Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH2:14][CH2:13][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:11][CH:10]=2)=[CH:5][CH:4]=1)#[N:2]>C(OCC)(=O)C>[C:1]([C:3]1[CH:4]=[CH:5][C:6]([CH:9]2[CH2:10][CH2:11][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:13][CH2:14]2)=[CH:7][CH:8]=1)#[N:2]
Reactant: CC(C)(C)OC(=O)N1CC=C(c2ccc(C#N)cc2)CC1
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CCC(c2ccc(C#N)cc2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 39.7 %

Procedure:
Around-bottom flask, containing a solution of tert-butyl 4-(4-cyanophenyl)-5,6-dihydropyridine-1(2H)-carboxylate (compound 1.3, 500 mg, 1.76 mmol, 1.00 equiv) in ethyl acetate (20 mL) was purged with nitrogen gas. To the solution was then added palladium on carbon (0.1 g, 10%, 60% water) and the flask was then further purged with nitrogen. The atmosphere was then changed to hydrogen and the mixture was stirred overnight at room temperature. After purging the system with nitrogen, the solids were removed by filtration and the filtrate was concentrated under reduced pressure to yield 0.2 g (40%) of the title compound as a yellow oil.
Reaction SMILES: [I:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([C:11]([O:13]C)=[O:12])[CH:9]=2)[N:4]([CH:15]2[CH2:20][CH2:19][CH2:18][CH2:17][O:16]2)[N:3]=1.[Li+].[OH-]>C1COCC1.CO>[I:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([C:11]([OH:13])=[O:12])[CH:9]=2)[N:4]([CH:15]2[CH2:20][CH2:19][CH2:18][CH2:17][O:16]2)[N:3]=1
Reactant: COC(=O)c1ccc2c(c1)c(I)nn2C1CCCCO1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: O=C(O)c1ccc2c(c1)c(I)nn2C1CCCCO1
Temperature: 25 °C
Reaction time: 12 h
Yield: 87 %

Procedure:
To a solution of methyl 3-iodo-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole-5-carboxylate ((5.0 g, 12.9 mmol) in THF: MeOH (70:30) (50 mL) was added LiOH (3.10 g, 129.0 mmol) in one lot and the reaction was stirred at RT for 12 h. The solvent were removed in vacuo and the residue was diluted with water and quenched with 1N HCl (50 mL) to obtain off white precipitate. The suspension was stirred for 10 min and filtered and dried to give 3-iodo-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole-5-carboxylic acid (4.2 g, 87%) as an off white solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 13.09 (s, 1H), 8.03-8.06 (m, 2H), 7.84-7.86 (m, 1H), 5.93 (dd, 1 H, J=9.7, 2.3 Hz), 3.90 (d, 1 H, J=11.9 Hz), 3.74-3.76 (m, 1H), 2.35-2.41 (m, 1H), 1.97-2.00 (m, 2H), 1.69-1.80 (m, 1H), 1.41-1.58 (m, 2H).
Reaction SMILES: [NH2:1][C:2]1[CH:6]=[CH:5][S:4][C:3]=1[C:7]([NH2:9])=[O:8].Cl[C:11](Cl)([O:13]C(=O)OC(Cl)(Cl)Cl)Cl>O1CCOCC1>[N:1]1[C:2]2[CH:6]=[CH:5][S:4][C:3]=2[C:7]([OH:8])=[N:9][C:11]=1[OH:13]
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: NC(=O)c1sccc1N
Solvent: C1COCCO1
Product: Oc1nc(O)c2sccc2n1
Yield: 146.9 %

Procedure:
500 mg (3.5 mmol) 3-amino-thiophene-2-carboxamide is dissolved in 30 mL dioxane. 520 mg (1.75 mmol, 0.5 eq) triphosgene is added and the mixture is heated at 80 C for 1 h. The mixture is concentrated and triturated from hot methanol. The resulting solids are collected. The filtrate is concentrated and triturated again from hot methanol. The 2 crops of solids are combined to give 432 mg of the title compound (2.57 mmol, 73%).
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]([NH2:10])=[O:9])=[C:6]([N:11]2[CH2:16][CH2:15][CH:14]([C:17]3[N:18]([CH3:33])[CH:19]=[C:20]([C:22]4[CH:27]=[CH:26][C:25]([F:28])=[C:24]([C:29]([F:32])([F:31])[F:30])[CH:23]=4)[N:21]=3)[CH2:13][CH2:12]2)[N:5]=[CH:4][N:3]=1.NC1C(C#N)=C(N2CCC(C3N(C[CH2:66][NH:67][CH:68]4[CH2:72][CH2:71][CH2:70][CH2:69]4)C=C(C4C=CC(F)=C(C(F)(F)F)C=4)N=3)CC2)N=CN=1>>[NH2:1][C:2]1[C:7]([C:8]([NH2:10])=[O:9])=[C:6]([N:11]2[CH2:16][CH2:15][CH:14]([C:17]3[N:18]([CH2:33][CH2:66][NH:67][CH:68]4[CH2:72][CH2:71][CH2:70][CH2:69]4)[CH:19]=[C:20]([C:22]4[CH:27]=[CH:26][C:25]([F:28])=[C:24]([C:29]([F:32])([F:31])[F:30])[CH:23]=4)[N:21]=3)[CH2:13][CH2:12]2)[N:5]=[CH:4][N:3]=1
Reactant: Cn1cc(-c2ccc(F)c(C(F)(F)F)c2)nc1C1CCN(c2ncnc(N)c2C(N)=O)CC1
Reactant: N#Cc1c(N)ncnc1N1CCC(c2nc(-c3ccc(F)c(C(F)(F)F)c3)cn2CCNC2CCCC2)CC1
Product: NC(=O)c1c(N)ncnc1N1CCC(c2nc(-c3ccc(F)c(C(F)(F)F)c3)cn2CCNC2CCCC2)CC1

Procedure:
The title compound was prepared in an analogous manner as 4-Amino-6-{4-[4-(4-fluoro-3-trifluoromethyl-phenyl)-1-methyl-1H-imidazol-2-yl]-piperidin-1-yl}-pyrimidine-5-carboxamide using 4-Amino-6-{4-[1-(2-cyclopentylamino-ethyl)-4-(4-fluoro-3-trifluoromethyl-phenyl)-1H-imidazol-2-yl]-piperidin-1-yl}-pyrimidine-5-carbonitrile instead of 4-amino-6-(4-{4-[4-fluoro-3-(trifluoromethyl)phenyl]-1-methyl-1H-imidazol-2-yl}piperidin-1-yl)pyrimidine-5-carbonitrile. LC-MS: (M+1=561, obsd.=561).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH2:15][CH2:16][CH2:17][N:18]3[CH2:23][CH2:22][N:21]([CH3:24])[CH2:20][CH2:19]3)=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][N:3]=1.[F:25][C:26]1[C:34]([OH:35])=[CH:33][CH:32]=[C:31]2[C:27]=1[CH:28]=[CH:29][NH:30]2.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[F:25][C:26]1[C:34]([O:35][C:2]2[C:11]3[C:6](=[CH:7][C:8]([O:14][CH2:15][CH2:16][CH2:17][N:18]4[CH2:23][CH2:22][N:21]([CH3:24])[CH2:20][CH2:19]4)=[C:9]([O:12][CH3:13])[CH:10]=3)[N:5]=[CH:4][N:3]=2)=[CH:33][CH:32]=[C:31]2[C:27]=1[CH:28]=[CH:29][NH:30]2
Reactant: Oc1ccc2[nH]ccc2c1F
Reactant: COc1cc2c(Cl)ncnc2cc1OCCCN1CCN(C)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1cc2c(Oc3ccc4[nH]ccc4c3F)ncnc2cc1OCCCN1CCN(C)CC1
Temperature: 95 °C
Reaction time: 3 h
Yield: 42.2 %

Procedure:
A mixture of 4-chloro-6-methoxy-7-(3-(4-methylpiperazin-1-yl)propoxy)quinazoline (232 mg, 0.662 mmol), (prepared as described for the starting material in Examples 176 or 244), and 4-fluoro-5-hydroxyindole (120 mg, 0.794 mmol), (prepared as described for the starting material in Example 242), in DMF (3 ml) containing potassium carbonate (137 mg, 1 mmol) was stirred at 95° C. for 3 hours. After cooling, the residue was poured onto water (12 ml) and extracted with ethyl acetate. The organic layer was washed with water, brine, dried (MgSO4) and evaporated. The residue was purified by reversed phase C18 column chromatography eluting with methanol/ammonium carbonate (2g of ammonium carbonate/liter saturated with CO2) (60/40 followed by 70/30). The fractions containing the expected product were combined and evaporated. The residue was dissolved in ethyl acetate, dried (MgSO4) and the volatiles were removed under vacuum. The residue was triturated with ether, filtered and dried under vacuum to give 4-(4-fluoroindol-5-yloxy)-6-methoxy-7-(3-(4-methylpiperazin-1-yl)propoxy)quinazoline (130 mg, 42%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][C:10]=1[Cl:11])[NH:7][C:6]([C:12]1[CH:30]=[CH:29][C:15]([C:16]([NH:18][CH:19]3[CH2:24][C:23]([CH3:26])([CH3:25])[NH:22][C:21]([CH3:28])([CH3:27])[CH2:20]3)=[O:17])=[CH:14][C:13]=1[O:31]CC1C=CC=CC=1)=[CH:5]2.CCO.CC#N>Cl>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][C:10]=1[Cl:11])[NH:7][C:6]([C:12]1[CH:30]=[CH:29][C:15]([C:16]([NH:18][CH:19]3[CH2:20][C:21]([CH3:27])([CH3:28])[NH:22][C:23]([CH3:25])([CH3:26])[CH2:24]3)=[O:17])=[CH:14][C:13]=1[OH:31])=[CH:5]2
Reactant: CC1(C)CC(NC(=O)c2ccc(-c3cc4cc(Cl)c(Cl)cc4[nH]3)c(OCc3ccccc3)c2)CC(C)(C)N1
Agent: Cl
Solvent: CC#N
Solvent: CCO
Product: CC1(C)CC(NC(=O)c2ccc(-c3cc4cc(Cl)c(Cl)cc4[nH]3)c(O)c2)CC(C)(C)N1
Yield: 30 %

Procedure:
A mixture of 4-(5,6-dichloro-1H-indol-2-yl)-3-benzyloxy-N-(2,2,6,6-tetramethylpiperidin-4-yl)-benzamide (0.08 g, 0.145 mmol), prepared as described in Example 2, in 37% HCl (5 ml) and EtOH (5 ml) was refluxed for 3 h. After cooling the solvent was removed under vacuum. The resulting solid was purified by column chromatography over silica gel (CH2Cl2/MeOH/NH4OH 86:10:0.6) to yield, after trituration with CH3CN, 0.02 g (yield 39%) of the title compound as a white solid, mp>270° C.
Reaction SMILES: C(O[C:5]1[C:6](=[O:18])[C:7](=[O:17])[C:8]=1[C:9]1[CH:14]=[CH:13][C:12]([C:15]#[N:16])=[CH:11][CH:10]=1)(C)C.[NH2:19][CH:20]([C:22]([CH3:25])([CH3:24])[CH3:23])[CH3:21]>C(#N)C>[O:18]=[C:6]1[C:7](=[O:17])[C:8]([C:9]2[CH:10]=[CH:11][C:12]([C:15]#[N:16])=[CH:13][CH:14]=2)=[C:5]1[NH:19][CH:20]([CH3:21])[C:22]([CH3:25])([CH3:24])[CH3:23]
Reactant: CC(C)Oc1c(-c2ccc(C#N)cc2)c(=O)c1=O
Reactant: CC(N)C(C)(C)C
Solvent: CC#N
Product: CC(Nc1c(-c2ccc(C#N)cc2)c(=O)c1=O)C(C)(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 50.6 %

Procedure:
To a solution of 3-isopropoxy-4-(4-cyano-phenyl)-cyclobut-3-ene-1,2-dione (0.27 g, 1.12 mmol) in acetonitrile (6 mL) was added 2-amino-3,3-dimethylbutane (0.23 mL, 1.68 mmol). The mixture was stirred at room temperature overnight then filtered. The solid was recrystallized from ethyl acetate/hexanes to give 0.160 g (50%) of the title product as a white solid: m.p. 192-194° C.; 1H NMR (DMSO-d6) δ 9.01(br d,1H), 8.19(ABq,2H), 8.01(ABq,2H), 4.29(m,1H), 1.25(d,3H), 0.92(s,9H); IR (KBr) 3160, 2950, 2220, 1760, 1600, 1440, 1160, 1100, 850 cm−1; MS (m/z) 282 [M+].
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH2:11][CH2:12][NH:13][C:14](=[O:22])[C@@H:15]([NH2:21])[CH2:16][C:17]([CH3:20])([CH3:19])[CH3:18])[CH2:6][CH2:5]2.Cl[C:24]1[CH:29]=[N:28][CH:27]=[CH:26][N:25]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.[Cu]I>[F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH2:11][CH2:12][NH:13][C:14](=[O:22])[C@@H:15]([NH:21][C:24]1[CH:29]=[N:28][CH:27]=[CH:26][N:25]=1)[CH2:16][C:17]([CH3:18])([CH3:19])[CH3:20])[CH2:6][CH2:5]2
Reactant: Clc1cnccn1
Reactant: CC(C)(C)C[C@H](N)C(=O)NCCN1CCc2cc(F)ccc21
Agent: [Cu]I
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)(C)C[C@H](Nc1cnccn1)C(=O)NCCN1CCc2cc(F)ccc21
Temperature: 240 °C
Yield: 30.3 %

Procedure:
(S)-2-Amino-4,4-dimethyl-pentanoic acid [2-(5-fluoro-2,3-dihydro-indol-1-yl)-ethyl]-amide (20 mg, 0.066 mmol) was dissolved in DMF (0.7 mL) containing equimolar amounts of 2-chloropyrazine (6 μL, 0.066 mmol), 0.1 equivalents of CuI (1.3 mg, 0.006 mmol), and 1.5 equivalents of potassium carbonate (13.9 mg, 0.099 mmol). The mixture was stirred and heated by microwave to 240° C. for 30 minutes. After completion the mixture was purified by reverse phase LC to afford (S)-4,4-Dimethyl-2-(pyrazin-2-ylamino)-pentanoic acid [2-(5-fluoro-2,3-dihydro-indol-1-yl)-ethyl]-amide 2 (8.3 mg, 0.02 mmol, 32%): 1H-NMR (400 MHz, CD3OD) δ=8.37 (m, 2H), 6.82–6.41 (m, 4H), 4.57 (dd, J=9.2, J=3.2, 1H), 3.42 (t, J=6.2, 2H), 3.36 (t, J=8.2, 2H), 3.14 (m, 2H), 2.88 (t, J=8.2, 2H), 1.83–1.62 (m, 2H), 0.96 (s, 9H). MS calcd. for C21H29FN5O (M+H+) 386.23. found 386.5.
Reaction SMILES: [CH:1]1([CH2:6]I)[CH2:5][CH2:4][CH2:3][CH2:2]1.[F:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[C:15]1[N:19]2[N:20]=[C:21]([O:25][CH2:26][C:27]3[N:28]([CH3:32])[N:29]=[CH:30][N:31]=3)[C:22](I)=[CH:23][C:18]2=[N:17][N:16]=1>>[CH:1]1([CH2:6][C:22]2[C:21]([O:25][CH2:26][C:27]3[N:28]([CH3:32])[N:29]=[CH:30][N:31]=3)=[N:20][N:19]3[C:15]([C:10]4[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=4[F:8])=[N:16][N:17]=[C:18]3[CH:23]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: Cn1ncnc1COc1nn2c(-c3ccccc3F)nnc2cc1I
Reactant: ICC1CCCC1
Product: Cn1ncnc1COc1nn2c(-c3ccccc3F)nnc2cc1CC1CCCC1

Procedure:
This compound was prepared using the procedure described in Example 27 Step c) with cyclopentylmethyl iodide used instead of neopentyl iodide and 3-(2-fluorophenyl)-7-iodo-6-(2-methyl-2H-1,2,4-triazol-3-ylmethoxy)-1,2,4-triazolo[4,3-b]pyridazine used instead of 7-bromo-3-(2-fluorophenyl)-6-(2-methyl-2H-1,2,4-triazol-3-ylmethoxy)-1,2,4-triazolo[4,3-b]pyridazine. Data for the title compound: m.p. 135-137° C.; 1H NMR (360 MHz, CDCl3) δ 1.18-1.28 (2H, m), 1.36-1.74 (4H, m), 1.76-1.86 (2H, m), 2.16-2.28 (1H, m), 2.66 (2H, d, J=7 Hz), 3.84 (3H, s), 5.49 (2H, s), 7.25-7.30 (1H, m), 7.36 (1H, dd, J=7 and 7 Hz), 7.50-7.60 (1H, m), 7.82-7.86 (2H, m), 7.89 (1H, s); MS (ES+) m/e 382 [MH]+. Anal. Found C, 60.85; H, 5.38%. C21H22FN7O.0.4H2O requires C, 60.83; H, 5.54%.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]([N:17]3[CH:21]=[CH:20][N:19]=[C:18]3[CH3:22])[O:11][C:12]=2[CH2:13][CH2:14][CH2:15][OH:16])=[CH:4][CH:3]=1.O[CH:24]1[CH2:32][C:31]2[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=2)[CH2:25]1.C(P(CCCC)CCCC)CCC.N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O>O1CCCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:9]=[C:10]([N:17]3[CH:21]=[CH:20][N:19]=[C:18]3[CH3:22])[O:11][C:12]=2[CH2:13][CH2:14][CH2:15][O:16][C:28]2[CH:27]=[C:26]3[C:31](=[CH:30][CH:29]=2)[CH2:32][CH2:24][CH2:25]3)=[CH:6][CH:7]=1
Reactant: OC1Cc2ccccc2C1
Reactant: Cc1nccn1-c1nc(-c2ccc(Cl)cc2)c(CCCO)o1
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: C1CCOC1
Product: Cc1nccn1-c1nc(-c2ccc(Cl)cc2)c(CCCOc2ccc3c(c2)CCC3)o1
Reaction time: 1 h

Procedure:
To a mixture of 4-(4-chlorophenyl)-2-(2-methyl-1-imidazolyl)-5-oxazolepropanol (318 mg), 2-hydroxyindane (268 mg), tributylphosphine (405 mg) and tetrahydrofuran (10 ml) was added 1,1′-(azodicarbonyl)dipiperidine (400 mg) at room temperature, and the resulting mixture was stirred for 1 hour. After the reaction mixture was concentrated, the residue was subjected to silica gel column chromatography, and 4-(4-chlorophenyl)-5-[3-(5-indanyloxy)propyl]-2-(2-methyl-1-imidazolyl)oxazole was obtained as an oil (418 mg, 96%) from an ethyl acetate-hexane (1:1, v/v)-eluted fraction.
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH3:9])=[C:4]([CH:6]=[CH:7][CH:8]=1)N.C(ON=O)(C)(C)C.[S:17]1[CH:21]=[CH:20][CH:19]=[CH:18]1>>[Cl:1][C:2]1[C:3]([CH3:9])=[C:4]([C:18]2[S:17][CH:21]=[CH:20][CH:19]=2)[CH:6]=[CH:7][CH:8]=1
Reactant: Cc1c(N)cccc1Cl
Reactant: c1ccsc1
Agent: CC(C)(C)ON=O
Product: Cc1c(Cl)cccc1-c1cccs1

Procedure:
3-Chloro-2-methylaniline was treated with t-butylnitrite in excess thiophene as described in J. Chem. Soc., 4257 (1963) to produce 2-(3-chloro-2-methylphenyl)thiophene as an oil. Reaction of the oil with N-bromosuccinimide as described in J. Am. Chem. Soc., 89, 2348 (1967) yielded 2-(2-bromomethyl-3-chlorophenyl)thiophene as an oil, which was reacted without further purification, as described in J. Chem. Soc., 2708 (1955), with diethyl malonate in the presence of tetrabutyl ammonium bromide and potassium hydroxide in dry tetrahydrofuran, producing ethyl [2-carboethoxy-3-[2-chloro-6-(thien-2-yl)phenyl]]propionate. Hydrolysis of the latter with hydrochloric acid in glacial acetic acid provided 3-[2-chloro-6-(thien-2-yl)phenyl]propionic acid; mp 83°-86°.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([CH2:7][CH2:8][O:9][C:10]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][C:18]=3[OH:20])[O:13][C:12](=[O:21])[C:11]=2[C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH2:3][CH2:2]1.[C:28](=O)([O-])[O-].[K+].[K+].[I-].[K+].S(OC)(OC)(=O)=O>C(C(C)=O)C(C)C>[CH3:28][O:20][C:18]1[CH:17]=[CH:16][CH:15]=[C:14]2[C:19]=1[C:10]([O:9][CH2:8][CH2:7][N:4]1[CH2:3][CH2:2][O:1][CH2:6][CH2:5]1)=[C:11]([C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1)[C:12](=[O:21])[O:13]2
Reactant: O=C([O-])[O-]
Reactant: O=c1oc2cccc(O)c2c(OCCN2CCOCC2)c1-c1ccccc1
Agent: [I-]
Agent: [K+]
Solvent: COS(=O)(=O)OC
Solvent: CC(=O)CC(C)C
Product: COc1cccc2oc(=O)c(-c3ccccc3)c(OCCN3CCOCC3)c12
Yield: 25.2 %

Procedure:
18.4 g. (0.05 mol) of 4-(2'-morpholinoethoxy)-5-hydroxy-3-phenyl coumarin (Example 30), 9.7 g. (0.07 mol) of potassium carbonate, 0.5 g. of potassium iodide and 250 ml. of methyl isobutyl ketone are brought over one hour to 80° C. The temperature is then brought to 60° C. and 7.6 g. (0.06 mol) of freshly distilled dimethyl sulphate are added dropwise in 20 minutes. Refluxing takes place for 8 hours and, after cooling, filtering is carried out. The filtrate is evaporated under vacuum and then, after washing with sodium bicarbonate and then water, and extraction with chloroform, there are obtained, after evaporation, 4.8 g. of an oil which cannot be crystallised. Yield 25.2% (theoretical yield 19.1 g.).
Reaction SMILES: C(=O)(O)[O-:2].[Na+].Br[CH:7]([CH3:16])[C:8]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)=[O:9].C([O-])=O.[Na+].C(=O)=O>C(#N)C.O>[OH:2][CH:7]([CH3:16])[C:8]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)=[O:9]
Reactant: CC(Br)C(=O)c1ccccc1
Reactant: O=C([O-])O
Agent: O=C=O
Agent: O=C[O-]
Agent: [Na+]
Solvent: CC#N
Solvent: O
Product: CC(O)C(=O)c1ccccc1
Yield: 98 %

Procedure:
There was added 10.08 parts of sodium bicarbonate and about 60 parts of water to a mixture of 21.3 parts of α-bromopropiophenone, 6.8 parts of sodium formate and about 90 parts of acetonitrile. The resulting mixture was stirred vigorously for 48 hours at 65° C during which time carbon dioxide evolved. After cooling, the acetonitrile solution was separated from the aqueous layer and evaporated to dryness. The residue was dissolved into chloroform which was extracted once with water, dried over sodium sulfate, and evaporated to produce analytically pure (<98%) α-hydroxy-propiophenone. The yield of this isolated product was 77.1%,
Reaction SMILES: N1CCCCC1.C([Li])CCC.[CH3:12][O:13][CH2:14][O:15][C:16]1[CH:17]=[CH:18][C:19]([C:22]([F:25])([F:24])[F:23])=[N:20][CH:21]=1.[CH:26](=[O:28])[CH3:27]>C1COCC1>[CH3:12][O:13][CH2:14][O:15][C:16]1[C:17]([CH:26]([OH:28])[CH3:27])=[CH:18][C:19]([C:22]([F:25])([F:23])[F:24])=[N:20][CH:21]=1
Reactant: COCOc1ccc(C(F)(F)F)nc1
Reactant: CC=O
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: C1CCNCC1
Product: COCOc1cnc(C(F)(F)F)cc1C(C)O
Temperature: -78 °C
Reaction time: 0.08 h

Procedure:
To a stirred solution of piperidine, 2,2,6,6-tetramethyl-(9.2 ml, 54 mmol) in THF (400 ml) at −78° C. was added butyllithium (˜2.5 m in toluene; 18 ml, 45 mmol) dropwise. The reaction was then stirred at 0° C. for 5 min at −78° C., and a solution of 5-(methoxymethoxy)-2-(trifluoromethyl)pyridine (7.5 g, 36 mmol) in THF (100 ml) was added dropwise. The mixture was stirred for an additional 10 min, then acetaldehyde (20 ml, 362 mmol) was added and stirring continued for 15 min. the reaction was slowly quenched with H2O, warmed to RT, extracted with EtOAc (3×), combine organic layers were dried over MgSO4, filtered, concentrated and the crude product was purified by ISCO (20% EtOAc/Hexanes) to give the title compound as a light yellow solid. MS (m+1): 252.2.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([NH:10][C:11]2[C:16]([C:17]3[N:22]=[C:21]([CH3:23])[N:20]=[C:19]([N:24](CC4C=CC(OC)=CC=4)CC4C=CC(OC)=CC=4)[N:18]=3)=[CH:15][C:14]([CH:43]([C:45]3[CH:50]=[CH:49][C:48]([S:51]([CH3:54])(=[O:53])=[O:52])=[CH:47][CH:46]=3)[CH3:44])=[CH:13][N:12]=2)[CH:5]=[N:6][C:7]=1[O:8][CH3:9]>FC(F)(F)C(O)=O>[F:1][C:2]1[CH:3]=[C:4]([NH:10][C:11]2[C:16]([C:17]3[N:22]=[C:21]([CH3:23])[N:20]=[C:19]([NH2:24])[N:18]=3)=[CH:15][C:14]([CH:43]([C:45]3[CH:50]=[CH:49][C:48]([S:51]([CH3:54])(=[O:52])=[O:53])=[CH:47][CH:46]=3)[CH3:44])=[CH:13][N:12]=2)[CH:5]=[N:6][C:7]=1[O:8][CH3:9]
Reactant: COc1ccc(CN(Cc2ccc(OC)cc2)c2nc(C)nc(-c3cc(C(C)c4ccc(S(C)(=O)=O)cc4)cnc3Nc3cnc(OC)c(F)c3)n2)cc1
Solvent: O=C(O)C(F)(F)F
Product: COc1ncc(Nc2ncc(C(C)c3ccc(S(C)(=O)=O)cc3)cc2-c2nc(C)nc(N)n2)cc1F
Temperature: 75 °C
Reaction time: 8 h
Yield: 37.1 %

Procedure:
4-(2-(5-Fluoro-6-methoxypyridin-3-ylamino)-5-(1-(4-(methylsulfonyl)phenyl)ethyl)pyridin-3-yl)-N,N-bis(4-methoxybenzyl)-6-methyl-1,3,5-triazin-2-amine (744 mg, 0.992 mmol) was dissolved in trifluoroacetic acid (Aldrich, redistilled, 99+%, 10 mL) and the flask was fitted with a reflux condenser and placed in a preheated oil bath (75° C.) and stirred overnight. Then, the reaction was cooled to room temperature, concentrated, diluted with DCM (30 mL), and treated with saturated sodium bicarbonate (30 mL) and with 5 N NaOH to raise the pH of the aqueous phase to about 7. The layers were separated, and the aqueous phase was extracted with DCM and with 10:1 DCM/MeOH). The organic extracts were combined, dried over sodium sulfate, filtered, concentrated, and purified on a silica gel filter (150 mL fritted filter with about 2 inches of silica gel; 100:1 DCM/MeOH to 75:1 DCM/MeOH to 50:1 DCM/MeOH). The fractions with product were collected, concentrated, and purified on HPLC (10% to 100% MeCN/water with 0.1% TFA over 28 min using a total flow rate of 100 mL/min) to give 4-(2-(5-fluoro-6-methoxypyridin-3-ylamino)-5-(1-(4-(methylsulfonyl)phenyl)ethyl)pyridin-3-yl)-6-methyl-1,3,5-triazin-2-amine (187.7 mg 36% yield). 1H NMR (CDCl3, 400 MHZ) δ 11.60 (s, 1H), 8.73 (d, J=2.35 Hz, 1H), 8.24 (d, J=2.74 Hz, 1H), 8.06 (dd, J=11.93 Hz, 1.76 Hz, 1H), 8.01 (d, J=2.35 Hz, 1H), 7.90 (d, J=8.41 Hz, 2H), 7.45 (d, J=8.22 Hz, 2H), 4.30-4.23 (m, 1H), 4.04 (s, 3H), 2.64 (s, 3H), 1.74 (d, J=7.24 Hz, 3H). m/z (ESI, pos. ion) 510 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[C:3]([N:8]([CH2:21][O:22][CH2:23][CH2:24][O:25][CH3:26])[S:9]([C:12]2[C:20]3[C:15](=[N:16][CH:17]=[CH:18][CH:19]=3)[S:14][CH:13]=2)(=[O:11])=[O:10])=[N:4][O:5][C:6]=1[CH3:7].[Li]C(C)(C)C.[CH3:32][C:33]1[CH:40]=[C:39]2[O:41][CH2:42][O:43][C:38]2=[CH:37][C:34]=1[CH:35]=[O:36]>C1COCC1>[Cl:1][C:2]1[C:3]([N:8]([CH2:21][O:22][CH2:23][CH2:24][O:25][CH3:26])[S:9]([C:12]2[C:20]3[C:15](=[N:16][CH:17]=[CH:18][CH:19]=3)[S:14][C:13]=2[CH:35]([OH:36])[C:34]2[CH:37]=[C:38]3[O:43][CH2:42][O:41][C:39]3=[CH:40][C:33]=2[CH3:32])(=[O:11])=[O:10])=[N:4][O:5][C:6]=1[CH3:7]
Reactant: Cc1cc2c(cc1C=O)OCO2
Reactant: COCCOCN(c1noc(C)c1Cl)S(=O)(=O)c1csc2ncccc12
Agent: [Li]C(C)(C)C
Solvent: C1CCOC1
Product: COCCOCN(c1noc(C)c1Cl)S(=O)(=O)c1c(C(O)c2cc3c(cc2C)OCO3)sc2ncccc12
Yield: 35 %

Procedure:
The title compound was prepared by the method of Example 4(B) using N-(4-chloro-5-methyl-3-isoxazolyl)-N-(methoxyethoxymethyl)thieno [2,3-b]pyridine-3-sulfonamide (0.23 g, 0.54 mmoles), THF (5 ml), t-BuLi (1.7 M, 0.41 ml, 0.70 mmoles) and 2-methyl-4,5-(methylenedioxy)benzaldehyde (0.13 g, 0.81 mmoles)[Example 6(A)]. Flash chromatography (40% EtOAc/hexanes) provided 0.11 g (36%) of the title compound as a light orange oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:10]=[CH:9][CH:8]=[CH:7][C:4]=1[CH2:5][NH2:6].[C:11]([O:15][C:16](OC([O-])=O)=[O:17])([CH3:14])([CH3:13])[CH3:12]>O1CCCC1>[CH3:1][O:2][C:3]1[CH:10]=[CH:9][CH:8]=[CH:7][C:4]=1[CH2:5][NH:6][C:16](=[O:17])[O:15][C:11]([CH3:14])([CH3:13])[CH3:12]
Reactant: COc1ccccc1CN
Reactant: CC(C)(C)OC(=O)OC(=O)[O-]
Solvent: C1CCOC1
Product: COc1ccccc1CNC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 1 h
Yield: 84.5 %

Procedure:
13.0 g of 2-methoxybenzylamine was dissolved in 80 ml of tetrahydrofuran, and tetrahydrofuran solution (20 ml) containing 16 g of t-butyldicarbonate was added, followed by stirring for 1 hour at room temperature. The solvent was evaporated, and the residue was dissolved in ethyl acetate and successively washed with 1 N hydrochloric acid and saturated brine. After the organic layer was dried over anhydrous magnesium sulfate, the solvent was evaporated, to give 19.0 g of t-butyl N-(2-methoxybenzyl)carbamate.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[C:9]([F:11])[C:8]([Br:12])=[CH:7][C:3]=1[C:4](O)=[O:5].Cl.CN.[CH3:16][N:17](C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.CCN(C(C)C)C(C)C>C(Cl)Cl>[NH2:1][C:2]1[CH:10]=[C:9]([F:11])[C:8]([Br:12])=[CH:7][C:3]=1[C:4]([NH:17][CH3:16])=[O:5]
Reactant: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Reactant: Nc1cc(F)c(Br)cc1C(=O)O
Agent: CN
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CNC(=O)c1cc(Br)c(F)cc1N

Procedure:
A solution of 2-amino-5-bromo-4-fluorobenzoic acid (2.00 g, 8.55 mmol), methylamine hydrochloride (0.692 g, 10.2 mmol), TBTU (2.74 g, 8.55 mmol), and DIPEA (4.46 mL, 25.6 mmol) in DCM (15.0 mL) was stirred at rt for 30 minutes. The reaction was quenched with sat. aq. NaHCO3 (10 mL) and extracted with DCM (15 mL). The organic layer was washed with brine (10 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to a yellow oil. The crude material was purified on a Teledyne ISCO Combiflash® Rf system using DCM/MeOH (100:0→95:5) as eluent to afford the title compound as 2.54 g of a white solid. 1H NMR (CDCl3, 400 MHz): δ 7.48 (d, J=7.3 Hz, 1H), 6.44 (d, J=10.4 Hz, 1H), 6.11 (br. s., 1H), 5.66 (br. s., 2H), 2.96 (d, J=4.8 Hz, 3H). MS (ESI): m/z 248.91 [M+H]+. UPLC: tR=3.26 min (ZQ3: polar—5 min).