Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:3]1[N:4]=[C:5]([C:29]2[C:34]([F:35])=[CH:33][CH:32]=[CH:31][C:30]=2[F:36])[O:6][C:7]=1[NH:8][C:9]1[CH:14]=[CH:13][C:12]([NH:15][C:16](=[O:28])[CH2:17][CH2:18][N:19]([CH3:27])C(=O)OC(C)(C)C)=[CH:11][CH:10]=1)#[N:2].C(=O)(O)[O-:38].[Na+].[OH-].[Na+]>S(=O)(=O)(O)O>[F:35][C:34]1[CH:33]=[CH:32][CH:31]=[C:30]([F:36])[C:29]=1[C:5]1[O:6][C:7]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([NH:15][C:16](=[O:28])[CH2:17][CH2:18][NH:19][CH3:27])=[CH:11][CH:10]=2)=[C:3]([C:1]([NH2:2])=[O:38])[N:4]=1
Reactant: O=C([O-])O
Reactant: CN(CCC(=O)Nc1ccc(Nc2oc(-c3c(F)cccc3F)nc2C#N)cc1)C(=O)OC(C)(C)C
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Product: CNCCC(=O)Nc1ccc(Nc2oc(-c3c(F)cccc3F)nc2C(N)=O)cc1
Yield: 22 %

Procedure:
A solution of tert-butyl 3-(4-(4-cyano-2-(2,6-difluorophenyl)oxazol-5-ylamino)phenylamino)-3-oxopropyl(methyl)carbamate (0.021 g, 0.04 mmol) in concentrated sulfuric acid (1 ml) was stirred at room temperature overnight. The reaction was basified by addition to sat. sodium bicarbonate and then addition of 6M NaOH (to ˜pH12). The aqueous phase was then extracted with EtOAc, the combined organic phases dried over MgSO4 and the solvent removed in vacuo. The residue was purified by preparative HPLC to afford 2-(2,6-difluorophenyl)-5-(4-(3-(methylamino)propanamido)phenylamino)oxazole-4-carboxamide (0.0038 g, 0.009 mmol, 22%). 1H NMR (CD3OD) δ 2.64 (3H, s), 2.73 (2H, t), 3.20 (2H, masked by CD3OD peak), 7.08 (2H, t), 7.29 (2H, d), 7.45 (1H, m), 7.48 (2H, d), 8.45 (1H, br. s). LCMS (2) Rt: 2.28 min; m/z (ES+) 416.
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([CH:23]=[CH:24][CH:25]=1)[CH2:5][C@@H:6]([CH2:10][CH2:11][C@H:12]([CH2:16][CH:17]1[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1)[C:13]([OH:15])=[O:14])[C:7]([OH:9])=[O:8].[H][H]>CO.CCOC(C)=O.[Pd]>[CH2:5]([C@@H:6]([CH2:10][CH2:11][C@H:12]([CH2:16][CH:17]1[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22]1)[C:13]([OH:15])=[O:14])[C:7]([OH:9])=[O:8])[C:4]1[CH:23]=[CH:24][CH:25]=[CH:2][CH:3]=1
Reactant: O=C(O)[C@H](CC[C@H](CC1CCCCC1)C(=O)O)Cc1cccc(Cl)c1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CO
Product: O=C(O)[C@H](CC[C@H](CC1CCCCC1)C(=O)O)Cc1ccccc1
Yield: 30 %

Procedure:
To a solution of (2R,5R)-2-(3-chlorobenzyl)-5-(cyclohexylmethyl)hexanedioic acid (37 mg, 0.10 mmol) in MeOH (2 mL) and EtOAc (2 mL) was bubbled through Argon for 5 min. Then 5% Pd/C (40 mg) was added to the solution. The reaction was stirred at 1 atm of hydrogen (balloon) for 2 hr. The reaction was filtered through CELITE® and washed with MeOH. The combined filtrate and MeOH wash was concentrated. The resulting residue was purified using RP prep-HPLC (Method B). The desired fraction was concentrated in vacuum and lyophilized with CH3CN to give (2R,5R)-2-benzyl-5-(cyclohexylmethyl)hexanedioic acid (10 mg, 0.030 mmol, 30% yield) as a white solid.
Reaction SMILES: Cl.[CH:2]1([CH2:5][O:6][C:7]2[CH:12]=[C:11]([O:13][CH3:14])[CH:10]=[CH:9][C:8]=2[C:15]2[C:16]3[NH:23][C:22]([CH3:24])=[C:21]([C:25]([NH:27][C@@H:28]4[CH2:32][CH2:31][NH:30][CH2:29]4)=[O:26])[C:17]=3[N:18]=[CH:19][N:20]=2)[CH2:4][CH2:3]1.[CH3:33][O:34][CH2:35][C:36](Cl)=[O:37]>>[CH:2]1([CH2:5][O:6][C:7]2[CH:12]=[C:11]([O:13][CH3:14])[CH:10]=[CH:9][C:8]=2[C:15]2[C:16]3[NH:23][C:22]([CH3:24])=[C:21]([C:25]([NH:27][C@@H:28]4[CH2:32][CH2:31][N:30]([C:36](=[O:37])[CH2:35][O:34][CH3:33])[CH2:29]4)=[O:26])[C:17]=3[N:18]=[CH:19][N:20]=2)[CH2:4][CH2:3]1
Reactant: COc1ccc(-c2ncnc3c(C(=O)N[C@@H]4CCNC4)c(C)[nH]c23)c(OCC2CC2)c1
Reactant: COCC(=O)Cl
Agent: Cl
Product: COCC(=O)N1CC[C@@H](NC(=O)c2c(C)[nH]c3c(-c4ccc(OC)cc4OCC4CC4)ncnc23)C1

Procedure:
Starting from 4-[2-(cyclopropylmethoxy)-4-methoxyphenyl]-6-methyl-N-[(3R)-pyrrolidin-3-yl]-5H-pyrrolo[3,2-d]pyrimidine-7-carboxamide hydrochloride (example D.f21) and commercially methoxyacetyl chloride the title compound is obtained as colorless solid.
Reaction SMILES: [CH2:1]([C:8]1[O:12][C:11]([C:13]2[CH:18]=[C:17]([F:19])[CH:16]=[CH:15][C:14]=2[F:20])=[N:10][C:9]=1[CH:21]=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:23][C:24]([S:27]([NH2:29])=[O:28])([CH3:26])[CH3:25]>C1COCC1.[Cl-].[Na+].O.CCOC(C)=O>[CH2:1]([C:8]1[O:12][C:11]([C:13]2[CH:18]=[C:17]([F:19])[CH:16]=[CH:15][C:14]=2[F:20])=[N:10][C:9]=1[CH:21]=[N:29][S:27]([C:24]([CH3:26])([CH3:25])[CH3:23])=[O:28])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=Cc1nc(-c2cc(F)ccc2F)oc1Cc1ccccc1
Reactant: CC(C)(C)S(N)=O
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC(C)(C)S(=O)N=Cc1nc(-c2cc(F)ccc2F)oc1Cc1ccccc1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of 5-benzyl-2-(2,5-difluorophenyl)oxazole-4-carbaldehyde (898 mg, 3.0 mmol) in THF (30.0 mL) was added (±)-2-methylpropane-2-sulfinamide (364 mg, 3.0 mmol), and Ti(OEt)4 (1.37 mL, 6.6 mmol). The reaction mixture was stirred for 4 h at room temperature. The reaction mixture was diluted with brine (30 mL) and EtOAc (60 mL) followed by addition of Celite®. Then, the mixture was vigorously stirred for 1 h, and filtered. The filtrate was extracted by EtOAc. The organic layers was washed with water and brine, dried over anhydrous Na2SO4, filtered, and concentrated. The crude product (770 mg, 64%) was purified by automatic column chromatography to yield (±)—N-((5-benzyl-2-(2,5-difluorophenyl)oxazol-4-yl)methylene)-2-methylpropane-2-sulfinamide as pale yellow solid. LC/MS (uplc): MH+ 403.0, 1.21 min.
Reaction SMILES: OS(O)(=O)=O.[C:6]1([C@H:12]([N:14]2[CH2:18][CH2:17][C@H:16]([CH2:19][C:20]#N)[CH2:15]2)[CH3:13])[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.[OH-:22].[Na+].[CH3:24][CH2:25][OH:26]>>[C:6]1([C@H:12]([N:14]2[CH2:18][CH2:17][C@H:16]([CH2:19][C:20]([O:26][CH2:25][CH3:24])=[O:22])[CH2:15]2)[CH3:13])[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: [OH-]
Reactant: CCO
Reactant: C[C@H](c1ccccc1)N1CC[C@H](CC#N)C1
Agent: O=S(=O)(O)O
Agent: [Na+]
Product: CCOC(=O)C[C@H]1CCN([C@H](C)c2ccccc2)C1
Yield: 73 %

Procedure:
To a mixture of EtOH (30 mL) and H2SO4 (15 mL) at 25° C. was added (3R)-1-[(R)-1-phenylethyl]-3-(cyanomethyl)pyrrolidine 3a (7.5 g, 35 mmol) in EtOH (5 mL). The solution was heated at reflux for 7 hours, cooled, and the volume reduced by approximately one-half under reduced pressure. The residue was made basic with NaOH and extracted with EtOAc. The organic layer was dried, concentrated, and the residue distilled (bulb to bulb) to provide 4a (6.7 g, 73%); bp 120°-130° C. (0.1-0.2 mm).
Reaction SMILES: [CH2:1]([O:3][C:4]1[C:8]([CH2:9][CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:7][NH:6][N:5]=1)[CH3:2].Cl[CH2:17][C:18]1[CH:34]=[CH:33][C:21]([O:22][CH2:23][CH2:24][N:25]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][N:28]=2)[CH3:26])=[CH:20][CH:19]=1.CN(C)C=O.[H-].[Na+]>O>[CH2:1]([O:3][C:4]1[C:8]([CH2:9][CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:7][N:6]([CH2:17][C:18]2[CH:19]=[CH:20][C:21]([O:22][CH2:23][CH2:24][N:25]([CH3:26])[C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][N:28]=3)=[CH:33][CH:34]=2)[N:5]=1)[CH3:2]
Reactant: CCOC(=O)CCc1c[nH]nc1OCC
Reactant: CN(CCOc1ccc(CCl)cc1)c1ccccn1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)CCc1cn(Cc2ccc(OCCN(C)c3ccccn3)cc2)nc1OCC
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 87.1 %

Procedure:
To a mixture of ethyl 3-(3-ethoxy-1H-pyrazol-4-yl]propionate (415 mg), 2-[N-[2-(4-chloromethylphenoxy) ethyl]-N-methylamino]pyridine (554 mg), and N,N-dimethylformamide (10 ml), sodium hydride (60%, oily, 80.0 mg) was added at 0° C., and then the mixture was stirred at room temperature for 30 minutes. The reaction mixture was poured into water, which was extracted with ethyl acetate. The ethyl acetate layer was washed with water, then, with saturated aqueous sodium chloride solution, and dried (MgSO4) and concentrated. The residue was subjected to silica gel column chromatography, and ethyl 3-[3-ethoxy-1-[4-[2-[N-methyl-N-(2-pyridyl)amino]ethoxy]benzyl]-1H-pyrazol-4-yl]propionate (771 mg, yield: 85%) was obtained as a colorless oily substance from the fraction eluted with ethyl acetate-hexane (1:1, volume ratio).
Reaction SMILES: [C:1]([O:4][CH2:5][CH2:6][O:7][C:8]1[C:12]([C:13]2[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15][CH:14]=2)=[C:11]([NH2:20])[N:10]([CH3:21])[N:9]=1)(=[O:3])[CH3:2].[C:22]([C:26]1[CH:31]=[CH:30][C:29]([S:32](Cl)(=[O:34])=[O:33])=[CH:28][CH:27]=1)([CH3:25])([CH3:24])[CH3:23].[OH-:36].[K+]>ClCCl.S([O-])(O)(=O)=O.C([N+](CCCC)(CCCC)CCCC)CCC.O>[C:1]([O:4][CH2:5][CH2:6][O:7][C:8]1[C:12]([C:13]2[CH:14]=[CH:15][C:16]([CH3:19])=[CH:17][CH:18]=2)=[C:11]([N:20]([S:32]([C:29]2[CH:30]=[CH:31][C:26]([C:22]([CH3:25])([CH3:24])[CH3:23])=[CH:27][CH:28]=2)(=[O:33])=[O:36])[S:32]([C:29]2[CH:30]=[CH:31][C:26]([C:22]([CH3:25])([CH3:24])[CH3:23])=[CH:27][CH:28]=2)(=[O:34])=[O:33])[N:10]([CH3:21])[N:9]=1)(=[O:3])[CH3:2]
Reactant: [OH-]
Reactant: CC(C)(C)c1ccc(S(=O)(=O)Cl)cc1
Reactant: CC(=O)OCCOc1nn(C)c(N)c1-c1ccc(C)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=S(=O)([O-])O
Agent: [K+]
Solvent: ClCCl
Solvent: O
Product: CC(=O)OCCOc1nn(C)c(N(S(=O)(=O)c2ccc(C(C)(C)C)cc2)S(=O)(=O)c2ccc(C(C)(C)C)cc2)c1-c1ccc(C)cc1
Yield: 62.1 %

Procedure:
To 2-{[5-amino-1-methyl-4-(4-methylphenyl)-1H-pyrazol-3-yl]oxy}ethyl acetate (Preparation 5) (100 mg) in dichloromethane (3 ml) at room temperature was added 4-tert-butylbenzenesulfonylchloride (88 mg), tetrabutylammonium hydrogen sulfate (14 mg) and potassium hydroxide (42 mg), the mixture was sonicated for 3 hrs. The reaction was diluted with water (10 ml) and extracted with ethyl acetate (10 ml). The organic fraction was dried over magnesium sulfate, filtered and concentrated under reduced pressure. The residue was purified by column chromatography (silica, 10 g) eluted with dichloromethane to yield the title compound as a white solid (80 mg).
Reaction SMILES: C(N(CC)CC)C.[CH3:8][N:9]1[C:15]2[CH:16]=[CH:17][C:18]([Cl:20])=[CH:19][C:14]=2[CH:13]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[NH:12][CH2:11][C:10]1=[O:27].Cl[C:29]([O:31][CH2:32][CH3:33])=[O:30]>C(Cl)(Cl)Cl>[CH3:8][N:9]1[C:15]2[CH:16]=[CH:17][C:18]([Cl:20])=[CH:19][C:14]=2[CH:13]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[N:12]([C:29]([O:31][CH2:32][CH3:33])=[O:30])[CH2:11][C:10]1=[O:27]
Reactant: CCOC(=O)Cl
Reactant: CN1C(=O)CNC(c2ccccc2)c2cc(Cl)ccc21
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: CCOC(=O)N1CC(=O)N(C)c2ccc(Cl)cc2C1c1ccccc1
Reaction time: 3 h
Yield: 92.5 %

Procedure:
2.8 ml. (0.02 moles) of triethylamine are added to a solution of 5.73 g. (0.02 moles) of 1-methyl-5-phenyl-7-chloro-1,3,4,5-tetrahydro-2H-1,4-benzodiazepine-2-one in 30 ml. of chloroform, and a solution of 2 ml. of ethyl chloroformate in 10 ml. of chloroform is added to the stirred mixture at room temperature. After 3 hours of stirring 1.4 ml. (0.01 moles) of triethylamine and a solution of 1 ml. of ethyl chloroformate in 5 ml. of chloroform are added to the reaction mixture. The reaction mixture is stirred for an additional 2 hours and then evaporated to dryness under reduced pressure. The residue is crystallized from ethanol. 6.7 g. (92.5%) of crystalline 1-methyl-4-ethoxycarbonyl-5-phenyl-7-chloro-1,3,4,5-tetrahydro-2H-1,4-benzodiazepine-2-one are obtained; m.p.: 173°-174° C., Rf1 = 0.5.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][C:3]=1[CH3:9].[OH-].[Na+].[CH2:12](Br)[CH2:13][CH2:14][CH2:15][CH2:16][CH3:17].O>C(O)C>[CH2:12]([O:8][C:5]1[CH:6]=[CH:7][C:2]([Cl:1])=[C:3]([CH3:9])[CH:4]=1)[CH2:13][CH2:14][CH2:15][CH2:16][CH3:17]
Reactant: Cc1cc(O)ccc1Cl
Reactant: CCCCCCBr
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CCCCCCOc1ccc(Cl)c(C)c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 90 %

Procedure:
In 200 g of ethanol were dissolved 71.2 g (0.5 mol) of 4-chloro-3-methylphenol and 22 g (0.55 mol) of sodium hydroxide. To the solution at 70° C., 90.8 g (0.55 mol) of n-hexyl bromide was added dropwise. The solution was allowed to ripen for 4 hours and cooled to room temperature, after which 120 g of water was added. The oily matter was separated therefrom and concentrated by a rotary evaporator, followed by vacuum distillation (boiling point 115-117° C./0.3 Torr), yielding 102 g of 4-n-hexyloxy-2-methylphenyl chloride.
Reaction SMILES: [N+:1]([C:4]1[C:5](SC#N)=[N:6][C:7]([NH:10][C:11]2[CH:16]=[C:15]([O:17][C:18]([F:21])([F:20])[F:19])[CH:14]=[CH:13][C:12]=2[NH:22][C:23](=[O:29])[O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[N:8][CH:9]=1)([O-:3])=[O:2].[NH2:33][CH:34]1[CH2:39][CH2:38][O:37][CH2:36][CH2:35]1.C(N(CC)C(C)C)(C)C>C1COCC1.CCOC(C)=O>[C:25]([O:24][C:23](=[O:29])[NH:22][C:12]1[CH:13]=[CH:14][C:15]([O:17][C:18]([F:19])([F:20])[F:21])=[CH:16][C:11]=1[NH:10][C:7]1[N:6]=[C:5]([NH:33][CH:34]2[CH2:39][CH2:38][O:37][CH2:36][CH2:35]2)[C:4]([N+:1]([O-:3])=[O:2])=[CH:9][N:8]=1)([CH3:26])([CH3:28])[CH3:27]
Reactant: CC(C)(C)OC(=O)Nc1ccc(OC(F)(F)F)cc1Nc1ncc([N+](=O)[O-])c(SC#N)n1
Reactant: NC1CCOCC1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)Nc1ccc(OC(F)(F)F)cc1Nc1ncc([N+](=O)[O-])c(NC2CCOCC2)n1
Temperature: 25 °C
Reaction time: 3 h
Yield: 97.2 %

Procedure:
tert-Butyl 2-(5-nitro-4-thiocyanatopyrimidin-2-ylamino)-4-(trifluoromethoxy)phenylcarbamate (0.94 g, 2.0 mmol) was dissolved in 40 mL anhydrous THF, then added 0.22 g (2.2 mmol) 4-amino-tetrahydropyran, and 0.7 mL (4.0 mmol) N,N-diisopropylethylamine. The mixture was stirred at room temperature under Argon balloon for 3 hrs till HPLC showed the completion of reaction. The orange-red solution was diluted with EtOAc, washed with brine twice, and then dried over Na2SO4. Solvents were removed under vacuum to give 1.0 g orange-yellow solid as the crude product.
Reaction SMILES: [BH4-].[Na+].[CH3:3][CH:4]1[CH2:9][C:8](=[O:10])[CH2:7][CH2:6][N:5]1[C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12]>C(O)C>[OH:10][C@H:8]1[CH2:7][CH2:6][N:5]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[C@@H:4]([CH3:3])[CH2:9]1.[OH:10][C@@H:8]1[CH2:7][CH2:6][N:5]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[C@@H:4]([CH3:3])[CH2:9]1
Reactant: CC1CC(=O)CCN1C(=O)OC(C)(C)C
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: C[C@H]1C[C@@H](O)CCN1C(=O)OC(C)(C)C
Product: C[C@H]1C[C@H](O)CCN1C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 2 h
Yield: 20 %
Yield: 36 %

Procedure:
Following the procedure found in Plettenburg, Oliver et. Al (PCT Int. Appl., 2007012421), sodium borohydride (213 mg, 5.6 mmol) was added portion-wise to a solution of tert-butyl 2-methyl-4-oxopiperidine-1-carboxylate (1.0 g, 4.7 mmol) in ethanol (10 mL). The mixture was stirred at room temperature for 2 h. The solution was concentrated in vacuo and then partitioned between water (40 mL) and ethyl acetate (40 mL). The aqueous layer was extracted twice with ethyl acetate (40 mL). The combined organic layers were washed with brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The residue was purified via column chromatography on silica gel (Biotage 50 g column, gradient elution with 40-50% ethyl acetate in hexanes) to afford (rac)-tert-butyl (cis)-4-hydroxy-2-methylpiperidine-1-carboxylate (367 mg, 36%) and (rac)-tert-butyl (trans)-4-hydroxy-2-methylpiperidine-1-carboxylate (205 mg, 20%) as white solids.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:49]=[CH:48][C:6]([CH2:7][N:8]([CH2:39][C:40]2[CH:45]=[CH:44][C:43]([O:46][CH3:47])=[CH:42][CH:41]=2)[C:9]2[N:14]=[CH:13][C:12]([C:15]3[C:16]4[CH2:29][CH2:28][N:27]([C:30]5[CH:38]=[CH:37][C:33]([C:34](O)=[O:35])=[CH:32][CH:31]=5)[C:17]=4[N:18]=[C:19]([N:21]4[CH2:26][CH2:25][O:24][CH2:23][CH2:22]4)[N:20]=3)=[CH:11][N:10]=2)=[CH:5][CH:4]=1.[NH2:50][CH2:51][CH2:52][N:53]1[CH2:58][CH2:57][O:56][CH2:55][CH2:54]1>>[CH3:47][O:46][C:43]1[CH:44]=[CH:45][C:40]([CH2:39][N:8]([CH2:7][C:6]2[CH:48]=[CH:49][C:3]([O:2][CH3:1])=[CH:4][CH:5]=2)[C:9]2[N:10]=[CH:11][C:12]([C:15]3[C:16]4[CH2:29][CH2:28][N:27]([C:30]5[CH:31]=[CH:32][C:33]([C:34]([NH:50][CH2:51][CH2:52][N:53]6[CH2:58][CH2:57][O:56][CH2:55][CH2:54]6)=[O:35])=[CH:37][CH:38]=5)[C:17]=4[N:18]=[C:19]([N:21]4[CH2:26][CH2:25][O:24][CH2:23][CH2:22]4)[N:20]=3)=[CH:13][N:14]=2)=[CH:41][CH:42]=1
Reactant: COc1ccc(CN(Cc2ccc(OC)cc2)c2ncc(-c3nc(N4CCOCC4)nc4c3CCN4c3ccc(C(=O)O)cc3)cn2)cc1
Reactant: NCCN1CCOCC1
Product: COc1ccc(CN(Cc2ccc(OC)cc2)c2ncc(-c3nc(N4CCOCC4)nc4c3CCN4c3ccc(C(=O)NCCN4CCOCC4)cc3)cn2)cc1
Yield: 56.4 %

Procedure:
Using 4-(4-{2-[bis-(4-methoxy-benzyl)-amino]-pyrimidin-5-yl}-2-morpholin-4-yl-5,6-dihydro-pyrrolo[2,3-d]pyrimidin-7-yl)-benzoic acid (50.0 mg, 0.0758 mmol) obtained in Step A in Example 1-D-19 and N-(aminoethyl)morpholine (19.7 mg, 0.152 mmol) instead of 3-(aminomethyl)pyridine, amidation was conducted in the same manner as Step B in Example 1-D-19, to obtain a crude product of 4-[4-{2-[bis-(4-methoxy-benzyl)-amino]-pyrimidin-5-yl}-2-morpholin-4-yl-5,6-dihydro-pyrrolo[2,3-d]pyrimidin-7-yl]-N-(2-morpholin-4-yl-ethyl)-benzamide as a yellow solid (33.0 mg), and then the PMB groups were removed according to the above Deprotection method 2, to obtain the desired compound (D-94) as a yellow powder (20.7 mg, 51%).
Reaction SMILES: [C:1]([NH:6][C:7]1[CH:8]=[C:9]([CH:13]2[CH2:18][CH2:17][N:16](C(OC(C)(C)C)=O)[CH2:15][CH2:14]2)[CH:10]=[CH:11][CH:12]=1)(=[O:5])[CH:2]([CH3:4])[CH3:3].Cl>O1CCOCC1>[CH3:3][CH:2]([CH3:4])[C:1]([NH:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([CH:13]2[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]2)[CH:8]=1)=[O:5]
Reactant: CC(C)C(=O)Nc1cccc(C2CCN(C(=O)OC(C)(C)C)CC2)c1
Agent: Cl
Solvent: C1COCCO1
Product: CC(C)C(=O)Nc1cccc(C2CCNCC2)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 46 %

Procedure:
Into a stirred solution of 2.20 (6.50 mmol) of tert-butyl 4-[3-(isobutyrylamino)phenyl]-1-piperidinecarboxylate in 100 ml of 1,4-dioxane at 0° C. was bubbled HCl gas for 10 minutes. The reaction mixture was allowed to warm to room temperature and the bubbling of the HCl gas was continued for 1 hour. The solvent was removed in vacuo, the residue was dissolved in 50 mL of water and was neutralized by the addition of KOH pellets. The aqueous solution was extracted with 3×80 mL of dichloromethane, the combined organic extracts were dried (MgSO4), filtered and concentrated in vacuo. The residue was purified by column chromatography (silica, 9:1, dichloromethane:methanol+1% isopropyl amine) to afford 0.700 g (46.0% yield) of the desired product: 1H NMR (400 MHz, CDCl3) δ 7.47 (s, 1H), 7.40 (d, 1H, J=7.8 Hz), 7.24 (t, 1H, J=7.8 Hz), 7.00 (d, 1H, J=7.8 Hz), 3.23-3.14 (m, 5H), 2.82-2.57 (m, 4H), 1.20 (d, 6H, J=6.8 Hz); ESMS m/e: 247.2 (M+H)+; The hydrochloride salt was used for the combustion analysis: Anal. Calc. for C15H22N2O+HCl+0.15 CHCl3: C, 60.51; H, 7.76; N, 9.32. Found: C, 60.57; H, 7.83; N, 8.88.
Reaction SMILES: [C:1]([O:10]C)(=O)[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[SH:4].C[O-].[Na+].Br[CH2:16][C:17]([C:19]1[S:20][CH:21]=[CH:22][CH:23]=1)=[O:18].Cl>CO>[C:19]1([C:17]([C:16]2[S:4][C:3]3[CH:5]=[CH:6][CH:7]=[CH:8][C:2]=3[C:1]=2[OH:10])=[O:18])[S:20][CH:21]=[CH:22][CH:23]=1
Reactant: COC(=O)c1ccccc1S
Reactant: O=C(CBr)c1cccs1
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: O=C(c1cccs1)c1sc2ccccc2c1O
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
Methyl thiosalicylate (2.0 g) was added dropwise to a stirred solution of sodium methoxide (1.28 g) in methanol (50 ml) at ambient temperature. The mixture was stirred at ambient temperature for 15 minutes and then a solution of 2-(bromoacetyl)thiophene (2.26 g) in methanol (50 ml) was added dropwise. After the addition was complete the mixture was boiled under reflux for 3 hours, then cooled, and 10% aqueous hydrochloric acid (100 ml) was added. A solid was collected by filtration, dried and then recrystallized from ethanol to give 2-thenoylbenzo[b]thiophene-3-ol.
Reaction SMILES: Cl[C:2]1[N:3]=[CH:4][CH:5]=[C:6]2[C:10]([CH2:11][CH2:12][O:13][C:14]3[CH:19]=[CH:18][C:17]([O:20][C:21]([F:24])([F:23])[F:22])=[CH:16][CH:15]=3)=[C:9]([C:25]([O:27][CH2:28][CH3:29])=[O:26])[N:8](C(OC(C)(C)C)=O)[C:7]=12.[CH2:37]([O:39][C:40]1[CH:41]=[C:42](B(O)O)[CH:43]=[CH:44][CH:45]=1)[CH3:38].[F-].[K+]>CC(C)([P](C(C)(C)C)([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)C(C)(C)C)C.O1CCOCC1>[CH2:37]([O:39][C:40]1[CH:41]=[C:42]([C:2]2[N:3]=[CH:4][CH:5]=[C:6]3[C:10]([CH2:11][CH2:12][O:13][C:14]4[CH:19]=[CH:18][C:17]([O:20][C:21]([F:23])([F:22])[F:24])=[CH:16][CH:15]=4)=[C:9]([C:25]([O:27][CH2:28][CH3:29])=[O:26])[NH:8][C:7]=23)[CH:43]=[CH:44][CH:45]=1)[CH3:38]
Reactant: CCOC(=O)c1c(CCOc2ccc(OC(F)(F)F)cc2)c2ccnc(Cl)c2n1C(=O)OC(C)(C)C
Reactant: CCOc1cccc(B(O)O)c1
Agent: CC(C)(C)[P]([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)(C(C)(C)C)C(C)(C)C
Agent: [F-]
Agent: [K+]
Solvent: C1COCCO1
Product: CCOC(=O)c1[nH]c2c(-c3cccc(OCC)c3)nccc2c1CCOc1ccc(OC(F)(F)F)cc1
Reaction time: 4 h
Yield: 91.5 %

Procedure:
To a mixture of 1-tert-butyl 2-ethyl 7-chloro-3-{2-[4-(trifluoromethoxy)phenoxy]ethyl}-1H-pyrrolo[2,3-c]pyridine-1,2-dicarboxylate (88 mg, 0.17 mmol), 3-ethoxyphenylboronic acid (69 mg, 0.42 mmol), KF (38.7 mg, 0.67 mmol), and bis(tri-t-butylphosphine)palladium (0) (8.50 mg, 0.02 mmol) was added dioxane (3.5 mL) under a nitrogen atmosphere. The reaction was then heated to 100 C overnight. Another charge of 3-ethoxyphenylboronic acid (69 mg, 0.42 mmol), KF (38.7 mg, 0.67 mmol), and bis(tri-t-butylphosphine)palladium (0) (8.50 mg, 0.02 mmol) was then added and stirring was continued for 4 h. The crude reaction mixture was then concentrated in vacuo, and the crude material was purified on silica (gradient elution, 0-50% EtOAc/hexanes) to yield the title product (80 mg) as a mixture with Boc'd material 1-tert-butyl 2-ethyl 7-(3-ethoxyphenyl)-3-{2-[4-(trifluoromethoxy)phenoxy]ethyl}-1H-pyrrolo[2,3-c]pyridine-1,2-dicarboxylate. HRMS (ESI) calc (M+H)+=515.1788. found 515.1772.
Reaction SMILES: C[C:2]1[N:9]2[C:5]([S:6][CH:7]=[CH:8]2)=[N:4][C:3]=1[CH2:10][OH:11].[Cl:12][C:13]1[CH:21]=[CH:20][C:16]([C:17](Cl)=[O:18])=[CH:15][CH:14]=1.N1C=CC=C[CH:23]=1>C(Cl)(Cl)Cl.C(O)(C)C>[ClH:12].[CH3:23][C:8]1[N:9]2[CH:2]=[C:3]([CH2:10][O:11][C:17](=[O:18])[C:16]3[CH:20]=[CH:21][C:13]([Cl:12])=[CH:14][CH:15]=3)[N:4]=[C:5]2[S:6][CH:7]=1
Reactant: Cc1c(CO)nc2sccn12
Reactant: c1ccncc1
Reactant: O=C(Cl)c1ccc(Cl)cc1
Solvent: CC(C)O
Solvent: ClC(Cl)Cl
Product: Cc1csc2nc(COC(=O)c3ccc(Cl)cc3)cn12
Product: Cl
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solution of 5 g of 5-methyl-6-hydroxymethyl-imidazo-(2,1-b)thiazole in 100 ml of dry chloroform is dropped at room temperature into a solution of 20 ml of p-chlorobenzoyl chlorine and 12 ml of pyridine in 75 ml of dry chloroform. The solution is stirred for 30 minutes at room temperature and filtered. The filtrate is concentrated under vacuum; the residue obtained is dissolved in isopropanol and a stream of dry hydrogen chloride is bubbled into the solution to yield 6 g of 3-methyl-6-p-chlorobenzoyloxymethyl-imidazo-(2,1-b)thiazole hydrochloride; m.p. 198°-199°.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[CH:7]=[C:8]([NH2:18])[N:9]([C:11]2[CH:16]=[CH:15][C:14]([CH3:17])=[CH:13][CH:12]=2)[N:10]=1.Cl[C:20](OC1C=CC([N+]([O-])=O)=CC=1)=[O:21].[CH3:32][NH:33][C:34]([C:36]1[CH:41]=[C:40]([O:42][C:43]2[CH:48]=[CH:47][C:46]([NH2:49])=[CH:45][CH:44]=2)[CH:39]=[CH:38][N:37]=1)=[O:35]>ClCCl.CO>[CH3:32][NH:33][C:34]([C:36]1[CH:41]=[C:40]([O:42][C:43]2[CH:48]=[CH:47][C:46]([NH:49][C:20]([NH:18][C:8]3[N:9]([C:11]4[CH:16]=[CH:15][C:14]([CH3:17])=[CH:13][CH:12]=4)[N:10]=[C:6]([C:2]4[O:1][CH:5]=[CH:4][CH:3]=4)[CH:7]=3)=[O:21])=[CH:45][CH:44]=2)[CH:39]=[CH:38][N:37]=1)=[O:35]
Reactant: CNC(=O)c1cc(Oc2ccc(N)cc2)ccn1
Reactant: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Reactant: Cc1ccc(-n2nc(-c3ccco3)cc2N)cc1
Solvent: CO
Solvent: ClCCl
Product: CNC(=O)c1cc(Oc2ccc(NC(=O)Nc3cc(-c4ccco4)nn3-c3ccc(C)cc3)cc2)ccn1

Procedure:
2.2 Analogously to Example 1.3, reaction of “2a” with 4-nitrophenyl chloroformate and N-methyl-4-(4-aminophenoxy)pyridine-2-carboxamide gives the compound “2”; TLC in dichloromethane/methanol 9/1 Rf=0.63; HPLC-APCI-MS [M+H+] 509