Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([CH:3]([C:6]1[C:7]2[N:8]([CH:13]=[C:14]([CH3:16])[N:15]=2)[N:9]=[C:10]([CH3:12])[CH:11]=1)[CH2:4][CH3:5])[CH3:2].Br[C:18]1[C:19]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[N:20][N:21]([CH3:23])[CH:22]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C>[CH3:23][N:21]1[CH:22]=[C:18]([C:13]2[N:8]3[N:9]=[C:10]([CH3:12])[CH:11]=[C:6]([CH:3]([CH2:4][CH3:5])[CH2:1][CH3:2])[C:7]3=[N:15][C:14]=2[CH3:16])[C:19]([C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=2)=[N:20]1
Reactant: Cn1cc(Br)c(-c2ccccc2)n1
Reactant: CCC(CC)c1cc(C)nn2cc(C)nc12
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CCC(CC)c1cc(C)nn2c(-c3cn(C)nc3-c3ccccc3)c(C)nc12
Temperature: 130 °C
Yield: 6.4 %

Procedure:
8-(1-Ethyl-propyl)-2,6-dimethyl-imidazo[1,2-b]pyridazine (160 mg, 0.73 mmol), 4-bromo-1-methyl-3-phenyl-1H-pyrazole (250 mg, 1.1 mmol) and cesium carbonate (490 mg, 1.50 mmol) are stirred in DMF (5 ml) and degassed by bubbling a stream of nitrogen through the mixture. PdCl2(PPh3)2 (15 mg) is added and the mixture is heated to 130° C. overnight. The mixture is added to water and extracted twice with ethyl acetate. The combined organic extracts are dried over Na2SO4, filtered and concentrated. The crude product is purified by chromatography using a hexane-ethyl acetate gradient (100% hexane to 50% ethyl acetate in hexane) to elute the title compound (17.5 mg, 4% yield). ES-MS (m/z): calc'd for C23H27N5: 373.5; found 374.2 (M+H)+. 1H NMR (400 mHz, CDCl3): δ 7.68 (s, 1H), 7.37 (m, 2H), 7.20 (m, 3H), 6.59 (s, 1H), 4.04 (s, 3H), 3.36 (m, 1H), 2.38 (s, 3H), 2.15 (s, 3H), 1.82 (m, 4H), 0.86 (t, 6H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([CH3:20])[C:15]=2[N+:21]([O-])=O)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:24]OC(OC)N(C)C.N1CCCC1>CN(C=O)C>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]3[C:15]=2[NH:21][CH:24]=[CH:20]3)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: Cc1cccc(N2CCN(C(=O)OC(C)(C)C)CC2)c1[N+](=O)[O-]
Reactant: COC(OC)N(C)C
Solvent: CN(C)C=O
Solvent: C1CCNC1
Product: CC(C)(C)OC(=O)N1CCN(c2cccc3cc[nH]c23)CC1
Reaction time: 6 h
Yield: 26.8 %

Procedure:
A solution of 4-(3-methyl-2-nitrophenyl)-piperazine-1-carboxylic acid tert-butyl ester (10 g, 31 mmol), N,N-dimethylformamide dimethyl acetal (13.2 mL, 100 mmol) and pyrrolidine (4 mL, 50 mmol) in 45 mL of DMF was heated under reflux for 20 h. The mixture was concentrated in vacuo and the residue was partitioned between ethyl acetate and water. The ethyl acetate was dried and evaporated. The residue was hydrogenated in 200 mL of THF containing 2.5 g of 10% Pd-C at 50 psi for 6 h. The mixture was filtered, concentrated in vacuo, and partitioned between ethyl acetate and aqueous HCl. The ethyl acetate was washed with brine, dried and evaporated. Silica gel chromatography (10% ethyl acetate-hexane) afforded 2.5 g of 4-(1H-Indol-7-yl)-piperazine-1-carboxylic acid tert-butyl ester (19) as a white solid, m.p. 150-151° C.
Reaction SMILES: [CH2:1]([C:6]1[CH:11]=[CH:10][C:9]([C:12]2[CH:17]=[CH:16][C:15]([CH:18]=[CH:19][C:20]([O:22][CH3:23])=[O:21])=[CH:14][CH:13]=2)=[CH:8][CH:7]=1)[CH2:2][CH2:3][CH2:4][CH3:5].[H][H]>[Pd].O1CCCC1>[CH2:1]([C:6]1[CH:11]=[CH:10][C:9]([C:12]2[CH:13]=[CH:14][C:15]([CH2:18][CH2:19][C:20]([O:22][CH3:23])=[O:21])=[CH:16][CH:17]=2)=[CH:8][CH:7]=1)[CH2:2][CH2:3][CH2:4][CH3:5]
Reactant: CCCCCc1ccc(-c2ccc(C=CC(=O)OC)cc2)cc1
Reactant: [H][H]
Agent: [Pd]
Solvent: C1CCOC1
Product: CCCCCc1ccc(-c2ccc(CCC(=O)OC)cc2)cc1
Yield: 95.9 %

Procedure:
A mixture of Methyl 3-[4-(4-pentylphenyl)phenyl]acrylate (2.0 g) and 10% palladium on carbon (50% wet, 0.2 g) in tetrahydrofuran (20 ml) was stirred for 8 hours under atmospheric pressure of hydrogen at ambient temperature. The catalyst was filtered off, and the filtrate was evaporated under reduced pressure to give Methyl 3-[4-(4-pentylphenyl)phenyl]propionate (1.93 g).
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([O:12][C:13]3[CH:14]=[C:15]4[C:20](=[CH:21][CH:22]=3)[C:19]([C:23]([OH:25])=O)=[CH:18][CH:17]=[CH:16]4)=[CH:7][CH:8]=[N:9]2)=[CH:4][CH:3]=1.[NH2:26][CH2:27][C:28]1[CH:43]=[CH:42][C:31]([C:32]([NH:34][C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][C:36]=2[NH2:41])=[O:33])=[CH:30][CH:29]=1>>[NH2:41][C:36]1[CH:37]=[CH:38][CH:39]=[CH:40][C:35]=1[NH:34][C:32]([C:31]1[CH:42]=[CH:43][C:28]([CH2:27][NH:26][C:23]([C:19]2[C:20]3[C:15](=[CH:14][C:13]([O:12][C:6]4[C:5]5[C:10](=[CH:11][C:2]([Cl:1])=[CH:3][CH:4]=5)[N:9]=[CH:8][CH:7]=4)=[CH:22][CH:21]=3)[CH:16]=[CH:17][CH:18]=2)=[O:25])=[CH:29][CH:30]=1)=[O:33]
Reactant: NCc1ccc(C(=O)Nc2ccccc2N)cc1
Reactant: O=C(O)c1cccc2cc(Oc3ccnc4cc(Cl)ccc34)ccc12
Product: Nc1ccccc1NC(=O)c1ccc(CNC(=O)c2cccc3cc(Oc4ccnc5cc(Cl)ccc45)ccc23)cc1
Yield: 74 %

Procedure:
The title compound (42.4 mg, 74% yield) was prepared as a brown solid from 6-(7-chloroquinolin-4-yloxy)-1-naphthoic acid (35.0 mg, 0.1 mmol) and 4-(aminomethyl)-N-(2-aminophenyl)benzamide (28.9 mg, 0.12 mmol) by an analogous procedure to that described in example 16. 1H NMR (DMSO-d6) δ 4.64 (d, J=5.8 Hz, 2H, —CH2), 4.87 (s, 2H, benzene-NH2), 6.60 (t, J=7.0 Hz, 1H, Ar—H), 6.75-6.79 (m, 2H, Ar—H), 6.97 (t, J=7.5 Hz, 1H, Ar—H), 7.18 (d, J=7.7 Hz, 1H, Ar—H), 7.53-7.59 (m, 3H, Ar—H), 7.66 (t, J=8.0 Hz, 1H, Ar—H), 7.70-7.74 (m, 2H, Ar—H), 7.92 (d, J=2.0 Hz, 1H, Ar—H), 7.99 (d, J=7.9 Hz, 2H, Ar—H), 8.06 (d, J=8.2 Hz, 1H, Ar—H), 8.13 (s, 1H, Ar—H), 8.39-8.42 (m, 2H, Ar—H), 8.75 (d, J=5.1 Hz, 1H, Ar—H), 9.22 (t, J=5.6 Hz, 1H, —CONH), 9.62 (s, 1H, benzene-NH). LC-MS (m/z) 573 (M+1).
Reaction SMILES: N#N.[C:3]([SiH2:7][O:8][C:9]([CH3:20])([CH3:19])[C:10]1[CH:15]=[CH:14][N:13]=[C:12]([C:16](=[O:18])[CH3:17])[CH:11]=1)([CH3:6])([CH3:5])[CH3:4].[CH2:21](O)[CH2:22][OH:23].COC(OC)OC>C([O-])(O)=O.[Na+]>[C:3]([SiH2:7][O:8][C:9]([CH3:20])([CH3:19])[C:10]1[CH:15]=[CH:14][N:13]=[C:12]([C:16]2([CH3:17])[O:23][CH2:22][CH2:21][O:18]2)[CH:11]=1)([CH3:6])([CH3:4])[CH3:5]
Reactant: OCCO
Reactant: CC(=O)c1cc(C(C)(C)O[SiH2]C(C)(C)C)ccn1
Agent: N#N
Agent: O=C([O-])O
Agent: [Na+]
Solvent: COC(OC)OC
Product: CC(C)(C)[SiH2]OC(C)(C)c1ccnc(C2(C)OCCO2)c1
Temperature: 95 °C

Procedure:
In a flame dried round-bottomed flask equipped with a magnetic stir bar and a condenser under inert atmosphere (N2), a solution of 1-[4-(tert-butyl-dimethyl-silanyloxymethyl)-pyridin-2-yl]-ethanone (1.78 g, 6.71 mmol) in ethylene glycol (7.14 mL, 127.95 mmol) was treated with trimethylorthoformate (1.50 mL, 13.67 mmol) followed by LiBF4 (128 mg, 1.34 mmol). The reaction mixture was heated at 95° C. overnight. Sat. aq. NaHCO3 (50 mL) was added and the mixture was extracted with EA (50 mL). The org. extracts were washed with brine (2×50 mL), dried over MgSO4, filtered, and the solvent was removed under reduced pressure. Purification of the residue by FC (20:1 to 1:1 hept-EA) gave the title compound as a yellow oil. TLC: rf (1:1 hept-EA)=0.50. LC-MS-conditions 02: tR=0.91 min, [M+H]+=310.40.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:15]=[N:16][C:17]([O:20][CH2:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)=[CH:18][CH:19]=2)=[CH:10][C:9]=1[NH:28][C:29](=[O:43])[CH2:30][C:31](=O)[C:32]1[CH:37]=[CH:36][CH:35]=[C:34]([C:38]([F:41])([F:40])[F:39])[CH:33]=1)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH2:21]([O:20][C:17]1[N:16]=[CH:15][C:14]([C:11]2[CH:12]=[CH:13][C:8]3[N:7]=[C:31]([C:32]4[CH:37]=[CH:36][CH:35]=[C:34]([C:38]([F:40])([F:39])[F:41])[CH:33]=4)[CH2:30][C:29](=[O:43])[NH:28][C:9]=3[CH:10]=2)=[CH:19][CH:18]=1)[C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1
Reactant: CC(C)(C)OC(=O)Nc1ccc(-c2ccc(OCc3ccccc3)nc2)cc1NC(=O)CC(=O)c1cccc(C(F)(F)F)c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C1CC(c2cccc(C(F)(F)F)c2)=Nc2ccc(-c3ccc(OCc4ccccc4)nc3)cc2N1
Yield: 30.5 %

Procedure:
Prepared from {4-(6-benzyloxy-pyridin-3-yl)-2-[3-oxo-3-(3-trifluoromethyl-phenyl)-propionylamino]-phenyl}-carbamic acid tert.-butyl ester (Example K 23) (198 mg, 0.33 mmol) by treatment with TFA in CH2Cl2 according to the general procedure M. Obtained as a yellow solid (49 mg).
Reaction SMILES: [C:1]([O:5][C:6](=[O:13])[NH:7][C@H:8]1[CH2:11][C@@H:10]([NH2:12])[CH2:9]1)([CH3:4])([CH3:3])[CH3:2].[Cl:14][C:15]1[C:16]([C:21]([CH3:26])([CH3:25])[C:22](O)=[O:23])=[N:17][CH:18]=[CH:19][N:20]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)CC)C>C(Cl)Cl>[C:1]([O:5][C:6](=[O:13])[NH:7][C@H:8]1[CH2:11][C@@H:10]([NH:12][C:22](=[O:23])[C:21]([C:16]2[C:15]([Cl:14])=[N:20][CH:19]=[CH:18][N:17]=2)([CH3:26])[CH3:25])[CH2:9]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N[C@H]1C[C@@H](N)C1
Reactant: CC(C)(C(=O)O)c1nccnc1Cl
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N[C@H]1C[C@@H](NC(=O)C(C)(C)c2nccnc2Cl)C1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a round bottomed flask was added tert-butyl(cis-3-aminocyclobutyl)carbamate (0.4903 g, 2.63 mmol), 2-(3-chloropyrazin-2-yl)-2-methylpropanoic acid (Intermediate 29, 0.634 g, 3.16 mmol), HATU (1.301 g, 3.42 mmol, GenScript Corp), and triethylamine (1.465 ml, 10.53 mmol, Sigma-Aldrich Chemical Company, Inc.) in DCM (5.26 ml) to stir at room temperature for 24 h. The crude product was adsorbed onto a plug of silica gel and chromatographed through a Biotage SNAP HP-silica gel column (50 g), eluting with a gradient of 10% to 100% EtOAc in hexane, to provide the title compound (0.8210 g, 2.226 mmol, 85% yield). LCMS showed product peak at 1.86 min (m+1=313.0, product-tbutyl group). 1H NMR (400 MHz, DMSO-d6) δ ppm 1.36 (s, 7 H) 1.49 (s, 5 H) 1.82 (qd, J=9.00, 2.35 Hz, 2 H) 2.34-2.47 (m, 2 H) 2.69 (s, 3 H) 3.48-3.65 (m, 1 H) 3.72-3.87 (m, 1 H) 7.04 (d, J=6.85 Hz, 1 H) 7.63 (d, J=6.46 Hz, 1 H) 8.42 (d, J=2.54 Hz, 1 H) 8.65 (d, J=2.35 Hz, 1 H).
Reaction SMILES: C(O[C:6]([C:8]1[N:9]=[CH:10][C:11]2[C:16]([C:17]=1[OH:18])=[CH:15][CH:14]=[C:13]([S:19]([CH:22]1[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]1)(=[O:21])=[O:20])[CH:12]=2)=[O:7])CCC.[NH2:28][CH2:29][CH2:30][C:31]([OH:33])=[O:32].C[O-].[Na+].CO.Cl>O>[CH:22]1([S:19]([C:13]2[CH:12]=[C:11]3[C:16]([C:17]([OH:18])=[C:8]([C:6]([NH:28][CH2:29][CH2:30][C:31]([OH:33])=[O:32])=[O:7])[N:9]=[CH:10]3)=[CH:15][CH:14]=2)(=[O:20])=[O:21])[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27]1
Reactant: CCCCOC(=O)c1ncc2cc(S(=O)(=O)C3CCCCC3)ccc2c1O
Reactant: NCCC(=O)O
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CO
Product: O=C(O)CCNC(=O)c1ncc2cc(S(=O)(=O)C3CCCCC3)ccc2c1O
Yield: 46 %

Procedure:
A mixture of 7-cyclohexanesulfonyl-4-hydroxy-isoquinoline-3-carboxylic acid butyl ester (20 mg, 0.05 mmol) (prepared according to U.S. Pat. No. 7,629,357) and beta-alanine (45 mg, 0.5 mmol) in 0.5 M NaOMe/MeOH (0.8 mL, 0.4 mmol) was microwaved at 120° C. for 30 min. Reaction mixture was diluted with water (50 mL) and acidified by 1 N HCl to pH=3-4. Precipitate was collected, rinsed with water and dried in vacuo to provide the title compound 9.4 mg (0.023 mmol) in 46% yield. LC-MS ESI−: 405.05 (M−1)−.
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:14]([OH:16])=O)=[N:4][C:5]2[C:10]([N:11]=1)=[CH:9][C:8]([CH3:12])=[C:7]([CH3:13])[CH:6]=2.[NH2:17][C:18]1[NH:22][N:21]=[N:20][N:19]=1>O1CCCC1.CN(C)C=O>[Cl:1][C:2]1[C:3]([C:14]([NH:17][C:18]2[NH:22][N:21]=[N:20][N:19]=2)=[O:16])=[N:4][C:5]2[C:10]([N:11]=1)=[CH:9][C:8]([CH3:12])=[C:7]([CH3:13])[CH:6]=2
Reactant: Cc1cc2nc(Cl)c(C(=O)O)nc2cc1C
Reactant: Nc1nnn[nH]1
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: Cc1cc2nc(Cl)c(C(=O)Nc3nnn[nH]3)nc2cc1C

Procedure:
3-Chloro-6,7-dimethyl-2quinoxalinecarboxylic acid (10.5 g) and N,N'-carbonyldiimidazole (7.35 g) in tetrahydrofuran (350 ml) were heated under reflux for 1 hour. 5-Amino-1H-tetrazole (4.3 g) in dimethylformamide (10 ml) was added and the mixture was heated under reflux for a further hour and cooled. The solid was collected and dissolved in aqueous dimethylaminoethanol. Dilute hydrochloric acid was added to the solution and the solid was collected and crystallised from dimethylformamide. The product decomposed at 360° (39%).
Reaction SMILES: [NH2:1][C:2]1[CH2:7][CH2:6][CH2:5][CH2:4][C:3]=1[C:8]([OH:10])=O.[C:11](OCC)(=[O:18])[CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14].[Na].Cl>C(O)C.O>[C:13]([C:12]1[C:11](=[O:18])[NH:1][C:2]2[CH2:7][CH2:6][CH2:5][CH2:4][C:3]=2[C:8]=1[OH:10])([O:15][CH2:16][CH3:17])=[O:14]
Reactant: CCOC(=O)CC(=O)OCC
Reactant: NC1=C(C(=O)O)CCCC1
Agent: Cl
Agent: [Na]
Solvent: O
Solvent: CCO
Product: CCOC(=O)c1c(O)c2c([nH]c1=O)CCCC2
Reaction time: 30 h

Procedure:
A mixture of a 60:40 mixture of the ethyl and methyl esters of 2-amino cyclohex-1-ene carboxylic acid (47.2g; 0.29 mole) and diethyl malonate (46,4g; 0.29 mole) were added to a solution of sodium (7.2g; 0.29 mole) in ethanol (145 ml) stirred at ca 110° C for 30 hrs. in an autoclave. The product was acidified with 5N HCl to pH 4.0 and diluted with water. The precipitated ester was filtered off and recrystallised from ethanol with charcoalisation, m.p. 236° - 7°(d).
Reaction SMILES: [F:1][C:2]1[C:10]([O:11][C:12]2[C:21]3[C:16](=[CH:17][C:18]([O:24][CH2:25][CH2:26][CH2:27][N:28]4[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]4)=[C:19]([O:22][CH3:23])[CH:20]=3)[N:15]=[CH:14][N:13]=2)=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[C:5]([CH3:34])[NH:6]2.I[CH2:36][C:37]([NH2:39])=[O:38]>C(#N)C>[C:37]([CH2:36][N:31]1[CH2:32][CH2:33][N:28]([CH2:27][CH2:26][CH2:25][O:24][C:18]2[CH:17]=[C:16]3[C:21]([C:12]([O:11][C:10]4[C:2]([F:1])=[C:3]5[C:7](=[CH:8][CH:9]=4)[NH:6][C:5]([CH3:34])=[CH:4]5)=[N:13][CH:14]=[N:15]3)=[CH:20][C:19]=2[O:22][CH3:23])[CH2:29][CH2:30]1)(=[O:38])[NH2:39]
Reactant: NC(=O)CI
Reactant: COc1cc2c(Oc3ccc4[nH]c(C)cc4c3F)ncnc2cc1OCCCN1CCNCC1
Solvent: CC#N
Product: COc1cc2c(Oc3ccc4[nH]c(C)cc4c3F)ncnc2cc1OCCCN1CCN(CC(N)=O)CC1
Temperature: 25 °C
Yield: 31.6 %

Procedure:
A mixture of 4-[(4-fluoro-2-methyl-1H-indol-5-yl)oxy]-6-methoxy-7-(3-piperazin-1-ylpropoxy)quinazoline (370 mg, 0.8 mmol), (prepared as described for the starting material in Example 15), iodoacetamide (162 mg, 0.88 mmol) and N,N-diisopropylethylanmine (230 mg, 1.80 mmol) in acetonitrile (10 ml) was stirred at reflux for 1 hour and allowed to cool to ambient temperature. The solvent was removed under vacuum and the residue purified by column chromatography eluting with methylene chloride/methanol (saturated with ammonia) (92/8) solvent. The relevant fractions were combined and evaporated under vacuum to give a solid which was triturated with acetone, filtered and dried to give 7-[3-(4-carbamoylmethylpiperazin-1-yl)propoxy]-4-[(4-fluoro-2-methyl-1H-indol-5-yl)oxy]-6-methoxyquinazoline (132 mg, 32%).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[S:7][C:8]([CH3:13])=[C:9]([CH2:11]Cl)[CH:10]=1)=[O:5])[CH3:2].[C-:14]#[N:15].[K+]>CN(C=O)C.O>[CH2:1]([O:3][C:4]([C:6]1[S:7][C:8]([CH3:13])=[C:9]([CH2:11][C:14]#[N:15])[CH:10]=1)=[O:5])[CH3:2]
Reactant: [C-]#N
Reactant: CCOC(=O)c1cc(CCl)c(C)s1
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)c1cc(CC#N)c(C)s1
Temperature: 70 °C
Reaction time: 2 h
Yield: 18.8 %

Procedure:
A solution of the 4-chloromethyl-5-methyl-thiophene-2-carboxylic acid ethyl ester mixture from part 2 (25.6 g) in DMF (350 mL) is treated with potassium cyanide (20 g, 0.312 mol) and heated to 70° C. with stirring for 2 h. After cooling to room temperature, the solution is diluted with water and extracted with chloroform (2×). The combined organic layers are washed with saturated aq NaCl, dried over Na2SO4, filtered and concentrated in vacuo. The residue is purified by flash chromatography (10% ethyl acetate in heptane) to give 4-cyanomethyl-5-methyl-thiophene-2-carboxylic acid ethyl ester (4.7 g, 18.8%; 2 steps) as a white solid. mp 55-57° C.; 1H NMR (CDCl3, 300 MHz) δ 7.63 (s, 1 H), 4.28 (q, J=6.0 Hz, 2 H), 3.60 (s, 2 H), 2.48 (s, 3 H), 1.38 (t, J=6.0 Hz, 3 H).
Reaction SMILES: [NH2:1][C:2]1[N:6]([C:7]2[C:12]([Cl:13])=[CH:11][C:10]([C:14]([F:17])([F:16])[F:15])=[CH:9][C:8]=2[Cl:18])[N:5]=[C:4]([C:19]([F:22])([F:21])[F:20])[C:3]=1C#N.[CH:25]([Br:28])(Br)Br.N(OC(C)(C)C)=O>>[Br:28][C:25]1[N:6]([C:7]2[C:12]([Cl:13])=[CH:11][C:10]([C:14]([F:16])([F:17])[F:15])=[CH:9][C:8]=2[Cl:18])[N:5]=[C:4]([C:19]([F:20])([F:22])[F:21])[C:3]=1[C:2]#[N:1]
Reactant: BrC(Br)Br
Reactant: N#Cc1c(C(F)(F)F)nn(-c2c(Cl)cc(C(F)(F)F)cc2Cl)c1N
Agent: CC(C)(C)ON=O
Product: N#Cc1c(C(F)(F)F)nn(-c2c(Cl)cc(C(F)(F)F)cc2Cl)c1Br
Temperature: 50 °C

Procedure:
A stirred mixture of 5-amino-4-cyano-1-(2,6-dichloro-4-trifluoromethylphenyl)-3-trifluoromethylpyrazole (3.89 g) and bromoform (13 ml) was treated with tert-butyl nitrite (2.26 ml) at room temperature. After 15 minutes the mixture was heated to 50° C. for 1 hour, and evaporated in vacuo to yield a red oil. This was purified by chromatography on silica (Merck, 40-230 mesh, 0.7 kg cm-2) eluting with a mixture of dichloromethane and petroleum ether (1:2) to furnish 5-bromo-4-cyano-1-(2,6-dichloro-4-trifluoromethylphenyl)-3-trifluoromethylpyrazole as a fawn solid m.p. 85°-87° C. (3.7 g).
Reaction SMILES: [F:1][C:2]1[C:3]([C:10]2[CH:15]=[CH:14][C:13]([C:16]([O:18]C)=[O:17])=[CH:12][C:11]=2[C:20]([O:22][CH3:23])=[O:21])=[CH:4][C:5]([O:8][CH3:9])=[N:6][CH:7]=1.[OH-].[K+].Cl>C1COCC1.CO>[F:1][C:2]1[C:3]([C:10]2[CH:15]=[CH:14][C:13]([C:16]([OH:18])=[O:17])=[CH:12][C:11]=2[C:20]([O:22][CH3:23])=[O:21])=[CH:4][C:5]([O:8][CH3:9])=[N:6][CH:7]=1
Reactant: COC(=O)c1ccc(-c2cc(OC)ncc2F)c(C(=O)OC)c1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: COC(=O)c1cc(C(=O)O)ccc1-c1cc(OC)ncc1F
Temperature: 25 °C
Reaction time: 17 h
Yield: 99.5 %

Procedure:
To a stirred solution of 83.21A (0.860 g, 2.7 mmol) in THF (7.00 mL) and MeOH (7.00 mL) at 0° C. was added potassium hydroxide (1.5 mL, 3.0 mmol) slowly to maintain the temperature below 6° C. The reaction mixture was allowed to warm to room temperature and stirred for 17 hours. After which, the reaction was acidified with 1N HCl and extracted three times with EtOAc. After drying over anhydrous magnesium sulfate and filtering, the organic solvent was removed under reduced pressure to yield 83.21B as a colorless solid (0.82 g, 100% yield).
Reaction SMILES: [O:1]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[NH:4][C:3](=[O:11])[CH2:2]1.Br[CH2:13][CH2:14][O:15][C:16]1[CH:23]=[CH:22][C:19]([CH:20]=[O:21])=[CH:18][CH:17]=1.C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[O:11]=[C:3]1[N:4]([CH2:13][CH2:14][O:15][C:16]2[CH:23]=[CH:22][C:19]([CH:20]=[O:21])=[CH:18][CH:17]=2)[C:5]2[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=2[O:1][CH2:2]1
Reactant: O=Cc1ccc(OCCBr)cc1
Reactant: O=C1COc2ccccc2N1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: O=Cc1ccc(OCCN2C(=O)COc3ccccc32)cc1
Temperature: 80 °C
Reaction time: 10 h
Yield: 91.2 %

Procedure:
A mixture of 2H-1,4-benzoxazin-3-(4H)-one (1.6 g, 10.7 mmol), 4-(2-bromoethoxy)benzaldehyde (2.95 g, 12.8 mmol) and potassium carbonate (5.93 g, 42.97 mmol) in dry dimethyl formamide (30 mL) was stirred at 80° C. for 10 h. Water (100 mL) was added and extracted with ethyl acetate (2×75 mL). The combined organic layers were washed with water (50 mL), brine (50 mL), dried (Na2SO4), filtered and the solvent was evaporated. The residue was chromatographed over silica gel using a mixture of ethyl acetate and pet. ether (2:8) to afford the title compound (2.9 g, 91%) as a colorless solid. mp: 75-78° C.
Reaction SMILES: [OH:1][C@@H:2]([CH2:24][OH:25])[CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[C:16]([C:17]#[N:18])=[C:15]([SH:19])[N:14]=[C:13]([O:20][CH3:21])[C:12]=2[C:22]#[N:23])=[CH:7][CH:6]=1.Cl[CH2:27][C:28]1[N:29]=[C:30]([C:33]2[CH:38]=[CH:37][C:36]([Cl:39])=[CH:35][CH:34]=2)[S:31][CH:32]=1.C(=O)(O)[O-].[Na+]>>[Cl:39][C:36]1[CH:35]=[CH:34][C:33]([C:30]2[S:31][CH:32]=[C:28]([CH2:27][S:19][C:15]3[C:16]([C:17]#[N:18])=[C:11]([C:8]4[CH:9]=[CH:10][C:5]([O:4][CH2:3][C@@H:2]([OH:1])[CH2:24][OH:25])=[CH:6][CH:7]=4)[C:12]([C:22]#[N:23])=[C:13]([O:20][CH3:21])[N:14]=3)[N:29]=2)=[CH:38][CH:37]=1
Reactant: COc1nc(S)c(C#N)c(-c2ccc(OC[C@@H](O)CO)cc2)c1C#N
Reactant: ClCc1csc(-c2ccc(Cl)cc2)n1
Agent: O=C([O-])O
Agent: [Na+]
Product: COc1nc(SCc2csc(-c3ccc(Cl)cc3)n2)c(C#N)c(-c2ccc(OC[C@@H](O)CO)cc2)c1C#N

Procedure:
The solution from Example 29A is stirred together with 75 mg (0.306 mmol) of 4-(chloromethyl)-2-(4-chlorophenyl)-1,3-thiazole and 93 mg (1.112 mmol) of sodium bicarbonate at room temperature overnight. The reaction mixture is purified by preparative HPLC (acetonitrile/water: 10:90→95:5, with 0.1% TFA added). This gives 33 mg (20% of theory over two steps) of the target compound.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:4][C:3]=1[CH3:11].B1([C:18]2[CH:23]=[CH:22][CH:21]=[N:20][CH:19]=2)OCCCO1.C([O-])([O-])=O.[Na+].[Na+]>CCO.C1(C)C=CC=CC=1.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>[CH3:11][C:3]1[CH:4]=[CH:5][C:6]([N+:8]([O-:10])=[O:9])=[CH:7][C:2]=1[C:18]1[CH:19]=[N:20][CH:21]=[CH:22][CH:23]=1
Reactant: Cc1ccc([N+](=O)[O-])cc1Br
Reactant: c1cncc(B2OCCCO2)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCO
Product: Cc1ccc([N+](=O)[O-])cc1-c1cccnc1
Yield: 103.1 %

Procedure:
A mixture of 2-bromo-4-nitrotoluene (3 g, 13.0 mmol) and pyridine-3-boronic acid-1,3-propanediol cyclic ester (2.72 g, 16.7 mmol) in EtOH (30 ml) and toluene (30 ml) together with 2N Na2CO3 solution (13.9 ml) was degassed with a stream of N2 for 10 min. Tetrakis(triphenylphosphine)palladium(0) (0.3 g, 0.26 mmol) was added and the reaction heated at reflux for 4 h. The mixture was concentrated under reduced pressure to remove the organic solvents and water (100 ml) was added. The organics were extracted with EtOAc (200 ml) and then washed with brine (75 ml), dried (MgSO4), and concentrated under reduced pressure while dry loading onto silica. The resulting crude residue was purified by column chromatography on silica, using 60% diethyl ether in hexane as the eluent, to yield 3-(2-methyl-5-nitrophenyl)pyridine (2.87 g, 99%): δH (360 MHz, CDCl3) 2.38 (3H, s), 7.36-7.50 (2H, m), 7.67 (1H, dt, J 7.9 and 1.9), 8.10 (1H, d, J 2.4), 8.61 (1H, d, J 1.8), 8.67 (1H, dd, J 4.8 and 1.5).
Reaction SMILES: I[C:2]1[CH:23]=[CH:22][C:5]2[NH:6][C:7]([C@@H:9]3[CH2:13][C@H:12]([CH3:14])[CH2:11][N:10]3[C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])=[N:8][C:4]=2[CH:3]=1.[C:24]([C:26]1[CH:31]=[CH:30][C:29]([C:32]2[N:33]=[C:34]([C@@H:37]3[CH2:41][C@H:40]([CH3:42])[CH2:39][N:38]3[C:43]([O:45][C:46]([CH3:49])([CH3:48])[CH3:47])=[O:44])[NH:35][CH:36]=2)=[CH:28][CH:27]=1)#[CH:25].C(Cl)Cl>CN(C=O)C.[Cu]I>[C:18]([O:17][C:15]([N:10]1[CH2:11][C@@H:12]([CH3:14])[CH2:13][C@H:9]1[C:7]1[NH:6][C:5]2[CH:22]=[CH:23][C:2]([C:25]#[C:24][C:26]3[CH:31]=[CH:30][C:29]([C:32]4[N:33]=[C:34]([C@@H:37]5[CH2:41][C@H:40]([CH3:42])[CH2:39][N:38]5[C:43]([O:45][C:46]([CH3:47])([CH3:49])[CH3:48])=[O:44])[NH:35][CH:36]=4)=[CH:28][CH:27]=3)=[CH:3][C:4]=2[N:8]=1)=[O:16])([CH3:21])([CH3:20])[CH3:19]
Reactant: C#Cc1ccc(-c2c[nH]c([C@@H]3C[C@H](C)CN3C(=O)OC(C)(C)C)n2)cc1
Reactant: C[C@H]1C[C@@H](c2nc3cc(I)ccc3[nH]2)N(C(=O)OC(C)(C)C)C1
Agent: [Cu]I
Solvent: ClCCl
Solvent: CN(C)C=O
Product: C[C@H]1C[C@@H](c2nc(-c3ccc(C#Cc4ccc5[nH]c([C@@H]6C[C@H](C)CN6C(=O)OC(C)(C)C)nc5c4)cc3)c[nH]2)N(C(=O)OC(C)(C)C)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 66.2 %

Procedure:
To a solution of tert-butyl (2S,4S)-2-(5-iodo-1H-benzimidazol-2-yl)-4-methyl-pyrrolidine-1-carboxylate (68.5 mg, 0.16 mmol) in DMF (3 mL) are sequentially added tert-butyl (2S,4S)-2-[4-(4-ethynylphenyl)-1H-imidazol-2-yl]-4-methyl-pyrrolidine-1-carboxylate (47 mg, 0.13 mmol), Pd(DPPF)(Cl)2.CH2Cl2 (5.4 mg, 0.0067 mmol). The mixture is degassed well under vacuum and to it is added TEA (37 uL, 0.27 mmol), followed by CuI (1.2 mg, 0.0067 mmol). Then the reaction mixture is stirred under nitrogen at rt overnight. After removal of the solvent, the crude is purified by flash column chromatography on silica gel using methanol/CH2Cl2 0-5% to obtain tert-butyl (2S,4S)-2-[4-[4-[2-[2-[(2S,4S)-1-tert-butoxycarbonyl-4-methyl-pyrrolidin-2-yl]-1H-benzimidazol-5-yl]ethynyl]phenyl]-1H-imidazol-2-yl]-4-methyl-pyrrolidine-1-carboxylate (56 mg, 64%).