Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]([CH3:33])[S:3]([N:6]1[C:10]([CH3:11])=[C:9]([CH2:12][N:13]([CH2:20][CH2:21][C:22]2[N:23]([CH3:32])[C:24]3[C:29]([CH:30]=2)=[CH:28][CH:27]=[CH:26][C:25]=3[F:31])C(=O)C(F)(F)F)[N:8]=[CH:7]1)(=[O:5])=[O:4].C(=O)([O-])[O-].[K+].[K+]>CO.C(OCC)(=O)C>[F:31][C:25]1[CH:26]=[CH:27][CH:28]=[C:29]2[C:24]=1[N:23]([CH3:32])[C:22]([CH2:21][CH2:20][NH:13][CH2:12][C:9]1[N:8]=[CH:7][N:6]([S:3]([N:2]([CH3:33])[CH3:1])(=[O:4])=[O:5])[C:10]=1[CH3:11])=[CH:30]2
Reactant: Cc1c(CN(CCc2cc3cccc(F)c3n2C)C(=O)C(F)(F)F)ncn1S(=O)(=O)N(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CO
Product: Cc1c(CNCCc2cc3cccc(F)c3n2C)ncn1S(=O)(=O)N(C)C
Yield: 59.5 %

Procedure:
To a solution of N-[[1-[(dimethylamino)sulphonyl]-5-methyl-1H-imidazol -4-yl]methyl]-2,2,2-trifluoro-N-[2-(7-fluoro-1-methyl-1H-indol-2-yl)-ethyl]acetamide (230 mg) in methanol (10 ml) was added potassium carbonate (350 mg), and the mixture was heated at reflux for 2 h. The mixture was then diluted with ethyl acetate (100 ml), washed with 8% sodium bicarbonate solution (100 ml), dried, and evaporated in vacuo to leave an oil. This was purified by FCC eluting with System A (200:8:1) to give the title compound (110 mg) as a solid, m.p. 114°-115.5°.
Reaction SMILES: [O:1]=[C:2]1[CH:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[CH2:5][N:4]([C:13]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[O:14])[CH2:3]1.CCC(C)[BH-](C(C)CC)C(C)CC.[Li+]>O1CCCC1>[OH:1][CH:2]1[CH:6]([C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH2:5][N:4]([C:13]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[O:14])[CH2:3]1
Reactant: O=C1CN(C(=O)OCc2ccccc2)CC1c1ccccc1
Agent: CCC(C)[BH-](C(C)CC)C(C)CC
Agent: [Li+]
Solvent: C1CCOC1
Product: O=C(OCc1ccccc1)N1CC(O)C(c2ccccc2)C1
Yield: 60.1 %

Procedure:
To a solution of benzyl 3-oxo-4-phenylpyrrolidine-1-carboxylate (200 mg, 0.0007 mol) in tetrahydrofuran (2.0 mL, 0.025 mol) under a N2 atmosphere at −78° C. was added L-Selectride® in tetrahydrofuran (1M, 4.1 mL) with stirring. The mixture was stirred at this temperature for 1.5 hours. LCMS indicated that the starting material was consumed and the reaction was quenched with water. The solution was adjusted to pH ˜6 to 7 and was extracted with EtOAc. The organic extract was washed with brine, dried over Na2SO4, filtered and the filtrate was concentrated. The resulting residue was purified with Combiflash, eluting with EtOAc/hexane to afford the product (125 mg). LCMS: m/z 298.0 (M+H+); 320.0 (M+Na+).
Reaction SMILES: [NH2:1][CH:2]1[CH2:7][CH2:6][N:5]([CH2:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH2:4][CH2:3]1.Cl[C:16]1[C:21]([N+:22]([O-:24])=[O:23])=[CH:20][CH:19]=[CH:18][C:17]=1[CH3:25].O>CS(C)=O>[CH2:8]([N:5]1[CH2:6][CH2:7][CH:2]([NH:1][C:16]2[C:21]([N+:22]([O-:24])=[O:23])=[CH:20][CH:19]=[CH:18][C:17]=2[CH3:25])[CH2:3][CH2:4]1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: Cc1cccc([N+](=O)[O-])c1Cl
Reactant: NC1CCN(Cc2ccccc2)CC1
Solvent: O
Solvent: CS(C)=O
Product: Cc1cccc([N+](=O)[O-])c1NC1CCN(Cc2ccccc2)CC1
Temperature: 100 °C
Reaction time: 19 h
Yield: 16 %

Procedure:
4-Amino-1-benzylpiperidine (0.20 ml) was dissolved in dimethyl sulfoxide (0.2 ml), added with 2-chloro-3-nitrotoluene (0.13 ml) and stirred at 100° C. for 19 hours. The reaction mixture was added with water (2 ml) and extracted twice with ethyl acetate (2 ml). The organic layer was dried over anhydrous magnesium sulfate, and then the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent: hexane:ethyl acetate=3:1) to obtain 51.1 mg of the title compound. Yield: 16%.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH2:20][C:21]([O:23][CH3:24])=[O:22])[CH:5]=[CH:6][C:7]=1[O:8][CH2:9][C:10]1[CH:19]=[CH:18][C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[N:11]=1.[C:25]1(C)C=CC=C[CH:26]=1>>[CH:25]([C:2]1[CH:3]=[C:4]([CH2:20][C:21]([O:23][CH3:24])=[O:22])[CH:5]=[CH:6][C:7]=1[O:8][CH2:9][C:10]1[CH:19]=[CH:18][C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[N:11]=1)=[CH2:26]
Reactant: Cc1ccccc1
Reactant: COC(=O)Cc1ccc(OCc2ccc3ccccc3n2)c(Br)c1
Product: C=Cc1cc(CC(=O)OC)ccc1OCc1ccc2ccccc2n1
Reaction time: 20 h

Procedure:
200 mg (0.21 mmol) of the catalyst [P(phenyl)3 ]4Pd are weighed into a 50 ml brown glass flask (flushed with argon) and 2 g (5.2 mmol) of the compound from Example XX and 1.4 ml (5.2 mmol) of Bu3SnCH=CH2 (d=1.086), both dissolved in 10 ml of toluene, are added under argon. The mixture is heated to boiling for 20 hours with stirring in a light-protected apparatus. The solvent is then evaporated in vacuo and the residue is separated by column chromatography (silica gel 60, eluent: toluene/ethyl acetate=4:1).
Reaction SMILES: F[C:2]1[CH:12]=[CH:11][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:4][C:3]=1[C:13]1[C:14]2[CH:23]=[CH:22][N:21](S(C3C=CC(C)=CC=3)(=O)=O)[C:15]=2[C:16](=[O:20])[N:17]([CH3:19])[CH:18]=1.[C:34]1([OH:40])[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CS(C)=O>[CH3:19][N:17]1[CH:18]=[C:13]([C:3]2[CH:4]=[C:5]([CH:11]=[CH:12][C:2]=2[O:40][C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[C:6]([O:8][CH2:9][CH3:10])=[O:7])[C:14]2[CH:23]=[CH:22][NH:21][C:15]=2[C:16]1=[O:20]
Reactant: Oc1ccccc1
Reactant: CCOC(=O)c1ccc(F)c(-c2cn(C)c(=O)c3c2ccn3S(=O)(=O)c2ccc(C)cc2)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CS(C)=O
Product: CCOC(=O)c1ccc(Oc2ccccc2)c(-c2cn(C)c(=O)c3[nH]ccc23)c1
Temperature: 25 °C
Yield: 71.8 %

Procedure:
A mixture of Example 9a (1.43 g, 3.05 mmol), phenol (0.0344 g, 3.66 mmol) and cesium carbonate (0.995, 3.05 mmol), in DMSO (15 mL) was heated at 110° C. for 12 hours. After cooling to room temperature, the reaction mixture was partitioned between water and ethyl acetate. The aqueous layer was extracted with additional ethyl acetate twice. The combined organic layers were washed with brine, dried over MgSO4, filtered, and concentrated. The residue was purified by flash chromatography (silica gel, 30-80% ethyl acetate/hexane) to afford 0.85 g (72%) of the title compound. 1H NMR (500 MHz, DMSO-d6) δ 1.31 (t, J=7.02 Hz, 3H), 3.55 (s, 3H), 4.32 (q, J=7.22 Hz, 2H), 6.23 (t, J=2.29 Hz, 1H), 6.97 (d, J=8.54 Hz, 1H), 7.06 (d, J=8.24 Hz, 2H), 7.17 (t, J=7.32 Hz, 1H), 7.28 (t, J=2.75 Hz, 1H), 7.36-7.51 (m, 3H), 7.94 (dd, J=8.7, 2.29 Hz, 1H), 8.04 (d, J=2.14 Hz, 1H), 12.02 (s, 1H). MS (ESI+) m/z 389.2 (M+H)+.
Reaction SMILES: [C:1]([O:5][C:6](=[O:35])[NH:7][CH:8]([CH:29]1[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]1)[C:9]([N:11]1[CH2:15][CH2:14][CH:13]2[NH:16][CH2:17][CH:18]([C:19]3[C:27]4[C:22](=[CH:23][C:24]([F:28])=[CH:25][CH:26]=4)[NH:21][CH:20]=3)[CH:12]12)=[O:10])([CH3:4])([CH3:3])[CH3:2].[CH3:36][C:37](OC(C)=O)=[O:38]>C(Cl)Cl.CN(C1C=CN=CC=1)C>[C:1]([O:5][C:6](=[O:35])[NH:7][CH:8]([CH:29]1[CH2:30][CH2:31][CH2:32][CH2:33][CH2:34]1)[C:9]([N:11]1[CH2:15][CH2:14][CH:13]2[N:16]([C:37](=[O:38])[CH3:36])[CH2:17][CH:18]([C:19]3[C:27]4[C:22](=[CH:23][C:24]([F:28])=[CH:25][CH:26]=4)[NH:21][CH:20]=3)[CH:12]12)=[O:10])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(=O)OC(C)=O
Reactant: CC(C)(C)OC(=O)NC(C(=O)N1CCC2NCC(c3c[nH]c4cc(F)ccc34)C21)C1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: CC(=O)N1CC(c2c[nH]c3cc(F)ccc23)C2C1CCN2C(=O)C(NC(=O)OC(C)(C)C)C1CCCCC1
Reaction time: 16 h

Procedure:
To a solution containing 49 (200 mg, 0.41 mmol) in DCM (5 mL) was added Ac2O (65 mg, 0.63 mmol) and DMAP (5 mg, cat.) at ambient temperature. After 16 h, the reaction mixture was diluted with DCM, washed successively with 1M HCl and brine, dried over anhydrous Na2SO4, filtered, and concentrated to afford 170 mg (78%) of crude 68 which was used without further purification. Mass spectrum, m/z [527] (M+H)+.
Reaction SMILES: [C:1]([CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[C:10]1[CH:15]=[CH:14][C:13]([C:16]([N:18]2[C:24]3[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=3[CH2:22][N:21]3[C:29]([C:32]([NH:34][CH2:35][C:36]4[CH:37]=[N:38][CH:39]=[CH:40][CH:41]=4)=[O:33])=[CH:30][CH:31]=[C:20]3[CH2:19]2)=[O:17])=[CH:12][CH:11]=1)#[N:2].Cl.[NH2:43][OH:44].C(=O)([O-])[O-].[K+].[K+]>C(O)C.O>[NH2:2][C:1](=[N:43][OH:44])[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[C:10]1[CH:11]=[CH:12][C:13]([C:16]([N:18]2[C:24]3[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=3[CH2:22][N:21]3[C:29]([C:32]([NH:34][CH2:35][C:36]4[CH:37]=[N:38][CH:39]=[CH:40][CH:41]=4)=[O:33])=[CH:30][CH:31]=[C:20]3[CH2:19]2)=[O:17])=[CH:14][CH:15]=1
Reactant: N#CCc1ccccc1-c1ccc(C(=O)N2Cc3ccc(C(=O)NCc4cccnc4)n3Cc3ccccc32)cc1
Reactant: NO
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCO
Product: NC(Cc1ccccc1-c1ccc(C(=O)N2Cc3ccc(C(=O)NCc4cccnc4)n3Cc3ccccc32)cc1)=NO
Yield: 22.3 %

Procedure:
A mixture of 0.806 g (0015 mol) of 10-{[2′-(cyanomethyl)-1,1′-biphenyl-4-yl]carbonyl}-N-(pyridin-3-ylmethyl)-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-carboxamide of Example 17, 0.52 g (0.0075 mol) of hydroxylamine hydrochloride and 1.03 g (0.0075 mol) of potassium carbonate in 100 mL of ethanol and 25 mL of water was heated under reflux for 2 hours. An additional 1.04 g (0.015 mol) of hydroxylamine hydrochloride and 2.06 g (0.015 mol) of potassium carbonate was added to the and refluxing was allowed to continue until LC/MS indicated that all the starting nitrile was consumed. The solvents were removed in vacuo and the residue was washed with water and purified by chromatography to provide the title compound (0.191 g), m.p. 131-134° C.
Reaction SMILES: [CH3:1][C:2]([C:8]1[CH:9]=[C:10]2[C:15](=[C:16]([C:18]3[CH:19]=[C:20]([CH:24]=[CH:25][CH:26]=3)[C:21]([OH:23])=O)[CH:17]=1)[N:14]=[CH:13][CH:12]=[CH:11]2)([S:4]([CH3:7])(=[O:6])=[O:5])[CH3:3].C1N=CN(C(N2C=NC=C2)=O)C=1.[F:39][C:40]1[CH:45]=[CH:44][C:43]([C:46](=[N:48]O)[NH2:47])=[CH:42][CH:41]=1>CN(C=O)C.O>[F:39][C:40]1[CH:45]=[CH:44][C:43]([C:46]2[N:48]=[C:21]([C:20]3[CH:19]=[C:18]([C:16]4[CH:17]=[C:8]([C:2]([CH3:1])([S:4]([CH3:7])(=[O:5])=[O:6])[CH3:3])[CH:9]=[C:10]5[C:15]=4[N:14]=[CH:13][CH:12]=[CH:11]5)[CH:26]=[CH:25][CH:24]=3)[O:23][N:47]=2)=[CH:42][CH:41]=1
Reactant: CC(C)(c1cc(-c2cccc(C(=O)O)c2)c2ncccc2c1)S(C)(=O)=O
Reactant: NC(=NO)c1ccc(F)cc1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(c1cc(-c2cccc(-c3nc(-c4ccc(F)cc4)no3)c2)c2ncccc2c1)S(C)(=O)=O
Temperature: 120 °C
Reaction time: 18 h

Procedure:
To a solution of acid from step 2 in DMF (0.05M) was added CDI (2 eq) and 4-fluoro-N′-hydroxybenzenecarboximidamide (2 eq). The reaction mixture was stirred at rt for 15 min and 18 h at 120° C. The reaction mixture cooled to rt, diluted with water and extracted with EtOAc. The organic extracts were washed with brine, dried over MgSO4, filtered and concentrated. The residue was purified by flash chromatography (hexane:EtOAc, 20:80) to afforded the title compound.
Reaction SMILES: [Br:1][C:2]1[C:3]([CH3:17])=[CH:4][C:5]2[O:10][C:9]([CH3:12])([CH3:11])[C:8](=[O:13])[N:7]([CH2:14][CH3:15])[C:6]=2[CH:16]=1.[CH2:18](I)CC>>[Br:1][C:2]1[C:3]([CH3:17])=[CH:4][C:5]2[O:10][C:9]([CH3:12])([CH3:11])[C:8](=[O:13])[N:7]([CH:14]([CH3:18])[CH3:15])[C:6]=2[CH:16]=1
Reactant: CCN1C(=O)C(C)(C)Oc2cc(C)c(Br)cc21
Reactant: CCCI
Product: Cc1cc2c(cc1Br)N(C(C)C)C(=O)C(C)(C)O2

Procedure:
This was prepared using a procedure similar to that described to make Compound 1C, except using l-propyl iodide in Step C. MS (electrospray): mass calculated for C14H18BrNO2, 311.05; m/z found 312 [M+H]+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:12]2[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=2)([NH2:11])[CH2:9][NH2:10])=[CH:4][CH:3]=1.CO[C:21]([C:23]1[CH:28]=[N:27][CH:26]=[CH:25][N:24]=1)=N>CO>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2([C:12]3[CH:13]=[CH:14][C:15]([F:18])=[CH:16][CH:17]=3)[CH2:9][NH:10][C:21]([C:23]3[CH:28]=[N:27][CH:26]=[CH:25][N:24]=3)=[N:11]2)=[CH:6][CH:7]=1
Reactant: NCC(N)(c1ccc(F)cc1)c1ccc(F)cc1
Reactant: COC(=N)c1cnccn1
Solvent: CO
Product: Fc1ccc(C2(c3ccc(F)cc3)CNC(c3cnccn3)=N2)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 65.8 %

Procedure:
To a solution of 1,1-bis(4-fluorophenyl)-1,2-ethanediamine (500 mg) in methanol (10 mL) was added pyrazineimidic acid methyl ester (385 mg), and the mixture was stirred at room temperature for 18 hrs. After concentrating the reaction mixture, the residue was dissolved in ethyl acetate (50 ml), washed with saturated sodium hydrogen carbonate aqueous solution and saturated sodium chloride aqueous solution in this order, and dried over anhydrous sodium sulfate. Sodium sulfate was removed by filtration, and the organic solvent was evaporated in vacuo. The obtained residue was purified by silica gel column chromatography (C-300; hexane: ethyl acetate=1:1) to give the objective compound (446 mg).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH3:15])=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][CH:3]=1.[CH3:16][C:17]1[CH:22]=[CH:21][C:20]([OH:23])=[C:19]([N+:24]([O-:26])=[O:25])[CH:18]=1.O>ClC1C=CC=CC=1Cl>[CH3:13][O:12][C:9]1[CH:10]=[C:11]2[C:6](=[CH:7][C:8]=1[O:14][CH3:15])[N:5]=[CH:4][CH:3]=[C:2]2[O:23][C:20]1[CH:21]=[CH:22][C:17]([CH3:16])=[CH:18][C:19]=1[N+:24]([O-:26])=[O:25]
Reactant: COc1cc2nccc(Cl)c2cc1OC
Reactant: Cc1ccc(O)c([N+](=O)[O-])c1
Solvent: O
Solvent: Clc1ccccc1Cl
Product: COc1cc2nccc(Oc3ccc(C)cc3[N+](=O)[O-])c2cc1OC
Temperature: 180 °C
Reaction time: 23 h
Yield: 27.4 %

Procedure:
4-Chloro-6,7-dimethoxyquinoline (1.15 g) and 4-methyl-2-nitrophenol (1.52 g) were suspended in o-dichlorobenzene (7 ml), and the suspension was stirred at 180° C. for 23 hr. The reaction solution was cooled to room temperature. Water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was then washed with water and saturated brine and was dried over anhydrous sodium sulfate. The solvent was removed therefrom by distillation under the reduced pressure, and the residue was purified by column chromatography using acetone-chloroform to give the title compound (480 mg, yield 27%).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11](=[O:16])[C:12]([F:15])([F:14])[F:13])=[CH:7][NH:8]2)=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].I[CH2:24][CH2:25][CH2:26][CH3:27]>CN(C)C=O>[CH2:24]([N:8]1[C:9]2[C:5](=[CH:4][CH:3]=[C:2]([Cl:1])[CH:10]=2)[C:6]([C:11](=[O:16])[C:12]([F:13])([F:14])[F:15])=[CH:7]1)[CH2:25][CH2:26][CH3:27]
Reactant: CCCCI
Reactant: O=C(c1c[nH]c2cc(Cl)ccc12)C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCCCn1cc(C(=O)C(F)(F)F)c2ccc(Cl)cc21
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 115.3 %

Procedure:
A mixture of 1-(6-chloro-1H-indol-3-yl)-2,2,2-trifluoro-ethanone (200 mg, 0.81 mmol) and potassium carbonate (214 mg, 2.02 mmol) in N,N-dimethylformamide (2.0 mL) was stirred at 25° C. for 30 min. The reaction was then treated with 1-iodobutane (0.14 mL, 1.21 mmol) and heated at 60° C. for 5 h. At this time, the reaction was cooled to 25° C. and concentrated in vacuo. The residue was diluted with ethyl acetate (50 mL) and was washed with a saturated aqueous sodium bicarbonate solution (1×50 mL), water (2×50 mL) and a saturated aqueous sodium chloride solution (1×50 mL). The organic layer was dried over magnesium sulfate, filtered, and concentrated in vacuo to afford 1-(1-butyl-6-chloro-1H-indol-3-yl)-2,2,2-trifluoro-ethanone (283.7 mg) as an orange oil which was used without further purification or characterization.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([N:8]2[CH:13]=[C:12]([CH:14]3[C:20]4[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=4[CH:18]=[CH:17][C:16]4[CH:25]=[CH:26][CH:27]=[CH:28][C:15]3=4)[C:11](=[O:29])[NH:10][C:9]2=[O:30])[CH:5]=[CH:4][N:3]=1.Cl.[CH3:32][O:33][C:34](=[O:40])[C@@H:35]1[CH2:39][CH2:38][CH2:37][NH:36]1>>[CH:24]1[C:19]2[CH:18]=[CH:17][C:16]3[CH:25]=[CH:26][CH:27]=[CH:28][C:15]=3[CH:14]([C:12]3[C:11](=[O:29])[NH:10][C:9](=[O:30])[N:8]([C:6]4[CH:5]=[CH:4][N:3]=[C:2]([N:36]5[CH2:37][CH2:38][CH2:39][C@H:35]5[C:34]([O:33][CH3:32])=[O:40])[N:7]=4)[CH:13]=3)[C:20]=2[CH:21]=[CH:22][CH:23]=1
Reactant: COC(=O)[C@@H]1CCCN1
Reactant: O=c1[nH]c(=O)n(-c2ccnc(Cl)n2)cc1C1c2ccccc2C=Cc2ccccc21
Agent: Cl
Product: COC(=O)[C@@H]1CCCN1c1nccc(-n2cc(C3c4ccccc4C=Cc4ccccc43)c(=O)[nH]c2=O)n1

Procedure:
The subtitle compound was prepared from the product of example 6 step (i) (0.3 g) and L-proline methyl ester hydrochloride (0.6 g) by the method of example 10 step (ii). Purification was by chromatography eluting with 5% methanol in dichloromethane. Yield 0.55 g.
Reaction SMILES: Cl.[S:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[N:4]=[C:3]1[CH:11]([OH:17])[C@@H:12]1[CH2:16][CH2:15][CH2:14][NH:13]1.C1C=CC2N(O)N=NC=2C=1.[NH:28]([C:41]([O:43][C:44]([CH3:47])([CH3:46])[CH3:45])=[O:42])[C@H:29]([C:31]([NH:33][C@H:34]([C:38](O)=[O:39])C(C)C)=[O:32])[CH3:30]>>[S:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[N:4]=[C:3]1[CH:11]([OH:17])[C@@H:12]1[CH2:16][CH2:15][CH2:14][N:13]1[C:38](=[O:39])[CH2:34][NH:33][C:31](=[O:32])[C@H:29]([CH3:30])[NH:28][C:41]([O:43][C:44]([CH3:45])([CH3:47])[CH3:46])=[O:42]
Reactant: OC(c1nc2ccccc2s1)[C@@H]1CCCN1
Reactant: CC(C)[C@H](NC(=O)[C@H](C)NC(=O)OC(C)(C)C)C(=O)O
Agent: Cl
Agent: On1nnc2ccccc21
Product: C[C@H](NC(=O)OC(C)(C)C)C(=O)NCC(=O)N1CCC[C@H]1C(O)c1nc2ccccc2s1

Procedure:
36 (0.43 g, 1.23 mmol), HOBt (0.183 g, 1.35 mmol), WSCD (0.259 g, 1.35 mmol), Boc-Ala-Val-OH (0.303 g, 1.23 mmol), TEA (0.172 ml, 1.54 mmol)
Reaction SMILES: S(C1C=CC(C)=CC=1)([O-])(=O)=O.[CH3:12][O:13][C:14]1[C:19]2[O:20][C:21]([CH2:23][CH2:24]O)=[CH:22][C:18]=2[CH:17]=[CH:16][CH:15]=1.[NH3:26]>O1CCCC1>[CH3:12][O:13][C:14]1[C:19]2[O:20][C:21]([CH2:23][CH2:24][NH2:26])=[CH:22][C:18]=2[CH:17]=[CH:16][CH:15]=1
Reactant: COc1cccc2cc(CCO)oc12
Reactant: N
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Solvent: C1CCOC1
Product: COc1cccc2cc(CCN)oc12
Yield: 76 %

Procedure:
A mixture of 26.7 g of the tosylate of 7-methoxy-3-benzofuranethanol (Example 2a), prepared as described in Example 1b, 300 ml of tetrahydrofuran and 100 g of ammonia was heated in a pressure vessel to 100° for 4 hours. The crude product was partitioned into basic and neutral fractions, and the basic fraction short-path distilled (to 170° bath temperature, 1 micron pressure) to give 11.2 g (76%) of 7-methoxy-3-benzofuranethylamine; nmr spectrum (in CDCl3): τ2.6 (s, 1); 2.9-3.4 (m, 3); 6.1 (s, 3); 6.9-7.5 (m, 4) and 8.9 (s, 2).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([NH:9][C:10]([C:12]2[C:17]([NH:18][C:19]3[CH:20]=[N:21][CH:22]=[CH:23][CH:24]=3)=[CH:16][CH:15]=[C:14]([CH3:25])[N:13]=2)=[O:11])=[N:6][C:7]=1[CH3:8].Br[C:27]1C=C(C=C[CH:34]=1)C#N>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([NH:9][C:10]([C:12]2[C:17]([NH:18][C:19]3[CH:20]=[CH:34][CH:27]=[C:23]([C:22]#[N:21])[CH:24]=3)=[CH:16][CH:15]=[C:14]([CH3:25])[N:13]=2)=[O:11])=[N:6][C:7]=1[CH3:8]
Reactant: N#Cc1cccc(Br)c1
Reactant: Cc1ccc(Nc2cccnc2)c(C(=O)Nc2ccc(F)c(C)n2)n1
Product: Cc1ccc(Nc2cccc(C#N)c2)c(C(=O)Nc2ccc(F)c(C)n2)n1

Procedure:
The title compound, was prepared from 3-Amino-6-methyl-pyridine-2-carboxylic acid (5-fluoro-6-methyl-pyridin-2-yl)-amide (example 11) in accordance with the general method of example 20 using 3-Bromobenzonitrile instead of 3-Bromo-4-methylpyridine to yield the final compound as a yellow solid, MS (ISP): m/e=362.3 (M+H+).
Reaction SMILES: CC[O:3][C:4]([C:6]1[N:21]=[C:9]2[CH2:10][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:12][CH2:13][N:8]2[N:7]=1)=O.[BH4-].[Li+].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>C1COCC1>[C:17]([O:16][C:14]([N:11]1[CH2:12][CH2:13][N:8]2[N:7]=[C:6]([CH2:4][OH:3])[N:21]=[C:9]2[CH2:10]1)=[O:15])([CH3:20])([CH3:18])[CH3:19]
Reactant: CCOC(=O)c1nc2n(n1)CCN(C(=O)OC(C)(C)C)C2
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [BH4-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCn2nc(CO)nc2C1
Yield: 43.3 %

Procedure:
To 5,6-dihydro-8H-[1,2,4]triazolo[1,5-a]pyrazine-2,7-dicarboxylic acid 7-tert-butyl ester 2-ethyl ester (0.90 g, 3.0 mmol), in THF (20 ml) was added lithium borohydride (73 mg, 3.4 mmol), and the resultant mixture was stirred at room temperature overnight. Citric acid solution (10%, 25 ml) was added, then the mixture was washed with dichloromethane (2×50 ml). The combined organic layers were dried over magnesium sulfate and concentrated in vacuo. The residue was purified by flash chromatography on silica gel, eluting with ethyl acetate and then 5% methanol in ethyl acetate, yielding 2-hydroxymethyl-5,6-dihydro-8H-[1,2,4]triazolo[1,5-a]pyrazine-7-carboxylic acid tert-butyl ester as a colourless oil (330 mg). Data for the title compound: 1H NMR (400 MHz, CDCl3) δ 1.50 (9H, s), 2.41 (1H, br s), 3.93 (2H, t, J=5.3 Hz), 4.18 (2H, t, J=5.4 Hz), 4.74 (4H, s); MS (ES+) m/e 255 [MH]+.
Reaction SMILES: [OH:1][CH2:2][CH2:3][N:4]1[CH2:9][CH2:8][N:7]([CH2:10][C:11]([NH:13][C:14]2[C:15](Br)=[N:16][C:17]([CH3:21])=[CH:18][C:19]=2Br)=[O:12])[CH2:6][CH2:5]1.[NH:23]1[CH2:27][CH2:26][CH2:25][CH2:24]1>>[OH:1][CH2:2][CH2:3][N:4]1[CH2:9][CH2:8][N:7]([CH2:10][C:11]([NH:13][C:14]2[C:15]([N:23]3[CH2:27][CH2:26][CH2:25][CH2:24]3)=[N:16][C:17]([CH3:21])=[CH:18][C:19]=2[N:23]2[CH2:27][CH2:26][CH2:25][CH2:24]2)=[O:12])[CH2:6][CH2:5]1
Reactant: C1CCNC1
Reactant: Cc1cc(Br)c(NC(=O)CN2CCN(CCO)CC2)c(Br)n1
Product: Cc1cc(N2CCCC2)c(NC(=O)CN2CCN(CCO)CC2)c(N2CCCC2)n1

Procedure:
2-[4-(2-Hydroxyethyl)piperazin-1-yl]-N-[2,4-dibromo-6-methyl-3-pyridyl]acetamide (1.00 g, 2.29 mmol) was dissolved in pyrrolidine (10 mL), and the solution was subjected to reflux for 4 days. The reaction mixture was concentrated under reduced pressure, and the residue was subjected to separation through silica gel column chromatography (developer: hexane:acetone=2:1), to thereby yield a crude product of 2-[4-(2-hydroxyethyl)piperazin-1-yl]-N-[2,4-bis(pyrrolidin-1-yl)-6-methyl-3-pyridyl]acetamide (1.22 g) as a brown foamed substance. The crude product was dissolved in pyridine (20 mL), and acetic anhydride (10 mL) was added thereto under cooling with ice, followed by stirrng for 14 hours at room temperature. The reaction mixture was concentrated under reduced pressure. Toluene (70 mL) was added to the residue and then evaporated three times, followed by purification through silica gel column chromatography (developer: chloroform:methanol=20:1→chloroform: ammonia-saturated methanol=50:1→chloroform:ammonia-saturated methanol=20:1), to thereby yield a brown oil (1.05 g). The oil was dissolved in ammonia-saturated methanol (30 mL), and the solution was stirred for 14 hours at room temperature. The reaction mixture was concentrated under reduced pressure, and the residue was purified through silica gel column chromatography (developer: chloroform:ammonia-saturated methanol=100:1→chloroform:ammonia-saturated methanol=20:1), to thereby yield 2-[4-(2-hydroxyethyl)piperazin-1-yl]-N-[2,4-bis(pyrrolidin-1-yl)-6-methyl-3-pyridyl]acetamide (911 mg, yield 95%) as a pale brown foamed substance.
Reaction SMILES: Cl.[OH:2]/[N:3]=[C:4](/[C:10]1[N:11]=[C:12]([NH:15][C:16]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[S:13][CH:14]=1)\[C:5]([O:7][CH2:8][CH3:9])=[O:6].Br[CH2:36][CH:37]([CH3:39])[CH3:38]>C(Cl)(Cl)Cl>[CH3:36][CH:37]([CH3:39])[CH2:38][O:2]/[N:3]=[C:4](/[C:10]1[N:11]=[C:12]([NH:15][C:16]([C:29]2[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=2)([C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[S:13][CH:14]=1)\[C:5]([O:7][CH2:8][CH3:9])=[O:6]
Reactant: CC(C)CBr
Reactant: CCOC(=O)/C(=N\O)c1csc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Agent: Cl
Solvent: ClC(Cl)Cl
Product: CCOC(=O)/C(=N\OCC(C)C)c1csc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1

Procedure:
Ethyl (Z)-2-(hydroxyimino)-2-(2-tritylaminothiazol-4-yl)acetate hydrochloride (1 g) was alkylated with 1-bromo-2-methylpropane (0.48 ml) as described in Example 5a to give the title compound (0.8 g), νmax (CHCl3) 3400, 2960, 1725, 1520 and 1025 cm-1 m; δH (CDCl3) 1.09 (6H, d, J 7 Hz), 1.30 (3H, t), 1.90 (1H, m), 3.95 (2H, d, J 7 Hz), 4.30 (2H, q), 6.42 (1H, s), 6.93 (1H, br.s), 7.22 (15H, m). [Mass spectrum: +ve ion (3NOBA) MH+ (514)].