Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O-][Mn](=O)(=O)=O.[K+].[C:7]([O-:10])([O-])=[O:8].[K+].[K+].[Cl:13][C:14]1[N:19]=[C:18]([Cl:20])[CH:17]=[C:16]([CH2:21][CH2:22]C=C(C)C)[N:15]=1>O.C(O)(C)(C)C>[Cl:13][C:14]1[N:19]=[C:18]([Cl:20])[CH:17]=[C:16]([CH2:21][CH2:22][C:7]([OH:10])=[O:8])[N:15]=1
Reactant: CC(C)=CCCc1cc(Cl)nc(Cl)n1
Reactant: O=C([O-])[O-]
Agent: O=[Mn](=O)(=O)[O-]
Agent: [K+]
Solvent: O
Solvent: CC(C)(C)O
Product: O=C(O)CCc1cc(Cl)nc(Cl)n1
Reaction time: 16 h
Yield: 49.8 %

Procedure:
The above synthesis may be carried out as follows: To a solution of LDA (1.28 g, 12 mmol) in THF (30 mL) at −78° C. was added 2,4-dichloro-6-methylpyrimidine (1.96 g, 12 mmol) in THF (15 mL). After stirring for 15 minutes, 3,3-dimethylallyl bromide (1.79 g, 12 mmol) in THF (5 mL) was added dropwise. After the reaction warmed to ambient temperature, water and ethyl acetate was added. The organic layer was separated, the solvent was removed in vacuo, and the residue was chromatographed (ethyl acetate/hexane, 1/19) to give 2.06 g (74%) of 2,4-dichloro-6-(4-methyl-3-pentenyl)pyrimidine (1H NMR (CDCl3) δ 7.15 (s, 1), 5.10 (t, 1), 2.80 (t, 2), 2.45 (m, 21, 1.70 (s, 3), 1.55 (s, 3)). To a solution of NaIO4 (17 g, 81 mmol) and KMnO4 (251 mg, 1.59 mmol) in water was added K2CO3 (1.29 g, 9.38 mmol) and 2,4dichloro-6-(4-methyl-3-pentenyl)pyrimidine (2.06 g, 8.9 mmol) in t-butanol. After stirring for 16 hours, the reaction was acidified to pH 3 and extracted with ethyl acetate. The organic layer was extracted with aqueous NaHCO3. The aqueous layer was acidified to pH 3 and extracted with ethyl acetate. The organic layer was dried and the solvent removed in vacuo to give 980 mg of 3-(2,4-dichloropyrimidin-6-yl)propionic acid (the compound of formula (XIX)), 1H NMR (CDCl3) δ 7.30 (s, 1), 3.05 (t, 2), 2.90 (t, 2). The acid was coupled to piperonylamine under standard conditions with isobutyl chloroformate and N-methylmorpholine to give the compound of formula (XX). Imidazole was added under standard conditions (1-trimethylsilylimidazole and CsF in DMF at 60° C.) to give N-[(1,3-benzodioxol-5-yl)ethyl]-6-chloro-2-(1H-:imidazol-1-yl)pyrimidine-4-propionamide (the compound of formula (Ihh)); MS: 386 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([NH2:8])[N:3]=1.[C:9](Cl)(=[O:11])[CH3:10]>O1CCOCC1>[NH2:8][C:4]1[N:3]=[C:2]([NH:1][C:9](=[O:11])[CH3:10])[CH:7]=[CH:6][CH:5]=1
Reactant: CC(=O)Cl
Reactant: Nc1cccc(N)n1
Solvent: C1COCCO1
Product: CC(=O)Nc1cccc(N)n1
Temperature: 0 °C
Reaction time: 8 h
Yield: 76.1 %

Procedure:
Dissolve 2,6-diaminopyridine (9.822 g, 90 mmol) in dioxane (100 mL) and cool to 0° C. Add acetyl chloride (2.355 g, 2.1 mL, 30 mmol) slowly and stir for 1 hr. at 0° C. Remove the ice bath and stir at room temperature overnight. Quench the reaction mixture with saturated NaHCO3 solution, extract with ethyl acetate three times. Combine the organic layers, dry over Na2SO4, filter, and concentrate to give a solid. Chromatography on silica gel, eluting with a gradient of 60-70% ethylacetate in hexanes affords the title intermediate (3.45 g, 76%): mass spectrum (ion spray): m/z=152.1 (M+1); 1H NMR (CDCl3, ppm): 7.49 (m, 3H), 6.28 (d, 1H), 4.31 (s, br, 2H), 2.19 (s, 3H).
Reaction SMILES: C[O:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[CH2:18][C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[C:11](=[O:19])[N:10]2[CH3:20])=[CH:5][CH:4]=1.[Cl-].[Al+3].[Cl-].[Cl-].O>C1C=CC=CC=1>[OH:2][C:3]1[CH:4]=[CH:5][C:6]([CH:9]2[CH2:18][C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[C:11](=[O:19])[N:10]2[CH3:20])=[CH:7][CH:8]=1
Reactant: COc1ccc(C2Cc3ccccc3C(=O)N2C)cc1
Agent: [Al+3]
Agent: [Cl-]
Solvent: O
Solvent: c1ccccc1
Product: CN1C(=O)c2ccccc2CC1c1ccc(O)cc1
Yield: 56.4 %

Procedure:
To 500 ml of a solution containing 10 g of 3-(4-methoxyphenyl)-2-methyl-1-oxo-1,2,3,4-tetrahydroisoquinoline in benzene, 20 g of aluminum chloride was added and the mixture was heated to reflux for 7 hours. After allowing the resulting mixture to cool, water was added thereto and the generated insoluble materials were removed by filtration through Celite. The filtrate was extracted with ethyl acetate and the combined organic layers were washed with brine, followed by drying over anhydrous magnesium sulfate. After evaporating the solvent, the residue was purified by silica gel column chromatography [hexane/ethyl acetate (2/1) to obtain 5.34 g of 3-(4-hydroxyphenyl)-2-methyl-1-oxo-1,2,3,4-tetrahydroisoquinoline.
Reaction SMILES: [CH2:1]([C@H:3]1[CH2:8][CH2:7][C@H:6]([C:9]2[CH:33]=[CH:32][C:12]([O:13][CH2:14][CH2:15][CH2:16][O:17][C:18](=[O:31])[C:19]3[CH:24]=[C:23]([N+:25]([O-])=O)[CH:22]=[C:21]([N+:28]([O-])=O)[CH:20]=3)=[CH:11][CH:10]=2)[CH2:5][CH2:4]1)[CH3:2]>C(OCC)(=O)C.[C].[Pd]>[CH2:1]([C@H:3]1[CH2:4][CH2:5][C@H:6]([C:9]2[CH:33]=[CH:32][C:12]([O:13][CH2:14][CH2:15][CH2:16][O:17][C:18](=[O:31])[C:19]3[CH:24]=[C:23]([NH2:25])[CH:22]=[C:21]([NH2:28])[CH:20]=3)=[CH:11][CH:10]=2)[CH2:7][CH2:8]1)[CH3:2]
Reactant: CC[C@H]1CC[C@H](c2ccc(OCCCOC(=O)c3cc([N+](=O)[O-])cc([N+](=O)[O-])c3)cc2)CC1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CC[C@H]1CC[C@H](c2ccc(OCCCOC(=O)c3cc(N)cc(N)c3)cc2)CC1

Procedure:
In 300 ml of ethyl acetate was dissolved 15.0 g (0.033 mol) of [4-(trans-4-ethyl-cyclohexyl)phenoxypropyl]3,5-dinitrobenzoate, and 1.50 g of 5% palladium-carbon was then added thereto and catalytic reduction is carried out at ordinary temperature under atmospheric pressure. After the completion of the reaction, the catalyst was removed by filtration and the solvent was distilled off under reduced pressure to obtain a crystal. The thus obtained crystal was recrystallized from n-heptane/ethyl acetate twice to obtain 11.1 g (0.028 mol) of [4-(trans-4-ethyl-cyclohexyl)phenoxypropyl]3,5-diaminobenzoate. The melting point of this compound was in the range of 91.5° to 92.4° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([NH:8][C:9](=[O:20])[C:10]2[CH:15]=[CH:14][C:13](Cl)=[C:12]([N+:17]([O-:19])=[O:18])[CH:11]=2)[CH:5]=[CH:6][CH:7]=1.[NH2:21][C:22]1[CH:23]=[C:24]([OH:28])[CH:25]=[CH:26][CH:27]=1.[OH-].[K+].Cl>CS(C)=O>[NH2:21][C:22]1[CH:23]=[C:24]([CH:25]=[CH:26][CH:27]=1)[O:28][C:13]1[CH:14]=[CH:15][C:10]([C:9]([NH:8][C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([Br:1])[CH:3]=2)=[O:20])=[CH:11][C:12]=1[N+:17]([O-:19])=[O:18]
Reactant: O=C(Nc1cccc(Br)c1)c1ccc(Cl)c([N+](=O)[O-])c1
Reactant: Nc1cccc(O)c1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CS(C)=O
Product: Nc1cccc(Oc2ccc(C(=O)Nc3cccc(Br)c3)cc2[N+](=O)[O-])c1
Temperature: 25 °C
Yield: 93.4 %

Procedure:
A solution of N-(3-Bromo-phenyl)-4-chloro-3-nitro-benzamide (from Example 16A) (0.71 g, 2.0 mmol), 3-aminophenol (0.22 g, 2.0 mmol) and powdered potassium hydroxide (0.23 g, 4.0 mmol) in Dimethyl sulfoxide (5 mL) was heated at 100° C. for 30 minutes. After cooling to room temperature the mixture was poured into ice water (100 mL) and the resultant solution adjusted to pH 5 with 1N aqueous hydrochloric acid. The solution was then extracted with ethyl acetate (3×50 mL), the combined extracts dried over sodium sulfate, filtered and concentrated under vacuum to provide the title compound (0.8 g, 93%).
Reaction SMILES: [OH:1][CH:2]1[CH2:5][N:4]([C:6]([C:8]2[CH:13]=[C:12]([S:14]([CH3:17])(=[O:16])=[O:15])[CH:11]=[CH:10][C:9]=2[O:18][C@H:19]([CH3:24])[C:20]([F:23])([F:22])[F:21])=[O:7])[CH2:3]1.F[C:26]1[CH:31]=[CH:30][C:29]([C:32]([F:35])([F:34])[F:33])=[CH:28][CH:27]=1>>[CH3:17][S:14]([C:12]1[CH:11]=[CH:10][C:9]([O:18][C@H:19]([CH3:24])[C:20]([F:23])([F:22])[F:21])=[C:8]([C:6]([N:4]2[CH2:3][CH:2]([O:1][C:26]3[CH:31]=[CH:30][C:29]([C:32]([F:35])([F:34])[F:33])=[CH:28][CH:27]=3)[CH2:5]2)=[O:7])[CH:13]=1)(=[O:15])=[O:16]
Reactant: Fc1ccc(C(F)(F)F)cc1
Reactant: C[C@@H](Oc1ccc(S(C)(=O)=O)cc1C(=O)N1CC(O)C1)C(F)(F)F
Product: C[C@@H](Oc1ccc(S(C)(=O)=O)cc1C(=O)N1CC(Oc2ccc(C(F)(F)F)cc2)C1)C(F)(F)F
Yield: 9 %

Procedure:
Prepared in analogy to Example 21(b) from (3-hydroxy-azetidin-1-yl)-[5-methanesulfonyl-2-((R)-2,2,2-trifluoro-1-methyl-ethoxy)-phenyl]-methanone and 4-fluorobenzotrifluoride. The crude material was purified by flash chromatography (methanol/dichloromethane) to yield the title compound as a white crystalline solid (yield 9%). MS (m/e): 512.3 (M+H+, 100%).
Reaction SMILES: O.[C:2]1(C)C=CC(S(O)(=O)=O)=CC=1.[OH:13][CH2:14][C:15]1[C:16](=[O:23])[C@@H:17]2[O:22][CH2:21][C@H:19]([CH:20]=1)[O:18]2>CO>[CH3:2][O:13][CH2:14][C:15]1[C:16](=[O:23])[C@@H:17]2[O:22][CH2:21][C@H:19]([CH:20]=1)[O:18]2
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: O=C1C(CO)=C[C@H]2CO[C@@H]1O2
Solvent: O
Solvent: CO
Product: COCC1=C[C@H]2CO[C@H](O2)C1=O
Yield: 44.7 %

Procedure:
2 g of p-toluene sulfonic acid monohydrate was added to 150 ml of a methanol solution containing 2.8 g of 1,6-anhydro-3,4-dideoxy-3-hydroxymethyl-β-D-glycero-hex-3-enopyranos-2-ulose obtained in the above step (1), and the mixture was refluxed under heating for one hour. Disappearance of the starting material was confirmed by TLC, and then the solvent was distilled off under reduced pressure. The obtained crude product was purified by silica gel column chromatography (ethyl acetate: hexane =1:2) to obtain 0.8 g of the desired product (Intermediate No. 48). The NMR analytical data of this product are as follows.
Reaction SMILES: [CH2:1]([O:8][CH2:9][C@@H:10]([NH:14][C:15]1[CH:20]=[CH:19][C:18]([C:21]#[N:22])=[C:17]([NH:23][C:24]2[S:28][N:27]=[C:26]([CH3:29])[CH:25]=2)[CH:16]=1)[C:11]([NH2:13])=[O:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([O-])([O-])=[O:31].[K+].[K+].OO>CS(C)=O>[NH2:13][C:11](=[O:12])[C@H:10]([NH:14][C:15]1[CH:20]=[CH:19][C:18]([C:21]([NH2:22])=[O:31])=[C:17]([NH:23][C:24]2[S:28][N:27]=[C:26]([CH3:29])[CH:25]=2)[CH:16]=1)[CH2:9][O:8][CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C([O-])[O-]
Reactant: Cc1cc(Nc2cc(N[C@H](COCc3ccccc3)C(N)=O)ccc2C#N)sn1
Agent: OO
Agent: [K+]
Solvent: CS(C)=O
Product: Cc1cc(Nc2cc(N[C@H](COCc3ccccc3)C(N)=O)ccc2C(N)=O)sn1
Reaction time: 0.25 h
Yield: 7.8 %

Procedure:
To a solution of (R)-3-(benzyloxy)-2-(4-cyano-3-(3-methylisothiazol-5-ylamino)phenylamino)propanamide (73 mg, 0.18 mmol) in DMSO (2 mL), K2CO3 (200 mg, 1.44 mmol) and H2O2 (50% aq., 1.00 mL) were added. After being stirred at 90 C for 15 min, the mixture was purified by HPLC to give the titled compound (6 mg). MS 426.3 (M+H); UV 200.4, 293.4 nm
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([N:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)[C:5]2[N:10]=[C:9](I)[S:8][C:6]=2[N:7]=1.CC1(C)C(C)(C)OB([C:26]2[CH:27]=[CH:28][C:29]([N:32]3[CH2:37][CH2:36][O:35][CH2:34][CH2:33]3)=[N:30][CH:31]=2)O1>>[Cl:1][C:2]1[N:3]=[C:4]([N:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)[C:5]2[N:10]=[C:9]([C:26]3[CH:31]=[N:30][C:29]([N:32]4[CH2:33][CH2:34][O:35][CH2:36][CH2:37]4)=[CH:28][CH:27]=3)[S:8][C:6]=2[N:7]=1
Reactant: Clc1nc(N2CCOCC2)c2nc(I)sc2n1
Reactant: CC1(C)OB(c2ccc(N3CCOCC3)nc2)OC1(C)C
Product: Clc1nc(N2CCOCC2)c2nc(-c3ccc(N4CCOCC4)nc3)sc2n1

Procedure:
4-(5-Chloro-2-iodothiazolo[5,4-d]pyrimidin-7-yl)morpholine 18 was reacted with 4-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-yl)morpholine via General Procedure A to give crude 5-chloro-7-morpholino-2-(6-morpholinopyridin-3-yl)thiazolo[5,4-d]pyrimidine, which was then reacted with 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidin-2-amine via General Procedure A again to give 123 after purification by reverse HPLC. MS (Q1) 478 (M+)
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8]([C:12]([OH:14])=[O:13])=[CH:7][CH:6]=[CH:5]2.[C:15](OC(=O)C)(=[O:17])[CH3:16]>S(=O)(=O)(O)O.O>[C:15]([O:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8]([C:12]([OH:14])=[O:13])=[CH:7][CH:6]=[CH:5]2)(=[O:17])[CH3:16]
Reactant: O=C(O)c1cccc2cc(O)ccc12
Reactant: CC(=O)OC(C)=O
Agent: O=S(=O)(O)O
Solvent: O
Product: CC(=O)Oc1ccc2c(C(=O)O)cccc2c1
Temperature: 25 °C

Procedure:
6-Hydroxy-1-naphthoic acid (1 g) was mixed with acetic anhydride (5 ml) and sulfuric acid (5 drops). The mixture was refluxed for 3 hours and cooled at RT for 10 hours then mixed with water (15 ml). The solid was filtered and washed with water and cold MeOH to give the product as 6-acetoxy-1-naphthoic acid (900 mg) that was mixed with EDC (1.5 eq), HOBt (1 eq), MeNH2—HCl (2.5 eq, methylamine hydrochloride) and DIPEA (2.5 eq) in DCM (25 ml). The reaction was stirred at RT overnight and washed with NaHCO3 solution, dried. The solution was evaporated and mixed with 15% KOH (2 ml) in MeOH (10 ml) further stirred at RT for 30 minutes. The solvent was evaporated and the residue was adjusted to weak acidic with 2N HCl, the solid was filtered and washed with water twice and cold MeOH to give 6-Hydroxy-N-methyl-1-naphthamide (720 mg).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][O:4][CH2:5][CH2:6][OH:7].CC1C=CC(S(O[CH2:19][CH2:20][O:21][CH2:22][CH2:23][NH:24][C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])(=O)=O)=CC=1>C(#N)C>[OH:7][CH2:6][CH2:5][O:4][CH2:3][CH2:2][NH:1][CH2:19][CH2:20][O:21][CH2:22][CH2:23][NH:24][C:25](=[O:26])[O:27][C:28]([CH3:31])([CH3:30])[CH3:29]
Reactant: Cc1ccc(S(=O)(=O)OCCOCCNC(=O)OC(C)(C)C)cc1
Reactant: NCCOCCO
Solvent: CC#N
Product: CC(C)(C)OC(=O)NCCOCCNCCOCCO
Temperature: 75 °C
Reaction time: 1 h
Yield: 46.7 %

Procedure:
2-(2-Aminoethoxyl)ethanol (0.7 g, 5 eq.) was added to a solution of 2-[2-(tert-butoxycarbonylamino)ethoxy]ethyl 4-methylbenzenesulfonate (0.5 g, 1 eq.) in dry acetonitrile (10 mL) and the reaction mixture was heated to 75° C. for 3 h and then at 85° C. for 1 h. The acetonitrile was removed in vacuo. The crude residue was redissolved in DCM (25 mL) and washed with water (25 mL) the aqueous phase was re-extracted with DCM (2×25 mL). The combined organic phases were washed with water (50 mL), dried (MgSO4), filtered and concentrated at reduced pressure to a pale yellow oil (0.4 g). The crude product was purified by silica column chromatography eluting with 10% methanolic ammonia in DCM to give 0.19 g (50%) of 18 as a colourless oil. 13C NMR (CDCl3) δ 156.1, 72.5, 70.2, 70.1, 61.9, 49.2, 49.0, 40.5, 28.4. ESMS (C13H28N2O5) [M+H]+ calc. 293.2076. found 293.2076.
Reaction SMILES: [H-].[Na+].[CH3:3][O:4][C:5]1[CH:6]=[CH:7][C:8]2[N:12]3[CH2:13][C:14]4C([C:11]3=[C:10](C=O)[C:9]=2[N:22]=1)=CC=C[CH:15]=4.CN(C)C=[O:26]>>[CH3:3][O:4][C:5]1[CH:6]=[CH:7][C:8]2[N:12]3[C:11]([O:26][CH2:15][CH2:14][CH2:13]3)=[CH:10][C:9]=2[N:22]=1
Reactant: CN(C)C=O
Reactant: COc1ccc2c(n1)c(C=O)c1n2Cc2ccccc2-1
Agent: [H-]
Agent: [Na+]
Product: COc1ccc2c(cc3n2CCCO3)n1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
Under an inert atmosphere, 160 mg (4 mmol) of sodium hydride (60% in oil) are added slowly at 0° C., to a solution of 380 mg (1.34 mmol) of the compound obtained in Step E in 10 ml of N,N-dimethylformamide. The reaction mixture is stirred at 0° C., for 30 minutes before being hydrolysed with ice and then extracted with ethyl acetate. The organic phase is washed several times with water, dried over magnesium sulphate, concentrated and purified by flash chromatography over silica gel (eluant:ethyl acetate/petroleum ether, 95:5) to yield the title compound in the form of a brown solid.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[N:4][C:5]([NH:8][NH2:9])=[CH:6][CH:7]=1.[C:10](O)(=O)[CH2:11][OH:12].CC1C=CC(S(O)(=O)=O)=CC=1.O>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]2[N:4]([C:10]([CH2:11][OH:12])=[N:9][N:8]=2)[N:3]=1
Reactant: NNc1ccc(Cl)nn1
Reactant: O=C(O)CO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: O
Product: OCc1nnc2ccc(Cl)nn12

Procedure:
A mixture of 3-chloro-6-hydrazinopyridazine (1.44 g, 9.96 mmol), glycolic acid (0.76 g, 10 mmol) and p-TsOH.H2O (2.37 g, 12.4 mmol) in toluene was refluxed overnight. Some oil formed at the bottom of the flask. LC-MS of this oil showed the desired product was formed. Toluene was decanted off, and the oil residue was suspended in water (10 mL), then basified with 3N aq. NaOH to pH=10, the resulting off-white solid was collected, and dried to give the title compound. LC-MS (ES+): 185/187 (3/1) [MH+]. 1H NMR (CDCl3): δ=2.96 (br s, 1H, —OH), 5.25 (s, 2H), 7.17 (d, J=9.6 Hz, 1H), 8.11 (d, J=9.6 Hz, 1H).
Reaction SMILES: C(=O)(O)[O-:2].[Na+].Cl.NO.[Cl:9][C:10]1[C:11]([C:23]#[N:24])=[N:12][CH:13]=[C:14]([Cl:22])[C:15]=1[O:16][CH2:17][C:18]([F:21])([F:20])[F:19]>C(O)C>[Cl:9][C:10]1[C:11]([C:23]([NH2:24])=[O:2])=[N:12][CH:13]=[C:14]([Cl:22])[C:15]=1[O:16][CH2:17][C:18]([F:21])([F:19])[F:20]
Reactant: O=C([O-])O
Reactant: N#Cc1ncc(Cl)c(OCC(F)(F)F)c1Cl
Agent: Cl
Agent: NO
Agent: [Na+]
Solvent: CCO
Product: NC(=O)c1ncc(Cl)c(OCC(F)(F)F)c1Cl
Reaction time: 2 h
Yield: 100 %

Procedure:
To 5 ml of ethanol were added 0.41 g of sodium bicarbonate and 0.34 g of hydroxylamine hydrochloride, and the mixture was heated to reflux for 1 hour. After allowing to cool, 0.6 g of 3,5-dichloro-4-(2,2,2-trifluoroethoxy)pyridine-2-carbonitrile was added at room temperature, and the mixture was stirred for 2 hours, and concentrated. To the residue was added water, the resultant solution was extracted with ethyl acetate three times, and the organic layers were combined, washed with an aqueous saturated sodium chloride solution, dried with anhydrous magnesium sulfate, and concentrated. The residue was washed with hexane three times to obtain 0.64 g of 3,5-dichloro-4-(2,2,2-trifluoroethoxy)pyridine-2-carboxamide=oxime.
Reaction SMILES: [C:1]([CH2:3][CH:4]1[CH2:7][CH:6]([C:8]([OH:10])=O)[CH2:5]1)#[N:2].C(Cl)(=O)C([Cl:14])=O>ClCCl.CN(C)C=O>[C:1]([CH2:3][CH:4]1[CH2:7][CH:6]([C:8]([Cl:14])=[O:10])[CH2:5]1)#[N:2]
Reactant: O=C(Cl)C(=O)Cl
Reactant: N#CCC1CC(C(=O)O)C1
Solvent: CN(C)C=O
Solvent: ClCCl
Product: N#CCC1CC(C(=O)Cl)C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a stirred solution of 3-cyanomethylcyclobutane carboxylic acid (4.0 g, 28.8 mmol) in dichloromethane (50 ml) was added two drops of dimethylformamide followed by oxalyl chloride (12 ml). The mixture was stirred overnight at room temperature followed by removal of the solvent and excess reagent in vacuo. The resulting oil was dissolved in dry dichloromethane and the solvent evaporated to give the title compound as an oil.
Reaction SMILES: [Cl:1][C:2]1[S:6][C:5]([C:7]2[C:11]([C:12]3[CH:17]=[CH:16][N:15]=[C:14](S(C)(=O)=O)[N:13]=3)=[CH:10][N:9]([CH:22]([CH3:24])[CH3:23])[N:8]=2)=[CH:4][CH:3]=1.[CH2:25]([NH2:32])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>>[CH2:25]([NH:32][C:14]1[N:13]=[C:12]([C:11]2[C:7]([C:5]3[S:6][C:2]([Cl:1])=[CH:3][CH:4]=3)=[N:8][N:9]([CH:22]([CH3:24])[CH3:23])[CH:10]=2)[CH:17]=[CH:16][N:15]=1)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: NCc1ccccc1
Reactant: CC(C)n1cc(-c2ccnc(S(C)(=O)=O)n2)c(-c2ccc(Cl)s2)n1
Product: CC(C)n1cc(-c2ccnc(NCc3ccccc3)n2)c(-c2ccc(Cl)s2)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 96 %

Procedure:
A mixture of 4-[3-(5-chloro-2-thienyl)-1-isopropyl-1H-pyrazol-4-yl]-2-(methylsulfonyl)pyrimidine (1 eq, 5.2 mmol) in 25 mL benzylamine was stirred overnight at room temperature. The solvent was evaporated and the residue was diluted in dichloromethane and washed three times with HCl 1M. The organic layer was then dried over MgSO4 and evaporated to afford 2.3 g of N-benzyl-4-[3-(5-chloro-2-thienyl)-1-isopropyl-1H-pyrazol-4-yl]pyrimidin-2-amine (96% yield).
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](Cl)=[O:7])=[CH:4][CH:3]=1.[NH2:11][C:12]1[CH:17]=[CH:16][C:15]([C:18](=[O:25])[CH2:19][CH2:20][C:21]([O:23]C)=[O:22])=[CH:14][CH:13]=1>>[F:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([NH:11][C:12]2[CH:13]=[CH:14][C:15]([C:18](=[O:25])[CH2:19][CH2:20][C:21]([OH:23])=[O:22])=[CH:16][CH:17]=2)=[O:7])=[CH:4][CH:3]=1
Reactant: O=C(Cl)c1ccc(F)cc1
Reactant: COC(=O)CCC(=O)c1ccc(N)cc1
Product: O=C(O)CCC(=O)c1ccc(NC(=O)c2ccc(F)cc2)cc1
Yield: 27.8 %

Procedure:
In a manner similar to that described in Example 3, 4-fluorobenzoyl chloride (0.053 g, 0.00033 mol) was allowed to react with 4-(4-amino-phenyl)-4-oxo-butyric acid, methyl ester (0.052 g, 0.00025 mol) (Example 1, Step (c)), and the resulting intermediate was hydrolyzed to give 0.0219 g of 4-[4-(4-fluoro-benzoylamino)-phenyl]-4-oxo-butyric acid as an off-white solid; mp 253-255.° C.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:17]3[CH:18]=[C:19]([O:24][CH3:25])[C:20]([O:22][CH3:23])=[CH:21][C:16]=3[CH:15]3[CH:10]([CH2:11][CH2:12][N:13]([CH3:26])[CH2:14]3)[N:9]=2)=[CH:4][CH:3]=1.[C:27](Cl)(=[O:32])[CH2:28][CH2:29][CH2:30][CH3:31]>C(#N)C>[CH3:25][O:24][C:19]1[C:20]([O:22][CH3:23])=[CH:21][C:16]2[C@H:15]3[C@H:10]([CH2:11][CH2:12][N:13]([CH3:26])[CH2:14]3)[N:9]=[C:8]([C:5]3[CH:6]=[CH:7][C:2]([NH:1][C:27](=[O:32])[CH2:28][CH2:29][CH2:30][CH3:31])=[CH:3][CH:4]=3)[C:17]=2[CH:18]=1
Reactant: CCCCC(=O)Cl
Reactant: COc1cc2c(cc1OC)C1CN(C)CCC1N=C2c1ccc(N)cc1
Solvent: CC#N
Product: CCCCC(=O)Nc1ccc(C2=N[C@H]3CCN(C)C[C@H]3c3cc(OC)c(OC)cc32)cc1

Procedure:
3 g of 6-(4-aminophenyl)-8,9-dimethoxy-2-methyl-1,2,3,4,4a,10b-hexahydro-benzo[c][1,6]naphthyridine and 6,2 g of valeric acid chloride are heated to the boil under reflux in 70 ml of acetonitrile for 7 hours. The reaction mixture is evaporated to dryness in a vacuum, water is added to the residue, the reaction mixture is made alkaline with potassium carbonate and extracted with methylene chloride. The solution is concentrated by evaporation, the crude product is dissolved in ethanol and a slight excess of hydrochloric acid in ethanol is added, whereby the title compound crystallizes in dihydrochloride form (melting point: 230°-235°).
Reaction SMILES: [O:1]1[C:5]2([CH2:15][CH2:14][C:8]3([CH2:12][CH2:11][NH:10][C:9]3=[O:13])[CH2:7][CH2:6]2)[O:4][CH2:3][CH2:2]1.Br[C:17]1[CH:22]=[CH:21][C:20]([CH:23]2[CH2:26][C:25]([F:28])([F:27])[CH2:24]2)=[CH:19][CH:18]=1>>[F:27][C:25]1([F:28])[CH2:24][CH:23]([C:20]2[CH:19]=[CH:18][C:17]([N:10]3[CH2:11][CH2:12][C:8]4([CH2:14][CH2:15][C:5]5([O:4][CH2:3][CH2:2][O:1]5)[CH2:6][CH2:7]4)[C:9]3=[O:13])=[CH:22][CH:21]=2)[CH2:26]1
Reactant: O=C1NCCC12CCC1(CC2)OCCO1
Reactant: FC1(F)CC(c2ccc(Br)cc2)C1
Product: O=C1N(c2ccc(C3CC(F)(F)C3)cc2)CCC12CCC1(CC2)OCCO1

Procedure:
The title compound was prepared in analogy to example 336, step 1 from 1,4-dioxa-10-aza-dispiro[4.2.4.2]tetradecan-9-one (described in example 133, step 3, 165 mg) and 1-bromo-4-(3,3-difluoro-cyclobutyl)-benzene (193 mg, described above). White solid (270 mg, 70%). MS (m/e): 378.3 [MH+].
Reaction SMILES: [C:1]([C:3](=[CH:10][NH:11][C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([C:18]([F:21])([F:20])[F:19])[CH:13]=1)[C:4]([NH:6][C:7](=O)[O-:8])=[O:5])#[N:2].C(N(CC)CC)C>C(#N)C>[O:8]=[C:7]1[NH:6][C:4](=[O:5])[C:3]([C:1]#[N:2])=[CH:10][N:11]1[C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([C:18]([F:21])([F:20])[F:19])[CH:13]=1
Reactant: N#CC(=CNc1cccc(C(F)(F)F)c1)C(=O)NC(=O)[O-]
Solvent: CC#N
Solvent: CCN(CC)CC
Product: N#Cc1cn(-c2cccc(C(F)(F)F)c2)c(=O)[nH]c1=O
Reaction time: 6 h
Yield: 91.9 %

Procedure:
To a suspension of 2-cyano-3-(3-(trifluoromethyl)phenylamino)acryloylcarbamate (prepared in Reference Example 111) (26.2 g) in acetonitrile (300 ml) was added triethylamine (111 ml) and the resulting mixture was stirred for six hours with heating under reflux. The reaction solutions were concentrated under reduced pressure, and to the residue was added 1M hydrochloric acid and the resulting mixture was extracted with ethyl acetate twice. The organic layer was washed with 1M hydrochloric acid and saturated saline. The resulting mixture was dried over anhydrous magnesium and then concentrated under reduced pressure to afford 2,4-dioxo-1-(3-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydropyrimidin-5-carbonitrile (22.7 g).