Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][C:11]2[NH:14][N:15]=[C:16]([C:17]3[CH:22]=[CH:21][C:20]([Br:23])=[CH:19][CH:18]=3)[C:10]=2[CH2:9]1)=O)(C)(C)C.[C:24]([OH:30])([C:26]([F:29])([F:28])[F:27])=[O:25]>C(Cl)Cl>[F:27][C:26]([F:29])([F:28])[C:24]([O-:30])=[O:25].[Br:23][C:20]1[CH:19]=[CH:18][C:17]([C:16]2[C:10]3[CH2:9][NH:8][CH2:13][CH2:12][C:11]=3[NH2+:14][N:15]=2)=[CH:22][CH:21]=1
Reactant: O=C(O)C(F)(F)F
Reactant: CC(C)(C)OC(=O)N1CCc2[nH]nc(-c3ccc(Br)cc3)c2C1
Solvent: ClCCl
Product: Brc1ccc(C2=N[NH2+]C3=C2CNCC3)cc1
Product: O=C([O-])C(F)(F)F
Reaction time: 8 h

Procedure:
To a stirred solution of 10.0 g (26.4 mmol) of the 3-(4-bromo-phenyl)-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridine-5-carboxylic acid tert-butyl ester in CH2Cl2 (26.0 mL) was added 26.0 mL of TFA. The resulting mixture was allowed to stir overnight. The solvent was removed under reduced pressure and the solid was dried in vacuo. The dried solid was suspended in Et2O and stirred vigorously for 2 h and then filtered and dried in vacuo to give 10.1 g of a white solid, which was used without further purification. TLC (silica, 10% MeOH/CH2Cl2): Rf=0.05. MS (electrospray): m/z calculated for C12H12BrN3 [M++H] 278.02, observed 278.0.
Reaction SMILES: O=C[C:3]1[CH:11]=[CH:10][C:8]([OH:9])=[C:5]([O:6][CH3:7])[CH:4]=1.[OH-].[Na+].OO.I([O-])(=O)(=O)=[O:17].[Na+]>O.C(O)(=O)C>[CH3:7][O:6][C:5]1[C:8](=[O:9])[CH:10]=[CH:11][C:3](=[O:17])[CH:4]=1
Reactant: [O-][I+3]([O-])([O-])[O-]
Reactant: COc1cc(C=O)ccc1O
Agent: OO
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC(=O)O
Product: COC1=CC(=O)C=CC1=O
Temperature: 10 °C
Yield: 334.4 %

Procedure:
Vanillin (2.432 kg) was added to a solution of sodium hydroxide (640 g) in water (8 l) and cooled to 10° C. with an ice-bath. Then a solution of hydrogen peroxide (30%) (2.4 l) was added at a rate to keep the temperature of the reaction mixture below 30° C. The addition completed (about 2 hours), the reaction mixture was added over a period of 3 hours to a suspension of sodium periodate (880 g) in water (4 l) and acetic acid (640 ml) cooled with an ice-bath to 10° C. (the temperature of the reaction mixture was kept below 35° C.). The precipitate was filtered, washed with cold water followed by ethanol/hexane (1:1) mixture and air-dried to afford the title compound (1.9 kg), m.p. 144°-147° C.
Reaction SMILES: [CH3:1][C:2]1[CH:13]=[CH:12][C:5]2[CH:6]=[C:7]([C:9]([OH:11])=[O:10])[O:8][C:4]=2[CH:3]=1.[Si](C=[N+]=[N-])(C)(C)[CH3:15]>C1(C)C=CC=CC=1.CO>[CH3:1][C:2]1[CH:13]=[CH:12][C:5]2[CH:6]=[C:7]([C:9]([O:11][CH3:15])=[O:10])[O:8][C:4]=2[CH:3]=1
Reactant: C[Si](C)(C)C=[N+]=[N-]
Reactant: Cc1ccc2cc(C(=O)O)oc2c1
Solvent: Cc1ccccc1
Solvent: CO
Product: COC(=O)c1cc2ccc(C)cc2o1
Temperature: 25 °C
Reaction time: 6 h
Yield: 67.1 %

Procedure:
To a solution of 6-methylbenzofuran-2-carboxylic acid (11 g, 62.4 mmol) in 468 mL of toluene and 156 mL of MeOH was added 2N TMS-CHN2 (46.8 mL, 94 mmol) dropwise at room temperature. The reaction was stirred at room temperature for 6 hr. The reaction was then quenched by addition of acetic acid dropwise at 0° C. until the yellow color vanished, and gas evolution ceased. The reaction was concentrated under reduced pressure, and the residue was purified by silica gel flash chromatography, 100% Heptane-10% Ethyl Acetate/90% Heptane, to give methyl 6-methylbenzofuran-2-carboxylate (7.96 g). 1H NMR (400 MHz, DMSO-d6) δ 2.46 (s, 3H), 3.88 (s, 3H), 7.20 (dd, J=8.3, 1.0 Hz, 1H), 7.53 (s, 1H), 7.67 (d, J=8.1 Hz, 1H), 7.71 (d, J=1.0 Hz, 1H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:10]=[C:9]([O:11][CH3:12])[CH:8]=[CH:7][C:4]=1[CH:5]=O.[C:13]([C:16]1[C:17](=[O:23])[CH2:18][CH2:19][CH2:20][C:21]=1[OH:22])(=[O:15])[CH3:14].[C:24](C1C(=O)OC(C)=CC=1O)(=[O:26])C>>[OH:23][C:17]1[CH2:18][CH2:19][CH2:20][C:21](=[O:22])[C:16]=1[C:13](=[O:15])/[CH:14]=[CH:5]/[C:4]1[CH:7]=[CH:8][C:9]([O:11][CH3:12])=[C:10]([O:26][CH3:24])[C:3]=1[O:2][CH3:1]
Reactant: CC(=O)c1c(O)cc(C)oc1=O
Reactant: CC(=O)C1=C(O)CCCC1=O
Reactant: COc1ccc(C=O)c(OC)c1
Product: COc1ccc(/C=C/C(=O)C2=C(O)CCCC2=O)c(OC)c1OC

Procedure:
Proceeding as in Reference 5, Step 5.1, but substituting 2,3,4-trimethoxy-benzaldehyde for 2,4-dimethoxybenzaldehyde and 2-acetyl-3-hydroxy-cyclohex-2-enone for 3-acetyl-4-hydroxy-6-methyl-pyran-2-one, provided 3-hydroxy-2-[(E)-3-(2,3,4-trimethoxy-phenyl)-acryloyl]-cyclohex-2-enone.
Reaction SMILES: [N+:1]([C:4]1[CH:23]=[CH:22][C:7]([C:8]([O:10][C@H:11]2[C:15]3[N:16]=[CH:17][N:18]=[C:19](Cl)[C:14]=3[C@H:13]([CH3:21])[CH2:12]2)=[O:9])=[CH:6][CH:5]=1)([O-:3])=[O:2].[CH2:24]([N:31]1[CH2:36][CH2:35][C:34]2([C:44]3[C:39](=[CH:40][CH:41]=[CH:42][C:43]=3[CH2:45][NH:46][C:47](=[O:53])[O:48][C:49]([CH3:52])([CH3:51])[CH3:50])[NH:38][CH2:37]2)[CH2:33][CH2:32]1)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>>[N+:1]([C:4]1[CH:23]=[CH:22][C:7]([C:8]([O:10][C@H:11]2[C:15]3[N:16]=[CH:17][N:18]=[C:19]([N:38]4[C:39]5[C:44](=[C:43]([CH2:45][NH:46][C:47]([O:48][C:49]([CH3:52])([CH3:51])[CH3:50])=[O:53])[CH:42]=[CH:41][CH:40]=5)[C:34]5([CH2:35][CH2:36][N:31]([CH2:24][C:25]6[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=6)[CH2:32][CH2:33]5)[CH2:37]4)[C:14]=3[C@H:13]([CH3:21])[CH2:12]2)=[O:9])=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: CC(C)(C)OC(=O)NCc1cccc2c1C1(CCN(Cc3ccccc3)CC1)CN2
Reactant: C[C@@H]1C[C@@H](OC(=O)c2ccc([N+](=O)[O-])cc2)c2ncnc(Cl)c21
Product: C[C@@H]1C[C@@H](OC(=O)c2ccc([N+](=O)[O-])cc2)c2ncnc(N3CC4(CCN(Cc5ccccc5)CC4)c4c(CNC(=O)OC(C)(C)C)cccc43)c21

Procedure:
(5R,7R)-4-(1′-benzyl-4-((tert-butoxycarbonylamino)methyl)spiro[indoline-3,4′-piperidine]-1-yl)-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-7-yl 4-nitrobenzoate was prepared by the procedures described in Example 1, Step 8, substituting (R)-4-chloro-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidine with (5R,7R)-4-chloro-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-7-yl 4-nitrobenzoate, and substituting tert-butyl 5H-chlorospiro[indoline-3,4′-piperidine]-1′-carboxylate with tert-butyl (1′-benzylspiro[indoline-3,4′-piperidine]-4-yl)methylcarbamate. LCMS (APCI+) m/z 605 [M+H]+; Rt=4.33 min.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:9][CH:10]([OH:12])[CH3:11])[CH:6]=[CH:7][CH:8]=1.CCN(CC)CC.[CH3:20][S:21](O)(=[O:23])=[O:22]>C(Cl)Cl.CN(C1C=CN=CC=1)C>[CH3:20][S:21]([O:12][CH:10]([CH3:11])[CH2:9][C:5]1[CH:6]=[CH:7][CH:8]=[C:3]([O:2][CH3:1])[CH:4]=1)(=[O:23])=[O:22]
Reactant: CS(=O)(=O)O
Reactant: COc1cccc(CC(C)O)c1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1cccc(CC(C)OS(C)(=O)=O)c1
Yield: 98.2 %

Procedure:
To a cold solution (5° C.) of 1-[3-(methyloxy)phenyl]-2-propanol (1) (75 g, 0.45 mol) in CH2Cl2 (500 mL) were added Et3N (100 mL, 0.72 mol) and DMAP (2.75 g, 22.5 mmol). Methanesulfonic acid (52 mL, 0.675 mol) was added slowly (drop-wise) to the above reaction mixture at that temperature over a period of 40 min. The resultant mixture was stirred between 5° C. and 10° C. for 8 h under N2. The reaction mixture was washed with H2O (3×150 mL), brine (1×100 mL), dried (Na2SO4) and concentrated under reduced pressure to afford the crude product which was passed through a pad of silica to afford 108 g (98%) of the title compound. 1H NMR (400 MHz, CDCl3): δ 7.24 and 7.20 (dd, J1=15.2 Hz, J2=3.8 Hz, 1H), 6.81-6.76 (m, 3H), 4.87 (sextet, J=6.00 Hz, 1H), 3.77 (s, 3H), 2.96 and 2.92 (dd, J1=14.0 Hz, J2=8.0 Hz, 1H), 2.87 and 2.84 (dd, J1=14.0 Hz, J2=5.6, Hz, 1H), 2.54 (s, 3H), 1.44 (d, J=6.4 Hz, 3H).
Reaction SMILES: C(N(CC)CC)C.[CH:8]([C:10]1[CH:11]=[C:12]2[C:16](=[CH:17][CH:18]=1)[N:15]([CH2:19][CH2:20][CH3:21])[CH:14]=[C:13]2[CH2:22][C:23]1[CH:32]=[CH:31][C:26]([C:27]([O:29][CH3:30])=[O:28])=[CH:25][C:24]=1[O:33][CH3:34])=[O:9].[C:35]1(=[O:41])[O:40][C:38](=[O:39])[CH2:37][CH2:36]1.Cl>C(Cl)Cl.[Cl-].[Zn+2].[Cl-].C(OCC)(=O)C>[C:38]([CH:37]1[CH2:36][C:35](=[O:41])[O:9][CH:8]1[C:10]1[CH:11]=[C:12]2[C:16](=[CH:17][CH:18]=1)[N:15]([CH2:19][CH2:20][CH3:21])[CH:14]=[C:13]2[CH2:22][C:23]1[CH:32]=[CH:31][C:26]([C:27]([O:29][CH3:30])=[O:28])=[CH:25][C:24]=1[O:33][CH3:34])([OH:40])=[O:39]
Reactant: O=C1CCC(=O)O1
Reactant: CCCn1cc(Cc2ccc(C(=O)OC)cc2OC)c2cc(C=O)ccc21
Agent: Cl
Agent: [Cl-]
Agent: [Zn+2]
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCn1cc(Cc2ccc(C(=O)OC)cc2OC)c2cc(C3OC(=O)CC3C(=O)O)ccc21
Reaction time: 15 h

Procedure:
Triethylamine (8.32 g) was added slowly to a stirred mixture of methyl 4-[5-formyl-1-propylindol-3-ylmethyl]-3-methoxybenzoate (10 g), succinic anhydride (5.5 g) and zinc chloride (11.4 g) in methylene chloride (50 ml), under a nitrogen atmosphere, such that the temperature of the reaction did not exceed 25°. After complete addition, the mixture was stirred for 15 hr, poured into a mixture of 2M hydrochloric acid (500 ml) and ethyl acetate (500 ml), the layers separated and the aqueous layer extracted with ethyl acetate. The combined extracts were washed (water (three times), brine), dried (MgSO4) and evaporated. The product was dissolved in aqueous sodium bicarbonate (300 ml, 6% w/v), and the solution extracted with ether. The aqueous layer was neutralized with 6M hydrochloric acid, acidified to pH 4 with 1M hydrochloric acid, and extracted with ethyl acetate. The extracts were washed (water (twice), brine), dried (MgSO4) and evaporated to give methyl 4-[5-(3-carboxy-2,3,4,5-tetrahydro-5-oxofuran-2-yl)-1-propylindol-3-ylmethyl]-3-methoxybenzoate (12.36 g, 97%, as a mixture of diastereomers) as an off-white foam: partial NMR (300 MHz, DMSO-d6): 0.83(m, 3H, CH3, both isomers), 3.83(s, 3H, OCH3, both isomers), 3.91(s, 3H, OCH3, both isomers), 5.61(d, 0.5H, CHOC(O), isomer A), 5.87(d, 0.5H, CHOC(O) isomer B).
Reaction SMILES: [Cl:1][C:2]1[CH:19]=[CH:18][C:5]([C:6]([C:8]2[CH:13]=[CH:12][C:11]([S:14]([CH3:17])(=[O:16])=[O:15])=[CH:10][CH:9]=2)=O)=[CH:4][CH:3]=1.[C:20]([O:27][CH2:28][CH3:29])(=[O:26])[CH2:21][CH2:22][C:23]([O-:25])=[O:24].CC(C)([O-])C.[K+].C(O)(C)(C)C>C(OCC)C.O>[CH2:28]([O:27][C:20](/[C:21](=[C:6](\[C:5]1[CH:18]=[CH:19][C:2]([Cl:1])=[CH:3][CH:4]=1)/[C:8]1[CH:13]=[CH:12][C:11]([S:14]([CH3:17])(=[O:16])=[O:15])=[CH:10][CH:9]=1)/[CH2:22][C:23]([OH:25])=[O:24])=[O:26])[CH3:29]
Reactant: CS(=O)(=O)c1ccc(C(=O)c2ccc(Cl)cc2)cc1
Reactant: CCOC(=O)CCC(=O)[O-]
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CCOCC
Solvent: O
Solvent: CC(C)(C)O
Product: CCOC(=O)/C(CC(=O)O)=C(\c1ccc(Cl)cc1)c1ccc(S(C)(=O)=O)cc1
Temperature: 25 °C
Reaction time: 7 h
Yield: 20.8 %

Procedure:
341.5 g (1.16 moles) of 4-chloro-4'-methanesulfonylbenzophenone, prepared in example 2, 310 ml (1.85 moles) of ethyl succinate and 195.5 g (1.74 moles) of potassium t-butoxide are successively added to 2.5 liters of t-butanol. The temperature rises to 40°-45° C., the mixture is stirred for 7 hours at room temperature after this exothermic reaction and is then poured into iced water. After acidification to pH 3 with hydrochloric acid, the mixture is extracted with diethyl ether. The organic phase is washed with water, dried over magnesium sulfate and evaporated in vacuo. The oil obtained is dissolved in diethyl ether and then left overnight at room temperature. The crystals formed are filtered off and dried to provide 102 g of (Z)-3-ethoxycarbonyl-4-(4-chlorophenyl)-4-(4-methanesulfonylphenyl)but-3-enoic acid as crystals with a melting point of 184°-186° C. after recrystallization from isopropanol. The evaporation of the filtrate allows the recovery of 219 g of a mixture consisting of 82% of the (E)-isomer and 18% of the (Z)-isomer.
Reaction SMILES: [C:1]([CH2:5][C:6]([O:8][CH2:9][CH3:10])=[O:7])(=[O:4])[CH2:2][CH3:3].OCC[C:14]#[N:15]>CCO>[O:4]=[C:1]([CH2:2][CH3:3])[CH2:5][C:6]([O:8][CH2:9][CH2:10][C:14]#[N:15])=[O:7]
Reactant: CCOC(=O)CC(=O)CC
Reactant: N#CCCO
Solvent: CCO
Product: CCC(=O)CC(=O)OCCC#N
Yield: 62.5 %

Procedure:
A solution of ethyl propionylacetate (50 g, 0.35 mol, 1.0 equiv) and 3-hydroxypropionitrile (35 mL, 0.52 mol, 1.5 equiv) was heated at 190-210° C. while EtOH (19 mL) was collected by distillation. The residue was distilled in vacuo to afford 37 g (63%) of yellow oil (b.p. 120-125° C./0.4 mm Hg), which was characterized spectroscopically.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][CH2:10][CH2:11][N:12]2[CH:16]=[CH:15][N:14]=[CH:13]2)=[CH:4][CH:3]=1.Cl[CH2:18][C:19]1[O:23][N:22]=[C:21]([C:24]2[S:25][CH:26]=[CH:27][CH:28]=2)[N:20]=1>>[N:12]1([CH2:11][CH2:10][CH2:9][CH2:8][C:5]2[CH:6]=[CH:7][C:2]([O:1][CH2:18][C:19]3[O:23][N:22]=[C:21]([C:24]4[S:25][CH:26]=[CH:27][CH:28]=4)[N:20]=3)=[CH:3][CH:4]=2)[CH:16]=[CH:15][N:14]=[CH:13]1
Reactant: Oc1ccc(CCCCn2ccnc2)cc1
Reactant: ClCc1nc(-c2cccs2)no1
Product: c1csc(-c2noc(COc3ccc(CCCCn4ccnc4)cc3)n2)c1
Yield: 29 %

Procedure:
In substantially the same manner as in Working Example 72, 1-[4-(4-hydroxyphenyl)butyl]imidazole was reacted with 5-chloromethyl-3-(2-thienyl)-1,2,4-oxadiazole to obtain 5-[4-[4-(1-imidazolyl)butyl]phenoxymethyl]-3-(2-thienyl)-1,2,4-oxadiazole. The yield was 29%. Recrystallization from a ethyl acetate-MeOH gave colorless prisms, mp 94-95° C.
Reaction SMILES: [Br:1][C:2]1[C:7]([NH:8][S:9]([C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[C:14]([C:19]([CH3:22])([CH3:21])[CH3:20])[CH:13]=2)(=[O:11])=[O:10])=[CH:6][C:5]([Cl:23])=[CH:4][N:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH3:30][O:31][CH2:32]Cl>C1COCC1>[Br:1][C:2]1[C:7]([N:8]([CH2:30][O:31][CH3:32])[S:9]([C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[C:14]([C:19]([CH3:20])([CH3:22])[CH3:21])[CH:13]=2)(=[O:11])=[O:10])=[CH:6][C:5]([Cl:23])=[CH:4][N:3]=1
Reactant: COCCl
Reactant: CC(C)(C)c1cc(S(=O)(=O)Nc2cc(Cl)cnc2Br)ccc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: COCN(c1cc(Cl)cnc1Br)S(=O)(=O)c1ccc(Cl)c(C(C)(C)C)c1

Procedure:
Prepared from 480 mg (1.10 mmol) of N-(2-bromo-5-chloro-pyridin-3-yl)-3-tert-butyl-4-chloro-benzenesulfonamide, 400 mg of potassium carbonate and 170 μL (1.57 mmol) of methoxymethyl chloride in 2 mL THF using procedure x. Yield: 160 mg of a white solid. LC-MSD, m/z for C17H19BrCl2N2O3S [M+H]+=480.9, 482.9, 484.9
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][CH:10]=2)=[CH:5][CH:4]=1)#[N:2].CC#N.Br[CH2:20][CH2:21][CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24].C([O-])([O-])=O.[K+].[K+]>O>[CH2:26]([O:25][C:23](=[O:24])[CH2:22][CH2:21][CH2:20][O:15][C:12]1[CH:13]=[CH:14][C:9]([C:6]2[CH:5]=[CH:4][C:3]([C:1]#[N:2])=[CH:8][CH:7]=2)=[CH:10][CH:11]=1)[CH3:27]
Reactant: CCOC(=O)CCCBr
Reactant: N#Cc1ccc(-c2ccc(O)cc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC#N
Product: CCOC(=O)CCCOc1ccc(-c2ccc(C#N)cc2)cc1
Temperature: 85 °C
Yield: 109 %

Procedure:
A mixture of 4′-cyano-4-hydroxybiphenyl (4.0 g, 20.5 mmol), MeCN (30 ml), ethyl 4-bromobutyrate (3.75 ml, 5.11 g, 26.2 mmol), and K2CO3 (3.86 g, 27.9 mmol) was stirred at 85° C. After 20 h water (150 ml) was added, and the product was extracted with AcOEt. The combined extracts were washed with brine, dried over MgSO4, and concentrated, to yield 6.91 g (100%) of 4-(4′-cyanobiphenyl-4-yloxy)butyric acid ethyl ester as an oil.
Reaction SMILES: N(OCCC(C)C)=O.CS[S:11][CH3:12].[Br:13][C:14]1[CH:20]=[C:19]([Br:21])[CH:18]=[CH:17][C:15]=1N>>[Br:13][C:14]1[CH:20]=[C:19]([Br:21])[CH:18]=[CH:17][C:15]=1[S:11][CH3:12]
Reactant: Nc1ccc(Br)cc1Br
Reactant: CSSC
Agent: CC(C)CCON=O
Product: CSc1ccc(Br)cc1Br
Temperature: 85 °C
Yield: 18.4 %

Procedure:
A solution of isoamyl nitrite (8.06 mL, 60 mmol) in dimethyl disulfide (36.02 mL, 400 mmol) at 25° C. was slowly treated with 2,4-dibromoaniline (4.8 g, 20 mmol). The reaction was exothermic with gas evolution. The resulting brown reaction mixture was heated to 80-90° C. for 2 h, at which time, thin layer chromatography analysis of the reaction mixture indicated the absence of starting material. The reaction mixture was cooled to 25° C. and then concentrated in vacuo. The resulting residue was dissolved in ethyl acetate (200 mL). The organic layer was washed successively with a 1N aqueous hydrochloric acid solution (1×200 mL) and a saturated aqueous sodium chloride solution (1×200 mL), dried over anhydrous magnesium sulfate, filtered, and concentrated in vacuo. Purification using a plug of silica (Merck Silica gel 60, 230-400 mesh, 4/1 hexanes/ethyl acetate) afforded 2,4-dibromothioanisole (1 1.04 g, 99%) as a brown oil: EI-HRMS m/e calcd for C7H6Br2S (M+) 279.8623, found 279.8619.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8](=[O:10])[C:7]([CH2:17][C:18](Cl)=[O:19])([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[C:6]=2[CH:21]=1.[F:22][C:23]1[CH:28]=[CH:27][C:26]([N:29]2[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]2)=[CH:25][CH:24]=1>>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8](=[O:10])[C:7]([CH2:17][C:18]([N:32]3[CH2:31][CH2:30][N:29]([C:26]4[CH:25]=[CH:24][C:23]([F:22])=[CH:28][CH:27]=4)[CH2:34][CH2:33]3)=[O:19])([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[C:6]=2[CH:21]=1
Reactant: Cc1ccc2c(c1)C(CC(=O)Cl)(c1ccccc1)C(=O)O2
Reactant: Fc1ccc(N2CCNCC2)cc1
Product: Cc1ccc2c(c1)C(CC(=O)N1CCN(c3ccc(F)cc3)CC1)(c1ccccc1)C(=O)O2

Procedure:
This compound was prepared by condensing 2-(2,3-dihydro-5-methyl-2-oxo-3-phenyl-3-benzofuranyl)acetyl chloride with 4-(4-fluorophenyl)piperazine according to the process described in Example 9, Stage B.
Reaction SMILES: C(O)C.[CH3:4][O:5][C:6]1[CH:7]=[CH:8][C:9]2[N:14]=[CH:13][C:12](=[O:15])[N:11]([CH2:16][CH2:17][C@H:18]3[CH2:20][O:19]3)[C:10]=2[N:21]=1.[NH2:22][C@H:23]1[CH2:27][N:26]([C:28]2[CH:29]=[CH:30][C:31]3[O:32][CH2:33][C:34](=[O:38])[NH:35][C:36]=3[N:37]=2)[C:25](=[O:39])[CH2:24]1.C(OC(=O)N[C@@H]1CC(=O)NC1)(C)(C)C>O>[OH:19][C@@H:18]([CH2:17][CH2:16][N:11]1[C:12](=[O:15])[CH:13]=[N:14][C:9]2[CH:8]=[CH:7][C:6]([O:5][CH3:4])=[N:21][C:10]1=2)[CH2:20][NH:22][C@H:23]1[CH2:27][N:26]([C:28]2[CH:29]=[CH:30][C:31]3[O:32][CH2:33][C:34](=[O:38])[NH:35][C:36]=3[N:37]=2)[C:25](=[O:39])[CH2:24]1
Reactant: COc1ccc2ncc(=O)n(CC[C@H]3CO3)c2n1
Reactant: N[C@@H]1CC(=O)N(c2ccc3c(n2)NC(=O)CO3)C1
Agent: CC(C)(C)OC(=O)N[C@H]1CNC(=O)C1
Solvent: CCO
Solvent: O
Product: COc1ccc2ncc(=O)n(CC[C@H](O)CN[C@@H]3CC(=O)N(c4ccc5c(n4)NC(=O)CO5)C3)c2n1
Temperature: 80 °C
Reaction time: 16 h

Procedure:
In a mixed solvent (12 ml) of ethanol and water (9:1) were suspended 6-methoxy-4-{2-[(2S)-oxiran-2-yl]ethyl}pyrido[2,3-b]pyrazin-3(4H)-one (290 mg, 1.17 mmol) and 6-[(4R)-4-amino-2-oxopyrrolidin-1-yl]-2H-pyrido[3,2-b][1,4]oxazin-3(4H)-one (which was synthesized in the same manner as those of Reference Examples 20, 21 and 22, using the [(3R)-5-oxopyrrolidin-3-yl]carbamic acid tert-butyl ester synthesized with reference to WO2004/22536; 291 mg, 1.17 mmol). The obtained mixture was stirred in a sealed tube at 80° C. for 16 hours.
Reaction SMILES: [CH3:1][C:2]1[C:7]([CH3:8])=[CH:6][N:5]=[C:4]([C:9]2[CH:14]=[CH:13][C:12]([C:15]([F:18])([F:17])[F:16])=[CH:11][CH:10]=2)[N:3]=1.[Br:19]Br>C(O)(=O)C>[Br:19][CH2:1][C:2]1[C:7]([CH3:8])=[CH:6][N:5]=[C:4]([C:9]2[CH:14]=[CH:13][C:12]([C:15]([F:18])([F:17])[F:16])=[CH:11][CH:10]=2)[N:3]=1
Reactant: Cc1cnc(-c2ccc(C(F)(F)F)cc2)nc1C
Reactant: BrBr
Solvent: CC(=O)O
Product: Cc1cnc(-c2ccc(C(F)(F)F)cc2)nc1CBr
Temperature: 80 °C
Yield: 95.9 %

Procedure:
The title compound of Step B (2.0 g, 8 mmol) was dissolved in 10 mL of acetic acid and treated with bromine (0.4 mL, 8 mmol). The mixture was heated at 80° C. until the orange color was discharged (1 h). The mixture was evaporated under reduced pressure, diluted with 50 mL of ether and washed twice with 50 mL of sodium bicarbonate and then 50 mL of brine. The organic layer was dried over magnesium sulfate and concentrated under reduced pressure to yield 2.54 g of the title compound of Step C as a tan solid which was used immediately in the next step without further purification. 1H NMR (CDCl3): δ2.44 (s, 3H), 4.54 (s, 2H), 7.74 (d, 2H), 8.56 (d, 2H), 8.62 (s, 1H).
Reaction SMILES: Cl.[Br:2][C:3]1[CH:8]=[CH:7][C:6]([SH:9])=[C:5]([NH2:10])[CH:4]=1.[Br:11][C:12]1[CH:20]=[CH:19][C:15]([C:16](O)=O)=[CH:14][CH:13]=1.O.CO>S1(CCCC1)(=O)=O>[Br:11][C:12]1[CH:20]=[CH:19][C:15]([C:16]2[S:9][C:6]3[CH:7]=[CH:8][C:3]([Br:2])=[CH:4][C:5]=3[N:10]=2)=[CH:14][CH:13]=1
Reactant: Nc1cc(Br)ccc1S
Reactant: O=C(O)c1ccc(Br)cc1
Agent: Cl
Solvent: O=S1(=O)CCCC1
Solvent: CO
Solvent: O
Product: Brc1ccc(-c2nc3cc(Br)ccc3s2)cc1
Temperature: 70 °C

Procedure:
A mixture of 20 g (0.083 mole) of 4-bromo-2-aminothiophenol hydrochloride and 270 g of deoxygenated polyphosphoric acid was heated at 70° C. for 4 hours. To this mixture was added a solution containing 22 g (0.11 mole) of p-bromobenzoic acid dissolved in 109 g of sulfolane. The reaction mixture was slowly heated to 200° C. and maintained at that temperature for 1 hour. After cooling, the reaction mixture was poured into a 1:1 water-methanol solution to precipitate the product. The light tan precipitate was filtered, washed with dilute ammonium hydroxide, washed with water, and then air dried. The 2-(4-bromophenyl)-5-bromobenzothiazole was recrystallized from toluene to give 24.5 g (80% of theoretical), m.p. 162°-163° C.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][NH:4][C:5]([N:7]([CH2:17][CH2:18][CH3:19])[CH:8]1[O:16][CH2:15][C@H:13]([OH:14])[C@H:11]([OH:12])[C@H:9]1[OH:10])=[O:6].C(=O)([O-])[O-].[Na+].[Na+].[N+:26]([O-])([N+]([O-])=O)=[O:27]>O1CCCC1.C(Cl)Cl>[Cl:1][CH2:2][CH2:3][N:4]([N:26]=[O:27])[C:5]([N:7]([CH2:17][CH2:18][CH3:19])[CH:8]1[O:16][CH2:15][C@H:13]([OH:14])[C@H:11]([OH:12])[C@H:9]1[OH:10])=[O:6]
Reactant: O=[N+]([O-])[N+](=O)[O-]
Reactant: CCCN(C(=O)NCCCl)C1OC[C@H](O)[C@H](O)[C@H]1O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: ClCCl
Product: CCCN(C(=O)N(CCCl)N=O)C1OC[C@H](O)[C@H](O)[C@H]1O
Yield: 75.9 %

Procedure:
3.0 g of 1-(2-chloroethyl)-3-n-propyl-3-L-arabinopyranosylurea are dissolved in a mixture of 80 ml of tetrahydrofuran and 80 ml of methylene chloride, and 15 g of sodium carbonate are added thereto. 5 g of nitrogen tetroxide gas are introduced into the mixture for 10 minutes under ice-cooling. The mixture is treated in the same manner as described in Example 2. 2.5 g of 1-(2-chloroethyl)-1-nitroso-3-n-propyl-3-L-arabinopyranosylurea are thereby obtained as yellow caramel.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[C:14]([OH:16])=[O:15])=[CH:4][CH:3]=1.N1C=CC=CC=1.[CH3:23][Si:24]([CH:27](O)[CH3:28])([CH3:26])[CH3:25].C1(N=C=NC2CCCCC2)CCCCC1>C(#N)C>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[C:14]([O:16][CH2:28][CH2:27][Si:24]([CH3:26])([CH3:25])[CH3:23])=[O:15])=[CH:4][CH:3]=1
Reactant: CC(O)[Si](C)(C)C
Reactant: Cc1ccc(-c2ccccc2C(=O)O)cc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: CC#N
Solvent: c1ccncc1
Product: Cc1ccc(-c2ccccc2C(=O)OCC[Si](C)(C)C)cc1
Reaction time: 3 h

Procedure:
The starting material can be obtained, for example, as follows: 14.2 g of 4-methyl-2'-carboxybiphenyl (EP 253,310) are dissolved in 60 ml of acetonitrile and 10.7 ml of pyridine and 11.4 ml of trimethylsilylethanol are added. The mixture is treated at 0° with 15.1 g of dicyclohexylcarbodiimide and stirred at this temperature for 3 hours. After this, the reaction mixture is evaporated in a high vacuum, the residue is treated with ether, and dicyclohexylurea is filtered off. After flash chromatography (ethyl acetate/hexane 95:5), 4-methyl-2'-(trimethylsilylethoxycarbonyl)biphenyl is obtained as a slightly yellowish oil. (TLC: ethyl acetate/hexane 95:5) Rf : 0.42. 312 mg of 4-methyl-2'-(trimethylsilylethoxycarbonyl)biphenyl, 178 mg of N-bromosuccinimide, 5 mg of azoisobutyronitrile and 15 ml of carbon tetrachloride are heated to reflux for one hour. After cooling, the mixture is evaporated. Flash chromatography (ethyl acetate/hexane 95:5) yields 4-bromomethyl-2'-(trimethylsilylethoxycarbonyl)biphenyl as a slightly yellowish oil. 1H-NMR (CFCl3): 0 ppm (s, 9H), 0.7 ppm (t, 2H), 4.5 ppm (s, 2H), 7.1-8 ppm aromatics.