Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:3][C:4](=[O:28])[C:5]([C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([C:14]#[C:15][C:16]2[CH:21]=[CH:20][C:19]([CH2:22][C:23]([O:25][CH3:26])=[O:24])=[C:18]([F:27])[CH:17]=2)[CH:9]=1)([CH3:7])[CH3:6])C.[OH-].[Li+]>C(O)C.O1CCCC1>[F:27][C:18]1[CH:17]=[C:16]([C:15]#[C:14][C:10]2[CH:9]=[C:8]([C:5]([CH3:7])([CH3:6])[C:4]([OH:28])=[O:3])[CH:13]=[CH:12][CH:11]=2)[CH:21]=[CH:20][C:19]=1[CH2:22][C:23]([O:25][CH3:26])=[O:24]
Reactant: CCOC(=O)C(C)(C)c1cccc(C#Cc2ccc(CC(=O)OC)c(F)c2)c1
Agent: [Li+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Product: COC(=O)Cc1ccc(C#Cc2cccc(C(C)(C)C(=O)O)c2)cc1F
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 103.7 %

Procedure:
A solution of 2-[3-(3-fluoro-4-methoxycarbonylmethyl-phenylethynyl)-phenyl]-2-methyl-propionic acid ethyl ester (Intermediate 134, 0.13 g, 0.34 mmol) in ethanol (2 mL) and tetrahydrofuran (2 mL) was treated with 2M lithium hydroxide (1 mL, 2 mmol) and the resulting reaction mixture was stirred at ambient temperature for 45 minutes. The volatiles were evaporated in vacuo to a residue that was neutralized with saturated aqueous ammonium chloride solution and extracted with ethyl acetate. The organic phase was washed with water and brine, and dried over anhydrous magnesium sulfate, filtered and evaporated in vacuo to afford the title product (0.125 g,˜100%).
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[N:2]1.S(Cl)(Cl)=O.[CH3:14][C:15]([CH3:20])=[CH:16][C:17](O)=[O:18]>ClCCl>[N:1]1([C:17](=[O:18])[CH:16]=[C:15]([CH3:20])[CH3:14])[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[N:2]1
Reactant: c1ccc2[nH]nnc2c1
Reactant: CC(C)=CC(=O)O
Solvent: ClCCl
Solvent: O=S(Cl)Cl
Product: CC(C)=CC(=O)n1nnc2ccccc21
Temperature: 25 °C
Reaction time: 2 h
Yield: 89.5 %

Procedure:
1H-Benzotriazole (2.14 g, 18.0 mmol, 4 equiv.) was dissolved in dichloromethane (25 ml) and thionyl chloride (330 μl, 4.5 mmol, 1 equiv.) was added at room temperature. (450 mg, 4.5 mmol) 3-Methyl-but-2-enoic acid [CAS 541-47-9] was added and the mixture was stirred for 2 hours at room temperature. The suspension was filtered and the filtrate was extracted once with 2N NaOH solution and twice with dichloromethane. The organic extracts were combined, dried over sodium sulfate and evaporated to dryness. The crude product was purified by flash chromatography on a silica gel column eluting with an ethyl acetate:cyclohexane gradient 0:100 to 50:50. The desired 1-benzotriazol-1-yl-3-methyl-but-2-en-1-one (810 mg, 90% yield) was obtained as a light yellow solid, MS: m/e=202.1 (M+H+).
Reaction SMILES: CO.[OH-].[K+].[OH:5][C:6]1[CH:15]=[C:14]2[C:9]([C:10](=[O:18])[CH2:11][C:12]([CH3:17])([CH3:16])[O:13]2)=[CH:8][CH:7]=1.[CH2:19]1[O:22][CH:20]1[CH3:21]>O>[OH:22][CH:20]([CH3:21])[CH2:19][O:5][C:6]1[CH:15]=[C:14]2[C:9]([C:10](=[O:18])[CH2:11][C:12]([CH3:16])([CH3:17])[O:13]2)=[CH:8][CH:7]=1
Reactant: CC1CO1
Reactant: CC1(C)CC(=O)c2ccc(O)cc2O1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CC(O)COc1ccc2c(c1)OC(C)(C)CC2=O
Yield: 79.9 %

Procedure:
To a mixture of 40 ml of methanol, 5 ml of water 1.1 g (20 millimoles) of potassium hydroxide and 3.8 g (20 millimoles) of 7-hydroxy-2,2-dimethyl-4-chromanone under stirring 11.6 g (14 ml, 0.2 mole) of propene oxide are added and the reaction mixture is refluxed for 5 hours. The reaction mixture is diluted with 200 ml of water and worked up according to Example 12. Thus 4.0 g of the desired compound are obtained, yield 80%. Mp.: 111°-113° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH:12]=[CH:11][C:10]([C:13]([F:16])([F:15])[F:14])=[C:9]2[CH2:17][OH:18])=[CH:4][CH:3]=1.[F:19][C:20]1[C:25]([F:26])=[C:24](O)[CH:23]=[CH:22][C:21]=1[CH2:28][CH2:29][C:30]([O:32]CC)=[O:31]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[CH:12]=[CH:11][C:10]([C:13]([F:14])([F:15])[F:16])=[C:9]2[CH2:17][O:18][C:24]2[CH:23]=[CH:22][C:21]([CH2:28][CH2:29][C:30]([OH:32])=[O:31])=[C:20]([F:19])[C:25]=2[F:26])=[CH:6][CH:7]=1
Reactant: OCc1c(C(F)(F)F)ccn1-c1ccc(Cl)cc1
Reactant: CCOC(=O)CCc1ccc(O)c(F)c1F
Product: O=C(O)CCc1ccc(OCc2c(C(F)(F)F)ccn2-c2ccc(Cl)cc2)c(F)c1F

Procedure:
The title compound was prepared by reacting the product prepared in Step D of Example 1 and ethyl 3-(2,3-difluoro-4-hydroxyphenyl)propanoate, according to the procedures described in Example 1, Steps E and F.
Reaction SMILES: [Br:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([NH:8][NH2:9])=[O:7])=[CH:4][CH:3]=1.CO[C:14](OC)(N(C)C)[CH3:15].O.C1(C)C=CC(S(O)(=O)=O)=CC=1>CN(C)C=O>[Br:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]2[O:7][C:14]([CH3:15])=[N:9][N:8]=2)=[CH:4][CH:3]=1
Reactant: NNC(=O)c1ccc(Br)cc1
Reactant: COC(C)(OC)N(C)C
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CN(C)C=O
Solvent: O
Product: Cc1nnc(-c2ccc(Br)cc2)o1
Temperature: 60 °C

Procedure:
4-Bromo-benzoic acid hydrazide (12.90 g, 60 mmol) and N,N-dimethylacetamide dimethyl acetal (12 mL, 82.0 mmol) were dissolved in N,N-dimethylformamide (100 mL) and the solution heated to 60° C. for 2 hours. The solution was concentrated in vacuo and the residue taken up in toluene (80 mL) and treated with para-toluenesulfonic acid monohydrate (200 mg, 1.50 mmol). The mixture was heated to reflux for 2 hours, allowed to cool, and the product crystallised from the solution and was collected by filtration. The crude product was washed with ether and dried in vacuo to yield a white solid. The filtrate was concentrated in vacuo and the residue combined with the white solid, dissolved in toluene (50 mL) and treated with para-toluenesulfonic acid monohydrate (100 mg, 0.75 mmol). The mixture was heated to reflux for 3 hours, allowed to cool and concentrated in vacuo. The residue was purified by column chromatography on silica gel eluting with pentane:ethyl acetate 80:20 to 40:60 to yield the title product, 12.00 g.
Reaction SMILES: O[CH:2]=[C:3]1[C:12](=[O:13])[C:11]2[C:6](=[CH:7][C:8]([O:16][CH3:17])=[C:9]([O:14][CH3:15])[CH:10]=2)[N:5]([C:18]([O:20][CH2:21][CH3:22])=[O:19])[CH:4]1[CH3:23].[O:24]([CH2:31][CH2:32][NH2:33])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>C1C=CC=CC=1>[O:24]([CH2:31][CH2:32][NH:33][CH:2]=[C:3]1[C:12](=[O:13])[C:11]2[C:6](=[CH:7][C:8]([O:16][CH3:17])=[C:9]([O:14][CH3:15])[CH:10]=2)[N:5]([C:18]([O:20][CH2:21][CH3:22])=[O:19])[CH:4]1[CH3:23])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: CCOC(=O)N1c2cc(OC)c(OC)cc2C(=O)C(=CO)C1C
Reactant: NCCOc1ccccc1
Solvent: c1ccccc1
Product: CCOC(=O)N1c2cc(OC)c(OC)cc2C(=O)C(=CNCCOc2ccccc2)C1C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 1.6 g. of 3-hydroxymethylene-6,7-dimethoxy-2-methyl-4-oxo-1,2,3,4-tetrahydro-1-quinoline carboxylic acid, ethyl ester and 685 mg. of phenoxyethylamine in 15 ml. of benzene is allowed to stir overnight at room temperature. The reaction is concentrated to an oil and partitioned between 50 ml. of chloroform and 50 ml. of 1N aqueous sodium hdyroxide. The chloroform layer is separated, dried over magnesium sulfate and concentrated to give 1.9 g. of the desired product as a foam.
Reaction SMILES: FC(F)(F)C(O)=O.[CH2:8]([C:10]1[CH:15]=[CH:14][C:13]([CH:16]2[CH2:21][N:20]([C:22]([N:24]3[CH2:28][CH2:27][CH2:26][CH2:25]3)=[O:23])[CH2:19][CH:18]([NH2:29])[CH2:17]2)=[CH:12][CH:11]=1)[CH3:9].[F:30][C:31]1[CH:32]=[C:33]([C:37]2[CH:38]=[CH:39][C:40]([C:43](O)=[O:44])=[N:41][CH:42]=2)[CH:34]=[CH:35][CH:36]=1>>[CH2:8]([C:10]1[CH:11]=[CH:12][C:13]([CH:16]2[CH2:21][N:20]([C:22]([N:24]3[CH2:25][CH2:26][CH2:27][CH2:28]3)=[O:23])[CH2:19][CH:18]([NH:29][C:43]([C:40]3[CH:39]=[CH:38][C:37]([C:33]4[CH:34]=[CH:35][CH:36]=[C:31]([F:30])[CH:32]=4)=[CH:42][N:41]=3)=[O:44])[CH2:17]2)=[CH:14][CH:15]=1)[CH3:9]
Reactant: O=C(O)c1ccc(-c2cccc(F)c2)cn1
Reactant: CCc1ccc(C2CC(N)CN(C(=O)N3CCCC3)C2)cc1
Solvent: O=C(O)C(F)(F)F
Product: CCc1ccc(C2CC(NC(=O)c3ccc(-c4cccc(F)c4)cn3)CN(C(=O)N3CCCC3)C2)cc1

Procedure:
62 mg (0.11 mmol) of 5-(4-ethylphenyl)-1-(pyrrolidin-1-ylcarbonyl)piperidine-3-amine trifluoroacetate (Example 12A) and 27 mg (0.12 mmol, 1.1 eq.) of 5-(3-fluorophenyl)pyridine-2-carboxylic acid were reacted according to General Method 1. Yield: 31 mg (56% of theory)
Reaction SMILES: [CH3:1][Si:2](Cl)([CH3:4])[CH3:3].[Br:6][C:7]1[CH:12]=[CH:11][C:10]([OH:13])=[CH:9][CH:8]=1>C1(C)C=CC=CC=1.N1C=CC=CC=1>[CH3:1][Si:2]([O:13][C:10]1[CH:11]=[CH:12][C:7]([Br:6])=[CH:8][CH:9]=1)([CH3:4])[CH3:3]
Reactant: C[Si](C)(C)Cl
Reactant: Oc1ccc(Br)cc1
Solvent: Cc1ccccc1
Solvent: c1ccncc1
Product: C[Si](C)(C)Oc1ccc(Br)cc1
Temperature: 25 °C

Procedure:
Trimethylsilyl chloride (11 ml, 87 mmol) was added dropwise to a stirred solution of 4-bromophenol (10.0 g, 58 mmol) in toluene (25 ml) and pyridine (20 ml) at 0° C. The stirred mixture was heated to ambient temperature during 3 hours. The reaction mixture was filtered and the organic solution evaporated to yield pure 4-bromophenyl trimethylsilyl ether. The silyl ether can be further purified by distillation (b.p. 122° C., 20 mmHg). Yield after distillation: 13.70 g (75%)
Reaction SMILES: [CH:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Cl-].[Al+3].[Cl-].[Cl-].Cl[CH:12]([CH2:18]Cl)[CH2:13][Si:14]([Cl:17])([Cl:16])[Cl:15]>>[C:1]1([CH:18]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[CH2:12][CH2:13][Si:14]([Cl:17])([Cl:16])[Cl:15])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: ClCC(Cl)C[Si](Cl)(Cl)Cl
Reactant: c1ccccc1
Agent: [Al+3]
Agent: [Cl-]
Product: Cl[Si](Cl)(Cl)CCC(c1ccccc1)c1ccccc1
Reaction time: 0.5 h
Yield: 48.2 %

Procedure:
In the same apparatus and procedures as EXAMPLE 2 above, 17.8 ml (200 mmol) of benzene and 0.27 g (2.0 mmol) of aluminum chloride were alkylated with 4.51 g (18.3 mmol) of (2,3dichloropropyl)trichlorosilane for 10 min at 70° C. The aluminum chloride catalyst was quenched with POCl3 and then stirred for another 30 min to complete the deactivation. Freshly distilled hexane (50 ml) was added to the reaction mixture and insoluble solids in hexane were filtered from the organic soultion. After hexane and benzene were distilled, the reaction products were vacuum distilled to give 2.91 g of (3,3-diphenylpropyl)trichlorosilane (bp; 124-125° C./0.5 torr, yield; 48%).
Reaction SMILES: CS([O:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([C:12]2[O:13][C:14]([CH3:42])=[C:15]([CH2:17][O:18][C:19]3[CH:24]=[CH:23][C:22]([CH2:25][O:26][C:27]4[C:31]([CH:32]=O)=[CH:30][N:29]([C:34]5[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=5)[N:28]=4)=[CH:21][C:20]=3[O:40][CH3:41])[N:16]=2)[CH:7]=1)(=O)=O.[CH2:43]([P:52](=[O:59])([O:56][CH2:57][CH3:58])[O:53][CH2:54][CH3:55])P(=O)(OCC)OCC.CN(C)C=O.[H-].[Na+]>O>[OH:5][C:6]1[CH:7]=[C:8]([C:12]2[O:13][C:14]([CH3:42])=[C:15]([CH2:17][O:18][C:19]3[CH:24]=[CH:23][C:22]([CH2:25][O:26][C:27]4[C:31](/[CH:32]=[CH:43]/[P:52](=[O:59])([O:53][CH2:54][CH3:55])[O:56][CH2:57][CH3:58])=[CH:30][N:29]([C:34]5[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=5)[N:28]=4)=[CH:21][C:20]=3[O:40][CH3:41])[N:16]=2)[CH:9]=[CH:10][CH:11]=1
Reactant: CCOP(=O)(CP(=O)(OCC)OCC)OCC
Reactant: COc1cc(COc2nn(-c3ccccc3)cc2C=O)ccc1OCc1nc(-c2cccc(OS(C)(=O)=O)c2)oc1C
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOP(=O)(/C=C/c1cn(-c2ccccc2)nc1OCc1ccc(OCc2nc(-c3cccc(O)c3)oc2C)c(OC)c1)OCC
Reaction time: 15 h
Yield: 15.2 %

Procedure:
To a mixture of 3-{4-[(4-{[(4-formyl-1-phenyl-1H-pyrazol-3-yl)oxy]methyl}-2-methoxyphenoxy)methyl]-5-methyl-1,3-oxazol-2-yl}phenyl methanesulfonate (0.30 g), tetraethyl methylenediphosphonate (0.16 g) and N,N-dimethylformamide (10 mL) was added sodium hydride (60% in oil, 0.025 g) at room temperature, and the mixture was stirred at the same temperature for 15 hrs. Water was poured into the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated. The residue was subjected to silica gel column chromatography to give crystals from a fraction eluted with ethyl acetate-hexane (5:1, v/v). To a mixture of the obtained crystal, tetrahydrofuran (2 mL) and ethanol (2 mL) was added 1N aqueous sodium hydroxide solution (2 mL), and the mixture was stirred at 60° C. for 1 hr. To the reaction mixture was added dilute hydrochloric acid to acidify the solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated. The residue was subjected to silica gel column chromatography to give diethyl (E)-2-{3-[(4-{[2-(3-hydroxyphenyl)-5-methyl-1,3-oxazol-4-yl]methoxy}-3-methoxybenzyl)oxy]-1-phenyl-1H-pyrazol-4-yl}ethenylphosphonate as colorless crystals (0.050 g, yield 15%) from a fraction eluted with ethyl acetate-hexane (8:1, v/v). Recrystallization from ethyl acetate-hexane gave colorless prism crystals. melting point: 127-128° C.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:10][C:9]=1[NH:18][C:19](=[O:38])[CH2:20][C:21]([C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([C:29]2[CH:30]=[N:31][C:32]([CH:35]3[CH2:37][CH2:36]3)=[CH:33][CH:34]=2)[CH:24]=1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH:35]1([C:32]2[N:31]=[CH:30][C:29]([C:25]3[CH:24]=[C:23]([C:21]4[CH2:20][C:19](=[O:38])[NH:18][C:9]5[CH:10]=[C:11]([C:14]([F:16])([F:17])[F:15])[CH:12]=[CH:13][C:8]=5[N:7]=4)[CH:28]=[CH:27][CH:26]=3)=[CH:34][CH:33]=2)[CH2:36][CH2:37]1
Reactant: CC(C)(C)OC(=O)Nc1ccc(C(F)(F)F)cc1NC(=O)CC(=O)c1cccc(-c2ccc(C3CC3)nc2)c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C1CC(c2cccc(-c3ccc(C4CC4)nc3)c2)=Nc2ccc(C(F)(F)F)cc2N1

Procedure:
The title compound was prepared from (2-{3-[3-(6-cyclopropyl-pyridin-3-yl)-phenyl]-3-oxo-propionylamino}-4-trifluoromethyl-phenyl)-carbamic acid tert-butyl ester (Example M153) (300 mg, 0.556 mmol) by treatment with TFA in CH2Cl2 according to the general procedure N. Obtained as a white solid (125 mg, 53%).
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][CH:3]=[N:2]1.Cl[C:7]1[N:8]=[C:9]([NH:20][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([N+:28]([O-:30])=[O:29])[CH:23]=2)[C:10]2[C:15]3[CH2:16][CH2:17][CH2:18][CH2:19][C:14]=3[S:13][C:11]=2[N:12]=1>>[N:1]1([C:7]2[N:8]=[C:9]([NH:20][CH2:21][C:22]3[CH:27]=[CH:26][CH:25]=[C:24]([N+:28]([O-:30])=[O:29])[CH:23]=3)[C:10]3[C:15]4[CH2:16][CH2:17][CH2:18][CH2:19][C:14]=4[S:13][C:11]=3[N:12]=2)[CH:5]=[CH:4][CH:3]=[N:2]1
Reactant: c1cn[nH]c1
Reactant: O=[N+]([O-])c1cccc(CNc2nc(Cl)nc3sc4c(c23)CCCC4)c1
Product: O=[N+]([O-])c1cccc(CNc2nc(-n3cccn3)nc3sc4c(c23)CCCC4)c1

Procedure:
Following the procedure of Example 97, the reaction of pyrazole with 2-chloro-5,6,7,8-tetrahydro-4-(3-nitrobenzylamino)-[1]-benzothieno-[2,3-d]-pyrimidine gives 2-(pyrazol-1-yl)-5,6,7,8-tetrahydro-4-(3-nitrobenzylamino)-[1]-benzothieno-[2,3-d]-pyrimidine.
Reaction SMILES: [CH2:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH2:2]1.[Br:10][CH2:11][C:12](Br)=O.[Al+3].[Cl-].[Cl-].[Cl-].FC(F)(F)C(O)=O>C(Cl)Cl.C([SiH](CC)CC)C>[Br:10][CH2:11][CH2:12][C:6]1[CH:5]=[C:4]2[C:9](=[CH:8][CH:7]=1)[CH2:1][CH2:2][CH2:3]2
Reactant: O=C(Br)CBr
Reactant: c1ccc2c(c1)CCC2
Agent: CC[SiH](CC)CC
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: BrCCc1ccc2c(c1)CCC2
Reaction time: 2 h

Procedure:
2 ml (0.016 mol) of indan in 33 ml of methylene chloride and 1.6 ml (0.019 mol) of bromoacetyl bromide are mixed at 0° C. 2.27 g (0.017 mol) of AlCl3 are slowly added and the medium is allowed to return to room temperature and stirred for 2 hours. The mixture is poured into water/ice and extracted with methylene chloride. The organic phase is dried, filtered and the solvent is evaporated off under reduced pressure. The crude reaction product is crystallized from hexane. A white solid is separated (m.p. 57.8-58.1° C.) corresponding to the acylation product. 1.67 g (7 mmol) of this product are dissolved in 3.9 ml of triethylsilane and 3.9 ml of trifluoroacetic acid and the medium is heated at 80° C. for two hours. The medium is poured into an ice/NaOH mixture and extracted with ethyl acetate. The title compound is obtained.
Reaction SMILES: CCN(C(C)C)C(C)C.[Br:10][C:11]1[CH:20]=[C:19]2[C:14]([C:15]([OH:29])=[C:16]([C:24](OCC)=[O:25])[C:17](=[O:23])[C:18]2([CH3:22])[CH3:21])=[CH:13][CH:12]=1.Cl.[NH2:31][C@@H:32]([CH3:40])[C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34]>O1CCOCC1>[Br:10][C:11]1[CH:20]=[C:19]2[C:14]([C:15]([OH:29])=[C:16]([C:24]([NH:31][C@H:32]([C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])[CH3:40])=[O:25])[C:17](=[O:23])[C:18]2([CH3:21])[CH3:22])=[CH:13][CH:12]=1
Reactant: C[C@H](N)C(=O)OC(C)(C)C
Reactant: CCOC(=O)C1=C(O)c2ccc(Br)cc2C(C)(C)C1=O
Agent: Cl
Solvent: C1COCCO1
Solvent: CCN(C(C)C)C(C)C
Product: C[C@H](NC(=O)C1=C(O)c2ccc(Br)cc2C(C)(C)C1=O)C(=O)OC(C)(C)C
Temperature: 75 °C
Reaction time: 16 h
Yield: 67.9 %

Procedure:
DIPEA (120 μL, 690 μmol, 1.5 eq) was added to a mixture of ethyl 7-bromo-4-hydroxy-1,1-dimethyl-2-oxo-naphthalen-3-carboxylate (156 mg, 460 μmol, prepared in Example 53A-D) and (S)-tert-butyl 2-aminopropanoate hydrochloride (100 mg, 552 μmol) in dioxane (5 mL). The reaction mixture was stirred at 75° C. for 16 hours. The reaction mixture was cooled to room temperature and partitioned between EtOAc and water. The organic layer was separated, washed with brine, dried (MgSO4), and concentrated in vacuo to give a yellow oil. The crude oil was purified by silica flash chromatography (0-50% DCM/hexane) to give the desired ester as a transparent oil (137 mg). MS (m/e)=382.1 (M+H-tBu)+.
Reaction SMILES: [NH2:1][CH2:2][C@H:3]1[N:10]([C:11]([C:13]2[N:14]=[C:15]([CH3:25])[S:16][C:17]=2[C:18]2[CH:19]=[C:20]([CH3:24])[CH:21]=[CH:22][CH:23]=2)=[O:12])[CH2:9][C@H:8]2[C@@H:4]1[CH2:5][CH:6]([CH3:26])[CH2:7]2.[CH3:27][C:28]1[O:29][C:30]2[C:31](=[C:33]([C:37](O)=[O:38])[CH:34]=[CH:35][CH:36]=2)[N:32]=1.[OH-].[Na+]>O.CO>[CH3:26][CH:6]1[CH2:5][C@H:4]2[C@H:8]([CH2:9][N:10]([C:11]([C:13]3[N:14]=[C:15]([CH3:25])[S:16][C:17]=3[C:18]3[CH:19]=[C:20]([CH3:24])[CH:21]=[CH:22][CH:23]=3)=[O:12])[C@@H:3]2[CH2:2][NH:1][C:37]([C:33]2[CH:34]=[CH:35][CH:36]=[C:30]3[O:29][C:28]([CH3:27])=[N:32][C:31]=23)=[O:38])[CH2:7]1
Reactant: Cc1cccc(-c2sc(C)nc2C(=O)N2C[C@@H]3CC(C)C[C@@H]3[C@H]2CN)c1
Reactant: Cc1nc2c(C(=O)O)cccc2o1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: Cc1cccc(-c2sc(C)nc2C(=O)N2C[C@@H]3CC(C)C[C@@H]3[C@H]2CNC(=O)c2cccc3oc(C)nc23)c1

Procedure:
prepared by reaction of [(1S,2S,5R)-2-aminomethyl-7-methyl-3-aza-bicyclo[3.3.0]oct-3-yl]-(2-methyl-5-m-tolyl-thiazol-4-yl)-methanone with 2-methyl-benzoxazole-4-carboxylic acid which was synthesised by saponification of the corresponding methyl ester derivative (Goldstein S et al. J. of Heterocyclic. Chem. 1990, 27, 2, 335-336) with NaOH in a mixture water/MeOH.
Reaction SMILES: C(O[CH:5]([NH:10][C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[C:6]([O:8][CH3:9])=[O:7])(=O)C.[CH2:18](Br)[CH:19]=[CH2:20].[Br-]>CN(C=O)C.[Zn]>[CH3:9][O:8][C:6](=[O:7])[CH:5]([NH:10][C:11]([O:13][C:14]([CH3:15])([CH3:16])[CH3:17])=[O:12])[CH2:20][CH:19]=[CH2:18]
Reactant: C=CCBr
Reactant: COC(=O)C(NC(=O)OC(C)(C)C)OC(C)=O
Agent: [Br-]
Agent: [Zn]
Solvent: CN(C)C=O
Product: C=CCC(NC(=O)OC(C)(C)C)C(=O)OC
Temperature: 0 °C
Reaction time: 1 h
Yield: 100 %

Procedure:
To an ice cooled suspension of the product of Example 2 (0.525 mg, 2.12 mmol) and zinc dust (278 mg, 4.25 mmol) in DMF (4 mL) under nitrogen was added slowly via syringe neat allyl bromide (514 mg, 4.25 mmol). The bromide was added at such a rate as to maintain the internal temperature between 20° and 25° C., then stirred at that temperature for an additional 1 hour. Extractive workup and silica gel chromatography as described in Example 3 afforded 486 mg (100%) of product as a colorless oil.
Reaction SMILES: Cl.[C:2]([NH2:11])(=[O:10])[C:3]1[C:4](=[CH:6][CH:7]=[CH:8][CH:9]=1)[NH2:5].[C:12](OC(=O)C)(=O)[CH3:13]>>[CH3:12][C:13]1[NH:11][C:2](=[O:10])[C:3]2[C:4](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:5]=1
Reactant: CC(=O)OC(C)=O
Reactant: NC(=O)c1ccccc1N
Agent: Cl
Product: Cc1nc2ccccc2c(=O)[nH]1
Reaction time: 8 h
Yield: 42 %

Procedure:
Anthranilamide hydrochloride was prepared by adding 20 ml of concentrated hydrochloric acid (37% by weight) to a solution of 27.3 g of anthranilamide in 200 ml of methanol. This mixture was cooled in an ice bath to precipitate the hydrochloride which was then collected and dried to obtain a product melting at 234°C with decomposition. A 17.4 g (0.1 mole) portion of the hydrochloride obtained above was refluxed for 3 hours with 100 ml acetic anhydride and allows to stand overnight. The mixture was then cooled in an ice bath and the solids collected by filtration on a Buchner funnel. The filter cake was slurried in 100 ml of water, and warmed to aid solution and then 28% aqueous ammonia was added until the mixture was alkaline. After cooling the 2-methyl-4-(3H)quinazolinone precipitated as a solid, was then collected, washed with a small amount of cold water and dried at 70°C to obtain 6.72 g of the desired product. The 2-methyl-4-(3 H)quinazolinone melted at 236°-8°C and was obtained in a 42% yield.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]([CH:21]=[CH:22][CH:23]=1)[O:7][C:8]1[C:13]([CH2:14][C:15]([O:17][CH3:18])=[O:16])=[C:12]([O:19][CH3:20])[N:11]=[CH:10][N:9]=1)(=[O:3])[CH3:2].[CH2:24](O)[CH2:25][OH:26].C1(C)C=CC(S(O)(=O)=O)=CC=1>>[CH3:2][C:1]1([C:4]2[CH:5]=[C:6]([CH:21]=[CH:22][CH:23]=2)[O:7][C:8]2[C:13]([CH2:14][C:15]([O:17][CH3:18])=[O:16])=[C:12]([O:19][CH3:20])[N:11]=[CH:10][N:9]=2)[O:26][CH2:25][CH2:24][O:3]1
Reactant: OCCO
Reactant: COC(=O)Cc1c(OC)ncnc1Oc1cccc(C(C)=O)c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Product: COC(=O)Cc1c(OC)ncnc1Oc1cccc(C2(C)OCCO2)c1
Yield: 95.6 %

Procedure:
A mixture of methyl 4-(3-acetylphenoxy)-6-methoxy-pyrimidin-5-yl-acetate (15.0 g, 47 mmol), ethylene glycol (7.9 ml, 140 mmol) and p-toluene sulfonic acid is refluxed, removing the water azeotropically. After two hours the organic phase is washed with saturated sodium carbonate solution, dried (MgSO4) and evaporated to give the methyl 4-[3-(2-methyldioxolan-2-yl)-phenoxy]-6-methoxy-pyrimidin-5-yl-acetate as a yellow oil (16.2 g).
Reaction SMILES: [Cl:1][C:2]1[CH:13]=[C:12]([F:14])[C:11]([N:15]2[C:20](=[O:21])[CH:19]=[C:18]([C:22]([F:28])([F:27])[C:23]([F:26])([F:25])[F:24])[N:17]=[C:16]2Cl)=[CH:10][C:3]=1[C:4]([O:6][CH:7]([CH3:9])[CH3:8])=[O:5].ClC1C=C(F)C(N2C(Cl)=CC(C(F)(F)C(F)(F)F)=NC2=O)=CC=1[C:33](OC(C)C)=[O:34].C[O-].[Na+]>CO>[Cl:1][C:2]1[CH:13]=[C:12]([F:14])[C:11]([N:15]2[C:20](=[O:21])[CH:19]=[C:18]([C:22]([F:28])([F:27])[C:23]([F:24])([F:25])[F:26])[N:17]=[C:16]2[O:34][CH3:33])=[CH:10][C:3]=1[C:4]([O:6][CH:7]([CH3:9])[CH3:8])=[O:5]
Reactant: CC(C)OC(=O)c1cc(-n2c(Cl)nc(C(F)(F)C(F)(F)F)cc2=O)c(F)cc1Cl
Reactant: CC(C)OC(=O)c1cc(-n2c(Cl)cc(C(F)(F)C(F)(F)F)nc2=O)c(F)cc1Cl
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: COc1nc(C(F)(F)C(F)(F)F)cc(=O)n1-c1cc(C(=O)OC(C)C)c(Cl)cc1F
Temperature: 25 °C

Procedure:
The residue, a mixture of isopropyl 2-chloro-5-[2-chloro-6-oxo-4-pentafluoroethyl -1(6H)-pyrimidinyl]-4-fluorobenzoate and isopropyl 2-chloro-5-[6-chloro-2-oxo-4-pentafluoroethyl -1(2H)-pyrimidinyl]-4-fluorobenzoate, is dissolved in 20 ml of methanol and 3.8 ml of a 2N sodium methylate solution are added to the solution while stirring at 25° C. The temperature of the reaction mixture rises to 30° C. The mixture is subsequently stirred for 30 minutes and evaporated to dryness under reduced pressure. The residue is separated by chromatography on a silica gel column using n-hexane/diethyl ether (3:1). The first fraction, which still contains some diethylaniline, is dissolved in diethyl ether and the solution is extracted with 2N hydrochloric acid, washed to neutrality with water and dried over anhydrous sodium sulphate. The organic phase is evaporated to dryness under reduced pressure and the residue is recrystallized from n-hexane. There is obtained isopropyl 2-chloro-4-fluoro-5-[2-methoxy-6-oxo-4-pentafluoroethyl-1(6H)-pyrimidinyl]-benzoate, m.p. 82°-84° C. By further elution of the column with n-hexane/diethyl ether (1:2) there is obtained a second fraction which is recrystallized from diethyl ether/n-hexane. In this manner there is also obtained isopropyl 2-chloro-4-fluoro-5-[6-methoxy-2-oxo-4-pentafluoroethyl -1(2H)-pyrimidinyl]-benzoate, m.p. 127°-129° C.