Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1([CH2:10][CH:11]=[CH2:12])[C:7](=[O:8])[CH2:6][CH2:5][CH2:4]C1=O>C1(C)C(C)=CC=CC=1>[CH2:10]([C:2]1[C:7](=[O:8])[CH2:6][CH2:5][CH:4]=1)[CH:11]=[CH2:12]
Reactant: C=CCC1(Cl)C(=O)CCCC1=O
Solvent: Cc1ccccc1C
Product: C=CCC1=CCCC1=O
Reaction time: 4.5 h
Yield: 49.5 %

Procedure:
Anhydrous powdered sodium carbonate (670 g) and 1300 ml of dry (alumina) xylene were placed in a 3-l., three-necked flask equipped with a Dean-Stark trap, condenser, vibra-mixer, dropping funnel and argon inlet. The flask was flushed with argon and the contents brought to reflux. A solution of 2-chloro-2-allyl-1,3-cyclohexanedione (147 g, 0.79 mol) in 200 ml of xylene was added dropwise at such a rate that strong refluxing was maintained. After 4.5 hr, the reaction was cooled, filtered, and the sodium carbonate cake washed thoroughly with ethyl acetate. Evaporation of the solvent and careful fractionization of the residual oil gave 47.8 g (50 percent) of 2-allyl-2-cyclopenten-1-one, bp 73°-84°/4.2 mm.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([NH:8][C:9]2[CH:14]=[C:13]([CH3:15])[N:12]=[C:11]([NH2:16])[N:10]=2)[CH:5]=[CH:6][CH:7]=1.N1C=CC=CC=1.[N+:23]([C:26]1[CH:34]=[CH:33][C:29]([C:30](Cl)=[O:31])=[CH:28][CH:27]=1)([O-:25])=[O:24].N>O1CCOCC1.O>[NH2:16][C:11]1[N:10]=[C:9]([NH:8][C:4]2[CH:3]=[C:2]([NH:1][C:30](=[O:31])[C:29]3[CH:28]=[CH:27][C:26]([N+:23]([O-:25])=[O:24])=[CH:34][CH:33]=3)[CH:7]=[CH:6][CH:5]=2)[CH:14]=[C:13]([CH3:15])[N:12]=1
Reactant: O=C(Cl)c1ccc([N+](=O)[O-])cc1
Reactant: Cc1cc(Nc2cccc(N)c2)nc(N)n1
Agent: N
Solvent: c1ccncc1
Solvent: O
Solvent: C1COCCO1
Product: Cc1cc(Nc2cccc(NC(=O)c3ccc([N+](=O)[O-])cc3)c2)nc(N)n1
Temperature: 25 °C
Yield: 103.9 %

Procedure:
To a suspension of diamine E2 (5.25 g, 20.85 mmol) and dry pyridine (8.40 mL, 104.26 mmol) in dry dioxane (200 mL) was added 4-nitrobenzoyl chloride (10.79 g, 58.13 mmol), and the resulting solution was refluxed for ˜14 h. After this time, the reaction mixture was cooled to room temperature, and then basified by addition of aqueous ammonia solution. The resulting solution was diluted with H2O, and the resulting precipitate collected by filtration to afford amide E3 as an amorphous yellow-brown solid (7.89 g, 94%) [a small sample of this crude material was reprecipitated from acidified MeOH:EtOAc for characterisation, whilst the bulk was used without further purification]; 1H NMR (400 MHz, DMSO): δ 12.99 (br s, 1H, pyrimidinyl-N+—H), 10.82 (s, 1H, ArNHAr), 10.76 (br s, 1H, ArC(O)NHAr), 8.35 (dd, J=6.92, 1.99 Hz, 2H, ArH), 8.27 (d, J=6.92, 1.99 Hz, 2H, ArH), 7.90 (v v v br s, 2H, ArNH2), 8.20-7.50 (m, 4H, ArH & ArNH2), 7.45-7.10 (m, 2H, ArH), 6.25 (s, 1H, ArH), 2.28 (s, 3H, ArCH3); LCMS (APCI+): 365 (100%).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][N:3]=[C:2]1[CH2:6][NH:7][CH2:8][CH2:9][NH2:10].C(N)CN.ClCC1SC=CN=1.[CH3:22][N:23]=[C:24]=[O:25]>>[CH3:22][NH:23][C:24]([NH:10][CH2:9][CH2:8][NH:7][CH2:6][C:2]1[S:1][CH:5]=[CH:4][N:3]=1)=[O:25]
Reactant: NCCNCc1nccs1
Reactant: CN=C=O
Agent: ClCc1nccs1
Solvent: NCCN
Product: CNC(=O)NCCNCc1nccs1

Procedure:
N-(2-Thiazolylmethyl)ethylenediamine, prepared by reacting ethylenediamine with 2-chloromethylthiazole by the procedure of Example 40, is reacted with methyl isocyanate by the procedure of Example 24 to give, after concentrating and separating by column chromatography, the title compound.
Reaction SMILES: [C:1]([SiH2:5][O:6][C:7]([CH3:17])([CH3:16])[C:8]1[CH:9]=[C:10]([CH2:14]O)[CH:11]=[CH:12][CH:13]=1)([CH3:4])([CH3:3])[CH3:2].[CH2:18]([N:20](CC)CC)C.CS(Cl)(=O)=O.[C-]#N.[Na+]>ClCCl.CN(C=O)C>[C:1]([SiH2:5][O:6][C:7]([CH3:17])([CH3:16])[C:8]1[CH:9]=[C:10]([CH2:14][C:18]#[N:20])[CH:11]=[CH:12][CH:13]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)[SiH2]OC(C)(C)c1cccc(CO)c1
Reactant: CCN(CC)CC
Agent: CS(=O)(=O)Cl
Agent: [C-]#N
Agent: [Na+]
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CC(C)(C)[SiH2]OC(C)(C)c1cccc(CC#N)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 75.3 %

Procedure:
To a stirred solution of [3-(tert-butyl-dimethyl-silanyloxymethyl)-phenyl]-methanol (10.52 g, 41.67 mmol) in dichloromethane (80 ml) at 0° C. (ice bath), was added triethylamine (8.78 ml, 62.5 mmol) followed by methanesulfonyl chloride (3.87 ml, 50 mmol). After stirring for 2 hr, the reaction mixture was washed with aqueous saturated sodium bicarbonate solution, dried with anhydrous magnesium sulfate, filtered, and evaporated in vacuo to give a pale yellow oil. The crude product was then dissolved in anhydrous DMF (80 ml) and sodium cyanide (6.28 g, 128 mmol) was added into the mixture. The mixture was stirred in an oil bath (60° C.) for 2 hr. After cooling to room temperature, the mixture was partitioned between ether and water. The ether layer was taken, washed with water twice, dried with anhydrous magnesium sulfate, filtered, and evaporated in vacuo. The residue was purified by silica gel column chromatography (eluent, EA: hexanes (from 1:20 to 1:10)) to afford 8.2 g (75%) of a pale yellow oil. 1H NMR (200 MHz, CDCl3) δ 0.11 (6H, s), 0.95 (9H, s), 3.75 (2H, s), 4.75 (2H, s), 7.27-7.35 (4H, m).
Reaction SMILES: [CH3:1][C:2]1[S:6][C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[N:4][C:3]=1[C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14].[Br:20]N1C(=O)CCC1=O>C(Cl)(Cl)(Cl)Cl.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>[Br:20][CH2:1][C:2]1[S:6][C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[N:4][C:3]=1[C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14]
Reactant: Cc1sc(-c2ccccc2)nc1C(=O)OC(C)(C)C
Reactant: O=C1CCC(=O)N1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: CC(C)(C)OC(=O)c1nc(-c2ccccc2)sc1CBr
Yield: 74.4 %

Procedure:
A solution of tert-butyl 5-methyl-2-phenylthiazole-4-carboxylate (1.0 g 3.64 mmol), N-bromosuccinimide (NBS) (0.65 g 3.64 mmol), and benzoyl peroxide (BPO) (5.5 mg, 0.023 mmol) in CCl4 (30 ml) was heated at reflux for 16 h. The reaction mixture was concentrated in vacuo and purified by flash chromatography to give tert-butyl 5-(bromomethyl)-2-phenylthiazole-4-carboxylate as a light yellow solid (0.96 g, 75% yield).
Reaction SMILES: [Cl:1][C:2]1[C:3]([OH:10])=[N:4][N:5]([CH3:9])[C:6]=1[S:7][CH3:8].Cl[C:12]1[N:13]=[N:14][CH:15]=[C:16]([O:18][CH3:19])[CH:17]=1.N1C(C)=CC=CC=1C.[Cl-].[NH4+]>C1(C)C=CC=CC=1>[Cl:1][C:2]1[C:3]([O:10][C:12]2[N:13]=[N:14][CH:15]=[C:16]([O:18][CH3:19])[CH:17]=2)=[N:4][N:5]([CH3:9])[C:6]=1[S:7][CH3:8]
Reactant: COc1cnnc(Cl)c1
Reactant: CSc1c(Cl)c(O)nn1C
Agent: [Cl-]
Agent: [NH4+]
Solvent: Cc1cccc(C)n1
Solvent: Cc1ccccc1
Product: COc1cnnc(Oc2nn(C)c(SC)c2Cl)c1
Yield: 26 %

Procedure:
4-Chloro-1-methyl-5-(methylthio)-1H-pyrazol-3-ol which is a known compound (2.7 g, 0.015 mole), 3-chloro-5-methoxypyridazine (1.45 g, 0.01 mole), and 2,6-lutidine (1.4 mL, 0.012 moles) were heated to reflux in toluene (40 mL) under N2 for 18 h. The mixture was then poured into aqueous ammonium chloride and extracted 3×100 mL with ethyl acetate. The organic layers were washed with water and brine, dried (MgSO4), filtered and evaporated in vacuo. The crude solid was purified by flash chromatography to give 3-[[4-chloro-1-methyl-5-(methylthio)-1H-pyrazol-3-yl]oxy]-5-methoxypyridazine (1.1 g, 26% yield) as a white solid.
Reaction SMILES: [CH2:1]([O:5][CH2:6][CH2:7][C:8]1[CH:18]=[CH:17][C:11]([O:12][CH2:13][CH:14]2[O:16][CH2:15]2)=[CH:10][CH:9]=1)[CH:2]([CH3:4])[CH3:3].[NH2:19][CH2:20][CH2:21][O:22][C:23]1[CH:24]=[C:25]([C:29]2[CH2:30][CH2:31][C:32](=[O:35])[NH:33][N:34]=2)[CH:26]=[CH:27][CH:28]=1>>[CH2:1]([O:5][CH2:6][CH2:7][C:8]1[CH:18]=[CH:17][C:11]([O:12][CH2:13][CH:14]([OH:16])[CH2:15][NH:19][CH2:20][CH2:21][O:22][C:23]2[CH:24]=[C:25]([C:29]3[CH2:30][CH2:31][C:32](=[O:35])[NH:33][N:34]=3)[CH:26]=[CH:27][CH:28]=2)=[CH:10][CH:9]=1)[CH:2]([CH3:4])[CH3:3]
Reactant: CC(C)COCCc1ccc(OCC2CO2)cc1
Reactant: NCCOc1cccc(C2=NNC(=O)CC2)c1
Product: CC(C)COCCc1ccc(OCC(O)CNCCOc2cccc(C3=NNC(=O)CC3)c2)cc1

Procedure:
Prepared analogously to Example 1 from 1-[4-(2-isobutoxy-ethyl)phenoxy]-2,3-epoxypropane and 6-[3-(2-aminoethoxy)phenyl]-4,5-dihydro-3(2H)-pyridazinone.
Reaction SMILES: [CH2:1]([CH:8]([C:12](O)=O)[C:9]([OH:11])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C=O.C(NCC)C.Cl>C(OCC)(=O)C.O>[CH2:12]=[C:8]([CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[C:9]([OH:11])=[O:10]
Reactant: O=C(O)C(Cc1ccccc1)C(=O)O
Agent: C=O
Agent: Cl
Solvent: CCNCC
Solvent: CCOC(C)=O
Solvent: O
Product: C=C(Cc1ccccc1)C(=O)O
Yield: 89.8 %

Procedure:
A solution of benzylmalonic acid (20.0 g, 0.103 mol, 1 eq) and paraformaldehyde (4.94 g, 0.164 mol, 1.6 eq) in ethyl acetate (150 mL) was cooled (0° C.) and treated with diethylamine (10.65 mL, 0.103 mol, 1 eq) drop wise, keeping the reaction temperature below 20° C. The reaction was then warmed to reflux for 90 minutes and cooled again on ice. The homogeneous solution was treated with water (20 mL) and concentrated aqueous HCl (12N) (9.0 mL, 0.108 mol) drop wise, keeping the reaction temperature below 10° C. The phases were then separated. The organic layer was washed with brine (100 mL), dried over sodium sulfate, filtered, and the filtrate concentrated under vacuum giving 2-methylene-3-phenylpropanoic acid (10) as a white solid (15 g, 90%).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:29]=[CH:30][C:31]=1[O:32][CH:33]([CH3:35])[CH3:34])[CH2:6][O:7][C:8]1[CH:16]=[CH:15][C:14]2[N:13]3[CH2:17][CH2:18][CH:19]([CH2:20][C:21]([O:23]C(C)(C)C)=[O:22])[C:12]3=[C:11]([CH3:28])[C:10]=2[CH:9]=1)#[N:2].C(S)[C@H](N)C(O)=O.C(O)(C(F)(F)F)=O>CCOCC.C(Cl)Cl>[C:1]([C:3]1[CH:4]=[C:5]([CH:29]=[CH:30][C:31]=1[O:32][CH:33]([CH3:35])[CH3:34])[CH2:6][O:7][C:8]1[CH:16]=[CH:15][C:14]2[N:13]3[CH2:17][CH2:18][CH:19]([CH2:20][C:21]([OH:23])=[O:22])[C:12]3=[C:11]([CH3:28])[C:10]=2[CH:9]=1)#[N:2]
Reactant: Cc1c2n(c3ccc(OCc4ccc(OC(C)C)c(C#N)c4)cc13)CCC2CC(=O)OC(C)(C)C
Agent: N[C@@H](CS)C(=O)O
Solvent: O=C(O)C(F)(F)F
Solvent: CCOCC
Solvent: ClCCl
Product: Cc1c2n(c3ccc(OCc4ccc(OC(C)C)c(C#N)c4)cc13)CCC2CC(=O)O
Temperature: 0 °C
Reaction time: 3 h
Yield: 110.1 %

Procedure:
To a pre-cooled flask containing tert-butyl 2-(7-(3-cyano-4-isopropoxybenzyloxy)-9-methyl-2,3-dihydro-1H-pyrrolo[1,2-a]indol-1-yl)acetate (0.308 g, 0.649 mmol) was added a pre-cooled solution of D/L-2-Amino-3-mercaptopropanoic acid (0.079 g, 0.649 mmol) in TFA (6.49 mL, 0.649 mmol) at 0° C. After stirring for 3 h at 0° C., ice-cold water (65 mL) was added. The resulting suspension was diluted with Et2O (130 mL). The organic layer was separated, washed with water (2×30 mL), brine (30 mL), and dried over MgSO4. The solvent was coevaporated with toluene (25 mL) in vacuo at 25° C. The residue was coevaporated with toluene (20 mL) again to give an oil. The oil was dissolved in DCM (5 mL) and coevaporated with hexanes (25 mL) to give the title compound as a grey solid (0.299 g). LCMS m/z=419.4 [M+H]+; 1H NMR (400 MHz, DMSO-d6) δ ppm 1.32 (d, J=6.06 Hz, 6H), 2.16 (s, 3H), 2.19-2.29 (m, 1H), 2.47 (d, J=6.69 Hz, 1H), 2.70-2.82 (m, 2H), 3.54-3.65 (m, 1H), 3.92 (m, 1H), 4.03 (dt, J=8.05, 1.91 Hz, 1H), 4.79 (dt, J=12.13, 6.06 Hz, 1H), 5.04 (s, 2H), 6.74 (dd, J=8.72, 2.40 Hz, 1H), 7.00 (d, J=2.40 Hz, 1H), 7.13 (d, J=8.72 Hz, 1H), 7.28 (d, J=8.84 Hz, 1H), 7.72 (dd, J=8.78, 2.21 Hz, 1H), 7.78 (d, J=2.15 Hz, 1H), 12.27 (bs, 1H).
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]3[CH2:14][CH2:13][NH:12][C:11](=[O:15])[C:7]=3[NH:8]2)=[CH:4][C:3]=1[O:16][CH3:17].C([OH:20])C.[OH-].[K+]>O>[NH2:12][CH2:13][CH2:14][C:6]1[C:5]2[C:9](=[CH:10][C:2]([F:1])=[C:3]([O:16][CH3:17])[CH:4]=2)[NH:8][C:7]=1[C:11]([OH:20])=[O:15]
Reactant: CCO
Reactant: COc1cc2c3c([nH]c2cc1F)C(=O)NCC3
Agent: [K+]
Agent: [OH-]
Solvent: O
Product: COc1cc2c(CCN)c(C(=O)O)[nH]c2cc1F
Temperature: 80 °C
Reaction time: 8 h

Procedure:
To a mixture of 7-fluoro-6-methoxy-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-1-one (780 mg), ethanol (5.00 mL), and water (5.00 mL) was added potassium hydroxide (1.58 g), followed by stirring at 80° C. overnight. Potassium hydroxide (1.58 g) was added to the reaction mixture, followed by stirring at 100° C. for 6 hours. After cooling to room temperature, the solvent was evaporated under reduced pressure. The obtained residue was dissolved in water (10.0 mL), to the mixture was added acetic acid (3.00 mL), and the precipitated solid was collected by filtration and dried under reduced pressure to obtain 3-(2-aminoethyl)-6-fluoro-5-methoxy-1H-indole-2-carboxylic acid (607 mg) as a reddish brown solid.
Reaction SMILES: [CH3:1][C:2]1[NH:11][C:10](=[O:12])[C:9]2[C:4](=[CH:5][C:6]3[CH2:15][CH2:14][CH:13]([N:16]([C:20]4[CH:21]=[CH:22][C:23]([C:26](O)=[O:27])=[N:24][CH:25]=4)[CH2:17][C:18]#[CH:19])[C:7]=3[CH:8]=2)[N:3]=1.[NH2:29][C@@H:30]([CH2:35][CH2:36][C:37]1[NH:41][N:40]=[N:39][N:38]=1)[C:31]([O:33]C)=[O:32]>>[CH3:1][C:2]1[NH:11][C:10](=[O:12])[C:9]2[C:4](=[CH:5][C:6]3[CH2:15][CH2:14][CH:13]([N:16]([C:20]4[CH:21]=[CH:22][C:23]([C:26]([NH:29][C@@H:30]([CH2:35][CH2:36][C:37]5[NH:41][N:40]=[N:39][N:38]=5)[C:31]([OH:33])=[O:32])=[O:27])=[N:24][CH:25]=4)[CH2:17][C:18]#[CH:19])[C:7]=3[CH:8]=2)[N:3]=1
Reactant: COC(=O)[C@@H](N)CCc1nnn[nH]1
Reactant: C#CCN(c1ccc(C(=O)O)nc1)C1CCc2cc3nc(C)[nH]c(=O)c3cc21
Product: C#CCN(c1ccc(C(=O)N[C@@H](CCc2nnn[nH]2)C(=O)O)nc1)C1CCc2cc3nc(C)[nH]c(=O)c3cc21
Yield: 33 %

Procedure:
Using analogous procedures to those described in Example 12, 5-[N-((6RS)-2-methyl-4-oxo-3,4,7,8-tetrahydro-6H-cyclopenta[g]quinazolin-6-yl)-N-(prop-2-ynyl)amino]pyridine-2-carboxylic acid was reacted with methyl (2S)-2-amino-4-(tetrazol-5-yl)butyrate to give (2S)-2-{5-[N-((6RS)-2-methyl-4-oxo-3,4,7,8-tetrahydro-6H-cyclopenta[g]quinazolin-6-yl)-N-(prop-2-ynyl)amino]pyridine-2-carboxamido}-4-(tetrazol-5-yl)butyric acid in 33% yield, m.p. 189°-191° C.;
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:19]=[C:18]([C:20]([OH:22])=O)[O:17][N:16]=2)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.ClC(OCC(C)C)=O.Cl.[CH3:32][O:33][C:34](=[O:40])[C@H:35]([CH:37]([CH3:39])[CH3:38])[NH2:36].CCN(CC)CC>C1COCC1.CN1CCOCC1>[CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([C:15]2[CH:19]=[C:18]([C:20]([NH:36][CH:35]([CH:37]([CH3:39])[CH3:38])[C:34]([O:33][CH3:32])=[O:40])=[O:22])[O:17][N:16]=2)=[CH:13][CH:14]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)[C@@H](N)C(C)C
Reactant: O=C(O)c1cc(-c2ccc(OCc3ccccc3)cc2)no1
Agent: CC(C)COC(=O)Cl
Agent: Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Solvent: CN1CCOCC1
Product: COC(=O)C(NC(=O)c1cc(-c2ccc(OCc3ccccc3)cc2)no1)C(C)C
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To 3-(4-(benzyloxy)phenyl)isoxazole-5-carboxylic acid (300 mg) in THF (10 ml), N-methyl morpholine (0.111 ml) was added and reaction mixture was stirred for 10 minutes at RT. Reaction mixture was cooled to −20° C., isobutyl chloroformate (0.132 ml) was added and stirred for 15-20 minutes at −20 to −30° C. L-valine methyl ester hydrochloride (238 mg) neutralized with Et3N (0.198 ml) in THF (5 ml) and added to the above reaction mixture and stirred at −20 to −30° C. for 5 minutes. Then the reaction mixture was gradually allowed to warm to RT over a period of 1 hour. Solvent was evaporated to obtain pale brown solid, which was purified by column chromatography (silica gel, EtOAc—Chloroform) to obtain off white solid, which was crystallized using EtOAc—petroleum ether to obtain the title compound as white solid. Yield: 232 mg (55%); MS (ES+): m/z 409 (M+1); 1H NMR (DMSO-d6; 300 MHz): δ 9.19 (d, 1H), 7.87 (d, 2H), 7.68 (s, 1H), 7.32-7.49 (m, 5H), 7.19 (d, 2H), 5.19 (s, 2H), 4.31 (m, 1H), 3.67 (s, 3H), 2.22 (m, 1H), 0.96 (d, 6H).
Reaction SMILES: [NH:1]1[CH2:6][C@H:5]([C:7]([O:9][CH3:10])=[O:8])[CH2:4][CH2:3][C@@H:2]1[C:11]([O:13]C)=[O:12].C(=O)C1C(=CC=CC=1)O>C(O)(=O)C>[CH3:10][O:9][C:7]([C@H:5]1[CH2:6][NH:1][C@@H:2]([C:11]([OH:13])=[O:12])[CH2:3][CH2:4]1)=[O:8]
Reactant: COC(=O)[C@@H]1CC[C@H](C(=O)OC)NC1
Solvent: O=Cc1ccccc1O
Solvent: CC(=O)O
Product: COC(=O)[C@@H]1CC[C@H](C(=O)O)NC1
Temperature: 100 °C

Procedure:
Dimethyl cis-piperidine-2,5-dicarboxylate (112 g, 0.56 mol), 5 salicylaldehyde (3 ml, 0.056 mol) and glacial acetic acid (600 ml) were combined and the resulting mixture heated at about 100° C. for 60 hours. The mixture was cooled, than stripped in vacuo to a thick oil from which 61.7 g (59%) of title products crystallized upon stirring with 800 ml of isopropyl alcohol. Product ratio was determined by 1H-NMR (D2O, 300 MHz), a peak at 3.13 ppm (t, 1H, J=14.5 Hz) being diagnostic of trans, and a peak at 3.33 ppm (dd, 1H) being diagnostic of cis.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[O:10][C@@:9]([CH3:16])([CH:11]([O:14][CH3:15])[O:12][CH3:13])[C@@H:8]3[O:17][C@@H:7]3[C:6]=2[CH:18]=1.[F:19][C:20]1[CH:25]=[CH:24][C:23]([NH:26][CH2:27][C:28]2[N:29]=[N:30][N:31]([CH3:33])[N:32]=2)=[CH:22][CH:21]=1>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[O:10][C@@:9]([CH3:16])([CH:11]([O:14][CH3:15])[O:12][CH3:13])[C@H:8]([OH:17])[C@@H:7]([N:26]([C:23]3[CH:24]=[CH:25][C:20]([F:19])=[CH:21][CH:22]=3)[CH2:27][C:28]3[N:29]=[N:30][N:31]([CH3:33])[N:32]=3)[C:6]=2[CH:18]=1
Reactant: Cn1nnc(CNc2ccc(F)cc2)n1
Reactant: COC(OC)[C@]1(C)Oc2ccc(Br)cc2[C@H]2O[C@H]21
Product: COC(OC)[C@]1(C)Oc2ccc(Br)cc2[C@H](N(Cc2nnn(C)n2)c2ccc(F)cc2)[C@H]1O
Yield: 53.2 %

Procedure:
The same procedure as step 3 of example 1 was accomplished, except for using (2R,3R,4R)-6-bromo-2-methyl-2-dimethoxymethyl-3,4-epoxy-3,4-dihydro-2H-1-benzopyran (198 mg, 0.63 mmol) and N-(4-fluorophenyl)-N-(2-methyl-2H-tetrazol-5-ylmethyl)amine (130 mg, 0.63 mmol). The crude product was purified by silica gel column chromatography (developing solvent-n-hexane:ethyl acetate=4:1), to give desired compound (175 mg, yield: 53%).
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]=[C:7]=[O:8])=[O:5])[CH3:2].[OH:9][C:10]1[N:14]=[C:13]([O:15][CH2:16][CH3:17])[S:12][N:11]=1.C(N(CC)CC)C>O1CCCC1>[CH2:1]([O:3][C:4]([NH:6][C:7]([N:11]1[C:10](=[O:9])[N:14]=[C:13]([O:15][CH2:16][CH3:17])[S:12]1)=[O:8])=[O:5])[CH3:2]
Reactant: CCOc1nc(O)ns1
Reactant: CCOC(=O)N=C=O
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCOC(=O)NC(=O)n1sc(OCC)nc1=O
Temperature: 20 °C
Reaction time: 2 h
Yield: 69 %

Procedure:
23 g of ethoxycarbonyl isocyanate were added dropwise to a solution of 14.6 g of 3-hydroxy-5-ethoxy-1,2,4-thiadiazole in 140 ml of tetrahydrofuran containing 1 ml of triethylamine and the mixture was stirred for 11/2 hours at 20° C and was filtered. The filtrate was concentrated to dryness and the residue was empasted with isopropyl ether and vacuum filtered. The product was crystallized from ethyl acetate to obtain 18 g of 2-(N-ethoxycarbonylcarbamoyl)-5-ethoxy-1,2,4-thiadiazole-3-one melting at 119° C.
Reaction SMILES: [I:1][CH2:2][C:3]1[CH2:4][S:5][C@@H:6]2[CH:26]([NH:27][C:28](=[O:58])/[C:29](=[N:55]\[O:56][CH3:57])/[C:30]3[N:31]=[C:32]([NH:35][C:36]([C:49]4[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=4)([C:43]4[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=4)[C:37]4[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=4)[S:33][CH:34]=3)[C:25](=[O:59])[N:7]2[C:8]=1[C:9]([O:11][CH:12]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[O:10].ClC1C=CC=C(C(OO)=[O:68])C=1.O>C(Cl)Cl>[I:1][CH2:2][C:3]1[CH2:4][S:5](=[O:68])[C@@H:6]2[CH:26]([NH:27][C:28](=[O:58])/[C:29](=[N:55]\[O:56][CH3:57])/[C:30]3[N:31]=[C:32]([NH:35][C:36]([C:43]4[CH:44]=[CH:45][CH:46]=[CH:47][CH:48]=4)([C:49]4[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=4)[C:37]4[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=4)[S:33][CH:34]=3)[C:25](=[O:59])[N:7]2[C:8]=1[C:9]([O:11][CH:12]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1)=[O:10]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CO/N=C(\C(=O)NC1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(CI)CS[C@H]12)c1csc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Solvent: ClCCl
Solvent: O
Product: CO/N=C(\C(=O)NC1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(CI)CS(=O)[C@H]12)c1csc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 99.3 %

Procedure:
A mixture of benzhydryl 3-iodomethyl-7-[(Z)-2-methoxyimino-2-(2-tritylaminothiazol-4-yl)acetamido]-3-cephem-4-carboxylate (VIIa) (1.10 g, 1.19 mmoles) and m-chloroperbenzoic acid (m-CPBA) (322 mg, 1.30 mmoles) in CH2Cl2 (22 ml) was stirred at 0° C. for 15 minutes, poured into H2O (50 ml), and then extracted with CHCl3 (50 ml×3). The combined extracts were washed with saturated aqueous NaHCO3 (50 ml) and NaCl successively, dried and evaporated to afford the title compound (VIIa 1-oxide) (1.12 g, quantitative) as an amorphous powder.
Reaction SMILES: [N:1]1([CH2:7][CH2:8][OH:9])[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[CH2:10](Br)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>>[CH2:10]([N:4]1[CH2:5][CH2:6][N:1]([CH2:7][CH2:8][OH:9])[CH2:2][CH2:3]1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: BrCc1ccccc1
Reactant: OCCN1CCNCC1
Product: OCCN1CCN(Cc2ccccc2)CC1

Procedure:
The title compound was synthesized by using 2-(1-piperazinyl)ethanol and benzyl bromide according to the same process as in Preparation Example 4.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[N:10]=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1.[F:11][C:12]1[CH:13]=[C:14]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=2[O:33][C:34]2[N:39]=[CH:38][CH:37]=[CH:36][N:35]=2)[CH:15]=[CH:16][C:17]=1B1OC(C)(C)C(C)(C)O1>>[F:11][C:12]1[CH:13]=[C:14]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=2[O:33][C:34]2[N:35]=[CH:36][CH:37]=[CH:38][N:39]=2)[CH:15]=[CH:16][C:17]=1[C:2]1[CH:3]=[C:4]2[N:10]=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1
Reactant: CC1(C)OB(c2ccc(-c3ccccc3Oc3ncccn3)cc2F)OC1(C)C
Reactant: Brc1cnc2[nH]cnc2c1
Product: Fc1cc(-c2ccccc2Oc2ncccn2)ccc1-c1cnc2[nH]cnc2c1

Procedure:
The title compound was prepared in a manner similar to that described in Example 88 using 6-bromo-3H-imidazo[4,5-b]pyridine and 2-((3′-fluoro-4′-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-[1,1′-biphenyl]-2-yl)oxy)pyrimidine. MS (ESI): mass calcd. for C22H14FN5O, 383.12; m/z found, 384.1 [M+H]+. 1H NMR (500 MHz, CD3OD) δ 8.55-8.52 (m, 1H), 8.51-8.47 (d, J=4.9, 2H), 8.43 (s, 1H), 8.19-8.14 (t, J=1.7, 1H), 7.59-7.55 (dd, J=7.7, 1.8, 1H), 7.55-7.47 (m, 2H), 7.46-7.40 (m, 2H), 7.39-7.33 (dd, J=11.9, 1.7, 1H), 7.30-7.25 (dd, J=8.0, 1.2, 1H).
Reaction SMILES: Cl[C:2]1[N:6]([CH2:7][CH2:8][CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])[C:5]2[C:15]([CH:20]([CH2:23][CH3:24])[CH2:21][CH3:22])=[CH:16][CH:17]=[C:18]([Cl:19])[C:4]=2[N:3]=1.[Cl:25][C:26]1[CH:32]=[CH:31][C:29]([NH2:30])=[CH:28][CH:27]=1>CN1CCCC1=O.C(OCC)(=O)C>[Cl:19][C:18]1[C:4]2[N:3]=[C:2]([NH:30][C:29]3[CH:31]=[CH:32][C:26]([Cl:25])=[CH:27][CH:28]=3)[N:6]([CH2:7][CH2:8][CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])[C:5]=2[C:15]([CH:20]([CH2:23][CH3:24])[CH2:21][CH3:22])=[CH:16][CH:17]=1
Reactant: Nc1ccc(Cl)cc1
Reactant: CCOC(=O)CCCn1c(Cl)nc2c(Cl)ccc(C(CC)CC)c21
Solvent: CN1CCCC1=O
Solvent: CCOC(C)=O
Product: CCOC(=O)CCCn1c(Nc2ccc(Cl)cc2)nc2c(Cl)ccc(C(CC)CC)c21
Temperature: 150 °C
Reaction time: 12 h
Yield: 48.1 %

Procedure:
A mixture of ethyl 4-[2,4-dichloro-7-(1-ethylpropyl)-1H-benzimidazol-1-yl]butanoate (Reference Example 33; 1.00 g, 2.70 mmol) and 4-chloroaniline (1.04 g, 8.09 mmol) in 1-methyl-2-pyrrolidinone (10 mL) was stirred at 150° C. for 12 hr. After cooling, the mixture was diluted with ethyl acetate and washed with 1N hydrochloric acid, water and brine. Organic layer was dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was purified by flash chromatography on silica gel eluting with a 10-25% ethyl acetate/n-hexane gradient mixture. The filtrate was concentrated in vacuo to give the solid, which was recrystallized from ethyl acetate/n-hexane to give the title compound (600 mg, 1.30 mmol, 48%) as a colorless solid.