Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Si:1]([C:8]#[C:9][C:10]#[C:11][C:12]#[C:13][C:14]#[C:15][Si:16]([CH2:21][CH3:22])([CH2:19][CH3:20])[CH2:17][CH3:18])([CH2:6][CH3:7])([CH2:4][CH3:5])[CH2:2][CH3:3].[CH:23]#[C:24][C:25]#[C:26][C:27]#[C:28][C:29]#[CH:30]>>[Si:1]([C:8]#[C:9][C:10]#[C:11][C:12]#[C:13][C:14]#[CH:15])([CH2:6][CH3:7])([CH2:4][CH3:5])[CH2:2][CH3:3].[Si:1]([C:23]#[C:24][C:25]#[C:26][C:27]#[C:28][C:29]#[C:30][C:8]#[C:9][C:10]#[C:11][C:12]#[C:13][C:14]#[C:15][Si:16]([CH2:17][CH3:18])([CH2:19][CH3:20])[CH2:21][CH3:22])([CH2:6][CH3:7])([CH2:4][CH3:5])[CH2:2][CH3:3]
Reactant: CC[Si](C#CC#CC#CC#C[Si](CC)(CC)CC)(CC)CC
Reactant: C#CC#CC#CC#C
Product: C#CC#CC#CC#C[Si](CC)(CC)CC
Product: CC[Si](C#CC#CC#CC#CC#CC#CC#CC#C[Si](CC)(CC)CC)(CC)CC

Procedure:
Thus, by forming the appropriate alkynyl salt, the length of the alkynyl moiety, represented by the value of n, incorporated into the polymer formed in step 2 can be controlled. Typically, the value of n can be varied from 1 to 12. Acetylenic derivatives having the general formula H(C≡C)nH can be readily converted into the dilithio salts by reacting with n-butyllithium. The respective dilithio salts, with values of n varying from 1 to 12, can then be incorporated into the backbone of polymers (2) as shown in the aforementioned step 2. The value of n can be varied, typically, from 1 to 12, more often from 1 to 10 and 1 to 8, most often from 1 to 6 and, in particular, from 1 to 3 and 1 to 2. Acetylenic derivatives having the general formula H(C≡C)nH can be readily formed by the synthesis given by Eastmond et al. in Silylation as a Protective Method for Terminal Alkynes in Oxidative Couplings--A General Synthesis of the Parent Polyynes, 28 TETRAHEDRON 4601 (1972). Laboratory synthesis of the lower polyyne series H(C≡C)nH (n=2,3,4 and 5) is based upon low temperature sodamide dehydrohalogenation of α,ω-bis (chloromethyl)alkynes, ClCH2 (C≡C)n-1CH2Cl in liquid ammonia, a technique which provided a convenient route to diacetylene but which proved increasingly troublesome for tri- and for tetra-acetylene. Pentaacetylene, the highest member of the series was obtained in ca 1% yield from the precursor, ClCH2 (C≡C)4CH2Cl. Polyynes in the series H(C≡C)nH (n=4,5,6,7,8,9,10 and 12) have been prepared in solution by sequences involving Cu-catalyses oxidative couplings (Hay technique) of silyl-protected terminal alkynes, partial cleavage (desilylation) of the products by alkali, recoupling and complete desilylation. Thus using conditions established in a model coupling Et3SiC≡CH (I)→Et3Si(C≡C)2SiEt3 (II), coupling of the silyldiyne Et3Si(C≡C)2H (III) gives Et3Si(C≡C)4SiEt3 (IV) which upon controlled cleavage yields a chromatographically separable mixture of Et3Si(C≡ C)4SiEt3 (IV) , Et3Si(C=-C)4H (V) and H(C≡C)4H (VI). Coupling of Et3Si(C≡C)4H (V) in turn gives Et3Si(C≡C)8SiEt3 (VII) which upon cleavage yields Et3Si(C≡C)8H (VIII) and H(C≡C)8H (IX) and coupling of Et3Si(C≡C)8H (VIII) gives the bissilylhexadecaacetylene Et3Si (C≡C)16SiEt3 (X) .
Reaction SMILES: Cl[C:2]1[C:7]([CH:8]=[O:9])=[CH:6][CH:5]=[CH:4][N:3]=1.[Na+].[Cl:11][C:12]1[CH:17]=[CH:16][C:15]([S:18]([O-:20])=[O:19])=[CH:14][CH:13]=1>CS(C)=O.O>[Cl:11][C:12]1[CH:17]=[CH:16][C:15]([S:18]([C:2]2[C:7]([CH:8]=[O:9])=[CH:6][CH:5]=[CH:4][N:3]=2)(=[O:20])=[O:19])=[CH:14][CH:13]=1
Reactant: O=Cc1cccnc1Cl
Reactant: O=S([O-])c1ccc(Cl)cc1
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: O=Cc1cccnc1S(=O)(=O)c1ccc(Cl)cc1
Temperature: 100 °C
Yield: 46.9 %

Procedure:
2-Chloro-3-pyridinecarboxaldehyde (5.0 g, 35.0 mmol) and 4-chlorobenzenesulfinic acid sodium salt (7.75 g, 38.8 mmol) were dissolved in DMSO (120 ml) and the mixture was heated at 100° C. for 72 h under nitrogen. Upon cooling to ambient the mixture was diluted with water (500 ml) and extracted with EtOAc (3×). The combined organics were washed with water, brine, dried (MgSO4) and evaporated to dryness to afford 8.1 g of crude material. The crude compound was pre-absorbed onto silica and purified by dry pad suction column chromatography, eluting with heptane using an EtOAc gradient, to afford 4.62 g (61%) of the desired product as a white powdery solid (MP=100.5-101° C.; IR=1698 cm−1; HPLC=8.00 min >99%).
Reaction SMILES: [C:1]([C:5]1[C:6](=[O:16])[C:7]([C:12]([CH3:15])([CH3:14])[CH3:13])=[CH:8][C:9](=O)[CH:10]=1)([CH3:4])([CH3:3])[CH3:2].[NH2:17][C:18]1[CH:26]=[CH:25][C:21]([C:22]([OH:24])=[O:23])=[CH:20][CH:19]=1.B(F)(F)F>O1CCCC1>[C:1]([C:5]1[C:6](=[O:16])[C:7]([C:12]([CH3:15])([CH3:14])[CH3:13])=[CH:8][C:9](=[N:17][C:18]2[CH:26]=[CH:25][C:21]([C:22]([OH:24])=[O:23])=[CH:20][CH:19]=2)[CH:10]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: Nc1ccc(C(=O)O)cc1
Reactant: CC(C)(C)C1=CC(=O)C=C(C(C)(C)C)C1=O
Agent: FB(F)F
Solvent: C1CCOC1
Product: CC(C)(C)C1=CC(=Nc2ccc(C(=O)O)cc2)C=C(C(C)(C)C)C1=O
Temperature: 20 °C

Procedure:
A mixture of 22 g (0.10 mole) of 2,6-di(tertiary-butyl)-p-benzoquinone, 13.7 g (0.10 mole) of 4-aminobenzoic acid, 175 ml of tetrahydrofuran and 1 ml of boron trifluoride: diethyl ether complex was heated on a steam bath for 1.25 hours. The mixture was allowed to cool to about 20° C. over 16 hours under a nitrogen atmosphere. Evaporation provided a solid which was washed with hexane and recrystallized from ethanol to provide orange solid 2,6-di(tertiary-butyl)-4-(4'-carboxyphenylimino)-2,5-cyclohexadien-1-one, m.p. 305°-309° C. Analysis: Calculated for C21H25NO3 : % C, 74.3; % H, 7.4; % N, 4.1; Found: % C, 74.2; % H, 7.4; % N, 4.1.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5](/[C:11](=[CH:14]/[C:15]2[CH:20]=[CH:19][C:18]([C@@H:21]3[O:29][C@H:28]([CH2:30][OH:31])[C@@H:26]([OH:27])[C@H:24]([OH:25])[C@H:22]3[OH:23])=[CH:17][CH:16]=2)/[C:12]#[N:13])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].[P:32](Cl)(=[O:40])([O-:39])[O:33]CC(Cl)(Cl)Cl>N1C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:4]=[C:5](/[C:11](=[CH:14]/[C:15]2[CH:16]=[CH:17][C:18]([C@@H:21]3[O:29][C@H:28]([CH2:30][O:31][P:32]([OH:40])([OH:39])=[O:33])[C@@H:26]([OH:27])[C@H:24]([OH:25])[C@H:22]3[OH:23])=[CH:19][CH:20]=2)/[C:12]#[N:13])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: COc1ccc(/C(C#N)=C/c2ccc([C@@H]3O[C@H](CO)[C@@H](O)[C@H](O)[C@H]3O)cc2)cc1OC
Reactant: O=P([O-])(Cl)OCC(Cl)(Cl)Cl
Solvent: c1ccncc1
Product: COc1ccc(/C(C#N)=C/c2ccc([C@@H]3O[C@H](COP(=O)(O)O)[C@@H](O)[C@H](O)[C@H]3O)cc2)cc1OC
Reaction time: 2 h
Yield: 69.9 %

Procedure:
Compound 44 (100 mg) and (2,2,2-trichloroethyl) phosphorochloridate (256 mg) were dissolved in pyridine (2 mL), and the resultant solution was stirred for two hours. After completion of reaction, the resultant reaction mixture was concentrated to dryness under reduced pressure, followed by purification by means of silica gel chromatography employing a chloroform/methanol system. The thus-purified product was dissolved in a pyridine-acetic acid (4:1) solvent mixture, and zinc powder (140 mg) was added to the resultant solution, followed by stirring for two hours. After completion of reaction, the resultant reaction mixture was concentrated to dryness under reduced pressure, followed by purification by means of silica gel chromatography employing a chloroform/methanol system, to thereby produce the target product (83 mg, yield: 70%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]([C:12]([OH:14])=[O:13])[C:9]([OH:11])=[O:10].[C:15]([Cl:20])(=O)[C:16](Cl)=O.[Cl:21][C:22]1[CH:27]=[C:26]([Cl:28])[CH:25]=[C:24]([Cl:29])[C:23]=1O>ClCCl.CN(C)C=O>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]([C:9]([O:11][C:16]1[C:15]([Cl:20])=[CH:27][C:22]([Cl:21])=[CH:23][C:24]=1[Cl:29])=[O:10])[C:12]([O:14][C:27]1[C:22]([Cl:21])=[CH:23][C:24]([Cl:29])=[CH:25][C:26]=1[Cl:28])=[O:13]
Reactant: O=C(O)C(C(=O)O)c1ccccc1F
Reactant: O=C(Cl)C(=O)Cl
Reactant: Oc1c(Cl)cc(Cl)cc1Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: O=C(Oc1c(Cl)cc(Cl)cc1Cl)C(C(=O)Oc1c(Cl)cc(Cl)cc1Cl)c1ccccc1F
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 2-(2-fluorophenyl)propanedioic acid (0.60 g, 3 mmol, prepared by the method described in Eur. J. Biochem. 1992, 210, 475) in dichloromethane (5 mL) was added oxalyl chloride (0.65 mL, 7.5 mmol) and one drop of N,N-dimethylformamide. The reaction mixture was stirred for 1 h at room temperature. 2,4,6-Trichlorophenol (1.47 g, 7.5 mmol) was then added, and the reaction mixture was stirred at room temperature overnight. The reaction mixture was concentrated under reduced pressure, and the crude residue was triturated with a small amount of cold methanol to yield the title compound as a white solid (1.1 g).
Reaction SMILES: [O:1]=[C:2]1[CH2:6][CH2:5][CH:4]([O:7][CH2:8][CH3:9])[NH:3]1.C([Li])CCC.[CH:15]([S:23](Cl)(=[O:25])=[O:24])=[CH:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>O1CCCC1>[CH:15]([S:23]([N:3]1[CH:4]([O:7][CH2:8][CH3:9])[CH2:5][CH2:6][C:2]1=[O:1])(=[O:25])=[O:24])=[CH:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: O=S(=O)(Cl)C=Cc1ccccc1
Reactant: CCOC1CCC(=O)N1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CCOC1CCC(=O)N1S(=O)(=O)C=Cc1ccccc1
Temperature: -5 °C
Reaction time: 4 h
Yield: 22 %

Procedure:
2.6 g of 2-oxo-5-ethoxy pyrrolidine is dissolved in 80 cm3 of anhydrous tetrahydrofuran, then cooled to -5° C., and 12.6 cm3 of butyllithium is added. After 20 minutes under agitation, there is added slowly at the same temperature, 4.05 g of styrene-sulphonyl chloride (CA 47, 3262c (1953)) in 10 cm3 of tetrahydrofuran. After allowing this to return to ambient temperature, after 4 hours, it is concentrated to dryness and the residue is chromatographed on silica. 1.3 g of the expected product is obtained, which is crystallized from a mixture of ethyl ether and hexane. m.p.=61°-63° C.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4](F)[N:3]=1.[CH3:9][C:10]1([CH2:16][NH2:17])[CH2:15][CH2:14][O:13][CH2:12][CH2:11]1.C(N(CC)CC)C>CS(C)=O.CCOC(C)=O>[Br:1][C:2]1[N:3]=[C:4]([NH:17][CH2:16][C:10]2([CH3:9])[CH2:15][CH2:14][O:13][CH2:12][CH2:11]2)[CH:5]=[CH:6][CH:7]=1
Reactant: Fc1cccc(Br)n1
Reactant: CC1(CN)CCOCC1
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: CC1(CNc2cccc(Br)n2)CCOCC1
Temperature: 110 °C

Procedure:
To a solution of 2-bromo-6-fluoropyridine (619 mg, 3.52 mmol) in DMSO (3 mL) was added (4-methyltetrahydro-2H-pyran-4-yl)methanamine (500 mg, 3.87 mmol) and triethylamine (498 mg, 4.93 mmol). The mixture was heated at 110° C. for 18 hr. The mixture was allowed to cool to ambient temperature and diluted with EtOAc. The organic layer was washed with saturated aqueous NaHCO3 solution (1×), water (1×), brine (1×), dried over Na2SO4, filtered off and concentrated in vacuo. The resulting residue was purified by column chromatography [SiO2, 24 g, EtOAc/heptane=0/100 2 min, 0/100 to 40/60 2-25 min] providing 6-bromo-N-((4-methyltetrahydro-2H-pyran-4-yl)methyl)pyridin-2-amine as a white solid. Yield: 750 mg. LCMS (m/z): 285.0/287.0 [M+H]+; Retention time=0.88 min.
Reaction SMILES: [CH2:1]([N:8]1[CH2:14][CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:15]([O:19][C:20]([N:22]1[CH2:27][CH2:26][CH:25]([C:28](O)=[O:29])[CH2:24][CH2:23]1)=[O:21])([CH3:18])([CH3:17])[CH3:16].C1C=CC2N(O)N=NC=2C=1.C(Cl)CCl>C(Cl)Cl>[CH2:1]([N:8]1[CH2:14][CH2:13][CH2:12][N:11]([C:28]([CH:25]2[CH2:26][CH2:27][N:22]([C:20]([O:19][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:21])[CH2:23][CH2:24]2)=[O:29])[CH2:10][CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)N1CCC(C(=O)O)CC1
Reactant: c1ccc(CN2CCCNCC2)cc1
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCC(C(=O)N2CCCN(Cc3ccccc3)CC2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 89 %

Procedure:
1-Benzyl-[1,4]-diazepane (3.78 g) and 1-tert-butoxycarbonyl-piperidine-4-carboxylic acid (5.0 g) were dissolved in DCM (150 ml) and TEA (3.6 ml) was added followed by HOBT (1.34 g) and finally EDC (4.90 g). The reaction was stirred at rt overnight. The reaction mixture was then evaporated to a minimum, re-dissolved in DCM (50 ml) and washed with saturated sodium hydrogen carbonate solution (3×50 ml) and brine (50 ml). The organic layer was dried (MgSO4) and evaporated to a crude which was purified by column chromatography [silica gel, step gradient 0-10% MeOH (containing 10% 0.880 ammonia solution) in DCM]. Fractions containing pure desired product were combined and evaporated to give the subtitled compound as a pale brown solid (7.1 g).
Reaction SMILES: [CH3:1][NH:2][NH2:3].[Cl:4][C:5]1[CH:18]=[C:17]([Cl:19])[C:16]([CH3:20])=[CH:15][C:6]=1[C:7]([CH2:9][C:10](OCC)=[O:11])=O>CCOCC>[Cl:4][C:5]1[CH:18]=[C:17]([Cl:19])[C:16]([CH3:20])=[CH:15][C:6]=1[C:7]1[CH2:9][C:10](=[O:11])[N:2]([CH3:1])[N:3]=1
Reactant: CNN
Reactant: CCOC(=O)CC(=O)c1cc(C)c(Cl)cc1Cl
Solvent: CCOCC
Product: Cc1cc(C2=NN(C)C(=O)C2)c(Cl)cc1Cl
Temperature: 100 °C

Procedure:
13.5 g (292 mol) of methylhydrazine were added slowly to 80.4 g (292 mmol) of ethyl 2,4-dichloro-5-methylbenzoylacetate in 300 m of diethylene glycoldimethyl ether. The reaction solution was heated at 100° C. for 4 hours and then stirred into 11 of ice-water. The precipitate formed was filtered off, washed with a little-methylene chloride and dried. Yield: 38.8 g; m.p. 196°-198° C.;
Reaction SMILES: [Cl:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][C:5]([O:10][CH3:11])=[C:4]([Cl:12])[C:3]=1[C:13]1[CH:22]=[CH:21][C:20]([C:23](O)=[O:24])=[C:19]2[C:14]=1[CH:15]=[CH:16][CH:17]=[N:18]2.[CH3:26][N:27]1[CH2:32][CH2:31][N:30]([CH2:33][C:34]2[CH:35]=[CH:36][C:37]([NH:40]C(C3C4N=CC=NC=4C(C4C(Cl)=C(OC)C=C(OC)C=4Cl)=CC=3)=O)=[N:38][CH:39]=2)[CH2:29][CH2:28]1>C(Cl)Cl.CO>[CH3:26][N:27]1[CH2:32][CH2:31][N:30]([CH2:33][C:34]2[CH:35]=[CH:36][C:37]([NH:40][C:23]([C:20]3[CH:21]=[CH:22][C:13]([C:3]4[C:4]([Cl:12])=[C:5]([O:10][CH3:11])[CH:6]=[C:7]([O:8][CH3:9])[C:2]=4[Cl:1])=[C:14]4[C:19]=3[N:18]=[CH:17][CH:16]=[CH:15]4)=[O:24])=[N:38][CH:39]=2)[CH2:29][CH2:28]1
Reactant: COc1cc(OC)c(Cl)c(-c2ccc(C(=O)Nc3ccc(CN4CCN(C)CC4)cn3)c3nccnc23)c1Cl
Reactant: COc1cc(OC)c(Cl)c(-c2ccc(C(=O)O)c3ncccc23)c1Cl
Solvent: ClCCl
Solvent: CO
Product: COc1cc(OC)c(Cl)c(-c2ccc(C(=O)Nc3ccc(CN4CCN(C)CC4)cn3)c3ncccc23)c1Cl
Temperature: 25 °C
Reaction time: 20 h

Procedure:
The title compound was prepared in analogy to the procedure described in Step 14.1 but using 5-(2,6-dichloro-3,5-dimethoxy-phenyl)-quinoline-8-carboxylic acid (Step 159.1), 5-(4-methyl-piperazin-1-ylmethyl)-pyridin-2-ylamine (Example 31; purified by silica gel column chromatography), and stirring the reaction mixture for 20 h at rt. Title compound: ESI-MS: 566.1 [M+H]+; TLC: Rf=0.22 (DCM/MeOH, 9:1).
Reaction SMILES: C([N:8]1[CH2:26][CH2:25][C:10]2([CH2:14][N:13]([C:15]3[CH:24]=[CH:23][C:18]([C:19]([O:21][CH3:22])=[O:20])=[CH:17][N:16]=3)[CH2:12][CH2:11]2)[CH2:9]1)C1C=CC=CC=1>CCO.[OH-].[OH-].[Pd+2]>[CH2:14]1[C:10]2([CH2:25][CH2:26][NH:8][CH2:9]2)[CH2:11][CH2:12][N:13]1[C:15]1[CH:24]=[CH:23][C:18]([C:19]([O:21][CH3:22])=[O:20])=[CH:17][N:16]=1
Reactant: COC(=O)c1ccc(N2CCC3(CCN(Cc4ccccc4)C3)C2)nc1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CCO
Product: COC(=O)c1ccc(N2CCC3(CCNC3)C2)nc1
Reaction time: 20 h

Procedure:
A mixture of 2-benzyl-2,7-diazaspiro[4.4]nonane (1.00 g, 4.68 mmol), methyl 6-chloronicotinate (800 mg, 4.68 mmol) and K2CO3 (700 mg, 5.07 mmol) in 5 mL of DMSO was stirred under microwave irradiation for 20 min at a temperature of 150° C. The mixture was poured into EtOAc and washed with sat'd NaHCO3, dried (Na2SO4), filtered and concentrated, giving methyl 6-(7-benzyl-2,7-diazaspiro[4.4]non-2-yl)nicotinate. A bottle containing a suspension of the benzyl amine and 20% Pd(OH)2/C (600 mg, 0.857 mmol) in 20 mL of EtOH was evacuated and purged with H2 gas three times. Using a Parr shaker apparatus, the suspension was agitated under 50 psi of H2 for 20 h. The pressure was released and the mixture filtered through a pad of Celite and concentrated, giving methyl 6-(2,7-diazaspiro[4.4]non-2-yl)nicotinate: 1H NMR (600 MHz, DMSO-d6) δ 8.59 (d, J=2.1 Hz, 1H), 7.89 (dd, J=9.1, 2.3 Hz, 1H), 7.27 (d, J=4.4 Hz, 1H), 6.44 (d, J=8.8 Hz, 1H), 3.74 (s, 3H), 3.13 (br s, 4H), 2.89 (t, J=7.3 Hz, 2H), 2.72 (AB, J=7.6 Hz, 2H), 1.92 (br m, 2H), 1.69 (AB, J=7.3 Hz, 2H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[N:9]1[C:14]2[N:15]=[C:16]([S:29][CH3:30])[N:17]=[C:18]([C:19]3[CH:20]=[C:21]([CH:25]=[CH:26][C:27]=3[CH3:28])[C:22]([OH:24])=O)[C:13]=2[CH:12]=[CH:11][C:10]1=[O:31].CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[NH2:65][C:66]1[S:67][CH:68]=[CH:69][N:70]=1>CN(C=O)C.O>[F:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([F:1])[C:3]=1[N:9]1[C:14]2[N:15]=[C:16]([S:29][CH3:30])[N:17]=[C:18]([C:19]3[CH:20]=[C:21]([CH:25]=[CH:26][C:27]=3[CH3:28])[C:22]([NH:65][C:66]3[S:67][CH:68]=[CH:69][N:70]=3)=[O:24])[C:13]=2[CH:12]=[CH:11][C:10]1=[O:31]
Reactant: CSc1nc(-c2cc(C(=O)O)ccc2C)c2ccc(=O)n(-c3c(F)cccc3F)c2n1
Reactant: Nc1nccs1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: CSc1nc(-c2cc(C(=O)Nc3nccs3)ccc2C)c2ccc(=O)n(-c3c(F)cccc3F)c2n1
Yield: 81.5 %

Procedure:
A solution of 3-[8-(2,6-difluorophenyl)-2-(methylthio)-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-4-yl]-4-methylbenzoic acid (440 mg, 1.00 mmol) in DMF (15 mL) was mixed with DIEA (0.697 mL, 4.0 mmol), HATU (418 mg, 1.1 mmol) and 2-aminothiazole (150 mg, 1.5 mmol). The reaction mixture was stirred over night, diluted with H2O (0.5 mL), and concentrated under vaccum to remove DMF. Flash chromatography (load column with DCM, mobile phase EtOAc/Hexane) then provided the title compound as a white solid 425 mg (81%).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5](/[C:8](/[CH3:14])=[C:9](\[CH2:12][CH3:13])/[CH2:10][OH:11])=[CH:4][CH:3]=1.[CH2:15]([O:17][C@@H:18]([CH2:24][C:25]1[CH:30]=[CH:29][C:28](O)=[CH:27][CH:26]=1)[C:19]([O:21][CH2:22][CH3:23])=[O:20])[CH3:16]>>[Br:1][C:2]1[CH:3]=[CH:4][C:5](/[C:8](/[CH3:14])=[C:9](\[CH2:12][CH3:13])/[CH2:10][O:11][C:28]2[CH:27]=[CH:26][C:25]([CH2:24][C@H:18]([O:17][CH2:15][CH3:16])[C:19]([O:21][CH2:22][CH3:23])=[O:20])=[CH:30][CH:29]=2)=[CH:6][CH:7]=1
Reactant: CCOC(=O)[C@H](Cc1ccc(O)cc1)OCC
Reactant: CC/C(CO)=C(/C)c1ccc(Br)cc1
Product: CCOC(=O)[C@H](Cc1ccc(OC/C(CC)=C(\C)c2ccc(Br)cc2)cc1)OCC
Yield: 88.7 %

Procedure:
The title compound (843 mg, 89%) was prepared from (E)-3-(4-bromophenyl)-2-ethyl-but-2-en-1-ol (510 mg, 2.0 mmol) and (S)-ethyl 2-ethoxy-3-(4-hydroxyphenyl)-propionate (500 mg, 2.10 mmol) by a procedure analogous to that described in example 52c.
Reaction SMILES: Cl.[CH3:2][O:3][C:4]1[CH:5]=[C:6]([CH:13]([OH:17])[CH2:14]NC)[CH:7]=[C:8]([O:11][CH3:12])[C:9]=1[OH:10].C[O:19]C1C=CC=C(OC)C=1O.O=CC(Cl)(Cl)Cl.COC1C=C(C(O)C(Cl)(Cl)Cl)C=C(OC)C=1O>>[CH3:2][O:3][C:4]1[CH:5]=[C:6]([C:13]([CH:14]=[O:19])=[O:17])[CH:7]=[C:8]([O:11][CH3:12])[C:9]=1[OH:10]
Reactant: COc1cccc(OC)c1O
Reactant: CNCC(O)c1cc(OC)c(O)c(OC)c1
Agent: COc1cc(C(O)C(Cl)(Cl)Cl)cc(OC)c1O
Agent: Cl
Agent: O=CC(Cl)(Cl)Cl
Product: COc1cc(C(=O)C=O)cc(OC)c1O

Procedure:
A process for preparing 1-(3,5-dimethoxy-4-hydroxy phenyl)-2-(N-methylamino) ethanol hydrochloride is described by reacting 2,6-dimethoxyphenol with anhydrous chloral in the presence of a catalyst, hydrolyzing 1-(3,5-dimethoxy-4-hydroxyphenyl)2,2,2-trichloro ethanol and subsequently isolating the 3,5-dimethoxy-4-hydroxyphenyl glyoxal thus obtained; finally, this compound, in the form of the bisulfite, is directly converted to the desired product by amination with methylamine in the presence of hydrogen with a hydrogenation catalyst and the final product is converted into the hydrochloride.
Reaction SMILES: [CH3:1][C:2]1[C:7]([C:8]2[CH:13]=[CH:12][C:11]([C:14](O)=[O:15])=[CH:10][CH:9]=2)=[CH:6][C:5]([C:17]([NH:19][CH2:20][CH2:21][CH3:22])=[O:18])=[CH:4][CH:3]=1.C(N(CC)CC)C.CS([N:34]1[C:38]2[CH:39]=[CH:40][CH:41]=[CH:42][C:37]=2[N:36]=[N:35]1)(=O)=O.CN(C=O)C>C1COCC1>[N:34]1([C:14]([C:11]2[CH:12]=[CH:13][C:8]([C:7]3[C:2]([CH3:1])=[CH:3][CH:4]=[C:5]([C:17]([NH:19][CH2:20][CH2:21][CH3:22])=[O:18])[CH:6]=3)=[CH:9][CH:10]=2)=[O:15])[C:38]2[CH:39]=[CH:40][CH:41]=[CH:42][C:37]=2[N:36]=[N:35]1
Reactant: CCCNC(=O)c1ccc(C)c(-c2ccc(C(=O)O)cc2)c1
Reactant: CS(=O)(=O)n1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: CCCNC(=O)c1ccc(C)c(-c2ccc(C(=O)n3nnc4ccccc43)cc2)c1
Yield: 91.8 %

Procedure:
6′-Methyl-3′-[(propylamino)carbonyl]-1,1′-biphenyl-4-carboxylic acid (121 mg, 0.41 mmol), triethylamine (100 μl) and 1-(methylsulphonyl)-1H-benzotriazole (119 mg, 0.6 mmol) were mixed in THF (3 ml) and DMF (0.5 ml) and heated at reflux for 3 h. The reaction was concentrated under vacuum and partitioned between chloroform (5 ml) and water (5 ml). The aqueous was washed with chloroform (3 ml) and the combined organics reduced to dryness under vacuum. The residue was chromatographed on an SPE (silica, 5 g) eluting with chloroform, ether and ethylacetate, which after evaporation of the solvent under vacuum gave 4′-[(1H-1,2,3-benzotriazol-1-yl)carbonyl]-6-methyl-N-propyl-1,1′-biphenyl-3-carboxamide (150 mg).
Reaction SMILES: [CH3:1][O:2][CH2:3][C:4]1[O:8][N:7]=[CH:6][C:5]=1[C:9]([O:11]C)=[O:10].Cl.C(O)(=O)C.O>CC(C)=O>[CH3:1][O:2][CH2:3][C:4]1[O:8][N:7]=[CH:6][C:5]=1[C:9]([OH:11])=[O:10]
Reactant: COCc1oncc1C(=O)OC
Agent: Cl
Solvent: O
Solvent: CC(=O)O
Solvent: CC(C)=O
Product: COCc1oncc1C(=O)O

Procedure:
Methyl 5-(methoxymethyl)isoxazole-4-carboxylate (Preparation 42, 1.8 g, 11 mmol) was stirred in a 1:1:1 mixture of concentrated hydrochloric acid (2 ml), acetic acid (2 ml) and water (2 ml) at reflux for 6 hours. Acetone (6 ml) was added and the mixture concentrated in vacuo. The solid residue was triturated with ethyl acetate and the filtrate concentrated in vacuo to afford the title compound as an off white solid (1.4 g, 85% yield).
Reaction SMILES: [O:1]([CH2:8][C:9]([NH:11][CH:12]1[C:34](=[O:35])[N:14]2[CH:15]([C:21]([O:23][CH2:24][C:25]3[CH:30]=[CH:29][C:28]([N+:31]([O-:33])=[O:32])=[CH:27][CH:26]=3)=[O:22])[C:16](=[CH2:20])[CH2:17][S:18](=O)[C@H:13]12)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:36]([O:39]C(=O)C)(=[O:38])[CH3:37]>C(Cl)(=O)C.C1C=CC=CC=1>[O:1]([CH2:8][C:9]([NH:11][CH:12]1[C:34](=[O:35])[N:14]2[CH:15]([C:21]([O:23][CH2:24][C:25]3[CH:30]=[CH:29][C:28]([N+:31]([O-:33])=[O:32])=[CH:27][CH:26]=3)=[O:22])[C:16]([CH2:20][O:39][C:36](=[O:38])[CH3:37])=[CH:17][S:18][C@H:13]12)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C=C1CS(=O)[C@@H]2C(NC(=O)COc3ccccc3)C(=O)N2C1C(=O)OCc1ccc([N+](=O)[O-])cc1
Reactant: CC(=O)OC(C)=O
Solvent: CC(=O)Cl
Solvent: c1ccccc1
Product: CC(=O)OCC1=CS[C@@H]2C(NC(=O)COc3ccccc3)C(=O)N2C1C(=O)OCc1ccc([N+](=O)[O-])cc1
Temperature: 85 °C

Procedure:
To 10 ml. of benzene were added 500 mg. (1 millimole) of p-nitrobenzyl 7-phenoxyacetamido-3-methylenecepham-4-carboxylate-1-oxide. To the resulting slurry were added 2 ml. of acetic anhydride and 2 drops of acetyl chloride. The resulting mixture was refluxed at 85° C. for about 15 hours. The resulting reaction mixture then was treated as in Example 1 to obtain p-nitrobenzyl 7-phenoxyacetamido-3-acetoxymethyl-2-cephem-4-carboxylate.