Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C:8]1[N:9]=[C:10]([CH3:26])[C:11]2[CH2:17][CH2:16][N:15](CC3C=CC=CC=3)[CH2:14][CH2:13][C:12]=2[N:25]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>[Pd]>[CH2:1]([C:8]1[N:9]=[C:10]([CH3:26])[C:11]2[CH2:17][CH2:16][NH:15][CH2:14][CH2:13][C:12]=2[N:25]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cc1nc(Cc2ccccc2)nc2c1CCN(Cc1ccccc1)CC2
Agent: [Pd]
Product: Cc1nc(Cc2ccccc2)nc2c1CCNCC2
Yield: 90 %

Procedure:
The title compound was prepared according to a similar method to that of Example 64, except that 10% palladium on carbon was used, starting from 2,7-dibenzyl-4-methyl-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepine of Preparation 39, and obtained as a pale yellow solid in 90% yield (44 mg).
Reaction SMILES: C([O:4][CH2:5][C:6]([NH:35]C(=O)C)([CH2:30][O:31]C(=O)C)[CH2:7][CH2:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:20]=[CH:19][C:18]([O:21][C:22]3[CH:27]=[CH:26][C:25]([CH3:28])=[CH:24][CH:23]=3)=[CH:17][C:16]=2[F:29])=[CH:11][CH:10]=1)(=O)C.[OH-].[Li+]>CO>[NH2:35][C:6]([CH2:7][CH2:8][C:9]1[CH:10]=[CH:11][C:12]([C:15]2[CH:20]=[CH:19][C:18]([O:21][C:22]3[CH:23]=[CH:24][C:25]([CH3:28])=[CH:26][CH:27]=3)=[CH:17][C:16]=2[F:29])=[CH:13][CH:14]=1)([CH2:30][OH:31])[CH2:5][OH:4]
Reactant: CC(=O)NC(CCc1ccc(-c2ccc(Oc3ccc(C)cc3)cc2F)cc1)(COC(C)=O)COC(C)=O
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Product: Cc1ccc(Oc2ccc(-c3ccc(CCC(N)(CO)CO)cc3)c(F)c2)cc1
Reaction time: 2 h
Yield: 29.9 %

Procedure:
N-{1,1-Bis(acetoxymethyl)-3-[2′-fluoro-4′-(4-methylphenoxy)biphenyl-4-yl]propyl}acetamide (0.26 g) was dissolved in methanol (10 mL), 1M aqueous lithium hydroxide solution (10 mL) was added, and the mixture was refluxed with stirring for 2 hr. The reaction mixture was concentrated, and the precipitated crystals were collected by filtration. The crude crystals were purified by preparative HPLC to give the title compound (59 mg) as white crystals.
Reaction SMILES: [O:1]1[CH2:5][CH2:4][CH2:3][C@@H:2]1[C:6]([OH:8])=O.CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)[N:28]=[N:27]C=2C=1.O.NN>ClCCl>[O:1]1[CH2:5][CH2:4][CH2:3][C@@H:2]1[C:6]([NH:27][NH2:28])=[O:8]
Reactant: On1nnc2ccccc21
Reactant: O=C(O)[C@H]1CCCO1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: NN
Solvent: O
Solvent: ClCCl
Product: NNC(=O)[C@H]1CCCO1
Temperature: 25 °C
Reaction time: 8 h
Yield: 59.6 %

Procedure:
To a round-bottom flask was added a solution of (R)-tetrahydrofuran-2-carboxylic acid (3.00 g, 25.8 mmol, 1.00 equiv) in dichloromethane (60 mL). EDC.HCl (7.37 g, 38.5 mmol, 1.50 equiv), HOBt (5.24 g, 38.8 mmol, 1.50 equiv), and hydrazine hydrate (2.60 g, 51.9 mmol, 2.00 equiv) were added to the reaction. The resulting solution was stirred overnight at 25° C. The solids were removed with filtration. The filtrate was concentrated in vacuo to yield 2.00 g (59%) of (R)-tetrahydrofuran-2-carbohydrazide as a yellow oil.
Reaction SMILES: O.[NH2:2][NH2:3].[CH2:4]([O:6][C:7](=[O:21])[C:8](=O)[CH2:9][C:10](=O)[CH2:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[CH3:5]>CCO>[CH2:4]([O:6][C:7]([C:8]1[CH:9]=[C:10]([CH2:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[NH:3][N:2]=1)=[O:21])[CH3:5]
Reactant: NN
Reactant: CCOC(=O)C(=O)CC(=O)CCc1ccccc1
Solvent: O
Solvent: CCO
Product: CCOC(=O)c1cc(CCc2ccccc2)[nH]n1
Yield: 54.5 %

Procedure:
Hydrazine hydrate (0.109 mL, 2.24 mmol) was added to a stirring room temperature solution of 19 (0.5570 g, 2.24 mmol) in EtOH (2.2 mL, 1 M) under N2. The reaction was then heated to reflux until judged complete by HPLC. The reaction was concentrated and purified by silica gel chromatography (Combiflash column, 70:30:2 Hexanes: CH2Cl2:2N NH3 in EtOH). Only pure fractions were combined and concentrated to obtain 0.2983 g (54.4%) of 20. 1H (CDCl3, 400 MHz): δ 11.7 (1H, broad s), 7.30-7.11 (5H, m), 6.60 (1H, s), 4.32 (2H, q, J=7.1 Hz), 3.07-2.92 (4H, m), 1.31 (3H, t, J=7.1 Hz) ppm. Partial 13C (CDCl3, 100 MHz): δ 162.13, 147.42, 140.97, 128.72, 128.59, 126.48, 106.79, 61.16, 35.63, 28.18, 14.47 ppm. DEPT (CDCl3, 100 MHz): CH3 carbons: 14.47; CH2 carbons: 61.16, 35.63, 28.18; CH carbons: 128.72, 128.59, 126.48, 106.79 ppm. HPLC: 9.299 min.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH:12]=[C:11]([C:14]2[CH:19]=[CH:18][C:17](B3OCC(C)(C)CO3)=[C:16]([F:28])[CH:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl[C:30]1[N:35]=[CH:34][C:33]([F:36])=[CH:32][N:31]=1.C(=O)([O-])[O-].[Na+].[Na+].C1(C)C=CC=CC=1>[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(O)C>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH:12]=[C:11]([C:14]2[CH:19]=[CH:18][C:17]([C:30]3[N:35]=[CH:34][C:33]([F:36])=[CH:32][N:31]=3)=[C:16]([F:28])[CH:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:2])([CH3:4])[CH3:3]
Reactant: Fc1cnc(Cl)nc1
Reactant: CC1(C)COB(c2ccc(C3=CCN(C(=O)OC(C)(C)C)CC3)cc2F)OC1
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)N1CC=C(c2ccc(-c3ncc(F)cn3)c(F)c2)CC1
Reaction time: 8 h

Procedure:
4-[4-(5,5-Dimethyl-[1,3,2]dioxaborinan-2-yl)-3-fluoro-phenyl]-3,6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester (19AB)(1.55 g, 3.98 mmol, 1 equiv), 2-Chloro-5-fluoro-pyrimidine (20AB)(634 mg, 591 uL, 4.78 mmol, 1.2 equiv), and 2M sodium carbonate (9.95 mL) were added in a pressure vessel (350 mL) and a (1v:1v) mixture of toluene and ethanol (25 mL: 25 mL) was added. The mixture was then bubbled with nitrogen gas for about 10 minutes. Tetrakis(triphenylphosphine) palladium (0) (462 mg, 0.4 mmol, 0.1 equiv) was added to the mixture. The reaction vessel was tightly capped, placed in an oil bath at 90° C., and stirred overnight.
Reaction SMILES: [N+:1]([C:4]1[CH:15]=[CH:14][C:7]([CH2:8][C:9]2[O:10][CH:11]=[CH:12][N:13]=2)=[CH:6][CH:5]=1)([O-])=O.[Sn](Cl)(Cl)(Cl)Cl>C(O)C.[OH-].[Na+]>[O:10]1[CH:11]=[CH:12][N:13]=[C:9]1[CH2:8][C:7]1[CH:14]=[CH:15][C:4]([NH2:1])=[CH:5][CH:6]=1
Reactant: O=[N+]([O-])c1ccc(Cc2ncco2)cc1
Agent: Cl[Sn](Cl)(Cl)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Nc1ccc(Cc2ncco2)cc1
Temperature: 50 °C
Reaction time: 3 h
Yield: 73.9 %

Procedure:
To a solution of 2-(4-nitrobenzyl)oxazole (0.108 g, 0.59 mmol) in ethanol (3 mL) was added tin chloride (0.531 g, 2.35 mmol) and the mixture was stirred at 50° C. for 3 h. After this time, the reaction mixture was cooled, diluted with 1M sodium hydroxide, and extracted with ethyl acetate. The combined organic layer was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to afford the title compound (0.076 g, 63%) as a yellow oil. MW=174.20. 1H NMR (CD3OD, 500 MHz) δ 7.78 (d, J=0.8 Hz, 1H), 7.05 (d, J=0.8 Hz, 1H), 7.02-6.97 (m, 2H), 6.69-6.65 (m, 2H), 3.97 (s, 2H); APCI MS m/z 175 [M+H]+.
Reaction SMILES: Cl[C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH3:11])=[C:4]([NH:12][C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][N:14]=2)[N:3]=1.O.[NH2:21][NH2:22]>>[Cl:19][C:16]1[CH:17]=[CH:18][C:13]([NH:12][C:4]2[N:3]=[C:2]([NH:21][NH2:22])[N:10]=[C:9]3[C:5]=2[N:6]=[CH:7][N:8]3[CH3:11])=[N:14][CH:15]=1
Reactant: Cn1cnc2c(Nc3ccc(Cl)cn3)nc(Cl)nc21
Reactant: NN
Solvent: O
Product: Cn1cnc2c(Nc3ccc(Cl)cn3)nc(NN)nc21

Procedure:
Was prepared according to Example 8 from (2-chloro-9-methyl-9H-purin-6-yl)-(5-chloro-pyridin-2-yl)-amine and hydrazine monohydrate.
Reaction SMILES: Cl[CH2:2][CH2:3][N:4]1[C:13](=[O:14])[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([Cl:15])[CH:11]=2)[N:6]=[C:5]1Cl.C(O)C.[CH2:20]([NH2:23])[CH:21]=[CH2:22].CCCCC>CC(N(C)C)=O.O>[CH2:20]([N:23]1[C:5]2=[N:6][C:7]3[C:12]([C:13](=[O:14])[N:4]2[CH2:3][CH2:2]1)=[CH:11][C:10]([Cl:15])=[CH:9][CH:8]=3)[CH:21]=[CH2:22]
Reactant: C=CCN
Reactant: O=c1c2cc(Cl)ccc2nc(Cl)n1CCCl
Solvent: O
Solvent: CC(=O)N(C)C
Solvent: CCCCC
Product: C=CCN1CCn2c1nc1ccc(Cl)cc1c2=O

Procedure:
A solution of 1.0 g. of 3-(2-chloroethyl)-2,6-dichloro-3,4-dihydroquinazolin-4-one in 50 ml. of ethanol is combined with a solution of 0.62 g. of allylamine in 10 ml of dimethylacetamide and the resulting mixture heated to reflux with dimethylacetamide being added as required to dissolve any remaining solid starting material. After heating at reflux for about 5 hours the resulting reaction mixture is allowed to cool, the mixture stripped down to a dimethylacetamide slurry and pentane added. A white solid form which dissolves upon addition of water after which the organic layer is dried and concentrated in vacuo to a solid residue which is washed with pentane to obtain 1-allyl-7-chloro-2,3-dihydro-imidazo[2,1-b]quinazolin-5(1H)-one, m.p. 91°-93° C.
Reaction SMILES: [Si:1]([O:8][CH2:9][C@@H:10]([N:16]([CH3:29])[C:17]([NH:19][CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([F:27])[C:22]=1[Cl:28])=[O:18])[CH2:11][CH2:12][C:13](O)=[O:14])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[C:54]([N:61]1[CH2:66][CH2:65][NH:64][CH2:63][CH2:62]1)([O:56][C:57]([CH3:60])([CH3:59])[CH3:58])=[O:55].CCN(C(C)C)C(C)C>CN(C=O)C.[Cl-].[Na+].O.CCOCC>[Si:1]([O:8][CH2:9][C@@H:10]([N:16]([CH3:29])[C:17]([NH:19][CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([F:27])[C:22]=1[Cl:28])=[O:18])[CH2:11][CH2:12][C:13]([N:64]1[CH2:63][CH2:62][N:61]([C:54]([O:56][C:57]([CH3:60])([CH3:59])[CH3:58])=[O:55])[CH2:66][CH2:65]1)=[O:14])([C:4]([CH3:5])([CH3:7])[CH3:6])([CH3:2])[CH3:3]
Reactant: CN(C(=O)NCc1cccc(F)c1Cl)[C@@H](CCC(=O)O)CO[Si](C)(C)C(C)(C)C
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: [Cl-]
Solvent: CCOCC
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: CN(C(=O)NCc1cccc(F)c1Cl)[C@@H](CCC(=O)N1CCN(C(=O)OC(C)(C)C)CC1)CO[Si](C)(C)C(C)(C)C
Reaction time: 0.25 h
Yield: 68.3 %

Procedure:
To a solution of (S)-5-(tert-butyldimethylsilyloxy)-4-(3-(2-chloro-3-fluorobenzyl)-1-methylureido)pentanoic acid (4.46 g, 10 mmol, 1.0 equiv.) in DMF (50 mL), was added HBTU (5.69 g, 15 mmol, 1.5 equiv.), 1-N-Boc-piperazine (2.79 g, 15 mmol, 1.5 equiv.) and DIEA (5.21 mL, 30 mmol, 3.0 equiv.) in sequence. The reaction was completed in 15 min. Ether (100 mL) and brine (100 mL) were added to the reaction mixture. The organic layer was dried and concentrated. The residue was purified on silica gel column using a mixture of hexane and EtOAc to give (S)-tert-butyl 4-(5-(tert-butyldimethylsilyloxy)-4-(3-(2-chloro-3-fluorobenzyl)-1-methylureido)pentanoyl)piperazine-1-carboxylate (4.2 g, 68%). LRMS (M+H+) m/z 615.2.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[N:10]=[C:11]([C:23]2[CH:28]=[CH:27][N:26]=[C:25]([NH:29][C:30](=[O:32])[CH3:31])[CH:24]=2)[S:12][C:13]=1[C:14]1[NH:15][CH:16]=[C:17]([C:19](F)(F)F)[N:18]=1.O.[OH-].[NH4+:35]>>[C:19]([C:17]1[N:18]=[C:14]([C:13]2[S:12][C:11]([C:23]3[CH:28]=[CH:27][N:26]=[C:25]([NH:29][C:30](=[O:32])[CH3:31])[CH:24]=3)=[N:10][C:9]=2[C:3]2[CH:4]=[CH:5][C:6]([Cl:8])=[CH:7][C:2]=2[Cl:1])[NH:15][CH:16]=1)#[N:35]
Reactant: CC(=O)Nc1cc(-c2nc(-c3ccc(Cl)cc3Cl)c(-c3nc(C(F)(F)F)c[nH]3)s2)ccn1
Reactant: [NH4+]
Agent: [OH-]
Solvent: O
Product: CC(=O)Nc1cc(-c2nc(-c3ccc(Cl)cc3Cl)c(-c3nc(C#N)c[nH]3)s2)ccn1
Temperature: 60 °C
Reaction time: 6 h
Yield: 20 %

Procedure:
N-(4-{4-(2,4-dichlorophenyl)-5-[4-(trifluoromethyl)-1H-imidazol-2-yl]-1,3-thiazol-2-yl}pyridin-2-yl)acetamide (20 mg, 0.04 mmol) was taken up in 1 M of Ammonium hydroxide in water (2 mL, 3 mmol) and the mixture was stirred at 60° C. for 6 h. At that time, LCMS indicated complete conversion. Reaction mixture was evaporated under reduced pressure and was purified using preparative HPLC to give 0.004 g of the title compound (20%). LCMS: (FA) ES+ 455, 457. 1H NMR (400 MHz, d6-DMSO) 8.70 (s, 1H), 8.34 (dd, J=5.26, 0.71 Hz, 1H), 7.65 (dd, J=5.26, 1.60 Hz, 1H), 7.55-7.46 (m, 3H), 7.39 (dd, J=8.28, 2.06 Hz, 1H), 2.24 (s, 3H).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][CH:15]=1)[NH:12][CH:11]([C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([NH2:22])[CH:17]=1)[C:10]([CH3:24])([CH3:23])[CH2:9]2)=[O:5])[CH3:2].N1C=CC=CC=1.Cl.[CH3:32][N:33]1[CH2:38][CH2:37][N:36]([C:39](Cl)=[O:40])[CH2:35][CH2:34]1>ClCCl>[CH2:1]([O:3][C:4]([C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][CH:15]=1)[NH:12][CH:11]([C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([NH:22][C:39]([N:36]3[CH2:37][CH2:38][N:33]([CH3:32])[CH2:34][CH2:35]3)=[O:40])[CH:17]=1)[C:10]([CH3:23])([CH3:24])[CH2:9]2)=[O:5])[CH3:2]
Reactant: CN1CCN(C(=O)Cl)CC1
Reactant: CCOC(=O)c1ccc2c(c1)CC(C)(C)C(c1cccc(N)c1)N2
Agent: Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCOC(=O)c1ccc2c(c1)CC(C)(C)C(c1cccc(NC(=O)N3CCN(C)CC3)c1)N2
Temperature: 25 °C
Reaction time: 5 h
Yield: 99.9 %

Procedure:
To a solution of 2-(3-amino-phenyl)-3,3-dimethyl-1,2,3,4-tetrahydro-quinoline-6-carboxylic acid ethyl ester (441 mg, 1.36 mmol) in dichloromethane (5 mL) and pyridine (1.1 mL, 13.6 mmol) was added 4-methyl-piperazine-1-carbonyl chloride hydrochloride (297 mg, 1.49 mmol) at 0° C. The reaction mixture was stirred at 25° C. for 5 h. Then the reaction mixture was extracted with dichloromethane (2×50 mL), washed with water, dried over anhydrous sodium sulfate and concentrated in vacuo to afford 3,3-dimethyl-2-{3-[(4-methyl-piperazine-1-carbonyl)-amino]-phenyl}-1,2,3,4-tetrahydro-quinoline-6-carboxylic acid ethyl ester (612 mg, 100%) as a brown oil which was used for next step without further purification: LC/MS m/e calcd for C26H34N4O3 (M+H)+: 451.59, observed: 451.2.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[CH:5]2.[CH3:11][NH:12][S:13]([CH:16]=[CH2:17])(=[O:15])=[O:14].C(N(CC)CC)C>C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C.C(#N)C>[NH:7]1[C:8]2[C:4](=[CH:3][C:2](/[CH:17]=[CH:16]/[S:13]([NH:12][CH3:11])(=[O:15])=[O:14])=[CH:10][CH:9]=2)[CH:5]=[CH:6]1
Reactant: C=CS(=O)(=O)NC
Reactant: Brc1ccc2[nH]ccc2c1
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CNS(=O)(=O)/C=C/c1ccc2[nH]ccc2c1
Yield: 28.9 %

Procedure:
A mixture of 5-bromoindole (6.6 g), N-methylethenesulphonamide (5.1 g) palladium (II) acetate (75 mg), tri-o-tolylphosphine (0.2 g), triethylamine (12 ml), and acetonitrile (5 ml) was heated at 100° in an autoclave for 3 h. The reaction mixture was cooled and partitioned between hydrochloric acid (1N, 300 ml) and ethyl acetate (2×150 ml). The combined extracts were dried, (Na2SO4) and evaporated in vacuo to give an oil which was purified by `flash` chromatography (Q, 7 cm dia. col.) to give the title compound as a solid (2.3 g) m.p. 164√-166°.
Reaction SMILES: [Cl-].[Cl-].[Cl-].[Al+3].[C:5]1([CH3:21])[CH:10]=[C:9]([CH3:11])[CH:8]=[C:7]([CH3:12])[C:6]=1[C:13]1[N:18]=[C:17](Cl)[N:16]=[C:15](Cl)[N:14]=1.[C:22]1([CH:29]=[CH:28][CH:27]=[C:25]([OH:26])[CH:24]=1)[OH:23].Cl>S1(CCCC1)(=O)=O>[C:5]1([CH3:21])[CH:10]=[C:9]([CH3:11])[CH:8]=[C:7]([CH3:12])[C:6]=1[C:13]1[N:18]=[C:17]([C:27]2[CH:28]=[CH:29][C:22]([OH:23])=[CH:24][C:25]=2[OH:26])[N:16]=[C:15]([C:27]2[CH:28]=[CH:29][C:22]([OH:23])=[CH:24][C:25]=2[OH:26])[N:14]=1
Reactant: Oc1cccc(O)c1
Reactant: Cc1cc(C)c(-c2nc(Cl)nc(Cl)n2)c(C)c1
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: O=S1(=O)CCCC1
Product: Cc1cc(C)c(-c2nc(-c3ccc(O)cc3O)nc(-c3ccc(O)cc3O)n2)c(C)c1
Reaction time: 14 h
Yield: 84.6 %

Procedure:
148.7 g (1.21 mol) of anhydrous aluminium trichloride (purity 98%) are added with stirring to a suspension of 130.0 g (0.485 mol) of 2-mesityl-4,6-dichloro-1,3,5-triazine (compound 1a) in 300 ml of petroleum ether (boiling range 110°-140° C.) and 385 ml of sulfolane. During this addition, the mixture warms to 45° C. A solution of 133.5 g (1.21 mol) of resorcinol (purity 98%) in 155 ml of sulfolane is added over the course of 45 minutes. The mixture is warmed at 80°-85° C. for 5 hours 30 minutes with evolution of HCl. The upper phase (petroleum ether) is removed, and the lower, viscous phase is transferred while hot into a stirred mixture of 2.1 l of methanol and 2.1 l of water. After the mixture has been stirred for 14 hours, the solid is filtered off, stirred for 1 hour in 2.2 l of 1 molar HCl and filtered off again. The filter cake is suspended in 1000 ml of water, stirred for 30 minutes and re-filtered. This operation is repeated twice. The filter cake is dried for 24 hours at 80° C. and a pressure of 60 mmHg (8000 Pa), giving 170.5 g of the title product (compound 1b) of the formula ##STR104## of m.p. 230°-234° C.
Reaction SMILES: [C:1]([O:8]CC)(=[O:7])[C:2](OCC)=O.[K].[N+:12]([C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([CH3:21])[C:16]=1C)([O-:14])=[O:13]>CCOCC>[CH3:21][C:17]1[CH:18]=[CH:19][CH:20]=[C:15]([N+:12]([O-:14])=[O:13])[C:16]=1[CH2:2][C:1]([OH:8])=[O:7]
Reactant: Cc1cccc([N+](=O)[O-])c1C
Reactant: CCOC(=O)C(=O)OCC
Agent: [K]
Solvent: CCOCC
Product: Cc1cccc([N+](=O)[O-])c1CC(=O)O
Yield: 45 %

Procedure:
Diethyl oxalate (30 mL) in 20 mL dry ether was added with stirring to 19 g potassium eethoxide suspended in 50 mL of dry ether. The mixture was cooled in an ice bath and 20 mL of 3-nitro-o-xylene in 20 mL of dry ether was slowly added. The thick dark red mixture was heated to reflux for 0.5 hr, concentrated to a dark red solid, and treated with 10% sodium hydroxide until almost all of the solid dissolved. The dark red mixture was treated with 30% hydrogen peroxide until the red color changed to yellow. The mixture was treated alternatively with 10% sodium hydroxide and 30% hydrogen peroxide until the dark red color was no longer present. The solid was filtered and the filtrate acidified with 6 N hydrochloric acid. The resulting precipitate was collected by vacuum filtration, washed with water, and dried under vacuum to give 9.8 g (45% yield) of 2-methyl-6-nitrophenylacetic acid as an off-white solid. The solid was hydrogenated in methanol over 10% palladium on carbon to give 9.04 g of 4-methyl-2-oxindole as a white solid.
Reaction SMILES: Cl[C:2]([O:4][CH:5]([CH3:16])[CH2:6][C:7]([CH3:15])([O:9][O:10][C:11]([CH3:14])([CH3:13])[CH3:12])[CH3:8])=[O:3].[NH2:17][NH2:18]>>[C:2]([O:4][CH:5]([CH3:16])[CH2:6][C:7]([CH3:15])([O:9][O:10][C:11]([CH3:14])([CH3:13])[CH3:12])[CH3:8])(=[O:3])[NH:17][NH2:18]
Reactant: NN
Reactant: CC(CC(C)(C)OOC(C)(C)C)OC(=O)Cl
Product: CC(CC(C)(C)OOC(C)(C)C)OC(=O)NN

Procedure:
1,3-Dimethyl-3-(t-butylperoxy)butyl carbazate was prepared by reacting 1,3-dimethyl-3-(t-butylperoxy)butyl chloroformate with 11 molar excess of 54% aqueous hydrazine.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([NH:9][C:10](=[O:17])[CH2:11][CH:12]2[CH2:16][CH2:15][CH2:14][CH2:13]2)=[C:4]([CH3:18])[CH:3]=1.[F:19][C:20]([F:30])([F:29])[C:21]1[N:26]=[CH:25][C:24]([CH:27]=O)=[CH:23][CH:22]=1>C(#N)C>[CH:12]1([CH2:11][C:10]([NH:9][C:5]2[C:4]([CH3:18])=[CH:3][C:2]([NH:1][CH2:27][C:24]3[CH:25]=[N:26][C:21]([C:20]([F:30])([F:19])[F:29])=[CH:22][CH:23]=3)=[CH:7][C:6]=2[CH3:8])=[O:17])[CH2:16][CH2:15][CH2:14][CH2:13]1
Reactant: Cc1cc(N)cc(C)c1NC(=O)CC1CCCC1
Reactant: O=Cc1ccc(C(F)(F)F)nc1
Solvent: CC#N
Product: Cc1cc(NCc2ccc(C(F)(F)F)nc2)cc(C)c1NC(=O)CC1CCCC1
Temperature: 150 °C
Reaction time: 16 h
Yield: 92.6 %

Procedure:
N-(4-Amino-2,6-dimethyl-phenyl)-2-cyclopentyl-acetamide (204 mg) and 6-trifluoromethyl-pyridine-3-carbaldehyde (163 mg) were dissolved in acetonitrile (3 mL) and heated to 150° C. for 10 minutes in a sealed microwave process vial. The reaction mixture was concentrated in vacuo, redissolved in methanol (5 mL) followed by addition of acetic acid (0.5 mL) and sodium cyanoborohydride (244 mg) and stirred at 25° C. for 16 hours. Aqueous sodium carbonate (10%, 25 mL) was added, and the product was collected by filtration to furnish 0.311 g (92% yield) of the title compound as a white solid. LC-MS (m/z) 406 (MH+); tR=2.90, (UV, ELSD) 98%, 99%. 1H NMR (500 MHz, DMSO-d6): 1.20 (m, 2H), 1.51 (m, 2H), 1.60 (m, 2H), 1.75 (m, 2H), 1.97 (s, 6H), 2.22 (m, 3H), 4.39 (d, 2H), 6.20 (t, 1H), 6.28 (s, 2H), 7.85 (d, 1H), 7.99 (d, 1H), 8.75 (s, 1H), 8.77 (s, 1H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]2[NH:6][C:7]3[C:12]([C:13]=2[CH:14]=1)=[CH:11][C:10]([F:15])=[CH:9][CH:8]=3.[OH-].[K+].Cl[CH2:19][C:20]1([CH3:23])[CH2:22][O:21]1>CN(C)C=O>[F:15][C:10]1[CH:9]=[CH:8][C:7]2[N:6]([CH2:19][C:20]3([CH3:23])[CH2:22][O:21]3)[C:5]3[C:13]([C:12]=2[CH:11]=1)=[CH:14][C:2]([F:1])=[CH:3][CH:4]=3
Reactant: CC1(CCl)CO1
Reactant: Fc1ccc2[nH]c3ccc(F)cc3c2c1
Agent: [K+]
Agent: [OH-]
Solvent: CN(C)C=O
Product: CC1(Cn2c3ccc(F)cc3c3cc(F)ccc32)CO1
Temperature: 25 °C
Reaction time: 1 h
Yield: 63.5 %

Procedure:
To a stirred solution of 3,6-difluoro-9H-carbazole (2.0 g, 9.8 mmol) in N,N-dimethylformamide (50 mL) at 0° C. was added 85% potassium hydroxide (0.780 g, 11.8 mmol) and the mixture was stirred for 1 hr. 2-(Chloromethyl)-2-methyloxirane (2.098 g, 19.7 mmol) was added and the mixture was slowly warmed to room temperature and stirred for 16 hrs. The mixture was partitioned between water and ethyl acetate. The organic layer was washed with saturated aqueous sodium chloride, dried (anhydrous sodium sulfate), filtered, and concentrated in vacuo. The residue was purified by silica gel chromatography (10-50% methylene chloride/hexanes) to afford the desired product as a white solid (1.7 g, 63%). 1H NMR (300 MHz, CDCl3) δ 7.68 (dd, 2H, J=8.4, 2.4 Hz), 7.41 (dd, 2H, J=9.0, 4.2 Hz), 7.23 (td, 2H, J=9.0, 2.4 Hz), 4.62 and 4.22 (AB, 2H, J=15.6 Hz), 2.71 & 2.66 (AB, 2H, J=4.5 Hz), 1.33 (s, 3H).
Reaction SMILES: C1(C([O:14][C:15]([C:17]2[N:22]3[C:23](=[O:63])[C@@H:24]([NH:25][C:26](=[O:62])/[C:27](/[C:49]4[N:50]=[C:51]([NH:54]C(OC(C)(C)C)=O)[S:52][CH:53]=4)=[N:28]\[O:29]C(C4C=CC=CC=4)(C4C=CC=CC=4)C4C=CC=CC=4)[C@H:21]3[S:20][CH2:19][C:18]=2[S:64][CH2:65][S:66][C:67]2[CH:72]=[CH:71][CH:70]=[CH:69][N:68]=2)=[O:16])C2C=CC=CC=2)C=CC=CC=1.[Cl-].[Al+3].[Cl-].[Cl-]>C1(OC)C=CC=CC=1.[N+](C)([O-])=O.Cl.O>[NH2:54][C:51]1[S:52][CH:53]=[C:49](/[C:27](=[N:28]/[OH:29])/[C:26]([NH:25][C@@H:24]2[C:23](=[O:63])[N:22]3[C:17]([C:15]([OH:16])=[O:14])=[C:18]([S:64][CH2:65][S:66][C:67]4[CH:72]=[CH:71][CH:70]=[CH:69][N:68]=4)[CH2:19][S:20][C@H:21]23)=[O:62])[N:50]=1
Reactant: CC(C)(C)OC(=O)Nc1nc(/C(=N/OC(c2ccccc2)(c2ccccc2)c2ccccc2)C(=O)N[C@@H]2C(=O)N3C(C(=O)OC(c4ccccc4)c4ccccc4)=C(SCSc4ccccn4)CS[C@H]23)cs1
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: COc1ccccc1
Solvent: C[N+](=O)[O-]
Solvent: O
Product: Nc1nc(/C(=N/O)C(=O)N[C@@H]2C(=O)N3C(C(=O)O)=C(SCSc4ccccn4)CS[C@H]23)cs1
Temperature: -40 °C
Reaction time: 1 h
Yield: 78.7 %

Procedure:
To a solution of 7β-[(Z)-2-(2-t-butoxycarbonylaminothiazol-4-yl)-2-trityloxyiminoacetamido]-3-(2-pyridylthiomethylthio)-3-cephem-4-carboxylic acid diphenylmethyl ester (722 mg: 0.70 mMol.) in a mixture of anisole (2 ml) and nitromethane (8 ml) cooling at -40° C. is added a solution of aluminum chloride (744 mg; 5.59 mMol. ) in anisole (2 ml), and the mixture is stirred at -30° to -40° C. for 1 hour. The reaction mixture is diluted with 1N-hydrochloric acid (6 ml) and water, washed with ethyl acetate, concentrated under reduced pressure to remove the organic solvents, and passed through a styrene-divinylbenzene copolymer column. The adsorbed material is eluted with methanol-water (4:1). The eluate is concentrated. The residue is washed with ethyl acetate and dried to give 7β-[(Z)-2-(2-aminothiazol-4-yl)-2-hydroxyiminoacetylamino]-3-(2-pyridylthiomethylthio)-3-cephem-4-carboxylic acid (289 mg). Yield: 79%.
Reaction SMILES: [CH3:1][C:2]1[N:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([C:14]3([C:17]([NH:19][NH2:20])=O)[CH2:16][CH2:15]3)=[CH:10][CH:9]=2)=[CH:4][N:3]=1.[Si:21]([O:28][CH2:29][C@:30]1([CH3:39])[S:36][CH2:35][CH2:34][N:33]=[C:32](SC)[CH2:31]1)([C:24]([CH3:27])([CH3:26])[CH3:25])([CH3:23])[CH3:22]>C(O)(C)(C)C>[Si:21]([O:28][CH2:29][C@:30]1([CH3:39])[S:36][CH2:35][CH2:34][N:33]2[C:17]([C:14]3([C:11]4[CH:12]=[CH:13][C:8]([C:5]5[CH:6]=[N:7][C:2]([CH3:1])=[N:3][CH:4]=5)=[CH:9][CH:10]=4)[CH2:15][CH2:16]3)=[N:19][N:20]=[C:32]2[CH2:31]1)([C:24]([CH3:27])([CH3:25])[CH3:26])([CH3:22])[CH3:23]
Reactant: CSC1=NCCS[C@@](C)(CO[Si](C)(C)C(C)(C)C)C1
Reactant: Cc1ncc(-c2ccc(C3(C(=O)NN)CC3)cc2)cn1
Solvent: CC(C)(C)O
Product: Cc1ncc(-c2ccc(C3(c4nnc5n4CCS[C@@](C)(CO[Si](C)(C)C(C)(C)C)C5)CC3)cc2)cn1
Temperature: 25 °C
Yield: 74 %

Procedure:
A solution of the compound (591 mg, 2.23 mmol) obtained in Example 88-1) and the compound (750 mg, 2.35 mmol) obtained in Example 4-1) in t-butanol (10 mL) was stirred for 7 h under reflux conditions. The obtained reaction mixture was cooled to room temperature and concentrated under reduced pressure, and then the residue was purified by silica gel column chromatography (methanol:ethyl acetate=10:90 to 100:0) to obtain the title compound (861 mg, 70%) as a light yellow solid.