Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[C:4]1([C:36]3[C:27](=[CH:28][C:29]4[O:34][CH2:33][CH2:32][O:31][C:30]=4[CH:35]=3)[O:26][CH2:25]1)[C:5](=[O:24])[N:6]2[CH:11]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.[N:37]1[C:46]2[C:41](=[CH:42][CH:43]=[CH:44][CH:45]=2)[CH:40]=[C:39](B(O)O)[CH:38]=1.C(=O)([O-])[O-].[Na+].[Na+]>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.CN(C)C=O>[C:12]1([CH:11]([C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)[N:6]2[C:7]3[C:3](=[C:2]([C:39]4[CH:38]=[N:37][C:46]5[C:41]([CH:40]=4)=[CH:42][CH:43]=[CH:44][CH:45]=5)[CH:10]=[CH:9][CH:8]=3)[C:4]3([C:36]4[C:27](=[CH:28][C:29]5[O:34][CH2:33][CH2:32][O:31][C:30]=5[CH:35]=4)[O:26][CH2:25]3)[C:5]2=[O:24])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: OB(O)c1cnc2ccccc2c1
Reactant: O=C1N(C(c2ccccc2)c2ccccc2)c2cccc(Br)c2C12COc1cc3c(cc12)OCCO3
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=C1N(C(c2ccccc2)c2ccccc2)c2cccc(-c3cnc4ccccc4c3)c2C12COc1cc3c(cc12)OCCO3
Yield: 35.2 %

Procedure:
A 10 mL microwave reaction vessel was charged with 4′-bromo-1′-(diphenylmethyl)-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one (0.38 g, 1.40 mmol), tetrakis(triphenylphosphine)palladium (0.080 g, 0.14 mmol), quinolin-3-ylboronic acid (0.20 g, 2.3 mmol), 2 M aqueous sodium carbonate (1.8 mL) and N,N-dimethylformamide (3.mL). The reaction mixture was irradiated at 150° C. for 15 min in a microwave reactor. The reaction was repeated and both reaction mixtures were combined, poured into distilled water (75 mL) and extracted with ethyl acetate (150 mL). The combined organic extracts were washed with water (3×50 mL) and brine (100 mL), dried over magnesium sulfate, filtered and concentrated in vacuo. The residue was purified by column chromatography and eluted with a 20% to 50% gradient of ethyl acetate in hexanes to afford 1′-(diphenylmethyl)-4′-quinolin-3-yl-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one (0.29 g, 35%) as a light yellow solid: MS (ES+) m/z 589.0 (M+1).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:8]2[O:9][C:10]3[C:11](=[C:13]([C:17]([NH2:19])=[O:18])[CH:14]=[CH:15][CH:16]=3)[N:12]=2)[CH:5]=[CH:6][CH:7]=1.N1C=CC=CC=1.[C:26](Cl)(=[O:28])[CH3:27]>ClCCl>[C:26]([NH:1][C:2]1[CH:3]=[C:4]([C:8]2[O:9][C:10]3[C:11](=[C:13]([C:17]([NH2:19])=[O:18])[CH:14]=[CH:15][CH:16]=3)[N:12]=2)[CH:5]=[CH:6][CH:7]=1)(=[O:28])[CH3:27]
Reactant: CC(=O)Cl
Reactant: NC(=O)c1cccc2oc(-c3cccc(N)c3)nc12
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(=O)Nc1cccc(-c2nc3c(C(N)=O)cccc3o2)c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 39.1 %

Procedure:
To a solution of 2-(3-aminophenyl)benzo[d]oxazole-4-carboxamide (100 mg, 0.39 mmol) in dichloromethane (5 mL) was added pyridine (34 mg, 0.43 mmol), then acetyl chloride (32 mg, 0.41 mmol) was added at 0° C. stirred at room temperature for 4 hr. The solvent was evaporated under reduced pressure and re-crystallized in methanol to obtain a white solid of 2-(3-acetamidophenyl)benzo[d]oxazole-4-carboxamide (45 mg, yield 38%). 1H-NMR (400 MHz, DMSO-d6) δ 2.09 (s, 3H), 7.53-7.58 (m, 2H), 7.84-7.86 (d, J=8 Hz, 1H), 7.97-8.07 (m, 4H), 8.44 (s, 1H), 8.57 (s, 1H), 10.29 (s, 1H); LC-MS (ESI) m/z 296 [M+1]+.
Reaction SMILES: [C:1]([C:4]1[C:8]([CH3:9])=[C:7]([C:10]2[CH:15]=[CH:14][N:13]=[CH:12][CH:11]=2)[NH:6][C:5]=1Br)(=[O:3])[CH3:2].[S:17]1[CH:21]=[CH:20][CH:19]=[C:18]1B(O)O>>[C:1]([C:4]1[C:8]([CH3:9])=[C:7]([C:10]2[CH:15]=[CH:14][N:13]=[CH:12][CH:11]=2)[NH:6][C:5]=1[C:18]1[S:17][CH:21]=[CH:20][CH:19]=1)(=[O:3])[CH3:2]
Reactant: OB(O)c1cccs1
Reactant: CC(=O)c1c(Br)[nH]c(-c2ccncc2)c1C
Product: CC(=O)c1c(-c2cccs2)[nH]c(-c2ccncc2)c1C

Procedure:
The title compound was prepared from 3-acetyl-2-bromo-4-methyl-5-(4-pyridyl)-1H-pyrrole according to the procedure of Example 46 using 2-thienylboronic acid instead of 4-pyridylboronic acid in step 3.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[C:7]([CH2:9][CH:10]([O:16][CH:17]([CH3:19])[CH3:18])[C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH:6]=[CH:5][N:4]=1)#[N:2].[ClH:20].[H][H]>C(O)C.[C].[Pd]>[ClH:20].[NH2:2][CH2:1][C:3]1[CH:8]=[C:7]([CH2:9][CH:10]([O:16][CH:17]([CH3:18])[CH3:19])[C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH:6]=[CH:5][N:4]=1
Reactant: [H][H]
Reactant: CCOC(=O)C(Cc1ccnc(C#N)c1)OC(C)C
Agent: [Pd]
Agent: Cl
Solvent: CCO
Product: CCOC(=O)C(Cc1ccnc(CN)c1)OC(C)C

Procedure:
1.0 g of ethyl 3-(2-cyano-4-pyridyl)-2-isopropoxypropanoate was dissolved in 70 mL ethanol, and 1.9 mL conc. hydrochloric acid and 0.9 g of 10% palladium-carbon were added thereto, and the mixture was stirred at room temperature for 2 hours in a hydrogen atmosphere. After the catalyst was filtered off and the solvent was evaporated, the reaction product was subjected to azeotropic distillation with ethyl acetate and toluene, to give 1.21 g of ethyl 3-[2-(aminomethyl)-4-pyridyl]-2-isopropoxypropanoate hydrochloride was obtained as a crude product.
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][C:5]1[N:9]([CH3:10])[C:8]([CH2:11][CH3:12])=[N:7][CH:6]=1.[CH3:13][N:14]1[N:18]=[N:17][C:16]([C:19]2[CH:24]=[CH:23][C:22](O)=[CH:21][CH:20]=2)=[N:15]1.CCOC(/N=N/C(OCC)=O)=O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1COCC1>[CH3:13][N:14]1[N:18]=[N:17][C:16]([C:19]2[CH:20]=[CH:21][C:22]([O:1][CH2:2][CH2:3][CH2:4][C:5]3[N:9]([CH3:10])[C:8]([CH2:11][CH3:12])=[N:7][CH:6]=3)=[CH:23][CH:24]=2)=[N:15]1
Reactant: CCc1ncc(CCCO)n1C
Reactant: Cn1nnc(-c2ccc(O)cc2)n1
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CCc1ncc(CCCOc2ccc(-c3nnn(C)n3)cc2)n1C
Temperature: 20 °C
Reaction time: 2 h
Yield: 91.9 %

Procedure:
A mixture of 5-(3-hydroxypropyl)-1-methyl-2-ethylimidazole (150 mg, 0.89 mmol), 4-(2-methyl-tetrazol-5-yl)-phenol (172 mg, 0.98 mmol), and DEAD (171 mg, 0.98 mmol) was dissolved in 10 ml of THF under nitrogen at 0° C. To the above solution was added triphenylphosphine (257 mg, 0.89 mmol) at 0° C. and the mixture was stirred for 2 h allowing the mixture to warm to 20° C. The solvent was removed in vacuo, and the residue was purified by silica column chromatography (20 cm column, ethyl acetate/hexane, 1/1-3/1; methylene chloride/methanol 30/1-15/1) to afford 267 mg (92%) of 5-[3-[4-(2-methyl-tetrazol-5-yl)phenoxy]propyl]-1-methyl-2-ethylimidazole, as a white crystalline solid, m.p. 115°-117° C. (recrystallization from methylene chloride/hexane).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[N:12][N:11]3[C:14](=[O:17])[NH:15][N:16]=[C:10]3[C:9]=2[C:18]2[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=2)=[CH:4][CH:3]=1.C([O-])([O-])=O.[Cs+].[Cs+].Cl.Cl[CH2:33][CH2:34][N:35]1[CH2:40][CH2:39][O:38][CH2:37][CH2:36]1>CN(C=O)C.O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[N:12][N:11]3[C:14](=[O:17])[N:15]([CH2:33][CH2:34][N:35]4[CH2:40][CH2:39][O:38][CH2:37][CH2:36]4)[N:16]=[C:10]3[C:9]=2[C:18]2[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=2)=[CH:4][CH:3]=1
Reactant: O=c1[nH]nc2c(-c3ccc(Cl)cc3)c(-c3ccc(Cl)cc3)cnn12
Reactant: ClCCN1CCOCC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: O=c1n(CCN2CCOCC2)nc2c(-c3ccc(Cl)cc3)c(-c3ccc(Cl)cc3)cnn12
Temperature: 70 °C
Reaction time: 0.5 h
Yield: 67.6 %

Procedure:
To 7,8-bis(4-chlorophenyl)-[1,2,4]triazolo[4,3-b]pyridazin-3(2H)-one, (40 mg, 0.11 mmol), prepared as described in Example 1, in DMF (1 mL) was added Cs2CO3 (110 mg, 0.33 mmol) and 4-(2-chloroethyl)morpholine hydrochloride (31 mg, 0.166 mmol). The reaction mixture was stirred at 70° C. for 30 min under argon. After this time, the reaction mixture was diluted with water (5 mL). The resulting solution was extracted with EtOAc (3×5 mL). The combined organic layers were washed with water (2×5 mL) and saturated aqueous sodium chloride (2×5 mL). The organic layer was concentrated. The resultant crude material was purified by preparative HPLC to give the title compound, 7,8-bis(4-chlorophenyl)-2-(2-morpholinoethyl)-[1,2,4]triazolo[4,3-b]pyridazin-3(2H)-one (35 mg, 67%) as yellow solid. MS M+H=470; 1H NMR (CDCl3) δ 8.17 (1H, s), 7.28-7.34 (6H, m), 7.10 (2H, d, J=10.0 Hz), 4.44 (4H, t, J=5.0 Hz), 3.96-4.01 (4H), 3.50 (4H, t, J=5.0 Hz).
Reaction SMILES: [O:1]1[CH2:5][CH2:4][O:3][CH:2]1[CH2:6][CH2:7][C@H:8]1[CH2:13][CH2:12][C@H:11]([C@H:14]2[CH2:19][CH2:18][C@H:17]([C:20]([OH:22])=O)[CH2:16][CH2:15]2)[CH2:10][CH2:9]1.ClC(OCC)=O.[NH3:29]>C(Cl)(Cl)Cl>[O:1]1[CH2:5][CH2:4][O:3][CH:2]1[CH2:6][CH2:7][C@H:8]1[CH2:13][CH2:12][C@H:11]([C@H:14]2[CH2:19][CH2:18][C@H:17]([C:20]([NH2:29])=[O:22])[CH2:16][CH2:15]2)[CH2:10][CH2:9]1
Reactant: O=C(O)[C@H]1CC[C@H]([C@H]2CC[C@H](CCC3OCCO3)CC2)CC1
Reactant: N
Agent: CCOC(=O)Cl
Solvent: ClC(Cl)Cl
Product: NC(=O)[C@H]1CC[C@H]([C@H]2CC[C@H](CCC3OCCO3)CC2)CC1
Reaction time: 0.5 h

Procedure:
18 g of trans-4-[trans-4-(2-(1,3-dioxolan-2-yl)ethyl]-cyclohexyl)cyclohexanecarboxylic acid were dissolved in 600 ml of chloroform while gassing with argon and the solution was treated dropwise at 0° C. while stirring within 3 minutes with a solution of 7.2 ml of ethyl chloroformate in 40 ml of chloroform. The reaction solution was stirred for a further 30 minutes. Ammonia gas was then conducted into the solution during 10 minutes. The mixture was stirred at 0° C. for a further 30 minutes and then extracted twice with 300 ml of water each time. The aqueous phases were back-extracted with 100 ml of chloroform each time. The combined organic phases were dried over magnesium sulfate, filtered and evaporated. Recrystallization of the brown crystalline crude product obtained (19 g) from 800 ml of methylene chloride gave 13 g of trans-4-[trans-4-[2-(1,3-dioxolan-2-yl)ethyl]-cyclohexyl]cyclohexanecarboxamide as pale brown crystals.
Reaction SMILES: [NH2:1][C:2]1[O:6][N:5]=[C:4]([CH3:7])[C:3]=1[Br:8].[C:9]1([CH3:19])[CH:14]=[CH:13][C:12]([S:15](Cl)(=[O:17])=[O:16])=[CH:11][CH:10]=1>>[Br:8][C:3]1[C:4]([CH3:7])=[N:5][O:6][C:2]=1[NH:1][S:15]([C:12]1[CH:13]=[CH:14][C:9]([CH3:19])=[CH:10][CH:11]=1)(=[O:17])=[O:16]
Reactant: Cc1noc(N)c1Br
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Product: Cc1ccc(S(=O)(=O)Nc2onc(C)c2Br)cc1
Yield: 69 %

Procedure:
N-(4-Bromo-3-methyl-5-isoxazolyl)-4-toluenesulfonamide was prepared from 5-amino-4-bromo-3-methylisoxazole and 4-toluenesulfonyl chloride according to the procedures described in Example 25b. The crude product was purified by recrystallization from ethyl acetate/hexanes to give off-white crystals, m.p. 169-172° C., yield 69%.
Reaction SMILES: [Cl:1][C:2]1[CH:33]=[CH:32][C:5]([C:6]([N:8]2[CH2:12][CH2:11][C@@H:10]([NH:13][C:14]3[CH:19]=[CH:18][C:17](/[CH:20]=[CH:21]/[C:22]([NH:24][O:25]C4CCCCO4)=[O:23])=[CH:16][CH:15]=3)[CH2:9]2)=[O:7])=[CH:4][CH:3]=1.CO.Cl.CC#N>CO>[ClH:1].[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([N:8]2[CH2:12][CH2:11][C@@H:10]([NH:13][C:14]3[CH:19]=[CH:18][C:17](/[CH:20]=[CH:21]/[C:22]([NH:24][OH:25])=[O:23])=[CH:16][CH:15]=3)[CH2:9]2)=[O:7])=[CH:32][CH:33]=1
Reactant: O=C(/C=C/c1ccc(N[C@@H]2CCN(C(=O)c3ccc(Cl)cc3)C2)cc1)NOC1CCCCO1
Agent: Cl
Solvent: CO
Solvent: CC#N
Product: O=C(/C=C/c1ccc(N[C@@H]2CCN(C(=O)c3ccc(Cl)cc3)C2)cc1)NO
Temperature: 25 °C
Reaction time: 1 h
Yield: 187.7 %

Procedure:
To a solution of (2E)-3-(4-{[(3R)-1-(4-chlorobenzoyl)-3-pyrrolidinyl]amino}phenyl)-N-(tetrahydro-2H-pyran-2-yloxy) acrylamide (76 mg) in MeOH (1.3 mL) was added hydrogen chloride methanol reagent 10 (0.32 mL, Tokyo Kasei), and the mixture was stirred at ambient temperature for 1 hour. To the reaction mixture was added CH3CN and the solvent was removed in vacuo. Obtained colorless solid was triturated with CH3CN to give (2E)-3-(4-{[(3R)-1-(4-chlorobenzoyl)-3-pyrrolidinyl]amino}phenyl)-N-hydroxyacrylamide hydrochloride (64.1 mg) as colorless powder.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:13]=[CH:12][CH:11]=[CH:10][C:6]=1[C:7]([OH:9])=O)(=[O:4])=[O:3].[NH2:14][CH2:15][C@@H:16]([OH:33])[CH2:17][N:18]1[CH2:23][CH2:22][CH:21]([O:24][C:25]2[CH:30]=[CH:29][C:28]([Cl:31])=[C:27]([Cl:32])[CH:26]=2)[CH2:20][CH2:19]1.C(N(CC)C(C)C)(C)C.C(=O)(O)[O-].[Na+]>CN(C)C=O>[Cl:32][C:27]1[CH:26]=[C:25]([CH:30]=[CH:29][C:28]=1[Cl:31])[O:24][CH:21]1[CH2:20][CH2:19][N:18]([CH2:17][C@H:16]([OH:33])[CH2:15][NH:14][C:7](=[O:9])[C:6]2[CH:10]=[CH:11][CH:12]=[CH:13][C:5]=2[S:2]([CH3:1])(=[O:3])=[O:4])[CH2:23][CH2:22]1
Reactant: NC[C@@H](O)CN1CCC(Oc2ccc(Cl)c(Cl)c2)CC1
Reactant: CS(=O)(=O)c1ccccc1C(=O)O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CS(=O)(=O)c1ccccc1C(=O)NC[C@@H](O)CN1CCC(Oc2ccc(Cl)c(Cl)c2)CC1
Temperature: 0 °C
Yield: 35 %

Procedure:
A mixture of 2-(methylsulphonyl)benzoic acid (0.063 g), (2R)-1-amino-3-[4-(3,4-dichlorophenoxy)piperidin-1-yl]propan-2-ol (0.1 g) and N,N-diisopropylethylamine (0.1 ml) in dry dimethylformamide (3 ml) was cooled to 0° C. with stirring. 2-(1H-9-Azabenzotriazole-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (0.13 g) was added and the mixture was stirred at 0° C. for 1-2 h. Saturated sodium bicarbonate solution (10 ml) was added. The mixture was extracted with ethyl acetate. The organic layer was separated and washed with brine and dried over sodium sulphate. The mixture was filtered and the solvent was evaporated. The resulting oil was purified by normal phase chromatography using methanol/dichloromethane as eluent, and by reverse phase HPLC using acetonitrile and 0.1% aqueous ammonium acetate as eluent, to give the title compound as a white solid (0.055 g).
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[C:18]([C:20]1[CH:21]=[CH:22][C:23]([OH:30])=[C:24]([CH:29]=1)[C:25]([O:27][CH3:28])=[O:26])#[CH:19]>C(N(CC)CC)C.O1CCCC1.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I>[OH:30][C:23]1[CH:22]=[CH:21][C:20]([C:18]#[C:19][C:2]2[CH:7]=[CH:6][C:5]([S:8]([NH:11][C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=3)(=[O:10])=[O:9])=[CH:4][CH:3]=2)=[CH:29][C:24]=1[C:25]([O:27][CH3:28])=[O:26]
Reactant: O=S(=O)(Nc1ccccn1)c1ccc(I)cc1
Reactant: C#Cc1ccc(O)c(C(=O)OC)c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: COC(=O)c1cc(C#Cc2ccc(S(=O)(=O)Nc3ccccn3)cc2)ccc1O
Temperature: 60 °C

Procedure:
4-Iodo-N-(2-pyridinyl)benzenesulfonamide (35 g, 97 mmol) was dissolved in a mixture of triethylamine and tetrahydrofuran (750+750 ml). The mixture was deaerated with nitrogen and dichlorobis(triphenylphosphine)palladium (1.2 g, 1.7 mmol) and copper(I) iodide (0.6 g, 3.4 mmol) were added. Finally methyl 5-ethynyl-2-hydroxybenzoate (23 g, 130 mmol) was added. The mixture was heated to 60° C. for 4 h, evaporated to dryness. The residue was dissolved in chloroform (1000 ml) and washed with water (3×200 ml) and dried with MgSO4. The solvent was evaporated in vacuo. Yield 31 g (77%). The product can be purified by flash-chromatography on silica with chloroform as the eluent.
Reaction SMILES: [CH2:1]([N:3]([CH2:26][CH3:27])[C:4](=[O:25])[C:5]1[CH:10]=[CH:9][C:8]([N:11]([CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH:12]2[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]2)=[CH:7][CH:6]=1)[CH3:2].[CH3:28][C:29]([CH3:31])=O.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[OH-].[Na+]>ClCCl>[CH2:26]([N:3]([CH2:1][CH3:2])[C:4](=[O:25])[C:5]1[CH:6]=[CH:7][C:8]([N:11]([CH2:18][C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH:12]2[CH2:17][CH2:16][N:15]([CH:29]([CH3:31])[CH3:28])[CH2:14][CH2:13]2)=[CH:9][CH:10]=1)[CH3:27]
Reactant: CCN(CC)C(=O)c1ccc(N(Cc2ccccc2)C2CCNCC2)cc1
Reactant: CC(C)=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: CC(=O)O
Product: CCN(CC)C(=O)c1ccc(N(Cc2ccccc2)C2CCN(C(C)C)CC2)cc1
Reaction time: 40 h
Yield: 43.2 %

Procedure:
To a solution of N,N-diethyl-4-[benzyl(piperidin-4-yl)amino]benzamide (Compound 8) (0.27 g, 0.739 mmole), acetone (0.09 g, 1.48 mmol), and acetic acid (0.04 g, 0.739 mmol) in 10 mL of dry dichloromethane was added sodium triacetoxyborohydride (0.31 g, 1.48 mmol) under nitrogen. The mixture was stirred for 40 hours, and then aqueous 1 N NaOH (20 mL) solution was added. After 1 h of stirring, the layers were separated, and the aqueous layer was extracted twice with dichloromethane (15 mL). The organic extracts were combined, washed twice with 1 N NaOH (20 mL), dried (Na2SO4), and concentrated to give a brown-black glass. This material was purified on a flash silica gel column (5% methanol-chloroform to 10% methanol-chloroform) to provide 0.13 g (43%) of N,N-diethyl-4-[benzyl(1-isopropylpiperidin-4-yl)amino]benzamide as a colorless oil. MS (ES), m/z 408 (MH+). 300 MHz 1H NMR (CDCl3) δ1.06 (d, J=6.4 Hz, 6H), 1.17 (t, J=7.0 Hz, 6H), 1.68-1.92 (m, 4H), 2.29 (br t, 2H), 2.69-2.85 (br m, 1H), 2.97 (br d, J=10.3 Hz, 2H), 3.32-3.52 (m, 4H), 3.74-3.89 (br m, 1H), 4.53 (s, 2H), 6.65 (d, J=8.8 Hz, 2H), 7.18-7.42 (m, 7H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][C:18]=3[O:20][C@H:21]([CH3:28])[CH2:22][N:23]([CH3:27])[C:24](=[O:26])[CH3:25])[N:13]=[CH:12][N:11]=2)[CH:5]=[CH:6][C:7]=1[OH:8].CS(O[CH2:34][C:35]1[CH:40]=[N:39][CH:38]=[CH:37][N:36]=1)(=O)=O>>[Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][C:18]=3[O:20][C@H:21]([CH3:28])[CH2:22][N:23]([CH3:27])[C:24](=[O:26])[CH3:25])[N:13]=[CH:12][N:11]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH2:34][C:35]1[CH:40]=[N:39][CH:38]=[CH:37][N:36]=1
Reactant: CC(=O)N(C)C[C@@H](C)Oc1cccc2ncnc(Nc3ccc(O)c(Cl)c3)c12
Reactant: CS(=O)(=O)OCc1cnccn1
Product: CC(=O)N(C)C[C@@H](C)Oc1cccc2ncnc(Nc3ccc(OCc4cnccn4)c(Cl)c3)c12
Yield: 61 %

Procedure:
The procedure described in Example 4.1 was repeated using N-[(2R)-2-({4-[(3-chloro-4-hydroxyphenyl)amino]quinazolin-5-yl}oxy)propyl]-N-methylacetamide and pyrazin-2-ylmethyl methanesulfonate to give the title compound in 61% yield; NMR spectrum (DMSO-d6) 1.3 (d, 3H), 1.95 (s, 3H), 3.03 (s, 3H), 3.37 (1H obscured by H2O), 4.21 (dd, 1H), 5.08 (m, 1H), 5.37 (s, 2H), 7.29 (m, 3H), 7.70 (m, 2H), 8.11 (d, 1H), 8.46 (s, 1H), 8.66 (m, 2H), 8.85 (s, 1H), 9.94 (s, 1H); Mass Spectrum MH+ 493.
Reaction SMILES: C[Mg]Br.[CH2:4](OCC)C.[CH3:9][O:10][C:11]1[CH:16]=[CH:15][C:14]([C:17](=O)[CH3:18])=[CH:13][CH:12]=1.Cl>C(OCC)C>[CH3:9][O:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]([CH3:18])=[CH2:4])=[CH:13][CH:12]=1
Reactant: COc1ccc(C(C)=O)cc1
Reactant: CCOCC
Agent: C[Mg]Br
Agent: Cl
Product: C=C(C)c1ccc(OC)cc1
Reaction time: 0.5 h

Procedure:
To a 1000 mL three-necked flask equipped with a mechanical stirrer, methyl magnesium bromide/diethyl ether solution (200 mL, 3.0 mol) is added. A solution of 85.3 g of 4′-methoxy-acetophenone dissolved in 80 mL of anhydrous diethyl ether is charged to the Grignard reagent over 90 minutes at ambient temperature. Diethyl ether (200 mL) and 250 mL of 3N hydrochloric acid are added slowly to the reaction mixture. The solution is stirred for another 30 minutes. The aqueous layer is separated and washed twice with 100 mL of diethyl ether. The ethereal layers are combined and vacuum distilled. The desired product is obtained in a yield of 91.7 g as a yellow oil whose structure is verified by 1Hnmr and mass spectroscopy.
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[CH:11][C:7]([C:8](Cl)=[O:9])=[CH:6][CH:5]=1)([O-:3])=[O:2].[CH3:13][O:14][C:15]1[CH:16]=[C:17]([C:21]2([OH:27])[CH2:26][CH2:25][CH2:24][NH:23][CH2:22]2)[CH:18]=[CH:19][CH:20]=1>>[OH:27][C:21]1([C:17]2[CH:18]=[CH:19][CH:20]=[C:15]([O:14][CH3:13])[CH:16]=2)[CH2:26][CH2:25][CH2:24][N:23]([C:8]([C:7]2[CH:11]=[CH:12][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=2)=[O:9])[CH2:22]1
Reactant: COc1cccc(C2(O)CCCNC2)c1
Reactant: O=C(Cl)c1ccc([N+](=O)[O-])cc1
Product: COc1cccc(C2(O)CCCN(C(=O)c3ccc([N+](=O)[O-])cc3)C2)c1

Procedure:
The compound of Example 17 was prepared according to the general preparation protocol A from 4-nitrobenzoyl chloride and 3-(3-methoxy-phenyl)-piperidine-3-ol.
Reaction SMILES: [CH2:1]([O:11][C:12]1[CH:20]=[CH:19][C:15]([C:16]([OH:18])=O)=[CH:14][CH:13]=1)/[CH:2]=[C:3](/[CH2:5][CH2:6][CH:7]=[C:8]([CH3:10])[CH3:9])\[CH3:4].C1(P(Cl)(C2C=CC=CC=2)=O)C=CC=CC=1.[NH2:36][CH2:37][C:38]([NH:40][C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][N:42]=1)=[O:39]>C(Cl)(Cl)Cl.C(N(CC)CC)C>[CH2:1]([O:11][C:12]1[CH:13]=[CH:14][C:15]([C:16]([NH:36][CH2:37][C:38]([NH:40][C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][N:42]=2)=[O:39])=[O:18])=[CH:19][CH:20]=1)/[CH:2]=[C:3](/[CH2:5][CH2:6][CH:7]=[C:8]([CH3:9])[CH3:10])\[CH3:4]
Reactant: CC(C)=CCC/C(C)=C/COc1ccc(C(=O)O)cc1
Reactant: NCC(=O)Nc1ccccn1
Agent: O=P(Cl)(c1ccccc1)c1ccccc1
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: CC(C)=CCC/C(C)=C/COc1ccc(C(=O)NCC(=O)Nc2ccccn2)cc1
Reaction time: 0.5 h
Yield: 68.4 %

Procedure:
4-geranyloxybenzoic acid(1.81 g) was dissolved in chloroform(40 ml) and triethylamine(1.84 ml), and then diphenylphosphinic chloride(1.26 ml) was added thereto while being cooled with ice. After being stirred for 30 minutes, the mixture, with 2-(aminoacetylamino)pyridine(1.00 g) added thereto, was stirred for 2 hours at room temperature. The reaction mixture was washed with saturated sodium hydrogencarbonate aqueous solution and saturated brine successively, dried over sodium sulfate anhydride, and then concentrated under a vacuum. The residue was purified by silica gel column chromatography (chloroform:methanol=20:1). The resulting solid was recrystallized from n-hexane/ethyl acetate, thereby yielding 1.84 g of the aimed compound.
Reaction SMILES: [N:1]([CH2:4][C@@H:5]1[C@H:9]2[O:10][C:11]([CH3:14])([CH3:13])[O:12][C@H:8]2[C@H:7]([N:15]2[C:19]3[N:20]=[CH:21][N:22]=[C:23](Cl)[C:18]=3[CH:17]=[CH:16]2)[CH2:6]1)=[N+:2]=[N-:3].[CH3:25][O:26][C:27]1[CH:34]=[C:33]([O:35][CH3:36])[CH:32]=[CH:31][C:28]=1[CH2:29][NH2:30].C(N(CC)C(C)C)(C)C>C(O)CCC>[N:1]([CH2:4][C@@H:5]1[C@H:9]2[O:10][C:11]([CH3:14])([CH3:13])[O:12][C@H:8]2[C@H:7]([N:15]2[C:19]3[N:20]=[CH:21][N:22]=[C:23]([NH:30][CH2:29][C:28]4[CH:31]=[CH:32][C:33]([O:35][CH3:36])=[CH:34][C:27]=4[O:26][CH3:25])[C:18]=3[CH:17]=[CH:16]2)[CH2:6]1)=[N+:2]=[N-:3]
Reactant: COc1ccc(CN)c(OC)c1
Reactant: CC1(C)O[C@@H]2[C@@H](CN=[N+]=[N-])C[C@@H](n3ccc4c(Cl)ncnc43)[C@@H]2O1
Solvent: CCCCO
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc(CNc2ncnc3c2ccn3[C@@H]2C[C@H](CN=[N+]=[N-])[C@H]3OC(C)(C)O[C@H]32)c(OC)c1
Temperature: 80 °C

Procedure:
A solution of 7-((3aS,4R,6R,6aR)-6-(azidomethyl)-2,2-dimethyltetrahydro-3aH-cyclopenta[d][1,3]dioxol-4-yl)-4-chloro-7H-pyrrolo[2,3-d]pyrimidine and 2,4-dimethoxybenzylamine (1.2 mL, 7.8 mmol) in 1-butanol (18.6 mL) was treated with N,N-diisopropylethylamine (1.4 mL, 7.8 mmol) and heated at 80° C. for 22 h; HPLC/LC MS indicated ˜90% conversion to the desired product. The volatiles were removed and the yellow-brown paste was taken up in CH2Cl2 (90 mL) and washed with water (2×30 mL) and brine (1×45 mL). The separated organic layer was dried (Na2SO4) and concentrated in vacuo to afford an orange oil. Purification by column chromatography (2×22 cm silica; 0-50% EtOAc/Hex) afforded the title compound (2.23 g, 72%) as a pale yellow glass/foam: MS (ESI+) for C24H29N7O4 m/z 480.5 (M+H)+; MS (ESI−) for C24H29N7O4 m/z 524.3 (M+HCO2)−; HPLC purity >95% (ret. time, 3.551 min).