Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([C:4]1[CH:8]=[CH:7][NH:6][N:5]=1)([O-:3])=[O:2].[C:9]([O:13][C:14]([N:16]1[CH2:19][CH:18](I)[CH2:17]1)=[O:15])([CH3:12])([CH3:11])[CH3:10].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[N+:1]([C:4]1[CH:8]=[CH:7][N:6]([CH:18]2[CH2:17][N:16]([C:14]([O:13][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:15])[CH2:19]2)[N:5]=1)([O-:3])=[O:2]
Reactant: CC(C)(C)OC(=O)N1CC(I)C1
Reactant: O=[N+]([O-])c1cc[nH]n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CC(n2ccc([N+](=O)[O-])n2)C1
Temperature: 60 °C
Reaction time: 16 h
Yield: 81 %

Procedure:
A 100-mL single-neck round-bottomed flask equipped with a magnetic stirrer and nitrogen inlet was charged with DMF (20 mL), 3-nitro-1H-pyrazole (1.00 g, 8.84 mmol), N-tert-butoxycarbonyl-3-iodoazetidine (3.00 g, 10.6 mmol) and potassium carbonate (2.45 g, 17.7 mmol), and the reaction mixture was stirred at 60° C. for 16 h. After this time the reaction was concentrated to dryness under reduced pressure, and the resulting residue was mixed with methylene chloride (15 mL) and water (15 mL). The aqueous layer was separated and extracted with methylene chloride (2×15 mL). The combined organic extracts were dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography to afford an 80% yield (1.92 g) of 105a as a yellow oil: 1H NMR (300 MHz, CDCl3) δ 7.64 (d, 1H, J=2.4 Hz), 6.97 (d, 1H, J=2.4 Hz), 5.13 (m, 1H), 4.44 (m, 2H), 4.33 (m, 2H), 1.47 (s, 9H).
Reaction SMILES: [CH3:1][C:2]1[S:6][C:5]([CH2:7][C:8]([CH3:10])=[O:9])=[N:4][N:3]=1.[CH:11]([C:13]1[CH:20]=[CH:19][C:16]([C:17]#[N:18])=[CH:15][C:14]=1[O:21][CH3:22])=O.N1CCCCC1.C(O)(=O)C>ClCCl>[CH3:22][O:21][C:14]1[CH:15]=[C:16]([CH:19]=[CH:20][C:13]=1[CH:11]=[C:7]([C:5]1[S:6][C:2]([CH3:1])=[N:3][N:4]=1)[C:8](=[O:9])[CH3:10])[C:17]#[N:18]
Reactant: CC(=O)Cc1nnc(C)s1
Reactant: COc1cc(C#N)ccc1C=O
Solvent: ClCCl
Solvent: C1CCNCC1
Solvent: CC(=O)O
Product: COc1cc(C#N)ccc1C=C(C(C)=O)c1nnc(C)s1

Procedure:
1.34 g (8.32 mmol) of 1-(5-methyl-1,3,4-thiadiazol-2-yl)acetone [T. Saito et al., J. Heterocycl. Chem. 20, 73-75 (1983)] and 1.30 g (8.32 mmol) of the compound from example 3A are dissolved in 20 ml of dichloromethane, and 0.165 ml (1.66 mmol) of piperidine and 0.100 ml (1.66 mmol) of acetic acid are added. The reaction mixture is heated under reflux with an inverse water trap overnight. The volatile components are removed in a rotary evaporator, and the crude product is purified by column chromatography (silica gel; eluent: initially dichloromethane, then cyclohexane/ethyl acetate 4:1→1:1). 1.17 g (47% of theory) of the title compound are obtained as a mixture of the E/Z isomers which can be crystallized from ethyl acetate/n-pentane. 530 mg of the title compound are obtained as a crystalline solid in this way.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[OH:8].CC(C)([O-])C.[K+].[C:15]([O:20][CH2:21][CH3:22])(=[O:19])[C:16]#[C:17][CH3:18].[OH-].[Na+]>O1CCCC1.C(OC)(C)(C)C>[CH2:21]([O:20][C:15](=[O:19])/[CH:16]=[C:17](/[O:8][C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[Cl:1])\[CH3:18])[CH3:22]
Reactant: CC#CC(=O)OCC
Reactant: Oc1ccccc1Cl
Agent: CC(C)(C)[O-]
Agent: [K+]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: COC(C)(C)C
Product: CCOC(=O)/C=C(\C)Oc1ccccc1Cl
Temperature: 14.5 °C
Reaction time: 19.75 h
Yield: 104.3 %

Procedure:
To a solution of 2-chlorophenol (3186 g, 24.78 mol) in tetrahydrofuran (14000 mL) at 12° C. was added a 20% potassium t-butoxide solution in tetrahydrofuran (8150 mL, 13.48 mol) over 45 min maintaining an internal temperature between 12-17° C. The solution was warmed to 22° C. and stirred for 1 h before ethyl 2-butynoate (1400 g, 12.48 mol) was added in one portion. The resulting mixture was warmed to 40° C., and stirred for 19.75 h. The reaction mixture was transferred to an extractor and was diluted with methyl t-butyl ether (21 L) and an aqueous 1N aqueous sodium hydroxide solution (14 L). The mixture was stirred and separated and the organic phase washed with an 1N aqueous sodium hydroxide solution (14 L). The aqueous phases were combined and extracted with methyl t-butyl ether (10 L). The organic layer was washed with an 1N aqueous sodium hydroxide solution (7 L). The combined organic phases were washed with a 20% sodium chloride solution (14 L). The solution was evaporated to give (E)-3-(2-chloro-phenoxy)-but-2-enoic acid ethyl ester (96.9% pure by HPLC, 3134 g, 101%) as a light yellow oil.
Reaction SMILES: I[C:2]1[CH:12]=[CH:11][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH2:20]([C:22]1[N:23]([CH2:35][C:36]#[CH:37])[C:24]2[C:33]3[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=3[N:27]=[CH:26][C:25]=2[N:34]=1)[CH3:21]>CN(C=O)C.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C(Cl)(Cl)Cl.[Pd].[Pd].[Cu]I>[CH2:20]([C:22]1[N:23]([CH2:35][C:36]#[C:37][C:2]2[CH:12]=[CH:11][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:4][CH:3]=2)[C:24]2[C:33]3[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=3[N:27]=[CH:26][C:25]=2[N:34]=1)[CH3:21]
Reactant: CCOC(=O)c1ccc(I)cc1
Reactant: C#CCn1c(CC)nc2cnc3ccccc3c21
Agent: [Cu]I
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: ClC(Cl)Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCOC(=O)c1ccc(C#CCn2c(CC)nc3cnc4ccccc4c32)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Tris(dibenzylideneacetone)dipalladium(0) chloroform adduct (65.9 mg, 0.03 eq.), ethyl 4-iodobenzoate (388 μL, 1.1 eq.), triethylamine (887 μL, 3.0 eq.), and copper (I) iodide (24.2 mg, 0.06 eq.) were added sequentially to a solution of 2-ethyl-1-(2-propynyl)-1H-imidazo[4,5-c]quinoline (499 mg, 2.12 mmol, 1.0 eq.) in DMF (10.6 mL). The reaction mixture was stirred at ambient temperature for 1 hour and then concentrated under reduced pressure. The residue was purified by column chromatography (silica gel eluting with 5/95 methanol/chloroform) to provide 0.70 g of ethyl 4-[3-(2-ethyl-1H-imidazo[4,5-c]quinolin-1-yl)-1-propynyl]benzoate as a light tan solid.
Reaction SMILES: [Na].[N:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]=[CH:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[OH:16].[CH2:17]([O:19][C:20](=[O:26])[CH2:21][CH2:22][CH2:23][CH2:24]Br)[CH3:18]>CC(O)C>[CH2:17]([O:19][C:20](=[O:26])[CH2:21][CH2:22][CH2:23][CH2:24][O:16][C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=1[CH:9]=[CH:8][C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][N:2]=1)[CH3:18]
Reactant: Oc1ccccc1C=Cc1ccccn1
Reactant: CCOC(=O)CCCCBr
Agent: [Na]
Solvent: CC(C)O
Product: CCOC(=O)CCCCOc1ccccc1C=Cc1ccccn1

Procedure:
To the solution of 2.3 g (0.1 mol) sodium in 250 ml ethanol one adds 19.7 g 2-[2-(2-pyridinyl)-ethenyl]-phenol, stirs for 10 min at room temp., adds thereto 17.4 ml (0.11 mol) 5-bromovaleric acid ethyl ester and heats to reflux for 16 h. One evaporates, mixes with water, extracts with dichloromethane, dries the extract and evaporates. There remain 32.4 g of title compound (100% of theory) as oil.
Reaction SMILES: [CH2:1]([N:8]1[CH2:12][C@H:11]([C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[C:15]([Cl:20])[CH:14]=2)[C@@H:10]([NH:21][CH3:22])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:23][C:24]1[CH:29]=[CH:28][C:27]([CH2:30][C:31]([OH:33])=O)=[CH:26][CH:25]=1>>[CH2:1]([N:8]1[CH2:12][CH:11]([C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[C:15]([Cl:20])[CH:14]=2)[CH:10]([N:21]([CH3:22])[C:31](=[O:33])[CH2:30][C:27]2[CH:26]=[CH:25][C:24]([F:23])=[CH:29][CH:28]=2)[CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CN[C@H]1CN(Cc2ccccc2)C[C@@H]1c1ccc(Cl)c(Cl)c1
Reactant: O=C(O)Cc1ccc(F)cc1
Product: CN(C(=O)Cc1ccc(F)cc1)C1CN(Cc2ccccc2)CC1c1ccc(Cl)c(Cl)c1

Procedure:
In analogy to the procedure described for the synthesis of example 97, the title compound N-[(3RS,4SR)-1-benzyl-4-(3,4-dichloro-phenyl)-pyrrolidin-3-yl]-2-(4-fluoro-phenyl)-N-methyl-acetamide was prepared from [(3R,4S)-1-benzyl-4-(3,4-dichloro-phenyl)-pyrrolidin-3-yl]-methyl-amine using 4-fluorophenylacetic acid instead of 4-chloro-3-(trifluoromethyl)benzoic acid and was obtained as a light yellow oil. MS m/e: 471.2 [M]+.
Reaction SMILES: CCN(C(C)C)C(C)C.[Si:10](Cl)([C:13]([CH3:16])([CH3:15])[CH3:14])([CH3:12])[CH3:11].[CH3:18][NH:19][CH2:20][CH2:21][OH:22].C(OCC)C>C(Cl)Cl.O>[Si:10]([O:22][CH2:21][CH2:20][NH:19][CH3:18])([C:13]([CH3:16])([CH3:15])[CH3:14])([CH3:12])[CH3:11]
Reactant: CNCCO
Reactant: CC(C)(C)[Si](C)(C)Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOCC
Product: CNCCO[Si](C)(C)C(C)(C)C
Temperature: 25 °C
Reaction time: 16 h
Yield: 100.9 %

Procedure:
DIPEA (2.45 mL, 14.0 mmol) and tert-butyldimethylsilyl chloride (1.51 g, 10.0 mmol) were added to a solution of 2-(methylamino)ethanol (751 mg, 10.0 mmol) in dry DCM (25 mL) under argon and the reaction mixture allowed to stir at RT for 16 hours. Diethyl ether (50 mL) and water (50 mL) were added to the reaction mixture and the aqueous phase was extracted with diethyl ether (3×30 mL). The combined extracts were dried (MgSO4), filtered and evaporated to give a pale yellow oil which was dried under high vacuum to give the title compound (1.91 g).
Reaction SMILES: [Br:1][C:2]1[C:14](=[O:15])[N:13]([CH2:16][C:17]2[C:22]([F:23])=[CH:21][CH:20]=[CH:19][C:18]=2[CH:24]2[CH2:26][CH2:25]2)[C:5]2[N:6]=[C:7](S(C)=O)[N:8]=[CH:9][C:4]=2[CH:3]=1.[CH3:27][N:28]1[CH2:33][CH2:32][N:31]([C:34]2[CH:40]=[CH:39][C:37]([NH2:38])=[CH:36][CH:35]=2)[CH2:30][CH2:29]1>>[Br:1][C:2]1[C:14](=[O:15])[N:13]([CH2:16][C:17]2[C:22]([F:23])=[CH:21][CH:20]=[CH:19][C:18]=2[CH:24]2[CH2:26][CH2:25]2)[C:5]2[N:6]=[C:7]([NH:38][C:37]3[CH:36]=[CH:35][C:34]([N:31]4[CH2:30][CH2:29][N:28]([CH3:27])[CH2:33][CH2:32]4)=[CH:40][CH:39]=3)[N:8]=[CH:9][C:4]=2[CH:3]=1
Reactant: CN1CCN(c2ccc(N)cc2)CC1
Reactant: CS(=O)c1ncc2cc(Br)c(=O)n(Cc3c(F)cccc3C3CC3)c2n1
Product: CN1CCN(c2ccc(Nc3ncc4cc(Br)c(=O)n(Cc5c(F)cccc5C5CC5)c4n3)cc2)CC1
Yield: 53.3 %

Procedure:
6-Bromo-8-(2-cyclopropyl-6-fluorobenzyl)-2-methanesulfinyl-8H-pyrido[2,3-d]pyrimidin-7-one (9, 385 mg, 0.9 mmol) and 4-(4-methylpiperazino)aniline (169 mg, 0.9 mmol) were stirred at 140° C. for 6 h. The reaction mixture was purified by column chromatography using dichloromethane:methanol (100:1→100:3→100:5) to yield the title compound as a yellow solid (272 mg, 0.48 mmol, 55%). ESMS m/z 563 (M+H)+.
Reaction SMILES: [OH:1][CH:2]([C@@H:4]1[C@:21]2([CH3:22])[C@H:7]([C@H:8]3[C@H:18]([CH2:19][CH2:20]2)[C@:16]2([CH3:17])[C@H:11]([NH:12][C:13](=[O:23])[CH:14]=[CH:15]2)[CH2:10][CH2:9]3)[CH2:6][CH2:5]1)[CH3:3].[CH3:24][C:25]([CH3:30])([CH3:29])[C:26](Cl)=[O:27].OC([C@@H]1[C@]2(C)[C@H]([C@H]3[C@H](CC2)[C@]2(C)[C@H](N(C)C(=O)CC2)CC3)CC1)C.C(Cl)(=O)CCCCCCCCC=C>>[CH3:24][C:25]([CH3:30])([CH3:29])[C:26]([O:1][CH:2]([C@@H:4]1[C@:21]2([CH3:22])[C@H:7]([C@H:8]3[C@H:18]([CH2:19][CH2:20]2)[C@:16]2([CH3:17])[C@H:11]([NH:12][C:13](=[O:23])[CH:14]=[CH:15]2)[CH2:10][CH2:9]3)[CH2:6][CH2:5]1)[CH3:3])=[O:27]
Reactant: CC(C)(C)C(=O)Cl
Reactant: CC(O)[C@H]1CC[C@H]2[C@@H]3CC[C@H]4NC(=O)C=C[C@]4(C)[C@H]3CC[C@]12C
Agent: C=CCCCCCCCCC(=O)Cl
Agent: CC(O)[C@H]1CC[C@H]2[C@@H]3CC[C@H]4N(C)C(=O)CC[C@]4(C)[C@H]3CC[C@]12C
Product: CC(OC(=O)C(C)(C)C)[C@H]1CC[C@H]2[C@@H]3CC[C@H]4NC(=O)C=C[C@]4(C)[C@H]3CC[C@]12C

Procedure:
Employing substantially the same procedure as described in Example 6, but substituting 20-hydroxy-5α-4-azapregn-1-ene-3-one and trimethylacetyl chloride for the 20-hydroxy-4-methyl-5α-4-azapregnan-3-one and 10-undecenoyl chloride, respectively, used therein, the title compound was obtained. MS M-1 calculated for C25H39NO3, mw=402.53; observed m/e 401.
Reaction SMILES: [CH2:1]([NH:8][C:9]1[CH:14]=[CH:13][C:12]([NH2:15])=[CH:11][N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(O[CH:19]=[C:20]([C:26]([O:28][CH2:29][CH3:30])=[O:27])[C:21]([O:23][CH2:24][CH3:25])=[O:22])C>>[CH2:1]([NH:8][C:9]1[CH:14]=[CH:13][C:12]([NH:15][CH:19]=[C:20]([C:21]([O:23][CH2:24][CH3:25])=[O:22])[C:26]([O:28][CH2:29][CH3:30])=[O:27])=[CH:11][N:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC=C(C(=O)OCC)C(=O)OCC
Reactant: Nc1ccc(NCc2ccccc2)nc1
Product: CCOC(=O)C(=CNc1ccc(NCc2ccccc2)nc1)C(=O)OCC
Temperature: 130 °C
Yield: 84.1 %

Procedure:
A mixture of 2-benzylamino-5-aminopyridine (1.76 g) and diethyl ethoxymethylenemalonate (1.78 mL, 8.82 mmol) was heated at 130° C. for 2 h. While warm, the mixture was evacuated. After cooling, the product was triturated with 2:1 hexanes/ether and collected to give 2.74 g of diethyl (2-benzylamino-5-pyridylaminomethylene)malonate as a gold solid.
Reaction SMILES: C[Si](OS(C(F)(F)F)(=O)=O)(C)C.[Cl:13][C:14]([Cl:52])([Cl:51])[CH2:15][O:16][C:17]([C@@H:19]1[CH2:24][CH2:23][CH2:22][N:21]([C:25](=[O:50])[C@@H:26]([NH:42][C:43](OC(C)(C)C)=[O:44])[CH2:27][C:28]2[CH:33]=[CH:32][CH:31]=[C:30]([O:34][Si:35]([C:38]([CH3:41])([CH3:40])[CH3:39])([CH3:37])[CH3:36])[CH:29]=2)[NH:20]1)=[O:18].C(N(CC)C(C)C)(C)C.[C:62]([O:66][C:67]([NH:69][C@@H:70]([CH2:74][C:75]1[CH:80]=[CH:79][C:78]([O:81][CH3:82])=[CH:77][CH:76]=1)C(O)=O)=[O:68])([CH3:65])([CH3:64])[CH3:63]>ClCCl.C(#N)C>[Cl:13][C:14]([Cl:52])([Cl:51])[CH2:15][O:16][C:17]([C@@H:19]1[CH2:24][CH2:23][CH2:22][N:21]([C:25](=[O:50])[C@@H:26]([NH:42][C:43](=[O:44])[C@@H:70]([NH:69][C:67]([O:66][C:62]([CH3:65])([CH3:64])[CH3:63])=[O:68])[CH2:74][C:75]2[CH:76]=[CH:77][C:78]([O:81][CH3:82])=[CH:79][CH:80]=2)[CH2:27][C:28]2[CH:33]=[CH:32][CH:31]=[C:30]([O:34][Si:35]([C:38]([CH3:39])([CH3:41])[CH3:40])([CH3:37])[CH3:36])[CH:29]=2)[NH:20]1)=[O:18]
Reactant: COc1ccc(C[C@H](NC(=O)OC(C)(C)C)C(=O)O)cc1
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1cccc(O[Si](C)(C)C(C)(C)C)c1)C(=O)N1CCC[C@@H](C(=O)OCC(Cl)(Cl)Cl)N1
Agent: C[Si](C)(C)OS(=O)(=O)C(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: COc1ccc(C[C@H](NC(=O)OC(C)(C)C)C(=O)N[C@@H](Cc2cccc(O[Si](C)(C)C(C)(C)C)c2)C(=O)N2CCC[C@@H](C(=O)OCC(Cl)(Cl)Cl)N2)cc1
Temperature: 25 °C
Reaction time: 1.42 h
Yield: 66.5 %

Procedure:
Trimethylsilyltrifluoromethanesulfonate (341 μL, 1.89 mmol) was added dropwise to a solution of the (S)-1-{(S)-2-tert-butoxycarbonylamino-3-[3-(tert-butyl-dimethyl-silanyloxy)-phenyl]-propionyl}-hexahydro-pyridazine-3-carboxylic acid 2,2,2-trichloro-ethyl ester (670 mg, 1.05 mmol) in dichloromethane (15 mL) at 0° C. under N2 and the reaction was stirred for 85 minutes. To this was added N,N-diisopropylethylamine (730 μL, 4.19 mmol) and the reaction was warmed to room temperature. The volatiles were evaporated to afford a colourless foam which was dissolved in acetonitrile (15 mL). To this solution was added O-benzotriazole-N,N,N′,N′-tetramethyl-uronium-hexafluoro-phosphate (477 mg, 1.26 mmol), (S)-2-tert-butoxycarbonylamino-3-(4-methoxy-phenyl)-propionic acid (340 mg, 1.15 mmol) and N,N-diisopropylethylamine (730 μL, 4.19 mmol) and the reaction was stirred for 18 h. The volatiles were evaporated and the residue partitioned between pH=7 buffer and ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and the volatiles evaporated. The residue was purified by silica chromatography using a gradient of iso-hexanes/ethyl acetate 3:1 to 1:1 to afford the title compound (570 mg, 67%) as a colourless foam. 1H NMR (300 MHz, CDCl3) δ0.18 (s, 6H), 1.00 (s, 9H), 1.43 (s, 9H), 1.45-1.60 (m, 2H) 1.73-1.83 (m, 1H), 1.85-1.95 (m, 1H), 2.30 (br s, 1H), 2.65-3.00 (m, 5H), 3.50 (d, J=11.2 Hz, 1H), 3.80 (s, 3H), 4.24-4.37 (m, 2H), 4.65 (d, J=11.8 Hz, 1H), 4.95 (d, J=11.8 Hz, 1H), 4.96-5.04 (m, 1H), 5.62-5.75 (m, 1H), 6.45 (d, J=8.3 Hz, 1H), 6.64-6.75 (m, 2H), 6.78-6.86 (m, 3H), 7.07-7.16 (m, 3H). LCMS (m/z) 817.3 [M+H], Tr=5.89 min.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][C:4]1[N:8]=[CH:7][NH:6][CH:5]=1.[CH:9](=O)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.CO.[BH4-].[Na+]>CCO>[CH2:9]([NH:1][CH2:2][CH2:3][C:4]1[NH:8][CH:7]=[N:6][CH:5]=1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: O=Cc1ccccc1
Reactant: NCCc1c[nH]cn1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: CCO
Product: c1ccc(CNCCc2cnc[nH]2)cc1

Procedure:
Compound XIIIA is prepared by treatment of a mixture of compound XIIA, histamine, and benzaldehyde in a solvent such as MeOH or EtOH, with a reducing agent such as NaBH4 to provide N-benzyl-2-(1H-imidazol-5-yl)ethanamine (compound not shown). To this compound in water at 0° C., is added KOH followed by acetaldehyde. After approximately six hours at 80° C. followed by treatment with acid, compound XIIIA, PG=Bn, is isolated. Trifluoromethyl derivative XIVA is also prepared from compound XIIA. To a solution of compound XIIA in a solvent such as water at a temperature of about 0° C., is added a base such as KOH along with trifluoroacetaldehyde. After heating at a temperature of approximately 80° C. for approximately 6 hours and acidification, compound XIVA is isolated.
Reaction SMILES: C([O:8][C:9]1[CH:42]=[CH:41][C:12]([C:13]2[O:14][C:15]3[C:20]([C:21](=[O:40])[C:22]=2OC(CCCCC(OCC2C=CC=CC=2)=O)=O)=[CH:19][CH:18]=[CH:17][CH:16]=3)=[CH:11][CH:10]=1)C1C=CC=CC=1.[H][H]>C1COCC1.C(O)C.CC(O)=O.[OH-].[OH-].[Pd+2]>[OH:8][C:9]1[CH:10]=[CH:11][C:12]([C:13]2[O:14][C:15]3[C:20]([C:21](=[O:40])[CH:22]=2)=[CH:19][CH:18]=[CH:17][CH:16]=3)=[CH:41][CH:42]=1
Reactant: [H][H]
Reactant: O=C(CCCCC(=O)Oc1c(-c2ccc(OCc3ccccc3)cc2)oc2ccccc2c1=O)OCc1ccccc1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: O=c1cc(-c2ccc(O)cc2)oc2ccccc12
Yield: 88.6 %

Procedure:
A mixture of the 4′-(benzyloxy)-3-(benzyloxycarbonyl butylcarbonyloxy) flavone (400 mg, 0.711 mmol) and Pd(OH)2 (56 mg) in THF (10 mL), ethanol (1.2 mL) and AcOH (100 μL) was treated with hydrogen (50 psi) for 18 h. The reaction mixture was then filtered (Celite) and the pad washed with THF. The filtrate was concentrated and the solid residue was purified by flash chromatography (70% THF/toluene+1% AcOH) and the resultant solid recrystallised from THF/petrol to afford the acid as a colourless solid (150 mg, 55%); mp 177-180° C.; 1H NMR (500 MHz, d6-DMSO) δ 1.56-1.66 (m, 4H, CH2CH2), 2.25 (t, 2H, J=7.0 Hz, CH2CO), 2.64 (t, 2H, J=7.0 Hz, CH2CO), 6.96 (app. d, 2H, J=8.5 Hz, H2′,6′), 7.52 (t, 1H, J6,7=J7,8=7.5 Hz, H7), 7.80 (app. d, 2H, J=7.5 Hz, H3′,5′), 7.78 (m, 1H, H8), 7.85 (t, 1H, J5,6=J6,7=7.5 Hz, H6), 8.06 (d, 1H, J5,6=8.0 Hz, H5); 13C NMR (125 MHz, d6-DMSO) δ 23.8, 23.9, 32.9, 33.3 (4C, CH2), 115.9, 118.5, 119.7, 122.7, 125.0, 125.6, 130.1, 131.9, 134.5, 154.9, 155.8 160.6 (Ar), 170.4 170.9, 174.3 (3C, C═O); IR 3257, 2944, 2869, 1765, 1706, 1595, 854 cm−1; HRMS (ESI+) m/z 383.1123, C21H19O7 [M+H]+ requires 383.1131.
Reaction SMILES: [H-].[Na+].COC1C=CC(CCN2CCC[C@H]2C[N:17]2[C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=3[CH2:21][S:20][C:19]3[CH:28]=[CH:29][CH:30]=[CH:31][C:18]2=3)=CC=1.[CH3:34][C:35]1[CH:40]=[CH:39][C:38]([S:41]([N:44]2[CH2:48][CH2:47][CH2:46][C@H:45]2[CH2:49]OS(C2C=CC(C)=CC=2)(=O)=O)(=[O:43])=[O:42])=[CH:37][CH:36]=1>CN(C)C=O>[CH3:34][C:35]1[CH:36]=[CH:37][C:38]([S:41]([N:44]2[CH2:48][CH2:47][CH2:46][C@H:45]2[CH2:49][N:17]2[C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=3[CH2:21][S:20][C:19]3[CH:28]=[CH:29][CH:30]=[CH:31][C:18]2=3)(=[O:42])=[O:43])=[CH:39][CH:40]=1
Reactant: COc1ccc(CCN2CCC[C@H]2CN2c3ccccc3CSc3ccccc32)cc1
Reactant: Cc1ccc(S(=O)(=O)OC[C@@H]2CCCN2S(=O)(=O)c2ccc(C)cc2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1ccc(S(=O)(=O)N2CCC[C@H]2CN2c3ccccc3CSc3ccccc32)cc1
Temperature: 60 °C
Yield: 22.4 %

Procedure:
Sodium hydride (80% dispersion in oil, 40 mg) was added to a solution of 5,11-dihydrodibenzo[b,e][1,4]thiazepine (see Example 1 for source) (213 mg) in dimethylformamide (10 ml) and the mixture heated at 60° C. for 45 minutes, treated with a solution of (S)-1-(4-methylphenylsulphonyl)-2-(4-methylphenylsulphonyloxymethyl)pyrrolidine (see Preparation 15 for source) (440 mg) in dimethylformamide (5 ml), heated at 60° C. for 7 hours and evaporated under reduced pressure. The residue was partitioned between ethyl acetate and water and the organic layer washed with water, dried over sodium sulphate and evaporated under reduced pressure. The residue was purified by chromatography on silica gel, performing a gradient elution initially using hexane as eluant and changing to hexane/ethyl acetate (60:40). Appropriate fractions were combined and evaporated under reduced pressure to give the title compound as a colourless oil, (50 mg, 24%).
Reaction SMILES: [C:1]1(C)[CH:6]=[CH:5][C:4]([S:7]([OH:10])(=[O:9])=[O:8])=[CH:3][CH:2]=1.[NH2:12][C:13]1[S:14][CH:15]=[C:16](/[C:18](=[N:46]/[OH:47])/[C:19]([NH:21][CH:22]2[C:44](=[O:45])[N:24]3[C:25]([C:32]([O:34][CH:35]([O:37][C:38](=[O:43])[C:39]([CH3:42])([CH3:41])[CH3:40])[CH3:36])=[O:33])=[C:26]([CH2:29][O:30][CH3:31])[CH2:27][S:28][C@H:23]23)=[O:20])[N:17]=1.C(OC(C)C)(C)C>CC(C)=O>[C:3]1([CH3:13])[C:4]([S:7]([OH:10])(=[O:8])=[O:9])=[CH:5][CH:6]=[CH:1][CH:2]=1.[NH2:12][C:13]1[S:14][CH:15]=[C:16](/[C:18](=[N:46]/[OH:47])/[C:19]([NH:21][CH:22]2[C:44](=[O:45])[N:24]3[C:25]([C:32]([O:34][CH:35]([O:37][C:38](=[O:43])[C:39]([CH3:41])([CH3:42])[CH3:40])[CH3:36])=[O:33])=[C:26]([CH2:29][O:30][CH3:31])[CH2:27][S:28][C@H:23]23)=[O:20])[N:17]=1
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Agent: COCC1=C(C(=O)OC(C)OC(=O)C(C)(C)C)N2C(=O)C(NC(=O)/C(=N\O)c3csc(N)n3)[C@H]2SC1
Solvent: CC(C)=O
Solvent: CC(C)OC(C)C
Product: Cc1ccccc1S(=O)(=O)O

Procedure:
A solution of 1.8 g (15 mmol) of p-toluenesulfonic acid in 5 ml of acetone was added dropwise to a solution of 5 g (9.3 mmol) of α-(2,2-dimethylpropanoyloxy)ethyl 7-[2-(2-aminothiazol-4-yl)-2-(Z)-hydroxyimino-acetamido]-3-methoxymethyl-3-cephem-4-carboxylate in 35 ml of acetone. After stirring briefly, a thick precipitate formed. After stirring for 15 minutes, a total of 185 ml of diisopropyl ether were slowly added dropwise to complete crystallization and the mixture was stirred for a short time. The precipitate was then filtered off with suction, washed with a little diisopropyl ether and dried in vacuo over calcium chloride/paraffin. 5.9 g of crystalline title compound were obtained, which consisted of an approximately 1:1 mixture of the two diastereomers according to HPLC and was identical in its physical and chemical properties with the product from working example 2.
Reaction SMILES: [OH-].[K+].[CH:3]1([CH2:9]Br)[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]1.[Cl:11][C:12]1[CH:30]=[CH:29][C:15]([O:16][CH2:17][C:18]([CH3:28])([CH3:27])[C:19](=[O:26])[CH2:20][N:21]2[CH:25]=[N:24][CH:23]=[N:22]2)=[CH:14][CH:13]=1>O.CS(C)=O>[Cl:11][C:12]1[CH:13]=[CH:14][C:15]([O:16][CH2:17][C:18]([CH3:27])([CH3:28])[C:19](=[O:26])[CH:20]([N:21]2[CH:25]=[N:24][CH:23]=[N:22]2)[CH2:9][CH:3]2[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]2)=[CH:29][CH:30]=1
Reactant: BrCC1CCCCC1
Reactant: CC(C)(COc1ccc(Cl)cc1)C(=O)Cn1cncn1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CS(C)=O
Product: CC(C)(COc1ccc(Cl)cc1)C(=O)C(CC1CCCCC1)n1cncn1
Temperature: 25 °C
Reaction time: 15 h
Yield: 47.7 %

Procedure:
First 5.6 g of potassium hydroxide in 12 ml of water and then 17.7 g (0.1 mol) of cyclohexylmethylbromide in 5 ml of dimethylsulphoxide were added dropwise to 29.3 g (0.1 mol) of 1-(4-chlorophenoxy)-2,2-dimethyl-4-(1,2,4-triazol-1-yl)-butan-3-one (prepared as described in Example 3) in 100 ml of dimethylsulphoxide at 20° C. The reaction mixture was subsequently stirred at room temperature for 15 hours, poured into 200 ml of water and extracted with 200 ml of methylene chloride. The organic phase was washed three times with 100 ml of water each time, dried over sodium sulphate and concentrated by distilling off the solvent. The residue was taken up in 100 ml of ether, whereupon the product crystallized out. 18.6 g (47% of theory) of 1-(4-chlorophenoxy)-5-cyclohexyl-2,2-dimethyl-4-(1,2,4-triazol-1-yl)-pentan-3-one of melting point 58°-60° C. were obtained.