Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([C:18]([OH:20])=O)[CH2:10][C:11]1[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].ON1C(=O)CCC1=O.C1CCC(N=C=NC2CCCCC2)CC1.[NH:44]1[CH2:50][CH2:49][CH2:48][C@H:45]1[CH2:46][OH:47]>C1COCC1>[C:1]([O:5][C:6]([NH:8][C@H:9]([C:18]([N:44]1[CH2:50][CH2:49][CH2:48][C@H:45]1[CH:46]=[O:47])=[O:20])[CH2:10][C:11]1[CH:12]=[CH:13][C:14]([OH:17])=[CH:15][CH:16]=1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: OC[C@@H]1CCCN1
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccc(O)cc1)C(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: O=C1CCC(=O)N1O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N[C@@H](Cc1ccc(O)cc1)C(=O)N1CCC[C@H]1C=O
Temperature: 4 °C
Reaction time: 21 h

Procedure:
In 200 ml of THF was dissolved 28.1 g of t-butyloxycarbonyltyrosine. To this solution were added under cooling with edible salt and ice 11.5 g of HOSu and 20.6 of DCC, and the mixture was stirred for 21 hours at 4° C. The reaction liquid was filtered and the filtrate was evaporated whereby a semi-solid substance was obtained. This substance was recrystallized from chloroform to obtain a white solid substance which was then dissolved in 500 ml of THF. To this solution was added 6.0 g of L-prolinol, and the mixture was stirred for 72 hours at room temperature. After removal of THF by distillation, the residue was dissolved in 200 ml of ethyl acetate and the solution was washed with 100 ml of 1-M Na2CO3, dehydrated with anhydrous Na2SO4 and evaporated until dryness. To the resultant oily substance were added 20.3 g of WSCD.HCl and 90 ml of redistilled DMSO, and the mixture was stirred for 10 minutes. Subsequently, 3.9 ml of a DMSO solution of 2-M anhydrous H3PO4 was added and the mixture was stirred for further 2 hours. The reaction was stopped with 300 ml of a buffer solution of 1-M potassium phosphate of pH 7.5. The reaction mixture was extracted with 200 ml of ethyl acetate, and the extract was dried over anhydrous Na2SO4. The ethyl acetate was distilled off and the residue was dissolved in 200 ml of ethanol. To this solution was added 200 g of NaHSO3 in 350 ml of water, and the mixture was stirred vigorously for 10 minutes. After concentration of the ethanol up to about 350 ml, unreacted materials were eliminated twice with 100 ml of ether, and solid Na2CO3 was added until the pH value of the liquid became 9. After 5 minutes, the reaction liquid was extracted twice with 100 ml of ether, and the ether was then distilled off to leave an oily substance. Yield 0.8 g (2.2%).
Reaction SMILES: FC(F)(F)S(O[C:7]1[CH2:13][CH:12]2[N:14]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH:9]([CH2:10][CH2:11]2)[CH:8]=1)(=O)=O.CC1(C)C(C)(C)OB([C:32]2[CH:37]=[CH:36][N:35]=[CH:34][CH:33]=2)O1.[Cl-].[Li+].P([O-])([O-])([O-])=O.[K+].[K+].[K+]>CN(C1C(C2[C-]=CC=CC=2)=CC=CC=1)C.C1[C@H]2CC(PC3[C@H]4C[C@H](CC4)C3)[C@H](C2)C1.Cl[Pd+].C(OCC)(=O)C.O.O1CCOCC1>[N:35]1[CH:36]=[CH:37][C:32]([C:7]2[CH2:13][CH:12]3[N:14]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH:9]([CH2:10][CH2:11]3)[CH:8]=2)=[CH:33][CH:34]=1
Reactant: CC1(C)OB(c2ccncc2)OC1(C)C
Reactant: CC(C)(C)OC(=O)N1C2C=C(OS(=O)(=O)C(F)(F)F)CC1CC2
Agent: Cl[Pd+]
Agent: C1C[C@@H]2C[C@H]1CC2PC1C[C@@H]2CC[C@H]1C2
Agent: CN(C)c1ccccc1-c1[c-]cccc1
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Solvent: O
Product: CC(C)(C)OC(=O)N1C2C=C(c3ccncc3)CC1CC2
Temperature: 100 °C
Yield: 57.2 %

Procedure:
1 g of tert-butyl 3-{[(trifluoromethyl)sulfonyl]oxy}-8-azabicyclo[3.2.1]oct-2-ene-8-carboxylate, 0.975 g of 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine, 0.24 g of lithium chloride, 1.78 g of potassium phosphate, 0.157 g of 2′-(dimethylamino)-2-biphenylpalladium(II)chloride dinorbornylphosphine and 10 ml of dioxane are introduced into an 80 ml glass tube. The tube is sealed and then heated at 100° C. under microwave irradiation for 30 minutes. Water and ethyl acetate are added. The aqueous phase is extracted three times with ethyl acetate. The organic phases are combined and dried over sodium sulfate and the solvent is evaporated off under reduced pressure. The residue is chromatographed on silica gel with a mixture of heptane/ethyl acetate. 0.458 g of tert-butyl 3-pyridin-4-yl-8-azabicyclo[3.2.1]oct-2-ene-8-carboxylate is obtained.
Reaction SMILES: [H-].[H-].COCCO[Al+]OCCOC.[Na+].N1CCOCC1.[CH3:21][O:22][CH2:23][O:24][CH2:25][C:26]1[N:31]2[CH:32]=[CH:33][N:34]=[C:30]2[C:29]([C:35](OC)=[O:36])=[CH:28][CH:27]=1>C1(C)C=CC=CC=1>[CH3:21][O:22][CH2:23][O:24][CH2:25][C:26]1[N:31]2[CH:32]=[CH:33][N:34]=[C:30]2[C:29]([CH:35]=[O:36])=[CH:28][CH:27]=1
Reactant: COCOCc1ccc(C(=O)OC)c2nccn12
Agent: COCCO[Al+]OCCOC
Agent: [H-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: C1COCCN1
Product: COCOCc1ccc(C=O)c2nccn12
Temperature: -40 °C
Reaction time: 0.67 h
Yield: 56.2 %

Procedure:
To a stirred solution of sodium bis(2-methoxyethoxy)aluminium dihydride (65% wt. in toluene, 0.512 mL, 1.678 mmol) at 0° C. under a nitrogen atmosphere was added a solution of morpholine (0.147 mL, 1.678 mmol) in toluene (3.35 mL) dropwise over 15 min to give a solution of reducing agent (approx 4 mL, 4 eq). An aliquot of this solution (1.5 mL, ca 1.5 eq) was added dropwise over 2 min to a stirred solution of impure methyl 5-({[(methyloxy)methyl]oxy}methyl)imidazo[1,2-a]pyridine-8-carboxylate (105 mg, 0.420 mmol) in toluene (4 mL) at −40° C. The reaction was stirred at −40° C. for 40 min when LCMS indicated that the ester had been reduced to the aldehyde. The reaction was quenched carefully by addition of water (2 mL) and then allowed to warm to ambient temperature and concentrated in vacuo. The residue was pre-absorbed on florosil (100-200 mesh) and purified on a silica cartridge (20 g) using a 0-25% methanol-DCM gradient over 40 min. The appropriate fractions were combined and concentrated in vacuo to give impure 5-({[(methyloxy)methyl]oxy}methyl)imidazo[1,2-a]pyridine-8-carbaldehyde as a yellow oil (52 mg) which was used directly in the next step.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:11]=[C:12]3[C:16](=[CH:17][CH:18]=2)[C:15](=[O:19])[O:14][CH2:13]3)=[C:6]([OH:20])[C:5]=1[O:21][CH3:22])[CH3:2].C(=O)([O-])[O-].[K+].[K+].[CH2:29](I)[CH3:30]>C(#N)C>[CH2:29]([O:20][C:6]1[C:5]([O:21][CH3:22])=[C:4]([O:3][CH2:1][CH3:2])[CH:9]=[CH:8][C:7]=1[C:10]1[CH:11]=[C:12]2[C:16](=[CH:17][CH:18]=1)[C:15](=[O:19])[O:14][CH2:13]2)[CH3:30]
Reactant: CCOc1ccc(-c2ccc3c(c2)COC3=O)c(O)c1OC
Reactant: CCI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCOc1ccc(-c2ccc3c(c2)COC3=O)c(OCC)c1OC
Temperature: 75 °C
Yield: 60.9 %

Procedure:
To a stirring solution of 5-(4-ethoxy-2-hydroxy-3-methoxyphenyl)isobenzofuran-1(3H)-one (30 mg, 0.1 mmol) in acetonitrile (5 mL) was added potassium carbonate (41 mg, 0.30 mmol) and ethyl iodide (62 mg, 0.40 mmol) and the resultant reaction mixture was heated to 75° C. for 2 h. The reaction mixture was cooled to RT, filtered through celite and the filtrate was concentrated under reduced pressure. Purification of the residue by flash column chromatography (silica gel, 0-20% ethyl acetate in pet ether) afforded the title compound as a solid (20 mg, 61%).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:16]=[C:15]3[C:11]([CH2:12][N:13]([C@@H:18]([CH:23]([CH3:25])[CH3:24])[C:19]([O:21][CH3:22])=[O:20])[C:14]3=[O:17])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.[C:26]([C:28]1[CH:29]=[C:30]([N:34]=[C:35]=[O:36])[CH:31]=[CH:32][CH:33]=1)#[N:27]>>[C:26]([C:28]1[CH:29]=[C:30]([NH:34][C:35](=[O:36])[NH:1][C:2]2[CH:3]=[CH:4][C:5]([C:8]3[CH:16]=[C:15]4[C:11]([CH2:12][N:13]([C@@H:18]([CH:23]([CH3:25])[CH3:24])[C:19]([O:21][CH3:22])=[O:20])[C:14]4=[O:17])=[CH:10][CH:9]=3)=[CH:6][CH:7]=2)[CH:31]=[CH:32][CH:33]=1)#[N:27]
Reactant: COC(=O)[C@H](C(C)C)N1Cc2ccc(-c3ccc(N)cc3)cc2C1=O
Reactant: N#Cc1cccc(N=C=O)c1
Product: COC(=O)[C@H](C(C)C)N1Cc2ccc(-c3ccc(NC(=O)Nc4cccc(C#N)c4)cc3)cc2C1=O

Procedure:
The compound of example 41 was prepared analogous to compound of example 7 by reaction of compound of example 6 with 3-cyanophenyl isocyanate. The compound of example 41 was used directly without isolation for the preparation of compound of example 42.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[Mg]Br.[CH2:11]([N:18]1[CH2:26][CH:25]2[CH:20]([CH2:21][CH2:22][CH:23]([CH3:28])[C:24]2=[O:27])[CH2:19]1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.[Cl-].[NH4+]>O1CCCC1.C(OCC)(=O)C>[CH2:11]([N:18]1[CH2:26][CH:25]2[CH:20]([CH2:21][CH2:22][CH:23]([CH3:28])[C:24]2([C:4]2[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=2[O:2][CH3:1])[OH:27])[CH2:19]1)[C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: COc1ccccc1[Mg]Br
Reactant: CC1CCC2CN(Cc3ccccc3)CC2C1=O
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COc1ccccc1C1(O)C(C)CCC2CN(Cc3ccccc3)CC21
Yield: 98.9 %

Procedure:
To a suspension of 2.13 g of 2-methoxyphenylmagnesium bromide in 15 cm3 of tetrahydrofuran is added dropwise, at room temperature and with stirring, a solution of 0.7 g of (3aRS,5RS,7aSR)-2-benzyl-5-methyl-4-perhydroisoindolone in 15 cm3 of tetrahydrofuran. The reaction mixture is stirred at room temperature for 48 hours, treated with 50 cm3 of saturated aqueous ammonium chloride solution, taken up in ethyl acetate and washed with saturated aqueous sodium chloride solution. The organic phase is separated out after settling has taken place, dried over magnesium sulphate, filtered and concentrated to dryness under reduced pressure (2.7 kPa). The residue is chromatographed on a column of Merck silica gel (particle size 0.04-0.06 mm, diameter 2 cm, height 15 cm), eluting under a pressure of 0.5 bar of nitrogen with a mixture of cyclohexane and ethyl acetate (60/40 by volume) and collecting 25 cm3 fractions. Fractions 10 to 20 are combined and then concentrated to dryness under reduced pressure (2.5 kPa). 1 g of (3aRS,4RS,5RS,7aSR)-2-benzyl-4-(2-methoxyphenyl)-5methyl-4-perhydroisoindolol is obtained in the form of a yellow oil.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]([N:11]1[CH2:16][CH2:15][N:14]([C:17]2[C:22]([CH3:23])=[CH:21][C:20]([CH3:24])=[CH:19][N:18]=2)[CH2:13][CH2:12]1)=[O:10].[CH3:25][N:26]1[CH2:30][CH2:29][NH:28][C:27]1=[O:31]>>[Cl:8][C:6]1[CH:5]=[CH:4][C:3]([C:9]([N:11]2[CH2:16][CH2:15][N:14]([C:17]3[C:22]([CH3:23])=[CH:21][C:20]([CH3:24])=[CH:19][N:18]=3)[CH2:13][CH2:12]2)=[O:10])=[C:2]([N:28]2[CH2:29][CH2:30][N:26]([CH3:25])[C:27]2=[O:31])[CH:7]=1
Reactant: CN1CCNC1=O
Reactant: Cc1cnc(N2CCN(C(=O)c3ccc(Cl)cc3Br)CC2)c(C)c1
Product: Cc1cnc(N2CCN(C(=O)c3ccc(Cl)cc3N3CCN(C)C3=O)CC2)c(C)c1
Yield: 18.3 %

Procedure:
By reaction and treatment in the same manner as in Preparation Example 12 and using (2-bromo-4-chlorophenyl)[4-(3,5-dimethylpyridin-2-yl)piperazin-1-yl]methanone (960 mg) described in Preparation Example 119 and 1-methyl-2-imidazolidinone (235 mg), the title compound (184 mg) was obtained.
Reaction SMILES: [NH2:1][C:2]1[C:7](=[O:8])[C:6]2[CH:9]=[C:10]([O:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[C:11]([NH:13][S:14]([CH3:17])(=[O:16])=[O:15])=[CH:12][C:5]=2[O:4][CH:3]=1.[O-:25][C:26]#[N:27].[Na+]>C(O)(=O)C.O>[CH3:17][S:14]([NH:13][C:11]1[C:10]([O:18][C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)=[CH:9][C:6]2[C:7](=[O:8])[C:2]([NH:1][C:26]([NH2:27])=[O:25])=[CH:3][O:4][C:5]=2[CH:12]=1)(=[O:15])=[O:16]
Reactant: N#C[O-]
Reactant: CS(=O)(=O)Nc1cc2occ(N)c(=O)c2cc1Oc1ccccc1
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: CS(=O)(=O)Nc1cc2occ(NC(N)=O)c(=O)c2cc1Oc1ccccc1
Temperature: 35 °C
Reaction time: 0.5 h
Yield: 62.3 %

Procedure:
500 mg of 3-amino-7-methylsulfonylamino-6-phenoxy-4H-1-benzopyran-4-one was dissolved in 20 ml of acetic acid and 10 ml of water. The solution was heated to 35° C. Thereto was dropwise added a solution of 190 mg of sodium cyanate dissolved in 5 ml of water, in 5 minutes. The mixture was stirred for 30 minutes at the same temperature. 20 ml of water was added thereto. The resulting crystal was collected by filtration and recrystallized from acetic acid to obtain 350 mg (yield: 62.3%) of 7-methylsulfonylamino-6-phenoxy-3-ureido-4H-1-benzopyran-4-one having a melting point of >250° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[N:7]([CH2:13][CH:14]1[CH2:16][CH2:15]1)[C:6]([C:17]([O:19]CC)=[O:18])=[C:5]2[O:22][CH2:23][CH2:24][CH2:25][CH3:26].[OH-].[Na+].O.Cl>O1CCCC1.C(O)C>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[N:7]([CH2:13][CH:14]1[CH2:15][CH2:16]1)[C:6]([C:17]([OH:19])=[O:18])=[C:5]2[O:22][CH2:23][CH2:24][CH2:25][CH3:26]
Reactant: CCCCOc1c(C(=O)OCC)n(CC2CC2)c(=O)c2ccc(Br)cc12
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CCO
Product: CCCCOc1c(C(=O)O)n(CC2CC2)c(=O)c2ccc(Br)cc12
Yield: 95.6 %

Procedure:
To a solution of ethyl 6-bromo-4-butoxy-2-cyclopropylmethyl-1-oxo-1,2-dihydro-3-isoquinolinecarboxylate (7.18 g, 17 mmol) in tetrahydrofuran (20 mL) and ethanol (20 mL) was added an aqueous solution (10 mL) of sodium hydroxide (2.04 g, 51 mmol). The obtained mixture was refluxed under heating for 12 h. The reaction mixture was poured into water, acidified with 1N hydrochloric acid and extracted with ethyl acetate. The extract was washed with brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The obtained crystals was recrystallized from ethyl acetate-diisopropyl ether to give 6-bromo-4-butoxy-2-cyclopropylmethyl-1-oxo-1,2-dihydro-3-isoquinolinecarboxylic acid (6.41 g, 95.7%) as crystals.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:10]3[CH2:21][NH:20][CH2:19][CH2:18][C:11]=3[N:12]=[C:13]([NH:15][CH2:16][CH3:17])[N:14]=2)=[CH:5][CH:4]=1.I[CH2:23][CH3:24]>>[Cl:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:10]3[CH2:21][N:20]([CH2:23][CH3:24])[CH2:19][CH2:18][C:11]=3[N:12]=[C:13]([NH:15][CH2:16][CH3:17])[N:14]=2)=[CH:5][CH:4]=1
Reactant: CCNc1nc2c(c(-c3ccc(Cl)cc3)n1)CNCC2
Reactant: CCI
Agent: Cl
Product: CCNc1nc2c(c(-c3ccc(Cl)cc3)n1)CN(CC)CC2
Yield: 98.4 %

Procedure:
The title compound was prepared as described in Example 9 starting with 4-(4-chlorophenyl)-2-ethylamino-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidine hydrochloride (3.0 g, 9.3 mmol) and iodoethane (0.74 mL, 18.5 mmol) to produce 2.9 g (100%) of 4-(4-chlorophenyl)-6-ethyl-2- ethylamino-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidine. m.p. 129°-132° C. MS: 317 (MH+).
Reaction SMILES: [Si]([O:18][C:19]1[CH:56]=[CH:55][C:22]([O:23][CH2:24][C@@H:25]([OH:54])[CH2:26][NH:27][CH2:28][CH2:29][C:30]2[CH:53]=[CH:52][C:33]([NH:34][CH:35]3[CH2:40][CH2:39][N:38]([C:41]([O:43][CH2:44][C:45]4[CH:50]=[CH:49][C:48]([F:51])=[CH:47][CH:46]=4)=[O:42])[CH2:37][CH2:36]3)=[CH:32][CH:31]=2)=[CH:21][CH:20]=1)(C(C)(C)C)(C1C=CC=CC=1)C1C=CC=CC=1>C(Cl)(Cl)Cl.CO>[F:51][C:48]1[CH:47]=[CH:46][C:45]([CH2:44][O:43][C:41]([N:38]2[CH2:37][CH2:36][CH:35]([NH:34][C:33]3[CH:52]=[CH:53][C:30]([CH2:29][CH2:28][NH:27][CH2:26][C@H:25]([OH:54])[CH2:24][O:23][C:22]4[CH:21]=[CH:20][C:19]([OH:18])=[CH:56][CH:55]=4)=[CH:31][CH:32]=3)[CH2:40][CH2:39]2)=[O:42])=[CH:50][CH:49]=1
Reactant: CC(C)(C)[Si](Oc1ccc(OC[C@@H](O)CNCCc2ccc(NC3CCN(C(=O)OCc4ccc(F)cc4)CC3)cc2)cc1)(c1ccccc1)c1ccccc1
Solvent: CO
Solvent: ClC(Cl)Cl
Product: O=C(OCc1ccc(F)cc1)N1CCC(Nc2ccc(CCNC[C@H](O)COc3ccc(O)cc3)cc2)CC1
Yield: 84.9 %

Procedure:
4-Fluorobenzyl 4-[4-(2-{[(2S)-3-(4-{[tert-butyl(diphenyl)silyl]oxy}phenoxy)-2-hydroxypropyl]amino}ethyl)anilino]-1-piperidinecarboxylate (0.18 g, 0.232 mmol) was reacted according to Procedure H (eluant: 10:1 chloroform-methanol) to give the title compound (0.125 g, 0.197 mmol).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([N:8]2[CH2:16][CH:15]3[CH2:17][N:11]4[CH2:12][CH:13]([CH2:18][CH:9]2[CH2:10]4)[CH2:14]3)[CH:5]=[N:6][CH:7]=1.[C:19]([NH:22][C:23]1[CH:24]=[C:25](B(O)O)[CH:26]=[CH:27][CH:28]=1)(=[O:21])[CH3:20]>>[N:11]12[CH2:17][CH:15]3[CH2:14][CH:13]([CH2:18][CH:9]([N:8]([C:4]4[CH:3]=[C:2]([C:27]5[CH:28]=[C:23]([NH:22][C:19](=[O:21])[CH3:20])[CH:24]=[CH:25][CH:26]=5)[CH:7]=[N:6][CH:5]=4)[CH2:16]3)[CH2:10]1)[CH2:12]2
Reactant: Brc1cncc(N2CC3CC4CC2CN(C4)C3)c1
Reactant: CC(=O)Nc1cccc(B(O)O)c1
Product: CC(=O)Nc1cccc(-c2cncc(N3CC4CC5CC3CN(C5)C4)c2)c1

Procedure:
The title compound was prepared from the product of Example 65A and 3-acetamidophenylboronic acid according to General Method B: LC-MS Method D (ESI+) m/z 363.0 (M+H)+, retention time 1.21 minutes.
Reaction SMILES: [CH2:1]([NH:3][C:4]([CH:6]1[CH2:10][CH:9]([N:11]2[C:15]3[N:16]=[C:17]([S:30][CH2:31][CH2:32][CH3:33])[N:18]=[C:19]([NH:20][CH:21]4[CH2:23][CH:22]4[C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)[C:14]=3[N:13]=[N:12]2)[CH:8]([OH:34])[CH:7]1[OH:35])=[O:5])[CH3:2].[O:36]1[C:40]2[CH:41]=[CH:42]C(CN)=[CH:44][C:39]=2[O:38][CH2:37]1>>[O:36]1[C:40]2[CH:41]=[CH:42][C:2]([CH2:1][NH:3][C:4]([CH:6]3[CH2:10][CH:9]([N:11]4[C:15]5[N:16]=[C:17]([S:30][CH2:31][CH2:32][CH3:33])[N:18]=[C:19]([NH:20][CH:21]6[CH2:23][CH:22]6[C:24]6[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=6)[C:14]=5[N:13]=[N:12]4)[CH:8]([OH:34])[CH:7]3[OH:35])=[O:5])=[CH:44][C:39]=2[O:38][CH2:37]1
Reactant: CCCSc1nc(NC2CC2c2ccccc2)c2nnn(C3CC(C(=O)NCC)C(O)C3O)c2n1
Reactant: NCc1ccc2c(c1)OCO2
Product: CCCSc1nc(NC2CC2c2ccccc2)c2nnn(C3CC(C(=O)NCc4ccc5c(c4)OCO5)C(O)C3O)c2n1

Procedure:
The subtitle compound was prepared according to the method of example 39 step a) using the product of example 1, step c) and 2H-1,3-benzodioxol-5-ylmethylamine.
Reaction SMILES: [CH2:1]1[O:14][C:13]2[CH:12]=[CH:11][C:5]([CH:6]=[CH:7][C:8]([OH:10])=O)=[CH:4][C:3]=2[O:2]1.C(N(CC)CC)C.C(Cl)(=O)OCC.Cl.[N:29]1([C:35]2[N:44]=[C:43]([NH2:45])[C:42]3[C:37](=[CH:38][C:39]([O:48][CH3:49])=[C:40]([O:46][CH3:47])[CH:41]=3)[N:36]=2)[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]1>O.C(OCC)(=O)C>[CH2:1]1[O:14][C:13]2[CH:12]=[CH:11][C:5]([CH:6]=[CH:7][C:8]([N:32]3[CH2:33][CH2:34][N:29]([C:35]4[N:44]=[C:43]([NH2:45])[C:42]5[C:37](=[CH:38][C:39]([O:48][CH3:49])=[C:40]([O:46][CH3:47])[CH:41]=5)[N:36]=4)[CH2:30][CH2:31]3)=[O:10])=[CH:4][C:3]=2[O:2]1
Reactant: COc1cc2nc(N3CCNCC3)nc(N)c2cc1OC
Reactant: O=C(O)C=Cc1ccc2c(c1)OCO2
Agent: CCOC(=O)Cl
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: O
Product: COc1cc2nc(N3CCN(C(=O)C=Cc4ccc5c(c4)OCO5)CC3)nc(N)c2cc1OC
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 346 mg. of 3,4-methylenedioxycinnamic acid and 364 mg. of triethylamine in 20 ml. of ethyl acetate were added under ice-cooling 195 mg. of ethyl chlorocarbonate and the resulting mixture was then stirred for 4 hours. Then, 543 mg. of 2-(piperazin-1-yl)-4-amino-6,7-dimethoxyquinazoline.hydrochloride were added thereto and the resulting mixture was stirred at room temperature overnight. After 50 ml. of water were added, the precipitate thus separated was recovered by filtration. The resulting crystalline substance was recrystallized from ethanol to give 320 mg. of the desired product as the hydrochloride.
Reaction SMILES: Cl[C:2]1[C:7]([CH:8]=[O:9])=[C:6]([Cl:10])[N:5]=[C:4]([S:11][CH3:12])[N:3]=1.[F:13][C:14]1[CH:20]=[C:19]([F:21])[CH:18]=[C:17]([F:22])[C:15]=1[NH2:16].CCN(CC)CC.C([O-])([O-])=O.[Na+].[Na+]>C(Cl)(Cl)Cl>[Cl:10][C:6]1[C:7]([CH:8]=[O:9])=[C:2]([NH:16][C:15]2[C:14]([F:13])=[CH:20][C:19]([F:21])=[CH:18][C:17]=2[F:22])[N:3]=[C:4]([S:11][CH3:12])[N:5]=1
Reactant: Nc1c(F)cc(F)cc1F
Reactant: CSc1nc(Cl)c(C=O)c(Cl)n1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: CSc1nc(Cl)c(C=O)c(Nc2c(F)cc(F)cc2F)n1
Yield: 87 %

Procedure:
A solution of 4,6-dichloro-2-methylsulfanyl-pyrimidine-5-carbaldehyde [Santilli, et al., J. Heterocycl. Chem. 1971, 8, 445-45] (1.0 gram (hereinafter “g”), 4.48 millimoles (hereinafter “mmol”)) in CHCl3 (20 milliliters (hereinafter “mL”)) was added 2,4,6-tri-fluoroaniline (0.735 g, 5 mmol) followed by Et3N (0.94 mL, 6.72 mmol, 1.5 equivalents (hereinafter “eq”)). The reaction mixture turned yellow and was heated at 50° C. for 8 hours (hereinafter “h”), 1 M aq Na2CO3 solution (50 mL) was added and the layers were separated. The organic layer was washed with 50 ml sat'd. aqueous (hereinafter “satd aq”) NaCl solution, dried through anhydrous MgSO4 and evaporated. The crude product was purified by flash chromatography (Hex/AcOEt=95/5) to afford 1.3 g (87%) of pure 4-chloro-6-(2,4,6-trifluoro-phenylamino)-2-methylsulfanyl-pyrimidine-5-carbaldehyde.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]([C:13]2[NH:14][C:15]([CH3:19])=[CH:16][C:17]=2[CH3:18])=O)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].[NH:20]1[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH2:22][C:21]1=[O:29].N1CCCC1.[H-].[Na+]>N12CCCN=C1CCCCC2.CN(C)C=O.O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]([C:13]2[NH:14][C:15]([CH3:19])=[CH:16][C:17]=2[CH3:18])=[C:22]2[C:23]3[C:28](=[CH:27][CH:26]=[CH:25][CH:24]=3)[NH:20][C:21]2=[O:29])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: COc1ccc(C(=O)c2[nH]c(C)cc2C)cc1OC
Reactant: O=C1Cc2ccccc2N1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCNC1
Solvent: CN(C)C=O
Product: COc1ccc(C(=C2C(=O)Nc3ccccc32)c2[nH]c(C)cc2C)cc1OC
Reaction time: 72 h
Yield: 3.3 %

Procedure:
(3,4-Dimethoxy-phenyl)-(3,5-dimethyl-1H-pyrrol-2-yl)-methanone (100 mg, 0.4 mmol), oxindole (100 mg, 0.8 mmol), pyrrolidine (0.2 mL) and 1,8-diazabicyclo[5.4.0]undec-7-ene (a few drops) in dimethylforamide (1.5 mL) was heated at 160° C. for 2 hours. Sodium hydride (18 mg) was added to the reaction mixture and the heating was continued at 160° C. for 3 days. The reaction was poured into water and extracted with ethyl acetate. The organic layer was washed with water, dried and concentrated. The residue was chromatographed eluting with ethyl acetate and hexane to give 5 mg of 3-[(3,4-dimethoxy-phenyl)-(3,5-dimethyl-1H-pyrrol-2-yl)-methylene]-1,3-dihydro-indol-2-one. MS EI 374 [M]+.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([N:8]2[C@H:13]([CH3:14])[CH2:12][CH2:11][C@H:10]([C:15]([OH:17])=O)[CH2:9]2)[CH:5]=[C:4]([C:18]2[CH:23]=[CH:22][C:21]([C:24]#[N:25])=[C:20]([F:26])[CH:19]=2)[N:3]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[CH:60]1([CH2:66][NH2:67])[CH2:65][CH2:64][CH2:63][CH2:62][CH2:61]1>CN(C=O)C.O>[NH2:1][C:2]1[N:7]=[C:6]([N:8]2[C@H:13]([CH3:14])[CH2:12][CH2:11][C@H:10]([C:15]([NH:67][CH2:66][CH:60]3[CH2:65][CH2:64][CH2:63][CH2:62][CH2:61]3)=[O:17])[CH2:9]2)[CH:5]=[C:4]([C:18]2[CH:23]=[CH:22][C:21]([C:24]#[N:25])=[C:20]([F:26])[CH:19]=2)[N:3]=1
Reactant: NCC1CCCCC1
Reactant: C[C@@H]1CC[C@H](C(=O)O)CN1c1cc(-c2ccc(C#N)c(F)c2)nc(N)n1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: C[C@@H]1CC[C@H](C(=O)NCC2CCCCC2)CN1c1cc(-c2ccc(C#N)c(F)c2)nc(N)n1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 86.8 %

Procedure:
To a solution of (3S,6R)-1-[2-amino-6-(4-cyano-3-fluorophenyl)-4-pyrimidinyl]-6-methyl-3-piperidinecarboxylic acid (170 mg, 0.478 mmol) and HATU (218 mg, 0.574 mmol) in DMF (3 mL) was added Hunig's base (0.17 mL, 0.96 mmol), and the mixture was stirred at room temperature for 5 minutes. Then cyclohexylmethylamine (0.07 ml, 0.53 mmol) was added, and the reaction mixture was stirred at room temperature for 0.5 hours. LCMS showed reaction was completed. The reaction was poured into water, and the formed solid was filtered, washed by water, and dried to afford the title compound (187 mg) as a yellow solid. LC-MS (ES) m/z=451 [M+H]+.
Reaction SMILES: C1(S(CC2C(C(OCC)=O)=C(O[CH2:23][CH2:24][NH:25]C(OC(C)(C)C)=O)C(C3C=COC=3)=CC=2)(=O)=O)C=CC=CC=1.[CH2:38]([N:40]([CH2:74][CH3:75])[CH2:41]/[CH:42]=[CH:43]\[C:44]1[CH:49]=[C:48]([F:50])[CH:47]=[CH:46][C:45]=1[S:51]([CH2:54][C:55]1[C:60]([C:61]([O:63][C:64]([CH3:67])([CH3:66])[CH3:65])=[O:62])=[C:59]([OH:68])[C:58]([C:69]2[CH:73]=[CH:72][O:71][CH:70]=2)=[CH:57][CH:56]=1)(=[O:53])=[O:52])[CH3:39].BrCC#N>>[C:24]([CH2:23][O:68][C:59]1[C:58]([C:69]2[CH:73]=[CH:72][O:71][CH:70]=2)=[CH:57][CH:56]=[C:55]([CH2:54][S:51]([C:45]2[CH:46]=[CH:47][C:48]([F:50])=[CH:49][C:44]=2/[CH:43]=[CH:42]\[CH2:41][N:40]([CH2:38][CH3:39])[CH2:74][CH3:75])(=[O:52])=[O:53])[C:60]=1[C:61]([O:63][C:64]([CH3:66])([CH3:67])[CH3:65])=[O:62])#[N:25]
Reactant: CCOC(=O)c1c(CS(=O)(=O)c2ccccc2)ccc(-c2ccoc2)c1OCCNC(=O)OC(C)(C)C
Reactant: CCN(CC)C/C=C\c1cc(F)ccc1S(=O)(=O)Cc1ccc(-c2ccoc2)c(O)c1C(=O)OC(C)(C)C
Agent: N#CCBr
Product: CCN(CC)C/C=C\c1cc(F)ccc1S(=O)(=O)Cc1ccc(-c2ccoc2)c(OCC#N)c1C(=O)OC(C)(C)C

Procedure:
Prepared by proceeding in a similar manner to Intermediate 10, starting from (Z)-tert-butyl 6-((2-(3-(diethylamino)prop-1-enyl)-4-fluorobenzenesulfonyl)methyl)-3-(furan-3-yl)-2-hydroxybenzoate (Intermediate 194) and bromoacetonitrile.