Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:3]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[CH:16]=[N:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:4]([CH3:9])=[C:5]([CH3:8])[C:6]=1[CH3:7].[BH4-].[Na+].O.C1(C)C=CC=CC=1>C(O)C>[CH3:1][C:2]1[CH:3]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[CH2:16][NH:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:4]([CH3:9])=[C:5]([CH3:8])[C:6]=1[CH3:7]
Reactant: CC1=C(C)C(c2ccccc2C=Nc2ccccc2)C(C)=C1C
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Solvent: Cc1ccccc1
Product: CC1=C(C)C(c2ccccc2CNc2ccccc2)C(C)=C1C
Yield: 65.9 %

Procedure:
To a solution of N-[2-(2,3,4,5-tetramethylcyclopentadienyl)phenylmethylene]-N-phenylamine (3.0 mmol) in ethanol (9.0 ml) was added sodium borohydride (4.5 mmol) and the mixture was reacted at room temperature for 3 hrs. Water and toluene were then added to the mixture. The organic layer was dried and concentrated. The obtained oily substance was purified by silica gel column chromatography to give N-[2-(2,3,4,5-tetramethylcyclopentadienyl)phenylmethyl]-N-phenylamine (0.60 g, yield 66.0%) as a yellow oily substance.
Reaction SMILES: [CH2:1]([OH:4])[C:2]#[CH:3].[CH:5]([C:9]1[CH:14]=[CH:13][C:12]([N:15]2C(=O)C3[C:18](=[CH:19][CH:20]=[CH:21]C=3)[N:17]=[C:16]2[C:26]2[CH:31]=[CH:30][C:29]([NH:32][C:33](=O)[C:34](F)(F)F)=[C:28](I)[CH:27]=2)=[CH:11][CH:10]=1)([CH2:7][CH3:8])[CH3:6].CN([CH:43]=[O:44])C>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH:5]([C:9]1[CH:10]=[CH:11][C:12]([N:15]2[C:1](=[O:4])[C:2]3[C:18](=[CH:19][CH:20]=[CH:21][CH:3]=3)[N:17]=[C:16]2[C:26]2[CH:27]=[C:28]3[C:29](=[CH:30][CH:31]=2)[NH:32][C:33]([CH2:43][OH:44])=[CH:34]3)=[CH:13][CH:14]=1)([CH2:7][CH3:8])[CH3:6]
Reactant: CN(C)C=O
Reactant: C#CCO
Reactant: CCC(C)c1ccc(-n2c(-c3ccc(NC(=O)C(F)(F)F)c(I)c3)nc3ccccc3c2=O)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Product: CCC(C)c1ccc(-n2c(-c3ccc4[nH]c(CO)cc4c3)nc3ccccc3c2=O)cc1
Temperature: 60 °C
Yield: 29 %

Procedure:
Propargyl alcohol (0.045 mL, 0.76 mmol) and PdCl2(PPh3)2 (0.007 g, 0.01 mmol) were added to a solution of N-(4-(3-(4-sec-butylphenyl)-4-oxo-3,4-dihydroquinazolin-2-yl)-2-iodophenyl)-2,2,2-trifluoroacetamide (0.300 g, 0.51 mmol) in TEA (10 mL) and DMF (3 mL). After heating to 60° C. for 5 hours, the reaction mixture was concentrated in vacuo. The residue was dissolved in EtOAc, washed with saturated NaHCO3, then brine, dried (Na2SO4), filtered, and concentrated in vacuo. Purification by flash chromatography on silica gel, eluting with 20% to 80% EtOAc in heptane, plus further purification by flash chromatography on silica gel, eluting with 10% to 50% EtOAc in CH2Cl2, afforded the title compound as a white solid (0.065 g, 29%). 1H-NMR (300 MHz, DMSO-d6): δ11.09 (s, 1H), 8.18 (d, J=7.1 Hz, 1H), 7.87-7.90 (m, 1H), 7.75 (d, J=8.0 Hz, 1H), 7.47-7.64 (m, 2H), 6.93-7.25 (m, 6H), 6.19 (s, 1H), 5.23 (t, J=5.6 Hz, 1H), 4.54 (d, J=5.5 Hz, 2H), 2.53-2.61 (m, 1H), 1.30-1.62 (m, 2H), 1.12 (d, J=6.9 Hz, 3H), 0.63 (t, J=7.2 Hz, 3H). MS (APCI) m/z: 424 (M+H)+.
Reaction SMILES: COC1C=CC(C[NH:8][C:9]2[CH:14]=[C:13]([N:15]3[CH:19]=[N:18][C:17]([NH:20][C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=4)=[N:16]3)[CH:12]=[CH:11][N:10]=2)=CC=1.C(O)(=O)C>C(O)(C(F)(F)F)=O>[C:21]1([NH:20][C:17]2[N:18]=[CH:19][N:15]([C:13]3[CH:12]=[CH:11][N:10]=[C:9]([NH2:8])[CH:14]=3)[N:16]=2)[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1
Reactant: COc1ccc(CNc2cc(-n3cnc(Nc4ccccc4)n3)ccn2)cc1
Solvent: CC(=O)O
Solvent: O=C(O)C(F)(F)F
Product: Nc1cc(-n2cnc(Nc3ccccc3)n2)ccn1
Reaction time: 16 h

Procedure:
[1.5 g, 4.03 mMol] of (4-Methoxy-benzyl)-[4-(3-phenylamino-[1,2,4]triazol-1-yl)-pyridin-2-yl]-amine was dissolved in 25 mL of TFA and stirred at 40 C in a sealed tube for 16 hrs. Then, 10 mL of glacial acetic acid was added and the mixture was stirred at 40 C for an additional 24 hr. The solvent was removed under reduced pressure and the residue triturated with MTBE, The crude material was treated with water and neutralized with 11.4N ammonium hydroxide to pH 9. The resulting solid was isolated via suction filtration and washed with water. This crude product was treated with 0.25N HCl and particulates removed via suction filtration. The filtrates were neutralized with conc. ammonium hydroxide to a pH of 10 and the mixture was extracted with chloroform twice. The organics were combined and washed with water and brine, dried (Na2SO4), and concentrated under reduced pressure. Tan powder collected; 300 mg (33%). 1H NMR 500 MHz (DMSO-d6) ∂ 6.22 (s ex, 2H), 6.88 (m, 2H), 7.09d, 1H), 7.26 (t, 2H), 7.67 (d, 2H), 7.97 (d, 1H), 9.14 (s, 1H), 9.52 (s ex, 1H). LC/MS [M+H+] 253.
Reaction SMILES: [CH2:1]([NH:7][S:8]([C:11]1[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[C:13]([O:19][CH3:20])[CH:12]=1)(=[O:10])=[O:9])[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].[H-].[Na+].[CH3:23][O:24][C:25]1[CH:26]=[C:27]([S:33](Cl)(=[O:35])=[O:34])[CH:28]=[CH:29][C:30]=1[O:31][CH3:32].O>CN(C=O)C>[CH3:20][O:19][C:13]1[CH:12]=[C:11]([S:8]([N:7]([CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH3:6])[S:33]([C:27]2[CH:28]=[CH:29][C:30]([O:31][CH3:32])=[C:25]([O:24][CH3:23])[CH:26]=2)(=[O:35])=[O:34])(=[O:10])=[O:9])[CH:16]=[CH:15][C:14]=1[O:17][CH3:18]
Reactant: COc1ccc(S(=O)(=O)Cl)cc1OC
Reactant: CCCCCCNS(=O)(=O)c1ccc(OC)c(OC)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCCCCCN(S(=O)(=O)c1ccc(OC)c(OC)c1)S(=O)(=O)c1ccc(OC)c(OC)c1
Reaction time: 0.5 h
Yield: 24.7 %

Procedure:
To a stiffing solution of N-hexyl-3,4-dimethoxybenzenesulfonamide (0.250 g, 0.830 mmol) in 3.30 mL of DMF, NaH (0.037 g, 0.913 mmol; 60% in oil dispersion) was added. After 30 mins, 3,4-dimethoxybenzenesulfonyl chloride (0.222 g, 0.937 mmol) was added. After a further 1 hr, the reaction solution was poured over water (15 mL) forming a white solid. The solid was filtered and recrystallized from methanol to afford 0.103 g (25%) of N-(3,4-dimethoxyphenylsulfonyl)-N-hexyl-3,4-dimethoxybenzenesulfonamide as a white solid. 1H NMR (acetone-d6, 400 MHz) δ 7.62 (dd, J=2.9, 8.2 Hz, 2H), 7.57 (d, J=2.3 Hz, 2H), 6.94 (d, J=8.6 Hz, 2H), 3.95 (s, 12H), 3.60 (m, 2H), 1.63 (m, 2H), 1.21 (m, 6H), 0.85 (t, J=6.8 Hz, 3H); 13C NMR (acetone-d6, 100 MHz) δ 150.05, 144.99, 131.10, 121.34, 115.05, 115.00, 49.00, 31.65, 26.38, 22.45, 13.51.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C@H:9]([NH:13][C:14](=[O:20])[O:15][C:16]([CH3:19])([CH3:18])[CH3:17])[CH2:10][CH2:11]I)[CH:5]=[CH:6][C:7]=1[Cl:8].[CH3:21][S-:22].[Na+].O>CS(C)=O>[Cl:1][C:2]1[CH:3]=[C:4]([C@H:9]([NH:13][C:14](=[O:20])[O:15][C:16]([CH3:19])([CH3:18])[CH3:17])[CH2:10][CH2:11][S:22][CH3:21])[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: C[S-]
Reactant: CC(C)(C)OC(=O)N[C@H](CCI)c1ccc(Cl)c(Cl)c1
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: CSCC[C@@H](NC(=O)OC(C)(C)C)c1ccc(Cl)c(Cl)c1
Yield: 60 %

Procedure:
A solution of 366 (810 mg, 1.88 mmol) and sodium methanethiolate (158 mg, 2.26 mmol) in DMSO (4 mL) was stirred at 50° C. overnight. The mixture was poured into water, extracted with EtOAc, washed with brine, dried (MgSO4), and concentrated in vacuo to afford 395 mg (60%) of (R)-tert-butyl 1-(3,4-dichlorophenyl)-3-(methylthio)propylcarbamate (372).
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][N:3]=[C:2]1[C:6]1[CH:11]=[CH:10][C:9]([CH2:12][CH2:13][NH2:14])=[CH:8][CH:7]=1.C[Al](C)C.[CH3:19][O:20][C:21]1[CH:26]=[C:25]([CH3:27])[C:24]([S:28]([N:31]([CH2:33][C:34]2[N:38]=[C:37]([C:39](OCC)=[O:40])[O:36][N:35]=2)[CH3:32])(=[O:30])=[O:29])=[C:23]([CH3:44])[CH:22]=1.ClCCCl>C(Cl)Cl>[NH:3]1[CH2:4][CH2:5][N:1]=[C:2]1[C:6]1[CH:7]=[CH:8][C:9]([CH2:12][CH2:13][NH:14][C:39]([C:37]2[O:36][N:35]=[C:34]([CH2:33][N:31]([S:28]([C:24]3[C:23]([CH3:44])=[CH:22][C:21]([O:20][CH3:19])=[CH:26][C:25]=3[CH3:27])(=[O:30])=[O:29])[CH3:32])[N:38]=2)=[O:40])=[CH:10][CH:11]=1
Reactant: NCCc1ccc(C2=NCCN2)cc1
Reactant: CCOC(=O)c1nc(CN(C)S(=O)(=O)c2c(C)cc(OC)cc2C)no1
Agent: C[Al](C)C
Solvent: ClCCl
Solvent: ClCCCl
Product: COc1cc(C)c(S(=O)(=O)N(C)Cc2noc(C(=O)NCCc3ccc(C4=NCCN4)cc3)n2)c(C)c1
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
To a stirred solution of 2-[4-(4,5-dihydro-1H-imidazol-2-yl)phenyl]ethanamine (bis TFA salt, 108 mg, 0.26 mmol) in DCM (3 mL) at 0° C. was added trimethyl aluminium (2 M in toluene, 0.13 mL, 0.26 mmol) and the mixture was stirred at 0° C. for 15 min. Ethyl 3-({[(4-methoxy-2,6-dimethylphenyl)sulfonyl](methyl)amino}methyl)-1,2,4-oxadiazole-5-carboxylate (50 mg, 0.13 mmol) was added dropwise as a solution in DCM (2 mL), followed by TEA (0.045 mL, 0.32 mmol). The reaction was stirred at ambient temperature for 18 h, after which time TEA (0.110 mL, 0.79 mmol) and DCE (4 mL) were added. The reaction was heated to 60° C. for 18 h, then partitioned between saturated aqueous NH4Cl (20 mL) and EtOAc (2×20 mL). The aqueous layer was extracted with DCM (2×10 mL) and these extracts were dried over MgSO4 and solvents were removed in vacuo. A portion of the product was purified using prep method A.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([C:8]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12](C)[N:11]=2)=O)[O:5][C:6]=1[CH3:7].[NH3:17].[CH3:18]O>>[CH3:1][C:2]1[CH:3]=[C:4]([OH:5])[C:8]([C:10]2[CH:15]=[C:14]([CH3:18])[CH:13]=[CH:12][N:11]=2)=[N:17][C:6]=1[CH3:7]
Reactant: N
Reactant: CO
Reactant: Cc1cccc(C(=O)c2cc(C)c(C)o2)n1
Product: Cc1ccnc(-c2nc(C)c(C)cc2O)c1
Temperature: 160 °C
Reaction time: 8 h
Yield: 89 %

Procedure:
(4,5-Dimethylfuran-2-yl)-(6-methyl-pyridin-2-yl)methanone (690 mg), methanol (6 ml), and a 28% aqueous ammonia solution (6 ml) were placed in a sealed tube and were stirred at 160° C. overnight. The reaction solution was cooled to room temperature, the solvent was then removed by distillation under the reduced pressure, and the residue was purified by column chromatography using hexane-ethyl acetate to give 5,6,4′-trimethyl-[2,2′]bipyridin-3-ol (611 mg, yield 89%).
Reaction SMILES: [C:1]1(O)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][N:7]=1.COC.[ClH:12].[C:13]1([NH:19][NH2:20])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>C(O)C>[ClH:12].[C:13]1([NH:19][N:20]=[C:1]2[NH:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]2)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: NNc1ccccc1
Reactant: OC1=NCCCCC1
Agent: COC
Agent: Cl
Solvent: CCO
Product: c1ccc(NN=C2CCCCCN2)cc1
Reaction time: 2 h
Yield: 91.8 %

Procedure:
127 G (1 mole) of caprolactim-methyl-ether were added dropwise over the course of 30 minutes to a mixture of 144.5 g (1 mole) of phenylhydrazine hydrochloride and 700 ml of anhydrous ethanol at -10°C, while stirring well and cooling; the mixture was kept for a further hour at -10°C, then for 2 hours at room temperature and for 30 minutes at the reflux temperature. After cooling, the mixture was filtered and further crystal fractions were isolated by concentrating the mother liquor under reduced pressure. Recrystallization from 5 parts of ethanol yielded 220 g (92% of theory) of caprolactam-phenylhydrazone hydrochloride as almost colorless crystals of melting point 244° to 246°C (with decomposition).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[S:10][C:9]([N:11]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[N:8][C:7]=1[CH2:25]Br)=[O:5])[CH3:2].[CH2:27]([O:29][C:30](=[O:44])[CH2:31][NH:32][CH2:33][C:34]1[CH:39]=[CH:38][C:37]([O:40][CH3:41])=[CH:36][C:35]=1[O:42][CH3:43])[CH3:28].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[CH2:1]([O:3][C:4]([C:6]1[S:10][C:9]([N:11]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[N:8][C:7]=1[CH2:25][N:32]([CH2:33][C:34]1[CH:39]=[CH:38][C:37]([O:40][CH3:41])=[CH:36][C:35]=1[O:42][CH3:43])[CH2:31][C:30]([O:29][CH2:27][CH3:28])=[O:44])=[O:5])[CH3:2]
Reactant: CCOC(=O)c1sc(N(C(=O)OC(C)(C)C)c2ccccc2)nc1CBr
Reactant: CCOC(=O)CNCc1ccc(OC)cc1OC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)CN(Cc1ccc(OC)cc1OC)Cc1nc(N(C(=O)OC(C)(C)C)c2ccccc2)sc1C(=O)OCC
Temperature: 25 °C
Reaction time: 18 h
Yield: 89.8 %

Procedure:
A mixture of 4-bromomethyl-2-(tert-butoxycarbonyl-phenyl-amino)-thiazole-5-carboxylic acid ethyl ester (451 mg, 1.02 mmol), (2,4-dimethoxy-benzylamino)-acetic acid ethyl ester (260 mg, 1.02 mmol) and potassium carbonate (213 g, 1.54 mmol) in anhydrous dimethylformamide (4 mL) was stirred at room temperature for 18 h before it was quenched with water, extracted with ethyl acetate. The organic layer was washed with water, brine, dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel with a gradient of ethyl acetate and hexanes to give the title compound as a white solid (562 mg): MS: (+) m/z 614.13 (M+1).
Reaction SMILES: [Cl-].[NH4+:2].[Br:3][C:4]1[C:9]([F:10])=[CH:8][CH:7]=[C:6]([N+:11]([O-])=O)[C:5]=1CN.[CH3:16]O.O>[Fe]>[Br:3][C:4]1[C:9]([F:10])=[CH:8][CH:7]=[C:6]([NH2:11])[C:5]=1[NH:2][CH3:16]
Reactant: [NH4+]
Reactant: CO
Reactant: NCc1c([N+](=O)[O-])ccc(F)c1Br
Agent: [Fe]
Agent: [Cl-]
Solvent: O
Product: CNc1c(N)ccc(F)c1Br
Yield: 47 %

Procedure:
Ammonium chloride (6.24 g, 117 mmol) and iron powder (4.34 g, 77.7 mmol) were added to a stirred mixture of (2-bromo-3-fluoro-6-nitrophenyl)methylamine (4.84 g, 19.4 mmol) in 3:1 methanol/water (320 mL) and the resultant mixture heated at reflux for 24 h. The solid material was removed by filtration and the filtrate concentrated to approximately ⅓ volume. This mixture was partitioned between DCM (3×) and water then the combined DCM extracts were dried (Na2SO4) and concentrated in vacuo. The resulting residue was purified by chromatography (SiO2, eluting with 0-5% methanol in DCM) to give title compound as an oil (1.99 g, 47%). LCMS (Method C): RT 2.37 min [M+H]+ 219.0, 221.0
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([OH:31])[CH2:9][CH2:10][CH:11]2[CH:14]([C:15]3[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=3)[N:13]([C:23]3[CH:28]=[CH:27][C:26]([OH:29])=[CH:25][CH:24]=3)[C:12]2=[O:30])=[C:4]([F:32])[CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:39]1[S:44](=[O:46])(=[O:45])[O:43][CH2:42][CH2:41][CH2:40]1>CN(C)C=O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([OH:31])[CH2:9][CH2:10][CH:11]2[C:12](=[O:30])[N:13]([C:23]3[CH:24]=[CH:25][C:26]([O:29][CH2:42][CH2:41][CH2:40][CH2:39][S:44]([OH:46])(=[O:45])=[O:43])=[CH:27][CH:28]=3)[CH:14]2[C:15]2[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=2)=[C:4]([F:32])[CH:3]=1
Reactant: COc1ccc(C2C(CCC(O)c3ccc(F)cc3F)C(=O)N2c2ccc(O)cc2)cc1
Reactant: O=S1(=O)CCCCO1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1ccc(C2C(CCC(O)c3ccc(F)cc3F)C(=O)N2c2ccc(OCCCCS(=O)(=O)O)cc2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
160 mg of 3-[3-(4-fluorofluorophenyl)-3-hydroxypropyl]-1-(4-hydroxyphenyl)-4-(4-methoxyphenyl)azetidin-2-one (11) were dissolved in 4 ml of absolute dimethylformamide. 210 mg of powdered potassium carbonate and 42 mg of 1,4,-butanesultone were added. The mixture was stirred at room temperature overnight. The reaction solution was concentrated under oil pump vacuum, taken up in dichloromethane and washed 1× with water. The aqueous phase was acidified with 2N hydrochloric acid and extracted 2× with dichloromethane. The combined organic phases were dried over sodium sulfate and concentrated. The residue was chromatographed on a 10 g SiO2 cartridge (dichloromethane/methanol=5/1). The product (72 mg) was obtained as an oil.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.C(O)(=O)C.[NH2:12][C:13]1[N:18]=[CH:17][N:16]=[C:15]2[N:19]([CH:30]3[CH2:35][CH2:34][C:33](=O)[CH2:32][CH2:31]3)[N:20]=[C:21]([C:22]3[CH:27]=[CH:26][C:25]([NH2:28])=[C:24]([F:29])[CH:23]=3)[C:14]=12.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClC(Cl)C>[NH2:28][C:25]1[CH:26]=[CH:27][C:22]([C:21]2[C:14]3[C:15](=[N:16][CH:17]=[N:18][C:13]=3[NH2:12])[N:19]([CH:30]3[CH2:35][CH2:34][CH:33]([N:5]4[CH2:6][CH2:7][N:2]([CH3:1])[CH2:3][CH2:4]4)[CH2:32][CH2:31]3)[N:20]=2)=[CH:23][C:24]=1[F:29]
Reactant: CN1CCNCC1
Reactant: Nc1ccc(-c2nn(C3CCC(=O)CC3)c3ncnc(N)c23)cc1F
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CC(Cl)Cl
Product: CN1CCN(C2CCC(n3nc(-c4ccc(N)c(F)c4)c4c(N)ncnc43)CC2)CC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 283.3 %

Procedure:
N-methylpiperazine (3.6 g, 0.036 mol) and acetic acid (2.17 g, 0.036 mol) were added to a suspension of 4-[4-amino-3-(4-amino-3-fluorophenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl]-1-cyclohexanone (Intermediate R) (4.1 g, 0.012 mol) in dichloroethane (200 mL). Sodium triacetoxyborohydride (3.32 g, 0.016 mol) was then added portionwise to the reaction suspension. The reaction mixture was stirred at room temperature for 18 h. Additional sodium triacetoxyborohydride (1.79 g, 0.084 mol and 1.28 g, 0.06 mol) was added in two batches over 5 days. The reaction mixture was filtered, washed with dichloroethane (100 mL) and the filtrate was concentrated under reduced pressure to give 3-(4-amino-3-fluorophenyl)-1-[4-(4-methylpiperazino)cyclohexyl]-1H-pyrazolo[3,4-d]pyrimidin-4-amine as a yellow solid (14.5 g, 0.034 mol). The yellow solid was purified and the cis/trans isomers were separated by flash column chromatography on silica gel using dichloromethane/methanol/ammonium hydroxide (93:5:2) as the eluent to give trans 3-(4-amino-3-fluorophenyl)-1-[4-(4-methylpiperazino)cyclohexyl]-1H-pyrazolo[3,4-d]pyrimidin-4-amine (lower running component) as a white solid (115 mg, 0.27 mmol). 1H NMR (DMSO-d6, 400 MHz) 8.19 (s, 1H), 7.18 (m, 2H), 6.88 (m, 1H), 5.46 (s, 2H), 4.60 (m, 1H), 2.35 (br m, 4H), 2.14 (s, 3H), 1.95 (br m, 6H), 1.44 (m, 2H), 1.26 (m, 4H), 0.86 (m, 2H). TLC (dichloromethane/methanol/ammonium hydroxide=95:5) Rf 0.31.
Reaction SMILES: [CH:1]([C:3]1[C:13]2[O:12][CH2:11][CH2:10][C:9]([C:14]([O:16][CH3:17])=[O:15])=[CH:8][C:7]=2[CH:6]=[CH:5][CH:4]=1)=O.Cl.[CH3:19][NH:20][CH3:21].C(N(CC)CC)C.[BH4-].[Na+]>CO.O1CCCC1>[CH3:19][N:20]([CH2:1][C:3]1[C:13]2[O:12][CH2:11][CH2:10][C:9]([C:14]([O:16][CH3:17])=[O:15])=[CH:8][C:7]=2[CH:6]=[CH:5][CH:4]=1)[CH3:21]
Reactant: CNC
Reactant: COC(=O)C1=Cc2cccc(C=O)c2OCC1
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: CO
Solvent: C1CCOC1
Product: COC(=O)C1=Cc2cccc(CN(C)C)c2OCC1
Temperature: 25 °C
Reaction time: 20 h
Yield: 65.8 %

Procedure:
The mixture of methyl 2,3-dihydro-9-formyl-1-benzoxepin-4-carboxylate (1.0 g), dimethylamine hydrochloride (0.7 g), triethylamine (1.2 ml) and 4 Å molecular sieves (1.0 g) in methanol (20 ml) and tetrahydrofuran (10 ml) was stirred at ambient temperature for 3 hours. To the mixture was added sodium borohydride (0.33 g) under ice-cooling and the mixture was stirred at ambient temperature for 20 hours. The solvent was removed by concentration. The residue was dissolved in a mixture of ethyl acetate and water and the mixture was adjusted to pH 1 with 6N hydrochloric acid. The separated aqueous layer was adjusted pH 10 with 20% aqueous potassium carbonate and extracted with a solution of ethyl acetate and tetrahydrofuran. The extract layer was washed with brine, dried over magnesium sulfate and evaporated to give methyl 2,3-dihydro-9-dimethylaminomethyl-1-benzoxepin-4-carboxylate (0.74 g).
Reaction SMILES: O1CCCC1.[O:6]([CH2:13][C:14]1[N:19]=[CH:18][C:17]([CH2:20][C:21](Cl)=[N:22][OH:23])=[CH:16][CH:15]=1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[C:25]([C:27]1[C:28]([NH2:33])=[N:29][CH:30]=[CH:31][CH:32]=1)#[CH:26].C(N(CC)CC)C>O>[O:6]([CH2:13][C:14]1[N:19]=[CH:18][C:17]([CH2:20][C:21]2[CH:26]=[C:25]([C:27]3[C:28]([NH2:33])=[N:29][CH:30]=[CH:31][CH:32]=3)[O:23][N:22]=2)=[CH:16][CH:15]=1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: C#Cc1cccnc1N
Reactant: ON=C(Cl)Cc1ccc(COc2ccccc2)nc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Solvent: O
Product: Nc1ncccc1-c1cc(Cc2ccc(COc3ccccc3)nc2)no1
Temperature: 60 °C
Reaction time: 4.5 h
Yield: 6.6 %

Procedure:
To a tetrahydrofuran (3.00 mL) solution of (6-phenoxymethyl-pyridin-3-yl)-acetohydroximoyl chloride (80.0 mg, 0.289 mmol) described in Manufacturing Example 54-1-6 and 3-ethynyl-pyridin-2-ylamine (20.0 mg, 0.169 mmol) described in Manufacturing Example 1-2-3 was added triethylamine (70.7 μL, 0.507 mmol) at room temperature, which was stirred for 4.5 hours at 60° C. Water was added to the reaction solution at room temperature, which was then extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium chloride and dried over anhydrous magnesium sulfate, and the solvent was evaporated under a reduced pressure. The residue was purified by NH silica gel column chromatography (ethyl acetate:heptane=2:1→3:1) to obtain the title compound (4.00 mg, 6.60%).
Reaction SMILES: [NH2:1][C:2]1[C:3]([N:11]([CH3:13])[CH3:12])=[N:4][CH:5]=[N:6][C:7]=1[N:8]([CH3:10])[CH3:9].ClC1C([N+]([O-])=O)=C(Cl)N=CN=1.CNC.[C:28](Cl)(=[O:46])[CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35]/[CH:36]=[CH:37]\[CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH3:45]>>[CH3:12][N:11]([CH3:13])[C:3]1[C:2]([NH:1][C:28](=[O:46])[CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35]/[CH:36]=[CH:37]\[CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH3:45])=[C:7]([N:8]([CH3:9])[CH3:10])[N:6]=[CH:5][N:4]=1
Reactant: CCCCCCCC/C=C\CCCCCCCC(=O)Cl
Reactant: CN(C)c1ncnc(N(C)C)c1N
Agent: CNC
Agent: O=[N+]([O-])c1c(Cl)ncnc1Cl
Product: CCCCCCCC/C=C\CCCCCCCC(=O)Nc1c(N(C)C)ncnc1N(C)C

Procedure:
5-Amino-4,6-bis(dimethylamino)pyrimidine (prepared by reacting commercially available 4,6-dichloro-5-nitro pyrimidine with excess dimethylamine followed by reduction of the nitro group according to the procedure of Jacobs et al., J. Am. Chem. Soc., 42, 2278 (1920)) was coupled with oleoyl chloride using the procedure described in Example 4 to give the title compound.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:12]=[CH:13][CH:14]=1)[CH:7]=[CH:8][C:9]([OH:11])=[O:10])([O-])=O.[H][H]>C(O)C.O.[Pd]>[NH2:1][C:4]1[CH:5]=[C:6]([CH2:7][CH2:8][C:9]([OH:11])=[O:10])[CH:12]=[CH:13][CH:14]=1
Reactant: O=C(O)C=Cc1cccc([N+](=O)[O-])c1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Solvent: O
Product: Nc1cccc(CCC(=O)O)c1

Procedure:
3-Nitrocinnamic acid (1.5 g, 7.77 mM) was suspended in a mixture of ethanol (80 ml) and water (20 ml), and palladium on charcoal (10%, 100 mg) added. The mixture was shaken in an atmosphere of hydrogen for 4.5 hours, when uptake of gas complete. After filtration through diatomaceous earth, the solvent was removed to give title compound.
Reaction SMILES: [CH2:1]([C:3]1[C:4]([N+:11]([O-:13])=[O:12])=[C:5]([O:9][CH3:10])[CH:6]=[CH:7][CH:8]=1)[CH3:2].[N+:14]([O-])([OH:16])=[O:15].S(=O)(=O)(O)O>C(O)(=O)C>[N+:11]([C:4]1[C:3]([CH2:1][CH3:2])=[C:8]([N+:14]([O-:16])=[O:15])[CH:7]=[CH:6][C:5]=1[O:9][CH3:10])([O-:13])=[O:12]
Reactant: O=[N+]([O-])O
Reactant: CCc1cccc(OC)c1[N+](=O)[O-]
Agent: O=S(=O)(O)O
Solvent: CC(=O)O
Product: CCc1c([N+](=O)[O-])ccc(OC)c1[N+](=O)[O-]
Temperature: 0 °C
Reaction time: 1 h

Procedure:
A solution of 3-ethyl-2-nitroanisole (89.73 mmol) in acetic acid (200 mL) is treated dropwise with a mixture of concentrated nitric acid (89.73 mmol, d=1.41 g/mL) and acetic acid (40 mL). After addition of the nitric acid solution, concentrated sulfuric acid (40 mL) is added dropwise. The reaction is poured over crushed ice (500 g) and stirred for 1 hour while a white precipitate forms. The precipitate is filtered and dried in a vacuum to afford a white solid. This material is purified by chromatography (silica gel, 20% ethyl acetate/hexanes) to afford 2,4-dinitro-3-ethylanisole.