Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[Mg]Cl.O1CCC[CH2:5]1.[C:9]([N:12]([CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1[CH:33]=[O:34])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[O:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)(=[O:11])[CH3:10].[Cl-].[NH4+]>O1CCCC1>[C:9]([N:12]([CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1[CH:33]([OH:34])[CH3:5])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[O:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)(=[O:11])[CH3:10]
Reactant: C1CCOC1
Reactant: CC(=O)N(Cc1ccccc1C=O)c1ccccc1Oc1ccccc1
Agent: C[Mg]Cl
Agent: [Cl-]
Agent: [NH4+]
Product: CC(=O)N(Cc1ccccc1C(C)O)c1ccccc1Oc1ccccc1
Temperature: 25 °C

Procedure:
To an ice-cooled solution of 5.25 ml of 1M methylmagnesium chloride/tetrahydrofuran diluted with 15 ml of tetrahydrofuran was added dropwise a solution of 1.20 g of N-acetyl-N-(2-formylbenzyl)-2-phenoxyaniline in 7 ml of tetrahydrofuran, followed by stirring at room temperature for an hour. The reaction solution was again cooled on ice, and after addition of a saturated aqueous ammonium chloride solution, extracted with ethyl acetate, and the extract was washed with a saturated aqueous sodium chloride solution and dried over anhydrous sodium sulfate. After removal of the drying agent by filtration, the solvent was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent; ethyl acetate−hexane=1:1) to give 1.19 g of N-acetyl-N-[2-(1-hydroxyethyl)benzyl]-2-phenoxyaniline as an oil.
Reaction SMILES: C(NC[S:6][CH2:7][CH:8]([CH3:19])[C:9]([N:11]1[CH2:18][CH2:17][CH2:16][C@H:12]1[C:13]([OH:15])=[O:14])=[O:10])(=O)C.S>C(O)(=O)C.O>[SH:6][CH2:7][CH:8]([CH3:19])[C:9]([N:11]1[CH2:18][CH2:17][CH2:16][C@H:12]1[C:13]([OH:15])=[O:14])=[O:10]
Reactant: CC(=O)NCSCC(C)C(=O)N1CCC[C@H]1C(=O)O
Agent: S
Solvent: CC(=O)O
Solvent: O
Product: CC(CS)C(=O)N1CCC[C@H]1C(=O)O

Procedure:
1-[3-(acetamidomethylthio)-2-methylpropanoyl]-L-proline (1.4 g.) and mercuric acetate (1.93 g.) are dissolved in a mixture of acetic acid (25 ml.) and water (25 ml.). After 1 hour stirring on the steam bath, hydrogen sulfide is bubbled through until no more precipitation of mercuric sulfide is observed. The mixture is filtered, the precipitate is washed with ethanol, and the filtrate is concentrated to dryness in vacuo to yield 1-(3-mercapto-2-methylpropanoyl)-L-proline. Rf : 0.35 (Silica gel, Benzene/Acetic acid 3:1); Rf : 0.5 (Silica gel, Methyl-ethylketone/Acetic acid/pyridine/water 14:1:2:1) identical to the compound of Example 34.
Reaction SMILES: I[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13].[CH3:14][NH:15][CH2:16][CH2:17][OH:18]>C(O)(C)C.CCOCC>[CH3:14][N:15]([CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13])[CH2:16][CH2:17][OH:18]
Reactant: CCCCCCCCCCCCI
Reactant: CNCCO
Solvent: CC(C)O
Solvent: CCOCC
Product: CCCCCCCCCCCCN(C)CCO
Yield: 97.5 %

Procedure:
A solution of iodododecane (18.1 g, 61.09 mmol) and 2-(methylamino)ethanol (23.0 g, 0.3 mol) in isopropanol (75 ml) was heated under reflux for 3 h. The cooled mixture was diluted with ether (500 ml), washed with water, brine and dried (magnesium sulfate). Evaporation of the solvent under reduced pressure and distillation of the residue under vacuum gave 14.5 g (97%) of N-methyl-N-dodecylethanolamine as a clear oil: b.p. 100-111° C./0.3 torr (bulb to bulb distillation, air bath temperature).
Reaction SMILES: [CH2:1]([N:4]([CH2:19][CH2:20][CH3:21])[CH:5]1[CH2:14][C:13]2[C:8](=[CH:9][CH:10]=[CH:11][C:12]=2C(OC)=O)[O:7][CH2:6]1)[CH2:2][CH3:3].[OH-].[Na+].C1(P([N:38]=[N+]=[N-])(C2C=CC=CC=2)=O)C=CC=CC=1>CO.O>[CH2:1]([N:4]([CH2:19][CH2:20][CH3:21])[CH:5]1[CH2:14][C:13]2[C:8](=[CH:9][CH:10]=[CH:11][C:12]=2[NH2:38])[O:7][CH2:6]1)[CH2:2][CH3:3]
Reactant: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Reactant: CCCN(CCC)C1COc2cccc(C(=O)OC)c2C1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CCCN(CCC)C1COc2cccc(N)c2C1
Reaction time: 4 h

Procedure:
3-Dipropylamino-5-methyloxycarbonylchroman (Example 2; 1.0 g, 3.4 mmol) was dissolved in methanol (20 ml). Sodium hydroxide (0.16 g, 4.1 mmol) in water (1.0 ml) was added and the solution was refluxed with nitrogen overnight. The solution was evaporated to dryness, toluene (20 ml) was added and again the solution was evaporated to dryness. The residue was dissolved in toluene 20 ml, diphenylphosphoryl azid (1.87 g, 6.8 mmol) was added and the solution was refluxed for 2 hours. Methanol (2.0 ml) was added and reflux was continued for 4 hours. The solution was cooled, washed with water and extracted with dilute HCl (aq.). The acidic water phase was neutralized NaOH (aq.) and extracted with toluene. The toluene-phase was dried with sodium sulphate and evaporated to dryness. The residue was dissolved in ethanol containing 10% NaOH (20 ml) and the solution was refluxed overnight. The solution was cooled and diluted with toluene. Washing with water, drying of the organic phase and evaporation to dryness afforded the title compound as an oil, which was converted to a dihydrochloride salt. Mp 173°-174° C.
Reaction SMILES: [CH3:1][O:2][C:3](=O)[CH:4]([CH2:15][OH:16])[NH:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[N+:12]([O-])=O.C(N1C=CN=C1)(N1C=CN=C1)=[O:19].C1COCC1>C(N(CC)CC)C>[C:1]1(=[O:19])[N:5]2[C:6]3[C:7]([NH:12][C:15](=[O:16])[CH:4]2[CH2:3][O:2]1)=[CH:8][CH:9]=[CH:10][CH:11]=3
Reactant: COC(=O)C(CO)Nc1ccccc1[N+](=O)[O-]
Reactant: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: O=C1Nc2ccccc2N2C(=O)OCC12
Reaction time: 6 h

Procedure:
To 3-hydroxymethyl-1,2,3,4-tetrahydroquinoxalin-2-one (IV, EXAMPLE 286, 21.35 g), 1.00 g of carbonyldiimidazole, and 30 ml of THF are added 1.64. ml of triethylamine. The reaction is stirred at 20°-25° for 6 hr, then at 80° for 18 hr, at which time an additional 0.11 g carbonyldiimidazole are added. Heating is continued for another 6 hr, at which time the reaction mixture is cooled and the solvent is removed under reduced pressure. The residue is partitioned between methylene chloride and water, the organic layers are dried over sodium sulfate and concentrated. The residue is crystallized from methanol/dichloromethane to give the title compound, mp 230°-231°; MS (m/z) at 204; NMR (CDCl3) 4.60, 4.78, 6.93, 7.19, 7.82 and 8.48 δ.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2N(C3C=CC=CN=3)N=[C:11]([C:20]([OH:22])=[O:21])[CH:10]=2)[CH:5]=[C:6]([F:8])[CH:7]=1.Cl.[Cl:24][C:25]1[CH:26]=[C:27]([NH:31][NH2:32])[CH:28]=[N:29][CH:30]=1>>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[N:31]([C:27]3[CH:28]=[N:29][CH:30]=[C:25]([Cl:24])[CH:26]=3)[N:32]=[C:11]([C:20]([OH:22])=[O:21])[CH:10]=2)[CH:5]=[C:6]([F:8])[CH:7]=1
Reactant: O=C(O)c1cc(-c2cc(F)cc(Cl)c2)n(-c2ccccn2)n1
Reactant: NNc1cncc(Cl)c1
Agent: Cl
Product: O=C(O)c1cc(-c2cc(F)cc(Cl)c2)n(-c2cncc(Cl)c2)n1

Procedure:
785 mg (2.25 mmol) of the compound of Example 1A is reacted analogously to the synthesis of the compound of Example 20A with 608 mg (3.38 mmol) of 5-chloropyridin-3-yl-hydrazine hydrochloride. After hydrolysis, 270 mg (34% of theory) of the title compound is obtained.
Reaction SMILES: [CH3:1][C:2]1([S:5]([NH2:8])(=[O:7])=[O:6])[CH2:4][CH2:3]1.[F:9][C:10]1[CH:11]=[C:12]([CH:20]2[CH2:24][CH2:23][CH2:22][N:21]2[C:25]2[CH:26]=[CH:27][C:28]3[N:29]([C:31]([C:34](O)=[O:35])=[CH:32][N:33]=3)[CH:30]=2)[C:13]2[O:18][CH2:17][CH2:16][O:15][C:14]=2[CH:19]=1>>[F:9][C:10]1[CH:11]=[C:12]([CH:20]2[CH2:24][CH2:23][CH2:22][N:21]2[C:25]2[CH:26]=[CH:27][C:28]3[N:29]([C:31]([C:34]([NH:8][S:5]([C:2]4([CH3:1])[CH2:4][CH2:3]4)(=[O:7])=[O:6])=[O:35])=[CH:32][N:33]=3)[CH:30]=2)[C:13]2[O:18][CH2:17][CH2:16][O:15][C:14]=2[CH:19]=1
Reactant: O=C(O)c1cnc2ccc(N3CCCC3c3cc(F)cc4c3OCCO4)cn12
Reactant: CC1(S(N)(=O)=O)CC1
Product: CC1(S(=O)(=O)NC(=O)c2cnc3ccc(N4CCCC4c4cc(F)cc5c4OCCO5)cn23)CC1

Procedure:
The title compound was prepared by the method similar to that of Example 31 employing 1-Methylcyclopropane-1-sulfonamide (int-50) and 6-(2-(7-fluoro-2,3-dihydrobenzo[b][1,4]dioxin-5-yl)pyrrolidin-1-yl)imidazo[1,2-a]pyridine-3-carboxylic acid (Int 38) to afford an enantiomeric mixture which was separated by chiral chromatography using CHIRALPAK AD-H column and n-HEXANE:ETHANOL, 60:40 Isocratic solution as eluent to afford 6-(2-(7-fluoro-2,3-dihydrobenzo[b][1,4]dioxin-5-yl)pyrrolidin-1-yl)-N-((l-methylcyclopropyl)sulfonyl)imidazo[1,2-a]pyridine-3-carboxamide (Isomer-I)
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([C:9]2[N:10]=[CH:11][C:12]([NH:15][C:16]([C:18]3[CH:23]=[C:22]([N:24]4[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]4)[CH:21]=[CH:20][C:19]=3[NH:30][C:31]([C:33]3[CH:34]=[C:35]([CH:47]=[CH:48][CH:49]=3)[CH2:36][S:37][CH2:38][CH2:39][C:40]([O:42]C(C)(C)C)=[O:41])=[O:32])=[O:17])=[N:13][CH:14]=2)[CH:5]=[CH:6][C:7]=1[CH3:8].FC(F)(F)C(O)=O>ClCCl>[CH3:1][C:2]1[CH:3]=[C:4]([C:9]2[N:10]=[CH:11][C:12]([NH:15][C:16]([C:18]3[CH:23]=[C:22]([N:24]4[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]4)[CH:21]=[CH:20][C:19]=3[NH:30][C:31]([C:33]3[CH:34]=[C:35]([CH:47]=[CH:48][CH:49]=3)[CH2:36][S:37][CH2:38][CH2:39][C:40]([OH:42])=[O:41])=[O:32])=[O:17])=[N:13][CH:14]=2)[CH:5]=[CH:6][C:7]=1[CH3:8]
Reactant: Cc1ccc(-c2cnc(NC(=O)c3cc(N4CCCCC4)ccc3NC(=O)c3cccc(CSCCC(=O)OC(C)(C)C)c3)cn2)cc1C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1ccc(-c2cnc(NC(=O)c3cc(N4CCCCC4)ccc3NC(=O)c3cccc(CSCCC(=O)O)c3)cn2)cc1C
Temperature: 25 °C
Reaction time: 2 h
Yield: 12.7 %

Procedure:
Into a 100-mL round bottom flask, was placed a solution of tert-butyl 3-(3-((2-((5-(3,4-dimethylphenyl)pyrazin-2-yl)carbamoyl)-4-(piperidin-1-yl)phenyl)carbamoyl)benzylthio)-propanoate (480 mg, 0.71 mmol, 1.00 equiv) in dichloromethane (25 mL), and trifluoroacetic acid (12.5 mL). The resulting solution was stirred for 2 h at room temperature. The resulting mixture was concentrated under vacuum. The crude product (300 mg) was purified by reverse phase HPLC eluting with a water/CH3CN gradient containing 0.05% TFA to yield 56.1 mg (13%) of 3-(3-((2-((5-(3,4-dimethylphenyl)pyrazin-2-yl)carbamoyl)-4-(piperidin-1-yl)phenyl)carbamoyl)benzylthio)-propanoic acid as a yellow solid. 1H-NMR (300 MHz, DMSO, ppm): δ 11.34 (s, 1H), 11.06 (s, 1H), 9.39 (d, J=1.2 Hz, 1H), 9.03 (d, J=1.2 Hz, 1H), 8.13 (d, J=9 Hz, 1H), 7.92˜7.84 (m, 3H), 7.78 (d, J=7.2 Hz, 1H), 7.55˜7.46 (m, 3H), 7.29 (d, J=8.1 Hz, 1H), 3.83 (s, 1H), 3.28 (m, 4H), 2.73˜2.72 (m, 2H), 2.32 (s, 3H), 2.28˜2.27 (m, 4H), 1.61˜4.58 (m, 6H). MS (ES, m/z): 624 [M+H]+.
Reaction SMILES: C(O[C:5](=[O:7])C)(=O)C.[CH3:8][NH:9][CH2:10][C:11]1([N:17]([CH3:19])[CH3:18])[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1>C(O)=O>[CH:5]([N:9]([CH3:8])[CH2:10][C:11]1([N:17]([CH3:19])[CH3:18])[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1)=[O:7]
Reactant: CC(=O)OC(C)=O
Reactant: CNCC1(N(C)C)CCCCC1
Solvent: O=CO
Product: CN(C=O)CC1(N(C)C)CCCCC1
Reaction time: 1 h
Yield: 78.9 %

Procedure:
Formic acid (6.9 g. 0.15 mole) and acetic anhydride (15.3 g, 0.15 mole) were mixed without cooling and kept at room temperature for 1 hr. 1-methylaminomethylcyclohexyldimethylamine (5.9 g, 0.034 mole) was dissolved in formic acid (12 ml) and the formylating mixture (16 ml) added slowly. This produced vigorous effervesence and a temperature rise to 75°. The mixture was then left at room temperature for 2 hr. and then heated on a water bath at 55° for 0.75 hr. The solvents were removed under reduced pressure to give an amber oil (5.32 g, 77.7%) which crystallised as colourless prisms of 1-(N-formyl-1-methylaminomethyl) cyclohexyldimethylamine from light petroleum (b.p. 60°-80° ), m.p. 59°-60°.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([CH2:10][CH2:11]S)=[CH:2]1.C1C=CC2NC=C(CCO)C=2C=1.[C:25]([OH:32])(=[O:31])[CH2:26][CH2:27][C:28]([CH3:30])=[O:29].O=P12OP3(OP(OP(O3)(O1)=O)(=O)O2)=O>C1C=CC=CC=1>[CH3:30][C:28]1([CH2:27][CH2:26][C:25]([OH:32])=[O:31])[C:2]2[NH:1][C:9]3[C:4]([C:3]=2[CH2:10][CH2:11][O:29]1)=[CH:5][CH:6]=[CH:7][CH:8]=3
Reactant: CC(=O)CCC(=O)O
Reactant: SCCc1c[nH]c2ccccc12
Agent: O=P12OP3(=O)OP(=O)(O1)OP(=O)(O2)O3
Agent: OCCc1c[nH]c2ccccc12
Solvent: c1ccccc1
Product: CC1(CCC(=O)O)OCCc2c1[nH]c1ccccc21
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
A mixture of the starting material of formula II, tryptophol (500 mg.), levulinic acid (580 mg.), 75 ml. of benzene, 1.7 g. of phosphorus pentoxide and about 0.5 g. of diatomaceous earth (Celite) is stirred magnetically at room temperature for 15 minutes and then at 70° C. for 11/2 hr. The reaction mixture is filtered. The filtrate is washed three times with 5N NaOH; the combined aqueous phase is washed twice with ether and then rendered acidic with cold 50% HCl. The aqueous phase is extracted with chloroform. The chloroform extract is dried (Na2SO4) and evaporated to dryness. The residue is crystallized from ethyl acetate-petroleum ether to afford the title compound, m.p. 104° - 110° C., nmr (CDCl3) δ1.47 (3H), 2.18 (4H), 2.74 (2H), 3.96 (2H), 7.18 (1H), 9.60 (1H).
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]([CH2:8][C:9]([NH2:11])=[O:10])=[C:4]([NH:12][CH2:13][C:14]2[CH:19]=[C:18]([F:20])[CH:17]=[C:16]([F:21])[CH:15]=2)[CH:3]=1.O1CCN(C2C=CC(N)=C(N)C=2)CC1.[NH2:36][C:37]1[CH:42]=[C:41]([C:43]#[N:44])[CH:40]=[CH:39][C:38]=1[NH:45]C1N=CC(CC(N)=O)=C(NCC2C=C(F)C=C(F)C=2)C=1>>[NH2:45][C:38]1[CH:39]=[CH:40][C:41]([C:43]#[N:44])=[CH:42][C:37]=1[NH:36][C:2]1[N:7]=[CH:6][C:5]([CH2:8][C:9]([NH2:11])=[O:10])=[C:4]([NH:12][CH2:13][C:14]2[CH:19]=[C:18]([F:20])[CH:17]=[C:16]([F:21])[CH:15]=2)[CH:3]=1
Reactant: N#Cc1ccc(Nc2cc(NCc3cc(F)cc(F)c3)c(CC(N)=O)cn2)c(N)c1
Reactant: NC(=O)Cc1cnc(Cl)cc1NCc1cc(F)cc(F)c1
Agent: Nc1ccc(N2CCOCC2)cc1N
Product: N#Cc1ccc(N)c(Nc2cc(NCc3cc(F)cc(F)c3)c(CC(N)=O)cn2)c1

Procedure:
From 6-chloro-4-[(3,5-difluorobenzyl)amino]pyridine-3-carboxyamide (the compound of Example 20) and 4-morpholino-1,2-phenylenediamine in a manner similar to step 1 of Example 365, a mixture of 6-[(2-amino-4-cyanophenyl)amino]-4-[(3,5-difluorobenzyl)amino]pyridine-3-carboxyamide and 6-[(2-amino-5-cyanophenyl)amino]-4-[(3,5-difluorobenzyl)amino]pyridine-3-carboxyamide (1H-NMR integral ratio 1:1) was obtained as a red oil (yield 17%).
Reaction SMILES: [Cl-].[CH3:2][O:3][C:4](=[O:8])[C:5]([OH:7])=O.[NH2:9][C:10]1[C:15](=[O:16])[C:14]2[CH:17]=[C:18]([CH2:21][CH2:22][CH2:23][CH3:24])[CH:19]=[CH:20][C:13]=2[S:12][CH:11]=1.C(N(CC)CC)C>C(Cl)(Cl)Cl>[CH3:2][O:3][C:4](=[O:8])[C:5]([NH:9][C:10]1[C:15](=[O:16])[C:14]2[CH:17]=[C:18]([CH2:21][CH2:22][CH2:23][CH3:24])[CH:19]=[CH:20][C:13]=2[S:12][CH:11]=1)=[O:7]
Reactant: COC(=O)C(=O)O
Reactant: CCCCc1ccc2scc(N)c(=O)c2c1
Agent: [Cl-]
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: CCCCc1ccc2scc(NC(=O)C(=O)OC)c(=O)c2c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
2.94 g (0.024 mol) of oxalic acid monomethyl ester chloride are added to a solution of 5.05 g (0.0216 mol) of 3-amino-6-(n-butyl)-4H-1-benzothiopyran-4-one and 2.4 g (0.024 mol) of triethylamine in 325 ml of chloroform, the temperature of the reaction mixture rising to 30°. The mixture is then stirred for one hour at room temperature. The mixture is then concentrated to dryness by evaporation and the crystalline residue is stirred with ethanol, filtered with suction and washed first with ethanol and then with ether. After drying, N-[6-(n-butyl)-4H-1-benzothiopyran-4-on-3-yl]-oxalic acid amide methyl ester having a melting point of 192°-193.5° is obtained.
Reaction SMILES: [CH2:1]([O:4][C:5]1[CH:13]=[CH:12][CH:11]=[CH:10][C:6]=1[C:7]([NH2:9])=[NH:8])[CH:2]=[CH2:3].[O-]CC.[Na+].C([O:20][CH:21]=[C:22]([C:28](OCC)=O)[C:23]([O:25][CH2:26][CH3:27])=[O:24])C.C(O)(=O)C>C(O)C>[O:20]=[C:21]1[NH:9][C:7]([C:6]2[CH:10]=[CH:11][CH:12]=[CH:13][C:5]=2[O:4][CH2:1][CH:2]=[CH2:3])=[N:8][CH:28]=[C:22]1[C:23]([O:25][CH2:26][CH3:27])=[O:24]
Reactant: CCOC=C(C(=O)OCC)C(=O)OCC
Reactant: C=CCOc1ccccc1C(=N)N
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Solvent: CC(=O)O
Product: C=CCOc1ccccc1-c1ncc(C(=O)OCC)c(=O)[nH]1
Temperature: 0 °C
Reaction time: 18 h
Yield: 89.2 %

Procedure:
2-Allyloxybenzamidine hydrochloride1 (19.07 g., 0.0896 mole) was added to a cooled (ice-water), stirred solution of sodium ethoxide (12.25 g., 0.18 mole) in ethanol (100 ml.). To this cooled, stirred mixture was added a solution of diethyl ethoxymethylenemalonate (19.4 g., 0.0896 mole) in ethanol (15 ml.). The mixture was heated under reflux for 2.5 hours and then allowed to stand at room temperature for 18 hours. The mixture was poured into ice-water containing acetic acid. The solid was collected and recrystallized from cyclohexane to give the title compound (24.0 g., 89%), m.p. 118°-120°. Recrystallization from cyclohexane gave product with m.p. 118.5°-120.5°.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([CH3:25])=[C:5]([C:16]([O:23][CH3:24])=[C:17]([O:21][CH3:22])[C:18]=1[O:19][CH3:20])[CH2:6][C:7]1[CH:8]=[CH:9][C:10]([OH:15])=[C:11]([CH:14]=1)[CH:12]=[O:13].C(=O)([O-])[O-].[K+].[K+].[CH:32](Br)([CH3:34])[CH3:33]>CN(C=O)C>[CH3:1][O:2][C:3]1[C:4]([CH3:25])=[C:5]([C:16]([O:23][CH3:24])=[C:17]([O:21][CH3:22])[C:18]=1[O:19][CH3:20])[CH2:6][C:7]1[CH:8]=[CH:9][C:10]([O:15][CH:32]([CH3:34])[CH3:33])=[C:11]([CH:14]=1)[CH:12]=[O:13]
Reactant: CC(C)Br
Reactant: COc1c(C)c(Cc2ccc(O)c(C=O)c2)c(OC)c(OC)c1OC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1c(C)c(Cc2ccc(OC(C)C)c(C=O)c2)c(OC)c(OC)c1OC
Yield: 94.5 %

Procedure:
5-(3,4,5,6-Tetramethoxy-2-methylbenzyl)-2-hydroxybenzaldehyde (0.500 g, 1.45 mmol) was dissolved in DMF (15 ml) and after adding thereto in sequence anhydrous potassium carbonate (0.359 g, 2.60 mmol) and isopropyl bromide (0.320 g, 2.60 mmol), the solution was refluxed under heating for 3 hours. The reaction mixture was filtered, the filtrate was concentrated and the obtained residue was purified by silica gel column chromatography (hexand:ethyl acetate=4:1) to obtain the titled compound (0.530 g, 1.37 mmol, 94%).
Reaction SMILES: [C:1]1([NH2:8])[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[NH2:7].[OH-].[K+].[C:11](O)(=O)[CH3:12]>>[CH3:11][C:12]1[NH:7][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][C:1]=2[N:8]=1
Reactant: CC(=O)O
Reactant: Nc1ccccc1N
Agent: [K+]
Agent: [OH-]
Product: Cc1nc2ccccc2[nH]1
Yield: 77 %

Procedure:
Phenylene diamine (32 grams) and glacial acetic acid (60 ml) were refluxed for 2 hours. Ice and KOH were added to bring the pH to 8.0, and the resulting light violet solid was filtered and collected. Recrystallization from benzene yielded 30 grams of 2-methyl benzimidazole as a light yellow solid having a melting point of 170° C. and total yield of 77%.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([CH:12]3[CH2:17][CH2:16][CH2:15][N:14]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:13]3)[N:9]=[C:10](I)[C:3]=12.[CH3:25][C:26]1[CH:27]=[C:28]([CH3:51])[C:29]2[O:33][C:32]([NH:34][C:35]3[CH:40]=[CH:39][C:38](B4OC(C)(C)C(C)(C)O4)=[CH:37][CH:36]=3)=[N:31][C:30]=2[CH:50]=1.C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.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>[NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([CH:12]3[CH2:17][CH2:16][CH2:15][N:14]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:13]3)[N:9]=[C:10]([C:38]3[CH:37]=[CH:36][C:35]([NH:34][C:32]4[O:33][C:29]5[C:28]([CH3:51])=[CH:27][C:26]([CH3:25])=[CH:50][C:30]=5[N:31]=4)=[CH:40][CH:39]=3)[C:3]=12
Reactant: Cc1cc(C)c2oc(Nc3ccc(B4OC(C)(C)C(C)(C)O4)cc3)nc2c1
Reactant: CC(C)(C)OC(=O)N1CCCC(n2nc(I)c3c(N)ncnc32)C1
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: O
Solvent: COCCOC
Product: Cc1cc(C)c2oc(Nc3ccc(-c4nn(C5CCCN(C(=O)OC(C)(C)C)C5)c5ncnc(N)c45)cc3)nc2c1
Temperature: 80 °C
Reaction time: 5 h
Yield: 37.8 %

Procedure:
The mixture of tert-butyl 3-(4-amino-3-iodo-1H-pyrazolo[3,4-d]pyrimidin-1-yl)-1-piperidinecarboxylate (0.6 g, 0.00135 mol), N-(5,7-dimethyl-1,3-benzoxazol-2-yl)-N-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]amine (0.59 g, 0.00162 mol), tetrakis(triphenylphosphine)palladium (0.078 g, 0.000068 mol) and sodium carbonate (0.36 g, 0.00338 mol) in ethylene glycol dimethyl ether (50 mL) and water (10 mL) was heated at 80° C. for 16 hours under an atmosphere of nitrogen. After cooled the mixture to the room temperature, more N-(5,7-dimethyl-1,3-benzoxazol-2-yl)-N-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]amine (0.24 g, 0.00066 mol), tetrakis(triphenylphosphine)palladium (0.078 g, 0.000068 mol) were added, and the mixture was stirred at 80° C. for 5 hours. The mixture was allowed to cool to ambient temperature, and the solvent was removed under the reduced pressure. The residue was partitioned between water and dichloromethane. The aqueous layer was extracted with dichloromethane (3×50 mL). The combined organic extracts were washed with water, saturated aqueous sodium bicarbonate solution, and brine, and dried over magnesium sulfate. The solvents were evaporated under the reduced pressure to leave a brownish oil which was purified by flash column chromatography on silica using 5%-25% isopropanol/dichloromethane as a mobile phase, and the product was triturated with N,N-dimethylformamide to give tert-butyl 3-(4-amino-3-{4-[(5,7-dimethyl-1,3-benzoxazol-2-yl)amino]phenyl}-1H-pyrazolo[3,4-d]pyrimidin-1-yl)-1-piperidinecarboxylate (0.28 g, 0.00051 mol). RP-HPLC (Delta Pak C18, 5 μm, 300A, 15 cm; 5%-95% acetonitrile—0.1M ammonium acetate over 10 min, 1 mL/min) Rt 11.9 min.
Reaction SMILES: [CH3:1][O:2][CH2:3][Si](C)(C)C.C([Li])(CC)C.[Cl:13][C:14]1[CH:19]=[CH:18][C:17]([CH:20]2[CH2:25][CH2:24][CH2:23][C:22](=O)[CH2:21]2)=[CH:16][CH:15]=1>O1CCCC1>[Cl:13][C:14]1[CH:19]=[CH:18][C:17]([CH:20]2[CH2:25][CH2:24][CH2:23][C:22](=[CH:3][O:2][CH3:1])[CH2:21]2)=[CH:16][CH:15]=1
Reactant: O=C1CCCC(c2ccc(Cl)cc2)C1
Reactant: COC[Si](C)(C)C
Agent: [Li]C(C)CC
Solvent: C1CCOC1
Product: COC=C1CCCC(c2ccc(Cl)cc2)C1
Temperature: -25 °C
Reaction time: 0.5 h

Procedure:
To a solution of (methoxymethyl)trimethylsilane (694 mg, 5.75 mmol) in tetrahydrofuran (6.8 mL) at −78° C. was added drop-wise sec-butyllithium (1.4 M, 4.45 mL, 6.23 mmol). The solution was warmed to −25° C., held at that temperature for 30 minutes, then cooled to −78° C. To the reaction was added drop-wise 3-(4-chlorophenyl)cyclohexanone (prepared according to the method of G. A. Whitlock et al., Bioorg. Med. Chem. Lett. 2009, 19, 3118-3121) (1.0 g, 4.8 mmol). The reaction was warmed to −25° C. and stirred for 30 minutes, then allowed to slowly warm to room temperature and stir for 48 hours. The reaction was diluted with tetrahydrofuran (10 mL), quenched with saturated aqueous ammonium chloride solution, and extracted three times with ethyl acetate. The combined organic layers were dried over magnesium sulfate and concentrated in vacuo to provide the crude title compound as a pale yellow oil. Yield: 1.25 g. This material was used directly in the following step. GCMS m/z 236 (M+).
Reaction SMILES: C(O[C:4]([C:6]1[NH:7][N:8]=[C:9]([CH2:11][O:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:10]=1)=[O:5])C.C(OC(=O)[NH:25][CH2:26][CH:27](O)[CH3:28])(C)(C)C.C(OC(C1N(CC(NC(OC(C)(C)C)=O)C)N=C(COC2C=CC=CC=2)C=1)=O)C.O(CC1C=C2C(=O)NCCN2N=1)C1C=CC=CC=1>>[CH3:28][CH:27]1[N:7]2[N:8]=[C:9]([CH2:11][O:12][C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=3)[CH:10]=[C:6]2[C:4](=[O:5])[NH:25][CH2:26]1
Reactant: CC(O)CNC(=O)OC(C)(C)C
Reactant: CCOC(=O)c1cc(COc2ccccc2)n[nH]1
Agent: CCOC(=O)c1cc(COc2ccccc2)nn1CC(C)NC(=O)OC(C)(C)C
Agent: O=C1NCCn2nc(COc3ccccc3)cc21
Product: CC1CNC(=O)c2cc(COc3ccccc3)nn21

Procedure:
The compound was prepared from 5-phenoxymethyl-2H-pyrazole-3-carboxylic acid ethyl ester and rac-2-hydroxy-propyl-carbamic acid tert-butyl ester using the methods described in the preceding examples 7 ((rac)-2-(2-tert-butoxycarbonylamino-propyl)-5-phenoxymethyl-2H-pyrazole-3-carboxylic acid ethyl ester) and 6 (2-phenoxymethyl-6,7-dihydro-5H-pyrazolo[1,5-a]pyrazin-4-one).