Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1](=P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[CH3:2].[CH3:22][O:23][C:24]1[CH:25]=[C:26]([C:32](=O)[C:33]([O:35][CH2:36][CH3:37])=[O:34])[CH:27]=[CH:28][C:29]=1[O:30][CH3:31]>[Br-].C([P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)C.CCOCC>[CH3:22][O:23][C:24]1[CH:25]=[C:26](/[C:32](=[CH:1]\[CH3:2])/[C:33]([O:35][CH2:36][CH3:37])=[O:34])[CH:27]=[CH:28][C:29]=1[O:30][CH3:31]
Reactant: CCOC(=O)C(=O)c1ccc(OC)c(OC)c1
Reactant: CC=P(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: CC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Solvent: CCOCC
Product: C/C=C(/C(=O)OCC)c1ccc(OC)c(OC)c1

Procedure:
To a diethyl ether solution of ethylidenetriphenylphosphorane prepared in the usual way from 800 g. of ethyltriphenylphosphonium bromide, 400 g. of ethyl 3,4-dimethoxyphenylglyoxylate in 600 ml. of ether are added dropwise. After refluxing for 4-5 hours, the solvent is evaporated and substituted with tetrahydrofuran. The mixture is then heated for 36 hours and then evaporated to dryness and the residue is extracted with diethyl ether in a Soxhlet apparatus giving 150 g. of the title compound. Pursuant to this procedure, the following other α-arylcrotonate starting materials are prepared:
Reaction SMILES: B1([O-])OO1.[OH2:5].O.O.O.[Na+].[N:10]1([CH2:16][CH2:17][CH2:18][O:19][C:20]2[CH:25]=[CH:24][C:23]([C:26]3([C:32]#[N:33])[CH2:31][CH2:30][O:29][CH2:28][CH2:27]3)=[CH:22][CH:21]=2)[CH2:15][CH2:14][S:13][CH2:12][CH2:11]1>C(O)(=O)C>[O:5]=[S:13]1[CH2:14][CH2:15][N:10]([CH2:16][CH2:17][CH2:18][O:19][C:20]2[CH:21]=[CH:22][C:23]([C:26]3([C:32]#[N:33])[CH2:31][CH2:30][O:29][CH2:28][CH2:27]3)=[CH:24][CH:25]=2)[CH2:11][CH2:12]1
Reactant: O
Reactant: N#CC1(c2ccc(OCCCN3CCSCC3)cc2)CCOCC1
Agent: [Na+]
Agent: [O-]B1OO1
Solvent: CC(=O)O
Product: N#CC1(c2ccc(OCCCN3CCS(=O)CC3)cc2)CCOCC1
Temperature: 25 °C
Yield: 57.9 %

Procedure:
Sodium perborate tetrahydrate (221 mg, 1.43 mmol) and glacial acetic acid (5 ml) was heated to 50 to 60° C. and 4-[4-(3-Thiomorpholin-4-ylpropoxy)phenyl]tetrahydropyran-4-carbonitrile (500 mg, 1.43 mmol) was added in one portion and the heating was maintained for 3 hours. The reaction mixture was cooled to ambient temperature and filtered. The filtrate was added to ice water (15 ml) and extracted with EtOAc (3×5 ml), which was discarded. The aqueous phase was basified to pH 8-9 with 2M sodium hydroxide and extracted with DCM (3×25 ml), dried over MgSO4, filtered and concentrated in vacuo at 35° C. The crude material was subjected to chromatography on silica eluting with DCM:MeOH:NH3 (97:2:1 to 92:6:2) to provided the title compound (300 mg, 58%) as a white solid. 1H NMR (400 MHz, CDCl3), δ 7.38 (d, 2H), 6.92 (d, 2H), 4.11-4.05 (m, 2H), 4.03 (t, 2H), 3.89 (td, 2H), 3.15-3.03 (m, 2H), 2.94-2.67 (m, 6H), 2.63 (t, 2H), 2.16-1.92 (m, 6H).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([N:10]([CH3:12])[CH3:11])[CH:9]=1)[C:5]#[N:6].C(NCBr)(O[C:16](C)([CH3:18])[CH3:17])=O>>[CH3:11][N:10]([CH3:12])[C:8]1[CH:7]=[C:4]([CH:3]=[C:2]([C:16]([CH3:18])=[CH2:17])[CH:9]=1)[C:5]#[N:6]
Reactant: CC(C)(C)OC(=O)NCBr
Reactant: CN(C)c1cc(Br)cc(C#N)c1
Product: C=C(C)c1cc(C#N)cc(N(C)C)c1

Procedure:
3-(dimethylamino)-5-(prop-1-en-2-yl)benzonitrile was synthesized from 3-bromo-5-(dimethylamino)benzonitrile following the general procedure as described for the Cbz protected Boc aminomethyl bromide.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH:12]=[C:11]([CH2:14][NH:15][C:16]([C:18]2[N:19]=[N:20][C:21]([CH2:37][CH2:38][CH2:39][CH3:40])=[C:22]([C:24]3[CH:29]=[CH:28][C:27]([O:30][CH:31]4[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]4)=[CH:26][CH:25]=3)[CH:23]=2)=[O:17])[CH2:10][CH2:9]1)=O)(C)(C)C.[ClH:41]>C(Cl)Cl.O1CCOCC1>[ClH:41].[ClH:41].[NH:8]1[CH2:9][CH:10]=[C:11]([CH2:14][NH:15][C:16]([C:18]2[N:19]=[N:20][C:21]([CH2:37][CH2:38][CH2:39][CH3:40])=[C:22]([C:24]3[CH:25]=[CH:26][C:27]([O:30][CH:31]4[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]4)=[CH:28][CH:29]=3)[CH:23]=2)=[O:17])[CH2:12][CH2:13]1
Reactant: CCCCc1nnc(C(=O)NCC2=CCN(C(=O)OC(C)(C)C)CC2)cc1-c1ccc(OC2CCCCC2)cc1
Agent: Cl
Solvent: C1COCCO1
Solvent: ClCCl
Product: CCCCc1nnc(C(=O)NCC2=CCNCC2)cc1-c1ccc(OC2CCCCC2)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 4-({[6-butyl-5-(4-cyclohexyloxy-phenyl)-pyridazine-3-carbonyl]-amino}-methyl)-3,6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester (70 mg) in DCM (2 mL) was added 4 N HCl in dioxane (1.0 mL) at 0° C., and the reaction was stirred for 1 h at room temperature. The volatiles were removed under reduced pressure, and the residue was triturated with anhydrous ethyl ether and dried under high vacuum to provide 6-butyl-5-(4-cyclohexyloxy-phenyl)-pyridazine-3-carboxylic acid (1,2,3,6-tetrahydro-pyridin-4-ylmethyl)-amide dihydrochloride.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C:9]1[N:13]([CH3:14])[N:12]=[C:11]([O:15][CH3:16])[C:10]=1[CH:17]=[O:18].[F:19][C:20]1[CH:25]=[CH:24][C:23]([Mg]Br)=[C:22]([CH3:28])[CH:21]=1>O1CCCC1>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C:9]1[N:13]([CH3:14])[N:12]=[C:11]([O:15][CH3:16])[C:10]=1[CH:17]([C:23]1[CH:24]=[CH:25][C:20]([F:19])=[CH:21][C:22]=1[CH3:28])[OH:18]
Reactant: Cc1cc(F)ccc1[Mg]Br
Reactant: COc1nn(C)c(-c2c(F)cccc2F)c1C=O
Solvent: C1CCOC1
Product: COc1nn(C)c(-c2c(F)cccc2F)c1C(O)c1ccc(F)cc1C
Temperature: 0 °C
Yield: 83.6 %

Procedure:
To a mixture of 5-(2,6-difluorophenyl)-3-methoxy-1-methyl-1H-pyrazole-4-carboxaldehyde (0.25 g, 0.99 mmol) (i.e. the product of Step D) in tetrahydrofuran (5 mL) at −30° C. was added 4-fluoro-2-methylphenylmagnesium bromide (0.5 M in hexanes, 2.0 mL, 1.0 mmol). The reaction mixture was allowed to warm to 0° C., quenched with saturated ammonium chloride solution and concentrated under reduced pressure. The resulting material was diluted with dichloromethane and water, poured onto a solid phase extraction tube (Varian Chem Elute®, prepacked with diatomaceous earth) and eluted with dichloromethane. The dichloromethane eluant was concentrated under reduced pressure and the resulting material purified by silica gel chromatography (0 to 100% gradient of ethyl acetate in dichloromethane as eluant) to provide the title compound (0.3 g).
Reaction SMILES: [C:1](Cl)(Cl)=[S:2].C(=O)([O-])[O-].[Ca+2].[CH2:10]([O:17][C:18]1[CH:24]=[CH:23][C:21]([NH2:22])=[CH:20][CH:19]=1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>ClCCl.O>[CH2:10]([O:17][C:18]1[CH:19]=[CH:20][C:21]([N:22]=[C:1]=[S:2])=[CH:23][CH:24]=1)[C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1
Reactant: Nc1ccc(OCc2ccccc2)cc1
Reactant: S=C(Cl)Cl
Agent: O=C([O-])[O-]
Agent: [Ca+2]
Solvent: O
Solvent: ClCCl
Product: S=C=Nc1ccc(OCc2ccccc2)cc1
Temperature: 15 °C
Reaction time: 4 h

Procedure:
Thiophosgene (12.63 g) was added at 0° C. to a stirred suspension of calcium carbonate (11.05 g) in a mixture of dichloromethane (100 ml) and water (100 ml). A solution of p-benzyloxyaniline (16.5 g) in dichloromethane (100 ml) was added dropwise at 0° C. over 30 minutes. The mixture was stirred for four hours at 15° C. The organic layer was separated, dried and the solvent removed by evaporation to give a residue which was extracted into boiling hexane to give 4-benzyloxyphenylisothiocyanate (m.p. 69° C.).
Reaction SMILES: FC(F)(F)C(O)=O.ClCCl.O1CCCCC1[N:17]1[C:25]2[C:20](=[CH:21][C:22]([NH:26][C:27]3[CH:39]=[CH:38][C:30]([C:31]([O:33]C(C)(C)C)=[O:32])=[CH:29][CH:28]=3)=[CH:23][CH:24]=2)[CH:19]=[N:18]1.C(=O)([O-])O.[Na+]>C(OCC)(=O)C>[NH:17]1[C:25]2[C:20](=[CH:21][C:22]([NH:26][C:27]3[CH:39]=[CH:38][C:30]([C:31]([OH:33])=[O:32])=[CH:29][CH:28]=3)=[CH:23][CH:24]=2)[CH:19]=[N:18]1
Reactant: CC(C)(C)OC(=O)c1ccc(Nc2ccc3c(cnn3C3CCCCO3)c2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: O=C(O)c1ccc(Nc2ccc3[nH]ncc3c2)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 34.9 %

Procedure:
Trifluoroacetic acid (5 ml) was added to a dichloromethane solution (5 ml) of tert-butyl 4-{1-(2-tetrahydropyranyl)-1H-indazol-5-ylamino}benzoate (205 mg, 0.521 mmol), and the resulting mixture was stirred at room temperature for 3 hours. The mixture was added dropwise to saturated aqueous sodium hydrogencarbonate solution/ethyl acetate and then extracted with ethyl acetate. The extract solution was washed with a saturated aqueous sodium chloride solution, dried over sodium sulfate, and then distilled under reduced pressure to remove the solvent, whereby a crude product was obtained. The crude product was washed by the addition of chloroform containing a small amount of methanol, and then was collected by filtration to obtain 4-(1H-indazole-5-ylamino)benzoic acid (46 mg, 35%).
Reaction SMILES: Br[C:2]1[N:6]([CH:7]([CH3:9])[CH3:8])[C:5]2[CH:10]([C:22]3[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][CH:23]=3)[N:11]([CH:14]3[CH2:19][CH2:18][C:17](=[O:20])[N:16]([CH3:21])[CH2:15]3)[C:12](=[O:13])[C:4]=2[CH:3]=1.[CH3:29][O:30][C:31]1[C:36](B2OC(C)(C)C(C)(C)O2)=[CH:35][N:34]=[C:33]([NH2:46])[N:32]=1.BrC1N(C(C)C)C2C(C3C=CC(Cl)=CC=3)N(C3C=C(Cl)C=CC=3C)C(=O)C=2C=1.C(C1C=CC(OC)=C(B(O)O)C=1)#N>>[NH2:46][C:33]1[N:32]=[C:31]([O:30][CH3:29])[C:36]([C:2]2[N:6]([CH:7]([CH3:9])[CH3:8])[C:5]3[CH:10]([C:22]4[CH:23]=[CH:24][C:25]([Cl:28])=[CH:26][CH:27]=4)[N:11]([CH:14]4[CH2:19][CH2:18][C:17](=[O:20])[N:16]([CH3:21])[CH2:15]4)[C:12](=[O:13])[C:4]=3[CH:3]=2)=[CH:35][N:34]=1
Reactant: COc1nc(N)ncc1B1OC(C)(C)C(C)(C)O1
Reactant: CC(C)n1c(Br)cc2c1C(c1ccc(Cl)cc1)N(C1CCC(=O)N(C)C1)C2=O
Agent: COc1ccc(C#N)cc1B(O)O
Agent: Cc1ccc(Cl)cc1N1C(=O)c2cc(Br)n(C(C)C)c2C1c1ccc(Cl)cc1
Product: COc1nc(N)ncc1-c1cc2c(n1C(C)C)C(c1ccc(Cl)cc1)N(C1CCC(=O)N(C)C1)C2=O

Procedure:
The title compound was prepared in analogy to the procedure described for Example 17 but 2-bromo-6-(4-chloro-phenyl)-1-isopropyl-5-(1-methyl-6-oxo-piperidin-3-yl)-5,6-dihydro-1H-pyrrolo[3,4-b]pyrrol-4-one (Intermediate Q) and 4-methoxy-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyrimidin-2-ylamine (Intermediate U) were used instead of 2-bromo-5-(5-chloro-2-methyl-phenyl)-6-(4-chloro-phenyl)-1-isopropyl-5,6-dihydro-1H-pyrrolo[3,4-b]pyrrol-4-one and 5-cyano-2-methoxyphenylboronic acid respectively. The title compound was obtained as a beige solid. tR: 2.35 min (HPLC 5); ESI-MS: tR=0.81 min, [M+H]+ 509/511 (LC-MS 1).
Reaction SMILES: C(O[C:4]([C:6]1[NH:7][N:8]=[C:9]([CH2:11][O:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:10]=1)=[O:5])C.O[C:20]([CH3:31])([CH3:30])[CH2:21][NH:22]C(=O)OC(C)(C)C.C(OC(C1N(CC(NC(OC(C)(C)C)=O)C)N=C(COC2C=CC=CC=2)C=1)=O)C.O(CC1C=C2C(=O)NCCN2N=1)C1C=CC=CC=1>>[CH3:30][C:20]1([CH3:31])[N:7]2[N:8]=[C:9]([CH2:11][O:12][C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=3)[CH:10]=[C:6]2[C:4](=[O:5])[NH:22][CH2:21]1
Reactant: CCOC(=O)c1cc(COc2ccccc2)n[nH]1
Reactant: CC(C)(O)CNC(=O)OC(C)(C)C
Agent: CCOC(=O)c1cc(COc2ccccc2)nn1CC(C)NC(=O)OC(C)(C)C
Agent: O=C1NCCn2nc(COc3ccccc3)cc21
Product: CC1(C)CNC(=O)c2cc(COc3ccccc3)nn21

Procedure:
The compound was prepared from 5-phenoxymethyl-2H-pyrazole-3-carboxylic acid ethyl ester and tert-butyl (2-hydroxy-2-methylpropyl)carbamate using the methods described in the preceding examples 7 ((rac)-2-(2-tert-butoxycarbonylamino-propyl)-5-phenoxymethyl-2H-pyrazole-3-carboxylic acid ethyl ester) and 6 (2-phenoxymethyl-6,7-dihydro-5H-pyrazolo[1,5-a]pyrazin-4-one).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9]=[C:10]([O:14][CH3:15])[C:11]=1[O:12][CH3:13])[C:6](O)=[O:7].COCCOC.C(Cl)(=O)C([Cl:25])=O>CN(C)C=O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9]=[C:10]([O:14][CH3:15])[C:11]=1[O:12][CH3:13])[C:6]([Cl:25])=[O:7]
Reactant: O=C(Cl)C(=O)Cl
Reactant: COc1cc(C(=O)O)cc(OC)c1OC
Solvent: CN(C)C=O
Solvent: COCCOC
Product: COc1cc(C(=O)Cl)cc(OC)c1OC
Reaction time: 20 h

Procedure:
Combine 3,4,5-trimethoxybenzoic acid (3.5 kg, 16.5 mol) and 1,2-dimethoxyethane (14.2 kg) and dimethyl formamide (4 g). Cool in an ice bath. Add oxalyl chloride (2.99 kg, 23.5 mmol) over about 50 minutes not allowing the temperature of the reaction to raise above about 19° C. After 20 hours, concentrate in vacuo at 25° C. to remove about 3.7 kg of distillate to give a solution of 3,4,5-trimethoxybenzoyl chloride.
Reaction SMILES: [C:1]([N:9]=C=O)(=[O:8])C1C=CC=CC=1.C(O[C:15]([C:17]1[O:32][C:20]2=[N:21][C:22]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)=[CH:23][C:24]([CH3:25])=[C:19]2[C:18]=1[NH2:33])=[O:16])C.CC[O-].[Na+].C(O)C>CC(C)=O.O>[CH3:25][C:24]1[C:19]2[C:18]3[NH:33][C:1](=[O:8])[NH:9][C:15](=[O:16])[C:17]=3[O:32][C:20]=2[N:21]=[C:22]([C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=2)[CH:23]=1
Reactant: O=C=NC(=O)c1ccccc1
Reactant: CCOC(=O)c1oc2nc(-c3ccccc3)cc(C)c2c1N
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Solvent: CC(C)=O
Solvent: O
Product: Cc1cc(-c2ccccc2)nc2oc3c(=O)[nH]c(=O)[nH]c3c12
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 85.2 %

Procedure:
1.0 g (6.8 mmol) benzoylisocyanate is added to 1.0 g (3.4 mmol) 3-amino-4-methyl-6-phenyl-furo[2,3-b]pyridine-2-carboxylic acid ethyl ester (described in Wagner G., Prantz J. Pharmazie 1990, 45, 213-214) in 20 ml absolute acetone and stirred at room temperature for 30 minutes. The solvent is removed and the precipitate precipitated after the addition of water is sucked off and dried. The resulting precipitate is refluxed with 0.46 g (6.8 mmol) NaOEt and 20 ml ethanol for 15 min. Then, 20 ml water is added, the precipitate is sucked off, washed with some ethanol and dried. 0.85 g (85%) 9-methyl-7-phenyl-pyrido[3′,2′:4,5]furo[3,2-d]pyrimidin-2,4-dione is obtained
Reaction SMILES: [CH3:1][O:2][CH2:3][O:4][C:5]1[CH:13]=[CH:12][C:8]([CH2:9][CH2:10][NH2:11])=[CH:7][CH:6]=1.[C:14]([CH2:16][C:17](O)=[O:18])#[N:15].C(N(CC)CC)C.C(=O)(O)[O-].[Na+]>CN(C)C=O>[C:14]([CH2:16][C:17]([NH:11][CH2:10][CH2:9][C:8]1[CH:12]=[CH:13][C:5]([O:4][CH2:3][O:2][CH3:1])=[CH:6][CH:7]=1)=[O:18])#[N:15]
Reactant: COCOc1ccc(CCN)cc1
Reactant: N#CCC(=O)O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COCOc1ccc(CCNC(=O)CC#N)cc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 44.9 %

Procedure:
4-Methoxymethoxyphenethylamine (1.58 g, 8.7 mmol) and cyanoacetic acid (0.82 g, 9.6 mmol) were dissolved in dimethylformamide (10 ml) and under ice-cooling and stirring diethylphosphoric cyanide (1.51 ml, 9.6 mmol) and triethylamine (1.34 ml, 9.6 mmol) were sequentially added. After stirring at room temperature for 24 hours, saturated aqueous sodium bicarbonate solution was added to the reaction mixture, extracted with ethyl acetate, washed with water and dried over magnesium sulfate. The solvent was distilled out under reduced pressure and the residue was purified by silica gel column chromatography (chloroform:methanol=19:1) to yield 2-cyano-N-(4-methoxymethoxyphenethyl)acetamide (0.97 g, 45%).
Reaction SMILES: [Cl:1][CH:2]([Cl:16])[C:3]([O:5][N:6]=[C:7]([C:11]1[S:12][CH:13]=[CH:14][CH:15]=1)[C:8](Cl)=[O:9])=[O:4].[C:17]([O:20][CH2:21][C:22]1[CH2:23][S:24][C@@H:25]2[C@H:36]([NH2:37])[C:35](=[O:38])[N:26]2[C:27]=1[C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])(=[O:19])[CH3:18].C1OC1C>C(OCC)(=O)C>[C:17]([O:20][CH2:21][C:22]1[CH2:23][S:24][C@@H:25]2[C@H:36]([NH:37][C:8](=[O:9])[C:7](=[N:6][O:5][C:3](=[O:4])[CH:2]([Cl:16])[Cl:1])[C:11]3[S:12][CH:13]=[CH:14][CH:15]=3)[C:35](=[O:38])[N:26]2[C:27]=1[C:28]([O:30][C:31]([CH3:32])([CH3:33])[CH3:34])=[O:29])(=[O:19])[CH3:18]
Reactant: O=C(Cl)C(=NOC(=O)C(Cl)Cl)c1cccs1
Reactant: CC(=O)OCC1=C(C(=O)OC(C)(C)C)N2C(=O)[C@@H](N)[C@H]2SC1
Agent: CC1CO1
Solvent: CCOC(C)=O
Product: CC(=O)OCC1=C(C(=O)OC(C)(C)C)N2C(=O)[C@@H](NC(=O)C(=NOC(=O)C(Cl)Cl)c3cccs3)[C@H]2SC1

Procedure:
A solution of 2-dichloroacetoxyimino-(thien-2-yl)acetyl chloride (syn-isomer) in ethyl acetate (300 ml.) was added to a stirred solution of t-butyl 3-acetoxymethyl-7β-aminoceph-3-em-4-carboxylate (43 g) and propylene oxide (34 ml.) in ethyl acetate (400 ml.) at 20°. Initially a solid precipitated out but it gradually redissolved. The temperature was maintained between 20° and 30° by alternately cooling and warming the solution. After 4 hours the solution was washed with 2 N-hydrochloric acid, saturated sodium bicarbonate solution, water and brine, and was dried and concentrated under reduced pressure to give the title ester as an oil that was used directly in the next stage.
Reaction SMILES: [C:1]([N:8]1[CH2:13][CH2:12][CH2:11][CH:10]([C:14]([OH:16])=O)[CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].Cl.[CH3:18][NH:19][O:20][CH3:21].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)CC)C>CN(C=O)C.ClCCl>[CH3:21][O:20][N:19]([CH3:18])[C:14]([CH:10]1[CH2:11][CH2:12][CH2:13][N:8]([C:1]([O:3][C:4]([CH3:5])([CH3:6])[CH3:7])=[O:2])[CH2:9]1)=[O:16]
Reactant: CNOC
Reactant: CC(C)(C)OC(=O)N1CCCC(C(=O)O)C1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CON(C)C(=O)C1CCCN(C(=O)OC(C)(C)C)C1
Reaction time: 8 h
Yield: 124.8 %

Procedure:
To the solution of 1-Boc-piperidine-3-carboxylic acid (6.9 g, 30 mmol) in DMF (10 mL) and dichloromethane (40 mL) were added N,O-dimethylhydroxylamine hydrochloride (3.22 g, 33 mmol), HATU (12 g, 31.5 mmol) and triethylamine (9 mL). The reaction mixture was stirred overnight. After most of the solvent was removed and diluted with EtOAc, the organic layer was washed with water and brine, Dried and evaporation to give 10.2 g of crude product as light yellow oil.
Reaction SMILES: C(N(CC)CC)C.Br[CH2:9][CH2:10][CH2:11][OH:12].[CH3:13][CH:14]([CH3:40])[CH:15]([NH:27][C:28]([CH:30]1[CH2:34][CH:33]([CH2:35][CH2:36][CH2:37][CH2:38][CH3:39])[CH2:32][NH:31]1)=[O:29])[CH:16]1[CH:21]([OH:22])[CH:20]([OH:23])[CH:19]([OH:24])[CH:18]([S:25][CH3:26])[O:17]1>C(#N)C>[CH3:13][CH:14]([CH3:40])[CH:15]([NH:27][C:28]([CH:30]1[CH2:34][CH:33]([CH2:35][CH2:36][CH2:37][CH2:38][CH3:39])[CH2:32][N:31]1[CH2:9][CH2:10][CH2:11][OH:12])=[O:29])[CH:16]1[CH:21]([OH:22])[CH:20]([OH:23])[CH:19]([OH:24])[CH:18]([S:25][CH3:26])[O:17]1
Reactant: OCCCBr
Reactant: CCCCCC1CNC(C(=O)NC(C(C)C)C2OC(SC)C(O)C(O)C2O)C1
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CCCCCC1CC(C(=O)NC(C(C)C)C2OC(SC)C(O)C(O)C2O)N(CCCO)C1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
Triethylamine (0.2 mL, 1.38 mmol, 3 equiv), followed by 3-bromo-1-propanol (60 μL, 0.69 mmol, 1.5 equiv), were added to a stirred solution of crude 4-pentyl-pyrrolidine-2-carboxylic acid [2-methyl-1-(3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl)-propyl]-amide (192.5 mg, 0.46 mmol, 1 equiv), prepared as in Example 10, in anhydrous acetonitrile (2 mL), under nitrogen. The resulting mixture was stirred at rt for 18 h and evaporated to dryness. The residue obtained was purified by chromatography over silica gel with an eluent of 5% methanolic ammonia in dichloromethane. The desired fractions were pooled together, evaporated to dryness, and lyophilized to furnish the title compound as a white fluffy powder (13.5 mg, 6%).
Reaction SMILES: [Br:1][C:2]1[C:13](=[O:14])[NH:12][C:5]2[N:6]=[C:7]([S:10][CH3:11])[N:8]=[CH:9][C:4]=2[CH:3]=1.Cl[CH2:16][C:17]1[C:22]([F:23])=[CH:21][CH:20]=[CH:19][C:18]=1[CH:24]1[CH2:26][CH2:25]1>CN(C)C=O>[Br:1][C:2]1[C:13](=[O:14])[N:12]([CH2:16][C:17]2[C:22]([F:23])=[CH:21][CH:20]=[CH:19][C:18]=2[CH:24]2[CH2:25][CH2:26]2)[C:5]2[N:6]=[C:7]([S:10][CH3:11])[N:8]=[CH:9][C:4]=2[CH:3]=1
Reactant: CSc1ncc2cc(Br)c(=O)[nH]c2n1
Reactant: Fc1cccc(C2CC2)c1CCl
Solvent: CN(C)C=O
Product: CSc1ncc2cc(Br)c(=O)n(Cc3c(F)cccc3C3CC3)c2n1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 39.7 %

Procedure:
To a solution of 6-bromo-2-methylsulfanyl-8H-pyrido[2,3-d]pyrimidin-7-one (7, 2.12 g, 7.8 mmol) in anhydrous dimethylformamide (40 mL) sodium hydride (60% on mineral oil, 467 mg, 11.7 mmol) was added and the reaction was stirred at room temperature for 30 min. A solution of 2-chloromethyl-1-cyclopropyl-3-fluorobenzene (1.58 g, 8.6 mmol) in anhydrous dimethylformamide (10 mL) was added slowly and the reaction was stirred for 18 h. The mixture was poured onto ice water (250 g) and extracted with dichloromethane (3×80 mL). The combined organic layers were dried over magnesium sulfate, filtered and evaporated. The residue was triturated with n-hexane, the precipitated product was collected, washed with methanol, then diethyl ether. The crude product was recrystallized from ethyl acetate to give the title compound (1.31 g, 3.1 mmol, 54%) as a pale yellow solid. ESMS m/z 420 (M+H)+.
Reaction SMILES: [CH2:1]([Si:4]([Cl:7])(Cl)Cl)[CH:2]=[CH2:3].N12CCCN=C1CCCCC2.[OH:19][C:20]([C:23]([OH:26])([CH3:25])[CH3:24])([CH3:22])[CH3:21]>C(Cl)Cl>[CH2:1]([Si:4]1([Cl:7])[O:26][C:23]([CH3:25])([CH3:24])[C:20]([CH3:22])([CH3:21])[O:19]1)[CH:2]=[CH2:3]
Reactant: C=CC[Si](Cl)(Cl)Cl
Reactant: CC(C)(O)C(C)(C)O
Solvent: C1CCC2=NCCCN2CC1
Solvent: ClCCl
Product: C=CC[Si]1(Cl)OC(C)(C)C(C)(C)O1
Reaction time: 12 h
Yield: 69.3 %

Procedure:
To a cooled (0° C.) solution of allyltrichlorosilane (4.9 mL; 34 mmol) in CH2Cl2 (50 mL) was added 1,8-Diazabicyclo[5.4.0]undec-7-ene (13 mL; 84 mmol). A solution of pinacol (4.0 g; 34 mmol) in CH2Cl2 (50 mL) was then added slowly and the resultant solution was warmed to room temperature and stirred for 12 hours. The solution was concentrated and the residue was treated with diethylether (100 mL). The mixture was stirred for 1 hour during which time the formation of a precipitate was observed. The mixture was then filtered and the filtrate was concentrated. The residue was distilled under reduced pressure to give 5.2 g (72%) of 2-allyl-2-chloro-4,4,5,5-tetramethyl-[1,3,2]dioxasilolane as a clear, colorless liquid.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([N:8]2[CH2:17][CH2:16][C:15]3[C:10](=[CH:11][CH:12]=[C:13]([Cl:18])[CH:14]=3)[C:9]2=[O:19])[CH:5]=[N:6][CH:7]=1.C([O-])([O-])=O.[K+].[K+].[NH:26]1[CH:30]=[C:29](B2OC(C)(C)C(C)(C)O2)[CH:28]=[N:27]1.O>O1CCOCC1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Cl:18][C:13]1[CH:14]=[C:15]2[C:10](=[CH:11][CH:12]=1)[C:9](=[O:19])[N:8]([C:4]1[CH:5]=[N:6][CH:7]=[C:2]([C:29]3[CH:30]=[N:26][NH:27][CH:28]=3)[CH:3]=1)[CH2:17][CH2:16]2
Reactant: CC1(C)OB(c2cn[nH]c2)OC1(C)C
Reactant: O=C1c2ccc(Cl)cc2CCN1c1cncc(Br)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Product: O=C1c2ccc(Cl)cc2CCN1c1cncc(-c2cn[nH]c2)c1
Yield: 27.7 %

Procedure:
2-(5-Bromo-pyridin-3-yl)-6-chloro-3,4-dihydro-2H-isoquinolin-1-one (example 7) (34 mg, 0.1 mmol), Pd(PPh3)4 (5.8 mg, 0.005 mmol), K2CO3 (27.6 mg, 0.2 mmol) and 1H-pyrazole-4-boronic acid pinacol ester (29.1 mg, 0.15 mmol) were dissolved in dioxane (1 mL). The resulting reaction mixture was subject to microwave reaction at 150° C. for 45 min before it was poured into H2O (25 mL) and extracted with EtOAc (2×25 mL). The combined organic layers were washed with brine, dried over anhy. Na2SO4, filtered and concentrated in vacuo to give a crude product which was then purified by prep-HPLC to give title compound (9 mg, 28%) as a white solid. MS: 325.1 (M+H+).
Reaction SMILES: [F:1][CH:2]([F:18])[O:3][C:4]1[CH:17]=[CH:16][C:7]([CH:8](O)[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[CH:6][CH:5]=1.S(Cl)([Cl:21])=O>C(Cl)(Cl)Cl>[F:1][CH:2]([F:18])[O:3][C:4]1[CH:17]=[CH:16][C:7]([CH:8]([Cl:21])[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[CH:6][CH:5]=1
Reactant: OC(c1ccccc1)c1ccc(OC(F)F)cc1
Reactant: O=S(Cl)Cl
Solvent: ClC(Cl)Cl
Product: FC(F)Oc1ccc(C(Cl)c2ccccc2)cc1
Temperature: 0 °C
Reaction time: 24 h
Yield: 80 %

Procedure:
55 g of 4-difluoromethoxybenzhydrol are dissolved in 440 ml of chloroform, the mixture is cooled to 0° C. and 17.5 ml of thionyl chloride in 220 ml of chloroform are added. The mixture is allowed to stand for 24 hours at room temperature and excess thionyl chloride and chloroform are removed by distillation. 47 g (80%) of 4-difluoromethoxybenzhydryl chloride are obtained as a yellow oil.