Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[CH2:2][C:3](=O)[C:4](=[N:21][O:22][CH2:23][C:24]([O:26][CH3:27])=[O:25])[C:5]([NH:7][CH:8]1[C:19](=[O:20])[N:10]2[C:11]([C:16]([OH:18])=[S:17])=[C:12]([CH3:15])[CH2:13][S:14][C@H:9]12)=[O:6].[NH2:29][C:30]([NH2:32])=[S:31].C([O-])(=O)C.[Na+]>O1CCCC1.O>[NH2:32][C:30]1[S:31][CH:2]=[C:3]([C:4](=[N:21][O:22][CH2:23][C:24]([O:26][CH3:27])=[O:25])[C:5]([NH:7][CH:8]2[C:19](=[O:20])[N:10]3[C:11]([C:16]([OH:18])=[S:17])=[C:12]([CH3:15])[CH2:13][S:14][C@H:9]23)=[O:6])[N:29]=1
Reactant: COC(=O)CON=C(C(=O)CCl)C(=O)NC1C(=O)N2C(C(O)=S)=C(C)CS[C@H]12
Reactant: NC(N)=S
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: COC(=O)CON=C(C(=O)NC1C(=O)N2C(C(O)=S)=C(C)CS[C@H]12)c1csc(N)n1
Reaction time: 3 h
Yield: 73.4 %

Procedure:
A mixture of 7-[4-chloro-2-(methoxycarbonylmethoxyimino)-3-oxobutyramido]-3-methylthio-3-cephem-4-carboxylic acid (syn isomer) (2.6 g), thiourea (0.91 g) and sodium acetate (2.46 g) in tetrahydrofuran (10 ml) and water (20 ml) was stirred at 40° to 45° C. for 3 hours. Water (50 ml) was added to the reaction mixture and the resultant solution was washed with ethyl acetate. The separated aqueous layer was acidified to pH 2.2 with 10% hydrochloric acid and the acidified aqueous solution was extracted with ethyl acetate-tetrahydrofuran (8:2). The organic layer was washed with brine and dried over magnesium sulfate. The solution was evaporated and the residue was triturated with ether to give 7-[2-(2-aminothiazol-4-yl)-2-(methoxycarbonylmethoxyimino)acetamido]-3-methylthio-3-cephem-4-carboxylic acid (syn isomer) (2.0 g).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[CH2:9][CH2:10][C:11]1[N:12]([CH2:22][C:23](O)=[O:24])[C:13]2[C:18]([C:19](=[O:21])[N:20]=1)=[CH:17][CH:16]=[CH:15][CH:14]=2.[CH3:26][C:27]([N:34]1[CH2:39][CH2:38][CH:37]([NH:40][CH2:41][C:42]2[CH:47]=[CH:46][C:45]([C:48]3[CH:53]=[CH:52][C:51]([C:54]([F:57])([F:56])[F:55])=[CH:50][CH:49]=3)=[CH:44][CH:43]=2)[CH2:36][CH2:35]1)([CH3:33])[C:28]([O:30][CH2:31][CH3:32])=[O:29].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>CN(C=O)C>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[CH2:9][CH2:10][C:11]1[N:12]([CH2:22][C:23]([N:40]([CH2:41][C:42]2[CH:47]=[CH:46][C:45]([C:48]3[CH:49]=[CH:50][C:51]([C:54]([F:56])([F:55])[F:57])=[CH:52][CH:53]=3)=[CH:44][CH:43]=2)[CH:37]2[CH2:36][CH2:35][N:34]([C:27]([CH3:26])([CH3:33])[C:28]([O:30][CH2:31][CH3:32])=[O:29])[CH2:39][CH2:38]2)=[O:24])[C:13]2[C:18]([C:19](=[O:21])[N:20]=1)=[CH:17][CH:16]=[CH:15][CH:14]=2
Reactant: CCOC(=O)C(C)(C)N1CCC(NCc2ccc(-c3ccc(C(F)(F)F)cc3)cc2)CC1
Reactant: O=C(O)Cn1c(CCc2ccc(F)cc2F)nc(=O)c2ccccc21
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
Product: CCOC(=O)C(C)(C)N1CCC(N(Cc2ccc(-c3ccc(C(F)(F)F)cc3)cc2)C(=O)Cn2c(CCc3ccc(F)cc3F)nc(=O)c3ccccc32)CC1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 64.1 %

Procedure:
A mixture of [2-[2-(2,4-difluorophenyl)ethyl]-4-oxo-1(4H)-quinazolinyl]acetic acid (Int. C3) (120 mg, 1 equiv), ethyl 2-methyl-2-[4-({[4′-(trifluoromethyl)-4-biphenylyl]methyl}-amino)-1-piperidinyl]propanoate (Int. B2) (204 mg, 1.3 equiv), DMF (1.4 ml) and DIPEA (0.183 ml, 3 equiv) was shaken at room temperature, then HATU (206 mg, 1.5 equiv) was added with vigorous agitation and shaking continued for 1.5 h. A further portion of Intermediate D5 (12 mg, 0.1 equiv) was added then shaking was continued for 2 days. Reverse phase HPLC (Preparative Method B) gave ethyl 2-[4-({[2-[2-(2,4-difluorophenyl)ethyl]-4-oxo-1(4H)-quinazolinyl]acetyl} {[4′-(trifluoromethyl)-4-biphenylyl]methyl}amino)-1-piperidinyl]-2-methylpropanoate as a white solid (173 mg).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:10]=[O:11])[CH:6]=[CH:7][C:8]=1[OH:9].[OH-].[Na+].[CH2:14](I)[CH3:15]>O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:6]=[CH:7][C:8]=1[O:9][CH2:14][CH3:15])[CH:10]=[O:11]
Reactant: CCI
Reactant: COc1cc(C=O)ccc1O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CCOc1ccc(C=O)cc1OC
Reaction time: 15 h
Yield: 68.8 %

Procedure:
To a solution of 30.4 g (0.2 mole) of vanilline, 12 g (0.3 mole) of sodium hydroxide and 300 ml of water, then 37.4 g (0.24 mole) of ethyl iodide are added. The reaction mixture is heated to boiling for 15 hours, then cooled and extracted with benzene. The extract is evaporated. The crude residue is dissolved in 110 ml of a 25% aqueous sodium hydroxide solution, clarified with activated charcoal and made alkaline to pH 12. The precipitated crystals are filtered, washed with water and dried. Thus 24.8 g of 3-methoxy-4-ethoxy-benzaldehyde are obtained, yield 69%, m.p.: 65°-67° C.
Reaction SMILES: [CH2:1]([O:8][C:9]([C:11]1[CH:16]=[CH:15][C:14]([CH2:17][CH2:18][C:19]2[C:23]3[C:24]([OH:28])=[CH:25][CH:26]=[CH:27][C:22]=3[O:21][CH:20]=2)=[CH:13][CH:12]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:29]([O:32][C@@H:33]1[C@@H:45]([O:46][C:47](=[O:49])[CH3:48])[C@H:44]([O:50][C:51](=[O:53])[CH3:52])[C@@H:43]([CH2:54][O:55][C:56](=[O:58])[CH3:57])[O:42][C@@H:34]1OC(=N)C(Cl)(Cl)Cl)(=[O:31])[CH3:30].C(=O)([O-])O.[Na+]>ClCCl.C(OCC)(=O)C>[C:29]([O:32][C@@H:33]1[C@@H:45]([O:46][C:47](=[O:49])[CH3:48])[C@H:44]([O:50][C:51](=[O:53])[CH3:52])[C@@H:43]([CH2:54][O:55][C:56](=[O:58])[CH3:57])[O:42][C@H:34]1[O:28][C:24]1[C:23]2[C:19]([CH2:18][CH2:17][C:14]3[CH:15]=[CH:16][C:11]([C:9]([O:8][CH2:1][C:2]4[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=4)=[O:10])=[CH:12][CH:13]=3)=[CH:20][O:21][C:22]=2[CH:27]=[CH:26][CH:25]=1)(=[O:31])[CH3:30]
Reactant: O=C(OCc1ccccc1)c1ccc(CCc2coc3cccc(O)c23)cc1
Reactant: CC(=O)OC[C@H]1O[C@H](OC(=N)C(Cl)(Cl)Cl)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CC(=O)OC[C@H]1O[C@@H](Oc2cccc3occ(CCc4ccc(C(=O)OCc5ccccc5)cc4)c23)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Temperature: 25 °C
Reaction time: 3 h
Yield: 89.7 %

Procedure:
3-[2-(4-Benzyloxycarbonylphenyl)ethyl]-4-hydroxybenzofuran (0.26 g) and 2,3,4,6-tetra-O-acetyl-1-O-trichloroacetoimidoyl-α-D-glucopyranose (0.41 g) were dissolved in dichloromethane (5 mL)-ethyl acetate (3 mL). To the solution was added boron trifluoride-diethyl ether complex (0.44 mL), and the mixture was stirred at room temperature for 3 hours. The reaction mixture was poured into a saturated aqueous, sodium hydrogen carbonate solution, and the resulting mixture was extracted with ethyl acetate. The extract was washed with brine and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure, and the residue was purified by column chromatography on silica gel (eluent: n-hexane/ethyl acetate=3/2-2/3) to give 4-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyloxy)-3-[2-(4-benzyloxycarbonylphenyl)ethyl]-benzofuran (0.44 g). This material was dissolved in tetrahydrofuran (5 mL). To the solution was added 10% palladium-carbon powder (0.2 g), and the mixture was stirred at room temperature under a hydrogen atmosphere for 1 hour. The insoluble material was removed by filtration, and the filtrate was concentrated under reduced pressure to give the title compound (0.37 g).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[F:10])[CH2:5][OH:6].[H-].[Na+].[F:13][C:14]1[CH:21]=[CH:20][CH:19]=[C:18](F)[C:15]=1[C:16]#[N:17]>CN(C)C=O>[F:13][C:14]1[CH:21]=[CH:20][CH:19]=[C:18]([O:6][CH2:5][C:4]2[CH:7]=[CH:8][C:9]([F:10])=[C:2]([F:1])[CH:3]=2)[C:15]=1[C:16]#[N:17]
Reactant: N#Cc1c(F)cccc1F
Reactant: OCc1ccc(F)c(F)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: N#Cc1c(F)cccc1OCc1ccc(F)c(F)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
3,4-Difluorobenzyl alcohol (1.47 g; 10.1 mmol) was added to a cooled (0° C.) slurry of sodium hydride (0.414 g; 10.3 mmol) in dimethylformamide under nitrogen atmosphere. The reaction mixture was slowly warmed to room temperature, stirred for 1 hour. The reaction mixture was then added to a cooled (0° C.) solution of 2,6-difluorobenzonitrile in dimethylformamide, stirred for 3 hours at room temperature. The reaction mixture was poured on crushed ice-water, stirred, filtered, washed with water and dried to afford 1.47 grams of 2-fluoro-6-(3,4-diflurophenylmethoxy)benzonitrile.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[N:4][C:5]2[C:10]=1[C:9](=O)[N:8]=[CH:7][N:6]=2.C(N(C(C)C)CC)(C)C.P(Cl)(Cl)([Cl:23])=O>>[Cl:23][C:9]1[N:8]=[CH:7][N:6]=[C:5]2[NH:4][N:3]=[C:2]([CH3:1])[C:10]=12
Reactant: CC1=C2C(=O)N=CN=C2N=N1
Reactant: O=P(Cl)(Cl)Cl
Solvent: CCN(C(C)C)C(C)C
Product: Cc1n[nH]c2ncnc(Cl)c12

Procedure:
To a stirred suspension of 3-methyl-pyrazolo[3,4-d]pyrimidin-4-one (7.50 g, 50.0 mmol, Example 2) in phosphorus oxychloride (150 mL) was added diisopropylethylamine (31 mL, 175 mmol, Aldrich). The mixture was heated at reflux for 2.5 hours before the solvent was evaporated under reduced pressure. The residue was treated with ice (200 g) and made slightly basic with 4N aqueous sodium hydroxide solution and extracted with ethyl acetate (3×250 mL). The combined organic extracts were washed with water, brine, dried and concentrated to give 4-chloro-3-methyl-1H-pyrazolo[3,4-d]pyrimidine as a white solid. (Yield 6.38 g).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[N:13]([C:14]3[CH:19]=[CH:18][CH:17]=[C:16]([Cl:20])[CH:15]=3)[N:12]=[C:11]([C:21](O)=[O:22])[CH:10]=2)[CH:5]=[CH:6][C:7]=1[F:8].ClC1C=C(N2C(C3C=C(F)C=C(Cl)C=3)=CC(C([N:47]3[CH2:51][C:50](=[O:52])[NH:49][CH2:48]3)=O)=N2)C=CC=1F>>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[N:13]([C:14]3[CH:19]=[CH:18][CH:17]=[C:16]([Cl:20])[CH:15]=3)[N:12]=[C:11]([C:21]([N:47]3[CH2:51][C:50](=[O:52])[NH:49][CH2:48]3)=[O:22])[CH:10]=2)[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: O=C1CN(C(=O)c2cc(-c3cc(F)cc(Cl)c3)n(-c3ccc(F)c(Cl)c3)n2)CN1
Reactant: O=C(O)c1cc(-c2ccc(F)c(Cl)c2)n(-c2cccc(Cl)c2)n1
Product: O=C1CN(C(=O)c2cc(-c3ccc(F)c(Cl)c3)n(-c3cccc(Cl)c3)n2)CN1

Procedure:
The preparation of the title compound takes place starting from the compound of Example 79A in analogy to the synthesis of the compound of Example 1. 52 mg (87% of theory) of the title compound are obtained.
Reaction SMILES: [C:1]([OH:11])(=[O:10])[CH:2]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)O.[CH2:12]([CH:28]([C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=1O)[CH3:29])[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27]>O>[C:4]1([CH:2]2[C:32]3[CH:33]=[CH:34][CH:35]=[C:30]([CH:28]([CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])[CH3:29])[C:31]=3[O:11][C:1]2=[O:10])[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: CCCCCCCCCCCCCCCCC(C)c1ccccc1O
Reactant: O=C(O)C(O)c1ccccc1
Solvent: O
Product: CCCCCCCCCCCCCCCCC(C)c1cccc2c1OC(=O)C2c1ccccc1

Procedure:
4.8 g (31.5 mmol) of mandelic acid and 10.4 g (30 mmol) of 1-hexadecylethylphenol are heated together at 190°-200° C. for approx. 8 hours under reduced pressure (13.3 mbar). In the course of this the water formed in the reaction is removed by distillation. When the reaction is complete, the reaction product is filtered over silica gel (hexane) and is then treated with cold hexane. The product has a melting point of 60°-62° C. and is in the form of a white powder. The yield is 7 g (=50% of theory).
Reaction SMILES: [C:1]([C:5]1[CH:9]=[C:8]([NH:10][C:11](=[O:46])[NH:12][C:13]2[C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[C:16]([O:23][CH2:24][C:25]3[CH:30]=[CH:29][N:28]=[C:27]([NH:31][C:32](=[O:45])[C:33]([N:36](C)[C:37](=O)OC(C)(C)C)([CH3:35])[CH3:34])[CH:26]=3)=[CH:15][CH:14]=2)[N:7]([C:47]2[CH:52]=[CH:51][C:50]([CH3:53])=[CH:49][CH:48]=2)[N:6]=1)([CH3:4])([CH3:3])[CH3:2]>C(Cl)Cl.C(O)(C(F)(F)F)=O>[C:1]([C:5]1[CH:9]=[C:8]([NH:10][C:11](=[O:46])[NH:12][C:13]2[C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[C:16]([O:23][CH2:24][C:25]3[CH:30]=[CH:29][N:28]=[C:27]([NH:31][C:32](=[O:45])[C:33]([CH3:35])([NH:36][CH3:37])[CH3:34])[CH:26]=3)=[CH:15][CH:14]=2)[N:7]([C:47]2[CH:48]=[CH:49][C:50]([CH3:53])=[CH:51][CH:52]=2)[N:6]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: Cc1ccc(-n2nc(C(C)(C)C)cc2NC(=O)Nc2ccc(OCc3ccnc(NC(=O)C(C)(C)N(C)C(=O)OC(C)(C)C)c3)c3ccccc23)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CNC(C)(C)C(=O)Nc1cc(COc2ccc(NC(=O)Nc3cc(C(C)(C)C)nn3-c3ccc(C)cc3)c3ccccc23)ccn1
Yield: 80.7 %

Procedure:
A solution of the carbamate (6) (25 mg, 0.04 mmol) in DCM/TFA (1:1 v/v, 2.0 mL) was stirred at RT for 30 min. The reaction mixture was evaporated in vacuo and the resulting residue was subjected to SCX capture and release to afford the title compound (Example 8) as a pale brown solid (20 mg, 89%): m/z 620 (M+H)+ (ES+). 1H NMR (400 MHz, DMSO-d6) δ: 1.25 (6H, s), 1.27 (9H, s), 2.20 (3H, s), 2.39 (3H, s), 5.38 (2H, s), 6.35 (1H, s), 7.00 (1H, d), 7.27 (1H, dd), 7.36 (2H, m), 7.44 (2H, m), 7.58-7.62 (3H, overlapping m), 7.93 (1H, m), 8.29-8.34 (3H, overlapping m), 8.59 (1H, br s), 8.79 (1H, br s).
Reaction SMILES: [CH:1]([C:3]1[CH:11]=[CH:10][C:6]([C:7]([OH:9])=[O:8])=[CH:5][CH:4]=1)=O.[CH3:12][C:13]1([CH3:26])[C@@H:15]2[CH2:16][C:17]3[C:21]([C@H:14]12)=[C:20]([CH3:22])[S:19][C:18]=3[C:23](=[O:25])[CH3:24].C[O-].[Na+]>CO.C(OCC)C>[O:25]=[C:23]([C:18]1[S:19][C:20]([CH3:22])=[C:21]2[C:17]=1[CH2:16][C@H:15]1[C:13]([CH3:26])([CH3:12])[C@H:14]12)[CH:24]=[CH:1][C:3]1[CH:11]=[CH:10][C:6]([C:7]([OH:9])=[O:8])=[CH:5][CH:4]=1
Reactant: CC(=O)c1sc(C)c2c1C[C@@H]1[C@H]2C1(C)C
Reactant: O=Cc1ccc(C(=O)O)cc1
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Solvent: CCOCC
Product: Cc1sc(C(=O)C=Cc2ccc(C(=O)O)cc2)c2c1[C@H]1[C@@H](C2)C1(C)C
Reaction time: 2 h
Yield: 57.3 %

Procedure:
A solution of 4-formyl-benzoic acid (1.04 g mg, 6.93 mmol), (1aS,5aR)-1-(1,1,2-trimethyl-1,1a,5,5a-tetrahydro-3-thia-cyclopropa[a]pentalen-4-yl)-ethanone (850 mg, 3.86 mmol), NaOMe (4.17 g, 77.2 mmol) in methanol (30 mL) is stirred at 65° C. for 2 h. Another portion of 4-formyl-benzoic acid (400 mg, 2.66 mmol) is added and stirring is continued at 65° C. for 2 h. The reaction mixture is diluted with diethyl ether (200 mL) and washed with 5% aq. citric acid solution followed by water. The organic phase is dried over MgSO4 and evaporated. The crude product is purified by CC on silica gel eluting with DCM containing 2-7% methanol, followed by crystallisation from methanol:water 1:1 to give 4-[3-oxo-3-((1aS,5aR)-1,1,2-trimethyl-1,1a,5,5a-tetrahydro-3-thia-cyclopropa[a]pentalen-4-yl)-propenyl]-benzoic acid (780 mg) as beige yellow powder; LC-MS: tR=1.06 min, [M+1]+=353.03; 1H NMR (CDCl3): δ 8.13 (d, J=8.2 Hz, 2H), 7.76 (d, J=15.2 Hz, 1H), 7.68 (d, J=8.2 Hz, 2H), 7.29 8d, J=15.8 Hz, 1H), 3.14 (dd, J=5.9, 18.8 Hz, 1H), 2.96 (d, J=18.8 Hz, 1H), 2.44 (s, 3H), 2.00-1.91 (m, 2H), 1.15 (s, 3H), 0.75 (s, 3H).
Reaction SMILES: [Br:1][C:2]1[N:7]=[C:6]([CH2:8][C:9]([O:11][CH3:12])=[O:10])[CH:5]=[CH:4][CH:3]=1.C1C(=O)N([Br:20])C(=O)C1.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(Cl)(Cl)(Cl)Cl>[Br:20][CH:8]([C:6]1[CH:5]=[CH:4][CH:3]=[C:2]([Br:1])[N:7]=1)[C:9]([O:11][CH3:12])=[O:10]
Reactant: COC(=O)Cc1cccc(Br)n1
Reactant: O=C1CCC(=O)N1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: COC(=O)C(Br)c1cccc(Br)n1
Temperature: 25 °C

Procedure:
To a solution of methyl (6-bromopyridin-2-yl)acetate (Example 350, Step 1) (6.00 g, 26.1 mmol) in CCl4 (100 mL) were added NBS (4.87 g, 27.4 mmol) and benzoyl peroxide (474 mg, 1.96 mmol). The reaction was heated at reflux overnight. The solution was then cooled to room temperature, filtered, and evaporated. Silica gel chromatography (0-40% EtOAc/hexanes) afforded the title compound as a yellow oil.
Reaction SMILES: C(OC([N:8]1[CH2:14][CH2:13][CH2:12][N:11]([CH2:15][CH2:16][CH2:17][CH2:18][N:19]([C@@H:23]([CH3:35])[CH2:24][C:25]2[CH:30]=[CH:29][C:28]([S:31]([CH3:34])(=[O:33])=[O:32])=[CH:27][CH:26]=2)[CH2:20][CH2:21][CH3:22])[C:10](=[O:36])[CH2:9]1)=O)(C)(C)C.[ClH:37].C(=O)([O-])[O-].[Na+].[Na+]>>[ClH:37].[ClH:37].[CH3:34][S:31]([C:28]1[CH:29]=[CH:30][C:25]([CH2:24][C@@H:23]([N:19]([CH2:20][CH2:21][CH3:22])[CH2:18][CH2:17][CH2:16][CH2:15][N:11]2[CH2:12][CH2:13][CH2:14][NH:8][CH2:9][C:10]2=[O:36])[CH3:35])=[CH:26][CH:27]=1)(=[O:32])=[O:33]
Reactant: CCCN(CCCCN1CCCN(C(=O)OC(C)(C)C)CC1=O)[C@@H](C)Cc1ccc(S(C)(=O)=O)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Product: CCCN(CCCCN1CCCNCC1=O)[C@@H](C)Cc1ccc(S(C)(=O)=O)cc1
Temperature: 50 °C
Reaction time: 0.5 h

Procedure:
A mixture of 4-(4-{[(S)-2-(4-methanesulfonylphenyl)-1-methylethyl]-propylamino}butyl)-3-oxo-[1,4]diazepane-1-carboxylic acid tert-butyl ester (0.9 g, 1.75 mmole) and 3N hydrochloric acid (4 mL) was warmed to 50° C. The reaction mixture was stirred at room temperature for 30 minutes, and the pH was adjusted to 10 with saturated sodium carbonate. The mixture was extracted with ethyl acetate (30 mL), and the organic phase was dried (magnesium sulfate), and concentrated. The residue was dissolved in diethyl ether (10 mL) and 1 M hydrogen chloride in diethyl ether (2 mL) was added. The precipitate was collected, washed with diethyl ether and hexane, and dried in vacuo to give 1-(4-{[(S)-2-(−4-methanesulfonyl-phenyl)-1-methylethyl]propylamino}butyl)-[1,4]diazepan-2-one, dihydrochloride salt (0.49 g), 149, M+H=424.
Reaction SMILES: [CH2:1]([O:3][CH2:4][C@@H:5]1[CH2:9][O:8][C:7](=[O:10])[N:6]1[C:11]1[CH:16]=[CH:15][C:14]([C:17]([N:19]2[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]2)=[O:18])=[C:13]([F:25])[CH:12]=1)[CH3:2].Cl[C:27]1[C:32]([Cl:33])=[CH:31][C:30]([Cl:34])=[CH:29][N:28]=1>>[Cl:33][C:32]1[C:27]([N:22]2[CH2:23][CH2:24][N:19]([C:17]([C:14]3[CH:15]=[CH:16][C:11]([N:6]4[C@H:5]([CH2:4][O:3][CH2:1][CH3:2])[CH2:9][O:8][C:7]4=[O:10])=[CH:12][C:13]=3[F:25])=[O:18])[CH2:20][CH2:21]2)=[N:28][CH:29]=[C:30]([Cl:34])[CH:31]=1
Reactant: CCOC[C@@H]1COC(=O)N1c1ccc(C(=O)N2CCNCC2)c(F)c1
Reactant: Clc1cnc(Cl)c(Cl)c1
Product: CCOC[C@@H]1COC(=O)N1c1ccc(C(=O)N2CCN(c3ncc(Cl)cc3Cl)CC2)c(F)c1
Yield: 66.6 %

Procedure:
By reaction and treatment in the same manner as in Example 147 and using (R)-4-ethoxymethyl-3-[3-fluoro-4-(piperazine-1-carbonyl)phenyl]oxazolidin-2-one (1.23 g) described in Preparation Example 160 and 2,3,5-trichloropyridine (1.28 g), the title compound (1.16 g) was obtained. MS(ESI)m/z:497(M+H)+.
Reaction SMILES: [Br:1][C:2]1[CH:17]=[CH:16][C:5]2[S:6][C:7]3[CH:15]=[CH:14][CH:13]=[CH:12][C:8]=3[CH:9](O)[CH2:10][C:4]=2[CH:3]=1.[Cl-:18].[Ca+2].[Cl-].Cl>C1C=CC=CC=1>[Br:1][C:2]1[CH:17]=[CH:16][C:5]2[S:6][C:7]3[CH:15]=[CH:14][CH:13]=[CH:12][C:8]=3[CH:9]([Cl:18])[CH2:10][C:4]=2[CH:3]=1
Reactant: OC1Cc2cc(Br)ccc2Sc2ccccc21
Reactant: [Cl-]
Agent: Cl
Agent: [Ca+2]
Solvent: c1ccccc1
Product: ClC1Cc2cc(Br)ccc2Sc2ccccc21
Temperature: 25 °C
Reaction time: 3 h

Procedure:
50 g of 2-bromo-10,11-dihydro-dibenzo[b,f]thiepin-10-one are dispersed in 250 ml of ethanol, treated with 9.9 g of sodium borohydride and stirred for 1 hour. After the addition of water, the mixture is extracted with ether. The organic phase is washed with water, dried over magnesium sulphate and evaporated. There is obtained 2-bromo-10,11-dihydro-dibenzo[b,f]thiepin-10-ol of melting point 108°-110° C. 49.9 g of 2-bromo-10,11-dihydro-dibenzo[b,f]thiepin-10-ol, 250 ml of benzene and 18 g of finely powdered calcium chloride are saturated with hydrochloric acid gas at 15° C and then stirred for a further 3 hours at room temperature. The precipitate is filtered off and washed with benzene. The filtrate is concentrated under reduced pressure. There is obtained 2-bromo-10-chloro-10,11-dihydro-dibenzo[b,f]thiepin of melting point 122.5°-124° C.
Reaction SMILES: [C:1]([O:4][C@@H:5]1[C@@H:10]([O:11][C:12](=[O:14])[CH3:13])[C@H:9]([O:15][C:16](=[O:18])[CH3:17])[C@@H:8]([CH2:19][O:20][C:21](=[O:23])[CH3:22])[O:7][CH:6]1[N:24]=[C:25]=[S:26])(=[O:3])[CH3:2].[NH2:27][C:28]1[NH:29][C:30]2[CH:36]=[CH:35][CH:34]=[CH:33][C:31]=2[N:32]=1>C1(C)C(C)=CC=CC=1>[C:1]([O:4][C@@H:5]1[C@@H:10]([O:11][C:12](=[O:14])[CH3:13])[C@H:9]([O:15][C:16](=[O:18])[CH3:17])[C@@H:8]([CH2:19][O:20][C:21](=[O:23])[CH3:22])[O:7][C@H:6]1[NH:24][C:25]([NH:27][C:28]1[NH:29][C:30]2[CH:36]=[CH:35][CH:34]=[CH:33][C:31]=2[N:32]=1)=[S:26])(=[O:3])[CH3:2]
Reactant: Nc1nc2ccccc2[nH]1
Reactant: CC(=O)OC[C@H]1OC(N=C=S)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Solvent: Cc1ccccc1C
Product: CC(=O)OC[C@H]1O[C@@H](NC(=S)Nc2nc3ccccc3[nH]2)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Temperature: 100 °C

Procedure:
To 10 ml of anhydrous xylene were added 390 mg (1 mmol) of 2,3,4,6-tetra-O-acetyl-D-glucopyranosyl isothiocyanate and 135 mg (1 mmol) of 2-aminobenzimidazole (MW 133) and the mixture was heated at 100° C. for 1 hour and allowed to cool to room temperature. Crystals formed were filtered off and recrystallized from methanol to give colourless needles melting between 162° and 165° C. (uncorrected). Yield: 245 mg (47%).
Reaction SMILES: C1C=C[NH+]=CC=1.[O-][Cr](Cl)(=O)=O.[OH:12][CH2:13][CH:14]([NH:18][C:19](=[O:27])[C:20]1[CH:25]=[CH:24][C:23]([CH3:26])=[CH:22][CH:21]=1)[CH:15]([CH3:17])[CH3:16]>C(Cl)Cl.CCOCC>[CH:13]([CH:14]([NH:18][C:19](=[O:27])[C:20]1[CH:21]=[CH:22][C:23]([CH3:26])=[CH:24][CH:25]=1)[CH:15]([CH3:17])[CH3:16])=[O:12]
Reactant: Cc1ccc(C(=O)NC(CO)C(C)C)cc1
Agent: O=[Cr](=O)([O-])Cl
Agent: c1cc[nH+]cc1
Solvent: CCOCC
Solvent: ClCCl
Product: Cc1ccc(C(=O)NC(C=O)C(C)C)cc1
Reaction time: 1.5 h
Yield: 34.2 %

Procedure:
To a suspension of PCC in 20 mL of CH2Cl2 was added N-(1-hydroxymethyl-2-methyl-propyl)-4-methyl-benzamide (2.2 g, 10 mmol) in 15 mL of CH2Cl2. After the mixture was stirred for 1.5 h, it was diluted with Et2O and filtered through a celite bed. The filtrate was concentrated and the residue purified on a silica gel column with 20% EtOAc in hexane to give 0.75 g of N-(1-formyl-2-methyl-propyl)-4-methyl-benzamide as a white solid (M++1: 220).
Reaction SMILES: [CH3:1][C:2]1[O:8][CH:7]=[C:6]([OH:9])[C:4](=[O:5])[CH:3]=1.[CH:10](=[O:12])[CH3:11]>O>[OH:12][CH:10]([C:7]1[O:8][C:2]([CH3:1])=[CH:3][C:4](=[O:5])[C:6]=1[OH:9])[CH3:11]
Reactant: Cc1cc(=O)c(O)co1
Reactant: CC=O
Solvent: O
Product: Cc1cc(=O)c(O)c(C(C)O)o1
Reaction time: 8 h
Yield: 82.9 %

Procedure:
Allomaltol (12.6 g, 100 mmol, 1 eq.) was added to 100 ml water and the pH of the solution was adjusted to 10.5 using 50% aqueous sodium hydroxides. Acetaldehyde (5.5 g, 125 mmol, 1.25 eq.) dissolved in 25 ml water was slowly added dropwise over 1 hour and the solution allowed to stir overnight. After adjustment to pH 1 with 37% hydrochloric acid, the reaction mixture was extracted with 3×150 ml of dichioromethane. The combined organic extracts were dried over anhydrous sodium sulphate, filtered and concentrated to yield the crude product. Recrystallisation from toluene afforded the pure product (14.1 g, 83%) as white needles. m.p. 127-130° C. [lit. 126-128° C.]. Ellis (1993)
Reaction SMILES: [CH3:1][C:2]1([CH3:16])[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH:5]([CH2:14][CH3:15])[N:4]=[CH:3]1.S(O)(O)(=O)=O.[NH2:22][OH:23].S(=O)(=O)(O)O>O>[CH3:1][C:2]([CH3:16])([CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH:5]([CH2:14][CH3:15])[NH2:4])[CH:3]=[N:22][OH:23]
Reactant: CCC1CCCCCCCCC(C)(C)C=N1
Reactant: NO
Agent: O=S(=O)(O)O
Solvent: O
Product: CCC(N)CCCCCCCCC(C)(C)C=NO
Yield: 191 %

Procedure:
The procedure described in Example 1(b) is repeated, except that 223 g (1 mol) of 3,3-dimethyl-12-ethyl-1-aza-cyclododecene, 82 g (0.5 mol) of hydroxylamine sulfate, 150 g of sulfuric acid and 400 ml of water are used. Distillation yields 245 g (0.955 mol) of 2,2-dimethyl-11-ethyl-11-amino-undecanal oxime; yield 95.5% of theory; boiling point 155°-160° C./7 Pa.