Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1]C(C)([O-])C.[K+].[C:7]([O:11][C:12]([N:14]1[CH2:18][C:17](=O)[CH2:16][C@H:15]1[C:20]([OH:22])=[O:21])=[O:13])([CH3:10])([CH3:9])[CH3:8]>[Br-].C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.CC1CCCO1>[C:7]([O:11][C:12]([N:14]1[CH2:18][C:17](=[CH2:1])[CH2:16][C@H:15]1[C:20]([OH:22])=[O:21])=[O:13])([CH3:10])([CH3:9])[CH3:8]
Reactant: CC(C)(C)[O-]
Reactant: CC(C)(C)OC(=O)N1CC(=O)C[C@H]1C(=O)O
Agent: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Agent: [K+]
Solvent: CC1CCCO1
Product: C=C1C[C@@H](C(=O)O)N(C(=O)OC(C)(C)C)C1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
To a suspension of methyltriphenylphosphonium bromide (2.2 eq.) in 2-methyl tetrahydrofuran (3 vol) was added rapidly solid potassium tert-butoxide (2.3 eq.) maintaining the temperature around 0° C. The temperature was kept at +20° C. for 2 hours (a suspension remained) and re-cooled to 0° C. Keeping the temperature below 6° C., (S)-1-(tert-butoxycarbonyl)-4-oxopyrrolidine-2-carboxylic acid (1 eq.) was added over 40 minutes. The reaction was warmed to room temperature and stirred for 16 h and then cooled to 0° C. The reaction was quenched with saturated NaHCO3 (5 vol) and water (2 vol) and the aqueous layer was separated. The organic layer was extracted with saturated NaHCO3/water (1.8 vol/1.8 vol) and the combined aqueous layers were filtered through Celite®. The aqueous layer was acidified with 6 N HCl (2.6 vol) at ambient temperature and extracted twice with isopropyl acetate (16 vol, then 8 vol). The organic phase was dried (MgSO4) and the solvent removed. The crude product was dissolved in isopropyl acetate (10 vol) and extracted with 0.5 M NaOH (10 vol, then 1 vol). The combined aqueous layers were acidified at ambient temperature with 6 N HCl to pH=3, and extracted twice with ethyl acetate (10 vol, then 8 vol). The combined extracts were dried (Na2SO4), the solvent removed and the crude product was recrystallized from cyclohexane (5 vol) to afford the title compound. 1H-NMR (400 MHz, DMSO): δ 12.9, (broad, 1H); 5.00 (m, 2H); 4.24 (dt, J=1.9H, J=7.3 Hz, 1H), 3.91 (m, 2H); 2.98 (m, 1H); 2.50 (m, 1H, coincides with DMSO); 1.41 and 1.36 (2 s rotamers, 9H).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[NH:7][C:8]2[C:13]([C:14]=1[CH2:15][CH2:16][CH2:17][NH:18][C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])=[CH:12][C:11]([O:26]CC1C=CC=CC=1)=[CH:10][CH:9]=2)=[O:5])[CH3:2].[H][H]>CN(C=O)C.CCO.[OH-].[OH-].[Pd+2]>[CH2:1]([O:3][C:4]([C:6]1[NH:7][C:8]2[C:13]([C:14]=1[CH2:15][CH2:16][CH2:17][NH:18][C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])=[CH:12][C:11]([OH:26])=[CH:10][CH:9]=2)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1[nH]c2ccc(OCc3ccccc3)cc2c1CCCNC(=O)OC(C)(C)C
Reactant: [H][H]
Agent: [Pd+2]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: CCO
Product: CCOC(=O)c1[nH]c2ccc(O)cc2c1CCCNC(=O)OC(C)(C)C
Yield: 41.8 %

Procedure:
5-Benzyloxy-3-[3-(t-butoxycarbonylamino)-propyl]-1H-indole-2-carboxylic acid ethyl ester (170 mg, 0.37 mmol, 1.0 equiv) was dissolved in the mixture of DMF (3 mL) and EtOH (18 mL) and 30 mg of 20% Pd(OH)2 on carbon was added. The reaction was subjected to 40 psi of hydrogen gas in Parr apparatus for 10 h. The catalyst was filtered off over diatomaceous earth and the ethanol was removed on the rotovap. The residue was taken up in EtOAc and washed 3×20 ml, of brine. The organic layer was dried (Na2SO4), filtered, and evaporated. The crude product is a mixture of starting material and product. The crude residue was purified by flash chromatography on silica using 0% EtOAc in hexanes graded to 30% EtOAc in hexanes as the mobile phase to yield 5-hydroxy-3-[3-(t-butoxycarbonylamino)-propyl]-1H-indole-2-carboxylic acid ethyl ester (56 mg, 41%). This material was used without further manipulation.
Reaction SMILES: [CH2:1]1[C:8]2[N:4]([C:5]([C:9]([C:11]3[N:12]4[C:16](=[C:17]([C:20]([OH:22])=[O:21])[C:18]=3[CH3:19])[CH:15]([C:23]([OH:25])=[O:24])[CH2:14][CH2:13]4)=[O:10])=[CH:6][CH:7]=2)[CH2:3][CH2:2]1.[CH2:26](O)[CH3:27]>>[CH2:1]1[C:8]2[N:4]([C:5]([C:9]([C:11]3[N:12]4[C:16](=[C:17]([C:20]([OH:22])=[O:21])[C:18]=3[CH3:19])[CH:15]([C:23]([O:25][CH2:26][CH3:27])=[O:24])[CH2:14][CH2:13]4)=[O:10])=[CH:6][CH:7]=2)[CH2:3][CH2:2]1
Reactant: Cc1c(C(=O)O)c2n(c1C(=O)c1ccc3n1CCC3)CCC2C(=O)O
Reactant: CCO
Product: CCOC(=O)C1CCn2c(C(=O)c3ccc4n3CCC4)c(C)c(C(=O)O)c21

Procedure:
A stirred mixture of the diacid from Step C above (1.3 g, 0.0038 m), ethanol (30 ml) and resin catalyst (1.3 g; Biorad AG 50W-XB) was heated under reflux for 10 hours in an inert atmosphere, filtered hot, the solution allowed to cool, ice-bath cooled and filtered to yield ethyl 5-(2,3-dihydro-1H-pyrrolizine- 5-oyl)-7-carboxy-6-methyl-2,3-dihydro-1H-pyrrolizine-1-carboxylate (0.73 g) as a white solid.
Reaction SMILES: [CH3:1][CH:2]([CH3:12])[CH:3]([NH:5][C:6](=[O:11])[CH2:7][C:8](=[O:10])[CH3:9])[CH3:4].CO[CH:15](OC)[N:16]([CH3:18])[CH3:17]>CN(C)C=O>[CH3:15][N:16]([CH:18]=[C:7]([C:8](=[O:10])[CH3:9])[C:6]([NH:5][CH:3]([CH:2]([CH3:12])[CH3:1])[CH3:4])=[O:11])[CH3:17]
Reactant: CC(=O)CC(=O)NC(C)C(C)C
Reactant: COC(OC)N(C)C
Solvent: CN(C)C=O
Product: CC(=O)C(=CN(C)C)C(=O)NC(C)C(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 95.3 %

Procedure:
To a solution of N-(3-methylbutan-2-yl)-3-oxobutanamide obtained in Step A (500 mg) in N,N-dimethylformamide (6.0 mL) was added dropwise 1,1-dimethoxy-N,N-dimethylmethanamine (696 mg) over 5 min at room temperature, and the reaction mixture was stirred overnight at room temperature. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (methanol/ethyl acetate) to give the title compound (630 mg).
Reaction SMILES: [OH:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][C:10]=2[CH2:12][CH2:13][CH3:14])[C:5](/[CH:15]=[C:16](\[CH3:20])/[C:17]([OH:19])=[O:18])=[CH:4][C:3]=1[O:21][CH3:22].[C:23](OC(=O)C)(=[O:25])[CH3:24]>N1C=CC=CC=1>[C:23]([O:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][C:10]=2[CH2:12][CH2:13][CH3:14])[C:5](/[CH:15]=[C:16](/[CH3:20])\[C:17]([OH:19])=[O:18])=[CH:4][C:3]=1[O:21][CH3:22])(=[O:25])[CH3:24]
Reactant: CCCc1cccc2c(/C=C(\C)C(=O)O)cc(OC)c(O)c12
Reactant: CC(=O)OC(C)=O
Solvent: c1ccncc1
Product: CCCc1cccc2c(/C=C(/C)C(=O)O)cc(OC)c(OC(C)=O)c12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
7.1 g of (E)-3-(4-hydroxy-3-methoxy-5-propyl-1-naphthyl)-2-methylpropenoic acid was dissolved in 20 ml of pyridine and 2 ml of acetic anhydride was added, followed by stirring at room temperature overnight. The reaction mixture was concentrated in vacuo and the resultant crystals were filtered and washed with ethyl acetate to obtain 7.5 g of the titled compound as colorless crystals.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[C:13]([CH3:15])[C:12]([C:16]2[CH:20]=[CH:19][O:18][C:17]=2[CH2:21]O)=[C:11]([CH3:23])[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CC(C)=[O:26]>O>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH3:23])[C:12]([CH:16]2[C:20](=[O:26])[CH:19]=[CH:21][CH:17]2[OH:18])=[C:13]([CH3:15])[CH:14]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cc1cc(OCc2ccccc2)cc(C)c1-c1ccoc1CO
Reactant: CC(C)=O
Solvent: O
Product: Cc1cc(OCc2ccccc2)cc(C)c1C1C(=O)C=CC1O
Temperature: 55 °C

Procedure:
Polyphosphoric acid (5 g) is added to a warm (55° C.) solution of ([4-benzyloxy-2,6-dimethylphenyl]furan-2-yl)methanol (32 g) in a mixture of acetone (400 ml) and water (100 ml) and the mixture is heated at 55° C. for 20 hours. The reaction mixture is cooled to room temperature and most of the acetone is removed under reduced pressure. The mixture is extracted with diethyl ether (3×250 ml), and the organic fractions are washed with saturated aqueous sodium bicarbonate solution (2×200 ml), dried over anhydrous magnesium sulfate, filtered and the filtrate is evaporated under reduced pressure. The crude product (30.9 g) is used for the next step without further purification.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([NH2:9])=[N:5][CH:6]=[CH:7][CH:8]=1.[Cl:10]N1C(=O)CCC1=O>C(OCC)(=O)C>[NH2:9][C:4]1[C:3]([O:2][CH3:1])=[CH:8][C:7]([Cl:10])=[CH:6][N:5]=1
Reactant: COc1cccnc1N
Reactant: O=C1CCC(=O)N1Cl
Solvent: CCOC(C)=O
Product: COc1cc(Cl)cnc1N
Temperature: 25 °C
Reaction time: 8 h

Procedure:
3-Methoxy-2-aminopyridine (Wonda Science, cat #01683; 12.4 g, 0.01 mol) is dissolved by stirring in 500 ml of ethyl acetate. A thermometer is placed in the solution to monitor temperature. N-Chlorosuccinimide (13.3 g, 0.01 mol) is added in several portions to keep the solution at room temperature. The solution becomes dark in color and is stirred at room temperature overnight. The supernatant is decanted from the dark solids that formed and transferred to a separatory funnel. The organic solution is washed with 500 ml saturated aqueous sodium bisulfite and then 500 ml brine. The organic layer is dried with MgSO4 and concentrated on a rotovap. The dark brown crude product is chromatographed on 500 g of flash silica-gel eluting with 30% EtOAc/Hexanes. Concentration of the appropriate fractions on a rotovap gives a yellow solid. The solid is suspended in hexanes, stirred and filtered to give the product as a bright yellow solid. (MP 93-94° C.).
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[C:11]([O:12][CH3:13])=[CH:10][CH:9]=[CH:8][C:7]=2/[CH:14]=[CH:15]/[C:16]2[N:17]=[C:18]3[S:25][C:24]([CH3:26])=[C:23]([CH3:27])[N:19]3[C:20](=[O:22])[CH:21]=2)[CH2:3][CH2:2]1.[I:28]N1C(=O)CCC1=O>C(#N)C>[CH:1]1([CH2:4][O:5][C:6]2[C:11]([O:12][CH3:13])=[CH:10][CH:9]=[CH:8][C:7]=2/[CH:14]=[CH:15]/[C:16]2[N:17]=[C:18]3[S:25][C:24]([CH3:26])=[C:23]([CH3:27])[N:19]3[C:20](=[O:22])[C:21]=2[I:28])[CH2:3][CH2:2]1
Reactant: O=C1CCC(=O)N1I
Reactant: COc1cccc(/C=C/c2cc(=O)n3c(C)c(C)sc3n2)c1OCC1CC1
Solvent: CC#N
Product: COc1cccc(/C=C/c2nc3sc(C)c(C)n3c(=O)c2I)c1OCC1CC1

Procedure:
To a solution of Step 3 intermediate (500 mg, 1.568 mmol) in acetonitrile (10 ml) was added N-iodosuccinimide (494 mg, 2.195 mmol) and reacted according to the procedure described in Step 4, Intermediate 2 to afford 600 mg of the desired compound; 1H NMR (300 MHz, CDCl3) δ 0.32-0.34 (m, 2H), 0.54-0.56 (m, 2H), 1.17-1.20 (m, 1H), 2.29 (s, 3H), 2.58 (s, 3H), 3.75-3.77 (m, 2H), 3.80 (s, 3H), 7.04-7.13 (m, 2H), 7.25-7.27 (m, 1H), 7.47 (d, J=15.9 Hz, 1H), 8.12 (d, J=15.6 Hz, 1H); ESI-MS (m/z) 509.01 (M+H)+.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[CH:5][C:6]([N+:10]([O-])=O)=[C:7]([OH:9])[CH:8]=1)#[N:2].[Sn](Cl)Cl.[OH-].[Na+]>C(O)C>[NH2:10][C:6]1[CH:5]=[CH:4][C:3]([C:1]#[N:2])=[CH:8][C:7]=1[OH:9]
Reactant: N#Cc1ccc([N+](=O)[O-])c(O)c1
Agent: Cl[Sn]Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: N#Cc1ccc(N)c(O)c1
Temperature: 80 °C
Reaction time: 2 h
Yield: 87 %

Procedure:
A mixture of 5-cyano-2-nitrophenol(250 mg, 1.5 mmol) and tin (II) chloride (3.2 g, 14.4 mmol) in ethanol(50 mL) was heated at 80° C. under argon. After 2 hours, the starting material has disappeared and the solution was allowed to cool down and then poured into ice. The pH was made slightly basic (pH7-8), by addition of solid NaOH, before being extracted with ethyl acetate. The organic phase was washed with brine, dried over MgSO4 and filtered. The solvent was evaporated and chromatography of the resulting solid on silica gel (4%MeOH/CH2Cl2) gave the desired product(175 mg, 86%). 1H NMR (CD3OD): δ 7.00 (d, 1H), 6.88 (s,1H), 6.69 (d, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11]([N:13]3[CH2:18][CH2:17][CH:16]([C:19]4[C:24]([O:25][CH3:26])=[CH:23][CH:22]=[CH:21][C:20]=4[O:27][CH3:28])[CH2:15][CH2:14]3)=[O:12])=[CH:7][NH:8]2)=[CH:4][CH:3]=1.Cl[CH2:30][C:31]1[CH:32]=[N:33][CH:34]=[CH:35][CH:36]=1>>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11]([N:13]3[CH2:14][CH2:15][CH:16]([C:19]4[C:24]([O:25][CH3:26])=[CH:23][CH:22]=[CH:21][C:20]=4[O:27][CH3:28])[CH2:17][CH2:18]3)=[O:12])=[CH:7][N:8]2[CH2:30][C:31]2[CH:32]=[N:33][CH:34]=[CH:35][CH:36]=2)=[CH:4][CH:3]=1
Reactant: COc1cccc(OC)c1C1CCN(C(=O)c2c[nH]c3cc(Cl)ccc23)CC1
Reactant: ClCc1cccnc1
Product: COc1cccc(OC)c1C1CCN(C(=O)c2cn(Cc3cccnc3)c3cc(Cl)ccc23)CC1

Procedure:
Following general procedure II, the alkylation of (6-chloro-1H-indol-3-yl)-[4-(2,6-dimethoxy-phenyl)-piperidin-1-yl]-methanone (preparation described herein), with commercially available 3-chloromethyl-pyridine gave the title compound.
Reaction SMILES: [O:1]1[CH:5]2[O:6][CH2:7][CH2:8][CH:4]2[CH:3]([O:9][C:10](=[O:28])[NH:11][CH:12]([CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH:13]([OH:20])[CH2:14][NH:15][CH2:16][CH:17]([CH3:19])[CH3:18])[CH2:2]1.[F:29][C:30]1[CH:35]=[CH:34][C:33]([S:36](Cl)(=[O:38])=[O:37])=[CH:32][C:31]=1[C:40]#[N:41].C([O-])(O)=O.[Na+]>C(OCC)(=O)C>[O:1]1[CH:5]2[O:6][CH2:7][CH2:8][CH:4]2[CH:3]([O:9][C:10](=[O:28])[NH:11][CH:12]([CH2:21][C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH:13]([OH:20])[CH2:14][N:15]([S:36]([C:33]2[CH:34]=[CH:35][C:30]([F:29])=[C:31]([C:40]#[N:41])[CH:32]=2)(=[O:37])=[O:38])[CH2:16][CH:17]([CH3:19])[CH3:18])[CH2:2]1
Reactant: N#Cc1cc(S(=O)(=O)Cl)ccc1F
Reactant: CC(C)CNCC(O)C(Cc1ccccc1)NC(=O)OC1COC2OCCC12
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Product: CC(C)CN(CC(O)C(Cc1ccccc1)NC(=O)OC1COC2OCCC12)S(=O)(=O)c1ccc(F)c(C#N)c1
Yield: 92 %

Procedure:
To a solution of (1-benzyl-2-hydroxy-3-isobutylamino-propyl)-carbamic acid hexahydro-furo[2,3-b]furan-3-yl ester 19 in CH2C12 (4 mL) was added 4-fluoro-3-cyanobenzenesulfonyl chloride (92 mg, 0.42 mmol) followed by NaHCO3 (40 mg) and satd. NaHCO3 (0.4 mL) and stirred at RT for 1 h. The reaction mixture was diluted with ethyl acetate (25 mL) and washed with water, brine and dried with Na2SO4 and concentrated to furnish crude product (240 mg). The crude product was purified by column chromatography using 1/1 ethyl acetate/hexane to provide 200 mg product (92% yield).
Reaction SMILES: Cl[C:2]1[N:11]=[C:10]([C:12]2[CH:20]=[CH:19][CH:18]=[C:17]3[C:13]=2[C:14]([CH3:31])=[CH:15][N:16]3[S:21]([C:24]2[CH:30]=[CH:29][C:27]([CH3:28])=[CH:26][CH:25]=2)(=[O:23])=[O:22])[CH:9]=[C:8]([CH3:32])[C:3]=1[C:4]([O:6][CH3:7])=[O:5].[CH2:33]([Sn](CCCC)(CCCC)C=C)[CH2:34]CC>CN(C=O)C>[CH3:32][C:8]1[C:3]([C:4]([O:6][CH3:7])=[O:5])=[C:2]([CH:33]=[CH2:34])[N:11]=[C:10]([C:12]2[CH:20]=[CH:19][CH:18]=[C:17]3[C:13]=2[C:14]([CH3:31])=[CH:15][N:16]3[S:21]([C:24]2[CH:25]=[CH:26][C:27]([CH3:28])=[CH:29][CH:30]=2)(=[O:22])=[O:23])[CH:9]=1
Reactant: COC(=O)c1c(C)cc(-c2cccc3c2c(C)cn3S(=O)(=O)c2ccc(C)cc2)nc1Cl
Reactant: C=C[Sn](CCCC)(CCCC)CCCC
Solvent: CN(C)C=O
Product: C=Cc1nc(-c2cccc3c2c(C)cn3S(=O)(=O)c2ccc(C)cc2)cc(C)c1C(=O)OC
Temperature: 60 °C
Reaction time: 24 h

Procedure:
A solution of methyl 2-chloro-4-methyl-6-(3-methyl-1-tosyl-1H-indol-4-yl)nicotinate (0.348 g, 0.742 mmol) in DMF (5 mL) was sparged with argon for 10 min before trans-Pd(PPh3)2Cl2 (0.052 g, 0.074 mmol), tri-n-butyl(vinyl)tin (0.353 g, 1.11 mmol), and BHT (0.016 g, 0.074 mmol) were added. The resulting suspension was sparged with argon for 5 min and the vessel was sealed and heated at 60° C. After 24 h the reaction was allowed to cool to rt and 50% KF on Celite® was added. The resulting slurry was then filtered over Celite® eluting with EtOAc. The organic was then washed with 10% KF in water and then dried (Na2SO4), filtered and concentrated. The residue was then purified by FCC (5-40% EtOAc/heptane) to give the title compound. MS ESI m/z 461.1 (M+H)+.
Reaction SMILES: C(O)(=O)C.[CH3:5][O:6][P:7]([CH2:27][NH2:28])([CH2:9][CH:10]([C:15](=[O:26])[NH:16][C@H:17]([C:22](=[O:25])[NH:23][CH3:24])[CH2:18][CH:19]([CH3:21])[CH3:20])[CH2:11][CH:12]([CH3:14])[CH3:13])=[O:8].[C:29]1([C:35]2[C:36]([O:38][C:39](=O)[CH:40]=2)=[O:37])[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1>>[CH3:5][O:6][P:7]([CH2:9][CH:10]([C:15](=[O:26])[NH:16][C@H:17]([C:22](=[O:25])[NH:23][CH3:24])[CH2:18][CH:19]([CH3:21])[CH3:20])[CH2:11][CH:12]([CH3:14])[CH3:13])([CH2:27][N:28]1[C:39](=[O:38])[CH:40]=[C:35]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[C:36]1=[O:37])=[O:8]
Reactant: CNC(=O)[C@H](CC(C)C)NC(=O)C(CC(C)C)CP(=O)(CN)OC
Reactant: O=C1C=C(c2ccccc2)C(=O)O1
Solvent: CC(=O)O
Product: CNC(=O)[C@H](CC(C)C)NC(=O)C(CC(C)C)CP(=O)(CN1C(=O)C=C(c2ccccc2)C1=O)OC
Yield: 24.5 %

Procedure:
In a manner analogous to that described in Example 3(A), from 0.7 g of (aminomethyl)[(RS)-4-methyl-2-[[(S)-3-methyl-1-(methylcarbamoyl)butyl]carbamoyl]pentyl]phosphinic acid methyl ester acetate and 0.29 g of phenylmaleic anhydride, there was obtained 0.21 g of [(RS)-4-methyl-2-[[(S)-3-methyl-1-(methylcarbamoyl)butyl]carbamoyl]pentyl][(2-phenylmaleimido)methyl]phosphinic acid methyl ester in the form of a pale yellow foam.
Reaction SMILES: [H-].[Na+].[C:3]([C:5]1[C:13]2[C:8](=[N:9][C:10]([C:15]3[CH:20]=[CH:19][N:18]=[CH:17][CH:16]=3)=[N:11][C:12]=2[NH2:14])[NH:7][N:6]=1)#[N:4].[CH:21]1(Br)[CH2:25][CH2:24][CH2:23][CH2:22]1>CN(C=O)C>[CH:21]1([N:7]2[C:8]3=[N:9][C:10]([C:15]4[CH:20]=[CH:19][N:18]=[CH:17][CH:16]=4)=[N:11][C:12]([NH2:14])=[C:13]3[C:5]([C:3]#[N:4])=[N:6]2)[CH2:25][CH2:24][CH2:23][CH2:22]1
Reactant: N#Cc1n[nH]c2nc(-c3ccncc3)nc(N)c12
Reactant: BrC1CCCC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: N#Cc1nn(C2CCCC2)c2nc(-c3ccncc3)nc(N)c12
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 7.4 %

Procedure:
To a suspension of 97% NaH (0.64 g, 0.026 mol) in DMF (75 ml) was added 3-cyano-6-(4-pyridyl)-pyrazolo[3,4-d]pyrimidin-4-amine (4.7 g, 0.02 mol). The reaction mixture was stirred at room temperature for 30 minutes then cyclopentyl bromide (3.1 g, 0.021 mol) in DMF (25 ml) was added dropwise. The reaction mixture was heated on a steam bath for 3 hours, cooled to room temperature and stirred for 24 hours. Inorganic salts were removed by filtration and the filtrate was concentrated in vacuo. The residue was purified by column chromatography on silica eluting with ethyl acetate (100%) followed by preparative thin layer chromatography on silica eluting with ethyl acetate/hexanes (75/25) to afford 0.45 g (7%) of 1-cyclopentyl-3-cyano-6-(4-pyridyl)-pyrazolo[3,4-d]pyrimidin-4-amine, m.p. 219°-221° C. when recrystallized from ether and dried for 16 hours at 90° C. in high vacuum.
Reaction SMILES: Cl.[CH3:2][C:3]1(O)[C:7]([CH3:9])(O)[NH:6][C:5]([CH2:10][CH2:11][CH3:12])=[N:4]1.Cl.[OH2:15]>>[CH3:2][C:3]1[NH:4][C:5]([CH2:10][CH2:11][CH3:12])=[N:6][C:7]=1[CH2:9][OH:15]
Reactant: O
Reactant: CCCC1=NC(C)(O)C(C)(O)N1
Agent: Cl
Product: CCCc1nc(CO)c(C)[nH]1

Procedure:
The product from Example 4 is dissolvedi 900 ml. of water and 350 ml. of concentrated hydrochloride, heated on a steam bath for 5 hours and then chilled. The solution is concentrated in vacuo and a mixture of 100 ml. of acetone and 100 ml. of ethanol is added. The mixture is filtered. The filtrate is evaporated and the residue is dissolved in 50 ml. of water and neutralized with a concentrated solution of K2CO3, until bubbling ceases. The top layer is separated and combined with 5 ml. of methanol. On standing, a precipitate forms. The solid is collected and the filtrate is diluted with acetone to give a second precipitate which is also collected. The solids are combined and recrystallized from hot acetone giving the desired product, m.p 134°-136° C.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([N:11]2[CH2:16][CH2:15][N:14]([C:17]3[C:26]4[C:21](=[CH:22][C:23]([O:29][CH3:30])=[C:24]([O:27][CH3:28])[CH:25]=4)[N:20]=[CH:19][N:18]=3)[CH2:13][CH2:12]2)=[O:10])=[CH:4][CH:3]=1.[H-].[Na+].[CH3:33]I.[Cl-].[Na+]>CN(C)C=O.O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]([CH3:33])[C:9]([N:11]2[CH2:12][CH2:13][N:14]([C:17]3[C:26]4[C:21](=[CH:22][C:23]([O:29][CH3:30])=[C:24]([O:27][CH3:28])[CH:25]=4)[N:20]=[CH:19][N:18]=3)[CH2:15][CH2:16]2)=[O:10])=[CH:4][CH:3]=1
Reactant: COc1cc2ncnc(N3CCN(C(=O)Nc4ccc(Br)cc4)CC3)c2cc1OC
Reactant: CI
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1cc2ncnc(N3CCN(C(=O)N(C)c4ccc(Br)cc4)CC3)c2cc1OC
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 81 %

Procedure:
To a solution of 1.01 g (2.15 mmol) of N-(4-bromophenyl)-4-(6,7-dimethoxy-4-quinazolinyl)-1-piperazinecarboxamide obtained in Example 45 in 15 ml of dimethylformamide was added 171.9 mg (4.30 mmol) of 60% sodium hydride under ice-cooling, followed by stirring at room temperature for 30 minutes. To the reaction mixture was added 0.27 ml (4.34 mmol) of methyl iodide, followed by overnight stirring at room temperature. The resulting mixture was poured into water, and sodium chloride was added thereto. The precipitated crystals were collected by filtration, washed with water, and dried, followed by purification by silica gel column chromatography to give the desired compound as colorless crystals.
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([C:10](=O)[CH3:11])[N:5]=1)(=O)[CH3:2].[F:13][C:14]1[CH:20]=[CH:19][CH:18]=[C:17]([F:21])[C:15]=1[NH2:16]>C1(C)C=CC=CC=1>[F:13][C:14]1[CH:20]=[CH:19][CH:18]=[C:17]([F:21])[C:15]=1[N:16]=[C:1]([C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([C:10](=[N:16][C:15]2[C:14]([F:13])=[CH:20][CH:19]=[CH:18][C:17]=2[F:21])[CH3:11])[N:5]=1)[CH3:2]
Reactant: Nc1c(F)cccc1F
Reactant: CC(=O)c1cccc(C(C)=O)n1
Solvent: Cc1ccccc1
Product: CC(=Nc1c(F)cccc1F)c1cccc(C(C)=Nc2c(F)cccc2F)n1

Procedure:
2,6-Diacetylpyridine (1.76 g, 10.8 mmol) and 2,6-difluoroaniline (2.94 g, 22.8 mmol) were dissolved in 50 ml of toluene. To this solution, 4 Å molecular sieves were added. After standing for 3 days, with addition of more 4 Å molecular sieves the mixture was filtered. The solvent was removed in vacuo. The residue was crystallised from ethanol. Yield of 4: 1 g (24%). 1H-NMR (CDCl3) δ 8.44 (d, 2H, Py-Hm), 7.90 (t, 1H, Py-Hp), 7.05 (m, 2H, ArH) 6.96 (m, 4H, ArH), 2.44 (s, 6H, Me). 19F-NMR (CDCl3) δ −123.6.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7]2[N:11]=[C:10]3[NH:12][CH2:13][CH2:14][N:9]3[C:8]=2[CH:15]=1)([O-])=O.C([O-])=O.[NH4+]>CO.[Pd]>[NH2:1][C:4]1[CH:5]=[CH:6][C:7]2[N:11]=[C:10]3[NH:12][CH2:13][CH2:14][N:9]3[C:8]=2[CH:15]=1
Reactant: O=[N+]([O-])c1ccc2nc3n(c2c1)CCN3
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CO
Product: Nc1ccc2nc3n(c2c1)CCN3
Reaction time: 12 h
Yield: 35.6 %

Procedure:
1 g of palladium-on-charcoal at 10% is added, under argon, to a vigorously stirred solution of 2.7 g (13.22 mmol) of 2,3-dihydro-6-nitro-1H-imidazo[1,2-a]-benzimidazole (R. J. North et al., J. Het. Chem., 1969, 6, 655) in 100 ml of methanol. 15 g (0.23 mol) of ammonium formate are added to the reaction mixture and the suspension is subsequently stirred for 12 h. A solid is recovered by filtration and is purified by silica column chromatography (eluent: dichloromethane-methanol). 0.82 g of the expected product is obtained in the form of a grey solid after drying under reduced pressure.