Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[C:12]([O:13][CH2:14][CH3:15])=[CH:11][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[C:4]([O:16][CH2:17][CH3:18])[CH:3]=1.[CH3:19][N:20](C)C=O>[C-]#N.[Zn+2].[C-]#N.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.O>[C:19]([C:2]1[C:12]([O:13][CH2:14][CH3:15])=[CH:11][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[C:4]([O:16][CH2:17][CH3:18])[CH:3]=1)#[N:20]
Reactant: CN(C)C=O
Reactant: CCOC(=O)c1cc(OCC)c(Br)cc1OCC
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [C-]#N
Agent: [Zn+2]
Solvent: O
Product: CCOC(=O)c1cc(OCC)c(C#N)cc1OCC
Temperature: 80 °C
Yield: 81 %

Procedure:
Ethyl 4-bromo-2,5-diethoxybenzoate (0.615 g, 1.94 mmol), zinc cyanide (0.137 g, 1.17 mmol) and tetrakis(triphenylphosphine)palladium(0) (0.157 g, 0.136 mmol) were combined under nitrogen in a flame-dried Schlenk tube. Dimethylformamide (7 mL) was added and the reaction mixture was put through three freeze-pump-thaw cycles and then put under a nitrogen atmosphere and heated at 80° C. for 16 h. After cooling to room temperature, water (50 mL) was added and the resulting mixture was extracted with diethyl ether (100 mL, 2×50 mL). The combined organic phases were washed with brine (3×50 mL) and then dried over magnesium sulfate and concentrated. Purification of the crude residue by flash column chromatography (silica gel, eluting with 33% ethyl acetate in hexanes) gave ethyl 4-cyano-2,5-diethoxy-benzoate as an off-white solid (0.416 g, 81%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:14]=[CH:15][C:16]=1[Cl:17])[CH2:5][N:6]1[CH2:11][CH2:10][O:9][CH:8]([CH2:12][NH2:13])[CH2:7]1.[N:18]([CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[CH3:28])=[C:19]=[O:20]>>[Cl:1][C:2]1[CH:3]=[C:4]([CH:14]=[CH:15][C:16]=1[Cl:17])[CH2:5][N:6]1[CH2:11][CH2:10][O:9][CH:8]([CH2:12][NH:13][C:19]([NH:18][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=2[CH3:28])=[O:20])[CH2:7]1
Reactant: Cc1ccccc1CN=C=O
Reactant: NCC1CN(Cc2ccc(Cl)c(Cl)c2)CCO1
Product: Cc1ccccc1CNC(=O)NCC1CN(Cc2ccc(Cl)c(Cl)c2)CCO1
Yield: 70.1 %

Procedure:
Example 6 was prepared in an analogous manner to Example 1 using a mixture of Intermediate 3 (0.025 g) and 1-(isocyanatomethyl)-2-methylbenzene (0.0201 g) to give the title compound (0.0269 g). LC-MS (System A): Rt 2.31 mins, Mass Spectrum m/z 422 [MH+].
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[C:12]([C:14]([F:17])([F:16])[F:15])[CH:11]=[CH:10][C:9]=1[C:18]1[CH:23]=[C:22]([O:24][C:25]2[CH:34]=[C:33]3[C:28]([CH:29]=[CH:30][CH:31]=[N:32]3)=[CH:27][CH:26]=2)[N:21]=[CH:20][N:19]=1)(C)(C)C.FC(F)(F)C(O)=O>C(Cl)Cl>[N:32]1[C:33]2[C:28](=[CH:27][CH:26]=[C:25]([O:24][C:22]3[N:21]=[CH:20][N:19]=[C:18]([C:9]4[CH:10]=[CH:11][C:12]([C:14]([F:16])([F:15])[F:17])=[CH:13][C:8]=4[NH2:7])[CH:23]=3)[CH:34]=2)[CH:29]=[CH:30][CH:31]=1
Reactant: CC(C)(C)OC(=O)Nc1cc(C(F)(F)F)ccc1-c1cc(Oc2ccc3cccnc3c2)ncn1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Nc1cc(C(F)(F)F)ccc1-c1cc(Oc2ccc3cccnc3c2)ncn1
Temperature: 0 °C
Reaction time: 0.08 h

Procedure:
To a round-bottom flask was added {2-[6-(quinolin-7-yloxy)-pyrimidin-4-yl]-5-trifluoromethyl-phenyl}-carbamic acid tert-butyl ester, (Example 162), (3.2 g, 6.6 mmol) and CH2Cl2 (100 mL). The mixture was cooled to 0° C. and trifluoroacetic acid (25 mL) was added. After stirring for 5 min at 0° C., the mixture was allowed to warm to room temperature and stirred for 1.5 h. The reaction mixture was concentrated in vacuum and diluted with CH2Cl2 (200 mL) and satd NaHCO3 (200 mL). The phases were separated and the aqueous phase was extracted with CH2Cl2 (100 mL). The combined extracts were washed with aq NaHCO3 (20% satd NaHCO3/H2O), H2O, brine and then dried over Na2SO4, filtered and concentrated onto silica gel. Purification by silica gel chromatography (gradient, 40 to 75% EtOAc/hexanes) afforded the title compound as a yellow solid. Mp: 193-194° C. MS (ESI, pos. ion) m/z: 383.2 (M+1).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][CH:8]=1)[NH2:5].F[C:10]1[CH:15]=[CH:14][C:13]([C:16]([F:19])([F:18])[F:17])=[CH:12][CH:11]=1.CC(C)([O-])C.[K+].O>CS(C)=O>[F:17][C:16]([F:19])([F:18])[C:13]1[CH:14]=[CH:15][C:10]([O:1][C:2]2[CH:3]=[C:4]([CH:6]=[CH:7][CH:8]=2)[NH2:5])=[CH:11][CH:12]=1
Reactant: Fc1ccc(C(F)(F)F)cc1
Reactant: Nc1cccc(O)c1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: Nc1cccc(Oc2ccc(C(F)(F)F)cc2)c1
Temperature: 95 °C
Yield: 57.2 %

Procedure:
To a stirred solution of 3-hydroxyaniline (6.55 g) and 4-fluorobenzotrifluoride (9.85 g) in DMSO (50 mL) was added in one portion potassium tert-butoxide (7.86 g). The resulting dark solution was heated for 4 hours at 95° C., cooled to room temperature, then poured into water (600 mL). The mixture was extracted with ether (3×125 mL). The organic phase was washed with 2N sodium hydroxide (2×75 mL) and water (100 mL), dried (MgSO4) and the solvent evaporated to give a dark oil. This oil was distilled to give the title aniline as a colorless oil (8.7 g), b.p. 110-112° C. at 0.15 mm.
Reaction SMILES: C(O[C:4](=O)[CH2:5][C:6]([CH:8]=[CH:9][C:10]1[S:14][CH:13]=[CH:12][CH:11]=1)=O)C.[CH2:16]([O:18][C:19](=[O:24])[CH2:20][C:21](=[NH:23])[NH2:22])[CH3:17]>C(O)C>[CH2:16]([O:18][C:19]([C:20]1[CH:8]([CH2:9][C:10]2[S:14][CH:13]=[CH:12][CH:11]=2)[C:6]([C:19]([O:18][CH2:16][CH3:17])=[O:24])=[C:5]([CH3:4])[NH:23][C:21]=1[NH2:22])=[O:24])[CH3:17]
Reactant: CCOC(=O)CC(=O)C=Cc1cccs1
Reactant: CCOC(=O)CC(=N)N
Solvent: CCO
Product: CCOC(=O)C1=C(C)NC(N)=C(C(=O)OCC)C1Cc1cccs1
Yield: 73 %

Procedure:
Upon heataing a solution of 12.2 g of (2-thenylidene)acetoacetic acid ethyl ester and 6.5 g of amidinoacetic acid ethyl ester in 100 ml of ethanol for 4 hours, 2-amino-6-methyl-4-(2-thenyl)-1,4-dihydropyridine-3,5-dicarboxylic acid diethyl ester of melting point 170°C (ethanol) is obtained.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:15]2[CH:20]=[CH:19][C:18]([N+:21]([O-])=O)=[C:17]([CH3:24])[CH:16]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]>CO.[Pd]>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:15]2[CH:20]=[CH:19][C:18]([NH2:21])=[C:17]([CH3:24])[CH:16]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: Cc1cc(OC2CCN(C(=O)OC(C)(C)C)CC2)ccc1[N+](=O)[O-]
Agent: [Pd]
Solvent: CO
Product: Cc1cc(OC2CCN(C(=O)OC(C)(C)C)CC2)ccc1N
Temperature: 25 °C
Reaction time: 4 h
Yield: 102.6 %

Procedure:
To a solution of 4-(1-t-butoxycarbonylpiperidin-4-yloxy)-2-methylnitrobenzene (3.23 g) in methanol (30 ml) was added palladium on carbon (0.21 g) and the mixture was stirred under a hydrogen atmosphere at room temperature for 4 hours. The reaction mixture was filtered and the filtrate concentrated in vacuo. The residue was purified by chromatography on a silica gel column using hexane/ethyl acetate=1/1 as an eluant to give the desired compound (3.02 g, yield 99%) as a pale red oil.
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([I:12])[CH:10]=2)[N:5]=[C:4]([O:13][CH3:14])[C:3]=1[CH2:15]C1C=CC=C(C(F)(F)F)C=1.ClC1C(C[C:38]2[CH:43]=[CH:42][CH:41]=[C:40]([C:44]([F:47])([F:46])[F:45])[CH:39]=2)=C(Cl)C2C(=CC=C(I)C=2)N=1>>[Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([I:12])[CH:10]=2)[N:5]=[C:4]([O:13][CH3:14])[C:3]=1[CH2:15][C:39]1[CH:38]=[CH:43][CH:42]=[CH:41][C:40]=1[C:44]([F:47])([F:46])[F:45]
Reactant: COc1nc2ccc(I)cc2c(Cl)c1Cc1cccc(C(F)(F)F)c1
Reactant: FC(F)(F)c1cccc(Cc2c(Cl)nc3ccc(I)cc3c2Cl)c1
Product: COc1nc2ccc(I)cc2c(Cl)c1Cc1ccccc1C(F)(F)F

Procedure:
The title compound was prepared following the procedure described for the preparation of Intermediate 7: step c, substituting 2,4-dichloro-6-iodo-3-(3-(trifluoromethyl)benzyl)quinoline (Intermediate 7: step b) with 2,4-dichloro-6-iodo-3-(2-(trifluoromethyl)benzyl)quinoline (Intermediate 8: step b).
Reaction SMILES: CO[C:3](=[O:21])[C:4]([CH2:11][CH2:12][NH:13][C:14]1[CH:15]=[N:16][C:17]([Cl:20])=[N:18][CH:19]=1)([CH2:9][CH3:10])[CH2:5][CH2:6][O:7]C.CC(C)([O-])C.[K+]>C1COCC1.C(OCC)(=O)C>[Cl:20][C:17]1[N:16]=[CH:15][C:14]([N:13]2[CH2:12][CH2:11][C:4]3([CH2:9][CH2:10][O:7][CH2:6][CH2:5]3)[C:3]2=[O:21])=[CH:19][N:18]=1
Reactant: CCC(CCNc1cnc(Cl)nc1)(CCOC)C(=O)OC
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: O=C1N(c2cnc(Cl)nc2)CCC12CCOCC2
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 2-[2-(2-chloro-pyrimidin-5-ylamino)-ethyl]-2-ethyl-4-methoxy-butyric acid methyl ester (0.083 g, 0.277 mmol) in THF (6 mL) was added a solution of potassium t-butoxide (1 M in THF) (0.5 mL), and the solution was allowed to stir at room temperature for 1 hour. An additional 0.5 mL of potassium t-butoxide (1 M in THF) was added and stirred for 2 hours. The reaction was still not complete, thus 0.75 mL of potassium t-butoxide (1 M in THF) was added and stirred for 4 hours. The reaction mixture was then diluted with ethyl acetate (20 mL), quenched with water (3 mL). The aqueous layer was extracted with EtOAc (2×20 mL). The combined organics were washed with brine, and concentrated under vacuum to afford 0.07 (95%) of title compound.
Reaction SMILES: [C:1]([N:5]1[C:9]([C:10]2[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=2)=[C:8]([C:17]2[S:18][CH:19]=[C:20]([CH2:22][C:23](O)=[O:24])[N:21]=2)[CH:7]=[N:6]1)([CH3:4])([CH3:3])[CH3:2].[NH:26]1[CH2:31][CH2:30][O:29][CH2:28][CH2:27]1>>[C:1]([N:5]1[C:9]([C:10]2[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=2)=[C:8]([C:17]2[S:18][CH:19]=[C:20]([CH2:22][C:23]([N:26]3[CH2:31][CH2:30][O:29][CH2:28][CH2:27]3)=[O:24])[N:21]=2)[CH:7]=[N:6]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)n1ncc(-c2nc(CC(=O)O)cs2)c1-c1ccc(F)cc1
Reactant: C1COCCN1
Product: CC(C)(C)n1ncc(-c2nc(CC(=O)N3CCOCC3)cs2)c1-c1ccc(F)cc1

Procedure:
Using 2-(2-(1-tert-butyl-5-(4-fluorophenyl)-1H-pyrazol-4-yl)thiazol-4-yl)acetic acid and morpholine and by reaction and purification in the same manner as in the method described in Example 1, step 7, the title compound was obtained.
Reaction SMILES: [CH2:1]([O:3][C:4]1[C:8]([CH2:9][CH2:10][C:11]([O:13]CC)=[O:12])=[CH:7][N:6]([CH2:16][C:17]2[CH:22]=[CH:21][C:20]([OH:23])=[CH:19][CH:18]=2)[N:5]=1)[CH3:2].Cl[CH2:25][C:26]1[CH:27]=[CH:28][C:29]([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)=[N:30][CH:31]=1.C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[CH2:1]([O:3][C:4]1[C:8]([CH2:9][CH2:10][C:11]([OH:13])=[O:12])=[CH:7][N:6]([CH2:16][C:17]2[CH:18]=[CH:19][C:20]([O:23][CH2:25][C:26]3[CH:31]=[N:30][C:29]([C:32]4[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=4)=[CH:28][CH:27]=3)=[CH:21][CH:22]=2)[N:5]=1)[CH3:2]
Reactant: CCOC(=O)CCc1cn(Cc2ccc(O)cc2)nc1OCC
Reactant: ClCc1ccc(-c2ccccc2)nc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOc1nn(Cc2ccc(OCc3ccc(-c4ccccc4)nc3)cc2)cc1CCC(=O)O
Temperature: 80 °C
Reaction time: 5 h
Yield: 90.8 %

Procedure:
A mixture of ethyl 3-[3-ethoxy-1-(4-hydroxybenzyl)-1H-pyrazol-4-yl]propionate (690 mg), 5-chloromethyl-2-phenylpyridine (470 mg), potassium carbonate (450 mg) and N,N-dimethylformamide (10 ml) was stirred at 80° C. for 5 hours. The reaction mixture was poured into water, and extracted with ethyl acetate. The ethyl acetate layer was washed with saturated aqueous sodium chloride solution, dried (MgSO4), and concentrated. The residue was subjected to silica gel chromatography to obtain a colorless oily substance from the fraction eluted with ethyl acetate-hexane (1:1, volume ratio). After a mixture of the resulting colorless oily substance, 1N aqueous sodium hydroxide solution (5 ml), tetrahydrofuran (5 ml) and ethanol (5 ml) was stirred at room temperature for 2 hours, 1 N hydrochloric acid (5 ml) was added, and then the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated aqueous sodium chloride solution, dried (MgSO4) and concentrated. The resulting colorless crystals were collected by filtration to obtain 3-[3-ethoxy-1-[4-(6-phenyl-3-pyridylmethoxy)benzyl]-1H-pyrazol-4-yl]propionic acid (900 mg, yield: 91%). This was recrystallized from acetone-hexane. Melting point: 140–141° C.
Reaction SMILES: [Cl:1][CH:2]([Cl:6])[C:3](Cl)=[O:4].[CH2:7]1[O:16][C:10]2([CH2:15][CH2:14][NH:13][CH2:12][CH2:11]2)[O:9][CH2:8]1.N12CCCN=C1CCCCC2>C1(C)C=CC=CC=1>[CH2:7]1[O:16][C:10]2([CH2:15][CH2:14][N:13]([C:3](=[O:4])[CH:2]([Cl:6])[Cl:1])[CH2:12][CH2:11]2)[O:9][CH2:8]1
Reactant: O=C(Cl)C(Cl)Cl
Reactant: C1CC2(CCN1)OCCO2
Solvent: C1CCC2=NCCCN2CC1
Solvent: Cc1ccccc1
Product: O=C(C(Cl)Cl)N1CCC2(CC1)OCCO2
Yield: 49.2 %

Procedure:
12.4 g (0.084 mol) of dichloroacetyl chloride were added dropwise to a mixture of 12 g (0.084 mol) of piperid-4-one ethylene ketal and 12.8 g (0.084 mol) of 1,8-diazabicyclo[5.4.0]undec-7-ene in 100 ml of toluene, whilst stirring, at a rate such that the temperature of the reaction mixture did not exceed 40° C. Thereafter, the mixture was subsequently stirred at 20° C. for 2 hours. Working up was then effected by a procedure in which the reaction mixture was filtered, the filtrate was concentrated under reduced pressure and the residue was recrystallized from a mixture of toluene and petroleum ether. 10.5 g (49% of theory) of N-dichloroacetyl-piperid-4-one ethylene ketal were obtained in this manner in the form of colorless crystals of melting point 102° C.
Reaction SMILES: [CH3:1][S:2][C:3]1[CH:10]=[CH:9][C:6]([CH2:7]Br)=[CH:5][CH:4]=1.BrCC1CCCCO1.[NH:19]1[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[C:21]2([C:31]3=[CH:32][C:33]4[O:37][CH2:36][O:35][C:34]=4[CH:38]=[C:30]3[O:29][CH2:28]2)[C:20]1=[O:39]>>[CH3:1][S:2][C:3]1[CH:10]=[CH:9][C:6]([CH2:7][N:19]2[C:27]3[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=3)[C:21]3([C:31]4=[CH:32][C:33]5[O:37][CH2:36][O:35][C:34]=5[CH:38]=[C:30]4[O:29][CH2:28]3)[C:20]2=[O:39])=[CH:5][CH:4]=1
Reactant: CSc1ccc(CBr)cc1
Reactant: O=C1Nc2ccccc2C12COc1cc3c(cc12)OCO3
Agent: BrCC1CCCCO1
Product: CSc1ccc(CN2C(=O)C3(COc4cc5c(cc43)OCO5)c3ccccc32)cc1

Procedure:
Following the procedure as described in EXAMPLE 4 and making non-critical variations using 4-(methylthio)benzyl bromide to replace 2-(bromomethyl)tetrahydro-2H-pyran, and spiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one to replace 5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2″(1′H)-one, 1′-[4-(methylsulfanyl)benzyl]spiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one was obtained (86%) as a colorless solid: mp 128-130° C.; 1H NMR (300 MHz, DMSO-d6) δ 7.28-7.19 (m, 5H), 7.14 (d, J=7.0 Hz, 1H), 7.00 (d, J=7.5 Hz, 1H), 6.96 (d, J=7.8 Hz, 1H), 6.68 (s, 1H), 6.14 (s, 1H), 5.89 (d, J=1.9 Hz, 2H), 4.87-4.79 (m, 3H), 4.67 (d, J=9.3 Hz, 1H), 2.40 (s, 3H); 13C NMR (75 MHz, DMSO-d6) δ177.3, 155.9, 148.8, 142.6, 142.2, 137.8, 133.3, 132.1, 129.3, 128.4, 126.6, 124.2, 123.6, 120.1, 109.9, 103.3, 101.9, 93.8, 80.4, 57.9, 43.2, 15.1; MS (ES+) m/z 418.1 (M+1).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[O:8][CH3:9].C(Cl)(Cl)Cl.[Br:14]Br.S(=O)(O)[O-].[Na+]>O>[F:1][C:2]1[CH:7]=[C:6]([Br:14])[CH:5]=[CH:4][C:3]=1[O:8][CH3:9]
Reactant: BrBr
Reactant: COc1ccccc1F
Agent: O=S([O-])O
Agent: [Na+]
Solvent: O
Solvent: ClC(Cl)Cl
Product: COc1ccc(Br)cc1F
Temperature: 10 °C
Yield: 93.9 %

Procedure:
Into a flask of 5 l were charged 384 g (3.04 mol) of 2-fluoroanisole and 2.5 l of chloroform, to which was added dropwise 504 g (3.16 mol) of bromine over about 3 hours while cooling on an ice water bath at 10° C. The resulting mixture was stirred at room temperature over a night and heated under reflux for 8 hours. After the air cooling, the product was added with 1 l of water and 50 g of sodium bisulfite and sufficiently shaken to separate into two layers. The resulting organic layer was washed with an aqueous solution of 5% sodium hydrogen carbonate and further with 1 l of water and dried on magnesium sulfate. After magnesium sulfate was filtered off, the filtrate was concentrated and distilled under a reduced pressure (4 mmHg, bp: 93-°96° C.) to obtain 585 g (yield: 94%) of 3-fluoro-4-methoxybromobenzene.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:26]=[C:27]([O:31][CH3:32])[C:28]=1[O:29][CH3:30])[C:6]([N:8]1[CH2:12][CH2:11][C:10]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)([CH2:13][CH2:14]OS(C)(=O)=O)[CH2:9]1)=[O:7].I.[CH3:34][N:35]([N:39]1[C:43]2[CH:44]=[CH:45][CH:46]=[CH:47][C:42]=2[N:41]=[C:40]1[N:48]1[CH2:54][CH2:53][CH2:52][NH:51][CH2:50][CH2:49]1)[C:36](=[O:38])[CH3:37]>CO.ClCCl>[CH3:32][O:31][C:27]1[CH:26]=[C:5]([CH:4]=[C:3]([O:2][CH3:1])[C:28]=1[O:29][CH3:30])[C:6]([N:8]1[CH2:12][CH2:11][C:10]([CH2:13][CH2:14][N:51]2[CH2:52][CH2:53][CH2:54][N:48]([C:40]3[N:39]([N:35]([CH3:34])[C:36](=[O:38])[CH3:37])[C:43]4[CH:44]=[CH:45][CH:46]=[CH:47][C:42]=4[N:41]=3)[CH2:49][CH2:50]2)([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH2:9]1)=[O:7]
Reactant: COc1cc(C(=O)N2CCC(CCOS(C)(=O)=O)(c3ccccc3)C2)cc(OC)c1OC
Reactant: CC(=O)N(C)n1c(N2CCCNCC2)nc2ccccc21
Agent: I
Solvent: CO
Solvent: ClCCl
Product: COc1cc(C(=O)N2CCC(CCN3CCCN(c4nc5ccccc5n4N(C)C(C)=O)CC3)(c3ccccc3)C2)cc(OC)c1OC

Procedure:
Prepare by the method of Example 45.1 using 1-(3,4,5-trimethoxybenzoyl)-3-phenyl-3-(2-methanesulfonyloxyethyl)pyrrolidine (prepared from (−)-3-phenyl-3-(2-hydroxyethyl)pyrrolidine (R,R)-di-p-anisoyltartaric acid salt) and 4-(1-(N-methylacetamido)-1H-benzimidazol-2-yl)[1,4]diazepane hydriodic acid salt to give, after chromatography on silica gel eluting with 5% methanol/dichloromethane/0.5% concentrated aqueous ammonia solution, the title compound: Rf=0.32 (silica gel, 5% methanol/dichloromethane/0.5% concentrated aqueous ammonia solution).
Reaction SMILES: [C:1]([C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([O:13][C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[CH:11]=2)[C:6]([OH:20])=[C:5]([C:21](OC)=[O:22])[N:4]=1)#[N:2].[NH2:25][C@H:26]([C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)[CH2:27][C:28]([OH:30])=[O:29].C[O-].[Na+]>COCCO>[C:1]([C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([O:13][C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[CH:11]=2)[C:6]([OH:20])=[C:5]([C:21]([NH:25][C@H:26]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[CH2:27][C:28]([OH:30])=[O:29])=[O:22])[N:4]=1)#[N:2]
Reactant: N[C@@H](CC(=O)O)c1ccccc1
Reactant: COC(=O)c1nc(C#N)c2cc(Oc3ccccc3)ccc2c1O
Agent: C[O-]
Agent: [Na+]
Solvent: COCCO
Product: N#Cc1nc(C(=O)N[C@@H](CC(=O)O)c2ccccc2)c(O)c2ccc(Oc3ccccc3)cc12
Temperature: 25 °C

Procedure:
Methyl 1-cyano-4-hydroxy-7-phenoxyisoquinoline-3-carboxylate (20 mg, 0.06 mmol), (S)-3-amino-3-phenyl-propionic acid (62 mg, 0.38 mmol) (PepTech Corp., Burlington Mass.) and sodium methoxide (19 mg, 0.35 mmol) were suspended in 2-methoxyethanol (3 mL). The resulting mixture was heated to reflux for 3 hours and then cooled to room temperature. The solvent was removed in vacuo and the residue was dissolved in H2O (15 mL) and EtOAc (15 mL). To the stirred mixture was added 1 N hydrochloric acid until pH was 1. The layers were separated and the aqueous layer was extracted twice with EtOAc. The combined organic layers were dried over MgSO4, concentrated, and purified by flash chromatography (0-50% EtOAc/CH2Cl2 with 0.5% formic acid) to give the title compound in 15 mg. MS: (−) m/z 452.00 (M−1).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:40]=[CH:39][C:6]([CH2:7][N:8]([CH2:30][C:31]2[CH:36]=[CH:35][C:34]([O:37][CH3:38])=[CH:33][CH:32]=2)[C:9]2[N:14]=[CH:13][C:12]([C:15]3[C:16]4[CH2:29][CH2:28][NH:27][C:17]=4[N:18]=[C:19]([N:21]4[CH2:26][CH2:25][O:24][CH2:23][CH2:22]4)[N:20]=3)=[CH:11][N:10]=2)=[CH:5][CH:4]=1.Br[C:42]1[C:43]([CH3:59])=[C:44]([C:48]([N:50]2[CH2:55][CH2:54][N:53]([CH2:56][CH2:57][OH:58])[CH2:52][CH2:51]2)=[O:49])[CH:45]=[CH:46][CH:47]=1>>[CH3:38][O:37][C:34]1[CH:33]=[CH:32][C:31]([CH2:30][N:8]([CH2:7][C:6]2[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:40][CH:39]=2)[C:9]2[N:10]=[CH:11][C:12]([C:15]3[C:16]4[CH2:29][CH2:28][N:27]([C:42]5[C:43]([CH3:59])=[C:44]([C:48]([N:50]6[CH2:55][CH2:54][N:53]([CH2:56][CH2:57][OH:58])[CH2:52][CH2:51]6)=[O:49])[CH:45]=[CH:46][CH:47]=5)[C:17]=4[N:18]=[C:19]([N:21]4[CH2:26][CH2:25][O:24][CH2:23][CH2:22]4)[N:20]=3)=[CH:13][N:14]=2)=[CH:36][CH:35]=1
Reactant: Cc1c(Br)cccc1C(=O)N1CCN(CCO)CC1
Reactant: COc1ccc(CN(Cc2ccc(OC)cc2)c2ncc(-c3nc(N4CCOCC4)nc4c3CCN4)cn2)cc1
Product: COc1ccc(CN(Cc2ccc(OC)cc2)c2ncc(-c3nc(N4CCOCC4)nc4c3CCN4c3cccc(C(=O)N4CCN(CCO)CC4)c3C)cn2)cc1

Procedure:
Using bis-(4-methoxy-benzyl)-[5-(2-morpholin-4-yl-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-4-yl)-pyrimidin-2-yl]-amine (100 mg) and (3-bromo-2-methyl-phenyl)-[4-(2-hydroxy-ethyl)-piperazin-1-yl]-methanone (188 mg) instead of 4-chloropicolinic acid t-butylamide, in the same manner as Example 1-D-07, a crude product of [3-(4-{2-[bis-(4-methoxy-benzyl)-amino]-pyrimidin-5-yl}-2-morpholin-4-yl-5,6-dihydro-pyrrolo[2,3-d]pyrimidin-7-yl)-2-methyl-phenyl]-[4-(2-hydroxy-ethyl)-piperazin-1-yl]-methanone was obtained, and then the PMB groups were removed according to the above Deprotection method 3, to obtain the desired compound (D-159) as a pale yellow powder (23 mg, 23%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:11]([S:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:12]([OH:14])=O)[CH:6]=[C:7]([O:9][CH3:10])[CH:8]=1.C(N1C=CN=C1)(N1C=CN=C1)=O.[CH3:34][NH:35][CH2:36][C:37]1[CH:42]=[CH:41][CH:40]=[C:39]([O:43][CH3:44])[CH:38]=1>ClCCl>[CH3:44][O:43][C:39]1[CH:38]=[C:37]([CH:42]=[CH:41][CH:40]=1)[CH2:36][N:35]([CH3:34])[C:12](=[O:14])[CH:11]([C:5]1[CH:6]=[C:7]([O:9][CH3:10])[CH:8]=[C:3]([O:2][CH3:1])[CH:4]=1)[S:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: CNCc1cccc(OC)c1
Reactant: COc1cc(OC)cc(C(Sc2ccccc2)C(=O)O)c1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: ClCCl
Product: COc1cccc(CN(C)C(=O)C(Sc2ccccc2)c2cc(OC)cc(OC)c2)c1
Reaction time: 1 h
Yield: 105.5 %

Procedure:
A solution of 2-(3,5-dimethoxyphenyl)-2-(phenyl-sulfanyl)acetic acid (6.0 g) in dichloromethane (50 ml) was treated with 1,1′-carbonyldiimidazole (3.24 g) at room temperature for 2 hours. A solution of N-methyl-3-methoxy-benzylamine (3.4 g) in dichloromethane (15 ml) was added and the stirring was continued for one hour. The reaction mixture was washed with aqueous hydrochloric acid (1M, 50 ml) and aqueous sodium hydroxide (1M, 50 ml). The organic phase was dried and concentrated to dryness leaving crude N-(3-methoxy-benzyl)-N-methyl-2-(3,5-dimetoxyphenyl)-2-(phenylsulfanyl)-acetamide (9.1 g) as a viscous oil.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][N+:5]([O-])=[C:4]2[CH2:9][CH2:10][CH2:11][C:3]=12.[C:12]([O:15]C(=O)C)(=[O:14])[CH3:13]>>[C:12]([O:15][CH:9]1[C:4]2[N:5]=[CH:6][N:7]=[C:2]([Cl:1])[C:3]=2[CH2:11][CH2:10]1)(=[O:14])[CH3:13]
Reactant: CC(=O)OC(C)=O
Reactant: [O-][n+]1cnc(Cl)c2c1CCC2
Product: CC(=O)OC1CCc2c(Cl)ncnc21
Temperature: 110 °C
Reaction time: 2 h
Yield: 63 %

Procedure:
The solution of 4-chloro-6,7-dihydro-5H-cyclopenta[d]pyrimidine 1-oxide (2.93 g, 17.2 mmol) in acetic anhydride (50 mL) was added dropwise to the acetic anhydride (50 mL) at 50° C. After addition, the mixture was stirred at 110° C. for 2 hour. After cooling, the solvent was removed and the residue was treated with toluene and hexanes (1:1, 200 mL). The mixture was stirred and then the solvent was removed. The residue was subject to chromatography on silica gel, eluted by hexanes/ethyl acetate (4:1-3:1) to afford the 4-chloro-6,7-dihydro-5H-cyclopenta[d]pyrimidin-7-yl acetate (2.3 g, 63%). 1H NMR (CDCl3, 400 MHz) δ 8.92 (s, 1H), 6.20-6.16 (m, 1H), 3.20-3.10 (m, 1H), 3.03-2.93 (m, 1H), 2.76-2.67 (m, 1H), 2.20-2.05 (m, 4H).
Reaction SMILES: [CH2:1](Br)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+].[NH:15]1[CH2:22][CH2:21][CH2:20][CH:16]1[C:17]([OH:19])=[O:18]>CN(C=O)C.CCOC(C)=O>[CH2:1]([N:15]1[CH2:22][CH2:21][CH2:20][C@H:16]1[C:17]([O:19][CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)=[O:18])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(O)C1CCCN1
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: O=C(OCc1ccccc1)[C@@H]1CCCN1Cc1ccccc1
Temperature: 100 °C
Reaction time: 8 h
Yield: 43 %

Procedure:
Benzyl bromide (2 eq.) and K2CO3 (2.5 eq) were added to a solution (0.6 M) of DL-proline in DMF. The reaction was stirred at 100° C. overnight. The solution was allowed to cool to RT and then diluted with EtOAc and washed with 1 N HCl, brine, before being dried (Na2SO4), filtered and concentrated in vacuo. The crude material was purified by FC (PE/EtOAc 90:10) to afford the product (43%). (ES+) m/z 296 (M+H)+