Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CO[CH:3](OC)[CH2:4][CH2:5][CH2:6][CH2:7][N:8]1[CH2:13][CH2:12]N(C(OC(C)(C)C)=O)CC1.[C:23]([O-])([O-])=O.[K+].[K+]>S(=O)(=O)(O)O>[NH:8]1[C:7]2[C:6](=[CH:5][CH:4]=[CH:3][CH:23]=2)[CH:12]=[CH:13]1
Reactant: COC(CCCCN1CCN(C(=O)OC(C)(C)C)CC1)OC
Reactant: O=C([O-])[O-]
Agent: O=S(=O)(O)O
Agent: [K+]
Product: c1ccc2[nH]ccc2c1
Yield: 44 %

Procedure:
A mixture of Intermediate 1 (5.0 g, 28.6 mmol) and 5-[4-(tert-butyloxycarbonyl)piperazin-1-yl]pentanal dimethylacetal (9.03 g, 28.6 mmol) in 4% sulphuric acid (150 ml) was heated at reflux for 48 h. The solution was cooled in an ice-bath, basified with solid K2CO3 and extracted with butan-1-ol (×3). The solvent was removed under vacuum and azeotroped with hexane (×2). The crude product was purified by chromatography on silica gel eluting with CH2Cl2 /MeOH/NH3 (30:8:1) to give the title-indole (3.9 g, 44%). The 3.5 hydrogen oxalate salt was prepared using 200 mg of free base: mp 90-92° C. (Found: C, 45.97; H, 4.76; N, 13.77. C17H22N6.3.5(C2H2O4) requires C, 46.08; H, 4.76; N, 13.43%); δ(360 MHz, D2O) 2.12-2.24 (2H, m, CH2); 2.93 (2H, t, J=7 Hz, CH2); 3.46-3.76 (8H, m, 4 of CH2); 7.37 (1H, dd, J=1.9 and 8.7 Hz, Ar--H); 7.39 (1H, s, Ar--H); 7.66 (1H, d, J=8.7, Ar--H); 7.82 (1H, d, J=1.9 Hz, Ar--H); 9.13 (2H, s, Triazole-H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([OH:13])=O)[CH:10]=2)[CH:7]=1.[F:14][C:15]1[CH:24]=[CH:23][CH:22]=[C:21]2[C:16]=1[CH2:17][CH2:18][NH:19][CH:20]2[CH3:25]>>[Br:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([N:19]3[CH2:18][CH2:17][C:16]4[C:21](=[CH:22][CH:23]=[CH:24][C:15]=4[F:14])[CH:20]3[CH3:25])=[O:13])[CH:10]=2)[CH:7]=1
Reactant: O=C(O)c1cc2ncc(Br)cn2n1
Reactant: CC1NCCc2c(F)cccc21
Product: CC1c2cccc(F)c2CCN1C(=O)c1cc2ncc(Br)cn2n1

Procedure:
In close analogy to the procedure described in Example 1, 6-bromo-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid is reacted with 5-fluoro-1-methyl-1,2,3,4-tetrahydro-isoquinoline to provide the title compound in moderate yield.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][C:5]2[S:11](=[O:13])(=[O:12])[CH2:10][CH2:9][C:8]([C:14]([O:16][CH3:17])=[O:15])=[CH:7][C:6]=2[CH:18]=1.[F:19][C:20]1[CH:27]=[CH:26][C:23]([CH2:24]Cl)=[CH:22][CH:21]=1.C(=O)([O-])[O-].[K+].[K+].CN(C=O)C>O>[F:19][C:20]1[CH:27]=[CH:26][C:23]([CH2:24][O:1][C:2]2[CH:3]=[CH:4][C:5]3[S:11](=[O:13])(=[O:12])[CH2:10][CH2:9][C:8]([C:14]([O:16][CH3:17])=[O:15])=[CH:7][C:6]=3[CH:18]=2)=[CH:22][CH:21]=1
Reactant: Fc1ccc(CCl)cc1
Reactant: COC(=O)C1=Cc2cc(O)ccc2S(=O)(=O)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)C1=Cc2cc(OCc3ccc(F)cc3)ccc2S(=O)(=O)CC1
Temperature: 55 °C
Reaction time: 7 h

Procedure:
A mixture of methyl 7-hydroxy-1,1-dioxo-2,3-dihydro-1-benzothiepine-4-carboxylate (200 mg), 4-fluorobenzyl chloride (0.090 ml), potassium carbonate (134 mg) and DMF (5 ml) was stirred at 55° C. for 7 hours. The reaction mixture was mixed with water and was extracted with ethyl acetate. The organic layer was washed with an aqueous saturated solution of sodium chloride and was dried with magnesium sulfate. After concentration under reduced pressure, the residue was subjected to separation and purification using column chromatography (ethyl acetate/hexane 1:1) to obtain methyl 7-[(4-fluorobenzyl)oxy]-1,1-dioxo-2,3-dihydro-1-benzothiepine-4-carboxylate (162 mg) as colorless crystals.
Reaction SMILES: C(OC(=O)[N:7]([CH2:14][CH2:15][O:16][C:17]1[CH:22]=[C:21]([C:23](=[O:33])[N:24]([CH2:29][CH2:30][C:31]#[N:32])[CH:25]2[CH2:28][CH2:27][CH2:26]2)[CH:20]=[C:19]([Cl:34])[CH:18]=1)[C:8]1[CH:13]=[CH:12][N:11]=[CH:10][CH:9]=1)(C)(C)C.[OH2:36].[F:37][C:38]([F:43])([F:42])[C:39]([OH:41])=[O:40]>ClCCl>[F:37][C:38]([F:43])([F:42])[C:39]([OH:41])=[O:40].[C:31]([CH2:30][CH2:29][N:24]([CH:25]1[CH2:28][CH2:27][CH2:26]1)[C:23](=[O:33])[C:21]1[CH:22]=[C:17]([O:16][CH2:15][CH2:14][NH:7][C:8]2[CH:9]=[CH:10][N:11]=[CH:12][CH:13]=2)[CH:18]=[C:19]([Cl:34])[CH:20]=1)(=[O:36])[NH2:32]
Reactant: CC(C)(C)OC(=O)N(CCOc1cc(Cl)cc(C(=O)N(CCC#N)C2CCC2)c1)c1ccncc1
Reactant: O
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: NC(=O)CCN(C(=O)c1cc(Cl)cc(OCCNc2ccncc2)c1)C1CCC1
Reaction time: 24 h

Procedure:
A solution of (2-{3-chloro-5-[(2-cyano-ethyl)-cyclobutyl-carbamoyl]-phenoxy}-ethyl)-pyridin-4-yl-carbamic acid tert-butyl ester (0.042 g) and water (0.050 ml) in mixture of trifluoroacetic acid (1 ml) and dichloromethane (1 ml) was stored at room temperature for 24 h and then the solvent removed under reduced pressure. The residue was subjected to preparative hplc to give the title compound (0.027 g) as a colourless gum by concentration of the required fraction under reduced pressure and drying by repetitive addition of acetonitrile and concentration under reduced pressure.
Reaction SMILES: C(O[C:5](=[O:7])C)(=O)C.C(O)=O.[Br:11][C:12]1[CH:18]=[CH:17][C:15]([NH2:16])=[CH:14][CH:13]=1>C1COCC1>[Br:11][C:12]1[CH:18]=[CH:17][C:15]([NH:16][CH:5]=[O:7])=[CH:14][CH:13]=1
Reactant: Nc1ccc(Br)cc1
Reactant: CC(=O)OC(C)=O
Solvent: C1CCOC1
Solvent: O=CO
Product: O=CNc1ccc(Br)cc1
Temperature: 0 °C
Reaction time: 3 h
Yield: 99.2 %

Procedure:
A 5-Liter round bottom flask was charged with acetic anhydride (488 mL, 5.2 mol) and cooled to 0° C. Formic acid (240 mL, 6.4 mol) was then added at a rate that did not elevate the temperature of the reaction mixture above 10° C. After the formic acid was added, the temperature of the reaction was raised to 50-60° C. and stirred for 3 hours. The reaction was then cooled to 0° C. and 400 mL of THF was added. A solution of 4-bromoaniline (344 g, 2.0 mol) in 800 mL of THF was added dropwise. After the addition was complete, the reaction was allowed to stir at this temperature for 4 hours. The reaction was checked by thin-layer chromatography and found to be complete. The reaction mixture was transferred to a round bottom flask and the solvent was removed in vacuo. When the solvent had been removed, the residue crystallized. The solid was triturated with heptane and filtered. Obtained 396.8 grams of desired N-(4-bromo-phenyl)-formamide. Yield 99.2% The spectral properties of the solid were consistent with the desired material. Step (2): (4-bromo-phenyl)-methyl-amine
Reaction SMILES: C[O:2][CH:3](OC)[C:4]1[CH:9]=[C:8]([O:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH:7]=[CH:6][C:5]=1[N+:17]([O-:19])=[O:18].Cl.O>C1COCC1>[N+:17]([C:5]1[CH:6]=[CH:7][C:8]([O:10][C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=2)=[CH:9][C:4]=1[CH:3]=[O:2])([O-:19])=[O:18]
Reactant: COC(OC)c1cc(Oc2ccccc2)ccc1[N+](=O)[O-]
Agent: Cl
Solvent: C1CCOC1
Solvent: O
Product: O=Cc1cc(Oc2ccccc2)ccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 48 h

Procedure:
To a solution of 2-(dimethoxymethyl)-1-nitro-4-phenoxy-benzene (7.4 g, 0.0256 mol) in THF (80 mL) was added 12 N HCl (10 mL) and water (20 mL). The resulting mixture was stirred at room temperature for 2 days. Water was then added, and the mixture was extracted with diisopropyl ether. The organic layer was separated, washed with 10% aqueous NaHCO3 solution and then with water, dried (MgSO4), filtered, and concentrated to yield a yellow solid.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([N:10]2[C:14]([OH:15])=[CH:13][C:12]([C:16]([F:19])([F:18])[F:17])=[N:11]2)=[CH:6][CH:5]=1)([O-:3])=[O:2].C([O-])([O-])=O.[Cs+].[Cs+].Br[CH2:27][N:28]1[C:32](=[O:33])[C:31]2[C:34]([CH:40]([CH3:42])[CH3:41])=[CH:35][C:36]([O:38][CH3:39])=[CH:37][C:30]=2[S:29]1(=[O:44])=[O:43].O>CO.CN(C=O)C>[CH:40]([C:34]1[C:31]2[C:32](=[O:33])[N:28]([CH2:27][O:15][C:14]3[N:10]([C:7]4[CH:8]=[CH:9][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=4)[N:11]=[C:12]([C:16]([F:19])([F:18])[F:17])[CH:13]=3)[S:29](=[O:44])(=[O:43])[C:30]=2[CH:37]=[C:36]([O:38][CH3:39])[CH:35]=1)([CH3:42])[CH3:41]
Reactant: O=[N+]([O-])c1ccc(-n2nc(C(F)(F)F)cc2O)cc1
Reactant: COc1cc(C(C)C)c2c(c1)S(=O)(=O)N(CBr)C2=O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CO
Product: COc1cc(C(C)C)c2c(c1)S(=O)(=O)N(COc1cc(C(F)(F)F)nn1-c1ccc([N+](=O)[O-])cc1)C2=O
Temperature: 20 °C
Reaction time: 4 h
Yield: 47.3 %

Procedure:
A mixture of 1-(4-nitrophenyl)-3-trifluoromethyl-5-hydroxypyrazole (450 mg; 1.65 mmol) and Cs2CO3 (269 mg; 0.825 mmol) in methanol (9 ml) was stirred at 20° C. for 4 hours. The solvent was concentrated in vacuo, and the residue was dried in vacuo overnight. To a solution of the above residue in 7 ml of DMF was added 2-bromomethyl-4-isopropyl-6-methoxy-1,2-benzisothiazol-3(2H)-one 1,1-dioxide (479 mg, 1.37 mmol) and the resulting mixture was stirred at room temperature (20° C.) for 3 hours and then poured into water. The above mixture was extracted with ether (3×) and the organic layer was dried over sodium sulfate, and concentrated in vacuo. The residue was purified by column chromatography (silica gel; 18-33% ethyl acetate in hexane) and recrystallized from methylene chloride/hexane to afford 350 mg (47%) of 4-isopropyl-6-methoxy-2-[1-(4-nitrophenyl)-3-trifluoromethylpyrazol-5-yl-oxymethyl)-1,2-benzisothiazol-3(2H)-one 1,1-dioxide (Formula I: R1 =4-NO2 --Ph; R2 =CF3 ; R3 =H; R4 =CH(CH3)2 ; R5 =6-OCH3) as a white solid, m.p. 185°-187° C.
Reaction SMILES: [K].[OH:2][C:3]1[CH:4]=[CH:5][C:6]([CH3:9])=[N:7][CH:8]=1.Br[C:11]1[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:13][CH:12]=1>CN(C)C=O.CO.[Cu]>[F:18][C:17]([F:20])([F:19])[C:14]1[CH:15]=[CH:16][C:11]([O:2][C:3]2[CH:4]=[CH:5][C:6]([CH3:9])=[N:7][CH:8]=2)=[CH:12][CH:13]=1
Reactant: Cc1ccc(O)cn1
Reactant: FC(F)(F)c1ccc(Br)cc1
Agent: [Cu]
Agent: [K]
Solvent: CO
Solvent: CN(C)C=O
Product: Cc1ccc(Oc2ccc(C(F)(F)F)cc2)cn1
Temperature: 125 °C
Reaction time: 18 h

Procedure:
4 g of a potassium salt of 5-hydroxy-2-methylpyridine was suspended in 10 ml of dimethylformamide, and 6.15 g of p-bromobenzotrifluoride and 500 mg of a copper powder were added to the suspension, followed by stirring in a nitrogen stream at 125° C. for 18 hours to effect the reaction. The reaction mixture was allowed to cool, diluted with 50 ml of methanol and then filtered. The filtrate was immediately dried to a solid, and 150 ml of chloroform and 100 ml of water were added to the residue. The resulting mixture was adjusted to a pH of 9.5 with 5 N sodium hydroxide and any insoluble matter again separated by filtration. The chloroform layer was dried with anhydrous sodium sulfate and immediately concentrated to dryness to obtain 5.6 g of oily 5-(p-trifluoromethylphenoxy)-2-methylpyridine.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]([CH2:12][C:13]3[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=3)[CH2:10][CH2:9][C:8]([C:21]([O:23]C)=[O:22])=[CH:7][C:6]=2[CH:25]=1.[OH-].[Na+].O.Cl>O1CCCC1.CO>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]([CH2:12][C:13]3[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=3)[CH2:10][CH2:9][C:8]([C:21]([OH:23])=[O:22])=[CH:7][C:6]=2[CH:25]=1
Reactant: COC(=O)C1=Cc2cc(Br)ccc2N(Cc2ccc(OC)cc2)CC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: COc1ccc(CN2CCC(C(=O)O)=Cc3cc(Br)ccc32)cc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 72.5 %

Procedure:
To a solution of methyl 7-bromo-1-(4-methoxybenzyl)-2,3-dihydro-1-benzazepine-4-carboxylate (920 mg) in a mixture of tetrahydrofuran (70 ml) and methanol (70 ml) was added 1N sodium hydroxide solution (23 ml), and the mixture was stirred at room temperature for 1 day. Then, to the mixture was added water at 0° C., and 1N hydrochloric acid was further added to make acidic (pH=4), and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine and dried with magnesium sulfate. The solvent was evaporated under reduced pressure, and the resulting solid was recrystallized from hexane-ethyl acetate to give 7-bromo-1-(4-methoxybenzyl)-2,3-dihydro-1-benzazepine-4-carboxylic acid (644 mg) as yellow crystals.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([CH2:25][C@H:26]([NH:28][C:29](=[O:33])[CH2:30][C:31]#[N:32])[CH3:27])[N:9]=[C:10]([C:11]3[CH:16]=[CH:15][C:14]([O:17][C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)=[CH:13][C:12]=3[F:24])[C:3]=12.N1CCCCC1.[CH2:40]([O:42][C:43]([CH3:47])([CH3:46])[CH:44]=O)[CH3:41]>C(O)C>[NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([CH2:25][C@H:26]([NH:28][C:29](=[O:33])[C:30]([C:31]#[N:32])=[CH:44][C:43]([O:42][CH2:40][CH3:41])([CH3:47])[CH3:46])[CH3:27])[N:9]=[C:10]([C:11]3[CH:16]=[CH:15][C:14]([O:17][C:18]4[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=4)=[CH:13][C:12]=3[F:24])[C:3]=12
Reactant: C[C@H](Cn1nc(-c2ccc(Oc3ccccc3)cc2F)c2c(N)ncnc21)NC(=O)CC#N
Reactant: CCOC(C)(C)C=O
Solvent: CCO
Solvent: C1CCNCC1
Product: CCOC(C)(C)C=C(C#N)C(=O)N[C@H](C)Cn1nc(-c2ccc(Oc3ccccc3)cc2F)c2c(N)ncnc21
Temperature: 85 °C
Yield: 7.7 %

Procedure:
To a sealed tube was added N-[(1R)-2-[4-amino-3-(2-fluoro-4-phenoxy-phenyl)pyrazolo[3,4-d]pyrimidin-1-yl]-1-methyl-ethyl]-2-cyano-acetamide (105 mg, 0.24 mmol), piperidine (0.01 mL, 0.12 mmol), 2-ethoxy-2-methyl-propanal (0.07 mL, 0.47 mmol) and ethanol (4 mL). The tube was capped, and heated to 85° C. for 60 hrs. The reaction was cooled and evaporated. The resulting crude oil was dissolved in DCM (30 mL) and washed with water (30 mL) and brine, then dried (MgSO4), filtered and concentrated. The resulting material was purified by Isolera (10 g column, 3%-7% MeOH/DCM) to obtain 10 mg (8%) of the title compound. MS (pos. ion) m/z: 544 (M+1).
Reaction SMILES: [C:1]1([C:7]#[C:8][C:9]2[CH:18]=[CH:17][C:16]([N+:19]([O-])=O)=[CH:15][C:10]=2[C:11]([O:13][CH3:14])=[O:12])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1>[Pd].C(OCC)(=O)C>[CH2:8]([C:9]1[CH:18]=[CH:17][C:16]([NH2:19])=[CH:15][C:10]=1[C:11]([O:13][CH3:14])=[O:12])[CH2:7][C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: COC(=O)c1cc([N+](=O)[O-])ccc1C#Cc1ccccc1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: COC(=O)c1cc(N)ccc1CCc1ccccc1
Reaction time: 16 h
Yield: 99.6 %

Procedure:
A mixture of compound 76(9.4 g), 10% Pd/C (0.94 g) and ethyl acetate (1 L) was stirred under an hydrogen atmosphere at 1 bar pressure for 16 hours. The mixture was filtered through a pad of Celite and the filtrate evaporated under reduced pressure to give methyl 2-phenethyl-5-aminobenzoate (compound 77) as an oil(8.5 g).
Reaction SMILES: I[C:2]1[N:3]([S:24]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)(=[O:26])=[O:25])[C:4]2[C:9]([CH:10]=1)=[C:8]([N:11]1[CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:13][CH2:12]1)[CH:7]=[CH:6][CH:5]=2.[C:33]1(B(O)O)[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1.C([O-])([O-])=O.[K+].[K+]>C(COC)OC.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:33]1([C:2]2[N:3]([S:24]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)(=[O:25])=[O:26])[C:4]3[C:9]([CH:10]=2)=[C:8]([N:11]2[CH2:12][CH2:13][N:14]([C:17]([O:19][C:20]([CH3:22])([CH3:21])[CH3:23])=[O:18])[CH2:15][CH2:16]2)[CH:7]=[CH:6][CH:5]=3)[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1
Reactant: CC(C)(C)OC(=O)N1CCN(c2cccc3c2cc(I)n3S(=O)(=O)c2ccccc2)CC1
Reactant: OB(O)c1ccccc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: COCCOC
Product: CC(C)(C)OC(=O)N1CCN(c2cccc3c2cc(-c2ccccc2)n3S(=O)(=O)c2ccccc2)CC1

Procedure:
tert-Butyl 4-[2-iodo-1-(phenylsulfonyl)-1H-indol-4-yl]-1-piperazinecarboxylate(40 mg, 0.07 mmol), phenyl boronic acid (12 mg, 0.1 mmol), Pd(PPh3)4 (2 mg, 0.002 mmol) and a 2M aqueous solution of K2CO3 (0.075 mL) were stirred for 3 days at 80° C. in dimethoxyethane (2 mL). After evaporation of the solvent, the crude was purified by column chromatography (SiO2) and led to 30 mg of the desired compound (80%). 1H NMR (270 MHz, DMSO-d6) δ 8.02 (d, J=8 Hz, 1 H), 7.55–7.20 (in, 11 H), 6.78 (t, J=8 Hz, 1 H), 7.57 (s, 1 H), 3.58 (in, 4 H), 3.02 (in, 4 H), 1.48 (in, 9 H). MS (ESI+) for m/z 518 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[CH:29]=[CH:28][C:5]([CH2:6][O:7][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[CH2:14][CH2:15][NH:16][CH2:17][C:18]2[CH:27]=[CH:26][C:21]([C:22]([O:24][CH3:25])=[O:23])=[CH:20][CH:19]=2)=[CH:4][CH:3]=1.Br[CH2:31][CH2:32][C:33]1[CH:40]=[CH:39][C:36]([C:37]#[N:38])=[CH:35][CH:34]=1.C(=O)([O-])[O-].[Na+].[Na+]>C(#N)C>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][O:7][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[CH2:14][CH2:15][N:16]([CH2:17][C:18]2[CH:19]=[CH:20][C:21]([C:22]([O:24][CH3:25])=[O:23])=[CH:26][CH:27]=2)[CH2:31][CH2:32][C:33]2[CH:40]=[CH:39][C:36]([C:37]#[N:38])=[CH:35][CH:34]=2)=[CH:28][CH:29]=1
Reactant: N#Cc1ccc(CCBr)cc1
Reactant: COC(=O)c1ccc(CNCCc2ccccc2OCc2ccc(Br)cc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC#N
Product: COC(=O)c1ccc(CN(CCc2ccc(C#N)cc2)CCc2ccccc2OCc2ccc(Br)cc2)cc1
Yield: 70.5 %

Procedure:
200 mg (0.44 mmol) of methyl 4-({2-[2-(4-bromobenzyloxy)phenyl]ethylamino}methyl)benzoate from Example 5A, 101 mg (0.48 mmol) of 4-(2-bromoethyl)benzonitrile and 51.4 mg (0.48 mmol) of sodium carbonate are heated in 5 ml of acetonitrile to reflux for 5 hours. A further 101 mg (0.48 mmol) of 4-(2-bromoethyl)benzonitrile are then added, and the reaction solution is stirred further under reflux overnight. After the reaction solution has cooled, the mixture is concentrated to dryness, and the residue is taken up in ethyl acetate and washed with water and saturated sodium chloride solution. Drying over sodium sulfate is followed by filtration and concentration. The crude product is purified by preparative HPLC. 183 mg (0.31 mmol, 69% yield) of a pale yellow oil are obtained.
Reaction SMILES: [Si:1]([O:8][C@H:9]([C:33]1[CH:34]=[N:35][CH:36]=[CH:37][CH:38]=1)[C@H:10]1[CH2:14][CH2:13][C@@H:12]([CH2:15][C:16]2[CH:21]=[CH:20][C:19]([C:22]([O:24]C)=[O:23])=[CH:18][CH:17]=2)[N:11]1[C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[OH-].[Li+]>CO.O.O>[C:29]([O:28][C:26]([N:11]1[C@@H:10]([C@H:9]([O:8][Si:1]([C:4]([CH3:6])([CH3:5])[CH3:7])([CH3:3])[CH3:2])[C:33]2[CH:34]=[N:35][CH:36]=[CH:37][CH:38]=2)[CH2:14][CH2:13][C@H:12]1[CH2:15][C:16]1[CH:17]=[CH:18][C:19]([C:22]([OH:24])=[O:23])=[CH:20][CH:21]=1)=[O:27])([CH3:30])([CH3:31])[CH3:32]
Reactant: COC(=O)c1ccc(C[C@@H]2CC[C@H]([C@H](O[Si](C)(C)C(C)(C)C)c3cccnc3)N2C(=O)OC(C)(C)C)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CC(C)(C)OC(=O)N1[C@H](Cc2ccc(C(=O)O)cc2)CC[C@@H]1[C@H](O[Si](C)(C)C(C)(C)C)c1cccnc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 54.1 %

Procedure:
To a stirred solution of the title compound from Step D (2.5 g, 4.6 mmol) in methanol/water 4:1 (30 mL) was added lithium hydroxide (533 mg, 23.1 mmol). The resulting mixture was stirred at RT overnight. The mixture was diluted with water and extracted with ether. The aqueous layer was acidified with 1N citric acid to PH 4.5, and then extracted with ethyl acetate. The organic layer was separated and washed with water, brine, dried over Na2SO4, and concentrated. The residue was purified by reverse phase HPLC (Luna10u, 250×50 mm I.D.; 45-65% 0.1% trifluoroacetic acid in acetonitrile/0.1% trifluoroacetic acid in water gradient) to afford 1.31 g (74%) of the title compound (i-3) as a white solid. 1H NMR (400 MHz, CDCl3): δ 8.64 (s, 2H), 7.93 (d, J=7.8 Hz, 2H), 7.80 (s, 1H), 7.44-7.38 (m, 1H), 7.03 (s, 2H), 5.66-5.33 (m, 1H), 4.16 (s, 1H), 4.00-3.88 (m, 1H), 3.01-2.95 (m, 1H), 2.68-1.58 (m, 1H), 2.04-1.83 (m, 2H), 1.60 (s, 9H), 1.31-1.20 (m, 2H), 0.96 (s, 9H), 0.17 (s, 3H), 0.00 (s, 3H). MS: m/z (ESI) 527 (M+1).
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C:12]([CH3:30])([CH3:29])[CH2:13][C:14]([NH:16][C@@H:17]1[CH2:23][CH2:22][C:21]2[CH:24]=[CH:25][CH:26]=[CH:27][C:20]=2[NH:19][C:18]1=[O:28])=[O:15])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:31][NH:32][C:33]([NH:35][CH2:36][C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][C:38]=1[C:43]1[CH:48]=[CH:47][C:46]([CH2:49]O)=[CH:45][CH:44]=1)=[O:34]>>[CH2:1]([O:8][C:9]([NH:11][C:12]([CH3:30])([CH3:29])[CH2:13][C:14]([NH:16][C@@H:17]1[CH2:23][CH2:22][C:21]2[CH:24]=[CH:25][CH:26]=[CH:27][C:20]=2[N:19]([CH2:49][C:46]2[CH:45]=[CH:44][C:43]([C:38]3[CH:39]=[CH:40][CH:41]=[CH:42][C:37]=3[CH2:36][NH:35][C:33]([NH:32][CH3:31])=[O:34])=[CH:48][CH:47]=2)[C:18]1=[O:28])=[O:15])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CNC(=O)NCc1ccccc1-c1ccc(CO)cc1
Reactant: CC(C)(CC(=O)N[C@@H]1CCc2ccccc2NC1=O)NC(=O)OCc1ccccc1
Product: CNC(=O)NCc1ccccc1-c1ccc(CN2C(=O)[C@H](NC(=O)CC(C)(C)NC(=O)OCc3ccccc3)CCc3ccccc32)cc1

Procedure:
Prepared from 3-benzyloxycarbonylamino-3-methyl-N-[2,3,4,5-tetrahydro-2-oxo-1H-benzazepin-3(R)-yl]butanamide (Step D) and 2'-[[(methylamino)carbonyl]amino]methyl-1,1'-biphenyl-4-methanol, methanesulfonate ester (Step I) according to the procedure described in Example 35, Step H. 1H NMR (200 MHz, CDCl3): δ 1.33 (s,6H), 1.78 (m, 1H), 2.37-2.63 (m, 3H), 2.60 (d, 5 Hz, 3H), 4.20 (d, 6 Hz, 2H), 4.52 (m, 2H), 4.72 (t, 6 Hz, 1H), 4.86 (d, 16 Hz, 1H), 4.89 (s, 2H), 5.10 (d, 15 Hz, 1H), 5.69 (s, 1H), 6.73 (d, 7.5 Hz, 1H), 7.08-7.35 (m, 16H) 7.40 (m, 1H). FAB-MS: calculated for C39H43N5O5 661; found 662 (M+H, 40%).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:13])[C:5]([C:11]#[N:12])=[CH:6][CH2:7][CH:8]([CH3:10])[CH3:9])[CH3:2].[N+]([CH3:17])([O-])=O.C1CCN2C(=NCCC2)CC1>C(#N)C>[CH2:1]([O:3][C:4]([C:5]1([C:11]#[N:12])[CH2:17][CH:6]1[CH2:7][CH:8]([CH3:10])[CH3:9])=[O:13])[CH3:2]
Reactant: C[N+](=O)[O-]
Reactant: CCOC(=O)C(C#N)=CCC(C)C
Solvent: C1CCC2=NCCCN2CC1
Solvent: CC#N
Product: CCOC(=O)C1(C#N)CC1CC(C)C
Temperature: 60 °C
Yield: 70.3 %

Procedure:
To a solution of 2-cyano-5-methyl-hex-2-enoic acid ethyl ester (0.74 g, 4.08 mmol) in 16 mL acetonitrile was added nitromethane (1.11 mL, 20.4 mmol), followed by DBU (0.61 mL, 4.08 mmol) resulting in an orange solution. The reaction was heated to 60° C. for 16 hours, then cooled and partitioned between Et2O and 1N HCl (aq). The phases were separated, and the organic phase washed with brine, dried (MgSO4), and concentrated. Flash chromatography of the residue (5→10% EtOAc/hexanes) afforded 0.56 g (70%) of 1-cyano-2-isobutyl-cyclopropanecarboxylic acid ethyl ester as a pale yellow oil. 1H NMR (CDCl3) δ 4.22 (m, 2H), 1.75–1.90 (m, 3H), 1.63 (m, 1H), 1.36 (m, 2H), 1.30 (t, J=7.3 Hz, 3H), 0.95 (m, 6H). 13C NMR δ 168.25, 117.72, 62.94, 39.12, 30.25, 28.12, 25.66, 22.63, 22.40, 19.56, 14.30. LRMS: m/z 196.0 (M+1). Anal. Calcd for C11H17NO2: C, 67.66; H, 8.78; N, 7.17. Found: C, 67.32; H, 8.74; N, 7.32.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([C:14]3[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=3)[CH2:12][CH2:11][NH:10][C:9]2=[O:13])=[CH:4][CH:3]=1.CC(C)([O-])C.[K+].Br[CH2:28][CH2:29][N:30]1[CH2:35][CH2:34][N:33]([C:36]([O:38][C:39]([CH3:42])([CH3:41])[CH3:40])=[O:37])[CH2:32][CH2:31]1>O1CCCC1>[F:20][C:17]1[CH:18]=[CH:19][C:14]([C:8]2([C:5]3[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=3)[CH2:12][CH2:11][N:10]([CH2:28][CH2:29][N:30]3[CH2:35][CH2:34][N:33]([C:36]([O:38][C:39]([CH3:40])([CH3:42])[CH3:41])=[O:37])[CH2:32][CH2:31]3)[C:9]2=[O:13])=[CH:15][CH:16]=1
Reactant: CC(C)(C)OC(=O)N1CCN(CCBr)CC1
Reactant: O=C1NCCC1(c1ccc(F)cc1)c1ccc(F)cc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCN(CCN2CCC(c3ccc(F)cc3)(c3ccc(F)cc3)C2=O)CC1
Temperature: 75 °C

Procedure:
To a solution of 3,3-bis(4-fluorophenyl)pyrrolidin-2-one (Example 58B, 1.37 g, 5.00 mmol) in tetrahydrofuran (30 mL) was added potassium t-butoxide (1.0 M in tetrahydrofuran) (7.5 mL, 7.5 mmol) followed by the product from Example 63A (1.47 g, 5.00 mmol). The reaction mixture was heated at 75° C. for 18 hours. The reaction was concentrated, diluted with ethyl acetate, washed with water and brine, dried with MgSO4, filtered and concentrated. The residue was purified with silica gel chromatography eluting with 3% methanol/dichloromethane to give the title compound. MS (DCI) m/z 486.3 (M+H)+.