Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[C:10]([SH:12])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:20][C:21]([O:23][CH3:24])=[O:22].O>CN(C)C=O>[CH3:1][C:2]1[CH:11]=[C:10]([S:12][CH2:20][C:21]([O:23][CH3:24])=[O:22])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1
Reactant: Cc1cc(S)c2ccccc2n1
Reactant: COC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)CSc1cc(C)nc2ccccc12
Reaction time: 0.25 h
Yield: 88.5 %

Procedure:
2-methylquinoline-4-thiol 5a (1.00 g, 5.71 mmol, 1.00 eq.) was dissolved in dimethylformamide (10 mL) at room temperature. Potassium carbonate (0.87 g, 6.28 mmol, 1.10 eq.) was added and the mixture was stirred for 15 minutes. Methyl bromoacetate (921 mg, 6.02 mmol, 1.05 eq.) was added dropwise to the solution, and the reaction was stirred at room temperature for 2.5 hours. Water (20 mL) was added to the reaction mixture, and the aqueous layer was extracted with ethyl acetate (30 mL). The aqueous layer was further extracted with ethyl acetate (3×50 mL), and the combined organic layers were dried over magnesium sulfate, filtered and concentrated in vacuo. The resulting residue was dried on high vacuum to yield 5b as a brown solid (1.25 g, 88%).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([C:10]([F:13])([F:12])[F:11])[C:5]=1[NH2:14])([O-:3])=[O:2].[Br:15]Br>C(O)(=O)C>[Br:15][C:8]1[CH:7]=[C:6]([C:10]([F:11])([F:12])[F:13])[C:5]([NH2:14])=[C:4]([N+:1]([O-:3])=[O:2])[CH:9]=1
Reactant: BrBr
Reactant: Nc1c([N+](=O)[O-])cccc1C(F)(F)F
Solvent: CC(=O)O
Product: Nc1c([N+](=O)[O-])cc(Br)cc1C(F)(F)F
Temperature: 25 °C
Reaction time: 18 h
Yield: 99.8 %

Procedure:
2-Nitro-6-trifluoromethyl-phenylamine (10.0 g, 48.5 mmol) was placed in a 200 mL round-bottom flask equipped with a magnetic stir bar. Glacial acetic acid (100 mL) and bromine (3.24 mL, 63.1 mmol) were added, and the mixture was stirred at RT for 18 h. The mixture was poured into ice (200 mL), and the excess bromine was quenched with 10% aq Na2S2O3 (25 mL). The precipitate was isolated by filtration and washed with water. The solid was air-dried and then dried under vacuum to yield 13.8 g (100%) of the title compound. 1H-NMR (400 MHz, CDCl3) δ: 8.49 (d, J=2.3 Hz, 1H), 7.83 (d, J=1.8 Hz, 1H).
Reaction SMILES: [NH2:1][C:2]1[N:6]([C:7]2[C:12]([Cl:13])=[CH:11][C:10]([Cl:14])=[CH:9][C:8]=2[Cl:15])[N:5]=[CH:4][C:3]=1[C:16]#[N:17].[OH-:18].[Na+]>S(=O)(=O)(O)O>[NH2:1][C:2]1[N:6]([C:7]2[C:8]([Cl:15])=[CH:9][C:10]([Cl:14])=[CH:11][C:12]=2[Cl:13])[N:5]=[CH:4][C:3]=1[C:16]([NH2:17])=[O:18]
Reactant: N#Cc1cnn(-c2c(Cl)cc(Cl)cc2Cl)c1N
Reactant: [OH-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Product: NC(=O)c1cnn(-c2c(Cl)cc(Cl)cc2Cl)c1N
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a cooled concentrated sulfuric acid (10 ml) was added portionwise 5-amino-1-(2,4,6-trichlorophenyl)-1H-pyrazole-4-carbonitrile (4.000 g, 13.9 mmol) over a period of 45 minutes. The reaction mixture was allowed to stir at room temperature for 1 hour after addition. The mixture was poured over ice with stirring and the solution was neutralized with 15% NaOH in ice-bath. Precipitate formed and was filtered to give 3.57 g of yellow solid. 1H NMR (CDCl3): 5.3(brs,2H), 5.6(brs,2H), 7.5(s,2H), 7.7(s,1H)ppm.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][CH:8]=[N:7][C:6]=2[CH:10]=1.[Br:11]N1C(=O)CCC1=O.N(C(C)(C)C#N)=NC(C)(C)C#N>C(Cl)(Cl)(Cl)Cl>[Br:11][CH2:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][CH:8]=[N:7][C:6]=2[CH:10]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1ccc2ocnc2c1
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Product: BrCc1ccc2ocnc2c1
Yield: 39.6 %

Procedure:
A mixture of 5-methylbenzoxazole (200 mg, 1.50 mmol), N-bromosuccinimide (321 mg, 1.80 mmol), and 2,2′-azobisisobutyronitrile (37 mg, 0.23 mmol) in CCl4 (3 mL) was heated at reflux for 22 h. The mixture was filtered and the filtrate was concentrated under reduced pressure. Purification of the crude material on silica gel (5% EtOAc/hexanes) gave the title compound as a colourless crystals (126 mg, 39%). 1H NMR (CDCl3) δ 4.64 (s, 2H), 7.46 (dd, 1H, J=8.6, 1.7 Hz), 7.57 (d, 1H, J=8.4 Hz), 7.83 (d, 1H, J=1.2 Hz), 8.12 (s, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8](Cl)(=[O:10])=[O:9].Cl.[C:13]1([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[CH:18]=[CH:17][C:16]([NH:19][C:20](=[O:30])[CH2:21][C:22](=[O:29])[N:23]2[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]2)=[CH:15][CH:14]=1.CCN(C(C)C)C(C)C>ClCCl>[C:13]1([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[CH:14]=[CH:15][C:16]([NH:19][C:20](=[O:30])[CH2:21][C:22]([N:23]2[CH2:24][CH2:25][N:26]([S:8]([C:3]3[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=3[Cl:1])(=[O:10])=[O:9])[CH2:27][CH2:28]2)=[O:29])=[CH:17][CH:18]=1
Reactant: O=C(CC(=O)N1CCNCC1)Nc1ccc(-c2ccccc2)cc1
Reactant: O=S(=O)(Cl)c1ccccc1Cl
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: O=C(CC(=O)N1CCN(S(=O)(=O)c2ccccc2Cl)CC1)Nc1ccc(-c2ccccc2)cc1
Reaction time: 2 h
Yield: 35.4 %

Procedure:
2-Chlorobenzenesulfonyl chloride (35.4 mg, 0.17 mmol) was added at 0° C. to a stirred solution of N-biphenyl-4-yl-3-oxo-3-piperazin-1-yl-propionamide hydrochloride (60 mg, 0.17 mmol) and DIEA (24.6 mg, 0.19 mmol) in dichloromethane (2 mL). the resulting mixture was stirred for 2 hrs then the product was extracted with dichloromethane. The organics was separated and washed with saturated sodium bicarbonate solution, followed by brine, dried over Na2SO4 and evaporated to dryness. The residue was purified by column chromatography using silica gel 60-120 mesh with 60% ethyl acetate in hexane as eluant to afford 30 mg (36%) of N-Biphenyl-4-yl-3-[4-(2-chloro-benzenesulfonyl)-piperazin-1-yl]-3-oxo-propionamide. LCMS: 498.12 (M+1)+ 96.7%. 1H NMR: (CDCl3): δ 9.6 (s, 1H), 8.06 (d, 1H), 7.56 (m, 8H), 7.42 (t, 3H), 7.34 (t, 1H), 3.78 (t, 2H), 3.7 (t, 2H), 3.48 (s, 2H), 3.38 (m, 4H).
Reaction SMILES: Br[C:2]1[C:14]2[C:13]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[C:12]3[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=3)[C:6]=2[CH:5]=[CH:4][CH:3]=1.[NH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1.CC(C)([O-])C.[Na+]>C1(C)C=CC=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.[Fe+2].C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[C:21]1([C:13]2([C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=3)[C:14]3[CH:2]=[C:3]([NH:27][C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=4)[CH:4]=[CH:5][C:6]=3[C:7]3[C:12]2=[CH:11][CH:10]=[CH:9][CH:8]=3)[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: Brc1cccc2c1C(c1ccccc1)(c1ccccc1)c1ccccc1-2
Reactant: Nc1ccccc1
Agent: [Fe+2]
Agent: [Pd+2]
Agent: CC(=O)[O-]
Solvent: Cc1ccccc1
Product: c1ccc(Nc2ccc3c(c2)C(c2ccccc2)(c2ccccc2)c2ccccc2-3)cc1

Procedure:
40 g of bromo-9,9-diphenyl-9H-fluorene (100.7 mmol), 12 ml of aniline (121 mmol), 0.85 g of DPPF (1.5 mmol), 0.3 g of palladium(II)acetate and 25 g of sodium tert-butoxide (262 mmol) are heated at the boil in 1.5 l of toluene under a protective-gas atmosphere for 18 h. The mixture is subsequently partitioned between toluene and water, and the organic phase is washed three times with water, dried over Na2SO4 and evaporated in a rotary evaporator. The residue which remains is recrystallised from heptane/ethyl acetate. The yield is 26.8 g (65 mmol, 65%).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([CH:10](OC(=O)C)[O:11]C(=O)C)=[C:6]([O:19][CH3:20])[CH:5]=1)([O-:3])=[O:2].O1CCOCC1.Cl>O>[N+:1]([C:4]1[CH:9]=[CH:8][C:7]([CH:10]=[O:11])=[C:6]([O:19][CH3:20])[CH:5]=1)([O-:3])=[O:2]
Reactant: COc1cc([N+](=O)[O-])ccc1C(OC(C)=O)OC(C)=O
Agent: Cl
Solvent: O
Solvent: C1COCCO1
Product: COc1cc([N+](=O)[O-])ccc1C=O
Temperature: 0 °C
Reaction time: 20 h
Yield: 91.2 %

Procedure:
To a 2 L rounded bottom flask equipped with a condenser and a mechanical stirrer was placed 1A (250.7 g, 0.8851 mol), dioxane (300 mL) and concentrated HCl (60 mL). The reaction mixture was heated to reflux and stirred under N2 for 20 hours. Water (250 mL) was added dropwise while maintaining the reaction mixture at reflux. After cooling to 0° C. with an ice/water bath, the resulting slurry was stirred for 30 minutes and then filtered. The cake was washed with water (4×200 mL) and suction dried for 17 hours to give 1B (146.3 g, 91%) as yellow solid. 1H NMR (CDCl3) d 10.54 (s, 1H), 8.00 (d, J=8.3 Hz, 1H), 7.91 (s, 1H), 7.89 (d, J=8.3 Hz, 1H), 4.08 (s, 3H).
Reaction SMILES: [F:1][CH:2]([F:23])[O:3][C:4]1[C:5]([OH:22])=[C:6]([C:12]2[CH:13]=[C:14]3[C:18](=[CH:19][CH:20]=2)[C:17](=[O:21])[O:16][CH2:15]3)[CH:7]=[CH:8][C:9]=1[O:10][CH3:11].C(=O)([O-])[O-].[K+].[K+].[CH2:30](Br)[CH2:31][CH3:32]>C(#N)C>[F:23][CH:2]([F:1])[O:3][C:4]1[C:5]([O:22][CH2:30][CH2:31][CH3:32])=[C:6]([C:12]2[CH:13]=[C:14]3[C:18](=[CH:19][CH:20]=2)[C:17](=[O:21])[O:16][CH2:15]3)[CH:7]=[CH:8][C:9]=1[O:10][CH3:11]
Reactant: COc1ccc(-c2ccc3c(c2)COC3=O)c(O)c1OC(F)F
Reactant: CCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCCOc1c(-c2ccc3c(c2)COC3=O)ccc(OC)c1OC(F)F
Temperature: 70 °C
Yield: 22.3 %

Procedure:
To a stirring solution of 5-(3-(difluoromethoxy)-2-hydroxy-4-methoxyphenyl)isobenzofuran-1(3H)-one (80 mg, 0.246 mmol) in acetonitrile (10 mL) was added potassium carbonate (102 mg, 0.738 mmol) and propyl bromide (60 mg, 0.492 mmol) and the resultant reaction mixture was heated to 70° C. for 16 h. The reaction mixture was cooled to RT, filtered through celite and the filtrate was concentrated under reduced pressure. The obtained residue was purified by column chromatography (silica gel, 0-20% ethyl acetate in pet ether) to afford the title compound as a solid (20 mg, 22%).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([O:25][CH3:26])=[C:6]([C:8]([C:10]2[CH:15]=[CH:14][C:13]([NH:16][C:17]3[CH:22]=[CH:21][C:20]([F:23])=[CH:19][C:18]=3[F:24])=[CH:12][CH:11]=2)=[O:9])[CH:7]=1.[CH3:27][N:28]1[CH2:33][CH2:32][C:31](/[CH:35]=[CH:36]/[Sn](CCCC)(CCCC)CCCC)([OH:34])[CH2:30][CH2:29]1>>[F:24][C:18]1[CH:19]=[C:20]([F:23])[CH:21]=[CH:22][C:17]=1[NH:16][C:13]1[CH:14]=[CH:15][C:10]([C:8]([C:6]2[CH:7]=[C:2](/[CH:36]=[CH:35]/[C:31]3([OH:34])[CH2:32][CH2:33][N:28]([CH3:27])[CH2:29][CH2:30]3)[CH:3]=[CH:4][C:5]=2[O:25][CH3:26])=[O:9])=[CH:11][CH:12]=1
Reactant: CCCC[Sn](/C=C/C1(O)CCN(C)CC1)(CCCC)CCCC
Reactant: COc1ccc(Br)cc1C(=O)c1ccc(Nc2ccc(F)cc2F)cc1
Product: COc1ccc(/C=C/C2(O)CCN(C)CC2)cc1C(=O)c1ccc(Nc2ccc(F)cc2F)cc1

Procedure:
The title compound is prepared analogously to example 9 from (5-bromo-2-methoxy-phenyl)-[4-(2,4-difluoro-phenylamino)-phenyl]-methanone and 1-methyl-4-((E)-2-tributylstannanyl-vinyl)-piperidin-4-ol.
Reaction SMILES: [CH3:1][CH:2]1[CH2:7][CH:6]([C:8]2[NH:13][C:12]3=[C:14]([CH3:17])[CH:15]=[N:16][C:11]3=[CH:10][N:9]=2)[CH2:5][CH:4]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[NH:3]1.CC[O:26]C(C)=O.[ClH:30]>CO>[OH2:26].[ClH:30].[CH3:1][CH:2]1[CH2:7][CH:6]([C:8]2[NH:13][C:12]3=[C:14]([CH3:17])[CH:15]=[N:16][C:11]3=[CH:10][N:9]=2)[CH2:5][CH:4]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[NH:3]1
Reactant: CCOC(C)=O
Agent: Cc1cnc2cnc(C3CC(C)NC(c4ccccc4)C3)[nH]c1-2
Agent: Cl
Solvent: CO
Product: O

Procedure:
Using the method described in Example 30 by employing (1-phenylbut-1-enyl) pyrrolidine (freshly prepared before use) (2.13 g, 11.5 mmol), 4,6-dichloro-5-nitropyrimidine (Aldrich Chemical Company) (2.30 g, 11.5 mmol), N,N-diisopropylethyl amine (Aldrich Chemical Company) (2.0 mL, 11.5 mmol), piperidine (1.8 mL, 18.4 mmol), NEt3 (Aldrich Chemical Company) (2.0 mL) and SnCl2 (Aldrich Chemical Company) (35 mL of a 2M solution in DMF). The residue was purified by flash chromatography on silica gel with 95:5 CHCl3:MeOH as elutant to give 304 mg (9%) of the free base as a beige colored fluffy solid. 1H NMR (DMSO-d6; 400 MHz): δ 1.63 (br s, 6), 2.27 (s, 3), 2.44 (s, 3), 3.71 (br s, 4), 7.43 (t, 1, J=7.3), 7.52 (t, 2, J=7.6), 7.65 (d, 2, J=7.4), 10.79 (s, 1). MS m/z: 307 (M+1). To a solution of 2,7-dimethyl-6-phenyl-4-piperidylpyrrolo[3,2-d]pyrimidine (0.22 g, 0.76 mmol) in 5:1 EtOAc: MeOH (30 mL) was added 1M etheral HCl (Aldrich Chemical Company) (760 mL, 0.73 mmol). The precipitate was collected by filtration, washed with ether (3×15 mL) and dried under vacuum to give 224 mg (90%) of the title compound as a white colored solid. Mp: >280° C. 1H NMR (DMSO-d6; 400 MHz): δ 1.69 (br s, 6), 2.35 (s, 3), 2.64 (s, 3), 4.03 (br s, 4), 7.52-7.60 (m, 3), 7.65-7.68 (m, 2), 11.94 (s, 1), 14.16 (s, 1). MS m/z: 307 (M+1). Anal. Calcd. for C24H24N4.1.1HCl.H2O: C, 62.74; H, 6.95; N, 15.41; Cl, 10.50. Found C, 63.09; H, 7.00; N, 15.39; Cl, 10.54.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[Cl:12])[N:8]=[C:7]([SH:13])[C:6]([CH:14]([CH3:16])[CH3:15])=[N:5]2.C(=O)([O-])[O-].[K+].[K+].Br[CH2:24][CH2:25][C:26]([O:28][CH2:29][CH3:30])=[O:27]>CN(C=O)C>[CH2:29]([O:28][C:26](=[O:27])[CH2:25][CH2:24][S:13][C:7]1[C:6]([CH:14]([CH3:16])[CH3:15])=[N:5][C:4]2[C:9](=[CH:10][C:11]([Cl:12])=[C:2]([Cl:1])[CH:3]=2)[N:8]=1)[CH3:30]
Reactant: CCOC(=O)CCBr
Reactant: CC(C)c1nc2cc(Cl)c(Cl)cc2nc1S
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)CCSc1nc2cc(Cl)c(Cl)cc2nc1C(C)C
Temperature: 25 °C
Reaction time: 96 h

Procedure:
To a solution of 6,7-dichloro-3-isopropylquinoxaline-2-thiol (36 mg, 0.13 mmol) in DMF was added potassium carbonate (55 mg, 0.40 mmol) followed by ethyl 3-bromopropionate (0.02 ml, 0.16 mmol). The reaction was stirred at room temperature for 4 days. Purification by flash column chromatography using ethyl acetate:hexanes 1:40 afforded the title compound.
Reaction SMILES: C([NH2:5])(=O)C=C.C(C=CC(N)=O)C=CC(N)=O.O=O.S(OOS([O-])(=O)=O)([O-])(=O)=O.[NH4+].[NH4+].[C:31]([OH:41])(=[O:40])[CH:32]=[CH:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1.N>O>[NH2:5][C@H:32]([C:31]([OH:41])=[O:40])[CH2:33][C:34]1[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=1
Reactant: O=C(O)C=Cc1ccccc1
Reactant: C=CC(N)=O
Agent: N
Agent: NC(=O)C=CCC=CC(N)=O
Agent: O=O
Solvent: O
Product: N[C@@H](Cc1ccccc1)C(=O)O
Reaction time: 1 h

Procedure:
One gram of microbial cells of Syncephalastrum racemosum IFO-4814, grown by the method described in Example 1, and one gram each of microbial cells of AJ-117128 (FERM P-7736, FERM BP-693) and AJ-6307 (FERM P-7892, FERM BP-694) grown by the method described in Example 2, were each suspended in 4 ml of deionized water. After cooling on ice, 750 mg of acrylamide and 45 mg of methylene-bisacrylamide were dissolved in each suspension, the oxygen was completely displaced by introducing nitrogen gas, 3.5 mg of ammonium persulfate and 8 μl of N,N'-dimethylaminopropionitrile were added, and the mixture was allowed to stand under ice cooling. After one hour, the cell-containing gel thus formed was collected by filtration through a 50-mesh metal gauze and washed with physiological saline. Two grams of the immobilized cells thus obtained were added to an aqueous solution containing 2.0 g/dl of cinnamic acid and 5.5 ml of 28% ammonia (pH controlled to 10.5 with hydrochloric acid), and the reaction was continued at 30° C. for 24 hours. The amounts of phenylalanine formed are listed in Table 3.
Reaction SMILES: [OH:1][CH:2]([O:8][CH2:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[O:17][CH3:18])[C:3]([O:5][CH2:6][CH3:7])=[O:4].N1C=CC=CC=1.[C:25](Cl)(=[O:27])[CH3:26]>CN(C)C1C=CN=CC=1.CCCCCCC>[C:25]([O:1][CH:2]([O:8][CH2:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[O:17][CH3:18])[C:3]([O:5][CH2:6][CH3:7])=[O:4])(=[O:27])[CH3:26]
Reactant: CC(=O)Cl
Reactant: CCOC(=O)C(O)OCCc1ccccc1OC
Agent: CN(C)c1ccncc1
Solvent: CCCCCCC
Solvent: c1ccncc1
Product: CCOC(=O)C(OCCc1ccccc1OC)OC(C)=O
Temperature: 0 °C
Reaction time: 1 h

Procedure:
The solution of ethyl glyoxate (50% toluene sol, 11.66 ml) and 2-methoxybenzeneethano (12.73 ml) were stirred for 1 hr to yield ethyl 2-hydroxy-2-(2-methoxyphenethoxy)acetate. The formation of ethyl 2-hydroxy-2-(2-methoxyphenethoxy)acetate was detected by 1H NMR and the reaction mixture was cooled with ice-bath and treated with pyridine (48.4 ml), 4-dimethylaminopyridine (0.44 g), and acetyl chloride (12.85 ml). After stirring under +7° C. for 1 hr, heptane (50 ml) was added, and the ice-bath cooling was removed to let the reaction mixture reach ambient temperature followed by filtration. The filtare was washed with MTBE (3×50 ml), and the combined solvents were washed with NaHCO3 (sat aq sol), water and NaCl (sat aq sol), dried over Na2SO4, and filtered. Organics were evaporated, toluene added and evaporated. By-products and residual solvents were distilled of (0 mbar-1 mbar/72°-105° C.), and the residual was dissolved in ethyl acetate. Silica gel and active carbon were added, the solution stirred for 10 min, and filtered. Organics were evaporated to yield ethyl 2-acetoxy-2-(2-methoxyphenethoxy)acetate (12.3 g) which was used in the next step.
Reaction SMILES: [OH:1][NH:2][C:3](=[O:9])[O:4][C:5]([CH3:8])([CH3:7])[CH3:6].[CH2:10]([N:12]([CH2:16][CH3:17])[C:13](Cl)=[O:14])[CH3:11]>>[CH2:10]([N:12]([CH2:16][CH3:17])[C:13](=[O:14])[O:1][NH:2][C:3]([O:4][C:5]([CH3:8])([CH3:7])[CH3:6])=[O:9])[CH3:11]
Reactant: CCN(CC)C(=O)Cl
Reactant: CC(C)(C)OC(=O)NO
Product: CCN(CC)C(=O)ONC(=O)OC(C)(C)C

Procedure:
[(tert-Butoxy)carbonyl]amino N,N-diethylcarbamate is prepared from tert-butyl N-hydroxycarbamate and diethyl carbamoyl chloride according to Scheme 1. (0.67 g, 39%), 1H NMR (500 MHz, CHLOROFORM-d) δ ppm 7.84 (1H, br. s.), 3.33 (4H, q, 7.1 Hz), 1.48 (9H, s), 1.11-1.28 (6H, m).
Reaction SMILES: [F:1][CH:2]([F:43])[O:3][C:4]1[CH:5]=[CH:6][C:7]([C:16]2[N:33](COCC[Si](C)(C)C)[C:19]3[CH:20]=[N:21][N:22]([CH2:25][O:26][CH2:27][CH2:28][Si:29]([CH3:32])([CH3:31])[CH3:30])[C:23](=[O:24])[C:18]=3[C:17]=2[CH3:42])=[C:8]2[C:13]=1[O:12][C:11]([CH3:15])([CH3:14])[CH:10]=[CH:9]2.C1(OC2C=C(C3N(COCC[Si](C)(C)C)C4C=NN(COCC[Si](C)(C)C)C(=O)C=4C=3C)C=CC=2OC(F)F)CC1>>[F:43][CH:2]([F:1])[O:3][C:4]1[CH:5]=[CH:6][C:7]([C:16]2[NH:33][C:19]3[CH:20]=[N:21][N:22]([CH2:25][O:26][CH2:27][CH2:28][Si:29]([CH3:32])([CH3:31])[CH3:30])[C:23](=[O:24])[C:18]=3[C:17]=2[CH3:42])=[C:8]2[C:13]=1[O:12][C:11]([CH3:15])([CH3:14])[CH:10]=[CH:9]2
Reactant: Cc1c(-c2ccc(OC(F)F)c3c2C=CC(C)(C)O3)n(COCC[Si](C)(C)C)c2cnn(COCC[Si](C)(C)C)c(=O)c12
Agent: Cc1c(-c2ccc(OC(F)F)c(OC3CC3)c2)n(COCC[Si](C)(C)C)c2cnn(COCC[Si](C)(C)C)c(=O)c12
Product: Cc1c(-c2ccc(OC(F)F)c3c2C=CC(C)(C)O3)[nH]c2cnn(COCC[Si](C)(C)C)c(=O)c12
Yield: 43 %

Procedure:
Reaction and post treatment were carried out in the same manner as in Example 4-(b) except for using 574 mg (containing an amount corresponding to 0.754 mmol) of 2-(8-difluoromethoxy-2,2-dimethyl-2H-chromen-5-yl)-3-methyl-1,5-bis(2-trimethylsilylethoxymethyl)-1,5-dihydropyrrolo[2,3-d]pyridazin-4-one obtained in Example 53-(a) in place of 2-(3-cyclopropoxy-4-difluoromethoxyphenyl)-3-methyl-1,5-bis(2-trimethylsilylethoxymethyl)-1,5-dihydropyrrolo[2,3-d]-pyridazin-4-one, whereby 163 mg of the title compound was obtained as a white solid. (Yield: 43%)
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:13]=[C:12]2[C:8]([C:9]([CH2:14][C:15]3[CH:20]=[CH:19][CH:18]=[C:17]([O:21][CH2:22][C:23]4[CH:32]=[CH:31][C:30]5[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=5)[N:24]=4)[CH:16]=3)=[CH:10][NH:11]2)=[CH:7][CH:6]=1)=[O:4].CN1C2C(=CC=C(C(O)=O)C=2)C(CC2C=CC(OCC3C=CC4C(=CC=CC=4)N=3)=CC=2)=C1>>[N:24]1[C:25]2[C:30](=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH:31]=[CH:32][C:23]=1[CH2:22][O:21][C:17]1[CH:16]=[C:15]([CH:20]=[CH:19][CH:18]=1)[CH2:14][C:9]1[C:8]2[C:12](=[CH:13][C:5]([C:3]([OH:4])=[O:2])=[CH:6][CH:7]=2)[NH:11][CH:10]=1
Reactant: COC(=O)c1ccc2c(Cc3cccc(OCc4ccc5ccccc5n4)c3)c[nH]c2c1
Agent: Cn1cc(Cc2ccc(OCc3ccc4ccccc4n3)cc2)c2ccc(C(=O)O)cc21
Product: O=C(O)c1ccc2c(Cc3cccc(OCc4ccc5ccccc5n4)c3)c[nH]c2c1

Procedure:
This compound was prepared from the methyl ester (Example 15, part i) by the method described in Example 10, part iii, m.p. 221°-225° C.
Reaction SMILES: O.[NH2:2][CH2:3][CH2:4][CH2:5][N:6]([CH2:8][CH2:9][CH2:10][NH2:11])[CH3:7].CC1C=C(C)N=C(S[C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])N=1.Cl>O1CCOCC1.C(N(CC)CC)C>[C:24]([O:23][C:21]([NH:2][CH2:3][CH2:4][CH2:5][N:6]([CH2:8][CH2:9][CH2:10][NH2:11])[CH3:7])=[O:22])([CH3:27])([CH3:26])[CH3:25]
Reactant: CN(CCCN)CCCN
Reactant: Cc1cc(C)nc(SC(=O)OC(C)(C)C)n1
Agent: Cl
Solvent: C1COCCO1
Solvent: CCN(CC)CC
Solvent: O
Product: CN(CCCN)CCCNC(=O)OC(C)(C)C
Yield: 70.8 %

Procedure:
Into 180 ml of water, was dissolved 150 g of bis(3-aminopropyl)methylamine followed by 53 g of triethylamine. To the solution, while being cooled in ice and stirred, was added portionwise a solution of 83 g (1/3 equivalent) of 4,6-dimethyl-2-tert-butoxycarbonylthiopyrimidine in 200 ml of dioxane. The mixture was allowed to react at room temperature for 5 hours. The reaction mixture was stripped of the dioxane and triethyl amine by disillation under reduced pressure. The residue was adjusted to pH 2 with 6N hydrochloric acid and washed with chloroform. The aquoues layer was adjusted to pH 13.5 with sodium hydroxide and extracted with chloroform. The chloroform layer was dried over sodium sulfate and freed from the solvent by distillation under reduced pressure to yield 60 g (24% yield) of (3-tert-butoxycarbonylaminopropyl)-(3-aminopropyl)methylamine (BOC-APMP).
Reaction SMILES: O1[C:5]2([CH2:10][CH2:9][CH:8]([CH:11]([N:20]([CH3:22])[CH3:21])[CH2:12][CH2:13][C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[CH2:7][CH2:6]2)[O:4]CC1.Cl.C(OCC)C.[OH-].[Na+]>O>[CH3:22][N:20]([CH3:21])[CH:11]([CH:8]1[CH2:9][CH2:10][C:5](=[O:4])[CH2:6][CH2:7]1)[CH2:12][CH2:13][C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: CN(C)C(CCc1ccccc1)C1CCC2(CC1)OCCO2
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCOCC
Product: CN(C)C(CCc1ccccc1)C1CCC(=O)CC1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
The crude product of the ketal 7e (29.6 g, 97 mmole) was dissolved in water (44 ml), concentrated hydrochloric acid (64 ml) was added, and the mixture was stirred for 20 hours at RT. The reaction mixture was shaken with diethyl ether (2×100 ml), the aqueous phase was made alkaline with 5N NaOH while cooling with ice, and was extracted with dichloromethane (3×100 ml), dried, and concentrated by evaporation. The ketone was isolated as a colorless oil.
Reaction SMILES: [F:1][C:2]([F:26])([F:25])[C:3]1[CH:4]=[C:5]([S:9]([CH:12]([CH:14]2[CH2:17][N:16](C(OC(C)(C)C)=O)[CH2:15]2)[CH3:13])(=[O:11])=[O:10])[CH:6]=[CH:7][CH:8]=1.[C:27](#N)C>>[CH3:27][C:12]([CH:14]1[CH2:15][NH:16][CH2:17]1)([S:9]([C:5]1[CH:6]=[CH:7][CH:8]=[C:3]([C:2]([F:25])([F:26])[F:1])[CH:4]=1)(=[O:10])=[O:11])[CH3:13]
Reactant: CC(C1CN(C(=O)OC(C)(C)C)C1)S(=O)(=O)c1cccc(C(F)(F)F)c1
Reactant: CC#N
Product: CC(C)(C1CNC1)S(=O)(=O)c1cccc(C(F)(F)F)c1

Procedure:
To a 100 ml round bottom flask equipped with a reflux condenser was added tert-butyl 3-(1-{[3-(trifluoromethyl)phenyl]sulfonyl}ethyl)azetidine-1-carboxylate (0.85 g, 2.09 mmol), ceric ammonium nitrate (1.37 g, 2.5 mmol) and 15 ml acetonitrile. The resulting reaction mixture was refluxed for 3 hours. The volatiles were removed. The residue was diluted with 60 ml ethyl acetate and 50 ml saturated sodium carbonate. It was filtered through a pad of celite. The organic portion from the filtrate was washed with 50 ml brine, dried over sodium sulfate, filtered and concentrated. The residue was redissolved in hexane/CH2Cl2 (9:1), filtered and concentrated to give 0.62 g yellow sticky solid. It is about 90% pure based on 1H NMR spectra. It was used for next step without further purification.
Reaction SMILES: [N+:1]([C:4]1[CH:18]=[CH:17][C:7]([CH2:8]P(=O)(OCC)OCC)=[CH:6][CH:5]=1)([O-:3])=[O:2].[F:19][C:20]1[CH:27]=[CH:26][C:23]([CH:24]=O)=[CH:22][CH:21]=1>>[F:19][C:20]1[CH:27]=[CH:26][C:23](/[CH:24]=[CH:8]/[C:7]2[CH:6]=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:18][CH:17]=2)=[CH:22][CH:21]=1
Reactant: O=Cc1ccc(F)cc1
Reactant: CCOP(=O)(Cc1ccc([N+](=O)[O-])cc1)OCC
Product: O=[N+]([O-])c1ccc(/C=C/c2ccc(F)cc2)cc1

Procedure:
In an analogous manner to that described in Example 36 a), the reaction of diethyl (4-nitrobenzyl)phosphonate with 4-fluorobenzaldehyde yields the (E)-1-fluoro-4-[2-(4-nitrophenyl)ethenyl]-benzene as a yellow crystalline solid; MS: m/e=243 (M)+.