Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[C:3](=[O:21])[N:4]([CH3:20])[C:5]2[C:10]([N:11]=1)=[C:9]([O:12][C:13]1[CH:18]=[C:17](Cl)[N:16]=[CH:15][N:14]=1)[CH:8]=[CH:7][CH:6]=2.NC1C(=O)NC2C(N=1)=C(OC1C=C([N:40]3[CH2:45][CH2:44][N:43]([C@H:46]([C:48]4[CH:53]=[CH:52][C:51]([F:54])=[CH:50][CH:49]=4)[CH3:47])[CH2:42][CH2:41]3)N=CN=1)C=CC=2>>[NH2:1][C:2]1[C:3](=[O:21])[N:4]([CH3:20])[C:5]2[C:10]([N:11]=1)=[C:9]([O:12][C:13]1[CH:18]=[C:17]([N:40]3[CH2:41][CH2:42][N:43]([C@H:46]([C:48]4[CH:53]=[CH:52][C:51]([F:54])=[CH:50][CH:49]=4)[CH3:47])[CH2:44][CH2:45]3)[N:16]=[CH:15][N:14]=1)[CH:8]=[CH:7][CH:6]=2
Reactant: C[C@@H](c1ccc(F)cc1)N1CCN(c2cc(Oc3cccc4[nH]c(=O)c(N)nc34)ncn2)CC1
Reactant: Cn1c(=O)c(N)nc2c(Oc3cc(Cl)ncn3)cccc21
Product: C[C@@H](c1ccc(F)cc1)N1CCN(c2cc(Oc3cccc4c3nc(N)c(=O)n4C)ncn2)CC1

Procedure:
3-Amino-5-(6-chloropyrimidin-4-yloxy)-1-methylquinoxalin-2(1H)-one, Example 59(e), (80 mg, 0.26 mmol) was reacted with (S)-1-(1-(4-fluorophenyl)ethyl)piperazine (55 mg, 0.26 mmol, prepared as described in Example 27) under the conditions of Example 26(b) to give the title compound. MS (ESI, pos. ion.) m/z: 476 (M+1).
Reaction SMILES: [CH:1]([C:4]1[N:8]=[C:7]([NH2:9])[NH:6][N:5]=1)([CH3:3])[CH3:2].[NH:10]1[C:14]2[CH:15]=[CH:16][C:17]([C:19](=O)[CH2:20][C:21](OCC)=[O:22])=[CH:18][C:13]=2[N:12]=[N:11]1.CC1C=CC(S(O)(=O)=O)=CC=1>CCCCO>[NH:10]1[C:14]2[CH:15]=[CH:16][C:17]([C:19]3[NH:9][C:7]4[N:6]([N:5]=[C:4]([CH:1]([CH3:3])[CH3:2])[N:8]=4)[C:21](=[O:22])[CH:20]=3)=[CH:18][C:13]=2[N:12]=[N:11]1
Reactant: CC(C)c1n[nH]c(N)n1
Reactant: CCOC(=O)CC(=O)c1ccc2[nH]nnc2c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCCCO
Product: CC(C)c1nc2[nH]c(-c3ccc4[nH]nnc4c3)cc(=O)n2n1
Temperature: 130 °C
Reaction time: 5 h
Yield: 19.3 %

Procedure:
To a solution of 3-isopropyl-1H-1,2,4-triazol-5-amine (100 mg, 0.79 mmol) in n-BuOH (1 mL) was added ethyl 3-(1H-benzo[d][1,2,3]triazol-5-yl)-3-oxopropanoate (275 mg, 1.18 mmol) and TsOH (7 mg, 0.04 mmol), and the resulting mixture was stirred for 5 h at 130° C. The solids were collected by filtration and washed with MeOH (3×1 mL) to afford 5-(1H-benzo[d][1,2,3]triazol-5-yl)-2-isopropyl-[1,2,4]triazolo[1,5-α]pyrimidin-7(4H)-one as a off-white solid (45 mg, 19%).
Reaction SMILES: [F:1][C:2]1[N:7]=[C:6](B(O)O)[CH:5]=[CH:4][CH:3]=1.Cl[C:12]1[C:21]([N:22]([CH:24]([CH3:26])[CH3:25])[CH3:23])=[N:20][C:19]2[C:14](=[CH:15][CH:16]=[C:17]([C:27]([O:29][CH3:30])=[O:28])[CH:18]=2)[N:13]=1.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>O1CCOCC1.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[F:1][C:2]1[N:7]=[C:6]([C:12]2[C:21]([N:22]([CH:24]([CH3:26])[CH3:25])[CH3:23])=[N:20][C:19]3[C:14](=[CH:15][CH:16]=[C:17]([C:27]([O:29][CH3:30])=[O:28])[CH:18]=3)[N:13]=2)[CH:5]=[CH:4][CH:3]=1
Reactant: OB(O)c1cccc(F)n1
Reactant: COC(=O)c1ccc2nc(Cl)c(N(C)C(C)C)nc2c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: COC(=O)c1ccc2nc(-c3cccc(F)n3)c(N(C)C(C)C)nc2c1
Temperature: 90 °C
Reaction time: 1 h
Yield: 71.9 %

Procedure:
To a solution of 6-fluoropyridin-2-ylboronic acid (289.0 mg, 2.05 mmol) in dioxane (1 mL) was added methyl 2-chloro-3-(isopropyl(methyl)amino)quinoxaline-6-carboxylate (300.0 mg, 1.02 mmol), K3PO4 (434.0 mg, 2.05 mmol), and Pd(PPh3)4 (27.6 mg, 0.02 mmol) under nitrogen atmosphere. After stirring 1 h at 90° C., the reaction mixture was dissolved in water (50 mL), extracted with dichloromethane (3×20 mL), dried over anhydrous magnesium sulfate and concentrated under reduced pressure to afford a residue, which was purified by a silica gel column with 0.05%-0.2% ethyl acetate in petroleum ether to afford methyl 2-(6-fluoropyridin-2-yl)-3-(isopropyl(methyl)amino)quinoxaline-6-carboxylate as a light yellow solid (260.0 mg, 72%).
Reaction SMILES: C1([O:6][C:7](=[O:43])[C@@H:8]([NH:16][C:17](=[O:42])[CH2:18][CH2:19][C:20]2[CH:21]=[C:22]3[C:26](=[CH:27][CH:28]=2)[NH:25][C:24]([C:29](=[O:41])[NH:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][C:37](=[O:40])[NH:38][OH:39])=[CH:23]3)[CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)CCCC1.[OH-].[Na+]>C1COCC1.CO>[OH:39][NH:38][C:37]([CH2:36][CH2:35][CH2:34][CH2:33][CH2:32][CH2:31][NH:30][C:29]([C:24]1[NH:25][C:26]2[C:22]([CH:23]=1)=[CH:21][C:20]([CH2:19][CH2:18][C:17]([NH:16][C@@H:8]([CH2:9][C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1)[C:7]([OH:43])=[O:6])=[O:42])=[CH:28][CH:27]=2)=[O:41])=[O:40]
Reactant: O=C(CCCCCCNC(=O)c1cc2cc(CCC(=O)N[C@@H](Cc3ccccc3)C(=O)OC3CCCC3)ccc2[nH]1)NO
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: O=C(CCCCCCNC(=O)c1cc2cc(CCC(=O)N[C@@H](Cc3ccccc3)C(=O)O)ccc2[nH]1)NO
Temperature: 25 °C
Reaction time: 2 h
Yield: 47.7 %

Procedure:
Compound (100) (80 mg, 0.14 mmol) was dissolved in THF/MeOH (1 ml/0.5 ml) and 1.4 M NaOH (0.5 ml) added. The reaction was stirred at room temperature for 2 h. THF was removed by blowing a stream of N2 gas at the surface of the solution and the residual material purified by preparative HPLC to give compound (101) (34.9 mg), LCMS purity 95%, m/z 523 [M++H]+, 1H NMR (400 MHz, MeOD), δ: 1.35-1.50 (4H, m, alkyl), 1.60-1.75 (4H, m, alkyl), 2.15 (2H, br t, CH2), 2.55 (2H, br t, CH2), 2.95 (3H, m, CH+CH2), 3.10 (1H, dd, CH), 4.65, (1H, m, NHCHCO), 7.00-7.15 (7H, m, Ar), 7.35-7.41 (2H, m, Ar)
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:8][C:9](=[C:12]([C:15]#[N:16])[C:13]#[N:14])SC)[CH:5]=[CH:6][CH:7]=1.O.[NH2:18][NH2:19]>CCO>[NH2:14][C:13]1[NH:19][N:18]=[C:9]([NH:8][C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=2)[C:12]=1[C:15]#[N:16]
Reactant: CSC(Nc1cccc(Cl)c1)=C(C#N)C#N
Reactant: NN
Solvent: O
Solvent: CCO
Product: N#Cc1c(Nc2cccc(Cl)c2)n[nH]c1N
Temperature: 0 °C

Procedure:
Dissolved 2-(((3-chlorophenyl)amino)(methylthio)methylene)malononitrile in EtOH (100 mL) and added and hydrazine hydrate (1 eq., 2.44 mL), then heated to reflux until complete by TLC (absence of starting material, 18 hrs). Poured into ice water and filtered to obtain 5-amino-3-((3-chlorophenyl)amino)-1H-pyrazole-4-carbonitrile as yellow powder.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[CH2:14][CH:13]([CH2:15][CH:16]3[CH2:21][CH2:20][N:19](CC4C=CC=CC=4)[CH2:18][CH2:17]3)[C:11](=[O:12])[C:6]2=[CH:7][C:8]=1[O:9][CH3:10].Cl.S(C1C=CC(C)=CC=1)(O)(=O)=O.COC1C=C2C(=CC=1OC)C(=O)C(=CC1C=CN=CC=1)C2>[Pd].O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:6](=[CH:7][C:8]=1[O:9][CH3:10])[C:11](=[O:12])[CH:13]([CH2:15][CH:16]1[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]1)[CH2:14]2
Reactant: COc1cc2c(cc1OC)C(=O)C(CC1CCN(Cc3ccccc3)CC1)C2
Agent: [Pd]
Agent: COc1cc2c(cc1OC)C(=O)C(=Cc1ccncc1)C2
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Product: COc1cc2c(cc1OC)C(=O)C(CC1CCNCC1)C2
Reaction time: 8 h

Procedure:
US Patent Application published under the No. 2007/0135644A1 discloses the preparation of donepezil hydrochloride by reducing 5,6-dimethoxy-2-[1-(4-pyridinyl)methylidene]-1-indanone tosylate with 10% Pd/C catalyst in demi-water at 70-95° C., at 10 bar for 8 hours. The mixture is extracted three times with 1-butanol to afford a residue which is purified with methyl-tert-butyl ether to obtain 5,6-dimethoxy-2-(4-piperidinylmethyl)-1-indanone, followed by condensation with benzyl chloride in toluene for 8 hours at 145° C. to yield donepezil which is further converted to donepezil hydrochloride.
Reaction SMILES: Cl.[S:2]1[CH:6]=[CH:5][N:4]=[C:3]1[NH:7][NH:8][C:9]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[N:12]=[CH:11][C:10]=1[C:19]([O:21]CC)=O>C(O)CCC>[S:2]1[CH:6]=[CH:5][N:4]=[C:3]1[N:7]1[C:19](=[O:21])[C:10]2=[CH:11][NH:12][C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][C:18]=3[C:9]2=[N:8]1
Reactant: CCOC(=O)c1cnc2ccccc2c1NNc1nccs1
Agent: Cl
Solvent: CCCCO
Product: O=c1c2c[nH]c3ccccc3c-2nn1-c1nccs1
Temperature: 25 °C

Procedure:
A mixture of ethyl 4-(2-thiazolylhydrazino)-quinoline-3-carboxylate hydrochloride (1.16 g) and 20 ml of n-butanol is heated under reflux for 5 hours, cooled to room temperature and filtered. The resulting solid is washed with ethanol and ether, and dried to yield 2-(2-thiazolyl)-pyrazolo[4,3-c]quinolin-3(5H)-one, m.p. over 350°; IR (KBr) 818, 840, 871, 891 cm-1.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]2[C:13]3=[N:14][CH:15]=[N:16][C:17](=O)[CH:12]3[CH:11]=[N:10]2)=[CH:5][CH:4]=1.P(Cl)(Cl)([Cl:21])=O>>[Cl:21][C:17]1[N:16]=[CH:15][N:14]=[C:13]2[N:9]([C:6]3[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=3)[N:10]=[CH:11][C:12]=12
Reactant: O=P(Cl)(Cl)Cl
Reactant: COc1ccc(N2N=CC3C(=O)N=CN=C32)cc1
Product: COc1ccc(-n2ncc3c(Cl)ncnc32)cc1
Temperature: 100 °C

Procedure:
A mixture of compound 44B (2 g, 8.26 mmol) and phosphoryl trichloride (11.51 mL, 124 mmol) was heated at 100° C. for 2 h and cooled. The reaction mixture was slowly poured onto ice. The precipitate was collected, washed with water and dried to provide the desired product. MS (APCI): m/z 261 (M+H).
Reaction SMILES: ClS(N=C=O)(=O)=O.C(O)=O.[Si]([O:18][C@H:19]1[CH2:24][CH2:23][C@H:22]2[C@H:25]3[C@H:34]([CH2:35][CH2:36][C@:20]12[CH3:21])[C:33]1[CH:32]=[C:31]([CH:37]=[O:38])[C:30]([OH:39])=[CH:29][C:28]=1[CH2:27][CH2:26]3)(C(C)(C)C)(C)C.[H-].[Na+]>ClCl.CN(C=O)C.C(Cl)Cl>[OH:39][C:30]1[C:31]([CH:37]=[O:38])=[CH:32][C:33]2[C@@H:34]3[C@H:25]([C@H:22]4[C@@:20]([CH2:36][CH2:35]3)([CH3:21])[C@@H:19]([OH:18])[CH2:24][CH2:23]4)[CH2:26][CH2:27][C:28]=2[CH:29]=1
Reactant: CC(C)(C)[Si](C)(C)O[C@H]1CC[C@H]2[C@@H]3CCc4cc(O)c(C=O)cc4[C@H]3CC[C@]12C
Agent: ClCl
Agent: O=C=NS(=O)(=O)Cl
Agent: [H-]
Solvent: O=CO
Solvent: ClCCl
Solvent: CN(C)C=O
Product: C[C@]12CC[C@@H]3c4cc(C=O)c(O)cc4CC[C@H]3[C@@H]1CC[C@@H]2O
Temperature: 25 °C
Reaction time: 1 h
Yield: 18.3 %

Procedure:
To a solution of chlorosulfonyl isocyanate (0.13 mL, 1.5 mmol) in CH2 Cl2 (1.0 mL) was added formic acid (0.31 mL of a CH2Cl2 solution, 5.0M, 1.6 mmol) at 0° C. The reaction mixture was warmed to room temperature and stirred for 1h. To a solution of 17β-tert-butyl-dimethylsilyloxy-3-hydroxyestra-1,3,5(10)-triene-2-carbox aldehyde (9, 0.129 g, 0.31 mmol) in DMF (3.0 mL) was added sodium hydride (0.044 g of a mineral oil dispersion, 60%, 1.1 mmol) at 0° C. The reaction mixture was stirred for 1 h, the pre-prepared reagent was added, and stirring continued for 4 h at room temperature. The reaction mixture was quenched with saturated aqueous NH4Cl at 0° C. and extracted with EtOAc. The combined organic layers were washed with H2O, then with saturated aqueous NaCl, and dried (MgSO4). The desiccant was filtered and the solvent was evaporated at reduced pressure. The residue was purified by column chromatography (silica gel) using n-hexane:acetone (2:1→1:1, v/v) to afford 0.017 g of 2a (18% yield) and 0.030 g of 10 (27% yield), m.p. 170°-172° C.
Reaction SMILES: Cl.[F:2][C:3]1[CH:8]=[C:7]([S:9]([CH3:12])(=[O:11])=[O:10])[CH:6]=[CH:5][C:4]=1[NH:13][C:14]1[C:15]2[O:22][CH:21]=[C:20]([CH:23]3[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]3)[C:16]=2[N:17]=[CH:18][N:19]=1.[F:29][C:30]([F:46])([F:45])[C:31]1[CH:32]=[C:33]([S:41](Cl)(=[O:43])=[O:42])[CH:34]=[C:35]([C:37]([F:40])([F:39])[F:38])[CH:36]=1.O>N1C=CC=CC=1.C(Cl)Cl>[F:40][C:37]([F:38])([F:39])[C:35]1[CH:34]=[C:33]([S:41]([N:26]2[CH2:27][CH2:28][CH:23]([C:20]3[C:16]4[N:17]=[CH:18][N:19]=[C:14]([NH:13][C:4]5[CH:5]=[CH:6][C:7]([S:9]([CH3:12])(=[O:10])=[O:11])=[CH:8][C:3]=5[F:2])[C:15]=4[O:22][CH:21]=3)[CH2:24][CH2:25]2)(=[O:42])=[O:43])[CH:32]=[C:31]([C:30]([F:46])([F:45])[F:29])[CH:36]=1
Reactant: CS(=O)(=O)c1ccc(Nc2ncnc3c(C4CCNCC4)coc23)c(F)c1
Reactant: O=S(=O)(Cl)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Agent: Cl
Solvent: c1ccncc1
Solvent: O
Solvent: ClCCl
Product: CS(=O)(=O)c1ccc(Nc2ncnc3c(C4CCN(S(=O)(=O)c5cc(C(F)(F)F)cc(C(F)(F)F)c5)CC4)coc23)c(F)c1
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 41.1 %

Procedure:
N-[2-Fluoro-4-(methylsulfonyl)phenyl]-7-(piperidin-4-yl)furo[3,2-d]pyrimidine-4-amine hydrochloride (10 mg, 0.023 mmol) was dissolved in pyridine (0.1 mL), a solution of 3,5-bis(trifluoromethyl)benzene-1-sulfonyl chloride (14 mg, 0.046 mmol) in anhydrous methylene chloride (0.4 mL) was added under ice-cooling, followed by stirring at room temperature for 1 hour and 45 minutes. Water was added to the reaction liquid, followed by extraction with ethyl acetate, the organic layer was dried over anhydrous sodium sulfate and concentrated under a reduced pressure, and the obtained residue was purified by silica gel preparative thin layer chromatography (chloroform:methanol=50:1) to give the titled compound (6.3 mg, 41%) as a white solid.
Reaction SMILES: [C:1]([CH2:3][C:4]([O:6][CH3:7])=[O:5])#[N:2].[H-].[Na+].[F:10][C:11]1[C:19]([F:20])=[C:18]([F:21])[C:17]([F:22])=[CH:16][C:12]=1[C:13](Cl)=[O:14].C(Cl)Cl>O1CCCC1>[C:1]([C:3](=[C:13]([OH:14])[C:12]1[CH:16]=[C:17]([F:22])[C:18]([F:21])=[C:19]([F:20])[C:11]=1[F:10])[C:4]([O:6][CH3:7])=[O:5])#[N:2]
Reactant: O=C(Cl)c1cc(F)c(F)c(F)c1F
Reactant: COC(=O)CC#N
Agent: [H-]
Agent: [Na+]
Solvent: ClCCl
Solvent: C1CCOC1
Product: COC(=O)C(C#N)=C(O)c1cc(F)c(F)c(F)c1F
Reaction time: 0.5 h
Yield: 86.1 %

Procedure:
Methyl cyanoacetate (51.1 g) is added dropwise to a suspension of sodium hydride (43.3 g, in oil, 55-65 w/w %) in dry tetrahydrofuran (600 ml) while maintaining the internal temperature between 15° C. and 20° C. on an ice bath. To the reaction mixture is added dropwise the crude 2,3,4,5-tetrafluorobenzoyl chloride (110.5 g) as obtained above, and the mixture is stirred while maintaining the internal temprature as above. After 30 minutes, methylene chloride is added to the reaction mixture and the reaction product is extracted with 3% aqueous sodium bicarbonate. The extract is then washed with methylene chloride to remove the remaining methyl cyanoacetate. The extract is acidified with conc. HCl and the resulting precipitate is filtered and washed with dil. HCl to afford methyl 2-cyano-3-hydroxy-3-(2,3,4,5-tetrafluorophenyl)acrylate (122.2 g) as pale yellow crystals, m.p. 71°-73° C.
Reaction SMILES: [C:1]([CH:3](C(OCC)=O)[CH2:4][CH2:5][C:6]1[CH:7]=[CH:8][C:9]2[N:14]([CH3:15])[CH2:13][CH2:12][N:11](C(OC(C)(C)C)=O)[C:10]=2[N:23]=1)#[N:2].[OH-].[K+].O.CCOC(C)=O>C(O)CO>[CH3:15][N:14]1[CH2:13][CH2:12][NH:11][C:10]2[N:23]=[C:6]([CH2:5][CH2:4][CH2:3][C:1]#[N:2])[CH:7]=[CH:8][C:9]1=2
Reactant: CCOC(=O)C(C#N)CCc1ccc2c(n1)N(C(=O)OC(C)(C)C)CCN2C
Agent: [K+]
Agent: [OH-]
Solvent: OCCO
Solvent: CCOC(C)=O
Solvent: O
Product: CN1CCNc2nc(CCCC#N)ccc21
Temperature: 150 °C
Yield: 68.4 %

Procedure:
A mixture of tert-butyl 6-(3-cyano-4-ethoxy-4-oxobutyl)-1-methyl-2,3-dihydropyrido[2,3-b]pyrazine-4(1H)-carboxylate (5.78 g, 14.88 mmol) and KOH (powder, 1.25 g, 22.32 mmol) in ethylene glycol (30 mL) under N2 was heated at 150° C. for 3 hours. The mixture was cooled to 0° C. and portioned between water and EtOAc. The organic phase was washed with brine, dried over Na2SO4 and concentrated in vacuo. Flash chromatography (silica, 100% EtOAc) yielded a colorless oil (2.2 g, 66% yield). H NMR (CDCl3) δ 2.00 (t, 2H), 2.32 (t, 2H), 2.63 (t, 23H), 2.32 (s, 3H), 3.20 (t, 2H), 3.56 (t, 2H), 6.40 (d, 12H), 6.58(d, 1H), 4.20 (t, 2H), 6.41 (d, 1H), 6.89 (d, 1H).
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH:4]([C:7]2[CH:12]=[CH:11][C:10]([OH:13])=[CH:9][CH:8]=2)[CH2:3][CH2:2]1.[CH2:14]([CH:16]1[O:18][CH2:17]1)Cl>>[O:18]1[CH2:17][CH:16]1[CH2:14][O:13][C:10]1[CH:9]=[CH:8][C:7]([CH:4]2[CH2:5][CH2:6][O:1][CH2:2][CH2:3]2)=[CH:12][CH:11]=1
Reactant: Oc1ccc(C2CCOCC2)cc1
Reactant: ClCC1CO1
Product: c1cc(C2CCOCC2)ccc1OCC1CO1

Procedure:
The title compound was prepared from 4-(tetrahydropyran-4-yl)-phenol and epichlorohydrin according to the procedures employed for the preparation of the compound in Step 1 of Example 2.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:29])[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](Br)=[CH:17][C:16]=2[CH2:22][N:23]2[CH2:27][CH2:26][O:25][C:24]2=[O:28])[CH:7]=1)[CH3:2].[NH:30]1[CH2:35][CH2:34][O:33][CH2:32][CH2:31]1.C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1.CC(C)([O-])C.[Na+]>C1(C)C=CC=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.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH2:1]([O:3][C:4](=[O:29])[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]([N:30]3[CH2:35][CH2:34][O:33][CH2:32][CH2:31]3)=[CH:17][C:16]=2[CH2:22][N:23]2[CH2:27][CH2:26][O:25][C:24]2=[O:28])[CH:7]=1)[CH3:2]
Reactant: C1COCCN1
Reactant: CCOC(=O)Cc1ccc(OC)c(Oc2ccc(Br)cc2CN2CCOC2=O)c1
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: Cc1ccccc1
Product: CCOC(=O)Cc1ccc(OC)c(Oc2ccc(N3CCOCC3)cc2CN2CCOC2=O)c1
Temperature: 100 °C
Reaction time: 2 h

Procedure:
{3-[4-Bromo-2-(2-oxo-oxazolidin-3-ylmethyl)-phenoxy]-4-methoxy-phenyl}-acetic acid ethyl ester (0.2 g, 0.43 mmol), morpholine (0.05 mL, 0.52 mmol), tris(dibenzylideneacetone)dipalladium(0) (0.01 g, 0.01 mmol), BINAP (0.026 g, 0.04 mmol), and sodium tert-butoxide (0.09 g, 0.86 mmol) were combined in toluene (10 mL) and stirred at 100° C. for 2 hours. The mixture was worked-up to give the title compound.
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@H:18]1[CH2:23][CH2:22][C@H:21]([NH:24][C:25](=[O:31])[O:26][C:27]([CH3:30])([CH3:29])[CH3:28])[CH2:20][CH2:19]1.[CH3:32][O:33][C:34]1[CH:39]=[C:38](B2OC(C)(C)C(C)(C)O2)[CH:37]=[CH:36][C:35]=1[OH:49]>>[CH:14]1([C:12]([C:6]2[CH:7]=[N:8][C:9]3[C:4]([C:5]=2[NH:17][C@H:18]2[CH2:23][CH2:22][C@H:21]([NH:24][C:25](=[O:31])[O:26][C:27]([CH3:29])([CH3:30])[CH3:28])[CH2:20][CH2:19]2)=[CH:3][C:2]([C:38]2[CH:37]=[CH:36][C:35]([OH:49])=[C:34]([O:33][CH3:32])[CH:39]=2)=[CH:11][CH:10]=3)=[O:13])[CH2:16][CH2:15]1
Reactant: COc1cc(B2OC(C)(C)C(C)(C)O2)ccc1O
Reactant: CC(C)(C)OC(=O)N[C@H]1CC[C@H](Nc2c(C(=O)C3CC3)cnc3ccc(Br)cc23)CC1
Product: COc1cc(-c2ccc3ncc(C(=O)C4CC4)c(N[C@H]4CC[C@H](NC(=O)OC(C)(C)C)CC4)c3c2)ccc1O

Procedure:
Following general procedure D, tert-butyl trans-4-[6-bromo-3-(cyclopropanecarbonyl)quinolin-4-ylamino]cyclohexylcarbamate (49 mg, 0.100 mmol) was reacted with 2-methoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol (50 mg, 0.200 mmol) to afford the desired product (45 mg, 85%) as an off-white solid: ESI MS m/z 532 [C31H37N3O5+H]+.
Reaction SMILES: [OH:1][CH:2]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[NH:6][C:5](=[O:13])[C:4]2[CH:14]=[CH:15][N:16]=[CH:17][C:3]1=2.CC(C)=O.CC(C)=O.OS(O)(=O)=O.O=[Cr](=O)=O.C(=O)([O-])O.[Na+]>CN(C)C=O.CO>[CH:17]1[C:3]2[C:2](=[O:1])[C:8]3[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=3[NH:6][C:5](=[O:13])[C:4]=2[CH:14]=[CH:15][N:16]=1
Reactant: O=C1Nc2ccccc2C(O)c2cnccc21
Agent: O=[Cr](=O)=O
Agent: O=C([O-])O
Agent: O=S(=O)(O)O
Solvent: CC(C)=O
Solvent: CN(C)C=O
Solvent: CO
Product: O=c1[nH]c2ccccc2c(=O)c2cnccc12
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
In 190 ml of dimethylformamide was dissolved 8 g (79.6 mmol) of the compound (6a). To the solution was added 250 ml of acetone, and 19 ml of 4N Jones' reagent was then added thereto dropwise at room temperature. After the mixture was stirred at room temperature for 30 minutes, 100 ml of methanol and excess sodium hydrogencarbonate were added thereto. The solvent was removed by distillation under reduced pressure. To the residue was added 200 ml of water, and the precipitated crystals were collected by filtration to obtain the entitled compound (II-1) in a yield of 9.7 g (54.5%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][C:5]([O:8][C:9]2[CH:10]=[C:11]([CH:21]=[CH:22][CH:23]=2)[CH2:12]P(=O)(OCC)OCC)=[N:6][CH:7]=1.O1CCOCCOCCOCCOCC1.[H-].[Na+].[C:41]([O:45][C:46]([N:48]1[CH2:53][CH2:52][C:51](=O)[CH2:50][CH2:49]1)=[O:47])([CH3:44])([CH3:43])[CH3:42]>C1COCC1.O>[Br:1][C:2]1[CH:7]=[N:6][C:5]([O:8][C:9]2[CH:10]=[C:11]([CH:21]=[CH:22][CH:23]=2)[CH:12]=[C:51]2[CH2:52][CH2:53][N:48]([C:46]([O:45][C:41]([CH3:44])([CH3:43])[CH3:42])=[O:47])[CH2:49][CH2:50]2)=[N:4][CH:3]=1
Reactant: CCOP(=O)(Cc1cccc(Oc2ncc(Br)cn2)c1)OCC
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Agent: C1COCCOCCOCCOCCO1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)OC(=O)N1CCC(=Cc2cccc(Oc3ncc(Br)cn3)c2)CC1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 36.7 %

Procedure:
Diethyl 3-(5-bromopyrimidin-2-yloxy)benzylphosphonate (0.700 g, 1.74 mmol) from Step 3 and 1,4,7,10,13-pentaoxacyclopentadecane (15-Crown-5, 0.017 mL, 0.087 mmol) were suspended in THF (2 mL). The mixture was cooled to 0° C. and sodium hydride (84 mg, 60% dispersion in mineral oil, 2.1 mmol) was added. The reaction was warmed to room temperature, stirred for 30 min and then cooled back to 0° C. A solution of 4-oxo-piperidine-1-carboxylic acid tert-butyl ester (0.452 g, 2.27 mmol) in THF (1.5 mL) was added and the reaction was warmed to room temperature. After 40 h, water was added and the mixture was extracted twice with ethyl acetate. The combined organic layers were washed with water, brine, dried over anhydrous sodium sulfate, filtered and concentrated to an orange oil (about 1 g). This material was purified by flash chromatography on silica (10-40% EtOAc:heptane) to afford the title compound (0.285 g, 37% yield). MS (APCI) M−100=346; 1H NMR (400 MHz, CDCl3) δ ppm 1.48 (s, 9H) 2.30-2.37 (m, 2H) 2.43-2.52 (m, 2H) 3.37-3.45 (m, 2H) 3.48-3.55 (m, 2H) 6.36 (s, 1H) 6.99-7.07 (m, 2H) 7.11 (d, J=7.80 Hz, 1H) 7.39 (t, J=7.90 Hz, 1H) 8.58 (s, 2H).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[CH2:7]([N:14]1[C:22]2[C:21](=[O:23])[NH:20][C:19](=[O:24])[N:18]([CH2:25][CH:26]([CH3:28])[CH3:27])[C:17]=2[N:16]=[CH:15]1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.[CH2:29]([O:32][CH2:33]Cl)[CH2:30][CH3:31]>CN(C)C=O.O.CO>[CH2:7]([N:14]1[C:22]2[C:21](=[O:23])[N:20]([CH2:33][O:32][CH2:29][CH2:30][CH3:31])[C:19](=[O:24])[N:18]([CH2:25][CH:26]([CH3:28])[CH3:27])[C:17]=2[N:16]=[CH:15]1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: CCCOCCl
Reactant: CC(C)Cn1c(=O)[nH]c(=O)c2c1ncn2Cc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CO
Solvent: CN(C)C=O
Product: CCCOCn1c(=O)c2c(ncn2Cc2ccccc2)n(CC(C)C)c1=O
Reaction time: 1 h

Procedure:
0.86 g (6.2 mmol) of potassium carbonate was added at 60° C. to a suspension of 1.16 g (3.9 mmol) of 7-benzyl-3-isobutylxanthine from stage c) in 60 ml of dimethylformamide and the mixture was stirred at this temperature for 1 hour. 0.56 ml (5.1 mmol) of propoxymethyl chloride was then added dropwise and the mixture was stirred at 80° C. for 5.5 hours. 12 ml of water and 5 ml of methanol were then added, the mixture was allowed to stand overnight, 60 ml of water were again added and the mixture was extracted four times using 150 ml of methyl tert-butyl ether each time. The combined organic phases were washed with 200 ml of water, dried using magnesium sulfate and concentrated under reduced pressure. The crude product was purified by flash chromatography on a silica gel column, dichloromethane.