Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[S:23][C:5]2[N:6]([CH3:22])[C:7](=[O:21])[N:8]([CH2:11][CH2:12][CH2:13][O:14][CH:15]3[CH2:20][CH2:19][CH2:18][CH2:17][O:16]3)[C:9](=[O:10])[C:4]=2[C:3]=1[CH:24]=[O:25].[Cl:26][C:27]1[CH:32]=[CH:31][C:30]([Mg]Br)=[CH:29][CH:28]=1>C1COCC1.O>[Br:1][C:2]1[S:23][C:5]2[N:6]([CH3:22])[C:7](=[O:21])[N:8]([CH2:11][CH2:12][CH2:13][O:14][CH:15]3[CH2:20][CH2:19][CH2:18][CH2:17][O:16]3)[C:9](=[O:10])[C:4]=2[C:3]=1[CH:24]([C:30]1[CH:31]=[CH:32][C:27]([Cl:26])=[CH:28][CH:29]=1)[OH:25]
Reactant: Cn1c(=O)n(CCCOC2CCCCO2)c(=O)c2c(C=O)c(Br)sc21
Reactant: Clc1ccc([Mg]Br)cc1
Solvent: C1CCOC1
Solvent: O
Product: Cn1c(=O)n(CCCOC2CCCCO2)c(=O)c2c(C(O)c3ccc(Cl)cc3)c(Br)sc21
Reaction time: 0.08 h
Yield: 51.6 %

Procedure:
To a solution of 6-bromo-1-methyl-2,4-dioxo-3-(3-((tetrahydro-2H-pyran-2-yl)oxy)propyl)-1,2,3,4-tetrahydrothieno[2,3-d]pyrimidine-5-carbaldehyde (See Compound 2, Step 4, 185 mg, 0.428 mmol) in THF (5 mL) was added (4-chlorophenyl)magnesium bromide (0.77 mL, 0.772 mmol). The reaction was stirred for 5 min, diluted with water (10 mL) and extracted with DCM (3×10 mL). The combined organic layers were dried over Na2SO4 and concentrated to a residue which was purified by chromatography eluted with PE/EA (5:1 to 1:1) to give 6-bromo-5-((4-chlorophenyl) (hydroxy)methyl)-1-methyl-3-(3-((tetrahydro-2H-pyran-2-yl)oxy)propyl)thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione (120 mg, 51.4% yield) as a solid. LCMS: [M+-THP-OH] 441 and TR=2.021 min.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[C:4]([CH2:9][CH2:10][CH2:11][OH:12])[CH:3]=1.C(N(CC)CC)C.[C:20](OC(=O)C)(=[O:22])[CH3:21]>CN(C)C1C=CN=CC=1.ClCCl.O>[C:20]([O:12][CH2:11][CH2:10][CH2:9][C:4]1[CH:3]=[C:2]([Cl:1])[CH:7]=[CH:6][C:5]=1[CH3:8])(=[O:22])[CH3:21]
Reactant: Cc1ccc(Cl)cc1CCCO
Reactant: CC(=O)OC(C)=O
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: O
Solvent: ClCCl
Product: CC(=O)OCCCc1cc(Cl)ccc1C
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a solution of 4-chloro-2-(3-hydroxypropyl)toluene (3.7 g, 20 mmol), triethylamine (40 mmol) and 4-dimethylaminopyridine (4 mmol) in dichloromethane (20 mL) was added acetic anhydride (15 mmol) at 0° C. The mixture was stirred for ca. 1 h at 0° C., diluted with water, and extracted with AcOEt. The extract was washed with diluted aqueous HCl and brine, dried over MgSO4, and concentrated to give quantitatively the title compound: 1H NMR (CDCl3) δ7.11 (bs, 1H), 7.07 (bs, 2H), 4.07 (t, 2H, J=7.2 Hz), 2.65 (dd, 2H, J=7.2, 8.1 Hz), 2.28 (s, 3H), 2.05 (s, 3H), 1.84~1.96 (m, 2H). 5) 2-(3-Acethoxypropyl)-4-chloro-6-nitrotoluene
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:22]=[CH:23][N:24]=1)[C:5]([NH:7][CH:8]([C:10]1[CH:11]=[N:12][C:13]([O:16][CH2:17][C:18]([F:21])([F:20])[F:19])=[CH:14][CH:15]=1)[CH3:9])=[O:6].N1C=CC=CC=1.[C:31](Cl)(=[O:35])[CH:32]([CH3:34])[CH3:33]>CN(C)C(=O)C>[C:31]([NH:1][C:2]1[CH:3]=[C:4]([CH:22]=[CH:23][N:24]=1)[C:5]([NH:7][CH:8]([C:10]1[CH:11]=[N:12][C:13]([O:16][CH2:17][C:18]([F:21])([F:19])[F:20])=[CH:14][CH:15]=1)[CH3:9])=[O:6])(=[O:35])[CH:32]([CH3:34])[CH3:33]
Reactant: CC(NC(=O)c1ccnc(N)c1)c1ccc(OCC(F)(F)F)nc1
Reactant: CC(C)C(=O)Cl
Solvent: CC(=O)N(C)C
Solvent: c1ccncc1
Product: CC(C)C(=O)Nc1cc(C(=O)NC(C)c2ccc(OCC(F)(F)F)nc2)ccn1
Temperature: 25 °C
Reaction time: 2 h
Yield: 43.1 %

Procedure:
To a mixture of 2-amino-N-(1-(6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethyl)isonicotinamide (25 mg, 0.073 mmol, Step-1, single enantiomer) and pyridine (0.024 mL, 0.29 mmol) in N,N-dimethylacetamide (1 mL) is added isobutyryl chloride (16 mg, 0.15 mmol) at room temperature. After stirring at room temperature for 2 hours, the mixture is poured onto water (2 mL), and the mixture is extracted with ethyl acetate (3 mL). The organic layer is dried over sodium sulfate and concentrated under reduced pressure. The residue is purified by column chromatography on NH-silica gel eluting with ethyl acetate and then by preparative LC-MS to give 12.9 mg (43% yield) of the title compound.
Reaction SMILES: [OH:1][C@H:2]1[CH2:6][CH2:5][N:4]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[C@@H:3]1[C:14]([O:16][CH2:17][CH3:18])=[O:15].N1C=CN=C1.Cl[Si:25]([C:28]([CH3:31])([CH3:30])[CH3:29])([CH3:27])[CH3:26]>O.Cl.CN(C1C=CC=CN=1)C>[CH3:29][C:28]([Si:25]([CH3:27])([CH3:26])[O:1][C@H:2]1[CH2:6][CH2:5][N:4]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[C@@H:3]1[C:14]([O:16][CH2:17][CH3:18])=[O:15])([CH3:31])[CH3:30]
Reactant: CCOC(=O)[C@@H]1[C@@H](O)CCN1C(=O)OC(C)(C)C
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: CN(C)c1ccccn1
Agent: Cl
Agent: c1c[nH]cn1
Solvent: O
Product: CCOC(=O)[C@@H]1[C@@H](O[Si](C)(C)C(C)(C)C)CCN1C(=O)OC(C)(C)C
Yield: 88.4 %

Procedure:
1-(1,1-dimethylethyl) 2-ethyl(2S,3S)-3-hydroxy-1,2-pyrrolidinedicarboxylate (8.98 g, 34.7 mmol), imidazole (2.36 g, 34.7 mmol), dimethylaminopyridine (50 mg, catalytic) and chloro(1,1-dimethylethyl)dimethylsilane (4.96 g, 32.9 mmol) were stirred at room temperature for 16 hours. The reaction was diluted with water and 1N HCl to make the mixture acidic. The mixture was extracted three times with methylene chloride. The organic layer was washed with 1M HCl, dried over MgSO4 to give the title compound as a clear brown oil (10.88 g, 29.1 mmol). 1H NMR (400 MHz, DMSO-D6) δ ppm 0.0 (m, 6 H) 0.8 (m, 9 H) 1.2 (m, 3 H) 1.3 (m, 9 H) 1.7 (m, 1 H) 1.9 (m, 1 H) 3.4 (m, 2 H) 3.9 (m, 1 H) 4.1 (m, 2 H) 4.4 (m, 1 H). ES+=374.30.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:11])[C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=1.C(=O)([O-])[O-].[K+].[K+].CS(C)=O.[Cl:22][CH2:23][CH2:24]Cl>O>[CH3:1][O:2][C:3](=[O:11])[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:24][CH2:23][Cl:22])=[CH:6][CH:5]=1
Reactant: COC(=O)c1ccc(O)cc1
Reactant: ClCCCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: COC(=O)c1ccc(OCCCl)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
4-hydroxybenzoic acid methyl ester (1.52 g, 10 mmol), anhydrous potassium carbonate (1.38 g, 10 mmol), 10 ml of dimethylsulfoxide, and 20 ml of 1,2-dichloroethane are combined and heated to reflux. HPLC shows the reaction is at equilibrium at about 1 hour. Therefore, another equivalent of potassium carbonate is added. After the second addition of potassium carbonate, the ratio of product to bis alkylated biproduct is greatly enhanced. The reaction mixture is cooled to room temperature and diluted with 30 ml of water. The mixture is stirred then the layers separated. The organic layer is back extracted with 20 ml of brine and then filtered through sodium sulfate. The filtrate is concentrated in vacuo at about 60° C. to a yellow green oil which solidifies on cooling. This crude product is redissolved in 12 ml of hot methanol and water is added (total of 6 ml) dropwise until crystals appear. The crystallization is allowed to continue for one hour with cooling. The precipitate is filtered and rinsed with 12 ml of 1:1 methanol:water. The filter cake is dried in vacuo at about room temperature to give 2.00 g of product. (93.5%). HPLC.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[C:6]([C:14]2[CH:19]=[C:18]([C:20]([F:23])([F:22])[F:21])[N:17]3[N:24]=[CH:25][C:26]([C:27]#[CH:28])=[C:16]3[N:15]=2)[CH:7]=[CH:8][C:9]=1[C:10]([F:13])([F:12])[F:11])[CH3:2].[OH:29][CH2:30][C:31]([NH:34][S:35]([C:38]1[S:42][C:41](Cl)=[N:40][CH:39]=1)(=[O:37])=[O:36])([CH3:33])[CH3:32]>>[OH:29][CH2:30][C:31]([NH:34][S:35]([C:38]1[S:42][C:41]([C:28]#[C:27][C:26]2[CH:25]=[N:24][N:17]3[C:18]([C:20]([F:21])([F:22])[F:23])=[CH:19][C:14]([C:6]4[CH:7]=[CH:8][C:9]([C:10]([F:13])([F:11])[F:12])=[C:4]([O:3][CH2:1][CH3:2])[CH:5]=4)=[N:15][C:16]=23)=[N:40][CH:39]=1)(=[O:37])=[O:36])([CH3:33])[CH3:32]
Reactant: CC(C)(CO)NS(=O)(=O)c1cnc(Cl)s1
Reactant: C#Cc1cnn2c(C(F)(F)F)cc(-c3ccc(C(F)(F)F)c(OCC)c3)nc12
Product: CCOc1cc(-c2cc(C(F)(F)F)n3ncc(C#Cc4ncc(S(=O)(=O)NC(C)(C)CO)s4)c3n2)ccc1C(F)(F)F

Procedure:
The title compound was prepared from 5-(3-Ethoxy-4-trifluoromethyl-phenyl)-3-ethynyl-7-trifluoromethyl-pyrazolo[1,5-a]pyrimidine (example C.3) (400 mg, 1.0 mmol) and 2-chloro-thiazole-5-sulfonic acid(2-hydroxy-1,1-dimethyl-ethyl)-amide (example B.14) (244 mg, 1.0 mmol) according to general procedure II. Obtained as an orange solid (80 mg, 12%). MS (ISP) 634.1 [(M+H)+]; mp 209-211° C.
Reaction SMILES: Cl.[C:2]([NH:6][OH:7])([CH3:5])([CH3:4])[CH3:3].C[O-].[Na+].[Cl:11][C:12]1[C:13]([OH:21])=[C:14]([CH:17]=[C:18]([Cl:20])[CH:19]=1)[CH:15]=O>CO.Cl>[Cl:11][C:12]1[C:13]([OH:21])=[C:14]([CH:15]=[N+:6]([C:2]([CH3:5])([CH3:4])[CH3:3])[O-:7])[CH:17]=[C:18]([Cl:20])[CH:19]=1
Reactant: CC(C)(C)NO
Reactant: O=Cc1cc(Cl)cc(Cl)c1O
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: CC(C)(C)[N+]([O-])=Cc1cc(Cl)cc(Cl)c1O
Yield: 97.1 %

Procedure:
To a solution of tert-butylhyroxylamine hydrochloride (1.5 eq.) and sodium methoxide (1.2 eq.) in MeOH was added 3,5-dichloro-2-hydroxybenzaldehyde (1 eq.) and 5 drops of 37% HCl. The resulting solution was refluxed over molecular sieves (40 g) until no more aldehyde was detected by TLC. The mixture was then cold filtered to remove molecular sieves and sodium chloride, and rinsed with CH2Cl2. The solvent was removed in vacuo and the title compound was isolated in 97.1% yield as a yellow crystalline solid, m.p. 102.9° C. (Rf=0.33 on a silica gel plate using 7:3 hexanes/EtOAc as an eluant).
Reaction SMILES: [N:1]([C@@H:4]1[CH2:9][CH2:8][C@H:7]([C:10]2[CH:15]=[CH:14][C:13]([C:16]3[N:21]=[C:20]4[N:22]([CH2:42][O:43][CH2:44][CH2:45][Si:46]([CH3:49])([CH3:48])[CH3:47])[C:23]([O:25][C@@H:26]5[CH2:30][O:29][C@@H:28]6[C@H:31]([O:34][Si:35]([C:38]([CH3:41])([CH3:40])[CH3:39])([CH3:37])[CH3:36])[CH2:32][O:33][C@H:27]56)=[N:24][C:19]4=[CH:18][C:17]=3[Cl:50])=[CH:12][CH:11]=2)[CH2:6][CH2:5]1)=[N+]=[N-].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O>O1CCCC1>[Si:35]([O:34][C@H:31]1[C@H:28]2[O:29][CH2:30][C@@H:26]([O:25][C:23]3[N:22]([CH2:42][O:43][CH2:44][CH2:45][Si:46]([CH3:49])([CH3:48])[CH3:47])[C:20]4=[N:21][C:16]([C:13]5[CH:14]=[CH:15][C:10]([C@@H:7]6[CH2:8][CH2:9][C@H:4]([NH2:1])[CH2:5][CH2:6]6)=[CH:11][CH:12]=5)=[C:17]([Cl:50])[CH:18]=[C:19]4[N:24]=3)[C@H:27]2[O:33][CH2:32]1)([C:38]([CH3:40])([CH3:41])[CH3:39])([CH3:37])[CH3:36]
Reactant: CC(C)(C)[Si](C)(C)O[C@@H]1CO[C@H]2[C@@H]1OC[C@H]2Oc1nc2cc(Cl)c(-c3ccc([C@H]4CC[C@@H](N=[N+]=[N-])CC4)cc3)nc2n1COCC[Si](C)(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)[Si](C)(C)O[C@@H]1CO[C@H]2[C@@H]1OC[C@H]2Oc1nc2cc(Cl)c(-c3ccc([C@H]4CC[C@@H](N)CC4)cc3)nc2n1COCC[Si](C)(C)C
Temperature: 40 °C
Reaction time: 12 h

Procedure:
5-(4-((cis)-4-Azidocyclohexyl)phenyl)-2-((3R,3aR,6R,6aS)-6-(tert-butyldimethylsilyloxy)hexahydrofuro[3,2-b]furan-3-yloxy)-6-chloro-3-((2-(trimethylsilyl)ethoxy)methyl)-3H-imidazo[4,5-b]pyridine (210 mg) is dissolved in tetrahydrofurane (1 mL) treated with triphenylphosphine (90 mg) and stirred for 4 hours at room temperature and for 12 hours at 40° C. Water (220 μL) is added and the mixture is stirred for further 12 hours at 80° C. Then the mixture is partitioned between hydrochloric acid (1 M) and diethylether. The organic phase is washed with aqueous NaOH solution (1 M), dried (MgSO4) and concentrated. The residue is chromatographed over aluminium oxide (ethyl acetate/methanol 100:0→0:100) to give the title compound. LC (method 4): tR=0.61 min; Mass spectrum (ESI+): m/z=715 [M+H]+.
Reaction SMILES: C(#N)C.[S:4]([NH2:14])(=[O:13])([C:6]1[CH:11]=[CH:10][C:9]([NH2:12])=[CH:8][CH:7]=1)=[O:5].C(N(CC)CC)C.[C:22](Cl)(=[O:27])[C:23]([CH3:26])([CH3:25])[CH3:24]>O>[C:22]([NH:12][C:9]1[CH:8]=[CH:7][C:6]([S:4]([NH2:14])(=[O:13])=[O:5])=[CH:11][CH:10]=1)(=[O:27])[C:23]([CH3:26])([CH3:25])[CH3:24]
Reactant: Nc1ccc(S(N)(=O)=O)cc1
Reactant: CC(C)(C)C(=O)Cl
Solvent: O
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CC(C)(C)C(=O)Nc1ccc(S(N)(=O)=O)cc1
Reaction time: 0.5 h
Yield: 91.4 %

Procedure:
To a mixture of 200 ml of acetonitrile, 50 g of sulfanilamide, and 30 g of triethylamine was added dropwise 35 g of pivaloyl chloride at 50° C. They were then stirred for 30 minutes and the resulting suspension was poured into 1.5 l of water. The thus formed crystals were separated by filtration to yield 68 g of p-pivaloylaminobenzenesulfonamide (m.p., 219°-220° C.).
Reaction SMILES: [CH3:1][S:2][C:3]1[CH:8]=[CH:7][C:6]([C:9](=O)[CH2:10][C:11](=O)[C:12]([F:15])([F:14])[F:13])=[CH:5][CH:4]=1.Cl.[C:19]([C:21]1[CH:26]=[CH:25][C:24]([NH:27][NH2:28])=[CH:23][CH:22]=1)#[N:20].O>C(O)(=O)C.CN(C)C=O>[C:19]([C:21]1[CH:26]=[CH:25][C:24]([N:27]2[C:9]([C:6]3[CH:7]=[CH:8][C:3]([S:2][CH3:1])=[CH:4][CH:5]=3)=[CH:10][C:11]([C:12]([F:15])([F:14])[F:13])=[N:28]2)=[CH:23][CH:22]=1)#[N:20]
Reactant: N#Cc1ccc(NN)cc1
Reactant: CSc1ccc(C(=O)CC(=O)C(F)(F)F)cc1
Agent: Cl
Solvent: CN(C)C=O
Solvent: O
Solvent: CC(=O)O
Product: CSc1ccc(-c2cc(C(F)(F)F)nn2-c2ccc(C#N)cc2)cc1
Temperature: 110 °C
Reaction time: 3 h
Yield: 101.4 %

Procedure:
A mixture of 1-[4-(methylthio)phenyl]-4,4,4-trifluorobutane-1,3-dione (1.8 g) and 4-cyanophenylhydrazine hydrochloride (1.2 g) in acetic acid (30 ml) and N,N-dimethylformamide (1 ml) was stirred at 110° C. for 3 hours. The reaction mixture was poured into water and extracted with ethyl acetate. The extract was washed with water, dried over anhydrous magnesium sulfate, and evaporated to give a brown powder of 1-(4-cyanophenyl)-5-[4-(methylthio)phenyl]-3-(trifluoromethyl)pyrazole (2.5 g).
Reaction SMILES: [F:1][C:2]([F:17])([F:16])[C:3]1[CH:4]=[C:5]([C:9]2[S:10][CH:11]=[C:12]([CH2:14][OH:15])[N:13]=2)[CH:6]=[CH:7][CH:8]=1.[C:18](Cl)(=[O:20])[CH3:19].C(N(CC)CC)C>O1CCCC1>[C:18]([O:15][CH2:14][C:12]1[N:13]=[C:9]([C:5]2[CH:6]=[CH:7][CH:8]=[C:3]([C:2]([F:1])([F:16])[F:17])[CH:4]=2)[S:10][CH:11]=1)(=[O:20])[CH3:19]
Reactant: CC(=O)Cl
Reactant: OCc1csc(-c2cccc(C(F)(F)F)c2)n1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(=O)OCc1csc(-c2cccc(C(F)(F)F)c2)n1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Under a nitrogen atmosphere at 0° C., to a solution (21 mL) of the compound (5.4 g, 21 mmol) obtained in Example 64b in tetrahydrofuran were added acetyl chloride (2.0 g, 25 mmol) and triethylamine (3.8 mL, 27 mmol), and the mixture was stirred at room temperature for 30 min. The resulting salt was removed and the solvent was evaporated under reduced pressure to give a crude title compound as a colorless solid.
Reaction SMILES: [Cl-].[CH3:2][O:3][C:4]1[C:29]([CH3:30])=[C:28]([O:31][CH3:32])[CH:27]=[C:26]([CH3:33])[C:5]=1[CH2:6][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[CH2:34]([O:36][C:37](=[O:48])[CH:38]=[C:39]([CH3:47])[CH:40]=[CH:41][CH:42]=[C:43]([CH:45]=O)[CH3:44])[CH3:35]>>[CH2:34]([O:36][C:37](=[O:48])[CH:38]=[C:39]([CH3:47])[CH:40]=[CH:41][CH:42]=[C:43]([CH3:45])[CH:44]=[CH:6][C:5]1[C:26]([CH3:33])=[CH:27][C:28]([O:31][CH3:32])=[C:29]([CH3:30])[C:4]=1[O:3][CH3:2])[CH3:35]
Reactant: CCOC(=O)C=C(C)C=CC=C(C)C=O
Reactant: COc1cc(C)c(C[P+](c2ccccc2)(c2ccccc2)c2ccccc2)c(OC)c1C
Agent: [Cl-]
Product: CCOC(=O)C=C(C)C=CC=C(C)C=Cc1c(C)cc(OC)c(C)c1OC

Procedure:
By the procedure of Example 1, 2,4-dimethoxy-3,6-dimethyl-benzyltriphenyl-phosphonium chloride is reacted with 7-formyl-3-methyl-octa-2,4,6-trien-1-oic acid ethyl ester to obtain 9-(2,4-dimethoxy-3,6-dimethylphenyl)-3,7-dimethyl-nona-2,4,6,8-tetraen-1-oic acid ethyl ester.
Reaction SMILES: [F:1][C:2]1[C:7]([C:8](Cl)=[O:9])=[C:6]([F:11])[C:5]([F:12])=[C:4]([F:13])[C:3]=1[F:14].[H-].[Na+].O1[CH:22]=[CH:21][CH2:20][C:19](=[O:23])[NH:18]1.[CH2:24]1[CH2:28][O:27][CH2:26][CH2:25]1>>[CH2:21]([CH:20]1[O:27][C:26]2[C:2]([CH:3]=[CH:4][CH3:5])=[CH:7][CH:28]=[CH:24][C:25]=2[N:18]([C:8]([C:7]2[C:2]([F:1])=[C:3]([F:14])[C:4]([F:13])=[C:5]([F:12])[C:6]=2[F:11])=[O:9])[C:19]1=[O:23])[CH3:22]
Reactant: C1CCOC1
Reactant: O=C1CC=CON1
Reactant: O=C(Cl)c1c(F)c(F)c(F)c(F)c1F
Agent: [H-]
Agent: [Na+]
Product: CC=Cc1cccc2c1OC(CC)C(=O)N2C(=O)c1c(F)c(F)c(F)c(F)c1F
Yield: 63 %

Procedure:
Procedure & NMR Data: 265 μL of pentafluorobenzoyl chloride (2 eq, 1.84 mmol) was added to a mixture of 148 mg of NaH (4 eq, 3.68 mmol) and 200 mg (0.92 mmol) of oxazinone P2 in THF (22 ml). 240 mg of P5 were obtained, yield 63%.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([NH:8][C:9]2[N:14]=[C:13]([C:15]3[O:19][C:18]([CH:20]=[CH:21][C:22]4[CH:29]=CC(C#N)=CC=4)=[N:17][CH:16]=3)[CH:12]=[CH:11][CH:10]=2)[CH:3]=1.CC1C=C[N:34]=[C:33](NC2C=CC=C(C3OC=NC=3)N=2)C=1.BrC1C=NC=CC=1.O(C(C)(C)C)[Li]>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.O1CCOCC1>[CH3:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([NH:8][C:9]2[CH:10]=[CH:11][CH:12]=[C:13]([C:15]3[O:19][C:18]([C:20]4[CH:33]=[N:34][CH:29]=[CH:22][CH:21]=4)=[N:17][CH:16]=3)[N:14]=2)[CH:3]=1
Reactant: Cc1ccnc(Nc2cccc(-c3cnco3)n2)c1
Reactant: Cc1ccnc(Nc2cccc(-c3cnc(C=Cc4ccc(C#N)cc4)o3)n2)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Li]OC(C)(C)C
Solvent: C1COCCO1
Solvent: Brc1cccnc1
Product: Cc1ccnc(Nc2cccc(-c3cnc(-c4cccnc4)o3)n2)c1
Yield: 8 %

Procedure:
Prepared as for 4-(2-{5-[6-(4-methyl-pyridin-2-ylamino)-pyridin-2-yl]-oxazol-2-yl}-vinyl)-benzonitrile above using (4-methyl-pyridin-2-yl)-(6-oxazol-5-yl-pyridin-2-yl)-amine, 3-bromopyridine, Pd(PPh3)4, LiOtBu and anhydrous 1,4-dioxane to afford the title compound as a pale yellow solid (8%). 1H NMR (300 MHz, DMSO-d6) δ=9.81 (s, 1H), 9.31 (s, 1H), 8.76 (d, J=4.8 Hz, 1H), 8.46 (d, J=8.1 Hz, 1H), 8.12 (d, J=5.0 Hz, 1H), 7.91 (s, 2H), 7.84-7.76 (m, 1H), 7.69-7.52 (m, 2H), 7.45 (d, J=7.4 Hz, 1H), 6.79 (d, J=5.0 Hz, 1H), 2.36 (s, 3H). (ESI+) m/z 330 (M+H).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]([N:10]2[CH2:15][CH2:14][C@:13]([CH2:22][C:23]([OH:26])([CH3:25])[CH3:24])([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[O:12][C:11]2=[O:27])[CH3:9])=[CH:4][CH:3]=1.Cl[C:29]1[N:30]=[N:31][C:32]([CH3:35])=[CH:33][CH:34]=1>>[OH:26][C:23]([CH3:25])([CH3:24])[CH2:22][C@@:13]1([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[O:12][C:11](=[O:27])[N:10]([C@H:8]([C:5]2[CH:6]=[CH:7][C:2]([C:29]3[N:30]=[N:31][C:32]([CH3:35])=[CH:33][CH:34]=3)=[CH:3][CH:4]=2)[CH3:9])[CH2:15][CH2:14]1
Reactant: C[C@@H](c1ccc(Br)cc1)N1CC[C@](CC(C)(C)O)(c2ccccc2)OC1=O
Reactant: Cc1ccc(Cl)nn1
Product: Cc1ccc(-c2ccc([C@H](C)N3CC[C@](CC(C)(C)O)(c4ccccc4)OC3=O)cc2)nn1

Procedure:
The title compound was prepared from (S)-3-((S)-1-(4-bromophenyl)ethyl)-6-(2-hydroxy-2-methylpropyl)-6-phenyl-1,3-oxazinan-2-one following procedures analogous to those described in Example 313 Steps 3 and 4 using 3-chloro-6-methylpyridazine in Step 4. LC-MS Method 2 tR=1.118, m/z=446; 1H NMR (CD3OD) 0.96 (s, 3H), 1.26 (s, 3H), 1.58 (d, 3H), 2.17 (s, 2H), 2.26 (m, 1H), 2.50 (m, 2H), 2.69 (s, 3H), 3.08 (m, 1H), 5.59 (m, 1H), 7.11 (m, 2H), 7.25-7.40 (5H), 7.63 (m, 1H), 7.82 (m, 2H), 7.98 (d, 1H).
Reaction SMILES: [CH2:1]([CH2:3][NH2:4])[OH:2].Br[CH2:6][C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8].C(N(CC)CC)C>CN(C)C=O>[C:10]([O:9][C:7](=[O:8])[CH2:6][NH:4][CH2:3][CH2:1][OH:2])([CH3:13])([CH3:12])[CH3:11]
Reactant: NCCO
Reactant: CC(C)(C)OC(=O)CBr
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)CNCCO

Procedure:
The compound is prepared, in analogy with Example 1, from ethanolamine (18.33 g; 0.3 mol) and tert-butyl bromoacetate 58.6 g; 0.3 mol) in the presence of triethylamine (30.7 g; 0.3 mol) in anhydrous N,N-dimethylformamide (300 ml). The crude product is purified by chromatography on silica gel (eluent: chloroform/methanol, 16:1). Yield: 33.65 g (64%).
Reaction SMILES: [C:1]([O:5][C:6]1[C:11]([O:12][CH3:13])=[C:10]([F:14])[N:9]=[C:8](F)[C:7]=1[F:16])([CH3:4])([CH3:3])[CH3:2].O.[NH2:18][NH2:19]>C(O)CC>[C:1]([O:5][C:6]1[C:11]([O:12][CH3:13])=[C:10]([F:14])[N:9]=[C:8]([NH:18][NH2:19])[C:7]=1[F:16])([CH3:4])([CH3:3])[CH3:2]
Reactant: COc1c(F)nc(F)c(F)c1OC(C)(C)C
Reactant: NN
Solvent: O
Solvent: CCCO
Product: COc1c(F)nc(NN)c(F)c1OC(C)(C)C
Yield: 88.5 %

Procedure:
A mixture of 4-tert-butoxy-2,3,6-trifluoro-5-methoxypyridine (1.5 g. 6.4 mmol) and hydrazine monohydrate (1.7 mL, 34 mmol [Qun Li et al. J. Med. Chem. 1996, 39(16), 3070-3088]) in n-propanol (10 mL) was heated to reflux for 3 hours. The solvent was removed in vacuo and the residue was dissolved in dichlromethane, washed with water and concentrated to afford crude (4-tert-butoxy-3,6-difluoro-5-methoxypyridin-2-yl)hydrazine (1.4 g, 90%). 1.2 g of the material was redissolved in methanol (12 mL) and 20% aqueous sodium hydroxide (2.5 mL). Oxygen was passed through the solution with vigorous stirring for 20 hours. The deep blue solution was diluted with water (12 mL) and extracted with hexane (2×30 mL). The combined organics were washed with brine, dried over sodium sulfate and concentrated in vacuo. The residue was purified by column chromatography, eluting with ethyl acetate/hexane (1:16) to afford the title compound (0.9 g). 1H NMR (400 MHz, CDCl3) δ 7.74 (m, 1H), 3.93 (m, 3H), 1.41 (s, 9H). MSCI: m/z=218 (MH+).
Reaction SMILES: [CH2:1]([O:6][C:7]1[CH:8]=[C:9]([CH:33]=[CH:34][C:35]=1[O:36][CH2:37][CH2:38][CH:39]([CH3:41])[CH3:40])[C:10]([C:12]1[CH:13]=[CH:14][C:15]([O:27][CH2:28][CH2:29][CH:30]([CH3:32])[CH3:31])=[C:16]([CH2:18][C:19]([O:21]CCC(C)C)=[O:20])[CH:17]=1)=[O:11])[CH2:2][CH:3]([CH3:5])[CH3:4].[OH-].[Na+].C(Cl)(Cl)Cl.Cl>C(O)C.O>[CH2:1]([O:6][C:7]1[CH:8]=[C:9]([CH:33]=[CH:34][C:35]=1[O:36][CH2:37][CH2:38][CH:39]([CH3:41])[CH3:40])[C:10]([C:12]1[CH:13]=[CH:14][C:15]([O:27][CH2:28][CH2:29][CH:30]([CH3:31])[CH3:32])=[C:16]([CH2:18][C:19]([OH:21])=[O:20])[CH:17]=1)=[O:11])[CH2:2][CH:3]([CH3:4])[CH3:5]
Reactant: CC(C)CCOC(=O)Cc1cc(C(=O)c2ccc(OCCC(C)C)c(OCCC(C)C)c2)ccc1OCCC(C)C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: ClC(Cl)Cl
Solvent: O
Product: CC(C)CCOc1ccc(C(=O)c2ccc(OCCC(C)C)c(OCCC(C)C)c2)cc1CC(=O)O
Temperature: 50 °C
Reaction time: 1 h
Yield: 83.6 %

Procedure:
In 12 ml of ethanol is dissolved 1.20 g of isopentyl 2-[5-(3,4-diisopentyloxybenzoyl)-2-isopentyloxyphenyl]acetate. After adding 0.6 ml of 5 mol/L aqueous solution of sodium hydroxide, the mixture is stirred at 50° C. for one hour. Chloroform and water are added to the reaction mixture, pH is adjusted to 2 with 6 mol/L hydrochloric acid, and the organic layer is separated. The organic layer is washed with water and saturated aqueous solution of sodium chloride successively, and the solvent is distilled off from the reaction mixture under reduced pressure. Thus, 0.88 g of 2-[5-(3,4-diisopentyloxybenzoyl)-2-isopentyloxyphenyl]acetic acid is obtained as a white solid product.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][C:7](=O)[NH:8]2)=[CH:4][CH:3]=1.CN(C)C1C=CC=CC=1.O=P(Cl)(Cl)[Cl:23]>C1(C)C=CC=CC=1>[Cl:23][C:7]1[NH:8][C:9]2[C:5]([CH:6]=1)=[CH:4][CH:3]=[C:2]([Cl:1])[CH:10]=2
Reactant: O=P(Cl)(Cl)Cl
Reactant: O=C1Cc2ccc(Cl)cc2N1
Solvent: Cc1ccccc1
Solvent: CN(C)c1ccccc1
Product: Clc1ccc2cc(Cl)[nH]c2c1
Temperature: 110 °C
Reaction time: 1 h
Yield: 62.9 %

Procedure:
To a stirred solution of 6-chloroindolin-2-one 1 (500 mg, 2.99 mmol) in toluene (25 mL) under inert atmosphere were added N,N-dimethylaniline (362 mg, 2.99 mmol) and POCl3 (918 g, 5.98 mmol) at RT; heated to 110° C. and stirred for 1 h. The reaction was monitored by TLC; after completion of the reaction, the reaction mixture was quenched with 10% aq. NaHCO3 solution (30 mL) and extracted with EtOAc (2×30 mL). The combined organic extracts were dried over Na2SO4, filtered and concentrated under reduced pressure to obtain the crude. This was purified by silica gel column chromatography using 5% EtOAc/Hexanes to afford compound 2 (350 mg, 63%) as an off-white solid. 1H NMR (400 MHz, CDCl3): δ 8.09 (br s, 1H), 7.41 (d, J=8.4 Hz, 1H), 7.28 (s, 1H), 7.09 (d, J=8.4 Hz, 1H), 6.39 (s, 1H); MS (ESI): m/z 184 (M−H+)
Reaction SMILES: [CH3:1][C:2]1[N:18]=[C:5]2[N:6]=[C:7](O)[C:8]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)=[C:9]([CH3:10])[N:4]2[N:3]=1.CN(C)C1C=CC=CC=1.O=P(Cl)(Cl)[Cl:30]>>[Cl:30][C:7]1[C:8]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[C:9]([CH3:10])[N:4]2[N:3]=[C:2]([CH3:1])[N:18]=[C:5]2[N:6]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: Cc1nc2nc(O)c(-c3ccccc3)c(C)n2n1
Solvent: CN(C)c1ccccc1
Product: Cc1nc2nc(Cl)c(-c3ccccc3)c(C)n2n1
Temperature: 100 °C

Procedure:
1.34 g of the product of step 1 are suspended in 20 ml POCl3. 1.06 ml N,N-dimethylaniline is added and the mixture is heated to 100° C. for 45 min. The excess of POCl3 is removed by distillation and the residue is treated with ice. The desired product precipitates and is collected by filtration.