Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH:16]2[CH:11]([CH2:12][CH2:13][CH2:14][CH2:15]2)[CH2:10][C@H:9]1[CH2:17][O:18][C:19]1[CH:28]=[CH:27][C:22]([C:23]([O:25][CH3:26])=[O:24])=[CH:21][CH:20]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]>CCO.CC(O)=O.[Rh]>[C:1]([O:5][C:6]([N:8]1[CH:16]2[CH:11]([CH2:12][CH2:13][CH2:14][CH2:15]2)[CH2:10][C@H:9]1[CH2:17][O:18][C@@H:19]1[CH2:28][CH2:27][C@H:22]([C:23]([O:25][CH3:26])=[O:24])[CH2:21][CH2:20]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: COC(=O)c1ccc(OC[C@@H]2CC3CCCCC3N2C(=O)OC(C)(C)C)cc1
Agent: [Rh]
Solvent: CCO
Solvent: CC(=O)O
Product: COC(=O)[C@H]1CC[C@@H](OC[C@@H]2CC3CCCCC3N2C(=O)OC(C)(C)C)CC1
Reaction time: 48 h

Procedure:
A mixture of methyl 4-[1-tert-butoxycarbonyl-(2S)octahydroindolylmethoxy]benzoate (700 mg, 1.8 mmol) and 5% Rh on alumina (400 mg) in EtOH (10.0 ml) and AcOH (1.0 ml) was hydrogenated at room temperature at 5 atm for 48 hr. The catalyst was filtered off, and the filtrate was concentrated in vacuo. The residue was purified by column chromatography on silica gel with n-hexane-EtOAc (7:1, v/v) as eluent to give methyl cis-4-[1-tert-butoxycarbonyl-(2S)-octahydro indolylmethoxy]cyclohexanecarboxylate (600 mg, 85%) as a pale yellow oil. 1H-NMR (CDCl3) δ 1.10–2.35 (m, 20H), 1.44 (s, 9H), 3.45–3.90 (m, 5H), 3.80 (s, 3H).
Reaction SMILES: [Br:1][C:2]1[CH:17]=[CH:16][CH:15]=[CH:14][C:3]=1[CH2:4][N:5]1[C:9]([CH2:10][CH2:11][CH2:12]Cl)=[CH:8][N:7]=[CH:6]1.CN(CCN(C)C)C.[Li+].CC([N-]C(C)C)C>C1COCC1>[Br:1][C:2]1[CH:17]=[CH:16][CH:15]=[CH:14][C:3]=1[CH:4]1[N:5]2[CH:6]=[N:7][CH:8]=[C:9]2[CH2:10][CH2:11][CH2:12]1
Reactant: ClCCCc1cncn1Cc1ccccc1Br
Agent: CC(C)[N-]C(C)C
Agent: CN(C)CCN(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: Brc1ccccc1C1CCCc2cncn21
Temperature: -78 °C
Reaction time: 3.5 h

Procedure:
To a slurry of 1-(2-bromobenzyl)-5-(3-chloropropyl)-1H-imidazole (0.662 g, 2.12 mmol) and TMEDA (0.683 mL, 4.55 mmol) in THF (10 mL) at −78° C. is added LDA (1.8 M in heptane/THF/ethylbenzene, 2.5 mL, 4.5 mmol) and the yellow clear solution is stirred at −78° C. After 3.5 hr, the reaction is quenched by saturated aqueous NH4Cl, and the mixture is partitioned between EtOAc and saturated aqueous NaHCO3. The organic layer is washed with brine, dried and concentrated to give an oil, which is subjected to flash chromatography (silica gel) eluting with MeOH:CH2Cl2 to yield the desired compound. MS (ESI) m/z 277 (M+H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:28]=[C:27]([C:29]([F:32])([F:31])[F:30])[CH:26]=[C:25]([S:33][CH3:34])[C:4]=1[C:5]([NH:7][C:8]1([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH2:13][CH:12]([O:14]COC)[CH2:11][N:10]([CH3:18])[CH2:9]1)=[O:6].Cl>CO>[OH:14][CH:12]1[CH2:11][N:10]([CH3:18])[CH2:9][C:8]([NH:7][C:5](=[O:6])[C:4]2[C:25]([S:33][CH3:34])=[CH:26][C:27]([C:29]([F:30])([F:31])[F:32])=[CH:28][C:3]=2[O:2][CH3:1])([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH2:13]1
Reactant: COCOC1CN(C)CC(NC(=O)c2c(OC)cc(C(F)(F)F)cc2SC)(c2ccccc2)C1
Agent: Cl
Solvent: CO
Product: COc1cc(C(F)(F)F)cc(SC)c1C(=O)NC1(c2ccccc2)CC(O)CN(C)C1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 51.6 %

Procedure:
To a solution of 17 mg (0.0341 mmol) rac-2-methoxy-N-(5-methoxymethoxy-1-methyl-3-phenyl-piperidin-3-yl)-6-methylsulfanyl-4-trifluoromethyl-benzamide in 0.5 ml methanol were added 102 ul (0.102 mmol) of an aqueous 1N HCl solution. The mixture was stirred at room temperature for 30 minutes and then in a 65° C. oil bath for 24 hours. The solvent was removed in vacuo. The residue was taken in water. The aqueous layer was basified with a 2M Na2CO3 solution and extracted 3 times with dichloromethane. The combined extracts were dried over sodium sulfate, filtered and concentrated in vacuo. The crude product was purified on silica gel (Eluent: Heptane/ethyl acetate 0 to 100%) to provide 8 mg (52%) of the title compound as a white solid. MS (m/e): 455.2 (MH+).
Reaction SMILES: C([NH:5][C:6](=[O:69])[C@H:7]([CH:66]([CH3:68])[CH3:67])[CH2:8][C@H:9](O)[C@@H:10](NC(=O)C(C1N2C=C(C3C=NC=CC=3)N=C(CCC)C2=NN=1)CC1N=CN(C(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)C=1)[CH2:11]C1CCCCC1)CCC>FC(F)(F)C(O)=O.O>[CH:66]([CH:7]([CH2:8][CH2:9][CH2:10][CH3:11])[C:6]([NH2:5])=[O:69])([CH3:68])[CH3:67]
Reactant: CCCCNC(=O)[C@@H](C[C@H](O)[C@H](CC1CCCCC1)NC(=O)C(Cc1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1)c1nnc2c(CCC)nc(-c3cccnc3)cn12)C(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: O
Product: CCCCC(C(N)=O)C(C)C
Yield: 189.4 %

Procedure:
A solution of (2S,4S,5S)-N-butyl-6-cyclohexyl-4-hydroxy-2-isopropyl-5-[3-(1-triphenylmethylimidazol-4-yl)-(2RS)-2-(8-propyl-6-(3-pyridyl)-1,2,4-triazolo[4,3-a]pyrazin-3-yl)propionamido]hexanamide (A) (187 mg) in trifluoroacetic acid (8 ml) and water (2 ml) was stirred for 75 minutes. Volatile material was removed by evaporation and saturated sodium hydrogen carbonate solution (10 ml) added to the residue. The mixture was extracted with chloroform (2×20 ml) and the combined extracts were washed successively with water (10 ml) and saturated sodium chloride solution (10 ml) and dried (MgSO4). The solvent was removed by evaporation and the residue triturated with ether to give (2S,4S,5S)-N-butyl-6-cyclohexyl-4-hydroxy-5-[3-a]pyrazin-3-yl)propionamido]-2-isopropylhexanamide as a white powder (60 mg); NMR (d6 -DMSO/d4 -acetic acid): 0.3-1.7 (complex m, 32H), 2.0 (m, 3H), 2.9-3.9 (complex m, 8H), 4.9 (m, 1H), 7.3 (m, 1H), 7.6 (m, 1H), 8.5 (m, 2H), 8.7 (m, 1H), 9.25 and 9.35 (both S, ratio 1:1, total 1H), 9.3 (m, 1H); mass spectrum (+ve FAB, DMSO): 686 (M+H)+, 360, 332.
Reaction SMILES: [CH3:1][CH2:2][CH:3]([OH:6])[CH2:4][CH3:5].[H-].[Na+].Cl[C:10]1[C:15]([CH3:16])=[C:14]([O:17][C:18]2[C:23]([CH3:24])=[CH:22][C:21]([CH3:25])=[CH:20][C:19]=2[CH3:26])[N:13]=[C:12]([CH3:27])[N:11]=1>CS(C)=O>[CH2:2]([CH:3]([O:6][C:10]1[C:15]([CH3:16])=[C:14]([O:17][C:18]2[C:19]([CH3:26])=[CH:20][C:21]([CH3:25])=[CH:22][C:23]=2[CH3:24])[N:13]=[C:12]([CH3:27])[N:11]=1)[CH2:4][CH3:5])[CH3:1]
Reactant: Cc1cc(C)c(Oc2nc(C)nc(Cl)c2C)c(C)c1
Reactant: CCC(O)CC
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Product: CCC(CC)Oc1nc(C)nc(Oc2c(C)cc(C)cc2C)c1C
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
A mixture of 3-pentanol (0.3 ml) and sodium hydride (60% in oil, 32 mg, 0.81 mmol) in DMSO was stirred at room temperature for 5 minutes. 4--Chloro-2,5-dimethyl-6-(2,4,6-trimethylphenyoxy)-pyrimidine (150 mg, 0.54 mmol) was added and the resulting mixture was heated at 150° C. for 5 hours. The mixture was quenched with water and extracted with ethyl acetate. The organic layer was separated, dried and concentrated to give a beige solid. The solid was purified through silica gel column chromatography using 20% chloroform in hexane as eluent to give the title compound as white crystals, mp 93.5-95.5° C. 1H NMR (CDCl3) δ6.85 (s, 2H), 5.11 (t, 1H), 2.27 (s, 3H), 2.26 (s, 3H), 2.11 (s, 3H), 2.03 (s, 6H), 1.68 (p, 4H), 0.92 (t, 6H) ppm.
Reaction SMILES: [CH2:1]([C@:4]1([C:27]2[CH:32]=[CH:31][C:30]([F:33])=[CH:29][CH:28]=2)[CH2:9][CH2:8][N:7]([C@H:10]([C:12]2[CH:17]=[CH:16][C:15]([C:18]3[CH:23]=[CH:22][C:21]([F:24])=[CH:20][C:19]=3[F:25])=[CH:14][CH:13]=2)[CH3:11])[C:6](=[O:26])[NH:5]1)[CH:2]=[CH2:3].[OH-:34].[Na+].OO>C1COCC1>[F:25][C:19]1[CH:20]=[C:21]([F:24])[CH:22]=[CH:23][C:18]=1[C:15]1[CH:14]=[CH:13][C:12]([C@@H:10]([N:7]2[CH2:8][CH2:9][C@@:4]([C:27]3[CH:32]=[CH:31][C:30]([F:33])=[CH:29][CH:28]=3)([CH2:1][CH2:2][CH2:3][OH:34])[NH:5][C:6]2=[O:26])[CH3:11])=[CH:17][CH:16]=1
Reactant: [OH-]
Reactant: C=CC[C@]1(c2ccc(F)cc2)CCN([C@@H](C)c2ccc(-c3ccc(F)cc3F)cc2)C(=O)N1
Agent: OO
Agent: [Na+]
Solvent: C1CCOC1
Product: C[C@@H](c1ccc(-c2ccc(F)cc2F)cc1)N1CC[C@](CCCO)(c2ccc(F)cc2)NC1=O
Reaction time: 2 h
Yield: 18.6 %

Procedure:
To a solution of (R)-4-allyl-1-((S)-1-(2′,4′-difluorobiphenyl-4-yl)ethyl)-4-(4-fluorophenyl)tetrahydropyrimidin-2(1H)-one (42 mg, 0.092 mmol) in THF (10 mL) was added 1M BH3 in THF (1.5 mL, 1.5 mmol) at 0° C. under nitrogen. The mixture was stirred for 2 h. The reaction was quenched by water. 3 M aq NaOH (0.3 mL, 3 mmol) and H2O2 (3 mL) were added. The resulting mixture was stirred for 1.5 h. The mixture was extracted with EtOAc and the combined organic phase was concentrated to give the crude product, which was purified by preparative HPLC to give (R)-1-((S)-1-(2′,4′-difluorobiphenyl-4-yl)ethyl)-4-(4-fluorophenyl)-4-(3-hydroxypropyl)tetrahydropyrimidin-2(1H)-one (8 mg, 19%). LC-MS Method 1 tR=1.413 min, m/z=469.2; 1H NMR (CDCl3): δ=1.36 (m, 2H), 1.45 (m, 3H), 1.91-2.01 (m, 5H), 2.18 (m, 1H), 2.83 (m, 1H), 3.52 (m, 2H), 5.76 (m, 2H), 6.09 (m, 1H), 6.38-6.98 (m, 4H), 7.16 (m, 2H), 7.22 (m, 1H), 7.25 (m, 1H), 7.28 (m, 3H).
Reaction SMILES: [H-].[Na+].[NH:3]1[CH:7]=[CH:6][N:5]=[CH:4]1.Br[CH2:9][CH2:10][CH2:11][CH2:12][C:13]([O:15][CH3:16])=[O:14].O>CN(C)C=O>[N:3]1([CH2:9][CH2:10][CH2:11][CH2:12][C:13]([O:15][CH3:16])=[O:14])[CH:7]=[CH:6][N:5]=[CH:4]1
Reactant: c1c[nH]cn1
Reactant: COC(=O)CCCCBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)CCCCn1ccnc1
Reaction time: 18 h
Yield: 81.5 %

Procedure:
Add sodium hydride (0.212 g; 1.2 equiv; 5.29 mmoles) to a solution of 1H-imidazole (0.30 g; 1.0 equiv; 4.41 mmoles) and methyl 5-bromopentanoate (1.03 g; 1.2 equiv; 5.29 mmoles) in dimethylformamide (20 mL). Stir the mixture for 18 hours then add water (15 mL). Extract the mixture with dichloromethane and wash with brine (20 mL). Dry the organic phase over sodium sulfate, filter, and concentrate to give the crude product, which is purified by column chromatography (0 to 10% methanol in dichloromethane) to afford methyl 5-imidazol-1-ylpentanoate (0.655 g; 82%) as a yellow oil: MS (m/z): 183(M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:19]=[CH:18][C:5]([CH2:6][O:7][C:8]([N:10]2[CH2:17][CH2:16][CH2:15][C@H:11]2[C:12]([OH:14])=O)=[O:9])=[CH:4][CH:3]=1.ClC(OCC(C)C)=O.CN1CCOCC1.[NH2:35][C@H:36]([CH2:40][OH:41])[CH:37]([CH3:39])[CH3:38]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][O:7][C:8]([N:10]2[CH2:17][CH2:16][CH2:15][C@H:11]2[C:12]([NH:35][C@H:36]([CH2:40][OH:41])[CH:37]([CH3:39])[CH3:38])=[O:14])=[O:9])=[CH:18][CH:19]=1
Reactant: O=C(O)[C@@H]1CCCN1C(=O)OCc1ccc(Cl)cc1
Reactant: CC(C)[C@H](N)CO
Agent: CC(C)COC(=O)Cl
Solvent: CN1CCOCC1
Product: CC(C)[C@@H](CO)NC(=O)[C@@H]1CCCN1C(=O)OCc1ccc(Cl)cc1

Procedure:
The subject compound was prepared from 0.85 g (2.98 mmol) p-chlorobenzyloxycarbonyl-L-proline, 0.41 g (2.98 mmol) isobutyl chloroformate, 0.30 g (2.97 mmol) N-methylmorpholine, and 0.31 g (2.98 mmol) L-valinol, substantially according to the mixed anhydride procedure described in Example 1. N-(p-chlorobenzyloxycarbonyl)-L-prolyl-L-valinol obtained after recrystallization from ethyl acetate/n-hexane melted at 143°-144.5°.
Reaction SMILES: CO[C:3]([C:5]1[N:23]=[C:8]2[CH2:9][N:10]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:11]3[C:16]([N:7]2[N:6]=1)=[CH:15][CH:14]=[CH:13][CH:12]=3)=[O:4].[CH3:24][NH:25][CH3:26]>CO>[CH3:24][N:25]([CH3:26])[C:3]([C:5]1[N:23]=[C:8]2[CH2:9][N:10]([C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=3)[C:11]3[C:16]([N:7]2[N:6]=1)=[CH:15][CH:14]=[CH:13][CH:12]=3)=[O:4]
Reactant: COC(=O)c1nc2n(n1)-c1ccccc1N(c1ccccc1)C2
Reactant: CNC
Solvent: CO
Product: CN(C)C(=O)c1nc2n(n1)-c1ccccc1N(c1ccccc1)C2

Procedure:
A mixture of 7.00 g (0.023 mol) of the 5-phenyl-4,5-dihydro-[1,2,4]triazolo[1,5-a]quinoxaline-2-carboxylic acid methyl ester prepared according to Example 1(f) in 300 ml of methanol and 62.6 ml (0.457 mol) of 33% ethanolic dimethylamine solution is heated at 100° in an autoclave for 16 hours. The reaction mixture is then concentrated by evaporation in vacuo and the residue is dissolved in methylene chloride and a mixture of ice and water. The organic phase is washed twice with cold 5% potassium bicarbonate solution and once with saturated sodium chloride solution, dried over sodium sulphate and concentrated by evaporation in vacuo. The amorphous residue crystallises when triturated with 300 ml of ether. After filtration and drying in a high vacuum, there is obtained N,N-dimethyl-5-phenyl-4,5-dihydro-[1,2,4]triazolo[1,5-a]quinoxaline-2-carboxamide which sinters from 125° and gradually melts at 150°-165°.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[C:11]([Cl:17])[CH:10]=2)[N:5]=[C:4]([NH:18][CH:19]2[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]2)[N:3]=1.C(=O)([O-])[O-].[K+].[K+].[I:32][C:33]1[CH:38]=[CH:37][C:36]([OH:39])=[CH:35][CH:34]=1>CN(C)C=O.O>[Cl:17][C:11]1[CH:10]=[C:9]([NH:8][C:6]2[N:5]=[C:4]([NH:18][CH:19]3[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]3)[N:3]=[C:2]([O:39][C:36]3[CH:37]=[CH:38][C:33]([I:32])=[CH:34][CH:35]=3)[N:7]=2)[CH:14]=[CH:13][C:12]=1[O:15][CH3:16]
Reactant: COc1ccc(Nc2nc(Cl)nc(NC3CCCCCC3)n2)cc1Cl
Reactant: Oc1ccc(I)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccc(Nc2nc(NC3CCCCCC3)nc(Oc3ccc(I)cc3)n2)cc1Cl
Temperature: 80 °C
Yield: 90.1 %

Procedure:
A mixture of compound 133 (2.0 g, 5.22 mmol), potassium carbonate (3.6 g, 26.10 mmol) in dimethylformamide (10 mL) was added 4-iodophenol (1.38 g, 6.26 mmol). It was heated to 80° C. for 12 hours with stirring under nitrogen atmosphere. The mixture was then cooled, diluted with water (20 mL) and extracted with EtOAc (2×20 mL). The combined organic layers were washed with water (2×10 mL), dried over anhydrous sodium sulphate and concentrated under vacuum. The residue thus obtained was purified by column chromatography (10-20% EtOAc-Hexane) to afford the title compound as white solid (2.66 g, 90%). mp 80-82° C.; HPLC: Inertsil ODS 3V (250×4.6 mm) 5 microns [solvent A=0.01 M KH2PO4 (pH 7.0); solvent B=CH3CN], Gradient elution program: T/% B=0/60, 10/60, 25/80, 40/80, 45/60, 50/60; 268 nm, Rt 38.47 min, 97.83% purity; MS (CI): m/z 566 (M+H, 100).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11]([N:13]3[CH2:18][CH2:17][C:16]4([C:22]5[CH:23]=[CH:24][C:25]([F:27])=[CH:26][C:21]=5[C:20](=[O:28])[O:19]4)[CH2:15][CH2:14]3)=[O:12])=[CH:7][NH:8]2)=[CH:4][CH:3]=1.[Cl:29][C:30]1[N:31]=[N:32][C:33]([CH3:38])=[CH:34][C:35]=1[CH2:36]Cl>>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11]([N:13]3[CH2:18][CH2:17][C:16]4([C:22]5[CH:23]=[CH:24][C:25]([F:27])=[CH:26][C:21]=5[C:20](=[O:28])[O:19]4)[CH2:15][CH2:14]3)=[O:12])=[CH:7][N:8]2[CH2:36][C:35]2[CH:34]=[C:33]([CH3:38])[N:32]=[N:31][C:30]=2[Cl:29])=[CH:4][CH:3]=1
Reactant: O=C1OC2(CCN(C(=O)c3c[nH]c4cc(Cl)ccc34)CC2)c2ccc(F)cc21
Reactant: Cc1cc(CCl)c(Cl)nn1
Product: Cc1cc(Cn2cc(C(=O)N3CCC4(CC3)OC(=O)c3cc(F)ccc34)c3ccc(Cl)cc32)c(Cl)nn1

Procedure:
Following the general procedure III as described above, the alkylation of 1′-[(6-chloro-1H-indol-3-yl)carbonyl]-5-fluoro-3H-spiro[2-benzofuran-1,4′-piperidin]-3-one (prepared according to example 19 above) with 3-chloro-4-chloromethyl-6-methyl-pyridazine (prepared by U.S. Pat. No. 3,453,277) gave the title compound. ES-MS m/e (%): 539.1(M+H+).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([CH2:10][CH:11]([OH:13])[CH3:12])=[CH:6][CH:5]=1)([O-])=O.[Cl-].[NH4+].C(O)C>[Fe].O>[NH2:1][C:4]1[CH:5]=[CH:6][C:7]([CH2:10][CH:11]([OH:13])[CH3:12])=[CH:8][CH:9]=1
Reactant: CC(O)Cc1ccc([N+](=O)[O-])cc1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: CCO
Product: CC(O)Cc1ccc(N)cc1
Yield: 78 %

Procedure:
A mixture of 1-(4-nitrophenyl)-2-propanol (Schadt, F. L.; et al. J. Am. Chem. Soc., 1978, 100, 228., 2.2 g, 12.3 mmol), iron powder (3.3 g, 59.1 mmol), ammonium chloride (370 mg, 6.9 mmol), ethanol (48 mL) and water (24 mL) was heated at reflux temperature for 2 h. The mixture was cooled and filtered through a pad of Celite. The filtrate was concentrated. The residue was diluted with ethyl acetate (200 mL) and washed with water (2×100 mL). The organic layer was dried (MgSO4), and concentrated. Purification by flash column chromatography on silica gel eluting with hexane/ethyl acetate (1:1) to afford 1.45 g (78%) of the title compound as a yellow oil: 1H-NMR (CDCl3) δ 7.00 (2H, d, J=8.6 Hz), 6.64 (2H, d, J=8.8 Hz), 3.99–3.89 (1H, m), 3.60 (2H, br s), 2.72–2.52 (2H, m), 1.22 (3H, d, J=6.2 Hz).
Reaction SMILES: [C:1]1([CH:7]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[N:8]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[CH:10]([C:17]3[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][C:18]=3[OH:25])[C:9]2=[O:26])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:33]1(C(C2C=CC=CC=2)N2C3C(=CC=CC=3)C(C3C=C(C)C(OC)=CC=3O)C2=O)C=CC=CC=1>>[C:27]1([CH:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[N:8]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:10]3([C:17]4[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][C:18]=4[O:25][CH2:33]3)[C:9]2=[O:26])[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: COc1cc(O)c(C2C(=O)N(C(c3ccccc3)c3ccccc3)c3ccccc32)cc1C
Reactant: COc1ccc(C2C(=O)N(C(c3ccccc3)c3ccccc3)c3ccccc32)c(O)c1
Product: COc1ccc2c(c1)OCC21C(=O)N(C(c2ccccc2)c2ccccc2)c2ccccc21

Procedure:
Following the procedure as described in EXAMPLE 2 and making non-critical variations using 1-(diphenylmethyl)-3-(2-hydroxy-4-methoxyphenyl)-1,3-dihydro-2H-indol-2-one to replace 1-(diphenylmethyl)-3-(2-hydroxy-4-methoxy-5-methylphenyl)-1,3-dihydro-2H-indol-2-one, 1′-(diphenylmethyl)-6-methoxyspiro[1-benzofuran-3,3′-indol]-2′(1′H)-one was obtained (74%) as a colorless solid: 1H NMR (300 MHz, CDCl3) δ7.42-7.27 (m, 10H), 7.16-6.92 (m, 4H), 6.59-6.49 (m, 3H), 6.37 (dd, J=8.4, 2.4 Hz, 1H), 5.02 (d, J=9.0 Hz, 1H), 4.75 (d, J=9.0 Hz, 1H), 3.77 (s, 3H); MS (ES+) m/z 434.3 (M+1), 456.3 (M+23).
Reaction SMILES: [CH3:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([CH3:10])[C:3]=1[CH2:4][OH:5].N(C(OC(C)C)=O)=NC(OC(C)C)=O.O[C:26]1[CH:27]=[C:28]([C:32]2([C:35]#[N:36])[CH2:34][CH2:33]2)[CH:29]=[CH:30][CH:31]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1COCC1.CCOCC>[CH3:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([CH3:10])[C:3]=1[CH2:4][O:5][C:26]1[CH:27]=[C:28]([C:32]2([C:35]#[N:36])[CH2:33][CH2:34]2)[CH:29]=[CH:30][CH:31]=1
Reactant: N#CC1(c2cccc(O)c2)CC1
Reactant: Cc1cccc(C)c1CO
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOCC
Solvent: C1CCOC1
Product: Cc1cccc(C)c1COc1cccc(C2(C#N)CC2)c1
Reaction time: 16 h

Procedure:
A solution of 2,6-Dimethylbenzyl alcohol (2.81 g, 20.6 mmol) and diisopropyl azodicarboxylate (DIAD, 4.69 g, 23.2 mmol) in THF (20 ml) was added drop wise to a solution of 1-(3-hydroxyphenyl)cyclopropanecarbonitrile (Step B, 3.2 g, 20.1 mmol) and triphenylphosphine (5.37 g, 20.5 mmol) in THF (50 ml) at 0° C. under argon. The reaction mixture was stirred at the same temperature for 16 hours, diluted with ether and washed with water. The organic layer was dried over Na2SO4, filtered, concentrated, and purified by flash chromatography on a silica gel column (hex:ethyl acetate, 9:1) to give the title compound.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:8])[CH2:5][C:6]#[N:7])[CH3:2].[F:9][C:10]1[CH:11]=[C:12]([CH:15]=[CH:16][CH:17]=1)[CH:13]=O>C(O)C.N1CCCC1>[CH2:1]([O:3][C:4](=[O:8])[C:5]([C:6]#[N:7])=[CH:13][C:12]1[CH:15]=[CH:16][CH:17]=[C:10]([F:9])[CH:11]=1)[CH3:2]
Reactant: O=Cc1cccc(F)c1
Reactant: CCOC(=O)CC#N
Solvent: CCO
Solvent: C1CCNC1
Product: CCOC(=O)C(C#N)=Cc1cccc(F)c1
Yield: 98.5 %

Procedure:
A solution of cyanoacetic acid ethyl ester (1.1 g), 3-fluorobenzaldehyde (1.5 g) and pyrolidine (0.043 g) in ethanol (10 mL) was stirred at room temperature for 2 hours. The precipitated solid was collected by filtration, and this obtained solid was washed with ethanol (40 mL) to give the title compound (2.1 g).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:12]2[O:11][CH:10]=[CH:9][C:8](=[O:13])[C:7]=2[CH:6]=[CH:5][CH:4]=1.C(N(CC)CC)C>[Pd].C(O)C>[OH:13][CH:8]1[C:7]2[CH:6]=[CH:5][CH:4]=[C:3]([O:2][CH3:1])[C:12]=2[O:11][CH2:10][CH2:9]1
Reactant: COc1cccc2c(=O)ccoc12
Agent: [Pd]
Solvent: CCO
Solvent: CCN(CC)CC
Product: COc1cccc2c1OCCC2O

Procedure:
A solution of 8-methoxy-4-benzopyranone (31.6 g), triethylamine (4.9 ml) and 10% palladium on carbon (3.1 g) in absolute ethanol (1.7 l) is stirred under an atmosphere of hydrogen (P=52 lbs.) overnight. The resulting solid is filtered, washed with diethyl ether and evaporated in vacuo yielding the desired product as a solid.
Reaction SMILES: [C:1]([OH:7])([C:3]([F:6])([F:5])[F:4])=[O:2].C(OC([N:15]1[C@H:20]([C:21]2[NH:25][C:24]3[CH:26]=[C:27]([C:30]4[CH:31]=[C:32]5[C:37](=[CH:38][CH:39]=4)[N:36]=[C:35]([C:40]4[NH:44][C:43]([C@@H:45]6[CH2:50][C@@H:49]7[C@@H:47]([CH2:48]7)[N:46]6C(OC(C)(C)C)=O)=[N:42][CH:41]=4)[CH:34]=[N:33]5)[CH:28]=[CH:29][C:23]=3[N:22]=2)[CH2:19][C@@H:18]2[C@H:16]1[CH2:17]2)=O)(C)(C)C>C(Cl)Cl>[C:1]([OH:7])([C:3]([F:6])([F:5])[F:4])=[O:2].[C@@H:16]12[CH2:17][C@@H:18]1[CH2:19][C@@H:20]([C:21]1[NH:25][C:24]3[CH:26]=[C:27]([C:30]4[CH:31]=[C:32]5[C:37](=[CH:38][CH:39]=4)[N:36]=[C:35]([C:40]4[NH:44][C:43]([C@@H:45]6[CH2:50][C@@H:49]7[C@@H:47]([CH2:48]7)[NH:46]6)=[N:42][CH:41]=4)[CH:34]=[N:33]5)[CH:28]=[CH:29][C:23]=3[N:22]=1)[NH:15]2
Reactant: CC(C)(C)OC(=O)N1[C@@H]2C[C@@H]2C[C@H]1c1ncc(-c2cnc3cc(-c4ccc5nc([C@@H]6C[C@H]7C[C@H]7N6C(=O)OC(C)(C)C)[nH]c5c4)ccc3n2)[nH]1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: c1cc2nc(-c3cnc([C@@H]4C[C@H]5C[C@H]5N4)[nH]3)cnc2cc1-c1ccc2nc([C@@H]3C[C@H]4C[C@H]4N3)[nH]c2c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 147.5 %

Procedure:
TFA (0.25 mL, 3.24 mmol) was added to a solution of (1R,3S,5R)-tert-butyl 3-(5-(6-(2-((1R,3S,5R)-2-(tert-butoxycarbonyl)-2-azabicyclo[3.1.0]hexan-3-yl)-1H-benzo[d]imidazol-6-yl)quinoxalin-2-yl)-1H-imidazol-2-yl)-2-azabicyclo[3.1.0]hexane-2-carboxylate (10 mg, 0.015 mmol) in DCM (0.5 mL) and the mixture was stirred at rt for 16 h. The volatiles were removed under vacuum and the residue was triturated with Et2O. The resulting solid was rinsed with Et2O to yield a TFA salt of 6-(2-((1R,3S,5R)-2-azabicyclo[3.1.0]hexan-3-yl)-1H-benzo[d]imidazol-6-yl)-2-(2-((1R,3S,5R)-2-azabicyclo[3.1.0]hexan-3-yl)-1H-imidazol-5-yl)quinoxaline (10.5 mg) as yellow solid. LC-MS retention time 1.32 min; m/z 475 [M+H]+. (Column PHENOMENEX® Luna 3.0×50 mm S10. Solvent A=90% water: 10% methanol: 0.1% TFA. Solvent B=10% water: 90% methanol: 0.1% TFA. Flow Rate=4 mL/min. Start % B=0. Final % B=100. Gradient Time=3 min. Wavelength=220).
Reaction SMILES: [Cl:1][C:2]([Cl:24])([CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[C:3]([OH:5])=[O:4].[C:25](Cl)(=O)C(Cl)=O>CO>[CH3:25][O:4][C:3](=[O:5])[C:2]([Cl:24])([Cl:1])[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: O=C(Cl)C(=O)Cl
Reactant: O=C(O)C(Cl)(Cl)CCCCCCCCCCCCc1ccccc1
Solvent: CO
Product: COC(=O)C(Cl)(Cl)CCCCCCCCCCCCc1ccccc1
Yield: 56.8 %

Procedure:
1.98 g (5 mmol) 16 was stirred for 2 hours at 40° C. with 1.27 g (10 mmol) oxalyl chloride in 20 ml absolute methanol analogously to 103 (example 54). 1.1 g (57) 57 was obtained.
Reaction SMILES: [CH2:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH2:2]1.[C:10](OC(=O)C)(=[O:12])[CH3:11]>C(Cl)Cl>[CH2:1]1[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:10](=[O:12])[CH3:11])[CH:8]=2)[CH2:3][CH2:2]1
Reactant: CC(=O)OC(C)=O
Reactant: c1ccc2c(c1)CCC2
Solvent: ClCCl
Product: CC(=O)c1ccc2c(c1)CCC2
Temperature: 25 °C
Reaction time: 15 h
Yield: 88.1 %

Procedure:
A mixture of 2,3-dihydro-1H-indene (100.0 g, 0.85 mol) and acetic anhydride (104.2 g, 1.35 mol) was added drop-wise to a slurry of A1C13 (272.0 g, 2.04 mol) in CH2Cl2 (1000 ml) at 0° C. over a period of 3 h. The reaction mixture was stirred at room temperature under a nitrogen atmosphere for 15 h. Then the reaction mixture was poured into ice water (500 mL) and extracted with ethyl acetate (500 mL×3). The combined organic layers were washed with brine (500 mL), dried over Na2SO4 and evaporated in vacuo. The residue that was purified by column chromatography (petroleum ether:ethyl acetate=20:1) to give the product (120.0 g, 88%). 1H NMR (400 MHz, CDCl3) δ 2.08-2.15 (m, 2H), 2.58 (s, 3H), 2.95 (t, J=7.2, 4 H), 7.28 (d, J=8.0, 1H), 7.75 (d, J=8.0, 1H) 7.82 (s,1H).