Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[N:3]([CH2:32][O:33][CH3:34])[C:4]([CH3:31])=[C:5]([C:20]([O:22]COC(=O)C(C)(C)C)=[O:21])[C@H:6]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([N+:17]([O-:19])=[O:18])[CH:12]=2)[C:7]=1[C:8]([OH:10])=[O:9].[N+](=C)=[N-].[OH-].[K+].CC1N(COC)C(C)=C(C(OC)=O)[C@@H:45]([C:50]2[CH:55]=[CH:54][CH:53]=[C:52]([N+]([O-])=O)[CH:51]=2)C=1C(O)=O.[C:67]1(C=[N+]=[N-])C=CC=CC=1>C(OCC)C.CO>[CH3:31][C:4]1[N:3]([CH2:32][O:33][CH3:34])[C:2]([CH3:1])=[C:7]([C:8]([O:10][CH3:67])=[O:9])[C@@H:6]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([N+:17]([O-:19])=[O:18])[CH:12]=2)[C:5]=1[C:20]([O:22][CH2:45][C:50]1[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=1)=[O:21]
Reactant: COCN1C(C)=C(C(=O)O)[C@@H](c2cccc([N+](=O)[O-])c2)C(C(=O)OCOC(=O)C(C)(C)C)=C1C
Reactant: [N-]=[N+]=Cc1ccccc1
Reactant: COCN1C(C)=C(C(=O)O)[C@H](c2cccc([N+](=O)[O-])c2)C(C(=O)OC)=C1C
Agent: C=[N+]=[N-]
Agent: [K+]
Agent: [OH-]
Solvent: CCOCC
Solvent: CO
Product: COCN1C(C)=C(C(=O)OC)[C@@H](c2cccc([N+](=O)[O-])c2)C(C(=O)OCc2ccccc2)=C1C

Procedure:
The resulting (R)-1,4-dihydro-2,6-dimethyl-1-methoxymethyl-4-(3-nitrophenyl)5-pivaloyloxymethoxycarbonyl -3-pyridinecarboxylic acid was treated with a 0.5 M solution of diazomethane in diethyl ether and then treated with a 10% potassium hydroxide solution in methanol. The resulting (S) -1,4-dihydro-2,6-dimethyl-1-methoxymethyl-4-(3-nitrophenyl)-5-methoxycarbonyl-3-pyridinecarboxylic acid (recrystallized) was reacted with phenyldiazomethane to obtain (R)-benzyl methyl 1,4-dihydro-2,6-dimethyl-1-methoxymethyl-4-(3-nitrophenyl)-3,5-pyridinedicarboxylate. As a result of HPLC (isopropanol/hexane=1/10) using CHIRALCEL OD, the optical purity was found to be 69% ee.
Reaction SMILES: [NH2:1][C:2]1[N:3]=[C:4]([OH:27])[C:5]2[CH:11]=[C:10]([C:12]#[C:13][C:14]3[CH:19]=[CH:18][C:17]([C:20]([O:22]C(C)(C)C)=[O:21])=[CH:16][CH:15]=3)[CH:9]=[N:8][C:6]=2[N:7]=1.[N+](C)([O-])=O.Cl>CCOCC>[NH2:1][C:2]1[N:3]=[C:4]([OH:27])[C:5]2[CH:11]=[C:10]([C:12]#[C:13][C:14]3[CH:19]=[CH:18][C:17]([C:20]([OH:22])=[O:21])=[CH:16][CH:15]=3)[CH:9]=[N:8][C:6]=2[N:7]=1
Reactant: CC(C)(C)OC(=O)c1ccc(C#Cc2cnc3nc(N)nc(O)c3c2)cc1
Agent: Cl
Solvent: CCOCC
Solvent: C[N+](=O)[O-]
Product: Nc1nc(O)c2cc(C#Cc3ccc(C(=O)O)cc3)cnc2n1
Reaction time: 1 h
Yield: 96 %

Procedure:
Thirty-four milligrams of 2-amino-4-hydroxy-6-(4-tert.-butoxycarbonylphenylethynyl)pyrido[2,3-d]pyrimidine is added to 15 ml of nitromethane which has been saturated with hydrogen chloride gas at 0° C. The mixture is stirred for 1 hour. Anhydrous ether is added and the solid filtered to give 27.6 mg (62%) of 2-amino-4-hydroxy-6-(4-carboxyphenylethynyl)pyrido[2,3-d]pyrimidine as a pale yellowish solid: m.p. >260° C.; NMR (DMSO-d6, 80 MHz) delta 7.71 (d, 2H, J=8.4 Hz), 8.00 (d, 2H, J=8.4 Hz), 8.40 (d, 1H, J=2.3 Hz), 8.75 (d, 1H, J=2.3 Hz).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[C:2]1[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[NH2:16].[C:17]([C:21]1[CH:26]=[CH:25][C:24]([N:27]=[C:28]=[O:29])=[CH:23][CH:22]=1)([CH3:20])([CH3:19])[CH3:18].CCCCCC>ClCCl>[NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[C:2]1[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[NH:16][C:28]([NH:27][C:24]1[CH:25]=[CH:26][C:21]([C:17]([CH3:20])([CH3:19])[CH3:18])=[CH:22][CH:23]=1)=[O:29]
Reactant: CC(C)(C)c1ccc(N=C=O)cc1
Reactant: Nc1ccccc1-c1cc2ccccc2[nH]1
Solvent: CCCCCC
Solvent: ClCCl
Product: CC(C)(C)c1ccc(NC(=O)Nc2ccccc2-c2cc3ccccc3[nH]2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of commercially available 2-(1H-indol-2-yl)benzenamine (62 mg, 0.3 mmol) in dichloromethane (1.5 mL) at rt was added 4-tert-butylphenyl isocyanate (30 mg, 0.171 mmol). The reaction was stirred overnight at rt. Hexane (1 mL) was added to the reaction mixture and the reaction was allowed to set for ˜5 min. Example 1 was the solid formed which was collected by filtration (47.3 mg). (M+H)+=384.37.
Reaction SMILES: [NH2:1][C:2]1[C:7]([N+:8]([O-])=O)=[C:6]([CH3:11])[CH:5]=[CH:4][N:3]=1.CO.O1C[CH2:17][CH2:16][CH2:15]1>[Ni]>[CH2:16]([C:17]1[NH:1][C:2]2=[N:3][CH:4]=[CH:5][C:6]([CH3:11])=[C:7]2[N:8]=1)[CH3:15]
Reactant: C1CCOC1
Reactant: Cc1ccnc(N)c1[N+](=O)[O-]
Agent: [Ni]
Solvent: CO
Product: CCc1nc2c(C)ccnc2[nH]1
Temperature: 100 °C
Reaction time: 2 h

Procedure:
10 g (65.3 mmol) of 2-amino-4-methyl-3-nitropyridine are hydrogenated in 40 ml of tetrahydrofuran and 40 ml of methanol in the presence of Raney nickel. The catalyst is filtered off, the solvent is removed, the residue is treated with ethanolic HCl solution and the precipitated 2,3-diamino-4-methylpyridine hydrochloride is filtered off with suction. 7 g of this hydrochloride are dissolved in 57 g of polyphosphoric acid (from 28.5 g of P2O5 and 28.5 g of H3PO4 (85% strength)) and treated with 1.26 ml of propionic acid, and the solution is stirred at 100° C. for 2 h. After cooling, it is poured into ice-water, rendered alkaline by addition of Na2CO3 and extracted several times with EA. The combined EA phases are washed with saturated NaCl solution, dried over Na2SO4 and concentrated and the residue is chromatographed on SiO2 (EA/MeOH 5:1). 4.2 g of the title compound result.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][C:12]([OH:14])=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl.Cl.[CH2:17]([O:24][C:25](=[O:33])[CH2:26][C@@H:27]([NH2:32])[CH2:28][N:29]([CH3:31])[CH3:30])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>>[CH2:17]([O:24][C:25](=[O:33])[CH2:26][C@@H:27]([NH:32][C:12](=[O:14])[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)[CH2:28][N:29]([CH3:30])[CH3:31])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: CN(C)C[C@H](N)CC(=O)OCc1ccccc1
Reactant: O=C(O)CCCCCc1ccccc1
Agent: Cl
Product: CN(C)C[C@@H](CC(=O)OCc1ccccc1)NC(=O)CCCCCc1ccccc1

Procedure:
The title compound, m/e=321.3 ([M+H]+), was produced in analogy with example 1, steps 3 and 4. Thus, commercially available 6-phenylhexanoic acid was coupled in step 3 with (R)-3-amino-4-dimethylamino-butyric acid benzyl ester dihydrochloride to produce (R)-4-dimethylamino-3-(6-phenyl-hexanoylamino)-butyric acid benzyl ester, which was hydrogenated in step 4.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][NH:5][CH2:4][C:3]1=[O:8].[CH3:9][N:10]([CH2:53][CH:54]=O)[C:11](=[O:52])[C:12]1[CH:51]=[CH:50][CH:49]=[C:14]([C:15]([NH:17][C:18]2[CH:23]=[CH:22][C:21]([N:24]3[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]3)=[CH:20][C:19]=2[C:30]2[CH:35]=[C:34]([C:36](=[O:48])[NH:37][C@@H:38]3[C:47]4[C:42](=[CH:43][CH:44]=[CH:45][CH:46]=4)[CH2:41][CH2:40][CH2:39]3)[CH:33]=[CH:32][N:31]=2)=[O:16])[CH:13]=1.[BH3-]C#N.[Na+]>C(O)C.C(O)(=O)C.C(OCC)(=O)C>[CH3:9][N:10]([CH2:53][CH2:54][N:5]1[CH2:6][CH2:7][N:2]([CH3:1])[C:3](=[O:8])[CH2:4]1)[C:11](=[O:52])[C:12]1[CH:51]=[CH:50][CH:49]=[C:14]([C:15]([NH:17][C:18]2[CH:23]=[CH:22][C:21]([N:24]3[CH2:25][CH2:26][CH2:27][CH2:28][CH2:29]3)=[CH:20][C:19]=2[C:30]2[CH:35]=[C:34]([C:36](=[O:48])[NH:37][C@@H:38]3[C:47]4[C:42](=[CH:43][CH:44]=[CH:45][CH:46]=4)[CH2:41][CH2:40][CH2:39]3)[CH:33]=[CH:32][N:31]=2)=[O:16])[CH:13]=1
Reactant: CN1CCNCC1=O
Reactant: CN(CC=O)C(=O)c1cccc(C(=O)Nc2ccc(N3CCCCC3)cc2-c2cc(C(=O)N[C@H]3CCCc4ccccc43)ccn2)c1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Solvent: CCO
Product: CN1CCN(CCN(C)C(=O)c2cccc(C(=O)Nc3ccc(N4CCCCC4)cc3-c3cc(C(=O)N[C@H]4CCCc5ccccc54)ccn3)c2)CC1=O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
This compound was prepared according to the procedure described for the synthesis of Example 187 using methylpiperazin-2-one in place of L-proline-tert-butyl ester. Into a 50-mL round-bottom flask, was placed a solution of (S)—N1-methyl-N1-(2-oxoethyl)-N3-(4-(piperidin-1-yl)-2-(4-(1,2,3,4-tetrahydronaphthalen-1-ylcarbamoyl)pyridin-2-yl)phenyl)isophthalamide (100 mg, 0.16 mmol, 1.00 equiv) in ethanol (2 mL). This was followed by the addition of a solution of 1-methylpiperazin-2-one (18 mg, 0.16 mmol, 1.00 equiv) in ethanol (2 mL), two drop of acetic acid. To this was added NaBH3CN (20 mg, 0.32 mmol, 2.00 equiv). The resulting solution was stirred for 2 h at room temperature. The resulting solution was diluted with 50 mL of ethyl acetate. The resulting mixture was washed with 2×20 mL of brine. The mixture was dried over anhydrous sodium sulfate and concentrated under vacuum. The crude product (100 mg) was purified by Prep-HPLC with the following conditions (1#-Waters 2767-3): Column, SunFire Prep C18, 19*150 mm 5 um; mobile phase, water with 0.05% TFA and CH3CN (22% CH3CN up to 38% in 6 min); Detector, Waters2545 UvDector 254&270 nm. 70 mg product was obtained. This resulted in 70 mg (61%) of (S)—N1-methyl-N1-(2-(4-methyl-3-oxopiperazin-1-yl)ethyl)-N3-(4-(piperidin-1-yl)-2-(4-(1,2,3,4-tetrahydronaphthalen-1-ylcarbamoyl)pyridin-2-yl)phenyl)isophthalamide as a yellow solid. LC-MS (ES, m/z): 728 [M+H]+ H-NMR (300 MHz, DMSO, ppm): 12.25 (s, 1H), 9.18 (d, J=8.4 Hz, 1H), 8.80 (d, J=5.1 Hz, 1H), 8.29 (d, J=13.8 Hz 2H), 7.99 (t, J=6.9 Hz, 2H), 7.86 (d, J=4.8 Hz, 1H), 7.57˜7.67 (m, 3H), 7.10˜7.28 (m, 5H), 5.25 (d, J=5.4 Hz, 1H), 3.92˜3.85 (m, 4H), 3.30˜3.54 (m, 10H), 2.78˜2.95 (m, 9H), 1.99 (d, J=3.6 Hz, 2H), 1.72˜1.80 (m, 6H), 1.60 (s, 2H).
Reaction SMILES: [CH3:1][C:2](=[O:7])[CH2:3][C:4](=[O:6])[CH3:5].[CH:8]([S:10]([CH3:13])(=[O:12])=[O:11])=[CH2:9]>C(N(CC)CC)C.N12CCCN=C1CCCCC2.C(O)C>[C:4]([C:3]([C:2](=[O:7])[CH3:1])([CH2:9][CH2:8][S:10]([CH3:13])(=[O:12])=[O:11])[CH2:9][CH2:8][S:10]([CH3:13])(=[O:12])=[O:11])(=[O:6])[CH3:5]
Reactant: CC(=O)CC(C)=O
Reactant: C=CS(C)(=O)=O
Solvent: CCO
Solvent: C1CCC2=NCCCN2CC1
Solvent: CCN(CC)CC
Product: CC(=O)C(CCS(C)(=O)=O)(CCS(C)(=O)=O)C(C)=O
Temperature: 60 °C
Reaction time: 7 h

Procedure:
6 g of 2,4-pentandione and 3 drops of triethyl amine were mixed and 7 g of methyl vinyl sulfone was added dropwise at room temperature. After stirring at 60° C. for 7 hours, 5 drops of 1,8-diazabicyclo-[5.4.0]-undec-7-ene were added and the mixture was stirred at room temperature for 12 hours. The mixture was stirred with 25 ml of ethanol and neutralized after a white solid was precipitated. The mixture was poured into 200 ml of water and ice, and was kept in the refrigerator overnight. The solvent was filtered off, dried and recrystallized from 500 ml of ethanol. 2.9 g of white, long needles of the subject compound was obtained (melting point: 162° C.; purity: >99%; colorless).
Reaction SMILES: O[N:2]=[CH:3][C:4]1[CH:26]=[CH:25][C:7]([CH2:8][CH2:9][N:10]2[CH2:15][CH2:14][CH:13]([N:16]3[C:24]4[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=4)[CH2:18][CH2:17]3)[CH2:12][CH2:11]2)=[CH:6][CH:5]=1.C(N(CC)CC)C.FC(F)(F)C(OC(=O)C(F)(F)F)=O.C(=O)(O)[O-].[Na+]>C(Cl)Cl>[C:3]([C:4]1[CH:5]=[CH:6][C:7]([CH2:8][CH2:9][N:10]2[CH2:11][CH2:12][CH:13]([N:16]3[C:24]4[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=4)[CH2:18][CH2:17]3)[CH2:14][CH2:15]2)=[CH:25][CH:26]=1)#[N:2]
Reactant: ON=Cc1ccc(CCN2CCC(N3CCc4ccccc43)CC2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Solvent: ClCCl
Product: N#Cc1ccc(CCN2CCC(N3CCc4ccccc43)CC2)cc1
Reaction time: 3 h
Yield: 28.5 %

Procedure:
1-[1-(4-Hydroxyiminomethylphenethyl)piperidin-4-yl]indoline (0.466 g) was dissolved in methylene chloride (6.5 ml) and triethylamine (0.35 ml) was added thereto. In a nitrogen atmosphere at −78° C., trifluoroacetic anhydride (0.14 ml) was added dropwise into the resultant solution followed by stirring for 3 hr. After adding a saturated aqueous solution of sodium bicarbonate, the resultant mixture was extracted with ethyl acetate, washed with brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/methylene chloride/methanol system) to give the title compound (0.126 g) as a pale yellow oil (yield: 28.9%).
Reaction SMILES: [Br:1][C:2]1[C:7]([CH3:8])=[CH:6][C:5]([OH:9])=[C:4]([O:10][CH3:11])[CH:3]=1.CCN(C(C)C)C(C)C.[CH3:21][Si:22]([CH3:29])([CH3:28])[CH2:23][CH2:24][O:25][CH2:26]Cl>C(Cl)Cl>[Br:1][C:2]1[C:7]([CH3:8])=[CH:6][C:5]([O:9][CH2:26][O:25][CH2:24][CH2:23][Si:22]([CH3:29])([CH3:28])[CH3:21])=[C:4]([O:10][CH3:11])[CH:3]=1
Reactant: COc1cc(Br)c(C)cc1O
Reactant: C[Si](C)(C)CCOCCl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COc1cc(Br)c(C)cc1OCOCC[Si](C)(C)C
Reaction time: 1 h
Yield: 91 %

Procedure:
4-Bromo-2-methoxy-5-methyl-phenol (see Chien-Hsun et al., Syn. Lett., 12, 1351-1352 (1997)) was stirred in dry CH2Cl2 (100 mL) at 23° C. DIEA (6.05 mL, 34.6 mmol), and then 2-(trimethylsilyl)-ethoxymethyl chloride (5.6 mL, 31.7 mmol) were added. After stirring for 1 h, the solution was washed with H2O, 0.1 N HCl, H2O, saturated NaHCO3, and brine (25 mL each). Organics were dried (Na2SO4) and concentrated in vacuo. Purification by silica gel chromatography (6% ethyl acetate/hexanes) gave 9.06 g (91%) of [2-(4-bromo-2-methoxy-5-methyl-phenoxymethoxy)ethyl]-trimethyl-silane as a clear oil. 1H NMR (300 MHz, CDCl3) δ 7.06 (s, 1H), 7.02 (s, 1H), 5.24 (s, 2H), 3.84 (s, 3H), 3.79 (t, 2H, J=18.4 Hz), 2.31 (s, 3H), 0.96 (t, 2H, J=8.4 Hz), 0.01 (s, 9H).
Reaction SMILES: [CH2:1]([O:5][C:6]1[CH:11]=[CH:10][C:9]([CH:12]2[CH2:17][CH2:16][C:15]([CH:18]3[CH2:27][CH2:26][C:21]4(OCC[O:22]4)[CH2:20][CH2:19]3)=[CH:14][CH2:13]2)=[C:8]([F:28])[C:7]=1[F:29])[CH2:2][CH2:3][CH3:4].C(O)=O.O>C1(C)C=CC=CC=1>[CH2:1]([O:5][C:6]1[CH:11]=[CH:10][C:9]([CH:12]2[CH2:13][CH2:14][CH:15]([CH:18]3[CH2:27][CH2:26][C:21](=[O:22])[CH2:20][CH2:19]3)[CH2:16][CH2:17]2)=[C:8]([F:28])[C:7]=1[F:29])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCOc1ccc(C2CC=C(C3CCC4(CC3)OCCO4)CC2)c(F)c1F
Solvent: O=CO
Solvent: Cc1ccccc1
Solvent: O
Product: CCCCOc1ccc(C2CCC(C3CCC(=O)CC3)CC2)c(F)c1F
Temperature: 30 °C
Yield: 98.5 %

Procedure:
The compound (23) (7.7 g), formic acid (87%; 8.7 g) and toluene (100 ml) were mixed and the mixture was heated to reflux for 2 hours. After the reaction mixture had been cooled to 30° C., water (200 ml) and toluene (200 ml) were added to the mixture and mixed with it. The mixture was then allowed to stand until it had separated into two phases of organic and aqueous phases, and the extraction into an organic phase was carried out. The resulting organic phase was separated, and washed successively with water, a saturated aqueous solution of sodium hydrogencarbonate and water, and then dried over anhydrous magnesium sulfate. Then the solvent was distilled off under reduced pressure, and the residue was purified by recrystallization from heptane solvent and dried to give 4′-(4-butoxy-2,3-difluorophenyl)-bicyclohexyl-4-one (24) (6.8 g). The yield based on the compound (23) was 99.0%.
Reaction SMILES: CC(C)([O-])C.[K+].[N+:7]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[O:16][CH3:17])([O-:9])=[O:8].[Cl:18][CH:19](Cl)[C:20]([O:22][CH3:23])=[O:21]>C(O)(=O)C>[Cl:18][CH:19]([C:13]1[CH:14]=[CH:15][C:10]([N+:7]([O-:9])=[O:8])=[C:11]([O:16][CH3:17])[CH:12]=1)[C:20]([O:22][CH3:23])=[O:21]
Reactant: COc1ccccc1[N+](=O)[O-]
Reactant: COC(=O)C(Cl)Cl
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CC(=O)O
Product: COC(=O)C(Cl)c1ccc([N+](=O)[O-])c(OC)c1

Procedure:
A suspension of potassium t-butoxide (1.44 kg) in dimethylformamide(6.61), cooled to −5° C. to −10° C., was treated with a mixture of 2-nitroanisole (690 g) and methyl dichloroacetate (915 g) over 4 hours, whilst maintaining the temperature below −5° C. The reaction mixture was then treated with acetic acid (770 ml), then with water (6.6 l) and then extracted three times with tert-butyl methyl ether (5.5 l). The combined extracts were washed with water (5.5 l), then with saturated sodium bicarbonate solution (5.5 l), then with saturated brine (5.5 l) and then dried over magnesium sulphate to give a solution of methyl α-chloro-3-methoxy-4-nitrophenylacetate. This solution was concentrated to half volume under reduced pressure and then treated with tetrahydrofuran (2l), followed by triethylamine (751 ml), followed by 10 % palladium on chareoal (58.4 g) and the mixture was hydrogenated under a pressure of 50 psi hydrogen at 50° C. for 8 hours. The mixture was cooled to room temperature and filtered. The filtrate was dried over magnesium sulphate to give a solution of methyl 4-amino-3-methoxyphenylacetate which was heated to reflux and then treated with o-tolyl isocyanate (598.5 g) over 30 minutes. After heating at reflux temperature for a further 3 hours, during which time a solid was deposited, the mixture was cooled to room temperature. The solid was collected, washed twice with tert-butyl methyl ether (4 l), then dried in a vacuum oven at 60° C. to give the title compound (764.8 g) as a white solid, m.p. 167-168° C.
Reaction SMILES: [F:1][C:2]1[C:9]([CH2:10][O:11][CH2:12][CH2:13][OH:14])=[CH:8][C:7]([O:15][CH3:16])=[CH:6][C:3]=1[CH:4]=[O:5].N1C=CN=C1.Cl[Si:23]([CH:30]([CH3:32])[CH3:31])([CH:27]([CH3:29])[CH3:28])[CH:24]([CH3:26])[CH3:25].O>CN(C=O)C>[F:1][C:2]1[C:9]([CH2:10][O:11][CH2:12][CH2:13][O:14][Si:23]([CH:30]([CH3:32])[CH3:31])([CH:27]([CH3:29])[CH3:28])[CH:24]([CH3:26])[CH3:25])=[CH:8][C:7]([O:15][CH3:16])=[CH:6][C:3]=1[CH:4]=[O:5]
Reactant: COc1cc(C=O)c(F)c(COCCO)c1
Reactant: CC(C)[Si](Cl)(C(C)C)C(C)C
Agent: c1c[nH]cn1
Solvent: O
Solvent: CN(C)C=O
Product: COc1cc(C=O)c(F)c(COCCO[Si](C(C)C)(C(C)C)C(C)C)c1
Temperature: 50 °C
Reaction time: 2 h
Yield: 103.7 %

Procedure:
2-Fluoro-3-(2-hydroxyethoxymethyl)-5-methoxybenzaldehyde (305 mg) was dissolved in 3 ml of DMF, and 300 mg of imidazole and 283 mg of chlorotriisopropylsilane were added thereto. The resulting mixture was stirred at 50° C. for 2 hours, and then water was added thereto. The mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate. The desiccating agent was removed by filtration, and the filtrate was concentrated under reduced pressure to give a crude product of the title compound (533 mg).
Reaction SMILES: [NH2:1][CH2:2][C:3]1[O:7][C:6]([CH2:8][OH:9])=[CH:5][CH:4]=1.[Cl:10][C:11]1[C:16]([Cl:17])=[CH:15][CH:14]=[CH:13][C:12]=1[S:18]([NH:21][C:22]1[C:27](Cl)=[N:26][CH:25]=[CH:24][N:23]=1)(=[O:20])=[O:19]>>[NH2:1][CH2:2][C:3]1[O:7][C:6]([CH2:8][O:9][C:27]2[C:22]([NH:21][S:18]([C:12]3[CH:13]=[CH:14][CH:15]=[C:16]([Cl:17])[C:11]=3[Cl:10])(=[O:20])=[O:19])=[N:23][CH:24]=[CH:25][N:26]=2)=[CH:5][CH:4]=1
Reactant: O=S(=O)(Nc1nccnc1Cl)c1cccc(Cl)c1Cl
Reactant: NCc1ccc(CO)o1
Product: NCc1ccc(COc2nccnc2NS(=O)(=O)c2cccc(Cl)c2Cl)o1

Procedure:
Prepared by the method of Example 28 using (5-aminomethyl-2-furanyl)methanol (0.2 g) and 2,3-dichloro-N-(3-chloro-2-pyrazinyl)benzenesulphonamide (Example 28) (0.3 g). Purified by silica gel chromatography eluting with methanol/dichloromethane mixtures. Yield 0.2 g.
Reaction SMILES: C([C:4]1[C:12]([S:13][C:14]2[N:15]([CH3:19])[CH:16]=[CH:17][N:18]=2)=[CH:11][C:7]([C:8]([OH:10])=O)=[C:6](C(C)C)[C:5]=1[O:23][C:24]1[CH:29]=[CH:28][C:27]([P:30]([O:36][CH:37]([CH3:39])[CH3:38])([O:32][CH:33]([CH3:35])[CH3:34])=[O:31])=[CH:26][CH:25]=1)(C)C.[NH2:40][C:41]1[S:42][CH:43]=[CH:44][N:45]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CC(N(C)C)=O>C(Cl)Cl.CN(C=O)C>[CH:33]([O:32][P:30]([C:27]1[CH:28]=[CH:29][C:24]([O:23][C:5]2[CH:6]=[C:7]([C:8](=[O:10])[NH:40][C:41]3[S:42][CH:43]=[CH:44][N:45]=3)[CH:11]=[C:12]([S:13][C:14]3[N:15]([CH3:19])[CH:16]=[CH:17][N:18]=3)[CH:4]=2)=[CH:25][CH:26]=1)(=[O:31])[O:36][CH:37]([CH3:39])[CH3:38])([CH3:35])[CH3:34]
Reactant: CC(C)OP(=O)(OC(C)C)c1ccc(Oc2c(C(C)C)c(Sc3nccn3C)cc(C(=O)O)c2C(C)C)cc1
Reactant: Nc1nccs1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CC(=O)N(C)C
Solvent: CN(C)C=O
Product: CC(C)OP(=O)(OC(C)C)c1ccc(Oc2cc(Sc3nccn3C)cc(C(=O)Nc3nccs3)c2)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 62.8 %

Procedure:
A mixture of diisopropyl 3-[4-(diisopropoxy-phosphoryl)-phenoxy]-5-(1-methyl-1H-imidazol-2-ylsulfanyl)-benzoic acid (68 mg, 0.139 mmol), 2-aminothiazole (28 mg, 0.277 mmol), HATU (66 mg, 0.174 mmol), DMA (0.058 mL, 0.35 mmol) and 0.7 mL of DMF were stirred for 16 h at rt, diluted with CH2Cl2, washed with water, brine, dried and evaporated. The residue was adsorbed to SiO2 and subjected to MPLC on a 12 g column of SiO2 eluting with % MeOH in CH2Cl2 (time): 1% (5 min), 2.5% (10 min), 5% (10 min) which provided 50 mg (63%) of the title compound: 1H NMR (500 MHz, DMSO-d6): δ 1.20 (d, 6H, J=6 Hz). 1.28 (d, 6H, J=6 Hz), 3.66 (s, 3H). 4.56 (m, 2H), 6.95 (t, 1H, J=2 Hz), 7.13 (d, 1H, J=1 Hz), 7.15 (dd, 2H, J=8, 3 Hz), 7.30 (br s, 1H), 7.50 (d, 1H, J=1 Hz), 7.55 (d, 1H, J=3 Hz). 7.60 (br s, 1H), 7.67 (br s, 1H), 7.73 (dd, 2H, J=12, 8 Hz); LCMS (m/z): 573.7 [C26H29N4O5PS2+H]+.
Reaction SMILES: Br[C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][N:7]([CH2:12][CH2:13][C:14]3[CH:19]=[CH:18][C:17]([O:20][C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=4)=[CH:16][CH:15]=3)[C:8]2=[O:11])=[CH:4][CH:3]=1.[CH3:27][N:28]1[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]1.C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1.CC(C)([O-])C.[Na+]>C1(C)C=CC=CC=1.CCCCCC.C(OCC)(=O)C>[CH3:27][N:28]1[CH2:33][CH2:32][N:31]([C:2]2[CH:10]=[C:9]3[C:5]([CH2:6][N:7]([CH2:12][CH2:13][C:14]4[CH:19]=[CH:18][C:17]([O:20][C:21]5[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=5)=[CH:16][CH:15]=4)[C:8]3=[O:11])=[CH:4][CH:3]=2)[CH2:30][CH2:29]1
Reactant: O=C1c2cc(Br)ccc2CN1CCc1ccc(Oc2ccccc2)cc1
Reactant: CN1CCNCC1
Agent: CC(C)(C)[O-]
Agent: [Na+]
Agent: c1ccc(P(c2ccccc2)c2ccc3ccccc3c2-c2c(P(c3ccccc3)c3ccccc3)ccc3ccccc23)cc1
Solvent: CCOC(C)=O
Solvent: CCCCCC
Solvent: Cc1ccccc1
Product: CN1CCN(c2ccc3c(c2)C(=O)N(CCc2ccc(Oc4ccccc4)cc2)C3)CC1
Yield: 21.3 %

Procedure:
A mixture of 6-Bromo-2-[2-(4-phenoxy-phenyl)-ethyl]-2,3-dihydro-isoindol-1-one (0.134 g, 0.33 mmol), 1-methyl piperazine (0.048 mL, 0.43 mmol), Pd2.dba3 (0.009 g, 0.01 mmol), BINAP (0.012 g, 0.02 mmol), and sodium tertiary-butoxide (0.048 g, 0.5 mmol) in toluene (3 mL) was heated to reflux for 3 h. Workup and silica gel column chromatography using 30% ethyl acetate in hexane afforded 6-(4-Methyl-piperazin-1-yl)-2-[2-(4-phenoxy-phenyl)-ethyl]-2,3-dihydro-isoindol-1-one (0.03 g, 41%). 1H NMR (300 MHz, CDCl3): δ (ppm) 2.36 (s, 3H), 2.57 (m, 4H), 2.93 (t, 2H), 3.32 (m, 4H), 3.81 (t, 2H), 4.16 (s, 2H), 6.82-7.35 (m, 11H), 7.68 (d, 1H).
Reaction SMILES: [C:1]([O:5][C:6]1[CH:11]=[CH:10][C:9]([S:12]([C:14]2[CH:19]=[CH:18][C:17]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[CH:16][CH:15]=2)=O)=[CH:8][CH:7]=1)([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.C[Si]([Cl:36])(C)C.[C:37]([O:41][C:42]1[CH:47]=[CH:46][C:45](Cl)=[CH:44][CH:43]=1)([CH3:40])([CH3:39])[CH3:38].[Mg].[Cl-].[NH4+]>C1COCC1.C(Cl)(Cl)Cl>[Cl-:36].[C:1]([O:5][C:6]1[CH:11]=[CH:10][C:9]([S+:12]([C:45]2[CH:46]=[CH:47][C:42]([O:41][C:37]([CH3:40])([CH3:39])[CH3:38])=[CH:43][CH:44]=2)[C:14]2[CH:19]=[CH:18][C:17]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[CH:16][CH:15]=2)=[CH:8][CH:7]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)Oc1ccc(Cl)cc1
Reactant: CC(C)(C)Oc1ccc(S(=O)c2ccc(OC(C)(C)C)cc2)cc1
Reactant: C[Si](C)(C)Cl
Agent: [Cl-]
Agent: [Mg]
Agent: [NH4+]
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Solvent: ClC(Cl)Cl
Product: CC(C)(C)Oc1ccc([S+](c2ccc(OC(C)(C)C)cc2)c2ccc(OC(C)(C)C)cc2)cc1
Reaction time: 0.5 h
Yield: 34.7 %

Procedure:
A solution of 17.8 g (0.052 mol) of bis(4-tertbutoxyphenyl) sulfoxide in 52 g of THF was cooled on an ice bath. To the solution, 5.3 g (0.052 mol) of triethylamine was added and 14.1 g (0.13 mol) of trimethylsilyl chloride was dropwised at 0° to 10° C. Stirring was continued at 0 to 10° C. for 30 minutes. To this solution, a Grignard reagent which was conventionally prepared from 24.0 g (0.13 mol) of 4-tert-butoxychlorobenzene, 3.2 g (0.13 mol) of magnesium, and 40 g of THF was dropwised at 0° to 10° C. Stirring was continued at 0° to 10° C. for 30 minutes. 300 g of 20% ammonium chloride aqueous solution was added to the reaction mixture. To the organic layer was added 500 g of chloroform. The organic layer was washed twice with 200 g of water and the solvent was evaporated and residue was purifie by column chromatography (silica gel, eluent: chloroform/methanol), isolating 9.3 g (yield 35%) of tris(4-tert-butoxyphenyl)sulfonium chloride with 99% purity.