Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][CH:2]([CH3:38])[C@H:3]([N:8]1[CH2:16][C:15]2[C:10](=[CH:11][C:12]([C:17]3[CH:22]=[CH:21][C:20]([NH:23][C:24](C4SC(C5C=CC=CC=5)=CN=4)=[O:25])=[CH:19][CH:18]=3)=[CH:13][CH:14]=2)[C:9]1=[O:37])[C:4]([O:6][CH3:7])=[O:5].NC1C=CC(C2C=C3C(CN([C@@H](C(C)C)C(OC)=O)C3=O)=CC=2)=CC=1.[C:64]([C:66]([C:69]1[CH:78]=[CH:77][C:72](C(OC)=O)=[CH:71][CH:70]=1)([CH3:68])[CH3:67])#[N:65]>>[C:64]([C:66]([C:69]1[CH:78]=[CH:77][C:72]([C:24]([NH:23][C:20]2[CH:19]=[CH:18][C:17]([C:12]3[CH:11]=[C:10]4[C:15]([CH2:16][N:8]([C@@H:3]([CH:2]([CH3:1])[CH3:38])[C:4]([O:6][CH3:7])=[O:5])[C:9]4=[O:37])=[CH:14][CH:13]=3)=[CH:22][CH:21]=2)=[O:25])=[CH:71][CH:70]=1)([CH3:68])[CH3:67])#[N:65]
Reactant: COC(=O)c1ccc(C(C)(C)C#N)cc1
Reactant: COC(=O)[C@H](C(C)C)N1Cc2ccc(-c3ccc(NC(=O)c4ncc(-c5ccccc5)s4)cc3)cc2C1=O
Agent: COC(=O)[C@H](C(C)C)N1Cc2ccc(-c3ccc(N)cc3)cc2C1=O
Product: COC(=O)[C@H](C(C)C)N1Cc2ccc(-c3ccc(NC(=O)c4ccc(C(C)(C)C#N)cc4)cc3)cc2C1=O
Yield: 58 %

Procedure:
The compound of example 630B was prepared analogous to the compound of example 611 by reaction of compound of example 6 with compound of example 630A.
Reaction SMILES: Br[C:2]1[C:10]2[C:5](=[N:6][CH:7]=[CH:8][CH:9]=2)[NH:4][C:3]=1[C:11]([O:13][CH3:14])=[O:12].Cl.[NH2:16][C:17]1[CH:22]=[CH:21][C:20](B(O)O)=[CH:19][CH:18]=1.[Cl-].[Li+].C(=O)([O-])[O-].[Na+].[Na+]>C1(C)C=CC=CC=1.CO.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.O.C(N(CC)CC)C>[NH2:16][C:17]1[CH:22]=[CH:21][C:20]([C:2]2[C:10]3[C:5](=[N:6][CH:7]=[CH:8][CH:9]=3)[NH:4][C:3]=2[C:11]([O:13][CH3:14])=[O:12])=[CH:19][CH:18]=1
Reactant: Nc1ccc(B(O)O)cc1
Reactant: COC(=O)c1[nH]c2ncccc2c1Br
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: CO
Solvent: Cc1ccccc1
Solvent: O
Product: COC(=O)c1[nH]c2ncccc2c1-c1ccc(N)cc1
Reaction time: 0.25 h
Yield: 59.6 %

Procedure:
To a solution of 0.64 g of methyl 3-bromo-1H-pyrrolo[2,3-b]pyridine-2-carboxylate in 50 mL of toluene and 50 ml of methanol are added 1.08 g of 4-aminophenylboronic acid hydrochloride and 0.9 ml of triethylamine. The reaction mixture is then stirred under an argon atmosphere for 15 minutes. 144 mg of tetrakis(triphenylphosphine)palladium(0), 0.3 g of lithium chloride, 0.66 g of sodium carbonate and 7.5 mL of distilled water are successively added. The reaction mixture is stirred for 8 hours at reflux. After filtering through Celite®, the filtrate is concentrated under reduced pressure. The residue is purified by column chromatography on silica, eluting with a mixture of ethyl acetate and cyclohexane (7/3 by volume). 400 mg of methyl 3-(4-aminophenyl)-1H-pyrrolo[2,3-b]pyridine-2-carboxylate are obtained in the form of a yellow solid, the characteristics of which are as follows:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][C:10](=O)[CH3:11])=[CH:5][CH:4]=1.[C:13]([NH:16][C:17]([NH2:19])=[S:18])(=[O:15])[CH3:14].II>N1C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[S:18][C:17]([NH:16][C:13](=[O:15])[CH3:14])=[N:19][C:10]=2[CH3:11])=[CH:5][CH:4]=1
Reactant: COc1ccc(CC(C)=O)cc1
Reactant: CC(=O)NC(N)=S
Agent: II
Solvent: c1ccncc1
Product: COc1ccc(-c2sc(NC(C)=O)nc2C)cc1

Procedure:
4-methoxyphenylacetone (10 g, 60.9 mmol), N-acetylthiourea (7.2 g, 60.9 mmol), iodine (15.46 g, 60.9 mmol) in pyridine (50 ml) are stirred at 70° C. for 16 hours. The mixture is concentrated and the residue is purified by chromatography on silica with hexane-ethyl acetate (1:1) to give the titled compound.
Reaction SMILES: [NH2:1][C:2]1[N:6]([CH:7]([CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])[CH2:8][CH2:9][CH3:10])[N:5]=[C:4]([CH3:17])[C:3]=1[C:18]([NH2:20])=[O:19].[CH3:21][O:22][C:23]1[CH:24]=[C:25]([CH2:33][C:34](OC)=O)[CH:26]=[C:27]([O:31][CH3:32])[C:28]=1[O:29][CH3:30].CC(C)([O-])C.[K+].C(=O)([O-])O.[Na+]>ClCCl>[CH3:32][O:31][C:27]1[CH:26]=[C:25]([CH:24]=[C:23]([O:22][CH3:21])[C:28]=1[O:29][CH3:30])[CH2:33][C:34]1[NH:20][C:18](=[O:19])[C:3]2[C:4]([CH3:17])=[N:5][N:6]([CH:7]([CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])[CH2:8][CH2:9][CH3:10])[C:2]=2[N:1]=1
Reactant: COC(=O)Cc1cc(OC)c(OC)c(OC)c1
Reactant: CCCCCCC(CCC)n1nc(C)c(C(N)=O)c1N
Agent: CC(C)(C)[O-]
Agent: O=C([O-])O
Agent: [K+]
Solvent: ClCCl
Product: CCCCCCC(CCC)n1nc(C)c2c(=O)[nH]c(Cc3cc(OC)c(OC)c(OC)c3)nc21
Yield: 29.3 %

Procedure:
6 mg (0.021 mmol) of 5-amino-3-methyl-1-(4-decyl)-1H-pyrazole-4-carboxamide and 20 mg (0.083 mmol) of methyl 3,4,5-trimethoxyphenylacetate are refluxed for 6 hours in 0.3 ml of a 0.5M ethanolic potassium tert-butoxide solution. After dichloromethane and saturated aqueous sodium hydrogen carbonate solution have been added, the phases are separated. Purification by chromatography gives 2.9 mg (29%) of a solid, Rf=0.50 (dichloromethane/methanol=15:1).
Reaction SMILES: [Cl:1]N1C(=O)CCC1=O.[CH3:9][C:10]1[C:16]([CH3:17])=[CH:15][CH:14]=[CH:13][C:11]=1[NH2:12]>CN(C=O)C>[CH3:9][C:10]1[C:16]([CH3:17])=[CH:15][CH:14]=[C:13]([Cl:1])[C:11]=1[NH2:12]
Reactant: O=C1CCC(=O)N1Cl
Reactant: Cc1cccc(N)c1C
Solvent: CN(C)C=O
Product: Cc1ccc(Cl)c(N)c1C
Reaction time: 1 h
Yield: 98 %

Procedure:
used in the preparation of 389 was prepared as follows: N-Chlorosuccinimide (1.00 g; 8.2 mmol) was added to a solution of 2,3-dimethylaniline (1 ml; 8.2 mmol) in 20 ml of DMF in the dark. After stirring 1 hr. in the dark, the reaction mixture was partitioned between EtOAc (100 ml) and water (100 ml). The organic layer was washed with 1N NaOH (100 ml), water (100 ml) and brine (50 ml). Drying (MgSO4) and concentration afforded 1.25 g (99%) of 2,3-dimethyl-6-chloroaniline as a deep red liquid.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[CH2:7]([N:9]=[C:10]=[O:11])[CH3:8].[Cl:12][C:13]1[CH:18]=[C:17]([C:19]([F:22])([F:21])[F:20])[CH:16]=[C:15]([Cl:23])[C:14]=1[O:24][C:25]1[CH:29]=[C:28]([CH2:30][CH3:31])[NH:27][N:26]=1.Cl>C(OCC)(=O)C>[CH2:7]([NH:9][C:10]([N:27]1[C:28]([CH2:30][CH3:31])=[CH:29][C:25]([O:24][C:14]2[C:15]([Cl:23])=[CH:16][C:17]([C:19]([F:22])([F:20])[F:21])=[CH:18][C:13]=2[Cl:12])=[N:26]1)=[O:11])[CH3:8]
Reactant: CCN=C=O
Reactant: CCc1cc(Oc2c(Cl)cc(C(F)(F)F)cc2Cl)n[nH]1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Product: CCNC(=O)n1nc(Oc2c(Cl)cc(C(F)(F)F)cc2Cl)cc1CC
Temperature: 25 °C
Reaction time: 6 h
Yield: 66.5 %

Procedure:
Potassium carbonate (0.46 g, 3.3 mmol) and ethyl isocyanate (0.21 g, 3.0 mmol) were added to a solution of 3-(2,6-dichloro-4-trifluoromethylphenyloxy)-5-ethylpyrazole (0.98 g, 3.0 mmol) in ethyl acetate (10 ml), and the mixture was stirred at room temperature for 6 hours. After completion of the reaction, the reaction mixture was poured into 2N hydrochloric acid and extracted with ethyl acetate (10 ml×3). An organic layer was washed with water, dried over anhydrous magnesium sulfate and filtered to remove a desiccant, and the solvent was distilled off from the filtrate under reduced pressure. The resultant crude product was purified with a silica gel column (ethyl acetate/hexane=1/10), to give a white solid of N-ethyl-3-(2,6-dichloro-4-trifluoromethylphenyloxy)-5-ethylpyrazole-1-carboxamide (0.79 g, yield: 66.5%). mp: 86-89° C.; 1H-NMR (CDCl3, TMS, ppm): δ 1.19 (t, J=7.3 Hz, 3H), 1.27 (t, J=7.5 Hz, 3H), 3.06 (q, J=7.5 Hz, 2H), 3.34 (dq, J=6.1 and 7.3 Hz, 2H), 5.75 (s, 1H), 6.60-6.85 (m, 1H), 7.68 (s, 2H).
Reaction SMILES: [H-].[Na+].[C:3](=[O:10])([O:7][CH2:8][CH3:9])OCC.[C:11]([C:14]1[CH:15]=[C:16]([CH:19]=[CH:20][CH:21]=1)[C:17]#[N:18])(=[O:13])[CH3:12].Cl>O1CCCC1.C(OCC)(=O)C>[C:17]([C:16]1[CH:15]=[C:14]([C:11](=[O:13])[CH2:12][C:3]([O:7][CH2:8][CH3:9])=[O:10])[CH:21]=[CH:20][CH:19]=1)#[N:18]
Reactant: CC(=O)c1cccc(C#N)c1
Reactant: CCOC(=O)OCC
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCOC(=O)CC(=O)c1cccc(C#N)c1
Temperature: 65 °C
Reaction time: 1 h
Yield: 96.9 %

Procedure:
To a suspension of sodium hydride (1.2 g of 60% suspension in mineral oil, hexane-washed, 30.3 mmol) in 40 mL of tetrahydrofuran was added diethyl carbonate (3.7 mL, 30.3 mmol) and 3-acetyl benzonitrile (2.2 g, 15.2 mmol). The resulting suspension was stirred at 65° C. for 1 h and then was cooled to room temperature. There was added 40 mL of 10% aqueous HCl and the reaction mixture was diluted with ethyl acetate and the layers were separated. The organic layer was washed with brine, dried (MgSO4) and concentrated in vacuo to afford 3.2 g (96%) of the title compound, which was sufficiently pure to be used without purification. MS(NH3—CI) 218.3 (M+H)+.
Reaction SMILES: [CH3:1][C:2]([CH3:31])([CH3:30])[C:3]#[C:4][C:5]1[S:9][C:8]([C:10]([OH:12])=[O:11])=[C:7]([N:13]([C@H:23]2[CH2:28][CH2:27][C@H:26]([OH:29])[CH2:25][CH2:24]2)[C:14]([C@H:16]2[CH2:21][CH2:20][C@H:19]([CH3:22])[CH2:18][CH2:17]2)=[O:15])[CH:6]=1.F[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][N:34]=1.[H-].[Na+].C(OCC)(=O)C>CN(C=O)C>[CH3:31][C:2]([CH3:30])([CH3:1])[C:3]#[C:4][C:5]1[S:9][C:8]([C:10]([OH:12])=[O:11])=[C:7]([N:13]([C:14]([C@H:16]2[CH2:21][CH2:20][C@H:19]([CH3:22])[CH2:18][CH2:17]2)=[O:15])[C@H:23]2[CH2:28][CH2:27][C@H:26]([O:29][C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][N:34]=3)[CH2:25][CH2:24]2)[CH:6]=1
Reactant: Fc1ccccn1
Reactant: CC(C)(C)C#Cc1cc(N(C(=O)[C@H]2CC[C@H](C)CC2)[C@H]2CC[C@H](O)CC2)c(C(=O)O)s1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C)(C)C#Cc1cc(N(C(=O)[C@H]2CC[C@H](C)CC2)[C@H]2CC[C@H](Oc3ccccn3)CC2)c(C(=O)O)s1
Reaction time: 0.5 h

Procedure:
A mixture of 5-(3,3-Dimethyl-but-1-ynyl)-3-[(trans-4-hydroxy-cyclohexyl)-(trans-4-methyl-cyclohexanecarbonyl)-amino]-thiophene-2-carboxylic acid (78 mg, 0.175 mmol) and 2-fluoro-pyridine (145 μL, 1.68 mmol) in DMF (0.6 mL) was treated with sodium hydride (67 mg, 1.68 mmol, 60% oil dispersion) in two or three portions. The mixture was stirred until the bubbling slowed, and was sealed and heated by microwave at 100 deg C. for 30 min. After cooling, ethyl acetate (2-3 mL) was added and the mixture was carefully quenched with citric acid (10% aqueous solution, 2-3 mL). Water was added and the mixture was extracted with ethyl acetate (2×30 mL). The combined organic layers were dried over sodium sulfate, filtered and concentrated. The residue was purified by HPLC (Gemini column, 35% acetonitrile:water, 2 min, 35-50% acetonitrile:water, 2 min, 50-95% acetonitrile:water 13 min, both solvents containing 0.1% trifluoroacetic acid). This resulted in 65 mg (58% yield) of the title compound as a white powder (TFA salt): MS (m/z): 520.9 [M−H]−; HPLC retention time: 4.61 min (2-98% acetonitrile:water with 0.05% trifluoroacetic acid).
Reaction SMILES: [Br:1][CH2:2][CH2:3][CH2:4][OH:5].C(N(CC)CC)C.[CH3:13][O:14][CH2:15][C:16](Cl)=[O:17]>C(Cl)Cl>[Br:1][CH2:2][CH2:3][CH2:4][O:5][C:16](=[O:17])[CH2:15][O:14][CH3:13]
Reactant: COCC(=O)Cl
Reactant: OCCCBr
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COCC(=O)OCCCBr
Temperature: 0 °C
Reaction time: 17.5 h
Yield: 106.1 %

Procedure:
1-Bromopropan-3-ol (1.32 mL, 14.6 mmol) was dissolved in anhydrous methylene chloride and cooled to 0° C. under nitrogen atmosphere. The solution was treated with triethylamine (2.2 mL, 15.8 mmol) and methoxyacetyl chloride (1.42 mL, 15.5 mmol) then warmed to room temperature. The reaction mixture was stirred for 17.5 h. It was then diluted with methylene chloride (150 mL) and extracted with saturated sodium bicarbonate (2×50 mL). The aqueous phase was back extracted with methylene chloride (100 mL) and the organic phases were combined and concentrated in vacuo to yield a crude, pale yellow oil (3.27 g). 1H NMR δ 4.25 (t, 2H, J=6.1), 4.05 (s, 2H), 3.45 (s, 3H), 3.22 (t, 2H, I=6.9), 2.18 (quint, 2H, J=6.6). The product was used as such in the following reaction.
Reaction SMILES: [CH3:1][N:2]1[C:10]2[CH:9]=[C:8]([CH3:11])[N:7]=[C:6]([CH3:12])[C:5]=2[C:4](=[O:13])[N:3]1[CH3:14].C1C(=O)N([Br:22])C(=O)C1.OS(O)(=O)=O.[OH-].[Na+]>O>[Br:22][C:9]1[C:10]2[N:2]([CH3:1])[N:3]([CH3:14])[C:4](=[O:13])[C:5]=2[C:6]([CH3:12])=[N:7][C:8]=1[CH3:11]
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1cc2c(c(C)n1)c(=O)n(C)n2C
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: Cc1nc(C)c2c(=O)n(C)n(C)c2c1Br
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A mixture of 1,2,4,6-tetramethyl-1H,2H,3H-pyrazolo[4,3-c]pyridin-3-one (0.33 g, 1.7 mmol), NBS (0.34 g, 1.9 mmol) and conc. H2SO4 (8 ml) is stirred at RT for 18 h. The mixture is poured onto ice-water. The water phase is made basic with an aqueous solution of sodium hydroxide (1 mol/l) and extracted with DCM. The combined organic layers are dried over MgSO4 and concentrated in vacuo. 7-bromo-1,2,4,6-tetramethyl-1H,2H,3H-pyrazolo[4,3-c]pyridin-3-one is used without further purification. Yield: 0.37 g (80%). HPLC-MS: M+H=270/272; tR=0.77 min (METHOD—1).
Reaction SMILES: [NH2:1][C:2]1[C:3](Cl)=[N:4][C:5]([CH3:9])=[N:6][C:7]=1[Cl:8].[NH3:11]>C(O)(C)C>[Cl:8][C:7]1[N:6]=[C:5]([CH3:9])[N:4]=[C:3]([NH2:11])[C:2]=1[NH2:1]
Reactant: Cc1nc(Cl)c(N)c(Cl)n1
Reactant: N
Solvent: CC(C)O
Product: Cc1nc(N)c(N)c(Cl)n1
Temperature: 150 °C
Reaction time: 1 h
Yield: 91 %

Procedure:
A 200 mL stainless steel Parr vessel was loaded with 5-amino-4,6-dichloro-2-methylpyrimidine (7.2 g, 40 mmol) and 2 M ammonia in isopropanol (100 mL), and then was sealed and heated at 150° C. for 16 h. HPLC analysis indicated complete conversion. The mixture was concentrated in vacuo, and the residue was suspended in a mixture of H2O (10 mL) and isopropanol (35 mL). This was stirred at 50° C. for 1 h and then was cooled to room temperature. The precipitate was collected by suction filtration, washed sparingly with isopropanol, then air dried on the filter to afford 6-chloro-4,5-diamino-2-methylpyrimidine (5.8 g, 91%) as a brown powder, which was used without further purification in the next step.
Reaction SMILES: [Cl:1][C:2]1[S:6][C:5]([C:7]([OH:9])=O)=[CH:4][C:3]=1[C:10]1[N:14]([CH2:15][CH3:16])[N:13]=[CH:12][C:11]=1[Cl:17].C1CN([P+](Br)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[NH2:51][C@@H:52]([CH2:65][C:66]1[CH:71]=[CH:70][CH:69]=[C:68]([F:72])[CH:67]=1)[CH2:53][N:54]1[C:62](=[O:63])[C:61]2[C:56](=[CH:57][CH:58]=[CH:59][CH:60]=2)[C:55]1=[O:64]>C(Cl)Cl>[Cl:1][C:2]1[S:6][C:5]([C:7]([NH:51][C@@H:52]([CH2:65][C:66]2[CH:71]=[CH:70][CH:69]=[C:68]([F:72])[CH:67]=2)[CH2:53][N:54]2[C:62](=[O:63])[C:61]3[C:56](=[CH:57][CH:58]=[CH:59][CH:60]=3)[C:55]2=[O:64])=[O:9])=[CH:4][C:3]=1[C:10]1[N:14]([CH2:15][CH3:16])[N:13]=[CH:12][C:11]=1[Cl:17]
Reactant: CCn1ncc(Cl)c1-c1cc(C(=O)O)sc1Cl
Reactant: N[C@@H](Cc1cccc(F)c1)CN1C(=O)c2ccccc2C1=O
Agent: Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCn1ncc(Cl)c1-c1cc(C(=O)N[C@@H](Cc2cccc(F)c2)CN2C(=O)c3ccccc3C2=O)sc1Cl
Reaction time: 0.17 h
Yield: 80.7 %

Procedure:
To a solution of 5-chloro-4-(4-chloro-1-ethyl-1H-pyrazol-5-yl)-2-thiophenecarboxylic acid (180 mg, 0.618 mmol) [from Example 235(c)] in DCM (5 mL) at 25° C. was added PyBrOP in one portion, followed by addition of DIPEA (0.54 mL, 3.09 mmol). After stirring for 10 min, 2-[(2S)-2-amino-3-(3-fluorophenyl)propyl]-1H-isoindole-1,3(2H)-dione (203 mg, 0.68 mmol) was added to above solution in one portion. After stirring for 2 h, the solution was concentrated and purified via column chromatography (silica, 20-50% EtOAc/Hexane) affording the title compound (285 mg, 77%) as a white solid: LC-MS (ES) m/z=571 (M+H)+.
Reaction SMILES: C([O:4][C:5]1[C:10]2[CH:11]=[C:12]([CH2:14][CH3:15])[O:13][C:9]=2[CH:8]=[C:7]([C:16]([O:18][CH2:19][CH3:20])=[O:17])[CH:6]=1)(=O)C.C([O-])([O-])=O.[K+].[K+]>C(O)C>[CH2:14]([C:12]1[O:13][C:9]2[CH:8]=[C:7]([C:16]([O:18][CH2:19][CH3:20])=[O:17])[CH:6]=[C:5]([OH:4])[C:10]=2[CH:11]=1)[CH3:15]
Reactant: CCOC(=O)c1cc(OC(C)=O)c2cc(CC)oc2c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: CCOC(=O)c1cc(O)c2cc(CC)oc2c1
Yield: 88.3 %

Procedure:
A suspension of ethyl 4-(acetyloxy)-2-ethyl-1-benzofuran-6-carboxylate (8.0 g, 29.0 mmol) and K2CO3 (4.81 g, 34.8 mmol) in ethanol (80 mL) was refluxed for 24 hours. TLC (petroleum ether/EtOAc 4:1) showed complete consumption of the acetate. The solvent was removed under reduced pressure and the residue was poured into water (30 mL). The aqueous phase was acidified to pH˜2 with 10% aqueous HCl (50 mL) and extracted with EtOAc (100 mL×2). The organic layer was dried over Na2SO4 and concentrated. The residue was purified by column chromatography on silica gel eluted with petroleum ether/EtOAc (40:1) to afford the desired compound (6.0 g, 88%) as a yellow solid. 1H NMR (400 MHz, CDCl3): δ 7.87 (s, 1H), 7.45 (s, 1H), 6.46 (s, 1H), 6.36 (s, 1H), 4.34-4.27 (q, 2H), 2.77-2.71 (q, 2H), 1.40-1.31 (t, 3H), 1.31-1.21 (t, 3H).
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([C:7]2[C:8]3[N:9]([CH:13]=[C:14]([C:16]([O:18][CH2:19][CH3:20])=[O:17])[N:15]=3)[N:10]=[CH:11][CH:12]=2)[CH2:3][CH2:2]1.Br[C:22]1[CH:23]=[CH:24][C:25]([C:28]#[N:29])=[N:26][CH:27]=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CC([O-])=O.[K+]>CC(N(C)C)=O.CC([O-])=O.CC([O-])=O.[Pd+2]>[C:28]([C:25]1[N:26]=[CH:27][C:22]([C:13]2[N:9]3[N:10]=[CH:11][CH:12]=[C:7]([N:4]4[CH2:3][CH2:2][O:1][CH2:6][CH2:5]4)[C:8]3=[N:15][C:14]=2[C:16]([O:18][CH2:19][CH3:20])=[O:17])=[CH:23][CH:24]=1)#[N:29]
Reactant: CCOC(=O)c1cn2nccc(N3CCOCC3)c2n1
Reactant: N#Cc1ccc(Br)cn1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Product: CCOC(=O)c1nc2c(N3CCOCC3)ccnn2c1-c1ccc(C#N)nc1

Procedure:
Using the procedure described in Example 20, Step A, the title compound was prepared from Compound 5c (1.38 g, 5.00 mmol), 5-bromo-2-cyanopyridine (1.42 g, 7.50 mmol), Pd(OAc)2 (78.6 mg, 0.350 mmol), PPh3 (91.8 mg, 0.350 mmol), and KOAc (1.47 g, 15.0 mmol) in DMA (20 mL) at 110° C. for 16 h. 1H-NMR (400 MHz, CDCl3) δ (ppm): 9.00 (s, 1H), 8.20 (dd, J=8.1, 1.7 Hz, 1H), 8.05 (d, J=5.6 Hz, 1H), 7.83 (d, J=8.1 Hz, 1H), 6.17 (d, J=5.6 Hz, 1H), 4.36 (q, J=7.3 Hz, 2H), 4.02-4.13 (m, 4H), 3.90-3.99 (m, 4H), 1.30 (t, J=7.1 Hz, 3H). Mass Spectrum (LCMS, ESI pos.) Calcd. For C19H18N6O3: 379.2 (M+H). Found: 379.1.
Reaction SMILES: ClC(Cl)(Cl)[C:3]([C:5]1[N:14]2[C:8]([CH2:9][N:10]([C:19]([C:21]3[CH:26]=[CH:25][C:24]([C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=4[CH3:33])=[C:23]([O:34][CH3:35])[CH:22]=3)=[O:20])[C:11]3[CH:18]=[CH:17][CH:16]=[CH:15][C:12]=3[CH2:13]2)=[CH:7][CH:6]=1)=[O:4].[O:38]1[C:43]2[CH:44]=[CH:45][C:46]([CH2:48][NH2:49])=[CH:47][C:42]=2[O:41][CH2:40][CH2:39]1>>[O:38]1[C:43]2[CH:44]=[CH:45][C:46]([CH2:48][NH:49][C:3]([C:5]3[N:14]4[C:8]([CH2:9][N:10]([C:19]([C:21]5[CH:26]=[CH:25][C:24]([C:27]6[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=6[CH3:33])=[C:23]([O:34][CH3:35])[CH:22]=5)=[O:20])[C:11]5[CH:18]=[CH:17][CH:16]=[CH:15][C:12]=5[CH2:13]4)=[CH:7][CH:6]=3)=[O:4])=[CH:47][C:42]=2[O:41][CH2:40][CH2:39]1
Reactant: COc1cc(C(=O)N2Cc3ccc(C(=O)C(Cl)(Cl)Cl)n3Cc3ccccc32)ccc1-c1ccccc1C
Reactant: NCc1ccc2c(c1)OCCO2
Product: COc1cc(C(=O)N2Cc3ccc(C(=O)NCc4ccc5c(c4)OCCO5)n3Cc3ccccc32)ccc1-c1ccccc1C

Procedure:
The title compound was prepared in the manner of Example 36 from 2,2,2-trichloro-1-{10-[(2-methoxy-2′-methyl-1,1′-biphenyl-4-yl)carbonyl]-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepin-3-yl}ethanone of Example 35 and C-(2,3-dihydrobenzo[1,4]dioxin-6-yl)-methylamine. Purification was performed using HPLC with a normal phase column and eluting with a two phase solvent system (A=hexane, B=dichloromethane/methanol, 4:1), m.p. 153-155° C. MS [(+)ESI, m/z]: 600 [M+H]+
Reaction SMILES: [N:1]([CH:4]([C:6]1[N:11]=[CH:10][C:9]([F:12])=[CH:8][N:7]=1)[CH3:5])=[N+]=[N-]>[Pd]>[F:12][C:9]1[CH:8]=[N:7][C:6]([CH:4]([NH2:1])[CH3:5])=[N:11][CH:10]=1
Reactant: CC(N=[N+]=[N-])c1ncc(F)cn1
Agent: [Pd]
Product: CC(N)c1ncc(F)cn1
Temperature: 25 °C
Reaction time: 3 h
Yield: 98.7 %

Procedure:
A round-bottom flask containing 2-(1-azidoethyl)-5-fluoropyrimidine (Method 3, 0.60 g, 3.59 mmol) was charged with 10% Pd/C (0.191 g) and was evacuated and backfilled with H2 via a filled balloon. MeOH (10 ml) was added, and the mixture was allowed to stir at room temperature for 3 hours. The mixture was filtered through a plug of diatomaceous earth, which was subsequently washed well with MeOH. The filtrates were concentrated to give the title compound as a pale yellow oil (0.50 g, 99%). 1H NMR (CDCl3) δ 8.60 (s, 2H), 4.65 (br s 2H), 4.10 (m, 1H), 1.20 (d, 3H).
Reaction SMILES: [NH2:1][C@H:2]([C:8]([OH:10])=[O:9])[CH2:3][CH2:4][CH2:5][CH2:6][NH2:7].[C:11](Cl)([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[O:12].[OH-].[Na+]>O>[NH2:1][CH:2]([CH2:3][CH2:4][CH2:5][CH2:6][NH:7][C:11](=[O:12])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C:8]([OH:10])=[O:9]
Reactant: O=C(Cl)c1ccccc1
Reactant: NCCCC[C@H](N)C(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: NC(CCCCNC(=O)c1ccccc1)C(=O)O
Temperature: 0 °C
Reaction time: 1 h
Yield: 36 %

Procedure:
To a solution of L-lysine (1) (3.65 g, 0.02 mol) in water (50 mL) at 90° C. was added CuCO3 (2.5 g) portionwise. After being refluxed for 40 min, the mixture was cooled and filtered. The filtrate was further cooled to 0° C., and a solution of BzCl (3.5 mL, 0.03 mol) and NaOH (2.7 g, 0.0685 mol) in water (20 mL) were added. The reaction was stirred at 0° C. for 1 h and then allowed to warm to room temperature. After 2 days, the reaction mixture was filtered and the solid was washed with water and Et2O. This obtained solid was then added to a solution of EDTA (7.0 g) in water (350 mL), the mixture was heated to reflux until the reaction solution became clear blue. The reaction was cooled which gave a white precipitate. This precipitate was collected and washed with water and Et2O and dried which afforded the title compound as a white solid (1.8 g, 36%).
Reaction SMILES: [C:1]([O:5][C:6]([C@H:8]([C@@H:18]([CH2:22][CH:23]([CH3:25])[CH3:24])[C:19](O)=[O:20])[CH2:9][CH2:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].FC1C(O)=C(F)C(F)=C(F)C=1F.Cl.C(N=C=NCCCN(C)C)C.Cl.[NH2:51][NH2:52].CN1CCOCC1>CN(C)C=O>[C:1]([O:5][C:6]([C@H:8]([C@@H:18]([CH2:22][CH:23]([CH3:25])[CH3:24])[C:19]([NH:51][NH2:52])=[O:20])[CH2:9][CH2:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)C[C@@H](C(=O)O)[C@H](CCCc1ccccc1)C(=O)OC(C)(C)C
Reactant: NN
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: Oc1c(F)c(F)c(F)c(F)c1F
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Product: CC(C)C[C@@H](C(=O)NN)[C@H](CCCc1ccccc1)C(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 2.5 h
Yield: 43.7 %

Procedure:
A solution of 4.8 g of 2(R)-[1(S)-(tert-butoxycarbonyl)-4-phenylbutyl]-4-methylvaleric acid in 50 ml of dimethylformamide was cooled to 0° C. and treated with 2.80 g of pentafluorophenol and 2.65 g of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride. The mixture was stirred at 0° C. for 2.5 hours and then treated with 4.73 g of hydrazine monohydrochloride and 6.97 g of 4-methyl morpholine. The mixture was stirred for a further 18 hours at room temperature and then evaporated. The residue was dissolved in ethyl acetate and washed sequentially with 2M aqueous hydrogen chloride, 5% aqueous sodium hydrogen carbonate, water, and saturated aqueous sodium chloride. The organic layer was dried over anhydrous magnesium sulphate and evaporated. The residue was purified by flash column chromatography on silica gel using ethyl acetate/hexane (1:1) as the eluant to give 2.18 g of 2(R)-[1(S)-(tert-butoxycarbonyl)-4-phenylbutyl]-4-methylvalerohydrazide in the form of a pale yellow solid.