Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][C:3]=1[NH:10][C:11]1[C:12]([NH:21][S:22]([C:25]2[CH:26]=[C:27]([CH:31]=[CH:32][CH:33]=2)[C:28]([OH:30])=O)(=[O:24])=[O:23])=[N:13][C:14]2[C:19]([N:20]=1)=[CH:18][CH:17]=[CH:16][CH:15]=2.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.C(N(C(C)C)C(C)C)C.[CH3:67][N:68]([CH3:72])[CH2:69][CH2:70][NH2:71]>CN(C)C=O.C(OCC)(=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][C:3]=1[NH:10][C:11]1[C:12]([NH:21][S:22]([C:25]2[CH:26]=[C:27]([CH:31]=[CH:32][CH:33]=2)[C:28]([NH:71][CH2:70][CH2:69][N:68]([CH3:72])[CH3:67])=[O:30])(=[O:23])=[O:24])=[N:13][C:14]2[C:19]([N:20]=1)=[CH:18][CH:17]=[CH:16][CH:15]=2
Reactant: CN(C)CCN
Reactant: COc1ccc(Cl)c(Nc2nc3ccccc3nc2NS(=O)(=O)c2cccc(C(=O)O)c2)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc(Cl)c(Nc2nc3ccccc3nc2NS(=O)(=O)c2cccc(C(=O)NCCN(C)C)c2)c1
Reaction time: 8 h
Yield: 85.8 %

Procedure:
To a solution of 3-{[(3-{[2-chloro-5-(methoxy)phenyl]amino}quinoxalin-2-yl)amino]sulfonyl}benzoic acid (0.20 g, 0.42 mmol), prepared using procedures similar to Example 100, in dimethylformamide (4 mL) were added 2-(7-aza-1H-benzotriazole-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (HATU, 0.32 g, 0.83 mmol) and N-ethyldiisopropylamine (DIEA, 0.13 g, 1.04 mmol) at room temperature. The reaction was stirred for 15 min before N,N-dimethylethane-1,2-diamine (73 mg, 0.83 mmol) was added. The reaction mixture was allowed to stir overnight. The reaction was diluted with ethyl acetate (200 mL) and washed with water (50 mL), saturated aqueous sodium bicarbonate (40 mL), 1.0 N aqueous hydrochloric acid (30 mL), and saturated aqueous sodium chloride (25 mL). The organic layer was dried over magnesium sulfate, filtered and concentrated at reduced pressure to afford 3-{[(3-{[2-chloro-5-(methoxy)phenyl]amino}quinoxalin-2-yl)amino]sulfonyl}-N-[2-(dimethylamino)ethyl]benzamide (0.20 g, 87%) as yellow solid. MS (EI) m/z for C26H27ClN6O4S: 555.1 (MH+).
Reaction SMILES: [Cl:1][C:2]1[N:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[CH:5][NH:6]2.[F:11][C:12]1[CH:19]=[CH:18][C:15]([CH2:16]Br)=[CH:14][CH:13]=1.[H-].[Na+].O>CN(C=O)C.CCOC(C)=O>[Cl:1][C:2]1[C:3]2[CH:4]=[CH:5][N:6]([CH2:16][C:15]3[CH:18]=[CH:19][C:12]([F:11])=[CH:13][CH:14]=3)[C:7]=2[CH:8]=[CH:9][N:10]=1
Reactant: Fc1ccc(CBr)cc1
Reactant: Clc1nccc2[nH]ccc12
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Fc1ccc(Cn2ccc3c(Cl)nccc32)cc1
Yield: 48.8 %

Procedure:
To 4-Chloro-5-azaindole (120 mg, 079 mmol) in 5 ml DMF was added 4-Fluorobenzylbromide (0.120 ml, 0.95 mmol) then add NaH (32 mg, 0.79 mmol) and stir at room temperature overnight. Work up reaction by adding water and EtOAc then extract three times with EtOAc. Pool all organics and wash one time with brine then dry over sodium sulfate, filter and concentrate to dryness. The residue was purified by chromatography over silica gel (eluted with Hexanes/EtOAc 99:1 to 50:50) to provide 100 mg (50%) of product.
Reaction SMILES: [OH:1][CH2:2][CH2:3][N:4]([CH3:16])[C:5]1[CH:15]=[CH:14][C:8]([C:9]([O:11]CC)=[O:10])=[CH:7][CH:6]=1.[OH-].[Na+].O>CO>[OH:1][CH2:2][CH2:3][N:4]([CH3:16])[C:5]1[CH:15]=[CH:14][C:8]([C:9]([OH:11])=[O:10])=[CH:7][CH:6]=1
Reactant: CCOC(=O)c1ccc(N(C)CCO)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CN(CCO)c1ccc(C(=O)O)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 27.2 %

Procedure:
To a solution (10 ml) of ethyl 4-[(2-hydroxyethyl) (methyl)amino]benzoate (500 mg, 2.24 mmol) in methanol was added 1M aqueous sodium hydroxide solution (10 ml), and the mixture was stirred at room temperature for 3 hrs. Water was added to the reaction mixture, and the mixture was washed with diethyl ether. 1M Hydrochloric acid (10 ml) was added, and the mixture was extracted with dichloromethane and concentrated under reduced pressure to give the title compound (119 mg, 27%) as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[N:14]2[N:15]=[C:16]([S:22][CH3:23])[C:17]([NH:18][CH2:19][CH2:20][CH3:21])=[C:13]2[CH:12]=[CH:11][CH:10]=1.[CH:24](=O)[CH2:25][CH3:26].S(=O)(=O)(O)O.[BH4-].[Na+]>O1CCCC1.C(OCC)C.O>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[N:14]2[N:15]=[C:16]([S:22][CH3:23])[C:17]([N:18]([CH2:24][CH2:25][CH3:26])[CH2:19][CH2:20][CH3:21])=[C:13]2[CH:12]=[CH:11][CH:10]=1
Reactant: CCC=O
Reactant: CCCNc1c(SC)nn2c(-c3ccc(Cl)cc3Cl)cccc12
Agent: O=S(=O)(O)O
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Solvent: CCOCC
Product: CCCN(CCC)c1c(SC)nn2c(-c3ccc(Cl)cc3Cl)cccc12
Reaction time: 0.5 h

Procedure:
N-[7-(2,4-dichlorophenyl)-2-methylthiopyrazolo[1,5-a]pyridin-3-yl]-N-propylamine (59 mg) was dissolved in tetrahydrofuran (1 mL), and after adding propionaldehyde (0.035 mL) and 3 M aqueous sulfuric acid (0.16 mL), sodium borohydride (12 mg) was added in five portions while vigorously stirring on ice, and stirring was continued for 30 minutes. Water was added to the reaction mixture, extraction was performed with diethyl ether and the extract washed with saturated aqueous sodium hydrogencarbonate and brine. After drying over anhydrous magnesium sulfate and filtration, the solvent was concentrated under reduced pressure, the residue was purified by silica gel column chromatography, and the title compound (49 mg) was obtained from the n-hexane:ethyl acetate (100:1) fraction as a yellow oil.
Reaction SMILES: [C:1]12([CH:7]3[CH2:8][CH2:9][CH:4]1[C:5](=[O:10])[CH2:6]3)[CH2:3][CH2:2]2.C(O)(=[O:13])C>>[C:1]12([CH:4]3[CH2:9][CH2:8][CH:7]1[C:6](=[O:13])[C:5]3=[O:10])[CH2:3][CH2:2]2
Reactant: O=C1CC2CCC1C21CC1
Reactant: CC(=O)O
Product: O=C1C(=O)C2CCC1C21CC1
Temperature: 25 °C

Procedure:
A solution of spiro[bicyclo[2.2.1]heptane-7,1′-cyclopropan]-2-one (rac), 8.6 g (synthesis: N. J. Turro, JACS, 1980, 102, 6056) in acetic acid, 38 ml, was treated at RT with SeO2 (16.15 g) and the suspension was then heated at reflux for 12 h. The reaction mixture was cooled to RT, filtered and the filter cake was washed with ethyl acetate. The filtrate was made basic with 3N aqueous NaOH and more AcOEt was added. The layers were separated, the organic layer was dried over Na2SO4, filtered and evaporated. The residue was purified by flash chromatography (heptane/AcOEt: 100% to 90%) to give spiro[bicyclo[2.2.1]heptane-7,1′-cyclopropane]-2,3-dione, (2.5 g) as a yellow solid. MS (ESI): 168 (M+NH4)+.
Reaction SMILES: Cl.Cl.[NH2:3][CH2:4][C:5]1[CH:10]=[CH:9][C:8]([CH2:11][C:12]([N:14]([CH3:28])[C@@H:15]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH2:16][N:17]2[CH2:21][CH2:20][CH2:19][CH2:18]2)=[O:13])=[CH:7][CH:6]=1.Cl.Cl.NCC1C=CC=CC=1[CH2:39][C:40](N(C)[C@@H](C1C=CC=CC=1)CN1CCCC1)=[O:41]>>[C:40]([NH:3][CH2:4][C:5]1[CH:10]=[CH:9][C:8]([CH2:11][C:12]([N:14]([CH3:28])[C@@H:15]([C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH2:16][N:17]2[CH2:18][CH2:19][CH2:20][CH2:21]2)=[O:13])=[CH:7][CH:6]=1)(=[O:41])[CH3:39]
Reactant: CN(C(=O)Cc1ccc(CN)cc1)[C@H](CN1CCCC1)c1ccccc1
Reactant: CN(C(=O)Cc1ccccc1CN)[C@H](CN1CCCC1)c1ccccc1
Agent: Cl
Product: CC(=O)NCc1ccc(CC(=O)N(C)[C@H](CN2CCCC2)c2ccccc2)cc1

Procedure:
Compound 9c was prepared by following the procedure of Example 7, Step h, except 8c was substituted for 8a. (87%) 1H NMR (400 MHz, CDCl3) δ 7.07-7.36 (m, 9H), 6.11 (m, 1H), 5.80 (m, 1H), 4.39 (m, 2H), 3.76 (m, 2H), 2.78-3.19 (m, 2H), 2.71 (s, 4H), 2.49 (m, 2H), 2.01 (m, 3H), 1.75 (m, 5H). Mass Spectral Analysis m/z=394.3. (M+H)+ tR=3.13 min (99%)
Reaction SMILES: C([O:3][C:4](=O)[CH2:5][CH:6]1[S:10][C:9]([C:11]2[NH:12][C:13]3[C:18]([CH:19]=2)=[CH:17][C:16]([O:20][C:21]2[CH:22]=[N:23][C:24]([CH2:27][S:28]([CH3:31])(=[O:30])=[O:29])=[CH:25][CH:26]=2)=[CH:15][C:14]=3[O:32][CH:33]2[CH2:38][CH2:37][O:36][CH2:35][CH2:34]2)=[N:8][CH2:7]1)C.[BH4-].[Li+].O.C(OCC)(=O)C>O1CCCC1.CO.CCCCCC>[CH3:31][S:28]([CH2:27][C:24]1[N:23]=[CH:22][C:21]([O:20][C:16]2[CH:17]=[C:18]3[C:13](=[C:14]([O:32][CH:33]4[CH2:38][CH2:37][O:36][CH2:35][CH2:34]4)[CH:15]=2)[NH:12][C:11]([C:9]2[S:10][CH:6]([CH2:5][CH2:4][OH:3])[CH2:7][N:8]=2)=[CH:19]3)=[CH:26][CH:25]=1)(=[O:29])=[O:30]
Reactant: CCOC(=O)CC1CN=C(c2cc3cc(Oc4ccc(CS(C)(=O)=O)nc4)cc(OC4CCOCC4)c3[nH]2)S1
Agent: [BH4-]
Agent: [Li+]
Solvent: CCCCCC
Solvent: C1CCOC1
Solvent: CO
Product: CS(=O)(=O)Cc1ccc(Oc2cc(OC3CCOCC3)c3[nH]c(C4=NCC(CCO)S4)cc3c2)cn1
Temperature: 25 °C
Reaction time: 1 h
Yield: 52.8 %

Procedure:
To a solution of ethyl{2-[5-({6-[(methylsulfonyl)methyl]pyridin-3-yl}oxy)-7-(tetrahydro-2H-pyran-4-yloxy)-1H-indol-2-yl]-4,5-dihydro-1,3-thiazol-5-yl}acetate (290 mg) in tetrahydrofuran (10 mL) and methanol (15 mL) was added lithium tetrahydroborate (132 mg) at room temperature, and the mixture was stirred at room temperature for 1 hr. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over magnesium sulfate, filtered and concentrated under reduced pressure. The obtained crude product was subjected to basic silica gel column chromatography (ethyl acetate:hexane=0:100 to 100:0, volume ratio), and recrystallized from ethyl acetate to give the title compound (142 mg, yield 53%) as white crystals.
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[CH:8][C:7]([Br:10])=[CH:6][C:3]=1[C:4]#[N:5].C(N(CC)CC)C.[CH2:18]([O:20][P:21]([CH2:26][C:27]1[CH:35]=[CH:34][C:30]([C:31](Cl)=[O:32])=[CH:29][CH:28]=1)([O:23][CH2:24][CH3:25])=[O:22])[CH3:19].O>CN(C)C1C=CN=CC=1.ClCCl>[CH2:24]([O:23][P:21]([CH2:26][C:27]1[CH:28]=[CH:29][C:30]([C:31]([NH:1][C:2]2[CH:9]=[CH:8][C:7]([Br:10])=[CH:6][C:3]=2[C:4]#[N:5])=[O:32])=[CH:34][CH:35]=1)([O:20][CH2:18][CH3:19])=[O:22])[CH3:25]
Reactant: N#Cc1cc(Br)ccc1N
Reactant: CCOP(=O)(Cc1ccc(C(=O)Cl)cc1)OCC
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: O
Solvent: CCN(CC)CC
Product: CCOP(=O)(Cc1ccc(C(=O)Nc2ccc(Br)cc2C#N)cc1)OCC
Yield: 32.6 %

Procedure:
2-Amino-5-bromobenzonitrile (3.94 g, 20 millimoles), triethylamine (2.22 g, 22 millimoles) and 4-dimethylamino- pyridine (0.49 g, 4 millimoles) were dissolved in 40 ml of dry dichloromethane, to which was slowly added dropwise a solution of 4-diethoxyphosphinoylmethylbenzoyl chloride (5.81 g, 20 millimoles) in 40 ml dry dichloromethane while cooling the system with ice and stirring it. After stirring the resulting mixture at ambient temperature for 10 hours, the reaction mixture was mixed with 50 ml of water and extracted with chloroform. The chloroform layer was dried on anhydrous sodium sulfate and the solvent was removed by evaporation under reduced pressure. Purification of the residue by a silica gel column chromato-graphy using 1:2 mixture of chloroform and ethyl acetate as an eluent, followed by recrystallization from benzene-n-hexane mixture, gave 2.94 g of 4-diethoxyphosphinoylmethyl-N-(4-bromo-2-cyanophenyl)benzamide as a colorless crystalline product melting at 165°-166° C. (after recrystallization from benzene-n-hexane).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([C:8](=O)[CH3:9])[CH:5]=[CH:6][CH:7]=1.[CH2:11]([NH2:14])[CH2:12][NH2:13].[BH4-].[Na+].Cl>CO>[NH2:13][CH2:12][CH2:11][NH:14][CH:8]([C:4]1[CH:3]=[C:2]([OH:1])[CH:7]=[CH:6][CH:5]=1)[CH3:9]
Reactant: NCCN
Reactant: CC(=O)c1cccc(O)c1
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CC(NCCN)c1cccc(O)c1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
3′-Hydroxyacetophenone (1.0 g) and ethylenediamine (1.47 ml) were dissolved in methanol (10 ml), and the solution was stirred at room temperature for 16 hours. The mixture was added with sodium borohydride (277.9 mg), and the mixture was stirred at room temperature for 5 hours. The reaction mixture was added with 1 N hydrochloric acid, and then the solvent was evaporated. The residue was added with potassium carbonate and distilled water, thereby made alkaline, and then extracted with a mixed solvent of chloroform-ethanol (10:1), and the organic layer was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (chloroform:methanol:28% aqueous ammonia=10:1:0.1 to 5:1:0.1) to obtain the title compound (59.1 mg).
Reaction SMILES: [CH2:1]1[O:11][C:4]2([CH2:9][CH2:8][C:7](=[O:10])[CH2:6][CH2:5]2)[O:3][CH2:2]1.[F:12][C:13]1[CH:18]=[CH:17][C:16]([Mg]Br)=[CH:15][CH:14]=1>C(OCC)C>[F:12][C:13]1[CH:18]=[CH:17][C:16]([C:7]2([OH:10])[CH2:6][CH2:5][C:4]3([O:3][CH2:2][CH2:1][O:11]3)[CH2:9][CH2:8]2)=[CH:15][CH:14]=1
Reactant: O=C1CCC2(CC1)OCCO2
Reactant: Fc1ccc([Mg]Br)cc1
Solvent: CCOCC
Product: OC1(c2ccc(F)cc2)CCC2(CC1)OCCO2
Temperature: 25 °C
Yield: 94.1 %

Procedure:
To a solution of 1,4-cyclohexanedione mono-ethylene ketal (25 g, 0.16 mol) in diethylether (750 ml), cooled to −78° C. was added 4-fluorophenyl magnesium bromide (1 M in tetrahydrofuran, 190 ml, 0.19 mol) dropwise. The reaction mixture was warmed to room temperature, quenched with water and extracted twice with ethyl acetate. Washing with brine, drying and solvent evaporation gave 8-(4-fluorophenyl)-1,4-dioxa-spiro[4.5]decan-8-ol (38 g, 95%).
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[CH2:26][C:25]3[C:20](=[CH:21][CH:22]=[CH:23][C:24]=3[N+:27]([O-])=O)[C:19]2=[O:30])=[N:2]1.[Cl-].[NH4+].O>C(OCC)(=O)C.CCCCCC.[Fe]>[NH2:27][C:24]1[CH:23]=[CH:22][CH:21]=[C:20]2[C:25]=1[CH2:26][N:18]([C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=1/[CH:11]=[CH:10]/[C:3]1[C:4]3[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=3)[NH:1][N:2]=1)[C:19]2=[O:30]
Reactant: O=C1c2cccc([N+](=O)[O-])c2CN1c1ccccc1/C=C/c1n[nH]c2ccccc12
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: Nc1cccc2c1CN(c1ccccc1/C=C/c1n[nH]c3ccccc13)C2=O
Yield: 19.5 %

Procedure:
To a solution of (E)-2-{2-[2-(1H-indazol-3-yl)vinyl]phenyl}-4-nitro-2,3-dihydroisoindol-1-one (54 mg, 0.14 mmol) obtained in Step 1 in ethanol/water (2/1, 3.3 mL), ammonium chloride (40 mg, 0.75 mmol) and iron (38 mg, 0.68 mmol) were added, followed by heating under reflux for 4.0 hours under nitrogen atomosphere. The reaction mixture was added with water, extracted with ethyl acetate and the organic layer was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform to chloroform/methanol=90/10) and crystallized from hexane/ethyl acetate (1/1) to obtain Compound 216 (10 mg, 20%).
Reaction SMILES: Cl.[CH2:2]([O:6][NH2:7])[CH:3]([CH3:5])[CH3:4].[CH3:8][O:9][C:10]1[CH:15]=[CH:14][C:13]([S:16](Cl)(=[O:18])=[O:17])=[CH:12][CH:11]=1.C(N(C(C)C)CC)(C)C>C1COCC1>[CH2:2]([O:6][NH:7][S:16]([C:13]1[CH:12]=[CH:11][C:10]([O:9][CH3:8])=[CH:15][CH:14]=1)(=[O:18])=[O:17])[CH:3]([CH3:5])[CH3:4]
Reactant: COc1ccc(S(=O)(=O)Cl)cc1
Reactant: CC(C)CON
Agent: Cl
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc(S(=O)(=O)NOCC(C)C)cc1
Temperature: 25 °C
Reaction time: 15 h

Procedure:
Isobutoxyamine hydrochloride (7.96 mmol, 1.0 g), 4-methoxybenzenesulfonyl chloride (7.24 mmol, 1.5 g), diisopropylethylamine (18.09 mmol, 3.15 mL) and anhydrous THF (15 mL) were combined under nitrogen. The reaction stirred at room temperature for 15 hours. The reaction solution was concentrated to a white solid and partitioned between ethyl acetate and 1N HCl. The organic layer was separated and washed with saturated aqueous sodium bicarbonate and brine, dried over magnesium sulfate and concentrated under vacuum to yield an off-white colored solid. Rf: 0.5 (2:1 hexanes/ethyl acetate); H1-NMR (CDCl3): δ 7.84 (2H,d), 6.99 (2H,d), 6.81 (1H,s), 3.87 (3H,s), 3.74 (2H,d), 1.90 (1H, septet), 0.86 (6H,d).
Reaction SMILES: [NH2:1][C:2]1[C:7](=[O:8])[NH:6][C:5]2[O:9][CH2:10][C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[C:4]=2[CH:3]=1.N1C=CC=CC=1.[C:23](Cl)(=[O:25])[CH3:24]>C(Cl)(Cl)Cl>[C:23]([NH:1][C:2]1[C:7](=[O:8])[NH:6][C:5]2[O:9][CH2:10][C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[C:4]=2[CH:3]=1)(=[O:25])[CH3:24]
Reactant: CC(=O)Cl
Reactant: Nc1cc2c([nH]c1=O)OCc1ccccc1-2
Solvent: ClC(Cl)Cl
Solvent: c1ccncc1
Product: CC(=O)Nc1cc2c([nH]c1=O)OCc1ccccc1-2

Procedure:
To 2.0 gm of 2-amino-4,6-dihydro-3H-[2]benzopyrano[3,4-b]pyridin-3-one, in 100 ml of chloroform containing 1 ml of pyridine, add 0.80 gm of acetyl chloride. Stir the reaction at room temperature for 5 hours. Filter and wash the solution with water. Remove the solvent by stripping to give the title compound.
Reaction SMILES: [N:1]1([C:10]2[CH:15]=[CH:14][C:13]([CH2:16][C:17]([OH:19])=O)=[CH:12][CH:11]=2)[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[CH:2]1.[CH3:20][N:21]([CH3:37])[CH2:22][CH2:23][N:24]([CH3:36])[C:25]1[CH:30]=[CH:29][C:28]([NH2:31])=[CH:27][C:26]=1[C:32]([F:35])([F:34])[F:33]>C(Cl)Cl.CO>[N:1]1([C:10]2[CH:11]=[CH:12][C:13]([CH2:16][C:17]([NH:31][C:28]3[CH:29]=[CH:30][C:25]([N:24]([CH2:23][CH2:22][N:21]([CH3:37])[CH3:20])[CH3:36])=[C:26]([C:32]([F:33])([F:34])[F:35])[CH:27]=3)=[O:19])=[CH:14][CH:15]=2)[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[CH:2]1
Reactant: O=C(O)Cc1ccc(-n2cnc3ccccc32)cc1
Reactant: CN(C)CCN(C)c1ccc(N)cc1C(F)(F)F
Solvent: ClCCl
Solvent: CO
Product: CN(C)CCN(C)c1ccc(NC(=O)Cc2ccc(-n3cnc4ccccc43)cc2)cc1C(F)(F)F

Procedure:
The title compound is prepared as described in Example 1 but using (4-benzoimidazol-1-yl-phenyl)-acetic acid (Step 20.1) and 4-[(2-dimethylamino-ethyl)-methyl-amino]-3-trifluoromethyl-phenylamine (Step 6.1). Title compound: ES-MS: 496.0 [M+H]+; single peak at tR=3.00 min (System 1); Rf=0.14 (CH2Cl2/MeOH+1% NH3aq, 9:1).
Reaction SMILES: C1C=CC(P(C2C=CC3C(=CC=CC=3)C=2C2C3C(=CC=CC=3)C=CC=2P(C2C=CC=CC=2)C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[CH3:47][CH:48]1[CH2:52][CH2:51][C:50](=[CH:53][N:54]([CH3:61])[C:55]2[CH:60]=[CH:59][CH:58]=[CH:57][CH:56]=2)[C:49]1=[O:62].Br[C:64]1[CH:69]=[CH:68][C:67]([O:70][CH3:71])=[CH:66][CH:65]=1.CCCC[O-].[Na+]>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C1(C)C=CC=CC=1>[CH3:71][O:70][C:67]1[CH:68]=[CH:69][C:64]([C:48]2([CH3:47])[CH2:52][CH2:51][C:50](=[CH:53][N:54]([CH3:61])[C:55]3[CH:60]=[CH:59][CH:58]=[CH:57][CH:56]=3)[C:49]2=[O:62])=[CH:65][CH:66]=1
Reactant: CC1CCC(=CN(C)c2ccccc2)C1=O
Reactant: COc1ccc(Br)cc1
Agent: [Pd]
Agent: CCCC[O-]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: Cc1ccccc1
Product: COc1ccc(C2(C)CCC(=CN(C)c3ccccc3)C2=O)cc1
Temperature: 25 °C
Reaction time: 0.02 h
Yield: 54.8 %

Procedure:
An oven dried Schlenk tube equipped with a rubber septum was cooled under an argon purge. The septum was removed and the tube was charged with tris(dibenzylideneacetone)dipalladium (0) (11.5 mg, 0.025 mmol, 5 mol % Pd), (S)-BINAP (31.4 mg, 0.05 mmol, 10 mol %) and 2-methyl-5-(N-methyl-anilinomethylene)cyclopentanone (108 mg, 0.5 mmol). Toluene (2 mL) was added and the mixture was stirred for 1 min at room temperature. 4-Bromoanisole (187 mg, 1.0 mmol) and sodium 1-butoxide (96 mg, 1.0 mmol) were added to the tube. The tube was capped with the septum, purged with argon, and additional toluene (4 mL) was added through the septum. The mixture was heated to 100° C. with stirring until the starting ketone had been completely consumed as judged by GC analysis. The mixture was cooled to room temperature, quenched with saturated aqueous ammonium chloride (10 mL) and diluted with ether (20 mL). The mixture was poured into a separatory funnel and the layers were separated. The aqueous layer was extracted with ether (20 mL), and the combined organic layers were washed with brine (20 mL), dried over anhydrous magnesium sulfate, filtered, and concentrated in vacuo. The crude material was purified by flash chromatography on silica gel to afford 88 mg (55%) of the title compound. The ee was determined to be 62% by chiral HPLC analysis.
Reaction SMILES: [NH2:1][CH:2]1[N:8]=[C:7]([C:9]2[C:14]([O:15][CH3:16])=[CH:13][C:12]([CH3:17])=[CH:11][C:10]=2[O:18][CH3:19])[C:6]2[CH:20]=[CH:21][CH:22]=[CH:23][C:5]=2[N:4]([CH3:24])[C:3]1=[O:25].[C:26]([NH:33][C@@H:34]([C:42](O)=[O:43])[CH2:35][C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27].C(N(CC)CC)C.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1>CN(C)C=O.O>[C:29]([O:28][C:26]([NH:33][CH:34]([CH2:35][C:36]1[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=1)[C:42]([NH:1][CH:2]1[N:8]=[C:7]([C:9]2[C:14]([O:15][CH3:16])=[CH:13][C:12]([CH3:17])=[CH:11][C:10]=2[O:18][CH3:19])[C:6]2[CH:20]=[CH:21][CH:22]=[CH:23][C:5]=2[N:4]([CH3:24])[C:3]1=[O:25])=[O:43])=[O:27])([CH3:32])([CH3:30])[CH3:31]
Reactant: CC(C)(C)OC(=O)N[C@H](Cc1ccccc1)C(=O)O
Reactant: COc1cc(C)cc(OC)c1C1=NC(N)C(=O)N(C)c2ccccc21
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: O
Solvent: CN(C)C=O
Product: COc1cc(C)cc(OC)c1C1=NC(NC(=O)C(Cc2ccccc2)NC(=O)OC(C)(C)C)C(=O)N(C)c2ccccc21
Temperature: 5 °C
Reaction time: 8 h

Procedure:
1.73 g of 3-amino-1,3-dihydro-5-(2,6-dimethoxy-4-methylphenyl)-1-methyl-1,4-benzodiazepin-2-one are dissolved in 30 ml of dimethylformamide in the presence of 1.42 g of BOC-D-phenylalanine, followed by cooling to 5° C. and addition of 1.07 ml of triethylamine and then 2.4 g of BOP. The reaction mixture is allowed to return to room temperature and is left stirring overnight. It is then poured into water and extracted with ethyl acetate. The organic phase is washed with water, separated out after settling of the phases, dried over Na2SO4, filtered and concentrated under vacuum. An oily residue of 2-tert-butoxycarbonylamino-N-[2,3-dihydro-5-(2,6-dimethoxy-4-methylphenyl)-1-methyl-2-oxo-1H-1,4-benzodiazepin-3-yl]-3-phenylpropionamide, obtained in quantitative yield, is used as it is for the following step (Compound 16).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]2[C:13]3[C:14](=[O:31])[N:15]([C:18]4[CH:23]=[CH:22][C:21]([N:24]5[CH:29]=[CH:28][CH:27]=[CH:26][C:25]5=[O:30])=[CH:20][CH:19]=4)[CH2:16][CH2:17][C:12]=3[C:11]([C:32]#[N:33])=[N:10]2)=[CH:5][CH:4]=1.[N-:34]=[N+:35]=[N-:36].[Na+].[NH4+].[Cl-].C(Cl)(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>CN(C=O)C.N1C=CC=CC=1.O>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]2[C:13]3[C:14](=[O:31])[N:15]([C:18]4[CH:23]=[CH:22][C:21]([N:24]5[CH:29]=[CH:28][CH:27]=[CH:26][C:25]5=[O:30])=[CH:20][CH:19]=4)[CH2:16][CH2:17][C:12]=3[C:11]([C:32]3[NH:36][N:35]=[N:34][N:33]=3)=[N:10]2)=[CH:5][CH:4]=1
Reactant: COc1ccc(-n2nc(C#N)c3c2C(=O)N(c2ccc(-n4ccccc4=O)cc2)CC3)cc1
Reactant: [N-]=[N+]=[N-]
Agent: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cl-]
Agent: [NH4+]
Solvent: CN(C)C=O
Solvent: c1ccncc1
Solvent: O
Product: COc1ccc(-n2nc(-c3nnn[nH]3)c3c2C(=O)N(c2ccc(-n4ccccc4=O)cc2)CC3)cc1
Temperature: 105 °C
Reaction time: 24 h
Yield: 9 %

Procedure:
To 1-(4-methoxyphenyl)-7-oxo-6-[4-(2-oxo-1(2H)-pyridinyl)phenyl]-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carbonitrile (0.1 g, 0.23 mmol) in DMF (2 mL) was added NaN3 (19 mg, 0.29 mmol) and NH4Cl (21 mg, 0.38 mmol) and the reaction was heated to 105° C. for 24 h. The reaction was cooled, water (1 mL) was added, and the resulting solid filtered off and dried. The solid was placed in DMF (1 mL) and trityl chloride (60 mg, 0.2 mmol) and pyridine (0.2 mL) were added and stirred for 24 h. The reaction was quenched with water, extracted with EtOAc, and dried (Na2SO4). Purification on silica gel was not successful. The trityl group was removed with TFA (0.5 mL) in CH2Cl2 for 2 h. The solvents were removed and the compound was purified by HPLC and freeze-dried to afford 10 mg (9%) of a white solid; High Resolution Mass Spec (M+H)+ for C25H21N8O3 481.1749.