Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]([C:8]([F:11])([F:10])[F:9])=[CH:4][C:5](O)=[O:6].[CH:14]1([CH2:17][CH2:18][NH:19][C:20]([C:22]2[N:23]=[N:24][C:25]([N:28]3[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]3)=[CH:26][CH:27]=2)=[O:21])[CH2:16][CH2:15]1>>[CH:14]1([CH2:17][CH2:18][NH:19][C:20]([C:22]2[N:23]=[N:24][C:25]([N:28]3[CH2:33][CH2:32][N:31]([C:5](=[O:6])[CH:4]=[C:3]([C:8]([F:11])([F:10])[F:9])[C:2]([F:13])([F:12])[F:1])[CH2:30][CH2:29]3)=[CH:26][CH:27]=2)=[O:21])[CH2:16][CH2:15]1
Reactant: O=C(O)C=C(C(F)(F)F)C(F)(F)F
Reactant: O=C(NCCC1CC1)c1ccc(N2CCNCC2)nn1
Product: O=C(NCCC1CC1)c1ccc(N2CCN(C(=O)C=C(C(F)(F)F)C(F)(F)F)CC2)nn1

Procedure:
Following the procedure of Example 9, making variations only as required to use 4,4,4-trifluoro-3-trifluoromethylbut-2-enoic acid in place of 2,5-dichlorobenzoic acid to react with 6-piperazin-1-yl-pyridazine-3-carboxylic acid (2-cyclopropylethyl)amide, the title compound was obtained as a white powder (45.4% yield). 1H NMR (CDCl3) δ 8.07, 7.97, 7.10, 7.01, 3.87-3.74, 3.58-3.50, 1.54-1.47, 0.78-0.68, 0.48-0.42, 0.10-0.05.
Reaction SMILES: C[O:2][C:3]([C:5]1[S:6][C:7]([C:11](=[O:24])[NH:12][CH2:13][C:14]2[CH:22]=[CH:21][CH:20]=[C:19]3[C:15]=2[CH2:16][C:17](=[O:23])[NH:18]3)=[CH:8][C:9]=1[CH3:10])=[O:4].O[Li].O>C1COCC1.O>[CH3:10][C:9]1[CH:8]=[C:7]([C:11](=[O:24])[NH:12][CH2:13][C:14]2[CH:22]=[CH:21][CH:20]=[C:19]3[C:15]=2[CH2:16][C:17](=[O:23])[NH:18]3)[S:6][C:5]=1[C:3]([OH:4])=[O:2]
Reactant: COC(=O)c1sc(C(=O)NCc2cccc3c2CC(=O)N3)cc1C
Agent: [Li]O
Solvent: O
Solvent: C1CCOC1
Product: Cc1cc(C(=O)NCc2cccc3c2CC(=O)N3)sc1C(=O)O
Yield: 92.8 %

Procedure:
A solution of 3-methyl-5-[(2-oxo-2,3-dihydro-1H-indol-4-ylmethyl)-carbamoyl]-thiophene-2-carboxylic acid methyl ester (158 mg, 0.46 mmol) in THF/water (6 ml/3 ml) was treated with LiOH.H2O (206 mg, 4.6 mmol) at rt for 1 h. The reaction mixture was quenched with 1N HCl and extracted with EtOAc. The layers were separated. The organic layer was successively washed with water and brine, then dried over Na2SO4 and concentrated under reduced pressure to afford the desired product (141 mg, 95% yield).
Reaction SMILES: [CH:1](O)([CH3:3])[CH3:2].C(N(CC)CC)C.[F:12][C:13]([F:32])([F:31])[C:14]([N:16]([CH2:24][P:25]([O:29]Cl)([O:27]Cl)=[O:26])[CH2:17][C:18]([O:20][CH2:21][CH2:22][Cl:23])=[O:19])=[O:15].[CH:33]([NH2:36])([CH3:35])[CH3:34]>O1CCCC1.CCOCC>[F:12][C:13]([F:32])([F:31])[C:14]([N:16]([CH:24]([CH:1]([CH3:3])[CH3:2])[P:25]([OH:29])([O:27][NH:36][CH:33]([CH3:35])[CH3:34])=[O:26])[CH2:17][C:18]([O:20][CH2:21][CH2:22][Cl:23])=[O:19])=[O:15]
Reactant: O=C(CN(CP(=O)(OCl)OCl)C(=O)C(F)(F)F)OCCCl
Reactant: CC(C)O
Reactant: CC(C)N
Solvent: CCN(CC)CC
Solvent: CCOCC
Solvent: C1CCOC1
Product: CC(C)NOP(=O)(O)C(C(C)C)N(CC(=O)OCCCl)C(=O)C(F)(F)F
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A solution of isopropanol (1.0 ml, 0.025 mole) and triethylamine (3.5 ml, 0.025 mole) in 50 ml. of tetrahydrofuran was added to a solution of β-chloroethyl N-trifluoroacetyl-N-(dichlorophosphonomethyl)glycinate (9.1 g, 0.025 mole) in 250 ml. of ether at 0° C. After three hours, the solution was filtered and the filtrate was added to a cooled (0° C.) solution of isopropylamine (4.2 ml, 0.05 mole) in 50 ml. of tetrahydrofuran. After stirring for 16 hours at 25° C., the reaction mixture was filtered and the filtrate was concentrated in vacuo. The residual oil was dissolved in methylene chloride and washed with 3% hydrochloric acid, 3% ammonium hydroxide and saturated sodium chloride solution. The solution was dried over sodium sulfate and concentrated in vacuo to yield a solid. Recrystallization from ethyl acetate-hexane (1:10) yielded β-chloroethyl N-trifluoroacetyl-N-(isopropyl(isopropylamino)phosphonomethyl)glycinate as a white solid, m.p. 87.5°-89° C.
Reaction SMILES: [CH2:1]([CH:3]1[CH2:12][C:11]2[C:6](=[C:7]([OH:15])[CH:8]=[C:9]([CH:13]=[O:14])[CH:10]=2)[C:5](=[O:16])[CH2:4]1)[CH3:2].[H-].[Na+].[CH2:19](Br)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>>[CH2:1]([CH:3]1[CH2:12][C:11]2[C:6](=[C:7]([O:15][CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[CH:8]=[C:9]([CH:13]=[O:14])[CH:10]=2)[C:5](=[O:16])[CH2:4]1)[CH3:2]
Reactant: CCC1CC(=O)c2c(O)cc(C=O)cc2C1
Reactant: BrCc1ccccc1
Agent: [H-]
Agent: [Na+]
Product: CCC1CC(=O)c2c(cc(C=O)cc2OCc2ccccc2)C1

Procedure:
The product of Example 30 is treated with sodium hydride and benzyl bromide according to the procedure described in Example 15.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[NH:9][C:10](=[O:26])[C:11]([N:14]1[C:18](=[O:19])[CH:17]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)S[CH2:15]1)([CH3:13])[CH3:12].ClC1C=CC=C(C(OO)=O)C=1.[S:38]([O-:42])([O-])(=[O:40])=S.[Na+].[Na+]>ClCCl.C(Cl)(Cl)Cl>[F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[NH:9][C:10](=[O:26])[C:11]([N:14]1[C:18](=[O:19])[CH:17]([C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)[S:38](=[O:42])(=[O:40])[CH2:15]1)([CH3:12])[CH3:13]
Reactant: CC(C)(C(=O)Nc1cc(F)ccc1F)N1CSC(c2ccccc2)C1=O
Reactant: O=S([O-])([O-])=S
Agent: O=C(OO)c1cccc(Cl)c1
Agent: [Na+]
Solvent: ClCCl
Solvent: ClC(Cl)Cl
Product: CC(C)(C(=O)Nc1cc(F)ccc1F)N1CS(=O)(=O)C(c2ccccc2)C1=O
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of N-(2,5-difluorophenyl)-2-(5-phenylthiazolidin-4-on-3-yl)isobutyramide (1.3 g) prepared according to Example 13 in dichloromethane (25 mL) was added portionwise 70% m-chloroperbenzoic acid (1 g) under ice-cooling, and the mixture was stirred for 30 minutes at room temperature. After adding a small amount of sodium thiosulfate, the mixture was diluted with chloroform and washed with a saturated sodium hydrogencarbonate aqueous solution. After distilling off the solvent under reduced pressure, the resulting crude product was purified by preparative thin-layer chromatography (developing solvent: chloroform/ethyl acetate=3/1) to give crystals, which were washed with a mixture of isopropyl ether-ethanol (10:1) to give 0.26 g of the title compound as crystals.
Reaction SMILES: Cl.[CH3:2][C:3]1(O)[C:7]([CH3:9])(O)[NH:6][C:5]([CH2:10][CH2:11][CH3:12])=[N:4]1.Cl.[OH2:15]>>[CH3:2][C:3]1[NH:4][C:5]([CH2:10][CH2:11][CH3:12])=[N:6][C:7]=1[CH2:9][OH:15]
Reactant: CCCC1=NC(C)(O)C(C)(O)N1
Reactant: O
Agent: Cl
Product: CCCc1nc(CO)c(C)[nH]1

Procedure:
The product from Example 4 is dissolvedi 900 ml. of water and 350 ml. of concentrated hydrochloride, heated on a steam bath for 5 hours and then chilled. The solution is concentrated in vacuo and a mixture of 100 ml. of acetone and 100 ml. of ethanol is added. The mixture is filtered. The filtrate is evaporated and the residue is dissolved in 50 ml. of water and neutralized with a concentrated solution of K2CO3, until bubbling ceases. The top layer is separated and combined with 5 ml. of methanol. On standing, a precipitate forms. The solid is collected and the filtrate is diluted with acetone to give a second precipitate which is also collected. The solids are combined and recrystallized from hot acetone giving the desired product, m.p 134°-136° C.
Reaction SMILES: [CH3:1][CH:2]([CH3:24])[C:3](=[C:9]([C:17]1[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=1)[C:10]1[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=1)/[CH:4]=[CH:5]/[C:6]([OH:8])=O.[C:25](Cl)(=[O:29])C(Cl)=O.Cl.CONOOC.[N:38]1C=CC=C[CH:39]=1>C1C=CC=CC=1.C(OCC)C>[CH3:39][N:38]([O:29][CH3:25])[C:6](=[O:8])/[CH:5]=[CH:4]/[C:3](=[C:9]([C:10]1[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=1)[C:17]1[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=1)[CH:2]([CH3:1])[CH3:24]
Reactant: O=C(Cl)C(=O)Cl
Reactant: c1ccncc1
Reactant: CC(C)C(/C=C/C(=O)O)=C(c1ccc(F)cc1)c1ccc(F)cc1
Agent: CONOOC
Agent: Cl
Solvent: CCOCC
Solvent: c1ccccc1
Product: CON(C)C(=O)/C=C/C(=C(c1ccc(F)cc1)c1ccc(F)cc1)C(C)C
Temperature: 60 °C
Reaction time: 2 h
Yield: 83.9 %

Procedure:
To the above carboxylic acid (1.70 g, 5.2 mmol) dissolved in benzene (15 ml) was added under argon atmosphere oxalyl chloride (1.27 g, 0.87 ml, 10.0 mmol) distilled right before use. After stirring at 60° C. for 2 hours, the solvent and excess oxalyl chloride were removed by evaporation at 60° C. under 20 Torr. To the residue dissolved in dichloromethane (25 ml) were added N,O-dimethoxyhydroxylamine hydrochloride (0.52 g, 5.34 mmol) and pyridine (0.85 g, 0.86 ml, 10.7 mmol), and the whole was stirred at room temperature overnight. The mixture was diluted with diethyl ether (100 ml), and the organic layer was washed with saturated ammonium chloride aq solution (100 ml×twice), dried over anhydrous magnesium sulfate, and concentrated in vacuo. The resulting crude product was purified by column chromatography (silica gel, ethyl acetate:hexane=3:7) to give 1.62 g (82% yield) of N-methyl-N-methoxy-(E)-5-methyl-4-bis(4-fluorophenyl)methylidene-2-hexenamide.
Reaction SMILES: P(Cl)(Cl)(Cl)=O.[Cl:6][C:7]1[CH:31]=[CH:30][CH:29]=[CH:28][C:8]=1[CH2:9][N:10]1[C:18]2[C:13](=[CH:14][CH:15]=[C:16]([C:19]([NH2:21])=O)[CH:17]=2)[C:12]([C:22](=[O:25])[CH2:23][CH3:24])=[C:11]1[CH2:26][CH3:27].O.N>CN(C)C=O>[Cl:6][C:7]1[CH:31]=[CH:30][CH:29]=[CH:28][C:8]=1[CH2:9][N:10]1[C:18]2[C:13](=[CH:14][CH:15]=[C:16]([C:19]#[N:21])[CH:17]=2)[C:12]([C:22](=[O:25])[CH2:23][CH3:24])=[C:11]1[CH2:26][CH3:27]
Reactant: CCC(=O)c1c(CC)n(Cc2ccccc2Cl)c2cc(C(N)=O)ccc12
Agent: N
Solvent: O
Solvent: CN(C)C=O
Solvent: O=P(Cl)(Cl)Cl
Product: CCC(=O)c1c(CC)n(Cc2ccccc2Cl)c2cc(C#N)ccc12
Reaction time: 0.25 h
Yield: 87.3 %

Procedure:
To a solution of phosphorus oxychloride (0.031 ml) in dimethylformamide (1.2 ml) was added 1-(2-chlorobenzyl)-2-ethyl-3-propionylindole-6-carboxamide (112 mg) at 0° C., and the mixture was stirred for 15 minutes. The resulting mixture was poured into ammonia water and ice, and then extracted with ethyl acetate. The organic phase was washed with brine, dried over sodium sulfate and evaporated in vacuo. The residue was triturated with a mixture of hexane and isopropyl ether to give 1-(2-chlorobenzyl)-2-ethyl-3-propionylindole-6-carbonitrile (93 mg) as a solid.
Reaction SMILES: [CH2:1]([OH:11])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10].[CH3:12][CH2:13][CH2:14][CH:15]([OH:22])[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21]>>[CH:1](=[O:11])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10].[CH3:12][CH2:13][CH2:14][C:15](=[O:22])[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21]
Reactant: CCCCCCC(O)CCC
Reactant: CCCCCCCCCCO
Product: CCCCCCC(=O)CCC
Product: CCCCCCCCCC=O
Yield: 83 %
Yield: 3 %

Procedure:
The procedure of Example 1 was repeated, except that a mixture of 1-decanol (0.5 millimole) and 4-decanol (0.5 millimole) was used instead of 1-decanol, to give 1-decanal (yield 83%), and 4-decanone (yield 3%).
Reaction SMILES: [N:1]([CH2:4][C:5]1[CH:6]=[N:7][C:8]([CH3:11])=[N:9][CH:10]=1)=[N+]=[N-]>C(OCC)(=O)C.[Pd]>[CH3:11][C:8]1[N:9]=[CH:10][C:5]([CH2:4][NH2:1])=[CH:6][N:7]=1
Reactant: Cc1ncc(CN=[N+]=[N-])cn1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: Cc1ncc(CN)cn1
Reaction time: 1.5 h

Procedure:
A mixture of 5-(azidomethyl)-2-methylpyrimidine (2.0, 13.4 mmol) in ethyl acetate (100 mL), and 10% Pd—C (4.0 g) was stirred under H2 (1 atm) for 1.5 hr. The catalyst was filtered off and filtrate was concentrated in vacuo to afford a white solid.
Reaction SMILES: [NH2:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([CH:11]([CH2:19][CH3:20])[C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])=[CH:7][CH:6]=1)(=[O:4])=[O:3].[Cl:21][C:22]1[CH:23]=[C:24]([NH:32][C:33](OC2C=CC=CC=2)=[O:34])[C:25](=[CH:30][CH:31]=1)[C:26]([O:28][CH3:29])=[O:27]>>[C:15]([O:14][C:12]([CH:11]([C:8]1[CH:7]=[CH:6][C:5]([S:2]([NH:1][C:33]([NH:32][C:24]2[CH:23]=[C:22]([Cl:21])[CH:31]=[CH:30][C:25]=2[C:26]([O:28][CH3:29])=[O:27])=[O:34])(=[O:3])=[O:4])=[CH:10][CH:9]=1)[CH2:19][CH3:20])=[O:13])([CH3:16])([CH3:18])[CH3:17]
Reactant: COC(=O)c1ccc(Cl)cc1NC(=O)Oc1ccccc1
Reactant: CCC(C(=O)OC(C)(C)C)c1ccc(S(N)(=O)=O)cc1
Product: CCC(C(=O)OC(C)(C)C)c1ccc(S(=O)(=O)NC(=O)Nc2cc(Cl)ccc2C(=O)OC)cc1
Yield: 83.8 %

Procedure:
1.02 g (3.41 mmol) of t-butyl (±)-2-(4-aminosulfonylphenyl)butyrate acid and 1.04 g (3.41 mmol) of methyl 4-chloro-2-N-phenoxycarbonylanthranilate were treated in the same way as Example 1 to obtain 1.46 g (yield 84%) of methyl 2-[({4-[1-(t-butoxycarbonyl)propyl]benzenesulfonylamino}carbonyl)amino]-4-chlorobenzoate. Properties: colorless amorphous, PMR (δ ppm, CDCl3):0.89 (3H, t), 1.38 (9H, s), 1.69–1.76 (1H, m), 2.03–2.10 (1H, m), 3.42 (1H, t), 3.94 (3H, s), 7.04 (1H, d), 7.47 (2H, d), 7.93 (1H, d), 8.01 (2H, d), 8.45 (1H, br), 11.04 (1H, br).
Reaction SMILES: [CH2:1]([C:7]12[S:14][CH2:13][C:10]([CH2:15][CH2:16][CH3:17])([CH2:11][S:12]1)[CH2:9][S:8]2)[CH2:2][CH2:3][CH2:4][C:5]#[CH:6].ClC1C=CC=C(C(OO)=[O:26])C=1.C([O-])(=O)C.[Na+]>C(#N)C>[CH2:1]([C:7]12[S:12][CH2:11][C:10]([CH2:15][CH2:16][CH3:17])([CH2:9][S:8]1)[CH2:13][S:14]2=[O:26])[CH2:2][CH2:3][CH2:4][C:5]#[CH:6]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: C#CCCCCC12SCC(CCC)(CS1)CS2
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC#N
Product: C#CCCCCC12SCC(CCC)(CS1)CS2=O
Reaction time: 24 h
Yield: 41.6 %

Procedure:
A mixture of 1-(hex-5-ynyl)-4-n-propyl-2,6,7-trithiabicyclo [2.2.2]octane (1.07 g. 1.0 equivalent), 3-chloroperbenzoic acid (0.80 g., 1.05 equivalent, 85% Lancaster Synthesis), and anhydrous sodium acetate (1.0 g.) in anhydrous acetonitrile was stirred at 20° from 24 hours. The solvent was removed in vacuo and the residue partitioned between water and ethyl acetate. The organic phase was separated, washed with sodium hydrogen carbonate solution and brine before drying over anhydrous magnesium sulphate. The solvent was removed in vacuo and the residue was chromatographed on silica. Elution with hexane: ethyl acetate mixtures (20% 75%) ethyl acetate gave 1-(hex-5-ynyl)-4-n-propyl-2,6,7-trithiabicyclo[ 2.2.2]octane 2-oxide as a colourless solid (0.47 g).
Reaction SMILES: [Cl:1][C:2]1[C:7]([NH:8][S:9]([C:12]2[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=2)(=[O:11])=[O:10])=[CH:6][C:5]([C:19]2[CH:20]=[C:21]3[C:26](=[CH:27][CH:28]=2)[N:25]=[CH:24][CH:23]=[C:22]3Cl)=[CH:4][N:3]=1.O.[CH3:31][O:32][C:33]1[C:38](B(O)O)=[CH:37][CH:36]=[CH:35][N:34]=1.C(=O)([O-])[O-].[Na+].[Na+]>[Pd].O1CCOCC1>[Cl:1][C:2]1[C:7]([NH:8][S:9]([C:12]2[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=2)(=[O:11])=[O:10])=[CH:6][C:5]([C:19]2[CH:28]=[C:27]3[C:26](=[CH:21][CH:20]=2)[N:25]=[CH:24][CH:23]=[C:22]3[C:38]2[C:33]([O:32][CH3:31])=[N:34][CH:35]=[CH:36][CH:37]=2)=[CH:4][N:3]=1
Reactant: O=S(=O)(Nc1cc(-c2ccc3nccc(Cl)c3c2)cnc1Cl)c1ccc(F)cc1
Reactant: COc1ncccc1B(O)O
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: COc1ncccc1-c1ccnc2ccc(-c3cnc(Cl)c(NS(=O)(=O)c4ccc(F)cc4)c3)cc12
Reaction time: 0.33 h

Procedure:
(Some starting materials may be obtained from Frontier Scientific, Inc., Logan, Utah) To a 5 mL CEM microwave tube was added N-(2-chloro-5-(4-chloroquinolin-6-yl)pyridin-3-yl)-4-fluorobenzenesulfonamide (0.07 g, 0.2 mmol), 2-methoxypyridine-3-boronic acid hydrate (0.07 g, 0.5 mmol), sodium carbonate (0.2 mL, 0.5 mmol), Pd fibrecat PPh (20% wt, 15 mg), and dioxane (3 mL). The vial was sealed and placed into CEM microwave for 20 min. at 120° C., with 100 watts of power. LC/MS showed a desired product mass as a major peak. The reaction mixture was partitioned between DCM/water. The aqueous layer was extracted with DCM (2×10 mL). The combined organic layers were washed with water, brine, dried over MgSO4 and concentrated. The crude product was purified using SiO2 (12 g) chromatography with hexanes:acetone=80%:20% as the solvent system to afford the desired product as light yellow solid (25 mg). MS (ESI pos. ion) m/z: calc'd for C26H18ClFN4O3S: 520.1; found: 521.3 (M+1). 1H NMR (300 MHz, CHLOROFORM-d) δ ppm 3.95 (s, 3 H) 7.06-7.19 (m, 3 H) 7.42 (d, J=4.53 Hz, 1 H) 7.67 (dd, J=7.31, 1.90 Hz, 1 H) 7.72 (d, J=1.90 Hz, 1 H) 7.75-7.82 (m, 2 H) 7.90 (dd, J=8.77, 2.05 Hz, 1 H) 8.20 (d, J=2.34 Hz, 1 H) 8.31 (d, J=8.77 Hz, 1 H) 8.34 (d, J=2.19 Hz, 1 H) 8.40 (dd, J=5.04, 1.97 Hz, 1 H) 9.03 (d, J=4.38 Hz, 1 H).
Reaction SMILES: [C:1]([O:5][C:6](=[O:29])[NH:7][CH2:8][CH2:9][CH2:10][CH2:11][O:12][C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([O:19][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:14]=1[S:27][CH3:28])([CH3:4])([CH3:3])[CH3:2].C1C=C(Cl)C=C(C(OO)=[O:38])C=1.O>C(Cl)Cl>[C:1]([O:5][C:6](=[O:29])[NH:7][CH2:8][CH2:9][CH2:10][CH2:11][O:12][C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([O:19][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:14]=1[S:27]([CH3:28])=[O:38])([CH3:4])([CH3:3])[CH3:2]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CSc1c(OCCCCNC(=O)OC(C)(C)C)cccc1OCc1ccccc1
Solvent: O
Solvent: ClCCl
Product: CS(=O)c1c(OCCCCNC(=O)OC(C)(C)C)cccc1OCc1ccccc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of [4-(3-benzyloxy-2-methylsulfanylphenoxy)-butyl]-carbamic acid tert-butyl ester (600 mg, 1.44 mmol) in methylene chloride (15 mL) is added mCPBA (355 mg, 1.44 mmol) and the mixture is stirred at RT for 2 h. Water is added the organic phase is washed with saturated NaHCO3, water and brine then is dried over sodium sulfate. The solvent is removed under reduced pressure to give the title compound as an oil.
Reaction SMILES: [N:1]1([CH2:6][C:7]2[CH:16]=[CH:15][C:10]([O:11][CH2:12][CH2:13][OH:14])=[CH:9][CH:8]=2)[CH:5]=[CH:4][CH:3]=[N:2]1.C(N(CC)CC)C.[CH2:24]([N:26]=[C:27]=[O:28])[CH3:25]>C1(C)C=CC=CC=1>[N:1]1([CH2:6][C:7]2[CH:8]=[CH:9][C:10]([O:11][CH2:12][CH2:13][O:14][C:27](=[O:28])[NH:26][CH2:24][CH3:25])=[CH:15][CH:16]=2)[CH:5]=[CH:4][CH:3]=[N:2]1
Reactant: OCCOc1ccc(Cn2cccn2)cc1
Reactant: CCN=C=O
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: CCNC(=O)OCCOc1ccc(Cn2cccn2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 13.1 %

Procedure:
To a mixture of 2-[4-(1-pyrazolyl)methylphenoxy]ethanol (produced in Reference Production Example 3 described below) (500 mg), triethylamine (255 mg) and dry toluene (20 ml) was added dropwise an anhydrous toluene solution (1 ml) of ethyl isocyanate (179 mg). This mixture was then stirred at room temperature overnight, and concentrated under reduced pressure. The residue was subjected to silica gel chromatography, which afforded 87 mg of ethylcarbamic acid 2-[4-(1-pyrazolyl)methylphenoxy]-ethyl ester (compound 37). Yield, 13%.
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[C:3]([N:10]2[CH2:15][CH2:14][N:13]([CH2:16][CH2:17][C:18]3[CH:23]=[CH:22][C:21]([NH2:24])=[CH:20][CH:19]=3)[CH2:12][CH2:11]2)=[N:2]1.[CH2:25]([S:28](Cl)(=[O:30])=[O:29])[CH2:26][CH3:27]>N1C=CC=CC=1.ClCCl>[S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[C:3]([N:10]2[CH2:11][CH2:12][N:13]([CH2:16][CH2:17][C:18]3[CH:19]=[CH:20][C:21]([NH:24][S:28]([CH2:25][CH2:26][CH3:27])(=[O:30])=[O:29])=[CH:22][CH:23]=3)[CH2:14][CH2:15]2)=[N:2]1
Reactant: Nc1ccc(CCN2CCN(c3nsc4ccccc34)CC2)cc1
Reactant: CCCS(=O)(=O)Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCCS(=O)(=O)Nc1ccc(CCN2CCN(c3nsc4ccccc34)CC2)cc1
Temperature: 45 °C
Reaction time: 8 h

Procedure:
4-[2-(4-Benzo[d]isothiazol-3-yl-piperazin-1-yl)-ethyl]-phenylamine was diluted to 0.3 M with anhydrous pyridine, then delivered to an 8 mL vial via pipette (0.225 mmol). Propane-1-sulfonyl chloride was diluted to 1.0 M with anhydrous dichloromethane, and added to the amine solution at rt (0.40 mmol). The solution was stirred overnight at 45° C. To the reaction mixture was added polyamine scavenging resin (0.30 mmol). The solution was stirred overnight at 45° C., then filtered into an 8 mL vial. The filtrate was evaluated by MS and concentrated via HT-12 GeneVac. Crude was purified by HPLC (30×100 mm ODS-A C(18) 5u column). Propane-1-sulfonic acid {4-[2-(4-1,2-benzisothiazol-3-yl-piperazin-1-yl)-ethyl]-phenyl}-amide was isolated in 100% purity @ 254 nm; LCMS (APCI): 445 [M+H]+
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([NH:11][CH:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)=[C:6]([CH:10]=1)[C:7]([OH:9])=O.[CH2:18]([NH2:29])[C:19]1[CH:28]=[CH:27][C:24]([O:25][CH3:26])=[C:21]([O:22][CH3:23])[CH:20]=1.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([NH:11][CH:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)=[C:6]([CH:10]=1)[C:7]([NH:29][CH2:18][C:19]1[CH:28]=[CH:27][C:24]([O:25][CH3:26])=[C:21]([O:22][CH3:23])[CH:20]=1)=[O:9]
Reactant: O=C(O)c1cc(Br)ccc1NC1CCOCC1
Reactant: COc1ccc(CN)cc1OC
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COc1ccc(CNC(=O)c2cc(Br)ccc2NC2CCOCC2)cc1OC
Temperature: 25 °C
Reaction time: 48 h
Yield: 80.2 %

Procedure:
A mixture of 1 g of the compound obtained in Step 1.1, 0.646 g of veratrylamine, 1.152 g of DIEA and 1.69 g of HBTU in 50 ml of DMF is stirred for 2 days at room temperature. The reaction medium is evaporated under reduced pressure. The residue is chromatographed on silica gel, eluting with a DCM/EtOAc mixture from (100/0, v/v) to (80/20, v/v) to give 1.2 g of a solid, which is used without purification in the following step.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:13]=[CH:12][C:6]([CH:7]=[CH:8][C:9](O)=[O:10])=[CH:5][CH:4]=1.S(Cl)([Cl:16])=O>C1C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:13]=[CH:12][C:6]([CH:7]=[CH:8][C:9]([Cl:16])=[O:10])=[CH:5][CH:4]=1
Reactant: O=S(Cl)Cl
Reactant: COc1ccc(C=CC(=O)O)cc1
Solvent: c1ccccc1
Product: COc1ccc(C=CC(=O)Cl)cc1

Procedure:
100 ml of benzene was added to 17.8 grams of p-methoxycinnamic acid. 12 ml of thionyl chloride was added dropwise slowly thereto at ambient temperature. The temperature was elevated to 70° C. and the heating was continued until foaming ceased. Benzene and thionyl chloride were distilled off and the residue was dried thoroughly under reduced pressure.
Reaction SMILES: [CH2:1]([NH2:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[CH2:10][C:11]([NH:13][C:14]([CH3:21])([CH3:20])[CH2:15][CH2:16][CH2:17][CH2:18][CH3:19])=[O:12]>C1C=CC=CC=1>[CH2:1]([NH:8][CH2:10][C:11]([NH:13][C:14]([CH3:20])([CH3:21])[CH2:15][CH2:16][CH2:17][CH2:18][CH3:19])=[O:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NCc1ccccc1
Reactant: CCCCCC(C)(C)NC(=O)CCl
Solvent: c1ccccc1
Product: CCCCCC(C)(C)NC(=O)CNCc1ccccc1

Procedure:
A solution of benzylamine (21.4 g, 0.2 mol) and 2-chloro-N-(1,1-dimethylhexyl)acetamide (20.6 g, 0.1 mol) in benzene (100 ml) was held at room temperature for five days then refluxed for 24 hours.The mixture was filtered and the filtrate was evaporated then distilled under reduced pressure to give 2-benzylamino-N-(1,1-dimethylhexyl)acetamide as a pale yellow oil, b.p. 153°-156° C. at 0.05 mm Hg.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:15][CH2:14][CH2:13][C@H:12]1[C:16](=[O:33])[NH:17][C:18]1[CH:23]=[CH:22][CH:21]=[C:20](B2OC(C)(C)C(C)(C)O2)[CH:19]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[C:35]1[CH:36]=[C:37]([CH:45]=[CH:46][CH:47]=1)[CH2:38][NH:39][C:40]([CH:42]1[CH2:44][CH2:43]1)=[O:41].CN(C=O)C>CO.C([O-])(O)=O.[Na+]>[CH2:1]([O:8][C:9]([N:11]1[CH2:15][CH2:14][CH2:13][C@H:12]1[C:16](=[O:33])[NH:17][C:18]1[CH:19]=[C:20]([C:46]2[CH:47]=[CH:35][CH:36]=[C:37]([CH2:38][NH:39][C:40]([CH:42]3[CH2:44][CH2:43]3)=[O:41])[CH:45]=2)[CH:21]=[CH:22][CH:23]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(NCc1cccc(Br)c1)C1CC1
Reactant: CC1(C)OB(c2cccc(NC(=O)[C@@H]3CCCN3C(=O)OCc3ccccc3)c2)OC1(C)C
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CO
Product: O=C(NCc1cccc(-c2cccc(NC(=O)[C@@H]3CCCN3C(=O)OCc3ccccc3)c2)c1)C1CC1
Temperature: 70 °C

Procedure:
A solution of (S)-2-[3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenylcarbamoyl]-pyrrolidine-1-carboxylic acid benzyl ester (74 mg, 0.16 mmol), cyclopropanecarboxylic acid 3-bromo-benzylamide (41.7 mg, 0.16 mmol), and Pd[P(Ph)3]4 (15.1 mg, 8.0 mol %) in methanol (2 mL), NaHCO3 (sat. aq., 300 μL), and DMF (400 μL) was degassed and heated to 70° C. overnight in a sealed vial. The reaction was cooled, filtered, and purified by reverse phase HPLC to give the desired product. Yield 5.0 mg. MS: 498.3 (M+H+); H1 NMR (DMSO-d6): δ (ppm) 0.55-0.70 (m, 4H), 1.50-1.60 (m, 1H), 1.73-1.98 (m, 3H), 2.07-2.29 (m, 1H), 3.35-3.56 (m, 2H), 4.24-4.37 (m, 3H), 4.85-5.08 (m, 2H), 6.97-7.54 (m, 12H), 7.63-780 (m, 1H), 8.50-8.59 (m, 1H), 10.06-10.13 (s, 1H).