Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3](=[O:31])[C:4]1[CH:9]=[C:8]([O:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][O:17][C:18]2[CH:23]=[CH:22][C:21]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)=[CH:20][CH:19]=2)[CH:7]=[CH:6][C:5]=1[OH:30].[CH2:32](Br)[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1.C(=O)([O-])[O-].[K+].[K+]>CC(C)=O.CN(C=O)C>[CH3:1][O:2][C:3](=[O:31])[C:4]1[CH:9]=[C:8]([O:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][O:17][C:18]2[CH:19]=[CH:20][C:21]([C:24]3[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=3)=[CH:22][CH:23]=2)[CH:7]=[CH:6][C:5]=1[O:30][CH2:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1
Reactant: COC(=O)c1cc(OCCCCCCOc2ccc(-c3ccccc3)cc2)ccc1O
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: CN(C)C=O
Product: COC(=O)c1cc(OCCCCCCOc2ccc(-c3ccccc3)cc2)ccc1OCc1ccccc1
Yield: 89 %

Procedure:
A mixture of 1.4 g (3.3 mmol) of 5-[[6-([1,1'-biphenyl]-4-yloxy) hexyl]oxy]-2-hydroxybenzoic acid methyl ester, 0.6 ml (5 mmol) of benzyl bromide and 2.5 g (16.5 mmol) of potassium carbonate in 50 ml of acetone and 5 ml of DMF was stirred at reflux for 24 hours. After the usual workup, the crude product was recrystallized from ethyl acetate-hexane to give 1.5 g (89% yield, mp 85°-87°) of 5-[[6-([1,1'-biphenyl]-4-yloxy)hexyl]oxy]-2-(phenylmethoxy)benzoic acid methyl ester.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([C:10](=[N:12]O)[CH3:11])=[CH:2]1.C(O)(=O)C.[H][H]>C(O)C.[C].[Pd]>[NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([CH:10]([NH2:12])[CH3:11])=[CH:2]1
Reactant: [H][H]
Reactant: CC(=NO)c1c[nH]c2ccccc12
Agent: [Pd]
Solvent: CCO
Solvent: CC(=O)O
Product: CC(N)c1c[nH]c2ccccc12
Yield: 74.5 %

Procedure:
10% palladium-carbon (water content: 50%, 12.2 mg) was added to a solution of 1-(1H-indol-3-yl)ethanone oxime (0.20 g) obtained as above and acetic acid (0.7 mL) in ethanol (7 mL) at room temperature. The reaction mixture was stirred in a hydrogen stream at room temperature for 10 hours, and then filtered on a celite. The filtrate was concentrated under reduced pressure. The residue was extracted with chloroform. The organic layer was washed sequentially with a 1 N aqueous solution of sodium hydroxide and brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (Carrier: Chromatorex™ NH, elution solvent:chloroform-methanol system) to obtain 0.137 g of the title compound.
Reaction SMILES: [NH2:1][C:2]1[N:10]=[C:9]([SH:11])[N:8]=[C:7]2[C:3]=1[N:4]=[C:5]([OH:19])[N:6]2[CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C(=O)([O-])[O-].[K+].[K+].[CH3:26][O:27][CH2:28][CH2:29]Cl>CN(C)C=O>[NH2:1][C:2]1[N:10]=[C:9]([S:11][CH2:29][CH2:28][O:27][CH3:26])[N:8]=[C:7]2[C:3]=1[N:4]=[C:5]([OH:19])[N:6]2[CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: Nc1nc(S)nc2c1nc(O)n2Cc1ccccc1
Reactant: COCCCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COCCSc1nc(N)c2nc(O)n(Cc3ccccc3)c2n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 12.3 %

Procedure:
Crude 6-amino-9-benzyl-8-hydroxy-2-mercaptopurine (134 mg, 0.49 mmol) was suspended in dimethylformamide (65 ml). To the suspension were added potassium carbonate (100 mg, 0.72 mmol) and 2-chloroethyl methyl ether (0.067 ml, 0.73 mmol) in order. The mixture was stirred at room temperature for 8 hours. The solvent was removed in vacuo, and the residue was purified by silica gel chromatography (3% methanol/chloroform) to give the subject compound (20 mg, yield 12%).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:51])[NH:4][C@@H:5]([C:47]([CH3:50])([CH3:49])[CH3:48])[C:6](=[O:46])[NH:7][C@@H:8]([CH2:33][C:34]1[CH:39]=[CH:38][C:37]([C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][N:41]=2)=[CH:36][CH:35]=1)[C@@H:9]([OH:32])[CH2:10][C@H:11]([CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[NH:12][C:13](=[O:24])[C@H:14]([C:20]([CH3:23])([CH3:22])[CH3:21])[NH:15][C:16](=[O:19])[O:17][CH3:18].[CH3:52][S:53][CH3:54].C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(#N)C.C(OCC)(=O)C>[CH2:25]([C@H:11]([NH:12][C:13]([C@@H:14]([NH:15][C:16](=[O:19])[O:17][CH3:18])[C:20]([CH3:23])([CH3:22])[CH3:21])=[O:24])[CH2:10][C@H:9]([O:32][CH2:52][S:53][CH3:54])[C@@H:8]([NH:7][C:6](=[O:46])[C@H:5]([C:47]([CH3:50])([CH3:49])[CH3:48])[NH:4][C:3]([O:2][CH3:1])=[O:51])[CH2:33][C:34]1[CH:35]=[CH:36][C:37]([C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][N:41]=2)=[CH:38][CH:39]=1)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: CSC
Reactant: COC(=O)N[C@H](C(=O)N[C@@H](Cc1ccccc1)C[C@H](O)[C@H](Cc1ccc(-c2ccccn2)cc1)NC(=O)[C@@H](NC(=O)OC)C(C)(C)C)C(C)(C)C
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: CCOC(C)=O
Solvent: CC#N
Product: COC(=O)N[C@H](C(=O)N[C@@H](Cc1ccccc1)C[C@H](OCSC)[C@H](Cc1ccc(-c2ccccn2)cc1)NC(=O)[C@@H](NC(=O)OC)C(C)(C)C)C(C)(C)C
Temperature: 0 °C
Reaction time: 1 h
Yield: 76.5 %

Procedure:
To a solution of the compound of Example 25 (0.125 g, 0.178 mmol) and methyl sulfide (0.405 mL, 5.48 mmol) in acetonitrile (0.75 mL) at 0° C. was added benzoyl peroxide (0.63 g, 2.60 mmol), and the mixture was stirred at 0° C. for 1 hour. The reaction was diluted with ethyl acetate and washed with 10% Na2CO3 and brine. The organic was dried over MgSO4, filtered and evaporated. The residue was chromatographed on silica gel eluting with a gradient starting with dichloromethane and ending with ethyl acetate to give the title compound (0.104 g, 77% yield).
Reaction SMILES: [CH:1]([C:3]1[S:7][C:6]([C:8]2[S:9][C:10]([C:13]3[S:14][CH:15]=[CH:16][CH:17]=3)=[CH:11][CH:12]=2)=[CH:5][CH:4]=1)=O.[NH2:18][NH2:19]>C(O)C>[N:18](=[C:1]=[C:3]1[S:7][C:6]([C:8]2[S:9][C:10]([C:13]3[S:14][CH:15]=[CH:16][CH:17]=3)=[CH:11][CH:12]=2)=[CH:5][CH2:4]1)[NH2:19]
Reactant: NN
Reactant: O=Cc1ccc(-c2ccc(-c3cccs3)s2)s1
Solvent: CCO
Product: NN=C=C1CC=C(c2ccc(-c3cccs3)s2)S1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
0.5 g of 5-formyl-2,2':5',2"-terthiophene was dissolved in 200 ml of ethanol. 2 ml of hydrazine was dropped in slowly. After 2 ml of H2 SO4 (2N) was dropped in and stirred for 3 hours at room temperature, the reaction solution was monitored by thin layer chromatography to determine whether the reaction was completed. Ethanol was removed under reduced pressure. Then, it was extracted with ethyl acetate and treated in situ on column chromatographic separation. From the eluate of ethyl acetate/n-hexane (1/9) the mixture of syn-5-hydrazonomethylidene-2,2':5',2"-terthiophene and anti-5-hydrazonomethylidene-2,2':5',2"-terthiophene were thus obtained.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([CH2:7][C:8]2[O:13][C:12]([CH2:14][OH:15])=[CH:11][C:10](=[O:16])[C:9]=2[OH:17])[CH2:3][CH2:2]1.C(=O)([O-])[O-].[K+].[K+].[CH3:24][O:25][C:26]1[CH:33]=[CH:32][C:29]([CH2:30]Cl)=[CH:28][CH:27]=1>CN(C)C=O>[O:1]1[CH2:6][CH2:5][N:4]([CH2:7][C:8]2[O:13][C:12]([CH2:14][OH:15])=[CH:11][C:10](=[O:16])[C:9]=2[O:17][CH2:30][C:29]2[CH:32]=[CH:33][C:26]([O:25][CH3:24])=[CH:27][CH:28]=2)[CH2:3][CH2:2]1
Reactant: COc1ccc(CCl)cc1
Reactant: O=c1cc(CO)oc(CN2CCOCC2)c1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1ccc(COc2c(CN3CCOCC3)oc(CO)cc2=O)cc1
Temperature: 70 °C
Reaction time: 17 h

Procedure:
To a suspension of 5.45 g of 6-morpholinomethyl-5-hydroxy-2-hydroxymethyl-4-pyrone in 50 ml of dimethylformamide were successively added 3.32 g of potassium carbonate and 4 ml of p-methoxybenzyl chloride. The mixture was stirred at 70° C. for 4 hours and at room temperature for a further 17 hours. The reaction liquid was concentrated and 100 ml of water and 200 ml of dichloromethane were added to the concentrate. The organic phase was then washed with 100 ml of water. After drying over anhydrous magnesium sulfate, the organic phase was concentrated under reduced pressure. The concentrate was then separated and purified by flash column chromatography (eluting solution; chloroform: methanol=20:1) using Wako Gel C-300 (200 g) to give 1.8 g of the title compound.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:12]=[CH:13][C:14]=1[O:15][CH3:16])[C:5]([CH2:7][CH2:8][C:9](O)=[O:10])=O.O.[NH2:18][NH2:19]>>[NH2:1][C:2]1[CH:3]=[C:4]([C:5]2[CH2:7][CH2:8][C:9](=[O:10])[NH:18][N:19]=2)[CH:12]=[CH:13][C:14]=1[O:15][CH3:16]
Reactant: NN
Reactant: COc1ccc(C(=O)CCC(=O)O)cc1N
Solvent: O
Product: COc1ccc(C2=NNC(=O)CC2)cc1N
Yield: 95 %

Procedure:
This was prepared in 95% yield by reaction of 3-(3-amino-4-methoxybenzoyl)-propionic acid with hydrazine hydrate in ethanolic solution at reflux temperature for 5 hours. It had m.p. 218°-220°C after crystallisation from ethanol.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][C:11]([C:19]2[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][C:20]=2[C:26]#[C:27][C:28](OCC)([O:32]CC)[O:29][CH2:30][CH3:31])([C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>CCO.O>[CH2:1]([N:8]1[CH2:9][CH2:10][C:11]([C:19]2[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][C:20]=2[C:26]#[C:27][C:28]([O:29][CH2:30][CH3:31])=[O:32])([C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH2:12][CH2:13]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)C1(c2ccc(Cl)cc2C#CC(OCC)(OCC)OCC)CCN(Cc2ccccc2)CC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCO
Solvent: O
Product: CCOC(=O)C#Cc1cc(Cl)ccc1C1(C(=O)OCC)CCN(Cc2ccccc2)CC1
Reaction time: 0.5 h
Yield: 91.1 %

Procedure:
A solution of ethyl 1-benzyl-4-(4-chloro-2-(3,3,3-triethoxyprop-1-ynyl)phenyl)piperidine-4-carboxylate (820 mg, 1.5 mmol) and p-toluenesulfonic acid monohydrate (443 mg, 2.3 mmol) in EtOH (25 mL) and water (5 mL) was stirred at 23° C. After 30 minutes, the solvents were removed in vacuo, and the residue was diluted with EtOAc (200 mL) and washed with 10% HCl solution (100 mL), saturated NaHCO3 solution (100 mL) and brine (100 mL), dried over MgSO4, and concentrated in vacuo affording 620 mg of ethyl 1-benzyl-4-(4-chloro-2-(3-ethoxy-3-oxoprop-1-ynyl)phenyl)piperidine-4-carboxylate. MS m/e=454.1 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:20]3[C:19]4[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=4)[CH2:13][C:12]=3[C:11]([C:21]#[N:22])=[C:10]([N:23]3[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]3)[CH:9]=2)=[CH:4][CH:3]=1.[H-].[Na+].C1C[O:34]CC1>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:20]3[C:19]4[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=4)[C:13](=[O:34])[C:12]=3[C:11]([C:21]#[N:22])=[C:10]([N:23]3[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28]3)[CH:9]=2)=[CH:6][CH:7]=1
Reactant: N#Cc1c(N2CCCCC2)cc(-c2ccc(F)cc2)c2c1Cc1ccccc1-2
Reactant: C1CCOC1
Agent: [H-]
Agent: [Na+]
Product: N#Cc1c(N2CCCCC2)cc(-c2ccc(F)cc2)c2c1C(=O)c1ccccc1-2
Temperature: 2.5 °C

Procedure:
A solution of 4-(4-fluorophenyl)-2-(piperidin-1-yl)-9H-fluorene-1-carbonitrile (368 mg) in THF was added sodium hydride (38 mg) and was stirred at 0-5° C. for less than five minutes. After completion, the reaction solvent was evaporated under vacuum and the crude solid obtained was quenched with ice water and subsequently neutralized by dilute HCl. The precipitate thus obtained was filtered and purified on a silica gel column using ethyl acetate-hexane as eluent. Red solid; mp 152-154° C.; ESIMS 383 (M++1); IR (KBr) 1708 cm−1 (CO), 2221 (CN); HRMS calcd. for C25H19 FN2O 382.1481 found 382.1471.
Reaction SMILES: O=[C:2]([C:30]1[CH:35]=[CH:34][C:33]([C:36]2[NH:40][C:39]([C@@H:41]3[CH2:45][CH2:44][CH2:43][N:42]3C(OC(C)(C)C)=O)=[N:38][CH:37]=2)=[CH:32][CH:31]=1)[CH2:3][CH2:4][C:5]([C:7]1[CH:12]=[CH:11][C:10]([C:13]2[NH:17][C:16]([C@@H:18]3[CH2:22][CH2:21][CH2:20][N:19]3C(OC(C)(C)C)=O)=[N:15][CH:14]=2)=[CH:9][CH:8]=1)=O.Cl.Cl.[N:55]1([C:61]2[N:66]=[CH:65][C:64]([NH2:67])=[CH:63][CH:62]=2)[CH2:60][CH2:59][CH2:58][CH2:57][CH2:56]1.C(O)(C(F)(F)F)=O>C1(C)C=CC=CC=1>[NH:19]1[CH2:20][CH2:21][CH2:22][C@H:18]1[C:16]1[NH:15][CH:14]=[C:13]([C:10]2[CH:9]=[CH:8][C:7]([C:5]3[N:67]([C:64]4[CH:63]=[CH:62][C:61]([N:55]5[CH2:56][CH2:57][CH2:58][CH2:59][CH2:60]5)=[N:66][CH:65]=4)[C:2]([C:30]4[CH:35]=[CH:34][C:33]([C:36]5[N:40]=[C:39]([C@@H:41]6[CH2:45][CH2:44][CH2:43][NH:42]6)[NH:38][CH:37]=5)=[CH:32][CH:31]=4)=[CH:3][CH:4]=3)=[CH:12][CH:11]=2)[N:17]=1
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1c1ncc(-c2ccc(C(=O)CCC(=O)c3ccc(-c4cnc([C@@H]5CCCN5C(=O)OC(C)(C)C)[nH]4)cc3)cc2)[nH]1
Reactant: Nc1ccc(N2CCCCC2)nc1
Agent: Cl
Solvent: O=C(O)C(F)(F)F
Solvent: Cc1ccccc1
Product: c1cc(-c2ccc(-c3ccc(-c4c[nH]c([C@@H]5CCCN5)n4)cc3)n2-c2ccc(N3CCCCC3)nc2)ccc1-c1c[nH]c([C@@H]2CCCN2)n1
Temperature: 110 °C
Reaction time: 3 h
Yield: 170.4 %

Procedure:
To a solution of the product from Example 138B (0.20 g, 0.28 mmol) and the product from Example 144C (0.11 g, 0.42 mmol) in toluene (2.8 mL) was added TFA (22 μL, 0.28 mmol). The mixture was stirred at 110° C. for 3 hours. To the cooled mixture was added TFA (0.5 mL) and the mixture was stirred for 1 h at rt. The solvent was then removed under reduced pressure and triturated with diethylether and dried to provide 0.31 g of the desired compound as a TFA salt. 1HNMR (DMSO-d6; 400 MHz): δ 9.78 (br s, 2H), 7.84 (d, J=2.71 Hz, 1H), 7.75 (s, 2H), 7.67 (AA′XX′, J=8.34 Hz, 4H), 7.35 (dd, J=9.11, 2.71 Hz, 1H), 7.18 (AA′XX′, J=8.46 Hz, 4H), 6.79 (d, J=9.11 Hz, 1H), 6.53 (s, 2H), 4.79 (app t, J=7.81 Hz, 2H), 3.4-3.2 (m, 4H), 2.44-2.36 (m, 2H), 2.25-1.98 (m, 6H), 1.65-1.45 (m, 6H).
Reaction SMILES: [C:1](O)(=[O:5])[C:2]([CH3:4])=[CH2:3].[C:7]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[O:17][CH2:18][CH:19]([CH3:21])[CH3:20])([CH3:10])([CH3:9])[CH3:8].CS(O)(=O)=O.O=P12OP3(OP(OP(O3)(O1)=O)(=O)O2)=O>O>[CH2:18]([O:17][C:12]1[CH:13]=[C:14]2[C:15](=[CH:16][C:11]=1[C:7]([CH3:10])([CH3:9])[CH3:8])[C:1](=[O:5])[CH:2]([CH3:4])[CH2:3]2)[CH:19]([CH3:21])[CH3:20]
Reactant: CC(C)COc1ccccc1C(C)(C)C
Reactant: C=C(C)C(=O)O
Agent: CS(=O)(=O)O
Agent: O=P12OP3(=O)OP(=O)(O1)OP(=O)(O2)O3
Solvent: O
Product: CC(C)COc1cc2c(cc1C(C)(C)C)C(=O)C(C)C2
Temperature: 50 °C
Reaction time: 0.5 h
Yield: 76.8 %

Procedure:
A mixture of 75.1 g (0.872 mol) of methacrylic acid and 90.0 g (0.436 mol) of 1-tert-butyl-2-isobutoxybenzene was added dropwise to Eaton's reagent (prepared from 119 g of P4O10 and 600 ml of MeSO3H) for 2 h at 50° C. The resulting mixture was stirred at 50° C. for 30 min, then cooled to room temperature, and poured into 1 liter of cold water. The crude product was extracted with 3×200 ml of dichloromethane. The organic extract was washed with aqueous K2CO3, dried over Na2SO4, and then passed through a pad of silica gel (40-63 um). The silica gel pad was additionally washed by 100 ml of dichloromethane. The combined elute was evaporated to dryness. The residue was distilled in vacuum, b.p. 155-170° C./5 mm Hg. The product was purified by flash chromatography on silica gel 60 (40-63 um; eluent: n-hexane-dichloromethane-ether=25:25:1, vol.) to give 91.9 g (76%) of the title indanone.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:10](=[O:17])[CH:9]2[C:18]([O:20][CH2:21][CH3:22])=[O:19])=[CH:4][CH:3]=1.N1C=CN=C1.[C:28]([Si:32]([CH3:35])([CH3:34])Cl)([CH3:31])([CH3:30])[CH3:29].Cl>CN(C=O)C>[O:1]([C:2]1[CH:3]=[CH:4][C:5]([CH:8]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:10](=[O:17])[CH:9]2[C:18]([O:20][CH2:21][CH3:22])=[O:19])=[CH:6][CH:7]=1)[Si:32]([C:28]([CH3:31])([CH3:30])[CH3:29])([CH3:35])[CH3:34]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: CCOC(=O)C1C(=O)c2ccccc2C1c1ccc(O)cc1
Agent: Cl
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: CCOC(=O)C1C(=O)c2ccccc2C1c1ccc(O[Si](C)(C)C(C)(C)C)cc1
Temperature: 25 °C
Reaction time: 72 h
Yield: 128.9 %

Procedure:
To a solution of ethyl (2RS,3SR)-3-(4-hydroxyphenyl)-1-oxoindane-2-carboxylate (3.0 g, 10.2 mmol) in DMF (10 ml) under an argon atmosphere were added imidazole (1.72 g, 25.3 mmol) and t-butyldimethylchloro-silane (1.82 g, 12.1 mmol). The resulting mixture was allowed to stir at room temperature for 3 d, then was poured into dilute aqueous HCl and extracted with EtOAc (2×). The combined organic extracts were washed successively with H2O, aqueous NaHCO3, H2O and saturated aqueous NaCl and dried. The solvent was removed in vacuo to provide the title compound (5.40 g) which was used without further purification.
Reaction SMILES: [C:1]([OH:5])(=O)[CH2:2][OH:3].[Cl:6][C:7]1[CH:12]=[C:11]([NH:13][C:14]2[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][C:22]=3[O:24][CH2:25][C@@H:26]([NH:28][CH3:29])[CH3:27])[N:17]=[CH:16][N:15]=2)[CH:10]=[CH:9][C:8]=1[OH:30]>>[Cl:6][C:7]1[CH:12]=[C:11]([NH:13][C:14]2[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][C:22]=3[O:24][CH2:25][C@@H:26]([N:28]([CH3:29])[C:1](=[O:5])[CH2:2][OH:3])[CH3:27])[N:17]=[CH:16][N:15]=2)[CH:10]=[CH:9][C:8]=1[OH:30]
Reactant: O=C(O)CO
Reactant: CN[C@@H](C)COc1cccc2ncnc(Nc3ccc(O)c(Cl)c3)c12
Product: C[C@@H](COc1cccc2ncnc(Nc3ccc(O)c(Cl)c3)c12)N(C)C(=O)CO
Yield: 48 %

Procedure:
The procedure described in Example 3 (preparation of starting materials) was repeated using glycolic acid and 2-chloro-4-[(5-{[(2S)-2-(methylamino)propyl]oxy}quinazolin-4-yl)amino]phenol to give N-[(1S)-2-({4-[(3-chloro-4-hydroxyphenyl)amino]quinazolin-5-yl}oxy)-1-methylethyl]-2-hydroxy-N-methylacetamide in 48% yield; Mass spectrum MH+ 417.3.
Reaction SMILES: [Br-].[C:2]1([PH+](C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C[Si]([N-][Si](C)(C)C)(C)C.[K+].[CH2:31]([O:33][C:34]([N:36]1[CH2:42][CH2:41][C:40]2[C:43](Br)=[C:44]([C:46](=O)[C:47]([F:50])([F:49])[F:48])[S:45][C:39]=2[CH2:38][CH2:37]1)=[O:35])[CH3:32]>C1COCC1.CCOC(C)=O>[CH2:31]([O:33][C:34]([N:36]1[CH2:42][CH2:41][C:40]2[CH:43]=[C:44]([C:46]([C:47]([F:50])([F:49])[F:48])=[CH2:2])[S:45][C:39]=2[CH2:38][CH2:37]1)=[O:35])[CH3:32]
Reactant: c1ccc([PH+](c2ccccc2)c2ccccc2)cc1
Reactant: CCOC(=O)N1CCc2sc(C(=O)C(F)(F)F)c(Br)c2CC1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Br-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: C=C(c1cc2c(s1)CCN(C(=O)OCC)CC2)C(F)(F)F
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 55.9 %

Procedure:
Triphenyl phosphonium bromide (393 mg, 1.1 mmol) was stirred in 7 mL THF. KHMDS (199 mg, 1.0 mmol) was added and the yellow solution was stirred for 30 minutes at room temperature. The product of step (a) (180 mg, 0.56 mmol) was dissolved in 7 mL THF and added to the above reaction. The solution was allowed to stir for 1 hour at room temperature, then diluted with EtOAc (25 mL) and washed with water (2×20 mL). The crude product was purified by silica gel chromatography (30% EtOAc in Hex) to give 100 mg of the sub-title compound.
Reaction SMILES: [CH3:1][NH:2][CH2:3][CH2:4][C:5]#[C:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][N:8]=1.[CH3:13][C:14]1[C:18]([S:19](Cl)(=[O:21])=[O:20])=[C:17]([CH3:23])[O:16][N:15]=1>>[CH3:1][N:2]([CH2:3][CH2:4][C:5]#[C:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][N:8]=1)[S:19]([C:18]1[C:14]([CH3:13])=[N:15][O:16][C:17]=1[CH3:23])(=[O:21])=[O:20]
Reactant: Cc1noc(C)c1S(=O)(=O)Cl
Reactant: CNCCC#Cc1ccccn1
Product: Cc1noc(C)c1S(=O)(=O)N(C)CCC#Cc1ccccn1
Yield: 17.2 %

Procedure:
The title compound was prepared in accordance with the general method of Example 199(D), from N-methyl-4-(pyridin-2-yl)but-3-yn-1-amine (50 mg, 0.31 mmol) and 3,5-dimethylisoxazole-4-sulfonyl chloride (79 mg, 0.41 mmol). The crude residue was purified over silicagel chromatography (prepacked 10 g silicagel column, DCM/MeOH: from 100/0 to 98/2 as eluent) to afford 17 mg of N,3,5-trimethyl-N-(4-(pyridin-2-yl)but-3-ynyl)isoxazole-4-sulfonamide as a brown oil (Yield: 17%).
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:6][N:5]=[C:4]([Cl:13])[CH:3]=1.[CH3:14][O:15][C:16]1[CH:23]=[CH:22][C:19]([CH2:20][NH2:21])=[CH:18][CH:17]=1>CS(C)=O>[Cl:13][C:4]1[CH:3]=[C:2]([NH:21][CH2:20][C:19]2[CH:22]=[CH:23][C:16]([O:15][CH3:14])=[CH:17][CH:18]=2)[C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:6][N:5]=1
Reactant: CCOC(=O)c1cnc(Cl)cc1Cl
Reactant: COc1ccc(CN)cc1
Solvent: CS(C)=O
Product: CCOC(=O)c1cnc(Cl)cc1NCc1ccc(OC)cc1
Yield: 89.6 %

Procedure:
Stir a mixture of ethyl 4,6-dichloronicotinate (16 g, 73.1 mmol), (4-methoxybenzyl)amine (10 g, 73.1 mmol), and TEA (15.2 g, 146 mmol) in DMSO (150 mL) at RT overnight. Add EtOAc, wash with water (2×), then brine (1×), dry the organics over MgSO4 and concentrate to afford the title compound (21 g, 90%). 1H NMR (300 MHz, CDCl3): δ 8.62 (s, 1H), 8.39 (s, 1H), 7.16 (d, J=8.7 Hz, 2H), 6.85-6.80 (m, 2H), 6.49 (s, 1H), 4.33-4.25 (m, 4H), 3.77 (s, 3H), 1.31 (t, J=6.9 Hz, 3H).
Reaction SMILES: [C:1]([NH:5][C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1[NH:16][CH2:17][CH2:18][O:19][CH2:20][CH2:21][NH:22][C:23](=[O:29])[O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[CH:13][CH:12]=[CH:11][CH:10]=2)(=O)[CH2:2][CH3:3].C(N(CC)CC)C>CCO>[CH2:2]([C:1]1[N:16]([CH2:17][CH2:18][O:19][CH2:20][CH2:21][NH:22][C:23](=[O:29])[O:24][C:25]([CH3:28])([CH3:27])[CH3:26])[C:15]2[C:14]3[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=3[N:8]=[CH:7][C:6]=2[N:5]=1)[CH3:3]
Reactant: CCC(=O)Nc1cnc2ccccc2c1NCCOCCNC(=O)OC(C)(C)C
Solvent: CCN(CC)CC
Solvent: CCO
Product: CCc1nc2cnc3ccccc3c2n1CCOCCNC(=O)OC(C)(C)C
Reaction time: 72 h
Yield: 96.1 %

Procedure:
A solution of tert-butyl 2-(2-{[3-(propionylamino)quinolin-4-yl]amino}ethoxy)ethylcarbamate (15.00 g, 37.3 mmol) in 200 mL of EtOH was treated with triethylamine (13.0 mL, 93.2 mmol). The reaction was heated to reflux with stirring. After 3 days, the reaction was concentrated, triturated with ether and filtered to yield 13.78 g of tert-butyl 2-[2-(2-ethyl-1H-imidazo[4,5-c]quinolin-1-yl)ethoxy]ethylcarbamate as an off white solid.
Reaction SMILES: [C:1]1([C:7]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[N+]=[N-])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CCOCC.[CH:21]([NH:23][C@@H:24]1[C:35](=[O:36])[N:26]2[C:27]([C:32]([OH:34])=[O:33])=[C:28]([CH3:31])[CH2:29][S:30][C@H:25]12)=[O:22]>O1CCCC1>[CH:21]([NH:23][C@@H:24]1[C:35](=[O:36])[N:26]2[C:27]([C:32]([O:34][CH:7]([C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=3)[C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)=[O:33])=[C:28]([CH3:31])[CH2:29][S:30][C@H:25]12)=[O:22]
Reactant: [N-]=[N+]=C(c1ccccc1)c1ccccc1
Reactant: CC1=C(C(=O)O)N2C(=O)[C@@H](NC=O)[C@H]2SC1
Solvent: C1CCOC1
Solvent: CCOCC
Product: CC1=C(C(=O)OC(c2ccccc2)c2ccccc2)N2C(=O)[C@@H](NC=O)[C@H]2SC1
Reaction time: 8 h
Yield: 49.5 %

Procedure:
A solution of diphenyldiazomethane in ether (prepared from benzophenone hydrazone [21 g, 41.8 mmole]) was added to a solution of 7β-formamido-3-methylceph-3-em-4-carboxylic acid (9.7 g, 40.2 mmole) in tetrahydrofuran (150 ml) and the mixture was stirred overnight in the absence of light. The solvents were removed in vacuo and the residual oil was dissolved in methylene chloride (200 ml). The solution was washed with 3%-sodium hydrogen carbonate solution (2 × 100 ml), dried, and evaporated to a yellow oil which was triturated with ethyl acetate-ether to give the title ester as a white crystalline solid (8.15 g, 49.5%), m.p. 136° to 140°, [α]D23 + 38° (c 0.94; Me2SO), λmax. (EtOH) 258 nm (ε 6,800), νmax. (Nujol) 3330 (NH), 1771 (azetidin-2-one), 1707 (CO2R) and 1655 and 1523 cm-1 (CONH), τ (Me2SO-d6) 1.91 (1H, d, J 9.5 Hz; NH), 1.89 (1H, s; CHO), 2.4 to 2.8 (10H, m; (C6H5)2CH), 3.07 (1H, s; (C6H5)2CH), 3.19 (1H,dd, J 9.5 and 5 Hz; C7 --H), 4.83 (1H,d, 5 Hz; C6 --H), 6.33 and 6.57 (2H, AB-q, 18 Hz; C2 --H2), 7.95 (3H, S; C3 --CH2) (Found: C, 64.55; H, 4.9; N, 6.7; S, 7.7. C22H20N2O4S (408.5) requires C, 64.7; H, 4.9; N, 6.9; S, 7.85%).
Reaction SMILES: [NH2:1][CH:2]1[N:8]=[C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[C:6]2[CH:15]=[CH:16][CH:17]=[CH:18][C:5]=2[NH:4][C:3]1=[O:19].[CH2:20]([C:23]1[CH:31]=[CH:30][C:26]([C:27](Cl)=[O:28])=[CH:25][CH:24]=1)[CH2:21][CH3:22]>>[C:9]1([C:7]2[C:6]3[CH:15]=[CH:16][CH:17]=[CH:18][C:5]=3[NH:4][C:3](=[O:19])[CH:2]([NH:1][C:27](=[O:28])[C:26]3[CH:30]=[CH:31][C:23]([CH2:20][CH2:21][CH3:22])=[CH:24][CH:25]=3)[N:8]=2)[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: NC1N=C(c2ccccc2)c2ccccc2NC1=O
Reactant: CCCc1ccc(C(=O)Cl)cc1
Product: CCCc1ccc(C(=O)NC2N=C(c3ccccc3)c3ccccc3NC2=O)cc1

Procedure:
The procedure of Example 134 was carried out using 3(RS)-amino-1,3-dihydro-5-phenyl-2H-1,4-benzodiazepin-2-one (39.2 mg, 0.156 mmole) in place of 1,3-dihydro-3(RS)-amino-5-(2-fluorophenyl)-2H-1,4-benzodiazepin-2-one and 4-n-propylbenzoyl chloride (28.5 mg, 0.156 mmole) in place of p-trifluoromethylbenzoyl chloride. The product was chromatographed on silica gel (15% (v/v) Et2O in CH2Cl2 elution). The combined product fractions were evaporated to dryness in vacuo and crystallized from Et2O to give the title compound which was dried in vacuo at 82° C.: (m.p.. 158°-162° C.).