Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[CH2:2][C:3]1[CH:4]=[C:5]([NH:10][CH2:11][C:12]2[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=2)[CH:6]=[C:7]([F:9])[CH:8]=1.[CH:20]([C:23]1[C:24](=[O:41])[NH:25][C:26](=[O:40])[NH:27][C:28]=1[C:29](=[O:39])[C:30]1[CH:35]=[C:34]([CH3:36])[CH:33]=[C:32]([C:37]#[N:38])[CH:31]=1)([CH3:22])[CH3:21].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[F:9][C:7]1[CH:8]=[C:3]([CH:4]=[C:5]([NH:10][CH2:11][C:12]2[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=2)[CH:6]=1)[CH2:2][N:27]1[C:28]([C:29]([C:30]2[CH:31]=[C:32]([CH:33]=[C:34]([CH3:36])[CH:35]=2)[C:37]#[N:38])=[O:39])=[C:23]([CH:20]([CH3:22])[CH3:21])[C:24](=[O:41])[NH:25][C:26]1=[O:40]
Reactant: COc1ccc(CNc2cc(F)cc(CBr)c2)cc1
Reactant: Cc1cc(C#N)cc(C(=O)c2[nH]c(=O)[nH]c(=O)c2C(C)C)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1ccc(CNc2cc(F)cc(Cn3c(C(=O)c4cc(C)cc(C#N)c4)c(C(C)C)c(=O)[nH]c3=O)c2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 55.9 %

Procedure:
To a mixture of (3-bromomethyl-5-fluoro-phenyl)-(4-methoxy-benzyl)-amine (570 mg, 1.758 mmol), 5-isopropyl-6-(3′-cyano-5′-methylbenzoyl)-2,4-pyrimidinedione (522 mg, 1.758 mmol), and anhydrous powdered potassium carbonate (243 mg, 1.758 mmol), was added DMF (10 ml). The mixture was then stirred for overnight at room temperature and evaporated in vacuo. The residue was dissolved in methanol-dichloromethane (1:9), filtered through celite pad, and evaporated in vacuo to give a light yellow syrup. The crude product was purified by silica gel column chromatography (eluent, EA:hexane (1:4)) to afford 531 mg of 3-{3-[3-fluoro-5-(4-methoxy-benzylamino)-benzyl]-5-isopropyl-2,6-dioxo-1,2,3,6-tetrahydro-pyrimidine-4-carbonyl}-5-methyl-benzonitrile (151) as a yellow solid.
Reaction SMILES: C([O:3][C:4](=[O:34])[CH2:5][N:6]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([O:15][CH2:16][C:17]([CH3:33])([CH3:32])[CH2:18][C:19]#[C:20][C:21]3[CH:26]=[CH:25][C:24]([O:27][C:28]([F:31])([F:30])[F:29])=[CH:23][CH:22]=3)[CH:13]=2)[CH:8]=[CH:7]1)C.[Li+].[OH-]>>[CH3:32][C:17]([CH3:33])([CH2:18][C:19]#[C:20][C:21]1[CH:22]=[CH:23][C:24]([O:27][C:28]([F:31])([F:29])[F:30])=[CH:25][CH:26]=1)[CH2:16][O:15][C:12]1[CH:13]=[C:14]2[C:9]([CH:8]=[CH:7][N:6]2[CH2:5][C:4]([OH:34])=[O:3])=[CH:10][CH:11]=1
Reactant: CCOC(=O)Cn1ccc2ccc(OCC(C)(C)CC#Cc3ccc(OC(F)(F)F)cc3)cc21
Agent: [Li+]
Agent: [OH-]
Product: CC(C)(CC#Cc1ccc(OC(F)(F)F)cc1)COc1ccc2ccn(CC(=O)O)c2c1

Procedure:
In analogy to the procedure described for example 1 e], {6-[2,2-dimethyl-5-(4-trifluoromethoxy-phenyl)-pent-4-ynyloxy]-indol-1-yl}-acetic acid ethyl ester was treated with LiOH to obtain the title compound as brown oil.
Reaction SMILES: Cl[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:10]([NH:15][S:16]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[C:25]([F:28])([F:27])[F:26])(=[O:18])=[O:17])=[N:11][CH:12]=[CH:13][N:14]=2)=[CH:5][CH:4]=1.[C:29]1([OH:35])[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1>>[O:35]([CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:10]([NH:15][S:16]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[C:25]([F:28])([F:27])[F:26])(=[O:18])=[O:17])=[N:11][CH:12]=[CH:13][N:14]=2)=[CH:5][CH:4]=1)[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1
Reactant: O=S(=O)(Nc1nccnc1-c1ccc(CCl)cc1)c1ccccc1C(F)(F)F
Reactant: Oc1ccccc1
Product: O=S(=O)(Nc1nccnc1-c1ccc(COc2ccccc2)cc1)c1ccccc1C(F)(F)F
Yield: 75 %

Procedure:
Following the general method as outlined in Example 1 (Method A), starting from N-{3-[4-(chloromethyl)phenyl]pyrazin-2-yl}-2-(trifluoromethyl)benzenesulfonamide (Intermediate 9), and phenol, the title compound was isolated as a yellow solid in 75% yield (98% purity by HPLC).
Reaction SMILES: [NH2:1][C:2]1[C:11]2[N:12]=[C:13]([CH2:31][CH2:32][CH2:33][CH3:34])[N:14]([CH2:15][CH2:16][CH2:17][NH:18][CH2:19][C:20]3[CH:25]=[CH:24][C:23]([CH2:26][C:27]([O:29][CH3:30])=[O:28])=[CH:22][CH:21]=3)[C:10]=2[C:9]2[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=2[N:3]=1.C(Cl)Cl.Cl.[CH3:39][N:40]([CH3:45])[CH2:41][C:42](Cl)=[O:43].CCN(CC)CC>CN(C=O)C>[NH2:1][C:2]1[C:11]2[N:12]=[C:13]([CH2:31][CH2:32][CH2:33][CH3:34])[N:14]([CH2:15][CH2:16][CH2:17][N:18]([CH2:19][C:20]3[CH:21]=[CH:22][C:23]([CH2:26][C:27]([O:29][CH3:30])=[O:28])=[CH:24][CH:25]=3)[C:42](=[O:43])[CH2:41][N:40]([CH3:45])[CH3:39])[C:10]=2[C:9]2[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=2[N:3]=1
Reactant: CN(C)CC(=O)Cl
Reactant: CCCCc1nc2c(N)nc3ccccc3c2n1CCCNCc1ccc(CC(=O)OC)cc1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCCCc1nc2c(N)nc3ccccc3c2n1CCCN(Cc1ccc(CC(=O)OC)cc1)C(=O)CN(C)C
Reaction time: 72 h

Procedure:
The product from example 1 (15 mg) was dissolved in a mixture of DMF:DCM, 1:1 (5 mL) and N,N-dimethylglycyl chloride hydrochloride salt (8 mg) and Et3N (0.01 mL) were added. The reaction mixture was stirred for 72 h. More N,N-dimethylglycyl chloride hydrochloride salt (0.050 g) and Et3N (0.06 mL) were added, the mixture was stirred for a further 16 h. The product was purified via RPHPLC.
Reaction SMILES: [CH2:1]([C:7]1[CH:11]=[CH:10][S:9][CH:8]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].[Br:12]N1C(=O)CCC1=O>CN(C=O)C>[Br:12][C:8]1[S:9][CH:10]=[CH:11][C:7]=1[CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: O=C1CCC(=O)N1Br
Reactant: CCCCCCc1ccsc1
Solvent: CN(C)C=O
Product: CCCCCCc1ccsc1Br

Procedure:
3-hexylthiophene and N-bromosuccinimide (hereinafter, referred to as ‘NBS’) in the same amount were reacted in DMF at room temperature for 15 hours to obtain 2-bromo-3-hexylthiophene (d). 12.4 g (50 mmol) of the 2-bromo-3-hexylthiophene (d) was added to a solution of 28 mL (56 mmol) of lithium diisopropylamine (hereinafter, referred to as ‘LDA’, 2.0M in THF/Hexane) in 40 mL of anhydrous THF at about −80˜−90° C. with stirring. At this temperature, the reaction was allowed to proceed for 20˜30 minutes. A solution of 10.0 g (50 mmol) of Me3SnCl in THF was added to the mixture, and was then stirred at −50° C. for 1 hour. After completion of the reaction, the reaction mixture was extracted with ether and water. The obtained organic layer was concentrated, and distilled to afford the title compound (yield: 78%) as a colorless oil. The 1H-NMR spectrum (CDCl3) of the monomer (3) is shown in FIG. 2.
Reaction SMILES: [CH:1]1[C:9]2[C:8]3[CH:10]=[CH:11][CH:12]=[CH:13][C:7]=3[O:6][C:5]=2[CH:4]=[CH:3][CH:2]=1.C([Li:18])CCC.CCCCCC>CCOCC>[CH:1]1[C:9]2[C:8]3[CH:10]=[CH:11][CH:12]=[CH:13][C:7]=3[O:6][C:5]=2[C:4]([Li:18])=[CH:3][CH:2]=1
Reactant: c1ccc2c(c1)oc1ccccc12
Reactant: [Li]CCCC
Solvent: CCOCC
Solvent: CCCCCC
Product: [Li]c1cccc2c1oc1ccccc12
Temperature: 25 °C
Reaction time: 20 h

Procedure:
Into a solution of dibenzo[b,d]furan (4.98 g, 29.6 mmol) in ether (50 mL) at −78° C. was added n-butyllithium solution in hexane (2.5 M, 9.48 mL, 23.70 mmol) dropwise and the solution was allowed to warm to room temperature and stirred for 20 h to yield a dibenzo[b,d]furan-4-yl lithium solution. Into a solution of 1,3-dibromobenzene (2.56 mL, 21.20 mmol) in ether (50 mL) was added n-butyllithium solution in hexane (2.5 M, 9.48 mL, 23.70 mmol) dropwise at −78° C. The reaction solution was stirred at this temperature for 3.5 h before adding into a solution of dichlorodiphenylsilane (4.88 mL, 23.70 mmol) in ether (50.0 mL) at −78° C. The resultant reaction solution was stirred at this temperature for 2 h before the dibenzo[b,d]furan-4-yl lithium solution prepared above was introduced dropwise. The reaction mixture was allowed to slowly warm to room temperature overnight at which time it was quenched with water, extracted with ether, and dried over Na2SO4. Upon filtration and evaporation of the solvent, the residue was purified by column chromatography on silica gel with hexane/DCM (9/1, v/v) as eluent to yield (3-bromophenyl)(dibenzo[b,d]furan-4-yl)diphenylsilane (6.2 g, 52%) as a white powder.
Reaction SMILES: [F:1][C:2]1([F:12])[CH2:7][CH2:6][C:5]([OH:11])([C:8]([OH:10])=O)[CH2:4][CH2:3]1.[Cl:13][C:14]1[CH:15]=[C:16]([F:36])[C:17]([C:30]2[N:31]=[N:32][N:33]([CH3:35])[N:34]=2)=[C:18]([C:20]2[CH:21]=[C:22]([F:29])[C:23]([C@H:26]([NH2:28])[CH3:27])=[N:24][CH:25]=2)[CH:19]=1.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.C(N(CC)CC)C.C(=O)(O)[O-].[Na+]>CN(C=O)C.O>[Cl:13][C:14]1[CH:15]=[C:16]([F:36])[C:17]([C:30]2[N:31]=[N:32][N:33]([CH3:35])[N:34]=2)=[C:18]([C:20]2[CH:21]=[C:22]([F:29])[C:23]([C@H:26]([NH:28][C:8]([C:5]3([OH:11])[CH2:4][CH2:3][C:2]([F:1])([F:12])[CH2:7][CH2:6]3)=[O:10])[CH3:27])=[N:24][CH:25]=2)[CH:19]=1
Reactant: O=C(O)C1(O)CCC(F)(F)CC1
Reactant: C[C@@H](N)c1ncc(-c2cc(Cl)cc(F)c2-c2nnn(C)n2)cc1F
Agent: CCN=C=NCCCN(C)C
Agent: O=C([O-])O
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: O
Solvent: CN(C)C=O
Product: C[C@@H](NC(=O)C1(O)CCC(F)(F)CC1)c1ncc(-c2cc(Cl)cc(F)c2-c2nnn(C)n2)cc1F
Reaction time: 1 h

Procedure:
A mixture of 4,4-difluoro-1-hydroxy-cyclohexanecarboxylic acid (324 mg, 1.8 mmol) and the compound of Reference Example 4 (632 mg, 1.8 mmol) was dissolved in 3.6 ml of degassed DMF. HOBT (58 mg, 0.43 mmol) and EDCI (449 mg, 2.34 mmol) were added, and the reaction mixture was made basic with triethylamine (182 mg, 1.8 mmol). After 1 hour at ambient temperature, 20 ml of water and 2 ml of 10% aqueous sodium bicarbonate solution were added and the mixture was extracted with EtOAc. The combined organic extracts were washed with water and brine, and dried over sodium sulfate, filtered, and concentrated. The crude material was subjected to silical gel chromatography eluting with 10 to 30% EtOAc in hexanes to provide the title compound as a white solid which gave a proton NMR spectrum consistent with theory and a mass ion (ES+) of 513.0 for M+H+: 1H NMR (500 MHz, CDCl3) δ 8.14 (s, 1H), 7.67 (d, J=7 Hz, 1H), 7.35 (d, J=10 Hz, 1 H), 7.28 (m, 2H), 5.41 (m, 1H), 4.36 (s, 3H), 2.88 (s, 1H), 2.12 (m, 6H), 1.76 (m, 2H), 1.44 (d, J=7 Hz, 3H).
Reaction SMILES: Br[C:2]1[CH:39]=[CH:38][C:5]([CH2:6][N:7]2[C:11]3[CH:12]=[CH:13][C:14]([O:16][CH2:17][C:18]4[CH:27]=[CH:26][C:25]5[C:20](=[CH:21][CH:22]=[C:23]([F:28])[CH:24]=5)[N:19]=4)=[CH:15][C:10]=3[N:9]=[C:8]2[C@H:29]2[CH2:34][CH2:33][CH2:32][CH2:31][C@H:30]2[C:35]([OH:37])=[O:36])=[CH:4][CH:3]=1.[F:40][C:41]([F:49])([F:48])[CH:42]1[CH2:47][CH2:46][NH:45][CH2:44][CH2:43]1>>[F:28][C:23]1[CH:24]=[C:25]2[C:20](=[CH:21][CH:22]=1)[N:19]=[C:18]([CH2:17][O:16][C:14]1[CH:13]=[CH:12][C:11]3[N:7]([CH2:6][C:5]4[CH:4]=[CH:3][C:2]([N:45]5[CH2:46][CH2:47][CH:42]([C:41]([F:49])([F:48])[F:40])[CH2:43][CH2:44]5)=[CH:39][CH:38]=4)[C:8]([C@H:29]4[CH2:34][CH2:33][CH2:32][CH2:31][C@H:30]4[C:35]([OH:37])=[O:36])=[N:9][C:10]=3[CH:15]=1)[CH:27]=[CH:26]2
Reactant: FC(F)(F)C1CCNCC1
Reactant: O=C(O)[C@@H]1CCCC[C@@H]1c1nc2cc(OCc3ccc4cc(F)ccc4n3)ccc2n1Cc1ccc(Br)cc1
Product: O=C(O)[C@@H]1CCCC[C@@H]1c1nc2cc(OCc3ccc4cc(F)ccc4n3)ccc2n1Cc1ccc(N2CCC(C(F)(F)F)CC2)cc1

Procedure:
The title compound was prepared using analogous conditions to those described in Example 190 using racemic cis-2-(1-(4-bromobenzyl)-5-((6-fluoroquinolin-2-yl)methoxy)-1H-benzo[d]imidazol-2-yl)cyclohexanecarboxylic acid and 4-(trifluoromethyl)piperidine. MS (ESI): mass calcd. for C37H36F4N4O3, 660.27; m/z found, 661.2 [M+H]+. 1H NMR (500 MHz, CD3OD) δ 8.40 (d, J=8.6, 1H), 8.15-8.08 (m, 1H), 7.78 (d, J=8.6, 1H), 7.69-7.60 (m, 2H), 7.57 (d, J=9.1, 1H), 7.37-7.28 (m, 2H), 7.13-7.02 (m, 4H), 5.68 (d, J=3.9, 2H), 5.49 (s, 2H), 3.82-3.76 (m, 2H), 3.65-3.57 (m, 1H), 2.92-2.88 (m, 1H), 2.88-2.80 (m, 2H), 2.43-2.25 (m, 2H), 2.22-2.15 (m, 1H), 2.05-1.93 (m, 4H), 1.82-1.63 (m, 4H), 1.57-1.47 (m, 2H).
Reaction SMILES: Br[C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH2:4][CH2:5][C:6]2=[O:11].[F:12][C:13]([F:24])([F:23])[C:14]1[CH:19]=[CH:18][C:17](B(O)O)=[CH:16][CH:15]=1.C(=O)([O-])[O-].[Na+].[Na+].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1(C)C=CC=CC=1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.O.C(O)C>[F:12][C:13]([F:24])([F:23])[C:14]1[CH:19]=[CH:18][C:17]([C:2]2[CH:10]=[CH:9][CH:8]=[C:7]3[C:3]=2[CH2:4][CH2:5][C:6]3=[O:11])=[CH:16][CH:15]=1
Reactant: OB(O)c1ccc(C(F)(F)F)cc1
Reactant: O=C1CCc2c(Br)cccc21
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: O
Solvent: CCO
Solvent: Cc1ccccc1
Product: O=C1CCc2c1cccc2-c1ccc(C(F)(F)F)cc1

Procedure:
6.33 g (0.03 mol) of 4-bromo-1-indanone and 5.7 g (0.03 mol) of 4-trifluoromethylphenylboronic acid are suspended with 6.36 g (0.06 mol) of sodium carbonate in a mixture of 100 ml of toluene with 20 ml of ethanol and 20 ml of water. Under an argon atmosphere, 320 mg (1.42 mmol) of palladium(II) acetate and 787 mg (3 mmol) of triphenylphosphine are added, and the mixture is boiled under reflux for 5 h. After the reaction is complete, the ethanol content is evaporated off in vacuo, 50 ml of 0.5 N sodium hydroxide solution are added to the residue, and the mixture is stirred and filtered with suction through a clarifying layer. The organic phase of the filtrate is separated off, shaken 3× with 50 ml of water each time, shaken once with saturated brine, dried over sodium sulfate and concentrated in vacuo. The crude product is chromatographed on silica gel with n-heptane/ethyl acetate 3/1. 4-(4-Trifluoromethylphenyl)-1-indanone is obtained with a melting point of 75-78° C.
Reaction SMILES: [CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[C:13]([F:16])([F:15])[F:14])[C:3]=1[C:17]([OH:19])=O.Cl.C(N=C=NCCCN(C)C)C.OC1C2N=NNC=2C=CC=1.[N:42]1([C:48]2[CH:53]=[CH:52][CH:51]=[CH:50][C:49]=2[OH:54])[CH2:47][CH2:46][NH:45][CH2:44][CH2:43]1>>[OH:54][C:49]1[CH:50]=[CH:51][CH:52]=[CH:53][C:48]=1[N:42]1[CH2:47][CH2:46][N:45]([C:17]([C:3]2[C:4]([C:7]3[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=3[C:13]([F:14])([F:15])[F:16])=[N:5][O:6][C:2]=2[CH3:1])=[O:19])[CH2:44][CH2:43]1
Reactant: Cc1onc(-c2ccccc2C(F)(F)F)c1C(=O)O
Reactant: Oc1ccccc1N1CCNCC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: Oc1cccc2[nH]nnc12
Product: Cc1onc(-c2ccccc2C(F)(F)F)c1C(=O)N1CCN(c2ccccc2O)CC1
Yield: 57.1 %

Procedure:
In a similar manner as described in Example 1, by using dimethylformimide (15 mL), 5-methyl-3-(2-(trifluoromethyl)phenyl)isoxazol-4-carboxylic acid (500 mg, 1.84 mmol), 1-ethyl-3-(dimethylaminopropyl)carbodiimide hydrochloride (388 mg, 2.02 mmol), hydroxybenzotriazole (299 mg, 2.21 mmol) and 2-(piperazine-1-yl)phenol (328 mg, 1.84 mmol), a white solid required compound (451 mg, 1.05 mmol, 57%) was obtained.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:4]=1[CH:5]=[C:6]([CH3:12])[NH:7]2.[H-].[Na+].Cl[CH2:16][C:17]1[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH:20]=[CH:19][CH:18]=1>CN(C=O)C.O>[CH3:1][O:2][C:3]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:4]=1[CH:5]=[C:6]([CH3:12])[N:7]2[CH2:16][C:17]1[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH:20]=[CH:19][CH:18]=1
Reactant: ClCc1cccc2ccccc12
Reactant: COc1cccc2[nH]c(C)cc12
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1cccc2c1cc(C)n2Cc1cccc2ccccc12
Reaction time: 0.67 h
Yield: 97.1 %

Procedure:
4-Methoxy-2-methyl-1H-indole (644 mg, 4 mmol) was dissolved in 10 mL of DMF and 160 mg (4 mmol) of 60% NaH/mineral oil was added. After 0.67 hours, 707 mg (4 mmol) of 1-(chloromethyl)naphthalene was added. After 5 hours, the mixture was diluted with water and extracted twice with ethyl acetate. The combined ethyl acetate was washed with brine, dried (MgSO4) and concentrated at reduced pressure. The residue was chromatographed on silica gel and eluted with 20% EtOAc/hexane to give 1.17 g (97% yield) of 4-methoxy-2-methyl-1-[(1-naphthalenyl)methyl]-1H-indole.
Reaction SMILES: [O:1]=[C:2]1[C:6](=[CH:7][C:8]2[CH:13]=[CH:12][C:11]([N:14]3[CH2:19][CH2:18][C:17](=O)[CH2:16][CH2:15]3)=[CH:10][CH:9]=2)[S:5][C:4](=[S:21])[NH:3]1.[NH2:22][CH2:23][C@H:24]([OH:34])[CH2:25][O:26][C:27]1[CH:32]=[CH:31][C:30]([OH:33])=[CH:29][CH:28]=1>>[OH:34][C@H:24]([CH2:25][O:26][C:27]1[CH:32]=[CH:31][C:30]([OH:33])=[CH:29][CH:28]=1)[CH2:23][NH:22][CH:17]1[CH2:18][CH2:19][N:14]([C:11]2[CH:12]=[CH:13][C:8]([CH:7]=[C:6]3[S:5][C:4](=[S:21])[NH:3][C:2]3=[O:1])=[CH:9][CH:10]=2)[CH2:15][CH2:16]1
Reactant: O=C1CCN(c2ccc(C=C3SC(=S)NC3=O)cc2)CC1
Reactant: NC[C@H](O)COc1ccc(O)cc1
Product: O=C1NC(=S)SC1=Cc1ccc(N2CCC(NC[C@H](O)COc3ccc(O)cc3)CC2)cc1

Procedure:
The title compound was prepared from 1-[4-(4-oxo-2-thioxo-thiazolidin-5-ylidenemethyl)-phenyl]-piperidine-4-one (which was obtained in Example 34) and 4-[(2S)-3-amino-2-hydroxy-propoxy]-phenol (which was obtained in Example 5) according to the procedure of Example 73 as a pale yellowish solid; MS (ES) m/z: 485.9 (MH+).
Reaction SMILES: C(OC([NH:8][C:9]1[CH:10]=[N:11][CH:12]=[CH:13][C:14]=1[C:15]1([OH:30])[CH2:19][CH2:18][N:17]([C:20]([O:22][CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[O:21])[CH2:16]1)=O)(C)(C)C.C(Cl)Cl.[F:34][C:35]([F:40])([F:39])[C:36]([OH:38])=[O:37]>>[F:34][C:35]([F:40])([F:39])[C:36]([OH:38])=[O:37].[F:34][C:35]([F:40])([F:39])[C:36]([OH:38])=[O:37].[NH2:8][C:9]1[CH:10]=[N:11][CH:12]=[CH:13][C:14]=1[C:15]1([OH:30])[CH2:19][CH2:18][N:17]([C:20]([O:22][CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[O:21])[CH2:16]1
Reactant: CC(C)(C)OC(=O)Nc1cnccc1C1(O)CCN(C(=O)OCc2ccccc2)C1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Nc1cnccc1C1(O)CCN(C(=O)OCc2ccccc2)C1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a stirred solution of benzyl 3-{3-[(tert-butoxycarbonyl)amino]pyridin-4-yl}-3-hydroxypyrrolidine-1-carboxylate (4.38 g, 0.0106 mol) in methylene chloride (12.00 mL, 0.1872 mol) at rt was added trifluoroacetic acid (10.00 mL, 0.1298 mol) and the reaction mixture was stirred at rt for 4 h. LCMS (m+1, 314.2) indicated that the reaction was complete. The volatiles were removed and NMR data supported the formation of the desired product.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15]([C:17]2[C:21]([CH3:22])=[C:20]([C:23]3[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][CH:24]=3)[N:19]([C:30]3[CH:35]=[CH:34][C:33]([Cl:36])=[CH:32][C:31]=3[Cl:37])[N:18]=2)=[O:16])[CH2:10][CH2:9]1)=O)(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[Cl:29][C:26]1[CH:27]=[CH:28][C:23]([C:20]2[N:19]([C:30]3[CH:35]=[CH:34][C:33]([Cl:36])=[CH:32][C:31]=3[Cl:37])[N:18]=[C:17]([C:15]([NH:14][CH:11]3[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]3)=[O:16])[C:21]=2[CH3:22])=[CH:24][CH:25]=1
Reactant: Cc1c(C(=O)NC2CCN(C(=O)OC(C)(C)C)CC2)nn(-c2ccc(Cl)cc2Cl)c1-c1ccc(Cl)cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1c(C(=O)NC2CCNCC2)nn(-c2ccc(Cl)cc2Cl)c1-c1ccc(Cl)cc1
Yield: 95.1 %

Procedure:
tert-Butyl-4-[5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-amido]piperidine-1-carboxylate (1 eq, 531 mg, 0.941 mmol) was stirred in dichloromethane (4 mL) and trifluoroacetic acid (1 mL) for 16 h. The reaction was concentrated in vacuo. The crude reaction material was then purified by silica gel column chromatography using 0-100% CMA 80/ethyl acetate to yield pure 5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-N-(piperidin-4-yl)-1H-pyrazole-3-carboxamide (415 mg, 95%). 1H NMR (300 MHz, CHLOROFORM-d) d ppm 1.44 (qd, J=11.81, 3.86 Hz, 2H) 1.92-2.08 (m, 2H) 2.37 (s, 3H) 2.64-2.85 (m, 2H) 2.98-3.21 (m, 2H) 3.92-4.19 (m, 1H) 6.85 (d, J=8.29 Hz, 1H) 7.06 (d, J=8.38 Hz, 2H) 7.28 (s, 4H) 7.43 (s, 1H).
Reaction SMILES: [CH3:1][S:2]([O:5]S(C)(=O)=O)(=O)=[O:3].[NH2:10][CH2:11][CH2:12][O:13][C:14]1[CH:23]=[CH:22][C:21]2[N:20]=[C:19]([NH2:24])[C:18]3[N:25]=[C:26]([CH2:31][O:32][CH2:33][CH3:34])[N:27]([CH2:28][CH2:29][CH3:30])[C:17]=3[C:16]=2[CH:15]=1.[OH-].[Na+]>ClCCl>[NH2:24][C:19]1[C:18]2[N:25]=[C:26]([CH2:31][O:32][CH2:33][CH3:34])[N:27]([CH2:28][CH2:29][CH3:30])[C:17]=2[C:16]2[CH:15]=[C:14]([O:13][CH2:12][CH2:11][NH:10][S:2]([CH3:1])(=[O:5])=[O:3])[CH:23]=[CH:22][C:21]=2[N:20]=1
Reactant: CCCn1c(COCC)nc2c(N)nc3ccc(OCCN)cc3c21
Reactant: CS(=O)(=O)OS(C)(=O)=O
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Product: CCCn1c(COCC)nc2c(N)nc3ccc(OCCNS(C)(=O)=O)cc3c21
Reaction time: 0.5 h
Yield: 49.1 %

Procedure:
Methanesulfonic anhydride (0.265 g, 1.52 mmol) was added in one portion to a solution of 8-(2-aminoethoxy)-2-ethoxymethyl-1-propyl-1H-imidazo[4,5-c]quinolin-4-amine (0.500 g, 1.46 mmol) in dichloromethane (10 mL), and the reaction was stirred for 30 minutes. A precipitate formed. Aqueous sodium hydroxide (25 mL of 10%) was added, and the mixture was stirred for 20 minutes. The aqueous layer was separated and extracted with dichloromethane. The combined organic fractions were washed sequentially with water and brine, dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The resulting white solid was purified by column chromatography on silica gel (eluting with a dichloromethane:methanol ranging in ratios from 97:3 to 94:6) and then recrystallized from acetonitrile to yield 0.302 g of N-[2-(4-amino-2-ethoxymethyl-1-propyl-1H-imidazo[4,5-c]quinolin-8-yloxy)ethyl]methanesulfonamide as white, granular crystals, mp 178-179.5° C.
Reaction SMILES: C(OC([N:11]1[C:51]2[C:46](=[CH:47][C:48]([F:52])=[CH:49][CH:50]=2)[C:13]2([CH2:18][CH2:17][N:16]([C:19]([C@H:21]([NH:32][C:33](=[O:45])[C:34]([NH:37][C:38]([O:40][C:41]([CH3:44])([CH3:43])[CH3:42])=[O:39])([CH3:36])[CH3:35])[CH2:22][C:23]3[C:31]4[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=4)[NH:25][CH:24]=3)=[O:20])[CH2:15][CH2:14]2)[CH2:12]1)=O)C1C=CC=CC=1>[OH-].[OH-].[Pd+2].C(O)C>[F:52][C:48]1[CH:47]=[C:46]2[C:13]3([CH2:18][CH2:17][N:16]([C:19]([C@H:21]([NH:32][C:33](=[O:45])[C:34]([NH:37][C:38]([O:40][C:41]([CH3:44])([CH3:43])[CH3:42])=[O:39])([CH3:35])[CH3:36])[CH2:22][C:23]4[C:31]5[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=5)[NH:25][CH:24]=4)=[O:20])[CH2:15][CH2:14]3)[CH2:12][NH:11][C:51]2=[CH:50][CH:49]=1
Reactant: CC(C)(C)OC(=O)NC(C)(C)C(=O)N[C@H](Cc1c[nH]c2ccccc12)C(=O)N1CCC2(CC1)CN(C(=O)OCc1ccccc1)c1ccc(F)cc12
Agent: [Pd+2]
Agent: [OH-]
Solvent: CCO
Product: CC(C)(C)OC(=O)NC(C)(C)C(=O)N[C@H](Cc1c[nH]c2ccccc12)C(=O)N1CCC2(CC1)CNc1ccc(F)cc12
Yield: 88.9 %

Procedure:
To a solution of 0.363 g of the intermediate obtained from Step B in 5 mL of of ethanol was added 0.10 g of 20% palladium hydroxide on carbon and hydrogenated under H2 balloon for 1 h. the catalyst was filtered off and washed with more methanol. The filtrate was concentrated to yield 0.262 g of the desired material.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([C:7](=O)[NH:8][CH:9]=[N:10]2)=[CH:5][C:4]=1[O:14][CH2:15][CH2:16][CH2:17][N:18]1[CH2:23][CH2:22][O:21][CH2:20][CH2:19]1.CN(C=O)C.C1(C)C=CC=CC=1.S(Cl)([Cl:38])=O>>[Cl:38][C:7]1[C:6]2[C:11](=[CH:12][C:3]([O:2][CH3:1])=[C:4]([O:14][CH2:15][CH2:16][CH2:17][N:18]3[CH2:23][CH2:22][O:21][CH2:20][CH2:19]3)[CH:5]=2)[N:10]=[CH:9][N:8]=1
Reactant: COc1cc2nc[nH]c(=O)c2cc1OCCCN1CCOCC1
Reactant: O=S(Cl)Cl
Solvent: Cc1ccccc1
Solvent: CN(C)C=O
Product: COc1cc2ncnc(Cl)c2cc1OCCCN1CCOCC1
Temperature: 80 °C
Yield: 58 %

Procedure:
A solution of 7-methoxy-6-(3-morpholinopropoxy)-3,4-dihydroquinazolin-4-one (990 mg, 3.1 mmol) in thionyl chloride (10 ml) containing DMF (0.1 ml) was heated at 80° C. for 1.5 hours. After cooling, toluene was added and the solvent was removed by evaporation. The residue was triturated with ether, and the volatiles were removed by evaporation. The residue was partitioned between ethyl acetate and water and the aqueous layer was adjusted to pH7.5 with 2M sodium hydroxide. The organic layer was washed with brine, dried (MgSO4) and the volatiles removed by evaporation. The residue was purified by flash chromatography eluting with methylene chloride/methanol (1/9 followed by 95/5). The solid was triturated with hexane, collected by filtration and washed with ether to give 4-chloro-7-methoxy-6-(3-morpholinopropoxy)quinazoline (614 mg, 58%).
Reaction SMILES: [CH2:1]([C:3]1[CH:9]=[CH:8][CH:7]=[CH:6][C:4]=1[NH2:5])[CH3:2].[CH3:10][CH:11]([CH3:14])[CH2:12]O.[I-].[K+]>O.ClCCl>[CH2:1]([C:3]1[CH:9]=[CH:8][CH:7]=[CH:6][C:4]=1[NH:5][CH2:10][CH:11]([CH3:14])[CH3:12])[CH3:2]
Reactant: CC(C)CO
Reactant: CCc1ccccc1N
Agent: [I-]
Agent: [K+]
Solvent: ClCCl
Solvent: O
Product: CCc1ccccc1NCC(C)C
Temperature: 150 °C

Procedure:
2-ethylaniline (0.102 mL, 0.825 mmol), 2-methylpropan-1-ol (0.305 mL, 3.30 mmol), potassium iodide (274 mg, 1.650 mmol) and [Cp*IrCl2]2 (10.52 mg, 0.013 mmol) were added to a microwave vial with water (1.5 mL). This was heated, by microwaves, for 90 minutes at 150° C. Dichloromethane (10 mL) and water (10 mL) were added and the phases separated using a hydrophobic frit. The aqueous layer was further extracted with dichloromethane (15 mL). The combined organic layers were concentrated under vacuum and purified by silica (Si) chromatography (0-50% dichloromethane-cyclohexane gradient). The relevant fractions were concentrated to provide the product as a clear oil, 0.83 mg. LCMS [LCMS1] Rt 1.26 min, m/z (ES+) 178 (M+H).