Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[N:3]([C:7]2[CH:8]=[C:9]([NH2:17])[CH:10]=[C:11]([C:13]([F:16])([F:15])[F:14])[CH:12]=2)[CH:4]=[CH:5][N:6]=1.CC1N=CN(C2C=C(N)C=C(C(F)(F)F)C=2)C=1.[N:35]1[CH:40]=[CH:39][CH:38]=[C:37]([C:41]2[CH:46]=[CH:45][N:44]=[C:43]([NH:47][C:48]3[CH:56]=[CH:55][C:51]([C:52](O)=[O:53])=[CH:50][CH:49]=3)[N:42]=2)[CH:36]=1>>[CH3:1][C:2]1[N:3]([C:7]2[CH:8]=[C:9]([NH:17][C:52](=[O:53])[C:51]3[CH:50]=[CH:49][C:48]([NH:47][C:43]4[N:42]=[C:41]([C:37]5[CH:36]=[N:35][CH:40]=[CH:39][CH:38]=5)[CH:46]=[CH:45][N:44]=4)=[CH:56][CH:55]=3)[CH:10]=[C:11]([C:13]([F:16])([F:14])[F:15])[CH:12]=2)[CH:4]=[CH:5][N:6]=1
Reactant: O=C(O)c1ccc(Nc2nccc(-c3cccnc3)n2)cc1
Reactant: Cc1nccn1-c1cc(N)cc(C(F)(F)F)c1
Agent: Cc1cn(-c2cc(N)cc(C(F)(F)F)c2)cn1
Product: Cc1nccn1-c1cc(NC(=O)c2ccc(Nc3nccc(-c4cccnc4)n3)cc2)cc(C(F)(F)F)c1

Procedure:
3-(2-methyl-imidazol-1-yl)-5 -trifluoromethyl-phenylamine prepared in Preparation 31 was used instead of 3-(4-methyl-imidazol-1-yl)-5-trifluoromethyl-phenylamine and 4-(4-pyridin-3-yl-pyrimidin-2-ylamino)-benzoic acid prepared in Preparation 19 according to the similar procedure to Example 1 to give the titled compound as pale white solid.
Reaction SMILES: C([N:3]([CH2:22][CH3:23])[CH:4]=[C:5]([C:11](=[O:21])[C:12]1[CH:17]=[C:16]([F:18])[C:15]([Cl:19])=[CH:14][C:13]=1[Cl:20])[C:6]([O:8][CH2:9][CH3:10])=[O:7])C.[CH:24]1(N)CC1>C1(C)C=CC=CC=1>[CH:22]1([NH:3][CH:4]=[C:5]([C:11](=[O:21])[C:12]2[CH:17]=[C:16]([F:18])[C:15]([Cl:19])=[CH:14][C:13]=2[Cl:20])[C:6]([O:8][CH2:9][CH3:10])=[O:7])[CH2:23][CH2:24]1
Reactant: CCOC(=O)C(=CN(CC)CC)C(=O)c1cc(F)c(Cl)cc1Cl
Reactant: NC1CC1
Solvent: Cc1ccccc1
Product: CCOC(=O)C(=CNC1CC1)C(=O)c1cc(F)c(Cl)cc1Cl
Yield: 77.1 %

Procedure:
17.5 g of ethyl 3-diethylamino-2-(2,4-dichloro-5-fluorobenzoyl)acrylate are heated to boiling under reflux with 2.9 g of cyclopropylamine and 50 ml of toluene for 30 minutes. The toluene is removed by distillation in vacuo, and the residue, which solidifies to crystals, is recrystallized from cyclohexane/light petroleum. 12.9 g of ethyl 3-cyclopropylamino-2-(2,4-dichloro-5-fluorobenzoyl)acrylate of melting point 89°-90° C. are obtained.
Reaction SMILES: C([SiH](CC)CC)C.[S:8]1[C:12]([CH:13]([C:15]2[CH:24]=[C:23]([Br:25])[C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[CH:16]=2)O)=[CH:11][C:10]2[CH:26]=[CH:27][CH:28]=[CH:29][C:9]1=2.CO.O>C(Cl)Cl>[Br:25][C:23]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH:16]=[C:15]([CH2:13][C:12]2[S:8][C:9]3[CH:29]=[CH:28][CH:27]=[CH:26][C:10]=3[CH:11]=2)[CH:24]=1
Reactant: OC(c1cc(Br)c2ccccc2c1)c1cc2ccccc2s1
Agent: CC[SiH](CC)CC
Solvent: O
Solvent: CO
Solvent: ClCCl
Product: Brc1cc(Cc2cc3ccccc3s2)cc2ccccc12
Temperature: 25 °C
Reaction time: 3 h
Yield: 85.7 %

Procedure:
In a nitrogen stream, triethylsilane (0.48 ml, 3.01 mmol) and a boron trifluoride-diethyl ether complex (0.34 ml, 2.71 mmol) were added dropwise to a solution of (benzo[b]-thiophen-2-yl)-(4-bromonaphthalen-2-yl)methanol (1.0 g, 2.71 mmol) in methylene chloride (30 mL) at 0° C. The reaction mixture was stirred at room temperature for three hours, and then a 50% methanol aqueous solution (1 ml) was added and further water was added thereto and the mixture was extracted with methylene chloride. The organic layer was washed with a saturated sodium chloride aqueous solution and dried (anhydrous magnesium sulfate), and then the solvent was distilled under reduced pressure. The obtained residue was purified by silica gel column chromatography [developing solution=ethyl acetate:n-hexane (1:40)] to obtain the title compound (0.82 g, 85.6%).
Reaction SMILES: [C:1]([O:7][CH2:8][CH3:9])(=[O:6])[CH2:2][C:3]([CH3:5])=[O:4].[H-].[Na+].C([Li])CCC.[C:17]1([C:25]2[CH:30]=[CH:29]C=[CH:27][CH:26]=2)[CH:22]=[CH:21][C:20](C=O)=[CH:19][CH:18]=1>CCCCCC.O1CCCC1>[C:25]1([C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH:26]=[CH:27][C:9]([CH:8]2[O:7][C:1](=[O:6])[CH:2]=[C:3]([OH:4])[CH2:5]2)=[CH:29][CH:30]=1
Reactant: O=Cc1ccc(-c2ccccc2)cc1
Reactant: CCOC(=O)CC(C)=O
Agent: [H-]
Agent: [Li]CCCC
Agent: [Na+]
Solvent: CCCCCC
Solvent: C1CCOC1
Product: O=C1C=C(O)CC(c2ccc(-c3ccccc3)cc2)O1
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
The title compound was prepared as described in General Method 1 using 13.0 g of ethyl acetoacetate, 5.3 g of NaH 50% dispersion in oil, 60 mL of 1.6M n-butyl lithium in hexane, 16.3 g of 4-biphenylcarboxaldehyde and 300 mL of tetrahydrofuran. After addition of the aldehyde, the reaction was stirred for 15 minutes at 0° C. then allowed to warm to room temperature overnight. The crude product was triturated from diethyl ether to afford a solid (m.p. 150°-152° C.). 'H NMR (CDCl3) δ2.97 (dd, 2H), 3.60 (dd, 2H) 5.77 (dd, 1H), 7.27-7.68 (m, 9H).
Reaction SMILES: [CH2:1]([O:3][CH2:4][O:5][C:6](=[O:14])[C:7]1[CH:12]=[CH:11][C:10]([OH:13])=[CH:9][CH:8]=1)[CH3:2].[C:15]([O:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][O:26][C:27]1[CH:35]=[CH:34][C:30]([C:31](O)=[O:32])=[CH:29][CH:28]=1)(=[O:18])[CH:16]=[CH2:17]>ClCCl>[C:15]([O:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][O:26][C:27]1[CH:35]=[CH:34][C:30]([C:31]([O:13][C:10]2[CH:11]=[CH:12][C:7]([C:6]([O:5][CH2:4][O:3][CH2:1][CH3:2])=[O:14])=[CH:8][CH:9]=2)=[O:32])=[CH:29][CH:28]=1)(=[O:18])[CH:16]=[CH2:17]
Reactant: C=CC(=O)OCCCCCCOc1ccc(C(=O)O)cc1
Reactant: CCOCOC(=O)c1ccc(O)cc1
Solvent: ClCCl
Product: C=CC(=O)OCCCCCCOc1ccc(C(=O)Oc2ccc(C(=O)OCOCC)cc2)cc1
Temperature: 25 °C

Procedure:
To a solution of 42.2 g (0.20 mole) of 4-Hydroxy-benzoic acid ethoxymethyl ester (15) in 520 ml of dichloromethane were added 58.3 g (0.2 mole) of 4-(6-acryloyloxy-hexyloxy)-benzoic acid (5) and 2.4 g (0.02 mole) of 4-N,N-dimethylaminopyridine under N2 atmosphere. The mixture was cooled in an ice-water bath. After few minutes 41.15 g (0.2 mole) of N,N-dicyclohexyl carbodiimide were added. Then the ice-water bath was removed. It was stirred at room temperature under N2 for one night. Then the mixture was filtered and extracted twice with 300 ml of hydrochloric acid (2.4 M).
Reaction SMILES: [CH3:1][S:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:13]3=[N:14][C:15]([C:18]([NH:20][NH2:21])=[O:19])=[CH:16][CH:17]=[C:12]3[O:11][CH:10]=2)=[CH:5][CH:4]=1.[C:22](OCC)(OCC)(OCC)[CH3:23].N12CCCN=C1CCCCC2>C(O)CCC>[CH3:22][C:23]1[O:19][C:18]([C:15]2[N:14]=[C:13]3[C:9]([C:6]4[CH:7]=[CH:8][C:3]([S:2][CH3:1])=[CH:4][CH:5]=4)=[CH:10][O:11][C:12]3=[CH:17][CH:16]=2)=[N:20][N:21]=1
Reactant: CSc1ccc(-c2coc3ccc(C(=O)NN)nc23)cc1
Reactant: CCOC(C)(OCC)OCC
Solvent: CCCCO
Solvent: C1CCC2=NCCCN2CC1
Product: CSc1ccc(-c2coc3ccc(-c4nnc(C)o4)nc23)cc1
Yield: 68.2 %

Procedure:
A solution of 3-[4-(methylthio)phenyl]furo[3,2-b]pyridine-5-carbohydrazide (0.20 g, 0.68 mmol) and triethyl orthoacetate (0.27 mL, 1.49 mmol) in n-butanol (5 mL) was heated under reflux for 1.5 hr. 1,8-Diazabicyclo[5.4.0]undec-7-ene (0.10 mL, 0.68 mmol) was added to the reaction mixture, and the mixture was further heated under reflux overnight. After cooling, the precipitate was collected by filtration and recrystallized from hexane/ethyl acetate to give the title compound (0.15 g, yield 67%) as colorless crystals.
Reaction SMILES: [C:1]([C:9]1[CH:14]=[C:13]([Cl:15])[CH:12]=[CH:11][C:10]=1[N:16]([CH:31]=[N:32][NH:33]C(=O)CN1C(=O)C2C(=CC=CC=2)C1=O)[C:17](=O)[CH2:18][N:19]1[C:27](=[O:28])[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[C:20]1=[O:29])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.FC(F)(F)C(O)=O>C1(C)C=CC=CC=1>[Cl:15][C:13]1[CH:12]=[CH:11][C:10]([N:16]2[CH:31]=[N:32][N:33]=[C:17]2[CH2:18][N:19]2[C:20](=[O:29])[C:21]3=[CH:22][CH:23]=[CH:24][CH:25]=[C:26]3[C:27]2=[O:28])=[C:9]([CH:14]=1)[C:1]([C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)=[O:8]
Reactant: O=C(CN1C(=O)c2ccccc2C1=O)NN=CN(C(=O)CN1C(=O)c2ccccc2C1=O)c1ccc(Cl)cc1C(=O)c1ccccc1
Solvent: Cc1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: O=C(c1ccccc1)c1cc(Cl)ccc1-n1cnnc1CN1C(=O)c2ccccc2C1=O
Yield: 6.6 %

Procedure:
A stirred mixture of 1,3-dioxo-2-isoindolineacetic acid, [[N-(2-benzoyl-4-chlorophenyl)-1,3-dioxo-2-isoindolineacetamido]methylene]hydrazide (8.0 g, 0.0123 mole) and toluene (200 ml) is treated with trifluoroacetic acid (0.9 ml) and heated to 100°-110°C for 1.5 hours. The mixture is concentrated in vacuo, and the residue is mixed with cold water and chloroform and made alkaline with aqueous sodium hydroxide. This mixture is extracted with chloroform; the extract is washed with brine, dried over anhydrous sodium sulfate and concentrated. The residue is chromatographed on silica gel (400 g) with 1.5% methanol-98.5% chloroform. The product thus obtained is crystallized from methylene chloride-methanol to give: 2.54 g, melting point 228°- 228.5°C. and 0.361 g, melting point 229°-230°C. (53% yield) of 5-chloro-2-[3-(phthalimidomethyl)-4H-1,2,4-triazol-4-yl]benzophenone. The analytical sample has a melting point 229.5°-230.5°.
Reaction SMILES: [CH2:1]([N:5]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][N:13]=2)[C:8]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([C:21]#[C:22][CH2:23][CH2:24][N:25]3C(=O)C4=CC=CC=C4C3=O)[CH:16]=2)=[C:7]([NH:36][C:37]([NH:39][C:40]2[C:45]([CH:46]([CH3:48])[CH3:47])=[CH:44][CH:43]=[CH:42][C:41]=2[CH:49]([CH3:51])[CH3:50])=[O:38])[C:6]1=[O:52])[CH2:2][CH2:3][CH3:4].C(O)C.CN>C(O)C>[CH2:1]([N:5]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][N:13]=2)[C:8]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([C:21]#[C:22][CH2:23][CH2:24][NH2:25])[CH:16]=2)=[C:7]([NH:36][C:37]([NH:39][C:40]2[C:41]([CH:49]([CH3:50])[CH3:51])=[CH:42][CH:43]=[CH:44][C:45]=2[CH:46]([CH3:48])[CH3:47])=[O:38])[C:6]1=[O:52])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCn1c(=O)c(NC(=O)Nc2c(C(C)C)cccc2C(C)C)c(-c2cccc(C#CCCN3C(=O)c4ccccc4C3=O)c2)c2cccnc21
Agent: CN
Solvent: CCO
Product: CCCCn1c(=O)c(NC(=O)Nc2c(C(C)C)cccc2C(C)C)c(-c2cccc(C#CCCN)c2)c2cccnc21
Temperature: 25 °C
Yield: 80.6 %

Procedure:
To a solution of N-[1-butyl-4-{3-(4-phthalimido-1-butynyl)phenyl}-1,2-dihydro-2-oxo-1,8-naphthyridin-3-yl]-N'-(2,6-diisopropylphenyl)urea (50 mg, 0.072 mmol) in ethanol (1 ml) was added 30% methylamine ethanol solution (1.0 ml), and the mixture was stirred at room temperature. The mixture was concentrated under reduced pressure to remove the solvent, and the residue was purified by silica gel column chromatography (5% methanol in chloroform) to give the title compound (33 mg, 0.058 mmol).
Reaction SMILES: [CH2:1]([O:8][N:9]1[C:15](=[O:16])[N:14]2[CH2:17][C@H:10]1[CH2:11][CH2:12][C@H:13]2[C:18]([OH:20])=[O:19])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)([O-])O.[Na+].[CH2:26](Br)[CH:27]=[CH2:28].C(OCC)(=O)C>CN(C)C=O>[CH2:1]([O:8][N:9]1[C:15](=[O:16])[N:14]2[CH2:17][C@H:10]1[CH2:11][CH2:12][C@H:13]2[C:18]([O:20][CH2:28][CH:27]=[CH2:26])=[O:19])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C=CCBr
Reactant: O=C(O)[C@@H]1CC[C@@H]2CN1C(=O)N2OCc1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: C=CCOC(=O)[C@@H]1CC[C@@H]2CN1C(=O)N2OCc1ccccc1
Reaction time: 6.5 h
Yield: 14 %

Procedure:
46 mg of (2S,5R)-6-(benzyloxy)-7-oxo-1,6-diazabicyclo[3.2.1]octane-2-carboxylic acid was dissolved in N,N-dimethylformamide (0.5 mL), and 21 mg of sodium hydrogen carbonate and 30 μL of allyl bromide were added, followed by stirring for 6.5 hours. Ethyl acetate was added to the reaction solution, followed by sequential washing with water and saturated brine and drying over anhydrous sodium sulfate, and the solvent was concentrated under reduced pressure. The resulting residue was subjected to silica gel column chromatography (hexane/ethyl acetate=3/1) to afford 7.5 mg of the title compound as a colorless solid (yield 14%). The resulting solid was recrystallized from ethyl acetate-hexane, the generated precipitate was filtered off, the wet crystal was washed with hexane, and subsequently dried under reduced pressure at room temperature to afford the title compound as a colorless crystalline powder. Enantiomeric excess: 99.9% ee or more (CHIRALPAK AD-H, 4.6×150 mm, hexane/ethanol=2/1, UV 210 nm, flow rate 1 mL/min., retention time 8.0 minutes).
Reaction SMILES: [CH2:1]1[CH2:6][CH2:5][CH:4]([CH2:7][C@H:8]([NH2:12])[C:9]([OH:11])=[O:10])[CH2:3][CH2:2]1.[OH-].[Na+].Cl[C:16]1[O:17][C:18]2[CH:24]=[CH:23][CH:22]=[CH:21][C:19]=2[N:20]=1.Cl>CS(C)=O>[O:17]1[C:18]2[CH:24]=[CH:23][CH:22]=[CH:21][C:19]=2[N:20]=[C:16]1[NH:12][C@@H:8]([CH2:7][CH:4]1[CH2:3][CH2:2][CH2:1][CH2:6][CH2:5]1)[C:9]([OH:11])=[O:10]
Reactant: N[C@@H](CC1CCCCC1)C(=O)O
Reactant: Clc1nc2ccccc2o1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CS(C)=O
Product: O=C(O)[C@H](CC1CCCCC1)Nc1nc2ccccc2o1
Temperature: 25 °C

Procedure:
A slurry of L-cyclohexylalanine (2.44 g, 14.3 mmol) and powdered NaOH (1.14 g, 28.6 mmol) in DMSO (20 mL) was heated to 100° C. for 20 min until the mixture viscosity decreased and stirring was enabled. 2-Chlorobenzoxazole (1.99 g, 13.0 mmol) was added, and the solution was stirred at 100° C. for 4 h. Upon cooling to room temperature, the solution was poured into 1 M HCl. The precipitate was filtered and dried to afford 2-(S)-(benzooxazol-2-ylamino)-3-cyclohexyl propionic acid was isolated as a white powder (1.69 g, 41%). Step B. To a stirring solution of 2-(S)-(benzooxazol-2-ylamino)-3-cyclohexyl propionic acid (288 mg, 1.0 mmol), N1-(4-methoxy-phenyl)-ethane-1,2-diamine.2HCl (239 mg, 1.0 mmol), and iPr2NEt (0.87 mL, 5.0 mmol) in dichloromethane (4 mL) was added HATU (418 mg, 1.1 mmol). The solution was stirred at room temperature for 4 hours and then evaporated to dryness. The crude material was chromatographed over silica gel (Hexanes/EtOAc) to afford the title compound as a white powder (243 mg, 56%). HPLC-MS calcd. for C25H32N4O3 (M+H+) 437.25. found 437.5.
Reaction SMILES: C([N:4]1[CH2:9][CH2:8][CH:7]([CH2:10][C:11](=[O:21])[C:12]2[CH:17]=[CH:16][C:15]([N:18]([CH3:20])[CH3:19])=[CH:14][CH:13]=2)[CH2:6][CH2:5]1)(=O)C.[ClH:22]>>[ClH:22].[ClH:22].[CH3:20][N:18]([CH3:19])[C:15]1[CH:14]=[CH:13][C:12]([C:11]([CH2:10][CH:7]2[CH2:8][CH2:9][NH:4][CH2:5][CH2:6]2)=[O:21])=[CH:17][CH:16]=1
Reactant: CC(=O)N1CCC(CC(=O)c2ccc(N(C)C)cc2)CC1
Agent: Cl
Product: CN(C)c1ccc(C(=O)CC2CCNCC2)cc1
Temperature: 100 °C
Reaction time: 15 h

Procedure:
In 30 ml of concentrated hydrochloric acid was dissolved 1.73 g of the 1-acetyl-4-(4-dimethylaminobenzoylmethyl)piperidine prepared in Example 39 and the mixture was stirred at 100° C. for 15 hours. The solvent was then distilled off and the residue was recrystallized from ethanol-ethyl acetate to give 1.7 g of colorless crystals melting at 251°-255° C.
Reaction SMILES: [H-].[Na+].[CH3:3][N:4]([CH3:12])[S:5]([CH2:8][CH2:9][CH2:10][OH:11])(=[O:7])=[O:6].Cl[C:14]1[CH:15]=[CH:16][C:17]2[N:18]([N:20]=[CH:21][N:22]=2)[N:19]=1.Cl>CN(C)C=O>[CH3:3][N:4]([CH3:12])[S:5]([CH2:8][CH2:9][CH2:10][O:11][C:14]1[CH:15]=[CH:16][C:17]2[N:18]([N:20]=[CH:21][N:22]=2)[N:19]=1)(=[O:7])=[O:6]
Reactant: Clc1ccc2ncnn2n1
Reactant: CN(C)S(=O)(=O)CCCO
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CN(C)S(=O)(=O)CCCOc1ccc2ncnn2n1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 73.6 %

Procedure:
In 10 ml of dimethylformamide was suspended 0.252 g of 60% sodium hydride in oil followed by addition of 1.0 g of N,N-dimethyl-3-hydroxypropane-1-sulfonamide and the mixture was stirred under reduced pressure at room temperature for 30 minutes. Then, 0.928 g of 6-chloro[1,2,4]triazolo[1,5-b]pyridazine was added and the mixture was further stirred at room temperature for 1.5 hours. Following addition of 30 ml of ice water, the reaction mixture was adjusted to pH 4.0 with 1N-hydrochloric acid and the resulting crystals were collected by filtration and recrystallized from hot methanol to provide 1.255 g of the title compound. m.p. 151°-153° C.
Reaction SMILES: C([Li])CCC.[Br-].[OH:7][C:8]1[CH:33]=[CH:32][CH:31]=[CH:30][C:9]=1[CH2:10][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[C:34]([C:36]1[CH:57]=[CH:56][C:39]([CH2:40][CH:41]([CH:54]=O)[CH2:42][CH2:43][C:44]2[CH:53]=[CH:52][C:47]([C:48]([O:50][CH3:51])=[O:49])=[CH:46][CH:45]=2)=[CH:38][CH:37]=1)#[N:35].O>CCCCCC.C1COCC1>[C:34]([C:36]1[CH:37]=[CH:38][C:39]([CH2:40][CH:41](/[CH:54]=[CH:10]/[C:9]2[CH:30]=[CH:31][CH:32]=[CH:33][C:8]=2[OH:7])[CH2:42][CH2:43][C:44]2[CH:45]=[CH:46][C:47]([C:48]([O:50][CH3:51])=[O:49])=[CH:52][CH:53]=2)=[CH:56][CH:57]=1)#[N:35]
Reactant: Oc1ccccc1C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: COC(=O)c1ccc(CCC(C=O)Cc2ccc(C#N)cc2)cc1
Agent: [Br-]
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: O
Solvent: C1CCOC1
Product: COC(=O)c1ccc(CCC(/C=C/c2ccccc2O)Cc2ccc(C#N)cc2)cc1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
5.91 ml (9.45 mmol) of a 1.6 M solution of n-butyllithium in hexane are slowly added to a solution of 1820 mg (4.05 mmol) of (2-hydroxybenzyl)triphenylphosphonium bromide in 10 ml of anhydrous THF at 0° C. Then, at this temperature, 1085 mg (3.38 mmol) of methyl 4-[3-(4-cyanobenzyl)-4-oxobutyl]benzoate, dissolved in 10 ml of THF, are slowly metered in. After warming to room temperature, the reaction solution is stirred for 12 hours, then some water is added and the mixture is concentrated to dryness. The residue is taken up in ethyl acetate, washed with water and saturated sodium chloride solution and dried over sodium sulfate. After filtration, the solvent is concentrated to dryness. The resulting crude product is purified by flash chromatography on silica gel (mobile phase: cyclohexane/ethyl acetate 4:1→2:1). 1150 mg (2.79 mmol, 83% of theory) of a colorless solid are obtained.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:6][C:5]([C:13]#[N:14])=[C:4]([CH3:15])[N:3]=1.[CH2:16]([NH2:20])[CH2:17][CH2:18][CH3:19]>>[CH2:16]([NH:20][C:2]1[C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:6][C:5]([C:13]#[N:14])=[C:4]([CH3:15])[N:3]=1)[CH2:17][CH2:18][CH3:19]
Reactant: CCCCN
Reactant: CCOC(=O)c1cc(C#N)c(C)nc1Cl
Product: CCCCNc1nc(C)c(C#N)cc1C(=O)OCC

Procedure:
112 g of 2-chloro-5-cyano-6-methyl-3-pyridine-carboxylic acid, ethyl ester (0.5 mol) are dissolved in 300 ml of alcohol and 73 g of n-butylamine are dropped in at reflux temperature with stirring. After the addition is completed, the mixture is refluxed for an additional hour and then poured onto ice. 2-butylamino-5-cyano-6-methyl-3-pyridine-carboxylic acid, ethyl ester precipitates. Yield 116 g (89%); m.p. 61°-63° C. (petrol ether).
Reaction SMILES: [CH3:1][C:2]1([C:7]2[S:11][C:10]([CH2:12][N:13]3[CH:17]=[C:16]([NH2:18])[CH:15]=[N:14]3)=[CH:9][CH:8]=2)[O:6]CCO1.[C:19]1([CH3:33])[CH:24]=[CH:23][CH:22]=[C:21]([C:25]2[O:29][CH:28]=[N:27][C:26]=2[C:30](O)=[O:31])[CH:20]=1>>[C:2]([C:7]1[S:11][C:10]([CH2:12][N:13]2[CH:17]=[C:16]([NH:18][C:30]([C:26]3[N:27]=[CH:28][O:29][C:25]=3[C:21]3[CH:20]=[C:19]([CH3:33])[CH:24]=[CH:23][CH:22]=3)=[O:31])[CH:15]=[N:14]2)=[CH:9][CH:8]=1)(=[O:6])[CH3:1]
Reactant: Cc1cccc(-c2ocnc2C(=O)O)c1
Reactant: CC1(c2ccc(Cn3cc(N)cn3)s2)OCCO1
Product: CC(=O)c1ccc(Cn2cc(NC(=O)c3ncoc3-c3cccc(C)c3)cn2)s1

Procedure:
Following general procedure X followed by C, starting from 1-[5-(2-methyl-[1,3]dioxolan-2-yl)-thiophen-2-ylmethyl]-1H-pyrazol-4-ylamine and 5-m-tolyl-oxazole-4-carboxylic acid. LC-MS-conditions 05c: tR=0.72 min; [M+H]+=407.20.
Reaction SMILES: C(SCC1CS[C@@H]2C(NC(=O)C(C3N=C(N[C:29]([C:42]4[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=4)([C:36]4[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=4)[C:30]4[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=4)SC=3)=NOC)C(=O)N2C=1C(O)=O)(=O)C.C(O)=[O:51]>>[C:30]1([C:29]([C:42]2[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=2)([C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)[OH:51])[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1
Reactant: CON=C(C(=O)NC1C(=O)N2C(C(=O)O)=C(CSC(C)=O)CS[C@H]12)c1csc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Reactant: O=CO
Product: OC(c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 55 °C

Procedure:
A mixture of 4.58 g of the product of Example 16 and 30 ml of 50% aqueous formic acid was heated at 55° C. for 20 minutes and crystallization occured. The mixture was cooled and was diluted and stirred. The mixture was vacuum filtered and the product was rinsed and dried to obtain 1.257 g of triphenyl carbinol. The filtrate was evaporated to dryness under reduced pressure and the residue was taken up in water. Crystallization occured and the mixture was stirred for 30 minutes and was vacuum filtered. The solid was rinsed and dried to obtain 1.68 g of raw product. The latter was dissolved in 4 ml of a molar solution of sodium bicarbonate and the insolubles were ground up. The mixture was vacuum filtered and the filtrate was rinsed with water. 0.24 ml of acetic acid were added to the filtrate and the mixture was vacuum filtered. The precipitate was rinsed with water and dried to obtain 426 mg of purified product. 0.15 ml of formic acid were added to the filtrate and crystallization occured. The mixture was vacuum filtered and the product was rinsed with water and dried to obtain 505 mg of more pure anti isomer of 3-acetylthiomethyl-7-[{2-(2-amino-4-thiazolyl) -2-methoxyiminoacetyl}amino]-ceph-3-eme-4-carboxylic acid melting at 190° C.
Reaction SMILES: [CH3:1][N:2]1CC[O:5][CH2:4][CH2:3]1.[C:8]([O:12][C:13]([N:15]1[CH2:20][CH2:19][C:18](=[C:21]([Br:31])[C:22]2[CH:27]=[CH:26][C:25]([C:28](O)=[O:29])=[CH:24][CH:23]=2)[CH2:17][CH2:16]1)=[O:14])([CH3:11])([CH3:10])[CH3:9].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.CNCCO>CN(C=O)C.CCOC(C)=O>[C:8]([O:12][C:13]([N:15]1[CH2:20][CH2:19][C:18](=[C:21]([Br:31])[C:22]2[CH:27]=[CH:26][C:25]([C:28](=[O:29])[N:2]([CH2:3][CH2:4][OH:5])[CH3:1])=[CH:24][CH:23]=2)[CH2:17][CH2:16]1)=[O:14])([CH3:9])([CH3:10])[CH3:11]
Reactant: CN1CCOCC1
Reactant: CC(C)(C)OC(=O)N1CCC(=C(Br)c2ccc(C(=O)O)cc2)CC1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: CNCCO
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CN(CCO)C(=O)c1ccc(C(Br)=C2CCN(C(=O)OC(C)(C)C)CC2)cc1
Reaction time: 0.17 h
Yield: 772 %

Procedure:
N-Methylmorpholine (6.7 mL, 60 6 mmol) and 4-[bromo-(4-carboxy-phenyl)-methylene]-piperidine-1-carboxylic acid tert-butyl ester (prepared as for compound 5 in WO2001074806) (20.0 g, 50.5 mmol) in DMF (240 mL) were treated with TBTU (17.8 g, 55.6 mmol) under nitrogen. After stirring for 10 min., 2-(methylamino)ethanol (5.3 mL, 65.7 mmol) was added and the solution stirred for 2 h. The reaction was diluted with EtOAc (350 mL), washed with 2% citric acid, 3% NaHCO3, and brine. The aq. washes were extracted with EtOAc (50 mL). The combined organic phases were dried over Na2SO4 then concentrated in vacuo to a solid. After stirring in hexanes for 5 h, the white solid was collected by filtration and dried under high vacuum to afford 21.0 g (92%) of 1A. 1H NMR (500.333 MHz, CDCl3) δ 7.44 (d, J=8.0 Hz, 2H), 7.32 (d, J=8.0 Hz, 2H), 3.91 (br s, 2H), 3.74 (br s, 2H), 3.54 (t, J=5.8 Hz, 3H), 3.34 (t, J=5.7 Hz, 2H), 3.09 (s, 3H), 3.01 (br s, 1H), 2.64 (t, J=5.9 Hz, 2H), 2.23 (t, J=5.8 Hz, 2H), 1.47 (s, 9H). MS ES+ 453.1.
Reaction SMILES: [F:1][C:2]1[CH:22]=[C:21](I)[CH:20]=[CH:19][C:3]=1[NH:4][C:5]1[C:6]([C:12]([NH:14][CH2:15][CH2:16][CH2:17][OH:18])=[O:13])=[CH:7][NH:8][C:9](=[O:11])[CH:10]=1.[Si:24]([C:28]#[CH:29])([CH3:27])([CH3:26])[CH3:25]>C1COCC1.CN(C=O)C.[Cu]I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[F:1][C:2]1[CH:22]=[C:21]([C:29]#[C:28][Si:24]([CH3:27])([CH3:26])[CH3:25])[CH:20]=[CH:19][C:3]=1[NH:4][C:5]1[C:6]([C:12]([NH:14][CH2:15][CH2:16][CH2:17][OH:18])=[O:13])=[CH:7][NH:8][C:9](=[O:11])[CH:10]=1
Reactant: C#C[Si](C)(C)C
Reactant: O=C(NCCCO)c1c[nH]c(=O)cc1Nc1ccc(I)cc1F
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: C[Si](C)(C)C#Cc1ccc(Nc2cc(=O)[nH]cc2C(=O)NCCCO)c(F)c1
Yield: 94 %

Procedure:
4-(2-Fluoro-4-iodoanilino)-N-(3-hydroxypropyl)-6-oxo-1,6-dihydro-3-pyridinecarboxamide was reacted with TMS-acetylene in the presence of CuI, (Ph3P)2PdCl2 and TEA in THF/DMF (1:1) as for example 2. The residue resulting from removal of the reaction solvents under reduced pressure was purified by column chromatography on silica gel (10% MeOH/CH2Cl2 as eluant) to give 4-{2-fluoro-4-[(trimethylsilyl)ethynyl]anilino}-N-(3-hydroxypropyl)-6-oxo-1,6-dihydro-3-pyridinecarboxamide as an off-white solid (94%), used directly in the next step. 1H NMR [(CD3)2SO, 400 MHz] δ 11.48 (br s, 1H), 10.50 (s, 1H), 8.49 (t, J=5.4 Hz, 1H), 7.93 (s, 1H), 7.49 (t, J=8.5 Hz, 1H), 7.43 (dd, J=11.5, 1.8 Hz, 1H), 7.30 (dd, J=8.3, 1.5 Hz, 1H), 5.66 (s, 1H), 4.46 (t, J=5.1 Hz, 1H), 3.45 (q, J=5.9 Hz, 2H), 3.25 (q, J=6.5 Hz, 2H), 1.65 (pentet, J=6.7 Hz, 2H), 0.23 (s, 9H). HRMS (FAB+) calcd C20H25FN3O3Si (MH+) 402.1649, found 402.1649.