Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [I:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[NH:8][N:9]=[C:10]([C:11]([F:14])([F:13])[F:12])[C:3]=12.C(=O)([O-])[O-].[Cs+].[Cs+].Cl[C:22]1[CH:29]=[CH:28][C:25]([C:26]#[N:27])=[CH:24][C:23]=1[N+:30]([O-:32])=[O:31].[Cl-].[NH4+]>C(#N)C>[I:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[N:8]([C:22]3[CH:29]=[CH:28][C:25]([C:26]#[N:27])=[CH:24][C:23]=3[N+:30]([O-:32])=[O:31])[N:9]=[C:10]([C:11]([F:14])([F:12])[F:13])[C:3]=12
Reactant: N#Cc1ccc(Cl)c([N+](=O)[O-])c1
Reactant: FC(F)(F)c1n[nH]c2nccc(I)c12
Agent: O=C([O-])[O-]
Agent: [Cl-]
Agent: [Cs+]
Solvent: CC#N
Product: N#Cc1ccc(-n2nc(C(F)(F)F)c3c(I)ccnc32)c([N+](=O)[O-])c1
Temperature: 70 °C
Reaction time: 4 h
Yield: 98 %

Procedure:
Compound (153a) (5.00 g), cesium carbonate (6.72 g), and 4-chloro-3-nitrobenzonitrile (3.21 g) were suspended in acetonitrile (50 mL), followed by stirring at 70° C. for 4 hr. A saturated aqueous ammonium chloride solution was added to the reaction solution, and the precipitate was collected by filtration and dried under reduced pressure to obtain 4-{4-iodo-3-(trifluoromethyl)-1H-pyrazolo[3,4-b]pyridin-1-yl}-3-nitrobenzonitrile (7.19 g, 98%). The obtained 4-{4-iodo-3-(trifluoromethyl)-1H-pyrazolo[3,4-b]pyridin-1-yl}-3-nitrobenzonitrile (7.19 g) was suspended in THF (50 mL), MeOH (50 mL), and water (50 mL), and ammonium chloride (7.20 g) and iron powder (8.76 g) were added to the resulting suspension, followed by stirring at 80° C. for 2 hr. The reaction solution was diluted with ethyl acetate, and insoluble matters were filtered by celite. The solvent of the filtrate was distilled away, and water was added to the residue. Insoluble matters were collected by filtration and dried under reduced pressure to obtain compound (158a) (6.44 g, 96%).
Reaction SMILES: F[C:2]1[CH:9]=[C:8]([C:10]([F:13])([F:12])[F:11])[CH:7]=[CH:6][C:3]=1[CH:4]=[O:5].[CH3:14][O-:15].[Na+]>>[CH3:14][O:15][C:2]1[CH:9]=[C:8]([C:10]([F:13])([F:12])[F:11])[CH:7]=[CH:6][C:3]=1[CH:4]=[O:5]
Reactant: O=Cc1ccc(C(F)(F)F)cc1F
Reactant: C[O-]
Agent: [Na+]
Product: COc1cc(C(F)(F)F)ccc1C=O
Temperature: 50 °C
Reaction time: 6 h
Yield: 84.6 %

Procedure:
2-Fluoro-4-(trifluoromethyl)benzaldehyde (5.0 g, 26 mmol) was diluted with sodium methoxide (57 ml of 0.5 M in methanol; 29 mmol), heated to 50° C. and stirred for 6 hours. The reaction was then partially concentrated, diluted with ethyl acetate and water. The layers were separated and the organic layer was dried over MgSO4, filtered and concentrated to yield 2-methoxy-4-(trifluoromethyl)benzaldehyde (4.5 g, 22 mmol, 85% yield).
Reaction SMILES: [C:1]([O:5][C:6](=[O:27])[N:7]([C:19]1[CH:24]=[CH:23][C:22]([C:25]#[N:26])=[CH:21][CH:20]=1)[CH2:8][C:9]1[CH:10]=[N:11][C:12]([CH3:18])=[C:13]([OH:17])[C:14]=1[CH2:15][OH:16])([CH3:4])([CH3:3])[CH3:2].Br[CH2:29][C:30]1[CH:35]=[CH:34][C:33]([C:36]#[N:37])=[CH:32][CH:31]=1>>[C:1]([O:5][C:6](=[O:27])[N:7]([CH2:8][C:9]1[CH:10]=[N:11][C:12]([CH3:18])=[C:13]([O:17][CH2:29][C:30]2[CH:35]=[CH:34][C:33]([C:36]#[N:37])=[CH:32][CH:31]=2)[C:14]=1[CH2:15][OH:16])[C:19]1[CH:20]=[CH:21][C:22]([C:25]#[N:26])=[CH:23][CH:24]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: N#Cc1ccc(CBr)cc1
Reactant: Cc1ncc(CN(C(=O)OC(C)(C)C)c2ccc(C#N)cc2)c(CO)c1O
Product: Cc1ncc(CN(C(=O)OC(C)(C)C)c2ccc(C#N)cc2)c(CO)c1OCc1ccc(C#N)cc1
Yield: 70.3 %

Procedure:
The coupling of (4-cyano-phenyl)-(5-hydroxy-4-hydroxymethyl-6-methyl-pyridin-3-ylmethyl)-carbamic acid tert-butyl ester (105) (137.0 g, 0.37 mole) and α-bromo-p-tolunitrile (72.7 g, 370 mmol), as described in Example 1, gave [5-(4-cyano-benzyloxy)-4-hydroxymethyl-6-methyl-pyridin-3-ylmethyl]-(4-cyano-phenyl)-carbamic acid tert-butyl ester (124) (126.0 g, 70% yield) as a colorless solid.
Reaction SMILES: [CH3:1][C:2]1([CH3:29])[C@@H:4]([C:5]#[C:6][C:7](O)=[O:8])[C@H:3]1[C:10]([O:12][CH:13]([C:27]#[N:28])[C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([O:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH:15]=1)=[O:11].[H-].[Na+].Cl[CH2:33][O:34][CH2:35]Cl.COCOC.C(Cl)(=O)C.P(O)(O)([O-])=O.[Na+]>CN(C)C=O.CO>[CH3:29][C:2]1([CH3:1])[C@@H:4]([C:5]#[C:6][C:7](=[O:8])[CH2:33][O:34][CH3:35])[C@H:3]1[C:10]([O:12][CH:13]([C:27]#[N:28])[C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([O:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH:15]=1)=[O:11]
Reactant: ClCOCCl
Reactant: CC1(C)[C@H](C(=O)OC(C#N)c2cccc(Oc3ccccc3)c2)[C@@H]1C#CC(=O)O
Agent: O=P([O-])(O)O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: COCOC
Solvent: CO
Product: COCC(=O)C#C[C@H]1[C@@H](C(=O)OC(C#N)c2cccc(Oc3ccccc3)c2)C1(C)C
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
A solution of 3 g of (RS)α-cyano-3-phenoxy-benzyl (1R,cis) 2,2-dimethyl-3-(3-hydroxy-3-oxo-1-propynyl)-cyclopropane-carboxylate in 30 ml of anhydrous dimethylformamide was cooled to +10° C. and 300 mg of 61% sodium hydride in oil were added in portions thereto. Then, over 15 minutes, 2.5 ml of chloromethyl ether solution prepared by mixing 4.5 ml of methylal and 0.52 ml of methanol and slowly adding 3.53 ml of acetyl chloride after which the mixture was stirred for 36 hours at room temperature. The mixture was stirred for 2 hours and was then poured into an aqueous solution of monosodium phosphate. The mixture was extracted with ethyl acetate and the organic phase was washed with water, dried and evaporated to dryness. The residue was chromatographed over silica gel and eluted with a 75-25 mixture of cyclohexane-ethyl acetate to obtain 2 g of (RS) α-cyano-3-phenoxy-benzyl (1R,cis) 2,2-dimethyl-3-(3-oxo-3-methoxymethyl-1-propynyl)-cyclopropane-carboxylate.
Reaction SMILES: [N:1]([CH2:4][C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][CH:14]=1)[N:11]=[C:10]([CH3:15])[CH:9]=[CH:8]2)=[N+:2]=[N-:3].[CH3:16][C:17]1[C:22]([CH2:23][NH:24][C:25](=[O:28])[C:26]#[CH:27])=[C:21]([CH3:29])[N:20]=[C:19]([NH:30][C:31](=[O:37])[O:32][C:33]([CH3:36])([CH3:35])[CH3:34])[CH:18]=1.O.O=C1O[C@H]([C@H](CO)O)C([O-])=C1O.[Na+]>CC(O)(C)C.O.O.O.O.O.S([O-])([O-])(=O)=O.[Cu+2]>[CH3:16][C:17]1[C:22]([CH2:23][NH:24][C:25]([C:26]2[N:3]=[N:2][N:1]([CH2:4][C:5]3[CH:6]=[C:7]4[C:12](=[CH:13][CH:14]=3)[N:11]=[C:10]([CH3:15])[CH:9]=[CH:8]4)[CH:27]=2)=[O:28])=[C:21]([CH3:29])[N:20]=[C:19]([NH:30][C:31](=[O:37])[O:32][C:33]([CH3:35])([CH3:34])[CH3:36])[CH:18]=1
Reactant: C#CC(=O)NCc1c(C)cc(NC(=O)OC(C)(C)C)nc1C
Reactant: Cc1ccc2cc(CN=[N+]=[N-])ccc2n1
Agent: [Cu+2]
Agent: O=C1O[C@H]([C@@H](O)CO)C([O-])=C1O
Agent: O=S(=O)([O-])[O-]
Solvent: CC(C)(C)O
Solvent: O
Product: Cc1ccc2cc(Cn3cc(C(=O)NCc4c(C)cc(NC(=O)OC(C)(C)C)nc4C)nn3)ccc2n1
Temperature: 23 °C
Reaction time: 1.5 h

Procedure:
To a solution of 6-(azidomethyl)-2-methylquinoline (58.9 mg, 0.297 mmol) and tert-butyl (4,6-dimethyl-5-(propiolamidomethyl)pyridin-2-yl)carbamate (90 mg, 0.297 mmol) in t-BuOH (2 ml)/water (2 ml) were added copper(II) sulfate pentahydrate (14.84 mg, 0.059 mmol) and sodium ascorbate (58.9 mg, 0.297 mmol). Reaction mixture was stirred for 1.5 h at 23° C. Reaction mixture was poured into water and extracted twice with ethyl acetate. Combined organic layers were washed with brine, dried over sodium sulfate and evaporated to afford the crude material, which was purified by silicagel chromatography (DCM/methanol from 10/0 to 9/1) to afford the title compound. HPLC (Method G) Rt=1.308 min; MS (Method F) [M+H]+=502.5
Reaction SMILES: [CH3:1][N:2]([CH3:12])[C:3]1[CH:11]=[CH:10][CH:9]=[CH:8][C:4]=1[C:5]([OH:7])=[O:6].CN(C1C=CC=CN=1)C.[CH2:22]([N:29]1[CH2:34][CH2:33][CH:32](O)[CH2:31][CH2:30]1)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.Cl.C(N=C=NCCCN(C)C)C>CN(C)C=O>[CH3:1][N:2]([CH3:12])[C:3]1[CH:11]=[CH:10][CH:9]=[CH:8][C:4]=1[C:5]([O:7][CH:32]1[CH2:31][CH2:30][N:29]([CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH2:34][CH2:33]1)=[O:6]
Reactant: CN(C)c1ccccc1C(=O)O
Reactant: OC1CCN(Cc2ccccc2)CC1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccccn1
Agent: Cl
Solvent: CN(C)C=O
Product: CN(C)c1ccccc1C(=O)OC1CCN(Cc2ccccc2)CC1
Reaction time: 2 h
Yield: 45.8 %

Procedure:
0.33 g (0.002 mol) of 2-dimethylaminobenzoic acid was dissolved in 10 ml of dimethylformamide, treated with 0.122 g (0.001 mol) of dimethylaminopyridine and 0.383 g (0.002 mol) of 1-benzyl-4-hydroxypiperidine and cooled to 0°. 0.422 g (0.0022 mol) of N-ethyl-N'-(3-dimethylaminopropyl)-carbodiimide hydrochloride was added and the mixture was stirred at 0° for a further 2 hrs. Subsequently, the mixture was stirred at room temperature for 3 days, the solvent was distilled off and the residue was chromatographed on silica gel with ethyl acetate/hexane (1:2). 0.31 g (46%) of 1-benzyl-piperidin-4-yl 2-dimethylamino-benzoate was obtained as a colorless oil.
Reaction SMILES: [CH2:1]([N:8]([CH2:21][C:22]1[CH:42]=[CH:41][C:25]([O:26][C:27]2[CH:40]=[CH:39][C:30]([O:31][CH2:32][CH2:33][CH2:34][CH2:35][C:36](O)=[O:37])=[CH:29][CH:28]=2)=[CH:24][CH:23]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([NH:15][S:16]([CH3:19])(=[O:18])=[O:17])[C:10]=1[CH3:20])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.C[O:45][C:46](=[O:52])[C@@H:47]1[CH2:51][CH2:50][CH2:49][NH:48]1>>[CH2:1]([N:8]([CH2:21][C:22]1[CH:23]=[CH:24][C:25]([O:26][C:27]2[CH:28]=[CH:29][C:30]([O:31][CH2:32][CH2:33][CH2:34][CH2:35][C:36]([N:48]3[CH2:49][CH2:50][CH2:51][C@H:47]3[C:46]([OH:45])=[O:52])=[O:37])=[CH:39][CH:40]=2)=[CH:41][CH:42]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([NH:15][S:16]([CH3:19])(=[O:17])=[O:18])[C:10]=1[CH3:20])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)[C@@H]1CCCN1
Reactant: Cc1c(NS(C)(=O)=O)cccc1N(Cc1ccccc1)Cc1ccc(Oc2ccc(OCCCCC(=O)O)cc2)cc1
Agent: Cl
Product: Cc1c(NS(C)(=O)=O)cccc1N(Cc1ccccc1)Cc1ccc(Oc2ccc(OCCCCC(=O)N3CCC[C@H]3C(=O)O)cc2)cc1

Procedure:
The product from Example 234B and L-proline methyl ester hydrochloride were processed as described in Example 251A and B to provide the titled compound. 1H NMR (500 MHz, DMSO-d6) δ11.95-13.15 (br.s, 1 H), 8.94 (s, 1 H), 7.23 (m, 7 H), 7.03 (t, 1 H), 6.95 (m, 6 H), 6.82 (d, 2 H), 4.21 (dd, 1 H), 4.04 (s, 2 H), 4.00 (s, 2 H), 3.93 (m, 2 H), 3.52 (m, 2 H), 2.91 (s, 3 H), 2.39 (s, 3 H), 2.34 (t, 2 H), 1.99-2.27 (m, 2 H), 1.87 (m, 2 H), 1.68 (m, 4 H; MS (ESI+) m/z 686 (M+H)+.
Reaction SMILES: C(N(CC)CC)C.Cl.[CH3:9][C:10]1[CH:20]=[CH:19][CH:18]=[C:17]([CH3:21])[C:11]=1[O:12][CH:13]1[CH2:16][NH:15][CH2:14]1.[C:22](Cl)(=[O:24])[CH3:23]>O1CCCC1>[C:22]([N:15]1[CH2:14][CH:13]([O:12][C:11]2[C:17]([CH3:21])=[CH:18][CH:19]=[CH:20][C:10]=2[CH3:9])[CH2:16]1)(=[O:24])[CH3:23]
Reactant: Cc1cccc(C)c1OC1CNC1
Reactant: CC(=O)Cl
Agent: Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(=O)N1CC(Oc2c(C)cccc2C)C1
Temperature: 0 °C
Reaction time: 8 h
Yield: 96.1 %

Procedure:
Triethylamine (10.8 g, 106 mmol) was added to a stirred slurry of 3-(2,6-dimethylphenoxy)azetidine monohydrochloride (9.10 g, 42.7 mmol) in tetrahydrofuran (500 mL). After 10 minutes the reaction mixture was cooled to 0° C., and a solution of acetyl chloride (5.03 g, 64.1 mmol) in 50 mL of tetrahydrofuran was added dropwise. The reaction mixture was allowed to come to ambient temperature and was stirred overnight. The reaction mixture was then filtered and the filtrate concentrated in vacuo. The residue was chromatographed (flash, SiO2) eluting with methylene chloride/methanol (9:1) to give 9.00 g (99%) of yellow powder with a melting point of 40.0°-42.5° C.
Reaction SMILES: [CH3:1][C:2]([OH:8])([CH3:7])[CH2:3][CH2:4][CH2:5][OH:6].C(N(CC)CC)C.C1(C)C=CC=CC=1.[CH:23]12[CH2:29][CH:26]([CH:27]=[CH:28]1)[CH2:25][CH:24]2[C:30](Cl)=[O:31]>O>[CH:23]12[CH2:29][CH:26]([CH:27]=[CH:28]1)[CH2:25][CH:24]2[C:30]([O:6][CH2:5][CH2:4][CH2:3][C:2]([OH:8])([CH3:7])[CH3:1])=[O:31]
Reactant: O=C(Cl)C1CC2C=CC1C2
Reactant: CC(C)(O)CCCO
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Solvent: O
Product: CC(C)(O)CCCOC(=O)C1CC2C=CC1C2
Reaction time: 5 h
Yield: 90 %

Procedure:
To a mixture of 118 g of 4-methyl-1,4-pentanediol, 111 g of triethylamine and 400 ml of toluene at 20° C., 157 g of 5-norbornene-2-carbonyl chloride was added over one hour. After 5 hours of stirring, 200 ml of water was added to the reaction solution to stop the reaction whereupon the mixture separated. The organic layer was washed with water and saturated sodium chloride water, dried over anhydrous sodium sulfate, and concentrated in vacuum. It was purified by vacuum distillation, collecting 214 g of 0.4-hydroxy-4-methylpentyl 5-norbornene-2-carboxylate (boiling point: 111–113° C./27 Pa, yield: 90%).
Reaction SMILES: [Cl-].[NH4+].[N+:3]([C:6]1[CH:7]=[C:8]2[CH:14]=[N:13][N:12]([CH:15]3[CH2:20][CH2:19][O:18][CH2:17][CH2:16]3)[C:9]2=[N:10][CH:11]=1)([O-])=O>C(O)C.C1COCC1.O.[Fe]>[O:18]1[CH2:17][CH2:16][CH:15]([N:12]2[C:9]3=[N:10][CH:11]=[C:6]([NH2:3])[CH:7]=[C:8]3[CH:14]=[N:13]2)[CH2:20][CH2:19]1
Reactant: O=[N+]([O-])c1cnc2c(cnn2C2CCOCC2)c1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCO
Solvent: O
Solvent: C1CCOC1
Product: Nc1cnc2c(cnn2C2CCOCC2)c1
Temperature: 100 °C
Yield: 108.8 %

Procedure:
Iron (2.41 g, 42.3 mmol) and ammonium chloride (2.58 g, 48.4 mmol) are added to a solution of 5-nitro-1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazolo[3,4-b]pyridine (3 g, 12 mmol) in ethanol/THF/H2O (4:2:1, 35 mL). The mixture is heated at 100° C. for 2 h. The iron is removed by filtration through pad of Celite® and the filtrate was evaporated under reduced pressure. The residue is purified by flash column chromatography using a gradient of 70% ethyl acetate/petroleum ether to afford the title compound as an off-white solid (2.85 g, 93%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[C:4]([Cl:12])[C:3]=1[NH:13][NH:14][CH2:15][CH2:16][C:17]#[N:18]>ClC1C=CC=CC=1>[Cl:1][C:2]1[CH:7]=[C:6]([C:8]([F:10])([F:9])[F:11])[CH:5]=[C:4]([Cl:12])[C:3]=1[NH:13][N:14]=[CH:15][CH2:16][C:17]#[N:18]
Reactant: N#CCCNNc1c(Cl)cc(C(F)(F)F)cc1Cl
Solvent: Clc1ccccc1
Product: N#CCC=NNc1c(Cl)cc(C(F)(F)F)cc1Cl
Temperature: 65 °C

Procedure:
Cupric chloride (0.673 g, 2.5 equivalents) was added in one portion to a solution of 3-(2,6-dichloro-4-trifluoromethylphenylhydrazino)propionitrile (0591 g, 2 mmol) in chlorobenzene, and the mixture heated at 65° C. for 50 minutes. The reaction was judged to be complete and was cooled, washed (water), dried (magnesium sulphate), evaporated and separated by chromatography on silica gel to give 3-(2,6-dichloro-4-trifluoromethylphenylhydrazono)propionitrile,
Reaction SMILES: [OH:1][CH:2]1[CH2:6][NH:5][C@H:4]([C:7]([OH:9])=[O:8])[CH2:3]1.[NH:10]1[C:14]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[C:21]2[CH:39]=[CH:38][C:24]3[N:25]([CH:28]([CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH3:37])[C:29](O)=[O:30])[CH:26]=[N:27][C:23]=3[CH:22]=2)=[N:13][N:12]=[N:11]1.C(N(CC)C(C)C)(C)C.OC1C2N=NNC=2C=CC=1.C1(N=C=NC2CCCCC2)CCCCC1>CN(C=O)C>[O:30]=[C:29]([N:5]1[CH2:6][CH:2]([OH:1])[CH2:3][C@H:4]1[C:7]([OH:9])=[O:8])[CH:28]([N:25]1[C:24]2[CH:38]=[CH:39][C:21]([C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=3[C:14]3[N:10]=[N:11][NH:12][N:13]=3)=[CH:22][C:23]=2[N:27]=[CH:26]1)[CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH3:37]
Reactant: CCCCCCC(C(=O)O)n1cnc2cc(-c3ccccc3-c3nnn[nH]3)ccc21
Reactant: O=C(O)[C@@H]1CC(O)CN1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Oc1cccc2[nH]nnc12
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCCCCCC(C(=O)N1CC(O)C[C@H]1C(=O)O)n1cnc2cc(-c3ccccc3-c3nn[nH]n3)ccc21
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 52.2 %

Procedure:
4-Hydroxy-L-proline lacetone hydrobromide (0.74 mmoles, 143 mg) and 2-[5-(2-tetrazol-5-ylphenyl)benzimidazol-1-yl]octanoic acid (0.74 mmoles, 300 mg) were dissolved in 30 ml DMF and cooled to 0° C. N,N-Diisopropylethylamine (0.74 moles, 0.15 ml) was added. The solution was stirred for 10 minutes. Hydroxybenzotriazole (0.74 mmoles, 100 mg) and then dicyciohexylcarbodiimide (0.74 mmoles, 153 mg) were added. The solution was stirred at room temperature for 3 days. The intermediate was extracted in ethyl acetate. The ethyl acetate solution was washed with water, dried over sodium sulfate, concentrated. The residue was chromatographed over silica gel eluted with 10% methanol in ethyl acetate. The reaction yielded 200 mg of 1-[1-oxo-2-[5-[2-(2H-tetrazol-5-yl)phenyl]-1H-benzimidazol-1-yl]octyl]-4-hydroxy-L-proline lacetone. (MS). The lactone was dissolved in 2.0 ml methanol/2.0 ml 2N NaOH and stirred at room temperature for 16 hours The solvent was removed in vacuo. Water was added. The solution was extracted with ether. The pH of the aqueous layer was adjusted to 3.2 using 2N HCl. The precipitate was filtered, washed with water, and dried to yield 37 mg. The aqueous phase was extracted with ethyl acetate, dried and concentrated to yield an additional 60 mg of 1-[1-oxo-2-[5-[2-(2H-tetrazol-5-yl)phenyl]-1H-benzimidazole-1-yl]octyl]-4-hydroxy-L -prolite. (MS)
Reaction SMILES: N[C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][CH2:7][N:8]2[C:11](=[O:15])[CH2:12][CH2:13][Cl:14])=[CH:4][CH:3]=1.N([O-])=O.[Na+].[H+].[B-](F)(F)(F)[F:22]>O>[Cl:14][CH2:13][CH2:12][C:11]([N:8]1[C:9]2[C:5](=[CH:4][CH:3]=[C:2]([F:22])[CH:10]=2)[CH2:6][CH2:7]1)=[O:15]
Reactant: Nc1ccc2c(c1)N(C(=O)CCCl)CC2
Reactant: F[B-](F)(F)F
Agent: O=N[O-]
Agent: [H+]
Agent: [Na+]
Solvent: O
Product: O=C(CCCl)N1CCc2ccc(F)cc21
Temperature: 10 °C
Yield: 74 %

Procedure:
1.12 g (5.0 mmol) of 6-amino-1-(3-chloropropionyl)indoline (prepared as described in Preparation 6) were suspended in 10 ml of fluoboric acid (as a 42% w/v aqueous solution), and a solution of 380 mg (5.5 mmol) of sodium nitrite in 5 ml of water was added to the suspension while ice-cooling so that the internal temperature was maintained at 10° C. or lower. The mixture was then stirred while ice-cooling for 1 hour. The precipitated salt was collected by filtration and dried in a desiccator under reduced pressure by means of a vacuum pump to obtain 1.20 g (3.7 mmol) of the title compound as a solid (yield: 74%).
Reaction SMILES: [CH:1]([N:4]1[CH2:11][CH:10]2[CH2:12][CH:6]([CH2:7][NH:8][CH2:9]2)[CH2:5]1)([CH3:3])[CH3:2].[OH-].[Na+].[N+:15]([C:18]1[CH:23]=[CH:22][C:21]([CH2:24][C:25](Cl)=[O:26])=[CH:20][CH:19]=1)([O-:17])=[O:16]>C(Cl)Cl>[N+:15]([C:18]1[CH:19]=[CH:20][C:21]([CH2:24][C:25]([N:8]2[CH2:9][CH:10]3[CH2:12][CH:6]([CH2:5][N:4]([CH:1]([CH3:3])[CH3:2])[CH2:11]3)[CH2:7]2)=[O:26])=[CH:22][CH:23]=1)([O-:17])=[O:16]
Reactant: CC(C)N1CC2CNCC(C2)C1
Reactant: O=C(Cl)Cc1ccc([N+](=O)[O-])cc1
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Product: CC(C)N1CC2CC(CN(C(=O)Cc3ccc([N+](=O)[O-])cc3)C2)C1
Reaction time: 3 h
Yield: 69.2 %

Procedure:
A standard setup was used with a N2 inlet. Initially, the amine 105 (2.42 g, 14.38 mmol) in H2CCl2 (35 ml) was added followed by NaOH (10%, 14.42 g, 35.95 mmol) which resulted in a heterogenous mixture. To this mixture was added 4-nitrophenylacetyl chloride (3,16 g, 15.82 mmol) dropwise over a 15-min period. Stirring was continued for an additional 3 h upon which the brown mixture was transferred to a separatory funnel, and the layers were separated. The aqueous layer was extracted (H2CCl2, 3×25 ml), and the organic layers were combined. After drying (Na2SO4, 2 h), the organic solution was filtered and concentrated to give 94 as a light brown solid (3.3 g, 69.2 %); mp 93°-94°]C. IR (KBr) 3090 (Ar-H), 2960, 2920, 2800, 2740 (C-H), 1625 (NC=O) cm-1 ; 1H NMR (DCCl3) d 0.94 (dd, 6 H, CH3 isopropyl), 1.69 [q, 2 H, H(9)], 1.92 [bs, 2 H, H(1,5)], 2.46 [m, 3H, ring protons, C-H, isopropyl), 2.79 (d, 1 H, ring proton), 2.93 (td, 2 H, ring protons), 3.39 (d, 1 H, ring proton), 3.79 (s, 2 H, CH2 -Ar), 3.84 (d, 1 H, ring proton), 4.57 (d, 1 H, ring proton), 7.44 (d, 2 H; Ar-H), 8.15 (d, 2 H, Ar-H); 13C NMR (DCCl3) ppm 16.83, 18.44 (CH3 isopropyl), 28.76, 29.42 [C(1,5)1, 31.57 [C(9)], 40.62 (CH2 -Ar), 46.76 (C-H isopropyl), 50.60, 52.78, 54.03, 54.42 [C(2,4,6,8)], 123.37, 130.02, 143.58, 146.56 (Ar-C), 167.93 (NC=O). Amide 94 was used without further purification.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[N:18][C:17]([Br:20])=[C:16]([O:21][CH2:22][C:23]3[CH:28]=[CH:27][CH:26]=[C:25]([Cl:29])[CH:24]=3)[N:15]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.[CH3:30][S:31]([OH:34])(=[O:33])=[O:32].CCOCC>O1CCOCC1>[CH3:30][S:31]([OH:34])(=[O:33])=[O:32].[Br:20][C:17]1[N:18]=[CH:19][C:14]([N:11]2[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]2)=[N:15][C:16]=1[O:21][CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([Cl:29])[CH:24]=1
Reactant: CC(C)(C)OC(=O)N1CCN(c2cnc(Br)c(OCc3cccc(Cl)c3)n2)CC1
Agent: CS(=O)(=O)O
Solvent: CCOCC
Solvent: C1COCCO1
Product: Clc1cccc(COc2nc(N3CCNCC3)cnc2Br)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 104.2 %

Procedure:
A solution of 5′-bromo-6′-(3-chloro-benzyloxy)-3,4,5,6-tetrahydro-2H-[1,2′]bipyrazinyl-4-carboxylic acid tert-butyl ester I-3j (25 mg, 0.052 mmol) in 1,4-dioxane (0.5 ml) was treated with methanesulfonic acid (6.7 μl, 0.104 mmol) was stirred at room temperature for 16 h. The mixture was treated with ether to afford a precipitate. The supernatant was removed. The residue was treated with ether. The supernatant was again removed to provide a solid (26 mg, 87%).
Reaction SMILES: [N:1]1([CH2:14][CH2:15][NH:16][C:17](=[O:19])[CH3:18])[C:9]2[C:8]3[CH:10]=[CH:11][CH:12]=[CH:13][C:7]=3[CH2:6][CH2:5][C:4]=2[CH:3]=[CH:2]1.ClC1C(=O)C(C#N)=C(C#N)C(=O)C=1Cl>C1(C)C=CC=CC=1>[N:1]1([CH2:14][CH2:15][NH:16][C:17](=[O:19])[CH3:18])[C:9]2[C:4](=[CH:5][CH:6]=[C:7]3[CH:13]=[CH:12][CH:11]=[CH:10][C:8]3=2)[CH:3]=[CH:2]1
Reactant: CC(=O)NCCn1ccc2c1-c1ccccc1CC2
Agent: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Solvent: Cc1ccccc1
Product: CC(=O)NCCn1ccc2ccc3ccccc3c21
Temperature: 80 °C
Reaction time: 2 h
Yield: 30.2 %

Procedure:
N-[2-(4,5-Dihydro-1H-benzo[g]indol-1-yl)ethyl]acetamide (4.0 g) was dissolved in 50 ml of toluene under argon and treated with 3.8 g of 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (DDQ). The reaction mixture was stirred at 80° C. for 2 hours, a further 0.4 g of DDQ was then added and the mixture was stirred at 80° C. for a further 2 hours. The separated precipitate was filtered off at room temperature and the filtrate was freed from solvent. The crude product, 1.5 g of dark brown solid, was chromatographed on 60 g of neutral aluminium oxide with ethyl acetate as the eluent. There were obtained 1.2 g (30%) of N-[2-(1H-benzo[g]indol-1-yl)ethyl]acet-amide which was processed without further purification.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([O:18][CH3:19])=[C:6]([NH:8][C:9]([NH:11][C:12]2[CH:17]=[N:16][CH:15]=[CH:14][N:13]=2)=[O:10])[CH:7]=1.[F:20][C:21]([F:33])([F:32])[C:22]([N:24]1[CH2:31][CH2:30][CH2:29][C@H:25]1[C:26](Cl)=[O:27])=[O:23]>N1C=CC=CC=1>[CH3:19][O:18][C:5]1[CH:4]=[CH:3][C:2]([NH:1][C:26]([C@@H:25]2[CH2:29][CH2:30][CH2:31][N:24]2[C:22](=[O:23])[C:21]([F:33])([F:20])[F:32])=[O:27])=[CH:7][C:6]=1[NH:8][C:9]([NH:11][C:12]1[CH:17]=[N:16][CH:15]=[CH:14][N:13]=1)=[O:10]
Reactant: O=C(Cl)[C@@H]1CCCN1C(=O)C(F)(F)F
Reactant: COc1ccc(N)cc1NC(=O)Nc1cnccn1
Solvent: c1ccncc1
Product: COc1ccc(NC(=O)[C@@H]2CCCN2C(=O)C(F)(F)F)cc1NC(=O)Nc1cnccn1
Temperature: 25 °C
Reaction time: 2 h
Yield: 16.6 %

Procedure:
A solution of 1-(5-amino-methoxyphenyl)-3-pyrazin-2-yl-urea (Compound 14, Example 4) (105 mg, 0.4 mmol) in dry pyridine (2 mL) at 0° C. was treated with a solution of N-trifluoroacetyl-(S)-prolyl chloride (0.1 M in dichloromethane, 4.5 mL, 0.45 mmol) and stirred 2 h at room temperature. The reaction was quenched with 1 N HCl (50 mL) and extracted with ethyl acetate (3×50 mL). The combined organic layers were washed with 1 N HCl (2×20 mL), water (20 mL), brine (20 mL), dried over sodium sulfate, and concentrated in vacuo to a beige solid (60 mg). Recrystallization from acetonitrile yielded the final solid product (30 mg, 17%). 1H NMR (300 Mhz, d6-DMSO) δ: (10.16-10.06, m, 3H), 8.90 (s, 1H), 8.36-8.30 (m, 2H), 8.25 (d, J=2.6 Hz, 1H), 7.42 (dd, J=8.8, 2.6 Hz, 1H), 6.98 (d, J=8.8 Hz, 1H), 4.57 (dd, J=8.5, 4.4 Hz, 1H), 3.88 (s, 3H), 3.73 (t, J=6.5 Hz, 1H), 2.27-2.21 (m, 1H), 2.06-1.90 (m, 3H). LRMS (ESI, positive) m/e 453.1 (M+1).