Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[CH:7][NH:8]2)=[CH:4][CH:3]=1.[C:11]([C:14]1[CH:19]=[CH:18][C:17](B(O)O)=[CH:16][CH:15]=1)(=[O:13])[CH3:12]>>[NH:8]1[C:9]2[C:5](=[CH:4][CH:3]=[C:2]([C:17]3[CH:18]=[CH:19][C:14]([C:11](=[O:13])[CH3:12])=[CH:15][CH:16]=3)[CH:10]=2)[CH:6]=[CH:7]1
Reactant: Brc1ccc2cc[nH]c2c1
Reactant: CC(=O)c1ccc(B(O)O)cc1
Product: CC(=O)c1ccc(-c2ccc3cc[nH]c3c2)cc1

Procedure:
Prepared by Procedure I and Scheme T using 6-bromo-1H-indole and 4-acetylphenylboronic acid: ESMS m/e: 235.8 (M+H)+.
Reaction SMILES: Cl[Si:2]([Cl:12])([Cl:11])[CH2:3][CH:4]([CH2:9][CH3:10])[CH2:5][CH2:6][CH2:7][CH3:8].[CH2:13]([Mg]Br)[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20]>O1CCCC1.C(OCC)C>[Cl:12][Si:2]([Cl:11])([CH2:3][CH:4]([CH2:9][CH3:10])[CH2:5][CH2:6][CH2:7][CH3:8])[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20]
Reactant: CCCCC(CC)C[Si](Cl)(Cl)Cl
Reactant: CCCCCCCC[Mg]Br
Solvent: C1CCOC1
Solvent: CCOCC
Product: CCCCCCCC[Si](Cl)(Cl)CC(CC)CCCC
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 49 %

Procedure:
Trichloro(2-ethylhexyl)silane (synthesized in accordance with J. Am. Chem. Soc. 2008, 130, 16144-16145, 24.8 g) was placed in a 300 mL four-necked flask in a nitrogen atmosphere, and dissolved in tetrahydrofuran (100 mL). The resulting solution was cooled to 0° C., and a solution of n-octyl magnesium bromide in diethyl ether (Sigma-Aldrich Co. LLC., 2.00 M, 50.0 mL) was added dropwise. The reaction solution was agitated for about 30 minutes at 7° C., and then agitated for about 3 hours at room temperature. The solvent was then distilled off with an evaporator. Hexane was added to the resulting crude product, which was then filtered, after which the solvent was again distilled off. Finally, distillation purification (111° C., 0.61 torr) was performed to obtain the target dichloro(2-ethylhexyl)n-octylsilane (Compound G6, 15.9 g, yield 49%).
Reaction SMILES: [C:1]([NH:3][C:4]1[CH:9]=[CH:8][N:7]=[C:6]([S:10][CH3:11])[N:5]=1)#[N:2].[CH2:12]([NH2:15])[CH2:13][CH3:14]>C(#N)C>[CH2:12]([N:15]=[C:1]([NH2:2])[NH:3][C:4]1[CH:9]=[CH:8][N:7]=[C:6]([S:10][CH3:11])[N:5]=1)[CH2:13][CH3:14]
Reactant: CSc1nccc(NC#N)n1
Reactant: CCCN
Solvent: CC#N
Product: CCCN=C(N)Nc1ccnc(SC)n1

Procedure:
A mixture of 4-cyanoamino-2-methylthiopyrimidine (0.83 g.) and n-propylamine (0.6 ml.) was heated under reflux in acetonitrile (20 ml.) for 1 hour. The solvent was evaporated in vacuo and the residue suspended in dilute aqueous sodium hydroxide. The solid was collected, washed with water and dried to give 4-(2-propylguanidino)-2-methylthiopyrimidine, m.p. 177°-178°.
Reaction SMILES: [F:1][CH:2]([F:29])[O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[O:11][CH:12]=[C:13]([CH2:15][NH:16][C:17](=[O:27])[C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[O:24][CH2:25][CH3:26])[N:14]=2)=[CH:6][C:5]=1[OH:28].Br[CH:31]([CH3:33])[CH3:32]>>[F:29][CH:2]([F:1])[O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[O:11][CH:12]=[C:13]([CH2:15][NH:16][C:17](=[O:27])[C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[O:24][CH2:25][CH3:26])[N:14]=2)=[CH:6][C:5]=1[O:28][CH:31]([CH3:33])[CH3:32]
Reactant: CCOc1ccccc1C(=O)NCc1coc(-c2ccc(OC(F)F)c(O)c2)n1
Reactant: CC(C)Br
Product: CCOc1ccccc1C(=O)NCc1coc(-c2ccc(OC(F)F)c(OC(C)C)c2)n1

Procedure:
Using the compound obtained in Example 347 and 2-bromopropane, white powdery N-[2-(4-difluoromethoxy-3-isopropoxyphenyl)oxazol-4-ylmethyl]-2-ethoxybenzamide was obtained following the procedure of Example 348.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[C:11](=[O:26])[NH:12][C:13]1[CH:18]=[CH:17][C:16]([Cl:19])=[C:15]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=2)[CH:14]=1)[C:5]([OH:7])=O.[S:27]1[CH2:31][CH2:30][N:29]=[CH:28]1>>[Cl:1][C:2]1[CH:3]=[C:4]([C:5]([N:29]2[CH2:30][CH2:31][S:27][CH2:28]2)=[O:7])[CH:8]=[CH:9][C:10]=1[C:11]([NH:12][C:13]1[CH:18]=[CH:17][C:16]([Cl:19])=[C:15]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=2)[CH:14]=1)=[O:26]
Reactant: C1=NCCS1
Reactant: O=C(O)c1ccc(C(=O)Nc2ccc(Cl)c(-c3ccccn3)c2)c(Cl)c1
Product: O=C(Nc1ccc(Cl)c(-c2ccccn2)c1)c1ccc(C(=O)N2CCSC2)cc1Cl

Procedure:
50 mg of 3-chloro-4-(4-chloro-3-(pyridin-2-yl)phenylcarbamoyl)benzoic acid was coupled to thiazoline via Procedure G. The product was purified on reverse phase HPLC to yield 2-chloro-N-(4-chloro-3-(pyridin-2-yl)phenyl)-4-(thiazolidine-3-carbonyl)benzamide. MS (Q1) 459 (M)+.
Reaction SMILES: [C:1]1([OH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[N+:8]([C:11]1[CH:18]=[CH:17][C:14]([CH2:15]Br)=[CH:13][CH:12]=1)([O-:10])=[O:9].C(=O)([O-])[O-].[K+].[K+].C(C(C)=O)C>C(OCC)(=O)C>[N+:8]([C:11]1[CH:18]=[CH:17][C:14]([CH2:15][O:7][C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)=[CH:13][CH:12]=1)([O-:10])=[O:9]
Reactant: O=[N+]([O-])c1ccc(CBr)cc1
Reactant: Oc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CCC(C)=O
Product: O=[N+]([O-])c1ccc(COc2ccccc2)cc1
Temperature: 80 °C
Reaction time: 15.5 h
Yield: 90.6 %

Procedure:
A mixture of phenol (11.3 g), 4-nitrobenzyl bromide (25.9 g), potassium carbonate (16.6 g) and methyl ethyl ketone (100 ml) was stirred for 15.5 hours at 80° C. Ethyl acetate was added thereto, the insoluble material was removed by filtration, the solvent was evaporated in vacuo, and the resulting residue was recrystallized from hexane-ethyl acetate to provide the title compound (pale yellow powder) (24.9 g).
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH:5]=[CH2:6].Br[C:8]1[CH:17]=[CH:16][C:11]([C:12]([O:14][CH3:15])=[O:13])=[CH:10][CH:9]=1>C1COCC1.[Zn+2].[Br-].[Br-].[Pd]>[CH2:2]([C:8]1[CH:17]=[CH:16][C:11]([C:12]([O:14][CH3:15])=[O:13])=[CH:10][CH:9]=1)[CH2:3][CH2:4][CH:5]=[CH2:6]
Reactant: C=CCCCBr
Reactant: COC(=O)c1ccc(Br)cc1
Agent: [Pd]
Agent: [Br-]
Agent: [Zn+2]
Solvent: C1CCOC1
Product: C=CCCCc1ccc(C(=O)OC)cc1
Temperature: 56 °C
Reaction time: 24 h

Procedure:
A mixture of dry Mg (900 mg, 37 mmol) and ZnBr2 (5.63 g, 25 mmol) in THF (25 mL) was treated with 5-bromopent-1-ene (4.45 mL, 37.6 mmol) and the subsequent suspension was heated at 56° C. for 18 h. The mixture was cooled to room temperature and methyl 4-bromobenzoate (7.1 g, 33 mmol) and tetrakis-triphenylphosphine) palladium(0) (1.0 g, 0.865 mmol) were added, and the mixture was stirred at room temperature for 24 h. The mixture was quenched with 3N HCl (aqueous) and extracted with ethyl acetate. The combined organic extracts were dried over anhydrous MgSO4 and evaporated at reduced pressure. The residue was purified by flash chromatography (silica gel, 5% ethyl acetate/hexane) to give the crude title compound which was used without further purification.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:13]=[CH:12][C:11]([CH:14]([N:22]([CH3:39])[C:23](=[O:38])[CH2:24][N:25]3[C:30]4[CH:31]=[C:32]([Cl:36])[C:33]([Cl:35])=[CH:34][C:29]=4[O:28][CH2:27][C:26]3=[O:37])[CH2:15][N:16]3[CH2:21][CH2:20][O:19][CH2:18][CH2:17]3)=[CH:10][CH:9]=2)[CH:5]=[CH:6][CH:7]=1.[CH:40]([N:43]=[C:44]=[O:45])([CH3:42])[CH3:41].C(N(CC)CC)C>ClCCl>[Cl:36][C:32]1[C:33]([Cl:35])=[CH:34][C:29]2[O:28][CH2:27][C:26](=[O:37])[N:25]([CH2:24][C:23]([N:22]([CH3:39])[CH:14]([C:11]3[CH:12]=[CH:13][C:8]([C:4]4[CH:5]=[CH:6][CH:7]=[C:2]([NH:1][C:44]([NH:43][CH:40]([CH3:42])[CH3:41])=[O:45])[CH:3]=4)=[CH:9][CH:10]=3)[CH2:15][N:16]3[CH2:17][CH2:18][O:19][CH2:20][CH2:21]3)=[O:38])[C:30]=2[CH:31]=1
Reactant: CN(C(=O)CN1C(=O)COc2cc(Cl)c(Cl)cc21)C(CN1CCOCC1)c1ccc(-c2cccc(N)c2)cc1
Reactant: CC(C)N=C=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)NC(=O)Nc1cccc(-c2ccc(C(CN3CCOCC3)N(C)C(=O)CN3C(=O)COc4cc(Cl)c(Cl)cc43)cc2)c1
Reaction time: 0.2 h
Yield: 12.2 %

Procedure:
To a solution of N-[1-(3′-amino-4-biphenylyl)-2-(4-morpholinyl)ethyl]-2-(6,7-dichloro-3-oxo-2,3-dihydro-4H-1,4-benzoxazin-4-yl)-N-methylacetamide (52 mg, 0.6 mmol) in dichloromethane (1 mL) was added isopropylisocyanate (36.5 mg, 0.51 mmol). Triethylamine (60 mg, 0.60 mmol) was added and the resultant mixture was stirred at room temperature for 18 h. The mixture was concentrated under reduced pressure and the residue was purified by Gilson preparative HPLC (Sunfire Prep C18, 30×150 mm, 50 mL/min, A: acetonitrile with 0.1% TFA B: water with 0.1% TFA, A: 30 to 60% over 12 min, UV detection at 214 nm) to give 40.8 mg (52%) of the title compound as off white solid. MS (ES) m/e 654.3 [M+H]+.
Reaction SMILES: Br[CH:2]([CH3:16])[C:3]([C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][CH:14]=1)[NH:11][C:10](=[O:15])[CH2:9][CH2:8]2)=O.[C:17]([NH:20][C:21]([NH2:23])=[S:22])(=[NH:19])[NH2:18]>C(O)C>[NH:20]([C:21]1[S:22][C:2]([CH3:16])=[C:3]([C:5]2[CH:6]=[C:7]3[C:12](=[CH:13][CH:14]=2)[NH:11][C:10](=[O:15])[CH2:9][CH2:8]3)[N:23]=1)[C:17]([NH2:19])=[NH:18]
Reactant: N=C(N)NC(N)=S
Reactant: CC(Br)C(=O)c1ccc2c(c1)CCC(=O)N2
Solvent: CCO
Product: Cc1sc(NC(=N)N)nc1-c1ccc2c(c1)CCC(=O)N2

Procedure:
A mixture of 6-(α-bromopropionyl)-3,4-dihydrocarbostyril (7 g), amidinothiourea (3.1 g) and absolute ethanol (250 ml) is stirred under reflux overnight. The reaction mixture is cooled to ice bath temperature, and the solid filtered, washed with ethanol, dried, and suspended in aqueous sodium hydroxide. The neutralized solid is filtered, washed with water, dried and recrystallized from 50% aqueous DMF affording the desired product, M.P. >250° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[NH:9][C:8](=[O:15])[N:7]=[C:6]2[CH3:16].[N+:17]([O-])([OH:19])=[O:18].OS(O)(=O)=O>>[CH3:1][O:2][C:3]1[C:4]([N+:17]([O-:19])=[O:18])=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[NH:9][C:8](=[O:15])[N:7]=[C:6]2[CH3:16]
Reactant: O=[N+]([O-])O
Reactant: COc1cc2[nH]c(=O)nc(C)c2cc1OC
Agent: O=S(=O)(O)O
Product: COc1cc2[nH]c(=O)nc(C)c2c([N+](=O)[O-])c1OC
Temperature: 0 °C

Procedure:
One equivalent of 6,7-dimethoxy-4-methyl-2(1H)quinazolinone is added during 3/4 hr. to a mixture (5:1) of 6 equivalents of concentrated nitric acid (70%) and concentrated H2SO4 at 0°±3° C. After one hour at the same temperature the solution is poured onto crushed ice (1000 ml). The crude product is collected by filtration, digested with boiling alcohol and the suspension is filtered. Crystallization from ethyl alcohol affords 6,7-dimethoxy-5-nitro-4-methyl-2(1H)quinazolinone.
Reaction SMILES: [NH2:1][CH:2]([C:9]1[C:14]([O:15][CH3:16])=[CH:13][CH:12]=[CH:11][C:10]=1[O:17][CH3:18])[CH2:3][CH2:4][C:5]([O:7]C)=O.[N:19]1([C:25]2[CH:26]=[C:27]([CH:30]=[CH:31][CH:32]=2)[CH:28]=O)[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1>>[CH3:18][O:17][C:10]1[CH:11]=[CH:12][CH:13]=[C:14]([O:15][CH3:16])[C:9]=1[CH:2]1[N:1]([CH2:28][C:27]2[CH:30]=[CH:31][CH:32]=[C:25]([N:19]3[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]3)[CH:26]=2)[C:5](=[O:7])[CH2:4][CH2:3]1
Reactant: O=Cc1cccc(N2CCCCC2)c1
Reactant: COC(=O)CCC(N)c1c(OC)cccc1OC
Product: COc1cccc(OC)c1C1CCC(=O)N1Cc1cccc(N2CCCCC2)c1

Procedure:
Prepared according to the described general procedure 2 (GP2) by reaction of methyl 4-amino-4-(2,6-dimethoxyphenyl)butanoate with commercially available 3-(piperidin-1-yl)benzaldehyde. Subsequent purification by preparative HPLC afforded the target compound. LC-MS (conditions A): tR=0.57 min.; [M+H]+: 394.99 g/mol.
Reaction SMILES: [CH3:1][C:2]1[NH:3][CH:4]=[C:5]([C:7]#[C:8][C:9]2[CH:10]=[C:11]([CH:14]=[CH:15][CH:16]=2)[C:12]#[N:13])[N:6]=1.F[C:18]1[CH:23]=[CH:22][C:21]([CH3:24])=[CH:20][N:19]=1>>[CH3:1][C:2]1[N:3]([C:18]2[CH:23]=[CH:22][C:21]([CH3:24])=[CH:20][N:19]=2)[CH:4]=[C:5]([C:7]#[C:8][C:9]2[CH:10]=[C:11]([CH:14]=[CH:15][CH:16]=2)[C:12]#[N:13])[N:6]=1
Reactant: Cc1nc(C#Cc2cccc(C#N)c2)c[nH]1
Reactant: Cc1ccc(F)nc1
Product: Cc1ccc(-n2cc(C#Cc3cccc(C#N)c3)nc2C)nc1

Procedure:
The title compound, MS: m/e=299.2 (M+H+), was prepared in accordance with the general method of example 1 from 3-(2-methyl-1H-imidazol-4-ylethynyl)-benzonitrile and 2-fluoro-5-methylpyridine.
Reaction SMILES: [CH3:1][C:2]1[C:6]([C:7]([OH:9])=O)=[CH:5][O:4][N:3]=1.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.[NH2:31][C@H:32]1[C:41]2[C:36](=[CH:37][CH:38]=[CH:39][CH:40]=2)[CH2:35][CH2:34][CH2:33]1>C(Cl)Cl.CN(C=O)C>[CH:32]1([NH:31][C:7]([C:6]2[C:2]([CH3:1])=[N:3][O:4][CH:5]=2)=[O:9])[C:41]2[C:36](=[CH:37][CH:38]=[CH:39][CH:40]=2)[CH2:35][CH2:34][CH2:33]1
Reactant: N[C@@H]1CCCc2ccccc21
Reactant: Cc1nocc1C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: ClCCl
Product: Cc1nocc1C(=O)NC1CCCc2ccccc21
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 62.5 %

Procedure:
To a solution of 3-Methyl-isoxazole-4-carboxylic acid (0.52 g, 4.06 mmol) in DCM (15 mL) and DMF (2 mL), was added HOBt (1.1 g, 8.14 mmol) and EDCI (0.896 g 4.67 mmol). The clear yellow solution was cooled to 0 C and allowed to stir under Ar for 15 minutes. To the solution was added (R)-1-Amino-1,2,3,4-tetrahydronaphthalene (0.73 mL, 5.04 mmol and the reaction mixture was allowed to slowly warm to ambient temperature and was stirred for overnight. Dilution with DCM (50 mL) was followed by aqueous extraction (NaHCO3 water, brine (50 mL), drying over MgSO4, filtration and removal of solvent in vacuo. Silica gel chromatography (0-25% Hexane:EtOAc) afforded the title compound (650 mg; 62.5%) as a sticky solid. 1H NMR (CDCl3) δ 1.88 (m, 3H), 2.12 (m, 1H), 2.51 (s, 3H), 2.81 (m, 2H), 5.32 (m, 1H), 5.99 (bd, 1H), 7.13 (m, 1H), 7.20 (m, 2H) 7.20 (m, 2H); 13C NMR (CDCl3) δ 11.22, 20.15, 29.41, 30.35, 47.93, 116.73, 126.72, 127.88, 128.88, 129.65, 136.25, 138.00, 158.45, 160.28. ESIMS: 257 (M+H) EA calc'd for C15H16N2O2: C, 70.29; H, 6.29; N, 10.93; found C, 70.61; H, 6.11; N, 11.09.
Reaction SMILES: [Cl:1][C:2]1[C:7]([CH3:8])=[CH:6][CH:5]=[C:4]([Cl:9])[C:3]=1[NH:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[CH2:17][O:18][NH2:19].[CH:20]([C:22]1[NH:26][N:25]=[N:24][N:23]=1)=O>>[Cl:1][C:2]1[C:7]([CH3:8])=[CH:6][CH:5]=[C:4]([Cl:9])[C:3]=1[NH:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[CH2:17][O:18][N:19]=[CH:20][C:22]1[NH:26][N:25]=[N:24][N:23]=1
Reactant: Cc1ccc(Cl)c(Nc2ccccc2CON)c1Cl
Reactant: O=Cc1nnn[nH]1
Product: Cc1ccc(Cl)c(Nc2ccccc2CON=Cc2nnn[nH]2)c1Cl

Procedure:
The title compound is prepared by the reaction of O-[2-[(2,6-dichloro-3-methylphenyl)amino]phenylmethyl]hydroxylamine, prepared as in Example 1, steps 1-3, with 5-formyltetrazole.
Reaction SMILES: [CH2:1]([C@@H:4]1[C:9](=[O:10])[NH:8][C:7]2[CH:11]=[CH:12][CH:13]=[N:14][C:6]=2[NH:5]1)[C:2]#[CH:3].[C:15]1([CH3:25])[CH:20]=[CH:19][C:18]([S:21](Cl)(=[O:23])=[O:22])=[CH:17][CH:16]=1.CCOC(C)=O>N1C=CC=CC=1>[CH2:1]([C@@H:4]1[C:9](=[O:10])[NH:8][C:7]2[CH:11]=[CH:12][CH:13]=[N:14][C:6]=2[N:5]1[S:21]([C:18]1[CH:19]=[CH:20][C:15]([CH3:25])=[CH:16][CH:17]=1)(=[O:23])=[O:22])[C:2]#[CH:3]
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: C#CC[C@H]1Nc2ncccc2NC1=O
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Product: C#CC[C@@H]1C(=O)Nc2cccnc2N1S(=O)(=O)c1ccc(C)cc1
Reaction time: 7 h
Yield: 67.9 %

Procedure:
To (R)-3-(prop-2-ynyl)-3,4-dihydropyrido[3,2-b]pyrazin-2(1H)-one (0.42 g, 2244 μmol) in pyridine was added p-toluenesulfonyl chloride (642 mg, 3365 μmol). The reaction mixture was stirred for 7 h and then EtOAc was added. The organic layer was separated, washed with brine, brine/5mL 10% HCl, dried, evaporated to give 0.52 g of solid. Purification by column chromatograph (DCM to 20% EtOAc/DCM) gave the title compound. MS 342 (M+1).
Reaction SMILES: [H-].[Na+].CI.C(O[C:10]([NH:12][CH2:13][C:14]1[CH:23]=[CH:22][C:17]([C:18]([O:20][CH3:21])=[O:19])=[CH:16][CH:15]=1)=O)(C)(C)C>C1COCC1>[CH3:10][NH:12][CH2:13][C:14]1[CH:23]=[CH:22][C:17]([C:18]([O:20][CH3:21])=[O:19])=[CH:16][CH:15]=1
Reactant: COC(=O)c1ccc(CNC(=O)OC(C)(C)C)cc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CI
Product: CNCc1ccc(C(=O)OC)cc1
Reaction time: 8 h
Yield: 65.1 %

Procedure:
1.13 g of NaH at 60% in oil, and then 2.35 ml of methyl iodide are added to a solution of 5 g of methyl 4-[[(tert-butoxycarbonyl)amino]methyl]benzoate in 150 ml of THF and the mixture is left to stir at AT overnight. The reaction mixture is concentrated under vacuum, the residue is taken up with a water/ice mixture, the mixture is extracted with EtOAc, the organic phase is dried over Na2SO4, and the solvent is evaporated off under vacuum. The residue is taken up with 80 ml of 2N hydrochloric ether, 1 ml of water is added, and the mixture is left to stir at AT overnight. The reaction mixture is concentrated under vacuum, the residue is taken up with a 5% NaHCO3 solution, the mixture is extracted with DCM, the organic phase is dried over Na2SO4, and the solvent is evaporated off under vacuum. 2.2 g of the expected compound are obtained.
Reaction SMILES: [CH3:1][N:2]1[CH2:8][CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.[C:9]([C:11]1[CH:16]=[CH:15][C:14]([C:17]2[CH:18]=[N:19][N:20]([C:23]3[CH:31]=[CH:30][C:26]([C:27](O)=[O:28])=[CH:25][N:24]=3)[C:21]=2[OH:22])=[C:13]([CH3:32])[CH:12]=1)#[N:10].C(O)=O>>[OH:22][C:21]1[N:20]([C:23]2[CH:31]=[CH:30][C:26]([C:27]([N:5]3[CH2:6][CH2:7][CH2:8][N:2]([CH3:1])[CH2:3][CH2:4]3)=[O:28])=[CH:25][N:24]=2)[N:19]=[CH:18][C:17]=1[C:14]1[CH:15]=[CH:16][C:11]([C:9]#[N:10])=[CH:12][C:13]=1[CH3:32]
Reactant: CN1CCCNCC1
Reactant: Cc1cc(C#N)ccc1-c1cnn(-c2ccc(C(=O)O)cn2)c1O
Solvent: O=CO
Product: Cc1cc(C#N)ccc1-c1cnn(-c2ccc(C(=O)N3CCCN(C)CC3)cn2)c1O

Procedure:
The title compound was prepared in a manner similar to Example 284 using 1-methyl-1,4-diazepane and 6-(4-(4-cyano-2-methylphenyl)-5-hydroxy-1H-pyrazol-1-yl)nicotinic acid to give a formic acid salt (67 mg, 0.145 mmol, 77%) as an off-white solid. MS: 417 (M+H). 1H NMR (400 MHz, DMSO-d6) δ ppm 1.88 (br. s., 2H) 2.35 (s, 3H) 2.54 (br. s., 2H) 2.86 (d, J=17.7 Hz, 3H) 3.01 (br. s., 1H) 3.39-3.76 (m, 5H) 7.45 (d, J=8.1 Hz, 1H) 7.50 (s, 1H) 7.78-7.91 (m, 2H) 8.04 (d, J=7.6 Hz, 1H) 8.42 (br. s., 2H) 11.65 (br. s., 1H)
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[CH:4][C:3]=1[C:15](=[O:17])[CH3:16].[O:18]1[CH2:23][CH2:22][CH2:21][C:20](=O)[CH2:19]1.N1CCCC1>C1(C)C=CC=CC=1>[O:8]([C:5]1[CH:4]=[C:3]2[C:2](=[CH:7][CH:6]=1)[O:1][C:20]1([CH2:21][CH2:22][CH2:23][O:18][CH2:19]1)[CH2:16][C:15]2=[O:17])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: CC(=O)c1cc(Oc2ccccc2)ccc1O
Reactant: O=C1CCCOC1
Solvent: C1CCNC1
Solvent: Cc1ccccc1
Product: O=C1CC2(CCCOC2)Oc2ccc(Oc3ccccc3)cc21
Yield: 51.4 %

Procedure:
To a solution of 1-(2-hydroxy-5-phenoxyphenyl)ethanone (2.0 g, 8.77 mmol) in toluene (30 mL) was added dihydro-2H-pyran-3(4H)-one (1.14 g, 11.40 mmol) and pyrrolidine (0.81 g, 11.40 mmol), and the reaction mixture was refluxed overnight. After cooling, the mixture was concentrated. The residue was washed with 1 N HCl, brine, dried and concentrated to give the crude product, which was purified by chromatography to afford 6-phenoxy-2′,4′,5′,6′-tetrahydrospiro[chroman-2,3′-pyran]-4-one (1.40 g, 52%). 1H-NMR (CDCl3): 0.79 (m, 1H), 1.52 (m, 2H), 1.67 (m, 1H), 1.92 (m, 1H), 2.08 (m, 1H), 2.57-2.61 (q, 2H), 3.51 (m, 2H), 3.88 (m, 2H), 6.89 (d, 2H), 7.03 (m, 2H), 7.18 (m, 1H), 7.26 (t, 2H), 7.39 (m, 1H).
Reaction SMILES: FC(F)(F)C(O)=O.C([O:12][C:13]([CH2:15][O:16][N:17]=[C:18]([C:44]1[N:45]=[C:46]([NH2:49])[S:47][CH:48]=1)[C:19]([NH:21][CH:22]1[C:42](=[O:43])[N:24]2[C:25]([C:39]([OH:41])=[O:40])=[C:26]([CH2:29][S:30][C:31]3[N:35]([CH2:36][CH:37]=[CH2:38])[N:34]=[N:33][N:32]=3)[CH2:27][S:28][C@H:23]12)=[O:20])=[O:14])(C)(C)C>C1(OC)C=CC=CC=1>[C:13]([CH2:15][O:16][N:17]=[C:18]([C:44]1[N:45]=[C:46]([NH2:49])[S:47][CH:48]=1)[C:19]([NH:21][CH:22]1[C:42](=[O:43])[N:24]2[C:25]([C:39]([OH:41])=[O:40])=[C:26]([CH2:29][S:30][C:31]3[N:35]([CH2:36][CH:37]=[CH2:38])[N:34]=[N:33][N:32]=3)[CH2:27][S:28][C@H:23]12)=[O:20])([OH:14])=[O:12]
Reactant: C=CCn1nnnc1SCC1=C(C(=O)O)N2C(=O)C(NC(=O)C(=NOCC(=O)OC(C)(C)C)c3csc(N)n3)[C@H]2SC1
Solvent: O=C(O)C(F)(F)F
Solvent: COc1ccccc1
Product: C=CCn1nnnc1SCC1=C(C(=O)O)N2C(=O)C(NC(=O)C(=NOCC(=O)O)c3csc(N)n3)[C@H]2SC1
Yield: 42.8 %

Procedure:
Trifluoroacetic acid (20 ml) was added under ice-cooling to a stirred suspension of 7-[2-t-butoxycarbonylmethoxyimino-2-(2-aminothiazol-4-yl)acetamido]-3-(1-allyl-1H-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylic acid (syn isomer)(2.05 g) in anisole (2 ml), and the resultant mixture was stirred for 2 hours at ambient temperature. The reaction mixture was concentrated under reduced pressure and diethyl ether was added thereto. Precipitates were collected by filtration, washed with diethyl ether, dried and dissolved in an aqueous solution of sodium bicarbonate. An insoluble material was filtered off and the filtrate was adjusted to pH 3.2 with conc.hydrochloric acid. Precipitates were collected by filtration, washed with water and dried to give 7-[2-carboxymethoxyimino-2-(2-aminothiazol-4-yl)acetamido]-3-(1-allyl-1H-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylic acid (syn isomer)(0.8 g).
Reaction SMILES: [NH2:1][C@@H:2]1[CH2:7][N:6]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:5][C@H:4]([C:15]([O:17][CH3:18])=[O:16])[CH2:3]1.[CH:19](=O)[CH:20]([CH3:22])[CH3:21].C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>CO>[CH2:19]([NH:1][C@@H:2]1[CH2:7][N:6]([C:8]([O:10][C:11]([CH3:12])([CH3:13])[CH3:14])=[O:9])[CH2:5][C@H:4]([C:15]([O:17][CH3:18])=[O:16])[CH2:3]1)[CH:20]([CH3:22])[CH3:21]
Reactant: COC(=O)[C@@H]1C[C@H](N)CN(C(=O)OC(C)(C)C)C1
Reactant: CC(C)C=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: COC(=O)[C@@H]1C[C@H](NCC(C)C)CN(C(=O)OC(C)(C)C)C1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
1-tert-Butyl 3-methyl (3R,5S)-5-aminopiperidine-1,3-dicarboxylate (1.83 g), isobutyraldehyde (0.78 ml) and acetic acid (0.49 ml) were dissolved in methanol (50 ml), and the mixture was stirred at room temperature for 30 min. Sodium triacetoxyborohydride (3.80 g) was added to the reaction mixture, and the mixture was stirred at room temperature for 7 hr. The reaction mixture was concentrated under reduced pressure, the concentrated solution was basified with aqueous sodium hydrogen carbonate, and the mixture was extracted with ethyl acetate. The extract was washed with water and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography. The fraction eluted with ethyl acetate-hexane (1:1) to ethyl acetate 100% to ethyl acetate-methanol (9:1) was concentrated under reduced pressure to give the object compound (1.42 g) as an oil.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7]([O:10][C:11]2[CH:19]=[CH:18][CH:17]=[C:16]3[C:12]=2[C:13]([CH:20]=O)=[N:14][NH:15]3)=[N:8][CH:9]=1)([O-:3])=[O:2].[CH3:22][N:23]1[CH2:28][CH2:27][N:26]([C:29]2[CH:30]=[C:31]([NH2:36])[C:32]([NH2:35])=[CH:33][CH:34]=2)[CH2:25][CH2:24]1>>[CH3:22][N:23]1[CH2:24][CH2:25][N:26]([C:29]2[CH:34]=[CH:33][C:32]3[N:35]=[C:20]([C:13]4[C:12]5[C:16](=[CH:17][CH:18]=[CH:19][C:11]=5[O:10][C:7]5[CH:6]=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:9][N:8]=5)[NH:15][N:14]=4)[NH:36][C:31]=3[CH:30]=2)[CH2:27][CH2:28]1
Reactant: CN1CCN(c2ccc(N)c(N)c2)CC1
Reactant: O=Cc1n[nH]c2cccc(Oc3ccc([N+](=O)[O-])cn3)c12
Product: CN1CCN(c2ccc3nc(-c4n[nH]c5cccc(Oc6ccc([N+](=O)[O-])cn6)c45)[nH]c3c2)CC1

Procedure:
The formation of the tide compound is carried out using 4-(5-nitropyridin-2-yloxy)-1H-indazole-3-carbaldehyde and 4-(4-methylpiperazin-1-yl)-benzene-1,2-diamine using the method described above in Example 4.