Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1([C:10]2[CH:15]=[C:14]([Cl:16])[CH:13]=[CH:12][C:11]=2[C@@H:17]([O:22][C:23]2[N:28]=[C:27]([NH2:29])[N:26]=[C:25]([N:30]3[CH2:42][CH2:41][C:33]4([CH2:37][NH:36][C@H:35]([C:38]([OH:40])=[O:39])[CH2:34]4)[CH2:32][CH2:31]3)[CH:24]=2)[C:18]([F:21])([F:20])[F:19])[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2N=C1.[NH:43]1[C:51]2C(=CC=CC=2)C=N1>>[NH2:29][C:27]1[N:26]=[C:25]([N:30]2[CH2:31][CH2:32][C:33]3([CH2:37][NH:36][C@H:35]([C:38]([OH:40])=[O:39])[CH2:34]3)[CH2:41][CH2:42]2)[CH:24]=[C:23]([O:22][C@H:17]([C:11]2[CH:12]=[CH:13][C:14]([Cl:16])=[CH:15][C:10]=2[N:1]2[C:5]3[C:4](=[CH:9][CH:8]=[CH:7][CH:6]=3)[CH:51]=[N:43]2)[C:18]([F:20])([F:19])[F:21])[N:28]=1
Reactant: c1ccc2[nH]ncc2c1
Reactant: Nc1nc(O[C@H](c2ccc(Cl)cc2-n2cnc3ccccc32)C(F)(F)F)cc(N2CCC3(CC2)CN[C@H](C(=O)O)C3)n1
Product: Nc1nc(O[C@H](c2ccc(Cl)cc2-n2ncc3ccccc32)C(F)(F)F)cc(N2CCC3(CC2)CN[C@H](C(=O)O)C3)n1

Procedure:
The title compound was prepared as described for (S)-8-(6-((R)-1-(2-(1H-benzo[d]imidazol-1-yl)-4-chlorophenyl)-2,2,2-trifluoroethoxy)-2-aminopyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylic acid (Example 36b) starting with 1H-indazole and obtained as a white solid.
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.[CH3:14][CH:15]1[NH:20][CH2:19][C:18]2[CH:21]=[CH:22][S:23][C:17]=2[CH2:16]1>>[Br:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([N:20]3[CH:15]([CH3:14])[CH2:16][C:17]4[S:23][CH:22]=[CH:21][C:18]=4[CH2:19]3)=[O:13])[CH:10]=2)[CH:7]=1
Reactant: CC1Cc2sccc2CN1
Reactant: O=C(O)c1cc2ncc(Br)cn2n1
Product: CC1Cc2sccc2CN1C(=O)c1cc2ncc(Br)cn2n1
Yield: 62 %

Procedure:
In close analogy to the procedure described in Example 1, 6-bromo-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid is reacted with 6-Methyl-4,5,6,7-tetrahydro-thieno[3,2-c]pyridine to provide the title compound.
Reaction SMILES: [C:1]1([C:7](=[O:21])[C:8]#[C:9][CH2:10][CH2:11][CH2:12]/[CH:13]=[CH:14]/[C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1>ClCCCl>[CH2:12]1[C:13]2=[CH:14][C:15]3[C:16]([C:8]([C:7]([C:1]4[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=4)=[O:21])=[C:9]2[CH2:10][CH2:11]1)=[CH:17][CH:18]=[CH:19][CH:20]=3
Reactant: O=C(C#CCCC/C=C/c1ccccc1)c1ccccc1
Solvent: ClCCCl
Product: O=C(c1ccccc1)c1c2c(cc3ccccc13)CCC2
Temperature: 180 °C
Reaction time: 1.5 h

Procedure:
To a 2-5 mL microwave irradiation vial equipped with a stir bar was added enyne 5e (0.050 g, 0.18 mmol) in DCE (3.0 mL). The reaction was irradiated with stirring at 180° C. for 90 min until complete by TLC. The reaction turned golden in color. The reaction was then transferred to a vial, concentrated under reduced pressure, and dried under vacuum to yield naphthalene 6e as a black oil (0.050 g, quant.).
Reaction SMILES: C1(S(CC2C(C(OCC)=O)=C(O)C([C:23]3[CH:27]=[CH:26][O:25][CH:24]=3)=CC=2)(=O)=O)C=CC=CC=1.Br[C:29]1[C:30]([O:50][CH3:51])=[C:31]([C:36]([CH2:39][S:40]([C:43]2[CH:48]=[CH:47][CH:46]=[C:45]([F:49])[CH:44]=2)(=[O:42])=[O:41])=[CH:37][CH:38]=1)[C:32]([O:34][CH3:35])=[O:33].O1C=CC(B(O)O)=C1>>[F:49][C:45]1[CH:44]=[C:43]([S:40]([CH2:39][C:36]2[C:31]([C:32]([O:34][CH3:35])=[O:33])=[C:30]([O:50][CH3:51])[C:29]([C:23]3[CH:27]=[CH:26][O:25][CH:24]=3)=[CH:38][CH:37]=2)(=[O:42])=[O:41])[CH:48]=[CH:47][CH:46]=1
Reactant: CCOC(=O)c1c(CS(=O)(=O)c2ccccc2)ccc(-c2ccoc2)c1O
Reactant: COC(=O)c1c(CS(=O)(=O)c2cccc(F)c2)ccc(Br)c1OC
Agent: OB(O)c1ccoc1
Product: COC(=O)c1c(CS(=O)(=O)c2cccc(F)c2)ccc(-c2ccoc2)c1OC

Procedure:
Prepared by proceeding in a similar manner to Intermediate 36, starting from methyl 3-bromo-6-(3-fluorobenzenesulphonylmethyl)-2-methoxybenzoate (Intermediate 99) and furan-3-yl boronic acid.
Reaction SMILES: N#N.[Si:3]([O:10][CH2:11][C:12]1[O:13][CH:14]=[C:15]([C:17]([O-:19])=O)[N:16]=1)([C:6]([CH3:9])([CH3:8])[CH3:7])([CH3:5])[CH3:4].[CH2:20]([Mg]Br)[CH3:21].Cl>C1COCC1.CCOCC.C(O[Ti](OC(C)C)(OC(C)C)OC(C)C)(C)C.CC(=O)OCC>[Si:3]([O:10][CH2:11][C:12]1[O:13][CH:14]=[C:15]([C:17]2([OH:19])[CH2:21][CH2:20]2)[N:16]=1)([C:6]([CH3:7])([CH3:8])[CH3:9])([CH3:4])[CH3:5]
Reactant: CC(C)(C)[Si](C)(C)OCc1nc(C(=O)[O-])co1
Reactant: CC[Mg]Br
Agent: CC(C)O[Ti](OC(C)C)(OC(C)C)OC(C)C
Agent: Cl
Agent: N#N
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: CCOCC
Product: CC(C)(C)[Si](C)(C)OCc1nc(C2(O)CC2)co1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
In a flame dried round-bottomed flask equipped with a magnetic stir bar and under inert atmosphere (N2), a solution of method 2-(((tert-butyldimethylsilyl)oxy)methyl)oxazole-4-carboxylate (3.00 g, 11.05 mmol) in THF (110 mL) was treated with tetraisopropoxytitanium (IV) (3.27 mL, 11.05 mmol). To the resulting solution at rt, was added, over 30 min, via syringe pump, ethyl magnesium bromide (18.4 mL of a 3M sol. in ether, 55.27 mmol) and the resulting solution was stirred at rt for 3 h. EA (100 mL) and 1N HCl (50 mL) were added. The layers were separated and the aq. layer was extracted with EA (2×100 mL) and the combined org. layers were washed with sat. aq. sodium bicarbonate (200 mL), brine (200 mL). The org. layer was dried over Na2SO4, filtered, and the solvents were removed under reduced pressure. Purification of the residue by FC (4:1 hept-EA) gave the title compound as a yellow oil: TLC: rf (4:1 hept-EA)=0.28. LC-MS-conditions 06: tR=0.92 min, [M+H]+=270.41.
Reaction SMILES: C[O:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[CH2:14][CH2:13][CH2:12][NH:11][CH2:10]2)=[CH:5][CH:4]=1.Cl.[BrH:16]>>[BrH:16].[NH:11]1[CH2:12][CH2:13][CH2:14][CH:9]([C:6]2[CH:5]=[CH:4][C:3]([OH:2])=[CH:8][CH:7]=2)[CH2:10]1
Reactant: COc1ccc(C2CCCNC2)cc1
Agent: Br
Agent: Cl
Product: Oc1ccc(C2CCCNC2)cc1

Procedure:
HBr was prepared by heating 3-(4-methoxyphenyl)piperidine.HCl (46 mg, 0.20 mmol) with 48% HBr in a microwave reactor at 120° C. for one hour. After evaporation, 53 mg of the title compound was obtained.
Reaction SMILES: Cl[C:2]1([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[O:19][CH3:20])[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([Cl:11])[CH:9]=2)[NH:4][C:3]1=[O:12].FC(F)(F)C(O)=O.[NH2:28][C@@H:29]([CH2:35][CH:36]([CH3:38])[CH3:37])[C:30]([N:32]([CH3:34])[CH3:33])=[O:31]>>[Cl:11][C:8]1[CH:9]=[C:10]2[C:5](=[CH:6][CH:7]=1)[NH:4][C:3](=[O:12])[C:2]2([NH:28][C@@H:29]([CH2:35][CH:36]([CH3:38])[CH3:37])[C:30]([N:32]([CH3:34])[CH3:33])=[O:31])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[O:19][CH3:20]
Reactant: CC(C)C[C@H](N)C(=O)N(C)C
Reactant: COc1ccccc1C1(Cl)C(=O)Nc2ccc(Cl)cc21
Solvent: O=C(O)C(F)(F)F
Product: COc1ccccc1C1(N[C@@H](CC(C)C)C(=O)N(C)C)C(=O)Nc2ccc(Cl)cc21

Procedure:
With 4.40 of 3,5-dichloro-3-(2-methoxyphenyl)-1,3-dihydro-2H-indol-2-one and the compound obtained in Step 60-2 (crude form) as starting material, respectively 2.09 g (Isomer A: colorless powder) and 3.26 g (Isomer B: colorless powder) of two species of diastereoisomers of the title compound were obtained by a similar method to Step 4-2.
Reaction SMILES: [CH3:1][C:2]([C:9]1[CH:14]=[CH:13][C:12](B2OC(C)(C)C(C)(C)O2)=[CH:11][CH:10]=1)([CH3:8])[C:3]([O:5][CH2:6][CH3:7])=[O:4].Br[C:25]1[CH:30]=[CH:29][C:28]([C:31]([F:34])([F:33])[F:32])=[CH:27][N:26]=1.C(=O)([O-])[O-].[Na+].[Na+]>CN(C)C=O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[CH3:8][C:2]([C:9]1[CH:10]=[CH:11][C:12]([C:25]2[CH:30]=[CH:29][C:28]([C:31]([F:34])([F:33])[F:32])=[CH:27][N:26]=2)=[CH:13][CH:14]=1)([CH3:1])[C:3]([O:5][CH2:6][CH3:7])=[O:4]
Reactant: FC(F)(F)c1ccc(Br)nc1
Reactant: CCOC(=O)C(C)(C)c1ccc(B2OC(C)(C)C(C)(C)O2)cc1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: CN(C)C=O
Product: CCOC(=O)C(C)(C)c1ccc(-c2ccc(C(F)(F)F)cn2)cc1
Temperature: 90 °C

Procedure:
To a solution of the product of Example 26A (370 mg, 1.16 mmoles) and 2-bromo-5-(trifluoromethyl)pyridine (341 mg, 1.51 mmoles) in N,N-dimethylformamide (10.0 ml) were added 1,1′-bis(diphenylphosphino)ferrocenedichloropalladium (II) (28 mg, 0.04 mmoles) and a 2M aqueous solution of sodium carbonate (1.7 ml, 3.48 mmoles) and the reaction mixture was heated under a nitrogen atmosphere to about 80° C. for about 1 hour. Another portion of 1,1′-bis(diphenylphosphino)ferrocenedichloropalladium (II) (28 mg, 0.04 mmoles) was added and the mixture was heated to about 90° C. for about 2 hours. The solvent was evaporated in high vacuum, the residue was taken up in water (20.0 ml) and diethyl ether (20.0 ml), and was filtered through Celite. The layers were separated and the aqueous layer was extracted with diethyl ether. The combined organic extracts were dried over MgSO4 and filtered. The filtrate was concentrated under reduced pressure and the crude product was purified by flash column chromatography on silica gel using hexanes/ethyl acetate (2:1) as the mobile phase to provide the title compound.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[C:11]1[CH2:12][CH2:13][N:14]([CH3:17])[CH2:15][CH:16]=1.[Br:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[S:25](Cl)(=[O:27])=[O:26]>>[Br:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[S:25]([N:7]1[C:8]2[C:4](=[CH:3][C:2]([F:1])=[CH:10][CH:9]=2)[C:5]([C:11]2[CH2:12][CH2:13][N:14]([CH3:17])[CH2:15][CH:16]=2)=[CH:6]1)(=[O:27])=[O:26]
Reactant: O=S(=O)(Cl)c1ccccc1Br
Reactant: CN1CC=C(c2c[nH]c3ccc(F)cc23)CC1
Product: CN1CC=C(c2cn(S(=O)(=O)c3ccccc3Br)c3ccc(F)cc23)CC1

Procedure:
(32 mg, 53%), from 5-fluoro-3-(1-methyl-1,2,3,6-tetrahydro-4-pyridinyl)-1H-indole (Example 4b, 30.6 mg, 0.133 mmol) and 2-bromophenylsulfonyl chloride (67.9 mg, 0.27 mmol); HRMS-FAB+ for C20H19N2SO2BrF calculated MH+ : 449.03348; found: 449.03240.
Reaction SMILES: CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O.[S:23]1[CH:27]=[C:26]([C:28]2[CH:33]=[CH:32][C:31]([CH:34]([OH:36])[CH3:35])=[CH:30][CH:29]=2)[N:25]=[N:24]1.C(=O)(O)[O-].[Na+]>C(Cl)Cl>[S:23]1[CH:27]=[C:26]([C:28]2[CH:29]=[CH:30][C:31]([C:34](=[O:36])[CH3:35])=[CH:32][CH:33]=2)[N:25]=[N:24]1
Reactant: CC(O)c1ccc(-c2csnn2)cc1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CC(=O)c1ccc(-c2csnn2)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Dess-Martin periodinane (2.1 g, 5.0 mmol) was added to an ambient temperature solution of 1-[4-(1,2,3-thiadiazol-4-yl)phenyl]ethanol (513 mg, 2.5 mmol) in methylene chloride (20 mL). After stirring at ambient temperature for 1 h, a solution of saturated aqueous sodium bicarbonate/saturated aqueous sodium thiosulfate (1:1) was added and the solution stirred until clear. The reaction mixture was extracted with methylene chloride. The combined organic extracts were dried (magnesium sulfate) and concentrated in vacuo to afford the title compound which was used in subsequent steps without further purification.
Reaction SMILES: [Cl:1][C:2]1[C:10]2[N:9]=[C:8]3[N:11]([C:16]4[C:17]([CH3:24])=[CH:18][C:19]([C:22]#[N:23])=[N:20][CH:21]=4)[CH2:12][CH2:13][CH2:14][CH2:15][N:7]3[C:6]=2[C:5]([CH:25]([CH2:28][CH3:29])[CH2:26][CH3:27])=[CH:4][CH:3]=1.[OH-].[K+].C([OH:36])(C)(C)C>O>[Cl:1][C:2]1[C:10]2[N:9]=[C:8]3[N:11]([C:16]4[C:17]([CH3:24])=[CH:18][C:19]([C:22]([NH2:23])=[O:36])=[N:20][CH:21]=4)[CH2:12][CH2:13][CH2:14][CH2:15][N:7]3[C:6]=2[C:5]([CH:25]([CH2:28][CH3:29])[CH2:26][CH3:27])=[CH:4][CH:3]=1
Reactant: CC(C)(C)O
Reactant: CCC(CC)c1ccc(Cl)c2nc3n(c12)CCCCN3c1cnc(C#N)cc1C
Agent: [K+]
Agent: [OH-]
Solvent: O
Product: CCC(CC)c1ccc(Cl)c2nc3n(c12)CCCCN3c1cnc(C(N)=O)cc1C
Temperature: 80 °C
Reaction time: 0.25 h
Yield: 88 %

Procedure:
A mixture of 5-[10-chloro-7-(1-ethylpropyl)-2,3,4,5-tetrahydro-1H-[1,3]diazepino[1,2-a]benzimidazol-1-yl]-4-methylpyridine-2-carbonitrile (Example 59; 70.0 mg, 0.172 mmol), potassium hydroxide (38.5 mg, 0.687 mmol) and t-butyl alcohol (2 mL) was stirred at 80° C. for 15 min. After the reaction mixture was diluted with water at 0° C., the precipitate was collected by filtration and washed with water and diisopropyl ether to give the title compound as a solid (64.8 mg, 0.152 mmol, 88%). Analytically pure material was obtained by recrystallization from ethyl acetate/n-hexane.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[OH:21][C:22]1[CH:30]=[CH:29][C:25]([C:26](O)=[O:27])=[CH:24][CH:23]=1.CN1CCOCC1.C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F>CN(C=O)C>[OH:21][C:22]1[CH:30]=[CH:29][C:25]([C:26]([NH:1][C:2]2[CH:7]=[CH:6][C:5]([N:8]3[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10][CH2:9]3)=[CH:4][CH:3]=2)=[O:27])=[CH:24][CH:23]=1
Reactant: O=C(O)c1ccc(O)cc1
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc(N)cc2)CC1
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: CC(C)(C)OC(=O)N1CCN(c2ccc(NC(=O)c3ccc(O)cc3)cc2)CC1
Temperature: 60 °C
Reaction time: 60 h
Yield: 24 %

Procedure:
To a solution of tert-butyl 4-(4-aminophenyl)piperazine-1-carboxylate (1 eq), 4-hydroxybenzoic acid (1.1 eq), N-methylmorpholine (3 eq) in dry DMF (0.16 M), was added PyBop (1.5 eq). The reaction mixture was heated at 60° C. with stirring for 60 h. At this time the reaction was allowed to cool to RT partitioned between EtOAc and 1N aqueous HCl. The aqueous fraction was extracted with EtOAc and the combined organics washed with saturated aqueous Na2CO3, brine, before being dried over Na2SO4, filtered and evaporated in vacuo. Purification was by flash chromatography on silica gel (4:6) EtOAc/PE) to afford the title compound (24%).
Reaction SMILES: [CH2:1]([C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[CH2:13][CH3:14])[C:9](=[O:15])[C:8](O)=[CH:7][C:6]2=[O:17])[CH3:2].S(Cl)([Cl:20])=O>>[Cl:20][C:8]1[C:9](=[O:15])[C:10]2[C:5]([C:6](=[O:17])[CH:7]=1)=[CH:4][C:3]([CH2:1][CH3:2])=[C:12]([CH2:13][CH3:14])[CH:11]=2
Reactant: O=S(Cl)Cl
Reactant: CCc1cc2c(cc1CC)C(=O)C(O)=CC2=O
Product: CCc1cc2c(cc1CC)C(=O)C(Cl)=CC2=O

Procedure:
A solution of 6,7-diethyl-2-hydroxy-1,4-naphthoquinone (22 g; 0.096 mole) in thionyl chloride (250 ml) was refluxed for 12 hours and the solvent removed in vacuo. Repeated evaporation with dry benzene gave an orange solid which after recrystallisation from ethanol in the presence of charcoal weighed 18.04 g (76%) and had m.p. 90°-92° C. (Found; C, 67.21; H, 5.39; Cl, 14.21; C14H13ClO2 requires; C, 67.61; H, 5.27; Cl, 14.26%).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([CH2:8][CH2:9][C:10]([O:12][CH3:13])=[O:11])[CH:5]=[CH:4][C:3]=1[C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([N:20]([CH3:29])[C:21]([NH:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])=[O:22])[CH:15]=1.I[CH2:31][CH2:32][CH2:33][CH3:34].C(N(C(C)C)CC)(C)C.O>CN(C)C=O>[CH2:31]([NH:1][C:2]1[CH:7]=[C:6]([CH2:8][CH2:9][C:10]([O:12][CH3:13])=[O:11])[CH:5]=[CH:4][C:3]=1[C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([N:20]([CH3:29])[C:21]([NH:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])=[O:22])[CH:15]=1)[CH2:32][CH2:33][CH3:34]
Reactant: CCCCCNC(=O)N(C)c1cccc(-c2ccc(CCC(=O)OC)cc2N)c1
Reactant: CCCCI
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: CCCCCNC(=O)N(C)c1cccc(-c2ccc(CCC(=O)OC)cc2NCCCC)c1
Yield: 50.6 %

Procedure:
A solution of 200 mg (0.5 mmol, 1 eq) of methyl 3-[2-amino-3′-(1-methyl-3-pentylureido)biphenyl-4-yl]propanoate (prepared in Example 52c) and 60 μL (0.55 mmol, 1.1 eq) of 1-iodobutane in 2 ml of dimethylformamide in the presence of 170 μL (10.5 mmol, 2.1 eq) of diisopropylethylamine is heated at 80° C. for 16 hours. The reaction medium is hydrolyzed with water and then extracted with ethyl acetate. The organic phases are combined, washed with saturated sodium chloride solution and dried over sodium sulfate. The solvent is evaporated off and the residue is chromatographed on silica gel (70/30 heptane/ethyl acetate). 114.8 mg of methyl 3-[2-butylamino-3′-(1-methyl-3-pentylureido)biphenyl-4-yl]propanoate are obtained in the form of a yellow oil. Yield=51%
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:20])[CH2:5][N:6]=[C:7]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[CH3:2].C[Si]([N-][Si](C)(C)C)(C)C.[Li+].Br[CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH3:49]>C(OCC)(=O)C.O.CN1C(=O)N(C)CCC1.C1COCC1>[C:8]1([C:7]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[N:6][CH:5]([CH2:49][CH2:48][CH2:47][CH2:46][CH2:45][CH2:44][CH2:43][CH2:42][CH2:41][CH2:40][CH2:39][CH2:38][CH2:37][CH2:36][CH2:35][CH2:34][CH2:33][CH3:32])[C:4]([O:3][CH2:1][CH3:2])=[O:20])[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: CCCCCCCCCCCCCCCCCCBr
Reactant: CCOC(=O)CN=C(c1ccccc1)c1ccccc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CN1CCCN(C)C1=O
Solvent: CCOC(C)=O
Product: CCCCCCCCCCCCCCCCCCC(N=C(c1ccccc1)c1ccccc1)C(=O)OCC
Temperature: -78 °C
Reaction time: 1.5 h
Yield: 80 %

Procedure:
To a stirred solution of N-(diphenylmethylene)-glycine ethyl ester (67.3 g, 0.250 mol) in a 1:1 mixture of anhydrous THF (500 ml) and DMPU (500 ml) at -78° C. under a dry argon atmosphere was added a solution of lithium bis(trimethylsilyl)amide (250 ml-1.0M in THF, 0.25 mol) over a 10 min period. The resulting orange solution was stirred for 1.5 h at -78° C. While maintaining the temperature at -78° C., a solution of 1-bromooctadecane (83.4 g, 0.250 mol) in a 1:1 mixture of anhydrous THF (250 ml) and DMPU (250 ml) was added over a 10 min period and the resulting mixture was allowed to warm to room temperature. After stirring the mixture for 17 h, H2O (50 ml) and then ethyl acetate (2 l) were added. The solution was washed with H2O (4×2 l). The solution was dried over Na2CO3 --Na2SO4 and the volume was reduced in vacuo to 1 l. The product was crystallized by the addition of hexane to give 104 g (80% yield) of an off-white crystalline solid: mp 62°-5° C.; 1H NMR (CDCl3) δ 0.88 (t, J=6.6 Hz, 3H), 1.27 (m, 35H), 1.90 (m, 2H), 4.03 (m, 1H), 4.17 (m, 2H), 7.17 (m, 2H), 7.36 (m, 6H), 7.64 (m, 2H).
Reaction SMILES: [CH2:1]([C:8]1[S:9][C:10]([CH3:29])=[C:11]([CH3:28])[C:12]=1[C:13]([C:15]1[CH:20]=[CH:19][C:18]([O:21]C)=[C:17]([CH:23]2[CH2:27][CH2:26][CH2:25][CH2:24]2)[CH:16]=1)=[O:14])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.B(Br)(Br)Br.C(Cl)Cl>C(Cl)Cl>[CH2:1]([C:8]1[S:9][C:10]([CH3:29])=[C:11]([CH3:28])[C:12]=1[C:13]([C:15]1[CH:20]=[CH:19][C:18]([OH:21])=[C:17]([CH:23]2[CH2:27][CH2:26][CH2:25][CH2:24]2)[CH:16]=1)=[O:14])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COc1ccc(C(=O)c2c(Cc3ccccc3)sc(C)c2C)cc1C1CCCC1
Agent: BrB(Br)Br
Solvent: ClCCl
Product: Cc1sc(Cc2ccccc2)c(C(=O)c2ccc(O)c(C3CCCC3)c2)c1C
Yield: 19.7 %

Procedure:
The title compound was prepared according to the procedure in Example 5, step 3 using (2-benzyl-4,5-dimethyl-thiophen-3-yl)-(3-cyclopentyl-4-methoxy-phenyl)-methanone (3.32 g, 8.20 mmol) and 1M boron tribromide/CH2Cl2 (1.6 mL) in CH2Cl2. Purification on Biotage KP-Sil eluting with a 2, 5 & 10% EtOAc/hexane step gradient gave 0.63 g (18%) of the title compound. 1H NMR (DMSO-d6) δ consistent.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH3:7])[S:5][CH:6]=1.[B:8](OC(C)C)([O:13]C(C)C)[O:9]C(C)C.N#N.[Li]CCCC.CCCCCC.Cl>C1COCC1>[CH3:7][C:4]1[S:5][CH:6]=[C:2]([B:8]([OH:13])[OH:9])[CH:3]=1
Reactant: Cc1cc(Br)cs1
Reactant: CC(C)OB(OC(C)C)OC(C)C
Agent: Cl
Agent: N#N
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: Cc1cc(B(O)O)cs1
Temperature: -70 °C
Reaction time: 0.5 h

Procedure:
4-Bromo-2-methylthiophene (300 mg, 1.69 mmol) and triisopropyl borate (486 μL, 2.12 mmol) were dissolved in THF (1 mL) and the solution was vacuumed and filled with N2 3 times. The solution was cooled to −70° C. using an acetone/dry ice bath. 2.5 M of n-BuLi in hexane (1.0 mL, 2.54 mmol) was added drop wise and the mixture was stirred for an additional 30 minutes while the temperature was held at −70° C. The reaction mixture was allowed to warm up to −20° C. and 2 mL of 3 N HCl was added. When the mixture was warmed up to room temperature, two layers were separated. The water layer was neutralized to about pH 7, using 5 N NaOH. Both layers were extracted with EtOAc and washed with brine. The organic layer was dried over anhydrous Na2SO4. The material was not further purified and was used directly in the next step. MS (ESI): 143.05 [M+H]+; HPLC tR=1.30 min (HPLC: Anayltical—2 min).
Reaction SMILES: O[CH2:2][C:3]1[C:12]([C:13]2[CH:18]=[CH:17][C:16]([O:19][CH2:20][O:21][CH3:22])=[CH:15][C:14]=2[O:23][CH3:24])=[CH:11][CH:10]=[C:9]2[C:4]=1[C:5]([CH3:27])=[CH:6][C:7]([CH3:26])([CH3:25])[NH:8]2.C(N(CC)CC)C.CS([Cl:39])(=O)=O.C(Cl)(Cl)Cl>C(Cl)Cl.O>[Cl:39][CH2:2][C:3]1[C:12]([C:13]2[CH:18]=[CH:17][C:16]([O:19][CH2:20][O:21][CH3:22])=[CH:15][C:14]=2[O:23][CH3:24])=[CH:11][CH:10]=[C:9]2[C:4]=1[C:5]([CH3:27])=[CH:6][C:7]([CH3:26])([CH3:25])[NH:8]2
Reactant: CS(=O)(=O)Cl
Reactant: COCOc1ccc(-c2ccc3c(c2CO)C(C)=CC(C)(C)N3)c(OC)c1
Solvent: ClCCl
Solvent: ClC(Cl)Cl
Solvent: O
Product: COCOc1ccc(-c2ccc3c(c2CCl)C(C)=CC(C)(C)N3)c(OC)c1
Temperature: 25 °C
Reaction time: 5 h
Yield: 49 %

Procedure:
5-Hydroxymethyl-6-(2-methoxy-4-methoxymethoxyphenyl)-2,2,4-trimethyl-1,2-dihydroquinoline (Reference Compound No. 1, 1.02 g, mmol) was dissolved in anhydrous methylene dichloride (10 mL), and then triethylamine (0.490 mL, 3.52 mmol) and methanesulfonyl chloride (231 L, mmol) were added successively. The reaction mixture was stirred at room temperature for 5 hours. Chloroform (50 mL) and water (50 mL) were added to the reaction mixture and separated. The organic layer was washed with saturated brine (50 mL), dried over anhydrous magnesium sulfate, and then the solvent was removed under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane-ethyl acetate) to give the titled reference compound (515 mg) as an orange amorphous product. (Yield 49%)
Reaction SMILES: [NH2:1][C@H:2]1[CH2:7][CH2:6][CH2:5][N:4]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[C@H:3]1[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.[C:21]([CH:23]([C:25]1[CH:26]=[CH:27][C:28]([O:33][CH3:34])=[C:29]([CH:32]=1)[CH:30]=O)[CH3:24])#[N:22].[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].C([O-])(O)=O.[Na+]>C(Cl)Cl>[C:11]([O:10][C:8]([N:4]1[CH2:5][CH2:6][CH2:7][C@H:2]([NH:1][CH2:30][C:29]2[CH:32]=[C:25]([CH:23]([C:21]#[N:22])[CH3:24])[CH:26]=[CH:27][C:28]=2[O:33][CH3:34])[C@@H:3]1[C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1)=[O:9])([CH3:14])([CH3:13])[CH3:12]
Reactant: CC(C)(C)OC(=O)N1CCC[C@H](N)[C@@H]1c1ccccc1
Reactant: COc1ccc(C(C)C#N)cc1C=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: COc1ccc(C(C)C#N)cc1CN[C@H]1CCCN(C(=O)OC(C)(C)C)[C@H]1c1ccccc1
Yield: 103.8 %

Procedure:
To a stirred and ice-cooled solution of Compound 17 (160 mg, 0.60 mmol) and Compound 14 (120 mg, 0.60 mmol) in dry CH2Cl2 (5 ml) was added NaBH(OAc)3 (430 mg, 2.0 mmol) in one portion. The mixture was stirred at room temperature for 20 hours. The mixture was poured into NaHCO3 aq., and extracted with CH2Cl2. The combined extracts were dried (Na2SO4), and concentrated in vacuo to give Compound 18 as a yellow oil (280 mg).