Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([C:3]1[CH:14]=[CH:13][C:12]([CH3:15])=[CH:11][C:4]=1[O:5][CH2:6][C:7]([O:9][CH3:10])=[O:8])=[O:2].[BH4-].[Na+]>CO.C[O-].[Na+]>[OH:2][CH2:1][C:3]1[CH:14]=[CH:13][C:12]([CH3:15])=[CH:11][C:4]=1[O:5][CH2:6][C:7]([O:9][CH3:10])=[O:8]
Reactant: COC(=O)COc1cc(C)ccc1C=O
Agent: C[O-]
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: COC(=O)COc1cc(C)ccc1CO
Yield: 82.9 %

Procedure:
By the method of Example 1, Step G, 11.27 g (0.054 mole) of methyl (2-formyl-5-methylphenoxy)acetate was reacted with 0.54 g (0.014 mole) of sodium borohydride and 0.10 g (0.0018 mole) of sodium methoxide in 30 mL of methanol, yielding 9.41 g of methyl (2-hydroxymethyl-5-methylphenoxy)acetate as a yellow oil. The NMR spectrum was consistent with the proposed structure.
Reaction SMILES: [CH3:1][NH2:2].O.C(O[C:7]([C:9]1[C:14]([NH2:15])=[CH:13][CH:12]=[C:11]([Br:16])[N:10]=1)=[O:8])C>CO>[NH2:15][C:14]1[C:9]([C:7]([NH:2][CH3:1])=[O:8])=[N:10][C:11]([Br:16])=[CH:12][CH:13]=1
Reactant: CCOC(=O)c1nc(Br)ccc1N
Reactant: CN
Solvent: CO
Solvent: O
Product: CNC(=O)c1nc(Br)ccc1N
Temperature: 100 °C

Procedure:
A 10M solution of Methylamine in H2O (30.0 mL, 386 mmol) was added to a stainless steel reactor containing 3-amino-6-bromopyridine-2-carboxylic acid ethyl ester (Compound 6E, 7.614 g, 31.07 mmol) in MeOH (20.0 mL). The reactor was sealed and heated to 100° C. for 16 hours. The cooled reaction mixture was transferred to a round bottom flask and concentrated in vacuo forming a yellow precipitate which was collected by filtration. Further precipitate formed in the filtrate which was also collected. The combined precipitates were dried in vacuo to afford the title compound as 6.18 g of a yellow solid. 1H NMR (400 MHz, CDCl3) δ 7.80 (br. s., 1H), 7.27 (d, J=8.6 Hz, 1H), 6.91 (d, J=8.6 Hz, 1H), 6.02 (br. s., 2H), 2.97 (d, J=5.1 Hz, 3H).
Reaction SMILES: C([O:8][C:9]1[C:14]([N+:15]([O-])=O)=[CH:13][C:12]([N+:18]([O-])=O)=[C:11]([O:21]CC2C=CC=CC=2)[CH:10]=1)C1C=CC=CC=1.[ClH:29]>>[ClH:29].[ClH:29].[NH2:15][C:14]1[CH:13]=[C:12]([NH2:18])[C:11]([OH:21])=[CH:10][C:9]=1[OH:8]
Reactant: O=[N+]([O-])c1cc([N+](=O)[O-])c(OCc2ccccc2)cc1OCc1ccccc1
Agent: Cl
Product: Nc1cc(N)c(O)cc1O

Procedure:
An essential point for carrying out the process according to the invention is that the 1,3-dibenzyloxy-4,6-dinitrobenzene is reacted in a two-phase mixture in dilute aqueous hydrochloric acid and an organic solvent, which is immiscible or miscible only to a limited extent with dilute aqueous hydrochloric acid, at normal or elevated pressure and normal or elevated temperature by catalytic hydrogenation, preferably catalytic pump hydrogenation, to give 4,6-diamino-resorcinol dihydrochloride. In a preferred embodiment, a solution of the suspension of 1,3-dibenzyloxy-4,6-dinitrobenzene in an organic solvent is pumped under hydrogenation conditions into a hydrogenation autoclave, into which a suspension of the noble metal catalyst in dilute aqueous hydrochloric acid or an aqueous solution of 4,6-diamino-resorcinol dihydrochloride containing hydrochloric acid has been introduced beforehand under H2 pressure.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C@@H:12](/[CH:13]=[CH:14]/[C:15]2[CH:20]=[CH:19][C:18]([NH:21][C:22]([NH:24][C:25]3[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=3)=[O:23])=[CH:17][CH:16]=2)[CH2:11][O:10][C:9]1([CH3:33])[CH3:32])=[O:7])([CH3:4])([CH3:3])[CH3:2]>CO.[Pt](=O)=O>[C:1]([O:5][C:6]([N:8]1[C@@H:12]([CH2:13][CH2:14][C:15]2[CH:20]=[CH:19][C:18]([NH:21][C:22]([NH:24][C:25]3[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=3)=[O:23])=[CH:17][CH:16]=2)[CH2:11][O:10][C:9]1([CH3:33])[CH3:32])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1[C@@H](/C=C/c2ccc(NC(=O)Nc3ccc(Cl)cc3)cc2)COC1(C)C
Agent: O=[Pt]=O
Solvent: CO
Product: CC(C)(C)OC(=O)N1[C@@H](CCc2ccc(NC(=O)Nc3ccc(Cl)cc3)cc2)COC1(C)C
Temperature: 25 °C
Reaction time: 1 h
Yield: 104.8 %

Procedure:
To a stirred suspension of (S)-4-((E)-2-{4-[3-(4-chloro-phenyl)-ureido]-phenyl}-vinyl)-2,2-dimethyl-oxazolidine-3-carboxylic acid tert-butyl ester (57 mg) in methanol (8 ml) was added platinum(IV) oxide (14 mg) and the mixture was then stirred under an atmosphere of hydrogen at room temperature for 1 hour. The mixture was then filtered through celite and the filtrate was concentrated in vacuo to afford (S)-4-(2-{4-[3-(4-chloro-phenyl)-ureido]-phenyl}-ethyl)-2,2-dimethyl-oxazolidine-3-carboxylic acid tert-butyl ester (60 mg, quant) as an off-white solid. MS (ISP): 476.2 ([{37Cl}M−H]+), 474.3 ([{35Cl}M−H]+), 420.2 ([{37Cl}M+H—C4H8]+), 418.3 ([{35Cl}M+H—C4H8]+).
Reaction SMILES: [OH:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([N:8]([CH3:22])[S:9]([C:12]2[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][CH:13]=2)(=[O:11])=[O:10])[CH2:4][CH2:3]1.[Br:23][CH2:24][CH2:25][CH2:26]Br>>[Br:23][CH2:24][CH2:25][CH2:26][O:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([N:8]([CH3:22])[S:9]([C:12]2[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:19])[F:20])=[CH:14][CH:13]=2)(=[O:11])=[O:10])[CH2:4][CH2:3]1
Reactant: BrCCCBr
Reactant: CN([C@H]1CC[C@H](O)CC1)S(=O)(=O)c1ccc(C(F)(F)F)cc1
Product: CN([C@H]1CC[C@H](OCCCBr)CC1)S(=O)(=O)c1ccc(C(F)(F)F)cc1

Procedure:
In analogy to example 11.11, trans-N-(4-Hydroxy-cyclohexyl)-N-methyl-4-trifluoromethyl-benzenesulfonamide and 1,3-dibrompropane were converted to yield trans-N-[4-(3-Bromo-propoxy)-cyclohexyl]-N-methyl-4-trifluoromethyl-benzenesulfonamide as off-white semisolid, MS: 320 [M−C3H6BrO].
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4](O)=[CH:3][C:2]=1[OH:12].[CH2:13]([NH2:18])[C:14]([CH3:17])([CH3:16])[CH3:15].Cl.CN1C(=O)CCC1>C(O)(C)C>[CH3:15][C:14]([CH3:17])([CH3:16])[CH2:13][NH:18][C:4]1[C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[N:1]=[C:2]([OH:12])[CH:3]=1
Reactant: Oc1cc(O)c2ccccc2n1
Reactant: CC(C)(C)CN
Agent: Cl
Solvent: CN1CCCC1=O
Solvent: CC(C)O
Product: CC(C)(C)CNc1cc(O)nc2ccccc12
Temperature: 180 °C
Reaction time: 1 h

Procedure:
2,4-Quinolinediol (15 g, 93 mmol), neopentyl amine (33 mL, 280 mmol), 6 N HCl in isopropanol (15 mL), and 40 mL NMP were place in a sealed tube and heated to 180° C. for 40 h. The reaction was then poured onto water (800 mL), stirred for 1 h and filtered. The cake was washed with water, collected and dried in vacuo (50 mTorrr, 60° C.) to afford 17.85 g (81.5%). 1H NMR (360 MHz, DMSO): 0.97 (s, 9H), 3.02(d, 2H, J=6.06 Hz), 5.41(s, 1H), 6.58(t, 1H, J=6.06 Hz), 7.08(t, 1H, J=7.67 Hz), 7.21(d, 1H, J=8.07 Hz), 7.43(dd, 1H, J=7.67, 7.27 Hz), 8.03(d, 1H, J=8.07 Hz), 10.73(s, 1H).
Reaction SMILES: [Br:1][C:2]1[CH:12]=[CH:11][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:4][C:3]=1[OH:13].C(=O)([O-])[O-].[K+].[K+].Cl[CH2:21][CH:22]1[CH2:24][CH2:23]1>CN(C=O)C>[Br:1][C:2]1[CH:12]=[CH:11][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:4][C:3]=1[O:13][CH2:21][CH:22]1[CH2:24][CH2:23]1
Reactant: CCOC(=O)c1ccc(Br)c(O)c1
Reactant: ClCC1CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1ccc(Br)c(OCC2CC2)c1
Temperature: 80 °C
Yield: 31.4 %

Procedure:
Ethyl 4-bromo-3-hydroxybenzoate (2.0 g, 8.2 mmol), potassium carbonate (3.4 g, 24.48 mmol and (chloromethyl)cyclopropane (1.13 mL, 12.24 mmol) were placed in 50 mL DMF and the reaction was heated at 80° C. for 18 h. The mixture was cooled and partitioned between EtOAc and water. The organic layer was separated, washed with water, brine, dried (Na2SO4), filtered, and the filtrate was concentrated to an oil. Purification by column chromatography on silica gel using 0-50% EtOAc/hexane gave the product (0.77 g, 31%) as a clear oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]2[O:9][C:10]([C:12]#[N:13])=[CH:11][C:7]=2[CH:6]=[CH:5][CH:4]=1.Cl.[NH2:15][OH:16].C(=O)([O-])O.[Na+]>>[OH:16][N:15]=[C:12]([NH2:13])[C:10]1[O:9][C:8]2[C:3]([O:2][CH3:1])=[CH:4][CH:5]=[CH:6][C:7]=2[CH:11]=1
Reactant: COc1cccc2cc(C#N)oc12
Reactant: NO
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Product: COc1cccc2cc(C(N)=NO)oc12
Yield: 92.4 %

Procedure:
By the reactions in the same manner as in Starting Material Synthesis Example 28 using 7-methoxybenzo(b)furan-2-carbonitrile (3.0 g), hydroxylamine hydrochloride (1.4 g) and sodium hydrogencarbonate (2.1 g), the title compound (3.3 g) was obtained as brown crystals.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([CH2:11][S:12](Cl)(=[O:14])=[O:13])=[CH:7][CH:6]=1)(=[O:4])=[O:3].[NH2:16][C:17]1[S:18][CH:19]=[CH:20][N:21]=1>N1C=CC=CC=1>[CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([CH2:11][S:12]([NH:16][C:17]2[S:18][CH:19]=[CH:20][N:21]=2)(=[O:14])=[O:13])=[CH:7][CH:6]=1)(=[O:4])=[O:3]
Reactant: CS(=O)(=O)c1ccc(CS(=O)(=O)Cl)cc1
Reactant: Nc1nccs1
Solvent: c1ccncc1
Product: CS(=O)(=O)c1ccc(CS(=O)(=O)Nc2nccs2)cc1
Reaction time: 48 h

Procedure:
To the solution of the title B compound, (4-methanesulfonyl-phenyl)-methanesulfonyl chloride (1.86 mmol, 0.5 g) in 5 mL of pyridine is added 2-aminothiazole (2.5 mmol, 0.25 g) and the mixture is stirred for 48 h. The reaction mixture is quenched with aqueous 1 N HCl and the product is taken up in EtOAc, dried and concentrated to afford C-(4-methanesulfonyl-phenyl)-N-thiazol-2-yl-methanesulfonamide.
Reaction SMILES: [C:1]([N:3]=[C:4]([C:9]1[CH:10]=[N:11][CH:12]=[CH:13][CH:14]=1)OC(C)C)#[N:2].[C:15]1([CH:21]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH2:22][CH2:23][NH2:24])[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>CO>[C:1]([NH:3][C:4]([C:9]1[CH:10]=[N:11][CH:12]=[CH:13][CH:14]=1)=[N:24][CH2:23][CH2:22][CH:21]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)#[N:2]
Reactant: NCCC(c1ccccc1)c1ccccc1
Reactant: CC(C)OC(=NC#N)c1cccnc1
Solvent: CO
Product: N#CNC(=NCCC(c1ccccc1)c1ccccc1)c1cccnc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 62.5 %

Procedure:
Isopropyl N-cyano-3-pyridinecarboximidate (0.60 g, 3.2 mmol) was dissolved in methanol (10 ml), and 3,3-diphenylpropylamine (0.74 g, 3.5 mmol) was added. The mixture was stirred at room temperature for 1 hour. After the reaction was completed, the reaction solution was concentrated under reduced pressure. The residual concentrate thus obtained was subjected to chromatography on a silica gel column (WAKO GEL C-200, 50 g) eluting with chloroform-methanol (100:1). The eluted fractions were concentrated under reduced pressure and crystallized from methanol-diethyl ether to give the title compound (0.68 g, 2.0 mmol, yield: 63%) as colorless powder.
Reaction SMILES: [N+:1]([O-:4])(O)=[O:2].[N:5]1[N:9]2[C:10]3[C:15]([C:16]([OH:18])=[CH:17][C:8]2=[N:7][N:6]=1)=[CH:14][CH:13]=[CH:12][N:11]=3.C([O-])(=O)C.[Na+].O>C(O)(=O)C>[N+:1]([C:17]1[C:8]2[N:9]([N:5]=[N:6][N:7]=2)[C:10]2[C:15]([C:16]=1[OH:18])=[CH:14][CH:13]=[CH:12][N:11]=2)([O-:4])=[O:2]
Reactant: O=[N+]([O-])O
Reactant: Oc1cc2nnnn2c2ncccc12
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: O=[N+]([O-])c1c(O)c2cccnc2n2nnnc12
Temperature: 25 °C

Procedure:
Nitric acid (1.33 mL of 16M) was added to a suspension of tetrazolo[1,5-a][1,8]naphthyridin-5-ol (4 g, 21 mmole) in acetic acid (50 mL). The reaction mixture was heated on a steam bath for 5 minutes then cooled to ambient temperature. Sodium acetate (0.3 eq) in a small amount of water was added to the reaction mixture. The resulting solid was isolated by filtration and dried to provide 5 g of 4-nitrotetrazolo[1,5-a][1,8]naphthryidin-5-ol as a solid, m.p. 278° C. (decomposition). Analysis: Calculated for C8H4N6O3+1.1 H2O: %C, 38.12; %H, 2.48; %N, 33.35; Found: %C, 37.99; %H, 2.41; %N, 32.82.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([C:8](Cl)=[O:9])[CH:5]=[CH:4][N:3]=1.C([O-])(O)=O.[Na+].[CH2:16]([OH:20])[CH2:17][CH2:18][CH3:19]>>[CH2:16]([O:20][C:8]([C:6]1[CH:5]=[CH:4][N:3]=[C:2]([Cl:1])[N:7]=1)=[O:9])[CH2:17][CH2:18][CH3:19]
Reactant: CCCCO
Reactant: O=C(Cl)c1ccnc(Cl)n1
Agent: O=C([O-])O
Agent: [Na+]
Product: CCCCOC(=O)c1ccnc(Cl)n1
Yield: 85 %

Procedure:
A solution of 0.52 g (2.93 mmol) of 2-chloropyrimidine-4-carboxylic acid chloride in 10 ml of butanol was stirred for 1.5 hours at room temperature. Then the reaction solution was poured on 80 ml of NaHCO3 solution and extracted three times with 60 ml of ethyl acetate each. The combined organic phase was washed with 60 ml of saturated NaCl solution, dried on Na2SO4 and concentrated by evaporation on a rotary evaporator. After drying of the product on a high vacuum, 0.53 g of product was obtained as a white solid, corresponding to a yield of 85 percent relative to the 2-chloropyrimidine-4-carboxylic acid chloride used. The melting point of the product was 67.9° to 68.8° C. Other data for the product was:
Reaction SMILES: [N+:1]([C:4]1[CH:14]=[C:13]([S:15]([CH3:18])(=[O:17])=[O:16])[CH:12]=[CH:11][C:5]=1[C:6]([O:8][CH2:9][CH3:10])=[O:7])([O-])=O>CO.[Pd]>[NH2:1][C:4]1[CH:14]=[C:13]([S:15]([CH3:18])(=[O:17])=[O:16])[CH:12]=[CH:11][C:5]=1[C:6]([O:8][CH2:9][CH3:10])=[O:7]
Reactant: CCOC(=O)c1ccc(S(C)(=O)=O)cc1[N+](=O)[O-]
Agent: [Pd]
Solvent: CO
Product: CCOC(=O)c1ccc(S(C)(=O)=O)cc1N
Yield: 73 %

Procedure:
A solution of ethyl 2-nitro-4-methylsulphonylbenzoate (10.0 g) in methanol was hydrogenated over 5% palladium on charcoal catalyst (1.2 g) at room temperature and atmospheric pressure. The resultant slurry was filtered and the filtrate was evaporated to dryness to give ethyl 2-amino-4-methylsulphonylbenzoate (6.5 g) as a yellow solid NMR (CDC3) 1.4(t,3H) 3.1(s,3H) 4.35(q,2H) 6.1(bs,2H) 7.0(d, H) 7.2(s,1H) 7.95(d, 1H).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([N+:8]([O-])=O)[CH:5]=[C:4]([O:11][CH3:12])[CH:3]=1.[Cl-].[NH4+]>C1COCC1.O.[Zn]>[Br:1][C:2]1[CH:7]=[C:6]([CH:5]=[C:4]([O:11][CH3:12])[CH:3]=1)[NH2:8]
Reactant: COc1cc(Br)cc([N+](=O)[O-])c1
Agent: [Cl-]
Agent: [NH4+]
Agent: [Zn]
Solvent: C1CCOC1
Solvent: O
Product: COc1cc(N)cc(Br)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 92 %

Procedure:
To a solution of 1-bromo-3-methoxy-5-nitrobenzene (1 g, 4.33 mmol) in THF (10 ml) were added a solution of ammonium chloride (1.83 g, 34.6 mmol, 8 eq.) in water (5 ml) and zinc (1.93 g, 34.6 mmol, 8 eq.). The mixture was stirred at RT for 30 min and filtered. The filtrate was diluted with water and extracted as in Example 1(d). The solvent was distilled off to afford the product in 92% yield (0.8 g).
Reaction SMILES: [CH2:1]([CH:3]1[C:11]2[C:6](=[C:7]([CH3:12])[CH:8]=[CH:9][CH:10]=2)[NH:5][C:4]1=[O:13])[CH3:2].Br[CH2:15][CH2:16][CH2:17][CH2:18][Cl:19]>>[Cl:19][CH2:18][CH2:17][CH2:16][CH2:15][C:3]1([CH2:1][CH3:2])[C:11]2[C:6](=[C:7]([CH3:12])[CH:8]=[CH:9][CH:10]=2)[NH:5][C:4]1=[O:13]
Reactant: CCC1C(=O)Nc2c(C)cccc21
Reactant: ClCCCCBr
Product: CCC1(CCCCCl)C(=O)Nc2c(C)cccc21

Procedure:
The title compound is prepared according to process E starting from 3-ethyl-7-methyl-1,3-dihydro-2H-indol-2-one and 1-bromo-4-chloro-butane.
Reaction SMILES: [OH:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][N:5]=[C:4](SC)[N:3]=1.[NH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>C(O)C>[NH:13]([C:4]1[N:3]=[C:2]([OH:1])[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][N:5]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: Nc1ccccc1
Reactant: CSc1ncc([N+](=O)[O-])c(O)n1
Solvent: CCO
Product: O=[N+]([O-])c1cnc(Nc2ccccc2)nc1O

Procedure:
4.65 gm of 4-hydroxy-2-methylmercapto-5-nitropyrimidine (0.025 mol) are dissolved with heating in 150 ml of ethanol and refluxed for 5 hours with 4.68 gm of aniline (0.05 mol). The precipitated product is extracted in the cold, washed with ethanol and dried.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[N:10][CH:11]=1)[NH:8][C:7](=[O:12])[CH2:6][CH2:5]2.[CH2:13]([Sn](CCCC)(CCCC)C=C)[CH2:14]CC>CN(C=O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH:13]([C:2]1[CH:3]=[C:4]2[C:9](=[N:10][CH:11]=1)[NH:8][C:7](=[O:12])[CH2:6][CH2:5]2)=[CH2:14]
Reactant: O=C1CCc2cc(Br)cnc2N1
Reactant: C=C[Sn](CCCC)(CCCC)CCCC
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Product: C=Cc1cnc2c(c1)CCC(=O)N2
Temperature: 105 °C
Yield: 59.4 %

Procedure:
6-Bromo-3,4-dihydro-1H-[1,8]naphthyridin-2-one (113e) (4.6 g, 20.3 mmole) and tributyl(vinyl)tin (7.7 g, 24.4 mmole) were dissolved in DMF (200 mL) and the solution was degassed with nitrogen. (Ph3P)4Pd (590 mg, 0.5 mmole) was added to the solution. The reaction was heated to 105° C. under nitrogen overnight, then was cooled to room temperature and filtered through a sintered glass funnel. The filtrate was washed with NH4OH and extracted with EtOAc (2×150 mL). The combined organic phases were washed with brine, dried over Na2SO4 and concentrated in vacuo to afford the title compound (2.1 g, 60%) as an off white solid: MS (ES) m/e 175 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:27]=[C:26]([F:28])[CH:25]=[CH:24][C:3]=1[CH2:4][N:5]([CH2:16][C:17]1[CH:22]=[CH:21][C:20]([OH:23])=[CH:19][CH:18]=1)[C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([N+:12]([O-:14])=[O:13])[C:7]=1[CH3:15].[Br:29][C:30]1[CH:35]=[CH:34][C:33](B(O)O)=[CH:32][CH:31]=1.C(N(CC)CC)C>C(Cl)Cl.CC([O-])=O.CC([O-])=O.[Cu+2]>[Br:29][C:30]1[CH:35]=[CH:34][C:33]([O:23][C:20]2[CH:21]=[CH:22][C:17]([CH2:16][N:5]([CH2:4][C:3]3[CH:24]=[CH:25][C:26]([F:28])=[CH:27][C:2]=3[F:1])[C:6]3[CH:11]=[CH:10][CH:9]=[C:8]([N+:12]([O-:14])=[O:13])[C:7]=3[CH3:15])=[CH:18][CH:19]=2)=[CH:32][CH:31]=1
Reactant: OB(O)c1ccc(Br)cc1
Reactant: Cc1c(N(Cc2ccc(O)cc2)Cc2ccc(F)cc2F)cccc1[N+](=O)[O-]
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1c(N(Cc2ccc(Oc3ccc(Br)cc3)cc2)Cc2ccc(F)cc2F)cccc1[N+](=O)[O-]
Reaction time: 8 h
Yield: 62 %

Procedure:
The product from Example 33A (1.0 g, 2.6 mmoles), 4 Å molecular sieves, Cu(OAc)2 (0.71 g, 3.91 mmoles) and 4-bromophenylboronic acid (1.57 g, 7.81 mmoles) in CH2Cl2 (20 mL) was treated with triethylamine (1.81 mL, 13.0 mmoles) and the resulting solution was stirred vigorously overnight. An additional equivalent of Cu(OAc)2, 4-bromophenylboronic acid, and triethylamine were added and the reaction mixture was stirred vigorously for 5 hours. The mixture was filtered through a 1 inch pad of Celite using CH2Cl2 and the filtrate was concentrated under reduced pressure. The residue was purified by flash chromatography (silica gel, 10:1 hexanes:ethyl acetate) to provide the title compound as a yellow oil (0.87 g, 62%).
Reaction SMILES: [O:1]1[C:6]2[CH:7]=[CH:8][C:9]([OH:11])=[CH:10][C:5]=2[O:4][CH2:3][CH2:2]1.[H-].[Na+].I[CH3:15]>CN(C=O)C>[CH3:15][O:11][C:9]1[CH:8]=[CH:7][C:6]2[O:1][CH2:2][CH2:3][O:4][C:5]=2[CH:10]=1
Reactant: Oc1ccc2c(c1)OCCO2
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1ccc2c(c1)OCCO2
Reaction time: 0.5 h

Procedure:
3 g (18.05 mmol) of the alcohol obtained in Step A are dissolved in 10 ml of DMF in a flask. 2 eq. of NaH (60% in oil) are added slowly and allowed to act for 30 minutes under an inert atmosphere. 2 eq. of iodomethane are then added. The mixture is stirred for 2 hours; the DMF is then evaporated. Washing with ethyl acetate and with water is carried out and the two phases are separated. The combined organic phases are dried over MgSO4 and the solvent is evaporated. The oil obtained is purified on a silica column (eluant: PE/AcOEt 8/2), which allows the pure title product to be obtained.
Reaction SMILES: [C:1]([NH:20][C:21]1[S:22][CH:23]=[C:24]([C:26](=[N:53][O:54][CH3:55])[C:27]([NH:29][CH:30]2[CH:33]([CH2:34][S:35][C:36](=[C:46]3[CH:51]=[CH:50][CH:49]=[CH:48][NH:47]3)[C:37](=[O:45])[C:38]([O:40][C:41]([CH3:44])([CH3:43])[CH3:42])=[O:39])[NH:32][C:31]2=[O:52])=[O:28])[N:25]=1)([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1N2CCN(CC2)C1.Cl>C(Cl)Cl.CCOCC>[C:1]([NH:20][C:21]1[S:22][CH:23]=[C:24]([C:26](=[N:53][O:54][CH3:55])[C:27]([NH:29][CH:30]2[C:31](=[O:52])[N:32]3[CH:33]2[CH2:34][S:35][CH:36]([C:46]2[CH:51]=[CH:50][CH:49]=[CH:48][N:47]=2)[C:37]3([OH:45])[C:38]([O:40][C:41]([CH3:44])([CH3:43])[CH3:42])=[O:39])=[O:28])[N:25]=1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CON=C(C(=O)NC1C(=O)NC1CSC(C(=O)C(=O)OC(C)(C)C)=C1C=CC=CN1)c1csc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Agent: C1CN2CCN1CC2
Agent: Cl
Solvent: CCOCC
Solvent: ClCCl
Product: CON=C(C(=O)NC1C(=O)N2C1CSC(c1ccccn1)C2(O)C(=O)OC(C)(C)C)c1csc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Reaction time: 0.5 h
Yield: 61.7 %

Procedure:
3.053 g of the product of Step B and 1.3 g of triethylene diamine were dissolved in 30 ml of methylene chloride and the mixture was stirred for 1 hour and 30 minutes. Then 28 ml of N hydrochloric acid were added and extraction was effected with methylene chloride. The organic phase was dried and concentrated to dryness under reduced pressure. The residue was chromatographed on silica and eluted with a mixture of methylene chloride and ethyl acetate. The fraction rich in the expected product were recovered, the solvents were expelled and the crystals formed were taken up in ether to obtain 1.885 g of 1,1-dimethylethyl 7-[2-(2-tritylaminothiazol-4-yl)-2-methoxyimino-acetamido]-8-oxo-2-hydroxy-3-(2-pyridyl)-4-thia-1-azabicyclo[4,2,0]octane-2-carboxylate.
Reaction SMILES: Cl[C:2]1[C:3]2[N:10]([CH2:11][CH2:12][O:13][CH2:14][CH3:15])[C:9]([C:16]3[O:17][CH:18]=[CH:19][CH:20]=3)=[CH:8][C:4]=2[N:5]=[CH:6][N:7]=1.[CH3:21][C:22]1[CH:23]=[C:24]([CH:26]=[CH:27][C:28]=1[O:29][C:30]1[CH:31]=[N:32][C:33]([CH3:36])=[CH:34][CH:35]=1)[NH2:25].CN1CCCC1=O.C(=O)([O-])O.[Na+]>O>[CH2:14]([O:13][CH2:12][CH2:11][N:10]1[C:3]2[C:2]([NH:25][C:24]3[CH:26]=[CH:27][C:28]([O:29][C:30]4[CH:31]=[N:32][C:33]([CH3:36])=[CH:34][CH:35]=4)=[C:22]([CH3:21])[CH:23]=3)=[N:7][CH:6]=[N:5][C:4]=2[CH:8]=[C:9]1[C:16]1[O:17][CH:18]=[CH:19][CH:20]=1)[CH3:15]
Reactant: CCOCCn1c(-c2ccco2)cc2ncnc(Cl)c21
Reactant: Cc1ccc(Oc2ccc(N)cc2C)cn1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CN1CCCC1=O
Product: CCOCCn1c(-c2ccco2)cc2ncnc(Nc3ccc(Oc4ccc(C)nc4)c(C)c3)c21
Temperature: 140 °C
Reaction time: 2 h
Yield: 63.8 %

Procedure:
A mixture of 4-chloro-5-(2-ethoxyethyl)-6-(2-furyl)-5H-pyrrolo[3,2-d]pyrimidine (76 mg), 3-methyl-4-[(6-methylpyridin-3-yl)oxy]aniline (67 mg) and 1-methyl-2-pyrrolidinone (1.5 mL) was stirred at 140° C. for 2 hrs, poured into water (8 mL) and adjusted to pH 8 with saturated aqueous sodium hydrogen carbonate. The mixture was extracted with ethyl acetate (20 mL×2) and the organic layers were combined and dried over anhydrous magnesium sulfate. After concentration under reduced pressure, the residue was subjected to silica gel column chromatography (eluent, hexane:ethyl acetate=1:1→0:1). The object fraction was concentrated under reduced pressure. Diisopropyl ether-hexane was added to the residue, and the solid was collected by filtration and dried under reduced pressure at 60° C. to give the title compound (78 mg).
Reaction SMILES: [Br-].[Cl:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH2:9][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C([Li])CCC.[CH2:34]1[O:44][C:37]2([CH2:42][CH2:41][C:40](=O)[CH2:39][CH2:38]2)[O:36][CH2:35]1>O1CCCC1>[Cl:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH:9]=[C:40]1[CH2:41][CH2:42][C:37]2([O:44][CH2:34][CH2:35][O:36]2)[CH2:38][CH2:39]1
Reactant: O=C1CCC2(CC1)OCCO2
Reactant: Clc1ccccc1C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: Clc1ccccc1C=C1CCC2(CC1)OCCO2
Temperature: 25 °C
Reaction time: 1 h
Yield: 81.4 %

Procedure:
A stirred solution of 18.0 grams (0.039 mole) of 2-chlorophenylmethyltriphenylphosphonium bromide in about 50 mL of dry tetrahydrofuran was cooled in a dry ice-acetone bath, and 15.4 mL (0.039 mole) of n-butyllithium (2.5M in hexanes) was added dropwise. Upon completion of addition, the reaction mixture was stirred for 1 hour. After this time a solution of 5.0 grams (0.032 mole) of 1,4-cyclohexanedione mono-ethylene ketal in about 5.0 mL of dry tetrahydrofuran was added dropwise. Upon completion of addition, the reaction mixture was allowed to warm to ambient temperature where it was stirred for about 18 hours. After this time the reaction mixture was concentrated under reduced pressure, yielding about 6.9 grams of 8-(2-chlorophenylmethylene)-1,4-dioxaspiro[4.5]-decane. The NMR spectrum was consistent with the proposed structure.