Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][S:2]([C:5]1[S:9][C:8]([N:10]=[C:11]=[O:12])=[N:7][N:6]=1)(=[O:4])=[O:3].[CH3:13][NH:14][CH2:15][CH:16]=[O:17]>C1C=CC=CC=1>[CH3:13][N:14]([CH2:15][CH:16]=[O:17])[C:11]([NH:10][C:8]1[S:9][C:5]([S:2]([CH3:1])(=[O:4])=[O:3])=[N:6][N:7]=1)=[O:12]
Reactant: CS(=O)(=O)c1nnc(N=C=O)s1
Reactant: CNCC=O
Solvent: c1ccccc1
Product: CN(CC=O)C(=O)Nc1nnc(S(C)(=O)=O)s1

Procedure:
A mixture of 5-methylsulfonyl-1,3,4-thiadiazol-2-yl isocyanate dimer (0.05 mole), the dimethyl acetal of 2-methylaminoacetaldehyde (0.1 mole) and benzene (60 ml) are charged into a glass reaction vessel equipped with a mechanical stirrer and reflux condenser. The reaction mixture is heated at reflux for a period of about 15 minutes. After this time the mixture is stripped of benzene under reduced pressure to yield a solid product as the residue. The residue is then recrystallized to yield the desired product dimethyl acetal of 2-[1-methyl-3-(5-methylsulfonyl-1,3,4-thiadiazol-2 -yl)ureido]acetaldehyde.
Reaction SMILES: I[CH2:2][C:3]1[N:4]=[N:5][N:6]([CH2:8][CH2:9][N:10]2[C:18](=[O:19])[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[C:11]2=[O:20])[CH:7]=1>[Pd].C(O)C>[CH3:2][C:3]1[N:4]=[N:5][N:6]([CH2:8][CH2:9][N:10]2[C:11](=[O:20])[C:12]3[C:17](=[CH:16][CH:15]=[CH:14][CH:13]=3)[C:18]2=[O:19])[CH:7]=1
Reactant: O=C1c2ccccc2C(=O)N1CCn1cc(CI)nn1
Agent: [Pd]
Solvent: CCO
Product: Cc1cn(CCN2C(=O)c3ccccc3C2=O)nn1
Yield: 74.5 %

Procedure:
Stir a mixture of 2-(2-(4-(iodomethyl)-1H-1,2,3-triazol-1-yl)ethyl)isoindoline-1,3-dione (1 g, 2.62 mmol) and 0.2 g of 10% palladium on carbon in ethanol (10 mL) under hydrogen balloon overnight. Filter to remove the solid and concentrate. Purify by column chromatography (DCM to 20% ethyl acetate in DCM) to give the title compound as a yellow solid (0.5 g, 74%). MS (ES) m/z 257 [M+1]+.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:31])[CH:5]([NH:28]C=O)[CH:6]=[C:7]([CH:19]1[CH2:24][CH2:23][N:22]([C:25](=[O:27])[CH3:26])[CH2:21][CH2:20]1)[CH2:8][P:9]([O:15]C(C)C)([O:11]C(C)C)=[O:10])[CH3:2].C(O)C>ClCCl>[CH2:1]([O:3][C:4](=[O:31])[CH:5]([NH2:28])[CH:6]=[C:7]([CH:19]1[CH2:20][CH2:21][N:22]([C:25](=[O:27])[CH3:26])[CH2:23][CH2:24]1)[CH2:8][P:9]([OH:15])([OH:11])=[O:10])[CH3:2]
Reactant: CCOC(=O)C(C=C(CP(=O)(OC(C)C)OC(C)C)C1CCN(C(C)=O)CC1)NC=O
Solvent: ClCCl
Solvent: CCO
Product: CCOC(=O)C(N)C=C(CP(=O)(O)O)C1CCN(C(C)=O)CC1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
3.15 g (6.84 mmol) of 4-(1-acetylpiperidin-4-yl)-5-diisopropylphosphono-2-formylamino-pent-3-enoic acid ethyl ester are dissolved in 17 ml of dichloromethane, and 3.54 ml (27.3 mmol) of trimethylbromossilane are added dropwise at room temperature. The mixture is left to stand room at temperature for 16 hours, 17 ml of ethanol are added dropwise, the mixture is left to stand for a further 18 hours and is concentrated by evaporation in a rotary evaporator, the residue is dissolved in 12 ml of ethanol, and a mixture of 3 ml of propylene oxide and 3 ml of ethanol is added. A suspension forms, which is stirred for a further 2 hours at room temperature and for 2 hours with ice cooling and is then filtered with suction. 2-amino-4-(1-acetylpiperidin-4-yl)-5-phosphono-pent-3-enoic acid ethyl ester having a melting point of 225° (decomp.) is obtained.
Reaction SMILES: [CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:16])=[C:11](F)[C:12]=3[F:14])[C:7](=[O:17])[C:6]([C:18]([OH:20])=[O:19])=[CH:5]2)[CH2:3][CH2:2]1.[C:21]([O:25][C:26]([NH:28][C@H:29]1[C@@H:33]([CH3:34])[CH2:32][NH:31][CH2:30]1)=[O:27])([CH3:24])([CH3:23])[CH3:22].C1CCN2C(=NCCC2)CC1>C(#N)C>[C:21]([O:25][C:26]([NH:28][C@H:29]1[C@@H:33]([CH3:34])[CH2:32][N:31]([C:11]2[C:12]([F:14])=[C:13]3[C:8]([C:7](=[O:17])[C:6]([C:18]([OH:20])=[O:19])=[CH:5][N:4]3[CH:1]3[CH2:3][CH2:2]3)=[CH:9][C:10]=2[F:16])[CH2:30]1)=[O:27])([CH3:24])([CH3:22])[CH3:23]
Reactant: O=C(O)c1cn(C2CC2)c2c(F)c(F)c(F)cc2c1=O
Reactant: C[C@H]1CNC[C@H]1NC(=O)OC(C)(C)C
Solvent: C1CCC2=NCCCN2CC1
Solvent: CC#N
Product: C[C@H]1CN(c2c(F)cc3c(=O)c(C(=O)O)cn(C4CC4)c3c2F)C[C@H]1NC(=O)OC(C)(C)C
Yield: 88 %

Procedure:
A mixture of 1-cyclopropyl-6,7,8-trifluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid (0.5 g), anhydrous acetonitrile (6 ml), cis-3-t-butoxycarbonylamino-4-methylpyrrolidine (0.53 g) and DBU (0.27 g) was refluxed for an hour and the resulting precipitate was collected by filtration to give the title compound (0.72 g) as pale yellowish powder, mp 229°-230° C. Analysis (%) for C23H27F2N3O5, Calcd. (Found): C, 59.60 (59.47); H, 5.87 (5.85); N, 9.07 (9.01).
Reaction SMILES: [CH2:1]([O:4][C:5]1[CH:10]=[C:9]([CH3:11])[CH:8]=[CH:7][C:6]=1[C:12](=[O:14])[CH3:13])[CH:2]=[CH2:3].CO[CH:17](OC)[N:18]([CH3:20])[CH3:19]>>[CH2:1]([O:4][C:5]1[CH:10]=[C:9]([CH3:11])[CH:8]=[CH:7][C:6]=1[C:12](=[O:14])/[CH:13]=[CH:17]/[N:18]([CH3:20])[CH3:19])[CH:2]=[CH2:3]
Reactant: C=CCOc1cc(C)ccc1C(C)=O
Reactant: COC(OC)N(C)C
Product: C=CCOc1cc(C)ccc1C(=O)/C=C/N(C)C

Procedure:
To 1-[2-(allyloxy)-4-methylphenyl]ethanone (Step 1, 13.9 g, 73 mmol) was added dimethylformamide dimethylacetal (56 mL, 422 mmol), and the reaction was heated to reflux for 18 hours. The reaction was then concentrated in vacuo to give the title compound as an orange oil, 17.9 g, which was taken crude into the next reaction.
Reaction SMILES: [Cl:1][C:2]1[CH:18]=[CH:17][C:5]2[CH2:6][CH2:7][N:8]([C:11](=[O:16])[C:12]([F:15])([F:14])[F:13])[CH2:9][CH2:10][C:4]=2[C:3]=1OS(C(F)(F)F)(=O)=O.[C:27]1([C:33]2([NH2:36])[CH2:35][CH2:34]2)[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1.C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1.C(=O)([O-])[O-].[Cs+].[Cs+]>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[Cl:1][C:2]1[CH:18]=[CH:17][C:5]2[CH2:6][CH2:7][N:8]([C:11](=[O:16])[C:12]([F:15])([F:14])[F:13])[CH2:9][CH2:10][C:4]=2[C:3]=1[NH:36][C:33]1([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH2:35][CH2:34]1
Reactant: NC1(c2ccccc2)CC1
Reactant: O=C(N1CCc2ccc(Cl)c(OS(=O)(=O)C(F)(F)F)c2CC1)C(F)(F)F
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Agent: O=C([O-])[O-]
Product: O=C(N1CCc2ccc(Cl)c(NC3(c4ccccc4)CC3)c2CC1)C(F)(F)F

Procedure:
Use a method similar to the General Procedure 5-2 to couple 7-chloro-3-(2,2,2-trifluoroacetyl)-6-trifluoromethanesulfonyloxy-2,3,4,5-tetrahydro-1H-benzo[d]azepine (0.2 g, 0.47 mmol) with 1-phenyl-cyclopropylamine (0.2 g, 1.41 mmol) using tris(dibenzylideneacetone)dipalladium(0) (43.0 mg, 0.05 mmol), BINAP (0.1 g, 0.15 mmol) and cesium carbonate (0.3 g, 0.97 mmol) at 90° C. for 17 h to obtain 7-chloro-6-(1-phenyl-cyclopropylamino)-3-(2,2,2-trifluoroacetyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepine as a colorless oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([C:7](=[O:21])[CH:8]([C:13]3[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=3)[CH2:9][S:10]2)=[CH:5][CH:4]=1.O1CCC[CH2:23]1.C([N-]C(C)C)(C)C.[Li+].CI>O>[CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([C:7](=[O:21])[C:8]([C:13]3[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=3)([CH3:23])[CH2:9][S:10]2)=[CH:5][CH:4]=1
Reactant: COc1ccc(C2CSc3cc(OC)ccc3C2=O)cc1
Reactant: C1CCOC1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: CI
Solvent: O
Product: COc1ccc(C2(C)CSc3cc(OC)ccc3C2=O)cc1
Reaction time: 0.75 h
Yield: 72 %

Procedure:
To 7-methoxy-3-(4-methoxyphenyl)thiochroman-4-one (725 mg, 2.41 mmol) obtained in Example 25 was added dry tetrahydrofuran (30 ml). Then lithium diisopropylamide (2.41 ml, 4.83 mmol, 2.0 mol hexane/tetrahydrofuran solution) was added dropwise thereto at -78° C. The reaction mixture was stirred for 45 minutes and methyl iodide (7.5 ml, 120.6 mmol) was added thereto. The reaction solution was stirred for one hour at -78° C. and for 24 hours at -10° C. and, after adding water, extracted with ethyl acetate. The organic layer was washed with water and saturated sodium chloride solution, dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. The residue was purified with column chromatography (n-hexane:ethyl acetate=9:1) to obtain 550 mg (yield: 72%) of the title compound as a yellow solid.
Reaction SMILES: C[O:2][C:3](=[O:32])[CH2:4][O:5][C:6]1[CH:15]=[CH:14][C:13]([F:16])=[C:12]2[C:7]=1[C:8]([O:28][CH:29]([F:31])[F:30])=[C:9]([CH2:19][C:20]1[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=1)[C:10]([CH2:17][CH3:18])=[N:11]2.O.[OH-].[Na+].C(O)(=O)C>CO>[F:31][CH:29]([F:30])[O:28][C:8]1[C:7]2[C:12](=[C:13]([F:16])[CH:14]=[CH:15][C:6]=2[O:5][CH2:4][C:3]([OH:32])=[O:2])[N:11]=[C:10]([CH2:17][CH3:18])[C:9]=1[CH2:19][C:20]1[CH:21]=[CH:22][C:23]([O:26][CH3:27])=[CH:24][CH:25]=1
Reactant: CCc1nc2c(F)ccc(OCC(=O)OC)c2c(OC(F)F)c1Cc1ccc(OC)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC(=O)O
Solvent: CO
Product: CCc1nc2c(F)ccc(OCC(=O)O)c2c(OC(F)F)c1Cc1ccc(OC)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 29.6 %

Procedure:
A solution of [4-difluoromethoxy-2-ethyl-8-fluoro-3-(4-methoxybenzyl)quinolin-5-yloxy]acetic acid methyl ester (0.30 g) in methanol (10 mL), and water (1.0 mL) was treated with 5.0 M aqueous sodium hydroxide solution (0.67 mL) and the resulting mixture was stirred at room temperature for 1 hour. The mixture was acidified by the addition of glacial acetic acid, concentrated under reduced pressure, and the residue purified by preparative reverse-phase HPLC to afford title compound as a pale yellow solid (0.086 g).
Reaction SMILES: C(OC(N(C(OC(C)(C)C)=O)[C:9]1[S:10][C:11]([C:18]([O:20][CH2:21][CH3:22])=[O:19])=[C:12]([C:14](=[O:17])[CH2:15][CH3:16])[N:13]=1)=O)(C)(C)C.[ClH:30].C(OCC)(=O)C.N(OC(C)(C)C)=O>CO.[Cu](Cl)Cl>[Cl:30][C:9]1[S:10][C:11]([C:18]([O:20][CH2:21][CH3:22])=[O:19])=[C:12]([C:14](=[O:17])[CH2:15][CH3:16])[N:13]=1
Reactant: Cl
Reactant: CCOC(=O)c1sc(N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)nc1C(=O)CC
Agent: Cl[Cu]Cl
Agent: CC(C)(C)ON=O
Solvent: CCOC(C)=O
Solvent: CO
Product: CCOC(=O)c1sc(Cl)nc1C(=O)CC
Temperature: 50 °C
Reaction time: 0.83 h

Procedure:
Ethyl 2-[bis(tert-butoxycarbonyl)amino]-4-propanoyl-1,3-thiazole-5-carboxylate obtained in Example (62f) (270.5 mg, 0.63 mmol) was dissolved in methanol (2 mL). A 4 N hydrochloric acid/ethyl acetate solution (6 mL) was added, and the mixture was stirred at 50° C. for 50 minutes. The reaction solution was washed with saturated aqueous sodium bicarbonate solution, dried over anhydrous sodium sulfate, and then concentrated under reduced pressure. The same operation as in Example (22c) was performed using the resulting crude product, copper chloride (96 mg, 0.71 mmol) and tert-butyl nitrite (86 μL, 0.72 mmol), to obtain 49.0 mg of the title compound as a colorless oily substance (31%).
Reaction SMILES: [CH3:1][CH:2]([CH2:7][CH3:8])[CH2:3][C:4]([OH:6])=O.Cl.[CH3:10][N:11]1[CH2:16][CH2:15][N:14]([C:17]2[CH:22]=[C:21]([C:23]3[CH:32]=[C:31]4[C:26]([CH2:27][CH2:28][NH:29][CH2:30]4)=[CH:25][CH:24]=3)[N:20]=[C:19]([NH2:33])[N:18]=2)[CH2:13][CH2:12]1>>[CH3:1][CH:2]([CH2:7][CH3:8])[CH2:3][C:4]([N:29]1[CH2:28][CH2:27][C:26]2[C:31](=[CH:32][C:23]([C:21]3[CH:22]=[C:17]([N:14]4[CH2:13][CH2:12][N:11]([CH3:10])[CH2:16][CH2:15]4)[N:18]=[C:19]([NH2:33])[N:20]=3)=[CH:24][CH:25]=2)[CH2:30]1)=[O:6]
Reactant: CN1CCN(c2cc(-c3ccc4c(c3)CNCC4)nc(N)n2)CC1
Reactant: CCC(C)CC(=O)O
Agent: Cl
Product: CCC(C)CC(=O)N1CCc2ccc(-c3cc(N4CCN(C)CC4)nc(N)n3)cc2C1

Procedure:
This compound was prepared by using procedures analogous to those described for the synthesis of Example 41 starting from 3-methylpentanoic acid (Aldrich, Cat. #223453) and 4-(4-methylpiperazin-1-yl)-6-(1,2,3,4-tetrahydroisoquinolin-7-yl)pyrimidin-2-amine HCl salt. Analytic LCMS (M+H)+: m/z=423.2.
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][CH:11]([N:14]([CH3:26])[C:15]2[C:20]([NH:21][CH:22]([CH3:24])[CH3:23])=[CH:19][CH:18]=[C:17]([Cl:25])[N:16]=2)[CH2:10][CH2:9]1)C1C=CC=CC=1.ClC(OC(Cl)=O)C.CO.C1(C)C=CC=CC=1>ClCCl>[CH3:26][N:14]([CH:11]1[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]1)[C:15]1[C:20]([NH:21][CH:22]([CH3:24])[CH3:23])=[CH:19][CH:18]=[C:17]([Cl:25])[N:16]=1
Reactant: CC(C)Nc1ccc(Cl)nc1N(C)C1CCN(Cc2ccccc2)CC1
Agent: CC(Cl)OC(=O)Cl
Solvent: ClCCl
Solvent: Cc1ccccc1
Solvent: CO
Product: CC(C)Nc1ccc(Cl)nc1N(C)C1CCNCC1

Procedure:
1-Benzyl-4-[N-methyl-N-(3-isopropylamino-6-chloro-2-pyridinyl)amino]piperidine (EXAMPLE 184, 1.60 g, 4.84 mmol) is dissolved in dichloromethane (0.2M) and cooled to 0°. 1-Chloroethyl-chloroformate (0.57 ml, 5.32 mmol) is added dropwise. The mixture is allowed to warm to 20°-25°, then refluxed one half hour. The solvent is removed to one third volume, 15 ml methanol is added and the mixture is refluxed 2 hr. Extraction with chloroform, drying the extract over sodium sulfate and removal of the solvent gives the crude product. Flash column chromatography (silica gel, 100 g; methanol/chloroform (10/90)) gives the title compound, NMR (300 MHz, CD3OD) 6.88, 3.49, 3.23, 2.87, 2.50, 1.95, 1.70 and 1.12δ.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1[NH2:11].Cl.Cl[CH2:14][CH2:15][N:16]([CH2:18][CH2:19]Cl)[CH3:17]>ClC1C=CC=CC=1.ClCCl>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1[N:11]1[CH2:19][CH2:18][N:16]([CH3:17])[CH2:15][CH2:14]1
Reactant: Nc1cc([N+](=O)[O-])ccc1Br
Reactant: CN(CCCl)CCCl
Agent: Cl
Solvent: Clc1ccccc1
Solvent: ClCCl
Product: CN1CCN(c2cc([N+](=O)[O-])ccc2Br)CC1
Temperature: 25 °C
Reaction time: 15 h
Yield: 26.5 %

Procedure:
A suspension of 2-bromo-5-nitrobenzenamine (26.0 g) and 2-chloro-N-(2-chloroethyl)-N-methylethanamine hydrochloride (23.0 g) in chlorobenzene (150 ml) was heated to reflux under nitrogen and stirred for 15 hours before cooling to room temperature. The gummy mixture was diluted with dichloromethane (150 ml) and extracted with water (4×400 ml, acidified with 2N HCl). The combined aqueous extracts were basified with 2N sodium hydroxide (to pH 12) and extracted with dichloromethane (4×500 ml). The combined organic extracts were dried and concentrated in vacuo to give a brown oil which was purified by FCC eluting with System A (300:8:1 gradient to 200:8:1) to give the title compound as a brown solid (9.498 g) m.p. 100°-103° C.
Reaction SMILES: [N+:1]([O-:4])(O)=[O:2].C(OC(=O)C)(=O)C.[Br:12][C:13]1[C:17]([Br:18])=[CH:16][S:15][CH:14]=1>C(O)(=O)C>[Br:12][C:13]1[C:17]([Br:18])=[CH:16][S:15][C:14]=1[N+:1]([O-:4])=[O:2]
Reactant: O=[N+]([O-])O
Reactant: Brc1cscc1Br
Solvent: CC(=O)O
Solvent: CC(=O)OC(C)=O
Product: O=[N+]([O-])c1scc(Br)c1Br
Reaction time: 0.17 h

Procedure:
41.4 ml of fuming nitric acid was slowly added to 500 ml of acetic acid under ice-cooling, followed by stirring for 10 minutes, and a solution of 78 ml of acetic acid anhydride containing 50 g of 3,4-dibromothiophene was slowly added, followed by stirring at room temperature for 18 hours. Ice was added to the reaction solution, and the resulting crystals were collected by filtration, and washed with water and diethyl ether/n-hexane=1/5 successively, to give 40.2 g of the title compound.
Reaction SMILES: Br[C:2]1[N:3]=[C:4]2[C:10]([C:11]([C:13]3([CH3:19])[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]3)=[O:12])=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1.[CH2:20]([N:22]([CH2:32][CH3:33])[C:23]1[CH:28]=[CH:27][C:26](B(O)O)=[CH:25][CH:24]=1)[CH3:21]>>[CH2:32]([N:22]([CH2:20][CH3:21])[C:23]1[CH:28]=[CH:27][C:26]([C:2]2[N:3]=[C:4]3[C:10]([C:11]([C:13]4([CH3:19])[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]4)=[O:12])=[CH:9][NH:8][C:5]3=[N:6][CH:7]=2)=[CH:25][CH:24]=1)[CH3:33]
Reactant: CCN(CC)c1ccc(B(O)O)cc1
Reactant: CC1(C(=O)c2c[nH]c3ncc(Br)nc23)CCCCC1
Product: CCN(CC)c1ccc(-c2cnc3[nH]cc(C(=O)C4(C)CCCCC4)c3n2)cc1

Procedure:
[2-(4-Diethylamino-phenyl)-5H-pyrrolo[2,3-b]pyrazin-7-yl]-(1-methyl-cyclohexyl)-methanone was prepared starting from (2-bromo-5H-pyrrolo[2,3-b]pyrazin-7-yl)-(1-methyl-cyclohexyl)-methanone and 4-(diethylamino)phenylboronic acid following general procedures as described in these Examples. MP 211-213° C., M+H=391.
Reaction SMILES: [OH:1][CH2:2][CH2:3][N:4]1[CH:8]=[C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[NH:6][C:5]1=[O:15].[H][H]>[Pd].C(O)C>[OH:1][CH2:2][CH2:3][N:4]1[CH2:8][CH:7]([C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=2)[NH:6][C:5]1=[O:15]
Reactant: O=c1[nH]c(-c2ccccc2)cn1CCO
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: O=C1NC(c2ccccc2)CN1CCO

Procedure:
A slurry of 1-(2-hydroxyethyl)-4-phenyl-4-imidazolin-2-one (10.2 g.) and 10 percent palladium on carbon (1 g.) in ethanol (200 ml.) is hydrogenated in a Parr Shaker apparatus at approximately 30 psig of hydrogen for three hours. The catalyst is then filtered, washed with ethanol, and the combined filtrate and washings are concentrated to give a colorless oil which solidifies on standing to yield the title compound; m.p. 60°-63° C.
Reaction SMILES: [NH2:1][C:2]1[N:22]=[C:5]2[C:6]([C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[N:16]([CH3:21])[S:17]([CH3:20])(=[O:19])=[O:18])=[CH:7][CH:8]=[CH:9][N:4]2[N:3]=1.Br[C:24]1[CH:25]=[C:26]([CH:30]2[CH2:35][CH2:34][N:33]([CH3:36])[CH2:32][CH2:31]2)[CH:27]=[CH:28][CH:29]=1.Cl.C1(P(C2CCCCC2)C2C=CC=CC=2C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)CCCCC1>>[CH3:21][N:16]([C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=1[C:6]1[C:5]2[N:4]([N:3]=[C:2]([NH:1][C:28]3[CH:29]=[CH:24][CH:25]=[C:26]([CH:30]4[CH2:35][CH2:34][N:33]([CH3:36])[CH2:32][CH2:31]4)[CH:27]=3)[N:22]=2)[CH:9]=[CH:8][CH:7]=1)[S:17]([CH3:20])(=[O:19])=[O:18]
Reactant: CN1CCC(c2cccc(Br)c2)CC1
Reactant: CN(c1ccccc1-c1cccn2nc(N)nc12)S(C)(=O)=O
Agent: Cl
Agent: c1ccc(P(C2CCCCC2)C2CCCCC2)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c1
Product: CN1CCC(c2cccc(Nc3nc4c(-c5ccccc5N(C)S(C)(=O)=O)cccn4n3)c2)CC1

Procedure:
N-Methyl-N-(2-{2-[3-(1-methyl-piperidin-4-yl)-phenylamino]-[1,2,4]triazolo[1,5-a]pyridin-8-yl}-phenyl)-methanesulfonamide was prepared from N-[2-(2-amino-[1,2,4]triazolo[1,5-a]pyridin-8-yl)-phenyl]-N-methyl-methanesulfonamide (75.0 mg, 0.236 mmol) and 4-(3-bromo-phenyl)-1-methyl-piperidine; hydrochloride (76.0 mg, 0.262 mmol) with 2,2′-bis-dicyclohexylphosphanyl-biphenyl (25.0 mg, 0.0457 mmol) as the ligand in a manner analogous to Example 2d. Product isolated as a pale yellow foam (0.099 g, 85%). 1H NMR (400 MHz, CDCl3, δ, ppm): 8.48 (dd, J=6.8, 0.9 Hz, 1H), 7.59-7.36 (m, 7H), 7.28-7.23 (m, 1H), 6.98 (t, J=7.1 Hz, 1H), 6.86 (d, J=7.6 Hz, 1H), 6.76 (s, 1H), 3.17 (s, 3H), 3.02-2.95 (m, 2H), 2.74 (s, 3H), 2.53-2.43 (m, 1H), 2.34 (s, 3H), 2.10-2.00 (m, 2H), 1.89-1.78 (m, 4H). MS=491 (MH)+.
Reaction SMILES: [OH:1][CH:2]([C:15]1[CH:20]=[CH:19][C:18]([C:21]2[N:25]=[C:24]([C:26]3[O:30][N:29]=[C:28]([C:31]4[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=4)[C:27]=3[C:37]([F:40])([F:39])[F:38])[O:23][N:22]=2)=[CH:17][CH:16]=1)[C:3]([NH:5][CH2:6][CH2:7][C:8]([O:10]C(C)(C)C)=[O:9])=[O:4]>C(Cl)Cl.C(O)(C(F)(F)F)=O>[OH:1][CH:2]([C:15]1[CH:20]=[CH:19][C:18]([C:21]2[N:25]=[C:24]([C:26]3[O:30][N:29]=[C:28]([C:31]4[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=4)[C:27]=3[C:37]([F:38])([F:39])[F:40])[O:23][N:22]=2)=[CH:17][CH:16]=1)[C:3]([NH:5][CH2:6][CH2:7][C:8]([OH:10])=[O:9])=[O:4]
Reactant: CC(C)(C)OC(=O)CCNC(=O)C(O)c1ccc(-c2noc(-c3onc(-c4ccccc4)c3C(F)(F)F)n2)cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(O)CCNC(=O)C(O)c1ccc(-c2noc(-c3onc(-c4ccccc4)c3C(F)(F)F)n2)cc1
Reaction time: 1 h
Yield: 102.4 %

Procedure:
2-Hydroxy-2-(4-(5-(3-phenyl-4-(trifluoromethyl)isoxazol-5-yl)-1,2,4-oxadiazol-3-yl)phenyl)acetic acid (Int-Va, 70 mg, 0.162 mmol) was dissolved in DMF (2 mL) prior to the addition of 4-methylmorpholine (0.107 mL, 0.974 mmol), tert-butyl 3-aminopropanoate-HCl (53.1 mg, 0.292 mmol), and HATU (111 mg, 0.292 mmol). This was stirred overnight before EtOAc and brine were added. The organic layer was washed with brine, 1N HCl, and saturated NaHCO3. The organic layer was then dried (MgSO4), filtered, and concentrated to give tert-butyl 3-(2-hydroxy-2-(4-(5-(3-phenyl-4-(trifluoromethyl)isoxazol-5-yl)-1,2,4-oxadiazol-3-yl)phenyl)acetamido)propanoate (85 mg, 0.152 mmol, 94% yield): LCMS=559.3 [M+H]+, which was taken to the next step. This material, tert-butyl 3-(2-hydroxy-2-(4-(5-(3-phenyl-4-(trifluoromethyl)isoxazol-5-yl)-1,2,4-oxadiazol-3-yl)phenyl)acetamido)propanoate (160 mg, 0.286 mmol), was dissolved in CH2Cl2 (1 mL) and TFA (2.0 mL). This was stirred for 1 h and was then concentrated to give single enantiomer 3-(2-hydroxy-2-(4-(5-(3-phenyl-4-(trifluoromethyl)isoxazol-5-yl)-1,2,4-oxadiazol-3-yl)phenyl)acetamido)propanoic acid (147 mg, 0.293 mmol): LCMS=503.0 [M+H]+; 1H NMR (400 MHz, methanol-d4) δ ppm 8.17 (2 H, d, J=8.35 Hz), 7.69 (4 H, d, J=7.91 Hz), 7.52-7.65 (3 H, m), 5.11 (1 H, s), 3.50 (2 H, t, J=6.59 Hz), 2.54 (2 H, t, J=6.81 Hz).
Reaction SMILES: [C:1]([C:4]([C:16](=[O:18])[CH3:17])=[CH:5][C:6]1[CH:13]=[CH:12][C:9]([C:10]#[N:11])=[CH:8][C:7]=1[O:14][CH3:15])(=O)[CH3:2].[NH2:19][C:20]1[CH:25]=[CH:24][NH:23][C:22](=[O:26])[CH:21]=1>C(O)(C)C>[C:16]([C:4]1[CH:5]([C:6]2[CH:13]=[CH:12][C:9]([C:10]#[N:11])=[CH:8][C:7]=2[O:14][CH3:15])[C:21]2[C:22](=[O:26])[NH:23][CH:24]=[CH:25][C:20]=2[NH:19][C:1]=1[CH3:2])(=[O:18])[CH3:17]
Reactant: Nc1cc[nH]c(=O)c1
Reactant: COc1cc(C#N)ccc1C=C(C(C)=O)C(C)=O
Solvent: CC(C)O
Product: COc1cc(C#N)ccc1C1C(C(C)=O)=C(C)Nc2cc[nH]c(=O)c21

Procedure:
18 g (74 mmol) of 4-(2-acetyl-3-oxobut-1-en-1-yl)-3-methoxybenzonitrile and 8.14 g (74 mmol) of 4-aminopyridin-2(1H)-one [Searls, T., McLaughlin, L. W., Tetrahedron 55, 11985-11996 (1999)] are dissolved in 40 ml of isopropanol and heated under reflux under argon for 4 days. The mixture is then concentrated and the residue is recrystallized from methanol. 18.1 g (70% of theory) of the title compound are obtained as a pale yellow solid.
Reaction SMILES: [F:1][C:2]1[C:3](=[O:9])[NH:4][C:5](=[O:8])[NH:6][CH:7]=1.O1CCOCC1.[C:16](Cl)(=[O:23])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>N1C=CC=CC=1>[C:16]([N:6]1[CH:7]=[C:2]([F:1])[C:3](=[O:9])[NH:4][C:5]1=[O:8])(=[O:23])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: O=c1[nH]cc(F)c(=O)[nH]1
Solvent: C1COCCO1
Solvent: c1ccncc1
Product: O=C(c1ccccc1)n1cc(F)c(=O)[nH]c1=O
Yield: 42.7 %

Procedure:
2.6 g (0.02 mole) of 5-fluorouracil was suspended in a mixed solution of 35 ml. of dioxane and 10 ml. of pyridine and reacted with 6.7 g (0.048 mole) of benzoylchloride. The reaction mixture was treated in the same manner as in Example 1 and 2.00 g (42.5% yield) of 1-benzoyl-5-fluorouracil was obtained. The product was recrystallized from ethanol to give white needles melting at 170°-172°C. The results of an elementary analysis thereof were well in agreement with the calculated value as follows:
Reaction SMILES: [CH:1]([CH2:3][C:4]([CH3:12])([CH3:11])[CH2:5][C:6]([O:8][CH2:9][CH3:10])=[O:7])=[O:2].[CH2:13](O)[CH2:14][OH:15].O>C1(C)C=CC=CC=1>[O:8]1[CH2:9][CH2:10][O:7][CH:6]1[CH2:5][C:4]([CH3:11])([CH3:12])[CH2:3][C:1]([O:15][CH2:14][CH3:13])=[O:2]
Reactant: OCCO
Reactant: CCOC(=O)CC(C)(C)CC=O
Solvent: O
Solvent: Cc1ccccc1
Product: CCOC(=O)CC(C)(C)CC1OCCO1
Yield: 93.3 %

Procedure:
74 g of ethyl 4-formyl-3,3-dimethylbutanoate, prepared in Example 91, are dissolved in 450 ml of anhydrous toluene in the presence of 0.5 g of paratoluenesulfonic acid and 26.7 g of ethylene glycol. The mixture is heated to the reflux temperature and the water formed during the reaction is removed by means of a Dean-Stark apparatus. After refluxing for two hours, the solvent is evaporated off under vacuum and the residue is distilled to give 86.7 g of ethyl 4-(dioxolan-2-yl)-3,3-dimethylbutanoate in the form of a liquid with a boiling point b.p. 10 of 138°-140° C.
Reaction SMILES: Cl[CH2:2][C:3]1[CH:8]=[CH:7][N:6]=[C:5]([C:9]2[CH:14]=[C:13]([O:15][CH3:16])[C:12]([O:17][CH3:18])=[C:11]([O:19][CH3:20])[CH:10]=2)[CH:4]=1.[NH:21]1[CH2:27][CH2:26][CH2:25][NH:24][CH2:23][CH2:22]1>>[CH3:20][O:19][C:11]1[CH:10]=[C:9]([C:5]2[CH:4]=[C:3]([CH2:2][N:21]3[CH2:27][CH2:26][CH2:25][N:24]([CH2:2][C:3]4[CH:8]=[CH:7][N:6]=[C:5]([C:9]5[CH:14]=[C:13]([O:15][CH3:16])[C:12]([O:17][CH3:18])=[C:11]([O:19][CH3:20])[CH:10]=5)[CH:4]=4)[CH2:23][CH2:22]3)[CH:8]=[CH:7][N:6]=2)[CH:14]=[C:13]([O:15][CH3:16])[C:12]=1[O:17][CH3:18]
Reactant: COc1cc(-c2cc(CCl)ccn2)cc(OC)c1OC
Reactant: C1CNCCNC1
Product: COc1cc(-c2cc(CN3CCCN(Cc4ccnc(-c5cc(OC)c(OC)c(OC)c5)c4)CC3)ccn2)cc(OC)c1OC

Procedure:
4-Chloromethyl-2-(3,4,5-trimethoxyphenyl)pyridine (100 mg) and homopiperazine (17 mg) were reacted in the same manner as in Example 1 to obtain the title compound as a free base.