Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=1.[Cl:10][C:11]1[C:12](=O)C(Cl)=C(Cl)[C:15](=O)[C:16]=1Cl.Cl.CC(C=C)=O>CCO.O1CCCC1>[ClH:10].[C:6]([C:5]1[CH:4]=[C:3]2[C:2](=[CH:9][CH:8]=1)[N:1]=[CH:12][CH:11]=[C:16]2[CH3:15])#[N:7]
Reactant: N#Cc1ccc(N)cc1
Reactant: O=C1C(Cl)=C(Cl)C(=O)C(Cl)=C1Cl
Agent: C=CC(C)=O
Agent: Cl
Solvent: C1CCOC1
Solvent: CCO
Product: Cc1ccnc2ccc(C#N)cc12
Temperature: 75 °C
Reaction time: 0.06 h
Yield: 82.55 %

Procedure:
Add 95% ethanol (EtOH) (270 L, 9 vol.), 4-aminobenzonitrile (30.0 kg, 1 equiv) and 2,3,5,6-tetrachloro-2,5-cyclohexadiene-1,4-dione, (66.81 kg 1.07 equiv) to a 200 gallon reaction vessel equipped with nitrogen purge, condenser, thermocouple, and overhead agitation. Stir for 2-5 min, then add concentrated hydrochloric acid (HCl) (62.56 L, 3.0 equiv), then heat to 75° C. Dilute methyl vinylketone (33.06 L, 1.5 equiv) in 95% EtOH (30 L, 1 vol.) then add slowly to reaction mixture over 30 min. Monitor for reaction completion by high performance liquid chromatography (HPLC). Add tetrahydrofuran (THF) (11 vol., 330 L), at 75° C., then stir for 1 hour at 60° C. Cool to room temperature and stir for 1 additional hour. Filter on agitated filter/dryer, then rinse with THF (240 L, 8 volumes). Dry overnight under vacuum at 70° C. to give the title compound (42.9 kg, 82.55%).
Reaction SMILES: [NH2:1][C:2]1[C:3]([F:22])=[C:4]([C:18]([F:21])=[CH:19][CH:20]=1)[C:5]([C:7]1[C:15]2[C:10](=[N:11][CH:12]=[C:13]([C:16]#[N:17])[CH:14]=2)[NH:9][CH:8]=1)=[O:6].[CH3:23][N:24]([CH3:29])[S:25](Cl)(=[O:27])=[O:26]>N1C=CC=CC=1>[C:16]([C:13]1[CH:14]=[C:15]2[C:7]([C:5]([C:4]3[C:3]([F:22])=[C:2]([NH:1][S:25]([N:24]([CH3:29])[CH3:23])(=[O:27])=[O:26])[CH:20]=[CH:19][C:18]=3[F:21])=[O:6])=[CH:8][NH:9][C:10]2=[N:11][CH:12]=1)#[N:17]
Reactant: N#Cc1cnc2[nH]cc(C(=O)c3c(F)ccc(N)c3F)c2c1
Reactant: CN(C)S(=O)(=O)Cl
Solvent: c1ccncc1
Product: CN(C)S(=O)(=O)Nc1ccc(F)c(C(=O)c2c[nH]c3ncc(C#N)cc23)c1F
Temperature: 25 °C
Reaction time: 48 h
Yield: 41.1 %

Procedure:
To 3-(3-amino-2,6-difluoro-benzoyl)-1H-pyrrolo[2,3-b]pyridine-5-carbonitrile (28, 50.0 mg, 0.168 mmol), 0.50 mL of pyridine was added, followed by addition of N,N-dimethylamino-sulfonyl chloride (32, 54 μL, 0.51 mmol) and the solution was stirred at room temperature for 2 days. The reaction mixture was extracted with 1 M aqueous hydrochloric acid and with ethyl acetate. The organic layer was washed with water, then brine, dried over magnesium sulfate, filtered, and the filtrate was concentrated under vacuum. The crude material was purified by silica gel column chromatography eluting with ethyl acetate and hexane. Appropriate fractions were combined and the solvent removed under reduced pressure to provide the desired compound (P-0007, 28 mg). MS(ESI)[M+H+]+=405.8.
Reaction SMILES: [Br:1][C:2]1[C:9]([CH3:10])=[CH:8][C:5]([C:6]#[N:7])=[CH:4][C:3]=1[CH3:11].Cl.[NH2:13][OH:14].C(N(CC)CC)C>C(O)C>[Br:1][C:2]1[C:3]([CH3:11])=[CH:4][C:5]([C:6]([NH:13][OH:14])=[NH:7])=[CH:8][C:9]=1[CH3:10]
Reactant: NO
Reactant: Cc1cc(C#N)cc(C)c1Br
Agent: Cl
Solvent: CCO
Solvent: CCN(CC)CC
Product: Cc1cc(C(=N)NO)cc(C)c1Br
Temperature: 25 °C

Procedure:
A mixture of 4-bromo-3,5-dimethyl-benzonitrile (1.50 g), hydroxylamine hydrochloride (0.90 g), triethylamine (1.8 mL) and ethanol (30 mL) is stirred at reflux temperature for 4 h. After cooling to room temperature, the mixture is concentrated, the residue is taken up in water, and the resulting mixture is extracted with ethyl acetate. The combined extract is washed with brine, dried (Na2SO4), and concentrated. The residue is chromatographed on silica gel (cyclohexane/ethyl acetate 7:3→3:7) to give the title compound. LC (method 11): tR=0.73 min; Mass spectrum (ESI+): m/z=243/245 (Br) [M+H]+.
Reaction SMILES: Cl[C:2]([N:4]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[NH:7][C:6](=[O:14])[C:5]1([CH3:16])[CH3:15])=[O:3].CC1(C)NC2C(=CC=CC=2)NC1=O.FC1C=C2C(=CC=1)NC(=O)C(C)(C)N2.[CH3:44][CH:45]([CH3:47])[O-:46].[Li+]>CC(O)C>[CH3:15][C:5]1([CH3:16])[N:4]([C:2]([O:46][CH:45]([CH3:47])[CH3:44])=[O:3])[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[NH:7][C:6]1=[O:14]
Reactant: CC(C)[O-]
Reactant: CC1(C)C(=O)Nc2ccccc2N1C(=O)Cl
Agent: CC1(C)Nc2cc(F)ccc2NC1=O
Agent: CC1(C)Nc2ccccc2NC1=O
Agent: [Li+]
Solvent: CC(C)O
Product: CC(C)OC(=O)N1c2ccccc2NC(=O)C1(C)C
Reaction time: 1.5 h

Procedure:
To 2.28 g of 4-chlorocarbonyl-3,3-dimethyl-1,2,3,4-tetrahydroquinoxalin-2-one (prepared by the method of Example 32 but using 3,3-dimethyl-1,2,3,4-tetrahydroquinoxalin-2-one rather than 6-fluoro-3,3-dimethyl-1,2,3,4-tetrahydroquinoxalin-2-one) in 25 ml of 2-propanol (the starting material is not all in solution) are added 0.694 g of lithium isopropoxide. After about 1.5 hr the reaction mixture became homogeneous and then again heterogeneous as the product precipitated out. After a total of 2 hr the solvent is removed under reduced pressure and the residue is partitioned between dichloromethane and saline. The organic layers are dried over sodium sulfate and the filtrate is concentrated. Ether is added and the resulting solid is collected to give the title compound, NMR (CDCl3) 1.28, 1.63, 5.01, 6.80, 6.98-7.11, 7.27, 7.96 δ.
Reaction SMILES: [F:1][CH2:2][CH:3]([O:6][C:7]1[CH:12]=[C:11]([F:13])[CH:10]=[CH:9][C:8]=1[NH:14][C:15]1[C:16]2[C:23]([CH3:24])=[C:22]([C:25](O)=[O:26])[S:21][C:17]=2[N:18]=[CH:19][N:20]=1)[CH2:4][F:5].Cl.C(N=C=NCCCN(C)C)C.[CH3:40][S:41]([NH2:44])(=[O:43])=[O:42]>CN(C)C1C=CN=CC=1.ClCCl>[F:1][CH2:2][CH:3]([O:6][C:7]1[CH:12]=[C:11]([F:13])[CH:10]=[CH:9][C:8]=1[NH:14][C:15]1[C:16]2[C:23]([CH3:24])=[C:22]([C:25]([NH:44][S:41]([CH3:40])(=[O:43])=[O:42])=[O:26])[S:21][C:17]=2[N:18]=[CH:19][N:20]=1)[CH2:4][F:5]
Reactant: Cc1c(C(=O)O)sc2ncnc(Nc3ccc(F)cc3OC(CF)CF)c12
Reactant: CS(N)(=O)=O
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Product: Cc1c(C(=O)NS(C)(=O)=O)sc2ncnc(Nc3ccc(F)cc3OC(CF)CF)c12
Temperature: 25 °C
Reaction time: 24 h

Procedure:
4-(2-(1,3-Difluoropropan-2-yloxy)-4-fluorophenylamino)-5-methylthieno[2,3-d]pyrimidine-6-carboxylic acid (197 mg), 4-dimethylaminopyridine (76 mg) and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (125 mg) was dissolved in dichloromethane (20 ml). Methanesulfonamide (59.5 mg) was added and the reaction was stirred at room temperature for about 24 h. The mixture was washed with a KHSO4 solution. The organic layer was separated, dried and concentrated in vacuo. The residue was purified by chromatography (dichloromethane: methanol: NH3 80:20:1). The fractions were collected and triturated with diisopropyl ether.
Reaction SMILES: [CH2:1]([O:8][CH2:9][C@@H:10]1[CH:14]([CH:15]([CH:17]=C)[CH3:16])[O:13][C:12](=[O:19])[NH:11]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O.I([O-])(=O)(=O)=[O:22].[Na+].[BH4-].[Na+]>[Os](=O)(=O)(=O)=O.CO.O>[CH2:1]([O:8][CH2:9][C@@H:10]1[CH:14]([CH:15]([CH3:16])[CH2:17][OH:22])[O:13][C:12](=[O:19])[NH:11]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C=CC(C)C1OC(=O)N[C@@H]1COCc1ccccc1
Reactant: [O-][I+3]([O-])([O-])[O-]
Agent: O=[Os](=O)(=O)=O
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: CC(CO)C1OC(=O)N[C@@H]1COCc1ccccc1
Temperature: 0 °C
Reaction time: 3 h

Procedure:
To a solution of (4R)-4-(benzyloxymethyl)-5-(but-3-en-2-yl)oxazolidin-2-one (1.0 equiv.) in 2:1 MeOH/H2O (0.04 M) was added osmium tetroxide 4% in H2O (0.07 equiv) and sodium periodate (3.0 equiv.). After stirring for 3 hours, the white precipitate was filtered and rinsed with EtOAc. The combined filtrate was concentrated in vacuo and the residue was dissolved in EtOAc, washed with NaCl(sat.), dried over MgSO4, filtered and concentrated. The crude aldehyde was dissolved in EtOH (0.08 M) and upon cooling to 0° C., sodium borohydride (2.0 equiv.) was added. After stirring for 15 hours and coming to room temperature the reaction was quenched by addition of H2O. After stirring for 20 minutes, the EtOH was removed in vacuo, EtOAc was added and the solution was washed with 1N HCl, NaHCO3(sat.) and NaCl(sat.), dried over MgSO4, filtered and concentrated yielding after purification by silica gel chromatography (4R)-4-(benzyloxymethyl)-5-(1-hydroxypropan-2-yl)oxazolidin-2-one as a 3:1 mixture of isomers (60%). LCMS (m/z): 266.1 (MH+); LC Rt=2.28 min.
Reaction SMILES: [N:1]([C@H:4]1[C:29](=[O:30])[N:6]2[CH:7]([C:17]([O:19][CH2:20][C:21]3[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][CH:22]=3)=[O:18])[C:8](OS(C)(=O)=O)([CH3:11])[CH2:9][S:10][C@H:5]12)=[N+:2]=[N-:3].C1C=CC=CC=1.CCOC(C)=O>CCOC(C)=O>[N:1]([C@H:4]1[C:29](=[O:30])[N:6]2[C:7]([C:17]([O:19][CH2:20][C:21]3[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][CH:22]=3)=[O:18])=[C:8]([CH3:11])[CH2:9][S:10][C@H:5]12)=[N+:2]=[N-:3]
Reactant: COc1ccc(COC(=O)C2N3C(=O)[C@H](N=[N+]=[N-])[C@H]3SCC2(C)OS(C)(=O)=O)cc1
Solvent: CCOC(C)=O
Solvent: c1ccccc1
Product: COc1ccc(COC(=O)C2=C(C)CS[C@@H]3[C@@H](N=[N+]=[N-])C(=O)N23)cc1
Temperature: 25 °C
Reaction time: 93 h
Yield: 30.8 %

Procedure:
A mixture of p-methoxybenzyl 7α-azido-3-methanesulfonyloxy-3-methyl-cepham-4-carboxylate (210 mg., 0.46 mMol), EM silica gel 60 (2.5 g.), and 3:1 PhH-EtOAc (5 ml.) is stirred in a capped flask at room temperature for 93 hrs. The mixture is diluted with EtOAc and filtered. The silica gel is washed with more EtOAc. The filtrate and washings are combined, washed with 5% NaHCO3 and brine, dried with MgSO4, filtered, and evaporated in vacuo to a pale yellow oil (158 mg.). The material is purified by plc on a 1000μ × 20 × 20 cm silica gel GF plate using 9:1 PhH-EtOAc as developing solvent. Two major uv visible bands are removed and eluted with EtOAc to yield the products. Band A (Rf 0.47) provides p-methoxybenzyl 7α-azido-3-methyl-ceph-3-em-4-carboxylate (51 mg.) as an oil. Band B (Rf 0.26) yields 6α-azido-2-methyl-2-hydroxymethyl-penam-3-carboxylic acid lactone (27 mg.) as an oil which crystallizes from CHCl3 : mp 164°-166° C. (micro hot stage); ir (Nujol) 4.76, 5.57, 5.67, 7.74, 8.32, and 9.79μ; nmr (100 MHz, DMSO-d6) δ1.59 (s, 3, CH3), 4.30 and 4.52 (ABq, 2, J=10Hz, CH2O), 5.20 (d, l, J=1.8Hz, H5 or H6), 5.28 (s, l, H3) and 5.29 (d, l, J=1.8Hz, H6 or H5); mass spectrum, m/e 240 (M+), 212, and 157.
Reaction SMILES: [OH:1][C@@H:2]1[CH2:7][CH2:6][NH:5][CH2:4][C@@H:3]1[CH2:8][NH:9][C:10](=[O:19])[O:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.CO.[F:22][C:23]1[CH:32]=[C:31]2[C:26]([CH:27]=[CH:28][C:29](=[O:36])[N:30]2[CH2:33][CH:34]=O)=[CH:25][CH:24]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(Cl)Cl>[F:22][C:23]1[CH:32]=[C:31]2[C:26]([CH:27]=[CH:28][C:29](=[O:36])[N:30]2[CH2:33][CH2:34][N:5]2[CH2:6][CH2:7][C@@H:2]([OH:1])[C@@H:3]([CH2:8][NH:9][C:10](=[O:19])[O:11][CH2:12][C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[CH2:4]2)=[CH:25][CH:24]=1
Reactant: O=C(NC[C@H]1CNCC[C@H]1O)OCc1ccccc1
Reactant: O=CCn1c(=O)ccc2ccc(F)cc21
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CO
Solvent: ClCCl
Product: O=C(NC[C@H]1CN(CCn2c(=O)ccc3ccc(F)cc32)CC[C@H]1O)OCc1ccccc1
Reaction time: 18 h
Yield: 25 %

Procedure:
To a mixture of phenylmethyl {[(3R,4R)-4-hydroxy-3-piperidinyl]methyl}carbamate (for a preparation see Example 135(f); 0.72 g; 2.72 mmol) in anhydrous DCM (10 mL) and anhydrous MeOH (2 mL) was added (7-fluoro-2-oxo-1(2H)-quinolinyl)acetaldehyde (for a preparation see Example 88(a)) (0.559 g; 2.72 mmol) and activated 4A sieves. The reaction was stirred under N2 for 18 h. The crude intermediate was treated with sodium triacetoxyborohydride (2.72 mmol; 577 mg) and stirred for 2 h. The product was obtained as a pale yellow oil after column:chromatography (90:10:DCM:MeOH) to yield 306 mg (25%) of the product as its free base.
Reaction SMILES: ICI.[CH2:4]([O:11][C:12]([N:14]1[CH2:18][C@H:17]([CH:19]=O)[C@H:16]([NH:21][C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:15]1)=[O:13])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.Cl.[CH2:30](OCC)C>O1CCCC1.[Ti](Cl)(Cl)(Cl)Cl.[Zn]>[CH2:4]([O:11][C:12]([N:14]1[CH2:18][C@H:17]([CH:19]=[CH2:30])[C@H:16]([NH:21][C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:15]1)=[O:13])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1
Reactant: CC(C)(C)OC(=O)N[C@@H]1CN(C(=O)OCc2ccccc2)C[C@@H]1C=O
Reactant: CCOCC
Agent: Cl[Ti](Cl)(Cl)Cl
Agent: Cl
Agent: [Zn]
Solvent: ICI
Solvent: C1CCOC1
Product: C=C[C@H]1CN(C(=O)OCc2ccccc2)C[C@H]1NC(=O)OC(C)(C)C
Reaction time: 0.08 h

Procedure:
Under cooling with ice, titanium tetrachloride (3.30 mL, 1.0M toluene solution) was added to a suspension of zinc powder (1.86 g, 28.5 mmol) in tetrahydrofuran (15 mL) over 2 minutes, followed by stirring for 5 minutes at the same temperature. A solution of diiodomethane (1.15 mL, 14.3 mL) in tetrahydrofuran (5 mL) was added thereto over 8 minutes, and the resultant mixture was stirred for 15 minutes while the temperature thereof was elevated to room temperature. A solution of (3S,4S)-1-benzyloxycarbonyl-3-(tert-butoxycarbonyl)amino-4-formylpyrrolidine (900 mg, 2.58 mmol) in tetrahydrofuran (5.0 mL) was added thereto over 7 minutes, followed by stirring for 1.5 hours. Subsequently, under cooling with ice, the resultant mixture was poured to 0.5 mol/L hydrochloric acid (10 mL), followed by dilution with diethyl ether (60 mL). The obtained aqueous layer was extracted with diethyl ether (100 mL×2). The combined organic layer was washed by saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure. The obtained residue was purified through silica gel column chromatography (ethyl acetate:n-hexane=1:3), to thereby yield the title compound as a colorless oily substance (3.09 g, 31%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:8]2[CH2:13][CH2:12][CH:11]([C:14]([OH:16])=O)[CH2:10][CH2:9]2)[CH:5]=[CH:6][CH:7]=1.[OH:17][C@H:18]1[CH2:27][C:26]2[C:25]([NH2:28])=[CH:24][CH:23]=[CH:22][C:21]=2[CH2:20][CH2:19]1.ON1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC>CN(C)C=O.C(OCC)(=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([N:8]2[CH2:9][CH2:10][CH:11]([C:14]([NH:28][C:25]3[C:26]4[CH2:27][C@H:18]([OH:17])[CH2:19][CH2:20][C:21]=4[CH:22]=[CH:23][CH:24]=3)=[O:16])[CH2:12][CH2:13]2)[CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)C1CCN(c2cccc(Cl)c2)CC1
Reactant: Nc1cccc2c1C[C@H](O)CC2
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: O=C(Nc1cccc2c1C[C@H](O)CC2)C1CCN(c2cccc(Cl)c2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 32.2 %

Procedure:
120 mg (0.50 mmol) of 1-(3-chlorophenyl)-piperidine-4-carboxylic acid, 74 mg (0.46 mmol) of (7R)-7-hydroxy-5,6,7,8-tetrahydronaphthaleneamine, 74 mg (0.55 mmol) of 1-hydroxy-1H-benzotriazole and 113 mg (0.59 mmol) of (N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride were combined in 3 ml of N,N-dimethylformamide under an argon atmosphere and stirred at room temperature overnight. Ethyl acetate was added, the mixture washed with water and the aqueous phase re-extracted with ethyl acetate three times. The combined organic phases were dried over magnesium sulfate and evaporated under reduced pressure. The residue was purified by RP-BPLC in a water/acetonitrile gradient, yielding 57 mg (33% yield) of 1-[3-chlorophenyl]-N-[(7R)-7-hydroxy-5,6,7,8-tetrahydronaphthalen-1-yl]piperidine-4-carboxamide.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[C:5]2=[O:12].CN(C)C=O.Br[CH2:19][C:20]([O:22][CH3:23])=[O:21]>O>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH2:19][C:20]([O:22][CH3:23])=[O:21])[C:6](=[O:11])[C:5]2=[O:12]
Reactant: O=C1Nc2ccc(Cl)cc2C1=O
Reactant: COC(=O)CBr
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)CN1C(=O)C(=O)c2cc(Cl)ccc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 76 %

Procedure:
To a solution of 5-chloroisatin, compound VIII, (10.0 g, 55.07 mmol) in anhydrous N,N-dimethylformamide (100 ml) potassium carbonate (9.87 g, 71.59 mmol) was added portionwise at 0-5° C. After stirring at 0-5° C. for further 10 minutes and at ambient temperature for one additional hour methyl bromoacetate (8.25 ml, 60.58 mmol) was added dropwise at such a rate that the internal temperature did not exceed 35° C. The resulting orange suspension was allowed to stir at ambient temperature overnight. Water was added (350 ml) and the product was extracted with ethyl acetate (5×100 ml). The combined organic extracts were washed with brine (100 ml), dried (MgSO4) and evaporated under reduced pressure to give the title compound (10.83 g, 76%) as orange solid (HPLC purity 98%). MS (ESI+): 254.1; MS (ESI−): 252.1
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:9]2[C:17]3[C:12](=[CH:13][C:14]([OH:18])=[CH:15][CH:16]=3)[C:11](=[O:19])[C:10]=2[C:20]2[CH:21]=[N:22][CH:23]=[CH:24][CH:25]=2)[CH:5]=[C:6]([F:8])[CH:7]=1.BrC1C(=O)C2C(C=1C1C=CC=CC=1)=CC=C(O)C=2.[N:44]1[CH:49]=[CH:48][CH:47]=[CH:46][C:45]=1[CH2:50][CH2:51]O>>[F:8][C:6]1[CH:5]=[C:4]([C:9]2[C:17]3[C:12](=[CH:13][C:14]([O:18][CH2:51][CH2:50][C:45]4[CH:46]=[CH:47][CH:48]=[CH:49][N:44]=4)=[CH:15][CH:16]=3)[C:11](=[O:19])[C:10]=2[C:20]2[CH:21]=[N:22][CH:23]=[CH:24][CH:25]=2)[CH:3]=[C:2]([F:1])[CH:7]=1
Reactant: O=C1C(c2cccnc2)=C(c2cc(F)cc(F)c2)c2ccc(O)cc21
Reactant: OCCc1ccccn1
Agent: O=C1C(Br)=C(c2ccccc2)c2ccc(O)cc21
Product: O=C1C(c2cccnc2)=C(c2cc(F)cc(F)c2)c2ccc(OCCc3ccccn3)cc21
Reaction time: 168 h
Yield: 45 %

Procedure:
The procedure of Step 6 of Example 1 was repeated except for using 3-(3,5-difluorophenyl)-6-hydroxy-2-(pyridin-3-yl)-1H-inden-1-one obtained in Step 1 of Example 61 as a starting material instead of 2-bromo-6-hydroxy-3-phenyl-1H-inden-1-one, 2-(pyridin-2-yl)ethanol instead of 4-(2-hydroxyethyl)morpholine, being stirred for 7 d, and being purified by silica gel column chromatography (CH2Cl2/EtOAc=1:4) to obtain the title compound (45%).
Reaction SMILES: [C:1]([O:10]C)(=O)[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[SH:4].[CH2:12]([O:19][C:20]1[CH:21]=[C:22]([CH:25]=[CH:26][N:27]=1)[C:23]#[N:24])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C(N(CC)CC)C>C1(C)C=CC=CC=1>[CH2:12]([O:19][C:20]1[CH:21]=[C:22]([C:23]2[S:4][C:3]3[CH:5]=[CH:6][CH:7]=[CH:8][C:2]=3[C:1](=[O:10])[N:24]=2)[CH:25]=[CH:26][N:27]=1)[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: COC(=O)c1ccccc1S
Reactant: N#Cc1ccnc(OCc2ccccc2)c1
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: O=c1nc(-c2ccnc(OCc3ccccc3)c2)sc2ccccc12
Yield: 32.1 %

Procedure:
Methyl thiosalicylate (0.59 g, 3.5 mmol) and 2-(benzyloxy)isonicotinonitrile (0.37 g, 1.8 mmol) were dissolved in toluene (2.0 ml). Triethylamine (0.54 ml, 3.9 mmol) was added thereto and the mixture was refluxed for 6 hrs. The reaction mixture was subjected to a silica gel (50 g) column chromatography, eluted with hexane-ethyl acetate (2:1, v/v) and recrystallized from ethanol to give the titled compound (0.20 g, 32%) as white crystals.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([C:11](=O)[CH2:12][CH2:13][C:14](=O)[CH2:15][CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:7][CH:6]=1)(=[O:4])=[O:3].[F:24][C:25]1[CH:31]=[CH:30][C:28]([NH2:29])=[CH:27][CH:26]=1.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[F:24][C:25]1[CH:31]=[CH:30][C:28]([N:29]2[C:11]([C:8]3[CH:9]=[CH:10][C:5]([S:2]([CH3:1])(=[O:4])=[O:3])=[CH:6][CH:7]=3)=[CH:12][CH:13]=[C:14]2[CH2:15][CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:27][CH:26]=1
Reactant: Nc1ccc(F)cc1
Reactant: CCOC(=O)CCC(=O)CCC(=O)c1ccc(S(C)(=O)=O)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: CCOC(=O)CCc1ccc(-c2ccc(S(C)(=O)=O)cc2)n1-c1ccc(F)cc1
Yield: 74.9 %

Procedure:
A mixture of ethyl 4-(methylsulfonyl)-γ,ζ-dioxobenzeneheptanoate (Step 3), (270 mg, 0.79 mmol), 4-fluoroaniline (83 μl, 0.87 mmol) and p-toluenesulfonic acid (25 mg) in toluene (40 ml) was heated at reflux for 24 hours. The reaction mixture was cooled, filtered and concentrated. The crude solid (360 mg) was purified by chromatography (silica gel, hexane/ethyl acetate, 1/1) to give ethyl 1-(4-fluorophenyl)-5-[4-(methylsulfonyl)phenyl]-1H-pyrrole-2-propanoate (246 mg, 75%) as a white solid: mp (DSC) 134° C. Anal Calc'd. for C22H22NSFO4 : C, 63.60; H, 5.34; N, 3.37; S, 7.72. Found: C, 63.29; H, 5.51; N, 3.38; S, 8.05.
Reaction SMILES: [H-].[Na+].[NH:3]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[OH:14])=[N:4]1.[CH2:15]([O:17][C:18](=[O:26])[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24]Br)[CH3:16]>CN(C=O)C>[CH2:15]([O:17][C:18](=[O:26])[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][N:3]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[OH:14])=[N:4]1)[CH3:16]
Reactant: CCOC(=O)CCCCCCBr
Reactant: Oc1ccccc1-c1cc[nH]n1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)CCCCCCn1ccc(-c2ccccc2O)n1
Temperature: 75 °C
Yield: 48.2 %

Procedure:
Add sodium hydride (1.50 g, 31 mmol, 60% suspension in mineral oil) to a suspension of 2-(1H-pyrazol-3-yl)phenol (5.0 g, 31 mmol) and 7-bromoheptanoic acid ethyl ester (7.4 g, 31 mmol) in DMF (75 mL) at room temperature under nitrogen and heat the mixture at 75° C. for 16 hours. Remove the solvent under reduced pressure, dilute the residue with ethyl acetate (300 mL), wash with water (100 mL), and dry over sodium sulfate. Remove the solvent under reduced pressure and purify the residue by flash column chromatography on silica gel, eluting with hexanes/ethyl acetate (9:1), to provide 7-[3-(2-hydroxyphenyl)pyrazol-1-yl]heptanoic acid ethyl ester (4.73 g, 48%).
Reaction SMILES: [Cl:1][C:2]1[N:11]=[C:10](Cl)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.[CH3:13][O:14][C:15]1[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][C:16]=1[NH2:17]>>[Cl:1][C:2]1[N:11]=[C:10]([NH:17][C:16]2[CH:18]=[C:19]([O:22][CH3:23])[CH:20]=[CH:21][C:15]=2[O:14][CH3:13])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1
Reactant: COc1ccc(OC)c(N)c1
Reactant: Clc1nc(Cl)c2ccccc2n1
Product: COc1ccc(OC)c(Nc2nc(Cl)nc3ccccc23)c1

Procedure:
The title compound was prepared from 2,4-dichloroquinazoline and 2,5-dimethoxyaniline by a procedure similar to Example 28 (98% yield). 1H NMR (CDCl3): 8.59 (d, J=3.0 Hz, 1H), 8.53 (s, broad, 1H), 7.78-7.87 (m, 3H), 7.57 (ddd, J=8.4, 6.6 and 1.8 Hz, 1H), 6.88 (d, J=9.0 Hz, 1H), 6.60 (dd, J=8.7 and 3.0 Hz, 1H), 3.97 (s, 3H), 3.87 (s, 3H).