Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O:2][C:3]1[CH:8]=[CH:7][N:6]=[CH:5][CH:4]=1.Cl[C:10]([O:12][CH2:13][CH3:14])=[O:11].II.[Cl:17][C:18]1[CH:23]=[CH:22][C:21]([CH2:24]Cl)=[CH:20][C:19]=1[Cl:26].Cl>C1COCC1.CCOCC.C(Cl)Cl>[Cl:26][C:19]1[CH:20]=[C:21]([CH2:24][C:5]2[N:6]([C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH2:7][CH2:8][C:3](=[O:2])[CH:4]=2)[CH:22]=[CH:23][C:18]=1[Cl:17]
Reactant: ClCc1ccc(Cl)c(Cl)c1
Reactant: CCOC(=O)Cl
Reactant: COc1ccncc1
Agent: Cl
Agent: II
Solvent: ClCCl
Solvent: C1CCOC1
Solvent: CCOCC
Product: CCOC(=O)N1CCC(=O)C=C1Cc1ccc(Cl)c(Cl)c1
Yield: 44 %

Procedure:
A mixture of 4-methoxypyridine (0.4 mol) in THF (1000 ml) was stirred and cooled in a 2-propanol/CO2 bath. Ethyl chloroformate (0.4 mol) was added dropwise and the mixture was stirred for 3 hours while cooling (mixture I). In another round-bottom flask, the Grignard-reagent was prepared: MG (0.44 mol) was stirred in a small amount of (C2H5)2O. Some I2 was added. A small amount of 1,2-dichloro-4-(chloromethyl)benzene was added. Then, 1,2-dichloro-4-(chloromethyl)benzene (0.4 mol) in (C2H5)2O (600 ml) was added dropwise at reflux temperature. The mixture was stirred for one hour (mixture II). The Grignard-reagent was decanted off, added to mixture I at <−40° C., and the resulting reaction mixture was stirred, allowing the temperature to reach RT. The reaction mixture was stirred for one hour at RT. HCl (10%, 800 ml) was added and the mixture was stirred for 30 minutes, then CH2Cl2 was added. The organic layer was separated, dried, filtered and the solvent evaporated, yielding 57.8 g (44%) of (±)-ethyl 6-[(3,4-dichlorophenyl)methyl]-1,2,3,4-tetrahydro-4-oxo-1-pyridinecarboxylate (intermediate 9).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:25])[CH:5]([O:22][CH2:23][CH3:24])[CH:6]([C:8]1[CH:13]=[CH:12][C:11]([O:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[CH:10][CH:9]=1)O)[CH3:2].COC(=O)C(OCC)=CC1C=CC(OCC2C=CC=CC=2)=CC=1>>[CH2:1]([O:3][C:4](=[O:25])[C:5]([O:22][CH2:23][CH3:24])=[CH:6][C:8]1[CH:13]=[CH:12][C:11]([O:14][CH2:15][C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)=[CH:10][CH:9]=1)[CH3:2]
Reactant: CCOC(=O)C(OCC)C(O)c1ccc(OCc2ccccc2)cc1
Agent: CCOC(=Cc1ccc(OCc2ccccc2)cc1)C(=O)OC
Product: CCOC(=O)C(=Cc1ccc(OCc2ccccc2)cc1)OCC

Procedure:
The title compound was prepared from 3-(4-Benzyloxy-phenyl)-2-ethoxy-3-hydroxy-propionic acid ethyl ester (Preparation 2, step 1) via the same procedure used for the preparation of 3-(4-Benzyloxy-phenyl)-2-ethoxy-acrylic acid methyl ester. MS (ES) for C20H22O4 [M+H]+: 327.2.
Reaction SMILES: Cl[C:2]1[CH:8](OC)[N:7]=[C:6]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[Cl:17])[C:5]2[CH:18]=[C:19]([Cl:22])[CH:20]=[CH:21][C:4]=2[N:3]=1.[O-:23][CH2:24][CH3:25].[Na+].O.[O:28]1CCC[CH2:29]1>C(O)C>[Cl:22][C:19]1[CH:20]=[CH:21][C:4]2[NH:3][C:2]([O:23][CH2:24][CH3:25])([O:28][CH3:29])[CH2:8][N:7]=[C:6]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[Cl:17])[C:5]=2[CH:18]=1
Reactant: CC[O-]
Reactant: COC1N=C(c2ccccc2Cl)c2cc(Cl)ccc2N=C1Cl
Reactant: C1CCOC1
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: CCOC1(OC)CN=C(c2ccccc2Cl)c2cc(Cl)ccc2N1

Procedure:
For example, 2,7-dichloro-5-(o-chlorophenyl)-3-methoxy-3H-1,4-benzodiazepine is treated in a mixture of tetrahydrofuran and ethanol, at room temperature with sodium ethoxide. After addition of water, the reaction mixture is partitioned with diethyl ether, and the organic phase is then dried, concentrated and the crystalline product so formed, recovered to give 7-chloro-5-(o-chlorophenyl)-2-ethoxy-2-methoxy-3H-1,4-benzodiazepine.
Reaction SMILES: [CH3:1][CH:2]1[CH2:6][CH2:5][CH2:4][N:3]1[C:7]1[N:12]=[C:11]([NH:13][C:14]2[C:15]3[N:16]([CH:28]=[CH:29][N:30]=3)[N:17]=[C:18]([C:20]3[CH:21]=[C:22]([CH:25]=[CH:26][CH:27]=3)[CH:23]=O)[CH:19]=2)[CH:10]=[CH:9][CH:8]=1.[NH:31]1[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].CC(O)=O>ClCCCl>[CH3:1][CH:2]1[CH2:6][CH2:5][CH2:4][N:3]1[C:7]1[N:12]=[C:11]([NH:13][C:14]2[C:15]3[N:16]([CH:28]=[CH:29][N:30]=3)[N:17]=[C:18]([C:20]3[CH:27]=[CH:26][CH:25]=[C:22]([CH2:23][N:31]4[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]4)[CH:21]=3)[CH:19]=2)[CH:10]=[CH:9][CH:8]=1
Reactant: CC1CCCN1c1cccc(Nc2cc(-c3cccc(C=O)c3)nn3ccnc23)n1
Reactant: C1CCNCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Solvent: CC(=O)O
Product: CC1CCCN1c1cccc(Nc2cc(-c3cccc(CN4CCCCC4)c3)nn3ccnc23)n1
Reaction time: 1 h
Yield: 51.9 %

Procedure:
3-(8-(6-(2-methylpyrrolidin-1-yl)pyridin-2-ylamino)imidazo[1,2-b]pyridazin-6-yl)benzaldehyde (28 mg, 0.070 mmol) and piperidine (7 mg, 0.077 mmol) were dissolved in 1,2-dichloroethane (8 mL), stirred for 1 h, then sodium triacetoxyborohydride (44 mg, 0.21 mmol) was added followed by AcOH (0.1 mL). After 15 h, the solvent was removed and the residue was purified by chromatography (silica gel, dichloromethane/methanol 40/1) to give N-(6-(2-methylpyrrolidin-1-yl)pyridin-2-yl)-6-(3-(piperidin-1-ylmethyl)phenyl)imidazo[1,2-b]pyridazin-8-amine (17 mg, 21%) as an orange solid. 1H NMR (300 MHz, CD3OD): δ 8.80 (s, 1H), 8.00 (s, 1H), 7.91-7.84 (m, 2H), 7.59 (s, 1H), 7.48-7.41 (m, 3H), 6.30 (d, 1H, J=7.8 Hz), 6.09 (d, 1H, J=8.4 Hz), 4.30-4.26 (m, 1H), 3.60-3.43 (m, 4 h), 2.51-2.47 (m, 4 h), 2.15-2.05 (m, 3H), 1.78 (brs, 1H), 1.63-1.60 (m, 4 h), 1.51-1.46 (m, 2H), 1.19 (d, 3H, J=6.3 Hz). LC-MS: [M+H]+, 468, tR=1.397 min, HPLC: 99.52% at 214 nm, 98.65% at 254 nm, tR=5.76 min.
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[C:3]1[CH:13]=[CH:12][C:6](/[CH:7]=[CH:8]/[C:9]([OH:11])=O)=[CH:5][CH:4]=1.ClC(N(C)C)=C(C)C.CCN(C(C)C)C(C)C.[CH3:33][O:34][C:35](=[O:57])[C@@H:36]([NH:44][CH2:45][C:46]1[CH:51]=[CH:50][C:49]([CH2:52][CH2:53][CH2:54][CH2:55][CH3:56])=[CH:48][CH:47]=1)[CH2:37][C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1>C(Cl)Cl.O>[CH3:33][O:34][C:35](=[O:57])[C@@H:36]([N:44]([CH2:45][C:46]1[CH:51]=[CH:50][C:49]([CH2:52][CH2:53][CH2:54][CH2:55][CH3:56])=[CH:48][CH:47]=1)[C:9](=[O:11])[CH:8]=[CH:7][C:6]1[CH:5]=[CH:4][C:3]([C:2]([F:1])([F:15])[F:14])=[CH:13][CH:12]=1)[CH2:37][C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1
Reactant: O=C(O)/C=C/c1ccc(C(F)(F)F)cc1
Reactant: CCCCCc1ccc(CN[C@@H](Cc2ccccc2)C(=O)OC)cc1
Agent: CC(C)=C(Cl)N(C)C
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: CCCCCc1ccc(CN(C(=O)C=Cc2ccc(C(F)(F)F)cc2)[C@@H](Cc2ccccc2)C(=O)OC)cc1
Reaction time: 1 h
Yield: 60 %

Procedure:
In an inert atmosphere trans-4-(trifluoromethyl)-cinnamic acid (6.7 g, 31.2 mmol) was dissolved in DCM (150 mL) and 1-chloro-N,N,2-trimethylpropenylamine (4.7 g, 35.5 mmol) was slowly added via syringe. Stirring was continued for 1 h followed by the addition of DIPEA (10.7 mL, 62.6 mmol) and 2-(4-pentyl-benzylamino)-(S)-3-phenyl-propionic acid methyl ester (7.0 g, 20.8 mmol). Stirring was continued for 45 min. Water (250 mL) was added and the product was extracted with DCM (3×150 mL). The combined organic layers were dried over magnesium sulfate, filtered and the solvent was evaporated under reduced pressure to give the crude product which was purified by column chromatography (silicagel, EtOAc/heptane=¼) to give 6.71 g (59%) of 2-{(4-pentyl-benzyl)-[3-(4-trifluoromethyl-phenyl)-acryloyl]-amino}-(S)-3-phenyl-propionic acid methyl ester. LC-MS: tR=1.21 min; [M+H]+=538.38.
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([C:14]([NH:16][CH2:17][C:18]2[C:19](=[O:26])[NH:20][C:21]([CH3:25])=[CH:22][C:23]=2[CH3:24])=[O:15])[C:5]2[CH:10]=[N:9][N:8]([CH:11]([CH3:13])[CH3:12])[C:6]=2[N:7]=1.CC1(C)C(C)(C)OB([C:35]2[CH:36]=[C:37]3[C:41](=[CH:42][CH:43]=2)[NH:40][N:39]=[CH:38]3)O1.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.CS(C)=O>[CH3:24][C:23]1[CH:22]=[C:21]([CH3:25])[NH:20][C:19](=[O:26])[C:18]=1[CH2:17][NH:16][C:14]([C:4]1[C:5]2[CH:10]=[N:9][N:8]([CH:11]([CH3:13])[CH3:12])[C:6]=2[N:7]=[C:2]([C:35]2[CH:36]=[C:37]3[C:41](=[CH:42][CH:43]=2)[NH:40][N:39]=[CH:38]3)[CH:3]=1)=[O:15]
Reactant: CC1(C)OB(c2ccc3[nH]ncc3c2)OC1(C)C
Reactant: Cc1cc(C)c(CNC(=O)c2cc(Cl)nc3c2cnn3C(C)C)c(=O)[nH]1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CS(C)=O
Product: Cc1cc(C)c(CNC(=O)c2cc(-c3ccc4[nH]ncc4c3)nc3c2cnn3C(C)C)c(=O)[nH]1
Yield: 48.1 %

Procedure:
To a 5-mL microwave vial were added 6-chloro-N-[(4,6-dimethyl-2-oxo-1,2-dihydro-3-pyridinyl)methyl]-1-(1-methylethyl)-1H-pyrazolo[3,4-b]pyridine-4-carboxamide (70 mg, 0.187 mmol), 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indazole (59.4 mg, 0.243 mmol), DMSO(1.5 mL) and sodium carbonate (0.281 mL, 0.562 mmol), and the mixture was degassed with nitrogen for 10 min. Next was added bis(triphenylphosphine)palladium(II) chloride (10.51 mg, 0.015 mmol). The contents were sealed and irradiated (microwave) at 140° C. overnight. The mixture was filtered and the residue was washed with DMSO. The crude product in DMSO was purified using reverse-phase HPLC. The TFA salt of the product was neutralized using saturated NaHCO3, filtered, washed with water and dried under high vacuum to give 41 mg (48%) of product. LCMS E-S (M+H)=456.0 1H NMR (400 MHz, DMSO-d6) δ ppm 1.56 (d, J=6.8 Hz, 6 H), 2.14 (s, 3 H), 2.23 (s, 3 H), 4.38-4.53 (m, 2 H), 5.27-5.49 (m, 1 H), 5.91 (s, 1 H), 7.59-7.75 (m, 1 H), 8.24 (s, 2 H), 8.37 (s, 2 H), 8.69 (s, 1 H), 8.95-9.09 (m, 1 H), 11.49-11.67 (m, 1 H), 13.21-13.35 (m, 1 H).
Reaction SMILES: [O:1]([CH2:9][C:10]([CH2:14][O:15][Si:16]([C:19]([CH3:22])([CH3:21])[CH3:20])([CH3:18])[CH3:17])=[CH:11][CH2:12]O)[Si:2]([C:5]([CH3:8])([CH3:7])[CH3:6])([CH3:4])[CH3:3].[C:23]([O:31]CC)([O:28][CH2:29][CH3:30])(OCC)[CH3:24].C(O)(=O)CC>C(O)C>[O:15]([CH2:14][C:10]([CH2:9][O:1][Si:2]([C:5]([CH3:8])([CH3:7])[CH3:6])([CH3:4])[CH3:3])([CH:11]=[CH2:12])[CH2:24][C:23]([O:28][CH2:29][CH3:30])=[O:31])[Si:16]([C:19]([CH3:22])([CH3:21])[CH3:20])([CH3:18])[CH3:17]
Reactant: CC(C)(C)[Si](C)(C)OCC(=CCO)CO[Si](C)(C)C(C)(C)C
Reactant: CCOC(C)(OCC)OCC
Solvent: CCO
Solvent: CCC(=O)O
Product: C=CC(CO[Si](C)(C)C(C)(C)C)(CO[Si](C)(C)C(C)(C)C)CC(=O)OCC
Yield: 77.9 %

Procedure:
A mixture of 6a (9.36 g, 27 mmol), triethyl orthoacetate (34.75 mL, 189 mmol) and propionic acid (0.2 mL, 2.7 mmol) was heated at 138° C. for 20 h with removal of ethanol. The reaction mixture was cooled and concentrated under vacuum, and the residue was purified by flash column chromatography over silica gel with hexane:EtOAc (19:1) as eluant to give 7a (8.77 g, 78%) as an oil; IR (neat) 1737, 1471 cm-1 ; 1H NMR (CDCl3) δ 0.01 (br s, 12 H, SiCH3), 0.85 (br s, 18 H, C(CH3)3), 1.21 (t, 3 H, CH3CH2), 2.42 (s, 2 H, CH2COEt), 3.61 (AB q, J=9.3 Hz, 4 H), 4.06 (q, 2 H, CH2CH3), 5.06 (m, 2 H, CH=CH2), 5.84 (dd, J=19.9, 11.3, 1 H, CH=CH2); 13C NMR (CDCl3) δ -5.58, 14.24, 18.23, 25.84, 36.81, 45.97, 59.84, 64.63, 114.47, 139.73, 171.87. Anal. Calcd for C21H44O4Si2 : C, 60.52; H, 10.64. Found: C, 60.46; H, 10.62.
Reaction SMILES: [I:1]I.N1C=CN=C1.[C:8]([O:12][C:13](=[O:22])[NH:14][C@H:15]([CH2:19][O:20][CH3:21])[CH2:16][CH2:17]O)([CH3:11])([CH3:10])[CH3:9]>ClCCl>[C:8]([O:12][C:13](=[O:22])[NH:14][C@H:15]([CH2:19][O:20][CH3:21])[CH2:16][CH2:17][I:1])([CH3:11])([CH3:10])[CH3:9]
Reactant: II
Reactant: COC[C@H](CCO)NC(=O)OC(C)(C)C
Agent: c1c[nH]cn1
Solvent: ClCCl
Product: COC[C@H](CCI)NC(=O)OC(C)(C)C
Reaction time: 0.25 h

Procedure:
A suspension of polystyrene resin-bound triphenylphosphine (18.645 g, 3 mmol/g) in dry dichloromethane (250 ml) is treated with iodine (12.5 g, 49.22 mmol) and stirred for 15 minutes under argon. Imidazole (3.87 g, 55.94 mmol) is added and the reaction mixture stirred at room temperature for a further 15 minutes. The reaction mixture is then treated with a solution of ((S)-3-Hydroxy-1-methoxymethyl-propyl)-carbamic acid tert-butyl ester (4.9 g, 22.37 mmol) in dichloromethane (30 ml), and refluxed for 1.5 hours under argon. The resin is removed by filtration through a celite pad, washing with dichloromethane. The filtrate is washed with 5% aqueous sodium thiosulphate solution and water, dried over MgSO4 and evaporated to afford ((S)-3-Iodo-1-methoxymethyl-propyl)-carbamic acid tert-butyl ester as a crude oil. [M-BOC] 230.06.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][NH:15][C:16](=[O:38])[C:17]2[CH:22]=[C:21]([C:23]3[CH:28]=[CH:27][CH:26]=[C:25]([C:29]([F:32])([F:31])[F:30])[CH:24]=3)[C:20]([O:33][CH2:34][CH2:35]O)=[C:19]([Br:37])[CH:18]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH:39]1[CH2:44][CH2:43][NH:42][CH2:41][CH2:40]1>>[C:1]1([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][NH:15][C:16]([C:17]2[CH:22]=[C:21]([C:23]3[CH:28]=[CH:27][CH:26]=[C:25]([C:29]([F:32])([F:31])[F:30])[CH:24]=3)[C:20]([O:33][CH2:34][CH2:35][N:39]3[CH2:44][CH2:43][NH:42][CH2:41][CH2:40]3)=[C:19]([Br:37])[CH:18]=2)=[O:38])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: C1CNCCN1
Reactant: O=C(NCCCCCCCCc1ccccc1)c1cc(Br)c(OCCO)c(-c2cccc(C(F)(F)F)c2)c1
Product: O=C(NCCCCCCCCc1ccccc1)c1cc(Br)c(OCCN2CCNCC2)c(-c2cccc(C(F)(F)F)c2)c1

Procedure:
The tide compound was prepared as a yellow oil (0.302 g, 45%) from N-(8-phenyl-octyl)-3-bromo-5-(m-trifluoromethylphenyl)-4-(2-hydroxyethoxy)-benzamide and piperazine using a procedure similar to Example 185. 1H NMR (DMSO-d6) 8.58 (t, 1H); 8.12 (d, 1H); 7.90-7.84 (m, 3H); 7.69 (d, 1H); 7.52 (dd, 1H); 7.26-7.10 (m, 5H); 3.61 (t, 2H); 3.23 (dd, 2H); 2.62 (t, 4H); 2.52 (t, 2H); 2.36 (t, 2H); 2.18 (m, 5H); 1.50 (m, 4H); 1.24 (m, 8H); IR (film) 3290, 2920, 2850, 1720, 1630, 1600, 1545, 1460, 1330, 1170, 1120, 1080 cm−1; mass spectrum [(+)ESI], m/z 660/662 (M+H)+; Anal. Calcd. for C34H41Br F3N3O2: C, 61.82; H, 6.26; N, 6.36, Found: C, 58.20; H, 6.00; N, 5.47.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:26])[CH:4]([NH:8][S:9]([C:12]1[CH:17]=[CH:16][C:15]([C:18]2[CH:23]=[CH:22][C:21]([CH2:24][OH:25])=[CH:20][CH:19]=2)=[CH:14][CH:13]=1)(=[O:11])=[O:10])[CH:5]([CH3:7])[CH3:6].Cl[C:28]1[C:37]([CH3:38])=[CH:36][C:35]2[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=2)[N:29]=1.[H-].[Na+].O>CN(C=O)C>[CH3:1][O:2][C:3](=[O:26])[CH:4]([NH:8][S:9]([C:12]1[CH:17]=[CH:16][C:15]([C:18]2[CH:19]=[CH:20][C:21]([CH2:24][O:25][C:28]3[C:37]([CH3:38])=[CH:36][C:35]4[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=4)[N:29]=3)=[CH:22][CH:23]=2)=[CH:14][CH:13]=1)(=[O:11])=[O:10])[CH:5]([CH3:7])[CH3:6]
Reactant: COC(=O)C(NS(=O)(=O)c1ccc(-c2ccc(CO)cc2)cc1)C(C)C
Reactant: Cc1cc2ccccc2nc1Cl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)C(NS(=O)(=O)c1ccc(-c2ccc(COc3nc4ccccc4cc3C)cc2)cc1)C(C)C
Temperature: 100 °C
Reaction time: 5 h
Yield: 12.2 %

Procedure:
Step 1C [Intermediate 3: 2-(4′-Hydroxymethyl-biphenyl-4-sulfonylamino)-3-methyl-butyric acid methyl ester (1.2 g, 3.2 mmol, 1.0 equiv.), 2-chloro-3-methyl quinoline (2.26 g, 12.7 mmol, 4 equiv.) were dissolved in DMF (30 mL) followed by the addition of NaH (382 mg, 60% in oil, 9.54 mmol, 3 equiv.). The mixture was stirred at 100° C. for 5 hrs, then at room temperature overnight. The reaction mixture was then poured into cold water, solid precipitated from the mixture was collected by filtration and washed with water. Regular column chromatography (Silica gel, 1% MeOH/CH2Cl2) to yield 203 mg of 3-Methyl-2-[4′-(3-methyl -quinolin-2-yloxymethyl)-biphenyl-4-sulfonylamino]-butyric acid methyl ester in 12% yield.
Reaction SMILES: [F:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([CH:11]=1)[C:7](Cl)=[N:8][OH:9].[C:12]([C:14]1[CH:15]=[C:16]([CH:19]=[CH:20][CH:21]=1)[C:17]#[N:18])#[CH:13].N>>[F:1][C:2]1[CH:11]=[C:6]([C:7]2[CH:13]=[C:12]([C:14]3[CH:15]=[C:16]([CH:19]=[CH:20][CH:21]=3)[C:17]#[N:18])[O:9][N:8]=2)[CH:5]=[N:4][CH:3]=1
Reactant: C#Cc1cccc(C#N)c1
Reactant: ON=C(Cl)c1cncc(F)c1
Agent: N
Product: N#Cc1cccc(-c2cc(-c3cncc(F)c3)no2)c1

Procedure:
The titled compound was prepared according to Method CB using the product of Example 28B (88 mg, 0.5 mmol) and the product of Example 19A (64 mg, 0.5 mmol). 1H NMR (300 MHz, MeOH-d4) δ 7.55 (s, 1H), 7.75 (t, J=7.9 Hz, 1H), 7.88 (dt, J=7.9, 1.4 Hz, 1H), 8.18 (ddd, J=9.3, 2.8, 1.8 Hz, 1H), 8.23 (ddd, J=7.9, 2.0, 1.2 Hz, 1H), 8.31 (t, J=1.6 Hz, 1H), 8.62 (d, J=2.8 Hz, 1H), 8.98 (t, J=1.6 Hz, 1 H) ppm; MS (DCI/NH3) m/z 266 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]([C:8]([OH:10])=O)[CH:5]=[CH:4][CH:3]=1.[N:11]1([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]1.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C>CN(C=O)C>[CH3:1][C:2]1[N:7]=[C:6]([C:8]([N:14]2[CH2:13][CH2:12][N:11]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:16][CH2:15]2)=[O:10])[CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: Cc1cccc(C(=O)O)n1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: Cc1cccc(C(=O)N2CCN(C(=O)OC(C)(C)C)CC2)n1
Reaction time: 0.25 h
Yield: 95.5 %

Procedure:
6-Methylpicolinic acid (2.15 g) and t-butyl piperazine-1-carboxylate (3.21 g) was dissolved in 45 mL of DMF, and 4.24 g of HOBt was added to the solution at ice temperature. After stirring for 15 minutes, additionally 3.0 g of WSC was added thereto and the mixture was stirred at room temperature overnight. After the solvent was removed under reduced pressure from the reaction mixture, then water was added to the residue and the mixture was extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous magnesium sulfate, then the solvent was removed under reduced pressure. The residue was purified by chromatography on silica gel (methylene chloride-ethanol=30:1) to give 4.57 g of t-butyl 4-(6-methylpyridine-2-carbonyl)piperazine-1-carboxylate as a colorless oil.