Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[C:4]([Cl:12])[N:3]=1.[CH3:13][O:14][C:15]1[CH:20]=[CH:19][C:18]([NH2:21])=[CH:17][CH:16]=1>>[Cl:12][C:4]1[N:3]=[C:2]([NH:21][C:18]2[CH:19]=[CH:20][C:15]([O:14][CH3:13])=[CH:16][CH:17]=2)[C:11]2[C:6]([CH:5]=1)=[CH:7][CH:8]=[CH:9][CH:10]=2
Reactant: COc1ccc(N)cc1
Reactant: Clc1cc2ccccc2c(Cl)n1
Product: COc1ccc(Nc2nc(Cl)cc3ccccc23)cc1
Temperature: 170 °C
Yield: 18.4 %

Procedure:
A mixture of 1,3-dichloroisoquinoline (5.0 g; see Example 8) and p-anisidine (3.1 g) was heated at a temperature of 170° C. for a period of 2 hours. After cooling the product was purified by column chromatography over silica gel (eluant dichloromethane) to give 3-chloro-1-[N-(4-methoxyphenyl)amino]isoquinoline (1.32 g) mp 101° C.
Reaction SMILES: [CH:1]1([C@H:7]([NH:12][C:13]([C:15]2[O:16][C:17]([C:20]3[CH:25]=[CH:24][C:23]([NH2:26])=[C:22]([NH2:27])[CH:21]=3)=[CH:18][CH:19]=2)=[O:14])[C:8](=[O:11])[NH:9][CH3:10])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:28][N:29]1[CH:33]=[C:32](C=O)[C:31]([CH3:36])=[N:30]1.S(=O)(O)[O-].[Na+].[CH3:42]N(C=O)C>>[CH:1]1([C@H:7]([NH:12][C:13]([C:15]2[O:16][C:17]([C:20]3[CH:25]=[CH:24][C:23]4[N:26]=[C:42]([C:33]5[N:29]([CH3:28])[N:30]=[C:31]([CH3:36])[CH:32]=5)[NH:27][C:22]=4[CH:21]=3)=[CH:18][CH:19]=2)=[O:14])[C:8](=[O:11])[NH:9][CH3:10])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CNC(=O)[C@@H](NC(=O)c1ccc(-c2ccc(N)c(N)c2)o1)C1CCCCC1
Reactant: Cc1nn(C)cc1C=O
Reactant: CN(C)C=O
Agent: O=S([O-])O
Agent: [Na+]
Product: CNC(=O)[C@@H](NC(=O)c1ccc(-c2ccc3nc(-c4cc(C)nn4C)[nH]c3c2)o1)C1CCCCC1
Temperature: 130 °C

Procedure:
5-(3,4-Diamino-phenyl)-furan-2-carboxylic acid ((S)-cyclohexyl-methylcarbamoyl-methyl)-amide (25 mg, 67 mmol), 1,3-dimethyl-1H-pyrazole-4-carbaldehyde (9.2 mg, 74 mmol), and sodium bisulfite (7.73 mg, 74 mmol) are dissolved in DMF (1 mL) and the mixture is heated at 130° C. for 12 h. The mixture is filtered and purified on reversed phase (HPLC). The product is obtained as a beige solid. 4.2 mg, 13%, LC/MS ESI m/z (M+H)+=476.54.
Reaction SMILES: [F:1][C:2]1[C:7]([CH:8]=[O:9])=[CH:6][C:5]([O:10][CH3:11])=[C:4]([O:12][CH3:13])[CH:3]=1.B(Br)(Br)Br.O>C(Cl)Cl.CCOC(C)=O>[F:1][C:2]1[C:7]([CH:8]=[O:9])=[CH:6][C:5]2[O:10][CH2:11][CH2:13][O:12][C:4]=2[CH:3]=1
Reactant: COc1cc(F)c(C=O)cc1OC
Agent: BrB(Br)Br
Solvent: O
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: O=Cc1cc2c(cc1F)OCCO2
Temperature: 25 °C
Reaction time: 4 h
Yield: 103.2 %

Procedure:
To a solution of 6-fluoroveratraldehyde (1.2 g, 6.2 mmol) in CH2Cl2 (62 mL) was added BBr3 (6.2 mL, 62 mmol) and the solution was stirred at RT for 4 h. The solution was then cooled to 0° C., diluted with EtOAc (120 mL) and slowly treated with H2O (60 mL). The organic layer was washed with brine (2×100 mL), dried, filtered and concentrated to provide the desired catechol intermediate as a dark brown solid (1.0 g, 6.4 mmol). This solid was immediately treated with 1,2-dibromoethane (0.60 mL, 7.1 mmol) and heated to 100° C. The suspension was treated with NaOH (0.50 g, 13 mmol) in H2O (30 mL) dropwise over 1 h and stirred at 100° C. for 2 days. The suspension was then filtered. The collected solid was re-suspended in CHCl3 and filtered. The filtrate was concentrated to provide 0.22 g (19%) of the title compound as a tan solid. MS (ESI): exact mass calculated for C9H7FO3, 182.04; m/z not found. 1H NMR (500 MHz, CDCl3): 10.21 (s, 1H), 7.35 (d, J=6.7, 1H), 6.66 (d, J=10.9, 1H), 4.33 (m, 2H), 4.25 (m, 2H).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([C:10](=O)[CH3:11])[CH:5]=[CH:6][C:7]=1[O:8][CH3:9].Cl.[F:14][C:15]1[CH:16]=[C:17]([CH:21]=[CH:22][CH:23]=1)[CH2:18][O:19][NH2:20]>>[F:14][C:15]1[CH:16]=[C:17]([CH:21]=[CH:22][CH:23]=1)[CH2:18][O:19]/[N:20]=[C:10](/[C:4]1[CH:5]=[CH:6][C:7]([O:8][CH3:9])=[C:2]([OH:1])[CH:3]=1)\[CH3:11]
Reactant: COc1ccc(C(C)=O)cc1O
Reactant: NOCc1cccc(F)c1
Agent: Cl
Product: COc1ccc(/C(C)=N/OCc2cccc(F)c2)cc1O
Yield: 81.5 %

Procedure:
Acetophenone 12 (50 mg, 0.301 mmol) was condensed with O-(3-fluorobenzyl)hydroxylamine hydrochloride (26) (59 mg, 0.332 mmol) according to the general procedure II-B defined above. After being heated at reflux for 48 h the reaction mixture was cooled and the solvent removed under reduced pressure. The ensuing residue was dissolved in CH2Cl2 (15 mL), washed with H2O (2×10 mL) then dried (MgSO4), filtered and concentrated under reduced pressure. The oil thus obtained was subjected to flash chromatography (1:19 v/v ethyl acetate/hexane elution) to afford the title compound CP30262 (71 mg, 82%) as a pale-pink oil, Rf 0.6 in 1:1 v/v ethyl acetate/hexane.
Reaction SMILES: S(=O)(=O)(O)O.[CH2:6]([C:8]1[CH:13]=[CH:12][C:11]([CH2:14][C:15]([CH3:18])(O)[CH3:16])=[CH:10][CH:9]=1)[CH3:7].[C:19](#[N:21])[CH3:20].[OH-:22].[Na+]>C(O)(=O)C>[CH2:6]([C:8]1[CH:13]=[CH:12][C:11]([CH2:14][C:15]([NH:21][C:19](=[O:22])[CH3:20])([CH3:18])[CH3:16])=[CH:10][CH:9]=1)[CH3:7]
Reactant: CC#N
Reactant: CCc1ccc(CC(C)(C)O)cc1
Reactant: [OH-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: CC(=O)O
Product: CCc1ccc(CC(C)(C)NC(C)=O)cc1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
6.2 mL of concentrated sulfuric acid is added dropwise to 15.5 g (87 mmol) of 1-(4-ethylphenyl)-2-methylpropan-2-ol in 4.8 mL (91 mmol) acetonitrile and 15 mL glacial acetic acid within 15 minutes, during which time the temperature rises to 65° C. It is then stirred for one hour, diluted with ice water, and made alkaline with concentrated sodium hydroxide solution. After another 30 minutes' stirring, the solid precipitated is suction filtered and washed with water. The crude product is dissolved in ethyl acetate, dried with sodium sulfate, and evaporated down. The oil remaining is combined with petroleum ether, whereupon a solid is precipitated which is filtered off and dried. Yield: 16.3 g (85%); melting point 90° C.–92° C.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([S:8][CH3:9])=[CH:4][CH:3]=1.C([Li])CCC.[CH:15]([CH:17]1[CH2:22][CH2:21][N:20]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:19][CH2:18]1)=[O:16].[Cl-].[NH4+]>O1CCCC1.CCCCCC.O>[OH:16][CH:15]([C:2]1[CH:7]=[CH:6][C:5]([S:8][CH3:9])=[CH:4][CH:3]=1)[CH:17]1[CH2:22][CH2:21][N:20]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:19][CH2:18]1
Reactant: CC(C)(C)OC(=O)N1CCC(C=O)CC1
Reactant: CSc1ccc(Br)cc1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: O
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CSc1ccc(C(O)C2CCN(C(=O)OC(C)(C)C)CC2)cc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 23.8 %

Procedure:
380 mg of 1-bromo-4-methylsulfanyl benzene was dissolved in 10 mL anhydrous tetrahydrofuran, and 1.24 mL solution of 1.59 M n-butyl lithium in hexane was added dropwise thereto at −70° C. After the mixture was stirred for 1 hour, 3 mL solution of 400 mg t-butyl 4-formyl-piperidine-1-carboxylate in anhydrous tetrahydrofuran was added dropwise thereto, and the mixture was stirred at −70° C. for 2 hours. The temperature of the reaction mixture was increased gradually to 0° C., then water and an ammonium chloride solution were added thereto, and the reaction mixture was extracted with ethyl acetate. The extract was dried over magnesium sulfate and purified by silica gel column chromatography (ethyl acetate/hexane) to give 150 mg of the title compound as a colorless amorphous.
Reaction SMILES: [NH2:1][C@H:2]1[CH2:7][CH2:6][N:5]([CH2:8][CH:9]2[C:13]3=[C:14]([Cl:22])[CH:15]=[N:16][C:17]4[CH:18]=[CH:19][C:20](=[O:21])[N:11]([C:12]=43)[CH2:10]2)[CH2:4][C@H:3]1[OH:23].[O:24]1[C:29]2=[CH:30][N:31]=[C:32]([CH:34]=O)[CH:33]=[C:28]2[CH2:27][CH2:26][CH2:25]1>ClCCl.CO>[ClH:22].[Cl:22][C:14]1[CH:15]=[N:16][C:17]2[CH:18]=[CH:19][C:20](=[O:21])[N:11]3[CH2:10][CH:9]([CH2:8][N:5]4[CH2:6][CH2:7][C@H:2]([NH:1][CH2:34][C:32]5[CH:33]=[C:28]6[CH2:27][CH2:26][CH2:25][O:24][C:29]6=[CH:30][N:31]=5)[C@H:3]([OH:23])[CH2:4]4)[C:13]=1[C:12]=23
Reactant: N[C@H]1CCN(CC2Cn3c(=O)ccc4ncc(Cl)c2c43)C[C@H]1O
Reactant: O=Cc1cc2c(cn1)OCCC2
Solvent: ClCCl
Solvent: CO
Product: Cl
Product: O=c1ccc2ncc(Cl)c3c2n1CC3CN1CC[C@H](NCc2cc3c(cn2)OCCC3)[C@H](O)C1
Yield: 50 %

Procedure:
The free base of the title compound was prepared from racemic 4-{[(3R,4S)-4-amino-3-hydroxy-1-piperidinyl]methyl}-3-chloro-4,5-dihydro-7H-pyrrolo[3,2,1-de]-1,5-naphthyridin-7-one and 3,4-dihydro-2H-pyrano[2,3-c]pyridine-6-carbaldehyde (for a synthesis see WO2004058144, Example 126(e)) according to the general method of Example 24(b), chromatographing with dichloromethane/methanol/0.88 ammonia 95:5:0.5, in 50% yield.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:30]=[C:11]3[N:12]=[C:13]([CH3:29])[C:14]([C:23](=[O:28])[C:24]([O:26][CH3:27])=[O:25])=[C:15]([C:16]4[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=4)[N:10]3[N:9]=2)[CH:5]=[CH:6][CH:7]=1.CB1N2CCC[C@@H]2C(C2C=CC=CC=2)(C2C=CC=CC=2)O1.C1(C)C=CC=CC=1.[B]1OC2C(=CC=CC=2)O1.C1COCC1>C1(C)C=CC=CC=1.CCOC(C)=O>[Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:30]=[C:11]3[N:12]=[C:13]([CH3:29])[C:14]([C@H:23]([OH:28])[C:24]([O:26][CH3:27])=[O:25])=[C:15]([C:16]4[CH:17]=[CH:18][C:19]([F:22])=[CH:20][CH:21]=4)[N:10]3[N:9]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)C(=O)c1c(C)nc2cc(-c3cccc(Cl)c3)nn2c1-c1ccc(F)cc1
Agent: CB1OC(c2ccccc2)(c2ccccc2)[C@H]2CCCN12
Agent: [B]1Oc2ccccc2O1
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COC(=O)[C@@H](O)c1c(C)nc2cc(-c3cccc(Cl)c3)nn2c1-c1ccc(F)cc1
Temperature: -35 °C
Reaction time: 0.33 h
Yield: 93.9 %

Procedure:
To a stirred solution of methyl 2-(2-(3-chlorophenyl)-7-(4-fluorophenyl)-5-methylpyrazolo[1,5-a]pyrimidin-6-yl)-2-oxoacetate (0.083 g, 0.196 mmol) in toluene (5 mL) was added 1M (R)-1-methyl-3,3-diphenylhexahydropyrrolo[1,2-c][1,3,2]oxazaborole/toluene (0.039 ml, 0.039 mmol) and cooled to −35° C. To this was added dropwise 1M catecholborane/THF (0.294 ml, 0.294 mmol) over 10 min and stirred for additional 20 min. Then, the reaction was slowly warmed to −15 C over 30 min, diluted with EtOAc (10 ml) and quenched with sat. Na2CO3 (5 mL). The resulting mixture was vigorously stirred for 30 min, aq. larer removed and organic layer washed with sat. Na2CO3 (2×5 mL), dried (Na2SO4), filtered, concentrated to yellow residue which was purified by prep-HPLC to afford (S)-methyl 2-(2-(3-chlorophenyl)-7-(4-fluorophenyl)-5-methylpyrazolo[1,5-a]pyrimidin-6-yl)-2-hydroxyacetate (0.08 g, 0.184 mmol, 94% yield) as solid. 1H NMR (500 MHz, CDCl3) δ: 7.82 (s, 1H), 7.75-7.68 (m, 1H), 7.68-7.58 (m, 2H), 7.34-7.24 (m, 4H), 6.88 (s, 1H), 5.16 (s, 1H), 3.78 (s, 3H), 3.69-3.34 (br.s., 1H), 2.58 (s, 3H). LCMS (M+H) calcd for C22H18ClFN3O3: 426.1. found: 426.2.
Reaction SMILES: [F:1][C:2]([F:18])([F:17])[S:3]([O:6][CH2:7][CH2:8][O:9][Si:10]([C:13]([CH3:16])([CH3:15])[CH3:14])([CH3:12])[CH3:11])(=[O:5])=[O:4].[CH2:19]([O:22][C:23]([N:25]1[C@H:29]([CH2:30][C:31]2[N:32]3[CH:38]=[N:37][CH:36]=[C:33]3[S:34][CH:35]=2)[CH2:28][C@H:27]([S:39][C:40]2[C@H:41]([CH3:57])[C@@H:42]3[C@@H:52]([C@H:53]([OH:55])[CH3:54])[C:51](=[O:56])[N:43]3[C:44]=2[C:45]([O:47][CH2:48][CH:49]=[CH2:50])=[O:46])[CH2:26]1)=[O:24])[CH:20]=[CH2:21]>ClC(Cl)C>[F:1][C:2]([F:18])([F:17])[S:3]([O-:6])(=[O:5])=[O:4].[CH2:19]([O:22][C:23]([N:25]1[C@H:29]([CH2:30][C:31]2[N+:32]3[C:33](=[CH:36][N:37]([CH2:7][CH2:8][O:9][Si:10]([C:13]([CH3:14])([CH3:15])[CH3:16])([CH3:11])[CH3:12])[CH:38]=3)[S:34][CH:35]=2)[CH2:28][C@H:27]([S:39][C:40]2[C@H:41]([CH3:57])[C@@H:42]3[C@@H:52]([C@H:53]([OH:55])[CH3:54])[C:51](=[O:56])[N:43]3[C:44]=2[C:45]([O:47][CH2:48][CH:49]=[CH2:50])=[O:46])[CH2:26]1)=[O:24])[CH:20]=[CH2:21]
Reactant: C=CCOC(=O)C1=C(S[C@H]2C[C@@H](Cc3csc4cncn34)N(C(=O)OCC=C)C2)[C@H](C)[C@@H]2[C@@H]([C@@H](C)O)C(=O)N12
Reactant: CC(C)(C)[Si](C)(C)OCCOS(=O)(=O)C(F)(F)F
Solvent: CC(Cl)Cl
Product: C=CCOC(=O)C1=C(S[C@H]2C[C@@H](Cc3csc4cn(CCO[Si](C)(C)C(C)(C)C)c[n+]34)N(C(=O)OCC=C)C2)[C@H](C)[C@@H]2[C@@H]([C@@H](C)O)C(=O)N12
Product: O=S(=O)([O-])C(F)(F)F
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
2-(t-Butyldimethylsilyloxy)ethyl trifluoromethanesulfonate (63.5 mg) is added to a solution of 98.3 mg of allyl(1R,5S,6S)-2-[(3S,5R)-1-allyloxycarbonyl-5-(imidazo[5,1-b]thiazol-3-yl)methylpyrrolidin-3-yl]thio-6-((1R)-1-hydroxyethyl)-1-methylcarbapen-2-em-3-carboxylate described in Example 20-b) in 1.0 ml of dry dichloroethane, and the mixture is stirred in an argon atmosphere at room temperature for 1.5 hr. The excess reagent is removed by evaporation under reduced pressure to give allyl(1R,5S,6S)-2-[(3S,5R)-1-allyloxycarbonyl-5-[6-(2-t-butyldimethylsilyloxyethyl)imidazo[5,1-b]thiazolium-3-yl]methylpyrrolidin-3-yl]thio-6-((1R)-1-hydroxyethyl)-1-methylcarbapen-2-em-3-carboxylate trifluoromethane sulfonate as a brown viscous material. Acetic acid (0.01 ml) and 0.18 ml of a 1 M tetra-n-butylammonium fluoride/THF solution are added to a solution of this compound in 1 ml of anhydrous THF, and the mixture is stirred in an argon atmosphere at room temperature for 1.5 hr. Dry ethanol (1 ml) is added thereto. Thereafter, 9.3 mg of triphenylphosphine, 0.038 ml of morpholine, and 11.3 mg of tetrakis(triphenylphosphine)palladium(0) are successively added to the mixture, and the mixture is then stirred in an argon atmosphere at room temperature for one hr. THF (10 ml) is added thereto, and the resultant precipitate is further washed twice with 5 ml of THF and dried in vacuo to give a yellow powder. The yellow powder is then purified by column chromatography on Cosmosil 40C18-PREP (water-methanol) and then passed through an anion exchange resin Amberlyst A-26 (Cl− form) to give 13.3 mg of the title compound as a colorless flocculent material.
Reaction SMILES: Cl[CH:2]([C:7]1[S:11][C:10]([C:12]2[S:16][C:15]([O:17][C:18]3[CH:23]=[CH:22][C:21]([O:24][CH:25]([CH3:27])[CH3:26])=[CH:20][CH:19]=3)=[N:14][CH:13]=2)=[CH:9][CH:8]=1)[C:3]([F:6])([F:5])[F:4].[N-:28]=[N+:29]=[N-:30].[Na+].O>CN(C)C=O>[N:28]([CH:2]([C:7]1[S:11][C:10]([C:12]2[S:16][C:15]([O:17][C:18]3[CH:23]=[CH:22][C:21]([O:24][CH:25]([CH3:27])[CH3:26])=[CH:20][CH:19]=3)=[N:14][CH:13]=2)=[CH:9][CH:8]=1)[C:3]([F:6])([F:5])[F:4])=[N+:29]=[N-:30]
Reactant: CC(C)Oc1ccc(Oc2ncc(-c3ccc(C(Cl)C(F)(F)F)s3)s2)cc1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)Oc1ccc(Oc2ncc(-c3ccc(C(N=[N+]=[N-])C(F)(F)F)s3)s2)cc1
Yield: 71.6 %

Procedure:
A mixture of Example 5C (0.6 g, 0.0013 mol) and sodium azide (1.0 g, 0.013 mol) in N,N-dimethylformamide was heated at 80° C. under nitrogen for 4 hours. Water was added and the solution was extracted with ether. The organic layer was then washed with brine, dried and filtered. The filtrate was concentrated to give 0.5 g of crude as a yellow oil, which was purified on silica gel (10˜30% ethyl acetate in hexane) to give 0.41 g of pure product as a light yellow oil (72% yield), 1H NMR (300 MHz, CDCl3) δ ppm 1.35 (d, J=5.88 Hz, 6H) 4.44-4.61 (m, 1H) 5.10 (q, J=6.62 Hz, 1H) 6.87-6.96 (m, 2H) 6.97 (d, J=3.68 Hz, 1H) 7.08-7.14 (m, 1H) 7.16-7.24 (m, 2H) 7.32 (s, 1H).
Reaction SMILES: [H-].[Na+].[CH3:3][O:4][C:5]1[CH:6]=[CH:7]C2N[C:13](=O)[CH2:12][C:11](=[O:16])[N:10]([CH3:17])[C:9]=2[CH:18]=1.[CH3:19]I.O.[CH3:22][N:23]([CH:25]=[O:26])[CH3:24]>C(OCC)(=O)C>[CH3:3][O:4][C:5]1[CH:6]=[CH:7][C:22]2[N:23]([CH3:24])[C:25](=[O:26])[C:12]([CH3:13])([CH3:19])[C:11](=[O:16])[N:10]([CH3:17])[C:9]=2[CH:18]=1
Reactant: COc1ccc2c(c1)N(C)C(=O)CC(=O)N2
Reactant: CI
Reactant: CN(C)C=O
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Product: COc1ccc2c(c1)N(C)C(=O)C(C)(C)C(=O)N2C
Temperature: 0 °C
Reaction time: 1 h
Yield: 77 %

Procedure:
Sodium hydride (60% in oil, 128 mg, 3.2 mmol) was suspended in DMF (10 ml). 8-Methoxy-1-methyl-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione (176 mg, 0.8 mmol) was added thereto at 0° C., and stirring was conducted at the same temperature for 1 hour. Methyl iodide (0.25 ml, 4.0 mmol) was added to the mixture, and stirred at room temperature overnight. Water was added to the reaction mixture, and extraction with ethyl acetate was performed. The organic layer was washed with water, dried over sodium sulfate, and concentrated under reduced pressure. The residue was recrystallized from n-hexane to thereby obtain 161.6 mg (yield: 77%) of 7-methoxy-1,3,3,5-tetramethyl-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione as a white powder.
Reaction SMILES: C(O)C.[N+:4]([C:7]1[CH:15]=[CH:14][C:10]2[N:11]=[CH:12][NH:13][C:9]=2[CH:8]=1)([O-])=O.[CH2:16]([O:18][C:19](=[O:29])[CH2:20][C:21](=O)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[CH3:17].S([O-])([O-])(=O)=O.[Ca+2]>O.CC(O)=O>[N:11]1[C:10]2[CH:14]=[CH:15][C:7]([NH:4][C:24]3[CH:23]=[C:22]([CH:27]=[CH:26][CH:25]=3)[CH:21]=[CH:20][C:19]([O:18][CH2:16][CH3:17])=[O:29])=[CH:8][C:9]=2[NH:13][CH:12]=1
Reactant: O=[N+]([O-])c1ccc2nc[nH]c2c1
Reactant: CCOC(=O)CC(=O)c1ccccc1
Agent: O=S(=O)([O-])[O-]
Agent: [Ca+2]
Solvent: CCO
Solvent: CC(=O)O
Solvent: O
Product: CCOC(=O)C=Cc1cccc(Nc2ccc3nc[nH]c3c2)c1

Procedure:
A solution of 900 ml. of ethanol and 82 g. (0.5 mole) of 5-nitrobenzimidazole with 4 g. of 5% PdC, 50% H2O catalyst is reduced on the Parr Apparatus. A pressure drop of 104 psi. is observed (calcd. 100). After the reduction stopped, the bottle is removed from the apparatus, and the catalyst filtered. Then 96 g. (0.5 mole) of ethylbenzoylacetate, 20 g. of anhydrous calcium sulfate and 0.5 ml. of HOAc are added to the filtrate. The solution is refluxed for 2 hours and filtered. The filtrate is concentrated to a dark sticky resin. Crystallization is induced by scratching. The product after cooling is filtered, washed with ethanol and air-dried. The product weighs 55 g. m.p. 188°-190° C.
Reaction SMILES: [N+:1]([C:4]1[C:5](=[O:14])[NH:6][C:7](=[O:13])[N:8]([CH2:10][O:11][CH3:12])[CH:9]=1)([O-:3])=[O:2].Br[CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18]>[F-].C([N+](CCCC)(CCCC)CCCC)CCC.O1CCCC1>[N+:1]([C:4]1[C:5](=[O:14])[N:6]([CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18])[C:7](=[O:13])[N:8]([CH2:10][O:11][CH3:12])[CH:9]=1)([O-:3])=[O:2]
Reactant: CCOC(=O)CBr
Reactant: COCn1cc([N+](=O)[O-])c(=O)[nH]c1=O
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: CCOC(=O)Cn1c(=O)c([N+](=O)[O-])cn(COC)c1=O
Temperature: 25 °C

Procedure:
The compound of Example 41 (10.0 g, 50 mmole) is dissolved in tetrabutylammonium flouride (120 mL of a 1.0M solution in tetrahydrofuran, 0.124 mole). Ethyl bromoacetate (8.3 mL, 75 mmole) is added. The reaction mixture is stirred at room temperature. The reaction mixture is concentrated, then partitioned between dichloromethane and water. The aqueous layer is extracted with dichloromethane. The combined organic extracts are washed with water, brine, and dried over anhydrous magnesium sulfate. The solvent is removed under vacuum to afford the title compound.
Reaction SMILES: [Cl:1][CH2:2][C:3]([NH:5][C:6](=[O:37])[NH:7][CH:8]1[CH2:13][CH2:12][C:11]([CH2:15][S:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[CH2:24][OH:25])([OH:14])[CH:10]([C:26]2([CH3:34])[O:33][CH:27]2[CH2:28][CH:29]=[C:30]([CH3:32])[CH3:31])[CH:9]1[O:35][CH3:36])=[O:4].C(N(CC)CC)C.[CH3:45][S:46](Cl)(=[O:48])=[O:47].O>ClCCl>[Cl:1][CH2:2][C:3]([NH:5][C:6](=[O:37])[NH:7][CH:8]1[CH2:13][CH2:12][C:11]([CH2:15][S:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[CH2:24][O:25][S:46]([CH3:45])(=[O:48])=[O:47])([OH:14])[CH:10]([C:26]2([CH3:34])[O:33][CH:27]2[CH2:28][CH:29]=[C:30]([CH3:31])[CH3:32])[CH:9]1[O:35][CH3:36])=[O:4]
Reactant: COC1C(NC(=O)NC(=O)CCl)CCC(O)(CSCc2ccccc2CO)C1C1(C)OC1CC=C(C)C
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: O
Solvent: ClCCl
Product: COC1C(NC(=O)NC(=O)CCl)CCC(O)(CSCc2ccccc2COS(C)(=O)=O)C1C1(C)OC1CC=C(C)C
Reaction time: 0.17 h
Yield: 98 %

Procedure:
In dichloromethane (3 ml) were dissolved 4-(N'-chloroacetylureido)-2-(1,2-epoxy-1,5-dimethyl-4-hexenyl)-1-(2-hydroxymethylbenzyl)thiomethyl-3-methoxycyclohexanol (514 mg) and triethylamine (0.33 ml). To the solution was added dropwise at -20° C. methanesulfonyl chloride (96 μl). The mixture was stirred for 10 minutes, to which was added water to suspend the reaction. The reaction product was extracted with ethyl acetate. The extract solution was washed with a saturated aqueous solution of sodium chloride and, then, dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure to leave 4-(N'-chloroacetylureido)-2-(1,2-epoxy-1,5-dimethyl-4-hexenyl)-1-(2-methanesulfonyloxymethylbenzyl)thiomethyl-3-methoxycyclohexanol (550 mg; yield 98%) as a colorless powdery product.
Reaction SMILES: C([CH2:4][C:5]1[N:9]([CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[Cl:17])[C:8]([S:18][CH2:19][CH2:20][CH3:21])=[N:7][CH:6]=1)(O)=O.[H-].[O:23]1CCCC1>C1(C)C=CC=CC=1>[Cl:17][C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=1[CH2:10][N:9]1[C:5]([CH2:4][OH:23])=[CH:6][N:7]=[C:8]1[S:18][CH2:19][CH2:20][CH3:21]
Reactant: C1CCOC1
Reactant: CCCSc1ncc(CC(=O)O)n1Cc1ccccc1Cl
Agent: [H-]
Solvent: Cc1ccccc1
Product: CCCSc1ncc(CO)n1Cc1ccccc1Cl
Temperature: -78 °C
Reaction time: 1.5 h

Procedure:
A solution of 5-carboxymethyl-1-(2-chlorophenyl)methyl-2-propylthio-1H-imidazole (3.74 g, 11.5 mmol) in dry tetrahydrofuran (50 ml) was cooled to -78° C. under argon, and a solution of diisobutyl alumninum hydride in toluene (30 ml of 1M) was added dropwise. The mixture was stirred at -78° C. for 1.5 hours, then allowed to slowly warm to room temperature. The reaction was quenched by pouring onto iced dilute acetic acid, the product was extracted into methylene chloride and the organic extracts were washed with water, 5% sodium carbonate solution and brine The dried, concentrated product was a light tan solid (3.32 g). Crystallization from ethanol/water gave 1-(2-chlorophenyl)methyl-5-hydroxymethyl-2-propylthio-1H-imidazole; mp 98°-101° C.
Reaction SMILES: [Br:1][CH2:2][C@@H:3]([C:5]1[CH:16]=[CH:15][C:8]2[O:9][C:10]([CH3:14])([CH3:13])CO[C:7]=2[CH:6]=1)[OH:4].N1C=CN=C1.[Si:22](Cl)([C:25]([CH3:28])([CH3:27])[CH3:26])([CH3:24])[CH3:23].CN([CH:33]=[O:34])C>>[Br:1][CH2:2][C@@H:3]([C:5]1[CH:16]=[CH:15][C:8]2[O:9][C:10]([CH3:13])([CH3:14])[O:34][CH2:33][C:7]=2[CH:6]=1)[O:4][Si:22]([C:25]([CH3:28])([CH3:27])[CH3:26])([CH3:24])[CH3:23]
Reactant: CN(C)C=O
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: CC1(C)COc2cc([C@@H](O)CBr)ccc2O1
Agent: c1c[nH]cn1
Product: CC1(C)OCc2cc([C@H](CBr)O[Si](C)(C)C(C)(C)C)ccc2O1
Reaction time: 18 h

Procedure:
To the product of step (d) (10 g, 34.8 mmol) and imidazole (4.7 g, 69.7 mmol) dissolved in 100 mL DMF was added tert-butyldimethylsilyl chloride (5.78 g, 38.3 mmol). The reaction mixture was stirred for 18 hours. The reaction mixture was then partitioned between 200 mL of saturated sodium chloride and 200 mL of diethyl ether. The aqueous layer was extracted with 200 mL of diethyl ether. The organic layers were then combined, washed with saturated sodium chloride (3×100 mL), dried over MgSO4 and concentrated. The product was purified by silica gel chromatography, eluting with hexanes followed by 5% ethyl acetate in hexanes. The desired fractions were combined and concentrated to give the title compound as an oil.
Reaction SMILES: [Br:1][CH2:2][CH2:3][OH:4].[C:5](Cl)(=[O:9])[C:6]([CH3:8])=[CH2:7].C(N(CC)CC)C>O1CCCC1>[C:5]([O:4][CH2:3][CH2:2][Br:1])(=[O:9])[C:6]([CH3:8])=[CH2:7]
Reactant: C=C(C)C(=O)Cl
Reactant: OCCBr
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: C=C(C)C(=O)OCCBr
Yield: 89.6 %

Procedure:
A reactor was charged with 12.50 g (100 mmol) of 2-bromoethanol and 100 ml of tetrahydrofuran (THF) at 0° C. in a nitrogen atmosphere. After the dropwise addition of 10.45 g (100 mmol) of methacrylic chloride and 11.13 g (110 mmol) of triethylamine, the mixture was reacted at 25° C. for 30 minutes with stirring. After completion of the reaction, the reaction mixture was concentrated under reduced pressure, and the residue was purified by distillation to obtain 17.30 g of 2-bromoethyl methacrylate shown by the following formula (M-20′) (yield: 90%).