Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H][H].[C:3]([O:6][CH:7]=[CH:8][C:9]1([CH3:14])[NH:12][C:11](=[O:13])[CH2:10]1)(=[O:5])[CH3:4]>[Pd]>[C:3]([O:6][CH2:7][CH2:8][C:9]1([CH3:14])[NH:12][C:11](=[O:13])[CH2:10]1)(=[O:5])[CH3:4]
Reactant: CC(=O)OC=CC1(C)CC(=O)N1
Reactant: [H][H]
Agent: [Pd]
Product: CC(=O)OCCC1(C)CC(=O)N1

Procedure:
A solution of 4-(2-acetoxyvinyl)-4-methyl-2-azetidinone (10.0 g) 200 ml ethyl acetate containing 100 mg of 10% Pd/C is hydrogenated on a Parr shaker at 25° C. under 40 psi hydrogen for 15 minutes. The mixture is filtered through a bed of Supercel and washed with additional ethyl acetate. The combined filtrate is evaporated in vacuo to give 4-(2-acetoxyethyl)-4-methyl-2-azetidinone.
Reaction SMILES: C1(C(C2C=CC=CC=2)O[P:9]2[O:14][CH2:13][C:12]3([CH2:19][O:18][P:17](OC(C4C=CC=CC=4)C4C=CC=CC=4)[O:16][CH2:15]3)[CH2:11][O:10]2)C=CC=CC=1.C1(C(Br)C2C=CC=CC=2)C=CC=CC=1>>[CH2:19]1[C:12]2([CH2:11][O:10][PH:9][O:14][CH2:13]2)[CH2:15][O:16][PH:17][O:18]1
Reactant: c1ccc(C(OP2OCC3(CO2)COP(OC(c2ccccc2)c2ccccc2)OC3)c2ccccc2)cc1
Agent: BrC(c1ccccc1)c1ccccc1
Product: C1OPOCC12COPOC2
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 203 %

Procedure:
560.5 g (1.0 mol) of 3,9-bis(diphenylmethoxy)-2,4,8,10-tetraoxa-3,9-diphosphaspiro[5,5]undecane and 494.3 g (2.0 mol) of diphenylmethyl bromide were charged into a reactor equipped with a stirrer, thermometer and capacitor, and dry nitrogen was caused to flow into the reactor under agitation at room temperature. Thereafter, heating was started with an oil bath which was kept at 150° C. for 15 minutes. The oil bath was removed to cool the reactor to room temperature. 2,000 ml of acetone was added to the obtained reaction product which was a white solid and stirred to clean the reaction product, and the white powder was separated by filtration with a glass filter. Then, the separated white powder was cleaned with 2,000 ml of a 50 wt % aqueous solution of methanol and dried at 100 Pa and 120° C. for 8 hours to produce 398.0 g of 2,4,8,10-tetraoxa-3,9-diphosphaspiro[5,5]undecane, 3,9-bis(diphenylmethyl)-3,9-dioxide. It was confirmed from mass spectral analysis, 1H, 31P nuclear magnetic resonance spectral analysis and elemental analysis that the product was 2,4,8,10-tetraoxa-3,9-diphosphaspiro[5,5]undecane, 3,9-bis(diphenylmethyl)-3,9-dioxide. This compound had a yield of 71%, an HPLC purity of 99.1% and an acid value of 0.39 mgKOH/g.
Reaction SMILES: [CH3:1][C@H]1OC(=O)C2C(O)=CC(O)=C(Cl)C=2CC(=O)C=CC=C[C@H]2O[C@H]2C1.C[Si](C)(C)CCOCOCCCCCCCCCCCCCCCC(O)=O.[CH:53]1([N:59]=[C:60]=[N:61][CH:62]2[CH2:67][CH2:66][CH2:65]CC2)CCCCC1>O1CCCC1>[CH3:1][N:59]([C:60]1[CH:65]=[CH:66][CH:67]=[CH:62][N:61]=1)[CH3:53]
Reactant: C[C@@H]1C[C@@H]2O[C@@H]2C=CC=CC(=O)Cc2c(Cl)c(O)cc(O)c2C(=O)O1
Reactant: C(=NC1CCCCC1)=NC1CCCCC1
Agent: C[C@@H]1C[C@@H]2O[C@@H]2/C=C\C=C\C(=O)Cc2c(Cl)c(O)cc(O)c2C(=O)O1
Agent: C[Si](C)(C)CCOCOCCCCCCCCCCCCCCCC(=O)O
Solvent: C1CCOC1
Product: CN(C)c1ccccn1

Procedure:
Following a procedure similar to that described in Example 12, but using 121 mg of radicicol, 470 mg of 16-[(2-trimethylsilylethoxy)methoxy]hexadecanoic acid, 7 ml of dry tetrahydrofuran, 240 mg of dicyclohexylcarbodiimide and a catalytic amount of dimethylaminopyridine, 481 mg of the title compound were obtained.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][C:15]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])=[CH:16][CH2:17][CH:18]([CH3:20])[CH3:19])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(=O)([O-])[O-].[K+].[K+].[CH3:34][O:35][C:36]1[CH:41]=[CH:40][C:39]([CH2:42][SH:43])=[CH:38][CH:37]=1.O>CN(C=O)C>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][CH:15]([C:21]([O:23][C:24]([CH3:25])([CH3:26])[CH3:27])=[O:22])[CH:16]([S:43][CH2:42][C:39]2[CH:40]=[CH:41][C:36]([O:35][CH3:34])=[CH:37][CH:38]=2)[CH2:17][CH:18]([CH3:20])[CH3:19])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)CC=C(CC1CCN(C(=O)OC(C)(C)C)CC1)C(=O)OC(C)(C)C
Reactant: COc1ccc(CS)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccc(CSC(CC(C)C)C(CC2CCN(C(=O)OC(C)(C)C)CC2)C(=O)OC(C)(C)C)cc1
Temperature: 25 °C
Yield: 63 %

Procedure:
A solution of 4-(2-tert-butoxycarbonyl-5-methyl-hex-2-enyl)-piperidine-1-carboxylic acid tert-butyl ester (2.0 g, 5.24 mmol) in DMF (5 mL) was added to a mixture of potassium carbonate (0.54 g, 3.93 mmol) and 4-methoxy-α-toluenethiol (1.17 g, 10.48 mmol) in DMF (50 mL) under nitrogen. The mixture was refluxed for 5 h and allowed to cool to room temperature. The reaction mixture was then poured into H2O and extracted with ethyl acetate. The organic layers were combined and washed with water. The organic layer was dried, filtered and concentrated under reduced pressure to give 3.76 g of crude material. The crude product was purified by column chromatography (ethyl acetate/hexane, 1:10) to give 4-[2-tert-butoxycarbonyl-3-(4-methoxy-benzylsulfanyl)-5-methyl-hexyl]-piperidine-1-carboxylic acid tert-butyl ester (1.77 g, 63%).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8](O)[C:9]([N:11]2[CH2:15][CH2:14][CH2:13][CH:12]2[C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([O:22][CH3:23])[CH:17]=2)=O)=[CH:4][CH:3]=1.COC1C=[C:29]([CH:33]2C[CH2:36][CH2:35][NH:34]2)[CH:30]=[CH:31][CH:32]=1.OC(C1C=CC(Br)=CC=1)C(O)=O>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]2[C:21]3[C:16](=[CH:17][C:18]([O:22][CH2:23][CH2:36][CH2:35][N:34]4[CH2:33][CH2:29][CH2:30][CH2:31][CH2:32]4)=[CH:19][CH:20]=3)[C@@H:12]3[CH2:13][CH2:14][CH2:15][N:11]3[CH2:9]2)=[CH:4][CH:3]=1
Reactant: COc1cccc(C2CCCN2)c1
Reactant: COc1cccc(C2CCCN2C(=O)C(O)c2ccc(Br)cc2)c1
Agent: O=C(O)C(O)c1ccc(Br)cc1
Product: Brc1ccc([C@@H]2CN3CCC[C@H]3c3cc(OCCCN4CCCCC4)ccc32)cc1

Procedure:
2-(4-Bromo-phenyl)-2-hydroxy-1-[2-(3-methoxy-phenyl)-pyrrolidin-1-yl]-ethanone. A solution of 2-(3-methoxy-phenyl)-pyrrolidine (16.9 mmol, 1.0 equiv.) and hydroxy-(4-bromo-phenyl)-acetic acid (1.0 equiv.) in xylenes (0.2 M) was heated at reflux for 3 d under nitrogen. The bulk of the xylenes was removed by distillation and the residue was purified by chromatography (EtOAc/hexanes) to give the desired product as a mixture of diastereomers (3.66 g, 55%). MS: exact mass calcd for C19H20BrNO3, 389.1; m/z found, 390.0 [M+H]+, 392.0 [M+H]+.
Reaction SMILES: Cl.Cl.[F:3][C:4]1[CH:5]=[CH:6][C:7]2[N:11]=[C:10]([C@@H:12]([NH2:16])[CH2:13][O:14][CH3:15])[N:9]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:8]=2[C:23]=1[F:24].Cl[C:26]1[N:34]=[CH:33][N:32]=[C:31]2[C:27]=1[N:28]=[CH:29][N:30]2[CH:35]1[CH2:40][CH2:39][CH2:38][CH2:37][O:36]1.CCN(C(C)C)C(C)C>CC(O)CC>[F:3][C:4]1[CH:5]=[CH:6][C:7]2[N:11]=[C:10]([C@@H:12]([NH:16][C:26]3[N:34]=[CH:33][N:32]=[C:31]4[C:27]=3[N:28]=[CH:29][N:30]4[CH:35]3[CH2:40][CH2:39][CH2:38][CH2:37][O:36]3)[CH2:13][O:14][CH3:15])[N:9]([C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=3)[C:8]=2[C:23]=1[F:24]
Reactant: COC[C@H](N)c1nc2ccc(F)c(F)c2n1-c1ccccc1
Reactant: Clc1ncnc2c1ncn2C1CCCCO1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CCC(C)O
Product: COC[C@H](Nc1ncnc2c1ncn2C1CCCCO1)c1nc2ccc(F)c(F)c2n1-c1ccccc1
Temperature: 90 °C

Procedure:
To a solution of (R)-1-(6,7-difluoro-1-phenyl-1H-benzoimidazol-2-yl)-2-methoxyethylamine dihydrochloride (0.20 g, 0.68 mmol) in 2-butanol (5 mL) was added 6-chloro-9-(tetrahydro-pyran-2-yl)-9H-purine (0.195 mg, 0.81 mmol) and DIPEA (233 μL, 1.36 mmol) and the reaction mixture heated at 90° C. for 16 h. The reaction mixture was concentrated in vacuo and the resultant residue was subjected to flash chromatography (SiO2, eluting with 0-10% methanol in EtOAc) to give the title compound as an off white solid (290 mg, 84%). LCMS (Method C): RT=3.48 min, [M+H]+=506.
Reaction SMILES: Cl[CH2:2][CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]([C:22]2[CH:27]=[CH:26][C:25]([OH:28])=[CH:24][CH:23]=2)=[C:12]([C:15]2[N:20]=[CH:19][C:18]([OH:21])=[CH:17][CH:16]=2)[CH2:13][CH3:14])=[CH:7][CH:6]=1.[CH3:29][NH2:30]>CO>[OH:28][C:25]1[CH:26]=[CH:27][C:22]([C:11]([C:8]2[CH:9]=[CH:10][C:5]([O:4][CH2:3][CH2:2][NH:30][CH3:29])=[CH:6][CH:7]=2)=[C:12]([C:15]2[N:20]=[CH:19][C:18]([OH:21])=[CH:17][CH:16]=2)[CH2:13][CH3:14])=[CH:23][CH:24]=1
Reactant: CCC(=C(c1ccc(O)cc1)c1ccc(OCCCl)cc1)c1ccc(O)cn1
Reactant: CN
Solvent: CO
Product: CCC(=C(c1ccc(O)cc1)c1ccc(OCCNC)cc1)c1ccc(O)cn1

Procedure:
Following the same procedure as described in example 11, step D, 6-(1-(4-(2-chloroethoxy)phenyl)-1-(4-hydroxyphenyl)but-1-en-2-yl)pyridin-3-ol (0.22 g, 1.0 eq) was reacted with MeNH2 (30% wt in water, 10 mL) in MeOH (20 mL) under reflux to give the desired product (Z/E=1/1). 1H NMR (400 MHz, DMSO-d6) δ 9.31 (brs, 1H), 8.09 (d, J=2.4 Hz, 1H), 7.08 (d, J=8.0 Hz, 1H), 6.92-6.97 (m, 2H), 6.81 (d, J=8.8 Hz, 1H), 6.75 (d, J=8.4 Hz, 1H), 6.55-6.69 (m, 4H), 6.45 (d, J=8.4 Hz, 1H), 4.06 (t, J=5.2 Hz, 1H), 3.93 (t, J=5.2 Hz, 1H), 2.93 (t, J=5.6 Hz, 1H), 2.85 (t, J=5.6 Hz, 1H), 2.46-2.50 (m, 2H), 2.40 (s, 1.5H), 2.35 (s, 1.5H), 0.83 (t, J=7.2 Hz, 3H); m/z=391[M+1]+.
Reaction SMILES: O[CH:2]1[CH2:7][N:6]([C:8]([O:10][CH2:11][CH:12]=[CH2:13])=[O:9])[C@H:5]([CH3:14])[CH2:4][CH:3]1[C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16].CS(Cl)(=O)=O.C(N(CC)CC)C.Cl>ClCCl>[CH3:14][C@@H:5]1[CH2:4][C:3]([C:15]([O:17][C:18]([CH3:19])([CH3:20])[CH3:21])=[O:16])=[CH:2][CH2:7][N:6]1[C:8]([O:10][CH2:11][CH:12]=[CH2:13])=[O:9]
Reactant: C=CCOC(=O)N1CC(O)C(C(=O)OC(C)(C)C)C[C@H]1C
Agent: CS(=O)(=O)Cl
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C=CCOC(=O)N1CC=C(C(=O)OC(C)(C)C)C[C@H]1C
Temperature: 0 °C
Reaction time: 2 h
Yield: 76.2 %

Procedure:
To a solution of 1-allyl 4-tert-butyl (2R)-5-hydroxy-2-methyl-1,4-piperidinedicarboxylate (1.85 g, 6.2 mmol) in dichloromethane (40 ml) were added at −30° C. methanesulfonyl chloride and triethylamine, and the mixture was stirred 0° C. for 2 hours. The reaction mixture was poured into diluted hydrochloric-acid and the mixture was extracted three times with chloroform. The organic layer was washed with a saturated aqueous sodium chloride solution, dried over magnesium sulfate and the solvent was removed under reduced pressure. The residue was dissolved in a mixture of toluene (5 ml) and dichloromethane (10 ml). The solution was cooled to 0° C. and thereto was added DBU. The mixture was stirred for 1 hour. The reaction mixture was poured into diluted hydrochloric acid and extracted three times with ethyl acetate. The organic layer was washed with water and then a saturated aqueous sodium chloride solution, and dried over magnesium sulfate. The solvent was removed under reduced pressure and the residue was purified by silica gel (30 g) chromatography to give 1-allyl 4-tert-butyl (2R)-2-methyl-3,6-dihydro-1,4(2 H)-pyridinedicarboxylate (1.33 g, 76%).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:10]([N+:11]([O-:13])=[O:12])=[CH:9][NH:8][N:7]=1)=[O:5])[CH3:2].CS(O[CH2:19][C:20]([F:23])([F:22])[F:21])(=O)=O>>[CH2:1]([O:3][C:4]([C:6]1[C:10]([N+:11]([O-:13])=[O:12])=[CH:9][N:8]([CH2:19][C:20]([F:23])([F:22])[F:21])[N:7]=1)=[O:5])[CH3:2]
Reactant: CS(=O)(=O)OCC(F)(F)F
Reactant: CCOC(=O)c1n[nH]cc1[N+](=O)[O-]
Product: CCOC(=O)c1nn(CC(F)(F)F)cc1[N+](=O)[O-]

Procedure:
The product was obtained as a single regioisomer according to the method described in example 4, step 2 starting from 4-nitro-1H-pyrazole-3-carboxylic acid ethyl ester and 2,2,2-trifluoroethyl methanesulfonate after purification by silica gel chromatography using a heptane/ethyl acetate gradient as yellow oil (568 mg, 84%).
Reaction SMILES: [CH3:1][O:2][C:3]([NH:5][C@H:6]([C:11]([OH:13])=O)[C:7]([CH3:10])([CH3:9])[CH3:8])=[O:4].CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.CN1CCOCC1.[CH2:42]([NH:49][NH2:50])[C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1.CCN(CC)CC>>[CH3:1][O:2][C:3](=[O:4])[NH:5][C@H:6]([C:11]([NH:50][NH:49][CH2:42][C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1)=[O:13])[C:7]([CH3:10])([CH3:9])[CH3:8]
Reactant: COC(=O)N[C@H](C(=O)O)C(C)(C)C
Reactant: NNCc1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CN1CCOCC1
Solvent: CCN(CC)CC
Product: COC(=O)N[C@H](C(=O)NNCc1ccccc1)C(C)(C)C
Yield: 50 %

Procedure:
The general procedure for the preparation of hydrazides described above was followed using N-(methoxycarbonyl)-(L)-tert-leucine (J. Med. Chem., 41, 3387-3401, 1998) (1.56 g, 8.24 mmol), EDAC (1.74 g, 9.08 mmol), HOBT (1.22 g, 9.03 mmol), NMM (0.995 mL, 9.05 mmol), benzylhydrazine×2HCl (1.61 g, 8.25 mmol) and Et3N (2.53 mL, 18.0 mmol) which gave the title compound (1.21 g, 50%) as a light yellow solid.
Reaction SMILES: [O:1]=[C:2]([CH3:20])[C:3](=[CH:9][C:10]1[CH:15]=[C:14]([O:16][CH3:17])[CH:13]=[CH:12][C:11]=1[O:18][CH3:19])[C:4]([O:6][CH2:7][CH3:8])=[O:5].[H][H]>[Pd].C(OCC)(=O)C>[O:1]=[C:2]([CH3:20])[CH:3]([CH2:9][C:10]1[CH:15]=[C:14]([O:16][CH3:17])[CH:13]=[CH:12][C:11]=1[O:18][CH3:19])[C:4]([O:6][CH2:7][CH3:8])=[O:5]
Reactant: CCOC(=O)C(=Cc1cc(OC)ccc1OC)C(C)=O
Reactant: [H][H]
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CCOC(=O)C(Cc1cc(OC)ccc1OC)C(C)=O
Reaction time: 12 h
Yield: 91.2 %

Procedure:
A mixture of 32.0 grams (0.126 mole) of ethyl 3-oxo-2-(2,5-dimethoxyphenylmethylidene)butanoate and 1.5 grams (catalyst) of 5% palladium on charcoal in 250 mL of ethyl acetate is hydrogenated using a Parr hydrogenation apparatus with hydrogen pressure at 20-40 psi. The hydrogenation requires about 12 hours. After this time, the reaction mixture is removed from the hydrogenator and filtered. The filtrate is concentrated under reduced pressure, yielding 32.2 grams of ethyl 3-oxo-2-(2,5-dimethoxy-phenylmethyl)butanoate. The NMR spectrum is consistent with the proposed structure.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([C:8]([Cl:12])=[C:9]([Cl:11])[Cl:10])[C:5]([S:13]([NH2:16])(=[O:15])=[O:14])=[CH:4][C:3]=1[S:17]([NH2:20])(=[O:19])=[O:18].[CH2:21]([NH2:27])[C:22]1[O:26][CH:25]=[CH:24][CH:23]=1>>[CH2:21]([NH:27][C:2]1[CH:7]=[C:6]([C:8]([Cl:12])=[C:9]([Cl:11])[Cl:10])[C:5]([S:13]([NH2:16])(=[O:15])=[O:14])=[CH:4][C:3]=1[S:17]([NH2:20])(=[O:19])=[O:18])[C:22]1[O:26][CH:25]=[CH:24][CH:23]=1
Reactant: NS(=O)(=O)c1cc(S(N)(=O)=O)c(C(Cl)=C(Cl)Cl)cc1Br
Reactant: NCc1ccco1
Product: NS(=O)(=O)c1cc(S(N)(=O)=O)c(C(Cl)=C(Cl)Cl)cc1NCc1ccco1

Procedure:
4-Bromo-6-trichlorovinyl-1,3-benzenedisulfonamide and furfurylamine are reacted at 70° C. for 10 hours in analogy to above procedure to give 4-furfurylamino-6-(1,2,2-trichlorovinyl)-1,3-benzenedisulfonamide with m.p. 155°-155° C.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[C:6]([O:8][CH2:9][C:10]2[CH:19]=[CH:18][C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[N:11]=2)[CH:5]=[CH:4][C:3]=1[C:20](=[O:22])[CH3:21].Br[CH2:24][C:25]1[CH:37]=[CH:36][CH:35]=[C:34]([CH3:38])[C:26]=1[O:27][CH2:28][C:29]([O:31][CH2:32][CH3:33])=[O:30].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.C(#N)C>[C:20]([C:3]1[CH:4]=[CH:5][C:6]([O:8][CH2:9][C:10]2[CH:19]=[CH:18][C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[N:11]=2)=[CH:7][C:2]=1[O:1][CH2:24][C:25]1[CH:37]=[CH:36][CH:35]=[C:34]([CH3:38])[C:26]=1[O:27][CH2:28][C:29]([O:31][CH2:32][CH3:33])=[O:30])(=[O:22])[CH3:21]
Reactant: CC(=O)c1ccc(OCc2ccc3ccccc3n2)cc1O
Reactant: CCOC(=O)COc1c(C)cccc1CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: CN(C)C=O
Product: CCOC(=O)COc1c(C)cccc1COc1cc(OCc2ccc3ccccc3n2)ccc1C(C)=O
Temperature: 50 °C

Procedure:
1-[2-Hydroxy-4-(quinolin-2-ylmethoxy)-phenyl]-ethanone (185 mg, 0.63 mmol, example 58) is dissolved in 2:1 DMF/acetonitrile (6 mL). Ethyl (2-bromomethyl-6-methyl-phenoxy)-acetate (272 mg, 0.95 mmol, example 43b) and K2CO3 (177 mg, 1.26 mmol) are added and the contents are heated to 50° C. for 2 days. The reaction is cooled to r.t. and the volume reduced under a nitrogen stream at 40° C. The contents are partitioned between ethyl acetate (50 mL) and water (50 mL). The aqueous layer is further extracted with ethyl acetate (2×50 mL). The organic fractions are combined and washed with brine (3×75 mL), dried over MgSO4 and concentrated. The crude material is dissolved in 1:1 dichloromethane/methanol, preadsorbed onto silica gel, and purified by flash chromatography (silica, 20% ethyl acetate in hexanes) to give the title compound. MS (ion spray) 500 (M+H)+.
Reaction SMILES: [NH2:1][NH2:2].Cl[C:4]1[C:9]([N+:10]([O-:12])=[O:11])=[CH:8][C:7]([N+:13]([O-:15])=[O:14])=[CH:6][N:5]=1.N>CO>[N+:10]([C:9]1[C:4]([NH:1][NH2:2])=[N:5][CH:6]=[C:7]([N+:13]([O-:15])=[O:14])[CH:8]=1)([O-:12])=[O:11]
Reactant: O=[N+]([O-])c1cnc(Cl)c([N+](=O)[O-])c1
Reactant: NN
Agent: N
Solvent: CO
Product: NNc1ncc([N+](=O)[O-])cc1[N+](=O)[O-]

Procedure:
Hydrazine (anhydrous, 0.75 ml, 23.9 mmol) was added to a solution of 2-chloro-3,5-dinitro-pyridine (3.42 g, 16.8 mmol) in methanol (25 mL). The resultant mixture was stirred at room temperature overnight. Solvent was evaporated, and the residue was washed with water and methanol several times to remove the impurities. A dark solid powder was obtained (3.0 g). MS (DCI/NH3) m/e: 200 (M+1). 1H NMR (DMSO-d6, 300MHz) d: 9.25 (m, 1H), 9.06 (m, 1H).
Reaction SMILES: [NH2:1][C@@H:2]([C@H:38]([C:46]1[CH:54]=[CH:53][C:49]2[O:50][CH2:51][O:52][C:48]=2[CH:47]=1)[C:39]1[CH:44]=[CH:43][C:42]([Cl:45])=[CH:41][CH:40]=1)[C:3]([NH:5][C:6]1[CH:7]=[N:8][CH:9]=[C:10]([F:37])[C:11]=1[CH2:12][CH2:13][C@H:14]1[O:19][CH2:18][C@@H:17]([CH2:20][O:21][C:22](=[O:29])[NH:23][CH2:24][C:25]([F:28])([F:27])[F:26])[N:16]([C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[CH2:15]1)=[O:4].C(N(CC)CC)C.Cl[C:63]([O:65][CH3:66])=[O:64]>ClCCl>[O:50]1[C:49]2[CH:53]=[CH:54][C:46]([C@H:38]([C:39]3[CH:40]=[CH:41][C:42]([Cl:45])=[CH:43][CH:44]=3)[C@H:2]([NH:1][C:63]([O:65][CH3:66])=[O:64])[C:3]([NH:5][C:6]3[CH:7]=[N:8][CH:9]=[C:10]([F:37])[C:11]=3[CH2:12][CH2:13][C@H:14]3[O:19][CH2:18][C@@H:17]([CH2:20][O:21][C:22](=[O:29])[NH:23][CH2:24][C:25]([F:27])([F:26])[F:28])[N:16]([C:30]([O:32][C:33]([CH3:34])([CH3:35])[CH3:36])=[O:31])[CH2:15]3)=[O:4])=[CH:47][C:48]=2[O:52][CH2:51]1
Reactant: CC(C)(C)OC(=O)N1C[C@@H](CCc2c(F)cncc2NC(=O)[C@@H](N)[C@@H](c2ccc(Cl)cc2)c2ccc3c(c2)OCO3)OC[C@H]1COC(=O)NCC(F)(F)F
Reactant: COC(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)N[C@H](C(=O)Nc1cncc(F)c1CC[C@@H]1CN(C(=O)OC(C)(C)C)[C@H](COC(=O)NCC(F)(F)F)CO1)[C@@H](c1ccc(Cl)cc1)c1ccc2c(c1)OCO2
Temperature: 25 °C
Reaction time: 6 h

Procedure:
To a stirred solution of the product from step 3 (50 mg, 0.06 mmol) in dichloromethane (2 mL) was added triethylamine (0.02 mL, 0.13 mmol) and methyl chloroformate (0.006 mL, 0.07 mmol). The mixture was stirred at ambient temperature for 6 h, then diluted with dichloromethane (10 mL) and washed with aqueous NaHCO3 and brine. The organic phase was dried (MgSO4), filtered, and the solvents were removed in vacuo. The residue was chromatographed on a 12 g SiO2 column using a gradient elution of 0-100% EtOc in hexanes. Fractions containing product were combined and the solvents were removed in vacuo to give the title compound as a gum. (M+H)+=840.
Reaction SMILES: [F:1][C:2]1[C:3]([NH:12][C:13]2[CH:18]=[CH:17][C:16]([CH2:19][CH2:20][CH2:21][OH:22])=[CH:15][C:14]=2[F:23])=[C:4]([CH:8]=[CH:9][C:10]=1[F:11])[C:5]([OH:7])=O.[NH2:24][O:25][CH2:26][CH2:27][O:28][CH:29]=[CH2:30].C[N+]1(C2N=C(OC)N=C(OC)N=2)CCOCC1.[Cl-]>>[F:1][C:2]1[C:3]([NH:12][C:13]2[CH:18]=[CH:17][C:16]([CH2:19][CH2:20][CH2:21][OH:22])=[CH:15][C:14]=2[F:23])=[C:4]([CH:8]=[CH:9][C:10]=1[F:11])[C:5]([NH:24][O:25][CH2:26][CH2:27][O:28][CH:29]=[CH2:30])=[O:7]
Reactant: O=C(O)c1ccc(F)c(F)c1Nc1ccc(CCCO)cc1F
Reactant: C=COCCON
Agent: COc1nc(OC)nc([N+]2(C)CCOCC2)n1
Agent: [Cl-]
Product: C=COCCONC(=O)c1ccc(F)c(F)c1Nc1ccc(CCCO)cc1F
Yield: 46 %

Procedure:
The title compound was prepared from reaction of 3,4-difluoro-2-[2-fluoro-4-(3-hydroxypropyl)anilino]benzoic acid with 1-[2-(aminooxy)ethoxy]ethylene and DMT-MM by the general procedure of Example 6, Step B, then purified by column chromatography on silica gel (20% EtOAc/PE as eluant) to give 3,4-difluoro-2-[2-fluoro-4-(3-hydroxypropyl)anilino]-N-[2-(vinyloxy)ethoxy]benzamide as a white solid (46%), which was employed directly in the next step. 1H NMR [400 MHz, (CD3)2SO] δ 11.93 (br s, 1 H), 8.79 (br s, 1 H), 7.44–7.38 (m, 1 H), 7.14–7.05 (m, 1H), 7.04 (dd, J=12.6, 1.6 Hz, 1 H), 6.89 (dd, J=8.2, 1.6 Hz, 1 H), 6.82 (ddd, J=8.7, 8.7, 4.4 Hz, 1 H), 6.50 (dd, J=14.3, 6.7 Hz, 1 H), 4.45 (t, J=5.1 Hz, 1 H), 4.18 (dd, J=14.3, 1.9 Hz, 1 H), 4.06–4.01 (m, 2 H), 3.98 (dd, J=6.6, 1.9 Hz, 1 H), 3.89–3.82 (m, 2 H), 3.42–3.35 (m, 2 H), 2.56 (t, J=7.7 Hz, 2 H), 1.72–1.64 (m, 2 H). LCMS (APCI−) 409 (M−H).
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]2[S:12][C:11]([S:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])=[N:10][N:5]2[C:6](=[O:9])[C:7]=1[CH3:8].[F-:21].[K+].S1(CCCC1)(=O)=O>O>[F:21][C:2]1[N:3]=[C:4]2[S:12][C:11]([S:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])=[N:10][N:5]2[C:6](=[O:9])[C:7]=1[CH3:8]
Reactant: [F-]
Reactant: CCCCCCCSc1nn2c(=O)c(C)c(Cl)nc2s1
Agent: [K+]
Solvent: O=S1(=O)CCCC1
Solvent: O
Product: CCCCCCCSc1nn2c(=O)c(C)c(F)nc2s1
Yield: 63 %

Procedure:
A solution of 8.6 g of the thus obtained 7-chloro-2-heptylthio-6-methyl-5H-1,3,4-thiadiazolo[3,2-a]pyrimidin-5-one, 3.0 g of spray dry potassium fluoride and 32 ml of sulfolane was heated at 205°~225° C. in a stream of nitrogen for 1 and half hours. After cooling, water was added to the mixture, and the mixture was extracted with toluene. The toluene layer was collected and washed with water. The toluene phase was dried over anhydrous sodium sulfate, the solvent was distilled off. The residue was purified by column chromatography on a silica gel column with an ethyl acetate/n-hexane (1:3) mixture as an eluent. After the solvent was distilled off, 5.2 g of 7-fluoro-2-heptylthio-6-methyl-5H-1,3,4-thiadiazolo[3,2-a]pyrimidin-5-one was obtained. m.p. 78°~91° C. Yield 63%.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6](Cl)[C:5]([F:9])=[CH:4][N:3]=1.[CH3:10][O:11][C:12]1[CH:13]=[C:14]([CH:16]=[CH:17][CH:18]=1)[NH2:15]>>[CH3:10][O:11][C:12]1[CH:13]=[C:14]([NH:15][C:2]2[N:7]=[C:6]([NH:15][C:14]3[CH:16]=[CH:17][CH:18]=[C:12]([O:11][CH3:10])[CH:13]=3)[C:5]([F:9])=[CH:4][N:3]=2)[CH:16]=[CH:17][CH:18]=1
Reactant: COc1cccc(N)c1
Reactant: Fc1cnc(Cl)nc1Cl
Product: COc1cccc(Nc2ncc(F)c(Nc3cccc(OC)c3)n2)c1

Procedure:
In like manner to the preparation of N2,N4-bis(3-hydroxyphenyl)-5-fluoro-2,4-pyrimidinediamine, 2,4-dichloro-5-fluoropyrimidine and 3-methoxyaniline were reacted to yield N2,N4-bis(3-methoxyphenyl)-5-fluoro-2,4-pyrimidinediamine. 1H NMR (CD3OD): δ 7.96 (d, 1H, J=5.4 Hz), 7.24 (m, 6H), 7.06 (t, 1H, J=2.4 Hz), 7.00 (dt, 1H, J=1.2 Hz), 6.79 (m, 1H), 3.72 (s, 3H), 3.70 (s, 3H); 19F NMR (CD3OD): δ−46112; LCMS: ret. time: 23.46 min.; purity: 99%; MS (m/e): 341 (MH+).
Reaction SMILES: Br[C:2]1[S:6][C:5]([C:7]2[S:8][C:9]([CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])=[CH:10][CH:11]=2)=[CH:4][CH:3]=1.[CH3:18][Si:19]([C:22]#[CH:23])([CH3:21])[CH3:20]>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.[Cu]I.C1COCC1>[CH2:12]([C:9]1[S:8][C:7]([C:5]2[S:6][C:2]([C:23]#[C:22][Si:19]([CH3:21])([CH3:20])[CH3:18])=[CH:3][CH:4]=2)=[CH:11][CH:10]=1)[CH2:13][CH2:14][CH2:15][CH2:16][CH3:17]
Reactant: CCCCCCc1ccc(-c2ccc(Br)s2)s1
Reactant: C#C[Si](C)(C)C
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CCCCCCc1ccc(-c2ccc(C#C[Si](C)(C)C)s2)s1
Yield: 62 %

Procedure:
Sonogashira cross coupling reaction was carried out using 5-bromo-5′-hexyl-2,2′-bithiophene (0.46 g, 1.39 mmol), trimethylsilyl acetylene (0.35 ml, 3.50 mmol), N-diisopropylethylamine (4.8 ml), Pd(PPh3)4 (80 mg, 0.070 mmol), CuI (13 mg, 0.070 mmol) and THF (10 ml), and the reaction was treated in accordance with a conventional method, thereby producing an intended product (yield: 62%).