Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:9]=[CH:8][C:7]([N+:10]([O-])=O)=[CH:6][C:5]=1[C:13]1[NH:18][C:17](=[O:19])[C:16]2=[C:20]([CH3:32])[N:21]=[C:22]([CH2:23][CH:24]([CH2:30][CH3:31])[CH2:25][CH2:26][CH2:27][CH2:28][CH3:29])[N:15]2[N:14]=1)[CH3:2].C1CCCCC1.C(OCC)(=O)C>C(O)C.[Pd]>[NH2:10][C:7]1[CH:8]=[CH:9][C:4]([O:3][CH2:1][CH3:2])=[C:5]([C:13]2[NH:18][C:17](=[O:19])[C:16]3=[C:20]([CH3:32])[N:21]=[C:22]([CH2:23][CH:24]([CH2:30][CH3:31])[CH2:25][CH2:26][CH2:27][CH2:28][CH3:29])[N:15]3[N:14]=2)[CH:6]=1
Reactant: CCCCCC(CC)Cc1nc(C)c2c(=O)[nH]c(-c3cc([N+](=O)[O-])ccc3OCC)nn12
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: C1CCCCC1
Solvent: CCO
Product: CCCCCC(CC)Cc1nc(C)c2c(=O)[nH]c(-c3cc(N)ccc3OCC)nn12

Procedure:
Analogously to the procedure of example 42A, 1.95 g (4.42 mmol) of the compound from example 49A are hydrogenated in 120 g of ethanol using 200 mg of 10% Pd/C. Chromatography on 400 ml of silica gel using cyclohexane and ethyl acetate in a gradient system from 90:10 to 40:60 gives 1.26 g (69.4% of theory).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][NH:11][C:10](C)([C:14]([OH:16])=[O:15])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Br[C:19]1[CH:24]=[CH:23][C:22]([C:25]([F:28])([F:27])[F:26])=[CH:21][N:20]=1.[Cl-].[CH:30](C1C=CC=C(C(C)C)C=1[N+]1C=CN(C2C(C(C)C)=CC=CC=2C(C)C)C=1)(C)C.CC(C)([O-])C.[Na+]>C1(C)C=CC=CC=1>[CH3:30][O:16][C:14]([CH:10]1[N:11]([C:19]2[CH:24]=[CH:23][C:22]([C:25]([F:28])([F:27])[F:26])=[CH:21][N:20]=2)[CH2:12][CH2:13][N:8]([C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])[CH2:9]1)=[O:15]
Reactant: CC(C)(C)OC(=O)N1CCNC(C)(C(=O)O)C1
Reactant: CC(C)c1cccc(C(C)C)c1-n1cc[n+](-c2c(C(C)C)cccc2C(C)C)c1
Reactant: FC(F)(F)c1ccc(Br)nc1
Agent: CC(C)(C)[O-]
Agent: [Cl-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: COC(=O)C1CN(C(=O)OC(C)(C)C)CCN1c1ccc(C(F)(F)F)cn1
Temperature: 100 °C
Reaction time: 5 h
Yield: 282.5 %

Procedure:
3-Methyl-piperazine-1,3-dicarboxylic acid 1-tert-butyl ester (120 mg, 0.49 mmol) and 2-Bromo-5-trifluoromethyl-pyridine (133 mg, 0.59 mmol) were dissolved in 2.0 mL of anhydrous toluene (degassed). In a separate, septum-equipped vial were placed tri(dibenzylideneacetone)dipalladium(0) (22 mg, 0.024 mmol), 1,3-bis(2,6-di-i-propylphenyl)imidazolium chloride (42 mg, 0.1 mmol) and sodium t-butoxide (57 mg, 0.59 mmol). This “catalytic” vial was equipped with a magnetic stir bar and flushed with dry nitrogen. The reactant solution was next transferred to the “catalytic” vial and the mixture was stirred at 100° C. for 5 h. After this period the mixture was combined with 20 mL of hexane/EtOAc (2:1) and was passed through a pad of Celite. The resulting filtrate was evaporated in vacuo and purified using flash silica chromatography (0-20% EtOAc/Hexane) to yield 110 mg (58%) of 4-(5-Trifluoromethyl-pyridin-2-yl)-piperazine-1,3-dicarboxylic acid 1-tert-butyl ester 3-methyl ester.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:6]=[C:7](B(O)O)[CH:8]=[CH:9][CH:10]=1)=[O:4].P([O-])([O-])([O-])=O.[K+].[K+].[K+].Br[C:23]1[N:24]=[C:25]([C:32]([C:34]2[CH:35]=[C:36]3[C:41](=[CH:42][CH:43]=2)[N:40]([CH2:44][CH2:45][CH3:46])[C:39](=[O:47])[N:38]([CH2:48][CH2:49][O:50][C:51]2[CH:56]=[CH:55][C:54]([F:57])=[CH:53][CH:52]=2)[C:37]3=[O:58])=[O:33])[N:26]2[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=12>O.CN1C(=O)CCC1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[F:57][C:54]1[CH:53]=[CH:52][C:51]([O:50][CH2:49][CH2:48][N:38]2[C:37](=[O:58])[C:36]3[C:41](=[CH:42][CH:43]=[C:34]([C:32]([C:25]4[N:26]5[CH:31]=[CH:30][CH:29]=[CH:28][C:27]5=[C:23]([C:7]5[CH:6]=[C:5]([CH:10]=[CH:9][CH:8]=5)[C:3]([O:2][CH3:1])=[O:4])[N:24]=4)=[O:33])[CH:35]=3)[N:40]([CH2:44][CH2:45][CH3:46])[C:39]2=[O:47])=[CH:56][CH:55]=1
Reactant: COC(=O)c1cccc(B(O)O)c1
Reactant: CCCn1c(=O)n(CCOc2ccc(F)cc2)c(=O)c2cc(C(=O)c3nc(Br)c4ccccn34)ccc21
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: CN1CCCC1=O
Solvent: O
Product: CCCn1c(=O)n(CCOc2ccc(F)cc2)c(=O)c2cc(C(=O)c3nc(-c4cccc(C(=O)OC)c4)c4ccccn34)ccc21
Temperature: 120 °C
Yield: 69.1 %

Procedure:
2.178 g (12.1 mmol) of 3-methoxycarbonylphenylboronic acid, 4.279 g (20.16 mmol) of potassium phosphate dissolved in 30 ml of water, and 582.4 g (0.504 mmol) of tetrakis(triphenylphosphine)palladium are added to 5.7 g (10.08 mmol) of 6-[(1-bromoimidazo[1,5-a]pyridin-3-yl)carbonyl]-3-[2-(4-fluorophenoxy)ethyl]-1-propylquinazoline-2,4(1H,3H)-dione in 180 ml of NMP. The reaction medium is microwave-heated for 15 minutes at 120° C. and then concentrated under reduced pressure. The solid obtained is purified by silica gel column chromatography, elution being carried out with a dichloromethane/methanol (100/1) mixture. 4.32 g of a yellow solid are obtained.
Reaction SMILES: C1(S([N:10]2[CH2:17][C:16]3[S:15][CH:14]=[N:13][C:12]=3[CH2:11]2)(=O)=O)C=CC=CC=1.C1(O)C=CC=CC=1.[BrH:25].C(OCC)(=O)C>O>[BrH:25].[S:15]1[C:16]2[CH2:17][NH:10][CH2:11][C:12]=2[N:13]=[CH:14]1
Reactant: O=S(=O)(c1ccccc1)N1Cc2ncsc2C1
Agent: Br
Solvent: CCOC(C)=O
Solvent: O
Solvent: Oc1ccccc1
Product: c1nc2c(s1)CNC2
Temperature: 25 °C

Procedure:
A mixture of 5-(benzenesulfonyl)-4,6-dihydro-5H-pyrrolo[3,4-d]thiazole (800 mg), phenol (800 μl) and 47% hydrobromic acid (5.00 ml) was heated under reflux for 2 hours. After the reaction mixture was cooled to room temperature, ethyl acetate and water were added to conduct liquid separation. The resultant water layer was concentrated under reduced pressure. Ethyl acetate was added to the residue, colorless powder deposited was collected by filtration to obtain the title compound (521 mg).
Reaction SMILES: [CH3:1][O-:2].[Na+].Cl[C:5]1[C:10]([N+:11]([O-:13])=[O:12])=[CH:9][C:8]([Cl:14])=[CH:7][N:6]=1>CO.O>[Cl:14][C:8]1[CH:9]=[C:10]([N+:11]([O-:13])=[O:12])[C:5]([O:2][CH3:1])=[N:6][CH:7]=1
Reactant: O=[N+]([O-])c1cc(Cl)cnc1Cl
Reactant: C[O-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: COc1ncc(Cl)cc1[N+](=O)[O-]
Reaction time: 7 h
Yield: 96.9 %

Procedure:
A solution of sodium methoxide (0.84 g, 16.6 mmol) in methanol (4 mL) was added dropwise to a solution of 2,5-dichloro-3-nitropyridine (1.00 g, 5.2 mmol) in methanol (10 mL) and the mixture was stirred and heated to reflux. After 7 hours, the mixture was cooled and diluted with water and the precipitate was filtered, washed with water and dried to give the title compound (0.95 g, 97%) as a white solid.
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[C:5]([CH:10]=[CH:11][C:12]=1[O:13][CH3:14])[C:6]([O:8][CH3:9])=[O:7])=[O:2].S(=O)(=O)([OH:17])N.Cl([O-])=O.[Na+].CCOC(C)=O>O1CCOCC1.O>[CH3:14][O:13][C:12]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][C:3]=1[C:1]([OH:17])=[O:2]
Reactant: COC(=O)c1ccc(OC)c(C=O)c1
Reactant: NS(=O)(=O)O
Agent: [Na+]
Agent: [O-][Cl+][O-]
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Solvent: O
Product: COC(=O)c1ccc(OC)c(C(=O)O)c1

Procedure:
Crude methyl 3-formyl-4-(methyloxy)benzoate from the previous step was dissolved in 40 mL of dioxane with stirring. Sulfamic acid (5.87 g, 60.5 mmol) in 20 mL of H2O was added to the stirring solution. Sodium chlorite (1.68 g, 80% by weight, 18.6 mmol) in 20 mL of H2O was added dropwise via addition funnel. The reaction was stirred for 40 min and poured into EtOAc and H2O. The layers were separated, and the organic layer was washed with brine. The combined aqueous layers were extracted with EtOAc, and the combined organic layers were dried over MgSO4, filtered, and concentrated in vacuo. The solid was transferred to an Erlenmeyer flask with the aid of 30-40 mL of DCM. Approximately 50 mL of hexanes was added. Air was blown over the solution to allow most of the DCM to evaporate. Diethyl ether was added (20-30 mL), and the suspension was filtered. The solid was washed with hexanes, collected, and dried to afford 1.96 g (82% over 2 steps) of the desired compound. 1H NMR (400 MHz, DMSO-d6): δ 12.92 (br s, 1H), 8.22 (d, J=2.2 Hz, 1H), 8.07 (dd, J=8.8, 2.2 Hz, 1H), 7.24 (d, J=8.8 Hz, 1H), 3.88 (s, 3H), 3.82 (s, 3H).
Reaction SMILES: [NH2:1][C@@H:2]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)[CH2:3][OH:4].[Br:11][C:12]1[CH:19]=[CH:18][CH:17]=[CH:16][C:13]=1[CH:14]=O.S([O-])([O-])(=O)=O.[Mg+2]>C(Cl)Cl.CCOCC>[Br:11][C:12]1[CH:19]=[CH:18][CH:17]=[CH:16][C:13]=1/[CH:14]=[N:1]/[C@@H:2]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)[CH2:3][OH:4]
Reactant: O=Cc1ccccc1Br
Reactant: N[C@H](CO)c1ccccc1
Agent: O=S(=O)([O-])[O-]
Agent: [Mg+2]
Solvent: CCOCC
Solvent: ClCCl
Product: OC[C@@H](/N=C/c1ccccc1Br)c1ccccc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 79 %

Procedure:
To a stirred solution of (S)-(+)-2-amino-2-phenylethanol (271 mmol, 37.2 g) in methylene chloride (350 mL) was added 2-bromobenzaldehyde (271 mmol, 31.8 mL, 50.2 g) and anhydrous magnesium sulfate (50 g). The mixture stirred 3 h at room temperature then left to stand overnight. Filtered through dicalite and evaporated to dryness to give a pale yellow solid. This solid was stirred in dry ether (100 mL) for 30 min, then filtered, washed with ether, and dried in vacuo to give (S,E)-2-(2-bromobenzylideneamino)-2-phenylethanol (65.1 g) as a colourless solid.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][C:9]([OH:11])=[O:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:12]O>>[C:1]1([CH2:7][CH2:8][C:9]([O:11][CH3:12])=[O:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CO
Reactant: O=C(O)CCc1ccccc1
Product: COC(=O)CCc1ccccc1
Yield: 96.3 %

Procedure:
A mixture of 3-phenylpropionic acid (118.2 g, 788 mmol) sulfuric acid (5.9 g), and 100 mL of methanol was heated to reflux overnight. TLC analysis indicated the absence of starting material and the reaction was concentrated in vacuo. The residue was dissolved in 200 mL of ethyl ether, washed with sodium bicarbonate (100 mL), dried over magnesium sulfate, filtered and concentrated to give 124.4 g (96.3%) of the ester as a tan oil.
Reaction SMILES: CON(C)[C:4]([C@@H:6]1[CH2:10][CH2:9][N:8]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:7]1)=[O:5].[CH2:19]([Mg]Br)[CH2:20][CH:21]=[CH2:22].O1CCC[CH2:26]1>>[C:4]([C@@H:6]1[CH2:10][CH2:9][N:8]([C:11]([O:13][C:14]([CH3:15])([CH3:16])[CH3:17])=[O:12])[CH2:7]1)(=[O:5])[CH2:22][CH2:21][CH2:20][CH:19]=[CH2:26]
Reactant: CON(C)C(=O)[C@@H]1CCN(C(=O)OC(C)(C)C)C1
Reactant: C=CCC[Mg]Br
Reactant: C1CCOC1
Product: C=CCCCC(=O)[C@@H]1CCN(C(=O)OC(C)(C)C)C1
Temperature: 25 °C
Reaction time: 4 h
Yield: 96 %

Procedure:
In a 500 mL single necked round bottomed flask, a solution of tert-butyl (3R)-3-[methoxy(methyl)carbamoyl]pyrrolidine-1-carboxylate (7.00 g, 27.1 mmol) in tetrahydrofuran (100 mL) was cooled to 0° C. and treated with 0.5 M THF solution of 3-butenylmagnesium bromide (130 mL, 65 mmol) via a pressure equalizing addition funnel over a period of 20 minutes. Once the addition was complete, the cooling bath was removed and the mixture was allowed to warm to room temperature and stir for an additional 4 h. The reaction mixture was carefully quenched with 1 N HCl (300 mL) and stirred for an additional 20 min. The aqueous layer was extracted with ethyl acetate (3×200 mL) and the combined organic layers were dried over Na2SO4, filtered and concentrated to a yellow oil. Purification of the crude product by flash column chromatography (silica gel, 10% ethyl acetate in hexanes) afforded tert-butyl (3R)-3-hex-5-enoylpyrrolidine-1-carboxylate (6.62 g; 96%) as a light yellow oil. 1H NMR (400 MHz, CDCl3) δ 5.73-5.69 (m, 1H), 4.99-4.91 (m, 2H), 3.61-3.42 (m, 2H), 3.13-3.05 (m, 1H), 2.50 (t, J=7.2 Hz, 2H), 2.26 (q, J=7.2 Hz, 2H), 2.11-1.90 (m, 3H), 1.38 (s, 9H); ESI MS found for C14H23NO3 m/z [154.1 (M+1-Boc)].
Reaction SMILES: [F:1][C:2]1[CH:31]=[CH:30][C:5]2[CH2:6][CH2:7][CH2:8][C:9]3[S:13][C:12]([NH:14][C@H:15]4[CH2:20][CH2:19][C@H:18]([CH2:21][NH:22]C(=O)OC(C)(C)C)[CH2:17][CH2:16]4)=[N:11][C:10]=3[C:4]=2[CH:3]=1>CCOC(C)=O.Cl.O1CCOCC1>[NH2:22][CH2:21][C@H:18]1[CH2:19][CH2:20][C@H:15]([NH:14][C:12]2[S:13][C:9]3[CH2:8][CH2:7][CH2:6][C:5]4[CH:30]=[CH:31][C:2]([F:1])=[CH:3][C:4]=4[C:10]=3[N:11]=2)[CH2:16][CH2:17]1
Reactant: CC(C)(C)OC(=O)NC[C@H]1CC[C@H](Nc2nc3c(s2)CCCc2ccc(F)cc2-3)CC1
Agent: Cl
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: NC[C@H]1CC[C@H](Nc2nc3c(s2)CCCc2ccc(F)cc2-3)CC1

Procedure:
A solution of trans-tert-butyl N-({4-[(9-fluoro-5,6-dihydro-4H-benzo[6,7]cyclohepta-[d][1,3]thiazol-2-yl)amino]cyclohexyl}-methyl)-carbamate (34.5 g, 77.0 mmol) in 200 ml EtOAc and 100 ml 4N HCl in dioxane was stirred at room temperature for 2 hours. The resulting solid was collected by filtration and the solid product washed with Et2O and dried under vacuum to yield 25.9 g of the desired product as a pale yellow solid. An additional 1.43 g of the product was obtained by allowing the filtrate to stand in a closed flask for several days. The overall yield was 85%: 1H-NMR (CD3OD) δ 1.25 (2H, m), 1.51 (2H, m), 1.70 (1H, broad), 1.95 (2H, m), 2.18 (4H, m), 2.80 (6H, m), 3.63 (1H, broad), 7.11 (1H, dt, J=2.5 Hz, 8.4 Hz), 7.36 (2H, m); 346 (ESMS, MH+).
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:33])[CH:10]([NH:25][C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[C:11]1[CH:16]=[CH:15][C:14](OS(C(F)(F)F)(=O)=O)=[CH:13][CH:12]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:34]([O:36][P:37]([O-:41])[O:38][CH2:39][CH3:40])[CH3:35].CN1CCOCC1>C(#N)C.C(OCC)(=O)C>[CH2:1]([O:8][C:9](=[O:33])[CH:10]([NH:25][C:26]([O:28][C:29]([CH3:32])([CH3:30])[CH3:31])=[O:27])[C:11]1[CH:12]=[CH:13][C:14]([P:37]([O:38][CH2:39][CH3:40])([O:36][CH2:34][CH3:35])=[O:41])=[CH:15][CH:16]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOP([O-])OCC
Reactant: CC(C)(C)OC(=O)NC(C(=O)OCc1ccccc1)c1ccc(OS(=O)(=O)C(F)(F)F)cc1
Solvent: CC#N
Solvent: CN1CCOCC1
Solvent: CCOC(C)=O
Product: CCOP(=O)(OCC)c1ccc(C(NC(=O)OC(C)(C)C)C(=O)OCc2ccccc2)cc1
Temperature: 75 °C
Yield: 93.1 %

Procedure:
To a solution of tert-butoxycarbonylamino-(4-trifluoromethane-sulfonyloxy-phenyl)-acetic acid benzyl ester (2.2 g, 4.50 mmol) in acetonitrile (10 mL) was added diethylphosphite (643 μL, 5.00 mmol) followed by N-methylmorpholine (691 μL, 6.30 mmol). The mixture was purged with nitrogen and tetrakis-triphenylphosphine palladium (260 mg, 0.23 mmol, 15 mol %) was added. The reaction mixture was heated to 75° C. overnight then cooled to room temperature and diluted with ethyl acetate (50 mL). The mixture was poured into a separatory funnel containing ethyl acetate (100 mL) and washed with 0.2M aqueous hydrochloric acid (2×), water (2×), brine and dried over sodium sulfate. The solvent was removed in vacuo, and the product was chromatographed over silica gel gradient eluted between 10 to 75% ethyl acetate in hexanes to afforded tert-butoxycarbonylamino-[4-(diethoxy-phosphoryl)-phenyl]-acetic acid benzyl ester (2.0 g, 93%).
Reaction SMILES: Br[C:2]1[C:6]2[CH:7]([O:13][CH3:14])[NH:8][CH:9]=[C:10]([C:11]#[N:12])[C:5]=2[N:4]([CH:15]2[CH2:19][CH2:18][CH2:17][CH2:16]2)[CH:3]=1.CC1(C)C(C)(C)OB([C:28]2[CH:29]=[C:30]([CH2:33][C:34]#[N:35])[S:31][CH:32]=2)O1.C(=O)([O-])[O-].[Na+].[Na+].COCCOC>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.O>[C:34]([CH2:33][C:30]1[S:31][CH:32]=[C:28]([C:2]2[C:6]3[C:7]([O:13][CH3:14])=[N:8][CH:9]=[C:10]([C:11]#[N:12])[C:5]=3[N:4]([CH:15]3[CH2:19][CH2:18][CH2:17][CH2:16]3)[CH:3]=2)[CH:29]=1)#[N:35]
Reactant: COC1NC=C(C#N)c2c1c(Br)cn2C1CCCC1
Reactant: CC1(C)OB(c2csc(CC#N)c2)OC1(C)C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: COc1ncc(C#N)c2c1c(-c1csc(CC#N)c1)cn2C1CCCC1
Temperature: 80 °C
Reaction time: 8 h
Yield: 78.2 %

Procedure:
A mixture of 3-bromo-1-cyclopentyl-4-methoxy-4,5-dihydro-1H-pyrrolo[3,2-c]pyridine-7-carbonitrile (250 mg) obtained in Step H of Example 33, (4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-thienyl)acetonitrile (292 mg), tetrakis(triphenylphosphine)palladium(0) (90 mg), 2M aqueous sodium carbonate solution (0.781 mL) and DME (3.0 mL) was stirred overnight at 80° C. To the reaction mixture was added water, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (220 mg).
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8]([NH:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]3[NH:18][CH:19]=[CH:20][N:21]=3)=[CH:13][CH:12]=2)=[O:9])=[CH:6][CH:5]=[CH:4][N:3]=1.[NH2:22][CH2:23][C:24]1[CH:29]=[CH:28][N:27]=[CH:26][CH:25]=1>>[ClH:1].[NH:21]1[CH:20]=[CH:19][N:18]=[C:17]1[C:14]1[CH:15]=[CH:16][C:11]([NH:10][C:8]([C:7]2[C:2]([NH:22][CH2:23][C:24]3[CH:29]=[CH:28][N:27]=[CH:26][CH:25]=3)=[N:3][CH:4]=[CH:5][CH:6]=2)=[O:9])=[CH:12][CH:13]=1
Reactant: O=C(Nc1ccc(-c2ncc[nH]2)cc1)c1cccnc1Cl
Reactant: NCc1ccncc1
Product: Cl
Product: O=C(Nc1ccc(-c2ncc[nH]2)cc1)c1cccnc1NCc1ccncc1
Temperature: 120 °C

Procedure:
(2-Chloro-(3-pyridyl))-N-(4-imidazolylphenyl)-carboxamide was treated with 4-aminomethylpyridine (0.100 g, 0.93 mmol) and heated neat at 120° C. for 18 h. After cooling to RT, the material was purified by preparative HPLC. The final product was converted into an HCl salt by dissolution in a minimum of MeOH, treatment with an HCl ethereal solution, and evaporation of solvent. MS: (ES+) 371 (M+1)+; (ES−): 369 (M−1)−. Calc'd. for C21H18N6O—370.15.
Reaction SMILES: Cl[C:2]1[C:11]([C:12]([F:15])([F:14])[F:13])=[N:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([O:16]C)[CH:8]=2)[N:3]=1.B([C:21]1[CH:29]=[CH:28][C:24]([C:25]([OH:27])=[O:26])=[CH:23][CH:22]=1)(O)O>>[OH:16][C:7]1[CH:8]=[C:9]2[C:4](=[CH:5][CH:6]=1)[N:3]=[C:2]([C:21]1[CH:29]=[CH:28][C:24]([C:25]([OH:27])=[O:26])=[CH:23][CH:22]=1)[C:11]([C:12]([F:13])([F:14])[F:15])=[N:10]2
Reactant: O=C(O)c1ccc(B(O)O)cc1
Reactant: COc1ccc2nc(Cl)c(C(F)(F)F)nc2c1
Product: O=C(O)c1ccc(-c2nc3ccc(O)cc3nc2C(F)(F)F)cc1

Procedure:
Followed the procedure described for Compound VI-1, starting from Intermediate 11 and 4-boronobenzoic acid. 1H NMR (MeOH-d4 500 MHz): δ 8.07 (d, J=8.5 Hz, 2H), 7.96 (d, J=9.0 Hz, 1H), 7.61 (d, J=8.5 Hz, 2H), 7.51 (dd, J=2.5, 9.5 Hz; 1H), 7.35 (d, J=2.5 Hz, 1H); MS (ESI): m/z 335 [M+1]+.
Reaction SMILES: [C:1]1([C:7]2[O:11][N:10]=[C:9]([C:12]([NH:14][CH2:15][C:16]([OH:18])=O)=[O:13])[CH:8]=2)[CH:6]=[CH:5][CH:4]=[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.[Br:51][C:52]1[CH:57]=[CH:56][CH:55]=[CH:54][C:53]=1[N:58]([CH3:65])[CH:59]1[CH2:64][CH2:63][NH:62][CH2:61][CH2:60]1>CN(C=O)C.O>[Br:51][C:52]1[CH:57]=[CH:56][CH:55]=[CH:54][C:53]=1[N:58]([CH3:65])[CH:59]1[CH2:64][CH2:63][N:62]([C:16](=[O:18])[CH2:15][NH:14][C:12]([C:9]2[CH:8]=[C:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[O:11][N:10]=2)=[O:13])[CH2:61][CH2:60]1
Reactant: O=C(O)CNC(=O)c1cc(-c2ccccc2)on1
Reactant: CN(c1ccccc1Br)C1CCNCC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: CN(C)C=O
Product: CN(c1ccccc1Br)C1CCN(C(=O)CNC(=O)c2cc(-c3ccccc3)on2)CC1
Reaction time: 8 h
Yield: 31.4 %

Procedure:
To a stirred solution of [(5-phenyl-isoxazole-3-carbonyl)-amino]-acetic acid (62.9 mg, 0.00025 mol) in DMF (2 mL) was added DIPEA (0.159 g, 0.00123 mol), HOBt (41.4 mg, 0.00031 mol) and EDCI.HCl (58.8 mg, 0.0003° mol) at ambient temperature. After 2 minutes (2-bromo-phenyl)-methyl-piperidin-4-yl-amine hydrochloride (0.068 g, 0.00025 mol) was added and the resulting mixture was stirred overnight. The reaction mixture was then diluted with cold water and the resulting precipitate was isolated by filtration. Purification by column chromatography using basic aluminium oxide (50-100% ethyl acetate in hexane) afforded 0.039 g (35%) of 5-phenyl-isoxazole-3-carboxylic acid (2-{4-[(2-bromo-phenyl)-methyl-amino]-piperidin-1-yl}-2-oxo-ethyl)-amide. LCMS: 497.11 (M+1)+, 97.87%, 1H NMR (DMSO-d6): δ 8.58 (t, 1H), 7.93 (m, 2H), 7.52 (m, 4H), 7.4 (s, 1H), 7.15 (m, 2H), 6.9 (m, 1H), 4.3 (d, 1H), 4.15 (t, 2H), 3.8 (d, 1H), 3.0 (m, 1H), 2.65 (m, 1H), 2.55 (s, 3H), 1.75 (m, 3H), 1.5 (m, 2H).
Reaction SMILES: [Cl-].O[NH3+:3].[C:4](=[O:7])([O-])[OH:5].[Na+].CS(C)=O.[CH2:13]([C:15]1[S:53][C:18]2[N:19]([CH2:36][C:37]3[C:42]([F:43])=[CH:41][C:40]([C:44]4[C:45]([C:50]#[N:51])=[CH:46][CH:47]=[CH:48][CH:49]=4)=[CH:39][C:38]=3[F:52])[C:20](=[O:35])[N:21]([CH2:24][C:25]([C:27]3[CH:32]=[CH:31][C:30]([O:33][CH3:34])=[CH:29][CH:28]=3)=[O:26])[C:22](=[O:23])[C:17]=2[CH:16]=1)[CH3:14]>C(Cl)(Cl)Cl>[F:52][C:38]1[CH:39]=[C:40]([C:44]2[CH:49]=[CH:48][CH:47]=[CH:46][C:45]=2[C:50]2[NH:3][C:4](=[O:7])[O:5][N:51]=2)[CH:41]=[C:42]([F:43])[C:37]=1[CH2:36][N:19]1[C:18]2[S:53][C:15]([CH2:13][CH3:14])=[CH:16][C:17]=2[C:22](=[O:23])[N:21]([CH2:24][C:25]([C:27]2[CH:28]=[CH:29][C:30]([O:33][CH3:34])=[CH:31][CH:32]=2)=[O:26])[C:20]1=[O:35]
Reactant: [NH3+]O
Reactant: O=C([O-])O
Reactant: CCc1cc2c(=O)n(CC(=O)c3ccc(OC)cc3)c(=O)n(Cc3c(F)cc(-c4ccccc4C#N)cc3F)c2s1
Agent: [Cl-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: ClC(Cl)Cl
Product: CCc1cc2c(=O)n(CC(=O)c3ccc(OC)cc3)c(=O)n(Cc3c(F)cc(-c4ccccc4-c4noc(=O)[nH]4)cc3F)c2s1
Temperature: 40 °C
Reaction time: 0.5 h
Yield: 53.6 %

Procedure:
A mixture of hydroxylammonium chloride (1.2 g), sodium hydrogencarbonate (1.7 g) and dimethyl sulfoxide (40 mL) was stirred at 40° C. for 30 min, 4′-{[6-ethyl-3-[2-(4-methoxyphenyl)-2-oxoethyl]-2,4-dioxo-3,4-dihydrothieno[2,3-d]pyrimidin-1(2H)-yl]methyl}-3′,5′-difluorobiphenyl-2-carbonitrile (1.2 g) was added, and the mixture was stirred at 90° C. for 16 hr. The reaction mixture was diluted with chloroform, washed successively with water and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography and dissolved in methylene chloride (20 mL). N,N′-Carbonyldiimidazole (0.5 g) and then 1,8-diazabicyclo[5.4.0]undec-7-ene (0.47 mL) were added, and the mixture was stirred at room temperature for 2 hr. The reaction mixture was diluted with chloroform, washed successively with saturated aqueous potassium hydrogensulfate solution and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The obtained residue was purified by preparative HPLC to give the title compound as colorless crystals (0.71 g, 55%).
Reaction SMILES: [N+:1]([C:4]1[CH:13]=[CH:12][CH:11]=[C:10]2[C:5]=1[CH:6]=[CH:7][C:8](Cl)=[N:9]2)([O-])=O.[F:15][C:16]1[CH:17]=[C:18]([S:24](Cl)(=[O:26])=[O:25])[CH:19]=[C:20]([F:23])[C:21]=1[F:22].[CH3:28][O:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=1[CH2:36][CH2:37][NH2:38]>>[F:15][C:16]1[CH:17]=[C:18]([S:24]([NH:1][C:4]2[CH:13]=[CH:12][CH:11]=[C:10]3[C:5]=2[CH:6]=[CH:7][C:8]([NH:38][CH2:37][CH2:36][C:31]2[CH:32]=[CH:33][CH:34]=[CH:35][C:30]=2[O:29][CH3:28])=[N:9]3)(=[O:26])=[O:25])[CH:19]=[C:20]([F:23])[C:21]=1[F:22]
Reactant: O=S(=O)(Cl)c1cc(F)c(F)c(F)c1
Reactant: COc1ccccc1CCN
Reactant: O=[N+]([O-])c1cccc2nc(Cl)ccc12
Product: COc1ccccc1CCNc1ccc2c(NS(=O)(=O)c3cc(F)c(F)c(F)c3)cccc2n1

Procedure:
The title compound, MS: m/e=488.5 (M+H+), was prepared in accordance with the general method of example 61 from 5-nitro-2-chloroquinoline, 3,4,5-trifluorobenzenesulfonylchloride and 2-(2-methoxyphenyl)ethylamine.