Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([C:4]1[CH:5]=[CH:6][C:7]([O:22][CH3:23])=[C:8]([C:10]2[C:11]([C:20]#N)=[CH:12][C:13]([C:16]([F:19])([F:18])[F:17])=[CH:14][CH:15]=2)[CH:9]=1)([CH3:3])[CH3:2].[OH-:24].[K+]>C(O)CC>[CH:1]([C:4]1[CH:5]=[CH:6][C:7]([O:22][CH3:23])=[C:8]([C:10]2[CH:15]=[CH:14][C:13]([C:16]([F:19])([F:18])[F:17])=[CH:12][C:11]=2[CH2:20][OH:24])[CH:9]=1)([CH3:3])[CH3:2]
Reactant: COc1ccc(C(C)C)cc1-c1ccc(C(F)(F)F)cc1C#N
Reactant: [OH-]
Agent: [K+]
Solvent: CCCO
Product: COc1ccc(C(C)C)cc1-c1ccc(C(F)(F)F)cc1CO
Temperature: 0 °C
Reaction time: 36 h

Procedure:
To a solution of 1.08 g of 5′-isopropyl-2′-methoxy-4-(trifluoromethyl)biphenyl-2-carbonitrile (EXAMPLE 3) in 25 mL of n-PrOH, was added 0.97 g of KOH. The mixture was heated to reflux and stirred at this temperature for 36 h, then cooled and concentrated to a clear oil. This oil was partitioned between 15 mL of water and 10 mL of Et2O. The aqueous phase was extracted with 10 mL of Et2O. The combined organics were washed with brine (15 mL), dried over Na2SO4, and concentrated. The residue was purified by flash chromatography on a Biotage Horizon 40S column, eluting with 1 CV of 95% hexanes-5% of a mixture of 5% formic acid in acetone, followed by a linear gradient of the acetone mixture in hexanes from 5 to 100% over 10 CV. The resulting white solid was dissolved in 10 mL of 9:1 benzene-MeOH and excess TMSCH2N2 was added. The mixture was stirred for 10 min at room temperature, then quenched with trifluoroacetic acid and concentrated. The residue was dissolved in 15 mL of Et2O and cooled to 0° C. A 1-M solution of LiAlH4 in Et2O (5.4 mL) was added dropwise via addition funnel. The cooling bath was removed once the addition was complete, and the mixture was stirred 2 h at room temperature, then recooled to 0° C. and quenched by dropwise addition of 0.2 mL of water, 0.2 mL of 15% aqueous NaOH, and 0.5 mL of water. The cooling bath was removed once the addition was complete, and the mixture was stirred 30 min at room temperature, filtered (washing the solids liberally with Et2O), and concentrated. Flash chromatography on a Biotage Horizon, 40S column, eluting with 1 CV of 4% EtOAc in hexanes, followed by a linear gradient of EtOAc in hexanes from 4 to 100% over 10 CV provided the title compound. Mass spectrum (ESI) 307.2 (M−17). 1H NMR (500 MHz, CDCl3): δ 7.85 (s, 1H), 7.60 (d, J=8 Hz, 1H), 7.33 (d, J=8 Hz, 1H), 7.25 (dd, J=2 Hz, 9 Hz, 1H), 6.99 (d, J=2.5 Hz, 1H), 6.93 (d, J=8.5 Hz, 1H), 4.49 (m, 2H), 3.74 (s, 3H), 2.90 (septet, J=7 Hz, 1H), 1.25 (d, J=7 Hz, 6H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:20]([CH:21]=[O:22])=[C:19]([CH:23]([CH3:25])[CH3:24])[CH:18]=[C:17]3[C:9]=2[C:10](=[O:26])[CH2:11][C:12]2([O:16]3)[CH2:15][CH2:14][CH2:13]2)=[CH:4][CH:3]=1.[F:27][C:28]([F:39])([F:38])[O:29][C:30]1[CH:35]=[CH:34][C:33]([Mg]Br)=[CH:32][CH:31]=1.C(=O)(O)[O-].[Na+]>O1CCCC1.O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:20]([CH:21]([OH:22])[C:33]3[CH:32]=[CH:31][C:30]([O:29][C:28]([F:27])([F:38])[F:39])=[CH:35][CH:34]=3)=[C:19]([CH:23]([CH3:24])[CH3:25])[CH:18]=[C:17]3[C:9]=2[C:10](=[O:26])[CH2:11][C:12]2([O:16]3)[CH2:15][CH2:14][CH2:13]2)=[CH:4][CH:3]=1
Reactant: CC(C)c1cc2c(c(-c3ccc(F)cc3)c1C=O)C(=O)CC1(CCC1)O2
Reactant: FC(F)(F)Oc1ccc([Mg]Br)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)c1cc2c(c(-c3ccc(F)cc3)c1C(O)c1ccc(OC(F)(F)F)cc1)C(=O)CC1(CCC1)O2
Temperature: -70 °C
Reaction time: 1 h

Procedure:
Under argon, 0.60 g (1.70 mmol) of 5-(4-fluorophenyl)-7-isopropyl-4-oxo-3,4-dihydrospiro-[chromen-2,1′-cyclobutane]-6-carbaldehyde (Example 51A) is suspended in 15 ml of tetrahydrofuran and cooled to −70° C. 4.3 ml (2.13 mmol) of a freshly prepared 0.5 M solution of [4-(trifluoromethoxy)phenyl]magnesium bromide in tetrahydrofuran are added slowly. The mixture is stirred briefly at −78° C. and then warmed to 0° C. After 1 h, the mixture is hydrolyzed with sodium bicarbonate solution, diluted with water and extracted repeatedly with ethyl acetate. The combined organic phases are washed twice with saturated sodium chloride solution, dried over sodium sulfate, filtered and concentrated. The crude product is purified on a silica gel column (mobile phase: cyclohexane/ethyl acetate 25:1→10:1). This gives 710 mg (81% of theory) of the title compound in a purity of 70%.
Reaction SMILES: F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.[CH:28]1([CH2:34][C@H:35]([N:39]2[CH2:47][C:46]3[C:41](=[CH:42][CH:43]=[C:44]([N+:48]([O-:50])=[O:49])[CH:45]=3)[C:40]2=[O:51])[C:36](O)=[O:37])[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]1.Cl.[NH2:53][C:54]1[S:55][C:56]([Cl:59])=[CH:57][N:58]=1.C1(C[C@H](N2CC3C(=CC=CC=3)C2=O)C(NC2SC=CN=2)=O)CCCCC1>>[Cl:59][C:56]1[S:55][C:54]([NH:53][C:36](=[O:37])[C@@H:35]([N:39]2[CH2:47][C:46]3[C:41](=[CH:42][CH:43]=[C:44]([N+:48]([O-:50])=[O:49])[CH:45]=3)[C:40]2=[O:51])[CH2:34][CH:28]2[CH2:29][CH2:30][CH2:31][CH2:32][CH2:33]2)=[N:58][CH:57]=1
Reactant: O=C(O)[C@H](CC1CCCCC1)N1Cc2cc([N+](=O)[O-])ccc2C1=O
Reactant: Nc1ncc(Cl)s1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Product: O=C(Nc1ncc(Cl)s1)[C@H](CC1CCCCC1)N1Cc2cc([N+](=O)[O-])ccc2C1=O
Yield: 32.4 %

Procedure:
BOP coupling of ((S)-3-cyclohexyl-2-(5-nitro-1-oxo-1,3-dihydro-isoindol-2-yl)-propionic acid (ca. 1:1 mixture of 5,6-regioisomers, prepared in Step C; 307 mg; 0.92 mmol) and 2-amino-5-chlorothiazole hydrochloride (360 mg; 2.04 mmol) in a manner similar to that used for the preparation of (S)-3-cyclohexyl-2-(1-oxo-1,3-dihydro-isoindol-2-yl)-N-thiazol-2-yl-propionamide (as outlined in Example 1, Step B) provided after chromatography, (Biotage 40M, eluent: 25% ethyl acetate/hexanes) 134 mg of (S)- N-(5-Chloro-thiazol-2-yl)-3-cyclohexyl-2-(5-nitro-1-oxo-1,3-dihydro-isoindol-2-yl)-propionamide: EI-HRMS m/e calcd for C20H21ClN4O4S (M+) 448.0972, found 448.0970 and 111 mg of regioisomeric (S)-N-(5-Chloro-thiazol-2-yl)-3-cyclohexyl-2-(6-nitro-1-oxo-1,3-dihydro-isoindol-2-yl)-propionamide: EI-HRMS m/e calcd for C20H21ClN4O4S (M+) 448.0972, found 448.0972.
Reaction SMILES: [C:1]1([C:7]2[CH:12]=[CH:11][C:10]([OH:13])=[CH:9][CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(O)C.[OH-].[Na+].Cl[CH2:20][CH:21]([OH:30])[CH2:22][CH2:23][C:24]1[CH:25]=[N:26][CH:27]=[CH:28][CH:29]=1>O>[C:7]1([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[CH:8]=[CH:9][C:10]([O:13][CH2:20][CH:21]([OH:30])[CH2:22][CH2:23][C:24]2[CH:25]=[N:26][CH:27]=[CH:28][CH:29]=2)=[CH:11][CH:12]=1
Reactant: OC(CCl)CCc1cccnc1
Reactant: Oc1ccc(-c2ccccc2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: OC(CCc1cccnc1)COc1ccc(-c2ccccc2)cc1

Procedure:
Prepared according to the method described in Example 24b) from 4-phenylphenol (0.916 g), ethanol (10 ml), sodium hydroxide (0.215 g), water (5 ml) and (±)-α-(chloromethyl)-3-pyridinepropanol (1.0 g; from Example 24a) above) to give a yellow oil. This was purified by column chromatography over silica eluting with dichloromethane:ethanol (95:5) to give the title compound as a pale yellow gum which solidified on standing (0.307 g).
Reaction SMILES: Cl.[OH:2][C:3]1[C:4]([O:25][CH3:26])=[CH:5][C:6]2[CH2:15][CH:14]3[N:9]([CH2:10][CH2:11][C:12]4[CH:19]=[C:18]([O:20][CH3:21])[C:17]([O:22][CH3:23])=[CH:16][C:13]=43)[CH2:8][C:7]=2[CH:24]=1.[CH3:27][O:28][C:29]1[CH:30]=[C:31]([CH:37]=[C:38]([O:42][CH3:43])[C:39]=1[O:40][CH3:41])[CH:32]=[CH:33][C:34](Cl)=[O:35]>N1C=CC=CC=1>[CH3:23][O:22][C:17]1[C:18]([O:20][CH3:21])=[CH:19][C:12]2[CH2:11][CH2:10][N:9]3[CH:14]([CH2:15][C:6]4[CH:5]=[C:4]([O:25][CH3:26])[C:3]([O:2][C:34](=[O:35])[CH:33]=[CH:32][C:31]5[CH:30]=[C:29]([O:28][CH3:27])[C:39]([O:40][CH3:41])=[C:38]([O:42][CH3:43])[CH:37]=5)=[CH:24][C:7]=4[CH2:8]3)[C:13]=2[CH:16]=1
Reactant: COc1cc2c(cc1O)CN1CCc3cc(OC)c(OC)cc3C1C2
Reactant: COc1cc(C=CC(=O)Cl)cc(OC)c1OC
Agent: Cl
Solvent: c1ccncc1
Product: COc1cc2c(cc1OC)C1Cc3cc(OC)c(OC(=O)C=Cc4cc(OC)c(OC)c(OC)c4)cc3CN1CC2
Yield: 46 %

Procedure:
1.9 g of 10-hydroxy-2,3,11-trimethoxy-5,6,13,13a-tetrahydro-8H-dibenzo[a, g]quinolizine hydrochloride was treated in the same manner as described in Example 6, using 2.0 g of 3,4,5-trimethoxycinnamoyl chloride and 20 ml of anhydrous pyridine and there was obtained 1.3 g (46.4% yield) of 5,6,13,13a-tetrahydro-2,3,11-trimethoxy-10-(3', 4', 5'-trimethoxycinnamoyloxy)-8H-dibenzo[a, g]quinolizine as a pale yellow powder. The methiodide derived from this compound was found to be in agreement with the methiodide of the compound obtained in Example 5 as determined from the melting point and IR spectrum.
Reaction SMILES: C([S:4][CH2:5][C:6]1[N:7]=[C:8]([C:12]2[CH:21]=[CH:20][C:15]([C:16]([O:18][CH3:19])=[O:17])=[CH:14][CH:13]=2)[O:9][C:10]=1[CH3:11])(=O)C.C(=O)([O-])[O-].[K+].[K+].O>CO>[CH3:11][C:10]1[O:9][C:8]([C:12]2[CH:13]=[CH:14][C:15]([C:16]([O:18][CH3:19])=[O:17])=[CH:20][CH:21]=2)=[N:7][C:6]=1[CH2:5][SH:4]
Reactant: COC(=O)c1ccc(-c2nc(CSC(C)=O)c(C)o2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CO
Product: COC(=O)c1ccc(-c2nc(CS)c(C)o2)cc1
Temperature: 35 °C
Reaction time: 0.5 h
Yield: 102.7 %

Procedure:
A mixture of methyl 4-[4-[(acetylsulfanyl)methyl]-5-methyl-1,3-oxazol-2-yl]benzoate (4.29 g, 14.05 mmol, 1.00 equiv) and potassium carbonate (4.85 g, 34.84 mmol, 3.00 equiv) in methanol (50 mL) was stirred at 35° C. under an inert atmosphere of nitrogen for 30 min. Water (100 mL) was then added and the resulting solution was extracted with 3×150 mL of dichloromethane. The combined organic layers was washed with 2×300 mL of brine, dried over anhydrous sodium sulfate and concentrated under vacuum to yield 3.8 g of crude methyl 4-[5-methyl-4-(sulfanylmethyl)-1,3-oxazol-2-yl]benzoate as a white solid. LC-MS: (ES, m/z): 305 [M+CH3CN+H]+, 264 [M+H]+, 230.
Reaction SMILES: Cl[C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[CH:4][N:3]=1.O.C([O-])([O-])=O.[Na+].[Na+].B(O)(O)[C:17]1[CH:22]=[CH:21][C:20]([C:23]([OH:25])=[O:24])=[CH:19][CH:18]=1>COCCOC.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>[Cl:8][C:7]1[C:2]([C:17]2[CH:22]=[CH:21][C:20]([C:23]([OH:25])=[O:24])=[CH:19][CH:18]=2)=[N:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C(O)c1ccc(B(O)O)cc1
Reactant: Clc1cccnc1Cl
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: O=C(O)c1ccc(-c2ncccc2Cl)cc1
Temperature: 25 °C
Yield: 75.4 %

Procedure:
To a solution of 5.3 g (36.1 mmol) 2,3-dichloropyridine in 200 mL 1,2-dimethoxyethane and 200 mL distilled water were added 22.3 g (0.21 mol) Na2CO3, 5.0 g (30.1 mmol) 4-carboxylphenylboronic acid and 0.5 g Pd(PPh3)4, followed by mixing for 18 hours under a heat flux condition by stirring. After being cooled to room temperature, the solution was 50% concentrated in a vacuum. The aqueous layer was washed with ethyl acetate and adjusted into pH 1 with conc. HCl. Thereafter, extraction with ethyl acetate was conducted three times and the organic layer was dried over magnesium sulfate and concentrated in a vacuum. The concentrate was separated using column chromatography (developing solvent: chloroform/methanol=10/1) to afford 5.3 g of 4-(3-chloropyridin-2-yl)benzoic acid as a white precipitate (yield: 75%).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][CH2:9][CH2:10][CH2:11][CH2:12][CH:13]2[CH2:18][C:17]([CH3:20])([CH3:19])[N:16]([O:21][CH3:22])[C:15]([CH3:24])([CH3:23])[CH2:14]2)[N:5]=[C:4]([NH:25][CH2:26][CH2:27][CH2:28][CH2:29][CH:30]2[CH2:35][C:34]([CH3:37])([CH3:36])[N:33]([O:38][CH3:39])[C:32]([CH3:41])([CH3:40])[CH2:31]2)[N:3]=1.[CH2:42]([CH2:44][NH2:45])[OH:43]>>[OH:43][CH2:42][CH2:44][NH:45][C:2]1[N:7]=[C:6]([NH:8][CH2:9][CH2:10][CH2:11][CH2:12][CH:13]2[CH2:14][C:15]([CH3:24])([CH3:23])[N:16]([O:21][CH3:22])[C:17]([CH3:19])([CH3:20])[CH2:18]2)[N:5]=[C:4]([NH:25][CH2:26][CH2:27][CH2:28][CH2:29][CH:30]2[CH2:31][C:32]([CH3:41])([CH3:40])[N:33]([O:38][CH3:39])[C:34]([CH3:37])([CH3:36])[CH2:35]2)[N:3]=1
Reactant: NCCO
Reactant: CON1C(C)(C)CC(CCCCNc2nc(Cl)nc(NCCCCC3CC(C)(C)N(OC)C(C)(C)C3)n2)CC1(C)C
Product: CON1C(C)(C)CC(CCCCNc2nc(NCCO)nc(NCCCCC3CC(C)(C)N(OC)C(C)(C)C3)n2)CC1(C)C

Procedure:
The title compound is prepared from the reaction of 2-chloro-4,6-bis[N-(1-methoxy-2,2,6,6-tetramethylpiperidin-4-yl)butylamino]-1,3,5-triazine and ethanolamine according to the procedure of Example 1.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[C:9]([F:11])[CH:8]=[CH:7][C:6]=1[OH:12])([CH3:4])([CH3:3])[CH3:2].CCN(CC)CC.Cl[C:21]([O:23][CH3:24])=[O:22]>O1CCOCC1>[C:21](=[O:22])([O:23][CH3:24])[O:12][C:6]1[CH:7]=[CH:8][C:9]([F:11])=[CH:10][C:5]=1[C:1]([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)c1cc(F)ccc1O
Reactant: COC(=O)Cl
Solvent: C1COCCO1
Solvent: CCN(CC)CC
Product: COC(=O)Oc1ccc(F)cc1C(C)(C)C
Temperature: 25 °C
Reaction time: 1 h
Yield: 58.6 %

Procedure:
To a solution of 2-tert-butyl-4-fluorophenol (2.63 g, 15.7 mmol) and NEt3 (3.13 mL, 22.5 mmol) in dioxane (45 mL) was added methyl chloroformate (1.27 mL, 16.5 mmol). The mixture was stirred at room temperature for 1 h. The precipitate was removed via filtration. The filtrate was then diluted with water and extracted with ether. The ether extract was washed with water and dried over MgSO4. After removal of solvent, the residue was purified by column chromatography to give 2-tert-butyl-4-fluorophenyl methyl carbonate (2.08 g, 59%). 1H NMR (400 MHz, DMSO-d6) δ 7.24 (dd, J=8.8, 5.4 Hz, 1H), 7.17-7.10 (m, 2H), 3.86 (s, 3H), 1.29 (s, 9H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([O:9][CH3:10])=[CH:5][C:4]=1[CH2:11][C:12]([OH:14])=O.[Br:15]Br>C(O)(=O)C>[Br:15][C:7]1[C:6]([O:9][CH3:10])=[CH:5][C:4]([CH2:11][CH2:12][OH:14])=[C:3]([O:2][CH3:1])[CH:8]=1
Reactant: COc1ccc(OC)c(CC(=O)O)c1
Reactant: BrBr
Solvent: CC(=O)O
Product: COc1cc(CCO)c(OC)cc1Br
Temperature: 0 °C
Reaction time: 8 h
Yield: 77.6 %

Procedure:
(2,5-Dirnethoxy-phenyl)-acetic acid (3.00 g, 15.29 mmol) was dissolved in 30 ml of acetic acid and cooled to 0° C. To this solution was added bromine (2.44 g, 15.33 mmol), the reaction mixture was stirred overnight at room temperature and concentrated under reduced pressure, the solid residue was washed with cold hexane and dried overnight. The residue was dissolved in THF and cooled to 0° C. LAH (20 ml of 1.0 M in THF) was added slowly and then the reaction mixture was stirred at 0° C. for 2 h. Excess LAH was destroyed by careful addition of ethyl acetate and an aqueous solution of 0.10 M hydrogen chloride. The organic layer was separated, dried (MgSO4) and concentrated under reduced pressure to give an oil (3.1 g), which solidifies slowly. MS (m/z) 278 (M+NH4)+. 1HNMR(CDCl3): δ ppm 2.86 (m, 2H), 378-3.84 (2s+m, 8H), 6.77 (s, 1H), 7.04 (s, 1H).
Reaction SMILES: [Br-].[O:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[N:4]=[C:3]1[C:11]1[CH:16]=[CH:15][C:14]([CH3:17])=[C:13]([P+](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[CH:12]=1.[Li]CCCC.[OH:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][N:49]1[C:58]2[C:53](=[CH:54][C:55]([CH:59]=[CH:60][CH:61]=O)=[CH:56][CH:57]=2)[CH2:52][CH2:51][CH2:50]1.O>C1(C)C=CC=CC=1>[OH:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][N:49]1[C:58]2[C:53](=[CH:54][C:55]([CH:59]=[CH:60][CH:61]=[CH:17][C:14]3[CH:13]=[CH:12][C:11]([C:3]4[O:2][C:6]5[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=5[N:4]=4)=[CH:16][CH:15]=3)=[CH:56][CH:57]=2)[CH2:52][CH2:51][CH2:50]1
Reactant: O=CC=Cc1ccc2c(c1)CCCN2CCCCCCO
Reactant: Cc1ccc(-c2nc3ccccc3o2)cc1[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Agent: [Li]CCCC
Solvent: O
Solvent: Cc1ccccc1
Product: OCCCCCCN1CCCc2cc(C=CC=Cc3ccc(-c4nc5ccccc5o4)cc3)ccc21
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a stirred mixture of 110 g (0.2 mole) of 4-(benzoxazol-2-yl)tolyltriphenylphosphonium bromide in toluene is added dropwise 0.2 mole of n-BuLi at room temperature. After 2 hours a solution of 28.7 g (0.1 mole) of 3-(N-hydroxyhexyl-1,2,3,4-tetrahydroquinolin-6-yl)acrolein in toluene is added dropwise to the mixture, and the reaction is stirred for 18 hours at room temperature. Water is added, and the solids are isolated by vacuum filtration, washed with 60% ethanol/water, and dried under vacuum. The product is purified by recrystallization from benzene.
Reaction SMILES: ClC1C=C(Cl)C=CC=1C([C:13]1[C:21]2[C:16](=[C:17]([CH2:23][S:24][CH3:25])[CH:18]=[C:19](F)[CH:20]=2)[NH:15][CH:14]=1)CCO.[Cl:26][C:27]1[CH:32]=[CH:31][C:30]([C:33]([CH:36]2[CH2:38][CH2:37]2)(O)[CH3:34])=[C:29]([F:39])[CH:28]=1.C1(C(C2C3C(=C(CSC)C=CC=3)NC=2)(C2C=CC(F)=CC=2)C)CC1>>[Cl:26][C:27]1[CH:32]=[CH:31][C:30]([C:33]([C:13]2[C:21]3[C:16](=[C:17]([CH2:23][S:24][CH3:25])[CH:18]=[CH:19][CH:20]=3)[NH:15][CH:14]=2)([CH:36]2[CH2:38][CH2:37]2)[CH3:34])=[C:29]([F:39])[CH:28]=1
Reactant: CC(O)(c1ccc(Cl)cc1F)C1CC1
Reactant: CSCc1cc(F)cc2c(C(CCO)c3ccc(Cl)cc3Cl)c[nH]c12
Agent: CSCc1cccc2c(C(C)(c3ccc(F)cc3)C3CC3)c[nH]c12
Product: CSCc1cccc2c(C(C)(c3ccc(Cl)cc3F)C3CC3)c[nH]c12
Temperature: 0 °C
Reaction time: 2 h

Procedure:
The title compound was prepared starting from 3.00 g (16.92 mmol) of the compound from Example 8 and 4.00 g (18.62 mmol) of the compound from Example 79A in analogy to the synthesis of the compound from Example 95. As a difference, the reaction mixture was stirred at 0° C. for 2 h and then warmed to RT. 1.54 g (24% of theory) of the target compound were obtained.
Reaction SMILES: [Br:1]Br.[CH3:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:16]=[CH:15][C:14]([C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:13][CH:12]=2)=[CH:7][CH:6]=1>C(Cl)(Cl)(Cl)Cl>[Br:1][C:10]1[CH:9]=[C:8]([C:11]2[CH:16]=[CH:15][C:14]([C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:13][CH:12]=2)[CH:7]=[CH:6][C:5]=1[O:4][CH3:3]
Reactant: CCOC(=O)c1ccc(-c2ccc(OC)cc2)cc1
Reactant: BrBr
Solvent: ClC(Cl)(Cl)Cl
Product: CCOC(=O)c1ccc(-c2ccc(OC)c(Br)c2)cc1
Temperature: 20 °C
Reaction time: 4 h

Procedure:
A solution of bromine (14.6 g, 91.3 mmol) in carbon tetrachloride (100 mL) is added to a stirred mixture of 4'-Methoxy-[1,1'-biphenyl]-4-carboxylic acid, ethyl ester (23.4 g, 91.3 mmol) and silica gal (100 g of particle size 0.040-0.063 mm; Merck 1.09385) in carbon tetrachloride (350 mL). The mixture is stirred at 20° C. for 4 h after which the silica gel is removed by filtration. The filtrate is washed with aqueous sodium hydrogen carbonate (200 mL of 1 M) followed by aqueous sodium thiosulphate (50 mL of 2 M), dried (Na2SO4), filtered and evaporated to dryness under reduced pressure to give the crude product which is recrystallised from ether-cyclohexane to give 3'-bromo-4'-methoxy-[1,1'-biphenyl]-4-carboxylic acid, ethyl ester as a colourless crystalline solid, m.p. 114-115° C.
Reaction SMILES: [F:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[C:4]([C:9]([F:12])([F:11])[F:10])[CH:3]=1.[CH3:13][O:14][C:15](=[O:22])[CH2:16][CH2:17][S:18](Cl)(=[O:20])=[O:19].ClC(Cl)C.Cl>N1C=CC=CC=1>[CH3:13][O:14][C:15](=[O:22])[CH2:16][CH2:17][S:18](=[O:20])(=[O:19])[NH:6][C:5]1[CH:7]=[CH:8][C:2]([F:1])=[CH:3][C:4]=1[C:9]([F:10])([F:11])[F:12]
Reactant: COC(=O)CCS(=O)(=O)Cl
Reactant: Nc1ccc(F)cc1C(F)(F)F
Agent: Cl
Solvent: c1ccncc1
Solvent: CC(Cl)Cl
Product: COC(=O)CCS(=O)(=O)Nc1ccc(F)cc1C(F)(F)F
Reaction time: 0.33 h

Procedure:
8.96 g (50 mmol) of 4-fluoro-2-trifluoromethylaniline is dissolved in 100 ml of pyridine and under cold conditions combined under stirring with 9.52 g (50 mmol) of 3-chlorosulfonylpropionic acid methyl ester (98.5%). The mixture is agitated for 20 minutes, heated for 4 hours to 40° C., and the pyridine is exhausted under vacuum. The residue is distributed between dichloroethane and 4N hydrochloric acid. The organic solution is washed with water, dried over sodium sulfate, and concentrated to dryness under vacuum. The residue is purified by column chromatrography on silica gel. The title compound is eluted with ethyl acetate.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[C:9]1[CH:13]=[C:12]([C:14]2[CH:15]=[C:16]([NH:20][CH2:21][CH2:22][P:23](=[O:30])([O:27][CH2:28][CH3:29])[O:24][CH2:25][CH3:26])[CH:17]=[CH:18][CH:19]=2)[O:11][N:10]=1.C(N(CC)CC)C.[Cl:38][CH:39]([Cl:43])[C:40](Cl)=[O:41]>C(Cl)Cl>[Cl:38][CH:39]([Cl:43])[C:40]([N:20]([CH2:21][CH2:22][P:23](=[O:30])([O:27][CH2:28][CH3:29])[O:24][CH2:25][CH3:26])[C:16]1[CH:17]=[CH:18][CH:19]=[C:14]([C:12]2[O:11][N:10]=[C:9]([C:3]3[C:4]([Cl:8])=[CH:5][CH:6]=[CH:7][C:2]=3[Cl:1])[CH:13]=2)[CH:15]=1)=[O:41]
Reactant: CCOP(=O)(CCNc1cccc(-c2cc(-c3c(Cl)cccc3Cl)no2)c1)OCC
Reactant: O=C(Cl)C(Cl)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOP(=O)(CCN(C(=O)C(Cl)Cl)c1cccc(-c2cc(-c3c(Cl)cccc3Cl)no2)c1)OCC
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Diethyl 2-(3-(3-(2,6-dichlorophenyl)isoxazol-5-yl)phenylamino)ethylphosphonate (660 mg, 1.4 mmol) was dissolved in anhydrous methylene chloride (10 mL) with triethylamine (0.28 mL, 1.7 mmol). The mixture was cooled in an ice-bath under nitrogen, then a solution of dichloroacetyl chloride (161 μL, 1.7 mmol) in anhydrous dichloromethane (0.5 mL) was added dropwise. After the addition was completed the ice-bath was removed and the mixture was stirred at room temperature overnight. The reaction mixture was diluted with methylene chloride and then washed successively with water, 10% hydrochloric acid and saturated sodium bicarbonate solution. The organic solution was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The resulting residue was purified by flash column chromatography on silica gel, eluting with 1:1 ethyl acetate:hexanes followed by 98:2 methylene chloride:methanol to give diethyl 2-(2,2-dichloro-N-(3-(3-(2,6-dichlorophenyl)isoxazol-5-yl)phenyl)acetamido)ethylphosphonate (Cpd. No. 1) as a white solid. 1H NMR (CDCl3): 7.94 (m, 1H), 7.79 (m, 1H), 7.64 (m, 1H), 7.46-7.40 (m, 2H), 7.43-7.36 (m, 2H), 6.72 (s, 1H), 5.85 (s, 1H), 4.08 (m, 6H), 2.13 (m, 2H), 1.33 ppm (m, 6H). MW=580 confirmed by LC-MS, tr=11.55 min (Method A) MH+=578-582.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:10]2[C:14](=[O:15])[NH:13][C:12](=[O:16])[O:11]2)[CH:5]=[C:6]([Cl:9])[C:7]=1[Cl:8].C(N(CC)CC)C.[Br:24][C:25]1[CH:33]=[CH:32][CH:31]=[C:30]([Br:34])[C:26]=1[C:27](Cl)=[O:28]>C1(C)C=CC=CC=1>[Cl:9][C:6]1[CH:5]=[C:4]([N:10]2[C:14](=[O:15])[N:13]([C:27](=[O:28])[C:26]3[C:25]([Br:24])=[CH:33][CH:32]=[CH:31][C:30]=3[Br:34])[C:12](=[O:16])[O:11]2)[CH:3]=[C:2]([Cl:1])[C:7]=1[Cl:8]
Reactant: O=c1[nH]c(=O)n(-c2cc(Cl)c(Cl)c(Cl)c2)o1
Reactant: O=C(Cl)c1c(Br)cccc1Br
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: O=C(c1c(Br)cccc1Br)n1c(=O)on(-c2cc(Cl)c(Cl)c(Cl)c2)c1=O
Reaction time: 24 h

Procedure:
2-(3,4,5-Trichlorophenyl)-1,2,4-oxadiazolidin-3,5-dione (0.03 mole), toluene (100 ml) and triethylamine (5 ml) are charged into a glass reaction vessel equipped with a mechanical stirrer, thermometer and reflux condenser. 2,6-Dibromobenzoyl chloride (0.03 mole) dissolved in toluene (20 ml) is then added to the reaction flask and the resulting mixture is heated at reflux with stirring for a period of about 24 hours. After this time the reaction mixture is filtered and the filtrate is washed with water, dilute hydrochloric acid and with aqueous sodium bicarbonate. The washed solution is then dried over anhydrous magnesium sulfate. The dried solution is stripped of solvent under reduced pressure leaving a solid residue. The residue is recrystallized to yield the desired product 2-(3,4,5-trichlorophenyl)-4-(2,6-dibromobenzoyl)-1,2,4-oxadiazolidin-3,5-dione.