Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[CH:7]=[N:6][C:5]([C:8]2[O:9][CH:10]=[CH:11][CH:12]=2)=[CH:4][N:3]=1.[N:13]1[CH:18]=[CH:17][C:16](B(O)O)=[CH:15][CH:14]=1.C(COC)OC.[F-].[Cs+]>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.CO>[O:9]1[CH:10]=[CH:11][CH:12]=[C:8]1[C:5]1[CH:4]=[N:3][C:2]([C:16]2[CH:17]=[CH:18][N:13]=[CH:14][CH:15]=2)=[CH:7][N:6]=1
Reactant: OB(O)c1ccncc1
Reactant: Clc1cnc(-c2ccco2)cn1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cs+]
Agent: [F-]
Solvent: CO
Solvent: COCCOC
Product: c1coc(-c2cnc(-c3ccncc3)cn2)c1
Yield: 57.9 %

Procedure:
At room temperature, 2-chloro-5-(furan-2-yl)pyrazine (N. Sato, J. Heterocyclic Chem., 19, 407(1982)) (1.00 g) and (pyridin-4-yl)boronic acid (1.09 g) were suspended in a mixed solvent of dimethoxyethane (50 ml) and methanol (50 ml), followed by the successive addition of tetrakis(triphenylphosphine)palladium (O) (640 mg) and cesium fluoride (5.55 g). The resulting mixture was heated under reflux for 16 hours. After cooling, the reaction mixture was concentrated. Dichloromethane and water were added to the concentrate to separate the organic layer. The organic layer was dried over anhydrous sodium sulfate, treated with activated carbon and filtered through Celite. After the filtrate was concentrated to about 5 ml, petroleum ether (50 ml) was added to the concentrate. Yellow crystalline powder thus precipitated was collected by filtration and dried, whereby the title compound (716 mg, 58%) was obtained.
Reaction SMILES: N#N.[OH:3][CH:4]([C:6]1[O:7][C:8]([CH2:11][N:12]2[N:16]=[C:15]([NH:17][C:18]([C:20]3[N:21]=[C:22]([CH3:36])[O:23][C:24]=3[C:25]3[CH:30]=[CH:29][CH:28]=[C:27]([O:31][C:32]([F:35])([F:34])[F:33])[CH:26]=3)=[O:19])[CH:14]=[N:13]2)=[CH:9][N:10]=1)[CH3:5]>C(C#N)(C)=O.O=[Mn]=O>[C:4]([C:6]1[O:7][C:8]([CH2:11][N:12]2[N:16]=[C:15]([NH:17][C:18]([C:20]3[N:21]=[C:22]([CH3:36])[O:23][C:24]=3[C:25]3[CH:30]=[CH:29][CH:28]=[C:27]([O:31][C:32]([F:34])([F:35])[F:33])[CH:26]=3)=[O:19])[CH:14]=[N:13]2)=[CH:9][N:10]=1)(=[O:3])[CH3:5]
Reactant: Cc1nc(C(=O)Nc2cnn(Cc3cnc(C(C)O)o3)n2)c(-c2cccc(OC(F)(F)F)c2)o1
Agent: O=[Mn]=O
Agent: CC(=O)C#N
Agent: N#N
Product: CC(=O)c1ncc(Cn2ncc(NC(=O)c3nc(C)oc3-c3cccc(OC(F)(F)F)c3)n2)o1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
In a flame dried round-bottomed flask equipped with a magnetic stir bar and under inert atmosphere (N2), a solution of 2-methyl-5-(3-trifluoromethoxy-phenyl)-oxazole-4-carboxylic acid {2-[2-(1-hydroxy-ethyl)-oxazol-5-ylmethyl}-2H-[1,2,3]triazol-4-yl]-amide (54 mg, 0.11 mmol) in AcCN (1.5 mL) was treated at rt with MnO2 (85 mg, 0.85 mmol) and the reaction mixture was stirred at rt overnight before being filtered through Celite. The solvent was removed under reduced pressure and the residue was dissolved in EA (10 mL), washed with water (10 mL), and brine. The org. layer was dried over MgSO4, filtered, and the solvents were removed under reduced pressure to give the title compound as a white solid. LC-MS-conditions 02: tR=1.09 min; [M+H]+=476.95.
Reaction SMILES: [F:1][C:2]1[C:3]([NH:10][CH2:11][CH:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)=[N:4][C:5]([O:8]C)=[CH:6][CH:7]=1.[I-].[Na+].[Si](Cl)(C)(C)C>C(#N)C.CCOC(C)=O.O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[N:4][C:3]=1[NH:10][CH2:11][CH:12]1[CH2:17][CH2:16][O:15][CH2:14][CH2:13]1
Reactant: COc1ccc(F)c(NCC2CCOCC2)n1
Agent: C[Si](C)(C)Cl
Agent: [I-]
Agent: [Na+]
Solvent: O
Solvent: CC#N
Solvent: CCOC(C)=O
Product: Oc1ccc(F)c(NCC2CCOCC2)n1
Temperature: 95 °C
Reaction time: 20 h

Procedure:
To a solution of 3-fluoro-6-methoxy-N-((tetrahydro-2H-pyran-4-yl)methyl)pyridin-2-amine (4.6 g, 19.14 mmol) in acetonitrile (50 mL) was added sodium iodide (20.09 g, 134 mmol) and TMS-chloride (17.13 mL, 134 mmol). The resulting mixture was stirred at about 95° C. for 20 hr. The reaction mixture was cooled to ambient temperature and then diluted with EtOAc (80 mL) and water (40 mL). The diluted mixture was stirred vigorously for about 30 min. The organic layer was separated and washed with 0.1N aqueous HCl solution. The combined aqueous layers were carefully neutralized (pH ˜7) with solid NaHCO3 solution and extracted with EtOAc (1×100 mL) and DCM (2×50 mL). The combined organic layers were washed with saturated aqueous NaHCO3 solution and brine, dried over Na2SO4, filtered off and concentrated in vacuo. The resulting residue was purified by column chromatography [SiO2, 80 g, EtOAc/heptane=10/90 for 2 min, EtOAc/heptane=10/90 to 100/0 over 23 min, then EtOAc/heptane=100/0] providing 5-fluoro-6-((tetrahydro-2H-pyran-4-yl)methyl)aminopyridin-2-ol as a highly viscous oil which turned to purple upon standing at room temperature. Yield: 780 mg. LCMS (m/z): 227.1 [M+H]+; Retention time=0.42 min.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:6]=[C:7]([N:11]2[CH2:19][CH2:18][CH2:17][CH:13]([C:14]([OH:16])=O)[CH2:12]2)[CH:8]=[CH:9][CH:10]=1)=[O:4].Cl.[Cl:21][C:22]1[CH:27]=[CH:26][C:25]([C:28]2[CH:33]=[CH:32][C:31]([CH2:34][NH2:35])=[CH:30][CH:29]=2)=[CH:24][CH:23]=1>>[Cl:21][C:22]1[CH:23]=[CH:24][C:25]([C:28]2[CH:33]=[CH:32][C:31]([CH2:34][NH:35][C:14]([CH:13]3[CH2:17][CH2:18][CH2:19][N:11]([C:7]4[CH:6]=[C:5]([CH:10]=[CH:9][CH:8]=4)[C:3]([O:2][CH3:1])=[O:4])[CH2:12]3)=[O:16])=[CH:30][CH:29]=2)=[CH:26][CH:27]=1
Reactant: NCc1ccc(-c2ccc(Cl)cc2)cc1
Reactant: COC(=O)c1cccc(N2CCCC(C(=O)O)C2)c1
Agent: Cl
Product: COC(=O)c1cccc(N2CCCC(C(=O)NCc3ccc(-c4ccc(Cl)cc4)cc3)C2)c1
Yield: 69.3 %

Procedure:
Using 1-[3-(methoxycarbonyl)phenyl]nipecotic acid (108 mg, 0.410 mmol) and (4′-chlorobiphenyl-4-yl)methylamine hydrochloride (95.0 mg, 0.374 mmol), the same procedure was followed as in Step 3a of Example 3 to give 120 mg (69%) of the desired compound as colorless crystals.
Reaction SMILES: [CH3:1][C:2]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[CH:19]=[CH:18][C:17]([N:20]3[CH2:24][C@H:23]([CH2:25][NH2:26])[O:22][C:21]3=[O:27])=[CH:16][C:15]=2[F:28])[CH2:10][CH2:9]1)=[O:7])([CH3:4])[CH3:3].C(N(CC)CC)C.[Cl:36][CH:37]([Cl:41])[C:38](Cl)=[O:39]>C(Cl)Cl>[CH3:4][C:2]([O:5][C:6]([N:8]1[CH2:9][CH2:10][CH:11]([C:14]2[CH:19]=[CH:18][C:17]([N:20]3[CH2:24][C@H:23]([CH2:25][NH:26][C:38](=[O:39])[CH:37]([Cl:41])[Cl:36])[O:22][C:21]3=[O:27])=[CH:16][C:15]=2[F:28])[CH2:12][CH2:13]1)=[O:7])([CH3:1])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCC(c2ccc(N3C[C@H](CN)OC3=O)cc2F)CC1
Reactant: O=C(Cl)C(Cl)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CCC(c2ccc(N3C[C@H](CNC(=O)C(Cl)Cl)OC3=O)cc2F)CC1
Temperature: 0 °C
Reaction time: 3 h

Procedure:
A solution of (S)-(-)-4-[4-[5-(aminomethyl)-2-oxo-3-oxazolidinyl]-2-fluorophenyl]-1-piperidinecarboxylic acid 1,1-dimethylethyl ester (EXAMPLE 20, Step 8, 400 mg) in dry methylene chloride (4.1 mL) at 0° C. under N2 is treated with triethylamine (0.21 mL) and dichloroacetyl chloride (0.11 mL), and the resulting mixture is stirred at 0° C. for three hours, diluted with methylene chloride (10 mL), washed with water (10 mL), saturated aqueous sodium bicarbonate (10 mL) and saline (10 mL), dried over anhydrous sodium sulfate and concentrated under reduced pressure to give the crude product which is then chromatographed on silica gel (70-230 mesh, 50 g), eluting with methanol/chloroform (5/95). Pooling and concentration of those fractions with an Rf =0.53 by TLC (methanol/chloroform, 10/90), trituration with methylene chloride/diethyl ether and filtration gives the title compound, mp 168-170° C.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[CH:2]1.[CH:6]1([C:11](O)=[O:12])[CH2:10][CH2:9][CH2:8][CH2:7]1>O>[S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:11]([CH:6]1[CH2:10][CH2:9][CH2:8][CH2:7]1)=[O:12]
Reactant: c1ccsc1
Reactant: O=C(O)C1CCCC1
Solvent: O
Product: O=C(c1cccs1)C1CCCC1
Yield: 99 %

Procedure:
A solution of 8.8 g (105 mmol, 1.2 equivs.) of thiophene and 10.0 g (88 mmol) of cyclopentanecarboxylic acid in 20 g of polyphosphoric acid was stirred at 75° C. for 2 hours. The reaction mixture was diluted with water and extracted with o-dichlorobenzene to afford 99% pure product (GC, area % analysis). The mixture was azeotropically dried by stripping a small portion of the solvent. The crude cyclopentyl 2-thienyl ketone solution was then used without purification, for the bromination step of Example 2.
Reaction SMILES: [N:1]([CH2:4][C@H:5]([NH:11]C(OC(C)(C)C)=O)[C:6]([O:8][CH2:9][CH3:10])=[O:7])=[N+:2]=[N-:3].[ClH:19]>C(OCC)(=O)C>[ClH:19].[NH2:11][C@@H:5]([CH2:4][N:1]=[N+:2]=[N-:3])[C:6]([O:8][CH2:9][CH3:10])=[O:7]
Reactant: CCOC(=O)[C@H](CN=[N+]=[N-])NC(=O)OC(C)(C)C
Agent: Cl
Solvent: CCOC(C)=O
Product: CCOC(=O)[C@@H](N)CN=[N+]=[N-]
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of ethyl 3-azido-2(S)-(tert-butoxycarbonylamino)propionate (0.5 g) in ethyl acetate (5 ml) was added 4N HCl in ethyl acetate (5 ml) at 0° C. After stirring at room temperature for 2 hours, the mixture was evaporated in vacuo. The residue was recrystallized from diethyl ether to give ethyl 2(S)-amino-3-azidopropionate hydrochloride (0.3 g).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[CH2:14][CH2:13][N:12]([C:15]([C:17]3[C:18]([CH3:30])=[CH:19][C:20]([CH:26]4[CH2:29][CH2:28][CH2:27]4)=[C:21]([CH:25]=3)[C:22](O)=[O:23])=[O:16])[CH2:11][CH2:10]2)=[CH:5][CH:4]=1)#[N:2].C(Cl)(=O)C([Cl:34])=O>ClCCl.CN(C)C=O>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[CH2:14][CH2:13][N:12]([C:15]([C:17]3[C:18]([CH3:30])=[CH:19][C:20]([CH:26]4[CH2:29][CH2:28][CH2:27]4)=[C:21]([CH:25]=3)[C:22]([Cl:34])=[O:23])=[O:16])[CH2:11][CH2:10]2)=[CH:5][CH:4]=1)#[N:2]
Reactant: Cc1cc(C2CCC2)c(C(=O)O)cc1C(=O)N1CCC(c2ccc(C#N)cc2)CC1
Reactant: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: Cc1cc(C2CCC2)c(C(=O)Cl)cc1C(=O)N1CCC(c2ccc(C#N)cc2)CC1
Temperature: 40 °C
Reaction time: 1 h
Yield: 92 %

Procedure:
To a round-bottom flask was added a solution of 5-(4-(4-cyanophenyl)piperidine-1-carbonyl)-2-cyclobutyl-4-methylbenzoic acid (compound 234, 500 mg, 1.24 mmol, 1.00 equiv) in dichloromethane (5 mL). Oxalyl chloride (317 mg, 2.50 mmol, 2.00 equiv) and N,N-dimethylformamide (˜5 mg) were added dropwise to the mixture. The resulting solution was stirred for 1 h at 40° C., then concentrated and dried under reduced pressure to yield 480 mg (92%) of the title compound as a light yellow oil.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([Cl:20])[C:9]=1[N:10]1[CH:19]=[C:13]2[CH:14]=[N:15][CH:16]=[C:17]([Cl:18])[C:12]2=[N:11]1)C#N.N(C1C(Cl)=CN=CC=1/C=N/C1C(Cl)=CC=CC=1Cl)=[N+]=[N-]>C1(C)C=CC=CC=1>[Cl:18][C:17]1[C:12]2[C:13](=[CH:19][N:10]([C:9]3[C:8]([Cl:20])=[CH:7][CH:4]=[CH:3][C:2]=3[Cl:1])[N:11]=2)[CH:14]=[N:15][CH:16]=1
Reactant: N#Cc1cc(Cl)c(-n2cc3cncc(Cl)c3n2)c(Cl)c1
Agent: [N-]=[N+]=Nc1c(Cl)cncc1/C=N/c1c(Cl)cccc1Cl
Solvent: Cc1ccccc1
Product: Clc1cccc(Cl)c1-n1cc2cncc(Cl)c2n1
Yield: 66 %

Procedure:
Following the procedure described for 3,5-dichloro-4-(7-chloropyrazolo[4,3-c]pyridin-2-yl)benzonitrile, [1-(4-azido-5-chloropyridin-3-yl)-meth-(E)-ylidene]-(2,6-dichlorophenyl)-amine was heated under reflux in toluene to afford the title compound as a brown solid (2.7 g, 66% yield). LCMS (Method D): RT=2.96 min, m/z: 298 [M+H+].
Reaction SMILES: C([Li])CCC.Br[C:7]1[C:12]([CH3:13])=[C:11]([O:14][CH3:15])[C:10]([CH3:16])=[C:9]([CH3:17])[C:8]=1[O:18][CH3:19].[CH3:20][CH:21]([CH3:36])[C:22]([C:24]1[CH:29]=[CH:28][C:27]([N:30]2[CH2:35][CH2:34][O:33][CH2:32][CH2:31]2)=[CH:26][CH:25]=1)=[O:23].O>O1CCCC1>[CH3:19][O:18][C:8]1[C:9]([CH3:17])=[C:10]([CH3:16])[C:11]([O:14][CH3:15])=[C:12]([CH3:13])[C:7]=1[C:22]([C:24]1[CH:25]=[CH:26][C:27]([N:30]2[CH2:35][CH2:34][O:33][CH2:32][CH2:31]2)=[CH:28][CH:29]=1)([OH:23])[CH:21]([CH3:36])[CH3:20]
Reactant: CC(C)C(=O)c1ccc(N2CCOCC2)cc1
Reactant: COc1c(C)c(C)c(OC)c(Br)c1C
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: O
Product: COc1c(C)c(C)c(OC)c(C(O)(c2ccc(N3CCOCC3)cc2)C(C)C)c1C
Reaction time: 0.33 h
Yield: 76.9 %

Procedure:
n-Butyllithium (1.6 M, 18.1 mL, 29.0 mmol) was added to a solution of 1-bromo-2,5-dimethoxy-3,4,6-trimethylbenzene (7.52 g, 29.0 mmol) in tetrahydrofuran (50 mL) at −78° C., and the mixture was stirred for 20 minutes at the same temperature. To the reaction mixture was added 2-methyl-1-[4-(4-morpholinyl)phenyl] propan-1-one (6.15 g, 26.4 mmol), and the mixture was stirred for 30 minutes at room temperature. Water (40 mL) was poured into the reaction mixture, which was then extracted three times with ethyl acetate. The organic layers were combined, washed with water, dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was crystallized from ethanol to obtain the title compound (8.40 g, yield 90%).
Reaction SMILES: [NH2:1][C:2]1[N:25]=[C:24](Cl)[CH:23]=[CH:22][C:3]=1[C:4]([NH:6][CH2:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[CH:10][CH:9]=1)=[O:5].[CH:27]1([NH2:30])[CH2:29][CH2:28]1>O1CCCC1>[NH2:1][C:2]1[N:25]=[C:24]([NH:30][CH:27]2[CH2:29][CH2:28]2)[CH:23]=[CH:22][C:3]=1[C:4]([NH:6][CH2:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[CH:10][CH:9]=1)=[O:5]
Reactant: Nc1nc(Cl)ccc1C(=O)NCc1ccc(OCc2ccccc2)cc1
Reactant: NC1CC1
Solvent: C1CCOC1
Product: Nc1nc(NC2CC2)ccc1C(=O)NCc1ccc(OCc2ccccc2)cc1
Temperature: 140 °C
Yield: 14 %

Procedure:
2-Amino-6-chloro-N-(4-benzyloxy-benzyl)-nicotinamide described in Example A-27 (80 mg, 0.22 mmol) was dissolved in tetrahydrofuran (3 mL), cyclopropylamine (0.3 mL, 4.3 mmol) was added thereto, and the solution was heated in a sealed tube for 16 hours (oil bath temperature: 140° C.). The reaction solution was allowed to room temperature, the solution was concentrated, the obtained residue was purified by NH silica gel column chromatography (ethyl acetate:hexane=2:1), and the title compound (12 mg, 0.031 mmol, 14%) was obtained.
Reaction SMILES: [Cl:1][C:2]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[N:13]=[C:4]([C:5]([NH:7][C:8]2[NH:12][N:11]=[N:10][N:9]=2)=[O:6])[CH:3]=1.[CH3:20][N:21]1[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]1.[ClH:27]>O>[ClH:1].[ClH:27].[ClH:1].[CH3:20][N:21]1[CH2:26][CH2:25][N:24]([C:2]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[N:13]=[C:4]([C:5]([NH:7][C:8]3[NH:12][N:11]=[N:10][N:9]=3)=[O:6])[CH:3]=2)[CH2:23][CH2:22]1
Reactant: O=C(Nc1nnn[nH]1)c1cc(Cl)c2ccccc2n1
Reactant: CN1CCNCC1
Agent: Cl
Solvent: O
Product: CN1CCN(c2cc(C(=O)Nc3nnn[nH]3)nc3ccccc23)CC1

Procedure:
4-Chloro-N(1H-tetrazol-5-yl)quinaldamide (0.6 g), N-methylpiperazine (5 ml) and water (1 ml) were heated on a steam bath for 18 hours. Water (5 ml) and dilute hydrochloric acid were added to pH 1 and the solid was collected and washed with 0.1N hydrochloric acid and dried, m.p. 215° (d).
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6](=[O:13])[NH:7][C:8](=[O:12])[NH:9]2)=[CH:4][C:3]=1[O:14][CH3:15].[Cl:16][C:17]1[CH:27]=[C:26]([F:28])[C:25]([F:29])=[CH:24][C:18]=1[C:19]([N:21]=[C:22]=[O:23])=[O:20]>C(#N)C.CN1CCCC1=O>[Cl:16][C:17]1[CH:27]=[C:26]([F:28])[C:25]([F:29])=[CH:24][C:18]=1[C:19]([NH:21][C:22]([NH:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6](=[O:13])[NH:7][C:8](=[O:12])[NH:9]2)=[CH:4][C:3]=1[O:14][CH3:15])=[O:23])=[O:20]
Reactant: COc1cc2c(=O)[nH]c(=O)[nH]c2cc1N
Reactant: O=C=NC(=O)c1cc(F)c(F)cc1Cl
Solvent: CC#N
Solvent: CN1CCCC1=O
Product: COc1cc2c(=O)[nH]c(=O)[nH]c2cc1NC(=O)NC(=O)c1cc(F)c(F)cc1Cl
Yield: 28.4 %

Procedure:
100 mg (0.53 mmol) of 7-amino-6-methoxy-1H-quinazoline-2,4-dione were suspended in 20 ml of acetonitrile and 2 ml of N-methyl-2-pyrrolidinone, and 200 mg (0.97 mmol) of 2-chloro-4,5-difluorobenzoyl isocyanate (example 1a) were added. The reaction mixture was heated to boiling and then quenched with methanol and concentrated in vacuo. The residue was stirred with acetonitrile, and the resulting precipitate was filtered off. 64 mg (30%) of the desired product were obtained.
Reaction SMILES: [C:1]1([CH2:7][N:8]2[C:19](=O)[CH2:18][C:10]3([C:14](=O)[N:13]([CH3:16])[C:12](=O)[CH2:11]3)[CH2:9]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-].[OH-].[Na+].[ClH:29]>O1CCCC1.C(O)(C)C.O>[ClH:29].[ClH:29].[C:1]1([CH2:7][N:8]2[CH2:19][CH2:18][C:10]3([CH2:14][N:13]([CH3:16])[CH2:12][CH2:11]3)[CH2:9]2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CN1C(=O)CC2(CC(=O)N(Cc3ccccc3)C2)C1=O
Agent: Cl
Agent: [Al+3]
Agent: [H-]
Solvent: O
Solvent: C1CCOC1
Solvent: CC(C)O
Product: CN1CCC2(CCN(Cc3ccccc3)C2)C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 1.36 g (5.0 mmol) 7-phenylmethyl-2-methyl-2,7-diazaspiro[4.4]nonane-1,3,8-trione in 50 ml tetrahydrofuran was added dropwise to a suspension of 0.95 g (25 mmol) lithium aluminum hydride in 30 ml tetrahydrofuran. The mixture was stirred overnight at room temperature, refluxed one hour, cooled, and treated dropwise with 0.95 ml water, 0.95 ml 15% sodium hydroxide solution, and 2.8 ml water. After removal of the inorganic solids by filtration, the filtrate was concentrated in vacuo to give a syrup which was dissolved in isopropanol and treated with excess 6N hydrogen chloride in isopropanol. Crystallization afforded 0.97 g of the title compound, mp 233-234° C.
Reaction SMILES: I[CH2:2][C:3]#[C:4][CH2:5][O:6][CH2:7][C:8]([O-:10])=[O:9].[K+].[C:12]1(=[O:22])[NH:16][C:15](=[O:17])[C:14]2=[CH:18][CH:19]=[CH:20][CH:21]=[C:13]12.[K].Cl>C(O)C.O>[C:8]([CH2:7][O:6][CH2:5][C:4]#[C:3][CH2:2][N:16]1[C:15](=[O:17])[C:14]2=[CH:18][CH:19]=[CH:20][CH:21]=[C:13]2[C:12]1=[O:22])([OH:10])=[O:9]
Reactant: O=C([O-])COCC#CCI
Reactant: O=C1NC(=O)c2ccccc21
Agent: Cl
Agent: [K+]
Agent: [K]
Solvent: O
Solvent: CCO
Product: O=C(O)COCC#CCN1C(=O)c2ccccc2C1=O
Temperature: 25 °C

Procedure:
Potassium 7-iodo-3-oxa-5-heptynoate is added to a solution of potassium phthalimide (equimolar quantity) in ethanol at 25° C. The resulting solution is stirred and maintained at 25° C. until alkylation is complete. Evaporation of the reaction mixture in vacuo at 40° to 50° C. leaves a residue which is suspended in water. The aqueous suspension is acidified to Congo Red with dilute hydrochloric acid and extracted three times with ether. The combined organic extract is washed with saturated aqueous brine, dried over sodium sulfate, and filtered. In vacuo evaporation of the filtrate at 40° to 50° C. leaves the desired title compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]2[C:14](=[O:15])[CH:13]=[C:12]([C:16]([F:19])([F:18])[F:17])[NH:11][C:10]2=[O:20])=[CH:5][CH:4]=1.C(=O)([O-])[O-].[K+].[K+].[NH2:27]OS(C1C(C)=CC(C)=CC=1C)(=O)=O>O1CCCC1.O>[NH2:27][N:11]1[C:12]([C:16]([F:19])([F:17])[F:18])=[CH:13][C:14](=[O:15])[N:9]([C:6]2[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:8][CH:7]=2)[C:10]1=[O:20]
Reactant: COc1ccc(-n2c(=O)cc(C(F)(F)F)[nH]c2=O)cc1
Reactant: Cc1cc(C)c(S(=O)(=O)ON)c(C)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Product: COc1ccc(-n2c(=O)cc(C(F)(F)F)n(N)c2=O)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 68.2 %

Procedure:
A solution of 2.10 grams (0.0073 mole) of 3-(4-methoxyphenyl)-6-trifluoromethyl-2,4(1H,3H)-pyrimidinedione (recovered from previous reactions) and 1.21 grams (0.0088 mole) of potassium carbonate in 30 mL of tetrahydrofuran was stirred for five minutes at ambient temperature and then 1.58 grams (0.0073 mole) of 1-aminooxysulfonyl-2,4,6-trimethylbenzene (prepared in a manner known by one skilled in the art) was added. Upon completion of addition, the reaction mixture was stirred at ambient temperature for three hours. At the conclusion of this period, the reaction mixture was diluted with water, and the resulting mixture was extracted with two 50 mL portions of ethyl acetate. The combined ethyl acetate extracts were dried with magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure, yielding 0.9 gram of crude product. This 0.90 grams of crude product was combined with 0.92 grams of crude product prepared by a similar route to yield a total of 1.82 grams of crude product. The 1.82 grams of crude product was purified by flash chromatography, yielding 1.5 grams of 1-amino-3-(4-methoxyphenyl)-6-trifluoromethyl-2,4(1H,3H)-pyrimidinedione, m.p. 176°-178° C. The NMR spectrum was consistent with the proposed structure.
Reaction SMILES: C(N=C=NC(C)C)(C)C.[C:10]([OH:14])([CH3:13])([CH3:12])[CH3:11].[CH2:15]([O:22][CH2:23][O:24][CH2:25][CH2:26][C@H:27]([O:31][Si:32]([C:35]([CH3:38])([CH3:37])[CH3:36])([CH3:34])[CH3:33])[C:28](O)=[O:29])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>[Cu]Cl.ClCCl>[CH2:15]([O:22][CH2:23][O:24][CH2:25][CH2:26][C@H:27]([O:31][Si:32]([C:35]([CH3:38])([CH3:37])[CH3:36])([CH3:34])[CH3:33])[C:28]([O:14][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:29])[C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: CC(C)(C)[Si](C)(C)O[C@@H](CCOCOCc1ccccc1)C(=O)O
Reactant: CC(C)(C)O
Agent: Cl[Cu]
Agent: CC(C)N=C=NC(C)C
Solvent: ClCCl
Product: CC(C)(C)OC(=O)[C@H](CCOCOCc1ccccc1)O[Si](C)(C)C(C)(C)C
Temperature: 25 °C
Reaction time: 16 h
Yield: 18.9 %

Procedure:
(Step 4) To N,N′-diisopropylcarbodiimide (0.643 mL, 4.13 mmol), tert-butanol (0.415 mL, 4.34 mmol) and copper(I) chloride (20 mg, 0.21 mmol) were added, and the resulting mixture was stirred at room temperature for 16 hours. The reaction mixture was filtered, through Celite (registered trademark), and the solvent in the filtrate was evaporated under reduced pressure. To the obtained residue, dichloromethane (7.4 mL) and (S)-4-(benzyloxymethoxy)-2-(tert-butyldimethylsiloxy)butanoic acid (183 mg, 0.516 mmol) obtained in Step 3 were added, and the resulting mixture was stirred at room temperature for 24 hours. The reaction mixture was filtered through Celite (registered trademark), and the solvent of the filtrate was evaporated under reduced pressure. The resulting residue was purified by thin-layer chromatography (ethyl acetate/n-hexane=1/20), whereby tert-butyl (S)-4-(benzyloxymethoxy)-2-(tert-butyldimethylsiloxy)butanoate (40 mg, 19%) was obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:24]2[CH2:29][CH2:28][O:27][CH2:26][CH2:25]2)[C:5]2[N:6]([CH:8]=[C:9]([C@@H:11]3[CH2:13][C@@H:12]3[C:14]3[CH:23]=[CH:22][C:21]4[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=4)[N:15]=3)[N:10]=2)[N:7]=1.Br[C:31]1[CH:36]=[CH:35][C:34]([CH2:37][C:38]([O:40][CH3:41])=[O:39])=[CH:33][CH:32]=1>>[Cl:1][C:2]1[CH:3]=[C:4]([N:24]2[CH2:29][CH2:28][O:27][CH2:26][CH2:25]2)[C:5]2[N:6]([C:8]([C:31]3[CH:36]=[CH:35][C:34]([CH2:37][C:38]([O:40][CH3:41])=[O:39])=[CH:33][CH:32]=3)=[C:9]([C@@H:11]3[CH2:13][C@@H:12]3[C:14]3[CH:23]=[CH:22][C:21]4[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=4)[N:15]=3)[N:10]=2)[N:7]=1
Reactant: Clc1cc(N2CCOCC2)c2nc([C@@H]3C[C@@H]3c3ccc4ccccc4n3)cn2n1
Reactant: COC(=O)Cc1ccc(Br)cc1
Product: COC(=O)Cc1ccc(-c2c([C@@H]3C[C@@H]3c3ccc4ccccc4n3)nc3c(N4CCOCC4)cc(Cl)nn23)cc1

Procedure:
Compound 79d (60 mg, 0.14 mmol) was coupled with methyl 2-(4-bromophenyl)acetate (46 μL, 0.22 mmol) using the procedures described in Example 20, Step A to afford compound 82a. Mass Spectrum (LCMS, ESI pos.): Calcd. for C31H28ClN5O3: 554.2 (M+H). found: 544.2.