Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([C:12]([OH:14])=[O:13])[CH:10]=2)[CH:5]=[CH:4][N:3]=1.CC(OC1C=CC=C(OC(C)C)C=1C1C(P(C2CCCCC2)C2CCCCC2)=CC=CC=1)C.CC(C1C=C(C(C)C)C(C2C(P(C3CCCCC3)C3CCCCC3)=C(OC)C=CC=2OC)=C(C(C)C)C=1)C.CC(C)([O-])C.[Na+].[C:92]([NH2:96])([CH3:95])([CH3:94])[CH3:93].C[Si]([N-][Si](C)(C)C)(C)C.[Li+]>O1CCOCC1>[C:92]([NH:96][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([C:12]([OH:14])=[O:13])[CH:10]=2)[CH:5]=[CH:4][N:3]=1)([CH3:95])([CH3:94])[CH3:93]
Reactant: O=C(O)c1ccc2ccnc(Cl)c2c1
Reactant: CC(C)(C)N
Agent: CC(C)(C)[O-]
Agent: CC(C)Oc1cccc(OC(C)C)c1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Agent: COc1ccc(OC)c(P(C2CCCCC2)C2CCCCC2)c1-c1c(C(C)C)cc(C(C)C)cc1C(C)C
Solvent: C1COCCO1
Product: CC(C)(C)Nc1nccc2ccc(C(=O)O)cc12
Temperature: 110 °C
Reaction time: 8 h

Procedure:
To a suspension of 1-chloroisoquinoline-7-carboxylic acid (100 mg, 0.482 mmol), RuPhos (6.5 mg, 0.014 mmol), BrettPhos (11.2 mg, 0.014 mmol) and sodium tert-butoxide (70.2 mg, 0.723 mmol) in dioxane (0.5 mL) was added t-butylamine (0.254 mL, 2.41 mmol). The vessel was sealed and mixture was heated to 110° C. and stirred overnight. The reaction was cooled down to room temperature and lithium bistrimethylsilylamide (0.136 mL, 0.723 mmol) was added. The reaction mixture was heated to 110° C. and left stirring overnight. The reaction mixture was cooled down to room temperature and filtered through celite and rinsed with methanol. The filtrate was concentrated under reduced pressure and 1N aqueous sodium hydroxide (1 mL) was added. Partitioned between ethyl acetate and a mixture of water and 1N aqueous sodium hydroxide. The layers were separated and the aqueous layer was acidified to pH 4. The aqueous layer was extracted into ethyl acetate. The extracts were dried over magnesium sulfate, filtered and concentrated under reduced pressure to obtain 1-(tert-butylamino)isoquinoline-7-carboxylic acid.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][C:13]([OH:15])=[O:14].[ClH:16].[CH3:17]OC(OC)(C)C>>[ClH:16].[CH3:17][O:14][C:13](=[O:15])[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][NH2:1]
Reactant: COC(C)(C)OC
Reactant: NCCCCCCCCCCCC(=O)O
Agent: Cl
Product: COC(=O)CCCCCCCCCCCN
Reaction time: 8 h
Yield: 90.5 %

Procedure:
To the suspension of 12-aminododecanoic acid (2.15 g; 10 mmol) in 2,2-dimethoxypropane (100 ml) was added 36% aqueous HCl (10 ml) and the mixture was treated in an ultrasonic bath until all solid material was dissolved. The mixture was then left to stand overnight, concentrated to dryness, dissolved in 40 ml of methanol and precipitated with approximately 500 ml of dry ether to give 2.4 g of 1 (90.5% yield).
Reaction SMILES: [N+:1]([O-:4])(O)=[O:2].[Cl:5][C:6]1[CH:7]=[C:8]([N:22]2[C:27](=[O:28])[NH:26][C:25](=[O:29])[CH:24]=[N:23]2)[CH:9]=[C:10]([Cl:21])[C:11]=1[O:12][C:13]1[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=1.O>C(O)(=O)C>[Cl:5][C:6]1[CH:7]=[C:8]([N:22]2[C:27](=[O:28])[NH:26][C:25](=[O:29])[CH:24]=[N:23]2)[CH:9]=[C:10]([Cl:21])[C:11]=1[O:12][C:13]1[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[C:15]([N+:1]([O-:4])=[O:2])[CH:14]=1
Reactant: COc1ccc(Oc2c(Cl)cc(-n3ncc(=O)[nH]c3=O)cc2Cl)cc1
Reactant: O=[N+]([O-])O
Solvent: CC(=O)O
Solvent: O
Product: COc1ccc(Oc2c(Cl)cc(-n3ncc(=O)[nH]c3=O)cc2Cl)cc1[N+](=O)[O-]
Temperature: 0 °C
Reaction time: 1.5 h

Procedure:
To a cooled (0° C.), stirred solution of nitric acid (20 mL) in acetic acid (65 mL) was added 2-[3,5-dichloro-4-(4-methoxy-phenoxy)-phenyl]-2H-[1,2,4]triazine-3,5-dione (5.0 g) and the resulting mixture was allowed to stir at ambient temperature for 1.5 h. The resulting solution was poured into 400 mL of water, the resulting solids filtered and dried to afford the title compound of Step A as a yellow solid, 5.1 g. MS Calc.:425.2; Found: 422.9.
Reaction SMILES: Br[C:2]1[N:27]=[C:5]2[CH:6]=[C:7]([NH:10][C:11]([C:13]3[N:17]([CH3:18])[N:16]=[CH:15][C:14]=3[C:19]([N:21]3[CH2:26][CH2:25][O:24][CH2:23][CH2:22]3)=[O:20])=[O:12])[CH:8]=[CH:9][N:4]2[N:3]=1.[NH:28]1[CH2:32][CH2:31][CH2:30][C:29]1=[O:33].C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCOCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C1(P(C2C=CC=CC=2)C2C3OC4C(=CC=CC=4P(C4C=CC=CC=4)C4C=CC=CC=4)C(C)(C)C=3C=CC=2)C=CC=CC=1>[O:33]=[C:29]1[CH2:30][CH2:31][CH2:32][N:28]1[C:2]1[N:27]=[C:5]2[CH:6]=[C:7]([NH:10][C:11]([C:13]3[N:17]([CH3:18])[N:16]=[CH:15][C:14]=3[C:19]([N:21]3[CH2:26][CH2:25][O:24][CH2:23][CH2:22]3)=[O:20])=[O:12])[CH:8]=[CH:9][N:4]2[N:3]=1
Reactant: O=C1CCCN1
Reactant: Cn1ncc(C(=O)N2CCOCC2)c1C(=O)Nc1ccn2nc(Br)nc2c1
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Product: Cn1ncc(C(=O)N2CCOCC2)c1C(=O)Nc1ccn2nc(N3CCCC3=O)nc2c1
Temperature: 100 °C
Reaction time: 8 h
Yield: 57 %

Procedure:
To an argon purged solution of N-(2-bromo-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-1-methyl-4-(morpholine-4-carbonyl)-1H-pyrazole-5-carboxamide (40 mg, 92.1 μmol) in dioxane (1.84 ml) were added pyrrolidin-2-one (8.47 μl, 111 μmol), cesium carbonate (42.0 mg, 129 μmol), tris(dibenzylideneacetone)dipalladium(0) (1.69 mg, 1.84 μmol) and 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (2.13 mg, 3.68 μmol). The resulting mixture was heated to 100° C. and stirred overnight under argon atmosphere. The crude material was applied on SiO2 and purified by flash chromatography over a 5 g SiO2 column using heptane/ethyl acetate 10-100% to ethyl acetate/methanol 2% as eluent to give 2-methyl-4-(morpholine-4-carbonyl)-2H-pyrazole-3-carboxylic acid [2-(2-oxo-pyrrolidin-1-yl)-[1,2,4]triazolo[1,5-a]pyridin-7-yl]-amide (23 mg, 57%) as light yellow solid. mp: 269.9, MS: m/z=439.1 (M+H+).
Reaction SMILES: [CH:1]1[C:10]2[CH:9]=[CH:8][CH:7]=[C:6]([NH2:11])[C:5]=2[CH:4]=[CH:3][N:2]=1.O=[C:13]1[CH2:17][CH2:16][N:15](C(OC(C)(C)C)=O)[CH2:14]1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>CC(O)=O>[NH:15]1[CH2:16][CH2:17][CH:13]([NH:11][C:6]2[C:5]3[CH:4]=[CH:3][N:2]=[CH:1][C:10]=3[CH:9]=[CH:8][CH:7]=2)[CH2:14]1
Reactant: CC(C)(C)OC(=O)N1CCC(=O)C1
Reactant: Nc1cccc2cnccc12
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Product: c1cc(NC2CCNC2)c2ccncc2c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a homogenous solution of isoquinolin-5-amine (15 g, 104 mmol) and tert-butyl 3-oxopyrrolidine-1-carboxylate (23.12 g, 125 mmol, 1.2 eq) in AcOH (300 mL) at 0° C. was added dropwise a solution of NaBH(OAc)3 (44.1 g, 208 mmol, 2 eq) in AcOH (200 mL). The mixture was stirred at room temperature overnight and concentrated to dryness. Then, the residue was adjusted to pH 10 by addition of saturated aqueous solution of Na2CO3 and extracted with DCM (×3). The combined organic layers were dried over Na2SO4, filtered and then concentrated under vacuum to afford the expected compound, which was used directly in the next step without further purification.
Reaction SMILES: [O:1]=[C:2]1[C:10]2[C:5](=[CH:6][C:7]([C:11]([O:13]C)=[O:12])=[CH:8][CH:9]=2)[CH2:4][NH:3]1.[OH-].[Na+].Cl>CO>[O:1]=[C:2]1[C:10]2[C:5](=[CH:6][C:7]([C:11]([OH:13])=[O:12])=[CH:8][CH:9]=2)[CH2:4][NH:3]1
Reactant: COC(=O)c1ccc2c(c1)CNC2=O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)c1ccc2c(c1)CNC2=O
Temperature: 25 °C
Reaction time: 24 h
Yield: 94.8 %

Procedure:
To a methanol (5.0 mL) solution of methyl 1-oxo-2,3-dihydro-1H-isoindole-5-carboxylate (0.33 g), a 1 mol/L aqueous sodium hydroxide solution (4.3 mL) was added, and the resultant was stirred at room temperature for 24 hours. A 1 mol/L aqueous hydrochloric acid solution was added to the reaction solution. The deposited solid was collected by filtration and dried to obtain the title compound (0.29 g) as a white solid.
Reaction SMILES: Cl.[NH2:2][C@@H:3]([CH2:11][C:12]1[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=1)[C:4]([N:6]1[CH2:10][CH2:9][CH2:8][CH2:7]1)=[O:5].CCN(C(C)C)C(C)C.[Cl:27][C:28]1[CH:29]=[C:30]2[CH:36]=[C:35]([C:37](O)=[O:38])[NH:34][C:31]2=[CH:32][N:33]=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F>CN(C=O)C>[O:5]=[C:4]([N:6]1[CH2:7][CH2:8][CH2:9][CH2:10]1)[C@@H:3]([NH:2][C:37]([C:35]1[NH:34][C:31]2=[CH:32][N:33]=[C:28]([Cl:27])[CH:29]=[C:30]2[CH:36]=1)=[O:38])[CH2:11][C:12]1[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=1
Reactant: N[C@@H](Cc1cccnc1)C(=O)N1CCCC1
Reactant: O=C(O)c1cc2cc(Cl)ncc2[nH]1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(N[C@@H](Cc1cccnc1)C(=O)N1CCCC1)c1cc2cc(Cl)ncc2[nH]1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of (S)-2-amino-3-pyridin-3-yl-1-pyrrolidin-1-ylpropan-1-one hydrochloride (Preparation 54, 239 mg, 0.94 mmol) in DMF (5 mL) was added DIPEA (0.60 mL, 3.28 mmol), 5-chloro-1H-pyrrolo[2,3-c]pyridine-2-carboxylic acid (Preparation 18, 184 mg, 0.94 mmol) and TBTU (330 mg, 1.03 mmol). The reaction mixture was stirred at rt for 16 h. The solvent was removed in vacuo and the residue partitioned between ethyl acetate (100 mL) and sodium hydroxide solution (2×100 mL, 1N). The organic phase was dried (MgSO4) and evaporated to dryness give the title compound as a brown solid. δH (CD3OD): 1.74–1.94 (4H, m), 3.12–3.39 (4H, m), 3.41–3.48 (1H, m), 3.69–3.75 (1H, m), 5.07–5.12 (1H, m), 7.16 (1H, s), 7.34–7.39 (1H, m), 7.67 (1H, s), 7.79–7.83 (1H, m), 8.37–8.42 (1H, m), 8.45–8.51 (1H, m), 8.56 (1H, s); m/z (ES+)=398 [M+H]+.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([S:12]([CH2:15][CH2:16][CH2:17][OH:18])(=[O:14])=[O:13])[CH:5]=[C:6]([CH3:11])[C:7]=1[N+:8]([O-:10])=[O:9].[C:19](=O)([O-])[O-].[Cs+].[Cs+].IC.O>C(#N)C>[CH3:19][O:18][CH2:17][CH2:16][CH2:15][S:12]([C:4]1[CH:5]=[C:6]([CH3:11])[C:7]([N+:8]([O-:10])=[O:9])=[C:2]([CH3:1])[CH:3]=1)(=[O:14])=[O:13]
Reactant: O=C([O-])[O-]
Reactant: Cc1cc(S(=O)(=O)CCCO)cc(C)c1[N+](=O)[O-]
Agent: [Cs+]
Solvent: CC#N
Solvent: CI
Solvent: O
Product: COCCCS(=O)(=O)c1cc(C)c([N+](=O)[O-])c(C)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
3-(3,5-Dimethyl-4-nitro-benzenesulfonyl)-propan-1-ol (1.4 g) is dissolved in 20 mL of acetonitrile, cesium carbonate (3.34 g) and iodometane (638 mL) are added and the reaction mixture is stirred at room temperature overnight. Water is added and the reaction mixture is extracted with ethyl ether. The organic phase is separated, dried over sodium sulfate and concentrated under vacuum. The residue is chromatographed on silica gel (hexane/ethyl acetate 100:0→50.50) to give the title compound. Yield: 1 g.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[Cl:7][C:8]1[C:9](F)=[CH:10][C:11]([F:21])=[C:12]([CH:20]=1)[C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14].[Cl:23][C:24]1[CH:25]=[C:26]([OH:38])[CH:27]=[N:28][C:29]=1[O:30][CH2:31][C:32]([F:37])([F:36])[CH:33]([F:35])[F:34].COC(C)(C)C>CS(C)=O>[Cl:7][C:8]1[C:9]([O:38][C:26]2[CH:27]=[N:28][C:29]([O:30][CH2:31][C:32]([F:36])([F:37])[CH:33]([F:35])[F:34])=[C:24]([Cl:23])[CH:25]=2)=[CH:10][C:11]([F:21])=[C:12]([CH:20]=1)[C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14]
Reactant: CC(C)(C)OC(=O)c1cc(Cl)c(F)cc1F
Reactant: Oc1cnc(OCC(F)(F)C(F)F)c(Cl)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: COC(C)(C)C
Product: CC(C)(C)OC(=O)c1cc(Cl)c(Oc2cnc(OCC(F)(F)C(F)F)c(Cl)c2)cc1F
Temperature: 25 °C
Reaction time: 3 h
Yield: 61 %

Procedure:
Potassium carbonate (3.02 g, 21.85 mmol) was added portionwise to a suspension of tert-butyl 5-chloro-2,4-difluorobenzoate (Preparation 59, 2.26 g, 9.09 mmol), 5-chloro-6-(2,2,3,3-tetrafluoropropoxy)pyridin-3-ol (Preparation 73, 2.25 g, 8.67 mmol) in DMSO (13.5 mL). The mixture was stirred at room temperature under nitrogen for 3 hours. tert-butyl methyl ether (50.0 mL) was added and the mixture was washed with water (3×50.0 mL). The organic layer was dried over sodium sulfate, filtered, and concentrated in vacuo. The resulting oil was suspended with heptane (20.0 mL) and concentrated in vacuo. The resulting solid was suspended in heptane (20.0 mL) and heated to 90° C. until full dissolution. The mixture was cooled with stirring and the residual solid collected by filtration. The filtrate was concentrated in vacuo and the resulting solid was suspended in heptane (10.0 mL) and heated to 90° C. until dissolution. The mixture was again cooled with stirring and the residual solid collected by filtration. The two crops were combined to yield the title compound as a white solid (2.58 g, 5.29 mmol, 61%):
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[N:6]=[CH:7][NH:8][CH:9]=1)=[O:4].[H-].[Na+].[Cl:12][C:13]1[CH:18]=[CH:17][C:16]([C@@H:19]2[C@:21]3([C:29]4[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=4)[N:23]([CH2:30][C:31]4C=CN=CC=4)[C:22]3=[O:37])[CH2:20]2)=[CH:15][CH:14]=1.BrCCN1C2C(=CC=CC=2)[C@@]2(C[C@@H]2C2C=CC(Cl)=CC=2)C1=O>CN(C=O)C>[CH3:1][O:2][C:3]([C:5]1[N:6]=[CH:7][N:8]([CH2:31][CH2:30][N:23]2[C:24]3[C:29](=[CH:28][CH:27]=[CH:26][CH:25]=3)[C@:21]3([CH2:20][C@H:19]3[C:16]3[CH:15]=[CH:14][C:13]([Cl:12])=[CH:18][CH:17]=3)[C:22]2=[O:37])[CH:9]=1)=[O:4]
Reactant: COC(=O)c1c[nH]cn1
Reactant: O=C1N(Cc2ccncc2)c2ccccc2[C@@]12C[C@@H]2c1ccc(Cl)cc1
Agent: O=C1N(CCBr)c2ccccc2[C@@]12C[C@@H]2c1ccc(Cl)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)c1cn(CCN2C(=O)[C@@]3(C[C@H]3c3ccc(Cl)cc3)c3ccccc32)cn1
Reaction time: 1 h
Yield: 35 %

Procedure:
To a solution of methyl-imidazole-4-carboxylate (100 mg, 0.2 mmol) in 1 mL of anhydrous DMF was added NaH (60% disp.) (8.8 mg, 0.22 mmol) at room temperature. The reaction mixture was stirred for 1 hour at that temperature. To the mixture was added a solution of racemic (1R,2S) and (1S,2R)-1′-(2-bromoethyl)-2-(4-chlorophenyl)spiro[cyclopropane-1,3′-indolin]-2′-one (75.2 mg, 0.2 mmol) in 1 mL of DMF. The reaction was stirred at room temperature for 14 hours and then concentrated under reduced pressure. The residue was dissolved in EtOAc and washed with saturated aqueous NaHCO3. The layers were separated and the aqueous layer was extracted with EtOAc. The organic layers were combined and washed with brine, dried over anhydrous Na2SO4, filtered and concentrated in vacuo to give the title compound as white solid (30 mg, 35%). LC/MS m/e calcd. for C23H20ClN3O3: 421, observed (M+H)+: 422.3.
Reaction SMILES: [F:1][CH:2]([F:38])[O:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[CH2:10][C:11]1[N:15]2[CH:16]=[C:17]([C:20]3[CH:21]=[N:22][C:23]([N:26]4[CH2:31][CH2:30][C:29]([CH3:36])([C:32]([O:34][CH3:35])=[O:33])[CH2:28][CH2:27]4)=[N:24][CH:25]=3)[CH:18]=[CH:19][C:14]2=[N:13][C:12]=1[CH3:37].CI.[CH3:41][Si](C)(C)N[Si](C)(C)C.[Li]>C1COCC1>[F:38][CH:2]([F:1])[O:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[CH:10]([C:11]1[N:15]2[CH:16]=[C:17]([C:20]3[CH:25]=[N:24][C:23]([N:26]4[CH2:27][CH2:28][C:29]([CH3:36])([C:32]([O:34][CH3:35])=[O:33])[CH2:30][CH2:31]4)=[N:22][CH:21]=3)[CH:18]=[CH:19][C:14]2=[N:13][C:12]=1[CH3:37])[CH3:41]
Reactant: C[Si](C)(C)N[Si](C)(C)C
Reactant: COC(=O)C1(C)CCN(c2ncc(-c3ccc4nc(C)c(Cc5ccccc5OC(F)F)n4c3)cn2)CC1
Agent: [Li]
Solvent: CI
Solvent: C1CCOC1
Product: COC(=O)C1(C)CCN(c2ncc(-c3ccc4nc(C)c(C(C)c5ccccc5OC(F)F)n4c3)cn2)CC1
Reaction time: 8 h
Yield: 24.6 %

Procedure:
A solution of Example 43 (1 g, 1.97 mmol) and methyl iodide (0.25 mL, 4.1 mmol) in THF (10 mL) was cooled under nitrogen to −78° C. and 1M lithium hexamethyldisilazane solution (8.0 mL, 8 mmol) was added dropwise. The mixture was left stirring overnight, allowing the temperature to rise slowly to ambient temperature. The reaction mixture was partitioned between EtOAc and brine. The organic layer was washed once with brine, dried over MgSO4, filtered and concentrated in vacuo, then purified by column chromatography on SiO2, eluting with EtOAc-hexane (4:1 v/v). The residue was crystallised from diethyl ether/hexane, filtered, and washed with diethyl ether/hexane, then dried, to give the title compound (0.26 g, 25%) as a white solid. δH (400 MHz, DMSO-d6) 8.63 (m, 2H), 8.35 (m, 1H), 7.56 (dd, J 7.6, 1.5 Hz, 1H), 7.50 (m, 1H), 7.43 (m, 1H), 7.34 (m, 1H), 7.28 (m, 1H), 7.16 (d, J 7.9 Hz, 1H), 7.12 (t, J 72, 76 Hz, 1H), 4.96 (m, 1H), 4.25 (m, 2H), 3.66 (s, 3H), 3.34 (m, 2H), 2.27 (s, 3H), 2.03 (m, 2H), 1.72 (d, J 7.3 Hz, 3H), 1.44 (m, 2H), 1.23 (m, 3H). LCMS (pH 10): MH+ 536, RT 2.31 minutes.
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][CH:10]=1)[C:6]#[N:7].Cl[C:12]1[CH:13]=[C:14]2[N:21]([CH3:22])[C@@H:20]([CH3:23])[CH2:19][N:15]2[C:16](=[O:18])[N:17]=1>>[CH3:22][N:21]1[C:14]2[N:15]([C:16](=[O:18])[N:17]=[C:12]([O:1][CH2:2][C:3]3[CH:4]=[C:5]([CH:8]=[CH:9][CH:10]=3)[C:6]#[N:7])[CH:13]=2)[CH2:19][C@@H:20]1[CH3:23]
Reactant: N#Cc1cccc(CO)c1
Reactant: C[C@H]1Cn2c(cc(Cl)nc2=O)N1C
Product: C[C@H]1Cn2c(cc(OCc3cccc(C#N)c3)nc2=O)N1C

Procedure:
The title compound was prepared by a procedure similar to that described for E9 starting from 3-(hydroxymethyl)benzonitrile and (S)-7-chloro-1,2-dimethyl-2,3-dihydroimidaz-o[1,2-c]pyrimidin-5(1H)-one.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:21]=[CH:22][CH:23]=1)[O:5][C:6]1[CH:7]=[CH:8][C:9]2[N:13]=[C:12]([NH:14][C:15]([CH:17]3[CH2:19][CH2:18]3)=[O:16])[NH:11][C:10]=2[CH:20]=1.[C:24]([C:26]([C:29]1[CH:30]=[C:31]([CH:35]=[CH:36][CH:37]=1)[C:32](O)=[O:33])([CH3:28])[CH3:27])#[N:25].Cl.C(N=C=NCCCN(C)C)C>CN(C)C1C=CN=CC=1.N1C=CC=CC=1>[C:24]([C:26]([C:29]1[CH:30]=[C:31]([CH:35]=[CH:36][CH:37]=1)[C:32]([NH:1][C:2]1[CH:23]=[CH:22][CH:21]=[C:4]([O:5][C:6]2[CH:7]=[CH:8][C:9]3[N:13]=[C:12]([NH:14][C:15]([CH:17]4[CH2:19][CH2:18]4)=[O:16])[NH:11][C:10]=3[CH:20]=2)[CH:3]=1)=[O:33])([CH3:28])[CH3:27])#[N:25]
Reactant: Nc1cccc(Oc2ccc3nc(NC(=O)C4CC4)[nH]c3c2)c1
Reactant: CC(C)(C#N)c1cccc(C(=O)O)c1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: c1ccncc1
Product: CC(C)(C#N)c1cccc(C(=O)Nc2cccc(Oc3ccc4nc(NC(=O)C5CC5)[nH]c4c3)c2)c1
Yield: 34 %

Procedure:
Using N-[6-(3-aminophenoxy)-1H-benzimidazol-2-yl]cyclopropanecarboxamide (156 mg, 506 mmol) produced in Example C1(vi), 3-(1-cyano-1-methylethyl)benzoic acid (195 mg, 1.03 mmol), pyridine (5 mL), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (407 mg, 2.12 mmol) and N,N-dimethylpyridine-4-amine (58.2 mg, 476 μmol) as starting materials, and in the same manner as in Example C1(vii), the title compound (168 mg, 69%) was obtained as colorless crystals.
Reaction SMILES: [CH3:1][C:2]1([CH3:11])[CH2:7][C:6]([CH3:9])([CH3:8])[CH2:5][C:4](=O)[CH2:3]1.[C:12]1([C:18]([C:20]2[CH:29]=[CH:28][C:23]([C:24]([O:26][CH3:27])=[O:25])=[CH:22][CH:21]=2)=O)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C1COCC1.Cl>C1(C)C=CC=CC=1.[Zn].Cl[Ti](Cl)(Cl)Cl.CCOC(C)=O.O>[C:12]1([C:18](=[C:4]2[CH2:3][C:2]([CH3:11])([CH3:1])[CH2:7][C:6]([CH3:9])([CH3:8])[CH2:5]2)[C:20]2[CH:21]=[CH:22][C:23]([C:24]([O:26][CH3:27])=[O:25])=[CH:28][CH:29]=2)[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: COC(=O)c1ccc(C(=O)c2ccccc2)cc1
Reactant: CC1(C)CC(=O)CC(C)(C)C1
Agent: Cl[Ti](Cl)(Cl)Cl
Agent: Cl
Agent: [Zn]
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Solvent: O
Product: COC(=O)c1ccc(C(=C2CC(C)(C)CC(C)(C)C2)c2ccccc2)cc1
Temperature: -10 °C
Reaction time: 0.17 h
Yield: 62.7 %

Procedure:
A stirred suspension of Zn dust (2.45 g, 37.5 mmol), 3,3,5,5-tetramethylcyclohexanone (1.93 g, 12.5 mmol), 19 (3.00 g, 12.5 mmol) and THF (100 mL) under N2 was cooled to −10° C. and a 1 M solution of TiCl4 in toluene (19.5 mL) was added, dropwise, over 10 min. After addition was complete the reaction was allowed to warm to room temperature and then heated at 90° C. for 7 h. The reaction was cooled to room temp and then chilled to −10° C. and concentrated HCl (15 mL) added dropwise followed by water (15 mL). The dark reaction turns a pale purple. EtOAc (60 mL) was added and the mixture washed with water (2×60 mL) and brine (1×60 mL) then dried (MgSO4) and concentrated to 5.1 g of a pale yellow oil. The crude product was purified by column chromatography on 200 g silica gel with a 100% hexanes to 2% EtOAc/hexanes gradient to afford 2.84 g of a white solid which was recrystallized from hexanes. Yield: 0.95 g (21%) of the title compound 20 which was contaminated with ˜5% of the pinacol intermediate. 1H NMR (400 MHz, DMSO-d6): δ 7.87 (d, J=8.2 Hz, 2H), 7.15-7.31 (m, 7H), 3.80 (s, 3H), 1.89 (s, 2H), 1.86 (s, 2H), 1.25 (s, 2H), 0.87 (s, 6H), 0.86 (s, 6H). Anal. Calcd for C25H30O2: C, 82.80; H, 8.36. Found: C, 82.94; H, 8.51.
Reaction SMILES: [NH:1]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[C@@H:2]([C:10]([OH:12])=O)[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.CN1CCOCC1.ClC(OCC(C)C)=O.[O:35]1[CH2:40][CH2:39][CH:38]([CH2:41][N:42]2[CH2:47][CH2:46][CH:45]([CH2:48][NH2:49])[CH2:44][CH2:43]2)[CH2:37][CH2:36]1.[OH-].[Na+]>ClCCl>[C:16]([O:15][C:13](=[O:14])[NH:1][C@@H:2]([C:10](=[O:12])[NH:49][CH2:48][CH:45]1[CH2:44][CH2:43][N:42]([CH2:41][CH:38]2[CH2:37][CH2:36][O:35][CH2:40][CH2:39]2)[CH2:47][CH2:46]1)[CH2:3][C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1)([CH3:19])([CH3:18])[CH3:17]
Reactant: NCC1CCN(CC2CCOCC2)CC1
Reactant: CC(C)(C)OC(=O)N[C@H](Cc1ccccc1)C(=O)O
Agent: CC(C)COC(=O)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CN1CCOCC1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N[C@H](Cc1ccccc1)C(=O)NCC1CCN(CC2CCOCC2)CC1
Temperature: 0 °C
Reaction time: 1 h
Yield: 82.5 %

Procedure:
A solution consisting of 10 g of Boc-D-Phe-OH, 40 ml of dichloromethane and 4.6 ml of N-methylmorpholine is slowly dripped into a solution of 5.4 ml of isobutyl chloroformate in 60 ml of dichloromethane cooled to 0° C., at a rate such that the inner temperature does not exceed 5° C. The resulting mixture is maintained under stirring at 0° C. for 1 hour. A solution consisting of 8.0 g of (11) in 20 ml of dichloromethane is dripped into the reaction mixture at a rate such that the temperature does not exceed 5° C. The solution is maintained under stirring at 0° C. for 1 hour, and at ambient temperature for 5 hours. After a process control, 100 ml of 1M NaOH is added to the mixture, the two phases are separated, the organic phase is washed with water (2×), and after a low-pressure solvent change with ethyl acetate compound (12) is crystallised from ethyl acetate, to obtain 14.29 g of white solid. Yield 83%.
Reaction SMILES: [K+].[CH2:2]([N:9]([CH3:14])[CH2:10][C:11]([O-:13])=[O:12])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[Br:15][CH2:16][CH2:17]O.Cl.CN(C)CCCN=C=NCC>ClCCl.CN(C)C1C=CN=CC=1>[Br:15][CH2:16][CH2:17][O:12][C:11](=[O:13])[CH2:10][N:9]([CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1)[CH3:14]
Reactant: CN(CC(=O)[O-])Cc1ccccc1
Reactant: OCCBr
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Product: CN(CC(=O)OCCBr)Cc1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 21.9 %

Procedure:
N-Benzyl-N-methyl glycine potassium salt (2.00 g, 11.16 mmol) and 2-Bromo ethanol (2.48 g, 17.86 mmol) was suspended in 20 mL of dichloromethane. To this solution was added 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (6.40 g, 33.5 mmol) and 4-(dimethylamino)pyridine (1.00 g) and the reaction was stirred at 25° C. overnight. The mixture was diluted with 40 mL of dichloromethane, and was washed with water (1×60 mL), saturated sodium bicarbonate solution (2×60 mL), and brine (1×60 mL). The organic phase was then dried over magnesium sulfate, and filtered through a pad of Celite. Evaporation of the solvent in vacuo afforded an oil, which was purified on silica gel eluting with ethyl acetate to afford N-Benzyl-N-methyl glycine 2-bromoethyl ester as an oil (0.70 g).