Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1[C:13]2[CH:12]([CH2:14][O:15][C:16]([NH:18][C:19]([CH3:27])([CH3:26])[CH2:20]/[CH:21]=[CH:22]/[C:23](O)=[O:24])=[O:17])[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.ON1C2N=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C.N1CCC[C@H]1COCC(N([C@H](CC1C=CC(C2C=CC=CC=2)=CC=1)C(N(C)[C@@H](C(=O)NC)CC1C=CC(OC)=CC=1)=O)C)=O.[CH3:94][N:95]([CH3:124])[C:96]([C@H:98]([N:106]([CH3:123])[C:107](=[O:122])[CH:108]([NH:120][CH3:121])[CH2:109][C:110]1[CH:119]=[CH:118][C:117]2[C:112](=[CH:113][CH:114]=[CH:115][CH:116]=2)[CH:111]=1)[CH2:99][C:100]1[CH:105]=[CH:104][CH:103]=[CH:102][CH:101]=1)=[O:97].C(N(C(C)C)CC)(C)C>ClCCl>[CH:1]1[C:13]2[CH:12]([CH2:14][O:15][C:16](=[O:17])[NH:18][C:19]([CH3:26])([CH3:27])[CH2:20]/[CH:21]=[CH:22]/[C:23](=[O:24])[N:120]([C@@H:108]([C:107](=[O:122])[N:106]([C@@H:98]([C:96](=[O:97])[N:95]([CH3:94])[CH3:124])[CH2:99][C:100]3[CH:101]=[CH:102][CH:103]=[CH:104][CH:105]=3)[CH3:123])[CH2:109][C:110]3[CH:119]=[CH:118][C:117]4[C:112](=[CH:113][CH:114]=[CH:115][CH:116]=4)[CH:111]=3)[CH3:121])[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1
Reactant: CC(C)(C/C=C/C(=O)O)NC(=O)OCC1c2ccccc2-c2ccccc21
Reactant: CNC(Cc1ccc2ccccc2c1)C(=O)N(C)[C@H](Cc1ccccc1)C(=O)N(C)C
Agent: CCN=C=NCCCN(C)C
Agent: CNC(=O)[C@@H](Cc1ccc(OC)cc1)N(C)C(=O)[C@@H](Cc1ccc(-c2ccccc2)cc1)N(C)C(=O)COC[C@@H]1CCCN1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CN(C)C(=O)[C@@H](Cc1ccccc1)N(C)C(=O)[C@@H](Cc1ccc2ccccc2c1)N(C)C(=O)/C=C/CC(C)(C)NC(=O)OCC1c2ccccc2-c2ccccc21
Reaction time: 0.5 h
Yield: 68.1 %

Procedure:
To a solution of (2E)-5-(((9H-flouren-9-yl)methoxy)-carbonylamino)-5-methylhex-2-enoic acid (280 mg, 0.77 mmol) in dichloromethane (5 ml) were added 1-hydroxy-7-azabenzotriazole (126 mg, 0.92 mmol) and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (207 mg, 1.08 mmol) and the mixture was stirred for 30 min. Then 2R)-N-((1R)-1-dimethylcarbamoyl-2-phenylethyl)-N-methyl-2-methylamino-3-(2-naphthyl)propionamide (386 mg, 0.92 mmol) in dichloromethane (5 ml) and diisopropylethylamine (0.17 ml, 1.00 mmol) were added and the mixture was stirred overnight at room temperature. The mixture was washed with water (20 ml), saturated aqueous sodium bicarbonate (20 ml), water (2×20 ml), brine (20 ml), dried over magnesium sulfate and concentrated in vacuo. The crude product was chromatographed on silica (400 g) with ethyl acetate/heptan 1:1 to give 401 mg of ((3E)-4-(N-((1R)-1-(N-((1R)-1-dimethylcarbamoyl-2-phenylethyl)-N-methylcarbamoyl)-2-(2-naphthyl)ethyl)-N-methylcarbamoyl)-1,1-dimethylbut-3-enyl)carbamic acid 9H-flouren-9-ylmethyl ester. The obtained product was dissolved in 20% piperidine in dimethylformamide (10 ml) and stirred for 30 min. The mixture was chromatographed on silica (20 g) with dichloromethane/methanol/ammonia 89:10:1 to give 228 mg of (2E)-5-amino-5-methylhex-2-enoic acid N-((1R)-1-(N-((1R)-1-(dimethylcarbamoyl)-2-phenylethyl)-N-methylcarbamoyl)-2-(2-naphthyl)ethyl)-N-methylamide as an oil. The product was redissolved in water (30 ml) and acetic acid (2 ml) was added and the mixture was lyophilized to give 645 mg of the acetate salt of the title compound as an amorphous powder.
Reaction SMILES: [C:1]([Si:5]([O:8][CH:9]([CH2:14][CH2:15][C:16]1[CH:21]=[CH:20][C:19]([C:22]([CH2:41][CH3:42])([C:25]2[CH:30]=[CH:29][C:28](B3OC(C)(C)C(C)(C)O3)=[C:27]([CH3:40])[CH:26]=2)[CH2:23][CH3:24])=[CH:18][C:17]=1[CH3:43])[C:10]([CH3:13])([CH3:12])[CH3:11])([CH3:7])[CH3:6])([CH3:4])([CH3:3])[CH3:2].[CH3:44][O:45][C:46](=[O:55])[CH2:47][C:48]1[CH:49]=[N:50][CH:51]=[C:52](Br)[CH:53]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>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.O>[CH3:44][O:45][C:46](=[O:55])[CH2:47][C:48]1[CH:49]=[N:50][CH:51]=[C:52]([C:28]2[CH:29]=[CH:30][C:25]([C:22]([C:19]3[CH:20]=[CH:21][C:16]([CH2:15][CH2:14][CH:9]([O:8][Si:5]([C:1]([CH3:4])([CH3:3])[CH3:2])([CH3:6])[CH3:7])[C:10]([CH3:13])([CH3:12])[CH3:11])=[C:17]([CH3:43])[CH:18]=3)([CH2:23][CH3:24])[CH2:41][CH3:42])=[CH:26][C:27]=2[CH3:40])[CH:53]=1
Reactant: CCC(CC)(c1ccc(CCC(O[Si](C)(C)C(C)(C)C)C(C)(C)C)c(C)c1)c1ccc(B2OC(C)(C)C(C)(C)O2)c(C)c1
Reactant: COC(=O)Cc1cncc(Br)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: O
Product: CCC(CC)(c1ccc(CCC(O[Si](C)(C)C(C)(C)C)C(C)(C)C)c(C)c1)c1ccc(-c2cncc(CC(=O)OC)c2)c(C)c1
Temperature: 86.5 °C
Reaction time: 3 h
Yield: 83.3 %

Procedure:
Degassed N,N-dimethylformamide (0.12 mL) was added to t-butyl-(1-{2-[4-(1-ethyl-1-{4-[4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl]-3-methyl-phenyl}-propyl)-2-methyl-phenyl]-ethyl}-2,2-dimethyl-propoxy)dimethylsilane (Example 23-(1); 11.0 mg, 0.0181 mmol), (5-bromo-pyridin-3-yl)acetic acid methyl ester (Example 24-(2); 6.3 mg, 0.027 mmol), tetrakis(triphenylphosphine)palladium (0) (2.6 mg, 0.0022 mmol) and potassium phosphate (9.0 mg, 0.042 mmol). After replacement with nitrogen, the mixture was heated while stirring at an external temperature of 81 to 92° C. for three hours. Water was added to the reaction mixture, followed by extraction with diethyl ether. The extract was dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. The residue was purified by silica gel chromatography (hexane/dichloromethane=3/1) to give the title compound (9.5 mg, 83%).
Reaction SMILES: N[C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][C:3]=1[OH:12].Cl.N([O-])=O.[Na+].[I-:18].[K+]>O.CCOC(C)=O.C1COCC1>[OH:12][C:3]1[CH:4]=[C:5]([CH:10]=[CH:11][C:2]=1[I:18])[C:6]([O:8][CH3:9])=[O:7]
Reactant: [I-]
Reactant: COC(=O)c1ccc(N)c(O)c1
Agent: Cl
Agent: O=N[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: C1CCOC1
Product: COC(=O)c1ccc(I)c(O)c1
Reaction time: 0.42 h

Procedure:
A cloudy, dark solution of the product from Step A (79 g, 0.47 mol), 3N HCl (750 mL), and THF (250 mL) was cooled to 0° C. A solution of NaNO2 (35.9 g, 0.52 mol) in 115 mL of water was added over ca. 5 minutes, and the solution was stirred for another 25 minutes. A solution of potassium iodide (312 g, 1.88 mol) in 235 mL of water was added all at once, and the reaction was stirred for an additional 15 minutes. The mixture was poured into EtOAc, shaken, and the layers were separated. The organic phase was washed with water and brine, dried (Na2SO4), and concentrated in vacuo to provide the crude product (148 g). Purification by column chromatography through silica gel (0%-50% EtOAc/hexane) provided the titled product.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[CH:4][N:5]([C:7]2[CH:12]=[C:11]([O:13][C:14]3[CH:15]=[N:16][C:17]([N+:20]([O-])=O)=[CH:18][CH:19]=3)[CH:10]=[CH:9][N:8]=2)[CH:6]=1.[NH4+].[Cl-]>CO.C1COCC1.[Zn]>[CH3:1][C:2]1[N:3]=[CH:4][N:5]([C:7]2[CH:12]=[C:11]([O:13][C:14]3[CH:19]=[CH:18][C:17]([NH2:20])=[N:16][CH:15]=3)[CH:10]=[CH:9][N:8]=2)[CH:6]=1
Reactant: Cc1cn(-c2cc(Oc3ccc([N+](=O)[O-])nc3)ccn2)cn1
Agent: [Cl-]
Agent: [NH4+]
Agent: [Zn]
Solvent: C1CCOC1
Solvent: CO
Product: Cc1cn(-c2cc(Oc3ccc(N)nc3)ccn2)cn1
Temperature: 25 °C
Reaction time: 2 h
Yield: 68.5 %

Procedure:
A solution of 2-(4-methyl-1H-imidazol-1-yl)-4-((6-nitropyridin-3-yl)oxy)pyridine (1.3 g, 4.37 mmol) in MeOH (20 mL)/THF (20 mL) was treated sequentially with NH4Cl (7.02 g, 131 mmol) and zinc dust (2.86 g, 43.7 mmol) and stirred at RT for 2 h. The mixture was diluted with THF, the solids removed via filtration through diatomaceous earth, washed with THF and the filtrate concentrated to dryness. The material was treated with THF, the solids removed via filtration and the filtrate concentrated to dryness, treated with DCM and sonicated. The resulting solid was collected via filtration and dried to afford 5-((2-(4-methyl-1H-imidazol-1-yl)pyridin-4-yl)oxy)pyridin-2-amine (800 mg, 68%). 1H NMR (400 MHz, DMSO-d6): δ 8.39 (d, J=1.4 Hz, 1 H), 8.28 (d, J=5.8 Hz, 1 H), 7.83 (d, J=2.9 Hz, 1 H), 7.63 (s, 1 H), 7.31-7.30 (m, 2 H), 6.70 (dd, J=5.8, 2.2 Hz, 1 H), 6.51 (d, J=8.9 Hz, 1 H), 6.05 (s, 2 H), 2.14 (d, J=1.0 Hz, 3 H); MS (ESI) m/z: 268.2 (M+H+).
Reaction SMILES: O.[C:2]1([OH:10])[CH:9]=[C:7]([CH3:8])[CH:6]=[C:4]([OH:5])[CH:3]=1.[H-].[Na+].[CH2:13](Br)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.O>CN(C)C=O>[CH2:13]([O:5][C:4]1[CH:3]=[C:2]([OH:10])[CH:9]=[C:7]([CH3:8])[CH:6]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: BrCc1ccccc1
Reactant: Cc1cc(O)cc(O)c1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1cc(O)cc(OCc2ccccc2)c1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 31.7 %

Procedure:
Orcinol monohydrate (7.10 g, 50 mmol) in N,N-dimethylformamide (20 mL) was added dropwise to NaH (2.4 g, 100 mmol) in N,N-dimethylformamide (60 mL). The reaction mixture was stirred at room temperature for 20 min. Benzyl bromide (8.55 g, 50 mmol) in N,N-dimethylformamide (20 mL) was then added, and the reaction mixture was stirred at ambient temperature for 2 hours. Water (100 mL) was added carefully followed by extraction by ethyl acetate (3×100 mL). The organic phase was washed with brine (2×50 mL), dried over Na2SO4, and concentrated in vacuo. The residue was purified by flash column chromatography (3:1 hexane/ethyl acetate) to give the title compound as a yellow oil (3.40 g, 32%). 1H-NMR (300 MHz, CDCl3) δ 7.39 (m, 5 H), 6.40 (s, 1 H), 6.29 (s, 1 H), 6.26 (s, 1 H), 5.00 (s, 2 H), 4.89 (s, 1 H), 2.26 (s, 3 H).
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][CH2:15][CH2:16][NH:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1(C)C=CC=CC=1.[OH-].[K+].[C:33](Cl)(Cl)=[O:34]>CO>[CH2:1]([N:8]1[CH2:9][CH2:10][CH:11]([N:14]2[CH2:15][CH2:16][N:17]([C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=3)[C:33]2=[O:34])[CH2:12][CH2:13]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: c1ccc(CN2CCC(NCCNc3ccccc3)CC2)cc1
Reactant: O=C(Cl)Cl
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: Cc1ccccc1
Product: O=C1N(c2ccccc2)CCN1C1CCN(Cc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
200 g of 1-benzyl-4-(2-anilino-ethylamino)-piperidine and 2000 ml of toluene and 1940 ml of potassium hydroxide solution are charged into a reaction vessel. The temperature is kept between 5° and 10° C with a mixture of ice and methanol while 300 g of phosgene are introduced in the course of 3 hours. Thereafter the reaction mixture is stirred for 2 hours at room temperature. During the dropwise addition of 860 ml of potassium hydroxide, the temperature is kept below 25° C with an ice-bath. The batch is then stirred for 14 hours. The precipitated crystals are collected with suction and dried. The two-phase filtrate is separated in a separating funnel. The toluene phase is dried over 200 g of sodium sulphate, filtered and concentrated. The residue is recrystallied from 400 ml of ethanol to give the 1-(1-benzyl-4-piperidyl)-3-phenyl-imidazolidin- 2-one with a melting point of 173°-174° C.
Reaction SMILES: [SH:1][CH:2]1[N:5]([C:6](=[C:20]([OH:23])[CH2:21]Br)[C:7]([O:9][CH2:10][C:11]2[CH:16]=[CH:15][C:14]([N+:17]([O-:19])=[O:18])=[CH:13][CH:12]=2)=[O:8])[C:4](=[O:24])[CH:3]1[NH:25][C:26](=[O:35])[CH2:27][O:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1>C1C=CC=CC=1>[OH:23][C:20]1[CH2:21][S:1][C@@H:2]2[CH:3]([NH:25][C:26](=[O:35])[CH2:27][O:28][C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[C:4](=[O:24])[N:5]2[C:6]=1[C:7]([O:9][CH2:10][C:11]1[CH:16]=[CH:15][C:14]([N+:17]([O-:19])=[O:18])=[CH:13][CH:12]=1)=[O:8]
Reactant: O=C(COc1ccccc1)NC1C(=O)N(C(C(=O)OCc2ccc([N+](=O)[O-])cc2)=C(O)CBr)C1S
Solvent: c1ccccc1
Product: O=C(COc1ccccc1)NC1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(O)CS[C@H]12
Temperature: 25 °C
Reaction time: 1 h
Yield: 66 %

Procedure:
To a solution of p-nitrobenzyl α-[4-mercapto-3-phenoxyacetamido-2-oxoazetidin-1-yl]-α-(2-bromo-1-hydroxyethylidene)-acetate (106 mg) in benzene (5ml) is added silica gel F-254 (500 mg) distributed by E. Merck Ag., and the mixture is shaken at room temperature for 1 hour. The insoluble material is removed by filtration, and washed several times with chloroform. The filtrate and washed solution are combined and evaporated under reduced pressure to give p-nitrobenzyl 3-hydroxy-7-phenoxyacetamido-3-cephem-4-carboxylate (60 mg). Yield: 66.3%. m.p. 95.5°-99.5° C. IR: νmaxCHCl3 3400, 1785, 1685, 1605. NMR: δCDCl3 2.03s2H, 4.60s2H, 5.07+5.37ABq(4)2H, 5.73d(4)1H, 5.68dd(9;4)1H, 6.83-8.32m9H.
Reaction SMILES: [C:1]([O:4][CH2:5][C:6](=[CH2:8])[CH3:7])(=[O:3])[CH3:2].[Cl-].[Al+3].[Cl-].[Cl-].[CH:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>>[C:1]([O:4][CH2:5][C:6]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)([CH3:7])[CH3:8])(=[O:3])[CH3:2]
Reactant: C=C(C)COC(C)=O
Reactant: c1ccccc1
Agent: [Al+3]
Agent: [Cl-]
Product: CC(=O)OCC(C)(C)c1ccccc1
Temperature: 5 °C
Reaction time: 0.5 h

Procedure:
Mix methallyl acetate (228 g, 2.0 mol) and benzene (1 L) and cool to 5° C. Add aluminum chloride (266 g, 2.0 mol) over approximately 30 minutes while maintaining the temperature below 10° C. Add, in portions of 50 mL to 80 mL each, to a 5° C. mixture of aluminum chloride (15 g) in benzene (600 mL). After addition is complete, stir at 0-3° C. for ½ hour, pour onto ice (2 kg) and separate the organic layer. Wash with water (2×300 mL), dry (Na2SO4), and distill to give neophyl acetate.
Reaction SMILES: [O-]CC.[Na+].C(O[C:8](=[O:19])[C:9](=[CH:15]OCC)[C:10]([O:12][CH2:13][CH3:14])=[O:11])C.[CH:20]([NH:23][NH2:24])([CH3:22])[CH3:21].Cl>C(O)C.[Cl-].[Na+].O>[CH2:13]([O:12][C:10]([C:9]1[C:8]([OH:19])=[N:24][N:23]([CH:20]([CH3:22])[CH3:21])[CH:15]=1)=[O:11])[CH3:14]
Reactant: CC(C)NN
Reactant: CCOC=C(C(=O)OCC)C(=O)OCC
Agent: CC[O-]
Agent: Cl
Agent: [Cl-]
Solvent: O
Solvent: CCO
Product: CCOC(=O)c1cn(C(C)C)nc1O
Temperature: 80 °C
Reaction time: 4 h
Yield: 35.1 %

Procedure:
To a solution of sodium ethoxide (23 g) in ethanol (150 mL) were added ethoxymethylene malonic acid diethyl ester (32.7 g) and isopropylhydrazine (11.2 g) at room temperature, and the mixture was stirred at 80° C. for 4 hours and then at 100° C. for 2 hours. The reaction mixture was poured into 2 mol/L hydrochloric acid (300 mL), the mixture was diluted with brine and extracted with ethyl acetate. The organic layer was washed with brine and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure, and the obtained residue was purified by column chromatography on silica gel (eluent: ethyl acetate/hexane=1/5) to give the title compound (10.5 g).
Reaction SMILES: CO[CH2:3][N:4]([CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[CH2:5][Si](C)(C)C.FC(F)(F)C(O)=O.[CH2:24]([O:26][C:27](=[O:32])[C:28]([CH2:30][F:31])=[CH2:29])[CH3:25]>ClCCl>[CH2:24]([O:26][C:27]([C:28]1([CH2:30][F:31])[CH2:29][CH2:3][N:4]([CH2:10][C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH2:5]1)=[O:32])[CH3:25]
Reactant: C=C(CF)C(=O)OCC
Reactant: COCN(Cc1ccccc1)C[Si](C)(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCOC(=O)C1(CF)CCN(Cc2ccccc2)C1
Temperature: 25 °C

Procedure:
N-(methoxymethyl)-N-(trimethylsilylmethyl)benzylamine (548 μl, 2.14 mmol) was dissolved in the dichloromethane solution of the 2-fluoromethyl-acrylic acid ethyl ester from the previous reaction and chilled to 0 C. A solution of trifluoroacetic acid (67 μl, 0.87 mmol) in dichloromethane (0.5 ml) was added slowly. The reaction mixture was allowed to warm to room temperature in two hours and directly chromatographed on silica gel. Elution with solutions of ethyl acetate in hexanes (1:5, 1:4, 1:3) obtained the title product (143 mg) as oil.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH:12]=[C:11]([C:13]3[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=3)[C:10]([CH2:20][C:21]([O-:23])=[O:22])=[N:9]2)=[CH:4][CH:3]=1>FC(F)(F)C(O)=O>[F:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[CH:12]=[C:11]([C:13]3[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=3)[C:10]([CH2:20][C:21]([OH:23])=[O:22])=[N:9]2)=[CH:6][CH:7]=1
Reactant: O=C([O-])Cc1nn(-c2ccc(F)cc2)cc1-c1ccc(Cl)cc1
Solvent: O=C(O)C(F)(F)F
Product: O=C(O)Cc1nn(-c2ccc(F)cc2)cc1-c1ccc(Cl)cc1

Procedure:
1,49 Grams of the ester prepared according to (a) are stirred in 30 ml of trifluoroacetic acid, at room temperature. The hydrolysis is followed by TLC; at the end the excess of CF3 --COOH is evaporated in vacuo and the residue is crystallized from acetic acid/ethanol. The title product is identical with a sample prepared according to EP 54812.
Reaction SMILES: CC1(C)[NH:7][C:6]2[CH:8]=[C:9]([C:11]3[CH:12]=[N:13][NH:14][C:15]=3[CH3:16])[S:10][C:5]=2[C:4](=[O:17])[NH:3]1.Cl.C([O-])(O)=O.[Na+]>CO>[NH2:7][C:6]1[CH:8]=[C:9]([C:11]2[CH:12]=[N:13][NH:14][C:15]=2[CH3:16])[S:10][C:5]=1[C:4]([NH2:3])=[O:17]
Reactant: Cc1[nH]ncc1-c1cc2c(s1)C(=O)NC(C)(C)N2
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Product: Cc1[nH]ncc1-c1cc(N)c(C(N)=O)s1
Temperature: 50 °C
Reaction time: 2 h
Yield: 94.8 %

Procedure:
A mixture of 2,2-dimethyl-6-(5-methyl-1H-pyrazol-4-yl)-2,3-dihydrothieno[3,2-d]pyrimidin-4(1H)-one (660 mg, 2.52 mmol), 1 M HCl (8.81 mL) and MeOH (27 mL) was stirred at 50° C. for 2 h. Then, the reaction mixture was poured into excess saturated aqueous NaHCO3 and extracted with EtOAc/THF, and the extract was dried over MgSO4, filtered and concentrated under reduced pressure to afford the title compound (531 mg, 95%) as a yellow solid.
Reaction SMILES: [C:1]([O:5][C:6](=[O:16])[NH:7][C:8]1[CH:13]=[C:12]([CH2:14]O)[CH:11]=[CH:10][N:9]=1)([CH3:4])([CH3:3])[CH3:2].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C(Br)(Br)(Br)[Br:37]>C(Cl)Cl>[C:1]([O:5][C:6](=[O:16])[NH:7][C:8]1[CH:13]=[C:12]([CH2:14][Br:37])[CH:11]=[CH:10][N:9]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)Nc1cc(CO)ccn1
Reactant: BrC(Br)(Br)Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)Nc1cc(CBr)ccn1
Temperature: 25 °C
Reaction time: 8 h
Yield: 82 %

Procedure:
(4-Hydroxymethyl-pyridin-2-yl)-carbamic acid tert-butyl ester (8.00 g, 35.6 mmol) was dissolved in CH2Cl2 (150 mL) and treated with PPh3 (11.2 g, 42.8 mmol) under nitrogen. The reaction flask was cooled in an ice bath and CBr4 (14.2 g, 42.8 mmol) was added in small portions. The ice bath was removed after 30 min and the reaction mixture was stirred overnight at room temperature. The reaction mixture was concentrated under reduced pressure and acetonitrile (50 mL) was added. The reaction flask was placed in a refrigerator for 3 h and the precipitate filtered and washed with cold acetonitrile. The white solid was dried in vacuo giving (4-bromomethyl-pyridin-2-yl)-carbamic acid tert-butyl ester (8.38 g, 82%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6](I)[CH:5]=[CH:4][N:3]=1.[Cl:9][C:10]1[C:15](B(O)O)=[CH:14][CH:13]=[CH:12][N:11]=1.C([O-])([O-])=O.[Na+].[Na+].P(C(C)(C)C)(C(C)(C)C)C(C)(C)C.[H+].[B-](F)(F)(F)F>CCOC(C)=O.CC([O-])=O.CC([O-])=O.[Pd+2].O.O1CCOCC1>[Cl:9][C:10]1[C:15]([C:6]2[CH:5]=[CH:4][N:3]=[C:2]([F:1])[CH:7]=2)=[CH:14][CH:13]=[CH:12][N:11]=1
Reactant: OB(O)c1cccnc1Cl
Reactant: Fc1cc(I)ccn1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)(C)P(C(C)(C)C)C(C)(C)C
Solvent: C1COCCO1
Solvent: O
Solvent: CCOC(C)=O
Product: Fc1cc(-c2cccnc2Cl)ccn1
Temperature: 100 °C

Procedure:
To 2-fluoro-4-iodopyridine (9.45 g, 42.4 mmol), 2-chloropyridine-3-boronic acid (10.0 g, 63.5 mmol), Na2CO3 (13.5 g, 127 mmol), Pd(OAc)2 (480 mg, 2.12 mmol) and P(tBu)3.HBF4 (1.23 g, 4.24 mmol) was added dioxane (125 mL) and water (45 mL). The mixture was heated overnight at 100° C. in a sealed tube. The resulting mixture was diluted with EtOAc and extracted with water and brine. The organic layer was dried over Na2SO4, filtered and concentrated. The resulting solid was triturated with n-Hexanes and dried to yield 2-chloro-2′-fluoro-[3,4′]bipyridinyl. MS m/z=209 [M+1]+. Calc'd for C10H6ClFN2: 208.62.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6](I)[CH:5]=[CH:4][N:3]=1.[Cl:9][C:10]1[C:15](B(O)O)=[CH:14][CH:13]=[CH:12][N:11]=1.C([O-])([O-])=O.[Na+].[Na+].P(C(C)(C)C)(C(C)(C)C)C(C)(C)C>CCOC(C)=O.CC([O-])=O.CC([O-])=O.[Pd+2].O.O1CCOCC1>[Cl:9][C:10]1[C:15]([C:6]2[CH:5]=[CH:4][N:3]=[C:2]([F:1])[CH:7]=2)=[CH:14][CH:13]=[CH:12][N:11]=1
Reactant: OB(O)c1cccnc1Cl
Reactant: Fc1cc(I)ccn1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)(C)P(C(C)(C)C)C(C)(C)C
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Solvent: O
Product: Fc1cc(-c2cccnc2Cl)ccn1
Temperature: 100 °C

Procedure:
To 2-fluoro-4-iodopyridine (9.45 g, 42.4 mmol), 2-chloropyridine-3-boronic acid (10.0 g, 63.5 mmol), Na2CO3 (13.5 g, 127 mmol), Pd(OAc)2 (480 mg, 2.12 mmol) and P(tBu)3●HBF4 (1.23 g, 4.24 mmol) was added dioxane (125 mL) and water (45 mL). The mixture was heated overnight at 100° C. in a sealed tube. The resulting mixture was diluted with EtOAc and extracted with water and brine. The organic layer was dried over Na2SO4, filtered and concentrated. The resulting solid was triturated with n-Hexanes and dried to yield 2-chloro-2′-fluoro-[3,4′]bipyridinyl. MS m/z=209 [M+1]+. Calc'd for C10H6ClFN2: 208.62.
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:7]=[N:8][NH:9][CH:10]=1)=[O:5])C.[H-].[Na+].[C:13]([O:17][C:18]([N:20]1[CH2:25][CH2:24][CH:23](OS(C)(=O)=O)[CH2:22][CH2:21]1)=[O:19])([CH3:16])([CH3:15])[CH3:14].[OH-].[Na+]>CN(C)C=O.O.CO>[C:13]([O:17][C:18]([N:20]1[CH2:25][CH2:24][CH:23]([N:9]2[CH:10]=[C:6]([C:4]([OH:3])=[O:5])[CH:7]=[N:8]2)[CH2:22][CH2:21]1)=[O:19])([CH3:16])([CH3:14])[CH3:15]
Reactant: CCOC(=O)c1cn[nH]c1
Reactant: CC(C)(C)OC(=O)N1CCC(OS(C)(=O)=O)CC1
Agent: [H-]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CN(C)C=O
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCC(n2cc(C(=O)O)cn2)CC1
Temperature: 100 °C
Reaction time: 1 h
Yield: 40 %

Procedure:
To a solution of 1H-pyrazole-4-carboxylic acid ethyl ester (701 mg, 5 mmol) in dry N,N-dimethylformamide (15 mL) at 0-5° C., under argon, was added 60% sodium hydride (480 mg, 1.2 eq). After stirring for 1 hour was added a solution of 4-methanesulfonyloxy-piperidine-1-carboxylic acid tert-butyl ester (1.53 g, 1.1 eq) in dry N,N-dimethylformamide (4 mL). The mixture was heated to 100° C., stirred for 6 hours then treated with water and extracted with ethyl acetate. The organic layer was separated (organic layer A). The aqueous layer was acidified with a 5% aqueous solution of potassium bisulfate and extracted with ethyl acetate giving, after separation, the organic layer B. The organic layer A was evaporated to dryness. The residue was treated with 20 mL of methanol, 5 mL of water and 1.12 g of sodium hydroxide (20 mmol) and stirred at room temperature for 2 days. The solvents were removed under reduced pressure, the residue treated with ethyl acetate and washed with 5% aqueous solution of potassium bisulfate giving the organic layer C. The combined organic layers B and C were dried over sodium sulfate and evaporated to dryness. The residue was triturated with diethyl ether and dried under vacuum affording 590 mg of title compound.
Reaction SMILES: Cl[C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=1.[C:10]1([NH:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.CC(C)([O-])C.[Na+]>>[C:6]([C:5]1[CH:8]=[CH:9][C:2]([N:16]([C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[CH:3][CH:4]=1)#[N:7]
Reactant: N#Cc1ccc(Cl)cc1
Reactant: c1ccc(Nc2ccccc2)cc1
Agent: CC(C)(C)[O-]
Agent: [Na+]
Product: N#Cc1ccc(N(c2ccccc2)c2ccccc2)cc1
Yield: 100.6 %

Procedure:
According to the general procedure A, 4-chlorobenzonitrile (76 mg, 0.55 mmol) reacted with diphenylamine (85 mg, 0.50 mmol) using 1 mol % of catalyst and sodium tert-butoxide (72 mg, 0.75 mmol) at 45° C. for 21 h to give the title compound (136 mg, 96%) as a white solid: 1H-NMR (400 MHz, CDCl3): δ 7.43 (d, 2H, J=8.8 Hz, Ar—H), 7.35 (m, 4H), 7.17 (m, 6H), 6.97 (d, 2H, J=8.8 Hz). 13C{1H}-NMR (100 MHz, CDCl3): δ 151.56, 145.93, 133.16, 129.75, 126.14, 125.11, 119.69, 119.67, 102.46. GC/MS(EI): m/z 270 (M+).