Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([NH2:8])=[O:7])=[CH:4][CH:3]=1.[CH3:11][C:12]([CH:15]=O)([CH3:14])[CH3:13].[NH:17]1[C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=2[N:19]=[N:18]1.C1(C)C=CC(S(O)(=O)=O)=CC=1>>[N:17]1([CH:15]([NH:8][C:6](=[O:7])[C:5]2[CH:9]=[CH:10][C:2]([Br:1])=[CH:3][CH:4]=2)[C:12]([CH3:13])([CH3:14])[CH3:11])[C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=2[N:19]=[N:18]1
Reactant: c1ccc2[nH]nnc2c1
Reactant: CC(C)(C)C=O
Reactant: NC(=O)c1ccc(Br)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Product: CC(C)(C)C(NC(=O)c1ccc(Br)cc1)n1nnc2ccccc21

Procedure:
4-Bromobenzamide, pivaldehyde, benzotriazole, and p-toluenesulfonic acid were processed as described in Example 53A to provide the desired product.
Reaction SMILES: [CH2:1]([C:8]1[C:13]([NH:14][NH2:15])=[N:12][CH:11]=[C:10]([C:16]2[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=2)[N:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH:22]1[CH:26]=[C:25]([CH2:27][CH:28]([C:34](OCC)=O)[C:29]([O:31][CH2:32][CH3:33])=[O:30])[N:24]=[CH:23]1>>[CH2:1]([C:8]1[C:13]2[N:12]([C:34]([CH:28]([CH2:27][C:25]3[N:24]=[CH:23][NH:22][CH:26]=3)[C:29]([O:31][CH2:32][CH3:33])=[O:30])=[N:15][N:14]=2)[CH:11]=[C:10]([C:16]2[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=2)[N:9]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)C(Cc1c[nH]cn1)C(=O)OCC
Reactant: NNc1ncc(-c2cccnc2)nc1Cc1ccccc1
Product: CCOC(=O)C(Cc1c[nH]cn1)c1nnc2c(Cc3ccccc3)nc(-c3cccnc3)cn12

Procedure:
In a manner analogous to that described in Example 1, by condensing 2-benzyl-3-hydrazino-6-(3-pyridyl)pyrazine with diethyl (imidazol-4-ylmethyl)malonate there is obtained ethyl rac-8-benzyl-α-(imidazol-4-ylmethyl)-6-(3-pyridyl)-s-triazolo[4,3-a]pyrazine-3-acetate, MS: 453 (M)+, which is converted into the above acid by alkaline saponification.
Reaction SMILES: [CH:1]1([C:4]2[N:9]=[CH:8][C:7]([C:10]3[CH:15]=[CH:14][N:13]=[C:12]([C:16]([NH:18][C:19]4[N:24]=[C:23]([C:25]([O:27]C)=O)[CH:22]=[CH:21][CH:20]=4)=[O:17])[CH:11]=3)=[CH:6][CH:5]=2)[CH2:3][CH2:2]1.O.[NH2:30][NH2:31]>C(O)C>[CH:1]1([C:4]2[N:9]=[CH:8][C:7]([C:10]3[CH:15]=[CH:14][N:13]=[C:12]([C:16]([NH:18][C:19]4[CH:20]=[CH:21][CH:22]=[C:23]([C:25]([NH:30][NH2:31])=[O:27])[N:24]=4)=[O:17])[CH:11]=3)=[CH:6][CH:5]=2)[CH2:3][CH2:2]1
Reactant: COC(=O)c1cccc(NC(=O)c2cc(-c3ccc(C4CC4)nc3)ccn2)n1
Reactant: NN
Solvent: O
Solvent: CCO
Product: NNC(=O)c1cccc(NC(=O)c2cc(-c3ccc(C4CC4)nc3)ccn2)n1
Yield: 47 %

Procedure:
The methyl 6-(6-cyclopropyl-3,4′-bipyridine-2′-carboxamido)picolinate from the previous step were suspended in ethanol (20 mL), hydrazine hydrate (700 μL, 14.4 mmol) was added, and the reaction was heated to reflux for 4 hours. The reaction mixture was concentrated and the resultant solids were suspended in acetronitrile and collected by filtration. The solids were washed with acetonitrile (2×100 mL) and diethyl ether (2×100 mL), and dried under reduced pressure to afford 1.21 g (47% yield) of 6-cyclopropyl-N-(6-(hydrazinecarbonyl)pyridin-2-yl)-3,4′-bipyridine-2′-carboxamide as a white solid.
Reaction SMILES: [CH:1]1([C:4]2[N:5]=[C:6]3[CH:11]=[CH:10][C:9]([N:12]4[CH:17]=[CH:16][C:15]([OH:18])=[CH:14][C:13]4=[O:19])=[CH:8][N:7]3[C:20]=2[CH3:21])[CH2:3][CH2:2]1.[Br:22][C:23]1[N:24]=[C:25]([CH2:28]O)[S:26][CH:27]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCCOC)=O)=NC(OCCOC)=O>C1COCC1.O>[Br:22][C:23]1[N:24]=[C:25]([CH2:28][O:18][C:15]2[CH:16]=[CH:17][N:12]([C:9]3[CH:10]=[CH:11][C:6]4[N:7]([C:20]([CH3:21])=[C:4]([CH:1]5[CH2:3][CH2:2]5)[N:5]=4)[CH:8]=3)[C:13](=[O:19])[CH:14]=2)[S:26][CH:27]=1
Reactant: OCc1nc(Br)cs1
Reactant: Cc1c(C2CC2)nc2ccc(-n3ccc(O)cc3=O)cn12
Agent: COCCOC(=O)N=NC(=O)OCCOC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: O
Product: Cc1c(C2CC2)nc2ccc(-n3ccc(OCc4nc(Br)cs4)cc3=O)cn12
Temperature: 25 °C
Reaction time: 3 h
Yield: 46.6 %

Procedure:
To a solution of 1-(2-cyclopropyl-3-methylimidazo[1,2-a]pyridin-6-yl)-4-hydroxypyridin-2(1H)-one (50 mg), (4-bromo-1,3-thiazol-2-yl)methanol (69 mg) and triphenylphosphine (140 mg) in THF (6 ml) was added bis(2-methoxyethyl) azodicarboxylate (125 mg), and the mixture was stirred at room temperature for 3 h. The reaction mixture was poured into water and extracted with EtOAc. The extract was washed with brine, dried over MgSO4, concentrated and purified by silica gel column chromatography (hexane/EtOAc then EtOAc/MeOH). The resulting solid was recrystallized from EtOH-hexane to give the title compound (37.9 mg) as a white solid.
Reaction SMILES: [C:1](Cl)(Cl)=[O:2].C1(C)C=CC=CC=1.[NH2:12][C:13]1[CH:25]=[C:24]([F:26])[C:23]([F:27])=[CH:22][C:14]=1[C:15]([NH:17][O:18][CH2:19][CH:20]=[CH2:21])=[O:16].O>O1CCOCC1>[CH2:19]([O:18][N:17]1[C:15](=[O:16])[C:14]2[C:13](=[CH:25][C:24]([F:26])=[C:23]([F:27])[CH:22]=2)[NH:12][C:1]1=[O:2])[CH:20]=[CH2:21]
Reactant: C=CCONC(=O)c1cc(F)c(F)cc1N
Reactant: O=C(Cl)Cl
Solvent: O
Solvent: Cc1ccccc1
Solvent: C1COCCO1
Product: C=CCOn1c(=O)[nH]c2cc(F)c(F)cc2c1=O

Procedure:
Phosgene, as a 12.5% solution in toluene (9.4 mL, 12 mmol), was added to a solution of 2-amino-N-allyloxy-4,5-difluorobenzamide (Example Y-3, 2.08 g, 9.1 mmol) in 75 mL of dioxane. The solution was heated at reflux for 20 hours and then poured into 200 mL of water. The aqueous solution was extracted with ethyl acetate, and the combined organic fractions were washed with water and brine and dried over magnesium sulfate. The solution was concentrated to give 2.18 g of the title compound as a solid, mp 220-221° C.
Reaction SMILES: [C:1]1([CH:7]([O:11][C:12]2[C:17]([Cl:18])=[CH:16][C:15]([CH2:19][CH2:20][CH3:21])=[C:14](O)[C:13]=2[C:23](=O)[CH3:24])C(O)=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:26]([O-:29])(=[O:28])[CH3:27].[Na+].C(OC(=O)C)(=O)C>C(OCC)C>[C:26]([O:29][C:14]1[C:13]2[C:23]([CH3:24])=[C:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[O:11][C:12]=2[C:17]([Cl:18])=[CH:16][C:15]=1[CH2:19][CH2:20][CH3:21])(=[O:28])[CH3:27]
Reactant: CC(=O)[O-]
Reactant: CCCc1cc(Cl)c(OC(C(=O)O)c2ccccc2)c(C(C)=O)c1O
Agent: [Na+]
Solvent: CCOCC
Solvent: CC(=O)OC(C)=O
Product: CCCc1cc(Cl)c2oc(-c3ccccc3)c(C)c2c1OC(C)=O

Procedure:
A mixture of 2-phenyl-2-(2-acetyl-3-hydroxy-4-propyl-6-chlorophenoxy) acetic acid (Step b)(3.4 g, 9.3 mmol), anhydrous sodium acetate (6.8 g, 82 mmol) and acetic anhydride (50 mL) was refluxed for 1 hour. The mixture was cooled, diluted with diethyl ether and the salts filtered off. The filtrate was concentrated and the residue chromatographed on silica gel with 10% ethyl acetate in hexane to obtain the title compound, m.p. 86°-87° C.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5](Br)=[C:4]([CH3:9])[N:3]=1.[N:10]1([S:16]([C:19]2[CH:24]=[CH:23][C:22]([SH:25])=[CH:21][CH:20]=2)(=[O:18])=[O:17])[CH2:15][CH2:14][O:13][CH2:12][CH2:11]1.[Cl:26][C:27]1[CH:32]=[C:31]([C:33]([F:36])([F:35])[F:34])[CH:30]=[CH:29][C:28]=1[S:37](Cl)(=[O:39])=[O:38]>>[Cl:26][C:27]1[CH:32]=[C:31]([C:33]([F:35])([F:34])[F:36])[CH:30]=[CH:29][C:28]=1[S:37]([NH:1][C:2]1[CH:7]=[CH:6][C:5]([S:25][C:22]2[CH:21]=[CH:20][C:19]([S:16]([N:10]3[CH2:11][CH2:12][O:13][CH2:14][CH2:15]3)(=[O:18])=[O:17])=[CH:24][CH:23]=2)=[C:4]([CH3:9])[N:3]=1)(=[O:39])=[O:38]
Reactant: Cc1nc(N)ccc1Br
Reactant: O=S(=O)(c1ccc(S)cc1)N1CCOCC1
Reactant: O=S(=O)(Cl)c1ccc(C(F)(F)F)cc1Cl
Product: Cc1nc(NS(=O)(=O)c2ccc(C(F)(F)F)cc2Cl)ccc1Sc1ccc(S(=O)(=O)N2CCOCC2)cc1

Procedure:
Prepared from 2-amino-5-bromo-6-methylpyridine and 4-(N -morpholinylsulfonyl)thiophenol according to General Method 11 step 1 followed by reaction with 2-chloro-4-trifluoromethylphenylsulfonyl chloride according to General Method 11 step 1. 1H NMR (CDCl3): 8.24 (1 H, d, J 10 Hz, Ar CH ortho to SO2NH), 7.65 (1 H, s, A-ring CH ortho to Cl & CF3), 7.61-7.48 (4 H, m, Ar CH's), 7.03 (2 H, d, J 9 Hz, Ar CH's), 6.81 (1 H, d, J 11 Hz, Ar CH), 3.66-3.58 (4H, m, CH2OCH2), 2.90-2.81 (4H, m, CH2NCH2), 2.41 (3H, s, CH3). Hplc (Luna 2, Gradient 5): rt=5.94 minutes. LC/MS rt=6.60 minutes, 608 (MH+).
Reaction SMILES: [CH:1]1([CH2:4][CH2:5][O:6][C:7]2[CH:19]=[CH:18][C:10]([C:11]([NH:13][CH2:14][C:15]([OH:17])=[O:16])=[O:12])=[CH:9][CH:8]=2)[CH2:3][CH2:2]1.OC1C=C[C:24]([C:25]([O:27][CH3:28])=O)=[CH:23]C=1.COC1C=CC(CCO)=CC=1>>[CH3:28][O:27][C:25]1[CH:2]=[CH:3][C:1]([CH2:4][CH2:5][O:6][C:7]2[CH:8]=[CH:9][C:10]([C:11]([NH:13][CH2:14][C:15]([OH:17])=[O:16])=[O:12])=[CH:18][CH:19]=2)=[CH:23][CH:24]=1
Reactant: COC(=O)c1ccc(O)cc1
Reactant: O=C(O)CNC(=O)c1ccc(OCCC2CC2)cc1
Agent: COc1ccc(CCO)cc1
Product: COc1ccc(CCOc2ccc(C(=O)NCC(=O)O)cc2)cc1
Yield: 79 %

Procedure:
Reactions similar to those described in Example 1 (1a) and (1b) were conducted using methyl 4-hydroxybenzoate (4.56 g, 30.0 mmol) and 2-(4-methoxyphenyl)ethanol (5.03 g, 33.0 mmol) to give 7.80 g of the title compound (white powder, yield: 79%).
Reaction SMILES: O[CH2:2][C:3]1([CH3:9])[CH2:7][O:6][C:5](=[O:8])[NH:4]1.S(Cl)([Cl:12])=O.N1C=CC=CC=1>ClCCCl>[Cl:12][CH2:2][C:3]1([CH3:9])[CH2:7][O:6][C:5](=[O:8])[NH:4]1
Reactant: O=S(Cl)Cl
Reactant: CC1(CO)COC(=O)N1
Solvent: c1ccncc1
Solvent: ClCCCl
Product: CC1(CCl)COC(=O)N1
Temperature: 110 °C
Yield: 70.6 %

Procedure:
To a suspension of 4-(hydroxymethyl)-4-methyloxazolidin-2-one (1.89 g, 14.4 mmol) in 1,2-dichloroethane (10 ml) was added thionyl chloride (5.0 ml, 69 mmol) dropwise over 10 min. Pyridine (5.0 ml, 62 mmol) was added, and the solution heated to 110° C. for 2 h. The solution was cooled to RT, concentrated, and the residue purified by flash chromatography (30%→100% EtOAc in hexanes) to give the title compound as a white solid (1.52 g, 10.2 mmmol, 71%). 1H NMR (CDCl3, 400 MHz) δ 1.49 (s, 3H), 3.55 (s, 2H), 4.12 (d, J=9.2 Hz, 1H), 4.33 (d, 8.8 Hz, 1H), 5.8 (br s, 1H). ESI/APCI calculated for C5H8ClNO2: 149.02. Found: 150 (MH+).
Reaction SMILES: [NH2:1][C:2]1[C:3]([NH:14][CH2:15][CH2:16][CH2:17][Cl:18])=[C:4]([CH:9]=[CH:10][C:11]=1[O:12][CH3:13])[C:5]([O:7][CH3:8])=[O:6].[N:19]([C:22]1[C:23]([CH3:31])=[N:24][C:25]([O:29][CH3:30])=[N:26][C:27]=1[CH3:28])=[C:20]=S.Cl.C(N=C=NCCCN(C)C)C.C(N(CC)CC)C>O1CCCC1.O>[Cl:18][CH2:17][CH2:16][CH2:15][N:14]1[C:3]2[C:4]([C:5]([O:7][CH3:8])=[O:6])=[CH:9][CH:10]=[C:11]([O:12][CH3:13])[C:2]=2[N:1]=[C:20]1[NH:19][C:22]1[C:27]([CH3:28])=[N:26][C:25]([O:29][CH3:30])=[N:24][C:23]=1[CH3:31]
Reactant: COC(=O)c1ccc(OC)c(N)c1NCCCCl
Reactant: COc1nc(C)c(N=C=S)c(C)n1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CCN(CC)CC
Solvent: O
Solvent: C1CCOC1
Product: COC(=O)c1ccc(OC)c2nc(Nc3c(C)nc(OC)nc3C)n(CCCCl)c12
Temperature: 40 °C
Reaction time: 72 h
Yield: 57.2 %

Procedure:
A mixture of methyl 3-amino-2-[(3-chloropropyl)amino]-4-methoxybenzoate (965 mg, 3.55 mmol) and 5-isothiocyanato-2-methoxy-4,6-dimethylpyrimidine (1.04 g, 5.32 mmol) in tetrahydrofuran (15 mL) was stirred at 40° C. for 3 days. The solvent was removed in vacuo and the solid was collected by filtration, washed with diisopropyl ether. A mixture of the solid (1.589 g), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (0.72 g, 3.76 mmol) and triethylamine (0.52 mL, 3.73 mmol) in tetrahydrofuran (16 mL) was stirred at 50° C. for 3 hr. 1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (130 mg, 0.678 mmol) and triethylamine (0.095 mL, 0.682 mmol) were added to the reaction mixture at room temperature and the mixture was stirred at 50° C. for 1 hr. Water was added to the reaction mixture at room temperature and the mixture was extracted with a mixture of ethyl acetate, THF and N,N-dimethylformamide. The organic layer was washed with water and brine, dried over anhydrous magnesium sulfate and concentrated in vacuo to give the title compound (878.9 mg, 2.03 mmol, 66%) as a pale red solid.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:20])[CH:5]([NH:17][CH:18]=[O:19])[CH:6](O)[C:7](=[CH2:15])[CH2:8][CH2:9][N:10]([C:12](=[O:14])[CH3:13])[CH3:11])[CH3:2].S(Br)([Br:23])=O.O>ClCCl>[CH2:1]([O:3][C:4](=[O:20])[CH:5]([NH:17][CH:18]=[O:19])[CH:6]=[C:7]([CH2:15][Br:23])[CH2:8][CH2:9][N:10]([C:12](=[O:14])[CH3:13])[CH3:11])[CH3:2]
Reactant: O=S(Br)Br
Reactant: C=C(CCN(C)C(C)=O)C(O)C(NC=O)C(=O)OCC
Solvent: ClCCl
Solvent: O
Product: CCOC(=O)C(C=C(CBr)CCN(C)C(C)=O)NC=O
Reaction time: 1 h

Procedure:
15.8 g (55.2 mmol) of 6-(N-acetyl-N-methylamino)-2-formylamino-3-hydroxy-4-methylene-hexanoic acid ethyl ester are dissolved in 150 ml of dichloromethane, and 5.1 ml (66.2 mmol) of thionyl bromide are added dropwise at room temperature. After one hour, 100 ml of water are added and the mixture is stirred vigorously for 10 minutes. The organic phase is separated off, washed in succession with water, 1N KHCO3 solution and again with water, dried over MgSO4, filtered and concentrated by evaporation. 6-(N-acetyl-N-methylamino)-4-bromomethyl-2-formylamino-hex-3-enoic acid ethyl ester is obtained in the form of a yellowish-orange oil which is reacted further in the crude state.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([OH:9])=[CH:5][CH:4]=1)#[N:2].C([O-])([O-])=O.[K+].[K+].Cl[CH2:17][C:18]#[N:19].C>CC(Cl)(Cl)Cl.O.CN(C)C=O>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([O:9][CH2:17][C:18]#[N:19])=[CH:5][CH:4]=1)#[N:2]
Reactant: N#CCCl
Reactant: N#Cc1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CC(Cl)(Cl)Cl
Product: N#CCOc1ccc(C#N)cc1
Temperature: 5 °C
Reaction time: 3 h

Procedure:
The compound of 4-cyanophenoxyacetonitrile was prepared by heating 29.8 g of 4-cyanophenol, 44.8 g of anhydrous K2CO3, 40 ml of dimethylformamide and 18.75 g of chloroacetonitrile with stirring in a round-bottomed three-necked flask at 70°-80° C. for 3 hours, after which time the reaction mixture was poured into an ice and water mixture, which resulted in crystal formation. The crystals were separated by filtering and were then washed with water. After drying a pale tan solid was obtained which was then dissolved in methylchloroform at reflux temperature, treated with activated charcoal and filtered. The filtrate was cooled to 5° C. and the resulting crystals filtered and dried to give the 4-cyanophenoxyacetonitrile.
Reaction SMILES: [F:1][C:2]1[CH:12]=[C:11](F)[C:10]([F:14])=[CH:9][C:3]=1[C:4]([O:6][CH2:7][CH3:8])=[O:5].C(=O)([O-])[O-].[K+].[K+].[Cl:21][C:22]1[CH:23]=[C:24]([OH:33])[CH:25]=[N:26][C:27]=1[O:28][CH2:29][CH:30]([CH3:32])[CH3:31]>CS(C)=O.CCOC(C)=O>[Cl:21][C:22]1[CH:23]=[C:24]([O:33][C:11]2[C:10]([F:14])=[CH:9][C:3]([C:4]([O:6][CH2:7][CH3:8])=[O:5])=[C:2]([F:1])[CH:12]=2)[CH:25]=[N:26][C:27]=1[O:28][CH2:29][CH:30]([CH3:31])[CH3:32]
Reactant: CCOC(=O)c1cc(F)c(F)cc1F
Reactant: CC(C)COc1ncc(O)cc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: CCOC(=O)c1cc(F)c(Oc2cnc(OCC(C)C)c(Cl)c2)cc1F
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Ethyl 2,4,5-trifluorobenzoate (135 mg, 0.661 mmol) and potassium carbonate (156 mg, 1.129 mmol) were dissolved in DMSO (3.0 mL). 5-Chloro-6-isobutoxypyridin-3-ol (Preparation 16, 127.5 mg, 0.632 mmol) was added portion wise and the mixture was stirred at room temperature for 2 hours. The reaction was diluted in EtOAc (10.0 mL) and washed with brine (3×10 mL). The organic layer was dried over sodium sulfate, filtered and concentrated in vacuo. The residue was purified by silica gel chromatography eluting with 0 to 10% EtOAc in heptane to yield the title compound as a clear oil that solidified upon standing (155 mg, 35%):
Reaction SMILES: [Cl:1][C:2]1[CH:16]=[CH:15][C:5]([CH2:6][N:7]2[CH:12]=[C:11](Br)[CH:10]=[CH:9][C:8]2=[O:14])=[C:4]([F:17])[CH:3]=1.[CH3:18][O:19][C:20]1[N:25]=[CH:24][C:23](B(O)O)=[CH:22][CH:21]=1>O1CCOCC1.[O-]P([O-])([O-])=O.[K+].[K+].[K+].CCOC(C)=O.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:1][C:2]1[CH:16]=[CH:15][C:5]([CH2:6][N:7]2[CH:12]=[C:11]([C:23]3[CH:24]=[N:25][C:20]([O:19][CH3:18])=[CH:21][CH:22]=3)[CH:10]=[CH:9][C:8]2=[O:14])=[C:4]([F:17])[CH:3]=1
Reactant: O=c1ccc(Br)cn1Cc1ccc(Cl)cc1F
Reactant: COc1ccc(B(O)O)cn1
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: C1COCCO1
Solvent: CCOC(C)=O
Product: COc1ccc(-c2ccc(=O)n(Cc3ccc(Cl)cc3F)c2)cn1
Temperature: 80 °C
Yield: 91 %

Procedure:
According to Scheme 3 Method A: To a mixture of 1-(4-chloro-2-fluorobenzyl)-5-bromopyridin-2(1H)-one (1 eq, 1.00 mmol, 0.40 g) in dioxane/K3PO4 (2M, 10 mL), were added Pd(PPh3)4 (0.3 eq, 0.4 mmol, 0.4 g) and 6-methoxypyridin-3-ylboronic acid (1.5 eq, 2.00 mmol, 0.30 g) then the reaction mixture was heated at 80° C. for 17 hours. The mixture was diluted with AcOEt. The organic fraction washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure. The crude product was purified by silica gel chromatography (AIT Flashsmart prepacked column 25 g SiO2, CH2Cl2/AcOEt 70/30) and by crystallization in pentane/Et2O to afford 1-(4-chloro-2-fluorobenzyl)-5-(6-methoxypyridin-3-yl)pyridin-2(1H)-one (0.91 mmol, 0.40 g, 91%) as a white solid.
Reaction SMILES: [ClH:1].Cl.[CH2:3]([C:7]1[N:8]=[N:9][C:10]([O:27][CH:28]2[CH2:33][CH2:32][N:31]([CH3:34])[CH2:30][CH2:29]2)=[CH:11][C:12]=1[C:13]1[CH:18]=[CH:17][C:16]([O:19][CH2:20][CH:21]2[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]2)=[CH:15][CH:14]=1)[CH2:4][CH2:5][CH3:6].[C:35]([Cl:38])(=[O:37])[CH3:36].CCN(C(C)C)C(C)C.Cl>C(Cl)Cl.CN(C1C=CN=CC=1)C.CCOCC>[ClH:38].[ClH:1].[CH2:3]([C:7]1[N:8]=[N:9][C:10]([O:27][CH:28]2[CH2:29][CH2:30][N:31]([CH3:34])[CH2:32][CH2:33]2)=[CH:11][C:12]=1[C:13]1[CH:14]=[CH:15][C:16]([O:19][CH2:20][CH:21]2[CH2:26][CH2:25][N:24]([C:35](=[O:37])[CH3:36])[CH2:23][CH2:22]2)=[CH:17][CH:18]=1)[CH2:4][CH2:5][CH3:6]
Reactant: CC(=O)Cl
Reactant: CCCCc1nnc(OC2CCN(C)CC2)cc1-c1ccc(OCC2CCNCC2)cc1
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CCOCC
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCCCc1nnc(OC2CCN(C)CC2)cc1-c1ccc(OCC2CCN(C(C)=O)CC2)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 3-butyl-6-(1-methyl-piperidin-4-yloxy)-4-[4-(piperidin-4-ylmethoxy)-phenyl]-pyridazine dihydrochloride (0.2 mmol, 103 mg) in DCM (1 mL) at 0° C. was added acetyl chloride (0.4 mmol, 29 μL), DIEA (0.4 mmol, 70 μL) and DMAP (5 mg). The mixture was stirred at room temperature for 1 hour. The mixture was then condensed in vacuo and the residue was purified by silica gel chromatography (DCM to DCM+10% 2N NH3 in MeOH) to give a colorless sticky solid, which was dissolved in DCM (1.0 mL), 2N HCl in ether (1.0 mL) was added, kept at room temperature for 10 min, condensed, triturated with hexanes to provide the title compound. LCMS: m/z 482 [M+1]. 1H NMR (400 MHz, CD3OD): δ 7.63 and 7.75 (1H, s), 7.44-7.50 (2H, m), 7.12-7.17 (2H, m), 5.37-5.54 (1H, m), 4.37 (2H, d), 3.36-3.69 (3H, m), 3.08-3.30 (4H, m), 2.92 (3H, s), 2.11-2.74 (5H, m), 2.10 (3H, s), 1.86-2.08 (4H, m), 1.25-1.54 (7H, m), 0.82 (3H, t).
Reaction SMILES: [CH2:1]([N:8]1[C:16]2[C:11](=[CH:12][C:13]([C:17]([OH:26])([C:22]([F:25])([F:24])[F:23])[C:18]([F:21])([F:20])[F:19])=[CH:14][CH:15]=2)[CH:10]=[CH:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1CCN2C(=NCCC2)CC1.[Si:38](Cl)([CH2:43][CH3:44])([CH2:41][CH3:42])[CH2:39][CH3:40]>CN(C=O)C>[CH2:1]([N:8]1[C:16]2[C:11](=[CH:12][C:13]([C:17]([O:26][Si:38]([CH2:43][CH3:44])([CH2:41][CH3:42])[CH2:39][CH3:40])([C:18]([F:19])([F:20])[F:21])[C:22]([F:25])([F:23])[F:24])=[CH:14][CH:15]=2)[CH:10]=[CH:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC[Si](Cl)(CC)CC
Reactant: OC(c1ccc2c(ccn2Cc2ccccc2)c1)(C(F)(F)F)C(F)(F)F
Solvent: C1CCC2=NCCCN2CC1
Solvent: CN(C)C=O
Product: CC[Si](CC)(CC)OC(c1ccc2c(ccn2Cc2ccccc2)c1)(C(F)(F)F)C(F)(F)F
Temperature: 25 °C
Reaction time: 2 h
Yield: 87.7 %

Procedure:
A solution of 6.72 g (18 mmol) 2-(1-benzyl-1H-indol-5-yl)-1,1,1,3,3,3-hexafluoro-propan-2-ol (example 16) in DMF was treated with 4.03 mL (27.0 mmol) of DBU and at 0° C. then dropwise with 4.12 mL (27 mmol) TESCl. The mixture was stirred for 2 hrs at RT and the solvent was evaporated. Column chromatography on silicagel with n-heptane/EtOAc 6:1 yielded 7.7 g (88%) of 1-benzyl-5-(2,2,2-trifluoro-1-triethylsilanyloxy-1-trifluoromethyl-ethyl)-1H-indole, light yellow oil, MS: 489 (MH+).
Reaction SMILES: C([O:5][C:6](=[O:38])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[CH2:13][NH:14][C:15]([C@@H:17]1[CH2:21][C@@H:20]([F:22])[CH2:19][N:18]1[C:23](=[O:37])[NH:24][C:25]1[C:33]2[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=2)[N:27]([C:34](=[O:36])[NH2:35])[CH:26]=1)=[O:16])(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl.CCOCC>[C:34]([N:27]1[C:28]2[C:33](=[CH:32][CH:31]=[CH:30][CH:29]=2)[C:25]([NH:24][C:23]([N:18]2[CH2:19][C@H:20]([F:22])[CH2:21][C@H:17]2[C:15]([NH:14][CH2:13][C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[C:6]([OH:38])=[O:5])=[O:16])=[O:37])=[CH:26]1)(=[O:36])[NH2:35]
Reactant: CC(C)(C)OC(=O)c1ccccc1CNC(=O)[C@@H]1C[C@@H](F)CN1C(=O)Nc1cn(C(N)=O)c2ccccc12
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Solvent: CCOCC
Product: NC(=O)n1cc(NC(=O)N2C[C@H](F)C[C@H]2C(=O)NCc2ccccc2C(=O)O)c2ccccc21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 2-({[(2S,4R)-1-(1-carbamoyl-1H-indol-3-ylcarbamoyl)-4-fluoro-pyrrolidine-2-carbonyl]-amino}-methyl)-benzoic acid tert-butyl ester (prepared according to Scheme D1 using 2-aminomethyl-benzoic acid tert-butyl ester) (76 mg, 0.145 mm) in CH2Cl2 (1 mL) was added TFA (168 μl, 2.18 mmol) and the resulting solution was stirred at RT overnight. The crude mixture was concentrated to give a solid which was suspended in Et2O and filtered to give the desired material. MS (LC-MS): 468.1 [M+H]+, 490.1 [M+Na]+, 957.2 [2M+Na]+, 466.1 [M−H]−, 423.1 [M−CONH2]−, tR (HPLC conditions a): 2.64 min.
Reaction SMILES: [C:1](=[O:3])=O.[NH2:4][C:5]1[N:16]=[CH:15][CH:14]=[CH:13][C:6]=1[C:7]([NH:9][CH:10]([CH3:12])[CH3:11])=[O:8].C(Cl)(Cl)=O>>[CH:10]([N:9]1[C:7](=[O:8])[C:6]2[CH:13]=[CH:14][CH:15]=[N:16][C:5]=2[NH:4][C:1]1=[O:3])([CH3:12])[CH3:11]
Reactant: CC(C)NC(=O)c1cccnc1N
Reactant: O=C=O
Agent: O=C(Cl)Cl
Product: CC(C)n1c(=O)[nH]c2ncccc2c1=O

Procedure:
In addition to being useful as discussed above, acid anhydrides produced by the method of the invention are useful as intermediates for the production of pyrimidine diones which can be used as herbicides. For example, 3-azaisatoic anhydride can be dissolved in dimethylformamide and reacted with a substantially stoiciometric amount of isopropyl amine to produce 2-amino-N-isopropylnicotinamide. The reaction is conveniently conducted at a temperature of about 45°-50° until carbon dioxide evolution ceases. The 2-amino-N-isopropylnicotinamide can then be reacted with phosgene to produce 3-isopropyl pyrido[2,3-d]pyrimidine-2,4 (1H,3H)-dione. This reaction can be conducted under ambient pressure in p-dioxane as a solvent, preferably in the presence of triethylamine as an HCl absorber, at a temperature in the vicinity of 100°.
Reaction SMILES: [OH:1]CCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCO.N[C:57]([NH2:59])=[O:58].[CH3:60][CH:61]([OH:68])[CH2:62][O:63][CH:64]([CH2:66][OH:67])[CH3:65]>[Ni]>[C:57](=[O:1])([OH:58])[NH2:59].[CH3:60][CH:61]([OH:68])[CH2:62][O:63][CH:64]([CH2:66][OH:67])[CH3:65]
Reactant: OCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCO
Reactant: NC(N)=O
Agent: [Ni]
Agent: CC(O)COC(C)CO
Product: NC(=O)O
Temperature: 155 °C

Procedure:
810 parts of a polyethylene ether-diol of molecular weight 810 (H(OCH2CH2)18OH) and 60 parts of urea are heated in a stirred apparatus for 5 hours at 150° C., whilst passing a stream of nitrogen through the apparatus. After this time, the degree of conversion is 92%. Thereafter, 2,680 parts of dipropylene glycol, 1,200 parts of urea and 100 parts of the nickel-containing exchanger prepared as described in Example 1(a) are added. The reaction mixture is heated for 16 hours at 155° C., whilst passing a stream of nitrogen through the apparatus. After the mixture has cooled to about 100° C., the catalyst is filtered off. 4,350 parts of the co-carbamate mixture, consisting of 24% of a polyethylene ether-diol monocarbamate H(OCH2CH)18OCONH2 and 76% of dipropylene glycol monocarbamate, are obtained.