Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:5][C:6]([C:8]1[N:13]2[C:14](=[O:19])[C@:15]([NH2:18])([O:16][CH3:17])[C@H:12]2[S:11][CH2:10][C:9]=1[CH:20]([S:27][C:28]1[NH:32][N:31]=[N:30][N:29]=1)[CH2:21][CH2:22][S:23](=[O:26])(=[O:25])[NH2:24])=[O:7])(C)(C)C.C(N(CC)[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)C>C(Cl)Cl>[C:15]([NH:18][C@:15]1([O:16][CH3:17])[C:14](=[O:19])[N:13]2[C:8]([C:6]([OH:5])=[O:7])=[C:9]([CH:20]([S:27][C:28]3[NH:32][N:31]=[N:30][N:29]=3)[CH2:21][CH2:22][S:23](=[O:25])(=[O:26])[NH2:24])[CH2:10][S:11][C@H:12]12)(=[O:16])[C@@H:14]([C:36]1[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=1)[OH:19]
Reactant: CCN(CC)c1ccccc1
Reactant: CO[C@@]1(N)C(=O)N2C(C(=O)OC(C)(C)C)=C(C(CCS(N)(=O)=O)Sc3nnn[nH]3)CS[C@@H]21
Solvent: ClCCl
Product: CO[C@@]1(NC(=O)[C@H](O)c2ccccc2)C(=O)N2C(C(=O)O)=C(C(CCS(N)(=O)=O)Sc3nnn[nH]3)CS[C@@H]21
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solution of 0.95 g. (2 mmol.) of 7β-amino-7α-methoxy-3-[1-(2-sulfamoylethyl)tetrazol-5-ylthiomethyl]-3-cephem-4-carboxylic acid t-butyl ester and 0.30 g. (2 mmol.) of N,N-diethylaniline in 100 ml. of dry methylene chloride is stirred at 0 -5° while 0.56 g. (2 mmol.) of D-O-dichloroacetylmandeloyl chloride in 10 ml. of methylene chloride is added dropwise over a 10 minute period. The mixture is stirred in the cold for 30 minutes then warmed to room temperature and stirred for an additional 30 minutes. The solution is washed with 50 ml. of cold dilute hydrochloric acid and 50 ml. of cold 5% aqueous sodium bicarbonate, dried (MgSO4) and evaporated to dryness. The residue is dissolved in a mixture of 10 ml. of trifluoroacetic acid and 2 ml. of m-dimethoxybenzene and stirred at ambient temperature for 2 hours. The excess trifluoroacetic acid is evaporated under vacuum and the residue is partitioned between 50 ml. of ether and 50 ml. of water. The pH is adjusted to 9.3-9.5 with 5% aqueous sodium carbonate and the organic phase is separated and discarded. The aqueos phase is stirred at pH 9.3-9.5 for 30 minutes, extracted with 50 ml. of ethyl acetate which is discarded, layered with fresh ethyl acetate and adjusted to pH 1.5 with dilute hydrochloric acid. The aqueous layer is extracted with three 50 ml. portions of ethyl acetate and the combined extracts are dried and evaporated to a small volume. Petroleum ether is added dropwise to precipitate the title compound which is collected and dried.
Reaction SMILES: [C:1]1([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1C(=CC(O)C)C.[C:19]([O:22]C(=O)C)(=[O:21])[CH3:20].N1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>>[C:19]([O:22][CH:30]([CH3:31])[CH:29]=[C:28]([C:16]1[CH:15]=[CH:14][C:13]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)=[CH:18][CH:17]=1)[CH3:27])(=[O:21])[CH3:20]
Reactant: CC(=CC(C)O)c1ccccc1-c1ccccc1
Reactant: CC(=O)OC(C)=O
Reactant: c1ccncc1
Product: CC(=O)OC(C)C=C(C)c1ccc(-c2ccccc2)cc1
Reaction time: 18 h

Procedure:
To a solution of 0.9 g. of 2-(p-biphenylyl)-2-penten-4-ol (obtainable by Example 1) in 75 ml. of dry pyridine, 10 ml. of acetic anhydride is added. After 18 hours at room temperature, the mixture is poured onto ice and the solids filtered off and recrystallized from pentane to give 4-acetoxy-2-(4-biphenylyl)-2-pentene, m.p. 62°-64° C., which may also be designated 4-(p-biphenylyl)-penten-2-ol acetate.
Reaction SMILES: [CH3:1][S:2]([NH:5][C:6](=[O:12])[O:7][C:8]([CH3:11])([CH3:10])[CH3:9])(=[O:4])=[O:3].[Li+].CC([N-]C(C)C)C.[C:21]1([P:27](Cl)([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)=[O:28])[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.Cl>C1COCC1.C(OCC)(=O)C.O>[C:8]([O:7][C:6](=[O:12])[NH:5][S:2]([CH2:1][P:27]([C:29]1[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=1)([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)=[O:28])(=[O:4])=[O:3])([CH3:9])([CH3:11])[CH3:10]
Reactant: CC(C)(C)OC(=O)NS(C)(=O)=O
Reactant: O=P(Cl)(c1ccccc1)c1ccccc1
Agent: CC(C)[N-]C(C)C
Agent: Cl
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)NS(=O)(=O)CP(=O)(c1ccccc1)c1ccccc1
Reaction time: 0.17 h
Yield: 73.3 %

Procedure:
To a solution of tert-butyl methylsulfonylcarbamate (2 g, 10 mmol) in THF (25 mL) at −78° C. was added LDA (2 M in THF, 15.4 mL, 30.7 mmol). Upon completion of addition, the reaction mixture stirred for 10 min and then diphenylphosphinic chloride (2.42 g, 10.2 mmol) was added drop wise to the reaction at −78° C. After 90 min, water (100 mL) was added and the reaction mixture was diluted with ethyl acetate (250 mL). The aqueous layer was adjusted to pH 5 with 5% aqueous HCl. The white precipitate that formed was filtered and the solid dried in vacuo to give tert-butyl(diphenylphosphoryl)methylsulfonylcarbamate (2.9 g, 72% yield) as a white solid.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]2[C:11]([C:12]3[CH:13]=[C:14]([CH:35]=[CH:36][CH:37]=3)[CH2:15][NH:16][C:17]([C:19]3[C:20](=[O:34])[N:21]([CH2:25][C:26]4[CH:31]=[CH:30][C:29]([F:32])=[C:28]([F:33])[CH:27]=4)[CH:22]=[CH:23][CH:24]=3)=[O:18])=[CH:10][NH:9][C:6]2=[N:7][CH:8]=1)#N.FC1C=C(C=CC=1F)CN1C=CC=C(C(NCC2C=C(B(O)O)C=CC=2)=[O:50])C1=O.[B].N1C2=NC=C(CO)C=C2C=C1>>[OH:50][CH2:1][C:3]1[CH:4]=[C:5]2[C:11]([C:12]3[CH:13]=[C:14]([CH:35]=[CH:36][CH:37]=3)[CH2:15][NH:16][C:17]([C:19]3[C:20](=[O:34])[N:21]([CH2:25][C:26]4[CH:31]=[CH:30][C:29]([F:32])=[C:28]([F:33])[CH:27]=4)[CH:22]=[CH:23][CH:24]=3)=[O:18])=[CH:10][NH:9][C:6]2=[N:7][CH:8]=1
Reactant: O=C(NCc1cccc(B(O)O)c1)c1cccn(Cc2ccc(F)c(F)c2)c1=O
Reactant: N#Cc1cnc2[nH]cc(-c3cccc(CNC(=O)c4cccn(Cc5ccc(F)c(F)c5)c4=O)c3)c2c1
Agent: OCc1cnc2[nH]ccc2c1
Agent: [B]
Product: O=C(NCc1cccc(-c2c[nH]c3ncc(CO)cc23)c1)c1cccn(Cc2ccc(F)c(F)c2)c1=O

Procedure:
Except where indicated, 1-(3,4-Difluoro-benzyl)-2-oxo-1,2-dihydro-pyridine-3-carboxylic acid 3-(5-hydroxymethyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-benzylamide was synthesized as per Example 68, 1-(3,4-Difluoro-benzyl)-2-oxo-1,2-dihydro-pyridine-3-carboxylic acid 3-(5-cyano-1H-pyrrolo[2,3-b]pyridin-3-yl)-benzylamide using 3-({[1-(3,4-Difluoro-benzyl)-2-oxo-1,2-dihydro-pyridine-3-carbonyl]-amino}-methyl)-phenylboronic acid as activated boron species and (1H-Pyrrolo[2,3-b]pyridin-5-yl)-methanol as substituted bicyclic heterocycle, to yield the title compound. 1H NMR (400 MHz, DMSO-d6) d ppm 11.935 (s, 1H) 10.072 (t, J=5.9 Hz, 1H) 8.402 (dd, J=7.4, 2.0 Hz, 1H) 8.269-8.228 (m, 2H) 8.221 (dd, J=6.7, 2.0 Hz, 1H) 7.848 (d, J=2.6 Hz, 1H) 7.679 (s, 1H) 7.594 (d, J=7.4 Hz, 1H) 7.464-7.332 (m, 3H) 7.193 (d, J=7.7 Hz, 1H) 7.175-7.120 (m, 1H) 6.589 (t, J=6.9 Hz, 1H) 5.198 (s, 2H) 4.610-4.549 (m, 4H); MS m/z=501.21 M+H.
Reaction SMILES: [CH:1]1[N:6]=[C:5]([Cl:7])[C:4]2[N:8]=[CH:9][N:10]([C@@H:11]3[O:15][C@H:14]([CH2:16][OH:17])[C@@H:13]([OH:18])[C@H:12]3[OH:19])[C:3]=2[N:2]=1.P(Cl)(Cl)(Cl)=O.[OH-].[NH4+].[P:27](OC)([O:31]C)([O:29]C)=[O:28]>O>[CH:1]1[N:6]=[C:5]([Cl:7])[C:4]2[N:8]=[CH:9][N:10]([C@@H:11]3[O:15][C@H:14]([CH2:16][O:17][P:27]([OH:31])([OH:29])=[O:28])[C@@H:13]([OH:18])[C@H:12]3[OH:19])[C:3]=2[N:2]=1
Reactant: COP(=O)(OC)OC
Reactant: OC[C@H]1O[C@@H](n2cnc3c(Cl)ncnc32)[C@H](O)[C@@H]1O
Agent: [NH4+]
Agent: [OH-]
Solvent: O
Solvent: O=P(Cl)(Cl)Cl
Product: O=P(O)(O)OC[C@H]1O[C@@H](n2cnc3c(Cl)ncnc32)[C@H](O)[C@@H]1O
Temperature: 0 °C
Reaction time: 6 h
Yield: 75 %

Procedure:
6-Chloropurine riboside (100 mg, 0.35 mmol) was dissolved in 1.75 mL of trimethyl phosphate. Phosphoryl chloride (160 mg, 1.05 mmol) was dissolved in a mixture of 0.17 mL of trimethylphosphate and 6.3 μL of water. Both solutions were cooled to 0° C., mixed and stirred on a magnetic stirrer at 0° C. After 6 hours, ice was added to quench the reaction and the pH was adjusted to 7 by addition of ammonium hydroxide solution. The crude product was then concentrated and purified on a C18 reverse phase column using water as the mobile phase. The fractions containing desired product were combined and lyophilized to dryness to afford 6-chloropurine riboside 5′-phosphate (96 mg, 0.26 mmol, 75%) as a white solid. 1H NMR (D2O, 500 MHz) δ (ppm): 4.20 (m, 2H), 4.42 (m, 1H), 4.55 (t, J=4.6 Hz, 1H), 4.84 (m, 1H), 6.28 (d, J=5.1 Hz, 1H), 8.79 (s, 1H), 8.86 (s, 1H).
Reaction SMILES: [CH2:1]([CH:3]([CH2:14][CH3:15])[CH2:4][C:5]1([C:11](O)=[O:12])[CH2:10][CH2:9][CH2:8][CH2:7][CH2:6]1)[CH3:2].C1(C(O)=O)CCCCC1.C(N(CCCC)CCCC)CCC.S(Cl)([Cl:40])=O.C(C(CC)CC1(C(OC(C2(CC(CC)CC)CCCCC2)=O)=O)CCCCC1)C>>[CH2:1]([CH:3]([CH2:14][CH3:15])[CH2:4][C:5]1([C:11]([Cl:40])=[O:12])[CH2:10][CH2:9][CH2:8][CH2:7][CH2:6]1)[CH3:2]
Reactant: CCC(CC)CC1(C(=O)O)CCCCC1
Reactant: O=S(Cl)Cl
Agent: CCC(CC)CC1(C(=O)OC(=O)C2(CC(CC)CC)CCCCC2)CCCCC1
Solvent: O=C(O)C1CCCCC1
Solvent: CCCCN(CCCC)CCCC
Product: CCC(CC)CC1(C(=O)Cl)CCCCC1
Temperature: 50 °C
Reaction time: 0.25 h
Yield: 95.8 %

Procedure:
A mixture of 103.0 mmol 1-(2-ethyl-butyl)-cyclohexanecarboxylic acid, 38.9 mmol cyclo-hexanecarboxylic acid and 173 μL tributylamine (0.71 mmol=0.005 eq. relative to the sum of both acids) was warmed to 50° C. 12.4 mL (170.3 mmol=1.2 Eq. relative to the sum of both acids) of thionyl chloride was added during 16 minutes at a temperature of 44-51° C. (reaction is endothermic, vigorous gas evolution) and the reaction mixture was kept at 53-55° C. After 15 minutes the reaction was complete (0.08% 1-(2-ethyl-butyl)-cyclohexanecarboxylic acid and no 1-(2-ethyl-butyl)-cyclohexanecarboxylic acid anhydride). After removing volatile components in vacuo (60° C. bath, 2.7-1.9 mbar followed by 120° C. bath, 8.8-13 mbar) 24.86 g of the residue was obtained (assay 95.8% 1-(2-ethyl-butyl)-cyclohexanecarbonyl chloride, yield 100%).
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][CH2:3][C:2]1=[O:6].[CH:7](=O)[CH2:8][CH2:9][CH3:10].O=P12OP3(OP(OP(O3)(O1)=O)(=O)O2)=O>C1(C)C=CC=CC=1>[CH:7]([N:1]1[CH2:5][CH2:4][CH2:3][C:2]1=[O:6])=[CH:8][CH2:9][CH3:10]
Reactant: CCCC=O
Reactant: O=C1CCCN1
Agent: O=P12OP3(=O)OP(=O)(O1)OP(=O)(O2)O3
Solvent: Cc1ccccc1
Product: CCC=CN1CCCC1=O

Procedure:
A solution of 2-pyrrolidone (50 g, 0.588 mol), butanal (42.4 g, 0.588 mol) and P2O5 (2 g, 0.014 mol) in 300 ml toluene, were refluxed together for 10 hours using Dean-Stark apparatus to collect liberated water. The resulting solution was cooled and washed with 5% solution of sodium bicarbonate and dried over anhydrous sodium sulphate. After removing the solvent under reduced pressure, 1-(but-1-enyl)pyrrolidin-2-one (I) was obtained by distillation as a liquid. (68.2 g, 83.2%). 1H NMR (CDCl3): δ 1.02 (3H, t), 2.03-2.15 (4H, m), 2.45 (2H, t), 3.5 (2H, t), 5.01 (1H, m), and 6.85 (1H, d). 13C-NMR (CDCl3): δ 172.52, 122.91, 113.8, 45.09, 31.07, 23.03, 17.27, and 14.27. IR: 2962, 2930, 1698, 1663, 1253 Cm−1.
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:10]=[CH:9][N:8]2[CH:11]=[N:12][CH:13]=[C:7]2[C:6]=1[NH:14][C:15]1[CH:20]=[CH:19][C:18]([CH:21]2[CH2:24][CH2:23][CH2:22]2)=[CH:17][C:16]=1[F:25])=[O:4].[OH-].[Na+]>O.C(O)(=O)C>[CH:21]1([C:18]2[CH:19]=[CH:20][C:15]([NH:14][C:6]3[C:7]4[N:8]([CH:11]=[N:12][CH:13]=4)[CH:9]=[CH:10][C:5]=3[C:3]([OH:4])=[O:2])=[C:16]([F:25])[CH:17]=2)[CH2:22][CH2:23][CH2:24]1
Reactant: COC(=O)c1ccn2cncc2c1Nc1ccc(C2CCC2)cc1F
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC(=O)O
Product: O=C(O)c1ccn2cncc2c1Nc1ccc(C2CCC2)cc1F
Temperature: 60 °C
Yield: 102.9 %

Procedure:
A suspension of 8-(4-cyclobutyl-2-fluoro-phenylamino)-imidazo[1,5-a]pyridine-7-carboxylic acid methyl ester (150 mg, 0.46 mmol) and 1M NaOH (1.5 mL, 1.5 mmol) in IMS (2 mL) was heated at 60° C. for 2 hours. The reaction mixture was then cooled to room temperature, diluted with water and glacial acetic acid was added to adjust pH to 4. The precipitate was filtered off and dried in a drying pistol at 40° C. for 18 hours to afford the title compound as a cream solid (154 mg, 99%). 1H NMR (DMSO-d6):10.53 (1 H, s), 8.34 (1 H, s), 7.74 (1 H, d, J=7.3 Hz), 7.35 (1 H, t, J=8.3 Hz), 7.24 (1 H, d, J=11.2 Hz), 7.13(1 H, d, J=8.1 Hz), 7.01 (1H, d, J=9.3 Hz), 6.23 (1H, s), 3.61 (1 H, m), 2.38 (2 H, m), 2.14 (2 H, m), 1.99 (1 H, m), 1.84 (1 H, m).
Reaction SMILES: [CH3:1][C:2]1([CH3:9])[O:6][CH:5]([CH2:7][OH:8])[CH2:4][O:3]1.[CH3:10][S:11](Cl)(=[O:13])=[O:12]>>[CH3:10][S:11]([O:8][CH2:7][CH:5]1[CH2:4][O:3][C:2]([CH3:9])([CH3:1])[O:6]1)(=[O:13])=[O:12]
Reactant: CC1(C)OCC(CO)O1
Reactant: CS(=O)(=O)Cl
Product: CC1(C)OCC(COS(C)(=O)=O)O1

Procedure:
reacting an optically active isomer of 2,2-dimethyl-1,3-dioxolane-4-methanol with methanesulphonyl chloride to obtain the corresponding (2,2-dimethyl-1,3-dioxolan-4-yl)methyl methanesulphonate;
Reaction SMILES: [F:1][C:2]([F:37])([F:36])[C:3]([C:18]1[C:19]([CH2:33][CH2:34][CH3:35])=[CH:20][C:21]([N:24]2[CH2:29][CH2:28][N:27]([CH2:30][CH2:31]O)[CH2:26][CH2:25]2)=[N:22][CH:23]=1)([O:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][CH:11]=1)[C:4]([F:7])([F:6])[F:5].[CH3:38][C:39]1([C:46]2[CH:51]=[CH:50][C:49]([O:52][CH:53]([CH3:55])[CH3:54])=[CH:48][CH:47]=2)[NH:43][C:42](=[O:44])[NH:41][C:40]1=[O:45].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CCOC(/N=N/C(OCC)=O)=O.Cl>CN(C)C=O.O>[F:36][C:2]([F:1])([F:37])[C:3]([C:18]1[C:19]([CH2:33][CH2:34][CH3:35])=[CH:20][C:21]([N:24]2[CH2:29][CH2:28][N:27]([CH2:30][CH2:31][N:41]3[C:40](=[O:45])[C:39]([C:46]4[CH:51]=[CH:50][C:49]([O:52][CH:53]([CH3:55])[CH3:54])=[CH:48][CH:47]=4)([CH3:38])[NH:43][C:42]3=[O:44])[CH2:26][CH2:25]2)=[N:22][CH:23]=1)([O:8][CH2:9][C:10]1[CH:11]=[CH:12][C:13]([O:16][CH3:17])=[CH:14][CH:15]=1)[C:4]([F:7])([F:6])[F:5]
Reactant: CC(C)Oc1ccc(C2(C)NC(=O)NC2=O)cc1
Reactant: CCCc1cc(N2CCN(CCO)CC2)ncc1C(OCc1ccc(OC)cc1)(C(F)(F)F)C(F)(F)F
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: CN(C)C=O
Product: CCCc1cc(N2CCN(CCN3C(=O)NC(C)(c4ccc(OC(C)C)cc4)C3=O)CC2)ncc1C(OCc1ccc(OC)cc1)(C(F)(F)F)C(F)(F)F
Temperature: 25 °C
Reaction time: 1 h
Yield: 105 %

Procedure:
2-(4-{5-[1,1,1,3,3,3-Hexafluoro-2-(4-methoxybenzyloxy)propan-2-yl]-4-propylpyridin-2-yl}piperazin-1-yl)ethanol (20 mg, 0.0373 mmol), 5-methyl-5-(4-(1-methylethoxy)phenyl)imidazolidine-2,4-dione (34.3 mg, 0.138 mmol) and triphenylphosphine (34.5 mg, 0.132 mmol) were dried with a vacuum pump, dissolved in N,N-dimethylformamide (3 mL), added DEAD (51 μL, 0.111 mmol) under ice-cold conditions, and the mixture was stirred at room temperature for 1 hour. Under ice-cold conditions, the reaction solution was added water (1.0 mL) and 2N aqueous solution of hydrochloric acid (1.0 mL), extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous sodium sulfate, and concentrated in vacuo. The obtained residue was purified by silica-gel column chromatography (hexane/acetone). The title compound (30 mg (yield 99%)) was obtained as a yellow oil.
Reaction SMILES: COC1C=CC(C(C2C=CC(OC)=C(OC)C=2)=[CH:10][C:11]#[N:12])=CC=1[N+]([O-])=O.[CH3:26][O:27][C:28]1[CH:29]=[C:30]([C:37]([C:39]2[CH:44]=[C:43]([O:45][CH3:46])[C:42]([O:47][CH3:48])=[C:41]([O:49][CH3:50])[CH:40]=2)=O)[CH:31]=[CH:32][C:33]=1[N+:34]([O-:36])=[O:35].C[Si]([N-][Si](C)(C)C)(C)C.[Li+]>>[CH3:26][O:27][C:28]1[CH:29]=[C:30]([C:37]([C:39]2[CH:44]=[C:43]([O:45][CH3:46])[C:42]([O:47][CH3:48])=[C:41]([O:49][CH3:50])[CH:40]=2)=[CH:10][C:11]#[N:12])[CH:31]=[CH:32][C:33]=1[N+:34]([O-:36])=[O:35]
Reactant: COc1cc(C(=O)c2cc(OC)c(OC)c(OC)c2)ccc1[N+](=O)[O-]
Reactant: COc1ccc(C(=CC#N)c2ccc(OC)c([N+](=O)[O-])c2)cc1OC
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Product: COc1cc(C(=CC#N)c2cc(OC)c(OC)c(OC)c2)ccc1[N+](=O)[O-]
Yield: 70 %

Procedure:
3-(3-Methoxy-4-nitro-phenyl)-3-(3,4,5-trimethoxy-phenyl)-acrylonitrile (E and Z isomers) were prepared analogously to 3-(4-methoxy-3-nitro-phenyl)-3-(3,4-dimethoxy-phenyl)-acrylonitrile using (3-methoxy-4-nitro-phenyl)-(3,4,5-trimethoxy-phenyl)-methanone (1.2 g, 3.5 mmol), lithium bis(trimethylsilyl)amide (3.9 ml, 3.9 mmol) and diethyl cyanomethylphosphate (0.7 g, 3.9 mmol). The crude product was purified by flash chromatography (silica gel, CH2Cl2) to afford mixture isomers of 3-(3-methoxy-4-nitro-phenyl)-3-(3,4,5-trimethoxy-phenyl)-acrylonitrile (0.9 g, 70%): 1H NMR (CDCl3) δ 7.93 (dd, J=8.4 and 6 Hz, 1H), 7.06-6.96 (m, 2H), 6.65 (s, 1H), 6.46 (s, 2H), 5.80(5.71) (s, 1H), 4.00-3.81 (m, 12H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.C1(=O)O[CH2:12][CH2:11][O:10]1>[I-].C([N+](CC)(CC)CC)C.C(Cl)(Cl)Cl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:12][CH2:11][OH:10])=[CH:4][CH:3]=1
Reactant: O=C1OCCO1
Reactant: Oc1ccc(Cl)cc1
Agent: CC[N+](CC)(CC)CC
Agent: [I-]
Solvent: ClC(Cl)Cl
Product: OCCOc1ccc(Cl)cc1
Temperature: 160 °C
Yield: 105.3 %

Procedure:
A mixture of 4-chlorophenol (28.3 g, 0.22 mol), ethylene carbonate (19.4 g, 0.22 mol) and tetraethylammonium iodide (10 g, 3.6 mmol) was heated at 160° C. for 3 hours and then cooled to room temperature. Chloroform (500 ml) was added and the resultant solution was washed with water and then dried over anhydrous sodium sulphate. Evaporation of the solvent gave 2-(4-chlorophenoxy)ethanol (40.0 g) which was dissolved in ether (400 ml) containing triethylamine (20 g, 0.2 mol). A solution of 4-chlorophenylsulphonyl chloride (42.0 g, 0.2 mol) in ether (150 ml) was added dropwise and the resultant mixture was refluxed for 40 hours and then cooled. The precipitate was filtered off and washed well with dichloromethane. The combined filtrate and washings were dried over anhydrous sodium sulphate. After removal of the solvent by evaporation, the residue was recrystallised from ethyl acetate to give 2-(4-chlorophenoxy)-1-(4-chlorophenylsulphonyl)ethane as a white solid (34.6 g, m.pt. 108° C.
Reaction SMILES: [OH-].[Na+].[Cl:3][C:4]1[CH:11]=[CH:10][CH:9]=[CH:8][C:5]=1[CH:6]=O.[F:12][C:13]1[CH:18]=[CH:17][C:16]([CH2:19][CH:20]=[O:21])=[CH:15][CH:14]=1>O.CO>[F:12][C:13]1[CH:18]=[CH:17][C:16](/[C:19](=[CH:6]/[C:5]2[CH:8]=[CH:9][CH:10]=[CH:11][C:4]=2[Cl:3])/[CH:20]=[O:21])=[CH:15][CH:14]=1
Reactant: O=Cc1ccccc1Cl
Reactant: O=CCc1ccc(F)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: O=C/C(=C\c1ccccc1Cl)c1ccc(F)cc1
Temperature: 10 °C
Reaction time: 10 h

Procedure:
4.2 g of sodium hydroxide in 30 ml of water are added to a solution of 35 g of 2-chlorobenzaldehyde in 300 ml of methanol. The reaction mixture is cooled to 10° C. and 36 g of 4-fluorophenylacetaldehyde are rapidly added, during which the solution warms to 30°-40° C. The reaction solution is stirred at 40° C. for 10 hours and then cooled, and the crystals which separate out are filtered off with suction.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([F:8])[C:5]([N:9]2[C:14](=[O:15])[CH:13]=[C:12]([C:16]([F:19])([F:18])[F:17])[N:11]([CH3:20])[C:10]2=[O:21])=[C:4]([F:22])[CH:3]=1.[N+:23]([O-])([OH:25])=[O:24]>S(=O)(=O)(O)O>[Cl:1][C:2]1[C:7]([N+:23]([O-:25])=[O:24])=[C:6]([F:8])[C:5]([N:9]2[C:14](=[O:15])[CH:13]=[C:12]([C:16]([F:17])([F:19])[F:18])[N:11]([CH3:20])[C:10]2=[O:21])=[C:4]([F:22])[CH:3]=1
Reactant: Cn1c(C(F)(F)F)cc(=O)n(-c2c(F)cc(Cl)cc2F)c1=O
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Product: Cn1c(C(F)(F)F)cc(=O)n(-c2c(F)cc(Cl)c([N+](=O)[O-])c2F)c1=O
Temperature: 25 °C
Reaction time: 72 h

Procedure:
A stirred solution of 211.0 grams (0.619 mole) of 3-(4-chloro-2,6-difluorophenyl)-1-methyl-6-trifluoromethyl-2,4(1H,3H)-pyrimidinedione in 600 mL of concentrated sulfuric acid was cooled to less than 10° C., and 44 mL (0.689 mole) of aqueous 70% nitric acid was added dropwise at a rate to maintain the reaction temperature below 10° C. Upon completion of addition, the reaction mixture was analyzed by GC, which indicated the reaction was incomplete. The reaction was allowed to warm to ambient temperature and an additional 5 mL (0.078 mole) of aqueous 70% nitric acid was added. The reaction mixture was again analyzed by GC, which indicated the reaction was complete. The reaction mixture was poured into ice-water. The resulting solid was collected by filtration, washed with water, and then taken up in 600 mL of methylene chloride. The resulting solution was washed with two 600 mL portions of water, one 600 mL portion of an aqueous saturated sodium bicarbonate solution, and one 600 mL portion of an aqueous saturated sodium chloride solution. The organic layer was separated, dried with magnesium sulfate, and filtered. The filtrate was concentrated under reduced pressure, yielding a waxy tan solid. The solid was triturated with heptane and allowed to stand for about 72 hours. At the conclusion of this period, the solid was collected by filtration, washed with heptane, and dried under reduced pressure, yielding 201.4 grams of title compound. The NMR spectrum was consistent with the proposed structure.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[CH:6][C:7]2[O:12][C:11]([CH3:14])([CH3:13])[C@H:10]([OH:15])[C@@H:9]([NH:16][C:17](=[O:26])[C:18]3[CH:23]=[C:22]([F:24])[CH:21]=[C:20]([F:25])[CH:19]=3)[C:8]=2[CH:27]=1)(=[O:3])[CH3:2].O.FC(F)(F)C(O)=[O:32].FC(F)(F)C(OI(C1C=CC=CC=1)OC(=O)C(F)(F)F)=O>C(#N)C>[F:24][C:22]1[CH:23]=[C:18]([CH:19]=[C:20]([F:25])[CH:21]=1)[C:17]([NH:16][C@H:9]1[C:8]2[CH:27]=[C:4]([C:1](=[O:3])[CH2:2][OH:32])[CH:5]=[CH:6][C:7]=2[O:12][C:11]([CH3:14])([CH3:13])[C@@H:10]1[OH:15])=[O:26]
Reactant: CC(=O)c1ccc2c(c1)[C@H](NC(=O)c1cc(F)cc(F)c1)[C@@H](O)C(C)(C)O2
Reactant: O=C(O)C(F)(F)F
Agent: O=C(OI(OC(=O)C(F)(F)F)c1ccccc1)C(F)(F)F
Solvent: CC#N
Solvent: O
Product: CC1(C)Oc2ccc(C(=O)CO)cc2[C@H](NC(=O)c2cc(F)cc(F)c2)[C@H]1O
Yield: 35.8 %

Procedure:
(3R,4S)-6-Acetyl-4-(3,5-difluorobenzamido)-3,4-dihydro-2,2-dimethyl-3-hydroxy-2H-1-benzopyran D3 (1.88 g, 5.0 mmol) (Example 4 of WO95/34545) was dissolved in acetonitrile (25ml), water (5 ml) and trifluoroacetic acid (0.77 ml, 10.0 mmol). [Bis(trifluoroacetoxy)iodo]benzene (4.30 g, 10.0 mmol) was added and the reaction stirred under reflux for three hours. The reaction mixture was allowed to cool and the acetonitrile was removed in vacuo, the resulting material being partitioned between water (50 ml) and dichloromethane (125 ml). The aqueous layer was extracted with further portions of dichloromethane (3×25 ml) and the combined organic extracts were dried over magnesium sulphate, filtered and the solvent removed in vacuo. The resulting yellow solid was purified by column chromatography on silica, eluting with 20% to 40% ethyl acetate in hexane to afford the title compound as a white solid (0.70 g, 36%, m.p. 179.4° C.).
Reaction SMILES: [C:1]([O:4][CH2:5][CH2:6][CH:7]1[CH2:12][CH2:11][N:10](C(OC(C)(C)C)=O)[C:9](=[O:20])[CH2:8]1)(=[O:3])[CH3:2]>C(Cl)Cl.FC(F)(F)C(O)=O>[C:1]([O:4][CH2:5][CH2:6][CH:7]1[CH2:12][CH2:11][NH:10][C:9](=[O:20])[CH2:8]1)(=[O:3])[CH3:2]
Reactant: CC(=O)OCCC1CCN(C(=O)OC(C)(C)C)C(=O)C1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(=O)OCCC1CCNC(=O)C1
Reaction time: 1 h

Procedure:
The product from Step C is dissolved in 2:1 methylene chloride and trifluoroacetic acid. The reaction is stirred for 1 h, and evaporated, giving the title compound.
Reaction SMILES: [CH3:1][C:2]1[CH:20]=[CH:19][CH:18]=[C:17]([CH3:21])[C:3]=1[CH2:4][O:5][C:6]1[CH:7]=[C:8]([CH2:14][C:15]#[N:16])[CH:9]=[CH:10][C:11]=1[O:12][CH3:13].[N-:22]=[N+:23]=[N-:24].[Na+].[Cl-].[NH4+].C(OCC)(=O)C>CN(C=O)C.CCCCCC>[CH3:21][C:17]1[CH:18]=[CH:19][CH:20]=[C:2]([CH3:1])[C:3]=1[CH2:4][O:5][C:6]1[CH:7]=[C:8]([CH:9]=[CH:10][C:11]=1[O:12][CH3:13])[CH2:14][C:15]1[NH:24][N:23]=[N:22][N:16]=1
Reactant: [N-]=[N+]=[N-]
Reactant: COc1ccc(CC#N)cc1OCc1c(C)cccc1C
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CCCCCC
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COc1ccc(Cc2nnn[nH]2)cc1OCc1c(C)cccc1C
Temperature: 90 °C

Procedure:
A mixture of 2-(3-(2,6-Dimethylbenzyloxy)-4-methoxyphenyl)acetonitrile (Step E, 2.17 g, 7.5 mmol), sodium azide (0.590 g, 9.1 mmol) and ammonium chloride (0.486 g, 9.1 mmol) in dry DMF (20 ml) was heated under argon at 90° C. for 16 hours or until all the starting material is consumed, the reaction mixture was cooled, diluted with water and extracted with EtOAc (30 ml×4). The combined organic layer was washed with brine, dried over Na2SO4, filtered, concentrated and purified by flash chromatography on a silica gel column (chloroform:methanol 95:5) to give semi solid product. The semi solid was stirred with 1:2 ethyl acetate:hexane (15 ml) for 10 minutes, and filtered to give product as a white solid.