Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:18])([F:17])[C:3]1[CH:16]=[CH:15][C:6]([C:7]([NH:9][CH:10]([CH3:14])[C:11]([OH:13])=O)=O)=[CH:5][CH:4]=1.[C:19](Cl)(=[O:23])C(Cl)=O.C(N(CC)CC)C.Cl.[CH3:33][NH:34][O:35][CH3:36].Cl>CN(C=O)C.C(OCC)(=O)C>[CH3:36][O:35][N:34]([CH3:33])[C:19]([C:11]1[O:13][C:7]([C:6]2[CH:5]=[CH:4][C:3]([C:2]([F:1])([F:17])[F:18])=[CH:16][CH:15]=2)=[N:9][C:10]=1[CH3:14])=[O:23]
Reactant: CC(NC(=O)c1ccc(C(F)(F)F)cc1)C(=O)O
Reactant: O=C(Cl)C(=O)Cl
Reactant: CNOC
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CON(C)C(=O)c1oc(-c2ccc(C(F)(F)F)cc2)nc1C
Temperature: 0 °C
Reaction time: 8 h

Procedure:
To a solution of 2-(4-Trifluoromethyl-benzoylamino)-propionic acid (5.0 g, 19.14 mmol) is added oxalyl chloride (16.7 mL, 191.4 mmol) and 2 drops of DMF and the solution stirred overnight. The volatiles are removed in vacuo and toluene (20 mL) is added. The toluene is then removed in vacuo. To the resultant crude oil is dissolve in dichloromethane (100 mL), cooled to 0° C. and triethylamine (13.4 mL, 96 mmol) is added followed by N,O-dimethyl hydroxylamine hydrochloride (9.4 g, 96 mmol). After 1 hr the mixture is partioned between 1M aqueous hydrochloric acid and ethyl acetate. The organic layer is dried over anhydrous magnesium sulfate, filtered, concentrated in vacuo. The product is purified over silica eluting with 8:2 hexanes:ethyl acetate to afford 4-methyl-2-(4-trifluoromethyl-phenyl)-oxazole-5-carboxylic acid methoxy-methyl-amide as a white crystalline solid, 2.4 g, 40%. MS (M++1) 315.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:7]([O:9][CH3:10])=[O:8])[S:5][CH:6]=1.C(=O)([O-])[O-].[K+].[K+].[CH3:17][N:18]1[C:22](B2OC(C)(C)C(C)(C)O2)=[CH:21][CH:20]=[N:19]1>O1CCOCC1.O.CC(C)([P](C(C)(C)C)([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)C(C)(C)C)C>[CH3:17][N:18]1[C:22]([C:2]2[CH:3]=[C:4]([C:7]([O:9][CH3:10])=[O:8])[S:5][CH:6]=2)=[CH:21][CH:20]=[N:19]1
Reactant: Cn1nccc1B1OC(C)(C)C(C)(C)O1
Reactant: COC(=O)c1cc(Br)cs1
Agent: CC(C)(C)[P]([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)(C(C)(C)C)C(C)(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: COC(=O)c1cc(-c2ccnn2C)cs1
Reaction time: 1 h
Yield: 99.5 %

Procedure:
A solution of methyl 4-bromo-2-thiophenecarboxylate (2.5 g, 11.31 mmol), potassium carbonate (7.81 g, 56.5 mmol), 1-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (2.59 g, 12.44 mmol)[prepared according to Preparation 7] and bis(tri-t-butylphosphine)palladium(0) (0.289 g, 0.56 mmol) in 1,4-dioxane (47 ml) and water (9 ml) was stirred at 80° C. in a sealed tube for 1 h. 1-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (2.59 g, 12.44 mmol) and bis(tri-t-butylphosphine)palladium(0) (0.289 g, 0.56 mmol) were added and the reaction stirred an additional 1 h. The mixture was partitioned between H2O-DCM. The aqueous phase was washed several times with DCM and the combined organic fractions were dried over Na2SO4, concentrated and purified via column chromatography (10-40% EtOAc in hexanes) affording methyl 4-(1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxylate (2.5 g, 11.25 mmol, 99% yield) as a yellow solid: LCMS (ES) m/e 223 (M+H)+.
Reaction SMILES: CS[C:3]([C:9]1[S:10][C:11]([C:14](=[O:21])[C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[CH:12][CH:13]=1)([CH3:8])[C:4]([O:6]C)=[O:5].[Na].CS.O>CO>[C:14]([C:11]1[S:10][C:9]([CH:3]([CH3:8])[C:4]([OH:6])=[O:5])=[CH:13][CH:12]=1)(=[O:21])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: COC(=O)C(C)(SC)c1ccc(C(=O)c2ccccc2)s1
Agent: CS
Agent: [Na]
Solvent: CO
Solvent: O
Product: CC(C(=O)O)c1ccc(C(=O)c2ccccc2)s1
Yield: 67.7 %

Procedure:
Methyl α-methylthio-α-(5-benzoyl-2-thienyl)propionate (320 mg) was dissolved in 1 ml of anhydrous methanol, and 1.0 ml (2.34 M) of a methanol solution of sodium salt of methyl mercaptan was added. The mixture was heated under reflux for 1 hour. In order to hydrolyze the ester, 1 ml of water was added and the mixture was heated under reflux for an additional 2 hours. After cooling, 20 ml of water was added, and the mixture was washed twice with 15 ml of methylene chloride. The aqueous layer was acidified to a pH of 1 with conc. hydrochloric acid, and extracted three times with 15 ml of methylene chloride. The organic layer was washed with 10 ml of water, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure to afford 176 mg of α-(5-benzoyl-2-thienyl)propionic acid in a yield of 68%.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[S:10][C:9]([C:11]2[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:13][CH:12]=2)=[N:8][C:7]=1[CH2:21]Br)=[O:5])[CH3:2].C(=O)([O-])[O-].[K+].[K+].[NH:29]1[CH2:34][CH2:33][O:32][CH2:31][CH2:30]1.O>C(#N)C>[CH2:1]([O:3][C:4]([C:6]1[S:10][C:9]([C:11]2[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:13][CH:12]=2)=[N:8][C:7]=1[CH2:21][N:29]1[CH2:34][CH2:33][O:32][CH2:31][CH2:30]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1sc(-c2ccc(C(F)(F)F)cc2)nc1CBr
Reactant: C1COCCN1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC#N
Product: CCOC(=O)c1sc(-c2ccc(C(F)(F)F)cc2)nc1CN1CCOCC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 69.9 %

Procedure:
To a solution of 500 mg of 4-bromomethyl-2-(4-trifluoromethyl-phenyl)-thiazole-5-carboxylic acid ethyl ester in 5 mL of acetonitrile was added 190 mg of potassium carbonate and 110.5 mg of morpholine. The resulting mixture was stirred at room temperature overnight. Water was added and the mixture was extracted with dichloromethane. The organic extracts were dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by column chromatography on silica gel (gradient of dichloromethane/methanol from 100/0 to 50/50) followed by washing of the collected solid with diisopropyl ether to give 355 mg of 4-morpholin-4-ylmethyl-2-(4-trifluoromethyl-phenyl)-thiazole-5-carboxylic acid ethyl ester.
Reaction SMILES: O[CH2:2][C:3]1[CH:12]=[N:11][C:10]2[N:9]3[CH2:13][CH2:14][CH2:15][C@H:8]3[C:7](=[O:16])[NH:6][C:5]=2[CH:4]=1.[F:17][C:18]1[CH:23]=[C:22]([F:24])[CH:21]=[CH:20][C:19]=1[N:25]1[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]1.[I-].C(C[P+](C)(C)C)#N.C(N(CC)C(C)C)(C)C>C(#N)CC.CS(C)=O>[F:17][C:18]1[CH:23]=[C:22]([F:24])[CH:21]=[CH:20][C:19]=1[N:25]1[CH2:26][CH2:27][N:28]([CH2:2][C:3]2[CH:12]=[N:11][C:10]3[N:9]4[CH2:13][CH2:14][CH2:15][C@H:8]4[C:7](=[O:16])[NH:6][C:5]=3[CH:4]=2)[CH2:29][CH2:30]1
Reactant: Fc1ccc(N2CCNCC2)c(F)c1
Reactant: O=C1Nc2cc(CO)cnc2N2CCC[C@@H]12
Agent: C[P+](C)(C)CC#N
Agent: [I-]
Solvent: CS(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CCC#N
Product: O=C1Nc2cc(CN3CCN(c4ccc(F)cc4F)CC3)cnc2N2CCC[C@@H]12
Temperature: 90 °C
Yield: 23.1 %

Procedure:
(S)-3-(hydroxymethyl)-6a,7,8,9-tetrahydropyrido[3,2-e]pyrrolo[1,2-a]pyrazin-6(5H)-one (150 mg, 0.684 mmol), 1-(2,4-difluorophenyl)piperazine (136 mg, 0.684 mmol), (cyanomethyl)trimethylphosphonium iodide (249 mg, 1.026 mmol) and N,N-diisopropylethylamine (0.597 ml, 3.42 mmol) were suspended in propionitrile (2 ml) and heated in a closed vial at 90° C. for 2 h. The reaction mixture became a clear dark brown solution. It was cooled to room temperature, diluted with DMSO (2 mL) and purified using preparative HPLC (25-95% acetonitrile in water, NH4HCO3 buffered). The fractions containing product were concentrated in vacuo and crystallized from water (3 mL). The precipitate was filtered and dried in vacuum to afford (S)-3-((4-(2,4-difluorophenyl)piperazin-1-yl)methyl)-6a,7,8,9-tetrahydropyrido[3,2-e]pyrrolo[1,2-a]pyrazin-6(5H)-one (63.2 mg, 0.158 mmol, 23.13% yield) as a light brown solid. 1H NMR (400 MHz, DMSO-d6) δ (ppm): 1.84-2.03 (m, 3 H) 2.09-2.26 (m, 1 H) 2.41-2.49 (m, 4 H) 2.88-2.99 (m, 4 H) 3.34-3.43 (m, 3 H) 3.54-3.63 (m, 1 H) 3.94-4.02 (m, 1 H) 6.93-7.09 (m, 3 H) 7.18 (ddd, J=12.44, 9.16, 2.91 Hz, 1 H) 7.61 (d, J=1.77 Hz, 1 H) 10.44 (s, 1 H); [M+H] calc'd for C21H23F2N5O, 400; found, 400.
Reaction SMILES: [NH2:1][CH2:2][C:3]([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[CH2:4][CH2:5][CH2:6][N:7]1[CH2:12][CH2:11][CH:10]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH2:9][CH2:8]1.C(N(CC)CC)C.[CH3:38][S:39]([Cl:42])(=[O:41])=[O:40]>C(Cl)Cl>[ClH:42].[C:25]1([C:3]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)([CH2:2][NH:1][S:39]([CH3:38])(=[O:41])=[O:40])[CH2:4][CH2:5][CH2:6][N:7]2[CH2:12][CH2:11][CH:10]([C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=3)[CH2:9][CH2:8]2)[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: NCC(CCCN1CCC(c2ccccc2)CC1)(c1ccccc1)c1ccccc1
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)NCC(CCCN1CCC(c2ccccc2)CC1)(c1ccccc1)c1ccccc1
Product: Cl

Procedure:
To a solution of 5-amino-4,4-diphenyl-1-(4-phenylpiperidino)pentane (0.4 g) and triethylamine (0.42 ml) in methylene chloride (15 ml) was added methanesulfonyl chloride (0.1 ml) dropwise under ice-cooling and stirring. After completion of dropwise addition, the mixture was returned to room temperature and stirred for another 3 hours. This reaction mixture was washed with water, dried over anhydrous sodium sulfate, and concentrated to dryness. The group was purified by silica gel column chromatography to provide the hydrochloride of the title compound (0.25 g) as colorless powder.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@@:8]2([CH3:34])[C@:12]([C:14]3[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=3)([CH3:13])[NH:11][C:10]([C:21]3[CH:26]=[CH:25][C:24]([C:27]([OH:30])([CH3:29])[CH3:28])=[CH:23][C:22]=3[O:31][CH2:32][CH3:33])=[N:9]2)=[CH:4][CH:3]=1.[C:35](Cl)([Cl:37])=[O:36]>C(N(CC)CC)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([CH3:34])[C:12]([C:14]3[CH:15]=[CH:16][C:17]([Cl:20])=[CH:18][CH:19]=3)([CH3:13])[N:11]([C:35]([Cl:37])=[O:36])[C:10]([C:21]3[CH:26]=[CH:25][C:24]([C:27]([OH:30])([CH3:28])[CH3:29])=[CH:23][C:22]=3[O:31][CH2:32][CH3:33])=[N:9]2)=[CH:4][CH:3]=1
Reactant: CCOc1cc(C(C)(C)O)ccc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1
Reactant: O=C(Cl)Cl
Solvent: CCN(CC)CC
Product: CCOc1cc(C(C)(C)O)ccc1C1=NC(C)(c2ccc(Cl)cc2)C(C)(c2ccc(Cl)cc2)N1C(=O)Cl

Procedure:
In a manner analogous to the method described in example 3, rac-2-{4-[(4S*,5R*)-4,5-bis-(4-chloro-phenyl)-4,5-dimethyl-4,5-dihydro-1H-imidazol-2-yl]-3-ethoxy-phenyl}-propan-2-ol was reacted with phosgene in the presence of triethylamine to give the title compound.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:14])[C:4]([CH3:13])([CH3:12])[CH2:5][NH:6][CH:7]1[CH2:11][CH2:10][CH2:9][CH2:8]1.[Cl:15][C:16]1[N:21]=[C:20](Cl)[C:19]([N+:23]([O-:25])=[O:24])=[CH:18][N:17]=1.CCOCC.C(=O)(O)[O-].[K+]>O>[CH3:1][O:2][C:3](=[O:14])[C:4]([CH3:12])([CH3:13])[CH2:5][N:6]([C:18]1[C:19]([N+:23]([O-:25])=[O:24])=[CH:20][N:21]=[C:16]([Cl:15])[N:17]=1)[CH:7]1[CH2:8][CH2:9][CH2:10][CH2:11]1
Reactant: COC(=O)C(C)(C)CNC1CCCC1
Reactant: O=[N+]([O-])c1cnc(Cl)nc1Cl
Agent: O=C([O-])O
Agent: [K+]
Solvent: O
Solvent: CCOCC
Product: COC(=O)C(C)(C)CN(c1nc(Cl)ncc1[N+](=O)[O-])C1CCCC1
Temperature: 25 °C
Reaction time: 14 h
Yield: 96.4 %

Procedure:
To a mixture of 5.02 g (0.025 mole) of 3-cyclopentylamino-2,2-dimethyl-propanoic acid methyl ester, 5.30 g (0.0276 mole) of 2,4-dichloro-5-nitro-pyrimidine and 100 mL of ether was added 20 mL of water and 5.00 g (0.050 mole) of potassium bicarbonate. The mixture was stirred at room temperature for 14 hours. The resulting two-layer mixture was separated and the aqueous layer was extracted twice with 20 mL of ether. The combined ether extracts were washed successively with 20 mL of aqueous sodium carbonate, twice with 20 mL of brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give 8.60 g of 3-[(2-chloro-5-nitro-pyrimidin-4-yl)-cyclopentyl-amino]-2,2-dimethyl-propanoic acid methyl ester (IV-38) as a yellow solid.
Reaction SMILES: [CH3:1][N:2]1[C:15]2[C:10]3=[C:11]([C:16](=[O:26])[C:17]([CH2:19][C:20]4[CH:21]=N[CH:23]=[CH:24][CH:25]=4)=[CH:18][N:9]3[C:8]3[CH:7]=[CH:6][CH:5]=[CH:4][C:3]1=3)[CH:12]=[CH:13][CH:14]=2.[CH:27](=O)C1C=CC=CC=1>>[CH2:19]([C:17]1[C:16](=[O:26])[C:11]2[CH:12]=[CH:13][CH:14]=[C:15]3[C:10]=2[N:9]([CH:18]=1)[C:8]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:2]3[CH3:1])[C:20]1[CH:21]=[CH:27][CH:23]=[CH:24][CH:25]=1
Reactant: O=Cc1ccccc1
Reactant: CN1c2ccccc2-n2cc(Cc3cccnc3)c(=O)c3cccc1c32
Product: CN1c2ccccc2-n2cc(Cc3ccccc3)c(=O)c3cccc1c32
Yield: 30 %

Procedure:
According to Example 1<step 4>, the compound (200 mg) produced in Example 15<step 3> was reacted with benzaldehyde (0.13 mL) to obtain the title compound (102 mg; 30%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9]2[CH:14]=[CH:13][C:12]([CH2:15][CH2:16][N:17]3[C:21](=[O:22])[CH2:20][O:19][C:18]3=[O:23])=[CH:11][CH:10]=2)=[CH:4][CH:3]=1.[CH3:24][NH2:25]>O1CCCC1.CO>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9]2[CH:14]=[CH:13][C:12]([CH2:15][CH2:16][NH:17][C:18](=[O:23])[O:19][CH2:20][C:21]([NH:25][CH3:24])=[O:22])=[CH:11][CH:10]=2)=[CH:4][CH:3]=1
Reactant: CN
Reactant: O=C1COC(=O)N1CCc1ccc(Oc2ccc(Cl)cc2)cc1
Solvent: C1CCOC1
Solvent: CO
Product: CNC(=O)COC(=O)NCCc1ccc(Oc2ccc(Cl)cc2)cc1
Yield: 79.3 %

Procedure:
0.46 g (1.39 mmol) of 3-(2-(4-[(4-chlorophenyl)oxy]phenyl)ethyl)-1,3-oxazolidine-2,4-dione, prepared in step 14.2., is redissolved in a mixture of 3 ml of tetrahydrofuran and 6 ml of methanol. 3 ml of a 2M solution of methylamine (6 mmol) in tetrahydrofuran are added. The mixture is left to react at ambient temperature overnight and then 2 g of silica are added and the mixture is evaporated to dryness. The residue is purified by chromatography on silica gel, eluting with a 98/2 then 96/4 and 94/6 mixture of dichloromethane and methanol. The product is recrystallized from a mixture of ethyl acetate and diisopropyl ether, to give 0.40 g of product in the form of a white powder.
Reaction SMILES: [C:1]1([C:7]2[O:8][C:9]([C:15]([F:18])([F:17])[F:16])=[C:10]([C:12]([OH:14])=O)[N:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:19]([N:21]([CH2:29][CH2:30][O:31][CH3:32])[C:22]1[CH:27]=[CH:26][C:25]([NH2:28])=[CH:24][N:23]=1)[CH3:20]>>[CH2:19]([N:21]([CH2:29][CH2:30][O:31][CH3:32])[C:22]1[N:23]=[CH:24][C:25]([NH:28][C:12]([C:10]2[N:11]=[C:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[O:8][C:9]=2[C:15]([F:18])([F:17])[F:16])=[O:14])=[CH:26][CH:27]=1)[CH3:20]
Reactant: CCN(CCOC)c1ccc(N)cn1
Reactant: O=C(O)c1nc(-c2ccccc2)oc1C(F)(F)F
Product: CCN(CCOC)c1ccc(NC(=O)c2nc(-c3ccccc3)oc2C(F)(F)F)cn1

Procedure:
With a procedure similar to example 16 above, 2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid {6-[ethyl-(2-methoxy-ethyl)-amino]-pyridin-3-yl}-amide was prepared from 2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid and N2-ethyl-N2-(2-methoxy-ethyl)-pyridine-2,5-diamine. LCMS calcd for C21H21F3N4O3 (m/e) 434, obsd 435 (M+H).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][C:3]=1[OH:9].C(=O)([O-])[O-].[K+].[K+].[CH2:16](I)[CH3:17]>CC(C)=O.C(OCC)C.O>[Br:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][C:3]=1[O:9][CH2:16][CH3:17]
Reactant: Cc1ccc(O)c(Br)c1
Reactant: CCI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOCC
Solvent: O
Solvent: CC(C)=O
Product: CCOc1ccc(C)cc1Br
Yield: 81.7 %

Procedure:
To a solution of 2-bromo-4-methyl-phenol (1 g, 5.346 mmol) in acetone (10 mL) were added potassium carbonate (740 mg, 5.346 mmol) and ethyl iodide (868 μL, 10.69 mmol). The reaction mixture was heated at gentle reflux for 12 h. The solvent was removed to give a white paste. It was then taken in diethyl ether (5 mL) and water (2 mL). The product was extracted with diethyl ether (2×20 mL). The organic layers were washed with brine (1×5 mL) and dried over anhydrous sodium sulfate. The solid was then filtered off, and the filtrate was concentrated in vacuo. Purification of the crude residue by flash chromatography (Biotage system, KP-Sil™ 32-63 μm, 60 Å silica gel) eluting with 5% ethyl acetate in hexanes yielded 2-bromo-1-ethoxy-4-methyl-benzene (940 mg, 82%).
Reaction SMILES: N[C:2]1[N:7]=[C:6](N[C@H](C2N(C3C=CC=CC=3)C(=O)C3C(C=2)=CC=CC=3C2C=CN=C(OC)C=2)C)[C:5]([C:36]([OH:38])=O)=[CH:4][N:3]=1.[CH2:39]([N:41]=[C:42]=NCCCN(C)C)C.OC1C2N=NNC=2C=CC=1.CNC.C(N(CC)C(C)C)(C)C>CN(C)C=O>[CH3:39][N:41]([CH3:42])[C:36]([C:5]1[CH:6]=[N:7][CH:2]=[N:3][CH:4]=1)=[O:38]
Reactant: COc1cc(-c2cccc3cc([C@H](C)Nc4nc(N)ncc4C(=O)O)n(-c4ccccc4)c(=O)c23)ccn1
Reactant: CCN=C=NCCCN(C)C
Agent: CNC
Agent: Oc1cccc2[nH]nnc12
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CN(C)C(=O)c1cncnc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of (S)-2-amino-4-((1-(8-(2-methoxypyridin-4-yl)-1-oxo-2-phenyl-1,2-dihydroisoquinolin-3-yl)ethyl)amino)-pyrimidine-5-carboxylic acid (44 mg, 0.087 mmol) in anhydrous N,N-dimethylmethanamide (3 mL), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (25 mg, 0.13 mmol) and hydroxybenzotriazole (18 mg, 0.13 mmol) were added and the resulting mixture was stirred at RT for 30 min. To this mixture, dimethylamine (2M in THF, 0.065 mL, 0.13 mmol) and N,N-diisopropylethylamine (0.040 mL, 0.19 mmol) were added and the reaction mixture was stirred at RT for 3 h. The mixture was partitioned between water and ethyl acetate. The organic layer was washed with brine, dried over Na2SO4 and filtered. The filtrate was concentrated in vacuo to afford the product 112, (S)-2-amino-441-(8-(2-methoxypyridin-4-yl)-1-oxo-2-phenyl-1,2-dihydroisoquinolin-3-yl)ethyl)amino)-N,N-dimethylpyrimidine-5-carboxamide. ESI-MS m/z: 533.8 [M−H]+.
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[C:3]1[CH:4]=[CH:5][C:6]([NH:9][NH2:10])=[N:7][CH:8]=1.[C:13]([C:15](=[C:21](OCC)[CH3:22])[C:16]([O:18][CH2:19][CH3:20])=[O:17])#[N:14].C(O)C.Cl>O>[NH2:14][C:13]1[N:9]([C:6]2[CH:5]=[CH:4][C:3]([C:2]([F:1])([F:11])[F:12])=[CH:8][N:7]=2)[N:10]=[C:21]([CH3:22])[C:15]=1[C:16]([O:18][CH2:19][CH3:20])=[O:17]
Reactant: CCOC(=O)C(C#N)=C(C)OCC
Reactant: NNc1ccc(C(F)(F)F)cn1
Agent: Cl
Solvent: CCO
Solvent: O
Product: CCOC(=O)c1c(C)nn(-c2ccc(C(F)(F)F)cn2)c1N
Yield: 54.3 %

Procedure:
5-(Trifluoromethyl)pyridin-2-ylhydrazine (10.0 g) described in Reference Example 8 and ethyl 2-cyano-3-ethoxy-3-methylacrylate (10.3 g) were added to a mixed solvent of ethanol (40 ml) and 1N hydrochloric acid aqueous solution (40 ml), and the mixture was stirred at reflux temperature for three hours. Water was added to the reaction solution to give ethyl 5-amino-3-methyl-1-[5-(trifluoromethyl)pyridin-2-yl]-1H-pyrazole-4-carboxylate (9.6 g). Next, the compound was added to tetrahydrofuran (50 ml), isoamyl nitrite (20 g) was added and the mixture was stirred at reflux temperature for five hours. The reaction solution was concentrated, a mixed solvent of ethanol (40 ml) and water (40 ml) and sodium hydroxide (5 g) were added and the mixture was stirred at reflux temperature for two hours. Ethanol was evaporated, diluted hydrochloric acid was added and the precipitated solid was recrystallized from aqueous methanol to give the titled compound.
Reaction SMILES: C(O[C:4](=O)[CH2:5][C:6]([CH:8]=[C:9]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH:12]=[CH:11][CH2:10]1)=O)C.[CH2:20]([O:22][C:23](=[O:28])[CH2:24][C:25](=[NH:27])[NH2:26])[CH3:21]>C(O)C>[CH2:20]([O:22][C:23]([C:24]1[CH:8]([C:9]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[CH:12]=[CH:11][CH:10]=2)[C:6]([C:23]([O:22][CH2:20][CH3:21])=[O:28])=[C:5]([CH3:4])[NH:27][C:25]=1[NH2:26])=[O:28])[CH3:21]
Reactant: CCOC(=O)CC(=O)C=C1CC=Cc2ccccc21
Reactant: CCOC(=O)CC(=N)N
Solvent: CCO
Product: CCOC(=O)C1=C(C)NC(N)=C(C(=O)OCC)C1c1cccc2ccccc12
Yield: 62 %

Procedure:
Boiling a solution of 13.4 g of (1-naphthylidene)-acetoacetic acid ethyl ester and 6.5 g of amidinoacetic acid ethyl ester in 100 ml of ethanol for 8 hours yields 2-amino-6-methyl-4-(1-naphthyl)-1,4-dihydropyridine-3,5-dicarboxylic acid diethyl ester of melting point 174°C (ethanol).
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([Cl:12])=[CH:9][CH:10]=2)[N:5]=[CH:4][CH:3]=1.[OH:13]O>C[Re](=O)(=O)=O.ClCCl>[Cl:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([Cl:12])=[CH:9][CH:10]=2)[N+:5]([O-:13])=[CH:4][CH:3]=1
Reactant: OO
Reactant: Clc1ccc2c(Cl)ccnc2c1
Agent: C[Re](=O)(=O)=O
Solvent: ClCCl
Product: [O-][n+]1ccc(Cl)c2ccc(Cl)cc21

Procedure:
A mixture of 4,7-dichloroquinoline (9.9 g, 50 mmol) and methyltrioxorhenium (80 mg, 0.32 mmol) was stirred in the mixture of hydrogenperoxide (40%, 20 mL) and dichloromethane at room temperature for 24 hours. Pale yellow solid was collected by filtration and dried under vacuum. MS (ESI(+)Q1MS m/z 215 (M+H)+.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([O:9][CH2:10][O:11][CH3:12])=[CH:5][C:4]=1[CH3:13])#[CH:2].[Cl:14][C:15]1[C:16]([C:22]#[N:23])=[N:17][CH:18]=[C:19](Cl)[CH:20]=1.C(N(CC)CC)C>CN(C=O)C.[Cu]I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[Cl:14][C:15]1[C:16]([C:22]#[N:23])=[N:17][CH:18]=[C:19]([C:2]#[C:1][C:3]2[CH:8]=[CH:7][C:6]([O:9][CH2:10][O:11][CH3:12])=[CH:5][C:4]=2[CH3:13])[CH:20]=1
Reactant: C#Cc1ccc(OCOC)cc1C
Reactant: N#Cc1ncc(Cl)cc1Cl
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COCOc1ccc(C#Cc2cnc(C#N)c(Cl)c2)c(C)c1
Temperature: 60 °C
Reaction time: 8 h

Procedure:
A solution of 1-ethynyl-4-(methoxymethoxy)-2-methylbenzene (6-8) (1.0 equiv.), 3,5-dichloropicolinonitrile (6-9) (0.90 equiv.), CuI (0.10 equiv.), and Pd(PPh3)2Cl2 (0.10 equiv.), and triethylamine (5.0 equiv.) in DMF (0.25 M) was degassed and flushed with nitrogen. The reaction mixture was then heated to 60° C. and stirred overnight. After cooling to room temperature, water was added. The mixture was extracted with EA (2×). The combined organic layers were washed with 10% aq NH4OH (2×), brine, and concentrated. The crude material was filtered through a pad of silica (wetted with hexane). The silica was eluted with 10% EA in Hex. The fractions were combined and concentrated. The resulting solids were washed in hot ether and filtered to give a yellow solid, which was used in the next step without further purification. The filtrate was concentrated and purified by Combiflash using 0-10% EtOAc in Hexanes to give 3-chloro-5-((4-(methoxymethoxy)-2-methylphenyl)ethynyl)picolinonitrile (6-10) as a yellow solid.
Reaction SMILES: [C:1]([O:7][CH2:8][C@H:9]([CH3:38])[CH2:10][C@H:11]([O:36][CH3:37])[C@@H:12]([O:28][Si:29]([C:32]([CH3:35])([CH3:34])[CH3:33])([CH3:31])[CH3:30])[C@@H:13]([O:26][CH3:27])[CH2:14][C@@H:15]([CH3:25])[CH2:16][O:17][Si](C(C)(C)C)(C)C)(=[O:6])[C:2]([CH3:5])([CH3:4])[CH3:3].O1CCCC1.FC(F)(F)C(O)=O>O>[CH3:25][C@H:15]([CH2:14][C@H:13]([O:26][CH3:27])[C@H:12]([O:28][Si:29]([C:32]([CH3:35])([CH3:34])[CH3:33])([CH3:30])[CH3:31])[C@@H:11]([O:36][CH3:37])[CH2:10][C@@H:9]([CH3:38])[CH2:8][O:7][C:1](=[O:6])[C:2]([CH3:5])([CH3:4])[CH3:3])[CH2:16][OH:17]
Reactant: CO[C@@H](C[C@@H](C)COC(=O)C(C)(C)C)[C@@H](O[Si](C)(C)C(C)(C)C)[C@H](C[C@@H](C)CO[Si](C)(C)C(C)(C)C)OC
Solvent: C1CCOC1
Solvent: O
Solvent: O=C(O)C(F)(F)F
Product: CO[C@@H](C[C@@H](C)CO)[C@H](O[Si](C)(C)C(C)(C)C)[C@H](C[C@@H](C)COC(=O)C(C)(C)C)OC
Temperature: 25 °C
Reaction time: 5 h
Yield: 127.4 %

Procedure:
Bis-t-butyldimethylsilyloxy ether 25 (3.67 g, 6.36 mmol) was dissolved in asolution composed of 54 ml of tetrahydrofuran, 18 ml of water, and 0.9 ml of trifluoroacetic acid. The mixture was stirred at 25° C. for 5 hr. The mixture was partitioned between 200 ml of methylene chloride and 100 ml of saturated sodium bicarbonate solution. The aqueous phase was extracted with 2×200 ml of methylene chloride. The organic layers were combined, dried over magnesium sulfate, and concentrated in vacuo to yield 3.75 g of an oil. The oil was purified by chromatography on 190 g ofsilica gel eluting with hexanes:ethyl acetate (4:1) to give 2.675 g of primary alcohol 26. This material was homogeneous by both 1H and 13C NMR.