Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][CH:7]([N:12]3[CH:16]=[C:15]([C:17]([O:19][CH2:20][CH3:21])=[O:18])[N:14]=[C:13]3[C:22]([O:24]CC)=O)[C:8]2=O)=[CH:4][CH:3]=1.C([O-])(=O)C.[NH4+:31].C(O)(=O)C>C(#N)C.CO.CC(C)=O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[CH2:6][C:7]3[N:12]4[CH:16]=[C:15]([C:17]([O:19][CH2:20][CH3:21])=[O:18])[N:14]=[C:13]4[C:22](=[O:24])[NH:31][C:8]=3[C:9]=2[CH:10]=1
Reactant: CCOC(=O)c1cn(C2Cc3ccc(Cl)cc3C2=O)c(C(=O)OCC)n1
Reactant: [NH4+]
Agent: CC(=O)[O-]
Solvent: CO
Solvent: CC(C)=O
Solvent: CC#N
Product: CCOC(=O)c1cn2c3c([nH]c(=O)c2n1)-c1cc(Cl)ccc1C3
Yield: 61.7 %

Procedure:
The procedure is as in Example 1 but starting from 5 g of diethyl 1-(6-chloro-1-oxoindan-2-yl)imidazole-2,4-dicarboxylate, 118 g of ammonium acetate and 190 ml of acetic acid. After washing the precipitate with water and then with methyl ethyl ketone, the solid obtained is first of all ground in acetonitrile and then in methanol and finally in acetone to obtain 2.7 g of ethyl 7-chloro-4,5-dihydro-4-oxo-10H-imidazo[1,2-a]indeno[1,2-e]pyrazine-2-carboxylate in the form of a brown solid melting above 260° C. (analysis % calculated C: 58.28, H: 3.67, Cl: 10.75, N: 12.74; % found C: 58.6, H: 3.4, Cl: 10.4, N: 13.1).
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[C:11](Cl)=[O:12].[NH2:14][C:15]1[CH:24]=[C:23]2[C:18]([CH:19]=[CH:20][CH:21]=[N:22]2)=[CH:17][CH:16]=1>>[N:22]1[C:23]2[C:18](=[CH:17][CH:16]=[C:15]([NH:14][C:11]([C:2]3[CH:3]=[CH:4][C:5]4[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=4)[CH:1]=3)=[O:12])[CH:24]=2)[CH:19]=[CH:20][CH:21]=1
Reactant: Nc1ccc2cccnc2c1
Reactant: O=C(Cl)c1ccc2ccccc2c1
Product: O=C(Nc1ccc2cccnc2c1)c1ccc2ccccc2c1

Procedure:
This material was prepared analogous to the procedure described for Example 1(c). 2-Naphthoyl chloride (200 mg, 1 mmol, Aldrich) reacted with 7-amino-quinoline (102 mg, 0.95 mmol, prepared according to the procedure described in WO03099284) to give the title compound as an off-white amorphous solid. MS (ESI, pos. ion) m/z: 299 (M+1).
Reaction SMILES: C[CH:2]1[CH2:8][CH2:7][N:6]2[C:9](=[O:21])[C:10]3[C:15]4[CH2:16][CH2:17][CH2:18][C:19](=[O:20])[C:14]=4[S:13][C:11]=3[N:12]=[C:5]2[CH2:4]C1.C1C2C3C(=O)N4C=CC=CC4=NC=3SC=2CCC1>>[CH2:16]1[C:15]2[C:10]3[C:9](=[O:21])[N:6]4[CH:7]=[CH:8][CH:2]=[CH:4][C:5]4=[N:12][C:11]=3[S:13][C:14]=2[C:19](=[O:20])[CH2:18][CH2:17]1
Reactant: CC1CCc2nc3sc4c(c3c(=O)n2CC1)CCCC4=O
Agent: O=c1c2c3c(sc2nc2ccccn12)CCCC3
Product: O=C1CCCc2c1sc1nc3ccccn3c(=O)c21

Procedure:
Compound 26 was synthesized by the method described for compound 17 using compound 25 as a starting material.
Reaction SMILES: [C:1]([O:5][CH:6]1[CH2:11][C:10]([CH3:13])([CH3:12])[N:9]([O:14][CH3:15])[C:8]([CH3:17])([CH3:16])[CH2:7]1)(=[O:4])[NH:2][NH2:3].[C:18](OC(C)C)(=[O:24])[CH2:19][CH2:20][C:21]([NH2:23])=[O:22]>CO>[C:18]([NH:3][NH:2][C:1]([O:5][CH:6]1[CH2:7][C:8]([CH3:17])([CH3:16])[N:9]([O:14][CH3:15])[C:10]([CH3:12])([CH3:13])[CH2:11]1)=[O:4])(=[O:24])[CH2:19][CH2:20][C:21]([NH2:23])=[O:22]
Reactant: CON1C(C)(C)CC(OC(=O)NN)CC1(C)C
Reactant: CC(C)OC(=O)CCC(N)=O
Solvent: CO
Product: CON1C(C)(C)CC(OC(=O)NNC(=O)CCC(N)=O)CC1(C)C

Procedure:
The title compound is prepared by reacting the compound of Example 28 (1 mole) with isopropyl succinamate (1 mole), employing methanol as the solvent.
Reaction SMILES: [NH:1]([C:3]1[N:4]=[N:5][C:6]([I:9])=[CH:7][CH:8]=1)[NH2:2].CO.[CH2:12]([O:14][C:15](=[O:18])[CH:16]=O)[CH3:13].C(O)(=O)C.C(O)(=O)C.IC1C=CC=CC=1>C(Cl)Cl>[I:9][C:6]1[CH:7]=[CH:8][C:3]2[N:4]([C:16]([C:15]([O:14][CH2:12][CH3:13])=[O:18])=[N:2][N:1]=2)[N:5]=1
Reactant: CCOC(=O)C=O
Reactant: NNc1ccc(I)nn1
Solvent: ClCCl
Solvent: CC(=O)O
Solvent: Ic1ccccc1
Product: CCOC(=O)c1nnc2ccc(I)nn12
Temperature: 40 °C
Reaction time: 8 h
Yield: 65.9 %

Procedure:
In a 1 L round-bottomed flask was added 3-hydrazinyl-6-iodopyridazine (60.6 g, 257 mmol, prepared using General Procedure D from 3-chloro-6-iodopyridazine [Example #9 Step A] with hydrazine hydrate) and MeOH (600 mL) to give a tan suspension. A solution of glyoxylic acid ethyl ester (50 wt % in toluene, 54.9 mL, 270 mmol, Fluka) was added. The mixture was heated at about 40° C. for about 2 h. The reaction mixture was cooled to ambient temperature and the solvent was removed in vacuo. The residue was dissolved in DCM (600 mL) and iodobenzene diacetate (99.0 g, 308 mmol) was added and the mixture was stirred overnight. The reaction mixture was diluted with additional DCM (600 mL) and extracted with water (600 mL). The organic layer was dried over MgSO4 and concentrated in vacuo. The solid was triturated with EtOAc (500 mL) and then collected by filtration. The solid was washed with additional EtOAc (250 mL) and then dried in vacuo to give title compound (53.9 g, 65%). LC/MS (Table 1, Method g) Rt=1.18 min; MS m/z: 319.0 (M+H)+. 1H NMR (DMSO-d6) δ 8.29 (m, 1H), 7.84 (m, 1H), 4.48 (m, 2H), 1.39 (t, 3H).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[C:5]([OH:10])=[CH:4][C:3]=1[CH2:11][C:12]([OH:14])=[O:13].[C:15](=O)(O)[O-].[Na+]>CO.OS(O)(=O)=O>[CH3:15][O:13][C:12](=[O:14])[CH2:11][C:3]1[CH:4]=[C:5]([OH:10])[C:6]([O:8][CH3:9])=[CH:7][C:2]=1[Br:1]
Reactant: O=C([O-])O
Reactant: COc1cc(Br)c(CC(=O)O)cc1O
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: CO
Product: COC(=O)Cc1cc(O)c(OC)cc1Br
Temperature: 25 °C
Reaction time: 18 h

Procedure:
(2-Bromo-5-hydroxy-4-methoxy-phenyl)-acetic acid (11 g) was dissolved in 150 ml methanol and 0.8 ml conc. H2SO4. The solution was stirred at room temperature for 18 hours. Saturated aqueous sodium bicarbonate solution was added until the mixture was basic and the mixture was concentrated under reduced pressure. The residue was partitioned between bicarbonate solution and ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was taken up in ethyl acetate and crystallized by the addition of hexanes. Filtration gave 8.8 g (2-bromo-5-hydroxy-4-methoxy-phenyl)-acetic acid methyl ester.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:10]([O:12][CH3:13])=[O:11])[CH:8]=2)[CH:3]=[CH:2]1.Br[C:15]1[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][CH:16]=1.CN[C@H]1[C@H](NC)CCCC1.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>[Cu](I)I.C1(C)C=CC=CC=1>[CH3:21][C:18]1[CH:19]=[CH:20][C:15]([N:1]2[C:9]3[C:4](=[CH:5][CH:6]=[C:7]([C:10]([O:12][CH3:13])=[O:11])[CH:8]=3)[CH:3]=[CH:2]2)=[CH:16][CH:17]=1
Reactant: Cc1ccc(Br)cc1
Reactant: COC(=O)c1ccc2cc[nH]c2c1
Agent: I[Cu]I
Agent: CN[C@@H]1CCCC[C@H]1NC
Agent: O=P([O-])([O-])[O-]
Solvent: Cc1ccccc1
Product: COC(=O)c1ccc2ccn(-c3ccc(C)cc3)c2c1
Temperature: 180 °C
Yield: 48.1 %

Procedure:
To a mixture of methyl indole-6-carboxylate (2.03 g, 11.6 mmol), 4-bromotoluene (3.56 g, 20.8 mmol), trans-(1R,2R)—N,N′-bismethyl-1,2-cyclohexane diamine (0.18 mL, 1.14 mmol), copper iodide (0.12 g, 0.60 mmol) and tribasic potassium phosphate (5.50 g, 25.9 mmol) was added toluene (11.5 mL). The mixture was heated in a sealed tube at 180° C. for 10 min. The mixture was cooled to ambient temperature, filtered with Celite and concentrated under reduced pressure. Purification by silica gel chromatography (100% hexanes→75% hexanes/ethyl acetate) gave the title compound (1.48 g): LC-MS [M+1]=266.1.
Reaction SMILES: [Br:1][C:2]1[CH:14]=[CH:13][C:12]2[C:11]3[C:6](=[CH:7][C:8]([I:15])=[CH:9][CH:10]=3)[CH2:5][C:4]=2[CH:3]=1.[I-].[K+].[OH-].[K+].Br[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30]>CS(C)=O>[Br:1][C:2]1[CH:14]=[CH:13][C:12]2[C:11]3[C:6](=[CH:7][C:8]([I:15])=[CH:9][CH:10]=3)[C:5]([CH2:13][CH2:14][CH2:2][CH2:3][CH2:4][CH2:12][CH2:11][CH2:10][CH2:9][CH3:8])([CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30])[C:4]=2[CH:3]=1
Reactant: CCCCCCCCCCBr
Reactant: Brc1ccc2c(c1)Cc1cc(I)ccc1-2
Agent: [I-]
Agent: [K+]
Agent: [OH-]
Solvent: CS(C)=O
Product: CCCCCCCCCCC1(CCCCCCCCCC)c2cc(Br)ccc2-c2ccc(I)cc21
Reaction time: 24 h
Yield: 81 %

Procedure:
To a mechanically stirred mixture of 7-iodo-2-bromofluorene (from example 2; 41.34 g, 0.1114 mol), DMSO (100 mL), potassium iodide (1.7 g), and powdered potassium hydroxide (28 g) cooled in a cold water bath, 1-bromodecane (53 mL) was added dropwise, and the mixture was stirred for 24 hours. The oil that separated on dilution with water, was extracted with toluene. Toluene extract was washed with water, dried and concentrated. The residual oil was passed through a column of 300 g alumina. Elution with 900 mL hexanes gave the product as an oil, 65 g This was left in 200 mL of isopropanol, when the product solidified, 58.63 g (81% yield), m.p. 43-45° C. Mass Spec.: m/z 698 (M+ diiodo), 650,652 (M+).
Reaction SMILES: [C:1]1(=[O:7])[O:6][C:4](=[O:5])[CH2:3][CH2:2]1.[N+:8]([C:11]1[CH:18]=[CH:17][CH:16]=[CH:15][C:12]=1[CH2:13][OH:14])([O-:10])=[O:9]>>[N+:8]([C:11]1[CH:18]=[CH:17][CH:16]=[CH:15][C:12]=1[CH2:13][O:14][C:4](=[O:5])[CH2:3][CH2:2][C:1]([OH:6])=[O:7])([O-:10])=[O:9]
Reactant: O=[N+]([O-])c1ccccc1CO
Reactant: O=C1CCC(=O)O1
Product: O=C(O)CCC(=O)OCc1ccccc1[N+](=O)[O-]

Procedure:
Succinic acid mono-o-nitrobenzyl ester was prepared from succinic anhydride and o-nitrobenzyl alcohol by the procedure similar to that described in Example 174.
Reaction SMILES: [CH:1]1([N:6]2[C:11]3[N:12]=[C:13]([S:16][CH3:17])[N:14]=[CH:15][C:10]=3[CH:9]=[C:8]([F:18])[C:7]2=[O:19])[CH2:5][CH2:4][CH2:3][CH2:2]1.C1(S(N2C(C3C=CC=CC=3)O2)(=O)=[O:27])C=CC=CC=1>ClCCl>[CH:1]1([N:6]2[C:11]3[N:12]=[C:13]([S:16]([CH3:17])=[O:27])[N:14]=[CH:15][C:10]=3[CH:9]=[C:8]([F:18])[C:7]2=[O:19])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: CSc1ncc2cc(F)c(=O)n(C3CCCC3)c2n1
Reactant: O=S(=O)(c1ccccc1)N1OC1c1ccccc1
Solvent: ClCCl
Product: CS(=O)c1ncc2cc(F)c(=O)n(C3CCCC3)c2n1
Temperature: 25 °C
Reaction time: 18 h
Yield: 79.3 %

Procedure:
8-Cyclopentyl-6-fluoro-2-methylsulfanyl-8H-pyrido[2,3-d]pyrimidin-7-one (10.5 g, 37.9 mmol) and 2-benzenesulfonyl-3-phenyl-oxaziridine (11.8 g, 45.4 mmol) were combined in dichloromethane (120 ml) and stirred at room temperature for 18 hours. The mixture was evaporated to an oil, crystallized from ethyl acetate/diethyl ether, filtered and dried in vacuo to provide 8-cyclopentyl-6-fluoro-2-methanesulfinyl-8H-pyrido[2,3-d]pyrimidin-7-one as a white solid (8.88 g, 79.6%). 1H NMR δ (400 MHz, CDCl3) 8.94 (s, 1H), 7.25 (d, 1H), 6.06-5.99 (m, 1H), 2.98 (s, 3H), 2.28-2.21 (m, 2H), 2.18-2.12 (m, 2H), 2.02-1.94 (m, 2H), 1.74-1.67 (m, 2H).
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([S:11][C:12]2[CH:17]=[CH:16][C:15]([C:18]([CH3:21])([CH3:20])[CH3:19])=[CH:14][CH:13]=2)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].C(Cl)Cl.Cl[Sn](Cl)(Cl)Cl.[CH3:30][O:31]C(Cl)Cl>O>[C:1]([C:5]1[CH:10]=[CH:9][C:8]2[S:11][C:12]3[C:13](=[CH:14][C:15]([C:18]([CH3:21])([CH3:20])[CH3:19])=[CH:16][CH:17]=3)[C:30](=[O:31])[C:7]=2[CH:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)c1ccc(Sc2ccc(C(C)(C)C)cc2)cc1
Reactant: COC(Cl)Cl
Agent: Cl[Sn](Cl)(Cl)Cl
Solvent: ClCCl
Solvent: O
Product: CC(C)(C)c1ccc2sc3ccc(C(C)(C)C)cc3c(=O)c2c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 35.6 %

Procedure:
To a mixture of 12 g of bis-(4-t-butylphenyl)-sulfide, 100 mL of dry CH2Cl2 and 21 g of SnCl4 cooled in an ice bath for a period of 30 min., a solution of 9.27 g of α,α-dichloromethyl methyl ether in 50 mL of CH2CH2 was added dropwise. After addition was complete, a deep red mixture was obtained which was allowed to warm slowly to room temperature, stirred for 2 hours and then slowly poured into water. Extraction with CHCl3, followed by washing of the extracts successively with H2O, 5% NaHCO3, H2O and saturated NaCl solution, drying over (MgSO4), and evaporation of solvent gave a red oil which was chromatographed on silica gel. Elution by means of hexane-ethyl acetate (95/5) removed 4.6 g (37% of 2,7-di-t-butylthioxanthene after which there was obtained 4.65 g (37%) of the ketone which was recrystallized from hexane --CH2Cl2 as yellow crystals, m.p. 176°-178°, 'NMR (CDCl3) δ 1.35 (s, 18H, CH3), 7.5 (m, 4H, aryl), 8.75 (d, 2H, CHCCO). Anal. calculated for C21H24OS: C, 77.73; H, 7.46; S, 9.88. Found C, 77.83; H, 7.58; S, 9.75.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[NH:7][CH:8]=[C:9]([CH2:11][NH:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:10]=1)=[O:5])[CH3:2].C(N(CC)C(C)C)(C)C.[C:28](Cl)(=[O:30])[CH3:29]>C(Cl)Cl>[CH2:1]([O:3][C:4]([C:6]1[NH:7][CH:8]=[C:9]([CH2:11][N:12]([C:28](=[O:30])[CH3:29])[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:10]=1)=[O:5])[CH3:2]
Reactant: CC(=O)Cl
Reactant: CCOC(=O)c1cc(CNc2ccccc2)c[nH]1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)c1cc(CN(C(C)=O)c2ccccc2)c[nH]1
Temperature: 0 °C

Procedure:
4-Phenylaminomethyl-1H-pyrrole-2-carboxylic acid ethyl ester (183) (0.1523 g, 0.623 mmol) was weighed out into a 10 mL flask. A stir bar and septum were added, and the flask was purged with nitrogen. The amine was dissolved in methylene chloride (1.6 mL, 0.4 M) and then the flask was cooled to 0° C. N,N-diisopropyl ethyl amine (0.1194 mL, 0.686 mmol) was added, then acetyl chloride (0.0488 mL, 0.686 mmol) was added slowly by syringe to the stirring 0° C. solution. The reaction was then allowed to warm to room temperature. When the reaction was judged complete by HPLC (35 min) the reaction was diluted with methylene chloride and quenched with water. The organic phase was removed, washed with brine, dried with Na2SO4, filtered and concentrated en vacuo. The crude product was sufficiently pure by HPLC and NMR analysis that it was used in the next step without further purification (0.1625 g, 91%, white crystalline solid). 1H (CD3OD, 400 MHz): δ 11.22 (1H, broad s), 7.43-7.31 (3H, m), 7.08 (2H, dd, J=7.0, 1.5 Hz), 6.75 (1H, d, J=1.5 Hz), 6.68 (1H, d, J=1.5 Hz), 4.70 (2H, s), 4.24 (2H, q, J=7.0 Hz), 1.81 (3H, s), 1.31 (3H, t, J=7.0 Hz) ppm. 13C (CD3OD, 100 MHz): δ 172.47, 162.64, 143.86, 130.68, 129.34, 129.27, 124.50, 124.33, 122.19, 116.72, 61.16, 46.60, 22.64, 14.75 ppm. DEPT (CD3OD, 100 MHz): CH3 carbons: 22.64, 14.75; CH2 carbons: 61.16, 46.60; CH carbons: 130.68, 129.34, 129.27, 124.33, 116.72 ppm. HPLC: 8.738 min.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:16]([CH2:17][C:18]([OH:20])=O)[C:11]3=[N:12][CH:13]=[CH:14][CH:15]=[C:10]3[N:9]=2)=[CH:4][CH:3]=1.C(N1C=CN=C1)(N1C=CN=C1)=O.[CH2:33]([NH2:40])[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1>O1CCCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:16]([CH2:17][C:18]([NH:40][CH2:33][C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)=[O:20])[C:11]3=[N:12][CH:13]=[CH:14][CH:15]=[C:10]3[N:9]=2)=[CH:6][CH:7]=1
Reactant: NCc1ccccc1
Reactant: O=C(O)Cn1c(-c2ccc(Cl)cc2)nc2cccnc21
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Product: O=C(Cn1c(-c2ccc(Cl)cc2)nc2cccnc21)NCc1ccccc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 65 %

Procedure:
Under nitrogen bubbling, a mixture of 2-(4-chlorophenyl)-3H-imidazo[4,5-b]pyridine-3-acetic acid (4.0 g, 0.014 mole) and 1,1'-carbonyldiimidazole (2.27 g, 0.014 mole) in 150 ml of tetrahydrofuran was stirred at room temperature for 3 hours. Then, under nitrogen atmosphere, benzylamine (1.58 g, 0.0147 mole) was added and the reaction was allowed to stir at room temperature overnight. The tetrahydrofuran was evaporated, to give a solid. The solid was recrystallized from isopropyl alcohol, collected by filtration, washed with cold isopropyl alcohol and water, and dried under high vacuum at 50° C. overnight to give 3.43 g (65%) of title compound, mp 200°-200.5° C.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[C:6]([O:8]CCO)[CH:5]=[CH:4][C:3]=1[C:12]1[N:17]=[C:16]([C:18]2[CH:23]=[CH:22][C:21]([O:24]CCO)=[CH:20][C:19]=2[OH:28])[N:15]=[C:14]([C:29]2[CH:34]=[CH:33][C:32]([Cl:35])=[CH:31][CH:30]=2)[N:13]=1.OC1N=C(C2C=CC(OCCO)=CC=2O)N=C(C2C=CC(C)=CC=2C)N=1>>[OH:1][C:2]1[CH:7]=[C:6]([OH:8])[CH:5]=[CH:4][C:3]=1[C:12]1[N:17]=[C:16]([C:18]2[CH:23]=[CH:22][C:21]([OH:24])=[CH:20][C:19]=2[OH:28])[N:15]=[C:14]([C:29]2[CH:34]=[CH:33][C:32]([Cl:35])=[CH:31][CH:30]=2)[N:13]=1
Reactant: OCCOc1ccc(-c2nc(-c3ccc(Cl)cc3)nc(-c3ccc(OCCO)cc3O)n2)c(O)c1
Agent: Cc1ccc(-c2nc(O)nc(-c3ccc(OCCO)cc3O)n2)c(C)c1
Product: Oc1ccc(-c2nc(-c3ccc(Cl)cc3)nc(-c3ccc(O)cc3O)n2)c(O)c1

Procedure:
2,4-bis[2-hydroxy-4-(2-hydroxyethoxy)phenyl]-6-(4-chlorophenyl)-s-triazine; 2,4-bis[2-hydroxy-4-(2-hydroxy-4-(2-hydroxyethoxy)phenyl]-6-(2,4-dimethylphenyl)-s-triazine;
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 5N 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), 3.06 (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[CH2:2][C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH2:6][CH:5]([C:13]([F:16])([F:15])[F:14])[N:4]=1.[K].CC(C)([O-])C>O1CCCC1>[CH3:2][C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH:6]=[C:5]([C:13]([F:15])([F:14])[F:16])[N:4]=1
Reactant: FC(F)(F)C1Cc2ccccc2C(CCl)=N1
Agent: CC(C)(C)[O-]
Agent: [K]
Solvent: C1CCOC1
Product: Cc1nc(C(F)(F)F)cc2ccccc12

Procedure:
Prepared by treating 905 mg of 1-chloromethyl-3-trifluoromethyl-3,4-dihydro-isoquinoline with 420 mg of potassium-tert.butoxide in 10 ml of tetrahydrofuran at ambient temperature.
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][C:5]([NH:8][C:9](=[O:34])[C:10]2[CH:15]=[CH:14][C:13]([C:16]3[CH2:20][C:19]([C:25]4[CH:30]=[C:29]([Cl:31])[CH:28]=[C:27]([Cl:32])[CH:26]=4)([C:21]([F:24])([F:23])[F:22])[O:18][N:17]=3)=[CH:12][C:11]=2[CH3:33])=[N:6][CH:7]=1.O.N.O.[CH3:38][N:39](C)C(=O)C>[C-]#N.[Zn+2].[C-]#N.[Zn].C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C1(P(C2C=CC=CC=2)[C-]2C=CC=C2)C=CC=CC=1.[C-]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C1.[Fe+2]>[C:38]([C:2]1[CH:3]=[N:4][C:5]([NH:8][C:9](=[O:34])[C:10]2[CH:15]=[CH:14][C:13]([C:16]3[CH2:20][C:19]([C:25]4[CH:30]=[C:29]([Cl:31])[CH:28]=[C:27]([Cl:32])[CH:26]=4)([C:21]([F:23])([F:22])[F:24])[O:18][N:17]=3)=[CH:12][C:11]=2[CH3:33])=[N:6][CH:7]=1)#[N:39]
Reactant: CC(=O)N(C)C
Reactant: Cc1cc(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)ccc1C(=O)Nc1ncc(Br)cn1
Agent: [Fe+2]
Agent: [Pd]
Agent: N
Solvent: O
Product: Cc1cc(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)ccc1C(=O)Nc1ncc(C#N)cn1
Temperature: 100 °C
Reaction time: 2 h

Procedure:
In a solution of 0.20 g of N-(5-bromo-2-pyrimidinyl)-4-[5-(3,5-dichlorophenyl)-5-trifluoromethyl-4,5-dihydroisoxazole-3-yl]-2-methyl benzoic acid amide synthesized in Step 1 of Synthetic Example 13 in 3 mL of N,N-dimethylacetamide, 0.082 g of zinc cyanide, 0.011 g of zinc, 0.013 g of tris(dibenzylideneacetone)dipalladium and 0.015 g of 1,1′-bis(diphenylphosphino)ferrocene were added, and stirred under nitrogen atmosphere at 100° C. for 2 hours. After the completion of the reaction, the reaction mixture was left and cooled to room temperature, and 20 mL of concentrated ammonia water and 20 mL of water were added, and extracted with ethyl acetate (20 mL×2). The organic phases were washed with water, and dehydrated with and dried over saturated sodium chloride aqueous solution and anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified with silica gel column chromatography that was eluated with ethyl acetate-hexane (1:1) to obtain 0.15 g of the aimed product as white crystal.
Reaction SMILES: [OH:1][CH2:2][CH2:3][N:4]([CH2:17][C:18]([F:21])([F:20])[F:19])[C:5]1[CH:12]=[CH:11][C:8]([C:9]#[N:10])=[C:7]([C:13]([F:16])([F:15])[F:14])[CH:6]=1.[C:22]([NH:25][C:26]1[CH:31]=[CH:30][C:29](O)=[CH:28][CH:27]=1)(=[O:24])[CH3:23]>>[C:9]([C:8]1[CH:11]=[CH:12][C:5]([N:4]([CH2:17][C:18]([F:19])([F:20])[F:21])[CH2:3][CH2:2][O:1][C:29]2[CH:30]=[CH:31][C:26]([NH:25][C:22](=[O:24])[CH3:23])=[CH:27][CH:28]=2)=[CH:6][C:7]=1[C:13]([F:15])([F:16])[F:14])#[N:10]
Reactant: CC(=O)Nc1ccc(O)cc1
Reactant: N#Cc1ccc(N(CCO)CC(F)(F)F)cc1C(F)(F)F
Product: CC(=O)Nc1ccc(OCCN(CC(F)(F)F)c2ccc(C#N)c(C(F)(F)F)c2)cc1

Procedure:
Synthesized as described in Example 1C using 4-[(2-hydroxyethyl)(2,2,2-trifluoroethyl)amino]-2-(trifluoromethyl)benzonitrile and 4-acetamidophenol: MS (ES) m/z 446 (M+1).
Reaction SMILES: [CH:1]([C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[NH:6][C:5]=1[CH2:13][CH2:14][NH:15][C:16](N1C=CN=C1)=[O:17])([CH3:3])[CH3:2].N12CCCN=C1CCCCC2>C1(C)C=CC=CC=1>[CH:1]([C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[N:6]2[C:16](=[O:17])[NH:15][CH2:14][CH2:13][C:5]=12)([CH3:2])[CH3:3]
Reactant: CC(C)c1c(CCNC(=O)n2ccnc2)[nH]c2ccccc12
Solvent: C1CCC2=NCCCN2CC1
Solvent: Cc1ccccc1
Product: CC(C)c1c2n(c3ccccc13)C(=O)NCC2
Yield: 33.8 %

Procedure:
A mixture of N-[2-(3-isopropylindol-2-yl)ethyl]-1-imidazolecarboxamide (2.0 g), 1,8-diazabicyclo[5.4.0]-undec-7-ene (1 g) and toluene (100 ml) was reflux for 1 hour. After cooling, the mixture was washed with water and brine, dried over anhydrous magnesium sulfate, and evaporated in vacuo. The residue was purified by silica gel column chromatography (5% methanol-chloroform) to give 3,4-dihydro-5-isopropylpyrimido[1,6-a]indol-1(2H)-one (0.52 g).