Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6](=[O:20])[N:7]([CH2:12][C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH:8]=[N:9]2)=[CH:4][C:3]=1[O:21][CH3:22].Br[CH2:24][CH2:25][CH2:26][OH:27].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[OH:27][CH2:26][CH2:25][CH2:24][O:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6](=[O:20])[N:7]([CH2:12][C:13]([O:15][C:16]([CH3:17])([CH3:18])[CH3:19])=[O:14])[CH:8]=[N:9]2)=[CH:4][C:3]=1[O:21][CH3:22]
Reactant: COc1cc2c(=O)n(CC(=O)OC(C)(C)C)cnc2cc1O
Reactant: OCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1cc2c(=O)n(CC(=O)OC(C)(C)C)cnc2cc1OCCCO
Temperature: 80 °C
Reaction time: 20 h
Yield: 28.4 %

Procedure:
A mixture of tert-butyl 2-[7-hydroxy-6-methoxy-4-oxo-3(4H)-quinazolinyl]-acetate (100 g, 0.327 mol), 3-bromopropanol (49.3 g, 0.355 mol) and potassium carbonate (133 g, 0.967 mol) in dimethylformamide (500 ml) was stirred at 80° C. for 20 hours. The reaction was cooled and concentrated to quarter volume in vacuo. The residue was poured into ice/water (1500 ml) and the resulting solid collected by suction filtration. Purification by crystallisation from ethanol, yielded crude tert-butyl 2-[7-(3-hydroxypropoxy)-6-methoxy-4-oxo-3(4H)-quinazolinyl]acetate (33.8 g, 41% yield) as a beige solid:
Reaction SMILES: [C:1]([C:3]1[N:7]2[N:8]=[CH:9][CH:10]=[CH:11][C:6]2=[N:5][CH:4]=1)#[CH:2].[CH3:12][N:13]([CH3:41])[C@@H:14]1[CH2:18][CH2:17][N:16]([CH2:19][C:20]2[CH:25]=[CH:24][C:23]([NH:26][C:27](=[O:36])[C:28]3[CH:33]=[CH:32][C:31]([CH3:34])=[C:30](I)[CH:29]=3)=[CH:22][C:21]=2[C:37]([F:40])([F:39])[F:38])[CH2:15]1.C(N(CC)C(C)C)(C)C>CN(C=O)C.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.[Cu]I>[CH3:41][N:13]([CH3:12])[C@@H:14]1[CH2:18][CH2:17][N:16]([CH2:19][C:20]2[CH:25]=[CH:24][C:23]([NH:26][C:27](=[O:36])[C:28]3[CH:33]=[CH:32][C:31]([CH3:34])=[C:30]([C:2]#[C:1][C:3]4[N:7]5[N:8]=[CH:9][CH:10]=[CH:11][C:6]5=[N:5][CH:4]=4)[CH:29]=3)=[CH:22][C:21]=2[C:37]([F:40])([F:39])[F:38])[CH2:15]1
Reactant: Cc1ccc(C(=O)Nc2ccc(CN3CC[C@@H](N(C)C)C3)c(C(F)(F)F)c2)cc1I
Reactant: C#Cc1cnc2cccnn12
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1ccc(C(=O)Nc2ccc(CN3CC[C@@H](N(C)C)C3)c(C(F)(F)F)c2)cc1C#Cc1cnc2cccnn12
Temperature: 25 °C
Reaction time: 72 h
Yield: 13.1 %

Procedure:
A mixture of 3-ethynylimidazo[1,2-b]pyridazine (0.051 g, 0.34 mmol), 0.150 g (0.28 mmol) of (R)—N-(4-((3-(dimethylamino)pyrrolidin-1-yl)methyl)-3-(trifluoromethyl)phenyl)-3-iodo-4-methylbenzamide, 0.016 g (0.014 mmol) of Pd(PPh3)4, 0.004 g (0.021 mmol) of CuI, and 0.09 mL (0.51 mmol) of N,N-diisopropylethylamine in 3.5 mL of DMF was stirred at ambient temperature, under an atmosphere of N2, for 3 days (reaction pushed to completion with additional equivalents of reagents and heating to 80° C.). The reaction mixture was concentrated and the crude product was purified by silica gel chromatography (eluted with 0-10% MeOH/DCM; MeOH was pre-saturated with ammonia gas) to provide 0.020 g of product as a solid: 547 m/z (M+H).
Reaction SMILES: [Br:1]Br.[Cl:3][C:4]1[CH:9]=[C:8]([Cl:10])[CH:7]=[CH:6][C:5]=1[C:11](=[O:14])[CH2:12][CH3:13]>CO>[Br:1][CH:12]([CH3:13])[C:11]([C:5]1[CH:6]=[CH:7][C:8]([Cl:10])=[CH:9][C:4]=1[Cl:3])=[O:14]
Reactant: CCC(=O)c1ccc(Cl)cc1Cl
Reactant: BrBr
Solvent: CO
Product: CC(Br)C(=O)c1ccc(Cl)cc1Cl
Yield: 97.1 %

Procedure:
51.4 g (0.322 mol) of bromine was added dropwise to a solution of 63.2 g (0.311 mol) of 2′,4′-dichloropropiophenone in 140 g of methanol at a reaction temperature of 50 to 55° C. After the addition was complete, the methanol was evaporated off from the reaction solution under reduced pressure. The resultant concentrate was dissolved in 120 g of toluene and was then washed with water (150 ml×3 times). Thereafter, the toluene was distilled off under reduced pressure, giving 85.2 g (0.302 mol) of crude brown oily 2-bromo-2′,4′-dichloropropiophenone.
Reaction SMILES: [H-].[Na+].[CH2:3]([O:5][C:6]1[CH:21]=[CH:20][CH:19]=[CH:18][C:7]=1[O:8][CH2:9][CH:10]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=1)[OH:11])[CH3:4].Cl[CH2:23][C:24]([O:26][CH2:27][CH3:28])=[O:25]>O1CCCC1>[CH2:27]([O:26][C:24](=[O:25])[CH2:23][O:11][CH:10]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=1)[CH2:9][O:8][C:7]1[CH:18]=[CH:19][CH:20]=[CH:21][C:6]=1[O:5][CH2:3][CH3:4])[CH3:28]
Reactant: CCOC(=O)CCl
Reactant: CCOc1ccccc1OCC(O)c1ccccn1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOC(=O)COC(COc1ccccc1OCC)c1ccccn1
Reaction time: 0.5 h
Yield: 82.4 %

Procedure:
A mixture of sodium hydride (50%, 9.79 g, 0.204 mole, washed with hexane) in tetrahydrofuran (THF) was prepared. α-[(2-Ethoxyphenoxy)methyl]-2-pyridinemethanol (52.96 g, 0.204 mole) in 175 ml of THF was added dropwise under nitrogen with stirring over 1/2 hr. Stirring was continued for 1 hr at room temperature. Ethyl chloroacetate (24.98 g, 0.204 mole) in THF was added dropwise over 10 min. The resulting solution was heated at reflux for 2 hr and stirred at room temperature (72 hr). THF was removed, and the residue partitioned between diethyl ether and water. Removal of diethyl ether gave 57.9 g (0.168 mole, 82.4% yield) of the desired 2-[2-(2-ethoxy-phenoxy)-1-(2-pyridinyl)ethoxy]acetic acid ethyl ester as an oil. This structure of the product was confirmed by NMR.
Reaction SMILES: [O-:1][CH2:2][CH3:3].[Na+].[Na].CCO.[CH3:9][O:10][C:11]1[CH:38]=[CH:37][C:14]([CH2:15][N:16]([C:26]2[CH:31]=[CH:30][C:29]([C:32]([F:35])([F:34])[F:33])=[C:28](Cl)[N:27]=2)[CH2:17][C:18]2[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=2)=[CH:13][CH:12]=1>C1COCC1>[CH3:9][O:10][C:11]1[CH:38]=[CH:37][C:14]([CH2:15][N:16]([C:26]2[CH:31]=[CH:30][C:29]([C:32]([F:35])([F:34])[F:33])=[C:28]([O:1][CH2:2][CH3:3])[N:27]=2)[CH2:17][C:18]2[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=2)=[CH:13][CH:12]=1
Reactant: COc1ccc(CN(Cc2ccc(OC)cc2)c2ccc(C(F)(F)F)c(Cl)n2)cc1
Reactant: CC[O-]
Agent: [Na+]
Agent: [Na]
Solvent: C1CCOC1
Solvent: CCO
Product: CCOc1nc(N(Cc2ccc(OC)cc2)Cc2ccc(OC)cc2)ccc1C(F)(F)F
Temperature: 25 °C

Procedure:
Add freshly prepared sodium ethoxide [made by adding sodium (1.26 g, 54.9 mmol) to 25 mL of absolute EtOH, and stirring until all the sodium is dissolved] dropwise to a solution of N,N-bis-(4-methoxybenzyl)-(6-chloro-5-trifluoromethyl-pyridine-2-yl)amine (8.0 g, 18.3 mmol) in 150 mL THF. Heat the reaction mixture to reflux for 45 hours. During reflux, the reaction mixture turns brown. After cooling to room temperature, remove the solvent under vacuum. Take up the residue in CH2Cl2 (150 mL) and wash with water (100 mL). Extract the aqueous layer once more with 100 mL CH2Cl2. Wash the combined CH2Cl2 extracts with brine (100 mL), dry (Na2SO4), filter, and evaporate to give a brown oil/solid mix. Purification by column chromatography affords the title product as a white solid. 1H NMR (400 MHz, CDCl3) δ 7.51 (d, 1H, J=8.8 Hz), 7.13 (m, 4H), 6.86 (m, 4H), 6.0 (d, 1H, J=8.8 Hz), 4.67 (s, 4H), 4.37 (q, 2H, J=6.8 and 7.6 Hz), 3.80 (s, 6H), 1.32 (t, 3H, J=6.8 Hz). Mass spec. (447.34, M+H).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([F:12])=[C:6]([CH2:8][C:9]([OH:11])=[O:10])[CH:7]=1.S(=O)(=O)(O)O.C([O-])([O-])=O.[Na+].[Na+].[CH2:24](O)[CH3:25]>>[NH2:1][C:2]1[CH:3]=[CH:4][C:5]([F:12])=[C:6]([CH2:8][C:9]([O:11][CH2:24][CH3:25])=[O:10])[CH:7]=1
Reactant: Nc1ccc(F)c(CC(=O)O)c1
Reactant: CCO
Agent: O=C([O-])[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Product: CCOC(=O)Cc1cc(N)ccc1F
Temperature: 80 °C
Reaction time: 1 h

Procedure:
To a solution of 2-(5-amino-2-fluorophenyl)acetic acid (6.13 g, 36.2 mmol) in ethanol (15 mL) was added conc. sulfuric acid (2 mL) dropwise. The reaction mixture was stirred under N2 at 80° C. for 1 hr. After the reaction mixture was cooled to RT and neutralized with aqueous Na2CO3 to pH 7-8, the aqueous solution was extracted with ethyl acetate (3×100 mL). The combined organic layer was washed with brine, dried over Na2SO4 and evaporated under vacuum to afford ethyl 2-(5-amino-2-fluorophenyl)acetate as a yellow oil which was used for the next step without further purification (6.13 g, 95%).
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:8]=[CH:9][C:10]2[C:14]([C:15]3[CH:20]=[CH:19][C:18]([Br:21])=[CH:17][CH:16]=3)=[C:13]([CH3:22])[S:12][C:11]=2[CH:23]=1.[CH2:24]([NH:26][CH2:27][CH2:28][OH:29])[CH3:25]>>[Br:21][C:18]1[CH:19]=[CH:20][C:15]([C:14]2[C:10]3[CH:9]=[CH:8][C:7]([O:6][CH2:5][CH2:4][CH2:3][CH2:2][N:26]([CH2:24][CH3:25])[CH2:27][CH2:28][OH:29])=[CH:23][C:11]=3[S:12][C:13]=2[CH3:22])=[CH:16][CH:17]=1
Reactant: CCNCCO
Reactant: Cc1sc2cc(OCCCCBr)ccc2c1-c1ccc(Br)cc1
Product: CCN(CCO)CCCCOc1ccc2c(-c3ccc(Br)cc3)c(C)sc2c1

Procedure:
According to the method in example 31, 6-(4-Bromo-butoxy)-3-(4-bromo-phenyl)-2-methyl-benzo[b]thiophene and Ethyl-(2-hydroxy-ethyl)-amine were converted to yield 2-({4-[3-(4-Bromo-phenyl)-2-methyl-benzo[b]thiophen-6-yloxy]-butyl}-ethyl-amino)-ethanol, MS: 462 (MH+,1Br).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:20](=[O:21])[NH:19][N:18]=[CH:17][C:6]3=[C:7]([C:11]4[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=4)[NH:8][C:9]([CH:10]=1)=[C:5]23.[CH3:22][N:23]([CH3:35])[C@@H:24]([CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)[C:25](O)=[O:26].C(N(CC)CC)C.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1>C(Cl)Cl.CN(C)C=O>[CH3:35][N:23]([CH3:22])[C@@H:24]([CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)[C:25]([NH:1][C:2]1[CH:3]=[C:4]2[C:20](=[O:21])[NH:19][N:18]=[CH:17][C:6]3=[C:7]([C:11]4[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=4)[NH:8][C:9]([CH:10]=1)=[C:5]23)=[O:26]
Reactant: Nc1cc2c3c(c(-c4ccccc4)[nH]c3c1)C=NNC2=O
Reactant: CN(C)[C@@H](Cc1ccccc1)C(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CN(C)[C@@H](Cc1ccccc1)C(=O)Nc1cc2c3c(c(-c4ccccc4)[nH]c3c1)C=NNC2=O
Yield: 78.1 %

Procedure:
Preparation from the title compound of Example 7 (hydrochloride) (40 mg, 0.128 mmol), (S)-2-Dimethylamino-3-phenyl-propionic acid (30 mg, 0.154 mmol), triethylamine (0.071 mL, 0.512 mmol), and O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (59 mg, 0.154 mmol) in CH2Cl2 (0.4 mL) and N,N-dimethylformamide (0.4 mL) was carried out analogously to Example 11. Silica gel chromatography (elute with 1.5% triethylamine in CH2Cl2 followed by 1.5% triethylamine in 9:1 CH2Cl2:methanol), also in an analogous manner, afforded the freebase of the title compound (46 mg, 0.10 mmol) in three separate batches for a combined 80% yield. Two of the batches were carried on to Examples 71b and 71c respectively. To the third batch (8 mg, 0.018 mmol) was added tetrahydrofuran and 1.2 equivalents of HCl in dioxane (from a 4M stock solution). After evaporation, trituration with diethyl ether and 1:1 CH2Cl2:hexane gave the title compound (6 mg, 0.012 mmol) as a yellow powder in 67% yield for the salt formation.
Reaction SMILES: [Na].C(O)C.[NH2:5][C:6]1[CH:19]=[CH:18][CH:17]=[CH:16][C:7]=1[C:8]([NH:10][C:11]1[NH:15][N:14]=[N:13][N:12]=1)=[O:9].[C:20](OCC)(=[O:26])[C:21]([O:23][CH2:24][CH3:25])=[O:22]>O.C(O)(=O)C>[CH2:24]([O:23][C:21](=[O:22])[C:20](=[O:26])[NH:5][C:6]1[CH:19]=[CH:18][CH:17]=[CH:16][C:7]=1[C:8]([NH:10][C:11]1[NH:15][N:14]=[N:13][N:12]=1)=[O:9])[CH3:25]
Reactant: Nc1ccccc1C(=O)Nc1nnn[nH]1
Reactant: CCOC(=O)C(=O)OCC
Agent: [Na]
Solvent: CCO
Solvent: O
Solvent: CC(=O)O
Product: CCOC(=O)C(=O)Nc1ccccc1C(=O)Nc1nnn[nH]1
Temperature: 50 °C

Procedure:
To a solution of 2.3 g of sodium and 200 ml of ethanol was added 5.1 g of 2-amino-N-(1H-tetrazol-5-yl)benzamide and 11.0 g of diethyl oxalate. The resulting solution was heated at 50° C. for 20 hours and then acidified with glacial acetic acid. The clear acid solution obtained was diluted with water and the solid which formed was separated by filtration, washed with water and air-dried to give 2-oxo-N-[2-((1H-tetrazol-5-yl)aminocarbonyl)phenyl]glycine ethyl ester melting at about 231°-232° C.
Reaction SMILES: [F:1][C:2]1[C:7]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([CH3:14])[CH:9]=2)=[C:6]([C@:15]([C@@H:23]2[O:28][CH2:27][CH2:26][N:25]([C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[CH2:24]2)(O)[CH2:16][CH2:17][CH2:18][CH2:19][O:20][CH3:21])[CH:5]=[CH:4][CH:3]=1.CC[N+](S(N=C(OC)[O-])(=O)=O)(CC)CC>C1(C)C=CC=CC=1.CCOC(C)=O>[F:1][C:2]1[C:7]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([CH3:14])[CH:9]=2)=[C:6]([C:15]([C@@H:23]2[O:28][CH2:27][CH2:26][N:25]([C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[CH2:24]2)=[CH:16][CH2:17][CH2:18][CH2:19][O:20][CH3:21])[CH:5]=[CH:4][CH:3]=1
Reactant: COCCCC[C@@](O)(c1cccc(F)c1-c1cccc(C)c1)[C@H]1CN(C(=O)OC(C)(C)C)CCO1
Agent: CC[N+](CC)(CC)S(=O)(=O)N=C([O-])OC
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: COCCCC=C(c1cccc(F)c1-c1cccc(C)c1)[C@H]1CN(C(=O)OC(C)(C)C)CCO1
Temperature: 25 °C
Yield: 72.6 %

Procedure:
A mixture of (R)-tert-butyl 2-((R)-1-(6-fluoro-3′-methylbiphenyl-2-yl)-1-hydroxy-5-methoxypentyl)morpholine-4-carboxylate (188 mg, 0.39 mmol) and Burgess' reagent (186 mg, 0.78 mmol) in toluene (3 mL) was heated to reflux under a N2 atmosphere for 2 h, then cooled to rt and diluted with EtOAc, washed with H2O and brine, dried over Na2SO4, filtered and evaporated. The residue was purified by flash chromatography to give (S)-tert-butyl 2-(1-(6-fluoro-3′-methylbiphenyl-2-yl)-5-methoxypent-1-enyl)morpholine-4-carboxylate (133 mg, 73%). MS m/z 470 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([OH:8])[C:3]=1[C:9]1[N:18]=[C:17]([N:19]2[CH2:24][CH2:23][CH:22]([NH:25]C(=O)OC(C)(C)C)[CH2:21][CH2:20]2)[C:16]2[C:11](=[CH:12][C:13]([CH3:33])=[CH:14][CH:15]=2)[N:10]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH2:25][CH:22]1[CH2:21][CH2:20][N:19]([C:17]2[C:16]3[C:11](=[CH:12][C:13]([CH3:33])=[CH:14][CH:15]=3)[N:10]=[C:9]([C:3]3[C:2]([F:1])=[CH:7][CH:6]=[CH:5][C:4]=3[OH:8])[N:18]=2)[CH2:24][CH2:23]1
Reactant: Cc1ccc2c(N3CCC(NC(=O)OC(C)(C)C)CC3)nc(-c3c(O)cccc3F)nc2c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1ccc2c(N3CCC(N)CC3)nc(-c3c(O)cccc3F)nc2c1
Reaction time: 1 h
Yield: 92.5 %

Procedure:
To a solution of tert-butyl 1-(2-(2-fluoro-6-hydroxyphenyl)-7-methylquinazolin-4-yl)piperidin-4-ylcarbamate (1.05 g, 2.3 mmol) in 20 ml CH2Cl2 was slowly added TFA (5 mL). The reaction was stirred for one hour before it was evaporated to dryness. To the residue was added CH2Cl2, and the reaction was neutralized using an aqueous 1 M NaOH solution. The aqueous layer was extracted twice with CH2Cl2, and the combined organic layers were dried over MgSO4, filtered, and concentrated to obtain 2-(4-(4-aminopiperidin-1-yl)-7-methylquinazolin-2-yl)-3-fluorophenol (0.75 g, 92%). LC/MS: m/z 353.3 (M+H)+ at 1.35 min (10%-99% CH3CN (0.035% TFA)/H2O (0.05% TFA)).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:61])[NH:4][CH:5]([C:9]([N:11]1[CH2:15][CH2:14][CH2:13][CH:12]1[C:16]1[NH:17][C:18]([C:21]2[CH:30]=[CH:29][C:28]3[C:23](=CC=[C:26]([C:31]4[CH:36]=[CH:35][C:34]([C:37]5[NH:38][C:39]([C@@H:42]6[CH2:46][CH2:45][CH2:44][N:43]6[C:47](=[O:60])[CH:48]([NH:55][C:56]([O:58][CH3:59])=[O:57])[C:49]6[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=6)=[N:40][CH:41]=5)=[CH:33][CH:32]=4)[CH:27]=3)[CH:22]=2)=[CH:19][N:20]=1)=[O:10])[CH:6]([CH3:8])[CH3:7].COC(=O)N[CH:66](C(N1CCCC1C1NC(C2C=CC(Br)=CC=2)=CN=1)=O)[CH:67](C)C.C(OC(N1CCCC1C1NC(C2C=CC3C(=CC=C(B4OC(C)(C)C(C)(C)O4)C=3)C=2)=CN=1)=O)(C)(C)C>>[CH3:1][O:2][C:3](=[O:61])[NH:4][CH:5]([C:9]([N:11]1[CH2:15][CH2:14][CH2:13][CH:12]1[C:16]1[NH:17][C:18]([C:21]2[CH:22]=[CH:23][C:28]([C:27]3[CH:67]=[CH:66][C:32]4[C:31](=[CH:36][CH:35]=[C:34]([C:37]5[NH:38][C:39]([CH:42]6[CH2:46][CH2:45][CH2:44][N:43]6[C:47](=[O:60])[CH:48]([NH:55][C:56]([O:58][CH3:59])=[O:57])[C:49]6[CH:50]=[CH:51][CH:52]=[CH:53][CH:54]=6)=[N:40][CH:41]=5)[CH:33]=4)[CH:26]=3)=[CH:29][CH:30]=2)=[CH:19][N:20]=1)=[O:10])[CH:6]([CH3:8])[CH3:7]
Reactant: COC(=O)NC(C(=O)N1CCC[C@H]1c1ncc(-c2ccc(-c3ccc4cc(-c5cnc(C6CCCN6C(=O)C(NC(=O)OC)C(C)C)[nH]5)ccc4c3)cc2)[nH]1)c1ccccc1
Reactant: COC(=O)NC(C(=O)N1CCCC1c1ncc(-c2ccc(Br)cc2)[nH]1)C(C)C
Agent: CC(C)(C)OC(=O)N1CCCC1c1ncc(-c2ccc3cc(B4OC(C)(C)C(C)(C)O4)ccc3c2)[nH]1
Product: COC(=O)NC(C(=O)N1CCCC1c1ncc(-c2ccc3cc(-c4ccc(-c5cnc(C6CCCN6C(=O)C(NC(=O)OC)C(C)C)[nH]5)cc4)ccc3c2)[nH]1)c1ccccc1
Yield: 54 %

Procedure:
This compound was prepared following the procedure for [1-(2-{5-[6-(4-{2-[1-(2S)-(2-Methoxycarbonylamino-2-phenyl-acetyl)-pyrrolidin-2-yl]-3H-imidazol-4-yl}-phenyl)-naphthalen-2-yl}-1H-imidazol-2-yl]-pyrrolidine-1-carbonyl)-2-methyl-propyl]-carbamic acid methyl ester using (1-{2-[5-(4-Bromo-phenyl)-1H-imidazol-2-yl]-pyrrolidine-1-carbonyl}-2-methyl-propyl)-carbamic acid methyl ester (1.0 g, 2.2 mmol) and 2-{5-[6-(4,4,5,5-Tetramethyl-[1,3,2]dioxaborolan-2-yl)-naphthalen-2-yl]-1H-imidazol-2-yl}-pyrrolidine-1-carboxylic acid tert-butyl ester (1.6 g, 3.4 mmol, 1.5 equiv.) to provide [1-(2-{5-[4-(6-{2-[1-(2-Methoxycarbonylamino-2-phenyl-acetyl)-pyrrolidin-2-yl]-3H-imidazol-4-yl}-naphthalen-2-yl)-phenyl]-1H-imidazol-2-yl}-pyrrolidine-1-carbonyl)-2-methyl-propyl]-carbamic acid methyl ester (0.03 g, 54%) as a white powder. LCMS-ESI+: calc'd for C47H50N8O6: 822.4 (M+). Found: 823.9 (M+H+). 1H-NMR: 400 MHz, (CDCl3) δ: (Mixture of rotomers) 7.52-7.93 (m, 9H), 7.27-7.42 (m, 6H), 7.16 (s, 2H), 6.08 (m, 1H), 5.48-5.56 (m, 2H), 5.34 (s, 1H), 5.24 (s, 1H), 4.35 (t, 1H), 3.93 (m, 1H), 3.73 (m, 1H), 3.68 (s, 3H), 3.66 (s, 3H), 3.38 (m, 1H), 2.78-2.83 (m, 3H), 2.36 (m, 1H), 2.04-2.23 (m, 6H), 0.86-0.97 (m, 6H).
Reaction SMILES: [O:1]=[C:2]1[C:7]2[S:8][CH:9]=[CH:10][C:6]=2[CH:5]([NH2:11])[CH2:4][CH2:3]1.[C:12]([N:20]=[C:21]=[O:22])(=[O:19])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>C(Cl)Cl>[C:12]([NH:20][C:21]([NH:11][CH:5]1[C:6]2[CH:10]=[CH:9][S:8][C:7]=2[C:2](=[O:1])[CH2:3][CH2:4]1)=[O:22])(=[O:19])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: O=C=NC(=O)c1ccccc1
Reactant: NC1CCC(=O)c2sccc21
Solvent: ClCCl
Product: O=C(NC(=O)c1ccccc1)NC1CCC(=O)c2sccc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 38.1 %

Procedure:
A solution of 4,5,6,7-tetrahydro-7-oxobenzo[b]thiophen-4-amine (8.02 g) in methylene chloride (75 ml) is added to a stirred solution of benzoyl isocyanate (7.0 g) in methylene chloride (75 ml) under a nitrogen atmosphere. The mixture is stirred for an overnight period at room temperature and the title compound is collected by filtration. Recrystallization of the crude product from acetone/hexane affords 5.7 g of the title compound, m.p. 204° to 207° C.
Reaction SMILES: C[O:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]2[CH2:25][CH2:24][C:12]3([O:16][C:15](=[O:17])[N:14]([C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)[CH2:13]3)[CH2:11][CH2:10]2)=[CH:5][CH:4]=1.B(Br)(Br)Br.ClCCl>C(Cl)(Cl)Cl>[OH:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]2[CH2:10][CH2:11][C:12]3([O:16][C:15](=[O:17])[N:14]([C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)[CH2:13]3)[CH2:24][CH2:25]2)=[CH:5][CH:4]=1
Reactant: COc1ccc(N2CCC3(CC2)CN(c2ccccc2)C(=O)O3)cc1
Agent: BrB(Br)Br
Solvent: ClCCl
Solvent: ClC(Cl)Cl
Product: O=C1OC2(CCN(c3ccc(O)cc3)CC2)CN1c1ccccc1
Yield: 28 %

Procedure:
The methoxy compound (1.15 g, 3.39 mmol) obtained in (a) was dissolved in chloroform, and processed with 1.0 M boron tribromide/dichloromethane solution (11 ml, 11 mmol) at 0° C. according to the same method as in Example 5-(b) or according to a method similar to it, thereby obtaining the entitled compound as a crude product (308 mg, 28%).
Reaction SMILES: [C:1]([C:5]1[N:9]([CH2:10][CH:11]2[CH2:16][CH2:15][C:14]([F:18])([F:17])[CH2:13][CH2:12]2)[C:8]2[CH:19]=[CH:20][C:21]([S:23](Cl)(=[O:25])=[O:24])=[CH:22][C:7]=2[N:6]=1)([CH3:4])([CH3:3])[CH3:2].Cl.[NH:28]1[CH2:31][CH:30]([CH2:32][C:33]([OH:35])=[O:34])[CH2:29]1.CCN(C(C)C)C(C)C>C(Cl)Cl>[C:1]([C:5]1[N:9]([CH2:10][CH:11]2[CH2:16][CH2:15][C:14]([F:18])([F:17])[CH2:13][CH2:12]2)[C:8]2[CH:19]=[CH:20][C:21]([S:23]([N:28]3[CH2:31][CH:30]([CH2:32][C:33]([OH:35])=[O:34])[CH2:29]3)(=[O:25])=[O:24])=[CH:22][C:7]=2[N:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)c1nc2cc(S(=O)(=O)Cl)ccc2n1CC1CCC(F)(F)CC1
Reactant: O=C(O)CC1CNC1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)c1nc2cc(S(=O)(=O)N3CC(CC(=O)O)C3)ccc2n1CC1CCC(F)(F)CC1

Procedure:
Following the same procedure in Example 1, Step A, using 2-tert-butyl-1-[(4,4-difluorocyclohexyl)methyl]-1H-benzimidazole-5-sulfonyl chloride (1.06 g, 2.6 mmol), azetidin-3-ylacetic acid hydrochloride (1.17 g, 7.8 mmol) and DIPEA (4 mL) in CH2Cl2 (20 mL), provided the title compound as crude product (930 mg, 74% yield), which was used directly in Step A.
Reaction SMILES: [F:1][C:2]([F:19])([CH:16]([F:18])[F:17])[CH2:3][O:4][C:5]1[CH:15]=[CH:14][C:8]([C:9](OCC)=[O:10])=[CH:7][N:6]=1.[H-].C([Al+]CC(C)C)C(C)C>>[F:19][C:2]([F:1])([CH:16]([F:18])[F:17])[CH2:3][O:4][C:5]1[CH:15]=[CH:14][C:8]([CH2:9][OH:10])=[CH:7][N:6]=1
Reactant: CCOC(=O)c1ccc(OCC(F)(F)C(F)F)nc1
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Product: OCc1ccc(OCC(F)(F)C(F)F)nc1
Yield: 100 %

Procedure:
Ethyl 6-(2,2,3,3-tetrafluoropropoxy)nicotinate was reduced with diisobutyl aluminum hydride in the same manner as in Reference example 21 to obtain the title compound as an oil in a yield of 100%.
Reaction SMILES: [CH3:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH2:4]Cl.[OH-].[Na+].[C:12]([O:18][CH2:19][CH3:20])(=[O:17])[CH2:13][C:14]([CH3:16])=[O:15].C1(C)C=CC=CC=1>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.O>[CH3:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH2:4][CH:13]([C:14]([CH3:16])=[O:15])[C:12]([O:18][CH2:19][CH3:20])=[O:17]
Reactant: Cc1ccccc1CCl
Reactant: CCOC(=O)CC(C)=O
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: O
Product: CCOC(=O)C(Cc1ccccc1C)C(C)=O
Reaction time: 2 h

Procedure:
344 g (2.45 moles) of o-methylbenzyl chloride and 3.5 moles of 25% strength aqueous NaOH solution were added dropwise to a refluxed, thoroughly stirred solution of 455 g (3.5 moles) of ethyl acetoacetate, 35 g (0.11 moles) of tetrabutylammonium bromide and 1.2 liters of toluene in the course of 2 hours, simultaneously from two dropping funnels. Thereafter, stirring was continued for a further 2 hours with refluxing. After the reaction solution had cooled, water was added, the phases were separated and the organic phase was washed once with water, once with dilute phosphoric acid and again with water and was then stirred with solid sodium bicarbonate. The mixture was filtered, the solution was freed from toluene and the residue was subjected to vacuum distillation over a 10 cm Vigreux column. 390 g (68% of the theoretical yield) of ethyl 2-(o-methylbenzyl)-acetoacetate of boiling point 100°-105° C. at 0.01 mm Hg were obtained.