Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:3][C:4]([C:6]1[N:7]([C:26]2[CH:31]=[CH:30][C:29]([O:32][CH:33]([CH3:35])[CH3:34])=[CH:28][CH:27]=2)[C:8]2[C:13]([C:14]=1[Cl:15])=[CH:12][C:11]([C:16]1[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][N:17]=1)=[CH:10][CH:9]=2)=[O:5])C.[OH-].[Na+].Cl>O1CCOCC1.O>[Cl:15][C:14]1[C:13]2[C:8](=[CH:9][CH:10]=[C:11]([C:16]3[CH:21]=[CH:20][C:19]([C:22]([F:23])([F:25])[F:24])=[CH:18][N:17]=3)[CH:12]=2)[N:7]([C:26]2[CH:31]=[CH:30][C:29]([O:32][CH:33]([CH3:34])[CH3:35])=[CH:28][CH:27]=2)[C:6]=1[C:4]([OH:5])=[O:3]
Reactant: CCOC(=O)c1c(Cl)c2cc(-c3ccc(C(F)(F)F)cn3)ccc2n1-c1ccc(OC(C)C)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: CC(C)Oc1ccc(-n2c(C(=O)O)c(Cl)c3cc(-c4ccc(C(F)(F)F)cn4)ccc32)cc1
Temperature: 25 °C
Yield: 60.9 %

Procedure:
To a solution of 3-chloro-1-(4-isopropoxyphenyl)-5-(5-trifluoromethylpyrid-2-yl)-1H-indole-2-carboxylic acid ethyl ester (see step (a) above; 500 mg, 1.0 mmol) in dioxane (5 mL) was added NaOH (aq. 2N, 2.5 mL) and the reaction was refluxed for 4 h. After cooling to room temperature, the reaction was diluted with water and acidified by the addition of HCl (aq. 1N) to about pH 6. The precipitate was filtered, washed with water and dried. Recrystallisation (from EtOAc/petroleum ether) afforded the title compound (289 mg, 62%).
Reaction SMILES: [N+:1]([C:4]1[CH:23]=[CH:22][C:7]([CH2:8][O:9][C:10]2[CH:15]=[CH:14][C:13]([CH2:16][C:17]([O:19]CC)=[O:18])=[CH:12][CH:11]=2)=[CH:6][CH:5]=1)([O-:3])=[O:2].Cl>CO.O1CCOCC1.[OH-].[Na+]>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]([CH2:8][O:9][C:10]2[CH:15]=[CH:14][C:13]([CH2:16][C:17]([OH:19])=[O:18])=[CH:12][CH:11]=2)=[CH:22][CH:23]=1)([O-:3])=[O:2]
Reactant: CCOC(=O)Cc1ccc(OCc2ccc([N+](=O)[O-])cc2)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: CO
Product: O=C(O)Cc1ccc(OCc2ccc([N+](=O)[O-])cc2)cc1
Yield: 91.9 %

Procedure:
After 3.15 g (10.0 mmol) of ethyl 4-(4-nitrobenzyloxy)phenylacetate were dissolved in a mixed solvent of 50 ml of methanol and 50 ml of 1,4-dioxane, 70 ml of a 1 N aqueous solution of sodium hydroxide were added, and the resultant mixture was stirred at room temperature for 2 hours. After completion of the reaction, the reaction mixture was acidified with diluted hydrochloric acid and extracted with chloroform. The resultant extract was then dried over anhydrous sodium sulfate. After distilling off chloroform under reduced pressure, deposited crystals were ground with ether, thereby obtaining 2.64 g (yield: 92.0%) of the intended compound as crystals.
Reaction SMILES: [OH:1][C:2]1[CH:14]=[CH:13][C:5]2[C:6]([CH3:12])([CH3:11])[CH:7]=[C:8]([CH3:10])[O:9][C:4]=2[CH:3]=1.Cl[C:16]1[CH:21]=[CH:20][C:19]([N+:22]([O-:24])=[O:23])=[CH:18][CH:17]=1.[OH-].[K+].CN(C)C=O>C1(C)C=CC=CC=1>[N+:22]([C:19]1[CH:20]=[CH:21][C:16]([O:1][C:2]2[CH:14]=[CH:13][C:5]3[C:6]([CH3:11])([CH3:12])[CH:7]=[C:8]([CH3:10])[O:9][C:4]=3[CH:3]=2)=[CH:17][CH:18]=1)([O-:24])=[O:23]
Reactant: CC1=CC(C)(C)c2ccc(O)cc2O1
Reactant: O=[N+]([O-])c1ccc(Cl)cc1
Agent: [K+]
Agent: [OH-]
Solvent: Cc1ccccc1
Solvent: CN(C)C=O
Product: CC1=CC(C)(C)c2ccc(Oc3ccc([N+](=O)[O-])cc3)cc2O1
Temperature: 25 °C
Reaction time: 2 h
Yield: 67.9 %

Procedure:
One hundred grams of 7-hydroxy-2,4,4-trimethyl-4H-1-benzopyran (synthesized by the method of Japanese Laid-Open Patent Publication No. 5475/1981), 79 g of p-chloronitrobenzene, 42 g of potassium hydroxide, 500 ml of N,N-dimethylformamide and 500 ml of toluene were introduced into a flask equipped with the Dean-Stark condenser, and heated at 110° to 116° C. While removing the distilled water as an azeotrope with toluene, the mixture was stirred for 2 hours. The reaction mixture was cooled to room temperature, and 1 liter of water, 500 ml of ethyl acetate and 120 ml of 2N-HCl were added. The insoluble materials were separated by filtration. The filtrate was subjected to oil-water separation. The oil layer was washed with 500 ml of brine, and dried over magnesium sulfate. The solvent was evaporated. Methanol (650 ml) was added to the residue, and crystals that precipitated were collected, washed with 650 ml of hexane, and dried to give 106 g (yield 67%) of the desired product as a brown powder (melting point 80° C.).
Reaction SMILES: C([O:5][C:6](=[O:38])[CH:7]([NH:11][S:12]([C:15]1[CH:20]=[CH:19][C:18]([C:21]2[CH:26]=[CH:25][C:24]([O:27][C:28](=[O:37])[NH:29][C:30]3[CH:35]=[CH:34][C:33]([F:36])=[CH:32][CH:31]=3)=[CH:23][CH:22]=2)=[CH:17][CH:16]=1)(=[O:14])=[O:13])[CH:8]([CH3:10])[CH3:9])(C)(C)C.C(O)(C(F)(F)F)=O>ClC(Cl)C>[F:36][C:33]1[CH:32]=[CH:31][C:30]([NH:29][C:28]([O:27][C:24]2[CH:23]=[CH:22][C:21]([C:18]3[CH:19]=[CH:20][C:15]([S:12]([NH:11][CH:7]([CH:8]([CH3:10])[CH3:9])[C:6]([OH:38])=[O:5])(=[O:14])=[O:13])=[CH:16][CH:17]=3)=[CH:26][CH:25]=2)=[O:37])=[CH:35][CH:34]=1
Reactant: CC(C)C(NS(=O)(=O)c1ccc(-c2ccc(OC(=O)Nc3ccc(F)cc3)cc2)cc1)C(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: CC(Cl)Cl
Product: CC(C)C(NS(=O)(=O)c1ccc(-c2ccc(OC(=O)Nc3ccc(F)cc3)cc2)cc1)C(=O)O
Temperature: 25 °C
Reaction time: 5 h
Yield: 89 %

Procedure:
2-[4′-(4-Fluoro-phenylcarbamoyloxy)-biphenyl-4-sulfonylamino]-3-methyl-butyric acid tert-butyl ester (223 mg) was dissolved in dichloroethane (7.5 mL) and added with TFA (2.5 mL). The mixture was stirred at room temperature for 5 hrs and TLC indicated the reaction was complete. Regular work-up and column chromatography to give 2-[4′-(4-Fluoro-phenylcarbamoyloxy)-biphenyl-4-sulfonylamino]-3-methyl-butyric acid in 89% yield (178 mg).
Reaction SMILES: C[O:2][C:3]1(OC)[CH2:6][CH:5]([CH2:7][N:8]2[CH2:12][CH2:11][CH2:10][CH2:9]2)[CH2:4]1.CC(C)=O.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>O>[N:8]1([CH2:7][CH:5]2[CH2:4][C:3](=[O:2])[CH2:6]2)[CH2:12][CH2:11][CH2:10][CH2:9]1
Reactant: COC1(OC)CC(CN2CCCC2)C1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CC(C)=O
Solvent: O
Product: O=C1CC(CN2CCCC2)C1
Temperature: 25 °C
Yield: 76.7 %

Procedure:
To a stirring solution of 1-[(3,3-dimethoxy-cyclobutyl)methyl]-pyrrolidine (intermediate 5, general prcedure B, step B) (1.6 g, 8.0 mmol) in 3:1 acetone:H2O (100 mL) was added p-toluenesulfonic acid mono hydrate (1.5 g, 8.0 mmol). The reaction mixture was heated to 65 C for 1 hour. Both TLC and GS/MS analysis indicated complete consumption of starting material. The reaction was cooled to room temperature and then the acetone was removed under reduced pressure. The resulting mixture was diluted with CH2Cl2 and washed with an aqueous solution of NaHCO3. The aqueous layer was back extracted with 3:1 CHCl3:iso-propyl alcohol. The combined organic layers were dried over magnesium sulfate, filtered through a fritted funnel and then concentrated under reduced pressure to yield the title compound (0.94 g, 76% yield) as a colorless oil. This material was processed without further purification.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][CH2:11][C:12]([OH:14])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl.[NH2:37][C:38]1[CH:39]=[C:40]([CH:43]=[CH:44][C:45]=1[NH2:46])[C:41]#[N:42]>CN(C=O)C>[C:1]([O:5][C:6](=[O:7])[NH:8][CH2:9][CH2:10][CH2:11][C:12](=[O:14])[NH:37][C:38]1[CH:39]=[C:40]([C:41]#[N:42])[CH:43]=[CH:44][C:45]=1[NH2:46])([CH3:2])([CH3:3])[CH3:4]
Reactant: N#Cc1ccc(N)c(N)c1
Reactant: CC(C)(C)OC(=O)NCCCC(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)NCCCC(=O)Nc1cc(C#N)ccc1N
Reaction time: 0.5 h
Yield: 65.7 %

Procedure:
A DMF solution (30 ml) containing 4-(t-butoxycarbonylamino)-butyric acid (1.53 g) was added with HOBt (1.07 g) and WSCI hydrochloride (1.51 g) and the whole was stirred for 0.5 hours. The reaction solution was dropped to a DMF solution (12 ml) containing the compound (1.00 g) obtained in Example 46-1. The whole was stirred at room temperature for 12 hours and then the solvent was distilled off. The resultant was dissolved in chloroform, washed with a saturated aqueous ammonium chloride solution and a saturated aqueous sodium hydrogen carbonate solution in the stated order, and dried with anhydrous magnesium sulfate. The residue obtained by distilling the solvent off was purified through silica gel column chromatography (ethyl acetate/chloroform), thereby obtaining the subject compound (1.57 g) as a milky-white solid.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[C:4]([N:8]2[CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)[N:3]=1.[CH:14]1([NH:17][C:18](=[O:35])[NH:19][C:20]2[CH:25]=[CH:24][C:23](B3OC(C)(C)C(C)(C)O3)=[CH:22][CH:21]=2)[CH2:16][CH2:15]1.C([O-])([O-])=O.[Cs+].[Cs+]>O1CCOCC1.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>[CH:14]1([NH:17][C:18]([NH:19][C:20]2[CH:25]=[CH:24][C:23]([C:2]3[CH:7]=[CH:6][N:5]=[C:4]([N:8]4[CH2:13][CH2:12][O:11][CH2:10][CH2:9]4)[N:3]=3)=[CH:22][CH:21]=2)=[O:35])[CH2:16][CH2:15]1
Reactant: Clc1ccnc(N2CCOCC2)n1
Reactant: CC1(C)OB(c2ccc(NC(=O)NC3CC3)cc2)OC1(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1COCCO1
Product: O=C(Nc1ccc(-c2ccnc(N3CCOCC3)n2)cc1)NC1CC1
Yield: 5.7 %

Procedure:
To a solution of 4-(4-chloropyrimidin-2-yl)morpholine (80 mg, 0.40 mmol) and (4-(3-cyclopropylureido)phenyl)boronic acid pinacol ester (145 mg, 0.48 mmol) in dioxane (2 mL) was added Pd(PPh3)2Cl2 (14 mg, 0.02 mmol) and Cs2CO3 (2M aq solution, 0.3 mL). The reaction mixture was then heated to reflux for 16 h. The crude reaction mixture was then partitioned between water and EtOAc, the phases separated and the organic layer washed with aqueous NaHCO3 and brine, dried over magnesium sulfate, filtered and the solvent removed in vacuo. The residue was purified by flash chromatography (0-5% EtOAc/MeOH) to yield a white solid (7.8 mg, 6%).
Reaction SMILES: [CH3:1][N:2]1[C:6]2[CH:7]=[CH:8][C:9]([C:11]([NH:13][CH2:14][C:15]([OH:17])=O)=[O:12])=[CH:10][C:5]=2[N:4]=[C:3]1[NH:18][C:19]1[S:20][C:21]2[CH:27]=[C:26]([O:28][C:29]([F:32])([F:31])[F:30])[CH:25]=[CH:24][C:22]=2[N:23]=1.[OH:33][CH:34]1[CH2:39][CH2:38][CH2:37][NH:36][CH2:35]1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>>[OH:33][CH:34]1[CH2:39][CH2:38][CH2:37][N:36]([C:15](=[O:17])[CH2:14][NH:13][C:11]([C:9]2[CH:8]=[CH:7][C:6]3[N:2]([CH3:1])[C:3]([NH:18][C:19]4[S:20][C:21]5[CH:27]=[C:26]([O:28][C:29]([F:31])([F:30])[F:32])[CH:25]=[CH:24][C:22]=5[N:23]=4)=[N:4][C:5]=3[CH:10]=2)=[O:12])[CH2:35]1
Reactant: OC1CCCNC1
Reactant: Cn1c(Nc2nc3ccc(OC(F)(F)F)cc3s2)nc2cc(C(=O)NCC(=O)O)ccc21
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Product: Cn1c(Nc2nc3ccc(OC(F)(F)F)cc3s2)nc2cc(C(=O)NCC(=O)N3CCCC(O)C3)ccc21
Yield: 71.3 %

Procedure:
1-Methyl-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-1H-benzoimidazole-5-carboxylic acid [2-(3-hydroxy-piperidin-1-yl)-2-oxo-ethyl]-amide (63 mg) was prepared by following General Procedure F starting from {[1-methyl-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-1H-benzoimidazole-5-carbonyl]-amino}-acetic acid (75 mg), 3-hydroxypiperidine (18 mg), HBTU (73 mg), and DIEA (42 uL), with a modification of General Procedure F where DIEA was slowly added to the reaction mixture as the last reagent. LC/MS: m/z 549.8. 1H NMR (DMSO-d6, 400 MHz): δ 8.53-8.42 (m, 1H), 8.11 (s, 1H), 7.94 (s, 1H), 7.79 (d, 1H), 7.66 (bs, 1H), 7.51 (d, 1H), 7.37 (d, 1H), 4.19-4.08 (m, 4H), 3.75-3.60 (m, 5H), 3.20 (dd, 1H), 3.05 (t, 1H), 2.01-1.95 (m, 2H), 1.57-1.27 (m, 2H), —NH proton signal was not observed.
Reaction SMILES: [Cl:1][C:2]1[CH:24]=[CH:23][C:5]([CH2:6][NH:7][C:8]([C:10]2[C:11](=[O:22])[C:12]3[CH:19]=[C:18]([CH2:20]Cl)[O:17][C:13]=3[N:14]([CH3:16])[CH:15]=2)=[O:9])=[CH:4][CH:3]=1.[CH3:25][NH:26][CH2:27][CH:28]([C:30]1[C:35]([F:36])=[CH:34][C:33]([F:37])=[CH:32][C:31]=1[F:38])[OH:29]>>[Cl:1][C:2]1[CH:24]=[CH:23][C:5]([CH2:6][NH:7][C:8]([C:10]2[C:11](=[O:22])[C:12]3[CH:19]=[C:18]([CH2:20][N:26]([CH2:27][CH:28]([OH:29])[C:30]4[C:31]([F:38])=[CH:32][C:33]([F:37])=[CH:34][C:35]=4[F:36])[CH3:25])[O:17][C:13]=3[N:14]([CH3:16])[CH:15]=2)=[O:9])=[CH:4][CH:3]=1
Reactant: CNCC(O)c1c(F)cc(F)cc1F
Reactant: Cn1cc(C(=O)NCc2ccc(Cl)cc2)c(=O)c2cc(CCl)oc21
Product: CN(Cc1cc2c(=O)c(C(=O)NCc3ccc(Cl)cc3)cn(C)c2o1)CC(O)c1c(F)cc(F)cc1F

Procedure:
Analogous to the procedures described in Example 38, N-(4-chlorobenzyl)-2-(chloromethyl)-7-methyl-4-oxo-4,7-dihydrofuro[2,3-b]pyridine-5-carboxamide (Example 2) is treated with rac-2-(methylamino)-1-(2,4,6-trifluorophenyl)ethanol (Preparation 44) to afford the title compound.
Reaction SMILES: [CH:1]([N:4]1[C:8]([C:9](OC)=[O:10])=[CH:7][N:6]=[CH:5]1)([CH3:3])[CH3:2].[OH-].[Na+].C=O>O>[CH:1]([N:4]1[C:8]([CH2:9][OH:10])=[CH:7][N:6]=[CH:5]1)([CH3:3])[CH3:2]
Reactant: COC(=O)c1cncn1C(C)C
Agent: C=O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CC(C)n1cncc1CO

Procedure:
1.68 g (0.01 mol) of 1-isopropyl-5-carbmethoxyimidazole is suspended in 5 ml of water. To the suspension are added 0.8 g (0.02 mol) of sodium hydroxide and 4 ml of ~37% aqueous formaldehyde. The resultant mixture is heated to reflux for 2 hours. After completion of the reaction, the solvent is stripped off, and the residue is extracted with ethyl acetate and concentrated to give 1-isopropyl-5-hydroxymethylimidazole as a solid, m.p. 83°-84° C.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH:6]=[C:5](B2OC(C)(C)C(C)(C)O2)[CH2:4][CH2:3]1.[O-]P([O-])([O-])=O.[K+].[K+].[K+].[CH2:25]([O:32][C:33]([NH:35][C:36]1[C:37]([C:47]([NH:49][C:50]2[CH:51]=[N:52][CH:53]=[CH:54][C:55]=2[N:56]2[CH2:61][C@H:60]([CH3:62])[C@H:59]([NH:63][C:64](=[O:67])[O:65][CH3:66])[C@H:58]([NH:68][C:69](=[O:75])[O:70][C:71]([CH3:74])([CH3:73])[CH3:72])[CH2:57]2)=[O:48])=[N:38][C:39]2[C:44]([CH:45]=1)=[CH:43][CH:42]=[C:41](Br)[CH:40]=2)=[O:34])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>O1CCOCC1.C1(P(C2CCCCC2)C2C=CC=CC=2C2C(C(C)C)=CC(C(C)C)=CC=2C(C)C)CCCCC1.NC1C=CC=CC=1C1C=CC=CC=1[Pd]Cl>[CH2:25]([O:32][C:33]([NH:35][C:36]1[C:37]([C:47]([NH:49][C:50]2[CH:51]=[N:52][CH:53]=[CH:54][C:55]=2[N:56]2[CH2:61][C@H:60]([CH3:62])[C@H:59]([NH:63][C:64](=[O:67])[O:65][CH3:66])[C@H:58]([NH:68][C:69](=[O:75])[O:70][C:71]([CH3:74])([CH3:73])[CH3:72])[CH2:57]2)=[O:48])=[N:38][C:39]2[C:44]([CH:45]=1)=[CH:43][CH:42]=[C:41]([C:5]1[CH2:6][CH2:7][N:2]([CH3:1])[CH2:3][CH:4]=1)[CH:40]=2)=[O:34])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: CN1CC=C(B2OC(C)(C)C(C)(C)O2)CC1
Reactant: 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
Agent: Nc1ccccc1-c1ccccc1[Pd]Cl
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Agent: O=P([O-])([O-])[O-]
Solvent: C1COCCO1
Product: COC(=O)N[C@H]1[C@@H](C)CN(c2ccncc2NC(=O)c2nc3cc(C4=CCN(C)CC4)ccc3cc2NC(=O)OCc2ccccc2)C[C@H]1NC(=O)OC(C)(C)C
Temperature: 60 °C
Yield: 19.6 %

Procedure:
A vial was charged with 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,2,3,6-tetrahydropyridine (107 mg, 0.477 mmol), dicyclohexyl(2′,4′,6′-triisopropylbiphenyl-2-yl)phosphine-(2′-aminobiphenyl-2-yl)(chloro)palladium (1:1) (36 mg, 0.046 mmol), and K3PO4 (175 mg, 0.824 mmol). The vial was sealed with a septum and purged with nitrogen three times. A solution of tert-butyl methyl [(3R,4S,5S)-1-(3-{[(3-{[(benzyloxy)carbonyl]amino}-7-bromoquinolin-2-yl)carbonyl]amino}pyridin-4-yl)-5-methylpiperidine-3,4-diyl]biscarbamate (200 mg, 0.262 mmol) in 1,4-dioxane (2.0 mL) was added, followed by deoxygenated water (0.50 mL). The reaction mixture was heated at 60° C. for 2 h. The mixture was purified by preparative LCMS (pH=10 method; XBridge™ preparative C18 5 μm OBD™ column, 30×10 mm, 60 mL/min., eluting with a gradient of MeCN and water with 0.1% NH4OH) to give the sub-title compound as a yellow solid (40 mg, 19%). LCMS calc. for C42H51N8O7 (M+H)+: m/z=779.4. Found: 779.4.
Reaction SMILES: Cl.[Br:2][C:3]1[CH:19]=[CH:18][C:6]([CH2:7][N:8]([C:10]2[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][CH:11]=2)N)=[CH:5][CH:4]=1.C1(C)C=CC=CC=1.[CH2:27]([O:29][C:30](=[O:43])[C:31]([CH3:42])([CH3:41])[CH2:32][C:33](=O)[CH2:34][S:35][C:36]([CH3:39])([CH3:38])[CH3:37])[CH3:28].C([O-])(=O)C.[Na+]>O.C(O)(=O)C>[CH2:27]([O:29][C:30](=[O:43])[C:31]([CH3:42])([CH3:41])[CH2:32][C:33]1[N:8]([CH2:7][C:6]2[CH:18]=[CH:19][C:3]([Br:2])=[CH:4][CH:5]=2)[C:10]2[C:15]([C:34]=1[S:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[CH:14][C:13]([O:16][CH3:17])=[CH:12][CH:11]=2)[CH3:28]
Reactant: CCOC(=O)C(C)(C)CC(=O)CSC(C)(C)C
Reactant: COc1ccc(N(N)Cc2ccc(Br)cc2)cc1
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CC(=O)O
Solvent: O
Product: CCOC(=O)C(C)(C)Cc1c(SC(C)(C)C)c2cc(OC)ccc2n1Cc1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 96 h

Procedure:
N-(4-Bromo-benzyl)-N-(4-methoxy-phenyl)-hydrazine hydrochloride (1.0 eq) was added to a reaction flask containing toluene (10.0-fold, V/W of starting material) under nitrogen. Acetic acid (5.0-fold, V/W of starting material) was added, followed by 5-tert-butylsulfanyl-2,2-dimethyl-4-oxo-pentanoic acid ethyl ester (1.05 eq) and sodium acetate (2.3 eq), and the reaction mixture was stirred at room temperature for 4 days. Cold water (15.0-fold, V/W of starting material) was then added to the reaction, and the mixture was agitated for 30 minutes. The organic layer was separated, and the aqueous layer was extracted with toluene (2.0-fold, V/W of starting material) to recover additional product. The combined organic layers were washed with water and brine, dried over sodium sulfate, and concentrated under reduced pressure. A slurry of the crude material was made in methanol (5.0-fold, V/W of starting material), and the mixture was cooled to 0-5° C. for 4 hours. The solid was collected by filtration and washed with cold methanol, and the isolated material was dried under reduced pressure at 28-30° C.
Reaction SMILES: [C:1]([C:5]1[CH:15]=[CH:14][C:8]([O:9][CH2:10][C:11]([OH:13])=O)=[CH:7][C:6]=1[F:16])([CH3:4])([CH3:3])[CH3:2].[Cl-].ClC1N(C)CC[NH+]1C.Cl.[NH2:27][CH2:28][C:29]1[CH:34]=[CH:33][C:32]([NH:35][S:36]([CH3:39])(=[O:38])=[O:37])=[C:31]([F:40])[CH:30]=1>C(N(CC)CC)C>[C:1]([C:5]1[CH:15]=[CH:14][C:8]([O:9][CH2:10][C:11]([NH:27][CH2:28][C:29]2[CH:34]=[CH:33][C:32]([NH:35][S:36]([CH3:39])(=[O:38])=[O:37])=[C:31]([F:40])[CH:30]=2)=[O:13])=[CH:7][C:6]=1[F:16])([CH3:2])([CH3:3])[CH3:4]
Reactant: CS(=O)(=O)Nc1ccc(CN)cc1F
Reactant: CC(C)(C)c1ccc(OCC(=O)O)cc1F
Agent: CN1CC[NH+](C)C1Cl
Agent: Cl
Agent: [Cl-]
Solvent: CCN(CC)CC
Product: CC(C)(C)c1ccc(OCC(=O)NCc2ccc(NS(C)(=O)=O)c(F)c2)cc1F
Yield: 8.4 %

Procedure:
Crude (4-tert-butyl-3-fluorophenoxy)acetic acid (124 mg, crude), 2-chloro-1,3-dimethylimidazolinium chloride (CDI) (90 mg, 0.55 mmol), triethylamine (0.35 ml) and-N[4-(aminomethyl)-2-fluorophenyl]methanesulfonamide hydrochloride (127 mg, 0.5 mmol) were mixed in the same procedure described in Example 2(b) to give 18 mg (7.8% yield) of the title compound as a white solid.
Reaction SMILES: [NH2:1][C:2]1[CH:31]=[CH:30][C:5]([CH2:6][C:7]2[NH:15][C:14]3[C:13](=[O:16])[N:12]([CH2:17][C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=4[F:24])[C:11](=[O:25])[N:10]([CH2:26][CH2:27][CH2:28][CH3:29])[C:9]=3[N:8]=2)=[CH:4][CH:3]=1.C[Si]([N:36]=[C:37]=[O:38])(C)C>ClCCl.CN(C)C=O>[CH2:26]([N:10]1[C:9]2[N:8]=[C:7]([CH2:6][C:5]3[CH:4]=[CH:3][C:2]([NH:1][C:37]([NH2:36])=[O:38])=[CH:31][CH:30]=3)[NH:15][C:14]=2[C:13](=[O:16])[N:12]([CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[F:24])[C:11]1=[O:25])[CH2:27][CH2:28][CH3:29]
Reactant: C[Si](C)(C)N=C=O
Reactant: CCCCn1c(=O)n(Cc2ccccc2F)c(=O)c2[nH]c(Cc3ccc(N)cc3)nc21
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CCCCn1c(=O)n(Cc2ccccc2F)c(=O)c2[nH]c(Cc3ccc(NC(N)=O)cc3)nc21
Temperature: 25 °C
Reaction time: 18 h

Procedure:
8-(4-Amino-benzyl)-3-butyl-1-(2-fluorobenzyl)-3,7-dihydro-purine-2,6-dione (25 mg, 0.06 mmol) was dissolved in 95:5 dichloromethane/N,N-dimethylformamide (2 mL), and treated with trimethylsilyl isocyanate (Aldrich) (47 μl, 0.3 mmol). The reaction was stirred at room temperature for 18 h. The reaction was then concentrated under reduced pressure and the residue was purified by reverse phase HPLC to afford the desired product. LCMS, m/z(M+H)=464.98.
Reaction SMILES: C([Li])CCC.O1CCCCC1OC1CCCCO1.[CH:19]#[C:20][CH:21]([OH:27])[CH2:22][CH2:23][CH2:24][CH2:25][CH3:26].C[Si](C)(C)[O:30][C:31]1([CH3:40])[CH2:36][CH2:35][CH2:34][C:33]([CH3:38])([CH3:37])[C:32]1=[O:39].[Cl-].[NH4+]>C1COCC1.CCCCCC>[OH:39][C:32]1([C:19]#[C:20][CH:21]([OH:27])[CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])[C:33]([CH3:38])([CH3:37])[CH2:34][CH2:35][CH2:36][C:31]1([OH:30])[CH3:40]
Reactant: CC1(C)CCCC(C)(O[Si](C)(C)C)C1=O
Reactant: C#CC(O)CCCCC
Agent: C1CCC(OC2CCCCO2)OC1
Agent: [Cl-]
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CCCCCC(O)C#CC1(O)C(C)(C)CCCC1(C)O
Reaction time: 0.17 h
Yield: 70 %

Procedure:
To 6.5 ml of a 1.6M n-hexane solution of n-butyl lithium was added 20 ml of anhydrous THF at -78° C. (bath temperature) in a nitrogen atmosphere, and 2.2 g of a tetrahydropyranyl ether of 1-octyn-3-ol was added dropwise thereto under the same conditions over 10 minutes. After the addition, the mixture was stirred for 30 minutes. Then, 30 ml of an anhydrous THF solution containing 2.0 g of 2-trimethylsiloxy-2,6,6-trimethylcyclohexanone was added dropwise to the mixture under the same conditions over 35 minutes. After the dropwise addition, the mixture was stirred for 5 hours. A saturated ammonium chloride aqueous solution was added to the reaction mixture, and the mixture was extracted with diethyl ether. The diethyl ether was removed from the extract by distillation, a 1N hydrochloric acid aqueous solution and methanol were added to the residue, followed by stirring at room temperature for 5 hours. The methanol was removed by distillation under reduced pressure, and the residue was extracted with diethyl ether. The organic layer was dried over anhydrous magnesium sulfate, and the solvent, etc. were removed by distillation under reduced pressure. The residue was purified by silica gel column chromatography to obtain 1.8 g (yield: 70%) of 1-(1,2-dihydroxy-2,6,6-trimethylcyclohexyl)oct-1-yn-3-ol.
Reaction SMILES: [CH3:1][C:2]([CH3:9])=[CH:3][CH2:4][CH2:5][C:6](=[O:8])[CH3:7].[OH-].[K+].[CH2:12](Cl)[CH:13]=[CH:14][CH3:15]>C1(C)C=CC=CC=1.[Cl-].C([N+](CCCCCCCC)(CCCCCCCC)C)CCCCCCC>[CH:12]([CH:5]([CH2:4][CH:3]=[C:2]([CH3:9])[CH3:1])[C:6](=[O:8])[CH3:7])=[CH:13][CH2:14][CH3:15]
Reactant: CC(=O)CCC=C(C)C
Reactant: CC=CCCl
Agent: CCCCCCCC[N+](C)(CCCCCCCC)CCCCCCCC
Agent: [Cl-]
Agent: [K+]
Solvent: Cc1ccccc1
Product: CCC=CC(CC=C(C)C)C(C)=O
Temperature: 70 °C

Procedure:
In a 1 liter 4-necked flask, equipped with a mechanical stirrer, 6-methylhept-5-en-2-one (126.81 g, 1.00 mol) was dissolved in toluene (125 ml). An aqueous solution of KOH (45%, 354.15 g, 2.84 mol) was added at room temperature. The biphasic mixture was heated to 70° C. under stirring. A solution of PTC catalyst (trioctyl methyl ammonium chloride, Aliquat 336, 6.46 g, 16 mmol), and crotyl chloride (136.4 g, 1.51 mol) in toluene (10.0 g) was then added over 2.5 hours at 70° C. The mixture was then cooled to room temperature and stirred overnight. A partial conversion into the desired compound was observed. The crude reaction mixture was poured onto water (250 ml), and washed successively with aqueous H3PO4 (12.5%, 400 ml), aqueous NaCl (15%, 250 ml), NaHCO3 (5%, 100 ml) and 3 times with aqueous NaCl (25%, 100 ml). After drying over Na2SO4 and filtration, the solvent was removed in vacuuo. The concentrated product was distilled through a Vigreux column A second distillation through a Fischer column afforded the desired product (as a 4/1 mixture of E and Z isomers).