Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([OH:11])[CH:9]=2)[CH2:4][CH2:3][NH:2]1.CO[C:14]1[CH:19]=[CH:18][CH:17]=[C:16](OC)[CH:15]=1.FC(F)(F)C(O)=O>C(O)(=O)C>[C:14]1([C:9]2[C:8]([OH:11])=[CH:7][CH:6]=[C:5]3[C:10]=2[CH2:1][NH:2][CH2:3][CH2:4]3)[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: COc1cccc(OC)c1
Reactant: Oc1ccc2c(c1)CNCC2
Solvent: O=C(O)C(F)(F)F
Solvent: CC(=O)O
Product: Oc1ccc2c(c1-c1ccccc1)CNCC2

Procedure:
Scheme 1 (FIG. 1): Protection of the hydroxyl group in vanillin with benzyl bromide yielded aldehyde 1 is shown in Scheme 1. Henry reaction between aldehyde 1 and nitromethane gave nitrostyrene 2. Reduction of compound 2 with lithium aluminum hydride in tetrahydrofuran (THF) afforded amine 3. The reaction of amine 3 with an excess amount of methyl formate provided formamide 4. Cyclization of amide 4 using phosphorus oxychloride (POCl3) via Bischler-Napieralski reaction obtained 3,4-dihydroisoquinoline 5. Alkylation of compound 5 with iodopropane followed by NaBH4 reduction produced tetrahydroisoquinoline 6 in high yield. Catalytic hydrogenation over Pd/C removed the protective groups of 6 to afford 1,2,3,4-tetrahydroisoquinolin-7-ol 7 in quantitative yield. Treatment of compound 7 with Pb(OAc)4 in acetic acid followed by acid-catalyzed aromatic substitution with 1,3-dimethoxybenzene using trifluoroacetic acid (TFA) furnished 8-phenyl-tetrahydroisoquinolin-7-ol 8.
Reaction SMILES: [I:1]I.[B-](F)(F)(F)F.[B-](F)(F)(F)F.C1[N+]2(CCl)CC[N+](F)(CC2)C1.[F:24][C:25]([F:45])([F:44])[C:26]1[CH:27]=[C:28]2[C:33](=[CH:34][CH:35]=1)[N:32]1[CH:36]=[CH:37][N:38]=[C:31]1[C:30]([NH:39][CH2:40][CH2:41][CH2:42][OH:43])=[N:29]2>C(#N)C>[I:1][C:36]1[N:32]2[C:33]3[C:28]([N:29]=[C:30]([NH:39][CH2:40][CH2:41][CH2:42][OH:43])[C:31]2=[N:38][CH:37]=1)=[CH:27][C:26]([C:25]([F:44])([F:24])[F:45])=[CH:35][CH:34]=3
Reactant: OCCCNc1nc2cc(C(F)(F)F)ccc2n2ccnc12
Reactant: II
Agent: F[B-](F)(F)F
Agent: F[N+]12CC[N+](CCl)(CC1)CC2
Solvent: CC#N
Product: OCCCNc1nc2cc(C(F)(F)F)ccc2n2c(I)cnc12
Yield: 62 %

Procedure:
To a 10-min stirred mixture of iodine (245 mg, 0.966 mmol, 0.6 eq) with Selectfluor™ (399 mg, 1.13 mmol, 0.7 eq) in acetonitrile (10 mL) under argon is added the 3-{[7-(trifluoromethyl)imidazo[1,2-a]quinoxalin-4-yl]amino}propan-1-ol (500 mg, 1.61 mmol, 1 eq). The dark red mixture is stirred at rt for 24 h. The precipitate is filtered out, washed with acetonitrile and dissolved in 150 mL of EtOAc. This organic phase is washed with a saturated solution of ammonium chloride, a saturated solution of sodium hydrogenocarbonate, a saturated solution of sodium hydrogen sulfite, then dried over magnesium sulfate and concentrated. A first batch of desired product is obtained as a white solid (135 mg, 0.31 mmol). To the remaining red liquor is added 0.7 additional equivalent of Selectfluor™ and 0.6 additional equivalent of iodine and the mixture is stirred under argon at rt for 16 h. Similar work-up allows the collection of a second batch (298 mg, 0.68 mmol, overall yield 62%).
Reaction SMILES: [C:1]1([C:7]2[N:8]=[C:9]([SH:18])[NH:10][C:11]=2[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl[CH2:20][CH2:21][O:22][CH2:23][CH2:24]Cl.C(=O)([O-])[O-].[K+].[K+].O>[I-].C([N+](CCCC)(CCCC)CCCC)CCC.O1CCCC1>[C:1]1([C:7]2[N:8]=[C:9]([S:18][CH2:20][CH2:21][O:22][CH2:23][CH2:24][S:18][C:9]3[NH:10][C:11]([C:12]4[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=4)=[C:7]([C:1]4[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=4)[N:8]=3)[NH:10][C:11]=2[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: ClCCOCCCl
Reactant: Sc1nc(-c2ccccc2)c(-c2ccccc2)[nH]1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=C([O-])[O-]
Agent: [I-]
Solvent: C1CCOC1
Solvent: O
Product: c1ccc(-c2nc(SCCOCCSc3nc(-c4ccccc4)c(-c4ccccc4)[nH]3)[nH]c2-c2ccccc2)cc1

Procedure:
A solution of 4,5-diphenyl-2-mercapto-1H-imidazole (2.63 g, 10.44 mmol), chloroethyl ether (0.6 mL, 5.22 mmol), potassium carbonate (1.59 g, 11.5 mmol) and tetra-n-butylammonium iodide (0.39 g, 1.04 mmol) in tetrahydrofuran (20 mL) was heated to reflux for 14 hours. The solution was cooled, then poured into water (100 mL). This was extracted with methylene chloride (2×100 mL), and the extracts were combined, dried over anhydrous magnesium sulfate, filtered and evaporated. The residue was separated by flash chromatography (3:7 ethyl acetate-hexane, then 1:1 ethyl acetate-hexane) to afford the title product, which was further purified by recrystallization from acetonitrile, mp 232°-234° C. (1.00 g, 1.74 mmol, 33%). 1H NMR (CDCl3): 11.70 (2H, br s); 7.60-7.16 (20H, m); 3.80 (4H, t, J=5.7 Hz); 3.21 (4H, t, J=5.7 Hz). Elemental analysis: calc. C 71.05, H 5.26, N 9.75; obs. C 70.84, H 5.17, N 9.68.
Reaction SMILES: [F:1][C:2]([F:48])([F:47])[C:3]1[CH:4]=[C:5]([CH:44]=[CH:45][CH:46]=1)[CH2:6][NH:7][C:8]([C:10]1[CH:15]=[CH:14][N:13]=[C:12]([C:16]2[CH:21]=[C:20]([O:22][CH2:23]C(F)(F)F)[CH:19]=[CH:18][C:17]=2[NH:28][C:29]([C:31]2[CH:32]=[C:33]([CH:41]=[CH:42][CH:43]=2)[CH2:34][S:35][CH2:36][CH2:37][C:38]([OH:40])=[O:39])=[O:30])[CH:11]=1)=[O:9]>C(O)C(C)C>[CH3:23][O:22][C:20]1[CH:19]=[CH:18][C:17]([NH:28][C:29]([C:31]2[CH:32]=[C:33]([CH:41]=[CH:42][CH:43]=2)[CH2:34][S:35][CH2:36][CH2:37][C:38]([OH:40])=[O:39])=[O:30])=[C:16]([C:12]2[CH:11]=[C:10]([C:8](=[O:9])[NH:7][CH2:6][C:5]3[CH:44]=[CH:45][CH:46]=[C:3]([C:2]([F:48])([F:47])[F:1])[CH:4]=3)[CH:15]=[CH:14][N:13]=2)[CH:21]=1
Reactant: O=C(O)CCSCc1cccc(C(=O)Nc2ccc(OCC(F)(F)F)cc2-c2cc(C(=O)NCc3cccc(C(F)(F)F)c3)ccn2)c1
Solvent: CC(C)CO
Product: COc1ccc(NC(=O)c2cccc(CSCCC(=O)O)c2)c(-c2cc(C(=O)NCc3cccc(C(F)(F)F)c3)ccn2)c1

Procedure:
This compound was prepared according to the procedure described for the synthesis of 3-(3-((2-(4-((3-(trifluoromethyl)benzyl)carbamoyl)pyridin-2-yl)-4-(2,2,2-trifluoroethoxy)-phenyl)carbamoyl)benzylthio)propanoic acid 32, using isobutanol in place of trifluoroethanol. 1H-NMR (300 MHz, DMSO-d6, ppm): δ 12.44 (s, 1H), 9.56 (m, 1H), 8.97 (m, 1H), 8.36 (m, 2H), 7.87-7.52 (m, 10H), 7.16 (m, 1H), 4.63 (d, 2H), 3.87 (m, 4H), 2.59 (m, 2H), 2.06 (m, 2H), 1.03 (m, 6H). MS (ES, m/z): 666 [M+H]+.
Reaction SMILES: C1([C@H]([NH:9][C@@H:10]2[CH2:15][CH2:14][N:13]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:12][C@@H:11]2[C:23]([O:25][CH2:26][CH3:27])=[O:24])C)C=CC=CC=1.C([O-])=O.[NH4+]>CCO.[Pd]>[NH2:9][C@@H:10]1[CH2:15][CH2:14][N:13]([C:16]([O:18][C:19]([CH3:20])([CH3:21])[CH3:22])=[O:17])[CH2:12][C@@H:11]1[C:23]([O:25][CH2:26][CH3:27])=[O:24]
Reactant: CCOC(=O)[C@H]1CN(C(=O)OC(C)(C)C)CC[C@H]1N[C@H](C)c1ccccc1
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CCO
Product: CCOC(=O)[C@H]1CN(C(=O)OC(C)(C)C)CC[C@H]1N
Yield: 95.8 %

Procedure:
A solution of 252C (2.6 g, 6.9 mmol) in EtOH (100 mL) was treated with ammonium formate (3.5 g, 55.3 mmol) and 10% Pd/C (390 mg). The reaction mixture was heated to reflux under a nitrogen atmosphere for three hours. The resulting suspension was filtered through a pad of celite and concentrated in vacuo to afford 1.8 g (yield: 96%) Compound 259A as a solid.
Reaction SMILES: [C:1]([CH2:3][C:4]([O:6][CH3:7])=[O:5])#[N:2].C(N(C(C)C)CC)(C)C.[CH2:17](Br)[C:18]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=[O:19]>O1CCCC1>[C:1]([CH:3]([CH2:17][C:18]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=[O:19])[C:4]([O:6][CH3:7])=[O:5])#[N:2]
Reactant: COC(=O)CC#N
Reactant: O=C(CBr)c1ccccc1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: COC(=O)C(C#N)CC(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 12 h
Yield: 94.6 %

Procedure:
To a suspension of methyl 2-chloro-5-phenyl-1H-pyrrole-3-carboxylate (4.66 g) synthesized from methyl cyanoacetate and phenacyl bromide in the same manner as in Reference Example 95 and Reference Example 97 in acetonitrile (200 mL) was added 2,6-dichloro-N-fluoropyridinium triflate (6.26 g) over 10 min under ice-cooling. The reaction mixture was stirred at the same temperature for 2 hr and at room temperature for 2 hr, and concentrated under reduced pressure. A saturated aqueous sodium hydrogencarbonate solution was added to the residue, and the mixture was extracted with ethyl acetate. The extract was dried over magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane-ethyl acetate=19:1→7:3) to give the title compound as a pale-yellow solid (yield 815 mg, 16%). More specifically, to a solution of methyl cyanoacetate (41 g) and diisopropylethylamine (117 g) in tetrahydrofuran (2600 mL) was added dropwise a solution of phenacyl bromide (75 g) in tetrahydrofuran (370 mL). The mixture was stirred at room temperature for 12 hr. The reaction mixture was filtered, and the obtained filtrate was concentrated under reduced pressure. The residue was dissolved in ethyl acetate, washed successively with 1 mol/L hydrochloric acid, water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was washed with diethyl ether to give methyl 2-cyano-4-phenyl-4-oxobutanoate as a brown oil (yield 77.4 g, 95%). To a solution (125 mL) of ethyl 2-cyano-4-(2,6-difluorophenyl)-4-oxobutanoate (25 g) in ethyl acetate was added dropwise 4 mol/L hydrogen chloride-ethyl acetate solution (25 mL). The mixture was stirred at room temperature for 18 hr, and concentrated under reduced pressure. Water was added to the residue, and the mixture was extracted with ethyl acetate. The organic layer was washed with 6% aqueous sodium hydrogencarbonate solution and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was washed with diisopropyl ether to give methyl 2-chloro-5-phenyl-1H-pyrrole-3-carboxylate as colorless crystals (yield 10.0 g, 37%). The title compound was synthesized from the thus-obtained methyl 2-chloro-5-phenyl-1H-pyrrole-3-carboxylate.
Reaction SMILES: [C:1]([N:9]1[CH2:13][CH2:12][CH2:11][C@H:10]1[CH2:14][OH:15])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.O>C(Cl)Cl>[C:1]([N:9]1[CH2:13][CH2:12][CH2:11][C@H:10]1[CH:14]=[O:15])(=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(c1ccccc1)N1CCC[C@H]1CO
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: O
Product: O=C[C@@H]1CCCN1C(=O)c1ccccc1
Reaction time: 0.5 h

Procedure:
A solution of (2S)-1-benzoylpyrrolidine-2-methanol (24.1 g) in methylene chloride (120 ml) was added dropiwise to the solution at -70° C. The mixture was stirred for 30 mins. Triethylamine (89.5 ml) was added dropwise to the reaction solution at -70° C. The mixture was stirred for 50 mins at the same temperature, and then rised to 0° C. gradually. Water was added to the solution.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:17]3[N:18]=[C:19]4[C:25]([C:26]([NH:28][CH:29]([CH3:31])[CH3:30])=[O:27])=[CH:24][N:23]([CH2:32][O:33]CC[Si](C)(C)C)[C:20]4=[N:21][CH:22]=3)=[N:7][N:8]2[CH2:11][C:12]2[CH:16]=[CH:15][O:14][N:13]=2)=[CH:4][CH:3]=1.FC(F)(F)C(O)=O>ClCCl>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:17]3[N:18]=[C:19]4[C:25]([C:26]([NH:28][CH:29]([CH3:30])[CH3:31])=[O:27])=[CH:24][N:23]([CH2:32][OH:33])[C:20]4=[N:21][CH:22]=3)=[N:7][N:8]2[CH2:11][C:12]2[CH:16]=[CH:15][O:14][N:13]=2)=[CH:4][CH:3]=1
Reactant: CC(C)NC(=O)c1cn(COCC[Si](C)(C)C)c2ncc(-c3nn(Cc4ccon4)c4cc(Cl)ccc34)nc12
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(C)NC(=O)c1cn(CO)c2ncc(-c3nn(Cc4ccon4)c4cc(Cl)ccc34)nc12
Reaction time: 120 h

Procedure:
2-(6-Chloro-1-(isoxazol-3-ylmethyl)-1H-indazol-3-yl)-N-isopropyl-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxamide was dissolved in dichloromethane and to this was added trifluoroacetic acid (1.79 g, 1.21 mL, 15.7 mmol). The mixture was stirred for 120 h. A precipitate had formed which was filtered off. The filtrates were concentrated in vacuo and combined with the solid to give intermediate 2-(6-chloro-1-(isoxazol-3-ylmethyl)-1H-indazol-3-yl)-5-(hydroxymethyl)-N-isopropyl-5H-pyrrolo[2,3-b]pyrazine-7-carboxamide (73 mg, 157 μmol). This was dissolved in 60:20:1 dichloromethane:methanol:ammonium hydroxide (10 mL), and the mixture was stirred for 2 h. The mixture was concentrated in vacuo, diluted with dichloromethane and reconcentrated to give 2-(6-chloro-1-(isoxazol-3-ylmethyl)-1H-indazol-3-yl)-N-isopropyl-5H-pyrrolo[2,3-b]pyrazine-7-carboxamide (67 mg, 154 μmol, 98.1%) as a white solid. MS (M+Na)+=458; 1H NMR (CDCl3) δ: 11.97 (br. s., 1H), 9.08 (s, 1H), 8.36 (d, J=8.3 Hz, 1H), 8.29 (d, J=1.5 Hz, 1H), 8.16 (d, J=3.0 Hz, 1H), 7.98-8.07 (m, 1H), 7.46 (s, 1H), 7.12 (dd, J=8.5, 1.3 Hz, 1H), 6.21 (d, J=1.5 Hz, 1H), 5.64 (s, 2H), 4.23-4.39 (m, 1H), 1.20-1.32 (m, 6H).
Reaction SMILES: [N+:1]([C:4]1[CH:13]=[CH:12][CH:11]=[C:10]2[C:5]=1[CH:6]=[C:7]([C:14]([O:16][CH3:17])=[O:15])[N:8]=[CH:9]2)([O-])=O.CO.C(Cl)Cl>C(O)(=O)C.O.[Fe]>[NH2:1][C:4]1[CH:13]=[CH:12][CH:11]=[C:10]2[C:5]=1[CH:6]=[C:7]([C:14]([O:16][CH3:17])=[O:15])[N:8]=[CH:9]2
Reactant: COC(=O)c1cc2c([N+](=O)[O-])cccc2cn1
Agent: [Fe]
Solvent: O
Solvent: CO
Solvent: CC(=O)O
Product: COC(=O)c1cc2c(N)cccc2cn1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
The product of Example 71A (10.33 g, 44.5 mmol) in acetic acid/water (3/1) (320 mL) was treated with iron powder (5.06 g, 90.7 mmol). After stirring for 16 hours at room temperature, the reaction mixture was filtered the filtrate concentrated under reduced pressure to approximately half the original volume. The mixture was then extracted with dichloromethane (3×200 mL). The organic fractions were combined, dried (MgSO4), and the filtrate concentrated under reduced pressure to afford crude material. A precipitate formed in the aqueous phase after sitting for several hours. This was filtered to afford additional crude material. The crude material was purfidied by column chromatography (2% methanol/CH2Cl2) to provide the title compound. MS (ESI+) m/z 203 (M+H)+; MS (ESI−) m/z 201 (M−H)−; 1H NMR (DMSO-d6, 300 MHz) δ 3.92 (s, 3H), 6.34 (s, 2H), 6.96 (dd, J 1.0, 7.8, 1H), 7.31 (d, J 8.1, 1H), 7.51 (t, J 7.9, 1H), 8.82 (s, 1H), 9.15 (s, 1H); Anal. Calcd for C11H10N2O2: C, 65.34; H, 4.99; N, 13.85. Found: C, 65.03; H, 4.95; N, 13.65.
Reaction SMILES: [CH3:1][C:2]1[NH:6][N:5]=[C:4]([C:7]([NH2:9])=[O:8])[N:3]=1.[Br:10][C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([CH2:17]Br)[CH:12]=1.C([O-])([O-])=O.[K+].[K+]>C1COCC1>[Br:10][C:11]1[CH:12]=[C:13]([CH:14]=[CH:15][CH:16]=1)[CH2:17][N:6]1[C:2]([CH3:1])=[N:3][C:4]([C:7]([NH2:9])=[O:8])=[N:5]1
Reactant: Cc1nc(C(N)=O)n[nH]1
Reactant: BrCc1cccc(Br)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: Cc1nc(C(N)=O)nn1Cc1cccc(Br)c1
Temperature: 50 °C
Reaction time: 18 h
Yield: 25.7 %

Procedure:
To a solution of 5-methyl-1H-1,2,4-triazole-3-carboxamide (2.5 g, 19.8 mmol) and 1-bromo-3-(bromomethyl)benzene (5.45 g, 21.8 mmol) in THF (99 mL), K2CO3 (5.5 g, 39.6 mmol) was added. The mixture was stirred at 50° C. for 18 h, and then the reaction was filtered under vacuum. The solvent was removed under reduced pressure and the crude product was purified on a Biotage pre-packed silica gel column with a gradient of 0% to 20% MeOH:DCM to afford 1-(3-bromobenzyl)-5-methyl-1H-1,2,4-triazole-3-carboxamide (1.5 g, 26%) as a viscous oil. MS (ES+) C11H11BrN4O requires: 294, 296. found: 295, 297 [MH]+(1:1).
Reaction SMILES: C(OCCOC1C=CC([C:15]2[CH:16]=[CH:17][C:18]3[N:24](CCCOCC)[CH2:23][CH2:22][C:21]([C:31](O)=[O:32])=[CH:20][C:19]=3[CH:34]=2)=CC=1)CCC.S(Cl)(Cl)=O.C[N:40](C=O)C>C1COCC1>[NH:24]1[C:18]2[CH:17]=[CH:16][CH:15]=[CH:34][C:19]=2[CH:20]=[C:21]([C:31]([NH2:40])=[O:32])[CH2:22][CH2:23]1
Reactant: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)O)CCN3CCCOCC)cc1
Reactant: CN(C)C=O
Solvent: O=S(Cl)Cl
Solvent: C1CCOC1
Product: NC(=O)C1=Cc2ccccc2NCC1
Reaction time: 1.5 h

Procedure:
To a solution of 7-[4-(2-butoxyethoxy)phenyl]-1-(3-ethoxypropyl)-2,3-dihydro-1H-1-benzazepine-4-carboxylic acid (250 mg) in THF (10 ml) were added thionyl chloride (0.078 ml) and DMF (one droplet) at room temperature, and the mixture was stirred for 1.5 hours. The solvent was evaporated under reduced pressure, and the resulting residue was dissolved in THF (20 ml), which was added dropwise to a solution of 4-[[N-methyl-N-(tetrahydropyran-4-yl)amino]methyl]aniline (128 mg) and triethylamine (0.44 ml) in THF (3 ml) at 0° C. The mixture was stirred at room temperature for 64 hours, water was added thereto, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried with magnesium sulfate. After concentration under reduced pressure, the residue was purified with column chromatography (ethanol:ethyl acetate=1:4), and the resulting crystals were purified by recrystallization (hexane-ethyl acetate) to give 7-[4-(2-butoxyethoxy)phenyl]-1-(3-ethoxypropyl)-N-[4-[N-methyl-N-tetrahydropyran-4-yl)amino]methyl]phenyl]-2,3-dihydro-1H-1-benzazepine-4-carboxamide (Compound 106) (224 mg) as yellow crystals.
Reaction SMILES: [O:1]=[C:2]1[NH:6][C:5](=[O:7])[C:4](=[CH:8][C:9]2[CH:10]=[C:11]3[C:16](=[CH:17][CH:18]=2)[N:15]=[CH:14][N:13]=[C:12]3[N:19]2[CH2:30][CH2:29][CH2:28][C@H:20]2[C:21]([O:23]C(C)(C)C)=[O:22])[S:3]1.C(O)(C(F)(F)F)=O.C(Cl)Cl>>[O:1]=[C:2]1[NH:6][C:5](=[O:7])[C:4](=[CH:8][C:9]2[CH:10]=[C:11]3[C:16](=[CH:17][CH:18]=2)[N:15]=[CH:14][N:13]=[C:12]3[N:19]2[CH2:30][CH2:29][CH2:28][CH:20]2[C:21]([OH:23])=[O:22])[S:3]1
Reactant: CC(C)(C)OC(=O)[C@@H]1CCCN1c1ncnc2ccc(C=C3SC(=O)NC3=O)cc12
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C1NC(=O)C(=Cc2ccc3ncnc(N4CCCC4C(=O)O)c3c2)S1
Yield: 80.6 %

Procedure:
10 mg of tert-butyl 1-{6-[(2,4-dioxo-1,3-thiazolidin-5-ylidene)methyl]quinazolin-4-yl}-L-prolinate (example 27) was stirred in a 25% (TFA/DCM) solution for 12 h at rt. The solvents were evaporated under vacuo and expected compound was precipitated with diethyl ether to give pure 1-[6-(2,4-Dioxo-thiazolidin-5-ylidenemethyl)-quinazolin-4-yl]-pyrrolidine-2-carboxylic acid (7 mg, 81%).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[C:9]([C:11]1[CH:16]=[CH:15][N:14]=[CH:13][CH:12]=1)=[O:10].[CH3:17][C:18]([C:25]1[CH:30]=[CH:29][C:28]([S:31](Cl)(=[O:33])=[O:32])=[CH:27][CH:26]=1)([C:20]1[N:21]=[CH:22][O:23][CH:24]=1)[CH3:19]>N1C=CC=CC=1>[Cl:8][C:5]1[CH:6]=[CH:7][C:2]([NH:1][S:31]([C:28]2[CH:27]=[CH:26][C:25]([C:18]([CH3:19])([C:20]3[N:21]=[CH:22][O:23][CH:24]=3)[CH3:17])=[CH:30][CH:29]=2)(=[O:32])=[O:33])=[C:3]([C:9]([C:11]2[CH:16]=[CH:15][N:14]=[CH:13][CH:12]=2)=[O:10])[CH:4]=1
Reactant: Nc1ccc(Cl)cc1C(=O)c1ccncc1
Reactant: CC(C)(c1ccc(S(=O)(=O)Cl)cc1)c1cocn1
Solvent: c1ccncc1
Product: CC(C)(c1ccc(S(=O)(=O)Nc2ccc(Cl)cc2C(=O)c2ccncc2)cc1)c1cocn1

Procedure:
Following the general procedure for synthesis of N-arylbenzenesulfonamides, 73 mg (0.32 mmol) of (2-Amino-5-chloro-phenyl)-pyridin-4-yl-methanone and 36 mg (0.1 3 mmol) of 4-(1-Methyl-1-oxazol-4-yl-ethyl)-benzenesulfonyl chloride were combined in 1 ml of anhydrous pyridine at 60° C. to give, after purification, the title product as a pale yellow solid: 1H NMR (CDCl3): δ (ppm): 1.61 (s, 6H), 7.26-7.66 (m, 12H), 8.90 (br, 1H), 10.13 (br, 1H) ppm; MS: (M+H)/z=482.0.
Reaction SMILES: FC(F)(F)S(O[C:7]1[CH:8]=[CH:9][CH:10]=[C:11]2[C:16]=1[N:15]=[C:14]([OH:17])[CH:13]=[CH:12]2)(=O)=O.[CH3:20][O:21][C:22]([C:24]1[CH:29]=[CH:28][C:27](B(O)O)=[CH:26][CH:25]=1)=[O:23].[F-].[Cs+]>COCCOC.CO.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>[OH:17][C:14]1[CH:13]=[CH:12][C:11]2[C:16](=[C:7]([C:27]3[CH:28]=[CH:29][C:24]([C:22]([O:21][CH3:20])=[O:23])=[CH:25][CH:26]=3)[CH:8]=[CH:9][CH:10]=2)[N:15]=1
Reactant: O=S(=O)(Oc1cccc2ccc(O)nc12)C(F)(F)F
Reactant: COC(=O)c1ccc(B(O)O)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cs+]
Agent: [F-]
Solvent: CO
Solvent: COCCOC
Product: COC(=O)c1ccc(-c2cccc3ccc(O)nc23)cc1

Procedure:
A mixture of Example 336A (2.93 g, 10 mmol), 4-(methoxycarbonyl)phenylboronic acid (1.80 g, 10 mmol), Pd(Ph3P)4 (0.346 g, 0.3 mmol), and CsF(l. 52 g, 10 mmol) in DME (60 mL) and methanol (30 mL) was heated to reflux for 18 hours and concentrated. The concentrate was dissolved in water (50 mL) and ethyl acetate (300 mL) and the organic phase was washed with water (2×50 mL) and brine (50 mL), dried (Na2SO4), filtered, and concentrated. The concentrate was purified by flash column chromatography on silica gel with 4:1 hexanes/ethyl acetate to provide the desired product. MS (APCI) m/e 280, 278 (M+H)+, (M−H)−.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH2:7][O:8][C:9]2[CH:10]=[CH:11][C:12]3[S:18](=[O:20])(=[O:19])[CH2:17][CH2:16][C:15]([C:21]([O:23]C)=[O:22])=[CH:14][C:13]=3[CH:25]=2)[CH:2]=1.[C:26](=O)([O-])[O-].[K+].[K+].Cl>C1COCC1.CO>[CH3:26][CH:17]1[CH2:16][C:15]([C:21]([OH:23])=[O:22])=[CH:14][C:13]2[CH:25]=[C:9]([O:8][CH2:7][C:3]3[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=3)[CH:10]=[CH:11][C:12]=2[S:18]1(=[O:20])=[O:19]
Reactant: O=C([O-])[O-]
Reactant: COC(=O)C1=Cc2cc(OCc3cccnc3)ccc2S(=O)(=O)CC1
Agent: Cl
Agent: [K+]
Solvent: C1CCOC1
Solvent: CO
Product: CC1CC(C(=O)O)=Cc2cc(OCc3cccnc3)ccc2S1(=O)=O
Temperature: 60 °C
Reaction time: 19 h
Yield: 75.8 %

Procedure:
Into a suspension of methyl 7-(3-pyridylmethoxy)-1,1-dioxo-2,3-dihydro-1-benzothiepine-4-carboxylate (650 mg) in THF/methanol (6/3 ml) was added at room temperature an aqueous solution (1.4 ml) of potassium carbonate (415 mg), and the resulting mixture was stirred at 60° C. for 19 hours. Into this reaction mixture was added further an aqueous solution (0.7 ml) of potassium carbonate (207 mg), and the resulting mixture was stirred further at 60° C. for 3 days. After cooling to room temperature, 1 N hydrochloric acid was added to the reaction mixture until the pH was adjusted to 7-8, and the precipitated crystals were collected by filtration. The crystals were washed with diisopropyl ether to obtain methyl 7-(3-pyridylmethoxy)-1,1-dioxo-2,3-dihydro-1-benzothiepine-4-carboxylic acid (493 mg) as colorless crystals.
Reaction SMILES: C[O:2][C:3]([C:5]1([C:15]([CH3:18])([CH3:17])[CH3:16])[CH2:9][C:8]2[CH:10]=[C:11]([OH:14])[CH:12]=[CH:13][C:7]=2[O:6]1)=[O:4].[Cl:19][C:20]1[CH:25]=[C:24]([O:26][C:27]([F:30])([F:29])[F:28])[CH:23]=[CH:22][C:21]=1[O:31][CH2:32][CH2:33]I>>[C:15]([C@@:5]1([C:3]([OH:2])=[O:4])[CH2:9][C:8]2[CH:10]=[C:11]([O:14][CH2:33][CH2:32][O:31][C:21]3[CH:22]=[CH:23][C:24]([O:26][C:27]([F:28])([F:29])[F:30])=[CH:25][C:20]=3[Cl:19])[CH:12]=[CH:13][C:7]=2[O:6]1)([CH3:18])([CH3:17])[CH3:16]
Reactant: FC(F)(F)Oc1ccc(OCCI)c(Cl)c1
Reactant: COC(=O)C1(C(C)(C)C)Cc2cc(O)ccc2O1
Product: CC(C)(C)[C@@]1(C(=O)O)Cc2cc(OCCOc3ccc(OC(F)(F)F)cc3Cl)ccc2O1

Procedure:
The title compound was prepared following the general procedure described in Example 1, Step 4, employing the phenol prepared in Example 21, Step 1 and the iodide prepared in Example 23, Step 1.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[CH:5][C:6]([O:9][C:10]2[CH:11]=[C:12]([CH3:26])[C:13]3[CH:17]([CH2:18][C:19]([O:21]CC)=[O:20])[O:16][B:15]([OH:24])[C:14]=3[CH:25]=2)=[N:7][CH:8]=1)#[N:2].[OH-].[Na+]>CO.C1COCC1>[C:1]([C:3]1[CH:4]=[CH:5][C:6]([O:9][C:10]2[CH:11]=[C:12]([CH3:26])[C:13]3[CH:17]([CH2:18][C:19]([OH:21])=[O:20])[O:16][B:15]([OH:24])[C:14]=3[CH:25]=2)=[N:7][CH:8]=1)#[N:2]
Reactant: CCOC(=O)CC1OB(O)c2cc(Oc3ccc(C#N)cn3)cc(C)c21
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: Cc1cc(Oc2ccc(C#N)cn2)cc2c1C(CC(=O)O)OB2O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of ethyl 2-(6-(5-cyanopyridin-2-yloxy)-1-hydroxy-4-methyl-1,3-dihydrobenzo[c][1,2]oxaborol-3-yl)acetate in MeOH/THF (12 mL, 1:1) was added aqueous NaOH solution (250 mg in 3 mL water). After stirring at room temperature for two hours, the reaction mixture was evaporated, acidified to pH 3 with 1 N HCl and then concentrated. HPLC purification gave product as a white powder. 1H NMR (400 MHz, DMSO-d6) δ 8.58 (s, 1H), 8.25 (dd, J=8.8, 2.4 Hz, 1H), 7.19 (m, 2H), 7.04 (s, 1H), 5.47 (dd, J=9.6, 2.4 Hz, 1H), 3.03 (dd, J=15.6, 2.4 Hz, 1H), 2.24 (s, 3H), 2.12 (dd, J=15.6, 9.6 Hz, 1H). 2 protons assumed to be exchanged with solvents. MS (ESI) m/z=323 [M−H]+.