Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:20]=[CH:19][C:8]([CH2:9][O:10][C:11]2[CH:12]=[CH:13][C:14]([CH2:17][OH:18])=[N:15][CH:16]=2)=[CH:7][CH:6]=1)(=[O:4])=[O:3]>C(Cl)(Cl)Cl.[O-2].[O-2].[Mn+4]>[CH3:1][S:2]([C:5]1[CH:6]=[CH:7][C:8]([CH2:9][O:10][C:11]2[CH:12]=[CH:13][C:14]([CH:17]=[O:18])=[N:15][CH:16]=2)=[CH:19][CH:20]=1)(=[O:4])=[O:3]
Reactant: CS(=O)(=O)c1ccc(COc2ccc(CO)nc2)cc1
Agent: [Mn+4]
Agent: [O-2]
Solvent: ClC(Cl)Cl
Product: CS(=O)(=O)c1ccc(COc2ccc(C=O)nc2)cc1
Temperature: 60 °C
Yield: 60.8 %

Procedure:
Manganese dioxide (14.0 g, 161 mmol) was added to a solution of [5-(4-methanesulfonyl-benzyloxy)-pyridin-2-yl]-methanol (4.04 g, 13.77 mmol) in chloroform. The resulting mixture was heated to 60° C. for 10 min after which it was filtered through Celite and the filtrate washed with CH2Cl2. Volatiles were removed under reduced pressure. The crude mixture was dry-loaded onto silica gel and 5-(4-methanesulfonyl-benzyloxy)-pyridine-2-carbaldehyde (2.44 g, 61%) was isolated by chromatography (60% ethyl acetate in hexane).
Reaction SMILES: C([O:3][C:4]([N:6]1[C:11]([S:12][CH2:13][CH3:14])=[CH:10][CH:9]=[CH:8][NH:7]1)=[O:5])C.[OH-].[Na+].Cl>CO>[CH2:13]([S:12][C:11]1[N:6]([C:4]([OH:5])=[O:3])[NH:7][CH:8]=[CH:9][CH:10]=1)[CH3:14]
Reactant: CCOC(=O)N1NC=CC=C1SCC
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CCSC1=CC=CNN1C(=O)O
Temperature: 85 °C
Reaction time: 4 h
Yield: 27.2 %

Procedure:
A mixture of 2.59 g of 3-ethylsulfanylpyridazine-2-carboxylic acid ethyl ester, 5 ml of a 5 M aqueous sodium hydroxide solution, and 8 ml of methanol was stirred at 85° C. for 4 hours. Concentrated hydrochloric acid was poured to the cooled reaction mixture, and the precipitated solid was filtered. The resulting solid was washed with water and dried to obtain 612 mg of 3-ethylsulfanylpyridazine-2-carboxylic acid. 3-Ethylsulfanylpyridazine-2-carboxylic acid
Reaction SMILES: [CH3:1][O:2][C:3]1([O:19][CH3:20])[C:9]([NH:10]C(=O)OC(C)(C)C)=[CH:8][C:7](=[O:18])[CH:6]2[CH:4]1[O:5]2.FC(F)(F)C(O)=O>ClCCl>[NH2:10][C:9]1[C:3]([O:2][CH3:1])([O:19][CH3:20])[CH:4]2[CH:6]([O:5]2)[C:7](=[O:18])[CH:8]=1
Reactant: COC1(OC)C(NC(=O)OC(C)(C)C)=CC(=O)C2OC21
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COC1(OC)C(N)=CC(=O)C2OC21
Reaction time: 3 h

Procedure:
A solution of compound 4 (300 mg, 1.1 mmol) in anhydrous dichloromethane (6 mL) was stirred in an ice bath under an inert nitrogen atmosphere. To this solution was added trifluoroacetic acid (1.5 mL) drop-wise and the solution was brought to room temperature, stirring 3 hours. After judging complete by thin layer chromatography, the solvents were evaporated and the residue was dissolved in ethyl acetate. Solid sodium bicarbonate (2 g) was carefully added and the solution was stirred 10 minutes. The salt was filtered and rinsed with ethyl acetate before evaporation of the solvent. The crude compound was purified over silica gel using a gradient of ethyl acetate (0 to 100%) in heptane. The product eluted in 100% ethyl acetate giving 178 mg (91%) of compound (5). The 1H NMR of the product was consistent with that reported in the literature (Synthesis 1998, 775).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].CI.NC1[CH:11]=[C:12]([C:22](=[O:24])[CH3:23])[CH:13]=[C:14]([C:18]([CH3:21])([CH3:20])[CH3:19])[C:15]=1[O:16][CH3:17].C(OCC)(=O)C.[CH3:31][N:32]([CH3:35])[CH:33]=O>>[C:18]([C:14]1[CH:13]=[C:12]([C:22](=[O:24])[CH3:23])[CH:11]=[C:33]([N:32]([CH3:35])[CH3:31])[C:15]=1[O:16][CH3:17])([CH3:21])([CH3:19])[CH3:20]
Reactant: COc1c(N)cc(C(C)=O)cc1C(C)(C)C
Reactant: CN(C)C=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CI
Product: COc1c(N(C)C)cc(C(C)=O)cc1C(C)(C)C
Temperature: 25 °C
Reaction time: 13 h

Procedure:
Potassium carbonate (8.5 g, 62 mmol) and methyl iodide (8.8 g, 62 mmol) were added to a solution of 1-[3-amino-5-(tert-butyl)-4-methoxyphenyl]-1-ethanone (6 g, 21 mmol) in dimethylformamide (50 ml) and the mixture was stirred at room temperature for 13 hours. Ethyl acetate was added, the reaction mixture was washed with water and brine in that order and the organic layer was dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure and then the residue was purified by silica gel column chromatography (solvent: n-hexane-ethyl acetate) to yield the title compound (1.9 g) as a light yellow oil.
Reaction SMILES: [C:1]1([N:7]2[C:25](=[O:26])[C:10]3=[CH:11][NH:12][C:13]4[CH:14]=[CH:15][C:16]([N:19]5[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]5)=[N:17][C:18]=4[C:9]3=[N:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:27]N1CCNCC1>>[CH3:27][N:22]1[CH2:21][CH2:20][N:19]([C:16]2[CH:15]=[CH:14][C:13]3[NH:12][CH:11]=[C:10]4[C:25](=[O:26])[N:7]([C:1]5[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=5)[N:8]=[C:9]4[C:18]=3[N:17]=2)[CH2:24][CH2:23]1
Reactant: O=c1c2c[nH]c3ccc(N4CCNCC4)nc3c-2nn1-c1ccccc1
Reactant: CN1CCNCC1
Product: CN1CCN(c2ccc3[nH]cc4c(=O)n(-c5ccccc5)nc-4c3n2)CC1

Procedure:
The title compound was prepared following the procedure described for 6a using 1-methylpiperazine instead of piperazine. 1H-NMR (DMSO-d6) δ (ppm): 2.52 (3H, s), 2.84 (4H, brm), 3.62 (4H, brm), 7.11 (1H, t, J=7.22 Hz), 7.20 (1H, d, J=9.28 Hz), 7.40 (2H, dd, J=8.30, 7.57 Hz), 7.80 (1H, d, J=9.28 Hz), 8.21 (2H, d, J=7.57 Hz), 8.50 (1H, s). m/z 361.4 (MH+).
Reaction SMILES: CS(O[CH2:6][CH2:7][C:8]1[CH:13]=[CH:12][C:11]([NH:14][C:15]2[N:24]=[CH:23][C:22]3[CH2:21][C@@H:20]([C:25]4[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=4)[C:19]4[CH:32]=[CH:33][CH:34]=[CH:35][C:18]=4[C:17]=3[N:16]=2)=[CH:10][CH:9]=1)(=O)=O.[CH3:36][NH:37][CH2:38][CH2:39][CH2:40][CH3:41]>C(N(CC)CC)C>[CH2:38]([N:37]([CH3:36])[CH2:6][CH2:7][C:8]1[CH:13]=[CH:12][C:11]([NH:14][C:15]2[N:24]=[CH:23][C:22]3[CH2:21][C@@H:20]([C:25]4[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=4)[C:19]4[CH:32]=[CH:33][CH:34]=[CH:35][C:18]=4[C:17]=3[N:16]=2)=[CH:10][CH:9]=1)[CH2:39][CH2:40][CH3:41]
Reactant: CS(=O)(=O)OCCc1ccc(Nc2ncc3c(n2)-c2ccccc2[C@H](c2ccc(F)cc2)C3)cc1
Reactant: CCCCNC
Solvent: CCN(CC)CC
Product: CCCCN(C)CCc1ccc(Nc2ncc3c(n2)-c2ccccc2[C@H](c2ccc(F)cc2)C3)cc1

Procedure:
This was synthesized by using (S)-4-(6-(4-fluorophenyl)-5,6-dihydrobenzo[h]quinazolin-2-ylamino)phenethyl methanesulfonate, N-methylbutan-1-amine and triethylamine as described in general procedure 2 to afford the desired product. M.p.=164-166° C. 1H NMR (DMSO-d6) 400 MHz δ 10.65 (brs, 1H), 9.78 (s, 1H), 8.32-8.35 (m, 2H), 7.79 (d, J=8.6 Hz, 2H), 7.51 (t, J=5.0 Hz, 2H), 7.26 (d, J=8.6 Hz, 2H), 7.02-7.08 (m, 5H), 4.46 (t, J=6.2 Hz, 1H), 3.13-3.18 (m, 5H), 2.99-3.03 (m, 3H), 2.79 (d, J=5.0 Hz, 3H), 1.17 (t, J=7.8 Hz, 2H), 1.31 (m, 2H), 1.27-1.32 (m, 3H), 0.91 (t, J=7.4 Hz, 3H) LCMS m/e 481 [M+H].
Reaction SMILES: [CH2:1]([N:8]1[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.[NH2:14][C:15]1[N:20]=[C:19](Cl)[CH:18]=[C:17]([Cl:22])[N:16]=1.C([O-])([O-])=O.[Cs+].[Cs+]>CN(C)C=O>[CH2:1]([N:8]1[CH2:13][CH2:12][N:11]([C:19]2[CH:18]=[C:17]([Cl:22])[N:16]=[C:15]([NH2:14])[N:20]=2)[CH2:10][CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Nc1nc(Cl)cc(Cl)n1
Reactant: c1ccc(CN2CCNCC2)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: Nc1nc(Cl)cc(N2CCN(Cc3ccccc3)CC2)n1
Temperature: 90 °C
Reaction time: 5 h

Procedure:
1-Benzyl-piperazine (5.86 g, 33.3 mmol), 2-amino-4,6-dichloro-pyrimidine (5.46 g, 33.3 mmol) and Cs2CO3 (10.8 g, 36.6 mmol) were combined in anhydrous N,N-dimethylformamide (DMF) (50 mL) and stirred at 90° C. in dry atmosphere for 5 h. The DMF was removed in vacuo, the residue was dissolved in acetone, and 4-(4-Benzyl-piperazin-1-yl)-6-chloro-pyrimidin-2-ylamine (8.5 g, 86%) was is crystallized form acetone.
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]([CH3:8])[CH:5]=[C:4]([Cl:9])[N:3]=1.ClC1C=CC=C(C(OO)=[O:18])C=1>ClCCl>[CH3:1][C:2]1[N+:7]([O-:18])=[C:6]([CH3:8])[CH:5]=[C:4]([Cl:9])[N:3]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: Cc1cc(Cl)nc(C)n1
Solvent: ClCCl
Product: Cc1cc(Cl)nc(C)[n+]1[O-]
Temperature: 5 °C
Reaction time: 24 h

Procedure:
20 g (14.03×10-2 mol) of 2,4-dimethyl-6-chloropyrimidine are dissolved in 300 ml of dichloromethane in a 500 ml three-necked flask fitted with a thermometer and a magnetic stirrer. The mixture is cooled to 5° C. and 65.3 g of 55% metachloroperbenzoic acid, which is about 1.5 equivalents, are then added in solid portions. The reaction mixture is then stirred for 24 hours at ambient temperature (25° C.) and then filtered through a 3 frit. The filtrate is washed with 150 ml of a 6% aqueous sodium hydroxide solution and then with 2×50 ml of water to render neutral. It is then dried over sodium sulphate and then filtered through paper and evaporated. The crude mass is recrystallised from n-hexane.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:28]([F:31])([F:30])[F:29])=[C:6]([CH:27]=1)[CH2:7][N:8]1[CH2:13][CH2:12][NH:11][C:10]2[N:14]=[CH:15][C:16]([C:18]3[CH:19]=[C:20]([CH:24]=[CH:25][CH:26]=3)[C:21](O)=[O:22])=[CH:17][C:9]1=2.[Cl:32][C:33]1[CH:45]=[CH:44][C:36]([CH2:37][N:38]2[CH2:43][CH2:42][NH:41][CH2:40][CH2:39]2)=[CH:35][CH:34]=1>>[Cl:32][C:33]1[CH:45]=[CH:44][C:36]([CH2:37][N:38]2[CH2:43][CH2:42][N:41]([C:21]([C:20]3[CH:24]=[CH:25][CH:26]=[C:18]([C:16]4[CH:15]=[N:14][C:10]5[NH:11][CH2:12][CH2:13][N:8]([CH2:7][C:6]6[CH:27]=[C:2]([Cl:1])[CH:3]=[CH:4][C:5]=6[C:28]([F:31])([F:29])[F:30])[C:9]=5[CH:17]=4)[CH:19]=3)=[O:22])[CH2:40][CH2:39]2)=[CH:35][CH:34]=1
Reactant: O=C(O)c1cccc(-c2cnc3c(c2)N(Cc2cc(Cl)ccc2C(F)(F)F)CCN3)c1
Reactant: Clc1ccc(CN2CCNCC2)cc1
Product: O=C(c1cccc(-c2cnc3c(c2)N(Cc2cc(Cl)ccc2C(F)(F)F)CCN3)c1)N1CCN(Cc2ccc(Cl)cc2)CC1

Procedure:
3-{1-[5-chloro-2-(trifluoromethyl)benzyl]-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl}benzoic acid was reacted with 1-(4-chlorobenzyl)piperazine as in General Procedure 10 to give the title compound. LCMS: m/z=639.99 (M+H+); retention time=0.7 minutes.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[Cl:7][C:8]1[C:18]([O:19][CH2:20][O:21][CH3:22])=[CH:17][CH:16]=[C:15]([Cl:23])[C:9]=1[C:10](OCC)=[O:11].O>O1CCCC1>[Cl:7][C:8]1[C:18]([O:19][CH2:20][O:21][CH3:22])=[CH:17][CH:16]=[C:15]([Cl:23])[C:9]=1[CH2:10][OH:11]
Reactant: CCOC(=O)c1c(Cl)ccc(OCOC)c1Cl
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: COCOc1ccc(Cl)c(CO)c1Cl
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a suspension of lithium aluminum hydride (347 mg) in tetrahydrofuran was dropwise added a solution of ethyl 2,6-dichloro-3-(methoxymethoxy)benzoate (2.55 g) in tetrahydrofuran at 0° C. under nitrogen atmosphere, and the mixture was stirred for 30 minutes at the same temperature and for 18 hour at ambient temperature. Water was dropwise added thereto at 0° C., and the mixture was extracted with ethyl acetate. The organic layer was washed with water and brine, dried over magnesium sulfate and evaporated in vacuo. The residue was purified by flash chromatography (n-hexane:ethyl acetate=6:1, V/V) to give 2,6-dichloro-3-(methoxymethoxy)benzyl alcohol.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]([CH2:14][CH:15]=[CH2:16])[C:10](=[O:13])[NH:11][N:12]=2)=[CH:4][CH:3]=1.CC([O-])(C)C.[K+].[C:23]([NH:27][C:28]([C:30]1[CH:35]=[CH:34][C:33]([S:36](Cl)(=[O:38])=[O:37])=[C:32]([O:40][CH3:41])[CH:31]=1)=[O:29])([CH3:26])([CH3:25])[CH3:24]>O1CCCC1>[C:23]([NH:27][C:28]([C:30]1[CH:35]=[CH:34][C:33]([S:36]([N:11]2[C:10](=[O:13])[N:9]([CH2:14][CH:15]=[CH2:16])[C:8]([C:5]3[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=3)=[N:12]2)(=[O:37])=[O:38])=[C:32]([O:40][CH3:41])[CH:31]=1)=[O:29])([CH3:26])([CH3:25])[CH3:24]
Reactant: COc1cc(C(=O)NC(C)(C)C)ccc1S(=O)(=O)Cl
Reactant: C=CCn1c(-c2ccc(Cl)cc2)n[nH]c1=O
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: C=CCn1c(-c2ccc(Cl)cc2)nn(S(=O)(=O)c2ccc(C(=O)NC(C)(C)C)cc2OC)c1=O
Temperature: -78 °C
Reaction time: 0.17 h

Procedure:
An amount of 231 mg (0.24 mmol) of the compound from Example 3A was suspended in 4 ml of tetrahydrofuran and cooled to −78° C. This suspension was admixed with stirring with 110 mg (0.981 mmol) of potassium tert-butylate. The mixture was allowed to warm to room temperature, and the solid dissolved. The reaction solution was stirred at room temperature for 10 minutes thereafter. Subsequently it was cooled again to −78° C. It was admixed with 300 mg (0.981 mmol) of 4-(tert-butylcarbamoyl)-2-methoxybenzenesulphonyl chloride (illustration as per Liotta et al., J. Org. Chem., 2001, 66, 3653-3661), the cooling bath was removed, and the solution was left with further stirring at room temperature overnight. The residue was admixed with water. It was extracted twice with ethyl acetate. The combined organic phases were dried over sodium sulphate and freed from the solvent on a rotary evaporator. The residue was purified by preparative HPLC (Method 6). This gave 275 mg (55% of theory) of the target compound.
Reaction SMILES: S(Cl)(Cl)(=O)=O.[CH3:6][C:7]1[CH:8]=[C:9](C2SCCS2)[CH:10]=[CH:11][CH:12]=1.[C:18]([Cl:22])(Cl)([Cl:20])[Cl:19]>>[CH3:6][C:7]1[CH:12]=[C:11]([C:18]([Cl:22])([Cl:20])[Cl:19])[CH:10]=[CH:9][CH:8]=1
Reactant: Cc1cccc(C2SCCS2)c1
Reactant: ClC(Cl)(Cl)Cl
Solvent: O=S(=O)(Cl)Cl
Product: Cc1cccc(C(Cl)(Cl)Cl)c1
Temperature: 25 °C
Yield: 89.9 %

Procedure:
0.38 moles of sulfuryl chloride in an equal volume of carbon tetrachloride was added dropwise to 21.6 gm (0.11 moles) of 2-(3-methylphenyl)-1,3-dithiolane dissolved in 22 mls of carbon tetrachloride while refluxing and stirring. After the addition, the reaction mixture was stirred for 1 hour at reflux and allowed to cool to room temperature. The solvent was evacuated and the residue Kugelrohr distilled at 65°-70° C. (0.43 mm/Hg) to give 18.32 gm (89.9% yield) of product. NMR and Gas Chromatograph/Mass Spectrometry (GC/MS) Analysis: 1H--NMR (CCl4) δ2.27 (S, CH3), 6.9 to 7.2 and 7.5 to 7.65 (m+ 4H, aryl protons); GCMS (70 ev), M/e (% rel. int.) 212 (M +4, 4), 210 (M+ +2, 12), 208 (M+, 13), 177 (13), 175 (79), 173 (100), 138 (15), 103 (26), 102 (25), 101 (19), 87 (20), 86 (16), 77 (23), 75 (19), 69 (22), 68 (24), 51 (64).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1([C:9]2[CH:14]=[CH:13][C:12]([C:15]3[CH:20]=[CH:19][C:18]([C:21]4[O:25][N:24]=[C:23]([CH3:26])[C:22]=4[CH2:27][CH:28]([OH:38])[CH2:29][NH:30][CH2:31][C:32]4[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=4)=[CH:17][CH:16]=3)=[CH:11][CH:10]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2].[CH3:39][S:40](Cl)(=[O:42])=[O:41]>>[CH2:1]([O:3][C:4]([C:6]1([C:9]2[CH:10]=[CH:11][C:12]([C:15]3[CH:20]=[CH:19][C:18]([C:21]4[O:25][N:24]=[C:23]([CH3:26])[C:22]=4[CH2:27][CH:28]([OH:38])[CH2:29][N:30]([CH2:31][C:32]4[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=4)[S:40]([CH3:39])(=[O:42])=[O:41])=[CH:17][CH:16]=3)=[CH:13][CH:14]=2)[CH2:7][CH2:8]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4CC(O)CNCc4ccccc4)cc3)cc2)CC1
Reactant: CS(=O)(=O)Cl
Product: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4CC(O)CN(Cc4ccccc4)S(C)(=O)=O)cc3)cc2)CC1

Procedure:
Prepared according to the procedure described in Example 3, Step 7, using 1-{4′-[4-(3-benzylamino-2-hydroxy-propyl)-3-methyl-isoxazol-5-yl]-biphenyl-4-yl}-cyclopropanecarboxylic acid ethyl ester and methanesulfonyl chloride.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[CH:5][C:6]2[O:11][C:10]([CH3:13])([CH3:12])[CH:9]([OH:14])[CH:8]([CH2:15][C:16]([N:18](C)[CH2:19]C3C=CC(OC)=CC=3)=[O:17])[C:7]=2[CH:29]=1)#[N:2]>O>[C:1]([C:3]1[CH:4]=[CH:5][C:6]2[O:11][C:10]([CH3:12])([CH3:13])[CH:9]([OH:14])[CH:8]([CH2:15][C:16]([NH:18][CH3:19])=[O:17])[C:7]=2[CH:29]=1)#[N:2]
Reactant: COc1ccc(CN(C)C(=O)CC2c3cc(C#N)ccc3OC(C)(C)C2O)cc1
Solvent: O
Product: CNC(=O)CC1c2cc(C#N)ccc2OC(C)(C)C1O

Procedure:
A solution of 6-cyano-3,4-dihydro-3-hydroxy-N-methyl-N-(4-methoxy-benzyl)-2,2-dimethyl-2H-1-benzopyran-4-acetamide (0.5 g) in methanesulpnonic acid (5 ml) was stirred at room temperature for 6 days. Water was added, and the mixture extracted into ethyl acetate. The combined organic layers were washed with sodium bicarbonate solution, brine, then dried (MgSO4), filtered and evaporated. Tne crude product was chromatographed (Si gel, ethyl acetate - pentane gradient elution) to give the title compound, which recrystallised from ethyl acetate as a colourless solid (40 mg) having m.pt. 141°-2° C.
Reaction SMILES: Cl/[CH:2]=[CH:3]\[C:4]#[C:5][CH2:6][O:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.C(N)CCC.[CH3:19][Si:20]([C:23]#[CH:24])([CH3:22])[CH3:21]>[Cu]I.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.C1COCC1>[O:7]([CH2:6][C:5]#[C:4]/[CH:3]=[CH:2]\[C:24]#[C:23][Si:20]([CH3:22])([CH3:21])[CH3:19])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: Cl/C=C\C#CCOc1ccccc1
Reactant: C#C[Si](C)(C)C
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: CCCCN
Product: C[Si](C)(C)C#C/C=C\C#CCOc1ccccc1
Reaction time: 7 h
Yield: 62.7 %

Procedure:
To a 1 L flask under Argon was added CuI (5.24 g, 27 mmol) and Pd(PPh3)4 (4.9 g, 4 mmol) and the catalyst covered with 500 mL of degassed THF. To this solution was added the product of step (a) (42.7 g, 220 mmol) and degassed butylamine (44 mL, 440 mmol). To this solution was added trimethylsilyl acetylene (29 g, 290 mmol) and the reaction mixture was stirred for 7 h. Air was bubbled through the solution for 15 min and the reaction mixture filtered through celite and washed with pentane. The filtrate was washed several times with water and the aqueous fractions extracted with ether. The organic fractions were combined, dried (MgSO4) and concentrated. The residue was chromatographed over silica gel (hexane) to give 35.1 g of a tan oil (62%).
Reaction SMILES: [OH:1][CH:2]1[CH:7]([C:8]2[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][CH:9]=2)[CH2:6][CH2:5][N:4]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:3]1.C1(C)C=CC(S(O[CH2:32][CH2:33][CH2:34][O:35][CH:36]2[CH2:41][CH2:40][CH2:39][CH2:38][CH2:37]2)(=O)=O)=CC=1>>[CH:36]1([O:35][CH2:34][CH2:33][CH2:32][O:14][C:11]2[CH:10]=[CH:9][C:8]([CH:7]3[CH2:6][CH2:5][N:4]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:3][CH:2]3[OH:1])=[CH:13][CH:12]=2)[CH2:41][CH2:40][CH2:39][CH2:38][CH2:37]1
Reactant: Cc1ccc(S(=O)(=O)OCCCOC2CCCCC2)cc1
Reactant: CC(C)(C)OC(=O)N1CCC(c2ccc(O)cc2)C(O)C1
Product: CC(C)(C)OC(=O)N1CCC(c2ccc(OCCCOC3CCCCC3)cc2)C(O)C1

Procedure:
Analogously to Method I, 0.795 g of tert-butyl 3-hydroxy-4-(4-hydroxyphenyl)piperidine-1-carboxylate and 1.07 g of 3-cyclohexyloxypropyl toluene-4-sulphonate are reacted. The title compound is obtained as a slightly yellowish oil. Rf=0.39 (1:1 EtOAc-heptane); Rt=5.43.
Reaction SMILES: [CH3:1][O:2][N:3]=[C:4]([C:8]1[S:12][C:11]2[CH:13]=[C:14]([Cl:16])[S:15][C:10]=2[CH:9]=1)[C:5](O)=[O:6].C(Cl)(=O)C([Cl:20])=O>>[CH3:1][O:2][N:3]=[C:4]([C:8]1[S:12][C:11]2[CH:13]=[C:14]([Cl:16])[S:15][C:10]=2[CH:9]=1)[C:5]([Cl:20])=[O:6]
Reactant: CON=C(C(=O)O)c1cc2sc(Cl)cc2s1
Reactant: O=C(Cl)C(=O)Cl
Product: CON=C(C(=O)Cl)c1cc2sc(Cl)cc2s1

Procedure:
Following the procedure of Example 1, 827 mg of α-methoxyimino-α-(5-chlorothieno[3,2-b]thien-2-yl)-acetic acid from Preparation 2 was reacted with oxalyl chloride to provide α-methoxyimino-α-(5-chlorothieno[3,2-b]thien-2-yl)acetyl chloride which was reacted with 642 mg of 7-amino-3-methyl-3-cephem-4-carboxylic acid silylated with 2.31 g of BSTFA. The reaction afforded 1.1 g of 7-[α-methoxyimino-α-(5-chlorothieno[3,2-b]thien-2-yl)acetamido]-3-methyl-3-cephem-4-carboxylic acid. The thienothienyl oxime was reacted with 544 mg of zinc dust in formic acid and methanol to provide 1.1 g of 7-(5-chlorothieno[3,2-b]thien-2-yl)glycylamido-3-methyl-3-cephem-4-carboxylic acid. Reverse phase high performance chromatography provided
Reaction SMILES: [N:1]1[S:5][N:4]=[C:3]2[C:6]([S:10]([NH:13][C:14]3[CH:22]=[C:21]([I:23])[CH:20]=[CH:19][C:15]=3[C:16](O)=[O:17])(=[O:12])=[O:11])=[CH:7][CH:8]=[CH:9][C:2]=12.[CH3:24][O:25][C:26](=[O:44])[C@@H:27]([NH2:43])[CH:28]([C:36]1[CH:41]=[CH:40][C:39]([Cl:42])=[CH:38][CH:37]=1)[C:29]1[CH:34]=[CH:33][C:32]([Cl:35])=[CH:31][CH:30]=1>>[CH3:24][O:25][C:26](=[O:44])[C@@H:27]([NH:43][C:16](=[O:17])[C:15]1[CH:19]=[CH:20][C:21]([I:23])=[CH:22][C:14]=1[NH:13][S:10]([C:6]1[C:3]2=[N:4][S:5][N:1]=[C:2]2[CH:9]=[CH:8][CH:7]=1)(=[O:11])=[O:12])[CH:28]([C:29]1[CH:34]=[CH:33][C:32]([Cl:35])=[CH:31][CH:30]=1)[C:36]1[CH:37]=[CH:38][C:39]([Cl:42])=[CH:40][CH:41]=1
Reactant: O=C(O)c1ccc(I)cc1NS(=O)(=O)c1cccc2nsnc12
Reactant: COC(=O)[C@@H](N)C(c1ccc(Cl)cc1)c1ccc(Cl)cc1
Product: COC(=O)[C@@H](NC(=O)c1ccc(I)cc1NS(=O)(=O)c1cccc2nsnc12)C(c1ccc(Cl)cc1)c1ccc(Cl)cc1
Yield: 84 %

Procedure:
The title compound (49 mg, 84%) was prepared from 2-(benzo[1,2,5]thiadiazole-4-sulfonylamino)-4-iodobenzoic acid (EXAMPLE 101, Part D) and (S)-2-amino-3,3-bis-(4-chloro-phenyl)-propionic acid methyl ester (EXAMPLE 106, Part H) as in Example 1, Part C. 1H NMR (500 MHz, CDCl3): 11.16 (s, 1H), 8.36 (dd, J=7.0, 1.0, 1H), 8.23 (dd, J=8.8, 1.0, 1H), 8.03 (d, J=1.6, 1H), 7.72 (dd, J=8.8, 7.1, 1H), 7.32-7.27 (m, 4H), 7.24 (dd, J=8.2, 1.6, 1H), 7.21-7.15 (m, 4H), 6.71 (d, J=8.3, 1H), 6.22 (br d, J=8.8, 1H), 5.48 (t, J=8.5, 1H), 4.48 (d, J=8.3, 1H), 3.62 (s, 3H).
Reaction SMILES: [CH3:1][C:2]([N:10]1[CH:14]=[C:13]([NH:15][C:16](=[O:22])[CH:17]([NH2:21])[CH2:18][CH2:19][CH3:20])[N:12]=[CH:11]1)([CH3:9])[CH2:3][N:4]1[CH2:8][CH2:7][CH2:6][CH2:5]1.[F:23][C:24]1[CH:25]=[C:26]2[C:31](=[C:32]([F:34])[CH:33]=1)[C:30]([CH3:36])([CH3:35])[C:29](=O)[CH2:28][CH2:27]2>>[CH3:1][C:2]([N:10]1[CH:14]=[C:13]([NH:15][C:16](=[O:22])[CH:17]([NH:21][CH:29]2[CH2:28][CH2:27][C:26]3[C:31](=[C:32]([F:34])[CH:33]=[C:24]([F:23])[CH:25]=3)[C:30]2([CH3:36])[CH3:35])[CH2:18][CH2:19][CH3:20])[N:12]=[CH:11]1)([CH3:9])[CH2:3][N:4]1[CH2:8][CH2:7][CH2:6][CH2:5]1
Reactant: CCCC(N)C(=O)Nc1cn(C(C)(C)CN2CCCC2)cn1
Reactant: CC1(C)C(=O)CCc2cc(F)cc(F)c21
Product: CCCC(NC1CCc2cc(F)cc(F)c2C1(C)C)C(=O)Nc1cn(C(C)(C)CN2CCCC2)cn1

Procedure:
2-Amino-pentanoic acid [1-(1,1-dimethyl-2-pyrrolidin-1-yl-ethyl)-1H-imidazol-4-yl]-amide was reacted with 6,8-Difluoro-1,1-dimethyl-3,4-dihydro-1H-naphthalen-2-one to afford the title compound: C13 NMR (100 MHz, CDCl3) 14.3, 19.4, 19.7, 22.5, 23.0, 24.3, 24.8, 26.3, 26.6, 27.4, 27.5, 29.7, 36.4, 37.1, 38.0, 45.8, 47.6, 56.0, 59.2, 60.7, 62.5, 63.0, 65.5, 67.3, 104.7, 104.8, 111.0, 110.2, 112.5, 131.1, 131.2, 137.2, 172.2; MS m/z 502.3. (M+1).
Reaction SMILES: [Na].N.[CH3:3][C:4]1[CH:5]=[C:6]([P:11]([C:20]2[CH:25]=[C:24]([CH3:26])[CH:23]=[C:22]([CH3:27])[CH:21]=2)C2C=C(C)C=C(C)C=2)[CH:7]=[C:8]([CH3:10])[CH:9]=1.[C:28]([O:32][C:33]1[C:42]2[C:37](=[CH:38][CH:39]=[CH:40][CH:41]=2)[CH:36]=[C:35](Cl)[N:34]=1)([CH3:31])([CH3:30])[CH3:29]>O1CCCC1>[C:28]([O:32][C:33]1[C:42]2[C:37](=[CH:38][CH:39]=[CH:40][CH:41]=2)[CH:36]=[C:35]([P:11]([C:20]2[CH:25]=[C:24]([CH3:26])[CH:23]=[C:22]([CH3:27])[CH:21]=2)[C:6]2[CH:7]=[C:8]([CH3:10])[CH:9]=[C:4]([CH3:3])[CH:5]=2)[N:34]=1)([CH3:31])([CH3:29])[CH3:30]
Reactant: Cc1cc(C)cc(P(c2cc(C)cc(C)c2)c2cc(C)cc(C)c2)c1
Reactant: CC(C)(C)Oc1nc(Cl)cc2ccccc12
Agent: N
Agent: [Na]
Solvent: C1CCOC1
Product: Cc1cc(C)cc(P(c2cc(C)cc(C)c2)c2cc3ccccc3c(OC(C)(C)C)n2)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 35.5 %

Procedure:
At −78° C., sodium (0.28 g, 12.3 mmol) is added slowly to liquid ammonia (40 mL) followed by tris(3,5-dimethylphenyl)phosphine (2.1 g, 6.0 mmol), and the resulting mixture is stirred for 2 hours. A solution of 1-tert-butoxy-3-chloroisoquinoline (1.4 g, 6.0 mmol) in tetrahydrofuran (6 mL) is then added drop-wise and the resulting mixture slowly warmed to ambient temperature over 16 hours. The residue is quenched with water (30 mL), extracted with diethyl ether (3×25 mL), and the combined extracts are percolated through a column of magnesium sulfate-ZSM-5. The filtrate is concentrated under reduced pressure and the opaque residue is purified by a re-crystallization from methanol, yielding 1-tert-butoxy-3-(bis(3,5-dimethylphenyl)phosphino)isoquinoline (0.94 g, 73%) as a white solid.