Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([CH2:11][CH2:12][C@H:13]([OH:21])[CH2:14][CH:15]2[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]2)=[CH:7][C:6]=1[NH:22][C:23](=[O:39])[CH2:24][CH:25]1[C:38]2[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=2[O:32][C:31]2[C:26]1=[CH:27][CH:28]=[CH:29][CH:30]=2)([CH3:4])([CH3:3])[CH3:2].[C:40]1(=[O:50])[O:45][C:43](=[O:44])[C:42]2=[CH:46][CH:47]=[CH:48][CH:49]=[C:41]12>>[C:40]([O:21][C@@H:13]([CH2:12][CH2:11][C:8]1[CH:9]=[CH:10][C:5]([C:1]([CH3:4])([CH3:2])[CH3:3])=[C:6]([NH:22][C:23](=[O:39])[CH2:24][CH:25]2[C:26]3[CH:27]=[CH:28][CH:29]=[CH:30][C:31]=3[O:32][C:33]3[C:38]2=[CH:37][CH:36]=[CH:35][CH:34]=3)[CH:7]=1)[CH2:14][CH:15]1[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20]1)(=[O:50])[C:41]1[C:42](=[CH:46][CH:47]=[CH:48][CH:49]=1)[C:43]([OH:45])=[O:44]
Reactant: O=C1OC(=O)c2ccccc21
Reactant: CC(C)(C)c1ccc(CC[C@H](O)CC2CCCCC2)cc1NC(=O)CC1c2ccccc2Oc2ccccc21
Product: CC(C)(C)c1ccc(CC[C@@H](CC2CCCCC2)OC(=O)c2ccccc2C(=O)O)cc1NC(=O)CC1c2ccccc2Oc2ccccc21

Procedure:
Following a procedure similar to that described in Example 54, but using (S)-N-[2-t-butyl-5-(4-cyclohexyl-3-hydroxybutyl)phenyl]-2-(9H-xanthen-9-yl)acetamide (prepared as described in Example 102) and phthalic anhydride as starting materials, in relative proportions similar to those used in that Example, the title compound was obtained as a foam-like material.
Reaction SMILES: F[C:2]1[CH:17]=[C:16]([C:18]([F:21])([F:20])[F:19])[CH:15]=[CH:14][C:3]=1[C:4]([NH:6][C:7]1[CH:12]=[CH:11][NH:10][C:9](=[O:13])[CH:8]=1)=[O:5].[F:22][C:23]1[CH:28]=[CH:27][C:26]([OH:29])=[C:25]([CH3:30])[CH:24]=1.C([O-])([O-])=O.[Cs+].[Cs+].CN(C=O)C>O>[F:22][C:23]1[CH:28]=[CH:27][C:26]([O:29][C:2]2[CH:17]=[C:16]([C:18]([F:21])([F:20])[F:19])[CH:15]=[CH:14][C:3]=2[C:4]([NH:6][C:7]2[CH:12]=[CH:11][NH:10][C:9](=[O:13])[CH:8]=2)=[O:5])=[C:25]([CH3:30])[CH:24]=1
Reactant: Cc1cc(F)ccc1O
Reactant: O=C(Nc1cc[nH]c(=O)c1)c1ccc(C(F)(F)F)cc1F
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1cc(F)ccc1Oc1cc(C(F)(F)F)ccc1C(=O)Nc1cc[nH]c(=O)c1
Temperature: 100 °C
Reaction time: 0.5 h
Yield: 71.2 %

Procedure:
A mixture of 2-fluoro-N-(2-oxo-1H-pyridin-4-yl)-4-(trifluoromethyl)-benzamide (13.6 g, 45.30 mmol), 4-fluoro-2-methyl-phenol (17.1 g, 135.9 mmol), Cs2CO3 (44.28 g, 135.9 mmol) and DMF (340.0 mL) was heated at 100° C. for 1.5 hours. The mixture was cooled to room temperature and was poured into water (500 mL). The mixture was stirred vigorously for 30 min before it was filtered. The solid was washed with water (250 mL) and was slurried with methyl tert-butyl ether (200 mL). The mixture was filtered and the solid was slurried with hexanes (2×400 mL) and the filtrate was dried under vacuum to give 2-(4-fluoro-2-methyl-phenoxy)-N-(2-oxo-1H-pyridin-4-yl)-4-(trifluoromethyl)benzamide (10) (13.1 g, 70%) as a solid. ESI-MS m/z calc. 406.09. found 407.5 (M+1)+; Retention time: 1.73 minutes (3 minutes run). 1H NMR (400 MHz, DMSO-d6) δ 11.28 (s, 1H), 10.63 (s, 1H), 7.84 (d, J=7.8 Hz, 1H), 7.60 (d, J=7.1 Hz, 1H), 7.31 (d, J=7.2 Hz, 1H), 7.26-7.20 (m, 1H), 7.14-7.06 (m, 2H), 7.00-6.95 (m, 1H), 6.75 (d, J=1.8 Hz, 1H), 6.38 (dd, J=7.2, 2.1 Hz, 1H), 2.16 (s, 3H) ppm.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([CH2:11][C:12]2[N:13]=[C:14]([C:17]3[CH:26]=[CH:25][C:20]([C:21]([O:23]C)=[O:22])=[CH:19][CH:18]=3)[S:15][CH:16]=2)(=[O:10])=[O:9])=[CH:4][CH:3]=1>Cl>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]([S:8]([CH2:11][C:12]2[N:13]=[C:14]([C:17]3[CH:26]=[CH:25][C:20]([C:21]([OH:23])=[O:22])=[CH:19][CH:18]=3)[S:15][CH:16]=2)(=[O:9])=[O:10])=[CH:6][CH:7]=1
Reactant: COC(=O)c1ccc(-c2nc(CS(=O)(=O)c3ccc(C)cc3)cs2)cc1
Agent: Cl
Product: Cc1ccc(S(=O)(=O)Cc2csc(-c3ccc(C(=O)O)cc3)n2)cc1
Yield: 100 %

Procedure:
Method C. Reaction of benzoate 52 (407 mg, 1.05 mmol) and 6 M HCl (20 mL) gave acid 53 (392 mg, 100%) as a white solid: mp (H2O) 270-272° C.; 1H NMR δ 13.15 (br s, 1 H, CO2 H), 8.01 (ddd, J=8.6, 1.9, 1.7Hz, 2 H, H-2, H-6), 7.83 (ddd, J=8.6, 1.9, 1.7Hz, 2 H, H-3, H-5), 7.70 (s, 1 H, H-5′), 7.65 (br d, J=8.3, 2 H, H-2″, H-6″), 7.41 (br d, J=8.3Hz, 2 H, H-3″, H-5″), 4.87 (s, 2 H, CH2SO2), 2.39 (s, 3H, CH3); MS m/z 374.6 (MH+, 100%). Anal. calcd for C18H15NO4S2: C, 57.89; H, 4.05; N, 3.75. Found: C, 57.89; H, 4.07; N, 3.63%.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[N:9]1[C:18]2[C:13](=[CH:14][C:15]([F:26])=[C:16]([F:25])[C:17]=2[C:19]#[C:20][Si](C)(C)C)[C:12](=[O:27])[C:11]([C:28]([O:30][CH2:31][CH3:32])=[O:29])=[CH:10]1.[F-].[K+].O.CN(C)C=O>C(Cl)(Cl)Cl>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[N:9]1[C:18]2[C:13](=[CH:14][C:15]([F:26])=[C:16]([F:25])[C:17]=2[C:19]#[CH:20])[C:12](=[O:27])[C:11]([C:28]([O:30][CH2:31][CH3:32])=[O:29])=[CH:10]1
Reactant: CCOC(=O)c1cn(-c2ccc(F)cc2F)c2c(C#C[Si](C)(C)C)c(F)c(F)cc2c1=O
Agent: [F-]
Agent: [K+]
Solvent: O
Solvent: ClC(Cl)Cl
Solvent: CN(C)C=O
Product: C#Cc1c(F)c(F)cc2c(=O)c(C(=O)OCC)cn(-c3ccc(F)cc3F)c12
Temperature: 20 °C
Reaction time: 1 h
Yield: 87.6 %

Procedure:
A solution of 4.6 g of ethyl 1-(2,4-difluorophenyl)-6,7-difluoro-1,4-dihydro-8-(trimethylsilylethinyl)-4-oxo-3-quinolinecarboxylate in 20 ml of chloroform is added dropwise at room temperature to a solution of 2 g of potassium fluoride in a solvent mixture of 3 ml of water, 25 ml of chloroform and 50 ml of dimethylformamide. The mixture is stirred for 1 hour at approx. 20° C., the reaction mixture is then treated with more chloroform and extracted several times by shaking with water, and the organic phase is dried and concentrated. The residue obtained is recrystallised from methanol. 3.4 g of ethyl 1-(2,4-difluorophenyl)-8-ethinyl-6,7-difluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylate are obtained (87% of theory).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][C:5]([O:8][C:9]2[CH:10]=[C:11]([NH:16][C:17]([C:19]3[N:23]([CH3:24])[N:22]=[C:21]([CH3:25])[CH:20]=3)=[O:18])[CH:12]=[C:13]([CH3:15])[CH:14]=2)=[CH:4][CH:3]=1.[C:26]1([CH3:36])[CH:31]=[CH:30][C:29]([S:32](Cl)(=[O:34])=[O:33])=[CH:28][CH:27]=1>N1C=CC=CC=1>[CH3:24][N:23]1[C:19]([C:17]([NH:16][C:11]2[CH:10]=[C:9]([O:8][C:5]3[CH:6]=[N:7][C:2]([NH:1][S:32]([C:29]4[CH:30]=[CH:31][C:26]([CH3:36])=[CH:27][CH:28]=4)(=[O:34])=[O:33])=[CH:3][CH:4]=3)[CH:14]=[C:13]([CH3:15])[CH:12]=2)=[O:18])=[CH:20][C:21]([CH3:25])=[N:22]1
Reactant: Cc1cc(NC(=O)c2cc(C)nn2C)cc(Oc2ccc(N)nc2)c1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: c1ccncc1
Product: Cc1ccc(S(=O)(=O)Nc2ccc(Oc3cc(C)cc(NC(=O)c4cc(C)nn4C)c3)cn2)cc1
Yield: 80.6 %

Procedure:
In the same manner as in Reference Example 4 and using N-{3-[(6-aminopyridin-3-yl)oxy]-5-methylphenyl}-1,3-dimethyl-1H-pyrazole-5-carboxamide (4.02 g, 9.79 mmol), p-toluenesulfonyl chloride (2.29 g, 12.0 mmol) and pyridine (30 mL) as starting materials, the title compound (3.88 g, 81%) was obtained as a colorless oil.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([S:8]([CH3:10])=[O:9])[C:5](Br)=[CH:4][C:3]=1[S:12]([CH3:14])=[O:13].CC1(C)C(C)(C)OB([C:23]2[S:24][C:25]([CH2:28][CH2:29][CH2:30][CH2:31][CH3:32])=[CH:26][CH:27]=2)O1>C1COCC1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:14][S:12]([C:3]1[CH:4]=[C:5]([C:23]2[S:24][C:25]([CH2:28][CH2:29][CH2:30][CH2:31][CH3:32])=[CH:26][CH:27]=2)[C:6]([S:8]([CH3:10])=[O:9])=[CH:7][C:2]=1[C:23]1[S:24][C:25]([CH2:28][CH2:29][CH2:30][CH2:31][CH3:32])=[CH:26][CH:27]=1)=[O:13]
Reactant: CCCCCc1ccc(B2OC(C)(C)C(C)(C)O2)s1
Reactant: CS(=O)c1cc(Br)c(S(C)=O)cc1Br
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CCCCCc1ccc(-c2cc(S(C)=O)c(-c3ccc(CCCCC)s3)cc2S(C)=O)s1
Temperature: 60 °C
Yield: 62.4 %

Procedure:
1,4-dibromo-2,5-bis(methylsulfinyl)benzene 3 (1 g, 2.8 mmol) was added to a solution of 4,4,5,5-tetramethyl-2-(5-pentylthiophen-2-yl)-1,3,2-dioxaborolane (3.4 g, 12.2 mmol) in anhydrous THF (17 mL), and the resulting mixture was purged with nitrogen for 30 min. Pd(PPh3)4 (87 mg, 0.075 mmol) was then added, and the 15 reaction mixture was heated to 60° C. overnight. The mixture was extracted with dichloromethane and washed with brine. The filtrate was dried over Mg2SO4, filtered, and the solvent removed in vacuo. The crude product was purified by flash chromatography (silica gel, eluent: hexane/EA) 3:1) to afford 0.885 g (63%) of 2a.
Reaction SMILES: C(Cl)(Cl)Cl.[Cl:5][C:6]1([CH:20]=[CH:19]N=[C:17]([CH:21]([OH:29])[C:22]2[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][CH:23]=2)[CH2:16]1)C(NC1C=CC=CC=1)=O.C([N:32]([CH2:35][CH3:36])[CH2:33][CH3:34])C.P(Br)(Br)Br>O>[Cl:5][C:6]1[CH:20]=[CH:19][C:35]2[N:32]=[C:33]([C:34]3[CH:34]=[CH:33][N:32]=[CH:35][CH:36]=3)[O:29][CH:21]([C:22]3[CH:23]=[CH:24][C:25]([Cl:28])=[CH:26][CH:27]=3)[C:17]=2[CH:16]=1
Reactant: CCN(CC)CC
Reactant: O=C(Nc1ccccc1)C1(Cl)C=CN=C(C(O)c2ccc(Cl)cc2)C1
Agent: BrP(Br)Br
Solvent: ClC(Cl)Cl
Solvent: O
Product: Clc1ccc(C2OC(c3ccncc3)=Nc3ccc(Cl)cc32)cc1
Reaction time: 1 h
Yield: 85 %

Procedure:
To chloroform (300 ml), 4-chloro-2-(4-chloro-α-hydroxybenzyl)-isonicotinanilide (12.4 g) and triethylamine (5.0 ml) were added. With stirring and under cooling with ice, phosphorus tribromide (9.1 g) was added slowly, and the stirring was continued for 1 hour. Following another 3-hour stirring at room temperature, the reaction mixture was poured into water. The chloroform layer was thoroughly washed with water and subsequently dried. The chloroform was completely distilled off under vacuum. Upon recrystallization from a mixed solvent of ethyl acetate and n-hexane, the titled compound was obtained in an amount of 10.1 g (yield: 85%). m.p. 140°-141° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][N:3]=1.[Br:9]N1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(Cl)(Cl)(Cl)Cl.ClCCl>[Br:9][CH2:8][C:6]1[CH:5]=[CH:4][N:3]=[C:2]([F:1])[CH:7]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1ccnc(F)c1
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Solvent: ClCCl
Product: Fc1cc(CBr)ccn1
Temperature: 90 °C
Reaction time: 20 h

Procedure:
To a solution of 2-fluoro-4-methylpyridine (0.510 g, 4.59 mmol) in 20 mL of carbon tetrachloride was added N-bromosuccinimide (0.899 g, 5.05 mmol) and benzoyl peroxide (0.148 g, 0.459 mmol). The mixture was heated to 90° C. for 1 h, and then additional benzoyl peroxide (0.074 g, 0.23 mmol) was added. After 20 h, the reaction was diluted with dichloromethane, washed 3× with water, dried over sodium sulfate, filtered, and concentrated in vacuo. The residue was purified via silica gel chromatography, eluting with 0-10% ethyl acetate in hexanes to provide the 4-(bromomethyl)-2-fluoropyridine that gave proton NMR spectra consistent with theory and a mass ion (ES+) of 191.9 (81Br) for [M+H]+.
Reaction SMILES: [CH:1]12[CH2:8][CH2:7][CH:4]([CH2:5][CH2:6]1)[C:3](=[O:9])[NH:2]2.Br[C:11]1[S:12][CH:13]=[CH:14][N:15]=1.C([O-])([O-])=O.[Cs+].[Cs+].CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.O1CCOCC1>[S:12]1[CH:13]=[CH:14][N:15]=[C:11]1[N:2]1[C:3](=[O:9])[CH:4]2[CH2:7][CH2:8][CH:1]1[CH2:6][CH2:5]2
Reactant: O=C1NC2CCC1CC2
Reactant: Brc1nccs1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Product: O=C1C2CCC(CC2)N1c1nccs1
Temperature: 125 °C
Reaction time: 3 h
Yield: 60 %

Procedure:
A mixture of 2-azabicyclo[2.2.2]octan-3-one (0.5 g, 4.0 mmol), 2-bromothiazole (0.79 g, 4.81 mmol), Cs2CO3 (2.0 g, 6.0 mmol), xantphos (0.19 g, 0.32 mmol) and 1,4-dioxane (25 ml) was degassed with argon gas for 15 min. Tetrakis(triphenylphosphine)palladium (0) (0.18 g, 0.16 mmol) was added, degassed for another 15 min and stirred at 125° C. for 3 h in a sealed tube. After cooling to room temperature the reaction mixture was filtered and the filtrate was evaporated under reduced pressure to afford the crude compound. Purification by column chromatography over neutral alumina using 10% ethyl acetate in petroleum ether as eluent afford 500 mg (60%) of 2-(thiazol-2-yl)-2-aza-bicyclo[2.2.2]octan-3-one as pale yellow solid.
Reaction SMILES: [Br:1][C:2]1[N:7]=[C:6]([CH2:8][NH:9][CH3:10])[CH:5]=[CH:4][CH:3]=1.[C:11]([O:15][C:16]([N:18]1[C@@H:22]([C@H:23]([O:30][Si:31]([C:34]([CH3:37])([CH3:36])[CH3:35])([CH3:33])[CH3:32])[C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH2:21][CH2:20][C@H:19]1[CH2:38][C:39]1[CH:47]=[CH:46][C:42]([C:43](O)=[O:44])=[CH:41][CH:40]=1)=[O:17])([CH3:14])([CH3:13])[CH3:12].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C.CCOC(C)=O>[Br:1][C:2]1[N:7]=[C:6]([CH2:8][N:9]([CH3:10])[C:43]([C:42]2[CH:41]=[CH:40][C:39]([CH2:38][C@H:19]3[CH2:20][CH2:21][C@@H:22]([C@H:23]([O:30][Si:31]([C:34]([CH3:37])([CH3:36])[CH3:35])([CH3:32])[CH3:33])[C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)[N:18]3[C:16]([O:15][C:11]([CH3:12])([CH3:13])[CH3:14])=[O:17])=[CH:47][CH:46]=2)=[O:44])[CH:5]=[CH:4][CH:3]=1
Reactant: CNCc1cccc(Br)n1
Reactant: CC(C)(C)OC(=O)N1[C@H](Cc2ccc(C(=O)O)cc2)CC[C@@H]1[C@H](O[Si](C)(C)C(C)(C)C)c1ccccc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Product: CN(Cc1cccc(Br)n1)C(=O)c1ccc(C[C@H]2CC[C@@H]([C@H](O[Si](C)(C)C(C)(C)C)c3ccccc3)N2C(=O)OC(C)(C)C)cc1
Temperature: 25 °C
Reaction time: 12 h
Yield: 27.2 %

Procedure:
1-(6-Bromopyridin-2-yl)-N-methylmethanamine (115 mg, 0.571 mmol) was added to a stirred, room temperature mixture of 4-({(2S,5R)-1-(tert-butoxycarbonyl)-5-[(R)-{[tert-butyl(dimethyl)silyl]oxy}(phenyl)methyl]pyrrolidin-2-yl}methyl)benzoic acid (300 mg, 0.571 mmol), HATU (260 mg, 0.685 mmol, 1.2 equivalents) and DIPEA (498 μL, 2.85 mmol, 5 equivalents) in DMF (2.8 mL). The reaction was stirred at room temperature for 12 hours, and then diluted with EtOAc and partitioned with water. The aqueous layer was extracted with EtOAc (3×), and the combined organic extracts were washed with brine, dried over MgSO4, filtered, and concentrated in vacuo. The residue was purified by normal phase flash chromatography using silica gel (0-50% hexanes/ethyl acetate). The product was collected and concentrated in vacuo to afford the title compound (110 mg, 27%). LC-MS=608.2 & 610.2 (M-Boc+H)+.
Reaction SMILES: [CH:1]1([N:4]2[C:13](=[O:14])[C:12]3[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=3)[NH:6][C:5]2=[O:15])[CH2:3][CH2:2]1.CC(N=P(N1CCCC1)(N1CCCC1)N1CCCC1)(C)C.Cl[CH2:38][C:39]1[N:43]([CH2:44][CH2:45][CH2:46][C:47]2[N:51]=[CH:50][O:49][N:48]=2)[C:42]2[CH:52]=[CH:53][CH:54]=[CH:55][C:41]=2[N:40]=1.Cl>CN(C=O)C>[CH:1]1([N:4]2[C:13](=[O:14])[C:12]3[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=3)[N:6]([CH2:38][C:39]3[N:43]([CH2:44][CH2:45][CH2:46][C:47]4[N:51]=[CH:50][O:49][N:48]=4)[C:42]4[CH:52]=[CH:53][CH:54]=[CH:55][C:41]=4[N:40]=3)[C:5]2=[O:15])[CH2:3][CH2:2]1
Reactant: O=c1[nH]c2ccccc2c(=O)n1C1CC1
Reactant: ClCc1nc2ccccc2n1CCCc1ncon1
Agent: CC(C)(C)N=P(N1CCCC1)(N1CCCC1)N1CCCC1
Agent: Cl
Solvent: CN(C)C=O
Product: O=c1c2ccccc2n(Cc2nc3ccccc3n2CCCc2ncon2)c(=O)n1C1CC1
Reaction time: 0.25 h
Yield: 14 %

Procedure:
To a solution of 3-cyclopropyl-1H-quinazoline-2,4-dione, 159a, (83 mg, 0.41 mmol) in DMF (6 mL) was added BTPP (269 mg, 0.86 mmol) and the solution was stirred for 15 min. 2-Chloromethyl-1-(3-[1,2,4]oxadiazol-3-yl-propyl)-1H-benzoimidazole, 205, HCl salt (128 mg, 0.41 mmol) was added and stirring was continued for 1 h. The solution was concentrated and water was added to the residue. The white precipitate was collected by filtration, washed with water and purified by flash chromatography (eluent dichloromethane-ethyl acetate 2:1, 1:1) to afford 3-cyclopropyl-1-[1-(3-[1,2,4]oxadiazol-3-yl-propyl)-1H-benzoimidazol-2-ylmethyl]-1H-quinazoline-2,4-dione (26 mg, 14%) as a white solid:
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[C:11]([F:12])=[CH:10][C:9]([C:13]3[O:14][C:15]4[CH:21]=[C:20]([O:22][CH2:23][C@@H:24]([NH:26][C:27](=O)[O:28]C(C)(C)C)[CH3:25])[CH:19]=[CH:18][C:16]=4[N:17]=3)=[CH:8][C:7]=2[F:34])[CH2:3][CH2:2]1.Cl.[C:36](OCC)(=O)C>>[CH:1]1([CH2:4][O:5][C:6]2[C:7]([F:34])=[CH:8][C:9]([C:13]3[O:14][C:15]4[CH:21]=[C:20]([O:22][CH2:23][C@@H:24]([NH:26][C:27](=[O:28])[CH3:36])[CH3:25])[CH:19]=[CH:18][C:16]=4[N:17]=3)=[CH:10][C:11]=2[F:12])[CH2:2][CH2:3]1
Reactant: CCOC(C)=O
Reactant: C[C@@H](COc1ccc2nc(-c3cc(F)c(OCC4CC4)c(F)c3)oc2c1)NC(=O)OC(C)(C)C
Agent: Cl
Product: CC(=O)N[C@@H](C)COc1ccc2nc(-c3cc(F)c(OCC4CC4)c(F)c3)oc2c1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To tert-butyl ((2S)-1-((2-(4-(cyclopropylmethoxy)-3,5-difluorophenyl)-1,3-benzoxazol-6-yl)oxy)propan-2-yl)carbamate (2.60 g) was added 4 M hydrogen chloride/ethyl acetate (10 mL), and the mixture was stirred at room temperature for 10 min, and concentrated. To the residue were added pyridine (10 mL) and acetic anhydride (10 mL), and the mixture was stirred at room temperature for 15 min. The reaction mixture was concentrated under reduced pressure, and the residue was dissolved in ethyl acetate/methanol, and the solution was subjected to silica gel column chromatography (NH, ethyl acetate). The solvent was evaporated, and the obtained solid was washed with diethyl ether to give the title compound (1.39 g).
Reaction SMILES: [CH3:1][C:2]1[CH2:11][S:10][C@@H:5]2[C@H:6](N)[C:7](=[O:8])[N:4]2[C:3]=1[C:12]([OH:14])=[O:13].C(O)C.[BrH:18].N([O-])=O.[Na+]>O>[Br:18][C@H:6]1[C:7](=[O:8])[N:4]2[C:3]([C:12]([OH:14])=[O:13])=[C:2]([CH3:1])[CH2:11][S:10][C@H:5]12
Reactant: CC1=C(C(=O)O)N2C(=O)[C@@H](N)[C@H]2SC1
Reactant: Br
Agent: O=N[O-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: CC1=C(C(=O)O)N2C(=O)[C@H](Br)[C@H]2SC1
Temperature: 0 °C
Reaction time: 2.5 h
Yield: 75.5 %

Procedure:
To an ice-cooled mixture of 7-ADCA (10.0 g, 0.4667 mol), ethanol (270 ml), water (83 ml) and hydrobromic acid (48%, 56.7 ml), sodium nitrite (4.67 g, 0.6769 mol) was added in small portions over 25 minutes and the mixture was stirred for 2.5 hours at ice-temperature. Ethanol was removed under reduced pressure and the residual mass was diluted with methylene chloride, washed with water. The aqueous washings were saturated with brine and re-extracted with methylene chloride. The combined organic layer was washed with brine, dried over anhydrous sodium sulfate and concentrated to give 9.8 g (75.5%) of 7α-bromo-3-methyl-3-cephem-4-carboxylic acid. This crude acid was directly used for the next step without further purification.
Reaction SMILES: [CH2:1]([C:3]1[S:4][CH:5]=[C:6](/[CH:8]=[CH:9]/[C:10]2[C:11]([O:21][CH2:22][C:23]3[CH:46]=[CH:45][C:26]([O:27][CH2:28][C:29]4[N:30]=[C:31]([C:35]5[CH:36]=[C:37]([CH:42]=[CH:43][CH:44]=5)[C:38]([O:40]C)=[O:39])[O:32][C:33]=4[CH3:34])=[C:25]([O:47][CH3:48])[CH:24]=3)=[N:12][N:13]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[CH:14]=2)[N:7]=1)[CH3:2].O1CCCC1.[OH-].[Na+].Cl>O.C(O)C>[CH2:1]([C:3]1[S:4][CH:5]=[C:6](/[CH:8]=[CH:9]/[C:10]2[C:11]([O:21][CH2:22][C:23]3[CH:46]=[CH:45][C:26]([O:27][CH2:28][C:29]4[N:30]=[C:31]([C:35]5[CH:36]=[C:37]([CH:42]=[CH:43][CH:44]=5)[C:38]([OH:40])=[O:39])[O:32][C:33]=4[CH3:34])=[C:25]([O:47][CH3:48])[CH:24]=3)=[N:12][N:13]([C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=3)[CH:14]=2)[N:7]=1)[CH3:2]
Reactant: CCc1nc(/C=C/c2cn(-c3ccccc3)nc2OCc2ccc(OCc3nc(-c4cccc(C(=O)OC)c4)oc3C)c(OC)c2)cs1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CCO
Product: CCc1nc(/C=C/c2cn(-c3ccccc3)nc2OCc2ccc(OCc3nc(-c4cccc(C(=O)O)c4)oc3C)c(OC)c2)cs1
Yield: 83.9 %

Procedure:
To a mixture of methyl 3-[4-({4-[({4-[(E)-2-(2-ethyl-1,3-thiazol-4-yl)ethenyl]-1-phenyl-1H-pyrazol-3-yl}oxy)methyl]-2-methoxyphenoxy}methyl)-5-methyl-1,3-oxazol-2-yl]benzoate (0.28 g), tetrahydrofuran (2 mL) and ethanol (2 mL) was added 1N aqueous sodium hydroxide solution (2 mL), and the mixture was heated under reflux for 2 hrs. To the reaction mixture were added 1N hydrochloric acid (2 mL) and water for neutralization, and the precipitated crystals were collected by filtration to give 3-[4-({4-[({4-[(E)-2-(2-ethyl-1,3-thiazol-4-yl)ethenyl]-1-phenyl-1H-pyrazol-3-yl}oxy)methyl]-2-methoxyphenoxy}methyl)-5-methyl-1,3-oxazol-2-yl]benzoic acid as colorless crystals (0.23 g, yield 85%). Recrystallization from tetrahydrofuran-hexane gave colorless prism crystals. melting point: 190-191° C.
Reaction SMILES: C1C([C:7]([C:15]2[CH:16]=[CH:17][C:18](N)=[CH:19][CH:20]=2)=[C:8]2[CH:14]=CC(=N)[CH:10]=[CH:9]2)=CC=C(N)C=1.S(S([O-])=O)([O-])(=O)=O.[Na+].[Na+]>>[CH:20]1[C:15]2=[C:16]3[C:14]4[C:9]([CH:8]=[CH:7]2)=[C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][C:15]2=[CH:7][C:8]=4[CH:9]=[CH:10][C:17]3=[CH:18][CH:19]=1
Reactant: N=C1C=CC(=C(c2ccc(N)cc2)c2ccc(N)cc2)C=C1
Agent: O=S([O-])S(=O)(=O)[O-]
Agent: [Na+]
Product: c1ccc2c(c1)cc1ccc3cccc4ccc2c1c34

Procedure:
Two spots were prepared by manual streaking on a glass plate. The bottom layer of each spot consisted of 0.15 mL of a 4 mg/mL porcine 300 Bloom gelatin solution containing 1.2 mg/mL pararosaniline (PRA) reduced with solid sodium metabisulfite, spread over an area of 1100-1500 mm2. After drying in air for two hours, the second layer, containing the following materials, was deposited. 0.05 mL of fresh rat liver microsomes containing approximately 62 mg/mL protein was added to 0.30 mL of a sodium phosphate buffer solution (pH=7.4) containing 4 mg/mL porcine 300 Bloom gelatin, and admixed with 0.02 mL of a solution containing 3 mM MgCl2, 50 mM tris(hydroxymethyl-)aminomethane buffer (pH=7.4) and 15 mM KCl. To this solution was added 10.5 mg solid reduced nicotinamide adenine dinucleotide phosphate (NADPH). 0.25 mL of this material was deposited over an area of 1300-1700 mm2, completely covering the bottom layer, and was air dried for two hours. Subsequently, 0.05 mL of a 0.5 mg/mL solution of benzo(a)pyrene was applied to one of the spots. Within less than five minutes, violet color began to appear, and was well developed within twenty minutes. The untreated spot, to which no benzo(a)pyrene had been added, remained transparent and clear, with no apparent violet color.
Reaction SMILES: [C:1]([C:4]1[CH:35]=[C:34]([CH3:36])[C:7]([O:8][C:9]2[C:10]3[N:26](CC4C=CC=CC=4)[CH:25]=[CH:24][C:11]=3[N:12]=[C:13]([NH:15][C:16]3[CH:23]=[CH:22][C:19]([C:20]#[N:21])=[CH:18][CH:17]=3)[N:14]=2)=[C:6]([CH3:37])[CH:5]=1)(=[O:3])[CH3:2].[Al+3].[Cl-].[Cl-].[Cl-].C(Cl)(Cl)Cl>ClC1C=CC=CC=1Cl>[C:1]([C:4]1[CH:5]=[C:6]([CH3:37])[C:7]([O:8][C:9]2[C:10]3[NH:26][CH:25]=[CH:24][C:11]=3[N:12]=[C:13]([NH:15][C:16]3[CH:17]=[CH:18][C:19]([C:20]#[N:21])=[CH:22][CH:23]=3)[N:14]=2)=[C:34]([CH3:36])[CH:35]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)c1cc(C)c(Oc2nc(Nc3ccc(C#N)cc3)nc3ccn(Cc4ccccc4)c23)c(C)c1
Agent: [Al+3]
Agent: [Cl-]
Solvent: Clc1ccccc1Cl
Solvent: ClC(Cl)Cl
Product: CC(=O)c1cc(C)c(Oc2nc(Nc3ccc(C#N)cc3)nc3cc[nH]c23)c(C)c1
Temperature: 160 °C
Yield: 79.4 %

Procedure:
To a suspension of 4-(4-(4-acetyl-2,6-dimethylphenoxy)-5-benzyl-5H-pyrrolo[3,2-d]pyrimidin-2-ylamino)benzonitrile (65 mg, 0.13 mmol) in 1,2-dichlorobenzene (5.3 mL) was added AlCl3 (178 mg, 1.3 mmol). The reaction mixture was heated at 160° C. for 1.5 h, after which time the reaction mixture became dark and homogeneous. Upon completion of the reaction, the reaction mixture was cooled, CHCl3 was added, and the mixture was washed with NH4Cl. The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated in vacuo. The crude product was purified by silica gel column chromatography, eluting with hexanes:ethyl acetate (3:1), to give the product as a brown solid (41 mg, 77%).