Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1](=O)([O-])[O-].[K+].[K+].IC.[C:9]([C:12]1[CH:13]=[C:14]([NH:24][C:25](=[O:30])[C:26]([F:29])([F:28])[F:27])[CH:15]=[C:16]([S:18]([F:23])([F:22])([F:21])([F:20])[F:19])[CH:17]=1)(=[O:11])[CH3:10]>C(COC)OC>[C:9]([C:12]1[CH:13]=[C:14]([N:24]([CH3:1])[C:25](=[O:30])[C:26]([F:29])([F:27])[F:28])[CH:15]=[C:16]([S:18]([F:22])([F:23])([F:21])([F:20])[F:19])[CH:17]=1)(=[O:11])[CH3:10]
Reactant: O=C([O-])[O-]
Reactant: CC(=O)c1cc(NC(=O)C(F)(F)F)cc(S(F)(F)(F)(F)F)c1
Agent: [K+]
Solvent: COCCOC
Solvent: CI
Product: CC(=O)c1cc(N(C)C(=O)C(F)(F)F)cc(S(F)(F)(F)(F)F)c1
Temperature: 100 °C

Procedure:
In a microwave insert, N-(3-acetyl-5-pentafluorosulfanylphenyl)-2,2,2-trifluoroacetamide (O3.075; 0.25 g) was dissolved in absolute dimethoxyethane (7.5 ml), powdered potassium carbonate was added and the mixture was admixed with iodomethane (80 μl). Subsequently, the mixture was heated in the microwave to 100° C. for 40 min. Once further N-(3-acetyl-5-pentafluorosulfanylphenyl)-2,2,2-trifluoroacetamide (4×250 mg) had been converted in the manner described, the five batches were worked up together, by decanting from potassium carbonate into 1 N hydrochloric acid with ice cooling. After repeatedly washing the potassium carbonate residue with dimethoxyethane, the aqueous phase was extracted five times with ethyl acetate. The combined extracts were dried over magnesium sulfate, filtered and concentrated. The residue was purified by means of preparative HPLC (met. A). The product-containing fractions were combined, freed of the acetonitrile and extracted five times with ethyl acetate. The combined extracts were dried over magnesium sulfate, filtered and concentrated. 1.03 g of the desired compound were obtained. LC-MS rt: 1.62 min [M+H]+: 372.0 (met. a)
Reaction SMILES: [C:1]([O:5][CH2:6][CH3:7])(=[O:4])[C:2]#[CH:3].[Li]CCCC.[N+:13]([C:16]1[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][C:17]=1[CH:18]=[O:19])([O-:15])=[O:14]>O1CCCC1>[Cl:24][C:21]1[CH:22]=[CH:23][C:16]([N+:13]([O-:15])=[O:14])=[C:17]([CH:18]([OH:19])[C:3]#[C:2][C:1]([O:5][CH2:6][CH3:7])=[O:4])[CH:20]=1
Reactant: C#CC(=O)OCC
Reactant: O=Cc1cc(Cl)ccc1[N+](=O)[O-]
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CCOC(=O)C#CC(O)c1cc(Cl)ccc1[N+](=O)[O-]
Temperature: -70 °C
Reaction time: 0.5 h
Yield: 59.3 %

Procedure:
To a solution of ethyl propiolate (4.05 mL, 40 mmol) in tetrahydrofuran (125 mL) at -78° C. under nitrogen was added n-BuLi (2.5 mL, 40 mmol, 1.6M in hexane). The reaction mixture was stirred at about -70° C. for 0.5 hours and then 2-nitro-5-chlorobenzaldehyde (6.75 g, 36.4 mmol) was added dropwise. The reaction mixture was stirred at -78° C. for 0.25 hours, warmed to -60° C., quenched with acetic acid (5 mL) and then warmed to room temperature. The reaction mixture was partitioned between ether (250 mL) and water (250 mL). The layers were separated and the organic layer was washed with brine (250 mL) and dried over Na2SO4. The mixture was filtered and the filtrate was concentrated in vacuo. The residue was purified by flash chromatography eluting with hexane/ethyl acetate (4:1) to afford 6.12 g (59%) of the title compound as a yellow oil which solidified on standing.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:10][C@H:9]1[CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:18]([NH2:25])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>C1(C)C=CC=CC=1>[CH2:11]([C@@H:9]([NH:8][C:6](=[O:7])[O:5][C:1]([CH3:2])([CH3:3])[CH3:4])[CH2:10][NH:25][CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: NCc1ccccc1
Reactant: CC(C)(C)OC(=O)N1C[C@H]1Cc1ccccc1
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)N[C@@H](CNCc1ccccc1)Cc1ccccc1
Temperature: 100 °C
Yield: 99.7 %

Procedure:
The product from Example 70A (1.77 g, 7.6 mmol) in toluene (15 mL) was treated with benzylamine (8.4 mL, 76 mmol) in a sealed tube. After heating at 100° C. for 4 days, the mixture was allowed to cool to ambient temperature and was concentrated. The residue was dissolved in ethyl acetate (50 mL) and the ethyl acetate was washed with 10% citric acid (2×50 mL) and brine (50 mL). A precipitate fell out of the brine. The brine wash was filtered and the filter cake dissolved in ethyl acetate. All the ethyl acetate solutions were combined, wash with aqueous 10% NaHCO3 (2×100 mL), brine, (100 mL), dried over magnesium sulfate, filtered, and the filtrate was concentrated to provide the title compound as a white solid (2.58 g). 1H NMR (CDCl3) δ 7.49-7.12 (m, 10H), 4.98 (m, 1H), 4.00 (br s, 1H), 3.87 (q, 2H), 2.94-2.73 (m, 5H); MS (ESI+) m/z 341 (M+H)+.
Reaction SMILES: [N:1]1([C:6]2[CH:14]=[CH:13][C:9]([C:10](O)=[O:11])=[CH:8][CH:7]=2)[CH:5]=[CH:4][CH:3]=[N:2]1.C(Cl)(=O)C([Cl:18])=O>ClCCl.CN(C)C=O>[N:1]1([C:6]2[CH:14]=[CH:13][C:9]([C:10]([Cl:18])=[O:11])=[CH:8][CH:7]=2)[CH:5]=[CH:4][CH:3]=[N:2]1
Reactant: O=C(O)c1ccc(-n2cccn2)cc1
Reactant: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: O=C(Cl)c1ccc(-n2cccn2)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 93.3 %

Procedure:
To a suspension of 4-(pyrazol-1-yl)benzoic acid (1.56 g) in dichloromethane (25 ml) was added oxalyl chloride (1.04 g) and one drop of dimethylformamide. The mixture was stirred at room temperature for 18 hours to yield a clear solution. The volatile material was removed under reduced pressure to afford 4-(pyrazol-1-yl)benzoyl chloride as a pale yellow solid (1.58 g), which was utilized without further purification.
Reaction SMILES: Br[C:2]1[CH:10]=[C:9]2[C:5]([C:6]([O:17][CH3:18])=[N:7][N:8]2[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[CH:4][CH:3]=1.C(OC([N:26]1[CH2:30][CH2:29][CH:28]([N:31]2[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]2)[CH2:27]1)=O)(C)(C)C.[ClH:37]>>[ClH:37].[CH3:18][O:17][C:6]1[C:5]2[C:9](=[CH:10][C:2]([N:34]3[CH2:33][CH2:32][N:31]([CH:28]4[CH2:29][CH2:30][NH:26][CH2:27]4)[CH2:36][CH2:35]3)=[CH:3][CH:4]=2)[N:8]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[N:7]=1
Reactant: CC(C)(C)OC(=O)N1CCC(N2CCNCC2)C1
Reactant: COc1nn(-c2ccccc2)c2cc(Br)ccc12
Agent: Cl
Product: COc1nn(-c2ccccc2)c2cc(N3CCN(C4CCNC4)CC3)ccc12

Procedure:
The title compound was prepared according to the procedure as described in Example 57 reacting 6-bromo-3-methoxy-1-phenyl-1H-indazole and 3-piperazin-1-yl-pyrrolidine-1-carboxylic acid tert-butyl ester, followed by de-protection with HCl.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[CH3:11])[C:5]([OH:7])=[O:6].C1C(=O)N([Br:19])C(=O)C1>CN(C=O)C>[NH2:1][C:2]1[C:10]([CH3:11])=[CH:9][C:8]([Br:19])=[C:4]([CH:3]=1)[C:5]([OH:7])=[O:6]
Reactant: Cc1ccc(C(=O)O)cc1N
Reactant: O=C1CCC(=O)N1Br
Solvent: CN(C)C=O
Product: Cc1cc(Br)c(C(=O)O)cc1N
Reaction time: 1 h
Yield: 81.2 %

Procedure:
To a cooled solution (5° C.) of 3-amino-4-methylbenzoic acid (3.02 g, 20 mmol) in DMF (20 mL) was added NBS (3.38 g, 19 mmol) in small portions at such a rate that the reaction mixture temperature was kept below 15° C. After being stirred for one hour, the reaction mixture was poured onto ice water (100 mL) with stirring. The solid formed was collected by filtration, and the filter cake was washed with ice water (3×100 mL) and then dried at 60° C. under high vacuum to give 5-amino-2-bromo-4-methylbenzoic acid (3.55 g, yield 77.5%) as a pink solid. MS: m/z=230.0 (M+1, ESI+).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[NH:9][C:10]1[N:15]2[N:16]=[CH:17][C:18]([C:19](O)=[O:20])=[C:14]2[N:13]=[CH:12][C:11]=1[C:22]([N:24]1[CH2:29][CH2:28][CH:27]([C:30]2[CH:35]=[CH:34][C:33]([F:36])=[CH:32][CH:31]=2)[CH2:26][CH2:25]1)=[O:23].[CH2:37]([S:39]([NH2:42])(=[O:41])=[O:40])[CH3:38]>>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[NH:9][C:10]1[N:15]2[N:16]=[CH:17][C:18]([C:19]([NH:42][S:39]([CH2:37][CH3:38])(=[O:41])=[O:40])=[O:20])=[C:14]2[N:13]=[CH:12][C:11]=1[C:22]([N:24]1[CH2:25][CH2:26][CH:27]([C:30]2[CH:31]=[CH:32][C:33]([F:36])=[CH:34][CH:35]=2)[CH2:28][CH2:29]1)=[O:23]
Reactant: Cc1ccc(C)c(Nc2c(C(=O)N3CCC(c4ccc(F)cc4)CC3)cnc3c(C(=O)O)cnn23)c1
Reactant: CCS(N)(=O)=O
Product: CCS(=O)(=O)NC(=O)c1cnn2c(Nc3cc(C)ccc3C)c(C(=O)N3CCC(c4ccc(F)cc4)CC3)cnc12
Yield: 67.4 %

Procedure:
In the same manner as in Example 1, step 6 and using 7-(2,5-dimethylphenylamino)-6-[4-(4-fluorophenyl)piperidine-1-carbonyl]pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (0.05 g, 0.10 mmol) obtained in step 2 and ethanesulfonamide (0.067 g, 0.62 mmol), the title compound (0.039 g, 65%) was obtained.
Reaction SMILES: [OH:1][CH2:2][CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[S:10]([NH:13][C:14]([CH3:17])([CH3:16])[CH3:15])(=[O:12])=[O:11].C(N(CC)CC)C.[C:25](OC(=O)C)(=[O:27])[CH3:26]>ClCCl>[C:25]([O:1][CH2:2][CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[S:10]([NH:13][C:14]([CH3:17])([CH3:16])[CH3:15])(=[O:12])=[O:11])(=[O:27])[CH3:26]
Reactant: CC(=O)OC(C)=O
Reactant: CC(C)(C)NS(=O)(=O)c1ccccc1CCO
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)OCCc1ccccc1S(=O)(=O)NC(C)(C)C
Temperature: 25 °C
Reaction time: 22 h

Procedure:
A solution of 29.0 g of the product from Example 1 and 24 ml triethylamine in 290 ml of dichloromethane was cooled to 0° C. and treated with 13 ml acetic anhydride. The reaction mixture was stirred at room temperature for 22 hours. Dichloromethane (200 ml) was added and the organic layer washed with three 50 ml portions of water and one portion of brine. Drying the organic layer over magnesium sulfate followed by concentrating in vacuo gave the crude product. Purification by silica gel chromatography (elution with hexanes-ethyl acetate, 70:30) affoded 19.5 g of pure 2-[2-(acetyloxy)ethyl]-N-(1,1-dimethylethyl)benzenesulfonamide as a colorless oil.
Reaction SMILES: Cl.[CH3:2][C@H:3]([NH2:13])[C:4]1[CH:9]=[CH:8][C:7]([N+:10]([O-:12])=[O:11])=[CH:6][CH:5]=1.[OH-].[Na+].[CH2:16]([O:23][C:24](Cl)=[O:25])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.CCOCC>CC(C)=O>[C:24]([NH:13][C@@H:3]([CH3:2])[C:4]1[CH:5]=[CH:6][C:7]([N+:10]([O-:12])=[O:11])=[CH:8][CH:9]=1)([O:23][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:25]
Reactant: O=C(Cl)OCc1ccccc1
Reactant: C[C@H](N)c1ccc([N+](=O)[O-])cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCOCC
Solvent: CC(C)=O
Product: C[C@H](NC(=O)OCc1ccccc1)c1ccc([N+](=O)[O-])cc1
Temperature: 25 °C

Procedure:
To a solution of (S)-(-)-α-methyl-4-nitrobenzylamine hydrochloride (7.96 gm, 48 mmol) in acetone (20 mL) was added 5N sodium hydroxide (10 mL, 50 imol) and the solution was cooled in an ice bath. Solutions of benzylchloroformate (9.8 mL, 53 mmol) in acetone (10 mL) and 5N sodium hydroxide (11 mL, 55 mmol) were simultaneously added over 0.5 hr and the reaction was then allowed to warm to rt over 16 hrs. The reaction was poured into a mixture of ice water and ether and the layers were separated. The ether layer was washed with water and brine and the aqueous layers were consecutively extracted with a second portion of ether. The pooled ether layers were dried over sodium sulfate and evaporated to give 14.3 gm (quantitative) of clean title compound which was used without purification.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[CH:8][C:7]([Cl:10])=[C:6]([OH:11])[CH:5]=1.[CH3:13][O:14][C:15]1[CH:20]=[CH:19][C:18]([CH2:21][CH2:22]O)=[CH:17][CH:16]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CCOC(/N=N/C(OCC)=O)=O>O1CCCC1>[CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[CH:8][C:7]([Cl:10])=[C:6]([O:11][CH2:22][CH2:21][C:18]2[CH:19]=[CH:20][C:15]([O:14][CH3:13])=[CH:16][CH:17]=2)[CH:5]=1
Reactant: COC(=O)c1ccc(Cl)c(O)c1
Reactant: COc1ccc(CCO)cc1
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COC(=O)c1ccc(Cl)c(OCCc2ccc(OC)cc2)c1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
g (5.36 mmol) of 4-Chloro-3-hydroxy-benzoic acid methyl ester was dissolved in 40 ml of anhydrous tetrahydrofuran. To this solution was added 0.897 g (5.9 mmol) of 2-(4-Methoxy-phenyl)-ethanol, 5.35 g (equivalent to 16.1 mmol PPh3) of triphenylphosphine derivatized polystyrene and 2.80 g (16.1 mmol) of DEAD. The solution was shaken for 16 h at RT. The polymer was filtered off and washed with ethyl acetate. The solvent was removed under reduced pressure. The residue was taken-up in ethyl acetate and the solution was washed three times with water and twice with saturated aqueous sodium chloride. The organic phase was dried with magnesium sulphate, filtered and the solvent was removed under reduced pressure. The residue was chromatographed on silica gel eluting with ethyl acetate/n-heptane (1/5).
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[C:5]([NH:12][C@@H:13]2[CH2:17][CH2:16][N:15]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:14]2)=[N:6][CH:7]=[C:8]([CH:10]=O)[CH:9]=1.[C:25]([O:28][CH2:29][CH3:30])([CH3:27])=[O:26].O>C1COCC1>[Cl:3][C:4]1[C:5]([NH:12][C@@H:13]2[CH2:17][CH2:16][N:15]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:14]2)=[N:6][CH:7]=[C:8](/[CH:10]=[CH:27]/[C:25]([O:28][CH2:29][CH3:30])=[O:26])[CH:9]=1
Reactant: CCOC(C)=O
Reactant: CC(C)(C)OC(=O)N1CC[C@@H](Nc2ncc(C=O)cc2Cl)C1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CCOC(=O)/C=C/c1cnc(N[C@@H]2CCN(C(=O)OC(C)(C)C)C2)c(Cl)c1
Temperature: 15 °C

Procedure:
A solution of diethylphosphonoacetcacid ethyl ester (980 mg), in THF (5 ml) was added dropwise to admixture of 60% sodium hydride in oil (187 mg) in THF (30 mL) with stirring at 10-20° C. under atmospheric pressure of nitrogen, and the reaction mixture was stirred at ambient temperature for 30 minutes. A solution of tert-butyl (3R)-3-[(3-chloro-5-formyl-2-pyridinyl)amino]-1-pyrrolidinecarboxylate (0.95 g) in THF (10 ml) solution was added the above mixture and resultant mixture was stirred at ambient temperature for 1.5 hours. The reaction mixture was poured into a mixture of AcOEt-H2O and the organic layer was washed with brine and dried over MgSO4. The solvent was evaporated in vacuo and the residue was chromatographed on silicagel eluting with AcOEt-n-hexane (6:4). The eluted fractions containing the desired product were collected and evaporated in vacuo to give tert-butyl (3R)-3-({3-chloro-5-[(1E)-3-ethoxy-3-oxo-1-propen-1-yl]-2-pyridinyl}amino)-1-pyrrolidinecarboxylate (0.98 g)
Reaction SMILES: [Cl:1][C:2]1[C:11]([C:12]([O:14][CH3:15])=[O:13])=[C:10](Cl)[CH:9]=[CH:8][C:3]=1[C:4]([O:6]C)=O.[C:17]([O:21][CH3:22])(=[O:20])[CH2:18][SH:19].O.[OH-].[Li+].Cl>CN(C)C=O.O>[Cl:1][C:2]1[C:3]2[C:4]([OH:6])=[C:18]([C:17]([O:21][CH3:22])=[O:20])[S:19][C:8]=2[CH:9]=[CH:10][C:11]=1[C:12]([O:14][CH3:15])=[O:13]
Reactant: COC(=O)c1ccc(Cl)c(C(=O)OC)c1Cl
Reactant: COC(=O)CS
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)c1ccc2sc(C(=O)OC)c(O)c2c1Cl
Temperature: 25 °C
Reaction time: 48 h
Yield: 98.4 %

Procedure:
Dimethyl 2,4-dichloroisophthaloate (11.95 g) and methyl thioglycolate (7.23 g) was dissolved in N,N-dimethylformamide, and lithium hydroxide monohydrate (3.81 g) added. The mixture was stirred at ambient temperature for 2 days, diluted with water and brought to pH 1 with hydrochloric acid. The solid was filtered, washed with boiling cyclohexane and dried by azeotropic removal of toluene to give dimethyl 4-chloro-3-hydroxybenzo[b]thiophene-2,5-dicarboxylate (13.44 g) as a beige solid, m.p. 127°-131° C.
Reaction SMILES: [F:1][C:2]1[C:7]([C:8]2[NH:12][CH:11]=[C:10]([CH2:13][N:14]([CH3:22])[C:15](=[O:21])[O:16][C:17]([CH3:20])([CH3:19])[CH3:18])[C:9]=2[F:23])=[CH:6][CH:5]=[CH:4][N:3]=1.[H-].[Na+].C1OCCOCCOCCOCCOC1.[F:41][C:42]1[N:47]=[C:46]([S:48](Cl)(=[O:50])=[O:49])[CH:45]=[CH:44][CH:43]=1>O1CCCC1.O>[F:23][C:9]1[C:10]([CH2:13][N:14]([CH3:22])[C:15](=[O:21])[O:16][C:17]([CH3:19])([CH3:20])[CH3:18])=[CH:11][N:12]([S:48]([C:46]2[CH:45]=[CH:44][CH:43]=[C:42]([F:41])[N:47]=2)(=[O:50])=[O:49])[C:8]=1[C:7]1[C:2]([F:1])=[N:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=S(=O)(Cl)c1cccc(F)n1
Reactant: CN(Cc1c[nH]c(-c2cccnc2F)c1F)C(=O)OC(C)(C)C
Agent: C1COCCOCCOCCOCCO1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CN(Cc1cn(S(=O)(=O)c2cccc(F)n2)c(-c2cccnc2F)c1F)C(=O)OC(C)(C)C
Reaction time: 0.25 h
Yield: 32.2 %

Procedure:
To a suspension of 2-(benzylthio)-6-fluoropyridine (310 mg) in acetic acid (3 mL) and water (1.5 mL) was added N-chlorosuccinimide (776 mg), and the mixture was stirred at room temperature for 5 hr. The reaction mixture was concentrated under reduced pressure, toluene was added to the residue, the mixture was filtrated, and the filtrate was concentrated under reduced pressure to give crude 6-fluoropyridine-2-sulfonyl chloride (240 mg). To a solution of tert-butyl {[5-(2-fluoropyridin-3-yl)-4-fluoro-1H-pyrrol-3-yl]methyl}methylcarbamate (102 mg) in tetrahydrofuran (3 mL) was added sodium hydride (60% in oil, 37 mg) at 0° C., and the mixture was stirred at the same temperature for 15 min. 15-Crown-5 (0.19 mL), then a solution of crude 6-fluoropyridine-2-sulfonyl chloride (240 mg) in tetrahydrofuran (2 mL) were added at the same temperature, and the mixture was stirred at room temperature for 30 min. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with saturated aqueous sodium hydrogen carbonate solution, water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane-ethyl acetate=2:1) to give the title compound as a brown oil (yield 49 mg, 7% from 2-(benzylthio)-6-fluoropyridine).
Reaction SMILES: [CH3:1][S-:2].[Na+].F[C:5]1[CH:10]=[CH:9][C:8]([I:11])=[C:7]([Cl:12])[CH:6]=1>O>[Cl:12][C:7]1[CH:6]=[C:5]([S:2][CH3:1])[CH:10]=[CH:9][C:8]=1[I:11]
Reactant: C[S-]
Reactant: Fc1ccc(I)c(Cl)c1
Agent: [Na+]
Solvent: O
Product: CSc1ccc(I)c(Cl)c1
Reaction time: 20 h

Procedure:
Sodium methanethiolate (5 g) was added to a solution of 4-fluoro-2-chloro-iodobenzene (18.3 g) and stirred for 20 h. The mixture was poured into water, extracted with ether, washed with brine, dried (MgSO4) and evaporated. Yield 18.5 g.
Reaction SMILES: CC(C)([O-])C.[K+].[C:7]1(=[O:13])[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]1.[CH2:14](Br)[CH2:15][CH:16]=[CH2:17].CCOC(C)=O>C1(C)C=CC=CC=1>[CH2:17]([CH:8]1[CH2:9][CH2:10][CH2:11][CH2:12][C:7]1=[O:13])[CH2:16][CH:15]=[CH2:14]
Reactant: C=CCCBr
Reactant: O=C1CCCCC1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: C=CCCC1CCCCC1=O
Temperature: 0 °C

Procedure:
A suspension of potassium t-butoxide in toluene cooled to 0° C. in an ice bath under N2 is treated with cyclohexanone. To the reaction mixture is slowly added 3-butenyl bromide. The reaction is warmed to room temperature. The reaction is then poured into EtOAc and washed once with 10% potassium hydrogen sulfate. The organic solution is then washed with brine, dried over magnesium sulfate, and the solvent evaporated under reduced pressure to afford 2-(3-butenyl) cyclohexanone.
Reaction SMILES: [CH:1]1([C:7]([OH:9])=O)[CH2:6][CH2:5][CH:4]=[CH:3][CH2:2]1.CCOCC.Cl.O.[CH3:17][CH2:18][CH2:19][CH2:20][CH2:21]C>>[CH:1]1([C:7](=[O:9])[CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])[CH2:6][CH2:5][CH:4]=[CH:3][CH2:2]1
Reactant: CCCCCC
Reactant: O=C(O)C1CC=CCC1
Agent: Cl
Solvent: CCOCC
Solvent: O
Product: CCCCCC(=O)C1CC=CCC1
Temperature: 25 °C

Procedure:
A 500 mL round bottom flask equipped with a mechanical stirrer was charged with 18.9 g (0.15 mol) 3-cyclohexene-1-carboxylic acid, and 300 mL of ether. 132 mL of hexylithium (2.5 M solution in hexane, 0.33 mol) was slowly added to above mixture in ice bath over 40 min. After the above mixture was reacted at 0° C. for 30 minutes, the reaction mixture was warmed to room temperature. The mixture is slowly added into a vigorously stirred mixture of 27 mL (0.32 mol) of concentrated HCl and 400 mL of water. The organic phase is separated, and aqueous phase is extracted with 3×150 mL of ether, the combined organic solution is dried over sodium sulfate, and the solution is evaporated and distilled to give pure product.
Reaction SMILES: [N:1]1([CH2:6]/[CH:7]=[CH:8]/[C:9]2[CH:10]=[CH:11][C:12]([CH2:29][CH2:30][C:31]3[CH:36]=[CH:35][C:34]([F:37])=[CH:33][CH:32]=3)=[C:13]([CH:28]=2)[C:14](OC2C(F)=C(F)C(F)=C(F)C=2F)=[O:15])[CH:5]=[CH:4][N:3]=[CH:2]1.[C:38]([O:42][C:43](=[O:50])[C@H:44]([CH2:46][CH2:47][S:48][CH3:49])[NH2:45])([CH3:41])([CH3:40])[CH3:39].ON1C2N=CC=CC=2N=N1>CN(C=O)C>[N:1]1([CH2:6]/[CH:7]=[CH:8]/[C:9]2[CH:10]=[CH:11][C:12]([CH2:29][CH2:30][C:31]3[CH:36]=[CH:35][C:34]([F:37])=[CH:33][CH:32]=3)=[C:13]([CH:28]=2)[C:14]([NH:45][C@@H:44]([CH2:46][CH2:47][S:48][CH3:49])[C:43]([O:42][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:50])=[O:15])[CH:5]=[CH:4][N:3]=[CH:2]1
Reactant: CSCC[C@H](N)C(=O)OC(C)(C)C
Reactant: O=C(Oc1c(F)c(F)c(F)c(F)c1F)c1cc(/C=C/Cn2ccnc2)ccc1CCc1ccc(F)cc1
Agent: On1nnc2cccnc21
Solvent: CN(C)C=O
Product: CSCC[C@H](NC(=O)c1cc(/C=C/Cn2ccnc2)ccc1CCc1ccc(F)cc1)C(=O)OC(C)(C)C
Yield: 50 %

Procedure:
A solution of pentafluorophenyl 5-[(E)-3-(imidazol-1-yl)prop-1-en-1-yl]-2-(4-fluorophenethyl)benzoate (0.36 g, 0.7 mmol), L-methionine-tert-butyl ester(0.173 g, 0.84 mmol) and 1-hydroxy-7-azabenzotriazole (0.1 g, 0.73 mmol) in DMF (2 ml) was stirred at ambient temperature overnight. After evaporation of the solvent, the residue was taken up in ethyl acetate, washed with 5% sodium hydrogen carbonate solution and saturated brine and evaporated to dryness. The residue was then purified by flash chromatography eluting with dichloromethane/ethanol (97/3) to give the title compound. Yield: 50%
Reaction SMILES: [C:1]1([CH:7]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[O:8][CH2:9][CH2:10]Cl)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH:18]1[CH2:24][CH2:23][CH2:22][NH:21][CH2:20][CH2:19]1>>[C:1]1([CH:7]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[O:8][CH2:9][CH2:10][N:18]2[CH2:24][CH2:23][CH2:22][NH:21][CH2:20][CH2:19]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: C1CNCCNC1
Reactant: ClCCOC(c1ccccc1)c1ccccc1
Product: c1ccc(C(OCCN2CCCNCC2)c2ccccc2)cc1
Yield: 68 %

Procedure:
Following a procedure similar to that described in Preparation 1, but using 2-(diphenylmethoxy)ethyl chloride and homopiperazine, the title compound was obtained ina yield of 68%.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:20]=[CH:19][C:6]([CH2:7][C:8]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[C:11](Cl)=[N:10][N:9]=2)=[CH:5][CH:4]=1.[C:21]1(B(O)O)[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.O1CCOCC1.C(=O)([O-])[O-].[Na+].[Na+]>CCOC(C)=O>[CH3:1][O:2][C:3]1[CH:20]=[CH:19][C:6]([CH2:7][C:8]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[C:11]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)=[N:10][N:9]=2)=[CH:5][CH:4]=1
Reactant: OB(O)c1ccccc1
Reactant: COc1ccc(Cc2nnc(Cl)c3ccccc23)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: COc1ccc(Cc2nnc(-c3ccccc3)c3ccccc23)cc1
Temperature: 100 °C

Procedure:
To 1,1′-bis(diphenylphosphoino)ferrocene-palladium dichloride (0.046 g, 0.063 mmol), 1-(4-methoxybenzyl)-4-chlorophthalazine (0.360 g, 1.3 mmol), and phenylboronic acid (0.39 g, 3.2 mmol) was added dioxane (4.0 mL) and sodium carbonate (2.0M, aq) (1.9 ml, 3.8 mmol). The resulting mixture was heated to 100° C. in a sealed tube for 1 hour. The reaction was diluted with EtOAc and extracted with water and brine. The organic layers were dried over sodium sulfate, filtered, concentrated, and the crude was purified by ISCO silica gel chromatography (10-100% EtOAc/hexanes, 40 g column). Concentrated the product fractions to yield 1-(4-methoxybenzyl)-4-phenylphthalazine as a light yellow solid. MS m/z=327 [M+1]+. Calc'd for C22H18N2O: 326.40.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([OH:8])[CH:5]=[CH:6][CH:7]=1.Cl[S:10]([N:13]=C=O)(=[O:12])=[O:11].C1(C)C=CC=CC=1>C1C=CC=CC=1>[Br:1][C:2]1[CH:3]=[C:4]([O:8][S:10](=[O:12])(=[O:11])[NH2:13])[CH:5]=[CH:6][CH:7]=1
Reactant: O=C=NS(=O)(=O)Cl
Reactant: Oc1cccc(Br)c1
Solvent: c1ccccc1
Solvent: Cc1ccccc1
Product: NS(=O)(=O)Oc1cccc(Br)c1
Yield: 78.5 %

Procedure:
This compound was prepared according to the procedure used in Example 84. A mixture of 17.3 g (0.1 mole) of 3-bromophenol, 9.1 ml (14.8 g, 0.105 mole) of chlorosulfonyl isocyanate and 100 ml of toluene gave 19.8 g (70%) of white solid, mp 90°-91.5° C. (benzene).