Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:3]=[N:4][C:5]2[C:10]([CH:11]=1)=[CH:9][CH:8]=[CH:7][C:6]=2[O:12][CH3:13].[OH-].[K+].I[CH3:17]>C(O)C>[CH3:17][O:1][C:2]1[CH:3]=[N:4][C:5]2[C:10]([CH:11]=1)=[CH:9][CH:8]=[CH:7][C:6]=2[O:12][CH3:13]
Reactant: CI
Reactant: COc1cccc2cc(O)cnc12
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: COc1cnc2c(OC)cccc2c1
Reaction time: 0.5 h
Yield: 87.3 %

Procedure:
175 mg of 3-hydroxy-8-methoxy quinoline [compound (V)] prepared in example 6 and 66 mg of potassium hydroxide were added to 3 ml of ethanol, and the solution was agitated for 30 minutes. To the solution was added 284 mg of iodomethane, and the solution was agitated for 24 hours. The solvent was removed, and the solution was extracted with dichloromethane. The dichloromethane layer was washed with water and aqueous sodium hydroxide, and dried with anhydrous magnesium sulfate. The dichloromethane was removed by vacuum distillation to give 165 mg of 3,8-dimethoxy quinoline.
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][N:3]=[C:2]1[NH2:6].N1C=CN=C1.[I-].[Li+].[CH2:14]([O:21][C:22]([NH:24][C@@H:25]([CH2:33][C:34]1[CH:39]=[CH:38][C:37]([O:40][CH2:41][CH2:42][CH2:43][C:44](OCC)=[O:45])=[CH:36][CH:35]=1)[C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])=[O:23])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>CN(C)C=O>[CH2:14]([O:21][C:22]([NH:24][C@@H:25]([CH2:33][C:34]1[CH:39]=[CH:38][C:37]([O:40][CH2:41][CH2:42][CH2:43][C:44](=[O:45])[NH:6][C:2]2[NH:3][CH2:4][CH2:5][N:1]=2)=[CH:36][CH:35]=1)[C:26]([O:28][C:29]([CH3:31])([CH3:30])[CH3:32])=[O:27])=[O:23])[C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: CCOC(=O)CCCOc1ccc(C[C@H](NC(=O)OCc2ccccc2)C(=O)OC(C)(C)C)cc1
Reactant: NC1=NCCN1
Agent: [I-]
Agent: [Li+]
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)[C@H](Cc1ccc(OCCCC(=O)NC2=NCCN2)cc1)NC(=O)OCc1ccccc1
Temperature: 40 °C
Reaction time: 4 h
Yield: 23.9 %

Procedure:
340 mg of 4,5-dihydro-1H-imidazol-2-ylamine, 13.6 mg of imidazole and 26.8 mg of lithium iodide were added to a solution of 970 mg of tert-butyl (2S)-2-benzyloxycarbonylamino-3-(4-(3-ethoxycarbonylpropyloxy)phenyl)propionate (Example 1a) in 5 ml of absolute dimethylformamide. The solution was stirred at 40° C. for 4 hours, an additional 170 mg of 4,5-dihydro-1H-imidazol-2-ylamine were added and the solution stirred at 55° C. for further 3 hours. After removal of the solvent in vacuo, the residue was treated with ethyl acetate, filtered, extracted with 10% strength aqueous KHCO3 solution, dried over MgSO4, filtered, concentrated in vacuo and precipitated with diisopropyl ether. The crude product was purified by silica gel chromatography (dichloromethane/methanol/glacial acetic acid 90/10/1). 250 mg of an amorphous product were obtained.
Reaction SMILES: Br[C:2]1[C:10]2[O:9][CH2:8][CH:7]([C:11]3[CH:16]=[CH:15][C:14]([CH:17]([CH3:19])[CH3:18])=[CH:13][CH:12]=3)[C:6]=2[C:5]([CH3:20])=[C:4]([NH:21][C:22](=[O:28])[CH2:23][C:24]([CH3:27])([CH3:26])[CH3:25])[C:3]=1[CH3:29].[CH3:30][C:31]1[CH:36]=[CH:35][C:34](B(O)O)=[CH:33][CH:32]=1>>[CH3:30][C:31]1[CH:36]=[CH:35][C:34]([C:2]2[C:10]3[O:9][CH2:8][CH:7]([C:11]4[CH:16]=[CH:15][C:14]([CH:17]([CH3:18])[CH3:19])=[CH:13][CH:12]=4)[C:6]=3[C:5]([CH3:20])=[C:4]([NH:21][C:22](=[O:28])[CH2:23][C:24]([CH3:26])([CH3:25])[CH3:27])[C:3]=2[CH3:29])=[CH:33][CH:32]=1
Reactant: Cc1c(Br)c2c(c(C)c1NC(=O)CC(C)(C)C)C(c1ccc(C(C)C)cc1)CO2
Reactant: Cc1ccc(B(O)O)cc1
Product: Cc1ccc(-c2c(C)c(NC(=O)CC(C)(C)C)c(C)c3c2OCC3c2ccc(C(C)C)cc2)cc1
Yield: 68 %

Procedure:
Using N-(7-bromo-3-(4-isopropylphenyl)-4,6-dimethyl-2,3-dihydro-1-benzofuran-5-yl)-3,3-dimethylbutanamide obtained in Example 35 and (4-methylphenyl)boronic acid, the title compound was obtained in the same manner as in Example 107. Yield: 68%. Melting point: 194-195° C. (ethyl acetate-hexane).
Reaction SMILES: C[O:2][C:3]1[CH2:7][N:6]([CH2:8][C:9]([OH:11])=[O:10])[C:5](=[O:12])[CH:4]=1.C([O-])(=O)C.[Na+].[Na+].[Cl-]>Cl.[Ru]>[OH:2][CH:3]1[CH2:7][N:6]([CH2:8][C:9]([OH:11])=[O:10])[C:5](=[O:12])[CH2:4]1
Reactant: COC1=CC(=O)N(CC(=O)O)C1
Agent: [Ru]
Agent: CC(=O)[O-]
Agent: Cl
Product: O=C(O)CN1CC(O)CC1=O
Temperature: 70 °C
Reaction time: 1 h
Yield: 60 %

Procedure:
2.0 g (11.7 mmol) of 4-methoxy-3-pyrrolin-2-on-1-yl-acetic acid was dissolved in 15 ml of HCl (1N) at room temperature and heated to 70° C. with stirring. After 1 hour, 2.04 g of sodium acetate was added to adjust the PH to 2.0. 100 mg of Ru/C was added to the reaction mixture. The reaction mixture was transferred to an autoclave and hydrogenated at 10 bars of H2 pressure with stirring. After 18 hours, the catalyst was filtered off by suction and the filtrate was concentrated by evaporation in a vacuum. The latter yielded 2.9 g of a crude mixture of NaCl and 4-hydroxy-pyrrolidin-2-on-1-yl-acetic acid (42 percent content, 60 percent yield).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:10]=[CH:11][CH:12]=1)[C:5]([O:7][CH2:8][CH3:9])=[O:6].N1C=CC=CC=1.Cl[C:20]([O:22][CH2:23][C:24]([Cl:27])([Cl:26])[Cl:25])=[O:21].C(OCC)(=O)C>O1CCCC1.O>[Cl:25][C:24]([Cl:27])([Cl:26])[CH2:23][O:22][C:20]([NH:1][C:2]1[CH:3]=[C:4]([CH:10]=[CH:11][CH:12]=1)[C:5]([O:7][CH2:8][CH3:9])=[O:6])=[O:21]
Reactant: CCOC(=O)c1cccc(N)c1
Reactant: O=C(Cl)OCC(Cl)(Cl)Cl
Solvent: c1ccncc1
Solvent: O
Solvent: C1CCOC1
Product: CCOC(=O)c1cccc(NC(=O)OCC(Cl)(Cl)Cl)c1
Yield: 91.7 %

Procedure:
To a solution prepared by adding 1.0 g of ethyl m-aminobenzoate and 0.72 g of pyridine to 10 ml of tetrahydrofuran and stirring the resultant mixture at room temperature was dropwise added a solution of 1.55 g of 2,2,2-trichloroethyl chloroformate in 5 ml of tetrahydrofuran. After the resultant mixture was stirred for 2 hours, ethyl acetate and water were added to the reaction solution, and a separating operation was performed. Then, an organic layer was separated and dried with anhydrous magnesium sulfate. The solution was filtered, and then the filtrate was collected, and the solvent of the filtrate was distilled off under reduced pressure. The residue was washed with hexane to obtain 1.89 g (yield 91%) of the title compound.
Reaction SMILES: [C:1]([O:5][C:6](=[O:22])[NH:7][C:8]1[CH:13]=[C:12]([O:14][CH2:15][CH3:16])[C:11]([C:17]([F:20])([F:19])[F:18])=[CH:10][C:9]=1[NH2:21])([CH3:4])([CH3:3])[CH3:2].C([O:27][C:28](=O)[CH2:29][C:30](=[O:51])[C:31]1[CH:36]=[CH:35][CH:34]=[C:33]([C:37]2[CH:42]=[CH:41][N:40]=[C:39]([CH2:43][O:44][CH:45]3[CH2:50][CH2:49][CH2:48][CH2:47][O:46]3)[CH:38]=2)[CH:32]=1)(C)(C)C>>[C:1]([O:5][C:6](=[O:22])[NH:7][C:8]1[CH:13]=[C:12]([O:14][CH2:15][CH3:16])[C:11]([C:17]([F:20])([F:19])[F:18])=[CH:10][C:9]=1[NH:21][C:28](=[O:27])[CH2:29][C:30](=[O:51])[C:31]1[CH:36]=[CH:35][CH:34]=[C:33]([C:37]2[CH:42]=[CH:41][N:40]=[C:39]([CH2:43][O:44][CH:45]3[CH2:50][CH2:49][CH2:48][CH2:47][O:46]3)[CH:38]=2)[CH:32]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)CC(=O)c1cccc(-c2ccnc(COC3CCCCO3)c2)c1
Reactant: CCOc1cc(NC(=O)OC(C)(C)C)c(N)cc1C(F)(F)F
Product: CCOc1cc(NC(=O)OC(C)(C)C)c(NC(=O)CC(=O)c2cccc(-c3ccnc(COC4CCCCO4)c3)c2)cc1C(F)(F)F

Procedure:
The title compound was prepared from [2-amino-5-ethoxy-4-trifluoromethyl-phenyl]-carbamic acid tert-butyl ester (Example J6) (320 mg, 1.0 mmol) and (RS)-3-oxo-3-{3-[2-(tetrahydro-pyran-2-yloxymethyl)-pyridin-4-yl]-phenyl}-propionic acid tert-butyl ester (Example K40) (412 mg, 1.0 mmol) according to the general procedure M. Obtained as an off-white solid (500 mg, 76%).
Reaction SMILES: C([O:3][C:4](=[O:39])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH3:13])=[C:8]([O:14][C:15]2[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][C:16]=2[CH2:25][N:26]2[C@@H:30]([CH3:31])[C@@H:29]([C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)[O:28][C:27]2=[O:38])[CH:7]=1)C.[OH-].[Li+].Cl>CO>[CH3:13][O:12][C:9]1[CH:10]=[CH:11][C:6]([CH2:5][C:4]([OH:39])=[O:3])=[CH:7][C:8]=1[O:14][C:15]1[CH:20]=[CH:19][C:18]([C:21]([F:23])([F:24])[F:22])=[CH:17][C:16]=1[CH2:25][N:26]1[C@@H:30]([CH3:31])[C@@H:29]([C:32]2[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=2)[O:28][C:27]1=[O:38]
Reactant: CCOC(=O)Cc1ccc(OC)c(Oc2ccc(C(F)(F)F)cc2CN2C(=O)O[C@H](c3ccccc3)[C@@H]2C)c1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Product: COc1ccc(CC(=O)O)cc1Oc1ccc(C(F)(F)F)cc1CN1C(=O)O[C@H](c2ccccc2)[C@@H]1C
Temperature: 60 °C
Reaction time: 8 h

Procedure:
To {4-methoxy-3-[2-((4S,5R)-4-methyl-2-oxo-5-phenyl-oxazolidin-3-ylmethyl)-4-trifluoromethyl-phenoxy]-phenyl}-acetic acid ethyl ester (0.08 g, 0.15 mmol) in MeOH (4 mL) was added 1N aqueous lithium hydroxide (2 mL), and the reaction was stirred at 60° C. overnight. The mixture was acidified with 1N aqueous HCl, and the aqueous layer was extracted twice with EtOAc. The combined organic layers were dried over MgSO4, filtered, and concentrated, and the residue was purified by preparative HPLC to give the desired product.
Reaction SMILES: [CH3:1][N:2]([CH2:6][CH:7]([CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[CH2:8][S:9][C:10]1[CH:15]=[CH:14][C:13]([CH3:16])=[CH:12][CH:11]=1)[C:3](=O)[CH3:4].[H-].[Al+3].[Li+].[H-].[H-].[H-].O.[OH-].[Na+]>CCOCC>[CH3:1][N:2]([CH2:6][CH:7]([CH2:17][C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1)[CH2:8][S:9][C:10]1[CH:11]=[CH:12][C:13]([CH3:16])=[CH:14][CH:15]=1)[CH2:3][CH3:4]
Reactant: CC(=O)N(C)CC(CSc1ccc(C)cc1)Cc1ccccc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: CCOCC
Product: CCN(C)CC(CSc1ccc(C)cc1)Cc1ccccc1

Procedure:
A solution of N-methyl-N-acetyl-2-benzyl-3-(4-methylthiophenoxy)propylamine (12.6 g) in dry ether (100 ml) is added dropwise to a stirred suspension of lithium aluminum hydride (4.0 g) in dry ether (250 ml). The reaction mixture is refluxed for 18 hours, and cooled to 0°. Water (3 ml) is added cautiously, followed by 15% sodium hydroxide (3 ml), and water (9 ml). The inorganic salts are filtered off, washed with ether (150 ml) and the combined ether solutions are dried over magnesium sulfate. The solvent is removed under reduced pressure to give N-methyl-N-ethyl-2-benzyl-3-(4-methylthiophenoxy)propylamine.
Reaction SMILES: [C:1]1([C:7]2[C:12]([C:13]3[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=3)=[C:11]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[N:10]=[C:9]3[NH:25][N:26]=[CH:27][C:8]=23)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH-].[K+].I[CH3:31].O>CC(C)=O>[CH3:31][N:26]1[CH:27]=[C:8]2[C:9]([N:10]=[C:11]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[C:12]([C:13]3[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=3)=[C:7]2[C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)=[N:25]1
Reactant: CI
Reactant: c1ccc(-c2nc3[nH]ncc3c(-c3ccccc3)c2-c2ccncc2)cc1
Agent: [K+]
Agent: [OH-]
Solvent: CC(C)=O
Solvent: O
Product: Cn1cc2c(-c3ccccc3)c(-c3ccncc3)c(-c3ccccc3)nc2n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 43.2 %

Procedure:
To a suspension of 4,6-diphenyl-5-(4-pyridyl)-1H-pyrazolo[3,4-b]pyridine (0.10 g, 0.3 mmol, obtained in example 2) in acetone (1 mL), KOH (21 mg, 0.4 mmol) was added under argon atmosphere. Then, a solution of iodomethane (47 mg, 0.3 mmol) in acetone (0.1 mL) was added and stirred overnight at room temperature. Water was added and extracted with CHCl3. The organic phase was dried over Na2SO4 and concentrated to dryness. The crude product obtained was purified by chromatography on silica gel using hexane-EtOAc mixtures of increasing polarity as eluent, to afford 47 mg of 2-methyl-4,6-diphenyl-5-(4-pyridyl)pyrazolo[3,4-b]pyridine (yield: 47%) and 38 mg of 1-methyl-4,6-diphenyl-5-(4-pirridyl)pyrazolo[3,4-b]pyridine (yield: 38%).
Reaction SMILES: O1C=CC([C:6]2([C:19](=[O:21])[CH3:20])[N:13]3[C:9]([S:10][C:11]4[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][C:12]=43)=[N:8][CH2:7]2)=C1.[O:22]1[CH:26]=[CH:25][CH:24]=[C:23]1[CH:27]=O>>[O:22]1[CH:26]=[CH:25][CH:24]=[C:23]1[CH:27]=[CH:20][C:19]([C:6]1[N:13]2[C:9]([S:10][C:11]3[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][C:12]=32)=[N:8][CH:7]=1)=[O:21]
Reactant: O=Cc1ccco1
Reactant: CC(=O)C1(c2ccoc2)CN=C2SC3=C(CCCCC3)N21
Product: O=C(C=Cc1ccco1)c1cnc2sc3c(n12)CCCCC3

Procedure:
3-(3-Furanyl)-1-(6,7,8,9-tetrahydro-5H-cyclohept[d]imidazo[2,1-b]thiazol-3-yl)-ethanone (Formula P-1), 3.51 g, was condensed with 2-Furaldehyde (1.99 g) by non-critical variations of PREPARATION 15 to give 3-(2-Furanyl)-1-(6,7,8,9-tetrahydro-5H-cyclohept[d]imidazo[2,1-b]thiazol-3-yl)-2-propene-1-one (Formula P-2, X=0), m.p. 161-162°.
Reaction SMILES: ClC1C=CC2N(C(CNC3N=C([O:26][C@@H:27]4C[CH2:30][N:29](C)[CH2:28]4)C=CN=3)=C(C3C=CC(F)=CC=3)N=2)C=1.Cl[C:34]1[N:39]=[C:38]([NH:40][CH2:41][C:42]2[N:46]3[CH:47]=[CH:48][CH:49]=[CH:50][C:45]3=[N:44][C:43]=2[C:51]2[CH:56]=[CH:55][C:54]([Cl:57])=[CH:53][CH:52]=2)[CH:37]=[CH:36][N:35]=1.CNCCO>>[Cl:57][C:54]1[CH:55]=[CH:56][C:51]([C:43]2[N:44]=[C:45]3[CH:50]=[CH:49][CH:48]=[CH:47][N:46]3[C:42]=2[CH2:41][NH:40][C:38]2[CH:37]=[CH:36][N:35]=[C:34]([O:26][CH2:27][CH2:28][NH:29][CH3:30])[N:39]=2)=[CH:52][CH:53]=1
Reactant: Clc1ccc(-c2nc3ccccn3c2CNc2ccnc(Cl)n2)cc1
Reactant: CN1CC[C@@H](Oc2ccnc(NCc3c(-c4ccc(F)cc4)nc4ccc(Cl)cn34)n2)C1
Agent: CNCCO
Product: CNCCOc1nccc(NCc2c(-c3ccc(Cl)cc3)nc3ccccn23)n1

Procedure:
The title compound was prepared in the same fashion as that described for compound 183 from 2-chloro-N-((2-(4-chlorophenyl)imidazo[1,2-a]pyridin-3-yl)methyl)pyrimidin-4-amine and 2-(methylamino)ethanol. M/e+ 409 for C21H22ClN6O (M+H)+; 1H-NMR (400 MHz, CD3OD) δ 8.61 (s, 1H), 7.74 (d, J=8.4 Hz, 2H), 7.68 (d, J=6.2 Hz, 1H), 7.50 (t, J=7.3 Hz, 2H), 7.43 (d, J=7.3 Hz, 1H), 7.39 (m, 1H), 5.84 (d, J=6.2 Hz, 2H), 5.08 (d, J=8.8 Hz, 2H), 3.74 (m, 2H), 3.17 (s, 3H) ppm.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5](=[O:8])[NH:6][CH:7]=1.C([O-])([O-])=O.[K+].[K+].BrC[CH2:17][CH2:18][O:19][CH2:20]CCBr>CC(C)=O>[Br:1][C:2]1[CH:3]=[CH:4][C:5](=[O:8])[N:6]([CH2:17][CH2:18][O:19][CH3:20])[CH:7]=1
Reactant: O=c1ccc(Br)c[nH]1
Reactant: BrCCCOCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: COCCn1cc(Br)ccc1=O
Temperature: 60 °C
Yield: 75.6 %

Procedure:
To a solution of 5-bromo-2(1H)-pyridone (0.10 g, 0.57 mmol) in acetone (5.0 ml) was added K2CO3 (0.18 g, 2.60 mmol followed by addition of 2-bromo-ethyl-methylether (0.24 g, 1.70 mmol). The resulting reaction mixture was heated to 60° C. for 16 h. After the completion of reaction (TLC monitoring), acetone was distilled off, added water and extracted with DCM (3×10 mL). The combined organics was washed with brine, dried (Na2SO4), filtered and concentrated. The crude residue was purified over silica gel (60-120 M, 1% MeOH-DCM) to obtain the desired product (0.10 g, 75%). MS: 232.01 (M+H)+.
Reaction SMILES: C([O-])([O-])=O.[Cs+].[Cs+].[F:7][C:8]([F:24])([F:23])[CH:9]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[C:17]1[CH:18]=[N:19][N:20]([CH3:22])[CH:21]=1)[OH:10].[NH2:25][C:26]1[N:31]=[C:30](Cl)[CH:29]=[C:28]([Cl:33])[N:27]=1.O>C1COCC1.C(OCC)(=O)C>[Cl:33][C:28]1[CH:29]=[C:30]([O:10][CH:9]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[C:17]2[CH:18]=[N:19][N:20]([CH3:22])[CH:21]=2)[C:8]([F:7])([F:23])[F:24])[N:31]=[C:26]([NH2:25])[N:27]=1
Reactant: Nc1nc(Cl)cc(Cl)n1
Reactant: Cn1cc(-c2ccccc2C(O)C(F)(F)F)cn1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: Cn1cc(-c2ccccc2C(Oc2cc(Cl)nc(N)n2)C(F)(F)F)cn1
Temperature: 110 °C
Reaction time: 0.33 h
Yield: 91.2 %

Procedure:
Cs2CO3 (325 mg, 1.0 mmol) was added to a solution of 2,2,2-trifluoro-1-[2-(1-methyl-1H-pyrazol-4-yl)-phenyl]-ethanol (60 mg, 0.2 mmol) in 10 ml of anhydrous THF, and the mixture was stirred for 20 minutes. 2-Amino-4,6-dichloro-pyrimidine (32 mg, 0.2 mmol) was added, and then the reaction mixture was heated at 110° C. until the reaction was complete. After cooling, 5 ml of water was added, and ethyl acetate (20 ml) was used to extract the product. The organic layer was dried over sodium sulfate. The solvent was removed by rotovap to afford 70 mg of 4-chloro-6-{2,2,2-trifluoro-1-[2-(1-methyl-1H-pyrazol-4-yl)-phenyl]-ethoxy}-pyrimidin-2-ylamine (yield: 92%).
Reaction SMILES: [Si]([O:8][C@H:9]1[CH2:14][CH2:13][C@H:12]([N:15]2[CH:19]=[C:18](B3OC(C)(C)C(C)(C)O3)[C:17]([O:29][CH3:30])=[N:16]2)[CH2:11][CH2:10]1)(C(C)(C)C)(C)C.Br[C:32]1[CH:33]=[C:34]2[C:40]([C@@H:41]([C:43]3[C:48]([O:49][CH:50]([F:52])[F:51])=[CH:47][CH:46]=[C:45]([F:53])[C:44]=3[Cl:54])[CH3:42])=[CH:39][N:38](C(OC(C)(C)C)=O)[C:35]2=[N:36][CH:37]=1.C(=O)([O-])[O-].[K+].[K+].ClCCl.N#N.Cl>O1CCOCC1.C1C=CC(P([C]2[CH][CH][CH][CH]2)C2C=CC=CC=2)=CC=1.C1C=CC(P([C]2[CH][CH][CH][CH]2)C2C=CC=CC=2)=CC=1.Cl[Pd]Cl.[Fe].O1CCOCC1.O>[Cl:54][C:44]1[C:45]([F:53])=[CH:46][CH:47]=[C:48]([O:49][CH:50]([F:51])[F:52])[C:43]=1[C@H:41]([C:40]1[C:34]2[C:35](=[N:36][CH:37]=[C:32]([C:18]3[C:17]([O:29][CH3:30])=[N:16][N:15]([C@H:12]4[CH2:11][CH2:10][C@H:9]([OH:8])[CH2:14][CH2:13]4)[CH:19]=3)[CH:33]=2)[NH:38][CH:39]=1)[CH3:42]
Reactant: C[C@H](c1c(OC(F)F)ccc(F)c1Cl)c1cn(C(=O)OC(C)(C)C)c2ncc(Br)cc12
Reactant: COc1nn([C@H]2CC[C@H](O[Si](C)(C)C(C)(C)C)CC2)cc1B1OC(C)(C)C(C)(C)O1
Agent: Cl[Pd]Cl
Agent: [Fe]
Agent: Cl
Solvent: ClCCl
Solvent: C1COCCO1
Solvent: O
Product: COc1nn([C@H]2CC[C@H](O)CC2)cc1-c1cnc2[nH]cc([C@H](C)c3c(OC(F)F)ccc(F)c3Cl)c2c1
Temperature: 100 °C

Procedure:
A solution of 1-(trans-4-{[tert-butyl(dimethyl)silyl]oxy}cyclohexyl)-3-methoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (0.0305 g, 0.0698 mmol), tert-butyl 5-bromo-3-{(1S)-1-[2-chloro-6-(difluoromethoxy)-3-fluorophenyl]ethyl}-1H-pyrrolo[2,3-b]pyridine-1-carboxylate (0.0330 g, 0.0635 mmol), potassium carbonate (0.0263 g, 0.190 mmol), and 1,1′-bis(diphenylphosphino)ferrocenepalladium (II) dichloride.dichloromethane (5.18 mg, 0.00635 mmol) in previously degassed dioxane/H2O (5:1)(2.03 mL) was evacuated and charged with N2 (3×) and heated to 100° C. for 1 h. The reaction mixture was charged with an additional amount 1-(trans-4-{[tert-butyl(dimethyl)silyl]oxy}cyclohexyl)-3-methoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (0.00800 g, 0.0183 mmol) and 1,1′-bis(diphenylphosphino)ferrocenepalladium (II) dichloride.dichloromethane (5.18 mg, 0.00634 mmol) and evacuated and charged with N2 gas (3×) and heated 100° C. for an additional 1 h. The reaction was charged with 4 M of HCl in 1,4-dioxane (0.500 mL) and heated to 50° C. for 45 min. The reaction mixture was partitioned between CHCl3 and sat. NaHCO3 and separated. The aqueous was re-extracted with CHCl3/MeOH (4×) and the combined organic fractions were dried over Na2SO4, filtered, and concentrated in vacuo resulting in a crude brown oil. The crude material was further purified by chromatography on silica gel [ISCO Combiflash, 4 g gold cartridge, eluting with 100% DCM→8% MeOH in DCM] resulting in the title compound as an orange solid. 1H NMR (400 MHz, CD3OD): δ=1.40-1.53 (m, 2H), 1.79-1.92 (m, 5H), 2.02-2.15 (m, 4H), 3.60-3.70 (m, 1H), 3.89-4.01 (m, 4H), 5.09 (q, J=7.2 Hz, 1H), 7.11 (br. s., 1H), 7.17-7.24 (m, 1H), 7.32 (d, J=1.3 Hz, 1H), 7.74 (s, 1H), 7.80 (d, J=1.8 Hz, 1H), 8.30 (d, J=2.0 Hz, 1H). MS (ES+): m/z 535.05 (75), 537.02 (25) [MH+], HPLC: tR=2.63 min (vvnonpolar—5 min, ZQ3).
Reaction SMILES: [O:1]=[C:2]1[C:11](=[O:12])[NH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([S:13](Cl)(=[O:15])=[O:14])[CH:8]=2)[NH:3]1.[OH-].[NH4+:18]>>[O:1]=[C:2]1[C:11](=[O:12])[NH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([S:13]([NH2:18])(=[O:15])=[O:14])[CH:8]=2)[NH:3]1
Reactant: [NH4+]
Reactant: O=c1[nH]c2ccc(S(=O)(=O)Cl)cc2[nH]c1=O
Agent: [OH-]
Product: NS(=O)(=O)c1ccc2[nH]c(=O)c(=O)[nH]c2c1
Temperature: 25 °C
Reaction time: 6 h
Yield: 15 %

Procedure:
A suspension of 5.21 g (0.02 mole) of 1,2,3,4-tetrahydro-2,3-dioxo-6-quinoxalinesulfonyl chloride and 40 ml of 25% ammonium hydroxide is stirred at room temperature for 6 hours. Then it is filtered, the separated material is washed with water and acetone, filtered, dried, dissolved in a slight amount of hot dimethyl sulfoxide, and the product is precipitated from the solution by adding a slight amount of 2-propanol to it. Thus 0.70 g (15%) of 1,2,3,4-tetrahydro-2,3-dioxo-6-quinoxaline sulfonamide is obtained, m.p.: >360° C.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:15]2[CH:20]=[CH:19][C:18]([NH:21][CH2:22][CH:23]=[CH:24][C:25]3[CH:30]=[CH:29][CH:28]=[C:27]([C:31]#[N:32])[CH:26]=3)=[CH:17][C:16]=2[N+:33]([O-:35])=[O:34])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C([O-])([O-])=O.[K+].[K+].Br[CH2:43][C:44]([O:46][CH3:47])=[O:45]>CN(C=O)C.O>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:15]2[CH:20]=[CH:19][C:18]([N:21]([CH2:43][C:44]([O:46][CH3:47])=[O:45])[CH2:22][CH:23]=[CH:24][C:25]3[CH:30]=[CH:29][CH:28]=[C:27]([C:31]#[N:32])[CH:26]=3)=[CH:17][C:16]=2[N+:33]([O-:35])=[O:34])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(=O)CBr
Reactant: CC(C)(C)OC(=O)N1CCC(Oc2ccc(NCC=Cc3cccc(C#N)c3)cc2[N+](=O)[O-])CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)CN(CC=Cc1cccc(C#N)c1)c1ccc(OC2CCN(C(=O)OC(C)(C)C)CC2)c([N+](=O)[O-])c1
Temperature: 55 °C
Reaction time: 6 h

Procedure:
To 4-(N′-(t-butoxycarbonyl)piperidin-4-yl)oxy-3-nitro-N-(3-(3-cyanophenyl)prop-2-en-1-yl)benzenamine (0.39 g) and K2CO3 (0.56 g) in DMF was added methyl bromoacetate. The mixture was stirred at 55° C. for 6 hours. The reaction was cooled, diluted with water and extracted with ethyl acetate (3×). The organic layer was concentrated and purified on silica gel column to afford 4-(N′-(t-butoxycarbonyl)piperidin-4-yl)oxy-3-nitro-N-(methoxycarbonylmethyl)-N-(3-(3-cyanophenyl)prop-2-en-1-yl)benzenamine (0.15 g).
Reaction SMILES: [NH2:1][CH2:2][C:3]([O:5][CH2:6][CH3:7])=[O:4].[C:8](Cl)(=[O:15])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>C(Cl)Cl>[CH2:6]([O:5][C:3](=[O:4])[CH2:2][NH:1][C:8](=[O:15])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[CH3:7]
Reactant: O=C(Cl)c1ccccc1
Reactant: CCOC(=O)CN
Solvent: ClCCl
Product: CCOC(=O)CNC(=O)c1ccccc1
Yield: 83.6 %

Procedure:
To a suspension of ethyl 2-amino-acetate (1.0 g, 7.16 mmol) in anhydrous CH2Cl2 (5 ml) was added TEA (1.82 g, 17.96 mmol). The reaction mixture was cooled in an ice bath, and a solution of benzoyl chloride (1.0 g, 7.17 mmol) in CH2Cl2 (2 ml) was added dropwise. After addition was completed, stirring was continued at RT for two more hours. The reaction mixture was washed with water, dried with MgSO4, filtered, and concentrated. Column chromatography (silica, 30% EtOAc in hexanes) gave benzoylaminoacetic acid ethyl ester (intermediate XXa, 1.24 g) as a white solid.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7](OC2C=C3C(=CC=2)OC(C2C=CC=CC=2)CC3)=[N:8][CH:9]=1)([O-:3])=[O:2].[OH:27][C:28]1[CH:29]=[C:30]([CH:34]2[CH2:43][CH2:42][C:41]3[C:36](=[CH:37][CH:38]=[C:39]([O:44][C:45]4[N:50]=[CH:49][C:48]([NH:51]S(C)(=O)=O)=[CH:47][CH:46]=4)[CH:40]=3)[O:35]2)[CH:31]=[CH:32][CH:33]=1>>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]([O:27][C:28]2[CH:29]=[C:30]([CH:34]3[CH2:43][CH2:42][C:41]4[C:36](=[CH:37][CH:38]=[C:39]([O:44][C:45]5[N:50]=[CH:49][C:48]([NH2:51])=[CH:47][CH:46]=5)[CH:40]=4)[O:35]3)[CH:31]=[CH:32][CH:33]=2)=[N:8][CH:9]=1)([O-:3])=[O:2]
Reactant: O=[N+]([O-])c1ccc(Oc2ccc3c(c2)CCC(c2ccccc2)O3)nc1
Reactant: CS(=O)(=O)Nc1ccc(Oc2ccc3c(c2)CCC(c2cccc(O)c2)O3)nc1
Product: Nc1ccc(Oc2ccc3c(c2)CCC(c2cccc(Oc4ccc([N+](=O)[O-])cn4)c2)O3)nc1

Procedure:
5-Nitropyridin-2-yl)(6-{2-[3-(5-nitropyridin-2-yloxy)phenyl]chroman-6-yloxy}pyridin-3-yl)amine was prepared using the same procedure as described for 5-nitro-2-(2-phenylchroman-6-yloxy)pyridine in Example 1 (b) starting from N-{6-[2-(3-hydroxyphenyl)chroman-6-yloxy]pyridine-3-yl}methanesulfonamide. 1H NMR (300 MHz, d6-DMSO) δ: 10.14 (s, 1H), 9.02 (m, 1H), 8.63 (dd, 1H, J 2.8, 8.8 Hz), 8.40 (d, 1H, J 2.8 Hz), 8.30 (dd, 1H, J 2.8, 9.2 Hz), 8.13 (dd, 1H, J 2.6, 8.6 Hz), 7.52 (t, 1H, J 7.9 Hz), 7.40 (d, 1H, J 7.8 Hz), 7.31 (s, 1H), 7.28 (d, 1H, J 9.2 Hz), 7.21 (dd, 1H, J 2.1, 7.9 Hz), 6.70 (d, 1H, J 8.8 Hz), 6.85-6.90 (m, 5H), 5.18 (d, 1H, J 8.1 Hz), 2.97 (m, 1H), 2.74 (m, 1H), 2.23 (m, 1H), 2.02 (m, 1H).