Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[N:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4](Cl)=[O:5].[Al+3].[Cl-].[Cl-].[Cl-].O.[CH:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>>[C:4]([C:3]1[C:2]([Cl:1])=[N:10][CH:9]=[CH:8][CH:7]=1)(=[O:5])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: c1ccccc1
Reactant: O=C(Cl)c1cccnc1Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: O
Product: O=C(c1ccccc1)c1cccnc1Cl

Procedure:
To a cooled solution of 150 g 2-chloro-nicotinoyl chloride in 400 ml benzene there is added slowly 238 g AlCl3. After refluxing 2 hrs. the reaction mixture is added with stirring to a slightly acidic ice: water mixture. The organic layer is separated and the aqueous one is extracted with ethyl ether. The combined organic layers are washed with HONa 1N, then with water, and dried over Na2SO4. The excess benzene is distilled at water pump pressure in a rotary evaporator and the residual oil is distilled in vacuo. Yield: 157 g of title product, b.p. 123° C./0.05 mm; m.p. 35°-7° C.; UV (ethanol): λmax. 254 nm., ε: 17,180; Cl 15.97 (16.29).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[O:7][C:8]2[CH:15]=[CH:14][CH:13]=[C:12]([O:16][CH2:17][C:18](=[O:20])[CH3:19])[C:9]=2[C:10]=1[CH3:11])=[O:5])[CH3:2].[BH4-].[Na+]>C(O)C>[CH2:1]([O:3][C:4]([C:6]1[O:7][C:8]2[CH:15]=[CH:14][CH:13]=[C:12]([O:16][CH2:17][CH:18]([OH:20])[CH3:19])[C:9]=2[C:10]=1[CH3:11])=[O:5])[CH3:2]
Reactant: CCOC(=O)c1oc2cccc(OCC(C)=O)c2c1C
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: CCOC(=O)c1oc2cccc(OCC(C)O)c2c1C
Temperature: 5 °C
Reaction time: 0.5 h

Procedure:
To a mixture of ethyl-3-methyl-4-(2-oxopropoxy)benzofuran-2-carboxylate (1.9 g, 6.8 mmoles, Example 117) in ethanol (100 ml) at 5° C. was added in portions, sodium borohydride (254 mg, 6.8 mmoles). The mixture was stirred for 10 minutes at 5° C. and 30 minutes at room temperature. The reaction was quenched with saturated ammonium chloride solution (1.5 ml) and concentrated. The residue was taken up in ether (100 ml), washed with water (25 ml), dried with Na2SO4, filtered and concentrated to obtain the title compound as an oil which crystallized on standing. The crystals were stirred with 25% ether in hexane (50 ml) for 30 minutes, filtered and then air dried, m.p. 94°-96° C.
Reaction SMILES: [C:1]([CH2:4][C:5]1([NH:9][C:10]([C:12]2[CH:17]=[C:16](Cl)[C:15]([CH:19]3[CH2:21][CH2:20]3)=[CH:14][N:13]=2)=[O:11])[CH2:8][O:7][CH2:6]1)(=[O:3])[NH2:2].[F:22][C:23]([F:28])([F:27])[C@H:24]([OH:26])[CH3:25].[H-].[Na+]>CN(C=O)C>[C:1]([CH2:4][C:5]1([NH:9][C:10]([C:12]2[CH:17]=[C:16]([O:26][C@H:24]([CH3:25])[C:23]([F:28])([F:27])[F:22])[C:15]([CH:19]3[CH2:21][CH2:20]3)=[CH:14][N:13]=2)=[O:11])[CH2:8][O:7][CH2:6]1)(=[O:3])[NH2:2]
Reactant: NC(=O)CC1(NC(=O)c2cc(Cl)c(C3CC3)cn2)COC1
Reactant: C[C@@H](O)C(F)(F)F
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: C[C@@H](Oc1cc(C(=O)NC2(CC(N)=O)COC2)ncc1C1CC1)C(F)(F)F
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 7 %

Procedure:
To a solution of 4-Chloro-5-cyclopropyl-pyridine-2-carboxylic acid (3-carbamoylmethyl-oxetan-3-yl)-amide (Example 63b, 40 mg, 129 μmol) in dry DMF (1.5 mL) in a microwave-vial were added (R)-1,1,1-trifluoropropan-2-ol (CAN 17628-73-8, 42.1 mg, 258 μmol) and sodium hydride 60% (15.5 mg, 387 μmol) and the reaction mixture was stirred at room temperature for 10 minutes. The reaction mixture was heated to 100° C. for 30 minutes under microwave radiation. The reaction was directly purified by preparative HPLC without any work-up to yield the title compound (3.5 mg, 7.0%) as a grey solid. MS (ESI, m/z): 388.0 (M+H+).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[OH:14])[CH:5]=[C:4]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([NH2:21])[CH:16]=2)[C:3]=1[CH2:22][OH:23].N1C=CC=CC=1.[Cl:30][CH2:31][CH2:32][C:33](Cl)=[O:34]>C1COCC1.O>[NH2:1][C:2]1[C:3]([CH2:22][OH:23])=[C:4]([C:15]2[CH:16]=[C:17]([NH:21][C:33](=[O:34])[CH2:32][CH2:31][Cl:30])[CH:18]=[CH:19][CH:20]=2)[CH:5]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[OH:14])[N:7]=1
Reactant: Nc1cccc(-c2cc(-c3ccccc3O)nc(N)c2CO)c1
Reactant: O=C(Cl)CCCl
Solvent: C1CCOC1
Solvent: c1ccncc1
Solvent: O
Product: Nc1nc(-c2ccccc2O)cc(-c2cccc(NC(=O)CCCl)c2)c1CO
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 55.7 %

Procedure:
To a cold (0° C.) solution of 2-[6-amino-4-(3-aminophenyl)-5-(hydroxymethyl)-2-pyridinyl]phenol (0.100 g, 0.325 mmol) in THF (3 mL) including pyridine (0.028 mL, 0.34 mmol) was added 3-chloropropionyl chloride (0.043 g, 0.34 mmol). After being stirred for 30 minutes, the mixture was allowed to warm to room temperature and the stirring was continued for 2 hrs. The resulting mixture was diluted with water and extracted with ethyl acetate. The separated organic phase was washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was crystallized with ethyl ether. The resulting solid was collected by filtration, washed with ethyl ether, and dried under reduced pressure to give N-{3-[2-amino-3-(hydroxymethyl)-6-(2-hydroxyphenyl)-4-pyridinyl]phenyl}-3-chloropropanamide as a pale yellow solid (0.072 g, yield 56%).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1.ClCCl.[Cl-].[CH2:12]([Zn+])[C:13]([CH3:16])([CH3:15])[CH3:14].[Cl-].[NH4+]>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[CH2:12]([C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1)[C:13]([CH3:16])([CH3:15])[CH3:14]
Reactant: Brc1ccccn1
Reactant: CC(C)(C)C[Zn+]
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: [Cl-]
Solvent: ClCCl
Product: CC(C)(C)Cc1ccccn1

Procedure:
2-Bromopyridine (Aldrich, 0.48 mL, 5.0 mmol) and [1, 1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II), complex with dichloromethane (1:1) (Aldrich, 200 mg, 0.25 mmol) were added to the neopentylzinc chloride suspension. The resulting suspension was stirred at rt for 21 h, whereupon saturated ammonium chloride solution (25 mL) was added. The mixture was extracted with ethyl acetate (3×). The combined organic extracts were dried (Na2SO4), filtered and concentrated under reduced pressure. The residue was dissolved in methylene chloride, and washed with 1 N HCl. The aqueous layer was separated, basified with 10 N NaOH (aq), and extracted with CH2Cl2. The organic layer was dried (Na2SO4), filtered and concentrated under reduced pressure to give 2-neopentylpyridine as an oil: Rf=0.33 in 5% MeOH/CH2Cl2.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]23[N:22]([C:23]([C:25]4[C:26]([CH3:30])=[N:27][O:28][CH:29]=4)=[O:24])[CH2:21][CH2:20][N:9]2[C:10](=[O:19])[C:11]2[N:12]([C:14]([CH:17]=O)=[CH:15][CH:16]=2)[CH2:13]3)=[CH:4][CH:3]=1.[NH:31]1[CH2:36][CH2:35][O:34][CH2:33][CH2:32]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]23[N:22]([C:23]([C:25]4[C:26]([CH3:30])=[N:27][O:28][CH:29]=4)=[O:24])[CH2:21][CH2:20][N:9]2[C:10](=[O:19])[C:11]2[N:12]([C:14]([CH2:17][N:31]4[CH2:36][CH2:35][O:34][CH2:33][CH2:32]4)=[CH:15][CH:16]=2)[CH2:13]3)=[CH:6][CH:7]=1
Reactant: C1COCCN1
Reactant: Cc1nocc1C(=O)N1CCN2C(=O)c3ccc(C=O)n3CC12c1ccc(Cl)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Product: Cc1nocc1C(=O)N1CCN2C(=O)c3ccc(CN4CCOCC4)n3CC12c1ccc(Cl)cc1
Yield: 89 %

Procedure:
10a-(4-chlorophenyl)-1-[(3-methyl-1,2-oxazol-4-yl)carbonyl]-5-oxo-2,3,10,10a-tetrahydro-1H,5H-imidazo[1,2-a]pyrrolo[1,2-d]pyrazine-8-carbaldehyde (25 mg, 0.059 mmol) and morpholine (10.2 μL) were combined and stirred at room temperature in 1,2-dichloroethane for 10 min. To the mixture was added sodium triacetoxyborohydride (24.7 mg). After 18 h at room temperature the reaction was quenched by the addition of a saturated aqueous solution of NaHCO3 (1 mL) and CH2Cl2 (5 mL). The organic layers were washed with brine, dried (MgSO4), filtered and evaporated in vacuo to give a yellow solid. The solid was purified by flash column chromatography (Biotage SP4, 4 g cartridge, 0-5% MeOH gradient in CH2Cl2) to give 10a-(4-chlorophenyl)-1-[(3-methyl-1,2-oxazol-4-yl)carbonyl]-8-(morpholin-4-ylmethyl)-2,3,10,10a-tetrahydro-1H,5H-imidazo[1,2-a]pyrrolo[1,2-d]pyrazin-5-one (25) as a white solid (26 mg, yield 89%).
Reaction SMILES: F[C:2]1[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][CH:5]=[CH:4][N:3]=1.C(=O)([O-])[O-].[Cs+].[Cs+].[OH:18][C:19]1[CH:29]=[CH:28][C:22]([C:23]([O:25][CH2:26][CH3:27])=[O:24])=[CH:21][CH:20]=1>CS(C)=O.O>[F:9][C:8]([F:11])([F:10])[C:7]1[C:2]([O:18][C:19]2[CH:20]=[CH:21][C:22]([C:23]([O:25][CH2:26][CH3:27])=[O:24])=[CH:28][CH:29]=2)=[N:3][CH:4]=[CH:5][CH:6]=1
Reactant: Fc1ncccc1C(F)(F)F
Reactant: CCOC(=O)c1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CS(C)=O
Solvent: O
Product: CCOC(=O)c1ccc(Oc2ncccc2C(F)(F)F)cc1
Temperature: 80 °C

Procedure:
Fluoro-3-(trifluoromethyl)pyridine (848 mg, 5137 μmol), cesium carbonate (2008 mg, 6164 μmol) and ethyl 4-hydroxybenzoate (854 mg, 5137 μmol) were combined in DMSO (12 mL) and heated to 80° C. overnight. After complete disappearance of starting material, the mixture was cooled to RT and diluted with water and extracted with ethyl acetate. The combined organics were washed with brine, dried over Na2SO4, filtered and concentrated to give the desired product which was used without further purification.
Reaction SMILES: [CH:1]1([NH:6][C:7]2[N:12]=[C:11]([C:13]3[C:14]([C:24]4[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=4)=[N:15][N:16]4[C:21]=3[CH:20]=[CH:19][N:18]=[C:17]4SC)[CH:10]=[CH:9][N:8]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.ClC1C=C(C=CC=1)C(OO)=O.[C:42]([NH2:46])([CH3:45])([CH3:44])[CH3:43]>ClCCl.O>[C:42]([NH:46][C:17]1[N:16]2[N:15]=[C:14]([C:24]3[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=3)[C:13]([C:11]3[CH:10]=[CH:9][N:8]=[C:7]([NH:6][CH:1]4[CH2:2][CH2:3][CH2:4][CH2:5]4)[N:12]=3)=[C:21]2[CH:20]=[CH:19][N:18]=1)([CH3:45])([CH3:44])[CH3:43]
Reactant: CC(C)(C)N
Reactant: CSc1nccc2c(-c3ccnc(NC4CCCC4)n3)c(-c3ccc(F)cc3)nn12
Agent: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Solvent: O
Product: CC(C)(C)Nc1nccc2c(-c3ccnc(NC4CCCC4)n3)c(-c3ccc(F)cc3)nn12
Temperature: 25 °C
Reaction time: 1 h
Yield: 14 %

Procedure:
To a solution of N-cyclopentyl-4-[2-(4-fluorophenyl)-7-(methylsulfanyl)pyrazolo[1,5-c]pyrimidin-3-yl]pyrimidin-2-amine (40 mg, 0.095 mmol) in dichloromethane (2 mL) was added 3-chloroperoxybenzoic acid (12 mg, 0.14 mmol) and the reaction mixture stirred at room temperature for 1 hour. t-Butylamine (3 mL) was added and heated to reflux for 3 hours. The reaction was allowed to cool and diluted with water. The mixture was extracted with ethyl acetate and the organic phase washed with brine before being concentrated under vacuum. The residue was purified by silica gel chromatography eluting with SO/5 acetone in dichloromethane to yield a 1:1 mixture of starting material and product. The residue was dissolved in dichloromethane (2 mL) and 3-chloroperoxybenzoic acid (18 mg, 0.21 mmol) was added. The mixture was stirred for 2 hours and then t-butylamine (3 mL) was added. The reaction mixture was stirred for 3 hours, diluted with water, extracted with ethyl acetate, washed with brine, concentrated, and the residue purified by silica gel chromatography eluting with 5% acetone in dichloromethane to yield N-(tert-butyl)-3-[2-(cyclopentylamino)pyrimidin-4-yl]-2-(4-fluorophenyl)pyrazolo[1,5-c]pyrimidin-7-amine (6 mg, 14%), 1H NMR (CDCl3): δ 8.02 (d, 1H), 7.72 (d, 1H), 7.60 (dd, 2H), 7.47 (d, 1H), 7.13 (t, 2H), 6.42 (s, 1H), 6.25 (d, 1H), 5.14 (bs, 1H), 4.28 (m, 1H), 2.04 (m, 2H), 1.45–1.78 (m, 15H). MS m/z 446 (M+1).
Reaction SMILES: [N:1]1[C:8]([NH2:9])=[N:7][C:5]([NH2:6])=[N:4][C:2]=1[NH2:3].[P:10]([OH:14])([O-:13])([O-:12])=[O:11].[NH4+].[NH4+]>>[P:10]([OH:14])([OH:13])([OH:12])=[O:11].[N:1]1[C:8]([NH2:9])=[N:7][C:5]([NH2:6])=[N:4][C:2]=1[NH2:3]
Reactant: O=P([O-])([O-])O
Agent: Nc1nc(N)nc(N)n1
Agent: [NH4+]
Product: O=P(O)(O)O

Procedure:
Purified diammonium phosphate is produced by neutralizing relatively pure melamine orthophosphate, prepared from wet-process phosphoric acid, with ammonia in a hot solution of diammonium phosphate to give a slurry of melamine in concentrated diammonium phosphate solution. The liberated melamine is virtually insoluble in concentrated diammonium phosphate solutions; it is filtered from the hot mixture, washed, and recycled to produce more melamine phosphate by reaction with wet-process phosphoric acid. The hot, concentrated diammonium phosphate filtrate is cooled to precipitate purified diammonium phosphate crystals. The product is separated from its mother liquor by filtration, and the resulting filtrate is recycled to the reactor. The small amount of impurities introduced with the melamine phosphate are removed partly with the liberated melamine and partly by centrifugation of the diammonium phosphate solution. The only starting materials for the process are phosphoric acid and ammonia.
Reaction SMILES: [C:1]([O:4][C:5]1[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[S:8](=[O:16])(=[O:15])[N:7]([CH3:17])[C:6]=1[C:18]1N=N[N:21]([C:23](=[O:25])[CH3:24])[N:22]=1)(=[O:3])[CH3:2]>C1(C)C=CC=CC=1>[C:1]([O:4][C:5]1[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[S:8](=[O:16])(=[O:15])[N:7]([CH3:17])[C:6]=1[C:18]1[O:25][C:23]([CH3:24])=[N:21][N:22]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)OC1=C(c2nnn(C(C)=O)n2)N(C)S(=O)(=O)c2ccccc21
Solvent: Cc1ccccc1
Product: CC(=O)OC1=C(c2nnc(C)o2)N(C)S(=O)(=O)c2ccccc21
Temperature: 25 °C
Yield: 99.1 %

Procedure:
A suspension of the product of (a) above (3.60 g), in toluene (40 ml) was refluxed for 2 hours, and the resulting solution concentrated to half volume and cooled to room temperature to give crystals. Filtration followed by drying in vacuo afforded colorless crystals, 3.29 g, in 99.1% yield of product (b).
Reaction SMILES: C(OC([N:8](C(OC(C)(C)C)=O)[C:9]1[N:10]=[CH:11][C:12]([C:21]2[CH:22]=[N:23][N:24]([C@H:26]3[CH2:31][CH2:30][C@H:29]([O:32][Si](C(C)(C)C)(C)C)[CH2:28][CH2:27]3)[CH:25]=2)=[C:13]2[CH:17]=[C:16](B(O)O)[O:15][C:14]=12)=O)(C)(C)C.I[C:48]1[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=1.C(=O)([O-])[O-].[K+].[K+].Cl>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.O.O1CCOCC1>[NH2:8][C:9]1[N:10]=[CH:11][C:12]([C:21]2[CH:22]=[N:23][N:24]([C@H:26]3[CH2:27][CH2:28][C@H:29]([OH:32])[CH2:30][CH2:31]3)[CH:25]=2)=[C:13]2[CH:17]=[C:16]([C:48]3[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=3)[O:15][C:14]=12
Reactant: CC(C)(C)OC(=O)N(C(=O)OC(C)(C)C)c1ncc(-c2cnn([C@H]3CC[C@H](O[Si](C)(C)C(C)(C)C)CC3)c2)c2cc(B(O)O)oc12
Reactant: Ic1ccccc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: O
Solvent: C1COCCO1
Product: Nc1ncc(-c2cnn([C@H]3CC[C@H](O)CC3)c2)c2cc(-c3ccccc3)oc12
Temperature: 70 °C

Procedure:
A mixture of {7-[bis(tert-butoxycarbonyl)amino]-4-[1-(trans-4-{[tert-butyl(dimethyl)silyl]oxy}cyclohexyl)-1H-pyrazol-4-yl]furo[2,3-c]pyridin-2-yl}boronic acid (15.0, 0.0228 mmol), iodobenzene (9.32 mg, 0.0456 mmol), Pd(PPh3)4 (2.64 mg, 0.0023 mmol), potassium carbonate (9.47 mg, 0.0685 mmol) and 4:1 1,4-dioxane:water (1 mL) was heated to 65° C. for 30 min. Concentrated HCl (0.0381 mL, 0.457 mmol) was added, and the solution was heated to 70° C. for 1 h. The solution was concentrated. Purification by ISCO chromatography (2 to 5% 7 N NH3/MeOH:DCM) afforded 2.6 mg (30%) of the title compound as a yellow solid. 1H NMR (400 MHz, CD3OD): δ 1.43-1.58 (m, 2 H), 1.91-2.07 (m, 2 H), 2.07-2.24 (m, 4 H), 3.70 (tt, J=10.9, 4.3 Hz, 1 H), 4.21-4.32 (m, 1 H), 7.45-7.57 (m, 3 H), 7.58 (s, 1 H), 7.82 (s, 1 H), 7.92 (s, 1 H), 8.07 (s, 1 H), 8.09 (d, J=1.5 Hz, 1 H), 8.17 (s, 1 H); MS (ESI): 375.16 [M+H]+; HPLC tR=0.75 min (TOF: polar—2 min).
Reaction SMILES: C[O:2][C:3](=[O:21])[C@H:4]([CH2:13][C:14]1[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][CH:15]=1)[NH:5]C(OC(C)(C)C)=O.[CH2:22]([C:24]1[S:28][C:27]([C:29]2[CH:34]=[CH:33][C:32]([F:35])=[CH:31][CH:30]=2)=[N:26][C:25]=1[CH2:36][CH2:37]O)[CH3:23]>>[NH2:5][C@@H:4]([CH2:13][C:14]1[CH:15]=[CH:16][C:17]([O:20][CH2:37][CH2:36][C:25]2[N:26]=[C:27]([C:29]3[CH:30]=[CH:31][C:32]([F:35])=[CH:33][CH:34]=3)[S:28][C:24]=2[CH2:22][CH3:23])=[CH:18][CH:19]=1)[C:3]([OH:2])=[O:21]
Reactant: COC(=O)[C@H](Cc1ccc(O)cc1)NC(=O)OC(C)(C)C
Reactant: CCc1sc(-c2ccc(F)cc2)nc1CCO
Product: CCc1sc(-c2ccc(F)cc2)nc1CCOc1ccc(C[C@H](N)C(=O)O)cc1
Yield: 94 %

Procedure:
Intermediate 56 was prepared as described above for the preparation of intermediate 52. From 534 mg of N-(Boc)-L-Tyrosine methyl ester and 500 mg of Intermediate 11B was prepared 900 mg of BOC-protected intermediate methyl ester (94% yield; 1H NMR (CDCl3, 300 MHz) δ7.9 (dd, 2H, 8.7, 5.2), 7.13 (t, 2H, J=8.6), 7.04 (d, 2H, J=8.5), 6.85 (d, 2H, J=8.6), 4.97 (d, 1H, J=7.9), 4.55 (m, 1H), 4.32 (t, 2H, J=6.8), 3.73 (s, 3H), 3.21 (t, 2H, J=6.7), 3.10-3.02 (m, 2H), 2.89 (q, 2H, J=7.5), 1.44 (s, 9H), 1.36 (t, 3H, J=7.5); From 850 mg of protected intermediate was prepared 900 mg of intermediate 56 as a solid. 1H NMR (DMSO-d6, 300 MHz) δ8.0 (br s, 2H), 7.91-7.87 (m, 2H), 7.30 (dt, 2H, J=8.8, 2.1), 7.14 (d, 2H, J=8.6), 6.90 (d, 2H, J=8.6), 4.27 (t, 2H, J=6.5), 4.12 (m, 1H), 3.11 (t, 2H, J=6.5), 3.0 (m, 2H), 2.86 (q, 2H, J=7.5), 1.26 (t, 3H, J=7.5); low resolution MS (ES+)m/e 414.85 (MH+).
Reaction SMILES: [F:1][C:2]1[C:9]([O:10][CH3:11])=[C:8]([O:12][CH3:13])[CH:7]=[CH:6][C:3]=1[CH:4]=O.Cl.[NH2:15]O>C(O)C>[F:1][C:2]1[C:9]([O:10][CH3:11])=[C:8]([O:12][CH3:13])[CH:7]=[CH:6][C:3]=1[C:4]#[N:15]
Reactant: COc1ccc(C=O)c(F)c1OC
Reactant: NO
Agent: Cl
Solvent: CCO
Product: COc1ccc(C#N)c(F)c1OC
Reaction time: 2.5 h

Procedure:
4.4 g of 2-fluoro-3,4-dimethoxybenzaldehyde and 1.83 g of hydroxylamine hydrochloride are heated under reflux for 5 hours together with 30 ml of ethanol. The reaction mixture is subsequently evaporated and the residue, dried in a high vacuum at 23°, is introduced into 40 ml of phosphorus oxychloride. After stirring at 23° for 2.5 hours the reaction mixture is evaporated, the residue is treated with ice-water, the precipitate which thereby forms is filtered off, washed with water, taken up in methylene chloride, the methylene chloride solution is dried over sodium sulfate and evaporated. By recrystallization of the residue from methylene chloride/hexane there is obtained 2-fluoro-3,4-dimethoxybenzonitrile of m.p. 64°-65°.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:20])[C:4]1[CH:9]=[CH:8][C:7](OS(C(F)(F)F)(=O)=O)=[C:6]([O:18][CH3:19])[CH:5]=1.[CH3:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1OB(O)O.[Cl-].[Li+].C(=O)([O-])[O-].[Na+].[Na+]>C1(C)C=CC=CC=1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.O>[CH3:1][O:2][C:3](=[O:20])[C:4]1[CH:9]=[CH:8][C:7]([C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=2[CH3:21])=[C:6]([O:18][CH3:19])[CH:5]=1
Reactant: Cc1ccccc1OB(O)O
Reactant: COC(=O)c1ccc(OS(=O)(=O)C(F)(F)F)c(OC)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Cl-]
Solvent: Cc1ccccc1
Solvent: O
Product: COC(=O)c1ccc(-c2ccccc2C)c(OC)c1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 99.8 %

Procedure:
To a solution of 3-methoxy-4-trifluoromethylsulfonyloxybenzoic acid methyl ester (5 g) in toluene (200 ml) is added tetrakis(triphenylphosphine)palladium (0.9 g) under argon atmosphere, and the mixture is stirred at room temperature for five minutes. To the mixture are added (2-methylphenyl)boric acid (3.2 g), lithium chloride (1.01 g) and a 2M aqueous sodium carbonate solution (11.9 ml), and the mixture is stirred at 100° C. for two hours. To the mixture is added water, and the mixture is filtered through celite to remove the palladium. The filtrate is extracted with diethyl ether, and the ether layer is washed with water, dried, and evaporated. The residue is purified by silica gel column chromatography (solvent; n-hexane→ethyl acetate:n-hexane=1:10) to give 3-methoxy-4-(2-methylphenyl)benzoic acid methyl ester (4.07 g) as oil.
Reaction SMILES: C(OC([N:8]1[C:12]([CH3:14])([CH3:13])[CH2:11][C:10](=[O:15])[N:9]1[C:16]1[N:21]=[CH:20][C:19]([C:22]#[C:23][C:24]2[CH:29]=[CH:28][CH:27]=[C:26]([F:30])[CH:25]=2)=[CH:18][N:17]=1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>ClCCl>[F:30][C:26]1[CH:25]=[C:24]([C:23]#[C:22][C:19]2[CH:20]=[N:21][C:16]([N:9]3[C:10](=[O:15])[CH2:11][C:12]([CH3:14])([CH3:13])[NH:8]3)=[N:17][CH:18]=2)[CH:29]=[CH:28][CH:27]=1
Reactant: CC(C)(C)OC(=O)N1N(c2ncc(C#Cc3cccc(F)c3)cn2)C(=O)CC1(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC1(C)CC(=O)N(c2ncc(C#Cc3cccc(F)c3)cn2)N1
Reaction time: 16 h
Yield: 67.8 %

Procedure:
(118 mg, 0.29 mmol) 2-[5-(3-Fluoro-phenylethynyl)-pyrimidin-2-yl]-5,5-dimethyl-3-oxo-pyrazolidine-1-carboxylic acid tert-butyl ester (Example 15, step 3) was dissolved in dichloromethane (2 ml) and TFA (0.55 ml, 7.2 mmol, 25 equiv.) was added at room temperature and stirred for 16 hours. The reaction mixture was extracted with saturated Na2CO3 solution and a small amount of dichloromethane. The organic extract was loaded directly to a silica gel column. The crude product was purified by flash chromatography on a silica gel column eluting with an ethyl acetate:heptane gradient 0:100 to 100:0. The desired 2-[5-(3-fluoro-phenylethynyl)-pyrimidin-2-yl]-5,5-dimethyl-pyrazolidin-3-one (61 mg, 69% yield) was obtained as a light yellow solid, MS: m/e=311.2 (M+H+).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[C:14]([C:15]([NH:17][CH2:18][CH2:19][CH2:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)=[O:16])=[C:13]([CH3:27])[N:12]=[C:11](SC)[N:10]=2)[CH:5]=[CH:6][C:7]=1[Cl:8].ClC1C=CC=C(C(OO)=O)C=1.S([O-])([O-])=O.[Na+].[Na+].[BH4-].[Na+].Cl>ClCCl>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[C:14]([C:15]([NH:17][CH2:18][CH2:19][CH2:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)=[O:16])=[C:13]([CH3:27])[N:12]=[CH:11][N:10]=2)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: CSc1nc(C)c(C(=O)NCCCc2ccccc2)c(-c2ccc(Cl)c(Cl)c2)n1
Agent: Cl
Agent: O=C(OO)c1cccc(Cl)c1
Agent: O=S([O-])[O-]
Solvent: ClCCl
Product: Cc1ncnc(-c2ccc(Cl)c(Cl)c2)c1C(=O)NCCCc1ccccc1
Temperature: 0 °C
Reaction time: 6 h

Procedure:
100 mg (0.224 mmol) of 4-(3,4-dichlorophenyl)-6-methyl-2-(methylthio)-N-(3-phenylpropyl)-5-pyrimidinecarboxamide was dissolved in 5 ml of dichloromethane. 77.3 mg (0.448 mmol) of mCPBA (m-chloroperbenzoic acid; hereinafter abbreviated as mCPBA) was added thereto at 0° C. and stirred at the same temperature for 6 hours. 1 ml of saturated aqueous sodium sulfite solution was added thereto at the same temperature and stirred for 30 minutes heating to room temperature. After the reaction mixture was diluted with dichloromethane, the organic layer was washed with saturated aqueous sodium chloride solution and dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. The obtained residue was dissolved in 5 ml of ethanol and 16.9 mg (0.448 mmol) of sodium borohydride was added at room temperature and stirred for 1 hour. 5 ml of 1N hydrochloric acid was added at the same temperature, stirred at room temperature for 30 minutes and then concentrated under reduced pressure. After the obtained residue was diluted with dichloromethane, the organic layer was washed with saturated aqueous sodium chloride solution and dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. The residue was purified by the silica gel chromatography (hexane/ethyl acetate=3/1) to obtain the title compound.