Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:3]1[C:4]([C:31]2[CH:36]=[CH:35][CH:34]=[C:33]([N+:37]([O-:39])=[O:38])[CH:32]=2)=[N:5][C:6]([S:29][CH3:30])=[N:7][C:8]=1[CH:9]=P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)#[N:2].[CH2:40]=O>>[C:1]([C:3]1[C:4]([C:31]2[CH:36]=[CH:35][CH:34]=[C:33]([N+:37]([O-:39])=[O:38])[CH:32]=2)=[N:5][C:6]([S:29][CH3:30])=[N:7][C:8]=1[CH:9]=[CH2:40])#[N:2]
Reactant: CSc1nc(C=P(c2ccccc2)(c2ccccc2)c2ccccc2)c(C#N)c(-c2cccc([N+](=O)[O-])c2)n1
Reactant: C=O
Product: C=Cc1nc(SC)nc(-c2cccc([N+](=O)[O-])c2)c1C#N
Temperature: 25 °C

Procedure:
A solution of 5-cyano-2-methylthio-4-(3-nitro-phenyl)-6-[(triphenylphosphanylidene)-methyl]-pyrimidine (example 27a, 7.04 g,)) in TBF (64 ml) was treated with aqueous formaldehyde (37 wt. %, 3.55 ml) at 60° C. for 1 h. After the mixture was cooled to room temperature, it was diluted with EtOAb (100 ml) and washed with water (2×50 ml), dried (MgSO4) and concentrated under reduced pressure. The title compound was purified by chromatography on silica gel using hept/EtOAc=9/1 to 3/2 (v/v) as the eluent.
Reaction SMILES: [CH2:1](/[C:3](=[CH:8]\[CH2:9][CH3:10])/[CH:4]=[CH:5]/[CH2:6][OH:7])[CH3:2].[C:11](OC(=O)C)(=[O:13])[CH3:12]>N1C=CC=CC=1>[C:11]([O:7][CH2:6]/[CH:5]=[CH:4]/[C:3](/[CH2:1][CH3:2])=[CH:8]/[CH2:9][CH3:10])(=[O:13])[CH3:12]
Reactant: CC(=O)OC(C)=O
Reactant: CC/C=C(/C=C/CO)CC
Solvent: c1ccncc1
Product: CC/C=C(/C=C/COC(C)=O)CC
Reaction time: 2 h
Yield: 74.3 %

Procedure:
To a solution of (E,E)-4-ethyl-2,4-heptadien-1-ol (10.1 g) in pyridine (29 g) at 0° C. was added dropwise acetic anhydride (22.2 g). After two hours at room temperature, the reaction mixture was evaporated in vacuo. The residue was diluted with ethyl acetate, washed with 0.5N hydrochloric acid and brine, dried over anhydrous magnesium sulfate, and evaporated in vacuo. The residue was chromatographed on silica gel (5% ethyl acetate in hexane) to give (E,E)-1-acetoxy-4-ethyl-2,4-heptadiene (9.75 g) as an oil.
Reaction SMILES: [CH:1]([NH:3][C:4]1[CH2:8][CH2:7][N:6]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([C:15]([F:18])([F:17])[F:16])[CH:10]=2)[N:5]=1)=O.[H-].[Al+3].[Li+].[H-].[H-].[H-].O>C(OCC)C>[CH3:1][NH:3][C:4]1[CH2:8][CH2:7][N:6]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([C:15]([F:18])([F:16])[F:17])[CH:10]=2)[N:5]=1
Reactant: O=CNC1=NN(c2cccc(C(F)(F)F)c2)CC1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Solvent: O
Product: CNC1=NN(c2cccc(C(F)(F)F)c2)CC1
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
3-Formamido-1-(3-trifluoromethylphenyl)-2-pyrazoline (2.4 g) was stirred with dry diethyl ether (60 ml) to produce a slurry which was gradually added to a stirred ice-cold suspension of lithium aluminium hydride (1.0 g) in dry diethyl ether (75 ml) under a nitrogen atmosphere. The addition took place over a period of about 20 minutes and was accompanied by a vigorous reaction. The final reaction mixture was stirred for a further 15 minutes and was then carefully and slowly decomposed by the addition of water (30 ml). The ethereal layer was then decanted off the aqueous sludge which was washed twice with diethyl ether. The combined ethereal solutions were dried over potassium carbonate, filtered and evaporated. The resulting 3-methylamino-1-(3-trifluoromethylphenyl)-2-pyrazoline was a colourless crystalline solid on precipitation by benzene and recrystallization with light petroleum, yield 1.8 g, m.p. 93.1°. The hydrochloride was recrystallized by precipitation from methanol with ether and light petroleum m.p. 206°-207°.
Reaction SMILES: [NH2:1][CH:2]1[CH:11]([CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([F:19])[CH:14]=2)[C:10]2[CH:9]=[C:8]([CH2:20][CH2:21][CH2:22][NH:23][S:24]([CH2:27][CH2:28][CH3:29])(=[O:26])=[O:25])[CH:7]=[CH:6][C:5]=2[CH2:4][CH2:3]1.C(N(CC)CC)C.[C:37](Cl)(=[O:39])[CH3:38]>ClCCl>[F:19][C:15]1[CH:14]=[C:13]([CH:18]=[CH:17][CH:16]=1)[CH2:12][CH:11]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([CH2:20][CH2:21][CH2:22][NH:23][S:24]([CH2:27][CH2:28][CH3:29])(=[O:26])=[O:25])[CH:9]=2)[CH2:4][CH2:3][CH:2]1[NH:1][C:37](=[O:39])[CH3:38]
Reactant: CC(=O)Cl
Reactant: CCCS(=O)(=O)NCCCc1ccc2c(c1)C(Cc1cccc(F)c1)C(N)CC2
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCS(=O)(=O)NCCCc1ccc2c(c1)C(Cc1cccc(F)c1)C(NC(C)=O)CC2
Temperature: 25 °C
Reaction time: 12 h

Procedure:
N-(3-(7-Amino-8-(3-fluorobenzyl)-5,6,7,8-tetrahydronaphthalen-2-yl)propyl)propane-1-sulfonamide (cf. example 209: 45 mg, 0.108 mmol) and triethylamine (15 μL, 0.108 mmol) were dissolved in dichloromethane (2 mL). Acetylchloride (7.64 μL, 0.108 mmol) were added. The reaction mixture was stirred for 12 hours at room temperature. The reaction mixture was diluted with dichloromethane and successively washed with hydrochloric acid, water and saturated sodium chloride solution. The organic layer was dried and concentrated in vacuo. The crude product was purified by flash-chromatography (silica gel, dichloromethane, methanol). Yield: 37 mg (0.08 mmol, 75%).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][N:3]=1.CC(C)([O-])C.[K+].Cl[C:16]1[CH:21]=[CH:20][N:19]=[C:18]([C:22]([NH:24][CH:25]2[CH2:27][CH2:26]2)=[O:23])[CH:17]=1>CC(N(C)C)=O.CCOC(C)=O>[NH2:1][C:2]1[N:3]=[CH:4][C:5]([O:8][C:16]2[CH:21]=[CH:20][N:19]=[C:18]([C:22]([NH:24][CH:25]3[CH2:26][CH2:27]3)=[O:23])[CH:17]=2)=[CH:6][CH:7]=1
Reactant: Nc1ccc(O)cn1
Reactant: O=C(NC1CC1)c1cc(Cl)ccn1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CC(=O)N(C)C
Product: Nc1ccc(Oc2ccnc(C(=O)NC3CC3)c2)cn1
Temperature: 25 °C
Reaction time: 1 h
Yield: 57.1 %

Procedure:
A solution of 2-amino-5-hydroxypyridine (0.578 g, 5.25 mmol) in DMA (8.75 mL) was treated with potassium tert-butoxide (0.663 g, 5.90 mmol), stirred at RT for 1 h, treated with a solution of 4-chloro-N-cyclopropylpicolinamide (0.86 g, 4.37 mmol) in DMA (8.75 mL) and stirred at RT for 20 h. The mixture was diluted with EtOAc, washed with 1N NaOH, then brine and the organic layer was dried over Na2SO4, concentrated to dryness and purified by silica gel chromatography (MeOH/EtOAc) to afford 4-((6-aminopyridin-3-yl)oxy)-N-cyclopropylpicolinamide (0.674 g, 57%). 1H NMR (400 MHz, DMSO-d6): δ 8.72 (d, J=5.0 Hz, 1H), 8.44 (d, J=5.6 Hz, 1H), 7.82 (d, J=2.9 Hz, 1H), 7.31-7.30 (m, 2H), 7.11 (dd, J=5.6, 2.6 Hz, 1H), 6.53 (d, J=8.9 Hz, 1H), 6.08 (s, 2H), 2.85-2.84 (m, 1H), 0.65-0.62 (m, 4H); MS (ESI) m/z: 271.1 (M+H+).
Reaction SMILES: C([O:3][C:4]([C:6]1[C:7]([CH3:41])=[C:8]2[C:13]([NH:14][C:15]3[CH:20]=[CH:19][C:18]([O:21][C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=4[O:28][C:29]([C:32](=[O:37])[NH:33][CH2:34][CH2:35][OH:36])([CH3:31])[CH3:30])=[CH:17][CH:16]=3)=[C:12]([C:38]#[N:39])[CH:11]=[N:10][N:9]2[CH:40]=1)=[O:5])C.[OH-].[Na+].O>CCO>[C:38]([C:12]1[CH:11]=[N:10][N:9]2[CH:40]=[C:6]([C:4]([OH:5])=[O:3])[C:7]([CH3:41])=[C:8]2[C:13]=1[NH:14][C:15]1[CH:16]=[CH:17][C:18]([O:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=2[O:28][C:29]([C:32](=[O:37])[NH:33][CH2:34][CH2:35][OH:36])([CH3:31])[CH3:30])=[CH:19][CH:20]=1)#[N:39]
Reactant: CCOC(=O)c1cn2ncc(C#N)c(Nc3ccc(Oc4ccccc4OC(C)(C)C(=O)NCCO)cc3)c2c1C
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: Cc1c(C(=O)O)cn2ncc(C#N)c(Nc3ccc(Oc4ccccc4OC(C)(C)C(=O)NCCO)cc3)c12
Temperature: 25 °C
Yield: 100 %

Procedure:
A mixture of 433E (180 mg, 0.323 mmol) and 1N NaOH (0.68 ml, 0.68 mmol) in EtOH (4 ml) was heated to reflux for 2 days, cooled to rt. Removal of the solvent in vacuo gave a gray oil. Treated with H2O (4 ml), the aqueous solution was washed with EtOAc (3×2 ml) and added to a mixture of 6N HCl (1.5 ml) and brine (5 ml). The resulting suspension was cooled to 0° C. and filtered, dried in vacuo to gave 433F (171 mg, 96%) as a dim dark solid. It has a retention time of 5.31 min (standard LC1 method, 8 min run). MS Found: (M+H)+=530.0
Reaction SMILES: [OH-].[Na+].O.[F:4][C:5]1[CH:6]=[CH:7][C:8]([CH3:13])=[C:9]([CH:12]=1)[CH:10]=O.[CH3:14][C:15]([CH3:17])=[O:16]>>[F:4][C:5]1[CH:6]=[CH:7][C:8]([CH3:13])=[C:9]([CH:10]=[CH:14][C:15](=[O:16])[CH3:17])[CH:12]=1
Reactant: Cc1ccc(F)cc1C=O
Reactant: CC(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CC(=O)C=Cc1cc(F)ccc1C
Reaction time: 1 h

Procedure:
A mixture of acetone (80 ml), sodium hydroxide (3.7 g) and water (100 ml) was treated at room temperature dropwise with a solution of 5-fluoro-2-methylbenzaldehyde (11.5 g) in acetone (30 ml) and stirred at the same temperature for 1 hour. Acetone was distilled off under reduced pressure, and the mixture was extracted with ethyl acetate. The organic layer was washed successively with water and saturated brine and concentrated under reduced pressure to obtain 4-(5-fluoro-2-methylphenyl)-3-buten-2-one (13.4 g).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:10]=[N:11][N:12]([C:15]3[CH:23]=[CH:22][C:18]([C:19](O)=[O:20])=[CH:17][N:16]=3)[C:13]=2[OH:14])=[C:5]([CH3:24])[C:4]=1[F:25])#[N:2].[CH2:26]([N:28]1[CH2:33][CH2:32][NH:31][CH2:30][C@H:29]1[CH3:34])[CH3:27]>>[CH2:26]([N:28]1[CH2:33][CH2:32][N:31]([C:19]([C:18]2[CH:22]=[CH:23][C:15]([N:12]3[C:13]([OH:14])=[C:9]([C:6]4[CH:7]=[CH:8][C:3]([C:1]#[N:2])=[C:4]([F:25])[C:5]=4[CH3:24])[CH:10]=[N:11]3)=[N:16][CH:17]=2)=[O:20])[CH2:30][C@H:29]1[CH3:34])[CH3:27]
Reactant: CCN1CCNC[C@H]1C
Reactant: Cc1c(-c2cnn(-c3ccc(C(=O)O)cn3)c2O)ccc(C#N)c1F
Product: CCN1CCN(C(=O)c2ccc(-n3ncc(-c4ccc(C#N)c(F)c4C)c3O)nc2)C[C@H]1C

Procedure:
The title compound was prepared in a manner similar to Example 303 using 6-(4-(4-cyano-3-fluoro-2-methylphenyl)-5-hydroxy-1H-pyrazol-1-yl)nicotinic acid and (R)-1-ethyl-2-methylpiperazine. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.22 (m, J=7.20, 7.20 Hz, 6H) 2.33 (d, J=2.27 Hz, 3 H) 2.91-4.72 (m, 9 H) 7.63 (br. s., 1 H) 7.71-7.79 (m, 1 H) 7.94-8.81 (m, 4 H) 9.52-10.21 (m, 1 H). ESI-MS m/z [M+H]+ 449.3.
Reaction SMILES: [Cl:1][C:2]1[C:19]([F:20])=[CH:18][CH:17]=[C:16]([F:21])[C:3]=1[CH2:4][N:5]1[CH2:10][CH2:9][NH:8][C:7]2[N:11]=[CH:12][C:13](I)=[CH:14][C:6]1=2.[CH3:22][N:23]1[CH2:28][CH2:27][N:26]([C:29]([C:31]2[CH:36]=[CH:35][C:34](B3OC(C)(C)C(C)(C)O3)=[CH:33][CH:32]=2)=[O:30])[CH2:25][CH2:24]1>>[Cl:1][C:2]1[C:19]([F:20])=[CH:18][CH:17]=[C:16]([F:21])[C:3]=1[CH2:4][N:5]1[CH2:10][CH2:9][NH:8][C:7]2[N:11]=[CH:12][C:13]([C:34]3[CH:33]=[CH:32][C:31]([C:29]([N:26]4[CH2:27][CH2:28][N:23]([CH3:22])[CH2:24][CH2:25]4)=[O:30])=[CH:36][CH:35]=3)=[CH:14][C:6]1=2
Reactant: CN1CCN(C(=O)c2ccc(B3OC(C)(C)C(C)(C)O3)cc2)CC1
Reactant: Fc1ccc(F)c(CN2CCNc3ncc(I)cc32)c1Cl
Product: CN1CCN(C(=O)c2ccc(-c3cnc4c(c3)N(Cc3c(F)ccc(F)c3Cl)CCN4)cc2)CC1
Yield: 17 %

Procedure:
1-(2-Chloro-3,6-difluorobenzyl)-7-iodo-1,2,3,4-tetrahydropyrido[2,3-b]pyrazine (100 mg) was reacted with (4-methylpiperazin-1-yl)-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)phenyl]methanone as in General Procedure 4A to give the title compound as a pale yellow foam (17% yield). M.p. (foam), LCMS: m/z=499.43 (M+H+), 1H-NMR (CDCl3, 400 MHz) δ 2.33 (s, 3H), 2.36-2.52 (m, 4H), 3.26-3.33 (m, 2H), 3.52-3.56 (m, 2H), 3.52-3.86 (m, 4H), 4.53 (s, 2H), 5.00 (bs, 1H), 6.97-7.04 (m, 1H), 7.10 (s, 1H), 7.11-7.17 (m, 1H), 7.44 (dd, J=8.4 Hz, 1.8 Hz, 2H), 7.52 (dd, J=8.3 Hz, 1.8 Hz, 2H), 7.74 (d, J=1.8 Hz, 1H).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].Br[CH2:8][C:9]1[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][C:10]=1[C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12].[I:26][C:27]1[CH:32]=[CH:31][C:30]([OH:33])=[CH:29][CH:28]=1.O>CN(C)C=O>[I:26][C:27]1[CH:32]=[CH:31][C:30]([O:33][CH2:8][C:9]2[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][C:10]=2[C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])=[CH:29][CH:28]=1
Reactant: Oc1ccc(I)cc1
Reactant: CC(C)(C)OC(=O)c1cc(C(F)(F)F)ccc1CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)c1cc(C(F)(F)F)ccc1COc1ccc(I)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 93.9 %

Procedure:
Potassium carbonate (1.30 g, 9.41 mmol) was added to a solution of tert-butyl 2-(bromomethyl)-5-(trifluoromethyl)benzoate (2.00 g, 5.90 mmol) obtained in Example (2-2) and 4-iodophenol (1.30 g, 5.91 mmol) in N,N-dimethylformamide (20 ml) under ice-cooling and the mixture was stirred at room temperature for 2 hours. The reaction mixture was poured into water and extracted with ethyl acetate (three times). After the organic layer was successively washed with water (three times) and a saturated aqueous NaCl solution and dried with anhydrous sodium sulfate, it was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluting solvent: n-hexane/ethyl acetate=100/1-50/1) to give tert-butyl 2-[(4-iodophenoxy)methyl]-5-(trifluoromethyl)benzoate as a colorless solid (2.65 g, yield: 94%).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:7]=[C:8]([CH2:12][N:13]([CH3:15])[CH3:14])[CH:9]=[CH:10][CH:11]=1.[CH3:16][S:17][CH:18](SC)[CH2:19][N+:20]([O-:22])=[O:21].O.O.C(O)(=O)C(O)=O>O1CCCC1>[CH3:15][N:13]([CH3:14])[CH2:12][C:8]1[CH:9]=[CH:10][CH:11]=[C:6]([O:5][CH2:4][CH2:3][CH2:2][NH:1][C:18]([S:17][CH3:16])=[CH:19][N+:20]([O-:22])=[O:21])[CH:7]=1
Reactant: CSC(C[N+](=O)[O-])SC
Reactant: CN(C)Cc1cccc(OCCCN)c1
Agent: O=C(O)C(=O)O
Solvent: O
Solvent: C1CCOC1
Product: CSC(=C[N+](=O)[O-])NCCCOc1cccc(CN(C)C)c1
Yield: 64 %

Procedure:
3-(3-Aminopropoxy)-N,N-dimethylbenzenemethanamine (10 g) and 1,1-bis-(methylthio)-2-nitroethane (16 g) were heated under reflux in tetrahydrofuran for 19 hours. Oxalic acid dihydrate (1.3 g) was added and the resulting precipitate was discarded. The solvent was removed to leave the title compound as a crystalline solid (10 g) m.p. 59°-63°.
Reaction SMILES: [C:1]([C:3]1[C:8]([O:9][C:10]2[C:24]([O:25][C:26]3[CH:27]=[N:28][C:29]([S:32]([CH2:35][CH3:36])(=[O:34])=[O:33])=[CH:30][CH:31]=3)=[CH:23][C:13]3[NH:14][C:15]([C:17]4[CH:22]=C[CH:20]=[CH:19][N:18]=4)=[N:16][C:12]=3[CH:11]=2)=[CH:7][CH:6]=[CH:5][N:4]=1)#[N:2].[N:37]1C=CN=CC=1C(O)=O>>[C:1]([C:3]1[C:8]([O:9][C:10]2[C:24]([O:25][C:26]3[CH:27]=[N:28][C:29]([S:32]([CH2:35][CH3:36])(=[O:34])=[O:33])=[CH:30][CH:31]=3)=[CH:23][C:13]3[NH:14][C:15]([C:17]4[CH:22]=[N:37][CH:20]=[CH:19][N:18]=4)=[N:16][C:12]=3[CH:11]=2)=[CH:7][CH:6]=[CH:5][N:4]=1)#[N:2]
Reactant: CCS(=O)(=O)c1ccc(Oc2cc3[nH]c(-c4ccccn4)nc3cc2Oc2cccnc2C#N)cn1
Reactant: O=C(O)c1cnccn1
Product: CCS(=O)(=O)c1ccc(Oc2cc3[nH]c(-c4cnccn4)nc3cc2Oc2cccnc2C#N)cn1

Procedure:
The entitled compound was obtained as a colorless solid in the same method as in Example 197 or in accordance with the method or by combining it with an ordinary method but using 4-(2-cyanopyridin-3-yloxy)-5-(6-ethanesulfonyl-pyridin-3-yloxy)-benzene-1,2-diamine obtained in Example 245 and pyrazine-2-carboxylic acid.
Reaction SMILES: [Si:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[N:16]=[C:17]([C:22]3[CH:27]=[CH:26][C:25]([N+:28]([O-:30])=[O:29])=[CH:24][CH:23]=3)[C:18]([NH2:21])=[N:19][CH:20]=2)=[CH:11][CH:10]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[Si:31]([O:38][C:39]1[CH:44]=[CH:43][C:42]([CH2:45][C:46](Cl)=[O:47])=[CH:41][CH:40]=1)([C:34]([CH3:37])([CH3:36])[CH3:35])([CH3:33])[CH3:32].O>CN(C)C1C=CN=CC=1.N1C=CC=CC=1>[Si:31]([O:38][C:39]1[CH:40]=[CH:41][C:42]([CH2:45][C:46]([NH:21][C:18]2[C:17]([C:22]3[CH:23]=[CH:24][C:25]([N+:28]([O-:30])=[O:29])=[CH:26][CH:27]=3)=[N:16][C:15]([C:12]3[CH:11]=[CH:10][C:9]([O:8][Si:1]([C:4]([CH3:7])([CH3:5])[CH3:6])([CH3:3])[CH3:2])=[CH:14][CH:13]=3)=[CH:20][N:19]=2)=[O:47])=[CH:43][CH:44]=1)([C:34]([CH3:37])([CH3:36])[CH3:35])([CH3:33])[CH3:32]
Reactant: CC(C)(C)[Si](C)(C)Oc1ccc(-c2cnc(N)c(-c3ccc([N+](=O)[O-])cc3)n2)cc1
Reactant: CC(C)(C)[Si](C)(C)Oc1ccc(CC(=O)Cl)cc1
Agent: CN(C)c1ccncc1
Solvent: O
Solvent: c1ccncc1
Product: CC(C)(C)[Si](C)(C)Oc1ccc(CC(=O)Nc2ncc(-c3ccc(O[Si](C)(C)C(C)(C)C)cc3)nc2-c2ccc([N+](=O)[O-])cc2)cc1
Temperature: 50 °C
Reaction time: 20 h
Yield: 48.1 %

Procedure:
Under an argon atmosphere, to a mixture of 5-[4-(tert-butyldimethylsilyloxy)phenyl]-3-(4-nitrophenyl)pyrazin-2-amine (7o) (317 mg, 751 μmol) and 4-(dimethylamino)pyridine (15.3 mg, 125 μmol) dissolved in anhydrous pyridine (15 mL) was added 2-[4-(tert-butyldimethylsilyl oxy)phenyl]acetyl chloride (10) prepared above at 0° C. and the mixture was heated with stirring at 50° C. for 20 hours. After cooling to room temperature, to this was added water and the product was extracted with ethyl acetate (100 mL×3). The combined organic extract was washed successively with water (200 mL) and brine (200 mL), followed by drying over anhydrous sodium sulfate. After filtration and concentration under reduced pressure, the residue was purified by column chromatography (silica gel 50 g, n-hexane/ethyl acetate=2/1) to give Compound 11o (242 mg, 361 μmol, 48.1%) as a yellow solid. Rf=0.30 (n-hexane/ethyl acetate=2/1); 1H NMR (400 MHz, DMSO-d6) δ 0.15 (s, 6H), 0.20 (s, 6H), 0.92 (s, 9H), 0.93 (s, 9H), 3.44 (s, 2H), 6.67-6.74 (AA′BB′, 2H), 6.94-7.07 (2AA′BB′, 4H), 7.80-7.86 (AA′BB′, 2H), 8.01-8.12 (2AA′BB′, 4H), 9.05 (s, 1H), 10.85 (s, 1H); 13C NMR (67.8 MHz, DMSO-d6) δ −4.5 (2C), −4.6 (2C), 17.9, 18.0, 25.50 (3C), 25.51 (3C), 41.6, 119.4 (2C), 120.4 (2C), 123.2 (2C), 127.4, 128.2, 128.52 (2C), 128.54 (2C), 130.4 (2C), 138.7, 143.0, 144.5, 145.0, 146.9, 147.9, 153.9, 156.9, 168.9; IR (KBr, cm−1) 700, 741, 781, 839, 914, 1169, 1265, 1348, 1443, 1508, 1603, 1670, 2857, 2930, 2955.
Reaction SMILES: Cl.[F:2][C:3]1[CH:4]=[C:5]([CH:29]=[CH:30][C:31]=1[O:32][C:33]([F:36])([F:35])[F:34])[CH2:6][NH:7][C:8]([C@H:10]1[CH2:15][NH:14][CH2:13][CH2:12][N:11]1[S:16]([C:19]1[CH:24]=[CH:23][C:22]([C:25]([F:28])([F:27])[F:26])=[CH:21][CH:20]=1)(=[O:18])=[O:17])=[O:9].Cl[C:38]1[S:39][C:40]2[C:45]([Cl:46])=[N:44][C:43]([CH:47]3[CH2:49][CH2:48]3)=[N:42][C:41]=2[N:50]=1.C(N(CC)C(C)C)(C)C>C(Cl)(Cl)Cl>[F:2][C:3]1[CH:4]=[C:5]([CH:29]=[CH:30][C:31]=1[O:32][C:33]([F:36])([F:34])[F:35])[CH2:6][NH:7][C:8]([C@H:10]1[CH2:15][N:14]([C:38]2[S:39][C:40]3[C:45]([Cl:46])=[N:44][C:43]([CH:47]4[CH2:48][CH2:49]4)=[N:42][C:41]=3[N:50]=2)[CH2:13][CH2:12][N:11]1[S:16]([C:19]1[CH:24]=[CH:23][C:22]([C:25]([F:28])([F:27])[F:26])=[CH:21][CH:20]=1)(=[O:17])=[O:18])=[O:9]
Reactant: O=C(NCc1ccc(OC(F)(F)F)c(F)c1)[C@H]1CNCCN1S(=O)(=O)c1ccc(C(F)(F)F)cc1
Reactant: Clc1nc2nc(C3CC3)nc(Cl)c2s1
Agent: Cl
Solvent: ClC(Cl)Cl
Solvent: CCN(C(C)C)C(C)C
Product: O=C(NCc1ccc(OC(F)(F)F)c(F)c1)[C@H]1CN(c2nc3nc(C4CC4)nc(Cl)c3s2)CCN1S(=O)(=O)c1ccc(C(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 74.1 %

Procedure:
To a mixture of the crude product (about 0.095 mmol) obtained in Step 5 and 2,7-dichloro-5-cyclopropyl-thiazolo[4,5-d]pyrimidine (24 mg) in chloroform (1.0 ml) was added N,N-diisopropylethylamine (42 μl) at room temperature. After stirring at room temperature for 2 hr, the reaction mixture was concentrated under reduced pressure, and the residue was purified by thin layer silica gel chromatography (methanol:chloroform=1:10) to give the title compound (52 mg). 1H-NMR (CDCl3, 300 MHz) δ: 1.03-1.09 (2H, m), 1.17-1.22 (2H, m), 2.18-2.27 (1H, m), 3.14-3.35 (2H, m), 3.43-3.53 (1H, m), 3.96 (1H, d, J=13.6 Hz), 4.22-4.36 (2H, m), 4.45-4.69 (3H, m), 6.97-7.06 (3H, m), 7.20 (1H, t, J=8.5 Hz), 7.83 (2H, d, J=8.3 Hz), 8.02 (2H, d, J=8.3 Hz).
Reaction SMILES: Br[C:2]1[C:3]2[N:10]([CH2:11][CH3:12])[C:9]([C:13]3[C:14]([NH2:18])=[N:15][O:16][N:17]=3)=[N:8][C:4]=2[CH:5]=[N:6][CH:7]=1.[CH3:19][O:20][C:21]1[CH:28]=[CH:27][C:24]([CH:25]=[CH2:26])=[CH:23][CH:22]=1.C(N(CC)CC)C>C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH2:11]([N:10]1[C:3]2[C:2](/[CH:26]=[CH:25]/[C:24]3[CH:27]=[CH:28][C:21]([O:20][CH3:19])=[CH:22][CH:23]=3)=[CH:7][N:6]=[CH:5][C:4]=2[N:8]=[C:9]1[C:13]1[C:14]([NH2:18])=[N:15][O:16][N:17]=1)[CH3:12]
Reactant: C=Cc1ccc(OC)cc1
Reactant: CCn1c(-c2nonc2N)nc2cncc(Br)c21
Agent: [Pd+2]
Agent: CC(=O)[O-]
Solvent: CCN(CC)CC
Product: CCn1c(-c2nonc2N)nc2cncc(/C=C/c3ccc(OC)cc3)c21

Procedure:
The product of example 100 (309 mg, 1 mmol), 4-methoxystyrene (167 uL, 1.25 mmol), palladium(II) acetate (12 mg, 0.05 mmol), o-tolyltriphenylphosphine (30 mg, 0.10 mmol) and triethylamine (349 uL, 2.5 mmol) were heated at 130° C. for 4 hours. The solution was partitioned between ethyl acetate and water, extracting with ethylacetate (×3). Combined extracts were washed with water (×3), brine, dried over anhydrous magnesium sulfate and concentrated to a crude solid, 450 mg, then purified by column chromatography eluting with 1:9:90.880 ammonia:ethanol:dichloromethane affording the title product, 176 mg (49%); MS (ES+) m/e 363 [M+H]+.
Reaction SMILES: [CH3:1][N:2]([CH3:13])[N:3]1[CH2:8][CH2:7][C:6]([NH:11][CH3:12])([C:9]#[N:10])[CH2:5][CH2:4]1.C(N(CC)CC)C.[CH3:21][C:22]1[CH:27]=[C:26]([CH3:28])[CH:25]=[C:24]([CH3:29])[C:23]=1[CH2:30][C:31](Cl)=[O:32].C(=O)(O)[O-].[Na+]>CN(C1C=CN=CC=1)C.O1CCCC1>[C:9]([C:6]1([N:11]([CH3:12])[C:31](=[O:32])[CH2:30][C:23]2[C:22]([CH3:21])=[CH:27][C:26]([CH3:28])=[CH:25][C:24]=2[CH3:29])[CH2:7][CH2:8][N:3]([N:2]([CH3:1])[CH3:13])[CH2:4][CH2:5]1)#[N:10]
Reactant: CNC1(C#N)CCN(N(C)C)CC1
Reactant: Cc1cc(C)c(CC(=O)Cl)c(C)c1
Agent: CN(C)c1ccncc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: Cc1cc(C)c(CC(=O)N(C)C2(C#N)CCN(N(C)C)CC2)c(C)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 57.7 %

Procedure:
1.2 g 1-Dimethylamino-4-methylamino-piperidine-4-carbonitrile (from Step 1), 1.67 g triethylamine and 10 mg N,N-Dimethyl-4-aminopyridine are dissolved in 35 ml tetrahydrofuran. The mixture is cooled in an ice bath and a solution of 1.3 g (2,4,6-trimethylphenyl)-acetyl chloride in 20 ml tetrahydrofuran is added. The temperature is kept around 0° C. during addition. Then the mixture is allowed to warm to room temperature and stirred for 18 hours. Then saturated aqueous sodium bicarbonate is added, the mixture is extracted with t-butyl methyl ether, dried over sodium sulfate, and the solvent evaporated. The residue is purified by chromatography on silica gel, using ethyl acetate/acetone (3:1) as a solvent. 1.3 g N-(4-Cyano-1-dimethylamino-piperidin-4-yl)-N-methyl-2-(2,4,6-trimethylphenyl)-acetamide is obtained. 1H-NMR (CDCl3): 6.85 ppm (s, 2H), 3.65 ppm (s, 2H), 3.10 ppm (s, 3H), 3.00 ppm (m, 2H), 2.78 ppm (m, 2H), 2.50 ppm (m, 2H), 2.38 ppm (s, 6H), 2.23 ppm (s, 3H), 2.18 ppm (s, 6H), 1.96 ppm (m, 2H).
Reaction SMILES: [H-].[Na+].[CH:3]1[C:13]2[CH2:12][O:11][C:10]3[CH:14]=[CH:15][CH:16]=[CH:17][C:9]=3[NH:8][C:7]=2[CH:6]=[CH:5][CH:4]=1.Cl[C@@H:19]1[CH2:24][CH2:23][CH2:22][N:21]([CH2:25][CH2:26][C:27]2[CH:32]=[CH:31][C:30]([O:33][CH3:34])=[C:29]([O:35][CH3:36])[CH:28]=2)[CH2:20]1>CS(C)=O>[CH3:36][O:35][C:29]1[CH:28]=[C:27]([CH:32]=[CH:31][C:30]=1[O:33][CH3:34])[CH2:26][CH2:25][N:21]1[CH2:22][CH2:23][CH2:24][C@H:20]1[CH2:19][N:8]1[C:7]2[CH:6]=[CH:5][CH:4]=[CH:3][C:13]=2[CH2:12][O:11][C:10]2[CH:14]=[CH:15][CH:16]=[CH:17][C:9]1=2
Reactant: COc1ccc(CCN2CCC[C@@H](Cl)C2)cc1OC
Reactant: c1ccc2c(c1)COc1ccccc1N2
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Product: COc1ccc(CCN2CCC[C@H]2CN2c3ccccc3COc3ccccc32)cc1OC
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 30.3 %

Procedure:
Sixty-percent sodium hydride (0.34 g, 8.6 mmols) was washed with petroleum ether, and then suspended in 30 ml of dimethyl sulfoxide. To the suspension were added 1.38 g (7.0 mmols) of 5,11-dihydrodibenzo[b,e][1,4]oxazepine. The mixture was stirred in a nitrogen atmosphere at room temperature for 30 minutes. To this reaction solution was added dropwise a solution of 1.8 g (6.3 mmols) of (R)-(−)-3-chloro-1-(3,4-dimethoxyphenethyl)piperidine[[α]D25=−20.3° (c=0.9, ethanol)] in 5 ml of dimethyl sulfoxide, and the mixed solution was stirred at room temperature for 12 hours and at 40° C. for 4 hours. The reaction solution was poured into ice water, and extracted with ethyl acetate. The organic layer was washed with water and with a saturated aqueous solution of sodium chloride in this order, and dried. Subsequently, the solvent was distilled off under reduced pressure. The resulting residue was subjected to column chromatography, and eluted with a mixed solvent of ethyl acetate and hexane at a ratio of 1:5. This mixed solvent was distilled off under reduced pressure. Further, the thus-obtained residue was subjected to column chromatography, and extracted with a mixed solvent of chloroform and methanol at a ratio of 200:1. This mixed solvent was then distilled off under reduced pressure to give 0.85 g of (S)-(−)-5,11-dihydro-5-[1-(3,4-dimethoxyphenethyl)-2-pyrrolidinyl-methyl]dibenzo[b,e][1,4]oxazepine as a pale yellow oil in a yield of 30%.