Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:8]1[CH:12]=[C:11]([CH2:13][OH:14])[N:10]=[C:9]1[CH3:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(Cl)Cl.CCCCCC>C(OCC)C.[O-2].[O-2].[Mn+4]>[CH2:1]([N:8]1[CH:12]=[C:11]([CH:13]=[O:14])[N:10]=[C:9]1[CH3:15])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cc1nc(CO)cn1Cc1ccccc1
Agent: [Mn+4]
Agent: [O-2]
Solvent: CCOCC
Solvent: CCCCCC
Solvent: ClCCl
Product: Cc1nc(C=O)cn1Cc1ccccc1
Yield: 81 %

Procedure:
A slurry of 9.0 g (0.446 mole) of 1-benzyl-4-hydroxymethyl-2-methylimidazole, 750 ml of methylene chloride and 50.0 g (0.575 mole) of manganese dioxide was stirred at room temperature for two hours. It was then filtered, the filter cake washed with methylene chloride and the combined filtrate and wash solutions evaporated under reduced pressure to give an oil. The oil was taken up in 100 ml of diethyl ether, 100 ml of hexane added and the solution seeded with a few crystals of the title compound. Concentration of the solution under a nitrogen sweep with periodic replacement of hexane afforded a crystalline product which was isolated by filtration: 7.2 g, 81% yield; m.p. 57°-60° C.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[N:15]=[CH:16][C:17]3[C:23](=[O:24])[C:22]([C:25]([O:27]CC)=[O:26])=[CH:21][N:20]([CH2:30][CH3:31])[C:18]=3[N:19]=2)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+]>>[CH2:1]([N:8]1[CH2:9][CH2:10][N:11]([C:14]2[N:15]=[CH:16][C:17]3[C:23](=[O:24])[C:22]([C:25]([OH:27])=[O:26])=[CH:21][N:20]([CH2:30][CH3:31])[C:18]=3[N:19]=2)[CH2:12][CH2:13]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)c1cn(CC)c2nc(N3CCN(Cc4ccccc4)CC3)ncc2c1=O
Agent: [Na+]
Agent: [OH-]
Product: CCn1cc(C(=O)O)c(=O)c2cnc(N3CCN(Cc4ccccc4)CC3)nc21

Procedure:
Saponification of 9.5 g. of this ester with an aqueous-alcoholic solution of sodium hydroxide (N NaOH, 15 cm3 + water, 30 cm3 + ethanol, 30 cm3) is complete in 1 hour at ordinary temperature. After acidification, the precipitate is filtered off and recrystallised from 160 cm3 of a mixture of dimethylformamide (1 volume) and ethanol (1 volume). 6.8 g. of 2-(4'-benzyl-piperazino)-5-oxo-8-ethyl-5,8-dihydro-pyrido(2,3-d)pyrimidine-6-carboxylic acid are obtained; melting point 207° C.
Reaction SMILES: [N+:1]([C:4]1[CH:22]=[CH:21][C:7]([CH2:8][C:9]2[S:13][C:12]([NH2:14])=[N:11][C:10]=2[C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[CH:6][CH:5]=1)([O-:3])=[O:2].[CH3:23][O:24][C:25]1[CH:26]=[C:27]([CH:31]=[CH:32][C:33]=1[O:34][CH3:35])[C:28](Cl)=[O:29]>>[CH3:23][O:24][C:25]1[CH:26]=[C:27]([CH:31]=[CH:32][C:33]=1[O:34][CH3:35])[C:28]([NH:14][C:12]1[S:13][C:9]([CH2:8][C:7]2[CH:21]=[CH:22][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=2)=[C:10]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[N:11]=1)=[O:29]
Reactant: COc1ccc(C(=O)Cl)cc1OC
Reactant: Nc1nc(-c2ccccc2)c(Cc2ccc([N+](=O)[O-])cc2)s1
Product: COc1ccc(C(=O)Nc2nc(-c3ccccc3)c(Cc3ccc([N+](=O)[O-])cc3)s2)cc1OC
Yield: 64.7 %

Procedure:
A procedure similar to that in Example 4 was used. 5-(4-nitro-benzyl)-4-phenyl-thiazol-2-ylamine prepared in Example 26 and 3,4-dimethoxy-benzoyl chloride prepared in the step 1 of Example 12 were used as starting materials, allowed to react at room temperature overnight, followed by post-treatment to obtain a crude product, which was purified by a silica gel column chromatography eluted with a gradient of dichloromethane and ethyl acetate (100:0-10:1) to obtain a product as a white solid in a yield of 64.7%, mp: 105-106 └. 1H-NMR (CDCl3, 400 MHz) δ: 3.90 (3H, s, OCH3), 3.96 (3H, s, OCH3), 4.35 (2H, s, CH2), 6.85 (1H, t, J=8.68 Hz, ArH), 7.30˜7.48 (9H, m, ArH), 8.18 (2H, t, J=8.68 Hz, ArH), 10.21 (1H, br, CONH); EI-MS m/e (%): 475.0 (M+, 20), 165.0 (100); HREI-MS Calcd. for C25H21N3O5S: 475.1202. found: 475.1210.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[C:6]([CH:12]([N:17]2[CH2:25][C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[C:18]2=[O:26])[CH2:13][C:14]([OH:16])=[O:15])[CH:7]=[CH:8][C:9]=1[O:10][CH3:11])[CH3:2].C(N1C=CN=C1)(N1C=CN=C1)=O.[CH:39]([NH:41][NH2:42])=[O:40]>O1CCCC1>[CH2:1]([O:3][C:4]1[CH:5]=[C:6]([CH:12]([N:17]2[CH2:25][C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[C:18]2=[O:26])[CH2:13][C:14]2[O:16][CH:39]=[N:41][N:42]=2)[CH:7]=[CH:8][C:9]=1[O:10][CH3:11])[CH3:2].[C:39](=[N:41][NH:42][C:14](=[O:15])[CH2:13][CH:12]([C:6]1[CH:7]=[CH:8][C:9]([O:10][CH3:11])=[C:4]([O:3][CH2:1][CH3:2])[CH:5]=1)[N:17]1[CH2:25][C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[C:18]1=[O:26])=[O:40]
Reactant: CCOc1cc(C(CC(=O)O)N2Cc3ccccc3C2=O)ccc1OC
Reactant: NNC=O
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Product: CCOc1cc(C(CC(=O)NN=C=O)N2Cc3ccccc3C2=O)ccc1OC
Product: CCOc1cc(C(Cc2nnco2)N2Cc3ccccc3C2=O)ccc1OC
Yield: 104.3 %

Procedure:
2-[1-(3-Ethoxy-4-methoxyphenyl)-2-(1,3,4-oxadiazol-2-yl)ethyl]isoindolin-1-one was prepared as described in Example 1. Reaction of 3-(3-ethoxy-4-methoxyphenyl)-3-(1-oxoisoindolin-2-yl)propanoic acid (1.50 g, 4.22 mmol), carbonyldiimidazole (0.80 g, 4.9 mmol) and formic hydrazide (310 mg, 5.16 mmol) in tetrahydrofuran (10 mL) yielded crude N-carbonylamino-3-(3-ethoxy-4-methoxyphenyl)-3-(1-oxoisoindolin-2-yl)propanamide (1.0 g, 2.2 mmol), which was then reacted with phosphorus pentoxide (2.32 g, 16.3 mmol) in chloroform (30 mL) at room temperature for 18 hours. The product was obtained as a white solid (250 mg, 16% overall yield): mp, 143.5-144.5° C.; 1H NMR (CDCl3); δ 1.43 (t, J=7.0 Hz, 3H, CH3), 3.65 (dd, J=6.1, 15.1 Hz, 1H, CHH), 3.85 (s, 3H, CH3), 3.87 (dd, J=9.9, 15.0 Hz, 1H, CHH), 4.01-4.12 (m, 3H, NCHH, CH2), 4.46 (d, J=16.6 Hz, 1H, NCHH), 5.99 (dd, J=6.1, 10.1 Hz, 1H, NCH), 6.83-6.87 (m, 1H, Ar), 6.94-7.01 (m, 2H, Ar), 7.34-7.52 (m, 3H, Ar), 7.78 (d, J=7.1 Hz,1H, Ar), 8.34 (s, 1H, NCH); 13C NMR (CDCl3) δ 14.60, 27.84, 46.19, 52.13, 55.86, 64.45, 111.32, 112.45, 118.98, 122.78, 123.72, 127.95, 129.95, 131.49, 131.98, 141.09, 148.66, 149.35, 153.31, 163.86, 168.25; Anal Calcd for C21H21N3O4+0.06 CH2Cl2: C, 65.79; H, 5.54; N, 10.93. Found: C, 65.87; H, 5.67; N, 10.89.
Reaction SMILES: [CH2:1]([NH:8][C:9]1[CH:13]=[C:12]([C:14]2[CH:19]=[CH:18][N:17]=[CH:16][CH:15]=2)[S:11][C:10]=1[C:20]([NH2:22])=[O:21])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:23][C:24]([CH3:26])=O.O.C1(C)C=CC(S(O)(=O)=O)=CC=1.C(=O)([O-])O.[Na+]>C(O)(=O)C>[CH2:1]([N:8]1[C:9]2[CH:13]=[C:12]([C:14]3[CH:19]=[CH:18][N:17]=[CH:16][CH:15]=3)[S:11][C:10]=2[C:20](=[O:21])[NH:22][C:24]1([CH3:26])[CH3:23])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)=O
Reactant: NC(=O)c1sc(-c2ccncc2)cc1NCc1ccccc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: CC1(C)NC(=O)c2sc(-c3ccncc3)cc2N1Cc1ccccc1
Temperature: 70 °C
Reaction time: 72 h
Yield: 60 %

Procedure:
A mixture of 3-(benzylamino)-5-(pyridin-4-yl)thiophene-2-carboxamide (0.124 g, 0.400 mmol), acetone (3.0 mL), p-toluenesulfonic acid monohydrate (0.0095 g, 0.050 mmol) and acetic acid (2.0 mL) was stirred for 3 days at 70° C. in a sealed tube. The mixture was poured into sat. aqueous sodium hydrogen carbonate (150 mL). Extraction with ethyl acetate (100 mL, 50 mL), drying over magnesium sulfate, filtration and concentration at reduced pressure gave an oil. This oil was purified by column chromatography (Combiflash, 40 g silica gel, dichloromethane to ethyl acetate), then triturated with ethyl acetate/hexanes (1:1), and the precipitate was collected by filtration to afford the title compound (0.0841 g, 60%) as a yellow solid:
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C:12]1[C:13]([C:23]([OH:25])=O)=[N:14][C:15]2[C:20]([CH:21]=1)=[CH:19][CH:18]=[C:17]([Br:22])[CH:16]=2)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:26][C:27]1[CH:28]=[N:29][CH:30]=[CH:31][C:32]=1[N:33]1[CH2:38][C@H:37]([CH3:39])[C@H:36]([NH:40][C:41](=[O:44])[O:42][CH3:43])[C@H:35]([NH:45][C:46](=[O:52])[O:47][C:48]([CH3:51])([CH3:50])[CH3:49])[CH2:34]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[CH2:1]([O:8][C:9]([NH:11][C:12]1[C:13]([C:23]([NH:26][C:27]2[CH:28]=[N:29][CH:30]=[CH:31][C:32]=2[N:33]2[CH2:38][C@H:37]([CH3:39])[C@H:36]([NH:40][C:41](=[O:44])[O:42][CH3:43])[C@H:35]([NH:45][C:46](=[O:52])[O:47][C:48]([CH3:51])([CH3:50])[CH3:49])[CH2:34]2)=[O:25])=[N:14][C:15]2[C:20]([CH:21]=1)=[CH:19][CH:18]=[C:17]([Br:22])[CH:16]=2)=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)N[C@H]1[C@@H](C)CN(c2ccncc2N)C[C@H]1NC(=O)OC(C)(C)C
Reactant: O=C(Nc1cc2ccc(Br)cc2nc1C(=O)O)OCc1ccccc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)N[C@H]1[C@@H](C)CN(c2ccncc2NC(=O)c2nc3cc(Br)ccc3cc2NC(=O)OCc2ccccc2)C[C@H]1NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 3 h
Yield: 183.8 %

Procedure:
To a mixture of 3-{[(benzyloxy)carbonyl]amino}-7-bromoquinoline-2-carboxylic acid (360 mg, 0.897 mmol), tert-butyl methyl [(3R,4S,5S)-1-(3-aminopyridin-4-yl)-5-methylpiperidine-3,4-diyl]biscarbamate (303 mg, 0.799 mmol) and HATU (914.8 mg, 2.406 mmol) in DMF (5.0 mL), DIPEA (539 mg, 4.17 mmol) was added. The mixture was stirred at room temperature for 3 h. The volatile solvents were removed under reduced pressure, and the residue was purified by flash chromatography (40 g, 0-100% EtOAc in hexanes) to give the sub-title compound as a red viscous oil (1.120 g, 184%). The product was used in the next step without further purification. LCMS calc. for C36H41BrN7O7 (M+H)+: m/z=762.2. Found: 762.3.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:10]2([C:25]([F:28])([F:27])[F:26])[O:14][N:13]=[C:12]([C:15]3[CH:23]=[CH:22][C:18]([C:19]([OH:21])=O)=[C:17]([CH3:24])[CH:16]=3)[CH2:11]2)[CH:5]=[C:6]([Cl:9])[C:7]=1[F:8].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.Cl.[NH2:63][CH2:64][CH2:65][C:66]1[CH:67]=[CH:68][C:69]2[C:73]([CH3:75])([CH3:74])[O:72][B:71]([OH:76])[C:70]=2[CH:77]=1>CN(C=O)C.O>[Cl:9][C:6]1[CH:5]=[C:4]([C:10]2([C:25]([F:28])([F:26])[F:27])[O:14][N:13]=[C:12]([C:15]3[CH:23]=[CH:22][C:18]([C:19]([NH:63][CH2:64][CH2:65][C:66]4[CH:67]=[CH:68][C:69]5[C:73]([CH3:74])([CH3:75])[O:72][B:71]([OH:76])[C:70]=5[CH:77]=4)=[O:21])=[C:17]([CH3:24])[CH:16]=3)[CH2:11]2)[CH:3]=[C:2]([Cl:1])[C:7]=1[F:8]
Reactant: Cc1cc(C2=NOC(c3cc(Cl)c(F)c(Cl)c3)(C(F)(F)F)C2)ccc1C(=O)O
Reactant: CC1(C)OB(O)c2cc(CCN)ccc21
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cc(C2=NOC(c3cc(Cl)c(F)c(Cl)c3)(C(F)(F)F)C2)ccc1C(=O)NCCc1ccc2c(c1)B(O)OC2(C)C
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 49.9 %

Procedure:
To a solution of 4-(5-(3,5-dichloro-4-fluorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)-2-methylbenzoic acid (390 mg, 0.9 mmol) and HATU (513 mg, 1.35 mmol) in DMF (18 mL), DIPEA (350 mg, 2.7 mmol) was added. The reaction mixture was stirred at rt for 10 min and crude 6-(2-aminoethyl)-3,3-dimethylbenzo[c][1,2]oxaborol-1(3H)-ol hydrochloride (1 mmol) was added. The reaction mixture was continued to stir overnight. Water was added and the mixture was extracted three times with ethyl acetate. The combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by prep-HPLC to give the final title compound 4-(5-(3,5-dichloro-4-fluorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)-N-(2-(1-hydroxy-3,3-dimethyl-1,3-dihydro-benzo[c][1,2]-oxaborol-6-yl)ethyl)-2-methylbenzamide (280 mg; yield 50.2%) as a white solid. 1H NMR (500 MHz, DMSO-d6) δ 8.99 (s, 1H), 8.44 (t, J=6.0 Hz, 1H), 7.83 (d, J=6.5 Hz, 2H), 7.55-7.59 (m, 3H), 7.36-7.37 (m, 3H), 4.36 (d, J=18.5 Hz, 1 H), 4.34 (d, J=18.5 Hz, 1 H), 3.51 (q, J=7.5 Hz, 2H), 2.88 (t, J=7.5 Hz, 2H), 2.23 (s, 3 H), 1.45 (s, 6H) ppm;
Reaction SMILES: [NH:1]([C:32]([C:45]1[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=1)([C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1)[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)[CH2:2][C:3]([NH:5][CH2:6][C:7]([NH:9][C@H:10]([C:18]([NH:20][CH2:21][C:22]([O:24]CC1C=CC=CC=1)=[O:23])=[O:19])[CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[O:8])=[O:4].C1CC=CCC=1>CN(C=O)C.[C].[Pd]>[NH:1]([C:32]([C:45]1[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=1)([C:39]1[CH:40]=[CH:41][CH:42]=[CH:43][CH:44]=1)[C:33]1[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=1)[CH2:2][C:3]([NH:5][CH2:6][C:7]([NH:9][C@H:10]([C:18]([NH:20][CH2:21][C:22]([OH:24])=[O:23])=[O:19])[CH2:11][C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1)=[O:8])=[O:4]
Reactant: O=C(CNC(c1ccccc1)(c1ccccc1)c1ccccc1)NCC(=O)N[C@@H](Cc1ccccc1)C(=O)NCC(=O)OCc1ccccc1
Agent: [Pd]
Solvent: CN(C)C=O
Solvent: C1=CCC=CC1
Product: O=C(O)CNC(=O)[C@H](Cc1ccccc1)NC(=O)CNC(=O)CNC(c1ccccc1)(c1ccccc1)c1ccccc1
Yield: 88.9 %

Procedure:
1.3 g of Trt-Gly-Gly-Phe-Gly-OBn (193) obtained in item (3) above was dissolved in 20 ml of DMF to obtain a solution. To the obtained solution were added 0.5 g of a 10% palladium-carbon catalyst and 0.4 g of 1,4-cyclohexadiene, followed by a reaction at room temperature for 30 minutes, to thereby obtain a reaction mixture. The obtained reaction mixture was subjected to filtration to remove the catalyst, thereby obtaining a solution. The solvents were distilled off from the obtained solution under reduced pressure. The resultant residue was purified by silica gel column chromatography (silica gel: Art No. 9365, Silica gel 60, 200-400 mesh, manufactured and sold by Merck KGaA, Germany; eluent: chloroform/methanol ratio=7/1), thereby obtaining 1.0 g of Trt-Gly-Gly-Phe-Gly (190).
Reaction SMILES: [C:1]1([C:7](=O)[CH2:8][CH2:9][CH2:10][C:11]2[CH:16]=[CH:15][N:14]=[CH:13][CH:12]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl.[NH2:19][OH:20].C([O-])(=O)C.[Na+].O>CCO>[C:1]1([C:7](=[N:19][OH:20])[CH2:8][CH2:9][CH2:10][C:11]2[CH:16]=[CH:15][N:14]=[CH:13][CH:12]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C(CCCc1ccncc1)c1ccccc1
Reactant: NO
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: ON=C(CCCc1ccncc1)c1ccccc1
Temperature: 80 °C
Yield: 95.7 %

Procedure:
To a solution of 1-phenyl-4-(pyridin-4-yl)butan-1-one (2.0 g, 8.7 mmol) in 20 mL of EtOH was added hydroxylamine hydrochloride (0.73 g, 10 mmol) and sodium acetate (1.4 g, 17 mmol). The reaction flask was heated at 80° C. for 4 h and was then cooled to room temperature. Addition of water and filtration of the resultant precipitate afforded 2.0 g (89%) of the title compound.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][CH:11]1[C:15]2[C:16]3[N:17]([N:20]=[C:21]([CH3:28])[C:22]=3[C:23]([O:25][CH2:26][CH3:27])=[O:24])[CH:18]=[CH:19][C:14]=2[CH2:13][CH2:12]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CC(NCCC#N)CC1C=CC=CC=1.Cl.CCCCCC>CCCCCC.C(O)C>[C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][C@H:11]1[C:15]2[C:16]3[N:17]([N:20]=[C:21]([CH3:28])[C:22]=3[C:23]([O:25][CH2:26][CH3:27])=[O:24])[CH:18]=[CH:19][C:14]=2[CH2:13][CH2:12]1)=[O:7])([CH3:3])([CH3:2])[CH3:4]
Reactant: CCOC(=O)c1c(C)nn2ccc3c(c12)C(CCNC(=O)OC(C)(C)C)CC3
Agent: CC(Cc1ccccc1)NCCC#N
Agent: Cl
Solvent: CCCCCC
Solvent: CCO
Product: CCOC(=O)c1c(C)nn2ccc3c(c12)[C@H](CCNC(=O)OC(C)(C)C)CC3
Yield: 48.7 %

Procedure:
Ethyl 9-{2-[(tert-butoxycarbonyl)amino]ethyl}-2-methyl-8,9-dihydro-7H-cyclopenta[c]pyrazolo[1,5-a]pyridine-1-carboxylate (300 mg) was fractionated by high performance liquid chromatography (instrument: Prep LC 2000 (manufactured by Nihon Waters K.K.), column: CHIRALPAK AD (50 mm ID×500 mm L, manufactured by Dicel Chemical Industries, Ltd.), mobile phase: A) hexane 100%, B) hexane/ethanol=70/30, mixing ratio: A/B=80/20, flow rate: 60 mL/min, column temperature: 30° C., sample concentration: 10 mg/mL (hexane/ethanol=95/5), injection amount: 300 mg). A fraction solution containing an optically active compound having a shorter retention time under the above-mentioned high performance liquid chromatography conditions was concentrated to give the title compound (146 mg, 99.7% ee). The enantiomer excess (ee) was measured by high performance liquid chromatography (column: CHIRALPAK AD (4.6 mm ID×250 mm L, manufactured by Dicel Chemical Industries, Ltd.), mobile phase: hexane/ethanol=95/5, flow rate: 0.5 mL/min, column temperature: 30° C., sample concentration: 0.25 mg/mL (hexane/ethanol=95/5), injection volume: 10 μL).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:22]=[CH:23][C:24]=1[Cl:25])[CH2:5][C:6]1[NH:7][C:8](=O)[C:9]2[C:14]([CH3:15])=[C:13]([C:16]([O:18][CH2:19][CH3:20])=[O:17])[S:12][C:10]=2[N:11]=1.P(Cl)(Cl)([Cl:28])=O.CN(C)C1C=CC=CC=1>>[Cl:28][C:8]1[C:9]2[C:14]([CH3:15])=[C:13]([C:16]([O:18][CH2:19][CH3:20])=[O:17])[S:12][C:10]=2[N:11]=[C:6]([CH2:5][C:4]2[CH:22]=[CH:23][C:24]([Cl:25])=[C:2]([Cl:1])[CH:3]=2)[N:7]=1
Reactant: CCOC(=O)c1sc2nc(Cc3ccc(Cl)c(Cl)c3)[nH]c(=O)c2c1C
Reactant: O=P(Cl)(Cl)Cl
Solvent: CN(C)c1ccccc1
Product: CCOC(=O)c1sc2nc(Cc3ccc(Cl)c(Cl)c3)nc(Cl)c2c1C
Reaction time: 4 h

Procedure:
Three (3.00) g of ethyl 2-(3,4-dichlorobenzyl)-5-methyl-4-oxo-3,4-dihydrothieno[2,3-d]pyrimidine-6-carboxylate and 37 mL of phosphorus oxychloride were mixed, and to which 1.4 mL of N,N-dimethylaniline was added, followed by stirring at 900 for 4 hours. The reaction liquid was poured on ice and stirred for 3 hours, and the precipitated crystals were recovered by filtration and washed with water. Drying the crystals under aeration, 3.05 g of the title compound was obtained.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[N:11]([CH:12]3[CH2:14][CH2:13]3)[CH2:10][CH2:9][C:8]([C:15]([NH:17][C:18]3[CH:23]=[CH:22][C:21]([CH2:24][N:25]([CH3:32])[CH:26]4[CH2:31][CH2:30][O:29][CH2:28][CH2:27]4)=[CH:20][CH:19]=3)=[O:16])=[CH:7][C:6]=2[CH:33]=1.B([O-])([O-])O[C:36]1[CH:41]=[CH:40][C:39]([O:42][CH2:43][CH2:44][O:45][CH2:46][CH2:47][CH2:48][CH3:49])=[CH:38][CH:37]=1.C(=O)([O-])[O-].[K+].[K+].C(O)C>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.C1(C)C=CC=CC=1>[CH2:46]([O:45][CH2:44][CH2:43][O:42][C:39]1[CH:38]=[CH:37][C:36]([C:2]2[CH:3]=[CH:4][C:5]3[N:11]([CH:12]4[CH2:14][CH2:13]4)[CH2:10][CH2:9][C:8]([C:15]([NH:17][C:18]4[CH:19]=[CH:20][C:21]([CH2:24][N:25]([CH3:32])[CH:26]5[CH2:31][CH2:30][O:29][CH2:28][CH2:27]5)=[CH:22][CH:23]=4)=[O:16])=[CH:7][C:6]=3[CH:33]=2)=[CH:41][CH:40]=1)[CH2:47][CH2:48][CH3:49]
Reactant: CCCCOCCOc1ccc(OB([O-])[O-])cc1
Reactant: CN(Cc1ccc(NC(=O)C2=Cc3cc(Br)ccc3N(C3CC3)CC2)cc1)C1CCOCC1
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: [K+]
Solvent: CCO
Solvent: Cc1ccccc1
Product: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(CN(C)C4CCOCC4)cc2)CCN3C2CC2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 45.5 %

Procedure:
A mixture of 7-bromo-1-cyclopropyl-N-[4-[[N-methyl-N-(tetrahydro-2H-pyran-4-yl)amino]methyl]phenyl]-2,3-dihydro-1H-1-benzazepine-4-carboxamide (0.45 g), 4-(2-butoxyethoxy)phenyl borate (0.23 g), 1M potassium carbonate solution (1.5 ml), ethanol (1.5 ml) and toluene (25 ml) was stirred under argon atmosphere at room temperature for 30 minutes. To the mixture was added tetrakis(triphenylphosphine)palladium (0.05 g), and the mixture was refluxed for 3 hours under argon atmosphere and extracted with ethyl acetate. The organic layer was washed with water and saturated brine and dried with anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified with silica gel column chromatography (ethyl acetate/methanol/triethylamine) to give crude crystals, which were recrystallized to give 7-[4-(2-butoxyethoxy)phenyl]-1-cyclopropyl-N-[4-[[N-methyl-N-(tetrahydro-2H-pyran-4-yl)amino]methyl]phenyl]-2,3-dihydro-1H-1-benzazepine-4-carboxamide (Compound 31) (0.25 g) as pale yellow crystals.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][O:9][C:10]1[CH:31]=[CH:30][C:13]([C:14]([NH:16][NH:17][C:18](=O)[C:19]2[CH:24]=[CH:23][C:22]([C:25]([O:27][CH3:28])=[O:26])=[CH:21][CH:20]=2)=O)=[CH:12][CH:11]=1.P12(SP3(SP(SP(S3)(S1)=S)(=S)S2)=S)=[S:33].O>O1CCCC1>[CH3:1][O:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][O:9][C:10]1[CH:31]=[CH:30][C:13]([C:14]2[S:33][C:18]([C:19]3[CH:24]=[CH:23][C:22]([C:25]([O:27][CH3:28])=[O:26])=[CH:21][CH:20]=3)=[N:17][N:16]=2)=[CH:12][CH:11]=1
Reactant: S=P12SP3(=S)SP(=S)(S1)SP(=S)(S2)S3
Reactant: COCCCCCCOc1ccc(C(=O)NNC(=O)c2ccc(C(=O)OC)cc2)cc1
Solvent: O
Solvent: C1CCOC1
Product: COCCCCCCOc1ccc(-c2nnc(-c3ccc(C(=O)OC)cc3)s2)cc1
Temperature: 25 °C
Yield: 165.2 %

Procedure:
A mixture of N-[4-(6-methoxy-n-hexyloxy)benzoyl]-N′-(4-methoxycarbonylbenzoyl)hydrazine (193.4 g) and phosphorus pentasulfide (113.34 g) in tetrahydrofuran (2.5 L) was heated to reflux for 1 hour then cooled to room temperature and poured into water (7 L). The resulting precipitate was collected by filtration, washed thoroughly with water then partially dried. The solid was added to 1:1 CH3CN—H2O (200 ml), sitrred then filtered. This procedure was repeated a further 2 times, and the resulting yellow powder washed thoroughly with acetonitrile (500 ml×5) then dried under hi-vacuum at 50° C. to give methyl 4-[5-[4-(6-methoxy-n-hexyloxy)phenyl]-1,3,4-thiadiazol-2-yl]benzoate (179.6 g) as a yellow powder.
Reaction SMILES: Cl[CH2:2][C:3]([O-:5])=O.[CH2:6]([Mg]Br)[CH3:7].[CH3:10][Si:11](Cl)([CH3:13])[CH3:12].Cl>CCOCC>[CH3:10][Si:11]([CH3:13])([CH3:12])[C:6]#[C:7][CH:3]([OH:5])[CH3:2]
Reactant: O=C([O-])CCl
Reactant: C[Si](C)(C)Cl
Reactant: CC[Mg]Br
Agent: Cl
Solvent: CCOCC
Product: CC(O)C#C[Si](C)(C)C
Temperature: 0 °C
Reaction time: 8 h

Procedure:
To a solution of ii (10.0 g, 0.14 mol) in ether (200 mL) was added ethylmagnesium bromide (105 mL, 3M in THF, 0.32 mol) dropwise at 0° C. The resulting solution was refluxed for 1.5 h. After the reaction solution was cooled to 0° C., trimethylsilyl chloride (40 mL, 0.32 mol) was added. The solution was warmed to room temperature and stirred overnight. Hydrochloric acid (100 mL, 10%) was added at 0° C. After 20 min, the two layers were separated. The aqueous layer was extracted with ether (2×50 mL). The combined organic solutions were dried over anhydrous magnesium sulfate, filtered and concentrated. Distillation of the residue gave 19.9 g (98%) ii-a as a colorless liquid: bp 80.5°-83.5° C./17.5 mm Hg; IR (neat) 3337, 2175, 1452, 1251, 1119, 1048, and 946 cm-1 ; 1H NMR (CDCl3, 300 MHz) δ 4.42 (q, J=6.6 Hz, 1 H, CHOH), 3.12 (br S, 1 H, OH), 1,16 (d, J=6.6 Hz, 3 H, CHCH3), and 0.08 (s, 9 H, SiCH3); 13C NMR (CDCl3, 75.5 MHz) δ 108.12, 88.19, 58.61, 24. 05, and 0.01.
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[C:6](=[O:18])[C:5]2=[O:19].[CH2:20]1[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH2:22][NH:21]1>C1COCC1>[CH2:20]1[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH2:22][N:21]1[C:6](=[O:18])[C:5]([C:4]1[CH:3]=[C:2]([I:1])[CH:10]=[CH:9][C:8]=1[NH:7][C:11](=[O:12])[O:13][C:14]([CH3:15])([CH3:16])[CH3:17])=[O:19]
Reactant: c1ccc2c(c1)CNC2
Reactant: CC(C)(C)OC(=O)N1C(=O)C(=O)c2cc(I)ccc21
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)Nc1ccc(I)cc1C(=O)C(=O)N1Cc2ccccc2C1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
62.41 g of tert-butyl 5-iodo-2,3-dioxo-2,3-dihydroindole-1-carboxylate are dissolved in dried THF, and 18.98 ml of 2,3-dihydro-1H-isoindole are added. The mixture is stirred at 25° C. for 30 min, evaporated to dryness in vacuo, and the residue is triturated with petroleum ether, filtration gives 82.3 g of tert-butyl {2-[2-(1,3-dihydroisoindol-2-yl)-2-oxoacetyl]-4-iodophenyl}carbamate (beige solid); LC-MS retention time: 2.63 min;