Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:13]#[N:14])=[CH:7][N:8]2[CH2:11][CH3:12])=[CH:4][CH:3]=1.ClC1C=C2C(C=CN2)=CC=1.[O-]P([O-])([O-])=O.[K+].[K+].[K+].C1(C2C=CC=CC=2)C=CC=CC=1P(C1CCCCC1)C1CCCCC1.[CH3:58][N:59]1[CH2:64][CH2:63][NH:62][CH2:61][CH2:60]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.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].ClCCl.COCCOC>[CH2:11]([N:8]1[C:9]2[C:5](=[CH:4][CH:3]=[C:2]([N:62]3[CH2:63][CH2:64][N:59]([CH3:58])[CH2:60][CH2:61]3)[CH:10]=2)[C:6]([C:13]#[N:14])=[CH:7]1)[CH3:12]
Reactant: CN1CCNCC1
Reactant: CCn1cc(C#N)c2ccc(Cl)cc21
Agent: [Pd]
Agent: Clc1ccc2cc[nH]c2c1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: COCCOC
Solvent: ClCCl
Product: CCn1cc(C#N)c2ccc(N3CCN(C)CC3)cc21
Temperature: 100 °C
Reaction time: 8 h
Yield: 71.5 %

Procedure:
6-chloro-1-ethylindole-3-carbonitrile (1.02 g, 5.0 mmol), prepared from 6-chloroindole using the procedures described in example 1A, is mixed with K3PO4 (1.48 g, 7.0 mmol), Pd2(dba)3 (0.11 g, 0.12 mmol), biphenyl-2-yldicyclohexylphosphane (0.17 g, 0.48 mmol), 1-methylpiperazine (0.60 g, 0.67 mL 6.0 mmol) and dry DME (10.0 mL). The mixture is stirred at 100° C. overnight. After cooling, the solvent is replaced with dichloromethane and chromatographed (silica gel, DCM, then EtOAc, finally DCM/MeOH, 9/1) to provide 1-ethyl-6-(4-methylpiperazin-1-yl)indole-3-carbonitrile (0.96 g, 72%).
Reaction SMILES: [CH3:1][C:2]1([CH3:16])[C:6]([CH3:8])([CH3:7])[O:5][B:4]([C:9]2[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][CH:10]=2)[O:3]1.C([O-])([O-])=O.[K+].[K+].[Br:23][CH2:24][CH2:25][CH2:26]Br>CC#N>[Br:23][CH2:24][CH2:25][CH2:26][O:15][C:12]1[CH:13]=[CH:14][C:9]([B:4]2[O:3][C:2]([CH3:16])([CH3:1])[C:6]([CH3:7])([CH3:8])[O:5]2)=[CH:10][CH:11]=1
Reactant: CC1(C)OB(c2ccc(O)cc2)OC1(C)C
Reactant: BrCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CC1(C)OB(c2ccc(OCCCBr)cc2)OC1(C)C
Temperature: 70 °C
Yield: 86.9 %

Procedure:
4-(4,4,5,5-Tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenol (CAS #269409-70-3) (10.5 g, 47 mmol) was dissolved in dry CH3CN (200 mL) and dry, pulverized K2CO3 (10.4 g, 75 mmol) was introduced. 1,3-dibromopropane (38.1 mL, 375 mmol) was added dropwise, and the reaction mixture was heated at 70° C. for 7 h under a nitrogen atmosphere. The cooled reaction mixture was filtered and the filtrate was evaporated to an oily residue, which was applied to a column of silica gel. Elution initially with hexanes, gradually increasing polarity to a mixture of hexanes/ethyl acetate (25:1, 20:1 and 10:1) as eluent, provided the title compound (13.93 g, 86%) which crystallized on standing to a white solid, m.p. 62-65° C.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11](=[CH2:14])[CH2:10][C@H:9]1[C:15]([O:17][CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[O:16])=[O:7])([CH3:4])([CH3:3])[CH3:2].[N+](=[CH2:27])=[N-]>C1COCC1.CCOCC>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11]2([CH2:27][CH2:14]2)[CH2:10][C@H:9]1[C:15]([O:17][CH2:18][C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1)=[O:16])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: C=C1CCN(C(=O)OC(C)(C)C)[C@H](C(=O)OCc2ccccc2)C1
Reactant: C=[N+]=[N-]
Solvent: CCOCC
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC2(CC2)C[C@H]1C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 10 h
Yield: 88 %

Procedure:
To a solution of (S)-4-methylene-piperidine-1,2-dicarboxylic acid 2-benzyl ester 1-tert-butyl ester (intermediate 15 prepared by Method A, 120 g, 0.36 mol) in anhydrous THF (1 L) was added diazomethane in ether (500 ml) [which was prepared from methyl-3-nitro-1-nitroxoguanide (213 g) in 40% KOH (1 L)] at −25° C. to −35° C. slowly under the protection of nitrogen and warmed to room temperature slowly (about 4 hours) and stirred at room temperature for 10 hours. The mixture is filtered and the liquid phase was evaporated to obtain a crude that was purified by silica gel chromatography (petroleum ether/ethyl acetate from 10/1 to 5/1). (S)-6-Aza-spiro[2.5]octane-5,6-dicarboxylic acid 5-benzyl ester 6-tert-butyl ester was obtained as colourless oil (110 g), yield:88%.
Reaction SMILES: [OH:1][CH2:2][CH2:3][C:4]#[C:5][C:6]1[CH:15]=[CH:14][C:9]([C:10]([O:12][CH3:13])=[O:11])=[CH:8][CH:7]=1.[H][H]>[Pd].C(O)C>[OH:1][CH2:2][CH2:3][CH2:4][CH2:5][C:6]1[CH:15]=[CH:14][C:9]([C:10]([O:12][CH3:13])=[O:11])=[CH:8][CH:7]=1
Reactant: COC(=O)c1ccc(C#CCCO)cc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: COC(=O)c1ccc(CCCCO)cc1
Yield: 96.2 %

Procedure:
A Parr flask was charged with 3.25 g (15.98 mmol) of methyl 4-(4-hydroxy-1-butynyl)benzoate (Taylor et al. J. Org. Chem., 1990, 55, 3222-3227) and 0.26 g (8% wt equivalent) of 10% palladium-on-carbon catalyst in 40 mL of ethanol. Hydrogenation was carried out at 50 psi of hydrogen for 18 hours. The mixture was filtered through a silica gel pad that was subsequently washed with ethanol. The combined filtrates were concentrated under reduced pressure to give 3.20 g (97%) of methyl 4-(4-hydroxybutyl)benzoate as a light yellow oil. 1H NMR (CDCl3) δ 1.51 (1H, s), 1.57-1.82 (4H, m), 2.74 (2H, t, J=7.3 Hz), 3.71 (2H, t, J=6.0 Hz), 3.94 (3H, s), 7.27 (2H, d, J=8.0 Hz), 7.99 (2H, d, J=8.0 Hz).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[CH:14]=[CH:13][C:12]([CH2:15]Br)=[CH:11][C:10]=2[F:17])[CH:5]=[CH:6][C:7]=1[Cl:8].[C-:18]#[N:19].[Na+]>C(O)C.O>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[CH:14]=[CH:13][C:12]([CH2:15][C:18]#[N:19])=[CH:11][C:10]=2[F:17])[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: Fc1cc(CBr)ccc1-c1ccc(Cl)c(Cl)c1
Reactant: [C-]#N
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: N#CCc1ccc(-c2ccc(Cl)c(Cl)c2)c(F)c1
Temperature: 50 °C
Reaction time: 0.5 h

Procedure:
3′,4′-dichloro-2-fluoro-4-bromomethyl-biphenyl (35.0 g, 0.105 mol) and sodium cyanide (5.4 g, 0.110 mol) were dissolved in a mixture of ethanol (228 ml) and water (25 ml), then heated at 50° C. for 3 hours. The solution was concentrated under vacuum and the residue was suspended in ethanol/water 1/1 v/v (35 ml) and cooled at 0-5° C. for 30 minutes. The obtained solid is filtered and dried at 40° C. under vacuum. The crude product was suspended in ethanol (56 ml) at 20 to 25° C. for 30 minutes, filtered and dried at 40° C. under vacuum. The compound 3′,4′-dichloro-2-fluoro-4-cyanomethyl-biphenyl was obtained as a light brown powder (16.8 g, 57% yield).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[C:2]1[C:10]([O:12]C)=[O:11].C(=O)([O-])[O-].[Cs+].[Cs+].CS(O[CH2:25][CH2:26][CH2:27][CH2:28][O:29][CH3:30])(=O)=O>CC(N(C)C)=O>[CH3:30][O:29][CH2:28][CH2:27][CH2:26][CH2:25][N:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[C:2]1[C:10]([OH:12])=[O:11]
Reactant: COC(=O)c1cc2ccccc2[nH]1
Reactant: COCCCCOS(C)(=O)=O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC(=O)N(C)C
Product: COCCCCn1c(C(=O)O)cc2ccccc21
Temperature: 60 °C
Reaction time: 4 h
Yield: 81.4 %

Procedure:
Methyl 1H-indole-2-carboxylate (0.67 g), cesium carbonate (1.9 g) and 4-methoxybutyl methanesulfonate (0.70 g) were suspended in DMA (20 ml), and the suspension was stirred at 60° C. for 4 hr. The reaction mixture was concentrated under reduced pressure, the residue was diluted with water, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The obtained residue was subjected to silica gel chromatography, and a fraction eluted with ethyl acetate-hexane (0:10-4:6) was concentrated under reduced pressure. The obtained residue was dissolved in methanol (10 ml), 4N aqueous sodium hydroxide solution (5 ml) was added, and the mixture was heated at 80° C. for 2 hr. The mixture was allowed to cool to room temperature, acidified with 1N aqueous hydrochloric acid and extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure to give the object product (0.77 g).
Reaction SMILES: N1C=CN=[C:2]1[NH:6][C:7]([C:9]1[C:17]2[N:16]=[C:15]([NH:18][C:19]([C:21]3[N:22]=[CH:23][C:24]4[C:29]([CH:30]=3)=[CH:28][CH:27]=[CH:26][CH:25]=4)=[O:20])[NH:14][C:13]=2[CH:12]=[CH:11][CH:10]=1)=[O:8].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[F:64][C:65]1[CH:73]=[CH:72][C:68]([CH2:69]NC)=[CH:67][CH:66]=1>CN(C=O)C>[F:64][C:65]1[CH:73]=[CH:72][C:68]([CH2:69][N:6]([CH3:2])[C:7]([C:9]2[C:17]3[NH:16][C:15]([NH:18][C:19]([C:21]4[N:22]=[CH:23][C:24]5[C:29]([CH:30]=4)=[CH:28][CH:27]=[CH:26][CH:25]=5)=[O:20])=[N:14][C:13]=3[CH:12]=[CH:11][CH:10]=2)=[O:8])=[CH:67][CH:66]=1
Reactant: O=C(Nc1nc2c(C(=O)Nc3ncc[nH]3)cccc2[nH]1)c1cc2ccccc2cn1
Reactant: CNCc1ccc(F)cc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CN(Cc1ccc(F)cc1)C(=O)c1cccc2nc(NC(=O)c3cc4ccccc4cn3)[nH]c12
Temperature: 70 °C
Reaction time: 0.08 h
Yield: 66.2 %

Procedure:
To a solution of 100 mg (0.3 mmol) of 2-[(isoquinoline-3-carbonyl)-amino]-3H-benzoimidazole-4-carboxylic acid (from Example 58) in DMF (2 mL) was added 200 mg (0.53 mmol) of HBTU and DIEA (0.5 mL). The mixture was stirred for 5 min then 140 mg (1.0 mmol) of N-(4-fluoro-benzyl)-N-methyl-amine was added. The resulted reaction mixture was heated at 70° C. for 1 h. After usual workup as described in general procedure A, the residue was purified by column chromatography eluting with DCM/EtOAc (v/v=1:1) to afford the 90 mg (66%) of isoquinoline-3-carboxylic acid {7-[(4-fluoro-benzyl)-methyl-carbamoyl]-1H-benzoimidazol-2-yl}-amide. LCMS: 454 (M+1)+.
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][C:7]([CH2:10][C:11](=O)[CH3:12])=[CH:6][CH:5]=1)([CH3:3])[CH3:2].[OH:14][CH:15]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[CH2:16][NH2:17]>C1C=CC=CC=1>[CH:1]([C:4]1[CH:9]=[CH:8][C:7]([CH2:10][CH:11]([NH:17][CH2:16][CH:15]([OH:14])[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH3:12])=[CH:6][CH:5]=1)([CH3:3])[CH3:2]
Reactant: NCC(O)c1ccccc1
Reactant: CC(=O)Cc1ccc(C(C)C)cc1
Solvent: c1ccccc1
Product: CC(Cc1ccc(C(C)C)cc1)NCC(O)c1ccccc1
Yield: 88.2 %

Procedure:
A mixture of 4-isopropylphenylacetone (2.64 g) and 2-hydroxy-2-phenylethanamine (2.05 g) were refluxed in benzene (70 ml) under Dean & Stark conditions for 4 h. The solvent was removed under reduced pressure, replaced with ethanol (100 ml) and the solution hydrogenated using Pt as catalyst. The filtered solution was evaporated and the residual oil chromatographed on Kieselgel 60 (150 g). Elution with 2% methanol-chloroform gave the title compound as an oil (3.92 g). Treatment of this with a methanolic solution of fumaric acid and recrystallisation of the solid from ethylacetate gave the title compound (58:42 mixture of diastereoisomers) as the hemi fumarate containing one mole of water, mp 55-57.
Reaction SMILES: [C:1]([O:5][C@@H:6]([C:12]1[C:21]([CH3:22])=[CH:20][C:19]2[C:14](=[CH:15][CH:16]=[C:17]([C:23]#[N:24])[CH:18]=2)[C:13]=1[O:25][S:26]([C:29]([F:32])([F:31])[F:30])(=[O:28])=[O:27])[C:7]([O:9][CH2:10][CH3:11])=[O:8])([CH3:4])([CH3:3])[CH3:2].[C:33](OC(CC)(C)C)(=O)C>>[C:23]([C:17]1[CH:18]=[C:19]2[C:14](=[CH:15][CH:16]=1)[C:13]([O:25][S:26]([C:29]([F:32])([F:30])[F:31])(=[O:27])=[O:28])=[C:12]([C@H:6]([O:5][C:1]([CH2:2][CH3:33])([CH3:3])[CH3:4])[C:7]([O:9][CH2:10][CH3:11])=[O:8])[C:21]([CH3:22])=[CH:20]2)#[N:24]
Reactant: CCC(C)(C)OC(C)=O
Reactant: CCOC(=O)[C@@H](OC(C)(C)C)c1c(C)cc2cc(C#N)ccc2c1OS(=O)(=O)C(F)(F)F
Product: CCOC(=O)[C@@H](OC(C)(C)CC)c1c(C)cc2cc(C#N)ccc2c1OS(=O)(=O)C(F)(F)F

Procedure:
(S)-ethyl 2-(6-cyano-3-methyl-1(trifluoromethylsulfonyloxy)-naphthalen-2-yl)-2-(tert-pentyloxy)acetate was prepared in a similar way to (S)-ethyl 2-tert-butoxy-2-(6-cyano-3-methyl-1-(trifluoromethylsulfonyloxy)naphthalen-2-yl)acetate in Example 5 except tert-amyl acetate was used instead of tert-butyl acetate. 1H NMR (400 MHz, CDCl3) 8.18 (s, 1H), 8.13 (d, J=8.7 Hz, 1H), 7.73 (s, 1H), 7.71 (d, J=8.9 Hz, 1H), 5.73 (s, 1H), 4.27-4.08 (m, 2H), 2.59 (s, 3H), 1.62-1.43 (m, 2H), 1.20 (s, 3H), 1.17 (t, J=7.2 Hz, 3H), 1.08 (s, 3H), 0.77 (t, J=7.4 Hz, 3H).
Reaction SMILES: [CH:1]1(N)[CH2:3][CH2:2]1.C(N(CC)CC)C.[N:12]1[C:19]([Cl:20])=[N:18][C:16](Cl)=[N:15][C:13]=1[Cl:14]>CC(C)=O>[CH:1]1([C:16]2[N:18]=[C:19]([Cl:20])[N:12]=[C:13]([Cl:14])[N:15]=2)[CH2:2][CH2:3]1
Reactant: NC1CC1
Reactant: Clc1nc(Cl)nc(Cl)n1
Solvent: CCN(CC)CC
Solvent: CC(C)=O
Product: Clc1nc(Cl)nc(C2CC2)n1

Procedure:
A mixture of 28.5 g of cyclopropylamine and 50.5 g of triethylamine was added drop-by-drop to a stirred solution of 92.3 g of cyanuric chloride in 1.5 liters of dry acetone at room temperature. Then the acetone was evaporated and the residue was treated with a 1:1 v:v mixture of ice water and ether. The ether phase was separated and dried (MgSO4), and the ether was evaporated to give 2-cyclopropyl-4,6-dichloro-1,3,5-triazine (9A), as a white solid, m.p.: 106°-107° C.
Reaction SMILES: Cl.[CH2:2]([O:9][C:10]1[CH:19]=[C:18]2[C:13]([C:14]([Cl:20])=[N:15][CH:16]=[N:17]2)=[CH:12][C:11]=1[O:21][CH3:22])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[Cl:23][C:24]1[C:30]([OH:31])=[CH:29][C:27]([NH2:28])=[C:26]([F:32])[CH:25]=1>C(O)(C)C>[ClH:20].[CH2:2]([O:9][C:10]1[CH:19]=[C:18]2[C:13]([C:14]([NH:28][C:27]3[CH:29]=[C:30]([OH:31])[C:24]([Cl:23])=[CH:25][C:26]=3[F:32])=[N:15][CH:16]=[N:17]2)=[CH:12][C:11]=1[O:21][CH3:22])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: Nc1cc(O)c(Cl)cc1F
Reactant: COc1cc2c(Cl)ncnc2cc1OCc1ccccc1
Agent: Cl
Solvent: CC(C)O
Product: COc1cc2c(Nc3cc(O)c(Cl)cc3F)ncnc2cc1OCc1ccccc1
Yield: 85.2 %

Procedure:
A suspension of 7-benzyloxy-4-chloro-6-methoxyquinazoline hydrochloride (169 mg, 0.5 mmol), (prepared as described for the starting material in Example 1), and 4-chloro-2-fluoro-5-hydroxyaniline (97 mg, 0.6 mmol), (EP 061741 A2), in isopropanol (5 ml) was heated at reflux for 2 hours. The resulting precipitate was collected by filtration, washed with isopropanol and ether and dried under vacuum to give 7-benzyloxy4-(4-chloro-2-fluoro-5-hydroxyanilino)-6-methoxyquinazoline hydrochloride (197 mg, 85%).
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:8]([C:11]([OH:13])=O)=[C:7]2[C:3]=1[CH:4]=[CH:5][NH:6]2.[C:14]([C:18]1[CH:33]=[CH:32][C:21]([CH2:22][NH:23][CH2:24][CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)=[CH:20][CH:19]=1)([CH3:17])([CH3:16])[CH3:15].C(Cl)Cl.CCN=C=NCCCN(C)C.Cl>>[C:14]([C:18]1[CH:33]=[CH:32][C:21]([CH2:22][N:23]([CH2:24][CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[C:11]([C:8]2[CH:9]=[CH:10][C:2]([F:1])=[C:3]3[C:7]=2[NH:6][CH:5]=[CH:4]3)=[O:13])=[CH:20][CH:19]=1)([CH3:17])([CH3:15])[CH3:16]
Reactant: O=C(O)c1ccc(F)c2cc[nH]c12
Reactant: CC(C)(C)c1ccc(CNCCc2ccccc2)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Product: CC(C)(C)c1ccc(CN(CCc2ccccc2)C(=O)c2ccc(F)c3cc[nH]c23)cc1
Temperature: 25 °C
Yield: 81.7 %

Procedure:
To a solution of 59 mg (0.33 mmol) of 4-fluoro-1H-indole-7-carboxylic acid and 80 mg (0.3 mmol) of (4-tert-butyl-benzyl)-2-phenyl-ethyl-amine in 3 ml DCM 63 mg (0.33 mmol) of EDC.HCl were added and the reaction mixture was stirred over night at rt. The product was purified by column chromatography (20 g silica gel; heptane/EtOAc 4:1) to yield 105 mg (72%) product as a white solid. MS (ISP) 429.6 (M+H)+.
Reaction SMILES: [CH3:1][O:2][CH2:3][C:4](=O)[CH2:5][C:6]([O:8]C)=O.Cl.[C:12](=[NH:17])([NH2:16])[CH2:13][CH2:14][CH3:15].C[O-].[Na+]>CO.C(OCC)(=O)C>[CH3:1][O:2][CH2:3][C:4]1[N:16]=[C:12]([CH2:13][CH2:14][CH3:15])[NH:17][C:6](=[O:8])[CH:5]=1
Reactant: CCCC(=N)N
Reactant: COCC(=O)CC(=O)OC
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Solvent: CCOC(C)=O
Product: CCCc1nc(COC)cc(=O)[nH]1
Reaction time: 8 h
Yield: 90.9 %

Procedure:
A mixture of methyl 4-methoxy-3-oxobutanoate (15.0 g), butanimidamide hydrochloride (15 g) and sodium methoxide (28% in methanol, 51 mL) in methanol (150 mL) was stirred overnight. The reaction mixture was diluted with ethyl acetate, washed with 1M hydrochloric acid, dried over sodium sulfate and concentrated. The residue was purified by silica gel column chromatography to give the title compound as a pale yellow oil (17 g, 91%).
Reaction SMILES: [Br:1][C:2]#[C:3][C:4]([O:6][CH3:7])=[O:5].[N:8]1([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH:12]=[CH:11][CH:10]=[CH:9]1>>[Br:1][C:2]1[CH:9]2[N:8]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH:12]([CH:11]=[CH:10]2)[C:3]=1[C:4]([O:6][CH3:7])=[O:5]
Reactant: CC(C)(C)OC(=O)n1cccc1
Reactant: COC(=O)C#CBr
Product: COC(=O)C1=C(Br)C2C=CC1N2C(=O)OC(C)(C)C
Temperature: 95 °C
Reaction time: 30 h

Procedure:
Into a 2000-mL 3-necked round-bottom flask was placed methyl 3-bromopropiolate (120 g, 736.33 mmol, 1.00 equiv) and tert-butyl 1H-pyrrole-1-carboxylate (615.61 g, 3.68 mol, 5.00 equiv). The resulting solution was stirred for 30 hr at 95° C. in an oil bath. The reaction mixture was cooled and distilled under reduced pressure (20 mm Hg). The fraction collected at 55° C. was purified by silica gel chromatography (ethyl acetate/petroleum ether, 1:20) to afford 7-tert-butyl 2-methyl 3-bromo-7-azabicyclo[2.2.1]hepta-2,5-diene-2,7-dicarboxylate as a yellow liquid.
Reaction SMILES: I[C:2]1[CH:11]=[CH:10][CH:9]=[C:4]([C:5]([O:7][CH3:8])=[O:6])[C:3]=1[C:12]([O:14][CH3:15])=[O:13].[C:16]1(B(O)O)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.C([O-])([O-])=O.[K+].[K+].C(Cl)Cl>O1CCOCC1.O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[C:2]1([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH:11]=[CH:10][CH:9]=[C:4]([C:5]([O:7][CH3:8])=[O:6])[C:3]=1[C:12]([O:14][CH3:15])=[O:13]
Reactant: OB(O)c1ccccc1
Reactant: COC(=O)c1cccc(I)c1C(=O)OC
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: O
Solvent: ClCCl
Solvent: C1COCCO1
Product: COC(=O)c1cccc(-c2ccccc2)c1C(=O)OC
Temperature: 100 °C
Yield: 77.1 %

Procedure:
A solution of dimethyl 3-iodophthalate (WO 2008/115516) (1.00 g, 3.12 mmol), phenylboronic acid (0.571 g, 4.69 mmol), K2CO3 (0.880 g, 9.30 mmol) in 1,4-dioxane (15 mL) and water (4 mL) was purged with nitrogen for 30 min. Pd(dppf)Cl2:DCM (0.219 g, 0.312 mmol) was added and the reaction mixture was heated at 100° C. for 12 h. The reaction mixture was filtered through a pad of CELITE® and the pad was washed with water (50 mL). The filtrate was extracted with EtOAc (2×100 mL). The combined organic extracts were dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The resulting residue was purified by combiflash (REDISEP®, silica gel, 12 g, 20% EtOAc/hexanes) to obtain dimethyl [1,1′-biphenyl]-2,3-dicarboxylate (0.65 g, 77.0%) as an off-white solid. LCMS (Condition 11): retention time 0.96 min, [M-MeOH+1]=239.3. 1H NMR (400 MHz, DMSO-d6) δ 3.59 (s, 3 H), 3.85 (s, 3 H), 7.33-7.49 (m, 5 H), 7.68-7.70 (m, 2 H), 7.95-8.00 (m, 1 H).
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([O:11][CH3:12])=[CH:7][CH:6]=1)=[O:4].[I-:13].[K+].CC(C)=O>O>[I:13][CH2:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([O:11][CH3:12])=[CH:7][CH:6]=1)=[O:4]
Reactant: [I-]
Reactant: COc1ccc(C(=O)CBr)cc1
Agent: [K+]
Solvent: O
Solvent: CC(C)=O
Product: COc1ccc(C(=O)CI)cc1
Yield: 94 %

Procedure:
A mixture of 2-bromo-1-(4'-methoxy-phenyl)-ethanone (22.9 g, 0.1 mol), potassium iodide (66.4 g, 0.4 mol) and acetone (200 ml) is heated at reflux for 3 h. The reaction mixture is cooled, poured into water (0.25 l) and extracted with ethyl ether (3×100 ml) The combined organic extract is washed with water and dried (Na2SO4). Evaporation of the solvent in vacuo leaves a residue which by crystallization from petroleum ether gives 2-iodo-1-(4'-methoxy-phenyl)-ethanone (22 g, 0.094 mol, yield 80%), m.p. 63°-65° C.
Reaction SMILES: [NH2:1][C:2]1[CH:12]=[CH:11][C:5]([CH:6]=[CH:7][C:8](O)=[O:9])=[CH:4][CH:3]=1.[ClH:13].[NH:14](C1C=C(C=CC=1)C([Cl:23])=O)[C:15](N)=[NH:16]>>[ClH:23].[NH:1]([C:2]1[CH:12]=[CH:11][C:5]([CH:6]=[CH:7][C:8]([Cl:13])=[O:9])=[CH:4][CH:3]=1)[C:15]([NH2:16])=[NH:14]
Reactant: N=C(N)Nc1cccc(C(=O)Cl)c1
Reactant: Nc1ccc(C=CC(=O)O)cc1
Agent: Cl
Product: N=C(N)Nc1ccc(C=CC(=O)Cl)cc1

Procedure:
The 4-guanidinocinnamoyl chloride hydrochloride was prepared from 4-aminocinnamic acid according to the procedure of Example XII for preparing 3-guanidinobenzoyl chloride hydrochloride.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[C:10]([O:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:9]([O:20][CH3:21])=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].CO[CH:24](OC)[N:25]([CH3:27])[CH3:26]>>[CH2:13]([O:12][C:10]1[C:9]([O:20][CH3:21])=[CH:8][C:3]([C:4]([O:6][CH3:7])=[O:5])=[C:2]([N:1]=[CH:24][N:25]([CH3:27])[CH3:26])[CH:11]=1)[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: COC(OC)N(C)C
Reactant: COC(=O)c1cc(OC)c(OCc2ccccc2)cc1N
Product: COC(=O)c1cc(OC)c(OCc2ccccc2)cc1N=CN(C)C
Temperature: 100 °C

Procedure:
A stirred mixture of 70.0 g (244 mmol) of methyl 2-amino-4-benzyloxy-5-methoxybenzoate (Phytochemistry 1976, 15, 1095) and 52 ml of dimethylformamide dimethyl acetal was heated at 100° C. for 1.5 h, cooled, and evaporated directly under high vacuum to give 81.3 g of off-white solid, mp 134-140° C.; NMR (CDCl3) d 3.01 (s, Me2N).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([CH3:11])[CH:10]=1)[C:5]([OH:7])=O.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[I-].[CH2:46]([N+:50]1[N:54]=[C:53]([CH3:55])[S:52][C:51]=1[CH3:56])[CH2:47][CH2:48][CH3:49]>>[CH2:46]([N:50]1[N:54]=[C:53]([CH3:55])[S:52]/[C:51]/1=[CH:56]\[C:5]([C:4]1[CH:8]=[C:9]([CH3:11])[CH:10]=[C:2]([CH3:1])[CH:3]=1)=[O:7])[CH2:47][CH2:48][CH3:49]
Reactant: CCCC[n+]1nc(C)sc1C
Reactant: Cc1cc(C)cc(C(=O)O)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: [I-]
Solvent: CCN(C(C)C)C(C)C
Product: CCCCN1N=C(C)S/C1=C\C(=O)c1cc(C)cc(C)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
In a 20 mL vial 3,5-dimethylbenzoic acid (0.9 mL of 0.2 M in DMA, 1.10 equiv) was added followed by the addition of HATU (76 mg in 0.7 mL of DMA, 0.2 mmol, 1.20 equiv.), DIEA (51 mg in 0.7 mL of DMA, 0.4 mmol, 2.40 equiv.), and finally 3-butyl-2,5-dimethyl-1,3,4-thiadiazol-3-ium iodide (49 mg in 0.7 mL of DMA, 0.17 mmol, 1 equiv.). The mixture was shaken overnight at room temperature and then concentrated in vacuo. The resulting residue was taken up in 1:1 DMSO/MeOH and purified by reverse phase HPLC using a method analogous to that described in Example 53 to provide the title compound. 1H NMR (500 MHz, DMSO-d6/D2O) δ ppm 0.87-0.96 (m, 3 H) 1.28-1.39 (m, 2 H) 1.68-1.80 (m, 2 H) 2.33 (s, 6 H) 2.47 (s, 3 H) 4.21 (t, 2 H) 6.66 (s, 1 H) 7.14 (s, 1 H) 7.62 (s, 2 H); MS (ESI) m/z 303 (M+H)+.
Reaction SMILES: C([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[C:19]3=[N:20][CH:21]=[CH:22][CH:23]=[C:18]3[NH:17][N:16]=2)=[CH:11][CH:10]=1)C1C=CC=CC=1.C([O-])([O-])=O.[Cs+].[Cs+].FC(F)(F)S(O[CH2:36][CH:37]([F:39])[F:38])(=O)=O.O>CN(C=O)C>[F:38][CH:37]([F:39])[CH2:36][N:17]1[C:18]2[C:19](=[N:20][CH:21]=[CH:22][CH:23]=2)[C:15]([C:12]2[CH:11]=[CH:10][C:9]([OH:8])=[CH:14][CH:13]=2)=[N:16]1
Reactant: O=S(=O)(OCC(F)F)C(F)(F)F
Reactant: c1ccc(COc2ccc(-c3n[nH]c4cccnc34)cc2)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: Oc1ccc(-c2nn(CC(F)F)c3cccnc23)cc1
Temperature: 25 °C
Reaction time: 12 h
Yield: 51.8 %

Procedure:
To a stirred mixture of 3-[4-(benzyloxy)phenyl]-1H-pyrazolo[4,3-b]pyridine (300 mg) and Cs2CO3 (649 mg) in DMF (4 ml) was added 2,2-difluoroethyl trifluoromethanesulfonate (234 mg) at 0° C. The mixture was stirred at room temperature for 12 h, treated with water, and extracted with AcOEt. The organic layer was dried over MgSO4 and concentrated under reduced pressure. The residue was dissolved in EtOH (8 mL) and 10% Pd—C (200 mg) was added. The mixture was stirred at room temperature for 30 min under H2 atmosphere, filtered and evaporated. The residue was purified by silica gel column chromatography (hexane/AcOEt) to give the title compound (142 mg).