Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([NH2:9])[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[CH3:10][O:11][C:12](=[O:30])[C:13]1[CH:18]=[CH:17][C:16]([C:19]2[N:20]=[C:21](Cl)[C:22]3[CH:27]=[C:26]([Cl:28])[S:25][C:23]=3[N:24]=2)=[CH:15][CH:14]=1>>[CH3:10][O:11][C:12](=[O:30])[C:13]1[CH:18]=[CH:17][C:16]([C:19]2[N:20]=[C:21]([NH:9][CH2:1][CH2:2][C:3]3[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=3)[C:22]3[CH:27]=[C:26]([Cl:28])[S:25][C:23]=3[N:24]=2)=[CH:15][CH:14]=1
Reactant: NCCc1ccccc1
Reactant: COC(=O)c1ccc(-c2nc(Cl)c3cc(Cl)sc3n2)cc1
Product: COC(=O)c1ccc(-c2nc(NCCc3ccccc3)c3cc(Cl)sc3n2)cc1

Procedure:
The reaction procedure as above wherein phenethylamine is reacted with 4-(4-chloro-6-chloro-thieno-[2,3-d]-pyrimidin-2-yl)-benzoic acid methylester yields 4-(4-phenethylamino-6-chloro-thieno-[2,3-d]-pyrimidin-2-yl)-benzoic acid methylester.
Reaction SMILES: [CH3:1][Sn:2](Cl)([CH3:4])[CH3:3].C1COCC1.[Cl:11][C:12]1[CH:17]=[CH:16][C:15]([Mg]Br)=[CH:14][CH:13]=1.CCOCC>>[Cl:11][C:12]1[CH:17]=[CH:16][C:15]([Sn:2]([CH3:4])([CH3:3])[CH3:1])=[CH:14][CH:13]=1
Reactant: C[Sn](C)(C)Cl
Reactant: Clc1ccc([Mg]Br)cc1
Solvent: CCOCC
Solvent: C1CCOC1
Product: C[Sn](C)(C)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 97 %

Procedure:
To a 1M solution of trimethyltin chloride in THF (92 ml, 92 mmol) was slowly added a 1M solution of 4-chlorophenylmagnesium bromide in Et2O (92 ml, 92 mmol) over a 40 min period at −10° C. so that the temperature never exceed 0° C. After the addition, the cooling bath was removed and the resulting suspension was stirred at RT for 1 h. A saturated aqueous solution of NH4Cl (14 ml) was added followed by water until complete dissolution of the precipitate. The mixture was transferred into a separating funnel and extracted with Et2O (3×). The combined organic fractions were dried over Na2SO4, filtered and evaporated to dryness. The resulting crude material was purified by Combi-Flash Companion™ (Isco Inc.) column chromatography (SiO2; isocratic elution with cyclohexane) to yield the title compound (24.47 g, 89 mmol, 97%) as a colorless oil. TLC: RF=0.76 (cyclohexane/AcOEt 95:5); HPLC: AtRet=3.25 min; 1H NMR (400 MHz, CDCl3): 0.31 (s, 9H) 7.32-7.36 (m, 2H) 7.41-7.45 (m, 2H).
Reaction SMILES: C([O:3][C:4]([C:6]1[C:7](=[O:24])[C:8]2[CH:9]=[C:10]3[CH:20]=[C:19]([F:21])[C:18]([F:22])=[C:17]([F:23])[C:11]3=[N:12][C:13]=2[N:14]([CH3:16])[CH:15]=1)=[O:5])C.O>C(O)(=O)C.Cl>[F:21][C:19]1[C:18]([F:22])=[C:17]([F:23])[C:11]2=[N:12][C:13]3[N:14]([CH3:16])[CH:15]=[C:6]([C:4]([OH:5])=[O:3])[C:7](=[O:24])[C:8]=3[CH:9]=[C:10]2[CH:20]=1
Reactant: CCOC(=O)c1cn(C)c2nc3c(F)c(F)c(F)cc3cc2c1=O
Agent: Cl
Solvent: O
Solvent: CC(=O)O
Product: Cn1cc(C(=O)O)c(=O)c2cc3cc(F)c(F)c(F)c3nc21
Temperature: 20 °C
Yield: 92.7 %

Procedure:
A suspension of 4 g of 3-ethoxycarbonyl-7,8,9-trifluoro-1-methyl-4-oxo-1,4-dihydro-benzo[b][1,8]naphthyridine in 30 cm3 of acetic acid and 30 cm3 of 50% hydrochloric acid is heated at a temperature close to 100° C. for 2 hours. After cooling to about 20° C., 100 cm3 of water are added. The precipitate formed is drained, washed with 3 times 50 cm3 of water and recrystallized from 80 cm3 of dimethylformamide. 3.4 g of 7,8,9-trifluoro-1-methyl-4-oxo-1,4-dihydro-benzo[b][1,8]naphthyridine-3-carboxylic acid are obtained in the form of a colourless solid melting at 350°-352° C.
Reaction SMILES: [Cl:1][C:2]1[C:3]([O:13]C)=[CH:4][CH:5]=[C:6]2[C:11]=1[C:10](=[O:12])[NH:9][CH2:8][CH2:7]2.B(Br)(Br)Br.O>C(Cl)Cl>[Cl:1][C:2]1[C:3]([OH:13])=[CH:4][CH:5]=[C:6]2[C:11]=1[C:10](=[O:12])[NH:9][CH2:8][CH2:7]2
Reactant: COc1ccc2c(c1Cl)C(=O)NCC2
Agent: BrB(Br)Br
Solvent: O
Solvent: ClCCl
Product: O=C1NCCc2ccc(O)c(Cl)c21
Temperature: 25 °C
Reaction time: 8 h
Yield: 902.6 %

Procedure:
To a 0° C. solution of 8-chloro-7-methoxy-3,4-dihydroisoquinolin-1(2H)-one (1d, 7.8 g, 3.7 mmol) in dry CH2Cl2 (120 mL) was added dropwise BBr3 (11 mL, 111 mmol). After the addition, the mixture was stirred at room temperature overnight. To the reaction mixture was added dropwise H2O (200 mL). The mixture was extracted with EtOAc (8×200 mL), dried over Na2SO4 and concentrated under vacuum. To the residue was added EtOAc (20 mL) and petroleum ether (40 mL). The mixture was filtered and the solids were dried under vacuum to give 8-chloro-7-hydroxy-3,4-dihydroisoquinolin-1(2H)-one (1e, 6.6 g, 91%) as a brown solid.
Reaction SMILES: C(O[C:4]1[CH:5]=C(C=C[C:11]=1C)C=O)C.[OH:13][C:14]1[CH:15]=[C:16]([CH:19]=[CH:20][C:21]=1[O:22][CH3:23])[CH:17]=[O:18].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[CH2:5]([O:13][C:14]1[CH:15]=[C:16]([CH:19]=[CH:20][C:21]=1[O:22][CH3:23])[CH:17]=[O:18])[CH:4]=[CH2:11]
Reactant: CCOc1cc(C=O)ccc1C
Reactant: COc1ccc(C=O)cc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: C=CCOc1cc(C=O)ccc1OC

Procedure:
The title compound was prepared analogously to 3-ethoxy-4-methyl-benzaldehyde (intermediate E10) by reaction of 3-hydroxy-4-methoxy-benzaldehyde with alkylbromide in DMF using K2CO3 as base (see also A. W. White, R. Almassy, A. H. Calvert, N. J. Curtin, R. J. Griffin, Z. Hostomsky, K. Maegley, D. R. Newell, S. Srinivasan and B. T. Golding J. Med. Chem. 2000, 43, 4084-4097).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([C:12]([CH:14]1[CH2:16][CH2:15]1)=[O:13])=[C:5]2[NH:17][C:18]1[CH:19]=[N:20][C:21]([NH:24][CH2:25][CH2:26][N:27]([CH3:29])[CH3:28])=[CH:22][CH:23]=1.[Cl:30][C:31]1[CH:36]=[C:35](B2OC(C)(C)C(C)(C)O2)[CH:34]=[C:33]([F:46])[C:32]=1[OH:47]>>[Cl:30][C:31]1[CH:36]=[C:35]([C:2]2[CH:3]=[C:4]3[C:9](=[CH:10][CH:11]=2)[N:8]=[CH:7][C:6]([C:12]([CH:14]2[CH2:16][CH2:15]2)=[O:13])=[C:5]3[NH:17][C:18]2[CH:19]=[N:20][C:21]([NH:24][CH2:25][CH2:26][N:27]([CH3:28])[CH3:29])=[CH:22][CH:23]=2)[CH:34]=[C:33]([F:46])[C:32]=1[OH:47]
Reactant: CN(C)CCNc1ccc(Nc2c(C(=O)C3CC3)cnc3ccc(Br)cc23)cn1
Reactant: CC1(C)OB(c2cc(F)c(O)c(Cl)c2)OC1(C)C
Product: CN(C)CCNc1ccc(Nc2c(C(=O)C3CC3)cnc3ccc(-c4cc(F)c(O)c(Cl)c4)cc23)cn1
Yield: 6.8 %

Procedure:
Following general procedure D, (6-bromo-4-(6-(2-(dimethylamino)ethylamino)pyridin-3-ylamino)quinolin-3-yl)(cyclopropyl)methanone (75 mg, 0.17 mmol) was reacted with 2-chloro-6-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol (69 mg, 0.25 mmol) to afford the desired product (6 mg, 7%) as a yellow-orange solid: 1H NMR (500 MHz, CD3OD+TFA-d) δ 9.40 (s, 1H), 8.25 (dd, J=8.8, 1.9 Hz, 1H), 8.22-8.15 (m, 2H), 8.03 (d, J=8.8 Hz, 1H), 7.69 (dd, J=9.1, 2.6 Hz, 1H), 7.27-7.18 (m, 2H), 6.95 (d, J=9.1 Hz, 1H), 3.87-3.81 (m, 2H), 3.46-3.39 (m, 2H), 2.97 (s, 6H), 2.89-2.78 (m, 1H), 1.28-1.17 (m, 4H); ESI MS m/z 520 [C28H27ClFN5O2+H]+; HPLC>99% (AUC), tR=10.34 min.
Reaction SMILES: C([O:3][C:4](=[O:27])[CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([O:12][C:13]2[CH:18]=[CH:17][C:16]([Br:19])=[CH:15][C:14]=2[CH2:20][N:21]2[CH2:25][CH2:24][CH2:23][C:22]2=[O:26])[CH:7]=1)C.[OH-].[Li+]>O1CCOCC1.O>[Br:19][C:16]1[CH:17]=[CH:18][C:13]([O:12][C:8]2[CH:7]=[C:6]([CH2:5][C:4]([OH:27])=[O:3])[CH:11]=[CH:10][CH:9]=2)=[C:14]([CH2:20][N:21]2[CH2:25][CH2:24][CH2:23][C:22]2=[O:26])[CH:15]=1
Reactant: CCOC(=O)Cc1cccc(Oc2ccc(Br)cc2CN2CCCC2=O)c1
Agent: [Li+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: O=C(O)Cc1cccc(Oc2ccc(Br)cc2CN2CCCC2=O)c1

Procedure:
{3-[4-Bromo-2-(2-oxo-pyrrolidin-1-ylmethyl)-phenoxy]-phenyl}-acetic acid ethyl ester (0.35 mmol) in 1,4-dioxane and H2O was treated with lithium hydroxide at 50° C. for 30 minutes. The crude material was purified by preparative HPLC to give the title compound.
Reaction SMILES: [CH2:1]([N:8]1[CH:16]=[C:15]2[C:10]([CH:11]=[C:12]([C:17]3[CH:18]=[C:19]([C@H:27]4[CH2:32][CH2:31][CH2:30][NH:29][CH2:28]4)[N:20]4[C:25]=3[C:24]([NH2:26])=[N:23][CH:22]=[N:21]4)[CH:13]=[CH:14]2)=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:33][N:34]([CH3:39])[CH2:35][C:36](O)=[O:37].CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1.C(N(CC)C(C)C)(C)C>CN(C=O)C>[CH2:1]([N:8]1[CH:16]=[C:15]2[C:10]([CH:11]=[C:12]([C:17]3[CH:18]=[C:19]([C@H:27]4[CH2:32][CH2:31][CH2:30][N:29]([C:36](=[O:37])[CH2:35][N:34]([CH3:39])[CH3:33])[CH2:28]4)[N:20]4[C:25]=3[C:24]([NH2:26])=[N:23][CH:22]=[N:21]4)[CH:13]=[CH:14]2)=[N:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CN(C)CC(=O)O
Reactant: Nc1ncnn2c([C@H]3CCCNC3)cc(-c3ccc4cn(Cc5ccccc5)nc4c3)c12
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CN(C)CC(=O)N1CCC[C@H](c2cc(-c3ccc4cn(Cc5ccccc5)nc4c3)c3c(N)ncnn23)C1
Temperature: 25 °C
Reaction time: 16 h
Yield: 31.3 %

Procedure:
A mixture of 5-(2-benzyl-2H-indazol-6-yl)-7-[(3S)-piperidin-3-yl]pyrrolo[2,1-f][1,2,4]triazin-4-amine (95 mg, 0.22 mmol), N,N-dimethylglycine (28 mg, 0.27 mmol), EDCl (47 mg, 0.25 mmol), HOBt (33 mg, 0.25 mmol), and N,N-diisopropylethylamine (117 μL, 0.67 mmol) in DMF (2 mL) was stirred at rt for 16 h. The crude reaction mixture was purified via preparative HPLC using a gradient elution from 15% to 45% acetonitrile in water followed by filtration through an acidic resin, washing with MeOH. The product was eluted with 2M NH3 in MOON and the filtrate was concentrated to provide 35 mg (27%) of the desired product. 1H NMR (400 MHz, DMSO-d6) δ 8.55 (s, 1 H), 7.92 (d, 1 H), 7.80 (d, 1 H), 7.59 (s, 1 H), 7.27-7.39 (m, 5 H), 7.14 (d, 1 H), 6.61-6.67 (m, 1 H), 5.65 (s, 2 H); 3.95-4.94 (m, 2 H), 2.62-3.32 (m, 5 H), 2.05-2.23 (m, 7 H), 1.70-1.91 (m, 2 H), 1.40-1.64 (m, 1 H); ES-MS m/z 509.18 [M+H]+, HPLC RT (min) 2.23.
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:19])=[C:4](B2OC(C)(C)C(C)(C)O2)[CH:5]=[C:6]([Cl:9])[C:7]=1[F:8].Br[C:21]([C:23]([F:26])([F:25])[F:24])=[CH2:22].C([O-])([O-])=O.[Cs+].[Cs+]>C1COCC1.O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[Cl:9][C:6]1[CH:5]=[C:4]([C:21]([C:23]([F:26])([F:25])[F:24])=[CH2:22])[C:3]([F:19])=[C:2]([Cl:1])[C:7]=1[F:8]
Reactant: C=C(Br)C(F)(F)F
Reactant: CC1(C)OB(c2cc(Cl)c(F)c(Cl)c2F)OC1(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1CCOC1
Solvent: O
Product: C=C(c1cc(Cl)c(F)c(Cl)c1F)C(F)(F)F
Temperature: 70 °C
Yield: 59.7 %

Procedure:
A mixture of 2-(3,5-dichloro-2,4-difluorophenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (7.34 g, 23.75 mmol), 2-bromo-3,3,3-trifluoroprop-1-ene (5.82 g, 33.25 mmol), Cs2CO3 (15.5 g, 47.5 mmol) and Pd(PPh3)2Cl2 (400 mg) in THF (30 mL) and water (15 mL) was heated at 70° C. in a sealed tube for 4 h under argon. The mixture was cooled to rt and partitioned between EA and H2O. The aqueous layer was extracted with EA and the combined organic layers were dried over Na2SO4. The solvent was removed and the residue was purified by column chromatography on silica gel eluted with hexanes to give crude compound of 1,3-dichloro-2,4-difluoro-5-(3,3,3-trifluoroprop-1-en-2-yl)benzene (3.93 g) as a colorless oil. It was used in next step without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([OH:8])[CH:5]=[CH:6][CH:7]=1.F[C:10]1[CH:17]=[CH:16][C:13]([CH:14]=[O:15])=[CH:12][CH:11]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.C(OCC)(=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([CH:5]=[CH:6][CH:7]=1)[O:8][C:10]1[CH:17]=[CH:16][C:13]([CH:14]=[O:15])=[CH:12][CH:11]=1
Reactant: O=Cc1ccc(F)cc1
Reactant: Oc1cccc(Cl)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: O=Cc1ccc(Oc2cccc(Cl)c2)cc1
Yield: 95 %

Procedure:
3-Chlorophenol (0.52 g, 4 mmol), 4-fluorobenzaldehyde (0.50 g, 4 mmol), and potassium carbonate (0.56 g, 4 mmol) were stirred in DMF (5 mL) at 80° C. for 48 hours. The reaction mixture was diluted with ethyl acetate and washed with water and brine, dried over Na2SO4, filtered and evaporated to give the title compound in 95% yield. 1H NMR (CDCl3, 300 MHz) δ 6.95-7.40 (m, 9H), 7.85-8.31 (m, 4H), 9.94 (s, 1H). MS m/e 233 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6](Cl)[CH:5]=[CH:4][C:3]=1[C:9]1[N:10]=[C:11]([CH2:28][CH3:29])[C:12]([NH:17][C@@H:18]2[C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[CH2:20][C@@H:19]2[OH:27])=[N:13][C:14]=1[CH2:15][CH3:16].ClC1C=[C:35]([N:37](C)[CH3:38])C=CC=1B(O)O>>[Cl:1][C:2]1[CH:7]=[C:6]([N:37]([CH3:38])[CH3:35])[CH:5]=[CH:4][C:3]=1[C:9]1[N:10]=[C:11]([CH2:28][CH3:29])[C:12]([NH:17][C@@H:18]2[C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[CH2:20][C@@H:19]2[OH:27])=[N:13][C:14]=1[CH2:15][CH3:16]
Reactant: CCc1nc(-c2ccc(Cl)cc2Cl)c(CC)nc1N[C@@H]1c2ccccc2C[C@@H]1O
Reactant: CN(C)c1ccc(B(O)O)c(Cl)c1
Product: CCc1nc(-c2ccc(N(C)C)cc2Cl)c(CC)nc1N[C@@H]1c2ccccc2C[C@@H]1O

Procedure:
Following the procedure for the preparation of (1R,2S)-1-{[5-(2,4-dichlorophenyl)-3,6-diethylpyrazin-2-yl]amino}-2,3-dihydro-1H-inden-2-ol but substituting 2-chloro-4-dimethylaminophenylboronic acid and making non-critical variations provided the title compound as a pale yellow amorphous solid. IR (diffuse reflectance) 2969, 2932, 1607, 1567, 1550, 1486, 1443, 1391, 1353, 1225, 1207, 1177, 1043, 961, 740 cm−1; OAMS ESI+ 437.2; MS (EI) m/z 436 (M+); HRMS (FAB) calcd for C25H29CLN4O+H1 437.2108, found 437.2089. [α]25D=−7 (c 0.70, methylene chloride); Anal. Calcd for C25H29ClN4O: C, 68.72; H, 6.69; N, 12.82. Found: C, 68.48; H, 6.84; N, 12.66.
Reaction SMILES: [C:1]([Si:5]([O:8][CH2:9][C:10]([O:15][CH3:16])([CH3:14])[CH2:11][CH:12]=[CH2:13])([CH3:7])[CH3:6])([CH3:4])([CH3:3])[CH3:2].O.B1([O-])O[O:19]1.O.O.O.O.[Na+]>C1COCC1>[Si:5]([O:8][CH2:9][C:10]([O:15][CH3:16])([CH3:14])[CH2:11][CH2:12][CH2:13][OH:19])([C:1]([CH3:4])([CH3:3])[CH3:2])([CH3:6])[CH3:7]
Reactant: C=CCC(C)(CO[Si](C)(C)C(C)(C)C)OC
Reactant: [O-]B1OO1
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: COC(C)(CCCO)CO[Si](C)(C)C(C)(C)C
Reaction time: 0.5 h

Procedure:
To a solution of tert-butyl [(2-methoxy-2-methylpent-4-en-1-yl)oxy]dimethylsilane (2.45 kg, 10.04 mol) in THF (3.5 L) at <5° C. was added BH3 in THF (1M solution, 11.05 L, 11.05 mol) via a funnel while maintaining the reaction temperature at <15° C. The reaction mixture was stirred for 30 minutes and quenched with water (11.75 L, 652 mol). To the stirred mixture was added sodium perborate tetrahydrate (4.64 kg, 30.2 mol) and the mixture was stirred overnight at ambient temperature. The reaction mixture was then filtered, and the filter cake washed with 14 L MTBE. The combined organic layers were washed with brine/water (7 L/3 L). The aqueous layer was extracted with MTBE (14 L). The combined organic layers were sequentially washed with 18.75 L of 5% aqueous sodium thiosulfate/brine/water (10 L/5 L/3.75 L) and then concentrated in vacuo to provide crude material. Flash column chromatography (multiple runs) eluted with 0% to 100% DCM in heptane, then 1% to 50% EtOAc in DCM provided the desired alcohol. 1H NMR (300 MHz, CDCl3): δ 3.65-3.59 (m, 2 H); 3.47 (dd, J=23.9, 10.1 Hz, 2 H); 3.24 (s, 3 H); 2.21-2.07 (m, 1 H); 1.63-1.54 (m, 4 H); 1.05-0.70 (m, 9 H); 0.04 (s, 6H).
Reaction SMILES: [CH2:1]([O:3][C:4]1[C:5]([C:24]#[C:25][Si](C)(C)C)=[CH:6][C:7]([F:23])=[C:8]([N:10]2[C:15](=[O:16])[CH:14]=[C:13]([C:17]([F:20])([F:19])[F:18])[N:12]([CH3:21])[C:11]2=[O:22])[CH:9]=1)[CH3:2].[F-].[K+]>C(O)C>[CH2:1]([O:3][C:4]1[C:5]([C:24]#[CH:25])=[CH:6][C:7]([F:23])=[C:8]([N:10]2[C:15](=[O:16])[CH:14]=[C:13]([C:17]([F:20])([F:18])[F:19])[N:12]([CH3:21])[C:11]2=[O:22])[CH:9]=1)[CH3:2]
Reactant: CCOc1cc(-n2c(=O)cc(C(F)(F)F)n(C)c2=O)c(F)cc1C#C[Si](C)(C)C
Agent: [F-]
Agent: [K+]
Solvent: CCO
Product: C#Cc1cc(F)c(-n2c(=O)cc(C(F)(F)F)n(C)c2=O)cc1OCC
Reaction time: 8 h
Yield: 82.5 %

Procedure:
3-{5-Ethoxy-2-fluoro-4-[2-(trimethylsilyl)-1-ethynyl]phenyl}-1-methyl-6-trifluoromethyl-2,4(1H,3H)-pyrimidinedione (1.37 g) was dissolved in ethanol (14 ml). To this solution, an aqueous solution (1 ml) of potassium fluoride (0.30 g) was added dropwise at room temperature and the mixture was stirred for further 8 hours. After the reaction, ethanol was distilled off under reduced pressure, extracted with ethyl acetate, washed with water, and then dried over anhydrous magnesium sulfate. Then, ethyl acetate was distilled off and the resulting oily substance was purified by chromatography on silica gel (ethyl acetate:n-hexane=1:3) to obtain the objective 3-[5-ethoxy-4-(1-ethynyl)-2-fluorophenyl]-1-methyl-6-trifluoromethyl-2,4(1H,3H)-pyrimidinedione (0.94 g).
Reaction SMILES: Cl.Cl[C:3]1[N:8]2[N:9]=[C:10]([CH:12]3[CH2:17][CH2:16][N:15]([CH:18]([CH3:20])[CH3:19])[CH2:14][CH2:13]3)[N:11]=[C:7]2[CH:6]=[C:5]([C:21]2[CH:26]=[CH:25][C:24]([F:27])=[CH:23][C:22]=2[Cl:28])[N:4]=1.Cl.[NH:30]1[CH2:35][CH2:34][CH2:33][CH:32]([NH:36][C:37]2[N:42]=[CH:41][C:40]([C:43]#[N:44])=[CH:39][CH:38]=2)[CH2:31]1.C(N(CC)C(C)C)(C)C>CS(C)=O>[Cl:28][C:22]1[CH:23]=[C:24]([F:27])[CH:25]=[CH:26][C:21]=1[C:5]1[N:4]=[C:3]([N:30]2[CH2:35][CH2:34][CH2:33][CH:32]([NH:36][C:37]3[N:42]=[CH:41][C:40]([C:43]#[N:44])=[CH:39][CH:38]=3)[CH2:31]2)[N:8]2[N:9]=[C:10]([CH:12]3[CH2:17][CH2:16][N:15]([CH:18]([CH3:20])[CH3:19])[CH2:14][CH2:13]3)[N:11]=[C:7]2[CH:6]=1
Reactant: CC(C)N1CCC(c2nc3cc(-c4ccc(F)cc4Cl)nc(Cl)n3n2)CC1
Reactant: N#Cc1ccc(NC2CCCNC2)nc1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CS(C)=O
Product: CC(C)N1CCC(c2nc3cc(-c4ccc(F)cc4Cl)nc(N4CCCC(Nc5ccc(C#N)cn5)C4)n3n2)CC1
Temperature: 130 °C

Procedure:
80 mg (0.2 mmol) of 5-chloro-7-(2-chloro-4-fluorophenyl)-2-[1-(propan-2-yl)piperidin-4-yl][1,2,4]triazolo[1,5-c]pyrimidine hydrochloride (Example 52A), 50 mg (0.2 mmol) of 6-(piperidin-3-ylamino)pyridine-3-carbonitrile hydrochloride (Example 19A) and 0.17 ml (0.99 mmol) of N,N-diisopropylethylamine were initially charged in 1 ml of DMSO. The mixture was heated in the microwave at 130° C. for 30 min. This gave, after purification of the crude product by preparative HPLC (Method 11), 39 mg (37% of theory) of the product as a solid.
Reaction SMILES: [OH-:1].[Na+].Cl[C:4]1[N:9]=[C:8]2[N:10]([CH3:19])[N:11]=[C:12]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[C:7]2=[CH:6][CH:5]=1.Cl>CS(C)=O>[CH3:19][N:10]1[C:8]2[NH:9][C:4](=[O:1])[CH:5]=[CH:6][C:7]=2[C:12]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[N:11]1
Reactant: [OH-]
Reactant: Cn1nc(-c2ccccc2)c2ccc(Cl)nc21
Agent: Cl
Agent: [Na+]
Solvent: CS(C)=O
Product: Cn1nc(-c2ccccc2)c2ccc(=O)[nH]c21
Temperature: 100 °C
Yield: 95.7 %

Procedure:
A mixture of aqueous NaOH (0.64 g, 16.00 mmol in 2.0 mL H2O) and 6-chloro-1-methyl-3-phenyl-1H-pyrazolo[3,4-b]pyridine (0.39 g, 1.6 mmol) in DMSO (2.0 mL) was heated at 100° C. for 10 h. The reaction mixture was cooled to rt and neutralized with diluted HCl. A white solid was obtained. The solid was collected by filtration, washed with diethyl ether and dried under vacuum to yield the title compound as white solid (0.345 g, 96%). [1H-NMR (DMSO-d6, 300 MHz) δ 8.27 (d, 1H), 7.92 (m, 2H), 7.55-7.35 (m, 3H), 6.46 (d, 1H), 3.9 (s, 3H); HPLC RtA=6.802 min (99.7%); LCMS RtA=0.360 min; [M+H]+=226.0]
Reaction SMILES: C[O:2][C:3](=O)[CH:4]([C:9]1[CH:14]=[CH:13][C:12]([Br:15])=[CH:11][CH:10]=1)[C:5](OC)=[O:6].[Na].Cl.[CH:19]([NH2:21])=[NH:20]>CO>[Br:15][C:12]1[CH:13]=[CH:14][C:9]([C:4]2[C:5]([OH:6])=[N:20][CH:19]=[N:21][C:3]=2[OH:2])=[CH:10][CH:11]=1
Reactant: N=CN
Reactant: COC(=O)C(C(=O)OC)c1ccc(Br)cc1
Agent: Cl
Agent: [Na]
Solvent: CO
Product: Oc1ncnc(O)c1-c1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 90.7 %

Procedure:
A solution of 2-(4-bromophenyl)-malonic acid dimethyl ester (11.73 g) in methanol (100 mL) is added at 0° C. to a solution of sodium (2.83 g) in methanol (100 mL). The mixture is stirred for 18 h at rt before formamidine hydrochloride (4.10 g) is added. The suspension is stirred at rt for 4 h. The solvent is removed and the residue is suspended in 10% aq. citric acid (100 mL) and stirred for 10 min. The white precipitate is collected, washed with 10% aq. citric acid, water, evaporated three times from CyHex and dried under high vacuum at 40° C. to give 5-(4-bromophenyl)-pyrimidine-4,6-diol (9.90 g) as a pale beige powder. LC-MS: tR=0.61 min, [M+H]+=267.07; 1H-NMR(D6-DMSO): 7.43-7.48 (m, 2H), 7.50-7.55 (m, 2H), 8.13 (s, 1H), 12.1 (s br, 2H).
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][O:5][CH2:6][C:7](=[O:14])[CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10].S(Cl)([Cl:18])(=O)=O>C(Cl)Cl.CCOC(C)=O>[Cl:18][CH:8]([C:7](=[O:14])[CH2:6][O:5][CH2:4][CH2:3][O:2][CH3:1])[C:9]([O:11][CH2:12][CH3:13])=[O:10]
Reactant: O=S(=O)(Cl)Cl
Reactant: CCOC(=O)CC(=O)COCCOC
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CCOC(=O)C(Cl)C(=O)COCCOC
Reaction time: 6 h
Yield: 70.8 %

Procedure:
Ethyl 4-(2-methoxyethoxy)-3-oxobutanoate (Intermediate 123) (0.5 g) was dissolved in anhydrous DCM (5 ml). Sulfuryl chloride (430 mg) was added dropwise at room temperature. The mixture was stirred for 6 h. The crude mixture was diluted with EtOAc (50 ml) and washed well with water and brine, dried over sodium sulfate and concentrated in vacuo to afford the title compound as a light orange oil (414 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]([O:17][CH2:18][C:19]([F:22])([F:21])[F:20])=[N:10][CH:11]=[C:12]([CH:16]=2)[C:13](O)=[O:14])=[CH:4][CH:3]=1.Cl.[F:24][C:25]([F:34])([F:33])[C:26]1[N:30]=[C:29]([CH2:31][NH2:32])[O:28][N:27]=1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:9]([O:17][CH2:18][C:19]([F:22])([F:21])[F:20])=[N:10][CH:11]=[C:12]([CH:16]=2)[C:13]([NH:32][CH2:31][C:29]2[O:28][N:27]=[C:26]([C:25]([F:34])([F:33])[F:24])[N:30]=2)=[O:14])=[CH:6][CH:7]=1
Reactant: NCc1nc(C(F)(F)F)no1
Reactant: O=C(O)c1cnc(OCC(F)(F)F)c(-c2ccc(Cl)cc2)c1
Agent: Cl
Product: O=C(NCc1nc(C(F)(F)F)no1)c1cnc(OCC(F)(F)F)c(-c2ccc(Cl)cc2)c1

Procedure:
The title compound was synthesized in analogy to Example 1, using 5-(4-chloro-phenyl)-6-(2,2,2-trifluoro-ethoxy)-nicotinic acid (CAS Registry No. 1018782-82-5) and C-(3-trifluoromethyl-[1,2,4]oxadiazol-5-yl)-methylamine hydrochloride (CAS registry No. 944905-93-5; example AK) as starting materials, LC-MS (UV peak area/ESI) 100%, 479.0355 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]([F:14])=[N:10][CH:11]=[CH:12][CH:13]=2)=[CH:4][C:3]=1[CH2:15][OH:16].[Cr](Cl)([O-])(=O)=O.[NH+]1C=CC=CC=1>ClCCl>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]([F:14])=[N:10][CH:11]=[CH:12][CH:13]=2)=[CH:4][C:3]=1[CH:15]=[O:16]
Reactant: OCc1cc(-c2cccnc2F)ccc1F
Agent: O=[Cr](=O)([O-])Cl
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Product: O=Cc1cc(-c2cccnc2F)ccc1F
Temperature: 25 °C
Yield: 187.2 %

Procedure:
(2-Fluoro-5-(2-fluoropyridin-3-yl)phenyl)methanol (2.54 g) was dissolved in dichloromethane (200 mL). Silica gel (30 mL) was added followed by pyridinium chlorochromate (5.31 g, 24.63 mmol). It was stirred at RT and monitored by TLC. Once the oxidation was complete the mixture was filtered through a pad of silica gel (10 mL) and washed with ethyl acetate. Evaporation under reduced pressure gave the desired 2-fluoro-5-(2-fluoropyridin-3-yl)benzaldehyde (4.71 g, 21.49 mmol, 87% yield) as an off white solid. MS m/z=220.1 [M+H]+. Calculated for C12H7F2NO: 219.05.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[C:4]([NH:9][C:10](=[O:14])[CH:11]([CH3:13])[CH3:12])[CH:3]=1.[C:15]([C:18]1[C:19](=[O:29])[O:20][C:21]([OH:28])=[C:22]([C:25](=O)[CH3:26])[C:23]=1[OH:24])(=[O:17])[CH3:16]>CO>[C:15]([C:18]1[C:19](=[O:29])[O:20][C:21](=[O:28])[C:22](=[C:25]([NH:1][C:2]2[CH:7]=[CH:6][C:5]([OH:8])=[C:4]([NH:9][C:10](=[O:14])[CH:11]([CH3:12])[CH3:13])[CH:3]=2)[CH3:26])[C:23]=1[OH:24])(=[O:17])[CH3:16]
Reactant: CC(=O)c1c(O)oc(=O)c(C(C)=O)c1O
Reactant: CC(C)C(=O)Nc1cc(N)ccc1O
Solvent: CO
Product: CC(=O)C1=C(O)C(=C(C)Nc2ccc(O)c(NC(=O)C(C)C)c2)C(=O)OC1=O

Procedure:
This phenol (0.86 g., 0.0045 mol) is refluxed with 3,5-diacetyl-4,6-dihydroxy-2H-pyran-2-one (0.96 g.) in 50 ml. of methanol for 10 hours. The reaction mixture is filtered and the solid is recrystallized from ethanol to furnish 5-acetyl-4-hydroxy-3-[1-(3-isobutyramido-4-hydroxyphenylamino)ethylidene]-2H-pyran-2,6(3H)-dione, m.p. 208°-209° C. (dec.).