Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3](=[O:37])[NH:4][C@H:5]([C:9]([N:11]1[CH2:15][C@@H:14]([CH3:16])[CH2:13][C@H:12]1[C:17]1[NH:18][CH:19]=[C:20]([C:22]2[CH:27]=[CH:26][C:25](B3OC(C)(C)C(C)(C)O3)=[CH:24][CH:23]=2)[N:21]=1)=[O:10])[CH:6]([CH3:8])[CH3:7].[C:38]([O:42][C:43]([N:45]1[CH2:50][CH2:49][N:48]([C:51]2[CH:56]=[CH:55][C:54]([C:57](=[O:72])[NH:58][C:59]3[CH:64]=[C:63]([O:65][C:66]([F:69])([F:68])[F:67])[C:62](Br)=[CH:61][C:60]=3[F:71])=[CH:53][N:52]=2)[C@H:47]([CH3:73])[CH2:46]1)=[O:44])([CH3:41])([CH3:40])[CH3:39].O.C(=O)([O-])[O-].[K+].[K+]>C1(C)C=CC=CC=1>[C:38]([O:42][C:43]([N:45]1[CH2:50][CH2:49][N:48]([C:51]2[CH:56]=[CH:55][C:54]([C:57](=[O:72])[NH:58][C:59]3[C:60]([F:71])=[CH:61][C:62]([C:25]4[CH:26]=[CH:27][C:22]([C:20]5[N:21]=[C:17]([C@@H:12]6[CH2:13][C@H:14]([CH3:16])[CH2:15][N:11]6[C:9](=[O:10])[C@@H:5]([NH:4][C:3]([O:2][CH3:1])=[O:37])[CH:6]([CH3:8])[CH3:7])[NH:18][CH:19]=5)=[CH:23][CH:24]=4)=[C:63]([O:65][C:66]([F:69])([F:68])[F:67])[CH:64]=3)=[CH:53][N:52]=2)[C@H:47]([CH3:73])[CH2:46]1)=[O:44])([CH3:41])([CH3:40])[CH3:39]
Reactant: C[C@@H]1CN(C(=O)OC(C)(C)C)CCN1c1ccc(C(=O)Nc2cc(OC(F)(F)F)c(Br)cc2F)cn1
Reactant: COC(=O)N[C@H](C(=O)N1C[C@@H](C)C[C@H]1c1nc(-c2ccc(B3OC(C)(C)C(C)(C)O3)cc2)c[nH]1)C(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: Cc1ccccc1
Product: COC(=O)N[C@H](C(=O)N1C[C@@H](C)C[C@H]1c1nc(-c2ccc(-c3cc(F)c(NC(=O)c4ccc(N5CCN(C(=O)OC(C)(C)C)C[C@H]5C)nc4)cc3OC(F)(F)F)cc2)c[nH]1)C(C)C
Temperature: 90 °C
Yield: 78.1 %

Procedure:
To a solution of [(S)-2-methyl-1-((2S,4S)-4-methyl-2-{4-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-phenyl]-1H-imidazol-2-yl}-pyrrolidine-1-carbonyl)-propyl]-carbamic acid methyl ester (170 mg, 0.33 mmol) and (R)-4-[5-(4-bromo-2-fluoro-5-trifluoromethoxy-phenylcarbamoyl)-pyridin-2-yl]-3-methyl-piperazine-1-carboxylic acid tert-butyl ester (192 mg, 0.33 mmol, Preparation 24) dissolved in toluene (2.1 mL) and water (0.8 mL) was added potassium carbonate (230 mg, 1.67 mmol). The reaction mixture was sparged with nitrogen, Pd(dppf)Cl2CH2Cl2 (25 mg, 0.03 mmol) was added and the reaction mixture was sparged with nitrogen and heated at 90° C. overnight. The reaction mixture was cooled to RT, filtered through a pad of Celite® and silica gel and washed with EtOAc. The filtrate was washed with water and brine to produce a brownish colored oil. The residue was purified by silica gel chromatography (24 g, 40% to 100% EtOAc/hexanes) to produce the title intermediate as a yellowish solid (227 mg, 78% yield). (m/z): [M+H]+ calcd for C44H52F4N8O7 881.39. found 881.4.
Reaction SMILES: [C:1]1([CH:7]([C:9]2[CH:10]=[C:11]3[C:16](=[CH:17][CH:18]=2)[N:15]=[CH:14][CH:13]=[N:12]3)[OH:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N(CC)CC)C.[CH3:26][S:27](Cl)(=[O:29])=[O:28]>ClCCl>[CH3:26][S:27]([O:8][CH:7]([C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)[C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[N:15]=[CH:14][CH:13]=[N:12]2)(=[O:29])=[O:28]
Reactant: CS(=O)(=O)Cl
Reactant: OC(c1ccccc1)c1ccc2nccnc2c1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CS(=O)(=O)OC(c1ccccc1)c1ccc2nccnc2c1
Yield: 100 %

Procedure:
To a stirred and cooled (0° C.) mixture of 12 parts of intermediate 3, namely α-phenyl-6-quinoxalinemethanol, 213 parts of dichloromethane and 15.4 parts of N,N-diethylethanamine was added a solution of 8.8 parts of methanesulfonyl chloride in 26.6 parts of dichloromethane under nitrogen atmosphere. After stirring overnight at room temperature, the reaction mixture was evaporated, yielding 54 parts (100%) of α-phenyl-6-quinoxalinemethanol methanesulfonate (ester) as an oily residue (interm. 4).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:14]=[CH:15][CH:16]=1)[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([NH2:13])=[CH:9][CH:8]=1.CC1(C)[O:25][C:24](=O)[C:21]2([CH2:23][CH2:22]2)[C:20](=[O:27])[O:19]1.C(OCC)C>ClCCl>[F:1][C:2]1[CH:3]=[C:4]([CH:14]=[CH:15][CH:16]=1)[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([N:13]2[CH2:23][CH2:22][CH:21]([C:20]([OH:27])=[O:19])[C:24]2=[O:25])=[CH:9][CH:8]=1
Reactant: Nc1ccc(OCc2cccc(F)c2)cc1
Reactant: CC1(C)OC(=O)C2(CC2)C(=O)O1
Solvent: CCOCC
Solvent: ClCCl
Product: O=C(O)C1CCN(c2ccc(OCc3cccc(F)c3)cc2)C1=O
Yield: 56.6 %

Procedure:
A solution of 561 mg (2.6 mmol) 4-(3-fluoro-benzyloxy)-phenylamine and 448 mg (2.6 mmol) 6,6-dimethyl-5,7-dioxa-spiro[2,5]octane-4,8-dione in 2 ml dichloromethane is refluxed for 16 hours. 5 ml of diethylether is added and the precipitate filtered off to yield 485 mg (57%) of a colorless solid. MS: m/e=330.2 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:21]=[CH:22][CH:23]=1)[O:5][C:6]1[CH:7]=[CH:8][C:9]2[N:10]([CH:12]=[C:13]([NH:15][C:16]([CH:18]3[CH2:20][CH2:19]3)=[O:17])[N:14]=2)[N:11]=1.[C:24]([C:26]1([C:29]2[CH:30]=[C:31]([CH:35]=[CH:36][CH:37]=2)[C:32](O)=[O:33])[CH2:28][CH2:27]1)#[N:25].Cl.CN(C)CCCN=C=NCC.ON1C2C=CC=CC=2N=N1>CN(C)C=O>[C:24]([C:26]1([C:29]2[CH:30]=[C:31]([CH:35]=[CH:36][CH:37]=2)[C:32]([NH:1][C:2]2[CH:23]=[CH:22][CH:21]=[C:4]([O:5][C:6]3[CH:7]=[CH:8][C:9]4[N:10]([CH:12]=[C:13]([NH:15][C:16]([CH:18]5[CH2:20][CH2:19]5)=[O:17])[N:14]=4)[N:11]=3)[CH:3]=2)=[O:33])[CH2:27][CH2:28]1)#[N:25]
Reactant: N#CC1(c2cccc(C(=O)O)c2)CC1
Reactant: Nc1cccc(Oc2ccc3nc(NC(=O)C4CC4)cn3n2)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: N#CC1(c2cccc(C(=O)Nc3cccc(Oc4ccc5nc(NC(=O)C6CC6)cn5n4)c3)c2)CC1
Yield: 46.4 %

Procedure:
Using N-[6-(3-aminophenoxy)imidazo[1,2-b]pyridazin-2-yl]cyclopropanecarboxamide (170 mg, 0.55 mmol), 3-(1-cyanocyclopropyl)benzoic acid (100 mg, 0.55 mmol), N-[3-(dimethylamino)propyl]-N′-ethylcarbodiimide hydrochloride (110 mg, 0.55 mmol), 1-hydroxybenzotriazole (74 mg, 0.55 mmol) and N,N-dimethylformamide (10 mL) as starting materials and in the same manner as in Example 318, the title compound (122 mg, 47%) was obtained as a white powder.
Reaction SMILES: C[O:2][C:3](=O)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[S:10][C:11]1[C:19]2[C:14](=[CH:15][C:16]([N:20]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH3:21])=[CH:17][CH:18]=2)[N:13]([CH2:29][C:30]2[CH:35]=[C:34]([F:36])[CH:33]=[C:32]([F:37])[CH:31]=2)[CH:12]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-]>C(OCC)C.O1CCCC1>[C:25]([O:24][C:22](=[O:23])[N:20]([C:16]1[CH:15]=[C:14]2[C:19]([C:11]([S:10][C:5]3[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=3[CH2:3][OH:2])=[CH:12][N:13]2[CH2:29][C:30]2[CH:35]=[C:34]([F:36])[CH:33]=[C:32]([F:37])[CH:31]=2)=[CH:18][CH:17]=1)[CH3:21])([CH3:28])([CH3:26])[CH3:27]
Reactant: COC(=O)c1ccccc1Sc1cn(Cc2cc(F)cc(F)c2)c2cc(N(C)C(=O)OC(C)(C)C)ccc12
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CCOCC
Product: CN(C(=O)OC(C)(C)C)c1ccc2c(Sc3ccccc3CO)cn(Cc3cc(F)cc(F)c3)c2c1
Reaction time: 1 h
Yield: 95.3 %

Procedure:
i)—A solution of 2-[6-(tert-butoxycarbonyl-methyl-amino)-1-(3,5-difluoro-benzyl)-1H-indol-3-ylsulfanyl]-benzoic acid methyl ester (Example 6, method 1, step ii; 0.163 g, 0.30 mmol) in a mixture of diethyl ether and tetrahydrofuran was treated with lithium aluminium hydride (1 M solution in tetrahydrofuran; 0.3 ml, 0.3 mmol). After 1 h stirring, the reaction mixture was quenched with a saturated aqueous solution of sodium sulfate. The mixture was filtered and the filtrate was concentrated under reduced pressure. Column chromatography (heptane/ethyl acetate 9:1→2:8) afforded [1-(3,5-difluoro-benzyl)-3-(2-hydroxymethyl-phenylsulfanyl)-1H-indol-6-yl]-methyl-carbamic acid tert-butyl ester (0.146 g).
Reaction SMILES: [C:1]1([C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][O:3]1)=[O:2].[Br:11]N1C(=O)CCC1=O.C1(=O)NC(=O)CC1>C(Cl)(Cl)(Cl)Cl>[Br:11][CH:4]1[C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[C:1](=[O:2])[O:3]1
Reactant: O=C1CCC(=O)N1Br
Reactant: O=C1OCc2ccccc21
Agent: O=C1CCC(=O)N1
Solvent: ClC(Cl)(Cl)Cl
Product: O=C1OC(Br)c2ccccc21
Yield: 81 %

Procedure:
Phthalide (10.0 g; 0.075 moles) and N-bromosuccinimide were refluxed in dry carbon tetrachloride (200 ml.) in the presence of a catalytic amount of α-azo-iso-butyronitrile for 3-4 hours. The end of the reaction was indicated by the disappearance of N-bromosuccinimide from the bottom of the reaction vessel and the accumulation of succinimide at the top. The succinimide was removed by filtration and the filtrate concentrated in vacuo to 15-20 ml. Cooling of this concentrate followed by filtration gave 13.0 g. (81% yield) of crude 3-bromophthalide, m.p. 75°-80°, as a white crystalline solid. The product was recrystallised from cyclohexane as colourless plates, m.p. 78°-80° with a 95% recovery.
Reaction SMILES: [H-].[Na+].[Br:3][C:4]1[C:14]([OH:15])=[CH:13][C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:6][C:5]=1[OH:16].CN(C=O)C.I[CH2:23][CH2:24][CH3:25]>O>[Br:3][C:4]1[C:5]([O:16][CH2:23][CH2:24][CH3:25])=[CH:6][C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:13][C:14]=1[OH:15]
Reactant: CCCI
Reactant: CCOC(=O)c1cc(O)c(Br)c(O)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCCOc1cc(C(=O)OCC)cc(O)c1Br
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Sodium hydride (60% oil, 10.1 g) was added to a mixture of ethyl 4-bromo-3,5-dihydroxybenzoate (30.0 g) and DMF (200 mL), and the resultant mixture was stirred at 0° C. for 30 minutes in a nitrogen atmosphere. 1-Iodopropane (11.2 mL) was added to the reaction mixture, and the mixture was stirred at room temperature for 2 hours. Water was added to the reaction mixture, followed by extraction with ethyl acetate. The obtained organic layer was washed with saturated saline and dried over anhydrous magnesium sulfate, and then, the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane/ethyl acetate) to obtain the title compound (14.1 g).
Reaction SMILES: Cl.[NH2:2][C:3]1[CH:19]=[CH:18][C:17]2[C:8]3[NH:9][C:10](=[O:16])[C:11]4[N:12]([CH:13]=[CH:14][N:15]=4)[C:7]=3[CH2:6][C:5]=2[CH:4]=1.[CH3:20][O:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[N:28]=[C:29]=[O:30]>C(N(CC)CC)C>[CH3:20][O:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[NH:28][C:29](=[O:30])[NH:2][C:3]1[CH:19]=[CH:18][C:17]2[C:8]3[NH:9][C:10](=[O:16])[C:11]4[N:12]([CH:13]=[CH:14][N:15]=4)[C:7]=3[CH2:6][C:5]=2[CH:4]=1
Reactant: Nc1ccc2c(c1)Cc1c-2[nH]c(=O)c2nccn12
Reactant: COc1ccccc1N=C=O
Agent: Cl
Solvent: CCN(CC)CC
Product: COc1ccccc1NC(=O)Nc1ccc2c(c1)Cc1c-2[nH]c(=O)c2nccn12
Reaction time: 6 h

Procedure:
The preparation is carried out in the same way as in Example 20, from 1 g of 8-amino-5H,10H-imidazo[1,2-a]indeno[1,2-e]pyrazine-4-one hydrochloride, 1 ml of triethylamine and 0.97 ml of 2-methoxyphenyl isocyanate. After reacting for 6 hours at a temperature in the region of 20° C., the insoluble material is filtered and washed with water and then with isopropyl ether. 0.3 g of 8-[3-(2-methoxyphenyl)ureido]-5H,10H-imidazo[1,2-a]indeno[1,2-e]pyrazine-4-one are thus obtained in the form of a beige solid, the melting point of which is greater than 260° C. (Analysis C21H17N5 O3.0.76H2O, % calculated C: 65.11, H: 4.42, N: 18.08, % found C: 64.8, H: 4.3, N: 18.4).
Reaction SMILES: Br[C:2]1[CH:6]=[CH:5][S:4][CH:3]=1.[CH2:7]([Sn:11](Cl)([CH2:16][CH2:17][CH2:18][CH3:19])[CH2:12][CH2:13][CH2:14][CH3:15])[CH2:8][CH2:9][CH3:10]>C(OCC)C>[CH2:16]([Sn:11]([CH2:7][CH2:8][CH2:9][CH3:10])([CH2:12][CH2:13][CH2:14][CH3:15])[C:2]1[CH:6]=[CH:5][S:4][CH:3]=1)[CH2:17][CH2:18][CH3:19]
Reactant: Brc1ccsc1
Reactant: CCCC[Sn](Cl)(CCCC)CCCC
Solvent: CCOCC
Product: CCCC[Sn](CCCC)(CCCC)c1ccsc1
Reaction time: 1 h
Yield: 74.3 %

Procedure:
5 g of 3-bromothiophene was dissolved in 35 ml of anhydrous ethyl ether, and with stirring under cooling at -70° to -65° C., 19 ml of a 15% n-butyllithium-hexane solution and 10.5 g of tributyltin chloride were added. The mixture was stirred at the above temperature for 1 hour and then at room temperature for 1 hour. The reaction mixture was washed with a saturated aqueous solution of sodium hydrogen carbonate, and then the solvent was evaporated. The residue was purified by distillation under reduced pressure to give 8.5 g (yield 74%) of tributyl(3-thienyl)tin, b.p. 150°-158° C./2 mmHg.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([CH2:7][CH2:8][O:9][C:10]2[CH:19]=[C:18]3[C:13]([C:14](=[O:28])[N:15]([CH2:20][O:21][C:22](=[O:27])[C:23]([CH3:26])([CH3:25])[CH3:24])[CH:16]=[N:17]3)=[CH:12][C:11]=2[O:29][CH3:30])[CH2:3][CH2:2]1.C=O.[C:33](O)(=O)C.C(O)(=O)C.C(O)(=O)C.C(O)(=O)C.[BH4-].[Na+]>CO.C(Cl)Cl>[CH3:33][N:1]1[CH2:6][CH2:5][CH:4]([CH2:7][CH2:8][O:9][C:10]2[CH:19]=[C:18]3[C:13]([C:14](=[O:28])[N:15]([CH2:20][O:21][C:22](=[O:27])[C:23]([CH3:26])([CH3:24])[CH3:25])[CH:16]=[N:17]3)=[CH:12][C:11]=2[O:29][CH3:30])[CH2:3][CH2:2]1
Reactant: CC(=O)O
Reactant: COc1cc2c(=O)n(COC(=O)C(C)(C)C)cnc2cc1OCCC1CCNCC1
Agent: C=O
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: ClCCl
Product: COc1cc2c(=O)n(COC(=O)C(C)(C)C)cnc2cc1OCCC1CCN(C)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 67.6 %

Procedure:
To a solution of 7-(2-(piperidin-4-yl)ethoxy)-6-methoxy-3-((pivaloyloxy)methyl)-3,4-dihydroquinazolin-4-one (6 g, 14.4 mmol) in methanol (30 ml) and methylene chloride (60 ml) was added 37% aqueous formaldehyde (2.2 ml; 28.9 mmol) followed by acetic acid (990 μl; 17.3 mmol). Sodium borohydride triacetate (4.6 g, 21.6 mmol) was added in portions. After stirring for 1 hour at ambient temperature, the volatiles were removed under vacuum and the residue was partitioned between water (50 ml) and methylene chloride (50 ml). The pH of the aqueous layer was adjusted to 7, washed with water, brine, dried (MgSO4) and evaporated. The solid was triturated with ether, filtered, washed with ether and dried under vacuum to give 7-(2-(1-methylpiperidin-4-yl)ethoxy)-6-methoxy-3-((pivaloyloxy)methyl)-3,4-dihydroquinazolin-4-one (4.2 g, 68%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([NH2:9])[C:4]=1[CH3:10].Cl[C:12](Cl)([O:14]C(=O)OC(Cl)(Cl)Cl)Cl>C1(C)C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([N:9]=[C:12]=[O:14])[C:4]=1[CH3:10]
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: COc1cccc(N)c1C
Solvent: Cc1ccccc1
Product: COc1cccc(N=C=O)c1C
Yield: 95.3 %

Procedure:
A mixture of 1-methoxy-2-methyl-3-aminobenzene 15.0 g, triphosgene 48.7 g and toluene 350 mL was stirred with heating under reflux for three hours. The reaction mixtures after standing to cool were concentrated under reduced pressure to give 1-methoxy-3-isocyanato-2-methylbenzene 17.0 g.
Reaction SMILES: Br[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([C:12]#[N:13])[CH:10]=2)[N:5]=[CH:4][CH:3]=1.C(OC(=O)[NH:20][C@@H:21]1[CH2:25][CH2:24][NH:23][CH2:22]1)(C)(C)C>>[NH2:20][C@@H:21]1[CH2:25][CH2:24][N:23]([C:2]2[C:11]3[C:6](=[CH:7][CH:8]=[C:9]([C:12]#[N:13])[CH:10]=3)[N:5]=[CH:4][CH:3]=2)[CH2:22]1
Reactant: CC(C)(C)OC(=O)N[C@@H]1CCNC1
Reactant: N#Cc1ccc2nccc(Br)c2c1
Product: N#Cc1ccc2nccc(N3CC[C@@H](N)C3)c2c1

Procedure:
Starting from 4-bromo-6-cyanoquinoline (commercial) and (R)-pyrrolidin-3-yl-carbamic acid tert-butyl ester (commercial) the title compound was prepared according to procedure F followed by procedure E and was isolated as a yellow solid (330 mg, 65% over two steps).
Reaction SMILES: [I:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1.[CH:10]([Mg]Cl)([CH3:12])[CH3:11]>C(OCC)C.O1CCCC1>[I:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]([OH:7])[CH:10]([CH3:12])[CH3:11])=[CH:4][CH:3]=1
Reactant: O=Cc1ccc(I)cc1
Reactant: CC(C)[Mg]Cl
Solvent: C1CCOC1
Solvent: CCOCC
Product: CC(C)C(O)c1ccc(I)cc1
Temperature: 0 °C
Reaction time: 12 h

Procedure:
2.5 g 4-Iodobenzaldehyde are dissolved in 25 ml diethylether, cooled to 0° C. and treated dropwise with 6.0 ml of a 2 M solution of isopropylmagnesium chloride in tetrahydrofurane. The temperature is slowly raised to room temperature and the mixture is stirred for further 12 hours. Then the reaction is quenched by addition of half saturated aqueous ammonium chloride. The aqueous phase is twice extracted with ethylacetate and the combined organic phases are washed twice with saturated aqueous ammonium chloride and brine. After drying with magnesium sulphate the solvents are evaporated in vacuo and the residue is chromatographed on silica gel (cyclohexane/ethylacetate 100:0 to 40:60).
Reaction SMILES: F[C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[C:8]1[O:9][C:10]2[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:13][C:11]=2[N:12]=1.[Br:21][C:22]1[CH:26]=[CH:25][NH:24][N:23]=1.C(=O)([O-])[O-].[K+].[K+].CN(C=O)C>O>[Br:21][C:22]1[CH:26]=[CH:25][N:24]([C:2]2[CH:3]=[N:4][CH:5]=[CH:6][C:7]=2[C:8]2[O:9][C:10]3[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:13][C:11]=3[N:12]=2)[N:23]=1
Reactant: Brc1cc[nH]n1
Reactant: Fc1cnccc1-c1nc2cc(C(F)(F)F)ccc2o1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: FC(F)(F)c1ccc2oc(-c3ccncc3-n3ccc(Br)n3)nc2c1
Temperature: 50 °C
Yield: 76.4 %

Procedure:
A mixture of 0.28 g of 2-(3-fluoropyridin-4-yl)-5-(trifluoromethyl)benzoxazole, 0.19 g of 3-bromopyrazole, 0.55 g of potassium carbonate and 2 ml of DMF was stirred while heating at 50° C. for 1.5 hours. Then, the reaction mixture was cooled to room temperature. Water was added to the reaction mixture, followed by extraction with ethyl acetate twice. The combined organic layers were washed with a saturated sodium chloride solution, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to give 0.31 g of 2-[3-(3-bromopyrazole-1-yl)pyridin-4-yl]-5-(trifluoromethyl)benzoxazole (hereinafter, referred to as “active compound 59”).
Reaction SMILES: OC1C2C(=CC=CC=2)C(NS(C2SC=CC=2)(=O)=O)=CC=1SCC(O)=O.Cl[C:27]1[C:36](=[O:37])[C:35]2[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=2)/[C:29](=[N:38]/[S:39]([C:42]2[CH:47]=[CH:46][C:45]([C:48]3[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=3)=[CH:44][CH:43]=2)(=[O:41])=[O:40])/[CH:28]=1.[SH:54][CH2:55][C:56]([O:58][CH2:59][CH3:60])=[O:57]>>[C:45]1([C:48]2[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=2)[CH:46]=[CH:47][C:42]([S:39]([NH:38][C:29]2[C:30]3[C:35](=[CH:34][CH:33]=[CH:32][CH:31]=3)[C:36]([OH:37])=[C:27]([S:54][CH2:55][C:56]([O:58][CH2:59][CH3:60])=[O:57])[CH:28]=2)(=[O:41])=[O:40])=[CH:43][CH:44]=1
Reactant: CCOC(=O)CS
Reactant: O=C1C(Cl)=C/C(=N\S(=O)(=O)c2ccc(-c3ccccc3)cc2)c2ccccc21
Agent: O=C(O)CSc1cc(NS(=O)(=O)c2cccs2)c2ccccc2c1O
Product: CCOC(=O)CSc1cc(NS(=O)(=O)c2ccc(-c3ccccc3)cc2)c2ccccc2c1O

Procedure:
5.2.60 Ethyl 2-(4-(biphenyl-4-ylsulfonamido)-1-hydroxynaphthalen-2-ylthio)acetate (14r) was prepared according to the procedure of procedure B for 10a except using (E)-N-(3-chloro-4-oxonaphthalen-1(4H)-ylidene)biphenyl-4-sulfonamide (12b) and ethyl mercapto-acetate, which afforded the title compound 71.5 mg (85.5%) as an off-white solid, m.p.: 166-168° C.
Reaction SMILES: [CH3:1][O:2][N:3]=[C:4]([C:8]1[S:9][C:10]([CH3:13])=[N:11][N:12]=1)[C:5]([OH:7])=O.[NH2:14][CH:15]1[C:32](=[O:33])[N:17]2[C:18]([C:29]([OH:31])=[O:30])=[C:19]([CH2:22][S:23][C:24]3[S:25][CH:26]=[N:27][N:28]=3)[CH2:20][S:21][C@H:16]12>>[CH3:1][O:2][N:3]=[C:4]([C:8]1[S:9][C:10]([CH3:13])=[N:11][N:12]=1)[C:5]([NH:14][CH:15]1[C:32](=[O:33])[N:17]2[C:18]([C:29]([OH:31])=[O:30])=[C:19]([CH2:22][S:23][C:24]3[S:25][CH:26]=[N:27][N:28]=3)[CH2:20][S:21][C@H:16]12)=[O:7]
Reactant: CON=C(C(=O)O)c1nnc(C)s1
Reactant: NC1C(=O)N2C(C(=O)O)=C(CSc3nncs3)CS[C@H]12
Product: CON=C(C(=O)NC1C(=O)N2C(C(=O)O)=C(CSc3nncs3)CS[C@H]12)c1nnc(C)s1
Yield: 42.9 %

Procedure:
2-Methoxyimino-2-(5-methyl-1,3,4-thiadiazol-2-yl)acetic acid (syn isomer) (0.21 g.) and 7-amino-3-(1,3,4-thiadiazol-2-yl)thiomethyl-3-cephem-4-carboxylic acid (0.41 g.) were reacted according to similar manners to those of Examples 12 and 15 to give 7-[2-methoxyimino-2-(5-methyl-1,3,4-thiadiazol-2-yl)acetamido]-3-(1,3,4-thiadiazol-2-yl)thiomethyl-3-cephem-4-carboxylic acid (syn isomer) (0.23 g.), mp 175° to 178° C. (dec.).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]([F:11])([F:10])[F:9].C([Li])CCC.C([O:20][B:21](OC(C)C)[O:22]C(C)C)(C)C>C1COCC1>[F:9][C:8]([F:11])([F:10])[C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[B:21]([OH:22])[OH:20]
Reactant: CC(C)OB(OC(C)C)OC(C)C
Reactant: FC(F)(F)c1ccccc1Br
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: OB(O)c1ccccc1C(F)(F)F
Reaction time: 1 h

Procedure:
To a stirred solution of 2-Bromo-(trifluoromethyl)benzene (18.2 mL, 0.133 moles) in dry THF (150 mL) at -78° was added dropwise over a 25 min period n-butyllithium (60 mL of 2.5M in hexanes, 0.147 moles). The solution was stirred at -78° for 1 hour, and then a solution of triisopropyborate (37 mL) in THF (50 mL) was added dropwise over 30 min at -78°. The cooling bath was removed and the reaction mixture was stirred at ambient temperature overnight. The solution was then cooled to 0°, and made acidic with 1N aqueous hydrochloric acid. The resulting mixture was extracted twice with ether, and the combined extracts were extracted twice with 1N sodium hydroxide. The combined aqueous extracts were acidified to pH 2 with 1N hydrochloric acid and extracted twice with ether. The combined extracts were dried over magnesium chloride, and concentrated in vacuo to a white solid (20.95 g). Two recrystallizations from water afforded the title compound as a colorless solid (11.35 g).
Reaction SMILES: [Si]([O:8][CH2:9][C:10]1[S:11][S:12][C:13]([CH2:16][O:17][C:18](=[O:25])[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[CH:14][CH:15]=1)(C(C)(C)C)(C)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC.C(O)(=O)C>C1COCC1>[C:18]([O:17][CH2:16][C:13]1[S:12][S:11][C:10]([CH2:9][OH:8])=[CH:15][CH:14]=1)(=[O:25])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: CC(C)(C)[Si](C)(C)OCC1=CC=C(COC(=O)c2ccccc2)SS1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: O=C(OCC1=CC=C(CO)SS1)c1ccccc1
Reaction time: 2.5 h
Yield: 52.9 %

Procedure:
To a stirred solution of the 3-[(tert-butyldimethysilyloxy)methyl]-6-(benzoyloxymethyl)-1,2-dithiin (250 mg, 0.63 mg) obtained above in THF (0.2-0.3M) was added a premixed solution of tetrabutylammonium fluoride (TBAF, 800-1250 mol % of a 1M solution in THF) and acetic acid (1.75-2:1, v/v, 1M TBAF/HOAc) at room temperature. The mixture was stired for 1-4 h. The solvent was concentrated and the residue was partitioned between water (40 mL) and EtOAc (60 mL). The organic phase was washed with dilute aqueous NaHCO3 (50 mL), water (50 mL), dried (Na2SO4), and concentrated to a small volume. Purification was done by chromatography, eluting with EtOAc/hexane mixtures, to yield 94 mg of the title compound (53.4%); 1H NMR (CDCl3) δ8.08-8.05 (m, 2 H), 7.57 (dd, J=7.2, 8.0, 1 H), 7.48-7.39 (m, 2 H), 6.47 (d, J=6.0, 1 H), 6.40 (d, J=6.0, 1 H), 4.96 (s, 2 H), 4.28 (s, 2 H), 2.2 (bs); MS 280.0 (M+).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:12][CH3:13])=[CH:9][CH:10]=2)[N:5]=[C:4]([C:14]([F:23])([F:22])[C:15]2[CH:20]=[CH:19][C:18]([F:21])=[CH:17][N:16]=2)[N:3]=1.[NH2:24][C:25]1[CH:29]=[C:28]([CH3:30])[N:27]([C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[N:26]=1.CCN(C(C)C)C(C)C>CN(C=O)C>[F:22][C:14]([F:23])([C:15]1[CH:20]=[CH:19][C:18]([F:21])=[CH:17][N:16]=1)[C:4]1[N:3]=[C:2]([NH:24][C:25]2[CH:29]=[C:28]([CH3:30])[N:27]([C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[N:26]=2)[C:11]2[C:6](=[CH:7][C:8]([O:12][CH3:13])=[CH:9][CH:10]=2)[N:5]=1
Reactant: Cc1cc(N)nn1C(=O)OC(C)(C)C
Reactant: COc1ccc2c(Cl)nc(C(F)(F)c3ccc(F)cn3)nc2c1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COc1ccc2c(Nc3cc(C)n(C(=O)OC(C)(C)C)n3)nc(C(F)(F)c3ccc(F)cn3)nc2c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 22.8 %

Procedure:
To 4-chloro-2-(difluoro(5-fluoropyridin-2-yl)methyl)-7-methoxyquinazoline (355 mg, 0.91 mmol) in DMF (5.0 mL) at rt were added tert-butyl 3-amino-5-methyl-1H-pyrazole-1-carboxylate (0.448 g, 2.27 mmol) and DIEA (0.40 mL, 2.3 mmol), and the mixture was stirred at rt for 3 h. The mixture was purified by preparative reverse-phase HPLC using TFA as a modifier, and the fractions containing the desired product were neutralized with saturated aq NaHCO3 and extracted with EtOAc (100 mL). The organic layer was separated, washed with brine (2×10 mL), dried over MgSO4, filtered, and concentrated under reduced pressure to afford tert-butyl 3-(2-(difluoro(5-fluoropyridin-2-yl)methyl)-7-methoxyquinazolin-4-ylamino)-5-methyl-1H-pyrazole-1-carboxylate as a clear oil (104 mg).