Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH-:1].[K+].[C:3]1(C)[C:4](C)=[CH:5][CH:6]=[CH:7][CH:8]=1>O>[CH2:3]=[O:1].[C:3]1([OH:1])[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1
Reactant: [OH-]
Reactant: Cc1ccccc1C
Agent: [K+]
Solvent: O
Product: C=O
Product: Oc1ccccc1
Reaction time: 4.5 h

Procedure:
Pure cyclic tetramer and 3 to 5% by weight of KOH, dissolved in an equal amount of water, are heated together with two to four times their weight of xylene, under azeotropic reflux, until catalyzation is complete and no more water can be removed. This usually takes from 3 to 6 hours depending upon the batch size. Since the tetramer is very poorly, if at all, soluble in the xylene, it is essential that efficient rapid stirring is applied to keep the very finely dispersed solid homogeneously distributed throughout the liquid. The mixture is then transferred to a pressure reactor or autoclave equipped with a means of external (electric) heating, internal cooling and efficient mechanical agitation. The resin is heated to 120°-140° C. and the alkyleneoxide or mixture of oxides is charged into the reactor until the pressure is 25-75 p.s.i. During the ensuing oxyalkylation reaction the original suspension gradually clears up and after all the oxide has been added and the reaction has been completed, which usually takes from 2 to 12 hours depending upon the nature of the reactants, the resulting product solution, the oxyalkylated derivative of the cyclic tetramer, now completely soluble in xylene, is cooled and ready to be applied for demulsifier use.
Reaction SMILES: Br[C:2]1[C:3]([O:13]C(C)(C)C)=[N:4][C:5]([O:8]C(C)(C)C)=[N:6][CH:7]=1.C([Li])CCC.[CH2:23]([C:25]1[O:26][C:27]2[CH2:34][CH2:33][C:32]3[CH:35]=[C:36]([CH3:39])[CH:37]=[CH:38][C:31]=3[C:30](=O)[C:28]=2[N:29]=1)[CH3:24]>O1CCCC1.[Cl-].[Na+].O>[CH2:23]([C:25]1[O:26][C:27]2[CH:34]=[CH:33][C:32]3[CH:35]=[C:36]([CH3:39])[CH:37]=[CH:38][C:31]=3[CH:30]([C:2]3[C:3](=[O:13])[NH:4][C:5](=[O:8])[NH:6][CH:7]=3)[C:28]=2[N:29]=1)[CH3:24]
Reactant: CCc1nc2c(o1)CCc1cc(C)ccc1C2=O
Reactant: CC(C)(C)Oc1ncc(Br)c(OC(C)(C)C)n1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CCc1nc2c(o1)C=Cc1cc(C)ccc1C2c1c[nH]c(=O)[nH]c1=O
Temperature: 25 °C

Procedure:
To a solution of the product of step (vi) (1.74 g) in dry tetrahydrofuran (20 ml) at −78° C. was added n-butyllithium (2.3 ml of a 2.5M solution in hexanes) dropwise. After 0.5 hours a solution of the product from step (v) (1.26 g) in tetrahydrofuran (10 ml) was added. The reaction mixture was allowed to warm to room temperature and saturated brine was added. The mixture was extracted with ethyl acetate, the organic phase was dried (MgSO4) and the solvent was evaporated under reduced pressure. The residue was dissolved in acetic acid (20 ml) and the solution was heated at reflux for 64 hours. The solvent was evaporated under reduced pressure and the residue was then dissolved in trifluoroacetic acid (20 ml) and the solution heated at reflux for 64 hours. The solvent was evaporated under reduced pressure. Purification was by trituration with diethyl ether and filtration.
Reaction SMILES: [Cl:1][C:2]1[CH:30]=[N:29][C:5]2[N:6]([S:20]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)(=[O:22])=[O:21])[C:7]3[C:12]([C:4]=2[CH:3]=1)=[CH:11][C:10]([C:13]1[CH:18]=[CH:17][C:16]([OH:19])=[CH:15][CH:14]=1)=[CH:9][CH:8]=3.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH3:50][N:51]1[CH2:56][CH2:55][N:54]([CH2:57][CH2:58]O)[CH2:53][CH2:52]1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>C1COCC1.C1COCC1.CO>[Cl:1][C:2]1[CH:30]=[N:29][C:5]2[N:6]([S:20]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)(=[O:22])=[O:21])[C:7]3[C:12]([C:4]=2[CH:3]=1)=[CH:11][C:10]([C:13]1[CH:18]=[CH:17][C:16]([O:19][CH2:58][CH2:57][N:54]2[CH2:55][CH2:56][N:51]([CH3:50])[CH2:52][CH2:53]2)=[CH:15][CH:14]=1)=[CH:9][CH:8]=3
Reactant: CN1CCN(CCO)CC1
Reactant: O=S(=O)(c1ccccc1)n1c2ccc(-c3ccc(O)cc3)cc2c2cc(Cl)cnc21
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CO
Solvent: C1CCOC1
Product: CN1CCN(CCOc2ccc(-c3ccc4c(c3)c3cc(Cl)cnc3n4S(=O)(=O)c3ccccc3)cc2)CC1
Temperature: 25 °C
Reaction time: 12 h
Yield: 80 %

Procedure:
To a solution of 4-(3-chloro-9-(benzenesulfonyl)-9H-pyrido[2,3-b]indol-6-yl)phenol (240 mg, 0.55 mmol, 1 equiv.) in anhydrous THF (14 ml), triphenylphosphin (577 mg, 2.2 mmol, 4 equiv.) and 2-(4-methylpiperazin-1-yl)ethanol (397 mg, 2.75 mmol, 5 equiv.) are added. DIAD (445 mg, 2.2 mmol, 4 equiv.) is then added dropwise to the solution which is stirred at room temperature for 12 hours. The mixture is then extracted with a solution of HCl 0.1M (3×10 ml). The aqueous layer is treated with Na2CO3 until pH=9 and then extracted with AcOEt (3×20 ml). The organic layers are dried over MgSO4, filtered and concentrated under reduced pressure. The residue (yellow solid) is purified over silica chromatography (eluted with AcOEt/MeOH 9:1 and then THF/MeOH 9:1) to give the product as a white solid (259 mg, 0.44 mmol) in 80% yield. 1H NMR (300 MHz, CDCl3) δ 8.47 (dd, 2H, J=2.5, 7.7 Hz), 8.17 (d, 1H, J=2.1 Hz), 8.13 (d, 2H, J=7.5 Hz), 8.00 (d, 1H, J=0.9 Hz), 7.76 (dd, 1H, J=1.5, 8.6 Hz), 7.57-7.39 (m, 5H), 7.55 (d, 2H, J=8.6 Hz), 7.01 (d, 2H, J=8.5 Hz), 4.17 (t, 2H, J=5.6 Hz), 2.87 (t, 2H, J=5.6 Hz), 2.70-2.58 (br d, 8H), 2.35 (s, 3H).
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8](O)=[O:9])=[C:6]([CH3:11])[CH:5]=[CH:4][N:3]=1.O=S(Cl)Cl.[NH3:16]>C1(C)C=CC=CC=1>[Cl:1][C:2]1[C:7]([C:8]([NH2:16])=[O:9])=[C:6]([CH3:11])[CH:5]=[CH:4][N:3]=1
Reactant: N
Reactant: Cc1ccnc(Cl)c1C(=O)O
Solvent: O=S(Cl)Cl
Solvent: Cc1ccccc1
Product: Cc1ccnc(Cl)c1C(N)=O
Temperature: 25 °C
Yield: 91 %

Procedure:
To a mixture of 2-chloro-4-methyl-3-pyridinecarboxylic acid (24.7 g, 157 mmol) and 75 mL of toluene at 70° C. was added 75 mL of SOCl2 (22.6 g, 190 mmol) within a period of 1 hour. The reaction mixture was refluxed for 4 hours and the resulting solution was cooled to room temperature. Dry NH3 gas was introduced at such a rate so as to maintain the internal temperature below 30° C. After removing toluene, the solid residue was washed successively with cold water and methanol, and dried to yield 22.72 g of the title compound (91%, m.p. 168°-170° C.).
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][C:8]([NH2:10])=[CH:9][C:4]=2[N:3]=[CH:2]1.[O:11]1[CH2:16][CH2:15][N:14]([C:17]2[CH:24]=[CH:23][C:20]([CH:21]=O)=[CH:19][CH:18]=2)[CH2:13][CH2:12]1.[Si](C#N)(C)(C)C.[N:31]1([C:36](N2C=CN=C2)=[O:37])C=CN=[CH:32]1>[Pd]>[NH:1]1[C:5]2[CH:6]=[CH:7][C:8]([N:10]3[CH:21]([C:20]4[CH:23]=[CH:24][C:17]([N:14]5[CH2:15][CH2:16][O:11][CH2:12][CH2:13]5)=[CH:18][CH:19]=4)[CH2:32][NH:31][C:36]3=[O:37])=[CH:9][C:4]=2[N:3]=[CH:2]1
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: Nc1ccc2[nH]cnc2c1
Reactant: O=Cc1ccc(N2CCOCC2)cc1
Agent: [Pd]
Agent: C[Si](C)(C)C#N
Product: O=C1NCC(c2ccc(N3CCOCC3)cc2)N1c1ccc2[nH]cnc2c1

Procedure:
The compound was synthesized starting from 1H-benzo[d]imidazol-5-amine (0.333 g, 2.5 mmol), 4-morpholinobenzaldehyde (0.473 g, 2.5 mmol), TMSCN (0.375 mL, 3 mmol), Pd/C (10%, 0.02 g), TEA 1 mL, 7.2 mmol), di-(imidazol-1-yl)methanone (0.600 g, 3.7 mmol) as described in method 2.
Reaction SMILES: [CH3:1][C:2]([CH3:7])=[CH:3][C:4](Cl)=[O:5].[Br:8][C:9]1[CH:15]=[CH:14][C:12]([NH2:13])=[CH:11][CH:10]=1.C(N(CC)CC)C>ClCCl>[Br:8][C:9]1[CH:15]=[CH:14][C:12]([NH:13][C:4](=[O:5])[CH:3]=[C:2]([CH3:7])[CH3:1])=[CH:11][CH:10]=1
Reactant: Nc1ccc(Br)cc1
Reactant: CC(C)=CC(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)=CC(=O)Nc1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 100.1 %

Procedure:
3,3-Dimethylacryloyl chloride (available from Aldrich, 4.16 g, 35.1 mmol) was slowly added to a solution of 4-bromoaniline (5.00 g, 29.2 mmol) in 25 mL of dichloromethane. After stirring at room temperature for 20 min triethylamine (2.5 mL) was added dropwise to the mixture. The resulting solution was stirred at room temperature for 3 h and poured to 100 mL of ice-water mixture. The organic layer was separated, washed with brine (2×20 mL), dried (MgSO4) and concentrated at reduced pressure to give a yellow residue. Purification by flash chromatography (90:10 hexane/ethyl acetate) afforded the title compound (7.43 g, 100% yield) as a yellow solid: 1H NMR (CDCl3, 300 MHz) δ 7.34 (s, 4H), 7.1 (bs, 1H), 5.69 (s, 1H), 2.23 (s, 3H), 1.91 (s, 3H).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[N:5][CH:6]=[CH:7][CH:8]=2)[N:3]=[C:2]1[SH:10].CI.[C:13]([O-])([O-])=O.[K+].[K+]>CC(C)=O>[CH3:13][S:10][C:2]1[NH:3][C:4]2=[N:5][CH:6]=[CH:7][CH:8]=[C:9]2[N:1]=1
Reactant: O=C([O-])[O-]
Reactant: Sc1nc2ncccc2[nH]1
Agent: [K+]
Solvent: CI
Solvent: CC(C)=O
Product: CSc1nc2cccnc2[nH]1
Reaction time: 10 h
Yield: 45.8 %

Procedure:
To a solution of 1H-imidazo[4,5-b]pyridine-2-thiol (2 g) in acetone (30 ml) were added MeI (0.910 mL) and K2CO3 (5.48 g) at room temperature. After stirring for 10 h, the mixture was concentrated under reduced pressure. The residue was purified by column chromatography (NH-silica gel, eluted with 10%-100% EtOAc in hexane) to give 2-(methylsulfanyl)-3H-imidazo[4,5-b]pyridine (1.0 g) as a white solid.
Reaction SMILES: [NH:1]1[C:5]2=[N:6][CH:7]=[CH:8][CH:9]=[C:4]2[CH2:3][C:2]1=[O:10].[N:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1/[CH:17]=[CH:18]/[C:19]1[C:27]2[C:22](=[CH:23][C:24]([CH:28]=O)=[CH:25][CH:26]=2)[NH:21][N:20]=1>>[N:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1/[CH:17]=[CH:18]/[C:19]1[C:27]2[C:22](=[CH:23][C:24](/[CH:28]=[C:3]3/[C:2](=[O:10])[NH:1][C:5]4[C:4]/3=[CH:9][CH:8]=[CH:7][N:6]=4)=[CH:25][CH:26]=2)[NH:21][N:20]=1
Reactant: O=C1Cc2cccnc2N1
Reactant: O=Cc1ccc2c(/C=C/c3ccccn3)n[nH]c2c1
Product: O=C1Nc2ncccc2/C1=C\c1ccc2c(/C=C/c3ccccn3)n[nH]c2c1
Yield: 28.2 %

Procedure:
The title compound (7 mg, 21%) was synthesized as yellow solid according to the method described for Example A67 using 1H-pyrrolo[2,3-b]pyridin-2(3H)-one (9.3 mg, 0.07 mmol) and (E)-3-(2-(pyridin-2-yl)vinyl)-1H-indazole-6-carbaldehyde (17 mg, 0.068 mmol). 1H NMR (400 MHz, DMSO-d6) δ 13.53 (s, 1H, NH), 11.27 (s, 1H, NH), 8.62 (d, J=4.0 Hz, 1H), 8.35 (d, J=8.4 Hz, 1H), 8.12 (d, J=5.2 Hz, 1H), 8.02-7.89 (m, 4H), 7.82 (t, J=8.0 Hz, 1H), 7.69 (d, J=7.6 Hz, 1H), 7.63 (d, J=16.8 Hz, 1H), 7.56 (d, J=8.4 Hz, 1H), 7.28 (t, J=6.0 Hz, 1H), 6.91 (dd, J=7.6 Hz, 5.6 Hz, 1H); MS ESI 366.1 [M+H]+, calcd for [C22H15N5O+H]+ 366.1.
Reaction SMILES: CC1(C)C(C)(C)OB([C:9]2[CH2:10][CH2:11][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:13][CH:14]=2)O1.C([O-])([O-])=O.[K+].[K+].Br[C:30]1[C:31]([F:43])=[CH:32][C:33]([F:42])=[C:34]([NH:36][C:37](=[O:41])[CH:38]([CH3:40])[CH3:39])[CH:35]=1>CN(C=O)C>[F:43][C:31]1[CH:32]=[C:33]([F:42])[C:34]([NH:36][C:37](=[O:41])[CH:38]([CH3:39])[CH3:40])=[CH:35][C:30]=1[C:9]1[CH2:10][CH2:11][N:12]([C:15]([O:17][C:18]([CH3:19])([CH3:20])[CH3:21])=[O:16])[CH2:13][CH:14]=1
Reactant: CC(C)(C)OC(=O)N1CC=C(B2OC(C)(C)C(C)(C)O2)CC1
Reactant: CC(C)C(=O)Nc1cc(Br)c(F)cc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)C(=O)Nc1cc(C2=CCN(C(=O)OC(C)(C)C)CC2)c(F)cc1F
Temperature: 80 °C
Yield: 59 %

Procedure:
To a 250-mL RB flask containing tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydro-1(2H)-pyridinecarboxylate (3.31 g, 10.7 mmol), K2CO3 (4.44 g, 32.1 mmol) and PdCl2dppf (870 mg, 1.07 mmol) was added a solution of N-(5-bromo-2,4-difluorophenyl)-2-methylpropanamide (3.28 g, 11.8 mmol) in DMF (100 mL) at room temperature under argon. The mixture was heated to 80° C. under argon overnight, cooled to room temperature, filtered through celite and the celite was washed with EtOAc (3×20 mL). The filtrates were washed with H2O (20 mL), brine (20 mL), dried over MgSO4, filtered and concentrated in vacuo. The crude material was purified by flash chromatography (10%–20% EtOAc/hexane) to give 2.4 g (6.31 mmol, 59%) of tert-butyl 4-[2,4-difluoro-5-(isobutyrylamino)phenyl]-3,6-dihydro-1(2H)-pyridine carboxylate: ESMS m/e: 379.3 (M−H)+.
Reaction SMILES: [F:1][C:2]1[C:14]([NH:15][CH2:16][C:17]2[CH:22]=[C:21]([CH3:23])[CH:20]=[C:19]([C:24]3[CH:29]=[CH:28][CH:27]=[C:26]([F:30])[CH:25]=3)[C:18]=2[F:31])=[C:13]([F:32])[CH:12]=[CH:11][C:3]=1[O:4][CH2:5][C:6]([O:8]CC)=[O:7].O[Li].O>C1COCC1.O>[F:1][C:2]1[C:14]([NH:15][CH2:16][C:17]2[CH:22]=[C:21]([CH3:23])[CH:20]=[C:19]([C:24]3[CH:29]=[CH:28][CH:27]=[C:26]([F:30])[CH:25]=3)[C:18]=2[F:31])=[C:13]([F:32])[CH:12]=[CH:11][C:3]=1[O:4][CH2:5][C:6]([OH:8])=[O:7]
Reactant: CCOC(=O)COc1ccc(F)c(NCc2cc(C)cc(-c3cccc(F)c3)c2F)c1F
Agent: [Li]O
Solvent: C1CCOC1
Solvent: O
Product: Cc1cc(CNc2c(F)ccc(OCC(=O)O)c2F)c(F)c(-c2cccc(F)c2)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 35.8 %

Procedure:
To a stirred solution of ethyl 2-[2,4-difluoro-3-[[2-fluoro-3-(3-fluorophenyl)-5-methyl-phenyl]methylamino]phenoxy]acetate (100 mg, 0.2 mmol, 1.0 eq) in a mixture of THF (20 mL) and water (20 mL) was added LiOH.H2O (38 mg, 0.9 mmol, 4.0 eq). The reaction was stirred at room temperature for 2 h. The THF was then removed in vacuo and the aqueous residue acidified by addition of 1M HCl and extracted with EtOAc. The combined organic extracts were washed with water and brine, dried (Na2SO4), filtered and evaporated in vacuo. The residue obtained was washed with a mixture of petroleum ether: EtOAc, 10:1 to give the title compound (I(g)) as white solid (30 mg, 32%).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Mg].[C:9]([O:24][C@@H:25]1[CH2:30][C@H:29]([CH3:31])[CH2:28][CH2:27][C@H:26]1[CH:32]([CH3:34])[CH3:33])(=[O:23])[C:10]([O:12][C@@H]1C[C@H](C)CC[C@H]1C(C)C)=O>C1COCC1>[O:12]=[C:10]([C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[C:9]([O:24][C@@H:25]1[CH2:30][C@H:29]([CH3:31])[CH2:28][CH2:27][C@H:26]1[CH:32]([CH3:33])[CH3:34])=[O:23]
Reactant: Brc1ccccc1
Reactant: CC(C)[C@@H]1CC[C@@H](C)C[C@H]1OC(=O)C(=O)O[C@@H]1C[C@H](C)CC[C@H]1C(C)C
Agent: [Mg]
Solvent: C1CCOC1
Product: CC(C)[C@@H]1CC[C@@H](C)C[C@H]1OC(=O)C(=O)c1ccccc1
Temperature: 25 °C
Yield: 32.4 %

Procedure:
A Grignard reagent prepared from bromobenzene (2.36 g, 15.0 mmol) and magnesium (0.39 g, 16.0 mmol) in THF (25 ml) was added dropwise to a stirred solution of bis((1R,2S,5R)-2-isopropyl-5-methylcyclohexyl) oxalate (5.00 g, 13.7 mmol) in THF (25 ml) at −78° C. The mixture was slowly warmed to room temperature, quenched with a saturated solution of NH4Cl (50 ml) and ice. The reaction mixture was extracted with ether (2×) and water (2×) and the organic phase dried (Na2SO4). Repetitive column chromatography (SiO2, heptane/ether 9:1) gave 1.28 g (32%) of the pure product as a slightly yellow oil.
Reaction SMILES: Cl[C:2]1[C:11]2[N:12]=[CH:13][N:14]([CH2:15][C:16]([CH3:25])([O:18][CH2:19][CH2:20][S:21]([CH3:24])(=[O:23])=[O:22])[CH3:17])[C:10]=2[C:9]2[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=2[N:3]=1.[NH3:26].C(=O)([O-])[O-].[Na+].[Na+]>CO.O>[CH3:17][C:16]([O:18][CH2:19][CH2:20][S:21]([CH3:24])(=[O:23])=[O:22])([CH3:25])[CH2:15][N:14]1[C:10]2[C:9]3[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=3[N:3]=[C:2]([NH2:26])[C:11]=2[N:12]=[CH:13]1
Reactant: CC(C)(Cn1cnc2c(Cl)nc3ccccc3c21)OCCS(C)(=O)=O
Reactant: N
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: CC(C)(Cn1cnc2c(N)nc3ccccc3c21)OCCS(C)(=O)=O
Temperature: 150 °C

Procedure:
A suspension of 4-chloro-1-{2-methyl-2-[2-(methylsulfonyl)ethoxy]propyl}-1H-imidazo[4,5-c]quinoline (4.30 g, 11.3 mmol) in a solution of ammonia in methanol (7 M, 43 mL) in a high pressure vessel was heated at 150° C. for 12 hours. The vessel was allowed to cool to room temperature. The mixture was concentrated under reduced pressure to afford a solid that was slurried in water (50 mL), saturated aqueous sodium carbonate, and methanol. The solid was isolated by filtration, washed with water, and purified by flash chromatography (silica gel, eluted with 10% methanol in dichloromethane) to provide a white solid. The solid was heated in methanol (200 mL) at reflux, isolated by filtration, washed with methanol, and dried to yield 2.2 g of 1-{2-methyl-2-[2-(methylsulfonyl)ethoxy]propyl}-1H-imidazo[4,5-c]quinolin-4-amine as a white powder, mp 261-264° C.
Reaction SMILES: [C:1]1([CH2:7][C:8]([NH:10][C@H:11]2[C@@H:14]([S:15][CH2:16][C:17]([CH:19]3[CH2:24][CH2:23][CH2:22][CH2:21][O:20]3)=[O:18])[NH:13][C:12]2=[O:25])=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:26]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])(=[O:29])[CH:27]=[O:28].C(N(CC)CC)C.C(OCC)(=O)C>ClCCCl>[OH:28][CH:27]([N:13]1[C@H:14]([S:15][CH2:16][C:17]([CH:19]2[CH2:24][CH2:23][CH2:22][CH2:21][O:20]2)=[O:18])[C@H:11]([NH:10][C:8](=[O:9])[CH2:7][C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[C:12]1=[O:25])[C:26]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29]
Reactant: CC(C)(C)OC(=O)C=O
Reactant: O=C(Cc1ccccc1)N[C@@H]1C(=O)N[C@@H]1SCC(=O)C1CCCCO1
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: ClCCCl
Product: CC(C)(C)OC(=O)C(O)N1C(=O)[C@@H](NC(=O)Cc2ccccc2)[C@H]1SCC(=O)C1CCCCO1
Yield: 82 %

Procedure:
(3R,4R)-3-Phenylacetamido-4-[(RS)-tetrahydropyran-2-yl-carbonylmethylthio]azetidin-2-one (1.7g) in 1,2-dichloroethane (20ml) was successively treated with 0.5M t-butyl glyoxylate in 1,2-dichlorethane (10ml) and triethylamine (50mg, 70μl) and monitored by t.l.c. (ethyl acetate) until no starting material remained. The reaction mixture was concentrated and flash chromatography (70% ethyl acetate in hexane, ethyl acetate) to afford the title compound as a yellow foam (1.9g, 82%); vmax (CH2Cl3) 3400 (w), 1780, 1736, 1687cm-1 ; δH (CDCl3) 1.49 (9H, s) overlapping 1.44-1.61 (4H, m), 1.8-2.0 (2H, m), 3.35-3.58 (3H, m), 3.65 (2H, s), 3.81-3.92 (1H, m), 4.01-4.06 (1H, m), 4.28-4.43 (1H, m), 4.99, 5.00, 5.07 (together 1H, 3d, J4.7Hz), 5.21, 5.32, 5.33 (together 1H, 3d, J6.8, 7.7, 7.6Hz), 5.42, 5.50 (together 1H, 2dd, J4.8, 8.7Hz, 6.35, 6.36, 6.61 (together 1H, 3d, J8.7Hz) and 7.27-7.38 (5H, m).
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][C:7]([C:11]#[C:12][C:13]#[N:14])=[CH:8][CH:9]=2)[CH:4]=[CH:3][N:2]=1.Cl.[NH2:16][OH:17]>CCO.[OH-].[Na+].CCOC(C)=O>[CH:1]1[C:10]2[C:5](=[CH:6][C:7]([C:11]3[O:17][N:16]=[C:13]([NH2:14])[CH:12]=3)=[CH:8][CH:9]=2)[CH:4]=[CH:3][N:2]=1
Reactant: NO
Reactant: N#CC#Cc1ccc2cnccc2c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: CCO
Product: Nc1cc(-c2ccc3cnccc3c2)on1
Reaction time: 3 h
Yield: 97.5 %

Procedure:
3-(Isoquinolin-6-yl)propiolonitrile (0.060 g, 0.34 mmol) was suspended in 3.0 mL of EtOH. Hydroxylamine hydrochloride (0.070 g, 1.0 mmol) was added to the mixture in 1.5 mL of 10% aq. NaOH. The solution turned a clear, light yellow color immediately. After 3 hours, the reaction mixture was diluted with 20 mL of EtOAc and transferred to a separatory funnel. The mixture was washed with 3 mL of water and 5 mL of brine. The organic extracts were dried over MgSO4, filtered, and concentrated under reduced pressure, affording 5-(isoquinolin-6-yl)isoxazol-3-amine (0.070 g, 98% yield) as a yellow solid. MS m/z: 212 (M+1); 1H NMR (400 MHz, DMSO-d6) δ ppm 9.36 (s, 1H), 8.56 (d, J=5.7 Hz, 1H), 8.40 (s, 1H), 8.23 (d, J=8.6 Hz, 1H), 8.05 (d, J=8.4 Hz, 1H), 7.93 (d, J=5.9 Hz, 1H), 6.57 (s, 1H).
Reaction SMILES: Br[C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH:7]([CH3:26])[N:8]([C:12]3[CH:17]=[C:16]([N:18]4[CH2:23][CH2:22][N:21]([CH3:24])[CH2:20][CH2:19]4)[N:15]=[C:14]([NH2:25])[N:13]=3)[CH2:9]2)=[CH:4][CH:3]=1.[O:27]=[S:28]1(=[O:47])[CH2:32][CH2:31][CH:30]([N:33]2[CH:37]=[C:36](B3OC(C)(C)C(C)(C)O3)[CH:35]=[N:34]2)[CH2:29]1.C(=O)(O)[O-].[Na+].O1CCOCC1>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.O>[O:47]=[S:28]1(=[O:27])[CH2:32][CH2:31][CH:30]([N:33]2[CH:37]=[C:36]([C:2]3[CH:11]=[C:10]4[C:5]([CH2:6][CH:7]([CH3:26])[N:8]([C:12]5[CH:17]=[C:16]([N:18]6[CH2:23][CH2:22][N:21]([CH3:24])[CH2:20][CH2:19]6)[N:15]=[C:14]([NH2:25])[N:13]=5)[CH2:9]4)=[CH:4][CH:3]=3)[CH:35]=[N:34]2)[CH2:29]1
Reactant: CC1Cc2ccc(Br)cc2CN1c1cc(N2CCN(C)CC2)nc(N)n1
Reactant: CC1(C)OB(c2cnn(C3CCS(=O)(=O)C3)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: CO
Solvent: C1COCCO1
Product: CC1Cc2ccc(-c3cnn(C4CCS(=O)(=O)C4)c3)cc2CN1c1cc(N2CCN(C)CC2)nc(N)n1
Temperature: 90 °C
Reaction time: 8 h
Yield: 26.8 %

Procedure:
A mixture of 4-(7-bromo-3-methyl-3,4-dihydroisoquinolin-2(1H)-yl)-6-(4-methylpiperazin-1-yl)pyrimidin-2-amine (10 mg, 0.02 mmol; Peak 1, Example 49, Step 7), 1-(1,1-dioxidotetrahydro-3-thienyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (12.0 mg, 0.026 mmol), tetrakis(triphenylphosphine)palladium(0) (1.4 mg, 0.0012 mmol) and sodium bicarbonate (6.0 mg, 0.072 mmol) in a solution of 1,4-dioxane (0.2 mL) and water (0.1 mL) in a reaction vial was stirred at 90° C. overnight. After cooling, it was diluted with methanol. The solid was filtered off. The filtrate was purified with RP-HPLC (pH=10) to afford the desired product (2.8 mg). LCMS (M+H)+: m/z=523.3.
Reaction SMILES: [OH:1][C@@H:2]([C@H:6]([OH:23])[C:7](=[O:22])[NH:8][C@H:9]([C:14](=[O:21])[NH:15][CH2:16][CH2:17][CH:18]([CH3:20])[CH3:19])[CH2:10][CH:11]([CH3:13])[CH3:12])[C:3]([OH:5])=[O:4].C(=O)(O)[O-].[Na+].[CH2:29](Br)[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1.O>CN(C)C=O>[OH:1][C@@H:2]([C@H:6]([OH:23])[C:7](=[O:22])[NH:8][C@H:9]([C:14](=[O:21])[NH:15][CH2:16][CH2:17][CH:18]([CH3:19])[CH3:20])[CH2:10][CH:11]([CH3:12])[CH3:13])[C:3]([O:5][CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)=[O:4]
Reactant: CC(C)CCNC(=O)[C@H](CC(C)C)NC(=O)[C@@H](O)[C@H](O)C(=O)O
Reactant: BrCc1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)CCNC(=O)[C@H](CC(C)C)NC(=O)[C@@H](O)[C@H](O)C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 63.5 %

Procedure:
(2S,3S)-2,3-dihydroxy-3-[(S)-3-methyl-1-(3-methylbutylcarbamoyl)butylcarbamoyl]propionic acid (1.40 g) obtained in Example 9 and sodium bicarbonate (712 mg) were suspended in dimethylformamide (20 ml). A dimethylformamide (20 ml) solution of benzyl bromide (3.56 g) was added to the resultant suspension, and the suspension was stirred at room temperature for 24 hours. Water was added after the reaction, and then was extracted with ethyl acetate. The organic layer was sequentially washed with water and saturated sodium chloride solution. After the resultant layer was dried with magnesium sulfate, the solvent was distilled off under reduced pressure to obtain a crude product. This crude product was purified by silica gel column chromatography (a developing solvent; hexane:ethyl acetate=1:1→1:3) to obtain 1.13 g of a target compound. NMR data of the compound were as follows.
Reaction SMILES: [CH2:1]([NH:5][C:6]1[CH:7]=[C:8]([CH:12]=[C:13]([S:22](=[O:25])(=[O:24])[NH2:23])[C:14]=1[O:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:9]([OH:11])=[O:10])[CH2:2][CH2:3][CH3:4].Cl[CH2:27][C:28]#[N:29].C(N(CC)CC)C>CC(C)=O>[C:28]([CH2:27][O:10][C:9](=[O:11])[C:8]1[CH:12]=[C:13]([S:22](=[O:25])(=[O:24])[NH2:23])[C:14]([O:15][C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)=[C:6]([NH:5][CH2:1][CH2:2][CH2:3][CH3:4])[CH:7]=1)#[N:29]
Reactant: N#CCCl
Reactant: CCCCNc1cc(C(=O)O)cc(S(N)(=O)=O)c1Oc1ccccc1
Solvent: CC(C)=O
Solvent: CCN(CC)CC
Product: CCCCNc1cc(C(=O)OCC#N)cc(S(N)(=O)=O)c1Oc1ccccc1

Procedure:
A mixture of 3-n-butylamino-4-phenoxy-5-sulphamyl-benzoic acid (1 g), chloroacetonitrile (0.625 g), triethylamine (0.28 g), and dry acetone (10 ml) was refluxed for 19 hours. After cooling, the precipitated triethylamine hydrochloride was removed by filtration, and the filtrate was evaporated in vacuo. To the residue, water (20 ml) and ethylacetate (50 ml) were added, and the pH of the aqueous layer was adjusted to pH 7.5. The organic layer was then separated, washed with dilute sosium hydrogen carbonate, dried, and evaporated in vacuo. The residue was recrystallized several times from chloroform/petroleum ether. Thereby the cyanomethyl-3-n-butylamino-4-phenoxy-5-sulphamyl-benzoate was obtained with a melting point of 159°-161° C.