Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:16])[CH:5]([NH:13][CH:14]=[O:15])[CH:6](O)[C:7](=[CH2:11])[CH2:8][CH2:9][F:10])[CH3:2].S(Br)([Br:19])=O.O>ClCCCl>[CH2:1]([O:3][C:4](=[O:16])[CH:5]([NH:13][CH:14]=[O:15])[CH:6]=[C:7]([CH2:11][Br:19])[CH2:8][CH2:9][F:10])[CH3:2]
Reactant: O=S(Br)Br
Reactant: C=C(CCF)C(O)C(NC=O)C(=O)OCC
Solvent: ClCCCl
Solvent: O
Product: CCOC(=O)C(C=C(CBr)CCF)NC=O
Reaction time: 0.75 h

Procedure:
1.40 g (6.0 mmol) of 6-fluoro-2-formylamino-3-hydroxy-4-methylene-hexanoic acid ethyl ester are dissolved in 14 ml of 1,2-dichloroethane, and 0.56 ml (7.2 mmol) of thionyl bromide is added dropwise at room temperature. After 45 minutes, 12 ml of water are added and the mixture is stirred vigorously for 15 minutes. The organic phase is separated off, washed in succession with water, 1N potassium hydrogen carbonate solution and again with water, dried over sodium sulfate, filtered and concentrated by evaporation. 4-bromomethyl-6-fluoro-2-formylamino-hex-3-enoic acid ethyl ester is obtained in the form of a brownish-yellow oil.
Reaction SMILES: [OH:1][CH2:2][CH2:3][C:4]#[C:5][C:6]1[CH:7]=[C:8]([C:11]([O:13][CH3:14])=[O:12])[S:9][CH:10]=1.[H][H]>C(O)C.[Pd]>[OH:1][CH2:2][CH2:3][CH2:4][CH2:5][C:6]1[CH:7]=[C:8]([C:11]([O:13][CH3:14])=[O:12])[S:9][CH:10]=1
Reactant: [H][H]
Reactant: COC(=O)c1cc(C#CCCO)cs1
Agent: [Pd]
Solvent: CCO
Product: COC(=O)c1cc(CCCCO)cs1
Yield: 81.9 %

Procedure:
A Parr flask was charged with 4.00 g of methyl 4-(4-hydroxybut-1-yn-1-yl)thien-2-ylcarboxylate in 100 mL of ethanol. Then 2.00 g (50% wt eq) of 5% palladium on charcoal was added. Parr hydrogenation was carried out at 50 psi of hydrogen for 6 hours. The reaction mixture was filtered through a Celite pad which was washed with ethanol. The filtrate was concentrated under reduced pressure to give 3.34 g (81.9%) of methyl 4-(4-hydroxybutyl)thien-2-ylcarboxylate as a clear oil; IR (KBr, cm-1): 1710, 1444, 1293, 1260, 1225; UV (Ethanol) :λmax =281 nm (epsilon=6450), 248 nm (epsilon=10,100); 1H NMR (CDCl3, 300 MHz) delta 7.59 (s, 1H), 7.12, (s, 1H), 3.81 (s, 3H), 3.60 (t, J=6.3 Hz, 2H), 2.59 (t, J=7.4 Hz, 2H), 2.10 (bs, 1H), 1.60-1.68 (m, 2H), 1.51-1.58 (m, 2H); MASS: M+ =2148 (EICEC).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][C:3]=1[OH:9].[H-].[Na+].B(OCC)(OCC)OCC.[CH2:22](Br)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>CN(C)C=O>[CH2:22]([O:8][C:5]1[CH:6]=[CH:7][C:2]([OH:1])=[C:3]([OH:9])[CH:4]=1)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: BrCc1ccccc1
Reactant: Oc1ccc(O)c(O)c1
Agent: CCOB(OCC)OCC
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Oc1ccc(OCc2ccccc2)cc1O
Reaction time: 1 h
Yield: 58 %

Procedure:
1.37 g of 1,2,4-trihydroxy benzene and 30 ml of anhydrous dimethylformamide were mixed together under an inert gas atmosphere and then 0.984 g of sodium hydride in suspension at 53% in oil was added at 15°-20° C. The mixture was stirred for one hour and 1.906 ml of triethyl borate were added. The mixture was stirred for one hour, and 1.29 ml of benzyl bromide in solution in 20 ml of dimethylformamide were added over 2 hours. The mixture was stirred for 16 hours at ambient temperature and then was poured into a water-ice-N hydrochloric acid mixture. Extraction took place with ethyl acetate followed by evaporation to dryness. The residue was washed with petroleum ether, and chromatographed on silica eluting with a cyclohexane-ethyl acetate (6-4) mixture to obtain 1.36 g of the crystallized expected product (Yield: 58%).
Reaction SMILES: [CH3:1][OH:2].[H-].[Na+].Br[CH2:6][C:7]1[N:8]([CH3:26])[C:9](=[O:25])[C:10]2[C:15]([C:16]=1[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[CH:14][C:13]([O:23][CH3:24])=[CH:12][CH:11]=2>CN(C)C=O>[CH3:24][O:23][C:13]1[CH:14]=[C:15]2[C:10](=[CH:11][CH:12]=1)[C:9](=[O:25])[N:8]([CH3:26])[C:7]([CH2:6][O:2][CH3:1])=[C:16]2[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: COc1ccc2c(=O)n(C)c(CBr)c(-c3ccccc3)c2c1
Reactant: CO
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COCc1c(-c2ccccc2)c2cc(OC)ccc2c(=O)n1C
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
To a solution of methanol (0.057 mL, 1.40 mmol) in 2 mL of dimethylformamide was added sodium hydride (45 mg, 60% dispersion in mineral oil, 1.11 mmol). After 10 minutes, 3-(bromomethyl)-6-methoxy-2-methyl-4-phenylisoquinolin-1(2H)-one was added (100 mg, 0.279 mmol). After 30 minutes, the reaction mixture was cooled to 0° C., and quenched with 1 mL of saturated NaHCO3 solution. The mixture was partitioned between EtOAc and saturated NaHCO3 solution, and the organic layer was washed with brine, dried over Na2SO4, filtered, and concentrated in vacuo. The crude residue was purified by flash chromatography through SiO2 (50% EtOAc/hexane) to provide the titled product as a white solid. 1H-NMR (500 MHz, CDCl3) δ 8.43 (d, J=9.0 Hz, 1H), 7.44-7.50 (m, 3H), 7.29-7.31 (m, 2H), 6.91 (dd, J=9.0, 2.5 Hz, 1H), 6.42 (d, J=2.5 Hz, 1H), 4.18 (s, 2H), 3.75, (s, 3H), 3.69 (s, 3H), 3.24 (s, 3H) ppm. ESI+ MS: 310.23 [M+H]+.
Reaction SMILES: C(OC([NH:11][C:12]([C:14]1[CH:42]=[CH:41][C:17]([O:18][CH2:19][CH2:20][CH2:21][N:22]2[CH2:27][CH2:26][N:25](CC3C=CC(OC)=CC=3OC)[C:24](=[O:39])[C:23]2=[O:40])=[CH:16][CH:15]=1)=[NH:13])=O)C1C=CC=CC=1.[F:43][C:44]([F:49])([F:48])[C:45]([OH:47])=[O:46]>C1(OC)C=CC=CC=1>[F:43][C:44]([F:49])([F:48])[C:45]([OH:47])=[O:46].[C:12]([C:14]1[CH:15]=[CH:16][C:17]([O:18][CH2:19][CH2:20][CH2:21][N:22]2[CH2:27][CH2:26][NH:25][C:24](=[O:39])[C:23]2=[O:40])=[CH:41][CH:42]=1)(=[NH:11])[NH2:13]
Reactant: COc1ccc(CN2CCN(CCCOc3ccc(C(=N)NC(=O)OCc4ccccc4)cc3)C(=O)C2=O)c(OC)c1
Solvent: O=C(O)C(F)(F)F
Solvent: COc1ccccc1
Product: N=C(N)c1ccc(OCCCN2CCNC(=O)C2=O)cc1
Reaction time: 0.5 h

Procedure:
In 16.5 ml of anisole was dissolved 8.25 g of 4-[3-(4-benzyloxycarbonylamidinophenoxy)propyl]-1-(2,4-dimethoxybenzyl)-2,3-dioxopiperazine, and 33 ml of trifluoroacetic acid was added to the solution, followed by refluxing for 5 hours. After cooling, the solvent was distilled off under reduced pressure. To the resulting residue was added 40 ml of ethyl acetate, and stirred for 30 minutes, after which the precipitate was collected by filtration and dried to obtain 8.23 g of 4-[3-(4-amidinophenoxy)propyl]-2,3-dioxopiperazine trifluoro-acetate. Then, the compound obtained was dissolved in a mixed solvent of 182 ml of dioxane and 82 ml of water, followed by adding thereto 8.37 g of sodium carbonate and 3.62 g of di-tert-butyl dicarbonate, and the resulting mixture was stirred at room temperature for 5 hours. The solvent was distilled off under reduced pressure and 80 ml of ethyl acetate and 80 ml of water were added to the resulting residue and stirred for 30 minutes. The crystals precipitated were collected by filtration and dried to obtain 4.27 g of 1-[3-(4-tert-butoxycarbonyl-amidinophenoxy)propyl]-2,3-dioxopiperazine as colorless crystals.
Reaction SMILES: [C:1]([N:8]([CH3:14])[C@H:9]([C:11]([OH:13])=O)[CH3:10])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CN1CCOCC1.[NH2:46][CH:47]([CH2:72][CH3:73])[C:48]([N:50]1[CH2:54][CH2:53][CH:52]2[N:55]([S:68]([CH3:71])(=[O:70])=[O:69])[CH2:56][CH:57]([C:58]3[C:66]4[C:61](=[CH:62][C:63]([F:67])=[CH:64][CH:65]=4)[NH:60][CH:59]=3)[CH:51]12)=[O:49]>CN1C(=O)CCC1.C(OCC)C.CCOC(C)=O>[C:4]([O:3][C:1](=[O:2])[N:8]([CH:9]([C:11](=[O:13])[NH:46][CH:47]([C:48]([N:50]1[CH2:54][CH2:53][CH:52]2[N:55]([S:68]([CH3:71])(=[O:69])=[O:70])[CH2:56][CH:57]([C:58]3[C:66]4[C:61](=[CH:62][C:63]([F:67])=[CH:64][CH:65]=4)[NH:60][CH:59]=3)[CH:51]12)=[O:49])[CH2:72][CH3:73])[CH3:10])[CH3:14])([CH3:5])([CH3:6])[CH3:7]
Reactant: CCC(N)C(=O)N1CCC2C1C(c1c[nH]c3cc(F)ccc13)CN2S(C)(=O)=O
Reactant: C[C@@H](C(=O)O)N(C)C(=O)OC(C)(C)C
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCOC(C)=O
Solvent: CN1CCCC1=O
Solvent: CN1CCOCC1
Product: CCC(NC(=O)C(C)N(C)C(=O)OC(C)(C)C)C(=O)N1CCC2C1C(c1c[nH]c3cc(F)ccc13)CN2S(C)(=O)=O
Temperature: 0 °C
Reaction time: 16 h

Procedure:
To a solution containing Boc-N(Me)Ala-OH (85 mg, 0.41 mmol) in anhydrous NMP (2 mL) was cooled to 0° C. HATU (156 mg, 0.41 mmol) and NMM (51 mg, 0.5 mmol) were added followed by the addition of crude 65 (150 mg, 0.37 mmol) in anhydrous NMP (4 mL). The reaction mixture was slowly warmed to ambient temperature. After 16 h, the reaction mixture was diluted with diethyl ether and EtOAc (10:1) and washed successively with aqueous NaHCO3 and brine, dried over anhydrous Na2SO4, filtered, and concentrated to afford 160 mg of crude 66 which was used without further purification. Mass spectrum, m/z [594.2] (M+H)+.
Reaction SMILES: [N:1]([CH2:4][CH2:5][CH2:6][O:7][C:8]1[CH:9]=[C:10]2[C:15](=[CH:16][CH:17]=1)[NH:14][C:13](=[O:18])[CH:12]=[CH:11]2)=[C:2]=[S:3].[CH:19]1([CH2:27][NH:28][CH2:29][CH2:30][N:31]2[CH2:36][CH2:35][CH:34]([O:37][CH2:38][O:39][CH3:40])[CH2:33][CH2:32]2)[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1>C(Cl)(Cl)Cl>[CH3:40][O:39][CH2:38][O:37][CH:34]1[CH2:33][CH2:32][N:31]([CH2:30][CH2:29][N:28]([CH:4]([N:1]=[C:2]=[S:3])[CH2:5][CH2:6][O:7][C:8]2[CH:9]=[C:10]3[C:15](=[CH:16][CH:17]=2)[NH:14][C:13](=[O:18])[CH:12]=[CH:11]3)[CH2:27][CH:19]2[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]2)[CH2:36][CH2:35]1
Reactant: O=c1ccc2cc(OCCCN=C=S)ccc2[nH]1
Reactant: COCOC1CCN(CCNCC2CCCCCCC2)CC1
Solvent: ClC(Cl)Cl
Product: COCOC1CCN(CCN(CC2CCCCCCC2)C(CCOc2ccc3[nH]c(=O)ccc3c2)N=C=S)CC1
Yield: 74.6 %

Procedure:
A solution of 0.22 g of 6-(3-isothiocyanatopropoxy)carbostyril and 0.3 g of 1-[2-(cyclooctylmethylamino)ethyl]-4-methoxymethoxypiperidine in 30 ml of chloroform was stirred at room temperature for 5 hours. The solvent was removed by distillation under reduced pressure. The resulting residue was purified by a silica gel column chromatography (eluant: 3% methanol/dichloromethane) to obtain 0.36 g of 6-[3-{N-2-(4-methoxymethoxy-1-piperidinyl)ethyl-N-cyclooctylmethylamino}-thiocarbonylaminopropoxy]carbostyril.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][C:5]([NH:8][C:9](=[O:34])[C:10]2[CH:15]=[CH:14][C:13]([C:16]3[CH2:20][C:19]([C:25]4[CH:30]=[C:29]([Cl:31])[CH:28]=[C:27]([Cl:32])[CH:26]=4)([C:21]([F:24])([F:23])[F:22])[O:18][N:17]=3)=[CH:12][C:11]=2[CH3:33])=[N:6][CH:7]=1.C(N(CC)CC)C.[CH3:42][O:43][CH2:44][C:45](Cl)=[O:46]>CN(C)C1C=CN=CC=1.O1CCCC1>[Cl:1][C:2]1[CH:7]=[N:6][C:5]([N:8]([C:45](=[O:46])[CH2:44][O:43][CH3:42])[C:9](=[O:34])[C:10]2[CH:15]=[CH:14][C:13]([C:16]3[CH2:20][C:19]([C:25]4[CH:26]=[C:27]([Cl:32])[CH:28]=[C:29]([Cl:31])[CH:30]=4)([C:21]([F:23])([F:24])[F:22])[O:18][N:17]=3)=[CH:12][C:11]=2[CH3:33])=[N:4][CH:3]=1
Reactant: Cc1cc(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)ccc1C(=O)Nc1ncc(Cl)cn1
Reactant: COCC(=O)Cl
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: COCC(=O)N(C(=O)c1ccc(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)cc1C)c1ncc(Cl)cn1
Yield: 71.7 %

Procedure:
In a solution of 0.27 g of N-(5-chloro-2-pyrimidinyl)-4-[5-(3,5-dichlorophenyl)-5-trifluoromethyl-4,5-dihydro-isoxazole-3-yl]-2-methyl benzoic acid amide synthesized in Step 1 of Synthetic Example 11, 0.08 g of triethylamine and a catalytic amount of 4-(dimethylamino)pyridine in 5 mL of tetrahydrofuran, 0.08 g of methoxyacetyl chloride was added at room temperature with stirring, and stirred at the same temperature for 0.5 hour. After the completion of the reaction, the solvent was distilled off under reduced pressure, the residue was passed through short-pass silica gel column that was eluated with ethyl acetate, and thereby insoluble material was removed. The solvent was distilled off under reduced pressure, and purified with silica gel column chromatography that was eluated with ethyl acetate-hexane (3:7) to obtain 0.22 g of the aimed product as colorless resinous substance.
Reaction SMILES: C([O:3][C:4](=[O:25])[C:5]1[CH:10]=[CH:9][C:8]([CH3:11])=[C:7]([NH:12][C:13]2[N:18]=[C:17]([C:19]3[CH:24]=[N:23][CH:22]=[CH:21][N:20]=3)[CH:16]=[CH:15][N:14]=2)[CH:6]=1)C.C(OC(=O)C1C=CC(NC2N=C(C3C=NC=CC=3)C=CN=2)=CC=1)C>>[CH3:11][C:8]1[CH:9]=[CH:10][C:5]([C:4]([OH:25])=[O:3])=[CH:6][C:7]=1[NH:12][C:13]1[N:18]=[C:17]([C:19]2[CH:24]=[N:23][CH:22]=[CH:21][N:20]=2)[CH:16]=[CH:15][N:14]=1
Reactant: CCOC(=O)c1ccc(C)c(Nc2nccc(-c3cnccn3)n2)c1
Agent: CCOC(=O)c1ccc(Nc2nccc(-c3cccnc3)n2)cc1
Product: Cc1ccc(C(=O)O)cc1Nc1nccc(-c2cnccn2)n1

Procedure:
4-methyl-3-(4-pyrazin-2-yl-pyrimidin-2-ylamino)-benzoic acid ethyl ester prepared in Preparation 11 was used instead of 4-(4-pyridin-3-yl-pyrimidin-2-ylamino)-benzoic acid ethyl ester according to the similar procedure to Preparation 19 to give the titled compound as yellow solid.
Reaction SMILES: Cl.[CH3:2][N:3]([CH3:7])[CH2:4][CH2:5]Cl.[F:8][C:9]1[CH:28]=[CH:27][C:12]2[S:13][C:14]3[CH:26]=[CH:25][CH:24]=[CH:23][C:15]=3[C:16]3[S:17][C:18]([CH2:21][OH:22])=[N:19][C:20]=3[C:11]=2[CH:10]=1>[OH-].[Na+].[Cl-].C([N+](CC)(CC)CC)C1C=CC=CC=1.C1(C)C=CC=CC=1.O>[F:8][C:9]1[CH:28]=[CH:27][C:12]2[S:13][C:14]3[CH:26]=[CH:25][CH:24]=[CH:23][C:15]=3[C:16]3[S:17][C:18]([CH2:21][O:22][CH2:5][CH2:4][N:3]([CH3:7])[CH3:2])=[N:19][C:20]=3[C:11]=2[CH:10]=1
Reactant: CN(C)CCCl
Reactant: OCc1nc2c(s1)-c1ccccc1Sc1ccc(F)cc1-2
Agent: CC[N+](CC)(CC)Cc1ccccc1
Agent: Cl
Agent: [Cl-]
Solvent: O
Solvent: Cc1ccccc1
Product: CN(C)CCOCc1nc2c(s1)-c1ccccc1Sc1ccc(F)cc1-2
Temperature: 25 °C

Procedure:
To a solution of 2-dimethylaminoethylchloride-hydrochloride (12 mmoles) in 50% sodium hydroxide (5 ml), benzyltriethylammonium chloride (0.65 mmole) and a solution of the alcohol 80 (1.1 mmole) in toluene (5 ml) were added. The reaction mixture was heated under vigorous stirring and refluxing for 3 hours. Then it was cooled to room temperature, diluted with water and extracted with dichloromethane. After purification by chromatography on a silica gel column, an oily product was isolated.
Reaction SMILES: [CH2:1]([C:3]1[C:11]2[N:10]=[CH:9][N:8](C(OC(C)(C)C)=O)[C:7]=2[CH:6]=[CH:5][C:4]=1[N+]([O-])=O)[CH3:2].C(O)(C(F)(F)F)=O.Cl.N([O-])=O.[Na+].[C-]#N.[Na+].[C:37]([Cu])#[N:38]>C(Cl)Cl.O.CCOC(C)=O>[CH2:1]([C:3]1[C:11]2[N:10]=[CH:9][NH:8][C:7]=2[CH:6]=[CH:5][C:4]=1[C:37]#[N:38])[CH3:2]
Reactant: CCc1c([N+](=O)[O-])ccc2c1ncn2C(=O)OC(C)(C)C
Reactant: N#C[Cu]
Agent: Cl
Agent: O=N[O-]
Agent: [C-]#N
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Solvent: O
Product: CCc1c(C#N)ccc2[nH]cnc12
Temperature: 40 °C
Reaction time: 0.5 h
Yield: 76.4 %

Procedure:
To a solution of tert-butyl 4-ethyl-5-nitro-1H-benzo[d]imidazole-1-carboxylate (13.6 g, 0.052 mol) in dry DCM (140 mL) was added TFA (20 mL, 0.26 mol, 5.0 equiv.), and the reaction mixture was heated at 40° C. for 16 h. The reaction mixture was concentrated and the crude solid re-dissolved in an acetone and water mixture (1:1, 40 mL). Concentrated HCl (14 mL) and sodium nitrite (3.95 g, 0.057 mol, 1.1 eq.) were then added at 0° C., and the reaction mixture was stirred at the same temperature for 30 min. The resulting solution was added dropwise to a solution of sodium cyanide (10.21 g, 0.21 mol, 4 equiv.) and CuCN (10.5 g, 0.084 mol, 1.6 equiv.) in an EtOAc and water mixture (1:1, 40 ml) at 0° C. The reaction mixture was then warmed to RT and stirred for a further 2 h. The reaction mixture was quenched with water and extracted with EtOAc. The combined organic layers were washed with brine then dried (Na2SO4), filtered and concentrated. The crude product was purified by SiO2 chromatography eluting with 25% EtOAc/hexane to afford 4-ethyl-1H-benzo[d]imidazole-5-carbonitrile (6.8 g, 76% yield) as a yellow solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([CH3:9])=[C:7]([CH3:10])[C:6]([O:11][CH3:12])=[C:5]([CH3:13])[C:4]=1[CH2:14]/[CH:15]=[C:16](\[CH3:22])/[CH2:17][CH2:18][CH2:19][C:20]#N.[BH4-].[Na+].O.CC([O:30]C)(C)C>CO>[CH3:1][O:2][C:3]1[C:8]([CH3:9])=[C:7]([CH3:10])[C:6]([O:11][CH3:12])=[C:5]([CH3:13])[C:4]=1[CH2:14]/[CH:15]=[C:16](\[CH3:22])/[CH2:17][CH2:18][CH2:19][CH2:20][OH:30]
Reactant: COC(C)(C)C
Reactant: COc1c(C)c(C)c(OC)c(C/C=C(\C)CCCC#N)c1C
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: COc1c(C)c(C)c(OC)c(C/C=C(\C)CCCCO)c1C
Reaction time: 12 h

Procedure:
Crude (E)-7-(2,5-dimethoxy-3,4,6-trimethylphenyl)-5-methylhept-5-enenitrile in MeOH (3 mL) was cooled to 0° C. and treated with NaBH4 (64.3 mg, 1.74 mmol), which gave immediate effervescence. After 12 h, H2O (10 mL) was added (caution: copious gas evolution), MTBE (10 mL) was added, separated and the aqueous phase extracted with MTBE (3×10 mL). The combined organics were washed with H2O (10 mL), brine (10 mL), dried over Na2SO4 and concentrated to give (E)-7-(2,5-dimethoxy-3,4,6-trimethylphenyl)-5-methylhept-5-en-1-ol as a pale yellow oil.
Reaction SMILES: Cl[C:2]([C:4]1[CH:19]=[CH:18][C:7]2[C:8](=[O:17])[NH:9][C:10]3[CH:16]=[CH:15][CH:14]=[CH:13][C:11]=3[S:12][C:6]=2[CH:5]=1)=[O:3].[Na].[OH:21][CH2:22][CH2:23][C:24]([OH:26])=[O:25]>O1CCCC1>[O:17]=[C:8]1[C:7]2[CH:18]=[CH:19][C:4]([C:2]([O:21][CH2:22][CH2:23][C:24]([OH:26])=[O:25])=[O:3])=[CH:5][C:6]=2[S:12][C:11]2[CH:13]=[CH:14][CH:15]=[CH:16][C:10]=2[NH:9]1
Reactant: O=C(Cl)c1ccc2c(c1)Sc1ccccc1NC2=O
Reactant: O=C(O)CCO
Agent: [Na]
Solvent: C1CCOC1
Product: O=C(O)CCOC(=O)c1ccc2c(c1)Sc1ccccc1NC2=O
Temperature: 25 °C
Reaction time: 18 h

Procedure:
Dissolve 1.0 gm. of 3-chlorocarbonyl-10,11-dihydro-11-oxodibenzo[b,f][1,4]thiazepine in 20 cc. of tetrahydrofuran and add 1.0 gm. of the sodium salt of β-hydroxypropionic acid. Stir the mixture at room temperature for 18 hours. Filter and evaporate the filtrate to dryness. Recrystallize the solid residue from ethanol to obtain the title product.
Reaction SMILES: [Br:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([S:12]([CH3:15])(=[O:14])=[O:13])=[CH:9][CH:10]=2)[CH:5]=[CH:4][C:3]=1[NH:16][C:17](=[O:23])[O:18][C:19]([CH3:22])([CH3:21])[CH3:20].[H-].[Na+].[Cl:26][CH:27]=[CH:28][CH2:29]Cl>CN(C=O)C.[Na+].[Cl-]>[Br:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([S:12]([CH3:15])(=[O:14])=[O:13])=[CH:9][CH:10]=2)[CH:5]=[CH:4][C:3]=1[N:16]([CH2:29][CH:28]=[CH:27][Cl:26])[C:17](=[O:23])[O:18][C:19]([CH3:20])([CH3:22])[CH3:21]
Reactant: ClC=CCCl
Reactant: CC(C)(C)OC(=O)Nc1ccc2cc(S(C)(=O)=O)ccc2c1Br
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N(CC=CCl)c1ccc2cc(S(C)(=O)=O)ccc2c1Br
Temperature: 25 °C
Reaction time: 6 h
Yield: 97.1 %

Procedure:
A stirred suspension of 162 (4.70 g, 11.74 mmol) in dry DMF (40 mL) was treated portionwise at 0° C. with NaH (564 mg, 60% in oil, 14.10 mmol). The mixture was warmed to room temperature for 1 h then cooled to O—C and treated with 1,3-dichloropropene (3.4 mL, 37 mmol, mixed isomers). The mixture was stirred at room temperature for a further 6 h, then diluted with 10% aqueous NaCl and extracted with EtOAc (×2). The combined organic layers were washed with water (×2), dried, and concentrated to dryness under reduced pressure at 100° C. The residue was chromatographed on silica gel, eluting with CH2Cl2/EtOAc (9:1) to give tert-butyl 1-bromo-6-(methylsulfonyl)-2-naphthyl(3-chloro-2-propen-1-yl)carbamate (163) (5.41 g, 970%) as a foam; 1H NMR [(CD3)2SO] (mixture of rotamers and E and Z forms) δ 8.73-8.69 (m, 1H), 8.46 (d, J=9.0 Hz, 1H, 8.30, 8.29 (2 d, J=8.6 Hz, 1H), 8.14 (dd, J=9.0, 1.8 Hz, 1H), 7.71, 7.68 (2 d, J=8.6 Hz, 1H), 6.43-6.28 (m, 1H), 6.19-6.01 (m, 1 H), 4.59-4.48, 4.44-4.23, 4.19-4.05 (3 m, 2H), 327 (after D2O exchange, s, 3H), 1.50, 1.26 (2 s, 9H). HRMS (FAB) calcd. for C19H2279Br35ClNO4S (MH+) m/z 474.0141, found 474.0142.
Reaction SMILES: C([NH:5][C:6]([C:8]1[N:9]=[C:10]([N:18]2[CH2:23][CH2:22][CH:21]([NH:24][C:25]([C:27]3[NH:28][C:29]([CH3:34])=[C:30]([Cl:33])[C:31]=3[Cl:32])=[O:26])[CH2:20][CH2:19]2)[S:11][C:12]=1[C:13]([O:15]CC)=[O:14])=O)(C)(C)C.[Li+].[OH-].C1COCC1.Cl>O.CO>[C:6]([C:8]1[N:9]=[C:10]([N:18]2[CH2:23][CH2:22][CH:21]([NH:24][C:25]([C:27]3[NH:28][C:29]([CH3:34])=[C:30]([Cl:33])[C:31]=3[Cl:32])=[O:26])[CH2:20][CH2:19]2)[S:11][C:12]=1[C:13]([OH:15])=[O:14])#[N:5]
Reactant: CCOC(=O)c1sc(N2CCC(NC(=O)c3[nH]c(C)c(Cl)c3Cl)CC2)nc1C(=O)NC(C)(C)C
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: Cc1[nH]c(C(=O)NC2CCN(c3nc(C#N)c(C(=O)O)s3)CC2)c(Cl)c1Cl
Yield: 79.1 %

Procedure:
A solution of ethyl 4-[(tert-butylamino)carbonyl]-2-(4-{[(3,4-dichloro-5-methyl-1H-pyrrol-2-yl)carbonyl]amino}piperidin-1-yl)-1,3-thiazole-5-carboxylate (Example 340; 140 mg, 0.31 mmol) and 2 N LiOH in water (0.93 ml, 1.86 mmol) in 6 ml 1:1 THF:MeOH was heated at 80° C. for 30 min in a microwave reactor. 1 N HCl (1.86 ml) was added and the mixture was diluted with water. Precipitated material was filtered and rinsed well with water. Drying of the precipitate in vacuo gave 105 mg of product.
Reaction SMILES: [Br:1]N1C(=O)CCC1=O.[C:9]([NH:17][CH:18]1[C:31](=[O:32])[N:20]2[C:21]([C:27]([O:29][CH3:30])=[O:28])=[C:22]([CH3:26])[CH2:23][S:24](=[O:25])[C@H:19]12)(=[O:16])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.O>ClCCl.C(O)(=O)C.[W]>[C:9]([NH:17][CH:18]1[C:31](=[O:32])[N:20]2[C:21]([C:27]([O:29][CH3:30])=[O:28])=[C:22]([CH2:26][Br:1])[CH2:23][S:24](=[O:25])[C@H:19]12)(=[O:16])[C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1
Reactant: COC(=O)C1=C(C)CS(=O)[C@@H]2C(NC(=O)c3ccccc3)C(=O)N12
Reactant: O=C1CCC(=O)N1Br
Agent: [W]
Solvent: O
Solvent: CC(=O)O
Solvent: ClCCl
Product: COC(=O)C1=C(CBr)CS(=O)[C@@H]2C(NC(=O)c3ccccc3)C(=O)N12
Temperature: 0 °C
Yield: 58.5 %

Procedure:
1.2 g (6.8 mmoles) of N-bromosuccinimide were added to an ice-cooled solution of 1.4 g (4 mmoles) of methyl 7-benzamido-3-methyl-3-cephem-4-carboxylate-1-oxide in a mixture of 25 ml of dichloromethane and 50 ml of acetic acid. The mixture was stirred and irradiated with a 150 W tungsten lamp for 1.5 hours. The reaction mixture was poured into water and dichloromethane and the organic layer was separated and washed three times with 500 ml of water. After treatment with activated charcoal, it was dried over magnesium sulfate and filtered. The filtrate was concentrated to about 20 ml in vacuo and the product was precipiated by addition of 150 ml of diethyl ether. The mixture was filtered and the product was washed with diethyl ether. It was crystallized by dissolving it in 100 ml of refluxing dichloromethane and precipitation by addition of 100 ml of diethyl ether to obtain 1.0 g pure methyl 7-benzamido-3-bromomethyl-3-cephem-4-carboxylate-1-oxide (yield 58.8%).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:16])[CH2:5][N:6]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([OH:15])[CH:13]=2)[CH:8]=[CH:7]1)[CH3:2].[CH:17]1([C:20]2[C:25]([CH2:26][CH2:27]O)=[CH:24][N:23]=[C:22]([C:29]3[CH:34]=[CH:33][C:32]([C:35]([F:38])([F:37])[F:36])=[CH:31][CH:30]=3)[N:21]=2)[CH2:19][CH2:18]1.N(C(OC(C)(C)C)=O)=NC(OC(C)(C)C)=O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>O1CCCC1>[CH2:1]([O:3][C:4](=[O:16])[CH2:5][N:6]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([O:15][CH2:27][CH2:26][C:25]3[C:20]([CH:17]4[CH2:19][CH2:18]4)=[N:21][C:22]([C:29]4[CH:34]=[CH:33][C:32]([C:35]([F:38])([F:36])[F:37])=[CH:31][CH:30]=4)=[N:23][CH:24]=3)[CH:13]=2)[CH:8]=[CH:7]1)[CH3:2]
Reactant: OCCc1cnc(-c2ccc(C(F)(F)F)cc2)nc1C1CC1
Reactant: CCOC(=O)Cn1ccc2ccc(O)cc21
Agent: CC(C)(C)OC(=O)N=NC(=O)OC(C)(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CCOC(=O)Cn1ccc2ccc(OCCc3cnc(-c4ccc(C(F)(F)F)cc4)nc3C3CC3)cc21

Procedure:
In analogy to the procedure described in example 5 f], (6-hydroxy-indol-1-yl)-acetic acid ethyl ester (example 6 b]) was reacted with 2-[4-cyclopropyl-2-(4-trifluoromethyl-phenyl)-pyrimidin-5-yl]-ethanol in the presence of di-tert-butyl azodicarboxylate and triphenylphosphine in tetrahydrofuran to yield the title compound as colorless liquid.