Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]1[CH:6]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:5][NH:4][C:3]1=[O:14].Br[C:16]1[N:17]=[CH:18][N:19]([CH3:21])[CH:20]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].CN(C)[C@@H]1CCCC[C@H]1N>O1CCOCC1.ClCCl.[Cu]I>[CH3:1][N:2]1[CH:6]([C:7]([O:9][C:10]([CH3:11])([CH3:13])[CH3:12])=[O:8])[CH2:5][N:4]([C:16]2[N:17]=[CH:18][N:19]([CH3:21])[CH:20]=2)[C:3]1=[O:14]
Reactant: Cn1cnc(Br)c1
Reactant: CN1C(=O)NCC1C(=O)OC(C)(C)C
Agent: [Cu]I
Agent: CN(C)[C@@H]1CCCC[C@H]1N
Agent: O=P([O-])([O-])[O-]
Solvent: ClCCl
Solvent: C1COCCO1
Product: CN1C(=O)N(c2cn(C)cn2)CC1C(=O)OC(C)(C)C
Temperature: 25 °C
Yield: 101.8 %

Procedure:
To a stirred mixture of 1,1-dimethylethyl 3-methyl-2-oxo-4-imidazolidinecarboxylate (200 mg, 0.999 mmol) (prepared as described in step (iii) of Example 13, starting from (4S)-2-oxo-3-{[(phenylmethyl)oxy]carbonyl}-4-imidazolidinecarboxylic acid) and 4-bromo-1-methyl-1H-imidazole (193 mg, 1.199 mmol) in 1,4-dioxane (8 ml) was added potassium phosphate (1060 mg, 4.99 mmol), copper(I) iodide (190 mg, 0.999 mmol) and trans-N,N-dimethylcyclohexane-1,2-diamine (0.158 ml, 0.999 mmol) and the reaction mixture was stirred at reflux under argon for 3 hours. The mixture was cooled to room temperature and diluted with dichloromethane (20 mL) and filtered and washed through with dichloromethane. The filtrate was concentrated under vacuum and taken up in dichloromethane. The solution was washed with 0.880 ammonia (×3), water then brine and separated by hydrophobic frit and the organic layer was reduced under vacuum. The residue was purified by Flashmaster automated silica gel chromatography eluting with 0-20% methanol in dichloromethane to leave an oil which crystallised on standing. The residue was dried under vacuum overnight to give 1,1-dimethylethyl 3-methyl-1-(1-methyl-1H-imidazol-4-yl)-2-oxo-4-imidazolidinecarboxylate (285 mg, 87% yield). LC/MS [M+H]+=281. (ii) Trifluoroacetic acid (1.0 ml, 12.98 mmol) was added to a solution of 1,1-dimethylethyl 3-methyl-1-(1-methyl-1H-imidazol-4-yl)-2-oxo-4-imidazolidinecarboxylate (220 mg, 0.785 mmol) in DCM (2 ml) and the reaction mixture was stirred at room temperature for 5 hours. The solvent was evaporated under vacuum, azeotroping with toluene and the residue was dried under vacuum over the weekend to give crude 3-methyl-1-(1-methyl-1H-imidazol-4-yl)-2-oxo-4-imidazolidinecarboxylic acid trifluoroacetate salt which was taken through to next step without further purification. LC/MS [M+H]+=225.
Reaction SMILES: FC(F)(F)S(O[C:7]1[C:8]([CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[N:9][C:10]([C:13]2[CH2:18][CH2:17][O:16][CH2:15][CH:14]=2)=[CH:11][CH:12]=1)(=O)=O.[C:28]([C:30]1([OH:38])[CH:35]2[CH2:36][CH2:37][N:32]([CH2:33][CH2:34]2)[CH2:31]1)#[CH:29].C(N(CC)CC)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.CN(C)C=O>[CH2:19]([C:8]1[C:7]([C:29]#[C:28][C:30]2([OH:38])[CH:35]3[CH2:36][CH2:37][N:32]([CH2:33][CH2:34]3)[CH2:31]2)=[CH:12][CH:11]=[C:10]([C:13]2[CH2:18][CH2:17][O:16][CH2:15][CH:14]=2)[N:9]=1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: O=S(=O)(Oc1ccc(C2=CCOCC2)nc1Cc1ccccc1)C(F)(F)F
Reactant: C#CC1(O)CN2CCC1CC2
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: OC1(C#Cc2ccc(C3=CCOCC3)nc2Cc2ccccc2)CN2CCC1CC2
Temperature: 60 °C
Reaction time: 1.5 h
Yield: 66.8 %

Procedure:
A mixture of 60.7 g of 2-benzyl-6-(5,6-dihydro-2H-pyran-4-yl)-3-pyridyl trifluoromethane sulfonate, 23.0 mg of 3-ethynyl-3-quinuclidinol, 17.6 mg of tetrakis(triphenylphosphine)palladium(0), 2.9 mg of cuprous iodide, 63.6 μl of triethylamine and 1 ml of N,N-dimethylformamide was stirred at 60° C. for 1.5 hours in a nitrogen atmosphere. NH-silica gel was added to the reaction solution, and the solvent was removed. The residue was subjected to NH-silica gel column chromatography using 3% methanol/ethyl acetate, to give 40.7 mg of the target compound.
Reaction SMILES: [CH3:1][NH:2][C:3]([CH:5]1[CH2:10][N:9]([CH2:11][C:12]([OH:14])=O)[CH2:8][CH2:7][O:6]1)=[O:4].[NH2:15][CH2:16][C:17]([N:19]([C:21]1[CH:26]=[CH:25][C:24]([Cl:27])=[C:23]([CH2:28][O:29][C:30]2[C:38]3[N:37]=[C:36]([O:39][CH3:40])[N:35]([CH2:41][C:42]4[CH:47]=[CH:46][CH:45]=[CH:44][N:43]=4)[C:34]=3[CH:33]=[CH:32][CH:31]=2)[C:22]=1[Cl:48])[CH3:20])=[O:18].CCN=C=NCCCN(C)C>>[Cl:48][C:22]1[C:23]([CH2:28][O:29][C:30]2[C:38]3[N:37]=[C:36]([O:39][CH3:40])[N:35]([CH2:41][C:42]4[CH:47]=[CH:46][CH:45]=[CH:44][N:43]=4)[C:34]=3[CH:33]=[CH:32][CH:31]=2)=[C:24]([Cl:27])[CH:25]=[CH:26][C:21]=1[N:19]([CH3:20])[C:17](=[O:18])[CH2:16][NH:15][C:12](=[O:14])[CH2:11][N:9]1[CH2:8][CH2:7][O:6][CH:5]([C:3]([NH:2][CH3:1])=[O:4])[CH2:10]1
Reactant: CNC(=O)C1CN(CC(=O)O)CCO1
Reactant: COc1nc2c(OCc3c(Cl)ccc(N(C)C(=O)CN)c3Cl)cccc2n1Cc1ccccn1
Agent: CCN=C=NCCCN(C)C
Product: CNC(=O)C1CN(CC(=O)NCC(=O)N(C)c2ccc(Cl)c(COc3cccc4c3nc(OC)n4Cc3ccccn3)c2Cl)CCO1

Procedure:
2-(2-(methylcarbamoyl)morpholino)acetic acid and 2-amino-N-(2,4-dichloro-3-(((2-methoxy-1-(pyridin-2-ylmethyl)-1H-benzo[d]imidazol-4-yl)oxy)methyl)phenyl)-N-methylacetamide were coupled using EDCI to give 4-(2-((2-((2,4-dichloro-3-(((2-methoxy-1-(pyridin-2-ylmethyl)-1H-benzo[d]imidazol-4-yl)oxy)methyl)phenyl)(methyl)amino)-2-oxoethyl)amino)-2-oxoethyl)-N-methylmorpholine-2-carboxamide. MS (APCI) 684 (M+); 1H NMR (CDCl3) 2.26-2.40 (m, 1H), 2.61-2.82 (m, 4H), 2.95-3.15 (m, 2H), 3.15-3.28 (m, 4H), 3.40-3.49 (m, 1H), 3.61-3.91 (m, 2H), 3.90-4.01 (m, 1H), 4.08-4.18 (m, 1H), 4.22 (s, 3H), 5.28 (s, 2H), 5.62-5.70 (m, 2H), 6.51-6.58 (m, 1H), 6.75-6.87 (m, 2H), 6.91 (d, 1H, J=5.7 Hz), 7.02-7.06 (t, 1H, J=6.2 Hz), 7.19-7.21 (m, 1H), 7.31-7.33 (m, 1H), 7.46-7.49 (m, 1H), 7.55-7.62 (m, 1H), 7.78-7.90 (m, 1H), 8.57 (m, 1H). C32H35Cl2N7O6+0.8 H2O, Calculated: C, 54.97; H, 5.28; N, 14.03. Found: C, 54.99; H, 5.20; N, 13.85.
Reaction SMILES: C(OC(=O)[NH:7][CH2:8][C:9]#[C:10][C:11]1[CH:12]=[C:13]2[C:18](=[CH:19][CH:20]=1)[N:17]=[CH:16][N:15]=[C:14]2[NH:21][C:22]1[CH:23]=[C:24]2[C:28](=[CH:29][CH:30]=1)[N:27]([CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[C:34]([F:38])[CH:33]=1)[N:26]=[CH:25]2)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH2:7][CH2:8][C:9]#[C:10][C:11]1[CH:12]=[C:13]2[C:18](=[CH:19][CH:20]=1)[N:17]=[CH:16][N:15]=[C:14]2[NH:21][C:22]1[CH:23]=[C:24]2[C:28](=[CH:29][CH:30]=1)[N:27]([CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[C:34]([F:38])[CH:33]=1)[N:26]=[CH:25]2
Reactant: CC(C)(C)OC(=O)NCC#Cc1ccc2ncnc(Nc3ccc4c(cnn4Cc4cccc(F)c4)c3)c2c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: NCC#Cc1ccc2ncnc(Nc3ccc4c(cnn4Cc4cccc(F)c4)c3)c2c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 85.8 %

Procedure:
(3-{4-[1-(3-Fluoro-benzyl)-1H-indazol-5-ylamino]-quinazolin-6-yl}-prop-2-ynyl)-carbamic acid tert-butyl ester (285 mg, 0.545 mmol) is suspended in DCM (6 ml) and TFA (6 ml) is added dropwise. The reaction is stirred at r.t. for 2 hours. The solvents are removed in a N2 stream, DCM (10 ml) is added, and the organic layer is treated with sat. aq. NaHCO3 and brine, dried, and concentrated to afford the pure product (197.6 mg, 86%).
Reaction SMILES: O.[OH-].[Li+].[C:4]([O:8][C:9]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[C:17]1[CH:22]=[CH:21][C:20]([CH2:23][N:24]2[C:28]([C:29]([O:31]C)=[O:30])=[C:27]([C:33](OC)=[O:34])[N:26]=[C:25]2[CH2:37][CH2:38][CH2:39][CH3:40])=[CH:19][CH:18]=1)=[O:10])([CH3:7])([CH3:6])[CH3:5]>O.O1CCOCC1>[C:4]([O:8][C:9]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[C:17]1[CH:22]=[CH:21][C:20]([CH2:23][N:24]2[C:28]([C:29]([OH:31])=[O:30])=[C:27]([CH2:33][OH:34])[N:26]=[C:25]2[CH2:37][CH2:38][CH2:39][CH3:40])=[CH:19][CH:18]=1)=[O:10])([CH3:7])([CH3:6])[CH3:5]
Reactant: CCCCc1nc(C(=O)OC)c(C(=O)OC)n1Cc1ccc(-c2ccccc2C(=O)OC(C)(C)C)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: CCCCc1nc(CO)c(C(=O)O)n1Cc1ccc(-c2ccccc2C(=O)OC(C)(C)C)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 97.2 %

Procedure:
A solution of 2.01 g of lithium hydroxide monohydrate in 97 ml of water was added to a solution of 4.78 g of methyl 1-[(2'-t-butoxycarbonylbiphenyl-4-yl)methyl]-2-butyl-4-hydroxymethylimidazole-5-carboxylate (prepared as described in Example 1) in 48 ml of dioxane, and the resulting mixture was stirred at room temperature for 18 hours. At the end of this time, the reaction mixture was freed from dioxane by distillation under reduced pressure, and 47.6 ml of 1N aqueous hydrochloric acid were added to the aqueous residue. The crystals which precipitated were collected by filtration and then washed with water and with diethyl ether, in that order, to give 4.26 g of the title compound, melting at 187° C. (with decomposition).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH3:10])[C:5]([CH3:9])=[C:6]([OH:8])[CH:7]=1.CI.[C:13](=O)([O-])[O-].[K+].[K+].O>CN(C=O)C>[Br:1][C:2]1[CH:3]=[C:4]([CH3:10])[C:5]([CH3:9])=[C:6]([O:8][CH3:13])[CH:7]=1
Reactant: O=C([O-])[O-]
Reactant: Cc1cc(Br)cc(O)c1C
Agent: [K+]
Solvent: CI
Solvent: CN(C)C=O
Solvent: O
Product: COc1cc(Br)cc(C)c1C
Temperature: 90 °C
Reaction time: 2 h
Yield: 91.1 %

Procedure:
5.49 g of 5-bromo-2,3-dimethylphenol (3-17) was dissolved in 100 ml of DMF, to which were added 6.80 g of methyl iodide and 11.32 g of potassium carbonate, and the resulting mixture was stirred at 90° C. for 2 hours. The reaction solution was poured into water, and extracted with ethyl acetate and the resulting organic layer was washed with saturated salt water, and thereafter, the resulting organic layer was dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure, and the resulting residue was purified by silica gel column chromatography (eluent; hexane:ethyl acetate=9:1) to obtain 5.35 g of 5-bromo-1-methoxy-2,3-dimethylbenzene (3-18).
Reaction SMILES: Cl[CH:2]1[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1.C1C=CC=CC=1.[Li].CC(C)([O-])C.[K+].C1(C2C=CC=CC=2)C=CC=CC=1.[C:33](=[O:35])=[O:34]>C1COCC1>[C:33]([OH:35])(=[O:34])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C=O
Reactant: ClC1CCCCC1
Agent: CC(C)(C)[O-]
Agent: [K+]
Agent: [Li]
Solvent: C1CCOC1
Solvent: c1ccccc1
Solvent: c1ccc(-c2ccccc2)cc1
Product: O=C(O)c1ccccc1
Yield: 79 %

Procedure:
A mixture of 0.2 mol of chlorocyclohexane and 0.2 mol of benzene is added dropwise to a suspension of 0.4 mol of lithium granules, 0.21 mol of potassium tert-butoxide and 35 mg of biphenyl in 300 g of THF at −72° C. After a conversion of the chlorocyclohexane of >97% determined by means of GC (total of 24 h), carbon dioxide is passed in until saturation is achieved. The work-up is carried out by a method analogous to that in example 3; benzoic acid is obtained in a yield of 79%.
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[CH3:5][C:6]1[S:10][C:9]([C:11](Cl)=[O:12])=[CH:8][CH:7]=1.[CH3:14][N:15]1[CH:19]=[CH:18][CH:17]=[C:16]1[CH2:20][C:21]#[N:22].Cl>ClCCCl>[CH3:14][N:15]1[C:19]([C:11](=[O:12])[C:9]2[S:10][C:6]([CH3:5])=[CH:7][CH:8]=2)=[CH:18][CH:17]=[C:16]1[CH2:20][C:21]#[N:22]
Reactant: Cn1cccc1CC#N
Reactant: Cc1ccc(C(=O)Cl)s1
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCCl
Product: Cc1ccc(C(=O)c2ccc(CC#N)n2C)s1
Temperature: 0 °C
Reaction time: 0.67 h

Procedure:
To a suspension of 25.54 g. (0.019 mole) anhydrous aluminum chloride in 70 ml. of 1,2-dichloroethane is added 30.7 g. (0.019 mole) 5-methyl-2-thenoyl chloride. The resulting solution is added dropwise to a chilled (0°C.) solution of 24 g. (0.02 mole) 1-methylpyrrole-2-acetonitrile. After the addition, the solution is stirred at room temperature for approximately 40 minutes and than heated at reflux for 3 minutes and poured onto ice acidified with dilute hydrochloric acid. The two phases are separated. The organic phase is washed successively with N,N-dimethyl-1,3-propanediamine, 3N hydrochloric acid and saturated sodium chloride solution. It is then dried over magnesium sulfate and the solvent evaporated. The resulting solid, 1-methyl-5-(5-methyl-2-thenoyl)-pyrrole-2-acetonitrile, is separated by filtration and purified by washing in cold methanol and benzene, m.p. 118°-121°C.
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[C:6]([NH:9][C:10]2[CH:15]=[CH:14][C:13]([I:16])=[CH:12][C:11]=2[F:17])[C:5]([NH2:18])=[CH:4][CH:3]=1.[Cl:19][C:20]1[S:21][C:22]([Cl:29])=[CH:23][C:24]=1[S:25](Cl)(=[O:27])=[O:26]>>[Cl:19][C:20]1[S:21][C:22]([Cl:29])=[CH:23][C:24]=1[S:25]([NH:18][C:5]1[CH:4]=[CH:3][C:2]([F:1])=[C:7]([F:8])[C:6]=1[NH:9][C:10]1[CH:15]=[CH:14][C:13]([I:16])=[CH:12][C:11]=1[F:17])(=[O:27])=[O:26]
Reactant: O=S(=O)(Cl)c1cc(Cl)sc1Cl
Reactant: Nc1ccc(F)c(F)c1Nc1ccc(I)cc1F
Product: O=S(=O)(Nc1ccc(F)c(F)c1Nc1ccc(I)cc1F)c1cc(Cl)sc1Cl

Procedure:
According to the general procedure B, 5,6-difluoro-N1-(2-fluoro-4-iodophenyl)benzene1,2-diamine was reacted with 2,5-dichlorothiophene-3-sulfonyl chloride to obtain the title compound. 1H NMR (300 MHz, CDCl3): δ 7.41 (dd, J=1.5 & 10.5 Hz, 1H), 7.28-7.20 (m, 2H), 7.08 (dd, J=9.0 & 17.4 Hz, 2H), 6.99 (s, 1H), 6.03 (dt, J=2.1, 8.7 & 17.4 Hz, 1H), 5.56 (br s, 1H).
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]([C:13]3[N:14]([CH3:18])[CH:15]=[CH:16][CH:17]=3)=[N:11][N:12]=2)=[CH:4][CH:3]=1.[CH:19]1([NH:22][C:23](=[O:40])[C:24]2[CH:29]=[CH:28][C:27]([CH3:30])=[C:26](B3OC(C)(C)C(C)(C)O3)[CH:25]=2)[CH2:21][CH2:20]1.C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.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>[CH:19]1([NH:22][C:23]([C:24]2[CH:29]=[C:28]([C:2]3[CH:7]=[CH:6][C:5]([C:8]4[O:9][C:10]([C:13]5[N:14]([CH3:18])[CH:15]=[CH:16][CH:17]=5)=[N:11][N:12]=4)=[CH:4][CH:3]=3)[C:27]([CH3:30])=[CH:26][CH:25]=2)=[O:40])[CH2:20][CH2:21]1
Reactant: Cc1ccc(C(=O)NC2CC2)cc1B1OC(C)(C)C(C)(C)O1
Reactant: Cn1cccc1-c1nnc(-c2ccc(I)cc2)o1
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: [Na+]
Solvent: COCCOC
Product: Cc1ccc(C(=O)NC2CC2)cc1-c1ccc(-c2nnc(-c3cccn3C)o2)cc1
Temperature: 80 °C

Procedure:
2-(4-Iodophenyl)-5-(1-methyl-1H-pyrrol-2-yl)-1,3,4-oxadiazole (intermediate 38) (35 mg), N-cyclopropyl-4-methyl-3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-benzamide (33 mg), tetrakis(triphenylphosphine)palladium (13 mg) and aqueous sodium carbonate (1M, 0.11 ml) in DME (3 ml) were mixed and heated at 80° C. for 18 hours. The reaction was purified by bond-elut (silica), eluting with an ethyl acetate/cyclohexane gradient to give, after evaporation of the solvent, N-cyclopropyl-6-methyl-4′-[5-(1-methyl-1H-pyrrol-2-yl)-1,3,4-oxadiazol-2-yl]-1,1′-biphenyl-3-carboxamide.
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[CH2:11][CH2:10][CH:9]([C:12]2[C:20]3[C:15](=[CH:16][CH:17]=[C:18]([O:21][CH3:22])[CH:19]=3)[NH:14][CH:13]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2].CS(O[CH2:28][CH2:29][C:30]1[CH:34]=[CH:33][S:32][CH:31]=1)(=O)=O>>[CH2:1]([O:3][C:4]([N:6]1[CH2:11][CH2:10][CH:9]([C:12]2[C:20]3[C:15](=[CH:16][CH:17]=[C:18]([O:21][CH3:22])[CH:19]=3)[N:14]([CH2:28][CH2:29][C:30]3[CH:34]=[CH:33][S:32][CH:31]=3)[CH:13]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: CS(=O)(=O)OCCc1ccsc1
Reactant: CCOC(=O)N1CCC(c2c[nH]c3ccc(OC)cc23)CC1
Product: CCOC(=O)N1CCC(c2cn(CCc3ccsc3)c3ccc(OC)cc23)CC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 56.8 %

Procedure:
This compound was prepared following the procedure described in example 13 (part B) starting with 8.7 g (28.6 mmol) of 4-(5-methoxy-1H-indol-3-yl)-piperidine-1-carboxylic acid ethyl ester and 6.9 g (33.4 mmol) of 2-thiophen-3-yl-ethyl methanesulfonate. The reaction mixture was stirred at room temperature for 18 hours. After standard work-up, 6.7 g (57% of yield) of 4-[5-methoxy-1-(2-thiophen-3-yl-ethyl)-1H-indol-3-yl]-piperidine-1-carboxylic acid ethyl ester were obtained.
Reaction SMILES: [CH3:1][C:2]1[C:3]([C:9]2[CH2:14][C:13]([CH3:16])([CH3:15])[CH2:12][C:11]([CH3:18])([CH3:17])[CH:10]=2)=[C:4]([NH2:8])[CH:5]=[CH:6][CH:7]=1.ClC1C=CC=CC=1Cl.Cl.Cl[CH2:29][CH2:30][NH:31][CH2:32][CH2:33]Cl.C(=O)([O-])O.[Na+]>C(Cl)(Cl)Cl>[CH3:1][C:2]1[C:3]([C:9]2[CH2:14][C:13]([CH3:16])([CH3:15])[CH2:12][C:11]([CH3:18])([CH3:17])[CH:10]=2)=[C:4]([N:8]2[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]2)[CH:5]=[CH:6][CH:7]=1
Reactant: Cc1cccc(N)c1C1=CC(C)(C)CC(C)(C)C1
Reactant: ClCCNCCCl
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: Clc1ccccc1Cl
Solvent: ClC(Cl)Cl
Product: Cc1cccc(N2CCNCC2)c1C1=CC(C)(C)CC(C)(C)C1
Temperature: 200 °C
Reaction time: 0.83 h
Yield: 73.5 %

Procedure:
To a mixture of 3-methyl-2-(3,3,5,5-tetramethylcyclohex-1-enyl)phenylamine (663 mg, 2.72 mmol) produced in Example (71b) and 1,2-dichlorobenzene (3 mL) was added bis(2-chloroethyl)amine hydrochloride (632 mg, 3.54 mmol), followed by stirring for 5 hours and 50 minutes at an external temperature of 200° C. under a nitrogen atmosphere. During the reaction, a nitrogen stream was passed through the reactor several times. The reaction mixture was cooled to room temperature, chloroform and saturated solution of sodium hydrogencarbonate were added, and the filtrate obtained by filtration through Celite was extracted with chloroform. The separated organic layer was washed with brine and then dried over anhydrous sodium sulfate. The desiccant was filtered off and the filtrate was concentrated under reduced pressure. The resultant residue was purified by NH silica gel column chromatography (ethyl acetate/hexane) to give 625 mg of the title compound as a yellow solid.
Reaction SMILES: [C:1]([O:5][C:6](=[O:18])[NH:7][CH:8]([C:11]1[CH:16]=[CH:15][C:14]([I:17])=[CH:13][CH:12]=1)[CH2:9][OH:10])([CH3:4])([CH3:3])[CH3:2].CO[C:21](OC)([CH3:23])[CH3:22].O.C1(C)C=CC(S(O)(=O)=O)=CC=1>ClCCl>[C:1]([O:5][C:6]([N:7]1[CH:8]([C:11]2[CH:16]=[CH:15][C:14]([I:17])=[CH:13][CH:12]=2)[CH2:9][O:10][C:21]1([CH3:23])[CH3:22])=[O:18])([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(C)(C)OC
Reactant: CC(C)(C)OC(=O)NC(CO)c1ccc(I)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1C(c2ccc(I)cc2)COC1(C)C
Temperature: 25 °C
Reaction time: 18 h
Yield: 89 %

Procedure:
To a stirred solution of (RS)-[2-hydroxy-1-(4-iodo-phenyl)-ethyl]-carbamic acid tert-butyl ester (7.97 g) in dichloromethane (400 ml) were added sequentially 2,2-dimethoxypropane (36 ml) and p-toluenesulphonic acid monohydrate (0.75 g) and the mixture was stirred at room temperature for 18 hours. The mixture was then washed with 0.5 N aq NaOH, the phases were separated and the organic phase was dried over sodium sulphate, filtered and concentrated in vacuo to afford (RS)-4-(4-iodo-phenyl)-2,2-dimethyl-oxazolidine-3-carboxylic acid tert-butyl ester (7.05 g, 89%) as a yellow solid. MS (EI): 403 (M+), 388 ([M-CH3]+), 332 ([M-CH3—C4H8]+), 288 ([M-CH3—C4H8—CO2]+), 57 ([C4H9]+).
Reaction SMILES: [CH2:1]([N:7]([CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH3:33])[C:8](=[O:27])[C@H:9]([CH3:26])[N:10]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[C:24]#[N:25])C(OC(C)(C)C)=O)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].FC(F)(F)C(O)=O>ClCCl>[CH2:28]([N:7]([CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH3:6])[C:8](=[O:27])[C@H:9]([CH3:26])[NH:10][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[C:24]#[N:25])[CH2:29][CH2:30][CH2:31][CH2:32][CH3:33]
Reactant: CCCCCCN(CCCCCC)C(=O)[C@H](C)N(C(=O)OC(C)(C)C)c1ccccc1C#N
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCCCCCN(CCCCCC)C(=O)[C@H](C)Nc1ccccc1C#N
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 99.3 %

Procedure:
To a solution of 0.98 g of N-t-butoxycarbonyl-(2-cyanophenyl)alanine dihexylamide in 1.7 ml of dichloromethane was added 1.7 ml of trifluoroacetic acid, followed by stirring at room temperature for 1.5 hours. The reaction solution was concentrated under reduced pressure, and to the residue was added an aqueous sodium bicarbonate solution, followed by extracting with dichloromethane. The extract was washed with a saturated sodium chloride solution, and dried over anhydrous sodium sulfate. After removal of the drying agent by filtration, the filtrate was concentrated under reduced pressure to give 0.76 g of a crude (2-cyanophenyl)alanine dihexylamide, which was then used for the next step without purification.
Reaction SMILES: [H-].[Na+].[CH3:3][C:4]1[CH:9]=[CH:8][C:7]([CH:10]([OH:15])[C:11]([F:14])([F:13])[F:12])=[CH:6][CH:5]=1.[NH2:16][C:17]1[N:22]=[C:21](Cl)[CH:20]=[C:19]([Cl:24])[N:18]=1.O>C1COCC1.C(OCC)(=O)C>[Cl:24][C:19]1[CH:20]=[C:21]([O:15][CH:10]([C:7]2[CH:8]=[CH:9][C:4]([CH3:3])=[CH:5][CH:6]=2)[C:11]([F:12])([F:13])[F:14])[N:22]=[C:17]([NH2:16])[N:18]=1
Reactant: Nc1nc(Cl)cc(Cl)n1
Reactant: Cc1ccc(C(O)C(F)(F)F)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: C1CCOC1
Product: Cc1ccc(C(Oc2cc(Cl)nc(N)n2)C(F)(F)F)cc1
Temperature: 70 °C
Reaction time: 0.33 h
Yield: 65.8 %

Procedure:
NaH (80 mg, 60%, 3.0 mmol) was added to a solution of 1-(4-methylphenyl)-2,2,2-trifluoro-ethanol (190 mg, 1 mmol) in 10 ml of anhydrous THF. The mixture was stirred for 20 minutes, 2-amino-4,6-dichloro-pyrimidine (164 mg, 1 mmol) was added and then the reaction mixture was heated at 70° C. for 1 hour. After cooling, 5 ml water was added and ethyl acetate (20 ml) was used to extract the product. The organic layer was dried over sodium sulfate. The solvent was removed by rotovap to give 209 mg of 4-chloro-6-[1-(4-methylphenyl)-2,2,2-trifluoro-ethoxy]-pyrimidin-2-ylamine, yield 66%.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([S:8]([CH3:11])(=[O:10])=[O:9])[CH:3]=1.[OH:12][CH2:13][C:14]1[CH:19]=[CH:18][C:17](B(O)O)=[CH:16][CH:15]=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.N(CC)CC.C([O-])(O)=O.[Na+]>C1(C)C=CC=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].O.C(O)CC>[CH3:11][S:8]([C:4]1[CH:3]=[C:2]([C:17]2[CH:18]=[CH:19][C:14]([CH2:13][OH:12])=[CH:15][CH:16]=2)[CH:7]=[CH:6][CH:5]=1)(=[O:10])=[O:9]
Reactant: OCc1ccc(B(O)O)cc1
Reactant: CS(=O)(=O)c1cccc(Br)c1
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Agent: O=C([O-])O
Solvent: CCCO
Solvent: O
Solvent: CCNCC
Product: CS(=O)(=O)c1cccc(-c2ccc(CO)cc2)c1
Yield: 95.5 %

Procedure:
To a degassed solution of the product of step 1 (5.7 g, 24.2 mmol,), and 4-hydroxymethylphenylboronic acid (5.47 g, 36 mmol) in toluene (150 mL) was added Pd2(dba)3 (1.09 g, 1.2 mmol). The mixture was degassed and Ph3P (2.5 g, 9.6 mmol), Et2NH (2.63 g, 36 mmol), n-propanol (18 mL) and H2O (18 mL) was added. The mixture was heated to reflux for 26 h. Aqueous NaHCO3 was added and the resulting mixture was extracted with EtOAc. The combined organic extracts were washed with brine, dried (anhyd. MgSO4) and concentrated in vacuo. The residue was purified by chromatography on silica gel to give 6.06 g (95%) of the title compound.
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:6]=[C:7]([CH2:11][N:12]2[C:21](=[O:22])[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[N:14]([CH2:23][CH2:24][CH2:25][CH2:26][N:27]3[CH2:32][CH2:31][CH:30]([O:33][CH:34]([C:41]4[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=4)[C:35]4[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=4)[CH2:29][CH2:28]3)[C:13]2=[O:47])[CH:8]=[CH:9][CH:10]=1)=[O:4].[ClH:48].COC(C1C=C(CN2C(=O)C3C(=CC=CC=3)N(CCCCN3CCC(OC(C4C=CC=CC=4)C4C=CC=CC=4)CC3)C2=O)C=CC=1)=O>>[ClH:48].[C:3]([C:5]1[CH:6]=[C:7]([CH2:11][N:12]2[C:21](=[O:22])[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[N:14]([CH2:23][CH2:24][CH2:25][CH2:26][N:27]3[CH2:28][CH2:29][CH:30]([O:33][CH:34]([C:35]4[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=4)[C:41]4[CH:42]=[CH:43][CH:44]=[CH:45][CH:46]=4)[CH2:31][CH2:32]3)[C:13]2=[O:47])[CH:8]=[CH:9][CH:10]=1)([OH:4])=[O:2]
Reactant: COC(=O)c1cccc(Cn2c(=O)c3ccccc3n(CCCCN3CCC(OC(c4ccccc4)c4ccccc4)CC3)c2=O)c1
Agent: Cl
Product: O=C(O)c1cccc(Cn2c(=O)c3ccccc3n(CCCCN3CCC(OC(c4ccccc4)c4ccccc4)CC3)c2=O)c1
Yield: 88 %

Procedure:
Using the method similar to that in Example 65 and starting from 3-[(3-methoxycarbonylphenyl)methyl]-2,4-dioxo-1-[4-(4-diphenylmethoxypiperidino)butyl]-1,2,3,4-tetrahydroquinazoline (0.38 g, 0.60 mmol) which is a free salt of the compound obtained in Example 63, the title compound (0.36 g, 88%) was obtained.