Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:31]=[CH:30][C:5]([C:6]([NH:8][C:9]2[C:10]([CH3:29])=[C:11]([CH3:28])[C:12]3[O:16][C:15]([CH3:18])([CH3:17])[CH:14]([C:19]4[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=4)[C:13]=3[C:26]=2[CH3:27])=O)=[CH:4][CH:3]=1>C(O)C>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][NH:8][C:9]2[C:10]([CH3:29])=[C:11]([CH3:28])[C:12]3[O:16][C:15]([CH3:18])([CH3:17])[CH:14]([C:19]4[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=4)[C:13]=3[C:26]=2[CH3:27])=[CH:30][CH:31]=1
Reactant: Cc1c(C)c2c(c(C)c1NC(=O)c1ccc(F)cc1)C(c1ccc(F)cc1)C(C)(C)O2
Solvent: CCO
Product: Cc1c(C)c2c(c(C)c1NCc1ccc(F)cc1)C(c1ccc(F)cc1)C(C)(C)O2
Yield: 66 %

Procedure:
By using 4-fluoro-N-[3-(4-fluorophenyl)-2,2,4,6,7-pentamethyl-2,3-dihydro-1-benzofuran-5-yl]benzamide, the title compound was synthesized according to Example 2b. Yield: 66%. Melting point: 118-120° C. (Ethanol).
Reaction SMILES: [N-:1]=[N+:2]=[N-:3].[Na+].S(O)(=O)(=O)C.[Cl:10][C:11]1[CH:16]=[C:15]([Cl:17])[CH:14]=[CH:13][C:12]=1[C:18]1([CH2:21][N:22]2[CH:26]=[N:25][CH:24]=[N:23]2)[CH2:20][O:19]1.ClCCl>O.CN(C)C=O>[N:1]([CH2:20][C:18]([C:12]1[CH:13]=[CH:14][C:15]([Cl:17])=[CH:16][C:11]=1[Cl:10])([OH:19])[CH2:21][N:22]1[CH:26]=[N:25][CH:24]=[N:23]1)=[N+:2]=[N-:3]
Reactant: Clc1ccc(C2(Cn3cncn3)CO2)c(Cl)c1
Reactant: [N-]=[N+]=[N-]
Agent: CS(=O)(=O)O
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Solvent: CN(C)C=O
Product: [N-]=[N+]=NCC(O)(Cn1cncn1)c1ccc(Cl)cc1Cl
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solution of sodium azide (22.75 g, 0.35 mole) in water (62.5 ml) was added to a solution of 2-(2,4-dichlorophenyl)-2-(1H-1,2,4-triazol-1-ylmethyl)oxirane monomesylate (25 g, 0.068 mole) in dimethylformamide (DMF) (250 ml) and the reaction mixture was stirred at room temperature for 0.5 hours and then at 60° for 16 hours. The reaction mixture was cooled and then poured into a mixture of dichloromethane (250 ml) and water (75 ml). The two phases were separated and the aqueous phase was extracted with dichloromethane (2×25 ml) and the combined organic extracts were then dried (MgSO4), filtered and evaporated. The residue was triturated with diethyl ether and the resulting solid filtered off and then recrystallized from an ethyl acetate-hexane mixture to furnish the title azide as a colorless crystalline solid, (16.9 g, 79%) m.p. 117°-19°.
Reaction SMILES: C[C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1OC)[CH:5]=[O:6].[CH2:12]([Mg]Br)[CH3:13]>>[CH3:12][CH2:13][CH:5]([OH:6])[C:4]1[CH:7]=[CH:8][CH:9]=[CH:2][CH:3]=1
Reactant: CC[Mg]Br
Reactant: COc1ccc(C=O)cc1C
Product: CCC(O)c1ccccc1

Procedure:
The synthesis of the title compound (26F) was accomplished in a four-step, three-pot reaction sequence- Commercially available 3-methyl-p-anisaldehyde was reacted with ethylmagnesium bromide to provide its phenylpropanol derivative. This alcohol was then oxidized to the corresponding ketone in the usual manner with PCC. This ketone was subsequently reacted with (R)-naphthyl-1-ethylamine in the presence of Ti(i-PrO)4 to provide the imine. This imine was reduced in high diastereoselective yield by catalytic hydrogenation in the presence of Raney-nickel.
Reaction SMILES: [C:1]([CH:3]=[C:4]([NH:15][C:16](=[O:20])OCC)[C:5]1[CH:10]=[CH:9][C:8]([C:11]([F:14])([F:13])[F:12])=[CH:7][CH:6]=1)#[N:2].[N:21]1([CH2:27][C:28]([NH:30][NH2:31])=O)[CH2:26][CH2:25][O:24][CH2:23][CH2:22]1.C(OCC)(=O)C.O>CN1C(=O)CCC1>[N:21]1([CH2:27][C:28]2[N:2]=[C:1]3[N:31]([C:16]([OH:20])=[N:15][C:4]([C:5]4[CH:6]=[CH:7][C:8]([C:11]([F:12])([F:13])[F:14])=[CH:9][CH:10]=4)=[CH:3]3)[N:30]=2)[CH2:26][CH2:25][O:24][CH2:23][CH2:22]1
Reactant: CCOC(=O)NC(=CC#N)c1ccc(C(F)(F)F)cc1
Reactant: NNC(=O)CN1CCOCC1
Solvent: CCOC(C)=O
Solvent: O
Solvent: CN1CCCC1=O
Product: Oc1nc(-c2ccc(C(F)(F)F)cc2)cc2nc(CN3CCOCC3)nn12
Temperature: 190 °C
Reaction time: 4 h

Procedure:
2.4 g (8.4 mmol) of ethyl {2-cyano-1-[4-(trifluoromethyl)phenyl]ethenyl}carbamate (Example 129A) and 1.34 g (8.4 mmol) of 2-morpholin-4-ylacetohydrazide are dissolved in NMP (12 ml) and stirred in a flask with a calcium chloride drying tube at an oil-bath temperature of 190° C. for 4 h. The reaction mixture is cooled to RT and ethyl acetate (150 ml) and water (100 ml) are added. The organic phase is washed with saturated sodium bicarbonate solution, separated off, dried with magnesium sulphate and concentrated. The residue is chromatographed on silica gel (mobile phase cyclohexane/ethyl acetate 10:1 to 1:1, then with dichloromethane/methanol 100:1). 850 mg (26% of theory) of the product are obtained.
Reaction SMILES: C([O:3][C:4]([C:6]1[C:7]([O:25]C(=O)C)=[C:8]2[C:14]([CH3:15])=[C:13]([CH3:16])[N:12]([CH2:17][C:18]3[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=3)[C:9]2=[CH:10][N:11]=1)=O)C.[NH2:29][CH2:30][C:31]([OH:33])=[O:32].C[O-].[Na+].CO>>[F:24][C:21]1[CH:22]=[CH:23][C:18]([CH2:17][N:12]2[C:9]3=[CH:10][N:11]=[C:6]([C:4]([NH:29][CH2:30][C:31]([OH:33])=[O:32])=[O:3])[C:7]([OH:25])=[C:8]3[C:14]([CH3:15])=[C:13]2[CH3:16])=[CH:19][CH:20]=1
Reactant: CCOC(=O)c1ncc2c(c(C)c(C)n2Cc2ccc(F)cc2)c1OC(C)=O
Reactant: NCC(=O)O
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: Cc1c(C)n(Cc2ccc(F)cc2)c2cnc(C(=O)NCC(=O)O)c(O)c12

Procedure:
Prepared in analogy to that of Example 1(e) from 4-acetoxy-1-(4-fluoro-benzyl)-2,3-dimethyl-1H-pyrrolo[2,3-c]pyridine-5-carboxylic acid ethyl ester, glycine and NaOMe/HOMe. The title compound, ESI MS (m/z): 372 (M+H)+.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[CH2:7][C:8]([C:11]([OH:13])=O)=[N:9][N:10]=1.[NH2:14][C:15]([CH3:32])([CH3:31])[CH2:16][N:17]1[CH:21]=[CH:20][C:19]([C:22]2[CH:29]=[CH:28][C:25]([C:26]#[N:27])=[C:24]([CH3:30])[CH:23]=2)=[N:18]1>>[C:26]([C:25]1[CH:28]=[CH:29][C:22]([C:19]2[CH:20]=[CH:21][N:17]([CH2:16][C:15]([NH:14][C:11]([C:8]3[NH:9][N:10]=[C:6]([C:2]4[O:1][CH:5]=[CH:4][CH:3]=4)[CH:7]=3)=[O:13])([CH3:31])[CH3:32])[N:18]=2)=[CH:23][C:24]=1[CH3:30])#[N:27]
Reactant: Cc1cc(-c2ccn(CC(C)(C)N)n2)ccc1C#N
Reactant: O=C(O)C1=NN=C(c2ccco2)C1
Product: Cc1cc(-c2ccn(CC(C)(C)NC(=O)c3cc(-c4ccco4)n[nH]3)n2)ccc1C#N

Procedure:
The title compound was prepared using the method of Example 54 but starting from 5-(2-furyl)-4H-pyrazole-3-carboxylic acid (56 mg; 0.32 mmol) and 4-(1-(2-amino-2-methylpropyl)-1H-pyrazol-3-yl)-2-methylbenzonitrile (80 mg; 0.32 mmol). Crude product was purified by chromatography (CombiFlash, silica-C18 column, eluent: 0-100% ACN/water) to obtain 16 mg of the product which was further purified by preparative HPLC (Waters Deltaprep 4000, SymmPrep 56.2, 25-80% ACN/AcONH4) to obtain 5.3 mg of he title compound. 1H-NMR (400 MHz; d1-CDCl3): δ 1.52 (s, 6H), 2.54 (s, 3H), 4.50 (s, 2H), 6.52 (dd, 1H), 6.57 (d, 1H), 6.64 (d, 1H), 6.90 (s, 1H), 7.44 (d, 1H), 7.48 (d, 1H), 7.59 (d, 1H), 7.70 (dd, 1H), 7.75 (d, 1H), 10.31 (broad s, 1H).
Reaction SMILES: [C:1]1([CH2:7][CH2:8][N:9]([C@H:17]2[C:30]3[CH:29]=[C:28]4[C:23]([NH:24][C:25](=[O:31])[CH2:26][O:27]4)=[CH:22][C:21]=3[O:20][C:19]([CH3:33])([CH3:32])[C@@H:18]2[OH:34])[C:10](=[O:16])[O:11][C:12]([CH3:15])([CH3:14])[CH3:13])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:35](=O)([O-])[O-].[K+].[K+].CI.[Cl-].[NH4+]>CN(C)C=O>[C:1]1([CH2:7][CH2:8][N:9]([C@H:17]2[C:30]3[CH:29]=[C:28]4[C:23]([N:24]([CH3:35])[C:25](=[O:31])[CH2:26][O:27]4)=[CH:22][C:21]=3[O:20][C:19]([CH3:33])([CH3:32])[C@@H:18]2[OH:34])[C:10](=[O:16])[O:11][C:12]([CH3:15])([CH3:14])[CH3:13])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C([O-])[O-]
Reactant: CC(C)(C)OC(=O)N(CCc1ccccc1)[C@H]1c2cc3c(cc2OC(C)(C)[C@@H]1O)NC(=O)CO3
Agent: [Cl-]
Agent: [K+]
Agent: [NH4+]
Solvent: CN(C)C=O
Solvent: CI
Product: CN1C(=O)COc2cc3c(cc21)OC(C)(C)[C@H](O)[C@H]3N(CCc1ccccc1)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 4 h
Yield: 100 %

Procedure:
To a solution of t-butyl (2-phenylethyl)(7R*,8S*)-[7-hydroxy-6,6-dimethyl-3-oxo-2,3,4,6,7,8-hexahydro-1,5-dioxa-4-aza-anthracene-8-yl]carbamate (106 mg, 0.23 mmol) in dimethylformamide (2 mL), potassium carbonate (79 mg, 0.57 mmol) and methyl iodide (28 δL, 0.46 mmol) were added at room temperature, and the resulting mixture was stirred at room temperature for 4 hours. Upon the completion of the reaction, saturated ammonium chloride aqueous solution was added thereto, the resulting solution was extracted with ethyl acetate, washed with saturated sodium chloride solution, dried over magnesium sulfate, and concentrated. The resulting mixture was purified by silica gel column (hexane/ethyl acetate=2/1) and the aimed product was obtained (yield: 100%).
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[C:5]([C:12]3[NH:20][C:19]4[CH2:18][CH2:17][NH:16][C:15](=[O:21])[C:14]=4[CH:13]=3)[CH:6]=[CH:7][CH:8]=2)[N:3]=1.[CH3:22][C:23]([NH2:26])([CH3:25])[CH3:24]>CN1C(=O)CCC1.C(Cl)Cl>[C:23]([NH:26][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[C:5]([C:12]3[NH:20][C:19]4[CH2:18][CH2:17][NH:16][C:15](=[O:21])[C:14]=4[CH:13]=3)[CH:6]=[CH:7][CH:8]=2)[N:3]=1)([CH3:25])([CH3:24])[CH3:22]
Reactant: O=C1NCCc2[nH]c(-c3cccc4ccc(Cl)nc34)cc21
Reactant: CC(C)(C)N
Solvent: CN1CCCC1=O
Solvent: ClCCl
Product: CC(C)(C)Nc1ccc2cccc(-c3cc4c([nH]3)CCNC4=O)c2n1
Yield: 21.4 %

Procedure:
A solution of 2-(2-chloroquinolin-8-yl)-6,7-dihydro-1H-pyrrolo[3,2-c]pyridin-4(5H)-one (1) (125 mg, 0.42 mmol) and 2-methylpropan-2-amine (154 mg, 2.10 mmol) (Sigma-Aldrich) in NMP (0.84 mL) was heated in a sealed tube at 165° C. for 2.5 d. The reaction mixture was diluted with DCM (100 mL), added to a separatory funnel, and washed with saturated aq. brine (4×100 mL) before the organic layer was separated, dried over Na2SO4, and concentrated. The crude product was adsorbed onto silica and was purified via automated flash chromatography (silica gel) with 1-4% of 2 M NH3 in MeOH/DCM to give 2-(2-(tert-butylamino)quinolin-8-yl)-6,7-dihydro-1H-pyrrolo[3,2-c]pyridin-4(5H)-one (30 mg) (0.09 mmol, 21% yield) as a yellow oil which was slightly impure. This material was dissolved in MeOH (˜20 mg/mL) and injected (2×1.0 mL) onto the Shimadzu preparatory LC (Phenomenex Gemini C18, 10 μm, 150×30 mm; 10-100% MeCN/water with 0.1% TFA); the pure fractions were combined, basicified with NaHCO3 (saturated, aq.), extracted with CHCl3/IPA(3:2), separated, dried over Na2SO4, and concentrated via rotary evaporation to give 2-(2-(tert-butylamino)quinolin-8-yl)-6,7-dihydro-1H-pyrrolo[3,2-c]pyridin-4(5H)-one (340) (19 mg, 0.08 mmol, 14% yield) as a light yellow solid. 1H NMR (400 MHz, CDCl3) δ ppm 1.62 (s, 9H) 2.99 (t, J=6.94 Hz, 2H) 3.65 (td, J=6.85, 2.35 Hz, 2H) 4.84 (s, 1H) 5.71 (br. s., 1H) 6.56 (d, J=9.00 Hz, 1H) 7.10 (d, J=1.76 Hz, 1H) 7.21 (t, J=7.73 Hz, 1H) 7.38 (d, J=7.63 Hz, 1H) 7.75 (d, J=9.00 Hz, 1H) 7.96 (d, J=7.63 Hz, 1H) 13.24 (br. s., 1H). MS (ESI, pos. ion) m/z: 353.3 (M+1).
Reaction SMILES: [C:1]([O:4][C:5]1[CH:10]=[CH:9][C:8]([CH3:11])=[C:7]([Cl:12])[CH:6]=1)(=[O:3])[CH3:2].[Br:13]N1C(=O)CCC1=O>C(Cl)(Cl)(Cl)Cl.N(C(C)(CC(OC)(C)C)C#N)=NC(C)(CC(C)(OC)C)C#N>[C:1]([O:4][C:5]1[CH:10]=[CH:9][C:8]([CH2:11][Br:13])=[C:7]([Cl:12])[CH:6]=1)(=[O:3])[CH3:2]
Reactant: O=C1CCC(=O)N1Br
Reactant: CC(=O)Oc1ccc(C)c(Cl)c1
Agent: COC(C)(C)CC(C)(C#N)N=NC(C)(C#N)CC(C)(C)OC
Solvent: ClC(Cl)(Cl)Cl
Product: CC(=O)Oc1ccc(CBr)c(Cl)c1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 59.2 %

Procedure:
To a solution of 4-acetoxy-2-chlorotoluene (13.4 g) in carbon tetrachloride (134 ml) were added N-bromosuccinimide (12.9 g) and 2,2′-azobis(4-methoxy-2,4-dimethylvaleronitrile) (1.12 g), and the mixture was refluxed under heating for 2.5 hr. The reaction mixture was concentrated to dryness under reduced pressure. To the residue was added hexane (270 ml) and the mixture was stirred at room temperature for 10 min. The insoluble matter was filtered off and washed with hexane. The filtrate and washing were combined and washed 3 times with saturated aqueous sodium hydrogen carbonate solution and once with saturated brine. The organic layer was dried over magnesium sulfate and concentrated to dryness under reduced pressure. The residue was crystallized from hexane to give 4-acetoxy-2-chlorobenzylbromide as colorless crystals (11.3 g).
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]([O:11][CH3:12])[CH:8]=[C:7]([F:13])[C:3]=1[C:4]([OH:6])=[O:5].S(=O)(=O)(O)O.[CH3:19]O>>[F:1][C:2]1[CH:10]=[C:9]([O:11][CH3:12])[CH:8]=[C:7]([F:13])[C:3]=1[C:4]([O:6][CH3:19])=[O:5]
Reactant: COc1cc(F)c(C(=O)O)c(F)c1
Reactant: CO
Agent: O=S(=O)(O)O
Product: COC(=O)c1c(F)cc(OC)cc1F

Procedure:
To methanol (300 ml) was dissolved 2,6-difluoro-4-methoxybenzoic acid (102 g) and then concentrated sulfuric acid (1 ml) was added and stirred under reflux for 3 hours. After the reaction, the mixture was extracted with ethyl acetate (400 ml). The organic layer separated was washed with water, dried over anhydrous magnesium sulfate, and then the solvent was distilled off under reduced pressure to give methyl 2,6-difluoro-4-methoxybenzoate (90 g).
Reaction SMILES: [CH2:1]([C:3]1[C:12]([CH2:13][C:14]2[CH:19]=[CH:18][C:17]([C:20]3[CH:24]=[CH:23][N:22]([CH3:25])[N:21]=3)=[CH:16][CH:15]=2)=[CH:11][C:6]([C:7](OC)=[O:8])=[C:5]([CH:26]=O)[CH:4]=1)[CH3:2].[O:28]1[CH2:32][CH2:31][CH2:30][CH:29]1[CH2:33][NH2:34].S([O-])([O-])(=O)=O.[Mg+2]>C1COCC1>[CH2:1]([C:3]1[CH:4]=[C:5]2[C:6](=[CH:11][C:12]=1[CH2:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]3[CH:24]=[CH:23][N:22]([CH3:25])[N:21]=3)=[CH:16][CH:15]=1)[C:7](=[O:8])[N:34]([CH2:33][CH:29]1[CH2:30][CH2:31][CH2:32][O:28]1)[CH2:26]2)[CH3:2]
Reactant: NCC1CCCO1
Reactant: CCc1cc(C=O)c(C(=O)OC)cc1Cc1ccc(-c2ccn(C)n2)cc1
Agent: O=S(=O)([O-])[O-]
Agent: [Mg+2]
Solvent: C1CCOC1
Product: CCc1cc2c(cc1Cc1ccc(-c3ccn(C)n3)cc1)C(=O)N(CC1CCCO1)C2
Temperature: 25 °C
Reaction time: 8 h
Yield: 24.3 %

Procedure:
A mixture of methyl 4-ethyl-2-formyl-5-(4-(1-methyl-1H-pyrazol-3-yl)benzyl)benzoate (0.11 g), (tetrahydrofuran-2-yl)methanamine (0.03 g) and anhydrous magnesium sulfate (0.07 g) in THF (3.00 mL) was stirred overnight at room temperature. The insoluble substance was removed by filtration, and the filtrate was concentrated under reduced pressure. The residue was diluted with acetic acid (3.00 mL), sodium triacetoxyborohydride (0.09 g) was added thereto, and the mixture was stirred overnight at room temperature. The reaction mixture was neutralized with saturated aqueous sodium bicarbonate solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by NH silica gel column chromatography (ethyl acetate/hexane), and crystallized from ethyl acetate/hexane to give the title compound (0.03 g).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([C:8]([OH:10])=O)[C:5]([CH3:11])=[CH:4][CH:3]=1.[NH2:12][C:13]1[C:23]([CH3:24])=[CH:22][C:16]([C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:15][C:14]=1[CH3:25].C(N(CC)C(C)C)(C)C.CCCP1(OP(CCC)(=O)OP(CCC)(=O)O1)=O>C(Cl)Cl>[Cl:1][C:2]1[N:7]=[C:6]([C:8]([NH:12][C:13]2[C:14]([CH3:25])=[CH:15][C:16]([C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:22][C:23]=2[CH3:24])=[O:10])[C:5]([CH3:11])=[CH:4][CH:3]=1
Reactant: Cc1ccc(Cl)nc1C(=O)O
Reactant: CCOC(=O)c1cc(C)c(N)c(C)c1
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)c1cc(C)c(NC(=O)c2nc(Cl)ccc2C)c(C)c1
Reaction time: 0.17 h
Yield: 57.5 %

Procedure:
To a solution of 6-chloro-3-methyl-pyridine-2-carboxylic acid (0.78 g, 4.55 mmol) in CH2Cl2 (15 mL) at room temperature are added ethyl 4-amino-3,5-dimethyl-benzoate (0.878 g, 4.55 mmol) and N,N-diisopropylethylamine (1.98 ml, 11.36 mmol). After stirring the reaction mixture for 10 minutes, 1-propanephosphonic acid cyclic anhydride (50% solution in ethyl acetate, 3.25 ml, 5.46 mmol) is added via syringe. After 48 hours, the solvent is removed under reduced pressure and the residue is diluted with water and extracted with ethyl acetate. The organic layers are combined and dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The resulting residue is purified by flash chromatography (silica gel) using a gradient of 0-40% ethyl acetate in hexanes. After purification, the solid is triturated with 30% ethyl acetate in hexanes and filtered to give the title compound as a white powder (0.907 g, 57.5%). Mass spectrum (m/z): 347.2 (M+1).
Reaction SMILES: [C:1]1([CH2:7][C:8]([OH:10])=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.CN1CCOCC1.[NH2:32][C:33]1[N:38]=[C:37]([C:39]2[CH:46]=[CH:45][C:42]([C:43]#[N:44])=[C:41]([F:47])[CH:40]=2)[CH:36]=[C:35]([N:48]2[CH2:53][C@@H:52]([NH2:54])[CH2:51][CH2:50][C@H:49]2[CH3:55])[N:34]=1>CN(C=O)C.O>[NH2:32][C:33]1[N:34]=[C:35]([N:48]2[C@H:49]([CH3:55])[CH2:50][CH2:51][C@H:52]([NH:54][C:8](=[O:10])[CH2:7][C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[CH2:53]2)[CH:36]=[C:37]([C:39]2[CH:46]=[CH:45][C:42]([C:43]#[N:44])=[C:41]([F:47])[CH:40]=2)[N:38]=1
Reactant: O=C(O)Cc1ccccc1
Reactant: C[C@@H]1CC[C@H](N)CN1c1cc(-c2ccc(C#N)c(F)c2)nc(N)n1
Agent: On1nnc2ccccc21
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Solvent: O
Product: C[C@@H]1CC[C@H](NC(=O)Cc2ccccc2)CN1c1cc(-c2ccc(C#N)c(F)c2)nc(N)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 85.6 %

Procedure:
A premixed solution of phenylacetic acid (45.0 mg, 0.331 mmol), EDC (79 mg, 0.413 mmol), HOBT (84 mg, 0.551 mmol), and N-methylmorpholine (0.152 mL, 1.378 mmol) in DMF (2 mL) was added to 4-{2-amino-6-[(2R,5S)-5-amino-2-methyl-1-piperidinyl]-4-pyrimidinyl}-2-fluorobenzonitrile (100 mg, 0.276 mmol) in DMF (2 mL). The solution was stirred at room temperature overnight. The reaction was diluted with water (10 mL), and then extracted with EtOAc (3×10 mL). The organics were combined, washed brine, dried over MgSO4, filtered and concentrated. The resulting oil was purified with a 10 g Biotage SNAP column with gradient of 0 to 85% EtOAc in Hexane for 25 minutes to afford the title compound (105 mg) as a yellow oil. LC-MS (ES) m/z=445 [M+H]+.
Reaction SMILES: [C:1]([O:4][C:5](=O)[CH3:6])(=O)C.[NH2:8][C:9]1[S:18][C:12]2[CH2:13][N:14]([CH3:17])[CH2:15][CH2:16][C:11]=2[C:10]=1[C:19]#[N:20]>C(OCC)(OCC)OCC>[CH2:5]([O:4][CH:1]=[N:8][C:9]1[S:18][C:12]2[CH2:13][N:14]([CH3:17])[CH2:15][CH2:16][C:11]=2[C:10]=1[C:19]#[N:20])[CH3:6]
Reactant: CC(=O)OC(C)=O
Reactant: CN1CCc2c(sc(N)c2C#N)C1
Solvent: CCOC(OCC)OCC
Product: CCOC=Nc1sc2c(c1C#N)CCN(C)C2
Yield: 3 %

Procedure:
3.5 ml of acetic anhydride were added to 46.0 g (238 mmol) of 2-amino-3-cyano-6-methyl-4,5,6,7-tetrahydrothieno[2,3-c]-pyridine in 250 ml of triethyl orthoformate and the mixture was boiled under nitrogen and at reflux for 4 h. After that, the mixture was filtered off with suction, in the hot, through a suction filter and the filtrate was evaporated right down at 80° C. on a rotary evaporator. The residue was taken up in 300 ml of methyl t-butyl ether and this mixture was heated to boiling. After the insoluble solids had been filtered off with suction, 45.4 g (77%) of the product crystallized out in an icebath with stirring. A further 1.7 g (3%) of product were obtained from the mother liquor as a second fraction. m.p.: 88-89° C.
Reaction SMILES: [CH:1]1[C:13]2[CH:12]([CH2:14][O:15][C:16]([NH:18][C@H:19]([C:24](O)=[O:25])[CH2:20][CH:21]([CH3:23])[CH3:22])=[O:17])[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.CN1CCOCC1.ClC(OCC(C)C)=O.[NH2:42][CH:43]([B:46]1[O:50][C:49]([CH2:52][CH2:53][CH:54]([CH3:63])[CH2:55][C:56]([O:58][C:59]([CH3:62])([CH3:61])[CH3:60])=[O:57])([CH3:51])[C:48]([CH3:65])([CH3:64])[O:47]1)[CH2:44][CH3:45]>ClCCl>[CH:10]1[C:11]2[CH:12]([CH2:14][O:15][C:16]([NH:18][C@H:19]([C:24]([NH:42][CH:43]([B:46]3[O:50][C:49]([CH2:52][CH2:53][CH:54]([CH3:63])[CH2:55][C:56]([O:58][C:59]([CH3:62])([CH3:61])[CH3:60])=[O:57])([CH3:51])[C:48]([CH3:64])([CH3:65])[O:47]3)[CH2:44][CH3:45])=[O:25])[CH2:20][CH:21]([CH3:23])[CH3:22])=[O:17])[C:13]3[C:5](=[CH:4][CH:3]=[CH:2][CH:1]=3)[C:6]=2[CH:7]=[CH:8][CH:9]=1
Reactant: CC(C)C[C@H](NC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)O
Reactant: CCC(N)B1OC(C)(C)C(C)(CCC(C)CC(=O)OC(C)(C)C)O1
Agent: CC(C)COC(=O)Cl
Solvent: ClCCl
Solvent: CN1CCOCC1
Product: CCC(NC(=O)[C@H](CC(C)C)NC(=O)OCC1c2ccccc2-c2ccccc21)B1OC(C)(C)C(C)(CCC(C)CC(=O)OC(C)(C)C)O1
Temperature: -10 °C
Reaction time: 0.12 h
Yield: 58.3 %

Procedure:
0.5 g (1.42 mmol) of N-[(9-fluorenyl)methoxycarbonyl]-L-leucine was dissolved in 7 ml of dichloromethane. 0.6 ml (5.7 mmol) of N-methylmorpholine was added and the solution was cooled to -10° C.under a nitrogen atmosphere. 0.22 ml (1.7 mmol) of isobutyl chloroformate was added and the solution was stirred for 7 minutes at -10° C. 1 g(2.13 mmol) of tert-butyl 5-[2-(1(RS)-aminopropyl)-4(RS),5,5-trimethyl-1,3,2-dioxaborolan-4-yl]-3(RS)-methylvalerate was added and the mixture was stirred at room temperature for 16 hours, then diluted with dichloromethane and extracted with 2M hydrochloric acid. The organic phase was extracted with 2M hydrochloric acid and saturated sodium hydrogen carbonate solution and then dried over anhydrous magnesium sulphate. After evaporation the residue was purified by chromatography on silica gel using ethyl acetate/hexane (1:2) for the elution. There was obtained 0.56 g of tert-butyl 5-[2-[1(RS)-[[N-[(9-fluorenyl)methoxycarbonyl]-L-leucyl]amino]propyl]-4(RS),5,5-trimethyl-1,3,2-dioxaborolan-4-yl]-3(RS)-methylvalerate as an oil; MS: m/e 677 [M+H]+.
Reaction SMILES: COC(=O)[CH2:4][C:5]1[N:9]2[C:10]3[CH:26]=[CH:25][CH:24]=[CH:23][C:11]=3[C:12]([C:15]3(Cl)[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]3[Cl:21])=[N:13][CH2:14][C:8]2=[N:7][N:6]=1.CNC.[CH3:31][N:32]([CH3:35])[CH:33]=[O:34]>>[CH3:31][N:32]([CH3:35])[C:33](=[O:34])[CH2:4][C:5]1[N:9]2[C:10]3[CH:26]=[CH:25][CH:24]=[CH:23][C:11]=3[C:12]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[Cl:21])=[N:13][CH2:14][C:8]2=[N:7][N:6]=1
Reactant: COC(=O)Cc1nnc2n1-c1ccccc1C(C1(Cl)C=CC=CC1Cl)=NC2
Reactant: CN(C)C=O
Agent: CNC
Product: CN(C)C(=O)Cc1nnc2n1-c1ccccc1C(c1ccccc1Cl)=NC2

Procedure:
In the manner given in Preparation 3, 6-(o-dichlorophenyl)-4H-s-triazolo[4,3-a][1,4]benzodiazepine-1-acetic acid methyl ester is reacted with dimethylamine in dimethyl formamide to give N,N-dimethyl-6-(o-chlorophenyl)-4H-s-triazolo[4,3-a][1,4]benzodiazepine-1-acetamide.
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([C:6]([OH:8])=O)[N:3]=[N:2]1.[CH3:9][NH:10][CH2:11][CH2:12][CH:13]1[CH2:18][CH2:17][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:15][CH2:14]1.CCN(C(C)C)C(C)C.C(P1(=O)OP(CCC)(=O)OP(CCC)(=O)O1)CC>CN(C=O)C.CCOC(C)=O>[CH3:9][N:10]([CH2:11][CH2:12][CH:13]1[CH2:18][CH2:17][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:15][CH2:14]1)[C:6]([C:4]1[N:3]=[N:2][NH:1][CH:5]=1)=[O:8]
Reactant: O=C(O)c1c[nH]nn1
Reactant: CNCCC1CCN(C(=O)OC(C)(C)C)CC1
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: CN(CCC1CCN(C(=O)OC(C)(C)C)CC1)C(=O)c1c[nH]nn1
Reaction time: 4 h

Procedure:
To 1H-1,2,3-triazole-4-carboxylic acid (150 mg, 1.327 mmol) and tert-butyl 4-(2-(methylamino)ethyl)piperidine-1-carboxylate (step 1) (322 mg, 1.327 mmol) in DMF (6 ml) was added DIPEA (0.695 ml, 3.98 mmol) and 50% T3P® in DMF (1.549 ml, 2.65 mmol). The resulting orange solution was stirred for 4 hrs. The mixture was diluted with EtOAc (200 ml) and washed with 1M HCl (2×50 ml). The organics were dried (MgSO4) and concentrated under reduced pressure. The crude residue in was dissolved in DCM and applied to a 12 g silica cartridge eluting with 0-100% EtOAc/iso-hexane. The product fractions were concentrated to give tert-butyl 4-(2-(N-methyl-1H-1,2,3-triazole-4-carboxamido)ethyl)piperidine-1-carboxylate as a gum.