Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C:5]1[N:6]([CH2:24][C:25]2[CH:30]=[CH:29][C:28]([C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=3[S:37](=[O:44])(=[O:43])[NH:38][C:39]([CH3:42])([CH3:41])[CH3:40])=[CH:27][CH:26]=2)[C:7](=[O:23])[N:8]([C:10]2[CH:15]=[C:14]([N+:16]([O-])=O)[CH:13]=[CH:12][C:11]=2[C:19]([F:22])([F:21])[F:20])[N:9]=1)[CH2:2][CH2:3][CH3:4].C(OCC)(=O)C.[H][H]>[Pt]=O.C(O)C>[NH2:16][C:14]1[CH:13]=[CH:12][C:11]([C:19]([F:20])([F:22])[F:21])=[C:10]([N:8]2[C:7](=[O:23])[N:6]([CH2:24][C:25]3[CH:26]=[CH:27][C:28]([C:31]4[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=4[S:37](=[O:43])(=[O:44])[NH:38][C:39]([CH3:40])([CH3:41])[CH3:42])=[CH:29][CH:30]=3)[C:5]([CH2:1][CH2:2][CH2:3][CH3:4])=[N:9]2)[CH:15]=1
Reactant: [H][H]
Reactant: CCCCc1nn(-c2cc([N+](=O)[O-])ccc2C(F)(F)F)c(=O)n1Cc1ccc(-c2ccccc2S(=O)(=O)NC(C)(C)C)cc1
Agent: O=[Pt]
Solvent: CCO
Solvent: CCOC(C)=O
Product: CCCCc1nn(-c2cc(N)ccc2C(F)(F)F)c(=O)n1Cc1ccc(-c2ccccc2S(=O)(=O)NC(C)(C)C)cc1
Yield: 99.6 %

Procedure:
A mixture of 200 mg (0.317 mmole) of 5-n-butyl-4-[[2'-(N-t-butylsulfamoyl)biphenyl-4-yl]methyl]-2,4-dihydro-2-[5-nitro-2-(trifluoromethyl)phenyl] -3H-1,2,4-triazol-3-one (from Step C), 15 mg of platinum oxide, 10 mL of ethyl acetate, and 2 mL of ethanol was shaken with hydrogen at approximately 4 atm for a few hours until complete and then centrifuged. The supernatant was decanted off, and the catalyst pellet was extracted 3× with ethanol in the same manner. The combined supernatant fractions were concentrated to give 190 mg (100%) of the title compound as a brown foam, which was suitable for use without further purification; TLC in 95:5 CH2Cl2 --MeOH; mass spectrum (FAB) m/e 608 (M+Li)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:15]=[C:14]([O:16][CH3:17])[CH:13]=[CH:12][C:4]=1[CH2:5][NH:6][C:7]1[S:8][CH:9]=[N:10][N:11]=1.N#N.C1COCC1.[O:25]=[C:26]1[NH:30][C:29]2[CH:31]=[CH:32][C:33]([S:35](Cl)(=[O:37])=[O:36])=[CH:34][C:28]=2[O:27]1>CCOC(C)=O>[CH3:1][O:2][C:3]1[CH:15]=[C:14]([O:16][CH3:17])[CH:13]=[CH:12][C:4]=1[CH2:5][N:6]([C:7]1[S:8][CH:9]=[N:10][N:11]=1)[S:35]([C:33]1[CH:32]=[CH:31][C:29]2[NH:30][C:26](=[O:25])[O:27][C:28]=2[CH:34]=1)(=[O:37])=[O:36]
Reactant: COc1ccc(CNc2nncs2)c(OC)c1
Reactant: O=c1[nH]c2ccc(S(=O)(=O)Cl)cc2o1
Agent: N#N
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COc1ccc(CN(c2nncs2)S(=O)(=O)c2ccc3[nH]c(=O)oc3c2)c(OC)c1
Temperature: -78 °C
Reaction time: 0.17 h
Yield: 71.8 %

Procedure:
A round bottom flask was charged with N-(2,4-dimethoxybenzyl)-1,3,4-thiadiazol-2-amine (INTERMEDIATE Y) (0.689 g, 2.74 mmol), a septum and N2 line were attached. THF (4.57 mL) was added and when the solution became homogeneous, it was cooled to −78° C. After 10 min, added a THF solution of 2-oxo-2,3-dihydrobenzo[d]oxazole-6-sulfonyl chloride (ASDI) (0.621 g, 2.66 mmol) dropwise over 5 minutes (still at −78° C.). When the addition was complete, the cold bath was removed and the mixture was allowed to warm to rt and stirred 18 h. The reaction mixture was poured into sat. aq. NH4Cl, and DCM was added. The layers were separated and the organic layer was extracted with DCM (2×10 mL). The combined organic extracts were dried over Na2SO4 and concentrated under a vacuum. The solution was concentrated for purification by silica gel MPLC. The residue was taken up in minimal DCM and absorbed onto a 25 g loading cartridge and passed through silica gel column (40 g) using 98:2 Heptane:EtOAc to 100% EtOAc gradient to afford N-(2,4-dimethoxybenzyl)-2-oxo-N-(1,3,4-thiadiazol-2-yl)-2,3-dihydrobenzo[d]oxazole-6-sulfonamide (0.856 g, 1.909 mmol) as a white amorphous solid. m/z (ESI) 449.0 (M+H)+.
Reaction SMILES: [S-:1][C:2]#[N:3].[Na+].[C:5]([N:9]=[N:10][C:11](Cl)([CH2:13][CH:14]([CH3:16])[CH3:15])[CH3:12])([CH3:8])([CH3:7])[CH3:6].O>C(O)(C)C>[C:5]([N:9]=[N:10][C:11]([N:3]=[C:2]=[S:1])([CH2:13][CH:14]([CH3:16])[CH3:15])[CH3:12])([CH3:8])([CH3:7])[CH3:6]
Reactant: N#C[S-]
Reactant: CC(C)CC(C)(Cl)N=NC(C)(C)C
Agent: [Na+]
Solvent: CC(C)O
Solvent: O
Product: CC(C)CC(C)(N=C=S)N=NC(C)(C)C
Temperature: 30 °C
Reaction time: 2 h

Procedure:
To a stirred solution of 26.1 grams (0.3 moles) of sodium thiocyanate in 150 ml of 75% aqueous isopropanol in a 500 ml erlenmeyer flask, cooled to 5° C., was added 61.2 grams (0.3 moles) of 2-t-butylazo- 2-chloro-4-methylpentane holding the reaction temperature at 10°-20° C. After the addition was complete, the reaction mixture was stirred an additional two hours at 30° C., poured into 300 ml water and the product extracted with 200 ml pentane. The pentane extract was washed with water, 10% NaHCO3 solution, dried over anhydrous sodium sulfate, filtered and the pentane evaporated under reduced pressure to leave 55.7 grams (80% crude yield) of a yellow liquid. The product had a strong broad band at 1980- 2080 cm-1 in its infrared spectrum which is indicative of the isothiocyano band.
Reaction SMILES: [CH:1]1[C:6]2[NH:7][C:8](=O)[C:9]3[C:10]4[CH:19]=[CH:18][CH:17]=[CH:16][C:11]=4[C:12](=[O:15])[NH:13][C:14]=3[C:5]=2[CH:4]=[CH:3][CH:2]=1.O=P(Cl)(Cl)[Cl:23]>>[Cl:23][C:8]1[N:7]=[C:6]2[CH:1]=[CH:2][CH:3]=[CH:4][C:5]2=[C:14]2[C:9]=1[C:10]1[CH:19]=[CH:18][CH:17]=[CH:16][C:11]=1[C:12](=[O:15])[NH:13]2
Reactant: O=c1[nH]c2c3ccccc3[nH]c(=O)c2c2ccccc12
Reactant: O=P(Cl)(Cl)Cl
Product: O=c1[nH]c2c3ccccc3nc(Cl)c2c2ccccc12

Procedure:
chlorinating a dibenzo[c,h][1,6]naphthyridine-6,11(5H,12H)-dione with a chlorinating reagent comprising POCl3 to give the corresponding 11-chlorodibenzo[c,h][1,6]-naphthyridin-6(5H)-one; and/or
Reaction SMILES: [C:1]([NH:11][C@H:12]([C:16]([O:18][CH2:19][CH:20]([O:28][C:29](=[O:47])[CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH3:46])[CH2:21][C:22]([CH3:27])([CH3:26])[C:23]([OH:25])=[O:24])=[O:17])[CH:13]([CH3:15])[CH3:14])([O:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:2].[OH-].C([N+](CCCC)(CCCC)CCCC)CCC.[Cl:66][CH2:67]I>O1CCOCC1>[C:1]([NH:11][C@H:12]([C:16]([O:18][CH2:19][CH:20]([O:28][C:29](=[O:47])[CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH3:46])[CH2:21][C:22]([CH3:26])([CH3:27])[C:23]([O:25][CH2:67][Cl:66])=[O:24])=[O:17])[CH:13]([CH3:15])[CH3:14])([O:3][CH2:4][C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=1)=[O:2]
Reactant: ClCI
Reactant: CCCCCCCCCCCCCCCCCC(=O)OC(COC(=O)[C@@H](NC(=O)OCc1ccccc1)C(C)C)CC(C)(C)C(=O)O
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [OH-]
Solvent: C1COCCO1
Product: CCCCCCCCCCCCCCCCCC(=O)OC(COC(=O)[C@@H](NC(=O)OCc1ccccc1)C(C)C)CC(C)(C)C(=O)OCCl
Reaction time: 0.08 h
Yield: 64.5 %

Procedure:
To a solution of 5-(N-CBz-L-valyloxy)-4-stearoyloxy-2,2-dimethylvaleric acid (16.0 g, 24 mmol) in dioxane (500 mL), was added dropwise a 40% aqueous solution of tetrabutylammonium hydroxide (14.3 mL). After stirring for 5 min, the solution was evaporated to dryness through co-evaporation with dioxane and toluene. The residue was dissolved in dichloromethane (500 mL) and then chloroiodomethane (17.5 mL, 240 mmol) was added and the solution was stirred for 6 h at room temperature. The solution was concentrated under reduced pressure and the residue was shaken with hexane/ethyl acetate (1:1 v/v, 400 mL). The yellow crystalline solid was filtered off and the filtrate was washed with aqueous solution of sodium thiosulfate (0.1 M) and the filtered through anhydrous sodium sulfate and evaporated to dryness. The residue was column chromatographed (silica gel, 1% MeOH in CH2Cl2), to give 11.0 g of chloromethyl 5-(N-CBz-L-valyloxy)4-stearoyloxy-2,2-dimethylvalerate.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8]([C:10]([F:13])([F:12])[F:11])=[CH2:9])[CH:5]=[C:4]([Cl:14])[C:3]=1[F:15].[CH2:16]([N:23]([CH2:29]OC)[CH2:24][Si](C)(C)C)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH2:16]([N:23]1[CH2:29][CH2:9][C:8]([C:6]2[CH:5]=[C:4]([Cl:14])[C:3]([F:15])=[C:2]([Cl:1])[CH:7]=2)([C:10]([F:13])([F:12])[F:11])[CH2:24]1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: C=C(c1cc(Cl)c(F)c(Cl)c1)C(F)(F)F
Reactant: COCN(Cc1ccccc1)C[Si](C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Fc1c(Cl)cc(C2(C(F)(F)F)CCN(Cc3ccccc3)C2)cc1Cl
Temperature: 0 °C
Reaction time: 5 h
Yield: 40.3 %

Procedure:
To a stirred solution of 1,3-dichloro-2-fluoro-5-(1-trifluoromethyl-vinyl)-benzene (10 g, 38.61 mmol) in DCM (150 mL) was added benzyl-methoxymethyl-trimethylsilanylmethyl-amine (36.6 g, 154.44 mmol) at room temperature and reaction mixture was cooled to 0° C. followed by slow addition of TFA (0.29 mL, 3.861 mmol). Resulting reaction mixture was stirred at room temperature for 5 hours. After complete consumption of starting material, the reaction mixture was quenched with aqueous Na2CO3 and extracted with DCM (3×100 mL). Combined organic layer was dried over Na2SO4 and concentrated under vacuum to afford brown oil (9.7 g, crude). Crude compound was purified by column chromatography using 100-200 mesh silica gel. Desired product was eluted in 4% ethyl acetate in hexane to afford product as brownish solid (6.1 g, impure). Impure compound was used as such for next reaction. 1H-NMR (400 MHz, CDCl3) δ: 2.24-2.31 (m, 1H), 2.53-2.59 (m, 1H), 2.68-2.78 (m, 1H), 2.80-2.83 (m, 1H), 3.01-3.08 (m, 2H), 3.61-3.69 (m, 2H), 7.29-7.34 (m, 7H). (m/z): 280.4 (M+H).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:18]=[CH:17][C:16]2[N:15]=[CH:14][C:13]3[N:19]=[C:20]([CH2:25][O:26][CH2:27][CH3:28])[N:21]([CH2:22][CH2:23][CH3:24])[C:12]=3[C:11]=2[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.ClC1C=C(C=CC=1)C(OO)=O.[OH-].[NH4+:41].C1(C)C=CC(S(Cl)(=O)=O)=CC=1>C(Cl)(Cl)Cl>[CH2:1]([O:8][C:9]1[CH:18]=[CH:17][C:16]2[N:15]=[C:14]([NH2:41])[C:13]3[N:19]=[C:20]([CH2:25][O:26][CH2:27][CH3:28])[N:21]([CH2:22][CH2:23][CH3:24])[C:12]=3[C:11]=2[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: [NH4+]
Reactant: CCCn1c(COCC)nc2cnc3ccc(OCc4ccccc4)cc3c21
Agent: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: O=C(OO)c1cccc(Cl)c1
Agent: [OH-]
Solvent: ClC(Cl)Cl
Product: CCCn1c(COCC)nc2c(N)nc3ccc(OCc4ccccc4)cc3c21
Reaction time: 0.42 h

Procedure:
8-Benzyloxy-2-ethoxymethyl-1-propyl-1H-imidazo[4,5-c]quinoline (2.0 g, 5.3 mmol) was dissolved in chloroform (20 mL). 3-Chloroperoxybenzoic acid (60% pure, 1.53 g, 5.3 mmol) was added in one portion and the mixture was stirred for 25 minutes. Ammonium hydroxide (20 mL) was added and the biphasic mixture was stirred for 10 minutes. p-Toluenesulfonyl chloride (1.0 g, 5.3 mmol) was added in one portion and the reaction was stirred for an additional 1 hour. The layers were separated and the aqueous fraction was extracted with dichloromethane. The organic fractions were combined and washed successively with 5% aqueous sodium carbonate, water and saturated aqueous sodium chloride. The organic fraction was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography. The purification was carried out eluting with chloroform:CMA in a gradient from 99:1 to 93:7 to provide a red-brown solid. The solid was recrystallized from acetonitrile to yield 1.1 g of 8-benzyloxy-2-ethoxymethyl-1-propyl-1H-imidazo[4,5-c]quinolin-4-amine as red brown crystals, mp 152.5-154.0° C.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3](/[CH:10]=[CH:11]/[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[N:18]2[CH:22]=[CH:21][C:20]([CH:23]=[O:24])=[CH:19]2)=[N:2]1.[BH4-].[Na+].O>CO>[NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3](/[CH:10]=[CH:11]/[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[N:18]2[CH:22]=[CH:21][C:20]([CH2:23][OH:24])=[CH:19]2)=[N:2]1
Reactant: O=Cc1ccn(-c2ccccc2/C=C/c2n[nH]c3ccccc23)c1
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: OCc1ccn(-c2ccccc2/C=C/c2n[nH]c3ccccc23)c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 45.6 %

Procedure:
Compound 167 (38 mg, 0.16 mmol) was dissolved in methanol (2.0 mL) and added with sodium borohydride (12 mg, 0.32 mmol) followed by stirring at room temperature for 4 hours. The reaction mixture was added with water, extracted with ethyl acetate and the organic layer was concentrated. Then, the residue was triturated in ethyl acetate to obtain Compound 168 (23 mg, 45%).
Reaction SMILES: [Br:1][C:2]1[C:6]2[C:7](=O)[NH:8][CH:9]=[CH:10][C:5]=2[S:4][CH:3]=1.O=P(Cl)(Cl)[Cl:14]>>[Br:1][C:2]1[C:6]2[C:7]([Cl:14])=[N:8][CH:9]=[CH:10][C:5]=2[S:4][CH:3]=1
Reactant: O=c1[nH]ccc2scc(Br)c12
Reactant: O=P(Cl)(Cl)Cl
Product: Clc1nccc2scc(Br)c12
Temperature: 25 °C

Procedure:
A suspension of Example 1A (35.91 g, 0.156 mol) in POCl3 (80 mL) was heated to reflux for 2.5 hours, cooled to room temperature, poured onto 800 g of ice, and extracted repeatedly with dichloromethane. The combined extracts were washed with water and brine, dried (Na2SO4), filtered, and concentrated. The residue was purified by flash column chromatography on silica gel with 0 to 5% methanol/dichloromethane to provide 29.3 g of 3-bromo-4-chlorothieno[3,2-c]pyridine (mp 158-159° C.), which was diluted with dioxane (500 mL) and concentrated aqueous NH3 (500 mL), heated to 150° C. under pressure (260 psi) for 20 hours, and concentrated. The residue was triturated from MTBE then from methanol to provide 20.29 g of the desired product. m.p. 153-155° C.
Reaction SMILES: [C:1](#[N:3])[CH3:2].[Li]CCCC.[Cl:9][C:10]1[C:24]([Cl:25])=[CH:23][C:13]2[NH:14][C:15]([C:17](=[O:22])[C:18]([F:21])([F:20])[F:19])=[N:16][C:12]=2[CH:11]=1>C1COCC1>[Cl:25][C:24]1[C:10]([Cl:9])=[CH:11][C:12]2[NH:16][C:15]([C:17]([OH:22])([C:18]([F:21])([F:19])[F:20])[CH2:2][C:1]#[N:3])=[N:14][C:13]=2[CH:23]=1
Reactant: CC#N
Reactant: O=C(c1nc2cc(Cl)c(Cl)cc2[nH]1)C(F)(F)F
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: N#CCC(O)(c1nc2cc(Cl)c(Cl)cc2[nH]1)C(F)(F)F
Temperature: -78 °C
Reaction time: 0.75 h

Procedure:
To a solution of dry acetonitrile (0.4 mL) in THF (10 mL) at −78° C. was added n-BuLi (2.9 mL of 2.5 M in hexanes). The resulting mixture was stirred for 45 min. at −78° C. To the solution was then added a solution of 1-(5,6-dichloro-1H-benzoimidazol-2-yl)-2,2,2-trifluoro-ethanone (930 mg) in THF (5 mL). The resulting mixture was stirred at −78° C. for 1 hr. The reaction was quenched with NH4Cl (aq) and the resulting mixture extracted with EtOAc. The combined extracts were washed with brine and dried over Na2SO4. The resulting crude material was purified by column chromatography (SiO2; 0-15% ethyl acetate/hexanes) to yield the title compound as a yellow solid.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([O:8][C:9]2[CH:10]=[C:11]([CH2:15]O)[CH:12]=[CH:13][CH:14]=2)[CH:3]=1.S(Cl)([Cl:19])=O.C(=O)(O)[O-].[Na+]>ClCCl>[Cl:19][CH2:15][C:11]1[CH:10]=[C:9]([CH:14]=[CH:13][CH:12]=1)[O:8][C:4]1[CH:3]=[C:2]([CH3:1])[CH:7]=[CH:6][N:5]=1
Reactant: O=S(Cl)Cl
Reactant: Cc1ccnc(Oc2cccc(CO)c2)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: Cc1ccnc(Oc2cccc(CCl)c2)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 99.9 %

Procedure:
[3-(4-Methyl-pyridin-2-yloxy)-phenyl]-methanol from Step 1 (4.75 g, 22.1 mmol), in dichloromethane (50 mL), was cooled to 0° C., and treated dropwise with thionyl chloride (1.93 mL, 26.5 mmol). The reaction mixture was allowed to warm to ambient temperature and was stirred for 3 h. Saturated aqueous sodium bicarbonate (20 mL) was added and the mixture was stirred at rt for 5 min. The organic layer was separated, dried over sodium sulfate, filtered and concentrated by evaporation to afford the desired product (5.16 g, 99% yield) as an oil.
Reaction SMILES: [C:1]12([C:11]([NH:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19]OS(C3C=CC(C)=CC=3)(=O)=O)=[O:12])[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.[NH:31]1[CH2:35][CH2:34][CH2:33][CH2:32]1>C(#N)C>[N:31]1([CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][NH:13][C:11]([C:1]23[CH2:8][CH:7]4[CH2:6][CH:5]([CH2:4][CH:3]([CH2:9]4)[CH2:2]2)[CH2:10]3)=[O:12])[CH2:35][CH2:34][CH2:33][CH2:32]1
Reactant: C1CCNC1
Reactant: Cc1ccc(S(=O)(=O)OCCCCCCNC(=O)C23CC4CC(CC(C4)C2)C3)cc1
Solvent: CC#N
Product: O=C(NCCCCCCN1CCCC1)C12CC3CC(CC(C3)C1)C2
Temperature: 25 °C
Reaction time: 20 h
Yield: 100 %

Procedure:
To an ice-cooled solution of the product from step b in acetonitrile (25 ml) was added pyrrolidine (6.41 ml, 76.8 mmol). The coolant was removed and the reaction mixture was stirred at ambient temperature for 20 h. The mixture was partitioned between ethyl acetate (100 ml) and water (100 ml). The aqueous phase was discarded and the organic phase extracted with aqueous 2M hydrochloric acid (100 ml). The organic phase was discarded and the aqueous phase was washed with further ethyl acetate (50 ml). The pH of the aqueous phase was adjusted to pH 11 and then extracted twice with chloroform (100 ml). The combined organic phases were washed with brine (100 ml) and dried over anhydrous magnesium sulfate. The filtrate was evaporated at reduced pressure to afford the title compound (4.34 g, 100%). 1H NMR 5.54 (1H, br s), 3.26-3.20 (2H, m), 2.50-2.40 (6H, m), 2.05 (3H, s), 1.85-1.73 (14H, m), 1.52-1.50 (4H, m), 1.36-1.33 (4H, m).
Reaction SMILES: [CH:1]([CH:5]([N:34]([CH3:51])[C:35]([CH:37]([NH:41][C:42](=[O:50])[CH:43]([N:47]([CH3:49])[CH3:48])[CH:44]([CH3:46])[CH3:45])[CH:38]([CH3:40])[CH3:39])=[O:36])[CH:6]([O:32][CH3:33])[CH2:7][C:8]([N:10]1[CH2:14][CH2:13][CH2:12][CH:11]1[CH:15]([S:30][CH3:31])[CH:16]([C:18](=[O:29])[NH:19][CH2:20][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([OH:28])[CH:23]=1)[CH3:17])=[O:9])([CH2:3][CH3:4])[CH3:2].[CH2:52]([N:54]=[C:55]=[O:56])[CH3:53].C(N(C(C)C)CC)(C)C>C(Cl)Cl>[CH3:49][N:47]([CH3:48])[CH:43]([CH:44]([CH3:46])[CH3:45])[C:42]([NH:41][CH:37]([CH:38]([CH3:39])[CH3:40])[C:35]([N:34]([CH3:51])[CH:5]([CH:1]([CH3:2])[CH2:3][CH3:4])[CH:6]([O:32][CH3:33])[CH2:7][C:8]([N:10]1[CH2:14][CH2:13][CH2:12][CH:11]1[CH:15]([S:30][CH3:31])[CH:16]([CH3:17])[C:18]([NH:19][CH2:20][CH2:21][C:22]1[CH:23]=[C:24]([O:28][C:55](=[O:56])[NH:54][CH2:52][CH3:53])[CH:25]=[CH:26][CH:27]=1)=[O:29])=[O:9])=[O:36])=[O:50]
Reactant: CCN=C=O
Reactant: CCC(C)C(C(CC(=O)N1CCCC1C(SC)C(C)C(=O)NCCc1cccc(O)c1)OC)N(C)C(=O)C(NC(=O)C(C(C)C)N(C)C)C(C)C
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCNC(=O)Oc1cccc(CCNC(=O)C(C)C(SC)C2CCCN2C(=O)CC(OC)C(C(C)CC)N(C)C(=O)C(NC(=O)C(C(C)C)N(C)C)C(C)C)c1
Temperature: 25 °C
Reaction time: 13 h

Procedure:
To a stirred solution of N-(1-{[1-sec-butyl-4-(2-{2-[2-(3-hydroxy-phenyl)-ethylcarbamoyl]-1-methylsulfanyl-propyl}-pyrrolidin-1-yl)-2-methoxy-4-oxo-butyl]-methyl-carbamoyl}-2-methyl-propyl)-2-dimethylamino-3-methyl-butyramide (30 mg, 0.035 mmol) in CH2Cl2 (0.5 mL) were added ethyl isocyanate (0.042 mL, 0.53 mmol) and diisopropylethylamine (0.062 mL, 0.35 mmol) at room temperature. After being stirred at room temperature for 13hr, the mixture was concentrated in vacuo to give a crude oil (58 mg), which was purified by preparative HPLC (column:ODS-8OTs, eluent: 35/35 H2O:CH3CN/0.05% TFA). The appropriate fractions were lyophilized to give the title compound as a white amorphous powder (13 mg, 39%).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([C@@H:25]3[CH2:30][CH2:29][CH2:28][N:27]([C:31](=[O:35])[CH2:32][C:33]#[N:34])[CH2:26]3)[N:9]=[C:10]([C:11]3[CH:16]=[CH:15][C:14]([O:17][C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)=[CH:13][C:12]=3[F:24])[C:3]=12.[CH3:36][C:37]([N:41]1[CH2:46][CH2:45][N:44]([CH3:47])[CH2:43][CH2:42]1)([CH3:40])[CH:38]=O.N1CCCCC1>C1(C)C=CC=CC=1>[NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([C@@H:25]3[CH2:30][CH2:29][CH2:28][N:27]([C:31]([C:32](=[CH:38][C:37]([CH3:40])([N:41]4[CH2:42][CH2:43][N:44]([CH3:47])[CH2:45][CH2:46]4)[CH3:36])[C:33]#[N:34])=[O:35])[CH2:26]3)[N:9]=[C:10]([C:11]3[CH:16]=[CH:15][C:14]([O:17][C:18]4[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=4)=[CH:13][C:12]=3[F:24])[C:3]=12
Reactant: N#CCC(=O)N1CCC[C@@H](n2nc(-c3ccc(Oc4ccccc4)cc3F)c3c(N)ncnc32)C1
Reactant: CN1CCN(C(C)(C)C=O)CC1
Solvent: C1CCNCC1
Solvent: Cc1ccccc1
Product: CN1CCN(C(C)(C)C=C(C#N)C(=O)N2CCC[C@@H](n3nc(-c4ccc(Oc5ccccc5)cc4F)c4c(N)ncnc43)C2)CC1
Temperature: 120 °C
Reaction time: 3 h

Procedure:
Into a 100-mL round-bottom flask, was placed a solution of toluene (10 mL), 3-[(3R)-3-[4-amino-3-(2-fluoro-4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl]piperidin-1-yl]-3-oxopropanenitrile (300 mg, 0.64 mmol, 1.00 equiv), 2-methyl-2-(4-methylpiperazin-1-yl)propanal (541.45 mg, 3.18 mmol, 5.00 equiv), and piperidine (108.29 mg, 1.27 mmol, 2.00 equiv). The resulting solution was stirred for 3 h at 120° C. in an oil bath. The resulting mixture was concentrated under vacuum. The residue was applied onto a silica gel column with ethyl acetate:MeOH (5:1). The crude product (70 mg) was purified by Flash-Prep-HPLC with the following conditions (IntelFlash-1): Column, C18 silica gel; mobile phase, H2O (0.5% TFA)/CH3CN=10% increasing to H2O (0.5% TFA)/CH3CN=40% within 10 min; Detector, UV 254 nm. This resulted in 46.4 mg (12%) of 2-[[(3R)-3-[4-amino-3-(2-fluoro-4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl]piperidin-1-yl]carbonyl]-4-methyl-4-(4-methylpiperazin-1-yl)pent-2-enenitrile as a white solid. LC-MS-PH-PBF-003-96-0: (ES, m/z): [M+H]+ 625
Reaction SMILES: C[Si](Cl)(C)C.[C:6]([O:10][C:11](=[O:14])[CH2:12]Br)([CH3:9])([CH3:8])[CH3:7].[CH3:15][O:16][C:17]1[C:22]([O:23][CH3:24])=[C:21]([C:25](=[O:28])[CH2:26][CH3:27])[CH:20]=[CH:19][N:18]=1>C(OCC)C.O1CCCC1.[Zn]>[C:6]([O:10][C:11](=[O:14])[CH2:12][C:25]([C:21]1[CH:20]=[CH:19][N:18]=[C:17]([O:16][CH3:15])[C:22]=1[O:23][CH3:24])([OH:28])[CH2:26][CH3:27])([CH3:9])([CH3:8])[CH3:7]
Reactant: CC(C)(C)OC(=O)CBr
Reactant: CCC(=O)c1ccnc(OC)c1OC
Agent: C[Si](C)(C)Cl
Agent: [Zn]
Solvent: CCOCC
Solvent: C1CCOC1
Product: CCC(O)(CC(=O)OC(C)(C)C)c1ccnc(OC)c1OC
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 72.6 %

Procedure:
To a mixture of zinc (23.1 g; 353.9 mmol) in anhydrous diethyl ether (400 mL) was added trimethylsilyl chloride (0.5 mL). The mixture was stirred for 15 minutes at room temperature and refluxed. Bromoacetic acid tert-butyl ester (56.5 g, 290.0 mmol) was added dropwise and the reaction continued refluxing for an additional 1 hour. The mixture was then cooled to room temperature and cannulated to a solution of 1-(2,3-dimethoxy-pyridin-4-yl)-propan-1-one (13.8 g; 70.8 mmol) in anhydrous tetrahydrofuran (300 mL). The reaction was stirred for 16 hours at room temperature and quenched with saturated ammonium chloride solution. The aqueous layer was extracted with dichloromethane. The combined extracts were dried over sodium sulfate and concentrated under reduced pressure and purified by chromatography (SiO2; 2-10% ethyl acetate/hexane) to give the product 3-(2,3-dimethoxy-pyridin-4-yl)-3-hydroxy-pentanoic acid tert-butyl ester (6) (16.0 g).
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:24]=[CH:23][CH:22]=[CH:21][C:4]=1[CH2:5][N:6]1[C:10]2[CH:11]=[C:12]([C:15](Cl)=[O:16])[CH:13]=[CH:14][C:9]=2[N:8]=[C:7]1[CH:18]1[CH2:20][CH2:19]1.[NH:25]1[CH2:30][CH2:29][O:28][CH2:27][CH2:26]1>C(Cl)Cl>[Cl:2][C:3]1[CH:24]=[CH:23][CH:22]=[CH:21][C:4]=1[CH2:5][N:6]1[C:10]2[CH:11]=[C:12]([C:15]([N:25]3[CH2:30][CH2:29][O:28][CH2:27][CH2:26]3)=[O:16])[CH:13]=[CH:14][C:9]=2[N:8]=[C:7]1[CH:18]1[CH2:19][CH2:20]1
Reactant: O=C(Cl)c1ccc2nc(C3CC3)n(Cc3ccccc3Cl)c2c1
Reactant: C1COCCN1
Agent: Cl
Solvent: ClCCl
Product: O=C(c1ccc2nc(C3CC3)n(Cc3ccccc3Cl)c2c1)N1CCOCC1
Reaction time: 1 h
Yield: 13.8 %

Procedure:
1-(2-Chlorobenzyl)-6-chlorocarbonyl-2-cyclopropylbenzimidazole hydrochloride (140 mg) was added to a solution prepared by adding 298 mg of morpholine (30% methanol solution) to 10 ml of methylene chloride at room temperature. The reaction mixture was stirred at the same temperature for 1 hour, then washed with water, dried, and concentrated under reduced pressure. The residue was recrystallized with ether to give 20 mg of 1-(2-chlorobenzyl)-2-cyclopropyl-6-morpholinocarbonylbenzimidazole (66).