3cn[nH]c3n2)cn1
Agent: I[Cu]I
Agent: N[C@@H]1CCCC[C@H]1N
Agent: O=P([O-])([O-])[O-]
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: CN(c1ccc(-n2ncc3cnc(Nc4cnn(C)c4)nc32)cc1)S(C)(=O)=O
Temperature: 160 °C

Procedure:
A suspension of N-(1-methyl-1H-pyrazol-4-yl)-1H-pyrazolo[3,4-d]pyrimidin-6-amine (see Example 1, step (i)) (60 mg, 0.28 mmol), N-(4-bromophenyl)-N-methylmethanesulfonamide (1.1 eq), copper iodide (0.1 eq), potassium phosphate (2 eq) and trans-1,2-diaminocyclohexane (0.1 eq) in dioxane (2 mL) was heated in the microwave at 160° C. for 2 h. After cooling to rt the mixture was diluted with EtOAc and washed with water. The organic phase was collected, dried (MgSO4) and concentrated in vacuo. The resultant residue was purified by column chromatography (petroleum ether: EtOAc) to give the title product. 1H NMR (d6-DMSO) δ 10.07 (s, 1H), 9.03 (s, 1H), 8.33 (s, 1H), 8.19 (d, 2H), 7.97 (s, 1H), 7.66 (d, 2H), 7.60 (s, 1H), 3.84 (s, 3H), 3.01 (s, 3H); LC-MS method B, (ES+) 399.1, RT=8.18 min.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:18])[C:5]1[CH:14]=[C:13]([N+:15]([O-:17])=[O:16])[CH:12]=[C:7]([C:8]([NH:10][CH3:11])=O)[CH:6]=1)[CH3:2].S(OS(C(F)(F)F)(=O)=O)(C(F)(F)F)(=O)=O.[N-:34]=[N+:35]=[N-:36].[Na+].C([O-])(O)=O.[Na+]>ClC(Cl)C>[CH2:1]([O:3][C:4](=[O:18])[C:5]1[CH:14]=[C:13]([N+:15]([O-:17])=[O:16])[CH:12]=[C:7]([C:8]2[N:10]([CH3:11])[N:36]=[N:35][N:34]=2)[CH:6]=1)[CH3:2]
Reactant: CCOC(=O)c1cc(C(=O)NC)cc([N+](=O)[O-])c1
Reactant: [N-]=[N+]=[N-]
Agent: O=C([O-])O
Agent: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Agent: [Na+]
Solvent: CC(Cl)Cl
Product: CCOC(=O)c1cc(-c2nnnn2C)cc([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 59.1 %

Procedure:
To a 2M solution of N-methyl-5-nitro-isophthalamic acid ethyl ester (10 g) in dichloroethane (200 ml) at −20° C. was added pre-cooled triflic anhydride (10 ml) dropwise. This was stirred for 30 min and then sodium azide (4.6 g) was added. This was allowed to warm to room temperature and stirred overnight. The reaction was neutralised with 5% NaHCO3 (aq) solution and the organic and aqueous layers were separated and the organic layer dried and concentrated in vacuum. Flash chromatography (100:0 to 50:50 gradient cyclohexane:EtOAc) afforded the title compound (6.5 g). Rt=1.52 min (method D).
Reaction SMILES: [CH3:1][S:2]([NH:5][C:6]1[CH:11]=[CH:10][C:9](B(O)O)=[CH:8][CH:7]=1)(=[O:4])=[O:3].Br[C:16]1[CH:21]=[CH:20][C:19]([O:22][CH2:23][CH:24]2[CH2:29][CH2:28][N:27]([C:30]([O:32][CH:33]([CH3:35])[CH3:34])=[O:31])[CH2:26][CH2:25]2)=[CH:18][CH:17]=1.C([O-])([O-])=O.[Na+].[Na+]>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.COCCOC>[CH3:1][S:2]([NH:5][C:6]1[CH:11]=[CH:10][C:9]([C:16]2[CH:17]=[CH:18][C:19]([O:22][CH2:23][CH:24]3[CH2:25][CH2:26][N:27]([C:30]([O:32][CH:33]([CH3:35])[CH3:34])=[O:31])[CH2:28][CH2:29]3)=[CH:20][CH:21]=2)=[CH:8][CH:7]=1)(=[O:4])=[O:3]
Reactant: CC(C)OC(=O)N1CCC(COc2ccc(Br)cc2)CC1
Reactant: CS(=O)(=O)Nc1ccc(B(O)O)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Product: CC(C)OC(=O)N1CCC(COc2ccc(-c3ccc(NS(C)(=O)=O)cc3)cc2)CC1
Yield: 24.6 %

Procedure:
The title compound (11 mg, 25%) was prepared as a tan solid from {4-[(methylsulfonyl)amino]phenyl}boronic acid (22 mg, 0.1 mmol), 1-methylethyl 4-{[(4-bromophenyl)oxy]methyl}-1-piperidinecarboxylate (prepared as in Example 9, Step 2, 36 mg, 0.1 mmol), Pd(PPh3)2Cl2 (25 mg, 0.04 mmol), 2M Na2CO3 (1 mL) and DME (1 mL) in a manner similar to Example 21, Step 3, and worked up in a manner similar to Example 9, Step 3. 1H NMR (400 MHz, CDCl3): δ 7.55-7.45 (m, 4H), 7.30-7.20 (m, 2H), 6.95 (d, 2H, J=8.6 Hz), 6.38 (s, 1H), 4.99-4.83 (m, 1H), 3.84 (d, 2 H, J=6.4 Hz), 3.03 (s, 3H), 2.84-2.74 (m, 2H), 2.05-1.94 (m, 1H), 1.90-1.80 (m, 2H), 1.37-1.18 (m, 10H); LRMS (ESI), m/z 447 (M+H).
Reaction SMILES: CO[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH2:9][CH:10]([CH3:15])[CH2:11][C:12]([OH:14])=[O:13].C1(CC(=O)C)C=CC=CC=1>>[CH3:15][CH:10]([CH2:9][C:4]1[CH:3]=[CH:8][CH:7]=[CH:6][CH:5]=1)[CH2:11][C:12]([OH:14])=[O:13]
Reactant: COc1ccccc1CC(C)CC(=O)O
Agent: CC(=O)Cc1ccccc1
Product: CC(CC(=O)O)Cc1ccccc1

Procedure:
3-Methyl-4-phenylbutanoic acid was prepared in a similar manner as 4-(2-methoxy-phenyl)-3-methyl-butyric acid of Example 32 except using 1-phenylpropan-2-one. 1H NMR (400 MHz, CDCl3) δ 7.31-7.14 (m, 5H), 2.65 (dd, J=13.3, 6.7 Hz, 1H), 2.53 (dd, J=13.3, 7.4 Hz, 1H), 2.38 (dd, 14.9, 5.5 Hz, 1H), 2.28 (app. sext. J=6.7 Hz, 1H), 2.17 (dd, 14.5, 7.8 Hz, 1H), 0.98 (d, J=6.6 Hz, 3H).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6]([NH:13][CH:14]=[C:15]([C:21]([O:23][CH2:24][CH3:25])=[O:22])[C:16](OCC)=[O:17])=[N:5][CH:4]=1.C1(OC2C=CC=CC=2)C=CC=CC=1>CCCCCC>[CH3:1][O:2][C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6]2=[N:13][CH:14]=[C:15]([C:21]([O:23][CH2:24][CH3:25])=[O:22])[C:16](=[O:17])[N:5]2[CH:4]=1
Reactant: CCOC(=O)C(=CNc1ncc(OC)c2ccccc12)C(=O)OCC
Solvent: c1ccc(Oc2ccccc2)cc1
Solvent: CCCCCC
Product: CCOC(=O)c1cnc2c3ccccc3c(OC)cn2c1=O
Yield: 79 %

Procedure:
A mixture A mixture of diethyl 4-methoxyisoquinolylaminomethylenemalonate (460 mg., 1.33 mmoles) and diphenyl ether (4.6 ml.) was placed in an oil bath at 210°, the temperature of which, was increased to 260° during 5 minutes. Dilution of the solution with Skellysolve B caused the product (315 mgs., 79% yield), m.p. 190°-193°, to separate. Recrystallization from ethyl acetate raised the m.p. to 202°-204°.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][N:5]=[CH:4][CH:3]=1.[Cl:8][C:9]1[CH:14]=[CH:13][N:12]=[C:11]2[CH:15]=[C:16]([C:18]([O-])=[O:19])[S:17][C:10]=12.[Li+]>>[N:5]1[CH:6]=[CH:7][C:2]([NH:1][C:18]([C:16]2[S:17][C:10]3[C:11](=[N:12][CH:13]=[CH:14][C:9]=3[Cl:8])[CH:15]=2)=[O:19])=[CH:3][CH:4]=1
Reactant: O=C([O-])c1cc2nccc(Cl)c2s1
Reactant: Nc1ccncc1
Agent: [Li+]
Product: O=C(Nc1ccncc1)c1cc2nccc(Cl)c2s1

Procedure:
The title compound was prepared from 4-aminopyridine and lithium 7-chloro-thieno[3,2-b]pyridine-2-carboxylate by a procedure analogous to Example 1B. MS: 290/292 (MH+); HPLC Rf: 4.63 min.; HPLC purity: 99%.
Reaction SMILES: [C:1]([NH:4][CH:5]1[CH2:10][CH2:9][CH2:8][N:7]([C:11]2[C:20](F)=[C:19]3[C:14]([C:15](=[O:28])[C:16]([C:25]([OH:27])=[O:26])=[CH:17][N:18]3[CH:22]3[CH2:24][CH2:23]3)=[CH:13][C:12]=2[F:29])[CH2:6]1)(=[O:3])[CH3:2].[CH3:30][O-:31].[Na+]>CN(C)C=O>[C:1]([NH:4][CH:5]1[CH2:10][CH2:9][CH2:8][N:7]([C:11]2[C:20]([O:31][CH3:30])=[C:19]3[C:14]([C:15](=[O:28])[C:16]([C:25]([OH:27])=[O:26])=[CH:17][N:18]3[CH:22]3[CH2:23][CH2:24]3)=[CH:13][C:12]=2[F:29])[CH2:6]1)(=[O:3])[CH3:2]
Reactant: C[O-]
Reactant: CC(=O)NC1CCCN(c2c(F)cc3c(=O)c(C(=O)O)cn(C4CC4)c3c2F)C1
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1c(N2CCCC(NC(C)=O)C2)c(F)cc2c(=O)c(C(=O)O)cn(C3CC3)c12
Reaction time: 2 h

Procedure:
A mixture of 7-(3-acetamidopiperidin-1-yl)-1-cyclopropyl-6,8-difluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid (4.05 g), sodium methoxide (2.16 g) and N,N-dimethylformamide (120 ml) was stirred for 2 hours at 100°-140° C. The reaction mixture was concentrated in vacuumand water was added to the residue. The mixture was neutralized with 1N hydrochloric acid and the neutralized mixture was then concentrated in vacuum. Purification of the concentrated mixture by silica gel column chromatography (chloroform-methanol) gave 7-(3-acetamidopiperidin-1-yl)-1-cyclopropyl-6-fluoro-1,4-dihydro-8-methoxy-4-oxoquinoline-3-carboxylic acid. m.p. 248°-250° C.
Reaction SMILES: [OH:1][CH2:2][C@@H:3]1[NH:7][C:6](=[O:8])[CH2:5][CH2:4]1.C(N(CC)CC)C.[CH3:16][S:17](Cl)(=[O:19])=[O:18]>C(Cl)Cl>[O:8]=[C:6]1[NH:7][CH:3]([CH2:2][O:1][S:17]([CH3:16])(=[O:19])=[O:18])[CH2:4][CH2:5]1
Reactant: O=C1CC[C@H](CO)N1
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CS(=O)(=O)OCC1CCC(=O)N1
Yield: 91.7 %

Procedure:
To 1.0 g (8.69 mmol) of (R)-(−)-5-(Hydroxymethyl)-2-pyrrolidinone and triethylamine (2.42 ml, 17.37 mmol) in 80 mL of methylene chloride at 0° C. was added 1.01 mL (13.03 mmol) of methanesulfonyl chloride. The resultant solution was stirred at 0° C. for 1 hour. The solvent was removed. Silica gel chromatography using (10:1 ethyl acetate/methanol) gave 1.54 g (92%) of methanesulfonic acid 5-oxo-pyrrolidin-2-ylmethyl ester as an off-white solid that was used in the next step. Rf=0.21 (10:1 ethyl acetate/methanol). 1H NMR (400 MHz, CDCl3): δ 1.82–1.88 (m, 1H), 2.25–2.40 (m, 3H), 3.06 (s, 3H), 3.98–4.02 (m, 1H), 4.05–4.09 (dd, J=10.2, 7.1 Hz 1H), 4.22–4.25 (dd, J=9.1, 3.7 Hz 1H), 6.96 (bs, 1H). To 150 mg (0.40 mmol) of 6-Methoxy-1-methyl-7-[(2S,3S)-(2-phenyl-piperidin-3-ylamino)-methyl]-3,4-dihydro-H-quinolin-2-one, potassium carbonate (55 mg, 0.40 mmol), and and catalytic KI in 5 mL of DMF was added methanesulfonic acid 5-oxo-pyrrolidin-2-ylmethyl ester (92 mg, 0.47 mmol) The suspension was heated to 70° C. for 16 hours. The reaction was diluted with methylene chloride and washed three times with water, twice with brine, dried over MgSO4, filtered, and concentrated. Silica gel chromatography using (9:1 ethyl acetate/methanol) gave 30 mg (16%) of the title compound, a white foam. Rf=0.20 (9:1 ethyl acetate/methanol). MS (M+H)+=477.2; 1H NMR (400 MHz, CDCl3): δ 1.45–1.60 (m, 2H), 1.65–1.78 (m, 1H), 1.90–2.15 (m, 5H), 2.18–2.30 (m, 3H), 2.36–2.41 (dd, J=13.1, 6.7 Hz, 1H), 2.53–2.57 (t, J=7.4 Hz, 2H), 2.75–2.80 (m, 3H), 3.03–3.06 (m, 1H), 3.14 (s, 3H), 3.45–3.49 (m, 2H), 3.53 (s, 3H), 3.67–3.75 (m, 2H), 6.08 (bs, 1H), 6.50 (s, 1H), 6.66 (s, 1H), 7.24–7.36 (m, 5H); 13C NMR (100 MHz, CDCl3): δ 21.2, 25.3, 25.5, 27.0, 29.7, 31.8, 45.3, 52.5, 55.5, 56.2, 61.5, 72.0, 109.9, 116.1, 127.3, 128.1, 129.4, 133.6, 140.4, 152.9, 170.0, 178.0. The dihydrochloride salt was prepared by the addition of 2 M HCl in ether to a solution of the product in ethyl acetate. Concentration gave a white solid.