Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:8]1[CH:15](O)[C@H:14]2[N:10]([C@H:11]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[S:12][CH2:13]2)[C:9]1=[O:23])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C[Si](C)(C)O[C:27]1([CH:34]=[CH:33][CH:32]=[CH:31][CH2:30]1)[CH:28]=[CH2:29].B(F)(F)F.CC[O:43]CC>ClCCl.CCOCC>[CH2:1]([N:8]1[C@@H:15]([CH2:29][C:28]([C:27]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)=[O:43])[C@H:14]2[N:10]([C@H:11]([C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=3)[S:12][CH2:13]2)[C:9]1=[O:23])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C1N(Cc2ccccc2)C(O)[C@@H]2CS[C@@H](c3ccccc3)N12
Reactant: CCOCC
Reactant: C=CC1(O[Si](C)(C)C)C=CC=CC1
Agent: FB(F)F
Solvent: ClCCl
Product: O=C(C[C@H]1[C@@H]2CS[C@@H](c3ccccc3)N2C(=O)N1Cc1ccccc1)c1ccccc1
Temperature: 0 °C
Yield: 98 %

Procedure:
To a solution of compound 6-benzyl-7-hydroxy-3-phenyl-(3S, 7aR)-perhydroimidazo[1,5-C][1,3]thiazol-5-one of formula (6) (0.326 parts, 1 mmol) in dichloromethane (10 parts) was added 1-trimethylsilyloxy styrene (0.384 parts, 2 mmol). Then the solution was cooled to 0° C, and Lewis acid for example borontrifluoride etherate (BF3.Et2O) (0.142 parts, 1 mmol) was added drop wise. The reaction mixture was stirred at 0° C. for 10 mints, and the reaction mixture was quenched with saturated ammonium chloride (10 parts). Then the organic layer was separated, concentrated and column purification with ethylacetate:pet.ether (15:85) as eluent provided compound 2-[6-benzyl-5-oxo-3-phenyl-(3S, 7S, 7aR)-perhydroimidazo[1,5-C][1,3]thiazol-7-yl]-1-phenyl-1-ethanone of formula (7a) (viscous liquid, 0.419 parts, 0.98 mmol) in 98% yield.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([OH:11])[CH:10]=1)[C:5]([O-:7])=[O:6].[K+].[CH:13]([CH:15](Cl)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[CH2:14].CS(C)=O>O>[OH:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([OH:11])[CH:10]=1)[C:5]([O:7][CH:15]([CH:13]=[CH2:14])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[O:6]
Reactant: C=CC(Cl)c1ccccc1
Reactant: O=C([O-])c1cc(O)cc(O)c1
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: C=CC(OC(=O)c1cc(O)cc(O)c1)c1ccccc1
Yield: 83.6 %

Procedure:
129.4 g of potassium 3,5-dihydroxybenzoate and 102.7 g of vinylbenzyl chloride were added to 700 ml of dimethylsulfoxide and stirred and reacted at 40° C. for 4 days. Then, 1,500 ml of water was added thereto, and the resulting mixture was extracted with 500 ml of ethyl acetate. After distilling off ethyl acetate, recrystallization of the residue from an ethyl acetate-toluene mixture solvent yielded 152 g of vinylbenzyl 3,5-dihydroxybenzoate (m.p. 117°-119° C.).
Reaction SMILES: C[O-].[Na+].[Cl:4][C:5]1[CH:6]=[C:7]([SH:11])[CH:8]=[CH:9][CH:10]=1.[C:12]([C:14]1[C:19]([CH2:20]Br)=[CH:18][CH:17]=[CH:16][N:15]=1)#[N:13]>CO>[C:12]([C:14]1[C:19]([CH2:20][S:11][C:7]2[CH:8]=[CH:9][CH:10]=[C:5]([Cl:4])[CH:6]=2)=[CH:18][CH:17]=[CH:16][N:15]=1)#[N:13]
Reactant: N#Cc1ncccc1CBr
Reactant: Sc1cccc(Cl)c1
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: N#Cc1ncccc1CSc1cccc(Cl)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a stirred, cloudy solution of sodium methoxide (14.7 g, 0.27 mol) in methanol (450 mL), contained in a water bath, add a solution of 3-chlorothiophenol (39.5 g, 0.27 mol) in methanol (95 mL). To the resultant solution add a solution of 2-cyano-3-(bromomethyl)pyridine (48.9 g, 0.25 mol) in methanol (195 mL), and stir the reaction mixture at room temperature for 1 h. Concentrate the reaction mixture under reduced pressure, add 500 mL of ether to the residue, stir, and filter to remove the sodium bromide. Evaporate ether under reduced pressure to obtain the title compound as an amber oil, which may be used without further purification.
Reaction SMILES: O([CH2:4][C:5]([O:7][CH2:8][CH3:9])=[O:6])C#N.[NH2:10][C:11]1[CH:16]=[CH:15][C:14]([N:17]2[C:30](=[O:31])[C:20]3=[CH:21][NH:22][C:23]4[C:24]([F:29])=[CH:25][CH:26]=[CH:27][C:28]=4[C:19]3=[N:18]2)=[CH:13][CH:12]=1.O.C[N:34](C)[CH:35]=[O:36]>>[CH2:8]([O:7][C:5](=[O:6])[CH2:4][NH:34][C:35]([NH:10][C:11]1[CH:16]=[CH:15][C:14]([N:17]2[C:30](=[O:31])[C:20]3=[CH:21][NH:22][C:23]4[C:24]([F:29])=[CH:25][CH:26]=[CH:27][C:28]=4[C:19]3=[N:18]2)=[CH:13][CH:12]=1)=[O:36])[CH3:9]
Reactant: CCOC(=O)COC#N
Reactant: CN(C)C=O
Reactant: Nc1ccc(-n2nc3c4cccc(F)c4[nH]cc-3c2=O)cc1
Solvent: O
Product: CCOC(=O)CNC(=O)Nc1ccc(-n2nc3c4cccc(F)c4[nH]cc-3c2=O)cc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
Ethyl cyanatoacetate (31 mg, 0.24 mmol) was added in one portion to a stirred solution of 2-(4-aminophenyl)-6-fluoro-2,5-dihydropyrazolo[4,3-c]quinolin-3-one (intermediate 2) (50 mg, 0.17 mmol) in N,N-dimethylformamide (2 ml) and the mixture stirred at room temperature for 16 h. Water (1 ml) was then added to the mixture to precipitate a solid, which was filtered, washed with water (1 ml) and then ethyl acetate (1 ml) and finally dried by suction to leave the urea as a yellow solid, LCMS m/z 424.40 [M+H]+ @ RT 1.06 min.
Reaction SMILES: [CH2:1]([O:4][C:5](=[O:17])[C@H:6]([CH2:15][OH:16])[NH:7][C:8]([O:10]C(C)(C)C)=O)[CH:2]=[CH2:3].C1C(=O)N(OC([CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][NH:33][C:34]2[CH:39]=[CH:38][C:37]([N+:40]([O-:42])=[O:41])=[CH:36][C:35]=2[N+:43]([O-:45])=[O:44])=O)C(=O)C1.C(N(CC)CC)C>Cl.O1CCOCC1>[CH2:1]([O:4][C:5](=[O:17])[C@H:6]([CH2:15][OH:16])[NH:7][C:8](=[O:10])[CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][NH:33][C:34]1[CH:39]=[CH:38][C:37]([N+:40]([O-:42])=[O:41])=[CH:36][C:35]=1[N+:43]([O-:45])=[O:44])[CH:2]=[CH2:3]
Reactant: O=C(CCCCCNc1ccc([N+](=O)[O-])cc1[N+](=O)[O-])ON1C(=O)CCC1=O
Reactant: C=CCOC(=O)[C@H](CO)NC(=O)OC(C)(C)C
Agent: Cl
Solvent: CCN(CC)CC
Solvent: C1COCCO1
Product: C=CCOC(=O)[C@H](CO)NC(=O)CCCCCNc1ccc([N+](=O)[O-])cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 71.6 %

Procedure:
A solution of N-(tert-butoxycarbonyl)-L-serine allyl ester (0.175 g, 0.731 mmol) in 4 M hydrogen chloride/dioxane (2 mL) was stirred at ambient temperature for 40 minutes. The reaction mixture was concentrated on a rotary evaporator and the crude HCl salt was taken up in anhydrous tetrahydrofuran (3 mL). To this solution was added N-succinimidyl 6-(2,4-dinitroanilino)hexanoate (0.288 g, 0.791 mmol) and triethylamine (102 mL, 0.731 mmol). The reaction mixture was stirred at room temperature for 30 minutes and the solvent was evaporated. The residue was partitioned between ethyl acetate and water and the phases were separated. The organic phase was washed with saturated NaHCO3 and saturated NaCl. It was dried over MgSO4, filtered, and concentrated under reduced pressure to yield the crude product (0.293 g) as a yellow oil. Purification using a Thomson Instruments Single Step 12 g silica gel cartridge eluting with 50% hexanes/50% ethyl acetate followed by ethyl acetate gave the product (0.222 g, 72%) as a yellow oil. 1H NMR (DMSO-d6) δ 1.32 (2H, m), 1.52-1.64 (4H, m), 2.15 (2H, t, J=7.0 Hz), 3.44 (2H, m), 3.59 (1H, m), 3.66 (1H, m), 4.33 (1H, m), 4.55 (2H, m), 5.02 (1H, t, J=5.5 Hz), 5.17 (1H, m), 5.28 (1H, m), 5.83 (1H, m), 7.21 (1H, d, J=9.5 Hz), 8.12 (1H, d, J=7.9 Hz), 8.23 (1H, dd, J=2.5 Hz, J=9.4 Hz), 8.85 (2H, m).
Reaction SMILES: [N:1]#[C:2][NH2:3].[N:4]([C:7]1[CH:20]=[CH:19][C:10]([O:11][CH2:12][CH2:13][N:14]2[CH2:18][CH2:17][CH2:16][CH2:15]2)=[CH:9][CH:8]=1)=[C:5]=[S:6].Br[CH2:22][C:23]([C:25]1[CH:30]=[CH:29][C:28]([OH:31])=[C:27]([F:32])[CH:26]=1)=[O:24]>>[C:10]([OH:24])(=[O:11])[CH3:19].[NH2:1][C:2]1[N:3]=[C:5]([NH:4][C:7]2[CH:8]=[CH:9][C:10]([O:11][CH2:12][CH2:13][N:14]3[CH2:15][CH2:16][CH2:17][CH2:18]3)=[CH:19][CH:20]=2)[S:6][C:22]=1[C:23]([C:25]1[CH:30]=[CH:29][C:28]([OH:31])=[C:27]([F:32])[CH:26]=1)=[O:24]
Reactant: N#CN
Reactant: O=C(CBr)c1ccc(O)c(F)c1
Reactant: S=C=Nc1ccc(OCCN2CCCC2)cc1
Product: CC(=O)O
Product: Nc1nc(Nc2ccc(OCCN3CCCC3)cc2)sc1C(=O)c1ccc(O)c(F)c1

Procedure:
This compound was prepared from cyanamide and 1-[2-(4-isothiocyanato-phenoxy)-ethyl]-pyrrolidine (from Example 5) and 2-bromo-1-(3-fluoro-4-hydroxyphenyl)-ethanone (from Example 119) following the procedure used in Example 118. Mass spectrum (ES) MH+=453.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[C:8]([N+:10]([O-:12])=[O:11])[CH:7]=[CH:6][C:5]=1F)([O-:3])=[O:2].[C:14]([NH:17][CH2:18][CH2:19][N:20]1[C:24]([SH:25])=[N:23][N:22]=[N:21]1)(=[O:16])[CH3:15].C(N(CC)CC)C>CC(C)=O>[C:14]([NH:17][CH2:18][CH2:19][N:20]1[C:24]([S:25][C:5]2[CH:6]=[CH:7][C:8]([N+:10]([O-:12])=[O:11])=[CH:9][C:4]=2[N+:1]([O-:3])=[O:2])=[N:23][N:22]=[N:21]1)(=[O:16])[CH3:15]
Reactant: O=[N+]([O-])c1ccc(F)c([N+](=O)[O-])c1
Reactant: CC(=O)NCCn1nnnc1S
Solvent: CCN(CC)CC
Solvent: CC(C)=O
Product: CC(=O)NCCn1nnnc1Sc1ccc([N+](=O)[O-])cc1[N+](=O)[O-]

Procedure:
A solution of 9.3 g. (0.050 mol) of 2,4-dinitrofluorobenzene in 50 ml. of acetone was added to a solution of 9.35 g. (0.050 mol) of 1-(2-acetamidoethyl)tetrazole-5-thiol and 6.85 ml. (0.050 mol) of triethylamine in 100 ml. of acetone and the reaction mixture was stirred for 1 hour. The solid material was collected by filtration and recrystallized from acetonitrile to give 1-(2-acetamidoethyl)-5-(2,4-dinitrophenylthio)tetrazole, mp 197°-198° C.
Reaction SMILES: [NH2:1][C:2]1[NH:3][C:4](=[O:22])[C:5]2[C:10]([CH2:11][CH2:12][C:13]3[CH:21]=[CH:20][C:16]([C:17]([OH:19])=O)=[CH:15][CH:14]=3)=[CH:9][NH:8][C:6]=2[N:7]=1.CN1CCOCC1.ClC1C=C(OC)NN(OC)N=1.Cl.[CH3:42][O:43][C:44](=[O:53])[C@H:45]([CH2:47][CH2:48][C:49]([O:51][CH3:52])=[O:50])[NH2:46]>CN(C)C=O>[CH3:42][O:43][C:44](=[O:53])[C@H:45]([CH2:47][CH2:48][C:49]([O:51][CH3:52])=[O:50])[NH:46][C:17](=[O:19])[C:16]1[CH:20]=[CH:21][C:13]([CH2:12][CH2:11][C:10]2[C:5]3[C:4](=[O:22])[NH:3][C:2]([NH2:1])=[N:7][C:6]=3[NH:8][CH:9]=2)=[CH:14][CH:15]=1
Reactant: Nc1nc2[nH]cc(CCc3ccc(C(=O)O)cc3)c2c(=O)[nH]1
Reactant: COC(=O)CC[C@H](N)C(=O)OC
Agent: COC1=CC(Cl)=NN(OC)N1
Agent: Cl
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: COC(=O)CC[C@H](NC(=O)c1ccc(CCc2c[nH]c3nc(N)[nH]c(=O)c23)cc1)C(=O)OC
Reaction time: 0.5 h
Yield: 42.3 %

Procedure:
To 2.00 g (6.74 mmol) of 4-[2-(2-amino-4,7-dihydro-4-oxo-3H-pyrrolo[2,3-d]pyrimidin-5-yl)ethyl]benzoic acid, prepared in Preparation 4, in 23 ml dimethylformamide under nitrogen was added 1.40 g (13.8 mmol) of N-methylmorpholine and 1.17 g (6.70 mmol) of 4-chloro-2,6-dimethoxytriazine. The formation of the active ester was monitored by the HPLC analysis of aliquots. After 40 minutes at room temperature 0.70 g (6.9 mmol) of N-methylmorpholine was added followed by 1.56 g (7.37 mmol) L-glutamic acid dimethyl ester hydrochloride. After 30 minutes HPLC analysis indicated substantially complete consumption of the active ester and formation of N-[4-[2-[2-Amino-4,7-dihydro-4-oxo-3H-pyrrolo[2,3-d]pyrimidin-5-yl]ethyl]benzoyl]glutamic acid dimethyl ester. The reaction mixture was filtered and the above product concentrated and purified by silica chromatography (elution 1:4 methanol:methylene chloride). The pure fractions were pooled and provided 1.30 g of the above product in a yield of 43 percent. 1H NMR (DMSO-d6) δ2.01 (m, 2H), 2.40 (t, J=7.4 Hz, 2H), 2.80 (m, 2H), 2.92 (m, 2H), 3.53 (s, 3H), 3.59 (s, 3H), 4.40 (m, 1H), 5.99 (s, 2H),6.26 (d, J=1.9 Hz, 1H), 7.23 (d, J=8.2 Hz, 2H), 7.73 (d, J=8.2 Hz, 2H), 8.62 (d, J=7.5 Hz, 1H), 10.15 (s, 1H), 10.57 (d, J=1.9 Hz, 1H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:9][CH2:10][C:11]2[CH:16]=[C:15]([F:17])[CH:14]=[CH:13][C:12]=2[OH:18])[CH:5]=[CH:6][C:7]=1[F:8].Br[CH2:20][CH2:21][C@@H:22]1[CH2:26][C@@H:25]([O:27][Si:28]([C:31]([CH3:34])([CH3:33])[CH3:32])([CH3:30])[CH3:29])[CH2:24][N:23]1[C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36].CC(C)([O-])C.[K+]>CN(C)C(=O)C>[C:38]([O:37][C:35]([N:23]1[CH2:24][C@H:25]([O:27][Si:28]([C:31]([CH3:34])([CH3:33])[CH3:32])([CH3:30])[CH3:29])[CH2:26][C@H:22]1[CH2:21][CH2:20][O:18][C:12]1[CH:13]=[CH:14][C:15]([F:17])=[CH:16][C:11]=1[CH2:10][CH2:9][C:4]1[CH:5]=[CH:6][C:7]([F:8])=[C:2]([F:1])[CH:3]=1)=[O:36])([CH3:41])([CH3:40])[CH3:39]
Reactant: CC(C)(C)OC(=O)N1C[C@H](O[Si](C)(C)C(C)(C)C)C[C@H]1CCBr
Reactant: Oc1ccc(F)cc1CCc1ccc(F)c(F)c1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Product: CC(C)(C)OC(=O)N1C[C@H](O[Si](C)(C)C(C)(C)C)C[C@H]1CCOc1ccc(F)cc1CCc1ccc(F)c(F)c1
Yield: 63.1 %

Procedure:
400 mg of 2-[2-(3,4-difluorophenyl)ethyl]-4-fluorophenol (prepared as described in Preparation 7), 690 mg of (2S,4R)-2-(2-bromoethyl)-1-t-butoxycarbonyl-4-t-butyldimethylsilyloxypyrrolidine and 208 mg of potassium t-butoxide were allowed to react together in 5 ml of N,N-dimethylacetamide and extracted in the same manner as described in step (a) of Example 2. The resulting oily substance was purified by silica gel column chromatography, using a 5:1 by volume mixture of hexane and ethyl acetate as the eluent, to give 580 mg (yield 63%) of the title compound as a colorless oily substance.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:18]=[C:19]([O:21][C:22]2[C:27]([C:28]3[CH:33]=[CH:32][N:31]=[C:30]([NH:34][CH3:35])[N:29]=3)=[CH:26][CH:25]=[CH:24][N:23]=2)[CH:20]=1)[C:5]([NH:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([C:14]([F:17])([F:16])[F:15])[CH:9]=1)=[O:6].[C:36](#N)[CH3:37].C[Si](C#C)(C)C>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.[Cu]I.CCN(CC)CC>[C:36]([C:2]1[CH:3]=[C:4]([CH:18]=[C:19]([O:21][C:22]2[C:27]([C:28]3[CH:33]=[CH:32][N:31]=[C:30]([NH:34][CH3:35])[N:29]=3)=[CH:26][CH:25]=[CH:24][N:23]=2)[CH:20]=1)[C:5]([NH:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([C:14]([F:16])([F:15])[F:17])[CH:9]=1)=[O:6])#[CH:37]
Reactant: CNc1nccc(-c2cccnc2Oc2cc(Br)cc(C(=O)Nc3cccc(C(F)(F)F)c3)c2)n1
Reactant: CC#N
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Agent: C#C[Si](C)(C)C
Solvent: CCN(CC)CC
Product: C#Cc1cc(Oc2ncccc2-c2ccnc(NC)n2)cc(C(=O)Nc2cccc(C(F)(F)F)c2)c1
Temperature: 85 °C
Reaction time: 1 h

Procedure:
To a solution of 3-Bromo-5-[3-(2-methylamino-pyrimidin-4-yl)-pyridin-2-yloxy]-N-(3-trifluoromethyl-phenyl)-benzamide (110 mg, 0.20 mmol), acetonitrile (5 mL) and Et3N (1 mL) in a sealed tube was added trimethylsilyl acetylene (0.14 mL, 1.0 mmol) followed by PdCl2(PPh3)2 (14 mg, 0.02 mmol) and CuI (4.0 mg, 0.02 mmol). The tube was sealed and heated at 85° C. for 15 h. The mixture was allowed to cool to room temperature and concentrated under reduced pressure. The resulting crude mixture was reconstituted in methanol (5 mL), saturated with solid K2CO3 (˜200 mg) and allowed to stir at room temperature for 1 h. The resulting mixture was concentrated under reduced pressure and reconstituted in EtOAc (20 mL). The organic phase was washed successively with water (2×5 mL) and brine (1×5 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The crude was purified via RP-HPLC to afford the title compound as an off-white solid. MS m/z=490 [M+1]+, Calc'd for C26H18F3N5O2: 489.45.
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:10]=[C:9]([N+:11]([O-:13])=[O:12])[C:8]([OH:14])=[C:7]([OH:15])[CH:6]=1)=[O:4].N[CH2:17][C:18]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=O.C[N:27](C)C=O>>[OH:15][C:7]1[CH:6]=[C:5]([CH:10]=[C:9]([N+:11]([O-:13])=[O:12])[C:8]=1[OH:14])[C:3]([C:2]1[NH:27][C:25]2[C:20]([C:18]=1[CH3:17])=[CH:21][CH:22]=[CH:23][CH:24]=2)=[O:4]
Reactant: CN(C)C=O
Reactant: O=C(CBr)c1cc(O)c(O)c([N+](=O)[O-])c1
Reactant: NCC(=O)c1ccccc1
Product: Cc1c(C(=O)c2cc(O)c(O)c([N+](=O)[O-])c2)[nH]c2ccccc12

Procedure:
A solution of 5.52 g of 2-bromo-3',4'-dihydroxy-5'-nitroacetophenone and 2.7 g of 2-aminoacetophenone in 100 ml of dry N,N-dimethylformamide is stirred at 90° for 24 hours. The reaction mixture is evaporated, the residue is dissolved in ethyl acetate, washed with water, dried over sodium sulfate, filtered and evaporated. There is obtained 2-(3,4-dihydroxy-5-nitrobenzoyl)-3-methylindole of m.p. 212°-214° (from n-butanol).
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[C:7]([CH3:13])[C:8]([Cl:12])=[CH:9][CH:10]=2)[N:5]=[CH:4][C:3]=1[C:14]([NH2:16])=[O:15].[CH3:17][O:18][C:19]1[CH:20]=[C:21]([CH:23]=[CH:24][CH:25]=1)[NH2:22].Cl.IC1C=C2C(=CC=1)N=CC(C(N)=O)=C2NC1C=CC=C(OC)C=1>>[ClH:1].[Cl:12][C:8]1[C:7]([CH3:13])=[C:6]2[C:11]([C:2]([NH:22][C:21]3[CH:23]=[CH:24][CH:25]=[C:19]([O:18][CH3:17])[CH:20]=3)=[C:3]([C:14]([NH2:16])=[O:15])[CH:4]=[N:5]2)=[CH:10][CH:9]=1
Reactant: COc1cccc(N)c1
Reactant: Cc1c(Cl)ccc2c(Cl)c(C(N)=O)cnc12
Agent: COc1cccc(Nc2c(C(N)=O)cnc3ccc(I)cc23)c1
Agent: Cl
Product: COc1cccc(Nc2c(C(N)=O)cnc3c(C)c(Cl)ccc23)c1

Procedure:
Intermediate 66 was prepared from Intermediate 68 using 3-methoxyaniline in a similar manner to Intermediate 14.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:10]2[CH:11]=[C:12]([C:17]([O:19][CH3:20])=[O:18])[C:13](=[O:16])[NH:14][N:15]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH3:9].[Cl:21][C:22]1[CH:29]=[CH:28][C:25]([CH2:26]Cl)=[CH:24][CH:23]=1>>[Cl:21][C:22]1[CH:29]=[CH:28][C:25]([CH2:26][N:14]2[C:13](=[O:16])[C:12]([C:17]([O:19][CH3:20])=[O:18])=[CH:11][C:10]([C:4]3[CH:5]=[CH:6][C:7]([O:8][CH3:9])=[C:2]([F:1])[CH:3]=3)=[N:15]2)=[CH:24][CH:23]=1
Reactant: COC(=O)c1cc(-c2ccc(OC)c(F)c2)n[nH]c1=O
Reactant: ClCc1ccc(Cl)cc1
Product: COC(=O)c1cc(-c2ccc(OC)c(F)c2)nn(Cc2ccc(Cl)cc2)c1=O
Yield: 97.6 %

Procedure:
Following the procedure of Example 1(6), 6-(3-fluoro-4-methoxyphenyl)-4-methoxycarbonyl-2H-pyridazin-3-one and 4-chlorobenzyl chloride were reacted to yield the title compound as yellow needles (yield: 97.6%).
Reaction SMILES: [F:1][C:2]([F:19])([F:18])[S:3]([O:6][C:7]1[CH:17]=[CH:16][C:10]2[C:11](=[O:15])[CH:12]=[CH:13][O:14][C:9]=2[CH:8]=1)(=[O:5])=[O:4].[CH:20](=O)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.N1CCCC1>CO>[F:19][C:2]([F:1])([F:18])[S:3]([O:6][C:7]1[CH:17]=[CH:16][C:10]2[C:11](=[O:15])[C:12]([CH2:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)=[CH:13][O:14][C:9]=2[CH:8]=1)(=[O:5])=[O:4]
Reactant: O=c1ccoc2cc(OS(=O)(=O)C(F)(F)F)ccc12
Reactant: O=Cc1ccccc1
Solvent: CO
Solvent: C1CCNC1
Product: O=c1c(Cc2ccccc2)coc2cc(OS(=O)(=O)C(F)(F)F)ccc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 75 %

Procedure:
To a stirred solution of the product of Step C (27 g, 91.2 mmole) in 183 mL of methanol was added benzaldehyde (11.1 mL, 109 mmole) followed by pyrrolidine (9.1 mL, 109 mmole). The mixture was stirred at room temperature overnight, cooled to 0° C. and filtered. The solid was washed once with 50 mL of ice-cold methanol and then dried in vacuo; 35.2 g, (75% yield) of the title product was recovered. M.P. 133°-135° C.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:10]1[CH:15]=[CH:14][C:13]([CH2:16]C#N)=[CH:12][C:11]=1[F:19].Cl.[C:21](=[O:24])(O)[O-:22].[Na+].C>>[O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:10]1[CH:15]=[CH:14][C:13]([CH2:16][C:21]([OH:22])=[O:24])=[CH:12][C:11]=1[F:19]
Reactant: N#CCc1ccc(-c2nc3ccccc3o2)c(F)c1
Reactant: O=C([O-])O
Agent: Cl
Agent: [Na+]
Product: O=C(O)Cc1ccc(-c2nc3ccccc3o2)c(F)c1

Procedure:
A mixture of 0.7 gm. of the above crude 4-(benzoxazol-2-yl)-3-fluorophenylacetonitrile and 30 cc. of concentrated hydrochloric acid is heated on the steam bath for 1 hour. The reaction mixture is then filtered through a sintered glass filter into ice water and the resulting precipitate collected to give 0.65 gm. of crude product. The crude acid is stirred with 50-60 cc. of saturated sodium bicarbonate solution, a small amount of charcoal is added, and the mixture is then filtered. The filtrate is acidified with concentrated hydrochloric acid and the resulting precipitate collected and dried to give 4-(benzoxazol-2-yl)-3-fluorophenylacetic acid, m.p. 207°-211° C. dec.
Reaction SMILES: [N+:1]([C:3]1[CH:14]=[CH:13][CH:12]=[CH:11][C:4]=1[CH2:5][NH:6][C:7]([NH:9][CH3:10])=[O:8])#[C-:2].[C:15]([CH2:17][C:18]([OH:20])=O)#[N:16].CN(C)C=O.CS(Cl)(=O)=O>O.C(O)(C)C.O>[C:15]([CH2:17][C:18]([N:9]([CH3:10])[C:7](=[O:8])[NH:6][CH2:5][C:4]1[CH:11]=[CH:12][CH:13]=[CH:14][C:3]=1[N+:1]#[C-:2])=[O:20])#[N:16]
Reactant: N#CCC(=O)O
Reactant: [C-]#[N+]c1ccccc1CNC(=O)NC
Agent: CS(=O)(=O)Cl
Solvent: CN(C)C=O
Solvent: O
Solvent: CC(C)O
Product: [C-]#[N+]c1ccccc1CNC(=O)N(C)C(=O)CC#N
Temperature: 25 °C
Yield: 68 %

Procedure:
Under nitrogen atmosphere, 1-(2-isocyanobenzyl)-3-methylurea (98.4 g) and cyanoacetic acid (80.0 g) was added to N,N-dimethylformamide (836 ml). The mixture was stirred at room temperature and methanesulfonyl chloride (72.8 ml) was added dropwise with stirring at this temperature. The mixture was stirred at room temperature for 4 hrs, cooled with water, and water-isopropanol [2:1 (volume ratio), 1670 ml] was added drop wise. The mixture was stirred under water-cooling for 1 hr, and the precipitated crystals were collected by filtration and dried to give 3-(2-cyano-acetyl)-3-methyl-1-(2-isocyanobenzyl)-urea with 68% yield.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([S:11]([N:14]([C:18]2[C:19]([C:25]([C:27]3[CH:28]=[N:29][C:30]([C:33]#[N:34])=[CH:31][CH:32]=3)=[O:26])=[N:20][CH:21]=[C:22]([Cl:24])[CH:23]=2)COC)(=[O:13])=[O:12])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2]>Cl.O1CCOCC1>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([S:11]([NH:14][C:18]2[C:19]([C:25]([C:27]3[CH:28]=[N:29][C:30]([C:33]#[N:34])=[CH:31][CH:32]=3)=[O:26])=[N:20][CH:21]=[C:22]([Cl:24])[CH:23]=2)(=[O:13])=[O:12])=[CH:7][CH:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: COCN(c1cc(Cl)cnc1C(=O)c1ccc(C#N)nc1)S(=O)(=O)c1ccc(C(C)(C)C)cc1
Agent: Cl
Solvent: C1COCCO1
Product: CC(C)(C)c1ccc(S(=O)(=O)Nc2cc(Cl)cnc2C(=O)c2ccc(C#N)nc2)cc1
Temperature: 90 °C
Reaction time: 12 h
Yield: 33.3 %

Procedure:
4-tert-Butyl-N-[5-chloro-2-(6-cyano-pyridine-3-carbonyl)-pyridin-3-yl]-N-methoxymethyl-benzenesulfonamide (15 mg, 0.030 mmol) was dissolved in 4N HCl (500 L) and dioxane (1 mL). The reaction was then stirred at 90° C. for 12 hours. The solvent was removed under reduced pressure and the crude solid was purified by preparatory TLC (1:4 EtOAc/hexanes) to give 5 mg (0.01 mmol, 40% yield) of the desired product as a white solid. MS calc'd for C22H20ClN4O3S. (MH+): expected 455.1. found 455.0.
Reaction SMILES: [C:1]([NH:20][C:21]1[S:22][CH:23]=[C:24]([C:26](=O)[C:27]([OH:29])=[O:28])[N:25]=1)([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:31]([NH:50][C:51]1[S:52][CH:53]=[C:54]([CH2:56][O:57][NH2:58])[N:55]=1)([C:44]1[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1)([C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1)[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1>CO>[C:1]([NH:20][C:21]1[S:22][CH:23]=[C:24](/[C:26](=[N:58]/[O:57][CH2:56][C:54]2[N:55]=[C:51]([NH:50][C:31]([C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)([C:38]3[CH:39]=[CH:40][CH:41]=[CH:42][CH:43]=3)[C:44]3[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=3)[S:52][CH:53]=2)/[C:27]([OH:29])=[O:28])[N:25]=1)([C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1)([C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: NOCc1csc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Reactant: O=C(O)C(=O)c1csc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Solvent: CO
Product: O=C(O)/C(=N\OCc1csc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1)c1csc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Temperature: 25 °C
Reaction time: 4 h
Yield: 87 %

Procedure:
3.1 g of 2-(2-tritylaminothiazol-4-yl)glyoxalic acid was dissolved in 170 ml of methanol, 2.9 g of the (2-tritylaminothiazol-4-yl)methoxyamine was added thereto, and stirred at room temperature for 4 hours. The formed precipitates were filtered off and washed with 20 ml of methanol to obtain 5.1 g of (Z)-2-(2-tritylaminothiazol-4-yl)-2-[(2-tritylaminothiazol-4-yl)methoxyimino]acetic acid.