Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[CH2:2][N:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10](=[O:30])[C:11]2[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:13][C:12]=2[O:21][C:22]2[CH:27]=[CH:26][C:25]([F:28])=[CH:24][C:23]=2[CH3:29])=[CH:5][C:4]1=[O:31].[C:32]([O:36][P:37]([O:44][K])([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38])([CH3:35])([CH3:34])[CH3:33]>CN(C)C=O.[I-].C([N+](CCCC)(CCCC)CCCC)CCC.C(OCC)(=O)C>[P:37]([O:44][CH2:2][N:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10](=[O:30])[C:11]2[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:13][C:12]=2[O:21][C:22]2[CH:27]=[CH:26][C:25]([F:28])=[CH:24][C:23]=2[CH3:29])=[CH:5][C:4]1=[O:31])([O:36][C:32]([CH3:35])([CH3:34])[CH3:33])([O:39][C:40]([CH3:42])([CH3:43])[CH3:41])=[O:38]
Reactant: CC(C)(C)OP(=O)(O[K])OC(C)(C)C
Reactant: Cc1cc(F)ccc1Oc1cc(C(F)(F)F)ccc1C(=O)Nc1ccn(CCl)c(=O)c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [I-]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: Cc1cc(F)ccc1Oc1cc(C(F)(F)F)ccc1C(=O)Nc1ccn(COP(=O)(OC(C)(C)C)OC(C)(C)C)c(=O)c1
Temperature: 70 °C
Reaction time: 4 h
Yield: 45 %

Procedure:
The crude N-[1-(chloromethyl)-2-oxo-4-pyridyl]-2-(4-fluoro-2-methyl-phenoxy)-4-(trifluoromethyl)benzamide from the previous step was taken up in N,N-dimethylformamide (5 mL). Di-tert-butoxyphosphoryloxypotassium (496.6 mg, 2.0 mmol) and tetrabutylammonium iodide (36.94 mg, 0.10 mmol) were added and the reaction mixture was stirred at 70° C. for 4 hours. The reaction mixture was then diluted with ethyl acetate and washed with water then brine, dried with Na2SO4, filtered and evaporated to dryness. The material was purified by column chromatography (40 g silica, 50-100% EtOAc in Hexanes), fractions with the product were pooled and evaporated to give di-tert-butyl [4-[[2-(4-fluoro-2-methyl-phenoxy)-4-(trifluoromethyl)benzoyl]amino]-2-oxo-1-pyridyl]methyl phosphate (20) (280 mg, 45%) as a yellow oil that was used in the next step without further purification. ESI-MS m/z calc. 628.20, found 629 (M+1)+; Retention time: 0.76 minutes (1 minute run).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]3[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][C:10]=3[S:11][CH:12]=2)=[CH:4][CH:3]=1.[Br:18][CH2:19][CH2:20][CH2:21]Br>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]3[CH:16]=[CH:15][C:14]([O:17][CH2:21][CH2:20][CH2:19][Br:18])=[CH:13][C:10]=3[S:11][CH:12]=2)=[CH:4][CH:3]=1
Reactant: BrCCCBr
Reactant: Oc1ccc2c(-c3ccc(Br)cc3)csc2c1
Product: BrCCCOc1ccc2c(-c3ccc(Br)cc3)csc2c1

Procedure:
In analogy to example 27.1, 3-(4-Bromo-phenyl)-benzo[b]thiophen-6-ol and 1,3-dibromopropane were converted to yield 3-(4-Bromo-phenyl)-6-(3-bromo-propoxy)-benzo[b]thiophene, MS: 424 (M, 2Br).
Reaction SMILES: CN(C)[N:3]1[CH:8]=[C:7]([CH2:9][CH3:10])[CH2:6][C:5]2[C:11]([O:13][C:14](=[O:15])[C:4]1=2)=[O:12].Cl.C1C[O:21]CC1>>[CH2:9]([C:7]1[CH:6]=[C:5]([C:11]([OH:21])=[O:12])[C:4]([C:14]([OH:13])=[O:15])=[N:3][CH:8]=1)[CH3:10]
Reactant: CCC1=CN(N(C)C)C2=C(C1)C(=O)OC2=O
Reactant: C1CCOC1
Agent: Cl
Product: CCc1cnc(C(=O)O)c(C(=O)O)c1

Procedure:
The above anhydride is dissolved in THF, and 100 ml of 2M HCl is added. The mixture is stirred and the THF is distilled off. The residue is recrystallized from THF to give 5-ethyl-2,3-pyridinedicarboxylic acid.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[C:3]([CH2:10]C(O)=O)=[N:2]1.Cl[S:15]([OH:18])(=[O:17])=[O:16]>O1CCOCC1>[O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[C:3]([CH2:10][S:15]([OH:18])(=[O:17])=[O:16])=[N:2]1
Reactant: O=S(=O)(O)Cl
Reactant: O=C(O)Cc1noc2ccccc12
Solvent: C1COCCO1
Product: O=S(=O)(O)Cc1noc2ccccc12
Temperature: 62.5 °C
Reaction time: 1 h
Yield: 90.5 %

Procedure:
1,2-Benzisoxazole-3-acetic acid (200 g; 1.13 mol) was suspended in 1,4-dioxane (600 mL). The mixture was cooled in an ice-bath and chlorosulfonic acid (82.6 mL, 1.24 mol, 1.1 eq) was added maintaining the internal temperature below 20° C. The mixture was heated to 60-65° C. for 9½ h and cooled to room-temperature. CELITE™ (20 g) was added followed by xylenes (1000 mL) and the mixture was stirred for one hour at room temperature. It was filtered and concentrated. The suspension obtained was heated to 50-60° C. for three hours and then gradually cooled to 0-5° C. and filtered. The precipitate was filtered off under a nitrogen atmosphere and washed with 400 mL 1,4-dioxane/xylenes (v/v=1:9). It was dried at 60° C. for approximately 16 hours in a vacuum oven (≦1 mm Hg) to give 218.14 g crystalline anhydrous 1,2-benzisoxazole-3-methanesulfonic acid (90.6%) with a HPLC purity of 99.4%.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][CH:3]=1.[Mg].C(O[C:13]([CH:15]1[CH2:20][CH2:19][N:18]([CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH2:17][CH2:16]1)=[O:14])C.[Cl-].[NH4+]>O1CCCC1>[CH3:8][C:5]1[CH:6]=[CH:7][C:2]([C:13]([C:2]2[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][CH:3]=2)([CH:15]2[CH2:16][CH2:17][N:18]([CH2:21][C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=3)[CH2:19][CH2:20]2)[OH:14])=[CH:3][CH:4]=1
Reactant: CCOC(=O)C1CCN(Cc2ccccc2)CC1
Reactant: Cc1ccc(Br)cc1
Agent: [Cl-]
Agent: [Mg]
Agent: [NH4+]
Solvent: C1CCOC1
Product: Cc1ccc(C(O)(c2ccc(C)cc2)C2CCN(Cc3ccccc3)CC2)cc1
Temperature: 25 °C
Yield: 95.4 %

Procedure:
A Grignard solution was prepared by the addition of 102.6 g (0.6 mole) of 4-bromotoluene in 500 ml of dry tetrahydrofuran to a mixture of 12.5 g (0.5 mole) of magnesium chips in 250 ml of tetrahydrofuran. After the addition was complete, the mixture was heated at reflux for 1 hr to complete formation. To this Grignard reagent at ambient temperature was added in a stream 42.9 g (0.173 mole) of 1-(phenylmethyl)-4-piperidinecarboxylic acid ethyl ester in 250 ml of dry tetrahydrofuran. The solution was stirred at ambient temperature and then poured into 2.5 liters of a saturated ammonium chloride solution. The layers were separated and the aqueous layer was extracted twice with 375 ml portions of methylene chloride. The combined organic layers were washed successively with 500 ml of water, 750 ml of a 3% sodium hydroxide solution, 250 ml of water and 250 ml of brine. The organic layer was dried over sodium sulfate and concentrated under pressure to give a gum as residue. The gum gradually cyrstallized. The solid was triturated with petroleum ether (30°-60° C.), collected by filtration and dried to yield 63.6 g (95%) of title compound as a white solid. An analytical sample was recrystallized from 2-propanol, mp 115°-117° C.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[C:5]([C:7]2[C:15]3[C:10](=[N:11][CH:12]=[C:13]([OH:16])[CH:14]=3)[N:9]([CH2:17][O:18][CH2:19][CH2:20][Si:21]([CH3:24])([CH3:23])[CH3:22])[CH:8]=2)[CH:4]=[N:3]1.Br[CH2:26][CH:27]1[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]1.C([O-])([O-])=O.[K+].[K+]>CC(C)=O>[CH:27]1([CH2:26][O:16][C:13]2[CH:14]=[C:15]3[C:7]([C:5]4[CH:4]=[N:3][N:2]([CH3:1])[CH:6]=4)=[CH:8][N:9]([CH2:17][O:18][CH2:19][CH2:20][Si:21]([CH3:24])([CH3:23])[CH3:22])[C:10]3=[N:11][CH:12]=2)[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]1
Reactant: Cn1cc(-c2cn(COCC[Si](C)(C)C)c3ncc(O)cc23)cn1
Reactant: BrCC1CCCCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: Cn1cc(-c2cn(COCC[Si](C)(C)C)c3ncc(OCC4CCCCC4)cc23)cn1
Yield: 52.2 %

Procedure:
According to the general procedure using: 27 (60 mg, 0.174 mmol), (bromomethyl)cyclohexane (146 μL, 1.05 mmol), K2CO3 (241 mg, 1.74 mmol) and n-Bu4M (6.4 mg, 17 μmol) in acetone (4.0 mL) were heated at reflux for 24 h. Standard workup and purification by PTLC using 80% AcOEt in hexane gave 28t as a clear oil (40 mg, 52%); 1H NMR (400 MHz, CDCl3) δ-0.059 (s, 9H), 0.93 (t, J=8.2 Hz, 2H), 1.09 (dq, J=12.2 Hz, J=3.3 Hz, 2H), 1.17-1.40 (m, 2H), 1.65-1.95 (m, 7H), 3.56 (t, J=8.3 Hz, 2H), 3.84 (d, J=6.3 Hz, 2H), 3.99 (s, 3H), 5.64 (s, 2H), 7.38 (s, 1H), 7.49 (d, J=2.6 Hz, 1H), 7.59 (s, 1H), 7.75 (d, J=0.3 Hz, 1H), 8.13 (d, J=2.6 Hz, 1H).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([F:20])[C:15]=2[Cl:21])[CH2:10][CH2:9]1)=O)(C)(C)C.Cl>C(Cl)Cl.CCOCC>[ClH:21].[Cl:21][C:15]1[C:16]([F:20])=[CH:17][CH:18]=[CH:19][C:14]=1[CH:11]1[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]1
Reactant: CC(C)(C)OC(=O)N1CCC(c2cccc(F)c2Cl)CC1
Agent: Cl
Solvent: CCOCC
Solvent: ClCCl
Product: Fc1cccc(C2CCNCC2)c1Cl
Temperature: 25 °C
Reaction time: 18 h
Yield: 148.8 %

Procedure:
To a solution of tert-butyl 4-(2-chloro-3-fluorophenyl) piperidine-1-carboxylate (13, 0.520 g, 1.66 mmol) in CH2Cl2 (10 mL) under an atmosphere of N2 was added HCl (2 N in Et2O, 10 mL) solution was stirred at ambient temperature for 18 h. The reaction mixture was diluted with Et2O (20 mL). The resulting precipitate was collected by filtration and washed with Et2O to provide 4-(2-chloro-3-fluorophenyl)piperidine hydrochloride (14) as a white solid (309 mg, 74%): 1H NMR (300 MHz, DMSO-d6) δ 8.81-8.55 (m, 2H), 7.47-7.37 (m, 1H), 7.36-7.27 (m, 1H), 7.21-7.13 (m, 1H), 3.43-3.20, (m, 3H), 3.17-2.97 (m, 2H), 2.00-1.73 (m, 4H).
Reaction SMILES: [CH2:1]([C:3]1[C:4]([NH:11][C@H:12]2[C@@H:16]([OH:17])[CH2:15][N:14]([C:18]([O:20][CH2:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)=[O:19])[CH2:13]2)=[N:5][C:6]([CH2:9][CH3:10])=[CH:7][N:8]=1)[CH3:2].[H-].[Na+].I[CH2:31][CH3:32]>CN(C=O)C>[CH2:1]([C:3]1[C:4]([NH:11][C@H:12]2[C@@H:16]([O:17][CH2:31][CH3:32])[CH2:15][N:14]([C:18]([O:20][CH2:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)=[O:19])[CH2:13]2)=[N:5][C:6]([CH2:9][CH3:10])=[CH:7][N:8]=1)[CH3:2]
Reactant: CCc1cnc(CC)c(N[C@@H]2CN(C(=O)OCc3ccccc3)C[C@@H]2O)n1
Reactant: CCI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCO[C@H]1CN(C(=O)OCc2ccccc2)C[C@H]1Nc1nc(CC)cnc1CC
Reaction time: 0.25 h
Yield: 77 %

Procedure:
To a solution of benzyl (3R,4S)-3-[(3,6-diethylpyrazin-2-yl)amino]-4-hydroxypyrrolidine-1-carboxylate (17.70 g, 47.8 mmole) in DMF (0.3 M) at 0° C. under N2 was added NaH portionwise (2.48 g, 1.3 eq.). After 15 minutes, iodoethane (4.93 mL, 1.3 eq.) was added dropwise. After 2 hours, the reaction mixture was quenched with brine (200 mL), extracted with ethyl acetate (2×200 mL), dried with MgSO4, filtered and concentrated. Vacuum chromatography was run on a 1 L frit funnel (20-40% ethyl acetate in heptane gradient) to give 14.64 g (77%) of benzyl (3R,4S)-3-[(3,6-diethylpyrazin-2-yl)amino]-4-ethoxypyrrolidine-1-carboxylate as an oil. IR (liq.) 2971, 2936, 2340, 1950, 1709, 1546, 1499, 1464, 1448, 1422, 1395, 1350, 1173, 1129, 1097 (s) cm−1 HRMS (ESI) calcd for C22H30N4O3+H1 399.2396. found 399.2392. [α]25D=−50° (c 0.55, 0.1N HCl).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[C:4]([C:9]([F:12])([F:11])[F:10])[N:3]=1.[Cl:13][C:14]1[CH:15]=[C:16](B(O)O)[CH:17]=[CH:18][CH:19]=1.C([O-])([O-])=O.[Cs+].[Cs+].C1(C)C=CC=CC=1>C(OCC)(=O)C.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.O.CCO>[Cl:8][C:6]1[CH:5]=[C:4]([C:9]([F:12])([F:11])[F:10])[N:3]=[C:2]([C:18]2[CH:17]=[CH:16][CH:15]=[C:14]([Cl:13])[CH:19]=2)[CH:7]=1
Reactant: OB(O)c1cccc(Cl)c1
Reactant: FC(F)(F)c1cc(Cl)cc(Cl)n1
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: [Cs+]
Solvent: O
Solvent: CCO
Solvent: CCOC(C)=O
Product: FC(F)(F)c1cc(Cl)cc(-c2cccc(Cl)c2)n1
Temperature: 90 °C
Reaction time: 4 h
Yield: 54.7 %

Procedure:
A 500-mL round bottomed flask was charged with 2,4-dichloro-6-trifluoromethylpyridine (2.00 g, 9.26 mmol), (3-chlorophenyl)boronic acid (1.59 g, 10.2 mmol), tetrakis(triphenylphosphine)palladium(0) (0.535 g, 0.46 mmol), and Cs2CO3 (9.05 g, 27.8 mmol). Toluene (40 ml), EtOH (10 ml) and water (20 ml) were added. The resulting mixture was stirred under Ar at 90° C. for 4 h. After cooling to room temperature, the reaction mixture was diluted with ethyl acetate (100 mL) and hexanes (100 mL). The aqueous layer was separated and the organic layer was washed with saturated sodium chloride (2×25 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by chromatography on silica using hexane/ethyl acetate (100:1 to 95:5) as eluent followed by chromatography on silica using hexane/dichloromethane (100:0 to 80:20) as eluent to afford the title compound (1.48 g, 55%) as a white solid. MW=292.08. 1H NMR (CDCl3, 500 MHz) δ 8.06-8.04 (m, 1H), 7.92 (dt, J=7.0, 2.0 Hz, 1H), 7.89 (d, J=1.5 Hz, 1H), 7.64 (d, J=1.5 Hz, 1H), 7.48-7.42 (m, 2H).
Reaction SMILES: [CH3:1][C:2]1([CH3:27])[CH2:7][CH:6]([NH:8][C:9]2[N:14]=[C:13]([C:15]3[S:19][C:18]4[CH:20]=[C:21]([OH:24])[CH:22]=[CH:23][C:17]=4[CH:16]=3)[CH:12]=[CH:11][N:10]=2)[CH2:5][C:4]([CH3:26])([CH3:25])[NH:3]1.[H-].[Na+].[CH2:30](Br)[CH:31]=[CH2:32].O>CN(C)C=O>[CH2:32]([O:24][C:21]1[CH:22]=[CH:23][C:17]2[CH:16]=[C:15]([C:13]3[CH:12]=[CH:11][N:10]=[C:9]([NH:8][CH:6]4[CH2:7][C:2]([CH3:27])([CH3:1])[NH:3][C:4]([CH3:26])([CH3:25])[CH2:5]4)[N:14]=3)[S:19][C:18]=2[CH:20]=1)[CH:31]=[CH2:30]
Reactant: C=CCBr
Reactant: CC1(C)CC(Nc2nccc(-c3cc4ccc(O)cc4s3)n2)CC(C)(C)N1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: C=CCOc1ccc2cc(-c3ccnc(NC4CC(C)(C)NC(C)(C)C4)n3)sc2c1
Temperature: 100 °C
Reaction time: 2 h

Procedure:
Compound of Example 153 (191 mg, 0.5 mmol) was suspended in 2 ml dimethylformamide. 24 mg (0.5 mmol) sodium hydride was added in small portions at room temperature. After 15 minutes 72 mg (0.6 mmol) allylbromide was added and the mixture was stirred at 100° C. for 2 hours. Then the cooled solution was poured on 200 ml water and extracted with EtOAc. The crude was purified by chromatography on silicagel (DCM/MeOH/ammonia:9/1/0.1). Yield: 110 mg (52%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.C(OC([N:16]1[CH2:21][CH2:20][C:19]2([CH2:26][CH2:25][CH:24](O)[CH2:23][CH2:22]2)[CH2:18][CH2:17]1)=O)(C)(C)C>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH:24]2[CH2:25][CH2:26][C:19]3([CH2:20][CH2:21][NH:16][CH2:17][CH2:18]3)[CH2:22][CH2:23]2)=[CH:4][CH:3]=1
Reactant: Oc1ccc(Cl)cc1
Reactant: CC(C)(C)OC(=O)N1CCC2(CCC(O)CC2)CC1
Product: Clc1ccc(OC2CCC3(CCNCC3)CC2)cc1

Procedure:
Was prepared according to method A from 4-chlorophenol and 9-hydroxy-3-aza-spiro[5.5]undecane-3-carboxylic acid tert-butyl ester. Mp. 140-142° C.
Reaction SMILES: C1(S(O[CH2:11][CH2:12][C:13]2[C:22]3[C:17](=[CH:18][CH:19]=[C:20]([O:23][CH3:24])[CH:21]=3)[CH:16]=[CH:15][CH:14]=2)(=O)=O)C=CC=CC=1.[C:25]1(=[O:35])[NH:29][C:28](=[O:30])[C:27]2=[CH:31][CH:32]=[CH:33][CH:34]=[C:26]12.[K].C(#N)C>O>[CH3:24][O:23][C:20]1[CH:21]=[C:22]2[C:17]([CH:16]=[CH:15][CH:14]=[C:13]2[CH2:12][CH2:11][N:29]2[C:28](=[O:30])[C:27]3=[CH:31][CH:32]=[CH:33][CH:34]=[C:26]3[C:25]2=[O:35])=[CH:18][CH:19]=1
Reactant: COc1ccc2cccc(CCOS(=O)(=O)c3ccccc3)c2c1
Reactant: O=C1NC(=O)c2ccccc21
Agent: [K]
Solvent: CC#N
Solvent: O
Product: COc1ccc2cccc(CCN3C(=O)c4ccccc4C3=O)c2c1
Temperature: 25 °C
Yield: 84.6 %

Procedure:
The compound IV (14 g, 0.041 mol) produced as described above and potassium phthalimide (9.3 g, 0.050 mol) were added into a reaction vessel, and acetonitrile (150 ml) was added. The mixture was heated and refluxed for 4 hours. After cooling it to room temperature, 200 ml of water was added, and the mixture was stirred and filtered. The filter cake formed was washed with water and dried, to produce 11.5 g of N-[2-(7-methoxy-1-naphthyl)ethyl]phthalimide (II). The yield was 85%. The melting point was 160-161° C.
Reaction SMILES: [O:1]([C:6]1[CH:11]=[CH:10][C:9]([S:12](Cl)(=[O:14])=[O:13])=[CH:8][CH:7]=1)[CH2:2][CH2:3][CH2:4][CH3:5].[NH2:16][C:17]1[N:22]=[C:21]([NH:23]C(=O)OC(C)(C)C)[CH:20]=[CH:19][CH:18]=1.FC(F)(F)C(O)=O>N1C=CC=CC=1>[NH2:23][C:21]1[N:22]=[C:17]([NH:16][S:12]([C:9]2[CH:10]=[CH:11][C:6]([O:1][CH2:2][CH2:3][CH2:4][CH3:5])=[CH:7][CH:8]=2)(=[O:14])=[O:13])[CH:18]=[CH:19][CH:20]=1
Reactant: CCCCOc1ccc(S(=O)(=O)Cl)cc1
Reactant: CC(C)(C)OC(=O)Nc1cccc(N)n1
Solvent: O=C(O)C(F)(F)F
Solvent: c1ccncc1
Product: CCCCOc1ccc(S(=O)(=O)Nc2cccc(N)n2)cc1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
The 4-butoxylphenyl sulfonyl chloride (160 μmol, 2.0 eq, 400 μL of a 0.40 M in anhydrous pyridine) and tert-butyl (6-aminopyridin-2-yl)carbamate (80 μmol, 1.0 eq, 400 μL of a 0.20 M in anhydrous pyridine) was added into a test tube (75×10 mm, dried by heating at 110° C. for 16 h before use) equipped with a stir bar. The test tube was covered with Parafilm, and was stirred for 24 h at ambient temperature. The solvent (pyridine) was evaporated in vacuo. Trifluoroacetic acid (320 μL, 52.0 eq., excess, neat) was added into the test tube. The test tube was capped and vortexed for 5 h at ambient temperature. The excess TFA was removed in vacuo, and the residue was dissolved in DMSO (1.340 mL) and purified by HPLC. 1H NMR (500 MHz, DMSO-d6) δ: 7.73 (d, J=7.7 Hz, 2H), 7.21 (t, J=7.2 Hz, 1H), 6.96 (d, J=6.9 Hz, 1H), 6.10 (d, J=6.1 Hz, 1H), 5.92 (d, J=5.9 Hz, 1H), 3.96 (t, J=6.6 Hz, 1H)), 1.64 (m, 2H), 1.37 (m, 2H), 0.87 (t, J=7.4 Hz, 3H). LRMS m/z: 322.0.
Reaction SMILES: [NH2:1][C:2](=O)[C@@H:3]([NH:25][C:26]([C:28]1([NH:34][C:35](=[O:41])[O:36][C:37]([CH3:40])([CH3:39])[CH3:38])[CH2:33][CH2:32][O:31][CH2:30][CH2:29]1)=[O:27])[CH2:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:12]=[CH:13][C:14]3[S:18][C:17](=[O:19])[N:16]([CH2:20][CH2:21][O:22][CH3:23])[C:15]=3[CH:24]=2)=[CH:7][CH:6]=1.CC[N+](S(N=C(OC)[O-])(=O)=O)(CC)CC>ClCCl>[C:2]([C@@H:3]([NH:25][C:26]([C:28]1([NH:34][C:35](=[O:41])[O:36][C:37]([CH3:39])([CH3:38])[CH3:40])[CH2:29][CH2:30][O:31][CH2:32][CH2:33]1)=[O:27])[CH2:4][C:5]1[CH:6]=[CH:7][C:8]([C:11]2[CH:12]=[CH:13][C:14]3[S:18][C:17](=[O:19])[N:16]([CH2:20][CH2:21][O:22][CH3:23])[C:15]=3[CH:24]=2)=[CH:9][CH:10]=1)#[N:1]
Reactant: COCCn1c(=O)sc2ccc(-c3ccc(C[C@H](NC(=O)C4(NC(=O)OC(C)(C)C)CCOCC4)C(N)=O)cc3)cc21
Agent: CC[N+](CC)(CC)S(=O)(=O)N=C([O-])OC
Solvent: ClCCl
Product: COCCn1c(=O)sc2ccc(-c3ccc(C[C@@H](C#N)NC(=O)C4(NC(=O)OC(C)(C)C)CCOCC4)cc3)cc21
Temperature: 25 °C
Reaction time: 18 h
Yield: 119.1 %

Procedure:
(S)-tert-Butyl 4-(1-amino-3-(4-(3-(2-methoxyethyl)-2-oxo-2,3-dihydrobenzo[d]thiazol-5-yl)phenyl)-1-oxopropan-2-ylcarbamoyl)tetrahydro-2H-pyran-4-ylcarbamate (Example 9, step (iii), 155 mg) in dichloromethane (8 mL) was treated with Burgess' reagent (123 mg) and the mixture was stirred at room temperature for 18 h. The solvent was partially evaporated and the mixture was purified by chromatography on silica using ethyl acetate/isohexane (1:1) as eluent to yield the sub-titled compound (179 mg).
Reaction SMILES: [Si](Cl)(C)(C)C.Br[C:7]([F:14])([F:13])[C:8]([O:10][CH2:11][CH3:12])=[O:9].[CH2:15]([O:17][C:18](=[O:39])[CH2:19][CH2:20][N:21]([CH2:29]N1C2C=CC=CC=2N=N1)[CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[CH3:16].C([O-])(O)=O.[Na+]>C1COCC1.[Zn]>[CH2:22]([N:21]([CH2:20][CH2:19][C:18]([O:17][CH2:15][CH3:16])=[O:39])[CH2:29][C:7]([F:14])([F:13])[C:8]([O:10][CH2:11][CH3:12])=[O:9])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: CCOC(=O)CCN(Cc1ccccc1)Cn1nnc2ccccc21
Reactant: CCOC(=O)C(F)(F)Br
Agent: C[Si](C)(C)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOC(=O)CCN(Cc1ccccc1)CC(F)(F)C(=O)OCC
Temperature: 25 °C
Reaction time: 12 h
Yield: 99.4 %

Procedure:
To a suspension of activated zinc dust (4.13 g, 63.2 mmol) in dry THF (100 mL) under argon was added TMS-Cl (3.60 g, 4.24 mL, 33.2 mmol). After 10 minutes ethyl bromodifluoroacetate (7.05 g, 4.49 mL, 34.7 mmol) was added slowly, whereby the temperature was kept below 30° C. (cooling with a waterbath). Then a solution of 3-(benzotriazol-1-ylmethyl-benzyl-amino)-propionic acid ethyl ester (10.69 g, 31.6 mmol) in dry THF (100 mL) was added. The exothermic reaction was kept between 20 and 25° C. with a waterbath. The reaction mixture was stirred at room temperature for 12 hours. The reaction mixture was poured on 5% aqueous NaHCO3 solution and filtered over dicalite. The filtrate was extracted three times with ethyl acetate. The organic layers were washed with water and 1 N HCl, then dried over Na2SO4, filtered and the solvents were evaporated. The residue was purified by flash chromatography (silica gel, 100 g, 0% to 50% EtOAc in heptane) to give the title compound as colorless liquid (10.78 g, 99%).
Reaction SMILES: [CH3:1][C:2]1[C:10]([CH3:11])=[C:9]([CH3:12])[C:5]2[O:6][CH2:7][CH2:8][C:4]=2[C:3]=1[CH:13]1[CH2:18][C:17](=[O:19])[CH:16]=[C:15]([OH:20])[CH2:14]1.[Na]>>[C:5]([C:16]1[C:17](=[O:19])[CH2:18][CH:13]([C:3]2[C:4]3[CH2:8][CH2:7][O:6][C:5]=3[C:9]([CH3:12])=[C:10]([CH3:11])[C:2]=2[CH3:1])[CH2:14][C:15]=1[OH:20])(=[O:6])[CH2:4][CH2:3][CH3:2]
Reactant: Cc1c(C)c2c(c(C3CC(=O)C=C(O)C3)c1C)CCO2
Agent: [Na]
Product: CCCC(=O)C1=C(O)CC(c2c(C)c(C)c(C)c3c2CCO3)CC1=O

Procedure:
2-Butyryl-5-(2,3-dihydro-5,6,7-trimethylbenzo[b]furan-4-yl)-3-hydroxycyclohex-2-en-1-one was prepared from 5-(2,3-dihydro-5,6,7-trimethylbenzo[b]furan-4-yl)-3-hydroxycyclohex-2-en-1-one following essentially the same procedure as that described in Example 6 part (iii), and was obtained as a yellow oil. Pmr spectrum (CDCl3 ; δ in ppm): 1.00 (3H,t); 1.60 (2H,m); 2.15 (3H,s); 2.17 (3H,s); 2.22 (3H,s); 2.26-3.38 (8H,m); 3.74 (1H,m); 4.49 (2H,t); 15.20 (1H,broad s).
Reaction SMILES: Br[C:2]1[CH:35]=[CH:34][C:5]([CH2:6][C:7]2[N:8]([C:20]3[CH:25]=[CH:24][C:23]([N:26]4[S:30](=[O:32])(=[O:31])[NH:29][C:28](=[O:33])[CH2:27]4)=[CH:22][CH:21]=3)[CH:9]=[C:10]([C:12]3[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][C:13]=3[Cl:19])[N:11]=2)=[CH:4][CH:3]=1.[CH2:36]([CH:38]1[CH2:41][CH:40]([C:42]2[CH:47]=[CH:46][C:45](B(O)O)=[CH:44][CH:43]=2)[CH2:39]1)[CH3:37].BrC1C=CC(C2CC(=O)C2)=CC=1.BrC1C=CC=CC=1C=O>>[Cl:19][C:13]1[CH:14]=[C:15]([Cl:18])[CH:16]=[CH:17][C:12]=1[C:10]1[N:11]=[C:7]([CH2:6][C:5]2[CH:34]=[CH:35][C:2]([C:45]3[CH:44]=[CH:43][C:42]([CH:40]4[CH2:41][CH:38]([CH2:36][CH3:37])[CH2:39]4)=[CH:47][CH:46]=3)=[CH:3][CH:4]=2)[N:8]([C:20]2[CH:21]=[CH:22][C:23]([N:26]3[S:30](=[O:32])(=[O:31])[NH:29][C:28](=[O:33])[CH2:27]3)=[CH:24][CH:25]=2)[CH:9]=1
Reactant: O=C1CN(c2ccc(-n3cc(-c4ccc(Cl)cc4Cl)nc3Cc3ccc(Br)cc3)cc2)S(=O)(=O)N1
Reactant: CCC1CC(c2ccc(B(O)O)cc2)C1
Agent: O=C1CC(c2ccc(Br)cc2)C1
Agent: O=Cc1ccccc1Br
Product: CCC1CC(c2ccc(-c3ccc(Cc4nc(-c5ccc(Cl)cc5Cl)cn4-c4ccc(N5CC(=O)NS5(=O)=O)cc4)cc3)cc2)C1

Procedure:
5-{-4-[2-(4-Bromo-benzyl)-4-(2,4-dichloro-phenyl)-imidazol-1-yl]-phenyl}-1,2,5-thiadiazolidine-3-one-1,1-dioxide (59 mg, 0.1 mmol) was treated as described in general procedure G using 4-(3-ethyl-cyclobutyl)phenylboronic acid (41 mg, 0.2 mmol, prepared according to general procedure Y using 3-(4-bromophenyl)cyclobutan-1-one in stead of bromobenzaldehyde) to give 5-(4-{4-(2,4-dichloro-phenyl)-2-[4′-(3-ethyl-cyclobutyl)-biphenyl-4-ylmethyl]-imidazol-1-yl}-phenyl)-1,2,5-thiadiazolidine-3-one-1,1-dioxide.
Reaction SMILES: [C:1]1([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:2]([S:7](Cl)(=[O:9])=[O:8])=[CH:3][CH:4]=[CH:5][CH:6]=1.[NH2:17][C:18]1[N:19]=[N:20][C:21]([Cl:24])=[CH:22][CH:23]=1>N1C=CC=CC=1>[C:11]1([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=2[S:7]([NH:17][C:18]2[N:19]=[N:20][C:21]([Cl:24])=[CH:22][CH:23]=2)(=[O:9])=[O:8])[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: Nc1ccc(Cl)nn1
Reactant: O=S(=O)(Cl)c1ccccc1-c1ccccc1
Solvent: c1ccncc1
Product: O=S(=O)(Nc1ccc(Cl)nn1)c1ccccc1-c1ccccc1
Reaction time: 0.33 h
Yield: 18.9 %

Procedure:
A solution of 2-biphenylsulphonyl chloride (0.31 g), 3-amino-6-chloropyridazine (0.5 g) in pyridine (5 ml) was stirred for 18 hours. Volatile material was removed by evaporation and 1M sodium hydroxide solution (4 ml) and methanol (10 ml) were added. The reaction mixture was stirred on a steam bath for 20 minutes and, after cooling, volatile material was again removed by evaporation. The residue was dissolved in water (100 ml) and acidified with concentrated hydrochloric acid to pH 1-2 and extracted with ethyl acetate (3×50 ml). The combined extracts were dried (MgSO4) and evaporated to give a solid. The solid was recrystallised twice from isopropanol to give 2-phenyl-N-(6-chloro-3-pyridazinyl)benzenesulphonamide (0.08 g), m.p. 196-198° C.; mass spectrum (+ve FAB, methanol/dichloromethane/NBA): 346 (M+H)+.