Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[C:2]1[CH:3]=[C:4]([C:10]2[NH:11][CH:12]=[C:13]([C:15]3[S:16][CH:17]=[CH:18][CH:19]=3)[N:14]=2)[CH:5]=[CH:6][C:7]=1[O:8]C.C(Cl)(Cl)[Cl:21]>>[Cl:21][C:2]1[CH:3]=[C:4]([C:10]2[NH:11][CH:12]=[C:13]([C:15]3[S:16][CH:17]=[CH:18][CH:19]=3)[N:14]=2)[CH:5]=[CH:6][C:7]=1[OH:8]
Reactant: COc1ccc(-c2nc(-c3cccs3)c[nH]2)cc1C
Reactant: ClC(Cl)Cl
Product: Oc1ccc(-c2nc(-c3cccs3)c[nH]2)cc1Cl
Yield: 86 %

Procedure:
Compound 29 was prepared as described for 24 except that 28 was used in place of 23; 86% yield; m.p. 152°-3° C. (CHCl3).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([O:19][CH:20]2[CH2:24][CH2:23][O:22][CH2:21]2)=[C:6]([C@H:8]([NH:12][S@](C(C)(C)C)=O)[CH2:9][CH:10]=[CH2:11])[CH:7]=1.[ClH:25]>O1CCOCC1>[ClH:25].[F:1][C:2]1[CH:3]=[CH:4][C:5]([O:19][CH:20]2[CH2:24][CH2:23][O:22][CH2:21]2)=[C:6]([C@H:8]([NH2:12])[CH2:9][CH:10]=[CH2:11])[CH:7]=1
Reactant: C=CC[C@@H](N[S@@](=O)C(C)(C)C)c1cc(F)ccc1OC1CCOC1
Agent: Cl
Solvent: C1COCCO1
Product: C=CC[C@@H](N)c1cc(F)ccc1OC1CCOC1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of (S)—N—((R)-1-(5-fluoro-2-((tetrahydrofuran-3-yl)oxy)phenyl)but-3-en-1-yl)-2-methylpropane-2-sulfinamide (30.0 g, 84 mmol) in Dioxane (60 ml) at 0° C. was added 4N solution of HCl in Dioxane (150 ml) and stirred the content for 16 h at room temperature. The solvent was evaporated completely and the crude was washed with diethyl ether to obtain title product 22.0 g (crude) as off white solid. MS m/z 252.05 (M+H).
Reaction SMILES: [CH2:1](/[C:3](=[CH:8]\[S:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)/[C:4]([O:6]C)=[O:5])[CH3:2].[OH-].[Na+].O>C(O)C>[CH2:1]([C:3](=[CH:8][S:9][C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1)[C:4]([OH:6])=[O:5])[CH3:2]
Reactant: CC/C(=C\Sc1ccccc1)C(=O)OC
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CCC(=CSc1ccccc1)C(=O)O
Temperature: 25 °C
Yield: 98.7 %

Procedure:
A solution of 4.39 g (19.8 mmol) of (E)-methyl 2-ethyl-3-(phenylthio)-2-propenoate and 20 ml of an aqueous 2N NaOH solution in 40 ml of ethanol was stirred at 80° C. for 2 hours and then cooled to room temperature. To the reaction mixture was added 100 ml of water and washed with t-butyl methyl ether. The aqueous layer was acidified to pH 2 with concentrated HCl and extracted with tert-butyl methyl ether. The organic layer was washed with a saturated NaCl solution, dried over anhydrous MgSO4, and concentrated to obtain 4.07 g of 2-ethyl-3-(phenylthio)-2-propenoic acid.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[CH:19]=[CH:18][C:17]([NH:20][C:21]([C:23]3[N:24](COCC[Si](C)(C)C)[CH:25]=[C:26]([C:28]#[N:29])[N:27]=3)=[O:22])=[C:16]([C:38]3[CH2:43][CH2:42][C:41]([CH3:45])([CH3:44])[CH2:40][CH:39]=3)[CH:15]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.CO.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH3:44][C:41]1([CH3:45])[CH2:42][CH2:43][C:38]([C:16]2[CH:15]=[C:14]([CH:11]3[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]3)[CH:19]=[CH:18][C:17]=2[NH:20][C:21]([C:23]2[NH:24][CH:25]=[C:26]([C:28]#[N:29])[N:27]=2)=[O:22])=[CH:39][CH2:40]1
Reactant: CC1(C)CC=C(c2cc(C3CCN(C(=O)OC(C)(C)C)CC3)ccc2NC(=O)c2nc(C#N)cn2COCC[Si](C)(C)C)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Solvent: CO
Product: CC1(C)CC=C(c2cc(C3CCNCC3)ccc2NC(=O)c2nc(C#N)c[nH]2)CC1
Yield: 88.5 %

Procedure:
A solution of 124 mg (0.196 mmol) 4-[4-{[4-cyano-1-(2-trimethylsilanyl-ethoxymethyl)-1H-imidazole-2-carbonyl]-amino}-3-(4,4-dimethyl-cyclohex-1-enyl)-phenyl]-piperidine-1-carboxylic acid tert-butyl ester (as prepared in the previous step) in 10 mL CH2Cl2 was treated with 200 μL MeOH and 3 mL TFA at RT for 3.5 h. Solvents were evaporated in vacuo. The residue was taken up in CH2Cl2 (30 mL) and washed with saturated aqueous NaHCO3 (1×20 mL). The organic layer was dried (MgSO4) and concentrated in vacuo to afford 70.0 mg (89%) of the title compound as a white solid: Mass spectrum (ESI, m/z): Calcd. for C24H29N5O, 404.2 (M+H), found 404.3.
Reaction SMILES: C(N(C(C)C)CC)(C)C.O=[C:11]1[CH2:17][C@H:16]2[N:13]([C:14](=[O:35])[C@H:15]2[C:18]([CH3:34])([O:20][C:21]([O:23][CH2:24][C:25]2[CH:30]=[CH:29][C:28]([N+:31]([O-:33])=[O:32])=[CH:27][CH:26]=2)=[O:22])[CH3:19])[C@H:12]1[C:36]([O:38][CH2:39][C:40]1[CH:45]=[CH:44][C:43]([N+:46]([O-:48])=[O:47])=[CH:42][CH:41]=1)=[O:37].P(Cl)(OC1C=CC=CC=1)(OC1C=CC=CC=1)=O.[NH2:66][C:67]1[CH:72]=[CH:71][CH:70]=[CH:69][C:68]=1[SH:73]>C(#N)C.CN(C1C=CN=CC=1)C>[NH2:66][C:67]1[CH:72]=[CH:71][CH:70]=[CH:69][C:68]=1[S:73][C:11]1[CH2:17][C@H:16]2[N:13]([C:14](=[O:35])[C@H:15]2[C:18]([CH3:19])([O:20][C:21]([O:23][CH2:24][C:25]2[CH:30]=[CH:29][C:28]([N+:31]([O-:33])=[O:32])=[CH:27][CH:26]=2)=[O:22])[CH3:34])[C:12]=1[C:36]([O:38][CH2:39][C:40]1[CH:45]=[CH:44][C:43]([N+:46]([O-:48])=[O:47])=[CH:42][CH:41]=1)=[O:37]
Reactant: Nc1ccccc1S
Reactant: CC(C)(OC(=O)OCc1ccc([N+](=O)[O-])cc1)[C@@H]1C(=O)N2[C@@H](C(=O)OCc3ccc([N+](=O)[O-])cc3)C(=O)C[C@H]12
Agent: CN(C)c1ccncc1
Agent: O=P(Cl)(Oc1ccccc1)Oc1ccccc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: CC(C)(OC(=O)OCc1ccc([N+](=O)[O-])cc1)[C@@H]1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(Sc3ccccc3N)C[C@H]12
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 78.7 %

Procedure:
A solution of N,N-diisopropyl-N-ethylamine (0.247 ml) in acetonitrile (2.2 ml) was added to a solution of 4-nitrobenzyl (2R,5R,6R)-3,7-dioxo-6-[1-methyl-1-(4-nitrobenzyloxycarbonyloxy)ethyl]-1-azabicyclo[3.2.0]heptane-2-carboxylate (640 mg) and 4-(N,N-dimethylamino)pyridine (14.4 mg) in acetonitrile (32 ml) at 0° C. A solution of diphenyl chlorophosphate (0.257 ml) in acetonitrile (2.3 ml) was then added thereto at 0° C. After the mixture was stirred at 0° C. for 30 minutes, N,N-diisopropyl-N-ethylamine (0.824 ml) and a solution of 2-aminobenzenethiol (155 mg) in acetonitrile (1.4 ml) were added at 0° C. After stirring at 0° C. for an hour, the mixture was evaporated in vacuo and the residue was dissolved in ethyl acetate (50 ml). This solution was washed twice with water (X2) and an aqueous sodium chloride, dried over magnesium sulfate, and then evaporated in vacuo. The residue was chromatographed on silica gel (20 g) eluting with a mixture of benzene and acetone (50:1 to 10:1) to give 4-nitrobenzyl (5R,6R)-3-(2-aminophenylthio)-6-[1-methyl-1-(4-nitrobenzyloxycarbonyloxy)ethyl]-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate (603 mg) as an oil.
Reaction SMILES: [CH3:1][C:2]1[C:10]([CH3:11])=[CH:9][C:5]2[N:6]=[CH:7][NH:8][C:4]=2[CH:3]=1.[H-].[Na+].Cl[CH2:15][CH2:16][CH2:17][OH:18].O>CN(C)C=O>[OH:18][CH2:17][CH2:16][CH2:15][N:6]1[C:5]2[CH:9]=[C:10]([CH3:11])[C:2]([CH3:1])=[CH:3][C:4]=2[N:8]=[CH:7]1
Reactant: Cc1cc2nc[nH]c2cc1C
Reactant: OCCCCl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1cc2ncn(CCCO)c2cc1C
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 1.46 g of 5,6-dimethylbenzimidazole dissolved in 50 ml of dry N,N-dimethylformamide was added 0.76 g of NaH, the mixture was stirred at room temperature for 30 minutes. To the mixture was added dropwise 5 ml of 3-chloro-1-propanol, and the reaction was carried out by stirring at room temperature for 2 days, followed by an addition of water to stop the reaction. Subsequently, according to the same processes as in Example 1, crude 1-(3-hydroxypropyl)-5,6-dimethylbenzimidazole was obtained. The conversion to this compound from 5,6-dimethylbenzimidazole was found to be 90%.
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[CH2:3][C:4]1[S:5][CH:6]=[C:7]([C:9]([O:11]CC)=[O:10])[N:8]=1>Cl.O>[F:15][C:2]([F:1])([F:14])[CH2:3][C:4]1[S:5][CH:6]=[C:7]([C:9]([OH:11])=[O:10])[N:8]=1
Reactant: CCOC(=O)c1csc(CC(F)(F)F)n1
Agent: Cl
Solvent: O
Product: O=C(O)c1csc(CC(F)(F)F)n1
Temperature: 80 °C

Procedure:
A mixture of ethyl 2-(2,2,2-trifluoroethyl)thiazole-4-carboxylate (example 67, step c) (0.3 g) in concentrated hydrochloric acid (7 mL) and water (7 mL) was heated at 80° C. for 5 hours under nitrogen. The solvent was evaporated under a stream of nitrogen and the residue partitioned between ethyl acetate (40 mL) and brine (3 mL). The organic layer was dried over sodium sulphate, filtered and the solvent evaporated under reduced pressure to afford the subtitled compound. Yield 0.23 g.
Reaction SMILES: C([BH3-])#N.[Na+].[CH:5]1([N:11]2[C:15]([CH2:16][O:17][CH3:18])=[C:14]([C:19]3[O:23][N:22]=[C:21]([C:24]4[CH:31]=[CH:30][C:27]([CH:28]=O)=[CH:26][CH:25]=4)[N:20]=3)[CH:13]=[N:12]2)[CH2:10][CH2:9][CH2:8][CH2:7][CH2:6]1.[CH:32]([NH2:35])([CH3:34])[CH3:33].C(O)(=O)C>CO>[CH:5]1([N:11]2[C:15]([CH2:16][O:17][CH3:18])=[C:14]([C:19]3[O:23][N:22]=[C:21]([C:24]4[CH:25]=[CH:26][C:27]([CH2:28][NH:35][CH:32]([CH3:34])[CH3:33])=[CH:30][CH:31]=4)[N:20]=3)[CH:13]=[N:12]2)[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10]1
Reactant: COCc1c(-c2nc(-c3ccc(C=O)cc3)no2)cnn1C1CCCCC1
Reactant: CC(C)N
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: COCc1c(-c2nc(-c3ccc(CNC(C)C)cc3)no2)cnn1C1CCCCC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Sodium cyanoborohydride (18.0 mg; 0.286 mmol) was added to a solution of 4-(5-(1-cyclohexyl-5-(methoxymethyl)-1H-pyrazol-4-yl)-1,2,4-oxadiazol-3-yl)benzaldehyde (95.3 mg; 0.26 mmol) and isopropylamine (44.3 μL; 0.52 mmol) in methanol (3 mL) and acetic acid (47 μL; 0.78 mmol) and the mixture was stirred at room temperature overnight. The solvent was removed in vacuo and water (3 mL) was added and the product extracted into DCM (3×2 mL). The combined organic fractions were passed through a hydrophobic frit and the solvent removed in vacuo. The residue was purified by flash chromatography on a 12+M Biotage column, eluting with DCM containing increasing amounts of 5% methanol in DCM to give Example 121 as an off white solid. 1H NMR: (CDCl3, 400 MHz) δ 8.15-8.06 (3 H, m), 7.48 (2 H, d, J=7.8 Hz), 5.03 (2 H, s), 4.36-4.26 (1 H, m), 3.89 (2 H, s), 3.47 (3 H, m), 3.00-2.88 (1 H, m), 2.04-1.90 (6 H, m), 1.75 (1 H, d, J=12.3 Hz), 1.50-1.40 (2 H, m), 1.40-1.25 (1 H, m), 1.18 (6 H, d, J=6.4 Hz). LC/MS: 410 (M+H)+. HPLC (Method A) Rt 2.46 min (Purity: 99.0%).
Reaction SMILES: [Br:1][C:2]1[C:3]([OH:16])=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]([C:12](=[O:14])[CH3:13])[C@@H:7]([CH3:15])[CH2:6][CH2:5]2.[C:17]([C:20]1[CH:25]=[CH:24][C:23](B(O)O)=[CH:22][CH:21]=1)(=[O:19])[NH2:18].N1C=CC=CC=1>C([O-])(=O)C.[Cu+2].C([O-])(=O)C.ClCCl>[C:12]([N:8]1[C:9]2[C:4](=[C:3]([O:16][C:23]3[CH:24]=[CH:25][C:20]([C:17]([NH2:18])=[O:19])=[CH:21][CH:22]=3)[C:2]([Br:1])=[CH:11][CH:10]=2)[CH2:5][CH2:6][C@@H:7]1[CH3:15])(=[O:14])[CH3:13]
Reactant: NC(=O)c1ccc(B(O)O)cc1
Reactant: CC(=O)N1c2ccc(Br)c(O)c2CC[C@@H]1C
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(=O)N1c2ccc(Br)c(Oc3ccc(C(N)=O)cc3)c2CC[C@@H]1C
Temperature: 25 °C
Reaction time: 72 h
Yield: 34.6 %

Procedure:
A 100-mL, round-bottom flask equipped with a balloon filled with air was charged with (S)-1-(6-bromo-5-hydroxy-2-methyl-3,4-dihydroquinolin-1(2H)-yl)ethanone (0.300 g, 1.06 mmol), 4-carbamoylphenylboronic acid (0.437 g, 2.65 mmol), pyridine (1 mL), dichloromethane (40 mL), copper (II) acetate (0.580 g, 3.20 mmol) and 4 Å molecular sieves (4.0 g). The resulting mixture stirred for 3 days at room temperature. The reaction mixture was filtered, and the filtrate was concentrated under vacuum. The residue was purified by preparative thin layer chromatography (eluting with 3:1, ethyl acetate/petroleum ether) to afford (S)-4-(1-acetyl-6-bromo-2-methyl-1,2,3,4-tetrahydroquinolin-5-yloxy)benzamide (0.148 g, 35%) as yellow oil. MS (ESI, pos. ion) m/z 403, 405 [M+H]+.
Reaction SMILES: [OH-].[CH3:2][N+:3]([CH3:6])([CH3:5])[CH3:4].[C:7]([OH:12])(=[O:11])[CH:8]([CH3:10])[OH:9]>>[C:7]([O-:12])(=[O:11])[CH:8]([CH3:10])[OH:9].[CH3:2][N+:3]([CH3:6])([CH3:5])[CH3:4]
Reactant: CC(O)C(=O)O
Agent: C[N+](C)(C)C
Agent: [OH-]
Product: CC(O)C(=O)[O-]

Procedure:
Tetramethylammonium lactate dehydrate was prepared by the addition of tetramethylammonium hydroxide (25% in methanol) to an equivalent amount of lactic acid (85% aqueous solution) with cooling on ice followed by solvent removal and the addition of sufficient water to form the dehydrate.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[CH:9]([C:14]1[C:22]2[C:17](=[C:18]([CH2:24][S:25][CH3:26])[CH:19]=[C:20]([F:23])[CH:21]=2)[NH:16][CH:15]=1)[CH2:10][CH2:11][C:12]#[N:13].ClC1C=CC=C(C(OO)=[O:35])C=1>ClCCl>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[CH:9]([C:14]1[C:22]2[C:17](=[C:18]([CH2:24][S:25]([CH3:26])=[O:35])[CH:19]=[C:20]([F:23])[CH:21]=2)[NH:16][CH:15]=1)[CH2:10][CH2:11][C:12]#[N:13]
Reactant: CSCc1cc(F)cc2c(C(CCC#N)c3ccc(Cl)cc3Cl)c[nH]c12
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: CS(=O)Cc1cc(F)cc2c(C(CCC#N)c3ccc(Cl)cc3Cl)c[nH]c12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
100 mg (0.25 mmol) of the compound from Example 42 were introduced into 14 ml of dichloromethane at 0° C., 60.5 mg (0.25 mmol) of 70% pure meta-chloroperbenzoic acid were added, and the mixture was stirred at RT overnight. It was concentrated, and the residue was purified by preparative HPLC (RP18 column; mobile phase: acetonitrile/water gradient with addition of 0.1% formic acid) to result in 80 mg (76% of theory) of the title compound as mixture of diastereomers.
Reaction SMILES: Br.[CH2:2]([O:4][C:5](=[O:34])[C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([O:12][CH2:13][CH2:14][CH2:15][N:16]2[C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=3[N:18]([CH2:25][C:26]3[CH:31]=[CH:30][C:29](Br)=[CH:28][CH:27]=3)[C:17]2=[NH:33])[CH:7]=1)[CH3:3].C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1.[Cl:81][C:82]1[CH:87]=[CH:86][C:85]([C:88]2[CH:93]=[CH:92][CH:91]=[CH:90][C:89]=2[CH2:94][N:95]2[CH2:100][CH2:99][NH:98][CH2:97][CH2:96]2)=[CH:84][CH:83]=1.C([O-])([O-])=O.[Cs+].[Cs+]>C1(C)C=CC=CC=1.CC([O-])=O.CC([O-])=O.[Pd+2]>[CH2:2]([O:4][C:5](=[O:34])[C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([O:12][CH2:13][CH2:14][CH2:15][N:16]2[C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=3[N:18]([CH2:25][C:26]3[CH:31]=[CH:30][C:29]([N:98]4[CH2:97][CH2:96][N:95]([CH2:94][C:89]5[CH:90]=[CH:91][CH:92]=[CH:93][C:88]=5[C:85]5[CH:86]=[CH:87][C:82]([Cl:81])=[CH:83][CH:84]=5)[CH2:100][CH2:99]4)=[CH:28][CH:27]=3)[C:17]2=[NH:33])[CH:7]=1)[CH3:3]
Reactant: CCOC(=O)c1cccc(OCCCn2c(=N)n(Cc3ccc(Br)cc3)c3ccccc32)c1
Reactant: Clc1ccc(-c2ccccc2CN2CCNCC2)cc1
Agent: [Pd+2]
Agent: Br
Agent: CC(=O)[O-]
Solvent: Cc1ccccc1
Product: CCOC(=O)c1cccc(OCCCn2c(=N)n(Cc3ccc(N4CCN(Cc5ccccc5-c5ccc(Cl)cc5)CC4)cc3)c3ccccc32)c1
Temperature: 95 °C
Reaction time: 0.03 h
Yield: 60.5 %

Procedure:
To a degassed solution of 3-{3-[3-(4-bromo-benzyl)-2-imino-2,3-dihydro-benzoimidazol-1-yl]-propoxy}-benzoic acid ethyl ester, hydrobromide salt (0.2 g, 0.34 mmol) in anhydrous toluene (3 ml) was added Pd(OAc)2 (33 mg, 0.077 mmol). Nitrogen was bubbled through the suspension for 10 min before BINAP (49 mg, 0.079 mmol) was added. After a further 2 min 1-(4′-chloro-biphenyl-2-ylmethyl)-piperazine (112 mg, 0.39 mmol) in degassed toluene (3 ml) was introduced and then after an additional 2 min Cs2CO3 (2.5 g, 7.69 mmol) was added and the reaction was stirred for 2 min. Throughout all of the additions nitrogen was continuously bubbled through the reaction mixture. The reaction was then sealed and heated to 95° C. where it was maintained for 5 h. After this time, the reaction was cooled to rt and filtered through Celite®. The collected solids were washed with additional dichloromethane and then the combined filtrate and washings were concentrated under reduced pressure to give the crude product. Purification by chromatography on silica eluting with 5% MeOH/dichloromethane provided 3-[3-(3-{4-[4-(4′-chloro-biphenyl-2-ylmethyl)-piperazin-1-yl]-benzyl}-2-imino-2,3-dihydro-benzoimidazol-1-yl)-propoxy]-benzoic acid ethyl ester (147 mg, 61%). HPLC-MS 715 [M+1]+, 358.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[OH:10])[CH:5]=[O:6].[CH2:11](Br)[CH:12]=[CH2:13].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[Br:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[O:10][CH2:13][CH:12]=[CH2:11])[CH:5]=[O:6]
Reactant: O=Cc1ccc(O)c(Br)c1
Reactant: C=CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: C=CCOc1ccc(C=O)cc1Br

Procedure:
3-Bromo-4-hydroxybenzaldehyde (20.1 g, 0.100 mol) and allyl bromide (14.5 g, 0.120 mol) were heated under reflux together with potassium carbonate (20.7 g, 0.150 mol) in 150 ml acetone (abs.) for 8 hours. After cooling, the solid was filtered off and washed with acetone. After complete concentration of the organic phase, there was obtained an oily residue that was used directly in the second step without further purification.
Reaction SMILES: [OH2:1].[OH-].[Li+].C([C@H]1COC(=O)N1[C:17](=[O:35])[C@H:18]([CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)[CH2:19][C:20]([N:22]1[CH2:27][CH2:26][O:25][CH2:24][CH2:23]1)=[O:21])C1C=CC=CC=1>O1CCCC1.O>[CH2:28]([C@H:18]([CH2:19][C:20]([N:22]1[CH2:23][CH2:24][O:25][CH2:26][CH2:27]1)=[O:21])[C:17]([OH:35])=[O:1])[C:29]1[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=1
Reactant: O=C(C[C@@H](Cc1ccccc1)C(=O)N1C(=O)OC[C@@H]1Cc1ccccc1)N1CCOCC1
Reactant: O
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Product: O=C(O)[C@@H](CC(=O)N1CCOCC1)Cc1ccccc1
Reaction time: 3 h
Yield: 74.2 %

Procedure:
711 mg (16.9 mmole) of lithium hydroxide monohydrate were added, whilst ice-cooling, to a solution of 3.70 g (8.5 mmole) of (4S)-(-)-4-benzyl-N-[2(R)-benzyl-3-(morpholinocarbonyl)propionyl]-2-oxazolidinone (prepared as described in Preparation 10) in a mixture of 80 ml of tetrahydrofuran and 30 ml of water, and the mixture was then stirred at the same temperature for 3 hours. At the end of this time, the tetrahydrofuran was stripped from the reaction mixture by distillation under reduced pressure, and the residue was mixed with a 10% w/v aqueous solution of sodium hydroxide and then extracted with methylene chloride. The aqueous layer was adjusted to a pH value of 1 by the addition of concentrated hydrochloric acid, whilst ice-cooling, and was again extracted with methylene chloride. The latter methylene chloride extracts were combined, dried over anhydrous magnesium sulfate and concentrated by distillation under reduced pressure to afford 1.75 g (yield 75%) of the title compound as a white oily substance.
Reaction SMILES: [CH3:1][N:2]([CH2:4][C:5]1[O:9][C:8]([CH2:10][S:11][CH2:12][CH2:13][NH2:14])=[CH:7][CH:6]=1)[CH3:3].CS[C:17](=[NH:22])[NH:18][N+:19]([O-:21])=[O:20]>C(O)C>[CH3:3][N:2]([CH2:4][C:5]1[O:9][C:8]([CH2:10][S:11][CH2:12][CH2:13][NH:14][C:17]([NH:18][N+:19]([O-:21])=[O:20])=[NH:22])=[CH:7][CH:6]=1)[CH3:1]
Reactant: CN(C)Cc1ccc(CSCCN)o1
Reactant: CSC(=N)N[N+](=O)[O-]
Solvent: CCO
Product: CN(C)Cc1ccc(CSCCNC(=N)N[N+](=O)[O-])o1

Procedure:
A solution of 2-[[[5-(dimethylamino)methyl-2-furanyl]methyl]thio]ethanamine (2.14 g) and S-methyl-N-nitroisothiourea (1.5 g) in ethanol (10 ml) was heated to 40° for 5 mins. The resulting precipitate was filtered and recrystallised from ethyl acetate and petroleum ether b.p. 80°-100° to give N-[2-[[[5-(dimethylamino)methyl-2-furanyl]methyl]thio]ethyl]-N'-nitroguanidine m.p. 103°-104°.
Reaction SMILES: [Cl:1][C:2]1[C:10]([C:11]#N)=[C:9]([Cl:13])[C:8]([F:14])=[CH:7][C:3]=1[C:4](Cl)=O.C(C1C(F)=C(C=C(F)C=1F)C(F)=O)#N.FC1C=C(C)C=C(C)C=1>>[Cl:1][C:2]1[C:10]([CH3:11])=[C:9]([Cl:13])[C:8]([F:14])=[CH:7][C:3]=1[CH3:4]
Reactant: N#Cc1c(Cl)c(F)cc(C(=O)Cl)c1Cl
Agent: Cc1cc(C)cc(F)c1
Agent: N#Cc1c(F)c(F)cc(C(=O)F)c1F
Product: Cc1cc(F)c(Cl)c(C)c1Cl

Procedure:
An alternative process for preparing the intermediate 2,4-dichloro-3-cyano-5-fluorobenzoyl chloride (European Patent Application 276 700), which can be converted into 3-cyano-2,4,5-trifluoro-benzoyl fluoride, starts with 5-fluoro-1,3-xylene: 5-fluoro-1,3-xylene is dichlorinated at the ring in the presence of a catalyst under ionic conditions to give 2,4-dichloro-5-fluoro-1,3-dimethylbenzene which is subsequently chlorinated in the side chains under radical conditions to give 2,4-dichloro-5-fluoro-3-dichloromethyl-1-trichloromethylbenzene. This is hydrolysed via the 2,4-dichloro-5-fluoro-3-dichloromethylbenzoic acid to give 2,4-dichloro-5-fluoro-3-formylbenzoic acid, which is subsequently converted into 2,4-dichloro-5-fluoro-3-N-hydroxyiminomethyl-benzoic acid. Treatment with thionyl chloride gives 2,4-dichloro-3-cyano-5-fluoro-benzoyl chloride which can then be converted into 3-cyano-2,4,5-trifluoro-benzoyl fluoride by chlorine-fluorine exchange.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][OH:7])=[CH:4][CH:3]=1.C1(C)C=CC=CC=1.Cl.Cl[CH2:19][CH2:20][N:21]1[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]1.[Br-]>[OH-].[Na+]>[N:21]1([CH2:20][CH2:19][O:1][C:2]2[CH:9]=[CH:8][C:5]([CH2:6][OH:7])=[CH:4][CH:3]=2)[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]1
Reactant: ClCCN1CCCCC1
Reactant: OCc1ccc(O)cc1
Agent: Cl
Agent: [Br-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: OCc1ccc(OCCN2CCCCC2)cc1
Reaction time: 1.5 h
Yield: 74.2 %

Procedure:
4-hydroxybenzyl alcohol (6.2 g, 0.0.05 mol) was dissolved in aqueus sodium hydroxide (5N, 30 mL). Toluene (30 mL) was added followed by 1-(2-chloroethyl)piperidine hydrochloride (9.29 g, 0.05 mol) and benzyltriethylamumonium bromide (0.3 g). The reaction mixture was heated with vigorous stirring for 1.5 h. The layers were separated, the aqueous layer was extracted with toluene (2×15 mL). Combined organic extracts and organic layer was washed with water (50 mL), brine (50 mL), dried over sodium sulfate, and concentrated on a rotary evaporator to give 8.725 g (75%) of alcohol (3a) as a yellowish brown oil.
Reaction SMILES: [C:1]([O:5][C:6]([C:8]1[N:13]2[C:14](=[O:17])[C@@H:15]([NH2:16])[C@H:12]2[S:11][CH2:10][C:9]=1[C:18]([CH2:28][PH:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])([S:22][C:23]1[NH:27][N:26]=[N:25][N:24]=1)[O:19][CH2:20][CH3:21])=[O:7])([CH3:4])([CH3:3])[CH3:2].C(C1C=C(C=C(C(C)(C)C)C=1O)[CH:43]=[O:44])(C)(C)C.[Pb](=O)=O>C1C=CC=CC=1.ClCCCl>[C:1]([O:5][C:6]([C:8]1[N:13]2[C:14](=[O:17])[C@:15]([NH2:16])([O:44][CH3:43])[C@H:12]2[S:11][CH2:10][C:9]=1[C:18]([CH2:28][PH:29]([O:31][C:32]([CH3:34])([CH3:33])[CH3:35])=[O:30])([S:22][C:23]1[NH:27][N:26]=[N:25][N:24]=1)[O:19][CH2:20][CH3:21])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)c1cc(C=O)cc(C(C)(C)C)c1O
Reactant: CCOC(C[PH](=O)OC(C)(C)C)(Sc1nnn[nH]1)C1=C(C(=O)OC(C)(C)C)N2C(=O)[C@@H](N)[C@H]2SC1
Agent: O=[Pb]=O
Solvent: c1ccccc1
Solvent: ClCCCl
Product: CCOC(C[PH](=O)OC(C)(C)C)(Sc1nnn[nH]1)C1=C(C(=O)OC(C)(C)C)N2C(=O)[C@](N)(OC)[C@H]2SC1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A solution of 1.32 g (2.4 mmol) of 7β-amino-3-(1-ethoxy-t-butoxyphosphinylmethyltetrazol-5-ylthiomethyl)-3-cephem-4-carboxylic acid t-butyl ester and 0.56 g (2.4 mmol) of 3,5-di-t-butyl-4-hydroxybenzaldehyde in 100 ml of dry benzene is refluxed for 4 hours under a Dean-Stark trap. The solution is evaporated under reduced pressure to leave a residue which is dissolved in 100 ml of 1,2-dichloroethane and cooled to ca. 5° in an ice bath. Three grams of freshly prepared lead dioxide is added in portions over 20 minutes until the starting material is completely consumed. The mixture is filtered through Celite and the filter cake is washed with two 20 ml portions of cold 1,2-dichloroethane. The filtrate is treated with 25 ml of methanol (distilled from magnesium) and the reaction mixture is allowed to stand at room temperature until complete consumption of the oxidized intermediate and formation of a new slower-moving product is shown by thin layer chromatography. The mixture is evaporated and the residue is dissolved in 30 ml of methanol and treated with 2.5 g of Girard reagent T (trimethylaminoacetohydrazide chloride). The reaction mixture is stirred at room temperature for 3 hours, then evaporated to give a residue which is partitioned between ethyl acetate and 20% sodium chloride solution. The organic phase is washed with 10% sodium chloride solution and saturated sodium chloride solution. The organic phase is dried (MgSO4), filtered and evaporated to dryness to give 7β-amino-7α-methoxy-3-(1-ethoxy-t-butoxyphosphinylmethyltetrazol-5-ylthiomethyl)-3-cephem-4-carboxylic acid t-butyl ester.