Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:14]=[CH:13][C:5]([C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7])=[C:4]([NH:15][C:16]2[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=2)[CH:3]=1.[CH3:23][O:24][C:25]1[CH:30]=[CH:29][C:28](B(O)O)=[CH:27][N:26]=1.C(=O)([O-])[O-].[Na+].[Na+]>CN(C)C(=O)C>[F:22][C:19]1[CH:20]=[CH:21][C:16]([NH:15][C:4]2[CH:3]=[C:2]([C:28]3[CH:29]=[CH:30][C:25]([O:24][CH3:23])=[N:26][CH:27]=3)[CH:14]=[CH:13][C:5]=2[C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7])=[CH:17][CH:18]=1
Reactant: CC(C)(C)OC(=O)c1ccc(Br)cc1Nc1ccc(F)cc1
Reactant: COc1ccc(B(O)O)cn1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC(=O)N(C)C
Product: COc1ccc(-c2ccc(C(=O)OC(C)(C)C)c(Nc3ccc(F)cc3)c2)cn1
Temperature: 110 °C
Reaction time: 15 h

Procedure:
To N,N-dimethylacetamide 2.5 mL solution of tert-butyl 4-bromo-2-(4-fluoroanilino)benzoate 0.10 g were added 2-methoxy-5-pyridinboronic acid 63 mg, sodium carbonate 72 mg and polymer-carried di(acetato)dicyclohexylphenylphosphine palladium(II) 8 mg, and it was stirred at 110° C. for 15 hours. After the reaction mixture was cooled to room temperature,2-methoxy-5-pyridinboronic acid 21 mg and polymer-carried di(acetato)dicyclohexylphenylphosphine palladium(II) 8 mg were added to it, and it was stirred at 110° C. for 36 hours. After the reaction mixture was cooled to room temperature, insoluble matter was filtrated, and ethyl acetate and 10% citric acid aqueous solution were added to it. The organic layer was separated and collected, dried over anhydrous magnesium sulfate after sequential washing with 10% citric acid aqueous solution and saturated sodium chloride aqueous solution, and the solvent was removed under reduced pressure. The obtained residue was refined by silica gel column chromatography [Trikonex company, Flash Tube 2008, eluent; hexane:ethyl acetate=4:1] to give tert-butyl 2-(4-fluoroanilino)-4-(2-methoxypyridin-5-yl)benzoate.
Reaction SMILES: [C:1]([O:4][CH2:5][CH2:6][O:7][C:8]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[CH:9]([OH:14])[C:10]([O:12][CH3:13])=[O:11])(=[O:3])[CH3:2].C([O-])([O-])=O.[K+].[K+].CS([C:37]1[N:42]=[C:41]([O:43][CH3:44])[CH:40]=[C:39]([CH3:45])[N:38]=1)(=O)=O>CN(C=O)C.O>[C:1]([O:4][CH2:5][CH2:6][O:7][C:8]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[CH:9]([O:14][C:37]1[N:42]=[C:41]([O:43][CH3:44])[CH:40]=[C:39]([CH3:45])[N:38]=1)[C:10]([O:12][CH3:13])=[O:11])(=[O:3])[CH3:2]
Reactant: COC(=O)C(O)C(OCCOC(C)=O)(c1ccccc1)c1ccccc1
Reactant: COc1cc(C)nc(S(C)(=O)=O)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)C(Oc1nc(C)cc(OC)n1)C(OCCOC(C)=O)(c1ccccc1)c1ccccc1
Temperature: 80 °C
Reaction time: 2 h
Yield: 90 %

Procedure:
4 g (11.1 mmol) of methyl 3-(2-acetoxyethoxy)-2-hydroxy-3,3-di-phenylpropionate were dissolved in 20 ml of DMF under N2, 770 mg (5.6 mmol) of K2CO3 and 2.24 g (11.1 mmol) of 2-methanesulfonyl-4-methoxy-6-methylpyrimidine were added, and the mixture was stirred at 80° C. for 2 h. It was subsequently diluted with 20 ml of H2O and extracted twice with 30 ml of diethyl ether, the organic phase was dried over MgSO4 and concentrated, and the residue was purified by chromatography on silica gel with ethyl acetate/cyclohexane mixtures. 4.8 g (90%) of a colorless oil were obtained.
Reaction SMILES: [OH:1][C:2]1[C:3](=[O:9])[CH:4]([CH3:8])[O:5][C:6]=1[CH3:7].[C:10](Cl)(=[O:15])[C:11]([CH3:14])([CH3:13])[CH3:12].Cl>CN(C)C1C=CN=CC=1.N1C=CC=CC=1.C(Cl)Cl>[CH3:7][CH:6]1[C:2](=[O:1])[C:3]([O:9][C:10](=[O:15])[C:11]([CH3:14])([CH3:13])[CH3:12])=[C:4]([CH3:8])[O:5]1
Reactant: CC(C)(C)C(=O)Cl
Reactant: CC1=C(O)C(=O)C(C)O1
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC1=C(OC(=O)C(C)(C)C)C(=O)C(C)O1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
4-Hydroxy-2,5-dimethyl-3(2H)-furanone (1.0 g, TOKYO KASEI KOGYO CO., LTD.) and 4-dimethylaminopyridine (0.05 g) were dissolved in a mixture solution of pyridine (10 ml) and methylene chloride (10 ml) under an argon stream in a 50 ml two-necked flask. To the resulting solution, pivaloyl chloride (1.06 ml) was added dropwise under cooling with ice and the mixture was stirred at room temperature for 1 hour. Subsequently, the reaction mixture solution was mixed with a 0.5N ice-cooled aqueous solution of HCl (10 ml) and subjected to extraction with diethyl ether (30 ml). The ether-extraction was repeated 3 times. The ether layer was washed 3 times with a 0.5N aqueous solution of HCl, twice with a saturated aqueous solution of sodium bicarbonate and once with a saturated saline solution and dried over sodium sulfate. The ether layer was then concentrated under a reduced pressure and applied to a silica gel column for separation and purification. Thus, 2,5-dimethyl-4-pivaloyloxy-3(2H)-furanone (1.40 g) was obtained.
Reaction SMILES: [CH:1]1[C:13]2[CH:12]([CH2:14][O:15][C:16](=[O:26])[NH:17][C:18]([CH3:25])([CH3:24])[CH2:19][S:20](Cl)(=[O:22])=[O:21])[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.[CH:27]([N:30]1[CH2:35][CH2:34][CH:33]([NH2:36])[CH2:32][CH2:31]1)([CH3:29])[CH3:28]>>[CH:1]1[C:13]2[CH:12]([CH2:14][O:15][C:16](=[O:26])[NH:17][C:18]([CH3:25])([CH3:24])[CH2:19][S:20](=[O:22])(=[O:21])[NH:36][CH:33]3[CH2:34][CH2:35][N:30]([CH:27]([CH3:29])[CH3:28])[CH2:31][CH2:32]3)[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)(CS(=O)(=O)Cl)NC(=O)OCC1c2ccccc2-c2ccccc21
Reactant: CC(C)N1CCC(N)CC1
Product: CC(C)N1CCC(NS(=O)(=O)CC(C)(C)NC(=O)OCC2c3ccccc3-c3ccccc32)CC1

Procedure:
[2-(1-Isopropyl-piperidin-4-ylsulfamoyl)-1,1-dimethyl-ethyl]-carbamic acid 9H-fluoren-9-ylmethyl ester was prepared by an analogous procedure as described in example 26 vi) starting from 479 mg (1.2 mmol) (2-chlorosulfonyl-1,1-dimethyl-ethyl)-carbamic acid 9H-fluoren-9-ylmethyl ester and 208 mg (1.2 equiv.) 1-isopropyl-piperidin-4-ylamine. The product was obtained in crude form as light yellow foam. Yield: 678 mg MS (ES+): m/e=500.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][O:5][C:6]1[CH:7]=[C:8]2[C:12](=[C:13]([N:15]([CH3:25])[S:16]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=3)(=[O:18])=[O:17])[CH:14]=1)[NH:11][C:10]([C:26]1[S:27][CH:28]([CH2:31][C:32]([O:34]CC)=[O:33])[CH2:29][N:30]=1)=[CH:9]2.[OH-].[Na+].O1CCCC1.Cl>C(O)C>[CH3:1][O:2][CH2:3][CH2:4][O:5][C:6]1[CH:7]=[C:8]2[C:12](=[C:13]([N:15]([CH3:25])[S:16]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=3)(=[O:18])=[O:17])[CH:14]=1)[NH:11][C:10]([C:26]1[S:27][CH:28]([CH2:31][C:32]([OH:34])=[O:33])[CH2:29][N:30]=1)=[CH:9]2
Reactant: CCOC(=O)CC1CN=C(c2cc3cc(OCCOC)cc(N(C)S(=O)(=O)c4ccccn4)c3[nH]2)S1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Product: COCCOc1cc(N(C)S(=O)(=O)c2ccccn2)c2[nH]c(C3=NCC(CC(=O)O)S3)cc2c1
Temperature: 50 °C
Reaction time: 1 h
Yield: 88 %

Procedure:
A mixture of ethyl (2-{5-(2-methoxyethoxy)-7-[methyl(pyridin-2-ylsulfonyl)amino]-1H-indol-2-yl}-4,5-dihydro-1,3-thiazol-5-yl)acetate (960 mg), 1N aqueous sodium hydroxide solution (5 mL), tetrahydrofuran (5 mL) and ethanol (5 mL) was stirred for 50° C. for 1 hr. 1N Hydrochloric acid (5 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried (MgSO4), and concentrated to give the title compound (800 mg, yield 88%) as a yellow amorphous solid. The solid was crystallized from ethyl acetate-hexane, and recrystallized from ethyl acetate-hexane to give pale-yellow powder. melting point 107-109° C.
Reaction SMILES: [C:1]([C:3]1[CH:11]=[CH:10][C:6]([C:7]([OH:9])=[O:8])=[C:5]([F:12])[CH:4]=1)#[N:2].O.[C:14]1(C)C=CC(S(O)(=O)=O)=CC=1>CO>[C:1]([C:3]1[CH:11]=[CH:10][C:6]([C:7]([O:9][CH3:14])=[O:8])=[C:5]([F:12])[CH:4]=1)#[N:2]
Reactant: N#Cc1ccc(C(=O)O)c(F)c1
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: CO
Product: COC(=O)c1ccc(C#N)cc1F
Yield: 1024.5 %

Procedure:
A solution of 4-cyano-2-fluorobenzoic acid (4.02 g, 24.36 mmol, Aldrich) in methanol (50 mL) was treated with p-toluenesulfonic acid monohydrate (0.46 g, 2.43 mmol) and heated to reflux overnight. The solvent was removed and the reaction residue was extracted with EtOAc, washed with saturated Na2CO3, brine and dried over Na2SO4 to give Methyl 4-cyano-2-fluorobenzoate (4.46 g, 95%). This Methyl ester (1.03 g, 5.77 mmol) was combined with methanol (60 mL) and Raney Ni (2 spatula tip fulls were added after washing with methanol under argon). It was then put under Hydrogen at 50 PSI on a PARR shaker for 18 hrs. The reaction was filtered through celite and washed with methanol while being kept under N2. It was then purified by silica gel chromatography with methanol and methylene chloride to give methyl 4-(aminomethyl)-2-fluorobenzoate (247.6 mg, 23%) as off-white solid.
Reaction SMILES: [C:1]([O:5][CH:6]([C:11]1[C:12]([CH3:27])=[N:13][C:14]2[N:15]([N:18]=[C:19]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[CH:20]=2)[C:16]=1[Cl:17])[C:7]([O:9][CH3:10])=[O:8])([CH3:4])([CH3:3])[CH3:2].C1C(=O)N([Br:35])C(=O)C1>C(#N)C>[Br:35][C:20]1[C:19]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[N:18][N:15]2[C:16]([Cl:17])=[C:11]([CH:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])[C:7]([O:9][CH3:10])=[O:8])[C:12]([CH3:27])=[N:13][C:14]=12
Reactant: COC(=O)C(OC(C)(C)C)c1c(C)nc2cc(-c3ccccc3)nn2c1Cl
Reactant: O=C1CCC(=O)N1Br
Solvent: CC#N
Product: COC(=O)C(OC(C)(C)C)c1c(C)nc2c(Br)c(-c3ccccc3)nn2c1Cl
Temperature: 25 °C
Reaction time: 1 h
Yield: 95.5 %

Procedure:
To a solution of methyl 2-(tert-butoxy)-2-(7-chloro-5-methyl-2-phenylpyrazolo[1,5-a]pyrimidin-6-yl)acetate (800 mg, 2.063 mmol) in acetonitrile (20 mL) was added NBS (367 mg, 2.063 mmol). The reaction mixture was stirred at r.t. for 1 h. The solvent was evaported and the residue was purified by silica gel chromatography to afford (920 mg, 96%) of the title compound. 1H NMR (500 MHz, CHLOROFORM-d) δ 8.09 (dd, J=8.1, 1.4 Hz, 2H), 7.61-7.39 (m, 3H), 5.65 (s, 1H), 3.73 (s, 3H), 2.73 (s, 3H), 1.26 (s, 9H).
Reaction SMILES: [NH2:1][NH2:2].C(N(CC)CC)C.[Cl:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]2([C:21](F)=[O:22])[CH2:20][CH2:19][CH2:18]2)=[CH:13][CH:12]=1>C(#N)C>[Cl:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]2([C:21]([NH:1][NH2:2])=[O:22])[CH2:20][CH2:19][CH2:18]2)=[CH:13][CH:12]=1
Reactant: NN
Reactant: O=C(F)C1(c2ccc(Cl)cc2)CCC1
Solvent: CC#N
Solvent: CCN(CC)CC
Product: NNC(=O)C1(c2ccc(Cl)cc2)CCC1
Temperature: 0 °C

Procedure:
Anhydrous hydrazine (2.02 mL, 1.4 eq) was dissolved in acetonitrile (100 μL) and cooled to 0° C. Triethylamine (12.8 mL, 2.0 eq.) was added followed by 1-(4-chlorophenyl)cyclobutanecarbonyl fluoride (10 g, 1.0 eq) in acetonitrile (25 mL). After stirring at room temperature for one hour the acetonitrile was removed by evaporation. Product was obtained after silica gel chromatography.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4](F)[CH:3]=1.[CH3:9][N:10]([CH3:17])[CH:11]1[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]1.C(=O)([O-])[O-].[K+].[K+].O>CS(C)=O>[Br:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([N:14]2[CH2:15][CH2:16][CH:11]([N:10]([CH3:17])[CH3:9])[CH2:12][CH2:13]2)[CH:3]=1
Reactant: Fc1cc(Br)ccn1
Reactant: CN(C)C1CCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: CN(C)C1CCN(c2cc(Br)ccn2)CC1
Temperature: 100 °C
Yield: 96 %

Procedure:
In a pressure vessel were dissolved 4-bromo-2-fluoropyridine (1 g, 5.68 mmol) and N,N-dimethylpiperidin-4-amine (1.1 g, 8.58 mmol) in DMSO (7 ml). Potassium carbonate (2.4 g, 17.36 mmol) was added and the reaction was heated at 100° C. overnight. The reaction mixture was poured into water and extracted twice with diethylether. The organics were combined, washed with brine, dried over magnesium sulphate, filtered and concentrated under reduced pressure to give 1.55 g (91% yield) of the title compound as a oil. Purity 95%.
Reaction SMILES: [C:1]1([O:11][CH3:12])[C:2](=[CH:4][CH:5]=[C:6]([CH:10]=1)[CH:7]=[CH:8][CH3:9])[OH:3].C(OC(=O)C)(=[O:15])C.C([O-])(=O)C.[Na+].S(=O)(O)[O-].[Na+]>C(O)(=O)C.C1(C)C=CC=CC=1>[CH3:9][C:8]([CH2:7][C:6]1[CH:5]=[CH:4][C:2]([OH:3])=[C:1]([O:11][CH3:12])[CH:10]=1)=[O:15]
Reactant: CC=Cc1ccc(O)c(OC)c1
Reactant: CC(=O)OC(C)=O
Agent: CC(=O)[O-]
Agent: O=S([O-])O
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CC(=O)O
Product: COc1cc(CC(C)=O)ccc1O
Temperature: 20 °C
Yield: 85.3 %

Procedure:
A mixture of isoeugenol (8.21 g., 50 mm.), acetic anhydride (5.62 g., 55 mm.) and anhydrous sodium acetate (0.41 g., 5 mm.) is heated at 100° C.-105° C. under nitrogen atmosphere for 2.5 hours. The reaction mixture is cooled and diluted with 65 ml. of toluene before a solution (11 ml.) of 38.6% peracetic and 0.85 g. of sodium acetate in acetic acid is added slowly. After heating at 50° C.-60° C. for 2-3 hours, the reaction mixture is cooled to 20° C. and treated with aqueous sodium bisulfite (2.8 g.) to destroy excess peracetic acid. The entire mixture is mixed with 8 ml. of toluene, 50 ml. of 14% aqueous sulfuric acid, and is heated with stirring to reflux for 12.5 hours. After cooling to ambient temperature, the toluene layer is separated, and the aqueous layer extracted 3×20 ml. of toluene. The toluene layers are combined, washed with saturated aqueous sodium sulfate, dried over anhydrous magnesium sulfate and concentrated in vacuo to give methylvanillyl ketone in 85.3% yield.
Reaction SMILES: [Cl:1][C:2]1[N:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[C:5]([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[C:6]([C:12]1[CH:17]=[CH:16][C:15](/[CH:18]=[N:19]/[S:20]([C:22]([CH3:25])([CH3:24])[CH3:23])=[O:21])=[CH:14][CH:13]=1)=[N:7]2.[CH3:32][Mg]Br>C(Cl)Cl>[Cl:1][C:2]1[N:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[C:5]([C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1)[C:6]([C:12]1[CH:17]=[CH:16][C:15]([C@H:18]([NH:19][S:20]([C:22]([CH3:25])([CH3:24])[CH3:23])=[O:21])[CH3:32])=[CH:14][CH:13]=1)=[N:7]2
Reactant: C[Mg]Br
Reactant: CC(C)(C)S(=O)/N=C/c1ccc(-c2nc3ccnc(Cl)c3cc2-c2ccccc2)cc1
Solvent: ClCCl
Product: C[C@@H](NS(=O)C(C)(C)C)c1ccc(-c2nc3ccnc(Cl)c3cc2-c2ccccc2)cc1
Reaction time: 0.5 h

Procedure:
To a solution of N-{(1E)-[4-(5-chloro-3-phenyl-1,6-naphthyridin-2-yl)phenyl]methylene}-2-methylpropane-2-sulfinamide (34-1, 4.53 g, 10.1 mmol) in methylene chloride (100 mL) was added methyl magnesium bromide (30 mL, 42.0 mmol, 1.4M in 75:25 toluene:THF) at −10° C. After 30 minutes, the reaction was quenched by addition of saturated ammonium chloride solution (while maintaining the temperature below 0° C.) and extracted with methylene chloride. The combined organics were washed with water, brine, dried over magnesium sulfate, filtered and concentrated to give the title compound as a pale yellow solid. MS (M+H+): calculated=464.03, observed=464.2
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]([CH2:32][C:33]([N:35]1[CH2:39][C@@H:38]([F:40])[CH2:37][C@H:36]1[C:41]#[N:42])=[O:34])[C:12]12[CH2:19][CH2:18][C:15]([C:20]([O:22]N3C4C=CC=CC=4N=N3)=O)([CH2:16][CH2:17]1)[CH2:14][CH2:13]2)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N:43]1([CH:49]2[CH2:54][CH2:53][NH:52][CH2:51][CH2:50]2)[CH2:48][CH2:47][CH2:46][CH2:45][CH2:44]1>>[CH2:1]([O:8][C:9]([N:11]([CH2:32][C:33]([N:35]1[CH2:39][C@@H:38]([F:40])[CH2:37][C@H:36]1[C:41]#[N:42])=[O:34])[C:12]12[CH2:19][CH2:18][C:15]([C:20]([N:52]3[CH2:53][CH2:54][CH:49]([N:43]4[CH2:48][CH2:47][CH2:46][CH2:45][CH2:44]4)[CH2:50][CH2:51]3)=[O:22])([CH2:14][CH2:13]1)[CH2:16][CH2:17]2)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C1CCN(C2CCNCC2)CC1
Reactant: N#C[C@@H]1C[C@H](F)CN1C(=O)CN(C(=O)OCc1ccccc1)C12CCC(C(=O)On3nnc4ccccc43)(CC1)CC2
Product: N#C[C@@H]1C[C@H](F)CN1C(=O)CN(C(=O)OCc1ccccc1)C12CCC(C(=O)N3CCC(N4CCCCC4)CC3)(CC1)CC2
Yield: 84.9 %

Procedure:
In a similar manner to Example 4, (2S,4S)-1-[[N-benzyloxycarbonyl-N-[4-(benzotriazol-1-yl)oxycarbonylbicyclo[2.2.2]oct-1-yl]amino]acetyl]-4-fluoropyrrolidine-2-carbonitrile (50.0 mg) and 4-(piperidin-1-yl)piperidine (22.0 mg) were used to obtain (2S,4S)-1-[[N-benzyloxycarbonyl-N-[4-[4-(piperidin-1-yl)piperidin-1-yl]carbonylbicyclo[2.2.2]oct-1-yl]amino]acetyl]-4-fluoropyrrolidine-2-carbonitrile (44.9 mg).
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][C:5]1[NH:9][N:8]=[CH:7][C:6]=1[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.[Br:16]N1C(=O)CCC1=O>CO>[Br:16][C:7]1[C:6]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[C:5]([CH2:4][CH2:3][O:2][CH3:1])[NH:9][N:8]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: COCCc1[nH]ncc1-c1ccccc1
Solvent: CO
Product: COCCc1[nH]nc(Br)c1-c1ccccc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 72 %

Procedure:
To a solution of 5-(2-methoxyethyl)-4-phenyl-1H-pyrazole (1.0 g, 4.94 mmol) in methanol (20 mL) was added N-bromosuccinimide (0.880 g, 4.94 mmol) in portions at room temperature. After stirred at room temperature for 16 h, the reaction was concentrated and extracted with EtOAc/H2O, purified by column chromatography to give the title compound as yellow oil (1.0 g). LCMS m/z=281.3 [M+H]+; 1H NMR (400 MHz, DMSO-d6) δ ppm 2.97 (t, J=6.63 Hz, 2H), 3.22 (s, 3H), 3.57 (t, J=7.07 Hz, 2H), 7.20-7.27 (m, 2H), 7.35-7.45 (m, 3H), 12.67 (bs, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:17]=[C:18]([Cl:20])[CH:19]=1)[CH2:5][C:6]1[C:7]([CH2:15][CH3:16])=[N:8][N:9]([CH2:13][OH:14])[C:10]=1[CH2:11][CH3:12].[N:21]([C:24]([O:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)=[O:25])=[C:22]=[O:23]>CN(C)C=O>[C:22]([NH:21][C:24]([O:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)=[O:25])([O:14][CH2:13][N:9]1[C:10]([CH2:11][CH3:12])=[C:6]([CH2:5][C:4]2[CH:17]=[C:18]([Cl:20])[CH:19]=[C:2]([Cl:1])[CH:3]=2)[C:7]([CH2:15][CH3:16])=[N:8]1)=[O:23]
Reactant: O=C=NC(=O)Oc1ccccc1
Reactant: CCc1nn(CO)c(CC)c1Cc1cc(Cl)cc(Cl)c1
Solvent: CN(C)C=O
Product: CCc1nn(COC(=O)NC(=O)Oc2ccccc2)c(CC)c1Cc1cc(Cl)cc(Cl)c1
Reaction time: 1.5 h

Procedure:
A solution of the alcohol of Example 41 (6.3 mg, 20 μmol) in dimethylformamide (250 μL) was treated with phenyl isocyanatoformate (3.6 mg, 22 μmol) and the mixture was shaken for 1.5 hours. The reaction mixture was filtered and the filtrate was purified by HPLC (Hypersil Thermoquest Luna C8 150×10 mm column; a gradient mobile phase was used, 10:90 (by volume)→95:5 (by volume) acetonitrile:(water, 95% by volume/trifluoroacetic acid, 0.1% by volume/acetonitrile 5%, by volume)).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][N:3]=[C:2]1[NH:6][C:7](=[O:9])[CH3:8].[Cl:10][CH:11]([C:13]1[O:18][C:17](=[O:19])[C:16]2[CH:20]=[CH:21][CH:22]=[C:23]([F:24])[C:15]=2[N:14]=1)[CH3:12]>O1CCCC1.C([Li])CCC.CCCCCC>[Cl:10][CH:11]([CH3:12])[C:13]([NH:14][C:15]1[C:23]([F:24])=[CH:22][CH:21]=[CH:20][C:16]=1[C:17](=[O:19])[CH2:8][C:7]([NH:6][C:2]1[S:1][CH:5]=[CH:4][N:3]=1)=[O:9])=[O:18]
Reactant: CC(Cl)c1nc2c(F)cccc2c(=O)o1
Reactant: CC(=O)Nc1nccs1
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CC(Cl)C(=O)Nc1c(F)cccc1C(=O)CC(=O)Nc1nccs1
Yield: 39.2 %

Procedure:
Using the procedure of Step A of Example 6, a solution of 17 g of N-(2-thiazolyl)-acetamide in 340 ml of tetrahydrofuran, 160 ml of butyllithium-hexane solution and 0.06 moles of the product of Step D in 130 ml of tetrahydrofuran were reacted to obtain 8.7 g of 2-[(2-chloro-1-oxo-propyl)amino]-β-oxo-N-(2-thiazolyl)-3-fluoro-benzene propanamide melting towards 170° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:11]=[C:12]([Cl:14])[CH:13]=1)[C:5](N(OC)C)=[O:6].[CH3:15][Mg]Br.Cl>O1CCCC1>[Cl:1][C:2]1[CH:3]=[C:4]([C:5](=[O:6])[CH3:15])[CH:11]=[C:12]([Cl:14])[CH:13]=1
Reactant: CON(C)C(=O)c1cc(Cl)cc(Cl)c1
Reactant: C[Mg]Br
Agent: Cl
Solvent: C1CCOC1
Product: CC(=O)c1cc(Cl)cc(Cl)c1
Temperature: 25 °C
Reaction time: 0.42 h

Procedure:
To the product from step A (5.42 g, 23.2 mmol) in 100 mL of tetrahydrofuran was added methylmagnesium bromide (11.6 mL, 34.8 mmol) drop-wise. After stirring at ambient temperature for 25 min, 1N hydrochloric acid was added and the mixture extracted with two portions of ethyl acetate. The combined organic layers were dried over magnesium sulfate and concentrated in vacuo to provide the title compound which was used without further purification. 1H NMR (500 MHz, CDCl3) δ: 7.84 (d, J=1.9 Hz, 2H); 7.58 (d, J=1.8 Hz, 1H); 2.63 (s, 3H).
Reaction SMILES: [CH:1]1([C:4]2[CH:11]=[C:10]([C:12]([F:15])([F:14])[F:13])[CH:9]=[C:8]([C:16]([F:19])([F:18])[F:17])[C:5]=2[CH:6]=[O:7])[CH2:3][CH2:2]1.Cl([O-])=[O:21].[Na+].P([O-])(O)(O)=O.[Na+]>C(O)(C)(C)C.CC(=CC)C.O>[CH:1]1([C:4]2[CH:11]=[C:10]([C:12]([F:15])([F:14])[F:13])[CH:9]=[C:8]([C:16]([F:17])([F:18])[F:19])[C:5]=2[C:6]([OH:21])=[O:7])[CH2:3][CH2:2]1
Reactant: O=Cc1c(C2CC2)cc(C(F)(F)F)cc1C(F)(F)F
Reactant: [O-][Cl+][O-]
Agent: CC=C(C)C
Agent: O=P([O-])(O)O
Agent: [Na+]
Solvent: O
Solvent: CC(C)(C)O
Product: O=C(O)c1c(C2CC2)cc(C(F)(F)F)cc1C(F)(F)F
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Crude 2-cyclopropyl-4,6-bis-trifluoromethyl-benzaldehyde (intermediate AM, 1.01 g, 3.58 mmol) was dissolved in 8.5 mL tert-butylalcohol and 4.5 mL 2-methyl-2-butene. At 0° C. a solution of sodium chlorite (340 mg, 3.76 mmol) and sodium dihydrogenphosphat (451 mg, 3.76 mmol) in 3 mL water was added. The reaction mixture was stirred at room temperature overnight. The solvents were evaporated off. The residue was taken up in 1N NaOH and extracted twice with tert-butyl methyl ether. The aqueous phase was adjusted to pH 2 by addition of 25% HCl and extracted twice with tert-butyl methyl ether. The combined organic phases were dried on sodium sulfate, filtered and evaporated. The crude material, off-white solid (1.01 g, 54%) was used without further purification.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5](I)=[CH:4][C:3]=1[O:9][CH3:10].[C:11]([OH:15])(=[O:14])[CH:12]=[CH2:13].CCN(CC)CC.Cl>CC#N.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[Br:1][C:2]1[CH:7]=[CH:6][C:5](/[CH:13]=[CH:12]/[C:11]([OH:15])=[O:14])=[CH:4][C:3]=1[O:9][CH3:10]
Reactant: C=CC(=O)O
Reactant: COc1cc(I)ccc1Br
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CC#N
Product: COc1cc(/C=C/C(=O)O)ccc1Br
Temperature: 90 °C
Reaction time: 0.5 h

Procedure:
To a solution of 1-bromo-4-iodo-2-methoxybenzene (L. A. Hasvold et al, US 2004/0254159, EXAMPLE 57B) (33.45 g, 107 mmol) in MeCN (100 mL) was added acrylic acid (9.61 g, 133 mmol), Et3N (37.2 mL, 267 mmol) and palladium acetate (719 mg, 3.2 mmol). The reaction mixture was heated to 90° C. for 40 minutes, cooled to RT and poured into 2.4 L 1M HCl. After stirring for 30 minutes, the solid was filtered, heated to reflux in EtOH (230 mL), allowed to cool to RT and stirred overnight. The solid was filtered and washed with 1:1 EtOH hexane (50 mL) to give desired product. LRMS ESI+ (M+H)+257.0.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[Cl:10])[CH2:5][NH2:6].Cl[C:12]1[C:13]2[CH:26]=[C:25]([N+:27]([O-:29])=[O:28])[S:24][C:14]=2[N:15]=[C:16]([C:18]2[CH:23]=[N:22][CH:21]=[CH:20][N:19]=2)[N:17]=1>>[N:19]1[CH:20]=[CH:21][N:22]=[CH:23][C:18]=1[C:16]1[N:17]=[C:12]([NH:6][CH2:5][C:4]2[CH:7]=[CH:8][C:9]([Cl:10])=[C:2]([Cl:1])[CH:3]=2)[C:13]2[CH:26]=[C:25]([N+:27]([O-:29])=[O:28])[S:24][C:14]=2[N:15]=1
Reactant: NCc1ccc(Cl)c(Cl)c1
Reactant: O=[N+]([O-])c1cc2c(Cl)nc(-c3cnccn3)nc2s1
Product: O=[N+]([O-])c1cc2c(NCc3ccc(Cl)c(Cl)c3)nc(-c3cnccn3)nc2s1

Procedure:
With the procedure of Example 1, the reaction of 3,4-dichlorobenzylamine with 4-chloro-2-(pyrazin-2-yl)-6-nitro-thieno-[2,3-d]-pyrimidine yields 2-(pyrazin-2-yl)-4-(3,4-dichlorobenzylamino)-6-nitro-thieno-[2,3-d]-pyrimidine.