Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][C:5]1[CH:6]=[N:7][C:8]2[C:13]([CH:14]=1)=[CH:12][CH:11]=[CH:10][CH:9]=2.[CH3:15][C:16]1[O:20][N:19]=[C:18]([C:21]2[CH:26]=[C:25]([CH3:27])[C:24](O)=[C:23]([CH3:29])[CH:22]=2)[N:17]=1.CCOC(/N=N/C(OCC)=O)=O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1COCC1>[CH3:15][C:16]1[O:20][N:19]=[C:18]([C:21]2[CH:22]=[C:23]([CH3:29])[C:24]([O:1][CH2:2][CH2:3][CH2:4][C:5]3[CH:6]=[N:7][C:8]4[C:13]([CH:14]=3)=[CH:12][CH:11]=[CH:10][CH:9]=4)=[C:25]([CH3:27])[CH:26]=2)[N:17]=1
Reactant: OCCCc1cnc2ccccc2c1
Reactant: Cc1nc(-c2cc(C)c(O)c(C)c2)no1
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: Cc1nc(-c2cc(C)c(OCCCc3cnc4ccccc4c3)c(C)c2)no1
Reaction time: 8 h
Yield: 72.7 %

Procedure:
A mixture of 3-(3-hydroxypropyl)-quinoline (250 mg, 1.34 mmol), 4-(5-methyl-1,2,4-oxadiazol-3-yl)-2,6-dimethylphenol (273 mg, 1.34 mmol), and DEAD (256 mg, 1.47 mmol) was dissolved in 12 ml of THF. To the above solution was added triphenylphosphine (385 mg, 1.47 mmol) at 20° C. and the mixture was stirred overnight. The solvent was removed in vacuo, and the residue was partitioned between an aqueous sodium bicarbonate solution and methylene chloride. The aqueous layer was extracted with methylene chloride (3x), and the organic layer dried over sodium sulfate and concentrated in vacuo. The residue was purified by silica column chromatography (20 cm column, ethyl acetate/hexane, from 1/5 to 1/3) to afford 364 mg (73%) of 3-[3-[4-(5-methyl-1,2,4-oxadiazol-3-yl)-2,6-dimethylphenoxy]-propyl]-quinoline, m.p. 105°-107° C.
Reaction SMILES: [Si:1]([O:18][CH2:19][C:20]1[C:25]([N:26]2[CH2:31][C@H:30]([CH3:32])[O:29][C@H:28]([CH3:33])[CH2:27]2)=[C:24]([Cl:34])[C:23]([F:35])=[CH:22][N:21]=1)([C:14]([CH3:17])([CH3:16])[CH3:15])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[S:36]1[C:40]([CH:41]=[O:42])=[CH:39][N:38]=[CH:37]1>>[Si:1]([O:18][CH2:19][C:20]1[N:21]=[C:22]([CH:41]([C:40]2[S:36][CH:37]=[N:38][CH:39]=2)[OH:42])[C:23]([F:35])=[C:24]([Cl:34])[C:25]=1[N:26]1[CH2:31][C@H:30]([CH3:32])[O:29][C@H:28]([CH3:33])[CH2:27]1)([C:14]([CH3:17])([CH3:15])[CH3:16])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: C[C@@H]1CN(c2c(CO[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)ncc(F)c2Cl)C[C@H](C)O1
Reactant: O=Cc1cncs1
Product: C[C@@H]1CN(c2c(CO[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)nc(C(O)c3cncs3)c(F)c2Cl)C[C@H](C)O1

Procedure:
Starting materials: (2R,6S)-4-(2-((tert-butyldiphenylsilyloxy)methyl)-4-chloro-5-fluoropyridin-3-yl)-2,6-dimethylmorpholine (Intermediate 45) and thiazole-5-carbaldehyde.
Reaction SMILES: S(Cl)([Cl:3])=O.[CH3:5][O:6][C:7]1[C:12]([CH2:13]O)=[CH:11][CH:10]=[CH:9][N:8]=1.[ClH:15]>C(Cl)Cl>[ClH:3].[CH3:5][O:6][C:7]1[C:12]([CH2:13][Cl:15])=[CH:11][CH:10]=[CH:9][N:8]=1
Reactant: O=S(Cl)Cl
Reactant: COc1ncccc1CO
Agent: Cl
Solvent: ClCCl
Product: COc1ncccc1CCl
Temperature: 25 °C
Reaction time: 1 h
Yield: 80.9 %

Procedure:
51 ml of thionyl chloride (696.67 mmol) were added dropwise to 17 g of 2-methoxy-3-picolyl alcohol.HCl (96.76 mmol) suspended in 60 ml of DCM, the solution was stirred at room temperature for 1 h, the solvent and excess thionyl chloride were removed under reduced pressure, and the residue was codistilled 4 times with methanol under reduced pressure and subsequently extracted by stirring with ether. 15.2 g of is 2-methoxy-3-picolyl chloride hydrochloride (81%) were obtained as a white crystalline salt.
Reaction SMILES: [CH3:1][CH:2]1[NH:7][CH2:6][C:5]2[S:8][C:9]([C:11]([O-:13])=O)=[N:10][C:4]=2[CH2:3]1.[Li+].Cl.[Cl:16][C:17]1[CH:18]=[C:19]2[C:24](=[CH:25][CH:26]=1)[CH:23]=[C:22]([S:27]([N:30]1[CH2:35][CH2:34][NH:33][CH:32]([C:36](=[O:47])[NH:37][CH2:38][C:39]([N:41]3[CH2:46][CH2:45][O:44][CH2:43][CH2:42]3)=[O:40])[CH2:31]1)(=[O:29])=[O:28])[CH:21]=[CH:20]2>>[ClH:16].[Cl:16][C:17]1[CH:18]=[C:19]2[C:24](=[CH:25][CH:26]=1)[CH:23]=[C:22]([S:27]([N:30]1[CH2:35][CH2:34][N:33]([C:11]([C:9]3[S:8][C:5]4[CH2:6][NH:7][CH:2]([CH3:1])[CH2:3][C:4]=4[N:10]=3)=[O:13])[CH:32]([C:36](=[O:47])[NH:37][CH2:38][C:39]([N:41]3[CH2:46][CH2:45][O:44][CH2:43][CH2:42]3)=[O:40])[CH2:31]1)(=[O:29])=[O:28])[CH:21]=[CH:20]2
Reactant: CC1Cc2nc(C(=O)[O-])sc2CN1
Reactant: O=C(NCC(=O)N1CCOCC1)C1CN(S(=O)(=O)c2ccc3cc(Cl)ccc3c2)CCN1
Agent: Cl
Agent: [Li+]
Product: CC1Cc2nc(C(=O)N3CCN(S(=O)(=O)c4ccc5cc(Cl)ccc5c4)CC3C(=O)NCC(=O)N3CCOCC3)sc2CN1

Procedure:
Starting materials : lithium 6-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridine-2-carboxylate, 1-[(6-chloronaphthalen-2-yl)sulfonyl]-3-[N-[[(morpholin-4-yl)carbonyl]methyl]carbamoyl]piperazine hydrochloride
Reaction SMILES: [CH:1]([NH:4][C:5]1[N:10]=[C:9]([O:11]C)[C:8]([C:13]2[CH:18]=[C:17]([CH3:19])[C:16]([O:20][C:21]3[CH:26]=[CH:25][N:24]=[C:23]([C:27]4[CH:28]=[N:29][N:30]([CH3:32])[CH:31]=4)[CH:22]=3)=[CH:15][N:14]=2)=[CH:7][N:6]=1)([CH3:3])[CH3:2].Br>C(O)(=O)C>[CH:1]([NH:4][C:5]1[NH:10][C:9](=[O:11])[C:8]([C:13]2[CH:18]=[C:17]([CH3:19])[C:16]([O:20][C:21]3[CH:26]=[CH:25][N:24]=[C:23]([C:27]4[CH:28]=[N:29][N:30]([CH3:32])[CH:31]=4)[CH:22]=3)=[CH:15][N:14]=2)=[CH:7][N:6]=1)([CH3:3])[CH3:2]
Reactant: COc1nc(NC(C)C)ncc1-c1cc(C)c(Oc2ccnc(-c3cnn(C)c3)c2)cn1
Agent: Br
Solvent: CC(=O)O
Product: Cc1cc(-c2cnc(NC(C)C)[nH]c2=O)ncc1Oc1ccnc(-c2cnn(C)c2)c1
Yield: 59.9 %

Procedure:
Using the procedure of Example 3, N-isopropyl-4-methoxy-5-(4-methyl-5-((2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yl)oxy)pyridin-2-yl)pyrimidin-2-amine (0.053 g, 0.12 mmol) and HBr (0.2 mL) were combined in acetic acid (3 mL) to afford 2-(isopropylamino)-5-(4-methyl-5-((2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yl)oxy)pyridin-2-yl)pyrimidin-4(3H)-one (0.03 g, 59%). 1H NMR (400 MHz, DMSO-d6): δ 10.86 (s, 1H), 8.65 (s, 1H), 8.34 (m, 2H), 8.30 (s, 1H), 8.25 (s, 1H), 7.96 (s, 1H), 7.21 (d, J=2.4 Hz, 1H), 6.63 (br s, 1H), 6.58 (dd, J=5.7, 2.4 Hz, 1H), 4.09-4.07 (m, 1H), 3.84 (s, 3H), 2.14 (s, 3H), 1.16 (d, J=6.5 Hz, 6H); MS (ESI) m/z: 418.2 (M+H+).
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[C:5]([C:7]([OH:9])=O)[CH:4]=[N:3]1.Cl.[F:11][CH:12]1[CH2:15][NH:14][CH2:13]1>>[F:11][CH:12]1[CH2:15][N:14]([C:7]([C:5]2[CH:4]=[N:3][N:2]([CH3:1])[CH:6]=2)=[O:9])[CH2:13]1
Reactant: Cn1cc(C(=O)O)cn1
Reactant: FC1CNC1
Agent: Cl
Product: Cn1cc(C(=O)N2CC(F)C2)cn1

Procedure:
From 1-methyl-1H-pyrazole-4-carboxylic acid (1.0 g, 7.93 mmol) and 3-fluoroazetidine hydrochloride (884 mg, 7.93 mmol). Off-white solid (597 mg, 41%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:19]=[CH:20][C:21]=1[Cl:22])[CH2:5][C:6]1[C:7](=[O:18])[O:8][C:9]2[C:14]([C:15]=1[CH3:16])=[CH:13][CH:12]=[C:11]([OH:17])[CH:10]=2.[I-].[CH3:24][N:25]([C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)[C:26](N1C=C[N+](C)=C1)=[O:27]>>[Cl:1][C:2]1[CH:3]=[C:4]([CH:19]=[CH:20][C:21]=1[Cl:22])[CH2:5][C:6]1[C:7](=[O:18])[O:8][C:9]2[C:14]([C:15]=1[CH3:16])=[CH:13][CH:12]=[C:11]([O:17][C:26](=[O:27])[N:25]([CH3:24])[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)[CH:10]=2
Reactant: Cc1c(Cc2ccc(Cl)c(Cl)c2)c(=O)oc2cc(O)ccc12
Reactant: CN(C(=O)n1cc[n+](C)c1)c1ccccc1
Agent: [I-]
Product: Cc1c(Cc2ccc(Cl)c(Cl)c2)c(=O)oc2cc(OC(=O)N(C)c3ccccc3)ccc12

Procedure:
The title compound was prepared from 3-(3,4-dichloro-benzyl)-7-hydroxy-4-methyl-2H-chromen-2-one and 3-(methyl-phenyl-carbamoyl)-1-methyl-3H-imidazol-1-ium iodide (white solid). HPLC-MS m/z=468 (M+1), Rt: 5.47 min.
Reaction SMILES: [CH3:1][C:2]([O:5][C:6](=[O:38])[CH:7]([NH:22][CH:23]([C:28]([NH:30][CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)=[O:29])[CH2:24][CH:25]([CH3:27])[CH3:26])[CH2:8][CH2:9][N:10]1[C:18](=[O:19])[C:17]2[C:12](=[CH:13][CH:14]=[C:15]([NH2:20])[CH:16]=2)[C:11]1=[O:21])([CH3:4])[CH3:3].ClCCl.[CH3:42][S:43](Cl)(=[O:45])=[O:44]>N1C=CC=CC=1>[CH3:1][C:2]([O:5][C:6](=[O:38])[C@H:7]([NH:22][C@H:23]([C:28]([NH:30][CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)=[O:29])[CH2:24][CH:25]([CH3:27])[CH3:26])[CH2:8][CH2:9][N:10]1[C:18](=[O:19])[C:17]2[C:12](=[CH:13][CH:14]=[C:15]([NH:20][S:43]([CH3:42])(=[O:45])=[O:44])[CH:16]=2)[C:11]1=[O:21])([CH3:4])[CH3:3]
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)CC(NC(CCN1C(=O)c2ccc(N)cc2C1=O)C(=O)OC(C)(C)C)C(=O)NCc1ccccc1
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(C)C[C@H](N[C@H](CCN1C(=O)c2ccc(NS(C)(=O)=O)cc2C1=O)C(=O)OC(C)(C)C)C(=O)NCc1ccccc1
Temperature: 0 °C
Reaction time: 8 h

Procedure:
100 mg of 2-[1-(benzylamino)carbonyl-3-methyl-butylamino]-4-(5-amino-1,3-dioxo-1,3-dihydro-isoindol-2-yl)-butanoic acid-1,1-dimethylethyl ester, prepared as in Example 73 where the protecting group Rp, 1,1-dimethylethyl, was not removed following the condensation reaction seen in Scheme 2, was added to 5 mL dichloromethane under nitrogen. The mixture was cooled to 0° C. and 0.1 mL of pyridine was added, followed by 0.014 mL methanesulfonyl chloride. The mixture was allowed to warm to room temperature and was stirred overnight. The solvent was removed by Evaporation and the residue was purified by reverse phase H.P.L.C. The solvent was removed by evaporation to give the title compound; 45 mg
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[CH2:9][OH:10].N1C=CN=C1.Cl[Si:17]([CH:24]([CH3:26])[CH3:25])([CH:21]([CH3:23])[CH3:22])[CH:18]([CH3:20])[CH3:19].O>CN(C)C=O.CN(C)C1C=CN=CC=1>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[CH2:9][O:10][Si:17]([CH:24]([CH3:26])[CH3:25])([CH:21]([CH3:23])[CH3:22])[CH:18]([CH3:20])[CH3:19]
Reactant: OCc1cc(F)ccc1Br
Reactant: CC(C)[Si](Cl)(C(C)C)C(C)C
Agent: CN(C)c1ccncc1
Agent: c1c[nH]cn1
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)[Si](OCc1cc(F)ccc1Br)(C(C)C)C(C)C
Temperature: 23 °C
Reaction time: 48 h
Yield: 93 %

Procedure:
To a solution of 5.00 g (24.4 mmol) (2-bromo-5-fluorophenyl)methanol in 100 mL N,N-dimethylformamide were added 2.49 g imidazole, 6.20 mL chloro(triisopropyl)silane, 1.49 g N,N-dimethylpyridin-4-amine and the mixture was stirred at 23° C. for 2 days. Water was added and the mixture was extracted with ethyl acetate. The organic layer was washed with brine and dried over sodium sulfate. After filtration and removal of the solvent the residue was purified by chromatography to give 8.17 g (93%) of the title compound.
Reaction SMILES: CN(C)/[CH:3]=[CH:4]/[C:5]([C:7]1[C:8]([C:21]2[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][CH:22]=2)=[N:9][N:10]2[C:15]([N:16]3[CH2:20][CH2:19][CH2:18][CH2:17]3)=[CH:14][CH:13]=[CH:12][C:11]=12)=O.S(O)(O)(=O)=O.[NH2:35][C:36]([NH2:38])=[NH:37].C(=O)([O-])[O-].[K+].[K+].C(OCC)(=O)C>CN(C)C=O.O>[CH3:28][O:27][C:24]1[CH:23]=[CH:22][C:21]([C:8]2[C:7]([C:5]3[CH:4]=[CH:3][N:35]=[C:36]([NH2:38])[N:37]=3)=[C:11]3[CH:12]=[CH:13][CH:14]=[C:15]([N:16]4[CH2:20][CH2:19][CH2:18][CH2:17]4)[N:10]3[N:9]=2)=[CH:26][CH:25]=1
Reactant: COc1ccc(-c2nn3c(N4CCCC4)cccc3c2C(=O)/C=C/N(C)C)cc1
Reactant: N=C(N)N
Agent: O=C([O-])[O-]
Agent: O=S(=O)(O)O
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COc1ccc(-c2nn3c(N4CCCC4)cccc3c2-c2ccnc(N)n2)cc1
Temperature: 25 °C
Yield: 89 %

Procedure:
To a solution of (2E)-3-(dimethylamino)-1-[2-(4-methoxyphenyl)-7-(1-pyrrolidinyl)pyrazolo[1,5-a]pyridin-3-yl]-2-propen-1-one (500 mg, 1.28 mmol) in dimethylformamide (10 mL) was added guanidine sulfate (277 mg, 1.28 mmol), followed by potassium carbonate (195 mg, 1.41 mmol). The resulting solution was heated at reflux for 6 hours. After cooling to room temperature, ethyl acetate and water were added. The phases were separated and aqueous phase extracted with additional ethyl acetate. The combined organics were dried (magnesium sulfate), filtered and concentrated in vacuo to give 4-[2-(4-methoxyphenyl)-7-(1-pyrrolidinyl)pyrazolo[1,5-a]pyridin-3-yl]-2-pyrimidinamine (440 mg, 89%) as a yellow solid. 1H NMR (CDCl3): δ 7.98 (d, 1H), 7.80 (d, 1H), 7.56 (dd, 2H), 7.20 (t, 1H), 6.92 (d, 2H), 6.43 (d, 1H), 6.05 (d, 1H), 4.95 (b, 2H), 3.83 (s, 3H), 3.74–3.70 (m, 4H), 2.01–1.98 (m, 4H); MS m/z 387 (M+1).
Reaction SMILES: P(=O)(O)(O)O.[CH3:6][N:7]([CH3:34])[C:8]([C:10]1[C:22]([CH2:23][CH2:24][CH:25]([OH:32])[C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)=[C:21](O)[C:13]2[N:14]=[C:15]([CH:18]([CH3:20])[CH3:19])[N:16]([CH3:17])[C:12]=2[CH:11]=1)=[O:9].[OH-].[Na+]>>[CH3:6][N:7]([CH3:34])[C:8]([C:10]1[C:22]2[CH2:23][CH2:24][CH:25]([C:26]3[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=3)[O:32][C:21]=2[C:13]2[N:14]=[C:15]([CH:18]([CH3:20])[CH3:19])[N:16]([CH3:17])[C:12]=2[CH:11]=1)=[O:9]
Reactant: CC(C)c1nc2c(O)c(CCC(O)c3ccccc3)c(C(=O)N(C)C)cc2n1C
Agent: O=P(O)(O)O
Agent: [Na+]
Agent: [OH-]
Product: CC(C)c1nc2c3c(c(C(=O)N(C)C)cc2n1C)CCC(c1ccccc1)O3
Temperature: 25 °C
Yield: 35.3 %

Procedure:
11.6 ml Phosphoric acid (85%) and 1.2 g (3.0 mmol) 2-isopropyl-7-hydroxy-6-(3-hydroxy-3-phenyl-propyl)-3-methyl-3H-benzoimidazole-5-carboxylic acid dimethylamide were heated at 80° C. for 90 min. After cooling to room temperature the reaction mixture was poured into ice-water, neutralized with 6 N sodium hydroxide solution and extracted with ethyl acetate. The organic layers were dried over magnesium sulphate and concentrated in vacuo. The residue was purified by chromatography on silica gel (dichloromethane/methanol=50:1) to afford 0.4 g (40%) of the title compound as a yellow solid.
Reaction SMILES: [OH:1][CH:2]([CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([C:18]([F:21])([F:20])[F:19])[CH:13]=1)[CH2:3][CH2:4][CH:5]1[NH:9][C:8](=[O:10])[CH2:7][CH2:6]1.[Si:22](Cl)([C:25]([CH3:28])([CH3:27])[CH3:26])([CH3:24])[CH3:23]>>[C:25]([Si:22]([CH3:24])([CH3:23])[O:1][CH:2]([CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([C:18]([F:21])([F:19])[F:20])[CH:13]=1)[CH2:3][CH2:4][CH:5]1[NH:9][C:8](=[O:10])[CH2:7][CH2:6]1)([CH3:28])([CH3:27])[CH3:26]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: O=C1CCC(CCC(O)Cc2cccc(C(F)(F)F)c2)N1
Product: CC(C)(C)[Si](C)(C)OC(CCC1CCC(=O)N1)Cc1cccc(C(F)(F)F)c1

Procedure:
Analogous to the procedure described for Example 1A, Step C, 5-[3-hydroxy-4-(3-trifluoromethyl-phenyl)-butyl]-pyrrolidin-2-one (1.19 g, 3.95 mmol) was protected with tert-butyldimethylsilyl chloride (893 mg, 6.22 mmol). Purification by medium pressure chromatography eluting with EtOAc provided 5-[3-(tert-butyl-dimethyl-silanyloxy)-4-(3-trifluoromethyl-phenyl)-butyl]-pyrrolidin-2-one. 1H NMR (CDCl3) δ7.47-7.32 (m, 4H), 5.73 (m, 1H), 3.86 (m, 1H), 3.59 (m, 1H), 2.75 (m, 2H), 2.35-2.20 (m, 3H), 1.70-1.40 (m, 5H), 0.81 (s, 9H), −0.05 (d, 3H), −0.3 (d, 3H); MS 416.1 (M+1).
Reaction SMILES: [OH-].[K+].[Cl:3][C:4]1[CH:18]=[CH:17][C:7]([O:8][C:9]2[CH:10]=[CH:11][CH:12]=[C:13]([CH3:16])[C:14]=2[OH:15])=[CH:6][CH:5]=1.S(OC)(O[CH3:23])(=O)=O>O>[CH3:23][O:15][C:14]1[C:13]([CH3:16])=[CH:12][CH:11]=[CH:10][C:9]=1[O:8][C:7]1[CH:6]=[CH:5][C:4]([Cl:3])=[CH:18][CH:17]=1
Reactant: Cc1cccc(Oc2ccc(Cl)cc2)c1O
Reactant: COS(=O)(=O)OC
Agent: [K+]
Agent: [OH-]
Solvent: O
Product: COc1c(C)cccc1Oc1ccc(Cl)cc1
Temperature: 25 °C

Procedure:
An aqueous solution (25 ml) of potassium hydroxide (7.5 g) was added to a mixture of 6-(4-chlorophenoxy)-o-cresol (10.5 g) and dimethyl sulfate (8.6 ml) with stirring at room temperature, and refluxed under heating for an hour. After cooling, water was added to the reaction mixture and extracted with n-hexane. The extract was washed with water, dried over magnesium sulfate and evaporated to give oily 4-chlorophenyl 2-methoxy-3-methylphenyl ether (10.7 g).
Reaction SMILES: Cl[C:2]1[C:7]([CH2:8][CH:9]([O:13][CH2:14][CH3:15])[O:10][CH2:11][CH3:12])=[C:6]([Cl:16])[N:5]=[CH:4][N:3]=1.[Cl-].[OH:18][C@@H:19]1[C@H:23]([OH:24])[C@@H:22]([CH2:25][OH:26])[CH2:21][C@H:20]1[NH3+:27].CCN(CC)CC>C(O)C>[Cl:16][C:6]1[N:5]=[CH:4][N:3]=[C:2]([NH:27][C@@H:20]2[CH2:21][C@H:22]([CH2:25][OH:26])[C@@H:23]([OH:24])[C@H:19]2[OH:18])[C:7]=1[CH2:8][CH:9]([O:13][CH2:14][CH3:15])[O:10][CH2:11][CH3:12]
Reactant: CCOC(Cc1c(Cl)ncnc1Cl)OCC
Reactant: [NH3+][C@@H]1C[C@H](CO)[C@@H](O)[C@H]1O
Agent: [Cl-]
Solvent: CCO
Solvent: CCN(CC)CC
Product: CCOC(Cc1c(Cl)ncnc1N[C@@H]1C[C@H](CO)[C@@H](O)[C@H]1O)OCC

Procedure:
A mixture of 4,6-dichloro-5-(2,2-diethoxyethyl)pyrimidine (5.35 g, 20.2 mmol) and (1R,2S,3R,4R)-2,3-dihydroxy-4-(hydroxymethyl)cyclopentanaminium chloride (9.29 g, 24.3 mmol) was taken up in ethanol (236 mL), treated with Et3N (11.2 mL, 80.8 mmol) and heated at reflux for 23 h; HPLC/LC MS indicated consumption of starting materials and presence of product. The reaction mixture was concentrated to afford a tan slurry, which was carried on crude: MS (ESI+) for C16H26ClN3O5 m/z 376.2 (M+H)+; MS (ESI−) for C16H26ClN3O5 m/z 374.2 (M−H)−; HPLC purity >95% (ret. time, 2.436 min). Variation on route from J. Med. Chem. 10, 665 (1967).
Reaction SMILES: Cl.[CH3:2][O:3][C:4](=[NH:6])[NH2:5].C[O-].[Na+].C(#N)C.[CH2:13]([C:20]1[O:21][C:22](=[O:27])[C:23](=[CH:25]O)[N:24]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>CO.O>[CH3:2][O:3][C:4]1[NH:5][C:22](=[O:27])[C:23]([NH:24][C:20](=[O:21])[CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[CH:25][N:6]=1
Reactant: COC(=N)N
Reactant: O=C1OC(Cc2ccccc2)=NC1=CO
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Solvent: CC#N
Solvent: O
Product: COc1ncc(NC(=O)Cc2ccccc2)c(=O)[nH]1
Temperature: 80 °C
Reaction time: 8 h
Yield: 62 %

Procedure:
O-Methylisourea hydrochloride (0.11 g, 1.0 mmol) was dissolved in methanol (2 ml), and 28% sodium methoxide (0.19 g, 1.0 mmol) was added. Acetonitrile was added, and the mixture was concentrated. 2-Benzyl-4-hydroxymethylene-5-oxazolone (0.203 g, 1.00 mmol) was added, and the mixture was stirred overnight at 80° C. Water (3 ml) was added, and the mixture was stirred at room temperature for 1 hour. Then, the precipitate was collected by filtration and vacuum dried to give 2-methoxy-6-oxo-5-phenylacetylamino-1,6-dihydropyrimidine (0.16 g, 0.62 mmol). The values of the shift in 1H-NMR were the same as those in Example 1.
Reaction SMILES: [H-].[Na+].[C:3]([O:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)(=[O:10])[CH2:4][C:5]([O:7][CH2:8][CH3:9])=[O:6].[F:19][C:20]1[CH:21]=[C:22]([N+:27]([O-:29])=[O:28])[CH:23]=[CH:24][C:25]=1F>CN(C=O)C>[F:19][C:20]1[CH:21]=[C:22]([N+:27]([O-:29])=[O:28])[CH:23]=[CH:24][C:25]=1[CH:4]([C:3]([O:11][CH2:12][C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1)=[O:10])[C:5]([O:7][CH2:8][CH3:9])=[O:6]
Reactant: CCOC(=O)CC(=O)OCc1ccccc1
Reactant: O=[N+]([O-])c1ccc(F)c(F)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)C(C(=O)OCc1ccccc1)c1ccc([N+](=O)[O-])cc1F
Temperature: 100 °C
Reaction time: 0.17 h
Yield: 84.1 %

Procedure:
Sodium hydride (504 mg, 12.6 mmol) was added portionwise to an ice bath chilled solution of benzyl ethyl malonate (2.9 g, 12.6 mmol) in dry DMF (20 ml) and stirred for 10 minutes. At room temperature 3,4-difluoronitrobenzene (2 g, 12.6 mmol) was added and stirred under argon. Heated at 100° C. for 20 hours. The reaction mixture was cooled and partitioned between 2N Hydrochloric acid (75 ml) and ethyl acetate (75 ml). The aqueous layer was extracted with ethyl acetate (2×75 ml) and the combined organics were evaporated to a yellow oil. Purified by chromatography on silica gel eluting with ethyl acetate/hexane (1:4) to give the title compound as a yellow oil (3.86 g, 10.6 mmol). LC/MS: Rt=3.40, [MH]+ 362
Reaction SMILES: CCC(C)[BH-](C(C)CC)C(C)CC.[Li+].[F:15][CH:16]1[C:21](=[O:22])[CH2:20][CH2:19][N:18]([C:23]([O:25][CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)=[O:24])[CH2:17]1>C1COCC1>[F:15][C@H:16]1[C@@H:21]([OH:22])[CH2:20][CH2:19][N:18]([C:23]([O:25][CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)=[O:24])[CH2:17]1
Reactant: O=C1CCN(C(=O)OCc2ccccc2)CC1F
Agent: CCC(C)[BH-](C(C)CC)C(C)CC
Agent: [Li+]
Solvent: C1CCOC1
Product: O=C(OCc1ccccc1)N1CC[C@H](O)[C@H](F)C1
Temperature: 0 °C
Reaction time: 12 h
Yield: 27.1 %

Procedure:
L-Selectride® (663 mL, 663 mmol) was added dropwise to an ice cold solution of benzyl 3-fluoro-4-oxopiperidine-1-carboxylate (138.9 g, 552.8 mmol) dissolved in anhydrous THF (421 mL). The ice bath was removed and the reaction was allowed to stand for 12 hours. The reaction mixture was carefully added (dropwise, via addition funnel) to a vigorously stirring mixture of 80 mL MeOH, 2 N NaOH (1400 mL) H2O2 (376 mL, 50%) in a large amount of ice, taking care to control the temperature rise. The mixture was stirred for 12 hours, then 2 L of EtOAc was added. The mixture was stirred an additional 1 hour. The layers were separated and the aqueous phase was extracted with EtOAc. The combined organic phases were dried over Na2SO4, filtered and concentrated in vacuo to an oil (112 g). The residue was purified by flash column chromatography (silica gel, eluting with a gradient of 30% EtOAc to 75% EtOAc in hexanes) to afford 38 g of the desired compound.
Reaction SMILES: N(C(OC(C)(C)C)=O)[C@H](C(O)=[O:5])C.[CH:14]1([N:20]=[C:21]=[N:22][CH:23]2[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]2)[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1>O1CCOCC1>[C:21]([NH:20][CH:14]1[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19]1)([NH:22][CH:23]1[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]1)=[O:5]
Reactant: C(=NC1CCCCC1)=NC1CCCCC1
Reactant: C[C@H](NC(=O)OC(C)(C)C)C(=O)O
Solvent: C1COCCO1
Product: O=C(NC1CCCCC1)NC1CCCCC1
Reaction time: 3 h

Procedure:
t-Boc-Ala (4.16 gr, 22 mmol) was dissolved in 11 ml dioxane. N,N′-Dicyclohexylcarbodiimide (DCC) (11 mmol in 11 ml 1 M DMF) was then added and the reaction was carried out for 3 hours at 25° C. under stirring. Dicyclohexylurea (DCU) formed was removed by centrifugation. The symmetrical anhydride product thus obtained (t-Boc-Ala-anhydride) was reacted overnight under stirring with 2-aminofluorene (0.925 g, 11 mmol) in 30 ml dioxane-water (1:1, v:v) containing 11 mmol of NaHCO3. The white solid formed was collected and dried under P2O5 in vacuum for 24 hours. Intermediate a was obtained in 60% yield (1.31 g, 3.34 mmol). It migrated on TLC (dichloromethane) with Rt=0.17. Mass-spectroscopy revealed a mass of 352.45 Da (calculated mass=352.2 Da).
Reaction SMILES: C(N(CC)CC)C.[C:8]([O:12][C:13]([NH:15][C@H:16]1[C@H:19]([CH3:20])[N:18]([OH:21])[C:17]1=[O:22])=[O:14])([CH3:11])([CH3:10])[CH3:9].[C:23]1([CH:29]([O:36][C:37](=[O:40])[CH2:38]Cl)[C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>CN(C)C=O>[C:8]([O:12][C:13]([NH:15][C@H:16]1[C@H:19]([CH3:20])[N:18]([O:21][CH2:38][C:37]([O:36][CH:29]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[O:40])[C:17]1=[O:22])=[O:14])([CH3:9])([CH3:11])[CH3:10]
Reactant: O=C(CCl)OC(c1ccccc1)c1ccccc1
Reactant: C[C@H]1[C@H](NC(=O)OC(C)(C)C)C(=O)N1O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: C[C@H]1[C@H](NC(=O)OC(C)(C)C)C(=O)N1OCC(=O)OC(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Triethylamine (0 61 g, 6.0 mmol was dropped into a solution of (3S-trans)-3-(t-butyloxy-carbonylamino)-1-hydroxy-4-methyl-2-azetidinone (1.08 g. 5.0 mmol) and diphenylmethylchloroacetate (1.43 g. 5.5 mmol) in 10 ml of dry dimethylformamide. The mixture was stirred overnight at room temperature. The precipitate was removed by filtration and the solvent was stripped in vacuo. The residue was taken up in ethyl acetate, filtered, washed with 5% NaHCO3 solution and with water, dried over MgSO4 and evaporated in vacuo to give a colorless oil; yield 2.0 g. By storing in a refrigerator the title compound crystallized, melting point 73°-74° C.
Reaction SMILES: F[C:2]1[C:10]([N+:11]([O-:13])=[O:12])=[CH:9][CH:8]=[C:7]2[C:3]=1/[C:4](=[CH:15]/[C:16]1[NH:20][CH:19]=[N:18][C:17]=1[CH3:21])/[C:5](=[O:14])[NH:6]2.CCN(C(C)C)C(C)C.C[Si]([N:35]=[N+:36]=[N-:37])(C)C>C1COCC1.CCO>[N:35]([C:2]1[C:10]([N+:11]([O-:13])=[O:12])=[CH:9][CH:8]=[C:7]2[C:3]=1/[C:4](=[CH:15]/[C:16]1[NH:20][CH:19]=[N:18][C:17]=1[CH3:21])/[C:5](=[O:14])[NH:6]2)=[N+:36]=[N-:37]
Reactant: Cc1nc[nH]c1/C=C1\C(=O)Nc2ccc([N+](=O)[O-])c(F)c21
Reactant: C[Si](C)(C)N=[N+]=[N-]
Solvent: CCN(C(C)C)C(C)C
Solvent: CCO
Solvent: C1CCOC1
Product: Cc1nc[nH]c1/C=C1\C(=O)Nc2ccc([N+](=O)[O-])c(N=[N+]=[N-])c21
Temperature: 25 °C

Procedure:
(Z)-1,3-Dihydro-4-fluoro-3-[(4-methyl-1H-imidazol-5-yl)methylene]-5-nitro-2H-indol-2-one (576 mg, 2.0 mmol) (from Example 42 above) was suspended in THF/EtOH (15 mL/8 mL). Hunig's base (diisopropylethyl amine, 5 mL, 30 mmol) (Aldrich) and trimethylsilyl azide (2.6 mL, 20 mmol) (Aldrich) were successively added at r.t. The mixture was heated at reflux for 3 h 20 min. The heterogeneous reaction mixture was cooled to r.t. and the orange suspension was collected by suction filtration. The precipitate was washed with ethanol and dried in a vacuum oven overnight. (Yield 490 mg, 79%).