Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[S:3](=[C:11]=[O:12])[C:4]([O:8][CH2:9][CH3:10])=[C:5]([OH:7])[N:6]=1.[Br:13]N1C(=O)CCC1=O>C(Cl)(Cl)(Cl)Cl>[Br:13][CH2:1][C:2]1[S:3](=[C:11]=[O:12])[C:4]([O:8][CH2:9][CH3:10])=[C:5]([OH:7])[N:6]=1
Reactant: CCOC1=C(O)N=C(C)S1=C=O
Reactant: O=C1CCC(=O)N1Br
Solvent: ClC(Cl)(Cl)Cl
Product: CCOC1=C(O)N=C(CBr)S1=C=O
Temperature: 0 °C
Reaction time: 1 h
Yield: 47 %

Procedure:
2-Methyl-5-ethoxy-carbonyl-4-hydroxy-thiazole (45 g, 0.24 mol) was dissolved in 1 L of carbon tetrachloride. The solution was cooled down to 0° C. N-Bromo succinimide (43 g, 0.24 mol) was added portion-wise at 0° C. The reaction mixture was stirred at 0° C. for 1 hour and then warmed to room temperature. The reaction mixture was stirred at room temperature for overnight. The reaction mixture was then passed through a short pad of celite. Removal of solvent gave crude product as solid, which was washed with ethyl acetate/hexane (1/3) three times (1×40 ml; 2×20 ml) to give 30 g of the title compound (yield: 50%; LC: Retention Time=1.66 min; MS: M+1=267).
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([NH2:11])[CH:9]=2)[CH:4]=[CH:3]1.[C:12](Cl)(=[O:16])[CH:13]([CH3:15])[CH3:14].C(OCC)(=O)C>N1C=CC=CC=1>[CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([NH:11][C:12](=[O:16])[CH:13]([CH3:15])[CH3:14])[CH:9]=2)[CH:4]=[CH:3]1
Reactant: Cn1ccc2ccc(N)cc21
Reactant: CC(C)C(=O)Cl
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Product: CC(C)C(=O)Nc1ccc2ccn(C)c2c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 36.2 %

Procedure:
To a solution of 1-methyl-1H-indol-6-amine (45 mg, 0.31 mmol) in pyridine (2 mL) at room temperature was added isobutyryl chloride (35 μL, 0.34 mmol). The resulting mixture was stirred at room temperature for 16 h. Ethyl acetate was added and the organic layer was washed three times with brine. The combined organic layers were dried over anhydrous MgSO4 and evaporated to afford 24.3 mg (36%) of the title compound (LCMS RT=5.73 min, MH+ 217.2)
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([F:23])[CH:18]=2)=[C:5]([C:7]([N:9]2[C@H:14]([CH2:15][NH2:16])[CH2:13][C@H:12]3[C@@H:10]2[CH2:11]3)=[O:8])[N:6]=1.[F:24][C:25]1([F:37])[O:29][C:28]2[CH:30]=[CH:31][CH:32]=[C:33]([C:34](O)=[O:35])[C:27]=2[O:26]1>>[NH2:1][C:2]1[S:3][C:4]([C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([F:23])[CH:18]=2)=[C:5]([C:7]([N:9]2[C@H:14]([CH2:15][NH:16][C:34]([C:33]3[C:27]4[O:26][C:25]([F:37])([F:24])[O:29][C:28]=4[CH:30]=[CH:31][CH:32]=3)=[O:35])[CH2:13][C@H:12]3[C@@H:10]2[CH2:11]3)=[O:8])[N:6]=1
Reactant: O=C(O)c1cccc2c1OC(F)(F)O2
Reactant: NC[C@@H]1C[C@@H]2C[C@@H]2N1C(=O)c1nc(N)sc1-c1cccc(F)c1
Product: Nc1nc(C(=O)N2[C@H](CNC(=O)c3cccc4c3OC(F)(F)O4)C[C@@H]3C[C@@H]32)c(-c2cccc(F)c2)s1

Procedure:
prepared by reaction of [2-amino-5-(3-fluoro-phenyl)-thiazol-4-yl]-((1S,3S,5S)-3-aminomethyl-2-aza-bicyclo[3.1.0]hex-2-yl)-methanone with 2,2-difluoro-benzo[1,3]dioxole-4-carboxylic acid. LC-MS (basic): tR=0.86 min; [M+H]+=517.1.
Reaction SMILES: BrBr.[NH2:3][C:4]1[CH:5]=[C:6]([C:12]2[C:17]([Cl:18])=[CH:16][C:15]([C:19]([F:22])([F:21])[F:20])=[CH:14][N:13]=2)[C:7]([F:11])=[CH:8][C:9]=1[Cl:10].[S-:23][C:24]#[N:25].[Na+].O>C(O)(=O)C>[NH2:25][C:24]1[S:23][C:5]2[C:6]([C:12]3[C:17]([Cl:18])=[CH:16][C:15]([C:19]([F:22])([F:21])[F:20])=[CH:14][N:13]=3)=[C:7]([F:11])[CH:8]=[C:9]([Cl:10])[C:4]=2[N:3]=1
Reactant: Nc1cc(-c2ncc(C(F)(F)F)cc2Cl)c(F)cc1Cl
Reactant: N#C[S-]
Agent: BrBr
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: Nc1nc2c(Cl)cc(F)c(-c3ncc(C(F)(F)F)cc3Cl)c2s1
Temperature: 25 °C
Reaction time: 10 h
Yield: 13 %

Procedure:
At about 20° C., a solution of 37 g (234 mmol) of bromine in 10 ml of glacial acetic acid was added over a period of 10 minutes to a solution of 38 g (117 mmol) of 2-(3-amino-4-chloro-6-fluorophenyl)-3-chloro-5-trifluoromethylpyridine and 38 g (468 mmol) of sodium thiocyanate in 500 ml of glacial acetic acid. The reaction mixture was subsequently stirred at room temperature for 10 hours and then poured into 2 l of water. The product was then extracted with 3×500 ml of ethyl acetate. The combined organic phases were dried over magnesium sulfate and (finally concentrated. The crude product was purified by silica gel chromatography (eluent: cyclohexane/ethyl acetate =4:1→1:1). Yield: 13%; m.p.: 230-235° C.
Reaction SMILES: N1C=CC(C2C(C3C=CC(OCC4C=CC5C(=CC=CC=5)N=4)=CC=3)=NN([CH2:12][C:13]([F:16])([F:15])[F:14])C=2)=CC=1.[CH2:35]([O:42][C:43]1[CH:48]=[CH:47][C:46]([C:49]2[C:53]([C:54]3[CH:59]=[CH:58][N:57]=[CH:56][CH:55]=3)=[CH:52][NH:51][N:50]=2)=[C:45]([F:60])[CH:44]=1)[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1>>[CH2:35]([O:42][C:43]1[CH:48]=[CH:47][C:46]([C:49]2[C:53]([C:54]3[CH:59]=[CH:58][N:57]=[CH:56][CH:55]=3)=[CH:52][N:51]([CH2:12][C:13]([F:16])([F:15])[F:14])[N:50]=2)=[C:45]([F:60])[CH:44]=1)[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1
Reactant: Fc1cc(OCc2ccccc2)ccc1-c1n[nH]cc1-c1ccncc1
Reactant: FC(F)(F)Cn1cc(-c2ccncc2)c(-c2ccc(OCc3ccc4ccccc4n3)cc2)n1
Product: Fc1cc(OCc2ccccc2)ccc1-c1nn(CC(F)(F)F)cc1-c1ccncc1

Procedure:
Following the procedure for the preparation of 2-{4-[-Pyridin-4-yl-1-(2,2,2-trifluoro-ethyl)-1H-pyrazol-3-yl]-phenoxymethyl}-quinoline but substituting 4-[3-(4-Benzyloxy-2-fluoro-phenyl)-1H-pyrazol4-yl]-pyridine provided the title compound. MS: (M+H m/z=428.4).
Reaction SMILES: Br[C:2]1[C:3](=[O:16])[C:4]2[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][C:5]=2[NH:6][C:7](=[O:10])[C:8]=1[OH:9].[C:17]1([Sn](C)(C)C)[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>C1COCC1>[Cl:15][C:12]1[CH:13]=[CH:14][C:4]2[C:3](=[O:16])[C:2]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)=[C:8]([OH:9])[C:7](=[O:10])[NH:6][C:5]=2[CH:11]=1
Reactant: O=c1[nH]c2cc(Cl)ccc2c(=O)c(Br)c1O
Reactant: C[Sn](C)(C)c1ccccc1
Solvent: C1CCOC1
Product: O=c1[nH]c2cc(Cl)ccc2c(=O)c(-c2ccccc2)c1O
Temperature: 25 °C
Yield: 58 %

Procedure:
To a solution of 4-Bromo-8-chloro-3-hydroxy-2,5-dioxo-2,5-dihydro-1H-benz[b]azepine (400 mg) in THF (10 mL) was added phenyltrimethylstannane (600 mg) and trans-Benzyl(chloro)bis(triphenyl-phosphinepalladium(II) (50 mg). The solution was heated to reflux for 5 hours at which time a dark gray precipitate formed. The reaction mixture was cooled to room temperature and diluted with an ether-tetrahydrofuran mixture (1:1). This mixture was washed with a 10% solution of potassium fluoride, dried (Na2 SO4), and evaporated to dryness. Chromatography, with ethyl acetate as the eluent, yielded the title compound as a white solid (230 mg); mp 193-196 degrees C.; NMR: 7.18(m,2H), 7.31(m, 4H), 7.52(s, 1H), 7.87(d, 1H, J=8.7), 10.28(brs, 1H), 11.81(s, 1H). Analysis for C16H10 ClNO3 -0.3H2O: Calculated: C, 62.98, H, 3.50, N, 4.59: Found: C, 62.82, H, 3.33, N, 4.67.
Reaction SMILES: [H-].[Na+].[CH3:3][C:4]1[CH:9]=[CH:8][C:7]([CH:10]2[CH2:15][C:14](=[O:16])[CH2:13][C:12](=[O:17])[CH2:11]2)=[CH:6][CH:5]=1.Cl[CH2:19][C:20](=O)[CH3:21]>CN(C)C=O>[CH3:21][C:20]1[C:13]2[C:14](=[O:16])[CH2:15][CH:10]([C:7]3[CH:6]=[CH:5][C:4]([CH3:3])=[CH:9][CH:8]=3)[CH2:11][C:12]=2[O:17][CH:19]=1
Reactant: CC(=O)CCl
Reactant: Cc1ccc(C2CC(=O)CC(=O)C2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1ccc(C2CC(=O)c3c(C)coc3C2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 21.5 %

Procedure:
In dimethylformamide (10 ml) was suspended 60% sodium hydride (0.44 g, washed with hexane thrice), and to the suspension were added 5-(4-methylphenyl)cyclohexane-1,3-dione (2.0 g) and chloroacetone (0.92 g). The mixture was stirred at room temperature for 1 hour and then at 150° C. for 13 hours. Under reduced pressure, the solvent was evaporated, and the residue was dissolved in ethyl acetate, water and saturated brine, dried with magnesium sulfate and concentrated under reduced pressure. The residue was purified with silica gel column chromatography (EtOAc/hexane), and the resulting crystals were recrystallized from hexane to give colorless crystals of 3-methyl-6-(4-methylphenyl)-4,5,6,7-tetrahydrobenzofuran-4-one (0.51 g).
Reaction SMILES: [C:1]([O:9][CH2:10][CH2:11][O:12][CH2:13]Cl)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:15][C:16]1[N:24]=[CH:23][N:22]=[C:21]2[C:17]=1[NH:18][CH:19]=[N:20]2.C(N(CC)CC)C>CN(C)C=O>[Cl:15][C:16]1[N:24]=[CH:23][N:22]=[C:21]2[C:17]=1[N:18]=[CH:19][N:20]2[CH2:13][O:12][CH2:11][CH2:10][O:9][C:1](=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(OCCOCCl)c1ccccc1
Reactant: Clc1ncnc2nc[nH]c12
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: O=C(OCCOCn1cnc2c(Cl)ncnc21)c1ccccc1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
Following substantially the procedure of Schaeffer, et al. supra but with minor modifications, 1-benzoyloxy-2-chloromethoxyethane (4.4 g) was added with stirring to a dry solution of 6-chloropurine (3.1 g) and triethylamine (6.5 ml) in dimethylformamide (50 ml). The reaction was exothermic, immediately precipitating, triethylamine hydrochloride. The reaction mixture was stirred at room temperature for 24 hours and filtered. The filtrate was evaporated on a rotary evaporator at 70° C. The remaining thick amber oil was dissolved in the minimum amount of benzene and purified by column chromatography using a silica gel column. Benzene elution removed a trace of an unidentified material. Elution with ether first remove a small amount of ethylene glycol monobenzoate then 6-chloro-9-(2-benzoyloxyethoxymethyl)purine. Recrystallization from ether gave a white material, m.p. 108.5°-111° C.
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH3:44])=[C:4]([C:28]2[CH:29]=[C:30]([C:34]([O:36]CC3C=CC=CC=3)=[O:35])[N:31]([CH3:33])[CH:32]=2)[C:5]([O:26][CH3:27])=[C:6]([CH:8]([NH:10][C:11]2[N:19]=[CH:18][N:17]=[C:16]3[C:12]=2[N:13]=[CH:14][N:15]3C2CCCCO2)[CH3:9])[CH:7]=1>CO.[Pd]>[Cl:1][C:2]1[C:3]([CH3:44])=[C:4]([C:28]2[CH:29]=[C:30]([C:34]([OH:36])=[O:35])[N:31]([CH3:33])[CH:32]=2)[C:5]([O:26][CH3:27])=[C:6]([CH:8]([NH:10][C:11]2[N:19]=[CH:18][N:17]=[C:16]3[C:12]=2[N:13]=[CH:14][NH:15]3)[CH3:9])[CH:7]=1
Reactant: COc1c(C(C)Nc2ncnc3c2ncn3C2CCCCO2)cc(Cl)c(C)c1-c1cc(C(=O)OCc2ccccc2)n(C)c1
Agent: [Pd]
Solvent: CO
Product: COc1c(C(C)Nc2ncnc3[nH]cnc23)cc(Cl)c(C)c1-c1cc(C(=O)O)n(C)c1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
Pd/C (5%, 20 mg) was added to a solution of benzyl 4-[3-chloro-6-methoxy-2-methyl-5-(1-{[9-(tetrahydro-2H-pyran-2-yl)-9H-purin-6-yl]amino}ethyl)phenyl]-1-methyl-1H-pyrrole-2-carboxylate (20 mg) in methanol (2.0 mL) and the reaction was stirred at room temperature under balloon pressure of H2 for 4 hours. The reaction mixture was filtered and to the filtrate was added conc. HCl (30 μL). The mixture was stirred for 0.5 h to remove the THP group. The solvent was removed to yield the crude product which was used in the next step without further purification. LCMS calculated for C21H22ClN6O3 (M+H)+: m/z=441.1. found: 441.2.
Reaction SMILES: Br[C:2]1[N:7]=[C:6]([C:8]([O:10][CH3:11])=[O:9])[CH:5]=[CH:4][C:3]=1[F:12].[F:13][C:14]1[CH:15]=[C:16]([C:30]([O:33][Si](C(C)C)(C(C)C)C(C)C)([CH3:32])[CH3:31])[CH:17]=[C:18]([F:29])[C:19]=1B1OC(C)(C)C(C)(C)O1>>[F:13][C:14]1[CH:15]=[C:16]([C:30]([OH:33])([CH3:32])[CH3:31])[CH:17]=[C:18]([F:29])[C:19]=1[C:2]1[N:7]=[C:6]([C:8]([O:10][CH3:11])=[O:9])[CH:5]=[CH:4][C:3]=1[F:12]
Reactant: CC(C)[Si](OC(C)(C)c1cc(F)c(B2OC(C)(C)C(C)(C)O2)c(F)c1)(C(C)C)C(C)C
Reactant: COC(=O)c1ccc(F)c(Br)n1
Product: COC(=O)c1ccc(F)c(-c2c(F)cc(C(C)(C)O)cc2F)n1
Yield: 90 %

Procedure:
Method 1 was followed using methyl 6-bromo-5-fluoropicolinate (1.0 equiv.) and (2-(3,5-difluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)propan-2-yloxy)triisopropylsilane (1.6 equiv.) at 100° C. for 30 min in the microwave to give methyl 6-(2,6-difluoro-4-(2-hydroxypropan-2-yl)phenyl)-5-fluoropicolinate in 90% yield. LC/MS=325.9 (MH+), Rt=0.81 min. 1H NMR (400 MHz, <cdcl3>) δ ppm 1.59 (s, 6 H), 4.00 (s, 3 H), 7.15 (d, J=9.00 Hz, 2 H), 7.62-7.68 (m, 1 H), 8.23-8.29 (m, 1 H).
Reaction SMILES: [Cl:1][C:2]1[C:6]([Cl:7])=[C:5]([C:8](O)=[O:9])[S:4][N:3]=1.C1(C)C=CC=CC=1.S(Cl)(Cl)=O>CN(C)C=O>[Cl:1][C:2]1[C:6]([Cl:7])=[C:5]([CH2:8][OH:9])[S:4][N:3]=1
Reactant: O=C(O)c1snc(Cl)c1Cl
Solvent: Cc1ccccc1
Solvent: CN(C)C=O
Solvent: O=S(Cl)Cl
Product: OCc1snc(Cl)c1Cl
Temperature: 100 °C
Reaction time: 0.08 h
Yield: 59.2 %

Procedure:
A mixture of 3,4-dichloroisothiazole-5-carboxylic acid (2.0 g) and toluene (20 mL) was treated with thionyl chloride (5.0 mL) and N,N-dimethylformamide (0.5 mL), and the resulting mixture was heated at 100° C. for 16 hours. The mixture was concentrated under reduced pressure and the residue was dissolved in tetrahydrofuran (5.0 mL). The mixture was cooled to −78° C. and treated dropwise over a period of 1 hour with a 2.0 M solution of sodium borohydride in N,N-dimethylformamide (8.5 mL). The mixture was stirred at −78° C. for 5 minutes, diluted with 1.0 M aqueous hydrochloric acid solution and extracted with ethyl acetate. The combined organic extract was washed with saturated aqueous sodium chloride solution, dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel, eluting with a mixture of cyclohexane and dichloromethane (1:0 to 0:1 by volume) to afford the title compound as a pale yellow solid (1.1 g).
Reaction SMILES: C([O-])(=O)C.[K+].[Br:6]Br.[CH3:8][O:9][CH2:10][CH2:11][N:12]1[C:16]([CH2:17][CH:18]2[CH2:23][CH2:22][O:21][CH2:20][CH2:19]2)=[CH:15][C:14]([C:24]#[N:25])=[N:13]1.S([O-])(O)=O.[Na+]>C(O)(=O)C.O>[Br:6][C:15]1[C:14]([C:24]#[N:25])=[N:13][N:12]([CH2:11][CH2:10][O:9][CH3:8])[C:16]=1[CH2:17][CH:18]1[CH2:23][CH2:22][O:21][CH2:20][CH2:19]1
Reactant: COCCn1nc(C#N)cc1CC1CCOCC1
Reactant: BrBr
Agent: CC(=O)[O-]
Agent: O=S([O-])O
Agent: [K+]
Solvent: O
Solvent: CC(=O)O
Product: COCCn1nc(C#N)c(Br)c1CC1CCOCC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 90.7 %

Procedure:
Potassium acetate (3.12 g, 31.7 mmol) and bromine (2.84 g, 17.7 mmol) were sequentially added to a solution of 1-(2-methoxyethyl)-5-(tetrahydro-2H-pyran-4-ylmethyl)-1H-pyrazole-3-carbonitrile (3.16 g, 12.7 mmol) in acetic acid (25 mL). The reaction was stirred for 16 hours at room temperature. Saturated aqueous sodium hydrogensulfite was added until the reaction became colorless. Water was added, and a precipitate formed, was isolated by filtration, washed with water, and dried on the vacuum filter funnel to provide 3.78 g of 4-bromo-1-(2-methoxyethyl)-5-(tetrahydro-2H-pyran-4-ylmethyl)-1H-pyrazole-3-carbonitrile as a white solid containing about 2 mol % acetic acid.
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH2:4][NH2:5].[CH3:10][O:11][C:12](=[O:20])[C:13]([N+:18]#[C-:19])=[CH:14]N(C)C>C1(C)C(C)=CC=CC=1.C(OCC)(=O)C>[CH3:10][O:11][C:12]([C:13]1[N:18]=[CH:19][N:5]([CH2:4][C:3]2[CH:6]=[CH:7][CH:8]=[CH:9][C:2]=2[F:1])[CH:14]=1)=[O:20]
Reactant: NCc1ccccc1F
Reactant: [C-]#[N+]C(=CN(C)C)C(=O)OC
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1C
Product: COC(=O)c1cn(Cc2ccccc2F)cn1
Temperature: 25 °C

Procedure:
8 g of o-fluorobenzylamine and 6.6 g of 2-isocyano-3-dimethylaminoacrylic acid methyl ester are dissolved in 66 ml of xylene and heated under reflux for 3 hours while stirring. After cooling to room temperature, the whole is diluted with ethyl acetate and extracted by shaking twice with 50 ml of 2N hydrochloric acid each time and then with water. The aqueous phases are washed twice with 50 ml of ethyl acetate each time. All the aqueous phases are combined, rendered alkaline with concentrated ammonia and then extracted by shaking three times with 100 ml of dichloromethane each time. The extracts are combined, washed twice with water, dried over magnesium sulphate and concentrated to dryness by evaporation. The residue is dissolved in ethyl acetate, filtered over silica gel, concentrated and caused to crystallise by the addition of diethyl ether. 1-(o-fluorobenzyl)-imidazole-4-carboxylic acid methyl ester having a melting point of 87°-89° is obtained.
Reaction SMILES: [CH3:1][O:2][P:3]([C:7]1[CH:8]=[C:9]([C:13]2[CH:18]=[CH:17][C:16]([C@@H:19]3[C@@H:22]([CH2:23][CH2:24][C@H:25]([O:33][Si:34]([C:37]([CH3:40])([CH3:39])[CH3:38])([CH3:36])[CH3:35])[C:26]4[CH:31]=[CH:30][C:29]([F:32])=[CH:28][CH:27]=4)[C:21](=[O:41])[N:20]3[C:42]3[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=3)=[C:15]([O:48][Si](C(C)(C)C)(C)C)[CH:14]=2)[CH:10]=[CH:11][CH:12]=1)(=[O:6])[O:4][CH3:5].[F-].[K+].C(OCC)(=O)C>CO>[CH3:1][O:2][P:3]([C:7]1[CH:8]=[C:9]([C:13]2[CH:18]=[CH:17][C:16]([C@@H:19]3[C@@H:22]([CH2:23][CH2:24][C@H:25]([O:33][Si:34]([C:37]([CH3:40])([CH3:39])[CH3:38])([CH3:36])[CH3:35])[C:26]4[CH:31]=[CH:30][C:29]([F:32])=[CH:28][CH:27]=4)[C:21](=[O:41])[N:20]3[C:42]3[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=3)=[C:15]([OH:48])[CH:14]=2)[CH:10]=[CH:11][CH:12]=1)(=[O:6])[O:4][CH3:5]
Reactant: COP(=O)(OC)c1cccc(-c2ccc([C@@H]3[C@@H](CC[C@H](O[Si](C)(C)C(C)(C)C)c4ccc(F)cc4)C(=O)N3c3ccccc3)c(O[Si](C)(C)C(C)(C)C)c2)c1
Agent: [F-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CO
Product: COP(=O)(OC)c1cccc(-c2ccc([C@@H]3[C@@H](CC[C@H](O[Si](C)(C)C(C)(C)C)c4ccc(F)cc4)C(=O)N3c3ccccc3)c(O)c2)c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Dimethyl(3′-{[tert-butyl(dimethyl)silyl]oxy}-4′-{(2S,3R)-3-[(3S)-3-{[tert-butyl(dimethyl)silyl]oxy}-3-(4-fluorophenyl)propyl]-4-oxo-1-phenylazetidin-2-yl}biphenyl-3-yl)phosphonate (0.047 g, 0.058 mmol) was stirred at room temperature in dry methanol (2 mL) under a nitrogen atmosphere. Potassium fluoride (0.02 g, 0.34 mmol) was added and the reaction mixture was stirred for 30 min at room temperature. The solution was poured into ethyl acetate and washed successively with water (2×), and brine. The organic solution was dried over sodium sulfate, filtered and the solvent was removed by rotary evaporation under reduced pressure. Dimethyl(4′-{(2S,3R)-3-[(3S)-3-{[tert-butyl(dimethyl)silyl]oxy}-3-(4-fluorophenyl)propyl]-4-oxo-1-phenylazetidin-2-yl}-3′-hydroxybiphenyl-3-yl)phosphonate was obtained as a colorless glass (0.041 g, 100%) was used directly in the next reaction without further purification; MS [M−H]+ 688
Reaction SMILES: I[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7].[OH:8][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[CH:15]=[C:14]([CH:19]([CH3:23])[C:20]([OH:22])=[O:21])[CH:13]=[CH:12]2>>[CH3:23][CH:19]([C:14]1[CH:13]=[CH:12][C:11]2[C:16](=[CH:17][CH:18]=[C:9]([O:8][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7])[CH:10]=2)[CH:15]=1)[C:20]([OH:22])=[O:21]
Reactant: CC(C(=O)O)c1ccc2cc(O)ccc2c1
Reactant: CCCCCCI
Product: CCCCCCOc1ccc2cc(C(C)C(=O)O)ccc2c1

Procedure:
The title compound is prepared according to the method of Example 7 using 1-iodohexane and racemic 6-hydroxy-α-methyl-2-naphthaleneacetic acid. White crystals are obtained having a melting point of 88°-9 1 ° C.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7](=O)[C:8]2[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][C:9]=2[NH:10][N:11]=1)=[O:5])[CH3:2].N1C=CC=CC=1.C1(C)C=CC(S([Cl:33])(=O)=O)=CC=1>ClCCl>[CH2:1]([O:3][C:4]([C:6]1[N:11]=[N:10][C:9]2[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][C:8]=2[C:7]=1[Cl:33])=[O:5])[CH3:2]
Reactant: CCOC(=O)c1n[nH]c2c(c1=O)CCCCC2
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCOC(=O)c1nnc2c(c1Cl)CCCCC2
Yield: 22.3 %

Procedure:
To a solution of 4-oxo-4,5,6,7,8,9-hexahydro-1H-cyclohepta[c]pyridazine-3-carboxylic acid ethyl ester (2.7 g) and pyridine (0.93 ml) in dichloromethane (150 ml) was added p-toluenesulphonyl chloride (2.2 g). The reaction mixture was heated at reflux for 20 h. The reaction mixture was washed with 1M potassium carbonate solution, brine, dried over magnesium sulphate, filtered and evaporated under reduced pressure to give an oil. The oil was purified by flash chromatography using a gradient elution: CH2Cl2 (500 ml), CH2Cl2/MeOH 99:1 (500 ml), CH2Cl2/MeOH 98:2 (500 ml), CH2Cl2/MeOH 97:3 (500 ml), CH2Cl2/MeOH 96:4 (500 ml). The appropriate fractions were combined and evaporated under reduced pressure to give a solid (0.65 g, 22%). C12H15ClN2O2 requires C, 56.58; H, 5.93; N, 11.00. Found C, 56.52; H, 6.06; N, 11.01%. δH (360 MHz; CDCl3) 1.44 (3H, t, J=7 Hz, CH3), 1.70 (2H, m, CH2), 1.77 (2H, m, CH2), 1.92 (2H, m, CH2), 3.06 (2H, m, CH2), 3.32 (2H, m, CH2), 4.51 (2H, t, J=7 Hz, CH2), m/z (ESP+) 255/257 (MH+).
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[CH:2]1.C[O-].[Na+].[Cl:9][C:10]1[CH:22]=[C:21]2[C:13]([C:14]3[CH:15]=[CH:16][C:17]([C:23]([OH:34])([CH2:32]Cl)[CH2:24][C:25]4[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=4)=[CH:18][C:19]=3[CH2:20]2)=[CH:12][CH:11]=1.O>CO.CN(C)C=O>[Cl:9][C:10]1[CH:22]=[C:21]2[C:13]([C:14]3[CH:15]=[CH:16][C:17]([C:23]([OH:34])([CH2:32][N:1]4[CH:5]=[CH:4][N:3]=[CH:2]4)[CH2:24][C:25]4[CH:26]=[CH:27][C:28]([Cl:31])=[CH:29][CH:30]=4)=[CH:18][C:19]=3[CH2:20]2)=[CH:12][CH:11]=1
Reactant: OC(CCl)(Cc1ccc(Cl)cc1)c1ccc2c(c1)Cc1cc(Cl)ccc1-2
Reactant: c1c[nH]cn1
Agent: C[O-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CO
Product: OC(Cc1ccc(Cl)cc1)(Cn1ccnc1)c1ccc2c(c1)Cc1cc(Cl)ccc1-2
Temperature: 60 °C
Yield: 62.5 %

Procedure:
9 g (0.12 mol) of imidazole are added to a solution of 4.2 g (0.078 mols) of sodium methylate in 22 ml of methanol; a solution of 2-(7-chlorofluoren-2-yl)-3-chloro-1-(4-chlorophenyl)-propan-2-ol in 45 ml of dimethylformamide is then added dropwise and the mixture is warmed to 60° C. for 90 minutes. The mixture is poured into 2,000 ml of water, the crystalline mass which has separated out is dissolved in methylene chloride, the solution is washed with water, dried over sodium sulphate and filtered and the filtrate is concentrated in vacuo. The residue is made to crystallise by stirring with diethyl ether; the crystals are stirred with a little methyl alcohol and filtered off. 16.2 g (62.5% of theory) of 2-(7-chlorofluoren-2-yl)-1-(4-chlorophenyl)-3-(imidazol-1-yl)-propan-2-ol of melting point 218° C. are obtained.
Reaction SMILES: N1C=CC=CC=1.[CH3:7][C:8]1[C:9]([NH2:15])=[N:10][CH:11]=[C:12]([CH3:14])[CH:13]=1.[CH3:16][C:17]1[C:21]([CH2:22][O:23][C:24]2[CH:29]=[CH:28][C:27]([S:30](Cl)(=[O:32])=[O:31])=[CH:26][CH:25]=2)=[C:20]([CH3:34])[O:19][N:18]=1.O>ClCCl>[CH3:16][C:17]1[C:21]([CH2:22][O:23][C:24]2[CH:25]=[CH:26][C:27]([S:30]([NH:15][C:9]3[C:8]([CH3:7])=[CH:13][C:12]([CH3:14])=[CH:11][N:10]=3)(=[O:32])=[O:31])=[CH:28][CH:29]=2)=[C:20]([CH3:34])[O:19][N:18]=1
Reactant: Cc1noc(C)c1COc1ccc(S(=O)(=O)Cl)cc1
Reactant: Cc1cnc(N)c(C)c1
Solvent: O
Solvent: c1ccncc1
Solvent: ClCCl
Product: Cc1cnc(NS(=O)(=O)c2ccc(OCc3c(C)noc3C)cc2)c(C)c1
Temperature: 70 °C
Yield: 14.1 %

Procedure:
To a solution of pyridine (0.083 mL, 1.023 mmol) and 3,5-dimethyl-2-pyridinamine (125 mg, 1.023 mmol) in dichloromethane (1 mL) was added 4-{[(3,5-dimethyl-4-isoxazolyl)methyl]oxy}benzenesulfonyl chloride (309 mg, 1.023 mmol). The mixture was heated at 70° C. for 4 hours. Water (5 mL) was added and the organic phase separated and purified by flash silica (Si) chromatography (50% dichloromethane-ethyl acetate gradient) to give the title compound (56 mg) as a bright yellow solid. LCMS (2 min, formic) Rt 0.93 min, m/z (ES+) 388 (M+H).