Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][NH:2][C:3]([NH:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[N:17]=[C:16]3[N:18]([CH:21]4[CH2:26][CH2:25][C:24](=O)[CH2:23][CH2:22]4)[N:19]=[CH:20][C:15]3=[C:14]([N:28]3[CH2:34][CH:33]4[O:35][CH:30]([CH2:31][CH2:32]4)[CH2:29]3)[N:13]=2)=[CH:8][CH:7]=1)=[O:4].[CH3:36][N:37]1[CH2:42][CH2:41][NH:40][CH2:39][CH2:38]1.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[CH3:1][NH:2][C:3]([NH:5][C:6]1[CH:7]=[CH:8][C:9]([C:12]2[N:17]=[C:16]3[N:18]([CH:21]4[CH2:22][CH2:23][CH:24]([N:40]5[CH2:41][CH2:42][N:37]([CH3:36])[CH2:38][CH2:39]5)[CH2:25][CH2:26]4)[N:19]=[CH:20][C:15]3=[C:14]([N:28]3[CH2:29][CH:30]4[O:35][CH:33]([CH2:32][CH2:31]4)[CH2:34]3)[N:13]=2)=[CH:10][CH:11]=1)=[O:4]
Reactant: CN1CCNCC1
Reactant: CNC(=O)Nc1ccc(-c2nc(N3CC4CCC(C3)O4)c3cnn(C4CCC(=O)CC4)c3n2)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Solvent: CC(=O)O
Product: CNC(=O)Nc1ccc(-c2nc(N3CC4CCC(C3)O4)c3cnn(C4CCC(N5CCN(C)CC5)CC4)c3n2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 1-methyl-3-{4-[4-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-1-(4-oxocyclohexyl)-1H-pyrazolo[3,4-d]pyrimidin-6-yl]phenyl}urea (65 mg) in DCE (2.0 mL) was added excess N-methylpiperizine, acetic acid (0.012 mL) and excess sodium triacetoxyborohydride. The mixture was stirred at room temperature overnight. The reaction was quenched with water and the organics were separated and concentrated under nitrogen and purified by Gilson HPLC to give the desired product (56 mg) MS m/z=560.3 (M+H).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([S:10]([N:13]2[CH2:20][CH2:19][CH2:18][C@H:14]2[C:15]([OH:17])=[O:16])(=[O:12])=[O:11])=[CH:6][CH:5]=1)([O-:3])=[O:2].[Br:21][C@H:22]1[C@H:27](O)[C:26]2[CH:29]=[C:30]([C:33]#[N:34])[CH:31]=[CH:32][C:25]=2[O:24][C:23]1([CH3:36])[CH3:35]>C(Cl)(Cl)Cl>[Br:21][C@H:22]1[C@H:27]([O:16][C:15](=[O:17])[C@@H:14]2[CH2:18][CH2:19][CH2:20][N:13]2[S:10]([C:7]2[CH:8]=[CH:9][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=2)(=[O:11])=[O:12])[C:26]2[CH:29]=[C:30]([C:33]#[N:34])[CH:31]=[CH:32][C:25]=2[O:24][C:23]1([CH3:36])[CH3:35]
Reactant: O=C(O)[C@@H]1CCCN1S(=O)(=O)c1ccc([N+](=O)[O-])cc1
Reactant: CC1(C)Oc2ccc(C#N)cc2[C@@H](O)[C@@H]1Br
Solvent: ClC(Cl)Cl
Product: CC1(C)Oc2ccc(C#N)cc2[C@@H](OC(=O)[C@@H]2CCCN2S(=O)(=O)c2ccc([N+](=O)[O-])cc2)[C@@H]1Br
Yield: 41.4 %

Procedure:
A similar procedure as in Example 1(1) was performed by using 6.7 g of N-4-nitrobenzenesulfonyl-L-proline and 5.7 g of (±)-trans-3-bromo-6-cyano-3,4-dihydro-2,2-dimethyl-2H-1-benzopyran-4-ol to give 4.72 g of trans-3-bromo-6-cyano-3,4-dihydro-2,2-dimethyl-4-(N-4-nitrobenzenesulfonyl-L-prolyloxy)-2H-1-benzopyran as a sparingly soluble diastereomer compound, melting at 226.5°-227° C. with decomposition, [α]23D =+44.7° (c=1, CHCl3) and 5.01 g of the corresponding readily soluble diastereomer compound, melting at 177°-180° C., [α]23D =-93.2° (c=1, CHCl3), respectively.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[CH:13]([C:14]3[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=3)[N:12]([C:21]([N:23]3[CH2:28][CH2:27][N:26](CCC#N)[CH2:25][CH2:24]3)=[O:22])[C:11]([C:33]3[CH:38]=[CH:37][C:36]([C:39]([F:42])([F:41])[F:40])=[CH:35][C:34]=3[O:43][CH2:44][CH3:45])=[N:10]2)=[CH:5][CH:4]=1.[CH3:46][N:47]=[C:48]=[S:49]>C(Cl)Cl>[CH3:46][NH:47][C:48]([N:26]1[CH2:27][CH2:28][N:23]([C:21]([N:12]2[CH:13]([C:14]3[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=3)[CH:9]([C:6]3[CH:5]=[CH:4][C:3]([Cl:2])=[CH:8][CH:7]=3)[N:10]=[C:11]2[C:33]2[CH:38]=[CH:37][C:36]([C:39]([F:42])([F:41])[F:40])=[CH:35][C:34]=2[O:43][CH2:44][CH3:45])=[O:22])[CH2:24][CH2:25]1)=[S:49]
Reactant: CCOc1cc(C(F)(F)F)ccc1C1=NC(c2ccc(Cl)cc2)C(c2ccc(Cl)cc2)N1C(=O)N1CCN(CCC#N)CC1
Reactant: CN=C=S
Agent: Cl
Solvent: ClCCl
Product: CCOc1cc(C(F)(F)F)ccc1C1=NC(c2ccc(Cl)cc2)C(c2ccc(Cl)cc2)N1C(=O)N1CCN(C(=S)NC)CC1
Reaction time: 3 h

Procedure:
[4,5-Bis-(4-chloro-phenyl)-2-(2-ethoxy-4-trifluoromethyl-phenyl)-4,5-dihydro-imidazol-1-yl]-piperazin-1-yl-methanone (279 mg, 0.47 mmol, example 8A) was dissolved in methylene chloride (3 mL) and methylisothiocyanate (64 uL) was added. After stirring 3 h, the reaction mixture was concentrated to dryness. Purification of the crude residue by flash chromatography (silica gel) eluting with ethyl acetate and hexanes gave 4-[4,5-bis-(4-chloro-phenyl)-2-(2-ethoxy-4-trifluoromethyl-phenyl)-4,5-dihydro-imidazole-1-carbonyl]-piperazine-1-carbothioic acid methylamide (195 mg). LR-MS: 664.4 [(M+H)+].
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([O:9][CH2:10][O:11][CH3:12])=[CH:7][C:6]([O:13][CH3:14])=[C:5]([O:15][CH2:16][O:17][CH3:18])[C:4]=1[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][C:24]1[C:29]([O:30][CH2:31][O:32][CH3:33])=[C:28]([O:34][CH3:35])[CH:27]=[C:26]([O:36][CH2:37][O:38][CH3:39])[C:25]=1[O:40][CH3:41].CN(C)CCN(C)C.C([Li])CCC.[I:55]N1C(=O)CCC1=O>O1CCCC1.CN(C)P(=O)(N(C)C)N(C)C>[CH3:41][O:40][C:25]1[C:26]([O:36][CH2:37][O:38][CH3:39])=[CH:27][C:28]([O:34][CH3:35])=[C:29]([O:30][CH2:31][O:32][CH3:33])[C:24]=1[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][C:4]1[C:5]([O:15][CH2:16][O:17][CH3:18])=[C:6]([O:13][CH3:14])[C:7]([I:55])=[C:8]([O:9][CH2:10][O:11][CH3:12])[C:3]=1[O:2][CH3:1]
Reactant: O=C1CCC(=O)N1I
Reactant: COCOc1cc(OC)c(OCOC)c(CCCCCc2c(OC)c(OCOC)cc(OC)c2OCOC)c1OC
Agent: CN(C)CCN(C)C
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: COCOc1cc(OC)c(OCOC)c(CCCCCc2c(OC)c(OCOC)c(I)c(OC)c2OCOC)c1OC
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
1.53 Grams of 2,2'-pentamethylenebis[1,4-dimethoxy-3,6-bis(methoxymethoxy)benzene] was dissolved in a mixed solvent of 40 ml of tetrahydrofuran with 4 ml of hexamethylphosphoric triamide, to this solution was added 0.79 ml of N,N,N',N'-tetramethylethylenediamine, then this mixture was cooled to -78° C. on a dry ice-acetone mixture bath. 3.49 Milliliters of n-butyllithium (1.6 M, n-hexane solution) was added dropwise to the reaction mixture and stirred for 30 minutes. Next, 15 ml of tetrahydrofuran solution containing 1.18 g of N-iodosuccinimide was added dropwise and the reaction mixture was stirred overnight. The solvent was removed under reduced pressure, and the residue obtained was extracted twice with 100 ml of diethyl ether, and the diethyl ether layer was washed twice with 100 ml of water, and washed twice with 100 ml of a saturated sodium chloride aqueous solution, then dried over anhydrous magnesium sulfate. The dried diethyl ether extract was concentrated under reduced pressure, the residue obtained was purified by means of a separative thin layer chromatography (thickness: 2 mm, adsorbent: Merk 5717 silica gel, developing solvent: ethyl acetate-dichloromethane (1:9). There were obtained 685 mg of 1-[2,5-dimethoxy-3,6-bis(methoxymethoxy)phenyl]-5-[2,5-dimethoxy-3,6-bis(methoxymethoxy)-4-iodophenyl]pentane, as well as 575 mg of 2,2'-pentamethylenebis[1,4-dimethoxy-3,6-bis(methoxymethoxy)-5-iodobenzene].
Reaction SMILES: [OH:1][CH2:2][C@H:3]1[CH2:14][CH2:13][C:12]2[S:11][C:10]3[N:9]=[CH:8][N:7]=[C:6]([O:15][CH:16]4[CH2:21][CH2:20][CH:19]([N:22]([CH3:30])[C:23](=[O:29])[O:24][C:25]([CH3:28])([CH3:27])[CH3:26])[CH2:18][CH2:17]4)[C:5]=3[C:4]1=2.[CH3:31][S:32](Cl)(=[O:34])=[O:33].C(N(CC)CC)C>C(Cl)Cl>[CH3:31][S:32]([O:1][CH2:2][C@H:3]1[CH2:14][CH2:13][C:12]2[S:11][C:10]3[N:9]=[CH:8][N:7]=[C:6]([O:15][CH:16]4[CH2:17][CH2:18][CH:19]([N:22]([CH3:30])[C:23](=[O:29])[O:24][C:25]([CH3:26])([CH3:27])[CH3:28])[CH2:20][CH2:21]4)[C:5]=3[C:4]1=2)(=[O:34])=[O:33]
Reactant: CS(=O)(=O)Cl
Reactant: CN(C(=O)OC(C)(C)C)C1CCC(Oc2ncnc3sc4c(c23)[C@@H](CO)CC4)CC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CN(C(=O)OC(C)(C)C)C1CCC(Oc2ncnc3sc4c(c23)[C@@H](COS(C)(=O)=O)CC4)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 110.6 %

Procedure:
A solution of tert-butyl N-(4-[[(3S)-3-(hydroxymethyl)-7-thia-9,11-diazatricyclo[6.4.0.0[2,6]]dodeca-1(8),2 (6),9,11-tetraen-12-yl]oxy]cyclohexyl)-N-methylcarbamate (691 mg, 1.59 mmol, 1.00 equiv) in 4 mL of DCM was added MsCl (366 mg, 3.18 mmol, 2.00 equiv) and triethylamine (643 mg, 6.35 mmol, 4.00 equiv) at 0° C. under nitrogen. The resulting solution was stirred for 2 h at room temperature and quenched with water. The resulting solution was extracted with 3×30 mL of DCM. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate and concentrated under vacuum afford tert-butyl N-(4-[[(3S)-3-[(methanesulfonyloxy)methyl]-7-thia-9,11-diazatricyclo[6.4.0.0[2,6]]dodeca-1(8),2 (6),9,11-tetraen-12-yl]oxy]cyclohexyl)-N-methylcarbamate (900 mg, crude) as a red oil. MS: m/z 512 (M+H)+.
Reaction SMILES: [CH2:1]([SH:13])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].[OH-].C([N+](C)(C)C)C1C=CC=CC=1.[CH3:26][O:27][C:28](=[O:31])[CH:29]=[CH2:30]>>[CH2:1]([S:13][CH2:30][CH2:29][C:28]([O:27][CH3:26])=[O:31])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12]
Reactant: C=CC(=O)OC
Reactant: CCCCCCCCCCCCS
Agent: C[N+](C)(C)Cc1ccccc1
Agent: [OH-]
Product: CCCCCCCCCCCCSCCC(=O)OC
Reaction time: 0.5 h
Yield: 100.7 %

Procedure:
Into a 1 liter 3 necked flask equipped with a mechanical stirrer, Claissen adaptor, thermometer and dropping funnel was charged 404 grams of 98% 1-dodecanethiol with stirring to 0.7 grams of Triton B (benzyltrimethyl ammonium hydroxide) and 180.6 grams of 99% methylacrylate. The addition was over a period of 1/2 hour and the temperature of the reaction mixture increased form 30° C. to 56° C. The reaction was stirred an extra hour wherein the temperature dropped from 56° C. to 35° C. The reaction mixture was stripped at 92° C. and 10 mm pressure. 580 grams of product was obtained. Product analysis by GC indicated a purity of 99%.
Reaction SMILES: [CH2:1]([O:3][CH:4]([P:8]([O-:12])[O:9][CH2:10][CH3:11])[O:5][CH2:6][CH3:7])[CH3:2].[Cl:13][C:14]1[CH:23]=[CH:22][C:17]([CH:18]=[CH:19][C:20]#[N:21])=[CH:16][CH:15]=1.[H-].[Na+].C(O)(=O)C>C(O)C>[Cl:13][C:14]1[CH:15]=[CH:16][C:17]([CH:18]([P:8]([CH:4]([O:5][CH2:6][CH3:7])[O:3][CH2:1][CH3:2])(=[O:12])[O:9][CH2:10][CH3:11])[CH2:19][C:20]#[N:21])=[CH:22][CH:23]=1
Reactant: CCOC(OCC)P([O-])OCC
Reactant: N#CC=Cc1ccc(Cl)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CCO
Product: CCOC(OCC)P(=O)(OCC)C(CC#N)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A solution of 25.8 g of ethyl (diethoxymethyl)phosphonite and 18.0 g of 4-chlorocinnamonitrile in 100 ml of ethanol is added to a stirred mixture of 1.2 g of sodium hydride (50% dispersion in oil) in 30 ml of ethanol at 0° C. under an atmosphere of nitrogen. The reaction mixture is allowed to warm to room temperature and stirred for 4 hours. 1 ml of glacial acetic acid is added and the mixture is concentrated under reduced pressure. The resulting crude product is dissolved in 50 ml of ethyl acetate, washed twice with 25 ml of water and the organic extract is dried over magnesium sulphate, and then concentrated under reduced pressure. The crude product is distilled under reduced pressure to give ethyl 1-(4-chlorophenyl)-2-cyanoethyl(diethoxymethyl)phosphinate, b.p. 180°-200° C./0.02 mbar, 31P=+37.9 and +37.8 ppm (CDCl3).
Reaction SMILES: CS(O[CH2:6][CH2:7][C@@:8]1([C:31]2[CH:36]=[CH:35][C:34]([F:37])=[CH:33][CH:32]=2)[O:13][C:12](=[O:14])[N:11]([C@H:15]([C:17]2[CH:22]=[CH:21][C:20]([C:23]3[CH:28]=[CH:27][C:26]([F:29])=[CH:25][C:24]=3[F:30])=[CH:19][CH:18]=2)[CH3:16])[CH2:10][CH2:9]1)(=O)=O.[NH:38]1[CH:42]=[CH:41][N:40]=[CH:39]1.C([O-])([O-])=O.[K+].[K+]>C(#N)C>[F:30][C:24]1[CH:25]=[C:26]([F:29])[CH:27]=[CH:28][C:23]=1[C:20]1[CH:21]=[CH:22][C:17]([C@@H:15]([N:11]2[CH2:10][CH2:9][C@@:8]([C:31]3[CH:32]=[CH:33][C:34]([F:37])=[CH:35][CH:36]=3)([CH2:7][CH2:6][N:38]3[CH:42]=[CH:41][N:40]=[CH:39]3)[O:13][C:12]2=[O:14])[CH3:16])=[CH:18][CH:19]=1
Reactant: C[C@@H](c1ccc(-c2ccc(F)cc2F)cc1)N1CC[C@](CCOS(C)(=O)=O)(c2ccc(F)cc2)OC1=O
Reactant: c1c[nH]cn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: C[C@@H](c1ccc(-c2ccc(F)cc2F)cc1)N1CC[C@](CCn2ccnc2)(c2ccc(F)cc2)OC1=O
Yield: 1.2 %

Procedure:
A mixture of 2-((S)-3-((S)-1-(2′,4′-difluorobiphenyl-4-yl)ethyl)-6-(4-fluorophenyl)-2-oxo-1,3-oxazinan-6-yl)ethyl methanesulfonate (230 mg, 0.43 mmol), imidazole (44 mg, 0.65 mmol), K2CO3 (178.7 mg, 1.29 mmol) in acetonitrile (4 mL) was heated to reflux overnight. The solvent was removed and the residue was partitioned between EtOAc and water. The aqueous layer was extracted with EtOAc and the combined organic layer was washed with brine, dried over Na2SO4, filtered and concentrated to give the crude product, which was purified by preparative HPLC to give (R)-3-[(S)-1-(2′,4′-difluoro-biphenyl-4-yl)-ethyl]-6-(4-fluoro-phenyl)-6-(2-imidazol-1-yl-ethyl)-[1,3]oxazinan-2-one (2.5 mg, 1.2%). LC-MS Method 2 tR=2.14, min, m/z=506; 1H NMR (CDCl3): 1.51 (d, 3H), 2.16-2.63 (m, 7H), 2.94 (m, 2H), 3.91 (m, 1H), 4.32 (m, 1H), 5.66 (m, 1H), 6.25 (m, 1H), 6.81-6.90 (m, 2H), 6.94-7.08 (m, 5H), 7.14-7.26 (m, 6H).
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]([S:8][CH:9]2[N:12]([C:13](=[C:22](N3CCCCC3)[CH2:23][Br:24])[C:14]([O:16][CH2:17][C:18]([Cl:21])([Cl:20])[Cl:19])=[O:15])[C:11](=[O:31])[CH:10]2[NH:32][C:33](=[O:42])[CH2:34][O:35][C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)=[O:7])[CH2:3][CH2:2]1.Cl.C[OH:45]>>[CH:1]1([CH2:4][O:5][C:6]([S:8][CH:9]2[N:12]([C:13](=[C:22]([OH:45])[CH2:23][Br:24])[C:14]([O:16][CH2:17][C:18]([Cl:19])([Cl:20])[Cl:21])=[O:15])[C:11](=[O:31])[CH:10]2[NH:32][C:33](=[O:42])[CH2:34][O:35][C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)=[O:7])[CH2:3][CH2:2]1
Reactant: CO
Reactant: O=C(COc1ccccc1)NC1C(=O)N(C(C(=O)OCC(Cl)(Cl)Cl)=C(CBr)N2CCCCC2)C1SC(=O)OCC1CC1
Agent: Cl
Product: O=C(COc1ccccc1)NC1C(=O)N(C(C(=O)OCC(Cl)(Cl)Cl)=C(O)CBr)C1SC(=O)OCC1CC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 83.5 %

Procedure:
To a solution of 2,2,2-trichloroethyl α-[4-cyclopropylmethoxycarbonylthio-3-phenoxyacetamido-2-oxoazetidin-1-yl]-α-[2-bromo-1-(piperidin-1-yl)ethylidene]acetate (573 mg) in methanol (30 ml) is added 10% hydrochloric acid (7 ml), and the mixture is stirred at room temperature or at 40° to 45° C. After 30 minutes, the reaction mixture is poured into ice water, and is extracted with benzene. The extract solution is washed with water, dried, and evaporated to give 2,2,2-trichloroethyl α-[4-cyclopropylmethoxycarbonylthio-3-phenoxyacetamido-2-oxoazetidin-1-yl]-α-(2-bromo-1-hydroxyethylidene)-acetate (434 mg). Yield: 83.5%. IR: νmaxCHCl3 3450, 1790, 1720, 1720 (sh), 1700 cm-1. NMR: δCDCl3 0.1-1.4m7H, 3.98d(7 Hz)2H, 4.27d(5 Hz)2H, 4.57s2H, 4.82d(3 Hz)2H, 5.27d(6;8 Hz)1H, 5.93d(5 Hz)1H, 6.8-7.5m6H, 11.67brs1H.
Reaction SMILES: [S:1]1[C:5]2=[CH:6][N+:7]([O-])=[CH:8][CH:9]=[C:4]2[CH:3]=[CH:2]1.C1(C)C=CC(S(Cl)(=O)=O)=CC=1.O.[NH3:23]>C(Cl)(Cl)Cl>[NH2:23][C:6]1[N:7]=[CH:8][CH:9]=[C:4]2[CH:3]=[CH:2][S:1][C:5]=12
Reactant: N
Reactant: [O-][n+]1ccc2ccsc2c1
Agent: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: ClC(Cl)Cl
Solvent: O
Product: Nc1nccc2ccsc12
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 16.6 g of thieno[2,3-c]pyridine-N-oxide in 500 ml of chloroform was added 25 g of p-toluenesulfonyl chloride portionwise with ice-cooling over a period of 1 hour. After the reaction mixture was stirred for further 30 minutes under the same conditions, 250 ml of 10% ammonia water was added, and stirred at ambient temperature for 16 hours. The reaction mixture was diluted with 400 ml of chloroform, washed with water and saturated saline, and dried over anhydrous magnesium sulfate. The drying agent was removed by filtration, and the solvent was removed under reduced pressure. The residue was purified by column chromatography on silica gel to give 2.8 g of the title compound as a brown oily material.
Reaction SMILES: Cl[C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][N:3]=1.[CH3:10][S-:11].[Na+].O>CN(C=O)C>[CH3:10][S:11][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][N:3]=1
Reactant: C[S-]
Reactant: O=Cc1ccc(Cl)nc1
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CSc1ccc(C=O)cn1
Temperature: 25 °C
Reaction time: 2 h
Yield: 73.6 %

Procedure:
In DMF (5.0 mL) was dissolved 6-chloronicotinaldehyde (300 mg, 2.12 mmol). Sodium thiomethoxide (178 mg, 2.54 mmol) was added and the mixture was stirred at room temperature for 2 hours. Water was added to the reaction mixture. Extraction with ethyl acetate, washing with saturated brine and drying over anhydrous sodium sulfate were performed. After filtration, the solvent in the filtrate was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate=4/1) to give 6-(methylthio)nicotinaldehyde (239 mg, 74%).
Reaction SMILES: [C:1]1(=[O:11])[NH:5][C:4](=[O:6])[C:3]2=[CH:7][CH:8]=[CH:9][CH:10]=[C:2]12.[K].[CH2:13]([O:15][C:16](=[O:22])[CH:17](Br)[CH2:18][CH2:19][CH3:20])[CH3:14].C(Cl)(Cl)Cl.O>CN(C)C=O>[C:1]1(=[O:11])[N:5]([CH:17]([CH2:18][CH2:19][CH3:20])[C:16]([O:15][CH2:13][CH3:14])=[O:22])[C:4](=[O:6])[C:3]2=[CH:7][CH:8]=[CH:9][CH:10]=[C:2]12
Reactant: CCCC(Br)C(=O)OCC
Reactant: O=C1NC(=O)c2ccccc21
Agent: [K]
Solvent: CN(C)C=O
Solvent: O
Solvent: ClC(Cl)Cl
Product: CCCC(C(=O)OCC)N1C(=O)c2ccccc2C1=O
Temperature: 60 °C

Procedure:
To a solution of potassium phthalimide (0.1 mole) in about 50 ml of dimethylformamide (DMF) is added 1 equivalent of ethyl-2-bromopentanoate. The temperature is maintained at about 60° C. for 10 minutes. Chloroform is added to the cooled DMF solution and the mixture is poured into water. The phases are separated and the aqueous phase is extracted with chloroform. The chloroform extracts are combined, extracted with 0.1 N sodium hydroxide and with water. After drying over sodium sulfate, the chloroform is removed to give ethyl α-phthalimidopentanoate.
Reaction SMILES: [CH2:1]([C:4]([O:11][CH3:12])([C:8](Cl)=[O:9])[C:5](Cl)=[O:6])[CH:2]=[CH2:3].[CH:13]([N:16]([C:34]1[CH:39]=[CH:38][C:37]([O:40][CH3:41])=[CH:36][CH:35]=1)[C:17](=[O:33])[CH2:18][NH:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[NH:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)([CH3:15])[CH3:14]>C1COCC1>[CH2:1]([C:4]1([O:11][CH3:12])[C:8](=[O:9])[N:19]([CH2:18][C:17]([N:16]([CH:13]([CH3:15])[CH3:14])[C:34]2[CH:39]=[CH:38][C:37]([O:40][CH3:41])=[CH:36][CH:35]=2)=[O:33])[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=2[N:26]([C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=2)[C:5]1=[O:6])[CH:2]=[CH2:3]
Reactant: COc1ccc(N(C(=O)CNc2ccccc2Nc2ccccc2)C(C)C)cc1
Reactant: C=CCC(OC)(C(=O)Cl)C(=O)Cl
Solvent: C1CCOC1
Product: C=CCC1(OC)C(=O)N(CC(=O)N(c2ccc(OC)cc2)C(C)C)c2ccccc2N(c2ccccc2)C1=O
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 58.4 %

Procedure:
To a stirring solution of 1.50 g (7.10 mmol) of 2-allyl-2-methoxy-propandioyl dichloride in 50 mL of THF at 0° C. is added dropwise over 2 min a solution of 1.85 g (4.74 mmol) of N-isopropyl-N-(4-methoxy-phenyl)-2-(2-phenylamino-phenylamino) acetamide, prepared as in Intermediate 43, in 20 mL of THF. The resulting solution is stirred at RT for 15 min then refluxed for 18 h. After cooling to RT the solvent is removed in vacuo and the crude product purified by silica gel flash column chromatography using hexane/EtOAc 3/1 as eluent to afford 1.46 g of the title compound as a clear, colorless oil: 1H NMR (CDCl3, 300 MHz) δ7.40-6.88 (m, 12H), 6.78 (d, 1H), 5.92 (m, 1H), 5.10 (m, 2H), 4.46 (d, 1H), 3.80 (s, 3H), 3.64 (m, 1H), 3.02 (s, 3H), 1.88 (m, 1H), 1.75 (m, 1H), 1.13 (m, 6H); low resolution MS (FAB) m/e 528 (MH+).
Reaction SMILES: [N+](C1C=CC(O[C:11]([N:13]2[CH:18]([C:19]3[CH:24]=[CH:23][C:22]([C:25]#[N:26])=[CH:21][CH:20]=3)[C:17]([C:27]([O:29][CH3:30])=[O:28])=[C:16]([CH3:31])[N:15]=[C:14]2OC)=[O:12])=CC=1)([O-])=O.Cl.[CH2:35]([NH:42][NH2:43])[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1.CCN(CC)CC>CC#N>[CH3:30][O:29][C:27]([C:17]1[CH:18]([C:19]2[CH:20]=[CH:21][C:22]([C:25]#[N:26])=[CH:23][CH:24]=2)[N:13]2[C:11](=[O:12])[N:42]([CH2:35][C:36]3[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=3)[N:43]=[C:14]2[NH:15][C:16]=1[CH3:31])=[O:28]
Reactant: COC(=O)C1=C(C)N=C(OC)N(C(=O)Oc2ccc([N+](=O)[O-])cc2)C1c1ccc(C#N)cc1
Reactant: NNCc1ccccc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CC#N
Product: COC(=O)C1=C(C)Nc2nn(Cc3ccccc3)c(=O)n2C1c1ccc(C#N)cc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 45.3 %

Procedure:
Intermediate 5 (250 mg, 0.55 mmol) and benzyl hydrazine hydrochloride (120 mg, 0.61 mmol) were suspended in CH3CN (10 mL) at 0° C., and Et3N (85 μl, 0.61 mmol) was added. The reaction mixture was stirred at 0° C. for 30 mins and then allowed to reach RT and stirred for a further 1 hour. The reaction mixture was filtered and the filtrate was concentrated in vacuo. The resulting residue was purified by silica gel chromatography eluting with a gradient of 0-100% to yield the title compound as a yellow solid (100 mg).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([CH:8]2[CH2:12][CH2:11][CH2:10][CH2:9]2)[C:5]([O:13][CH3:14])=[CH:4][C:3]=1[N+:15]([O-])=O.O>C(O)(=O)C.C(OCC)(=O)C.[Zn]>[Br:1][C:2]1[CH:7]=[C:6]([CH:8]2[CH2:12][CH2:11][CH2:10][CH2:9]2)[C:5]([O:13][CH3:14])=[CH:4][C:3]=1[NH2:15]
Reactant: COc1cc([N+](=O)[O-])c(Br)cc1C1CCCC1
Agent: [Zn]
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Solvent: O
Product: COc1cc(N)c(Br)cc1C1CCCC1
Reaction time: 1.5 h
Yield: 95.3 %

Procedure:
1-Bromo-5-cyclopentyl-4-methoxy-2-nitrobenzene (100 mg, 0.33 mmol) was dissolved in acetic acid (1 mL) and water (250 μL) and treated with Zn (109 mg, 1.67 mmol) at room temperature and stirred for 1.5 h. The reaction was diluted with ethyl acetate and filtered. The organic layer was washed with 50% saturated NaHCO3 and brine, dried over Na2SO4, filtered, and concentrated in vacuo to provide 2-bromo-4-cyclopentyl-5-methoxyaniline as a clear brown oil (85 mg, 94% yield). LC/MS m/z 270.2 [M+H]+.
Reaction SMILES: [CH3:1][CH:2]([CH3:29])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][NH:17][C:18]1[CH:28]=[CH:27][C:21]([C:22]([O:24]CC)=[O:23])=[CH:20][CH:19]=1.[OH-].[K+].C(O)C.Cl>O>[CH3:1][CH:2]([CH3:29])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][NH:17][C:18]1[CH:19]=[CH:20][C:21]([C:22]([OH:24])=[O:23])=[CH:27][CH:28]=1
Reactant: CCOC(=O)c1ccc(NCCCCCCCCCCCCCCC(C)C)cc1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CC(C)CCCCCCCCCCCCCCNc1ccc(C(=O)O)cc1

Procedure:
A solution of 3.5 g. of ethyl 4-(15-methylhexadecyl)aminobenzoate and 1.7 g. of 85% potassium hydroxide in 50 ml. of 95% ethanol is heated at reflux for 5 hours. The warm solution is diluted with 100 ml. water and adjusted to pH5 with 37% hydrochloric acid. The precipitate is collected, dried, and crystallized from acetic acid to yield the title compound as an amorphous, cream-colored solid.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8](OCCCNC2C(=O)N(C(C)(C)C)S(=O)(=O)C=2C2C=CC=CC=2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[C:34]([N:38]1[C:42](=[O:43])[C:41]([NH:44][CH2:45][CH2:46][OH:47])=[C:40]([C:48]2[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=2)[S:39]1(=[O:55])=[O:54])([CH3:37])([CH3:36])[CH3:35].CC1C=CC(S(Cl)(=O)=O)=CC=1>>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([O:47][CH2:46][CH2:45][NH:44][C:41]2[C:42](=[O:43])[N:38]([C:34]([CH3:37])([CH3:35])[CH3:36])[S:39](=[O:54])(=[O:55])[C:40]=2[C:48]2[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=2)(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: CC(C)(C)N1C(=O)C(NCCO)=C(c2ccccc2)S1(=O)=O
Reactant: Cc1ccc(S(=O)(=O)OCCCNC2=C(c3ccccc3)S(=O)(=O)N(C(C)(C)C)C2=O)cc1
Agent: Cc1ccc(S(=O)(=O)Cl)cc1
Product: Cc1ccc(S(=O)(=O)OCCNC2=C(c3ccccc3)S(=O)(=O)N(C(C)(C)C)C2=O)cc1
Yield: 76 %

Procedure:
The title compound was prepared as described for 3-[(2-tert-butyl-1,1-dioxido-3-oxo-5-phenyl-2,3-dihydroisothiazol-4-yl)amino]propyl 4-methylbenzenesulfonate from 2-tert-butyl-4-[(2-hydroxyethyl)amino]-5-phenylisothiazol-3(2H)-one 1,1-dioxide (Example 76) and 4-methylbenzenesulfonyl chloride with a reaction time of 17 h. The reaction mixture was purified by silica gel column chromatography (Horizons Biotage) using 50-100% DCM in petroleum ether 40-60° C. as eluent to give the title compound (1.93 g, 76%) as a solid; 1H NMR (500 MHz, CDCl3): δ 7.76 (d, 1H), 7.46-7.35 (m, 7H), 5.44 (t, 1H), 3.85 (t, 2H), 3.18-3.12 (m, 2H), 2.49 (s, 3H), 1.74 (s, 9H); Mass Spectrum M+H+ 479.