Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5](/[CH:15]=[CH:16]/[C:17]([OH:19])=[O:18])[CH:6]=[CH:7][C:8]=1[O:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14].Cl[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][OH:27]>C(#N)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5](/[CH:15]=[CH:16]/[C:17]([O:19][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][OH:27])=[O:18])[CH:6]=[CH:7][C:8]=1[O:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14]
Reactant: OCCCCCCCl
Reactant: CCCCCOc1ccc(/C=C/C(=O)O)cc1OC
Solvent: CC#N
Product: CCCCCOc1ccc(/C=C/C(=O)OCCCCCCO)cc1OC

Procedure:
7.30 g (27.6 mmol) (2E)-3-[3-methoxy-4-(pentyloxy)phenyl]prop-2-enoic acid were suspended in 3 ml acetonitrile. A mixture of 4.20 g (27.6 mmol) 1,8-diazabicyclo[5.4.0]undec-7-ene(1, 5-5) (DBU) and 3 ml acetonitrile was added dropwise over a period of 5 minutes. 3.43 g (25.1 mmol) 6-chlorohexanol were added and the resulting mixture was then refluxed for 6 hours. The reaction mixture was cooled and then extracted using ethyl acetate and water. The ethyl acetate phase was washed with water, dried over sodium sulphate, filtered and concentrated by rotary evaporation. Chromatography of the residue using a silica gel column yield 6-hydroxyhexyl (2E)-3-[3-methoxy-4-(pentyloxy)phenyl]prop-2-enoate.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][S:7](Cl)(=[O:9])=[O:8].[CH2:11]([CH2:14][OH:15])[CH2:12][NH2:13]>>[OH:15][CH2:14][CH2:11][CH2:12][NH:13][S:7]([CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][Cl:1])(=[O:9])=[O:8]
Reactant: O=S(=O)(Cl)CCCCCCl
Reactant: NCCCO
Product: O=S(=O)(CCCCCCl)NCCCO

Procedure:
The reaction was carried out in the same manner as in Preparation Example 4 except for using 5-chloropentanesulfonyl chloride (3.08 g, 15 mmol) in place of 6-chlorohexanesulfonyl chloride, and n-propanolamine (2.48 g, 33 mmol) in place of ethanolamine in Preparation Example 4, to give a by-product [N,O-bis(5-chloropetanesulfonyl)propanolamine] from a first eluted fraction in the amount of 0.64 g and N-(3-hydroxypropyl)-5-chloropentanesulfonamide from a second eluted fraction as a colorless waxy product in the amount of 2.76 g.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][NH:5][C:4](=[O:8])[C:3]=1[N+:9]([O-:11])=[O:10].[H-].[Na+].[CH3:14][O:15][C:16]1[CH:23]=[CH:22][C:19]([CH2:20]Cl)=[CH:18][CH:17]=1.C(OCC)(=O)C>CN(C=O)C>[CH3:14][O:15][C:16]1[CH:23]=[CH:22][C:19]([CH2:20][N:5]2[CH:6]=[CH:7][C:2]([CH3:1])=[C:3]([N+:9]([O-:11])=[O:10])[C:4]2=[O:8])=[CH:18][CH:17]=1
Reactant: Cc1cc[nH]c(=O)c1[N+](=O)[O-]
Reactant: COc1ccc(CCl)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COc1ccc(Cn2ccc(C)c([N+](=O)[O-])c2=O)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 56 %

Procedure:
To a stirred suspension of 4-methyl-3-nitro-2-pyridone (2.0 g, 3 mmol) in DMF (60 mL) was added NaH (60% suspension in oil, 0.52 g). After 1 hour, 4-methoxybenzyl chloride (1.8 mL) was added, and the mixture was stirred at rt overnight. Ethyl acetate was added, and the organic phase was washed with water, dried, filtered and evaporated. Chromatography of the residue over silica gel (ethyl acetate/hexane) gave 1-(4-methoxybenzyl)-4-methyl-3-nitro-2-pyridone (2.0 g, 7.3 mmol, 56%).
Reaction SMILES: P([O-])(O)(O)=O.SCC(C(CS)O)O.Cl[C:15]1[N:19]2[N:20]=[C:21]([C:24]3[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=3)[CH:22]=[CH:23][C:18]2=[N:17][N:16]=1.CC([C:35]1[C:40]2[N:41]=[C:42]([N:44]([CH2:48][CH2:49][N:50]3[CH2:55][CH2:54][O:53][CH2:52][CH2:51]3)C(=O)[O-])[S:43][C:39]=2[CH:38]=[C:37]([S:56]C#N)[CH:36]=1)(C)C>O.C(O)C>[F:30][C:27]1[CH:28]=[CH:29][C:24]([C:21]2[CH:22]=[CH:23][C:18]3[N:19]([C:15]([S:56][C:37]4[CH:36]=[CH:35][C:40]5[N:41]=[C:42]([NH:44][CH2:48][CH2:49][N:50]6[CH2:55][CH2:54][O:53][CH2:52][CH2:51]6)[S:43][C:39]=5[CH:38]=4)=[N:16][N:17]=3)[N:20]=2)=[CH:25][CH:26]=1
Reactant: Fc1ccc(-c2ccc3nnc(Cl)n3n2)cc1
Reactant: CC(C)(C)c1cc(SC#N)cc2sc(N(CCN3CCOCC3)C(=O)[O-])nc12
Agent: O=P([O-])(O)O
Agent: OC(CS)C(O)CS
Solvent: O
Solvent: CCO
Product: Fc1ccc(-c2ccc3nnc(Sc4ccc5nc(NCCN6CCOCC6)sc5c4)n3n2)cc1
Yield: 32.4 %

Procedure:
8 mg of dihydrogen phosphate in 1 cm3 of water, 680 mg of DL-dithiothreitol and 336 mg of 3-chloro-6-(4-fluorophenyl)[1,2,4]triazolo[4,3-b]pyridazine are added, at 20° C., to a solution of 636 mg of 1,1-dimethylethyl[2-(morpholin-4-yl)ethyl](6-thiocyanato-1,3-benzothiazol-2-yl)carbamate in 10 cm3 of ethanol degassed with argon for 5 min. The suspension is stirred at reflux for 18 h. The reaction is placed in a refrigerator overnight and then the greyish-white solid is spin-filter-dried. This solid is washed with diethyl ether and then made into a paste in dichloromethane and spin-filter-dried. 222 mg of 6-{[6-(4-fluorophenyl)[1,2,4]triazolo[4,3-b]pyridazin-3-yl]sulphanyl}-N-[2-(morpholin-4-yl)ethyl]-1,3-benzothiazol-2-amine are thus obtained in the form of a greyish-white powder, the characteristics of which are as follows:
Reaction SMILES: COC[O:4][C:5]1[C:10]([CH3:11])=[CH:9][CH:8]=[C:7]([O:12][CH2:13][O:14][CH3:15])[C:6]=1[C:16]1([C:19](OCC)=[O:20])[CH2:18][CH2:17]1.O.[H-].[Na+].C(Cl)OC.[H-].[H-].[H-].[H-].[Li+].[Al+3]>C(O)C>[OH:20][CH2:19][C:16]1([C:6]2[C:7]([O:12][CH2:13][O:14][CH3:15])=[CH:8][CH:9]=[C:10]([CH3:11])[C:5]=2[OH:4])[CH2:17][CH2:18]1
Reactant: CCOC(=O)C1(c2c(OCOC)ccc(C)c2OCOC)CC1
Agent: COCCl
Agent: [Al+3]
Agent: [H-]
Solvent: CCO
Solvent: O
Product: COCOc1ccc(C)c(O)c1C1(CO)CC1
Temperature: 50 °C
Reaction time: 8 h
Yield: 31.6 %

Procedure:
To a solution of ethyl 1-[2,6-bis(methoxymethoxy)-3-methyl-phenyl]cyclopropanecarboxylate (Intermediate 10, 300 mg, 0.93 mmol) in ethanol (10 ml) HCl 6N in water (0.4 mL, 2.4 mmol) was added and the reaction mixture was stirred overnight at 50° C. Combined solvents were removed under reduced pressure. The residue was suspended in dry toluene (10 mL) and the solvent evaporated. The obtained residue was dissolved in dry tetrahydrofuran (10 ml), the mixture was cooled to 0° C. and NaH (60% dispersion in mineral oil) (80 mg, 2 mmol) was added and the reaction mixture was stirred for 30 minutes at the same temperature. MOM-Cl (0.083 mL, 1.1 mmol) was then added and the reaction mixture was stirred for 1 hour at 0° C. LiAlH4 (1M in THF, 1.2 ml, 1.2 mmol) was added and the reaction mixture was further stirred for 1 hour at the same temperature. The reaction was quenched with an aqueous saturated solution of ammonium chloride (10 ml), diluted with water (20 ml) and extracted with ethyl acetate (2×50 ml). Combined organic layers were dried over sodium sulphate, filtered and evaporated and the residue was purified by flash chromatography (Biotage system) on silica gel using a 25 g SNAP column and cyclohexane to cyclohexane/ethyl acetate 7:3 as eluents affording the title compound (70 mg) as a white solid.
Reaction SMILES: [Li]CCCC.Br[C:7]1[N:8]([CH2:14][O:15][CH2:16][CH2:17][Si:18]([CH3:21])([CH3:20])[CH3:19])[C:9]([Br:13])=[C:10]([Br:12])[N:11]=1.C1C[O:25][CH2:24][CH2:23]1>>[Br:12][C:10]1[N:11]=[C:7]([CH2:23][CH2:24][OH:25])[N:8]([CH2:14][O:15][CH2:16][CH2:17][Si:18]([CH3:21])([CH3:20])[CH3:19])[C:9]=1[Br:13]
Reactant: C1CCOC1
Reactant: C[Si](C)(C)CCOCn1c(Br)nc(Br)c1Br
Agent: [Li]CCCC
Product: C[Si](C)(C)CCOCn1c(CCO)nc(Br)c1Br
Temperature: 25 °C
Reaction time: 0.42 h
Yield: 31 %

Procedure:
n-BuLi (4.30 mL of a 1.6 M solution in hexanes, 6.80 mmol) was added dropwise to a −78° C. solution of 2,4,5-tribromo-1-({[2-(trimethylsilyl)ethyl]oxy}methyl)-1H-imidazole (2.96 g, 6.80 mmol) in THF (55 mL). After 25 min, oxirane gas was bubbled through the solution for 25 mins. The reaction mixture was allowed to warm slowly to RT, stirred overnight, quenched by addition of sat'd NH4Cl and extracted with CH2Cl2. The organic phase was dried (Na2SO4), filtered, and purified by silica gel chromatography (5-50% EtOAc/hex) to afford the title compound (0.83 g, 31%) as a yellow oil. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 5.36 (s, 2H), 3.82 (t, J=6.09 Hz, 2H), 3.55 (dd, J=8.94, 7.65 Hz, 2H), 3.10 (br. s., 1H), 2.90 (t, J=6.09 Hz, 2H), 0.85-0.98 (m, 2H), −0.02 (s, 9H).
Reaction SMILES: [Br:1][CH2:2][C:3](Br)=[O:4].[CH2:6]([O:8][C:9](=[O:19])[C@H:10]([CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[NH2:11])[CH3:7].C(N(CC)CC)C>C(Cl)(Cl)Cl.C(Cl)Cl.CCCCCC>[CH2:6]([O:8][C:9](=[O:19])[C@H:10]([CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[NH:11][C:3](=[O:4])[CH2:2][Br:1])[CH3:7]
Reactant: O=C(Br)CBr
Reactant: CCOC(=O)[C@@H](N)Cc1ccccc1
Solvent: CCCCCC
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOC(=O)[C@H](Cc1ccccc1)NC(=O)CBr
Temperature: -30 °C
Reaction time: 2 h
Yield: 85.9 %

Procedure:
Under argon, bromoacetyl bromide (0.89 g, 10.2 mmol) in chloroform (10 mL) was added dropwise to a mixture of chloroform (40 mL), L-phenylalanine ethyl ester (2.3 g, 10 mmol), and triethylamine (3 mL), which was pre-cooled to −30° C. The mixture was stirred at r.t. for a further 2 hrs, and then washed with aqueous saturated potassium carbonate solution and water, then dried over sodium sulfate. The solvents were removed under reduced pressure, giving a dark oil, which was dissolved in a mixture of DCM (100 mL) and hexane (300 mL), form which a crystalline solid deposited. The crystals were dried in air, giving colourless needles (2.7 g, 79%). 1H-NMR (CDCl3): 7.29-7.31 (3H, m, Ar), 7.11-7.16 (2H, m, Ar), 4.79-4.89 (1H, m, α-H), 4.20 (2H, q, J 7.2, OCH2CH3), 3.86 (2H, s, BrCH2), 3.16 (2H, d, J 5.8, ArCH2), 1.26 (3H, t, J 7.2, OCH2CH3). m/z (ES+): 336 [M+Na]+.
Reaction SMILES: Cl.[CH3:2][O:3][C:4]([C:6]1([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH2:11][CH2:10][NH:9][CH2:8][CH2:7]1)=[O:5].[C:18]([N:26]1[CH2:30][CH2:29][C:28]([CH2:39][CH2:40]CS([O-])(=O)=O)([C:31]2[CH:36]=[CH:35][C:34]([Cl:37])=[C:33]([Cl:38])[CH:32]=2)[CH2:27]1)(=[O:25])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.C(=O)(O)[O-].[Na+]>C1COCC1.O.C(OCC)(=O)C>[CH3:2][O:3][C:4]([C:6]1([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH2:7][CH2:8][N:9]([CH2:40][CH2:39][C:28]2([C:31]3[CH:36]=[CH:35][C:34]([Cl:37])=[C:33]([Cl:38])[CH:32]=3)[CH2:29][CH2:30][N:26]([C:18](=[O:25])[C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=3)[CH2:27]2)[CH2:10][CH2:11]1)=[O:5]
Reactant: COC(=O)C1(c2ccccc2)CCNCC1
Reactant: O=C(c1ccccc1)N1CCC(CCCS(=O)(=O)[O-])(c2ccc(Cl)c(Cl)c2)C1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: C1CCOC1
Product: COC(=O)C1(c2ccccc2)CCN(CCC2(c3ccc(Cl)c(Cl)c3)CCN(C(=O)c3ccccc3)C2)CC1
Yield: 31.1 %

Procedure:
4-Phenyl-piperidine-4-carboxylic acid methyl ester hydrochloride (0.4143 g, 1.62 mmol) and 2-[1-benzoyl-3-(3,4-dichloro-phenyl)-pyrrolidin-3-yl]-ethylmethanesulfonate (0.7165 g, 1.62 mmol) were dissolved in THF/H2O (20 mL/4 mL) and treated with sodium bicarbonate (0.2592 g, 3.24 mmol) at reflux for 16 hours. The solution was diluted with ethyl acetate and the aqueous phase was extracted with dichloromethane. The combined organic phases were dried over magnesium sulfate, filtered, and concentrated in vacuo. The residue was chromatographed on silica gel with 1% methanol in dichloromethane to give 0.2850 g (31%) of the title compound.
Reaction SMILES: [Mg].[C:2]1(I)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:9]1([S:15]([NH:18][CH2:19][C:20]([C:22]2[CH:27]=[CH:26][C:25]([O:28][CH2:29][C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)=[CH:24][CH:23]=2)=[O:21])(=[O:17])=[O:16])[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.[Cl-].[NH4+]>O1CCCC1.BrCCBr>[C:9]1([S:15]([NH:18][CH2:19][C:20]([C:22]2[CH:27]=[CH:26][C:25]([O:28][CH2:29][C:30]3[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=3)=[CH:24][CH:23]=2)([C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[OH:21])(=[O:17])=[O:16])[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: Ic1ccccc1
Reactant: O=C(CNS(=O)(=O)c1ccccc1)c1ccc(OCc2ccccc2)cc1
Agent: [Cl-]
Agent: [Mg]
Agent: [NH4+]
Solvent: BrCCBr
Solvent: C1CCOC1
Product: O=S(=O)(NCC(O)(c1ccccc1)c1ccc(OCc2ccccc2)cc1)c1ccccc1
Temperature: 25 °C
Yield: 58.3 %

Procedure:
5.83 g of magnesium are suspended in 100 ml of dry tetrahydrofuran, and 5 drops of 1,2-dibromoethane are added thereto. After the mixture is stirred at room temperature, a solution of 28.3 g of phenyl iodide in 70 ml of tetrahydrofuran is added dropwise thereto. A solution of 7.65 g of 2-benzenesulfonylamino-1-(4-benzyloxyphenyl)ethanone in 100 ml of tetrahydrofuran is added dropwise to the reaction mixture under ice-cooling and stirring. The mixture is stirred at room temperature, and an aqueous ammonium chloride solution is added thereto. The mixture is extracted with ethyl acetate, and the extract is washed, dried and evaporated to remove the solvent. The residue is purified by silica gel flash column chromatography (solvent; chloroform), and recrystallized from a mixture of ethyl acetate and n-hexane. 5.37 g of 2-benzenesulfonylamino-1-(4-benzyloxyphenyl)-1-phenylethanol are obtained as colorless crystals. m.p. 147.5°-149° C.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([N:24]2[CH:29]=[CH:28][C:27](=[O:30])[NH:26][C:25]2=[O:31])[CH:8]=[C:9]([C:13]2[CH:22]=[CH:21][C:20]3[C:15](=[CH:16][CH:17]=[C:18]([OH:23])[CH:19]=3)[CH:14]=2)[C:10]=1[O:11][CH3:12])([CH3:4])([CH3:3])[CH3:2].C(=O)([O-])[O-].[K+].[K+].[C:38]([F:55])([F:54])([O:43][C:44]([F:53])([F:52])[C:45]([S:48](F)(=[O:50])=[O:49])([F:47])[F:46])[C:39]([F:42])([F:41])[F:40]>CN(C)C=O>[F:47][C:45]([F:46])([S:48]([O:23][C:18]1[CH:17]=[CH:16][C:15]2[C:20](=[CH:21][CH:22]=[C:13]([C:9]3[CH:8]=[C:7]([N:24]4[CH:29]=[CH:28][C:27](=[O:30])[NH:26][C:25]4=[O:31])[CH:6]=[C:5]([C:1]([CH3:4])([CH3:2])[CH3:3])[C:10]=3[O:11][CH3:12])[CH:14]=2)[CH:19]=1)(=[O:50])=[O:49])[C:44]([F:52])([F:53])[O:43][C:38]([F:54])([F:55])[C:39]([F:42])([F:41])[F:40]
Reactant: COc1c(-c2ccc3cc(O)ccc3c2)cc(-n2ccc(=O)[nH]c2=O)cc1C(C)(C)C
Reactant: O=S(=O)(F)C(F)(F)C(F)(F)OC(F)(F)C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1c(-c2ccc3cc(OS(=O)(=O)C(F)(F)C(F)(F)OC(F)(F)C(F)(F)F)ccc3c2)cc(-n2ccc(=O)[nH]c2=O)cc1C(C)(C)C

Procedure:
To a stirred solution of 0.53 g of 1-(3-tert-butyl-5-(6-hydroxynaphthalen-2-yl)-4-methoxyphenyl)pyrimidine-2,4(1H,3H)-dione (1.27 mmol, 1.0 equivalent) in 5 mL of N,N-dimethylformamide was added 0.35 g of 325-mesh potassium carbonate (2.6 mmol, 2.0 equivalents). Perfluoro(2-ethoxyethane)sulfonyl fluoride (0.46 g, 1.4 mmol, 1.1 equivalents) was added in one portion, and the mixture was stirred for an hour. The inorganic solids were separated by filtration, and the flask and filter cake were rinsed with 1 mL of N,N-dimethylformamide followed by 2 mL of ethyl acetate. The solution was diluted with 30 mL of ethyl acetate and the resultant solution was washed twice with 20 mL portions of 10 wt % aqueous sodium chloride, followed by 20 mL of saturated aqueous sodium chloride solution. The washing procedure was repeated once. The organic solution was dried over sodium sulfate, the drying agent was filtered off and the organic solution was concentrated in vacuo. The resultant solid was purified by chromatography over silica gel with gradient elution (30% ethyl acetate/hexanes to 60% ethyl acetate/hexanes). The title compound was isolated as a white solid (0.76 g, 84% yield). 1H NMR (400 MHz, CDCl3) δ ppm 8.54 (d, J=1.7 Hz, 1H), 8.04 (s, 1H), 7.95 (d, J=9.4 Hz, 1H), 7.92 (d, J=10.1 Hz, 1H), 7.83 (dd, J=8.5, 1.7 Hz, 1H), 7.78 (d, J=2.4 Hz, 1H), 7.40 (dd, J=9.0, 2.5 Hz, 1H), 7.36 (d, J=7.9 Hz, 1H), 7.27-7.23 (m, 2H), 5.81 (dd, J=7.9, 2.4 Hz, 1H), 3.29 (s, 3H), 1.46 (s, 9H). 13C NMR (101 MHz, CDCl3) δ ppm 162.6 (C), 157.5 (C), 149.8 (C), 147.1 (C), 145.0 (C), 144.5 (CH), 137.2 (C), 135.1 (C), 133.0 (C), 132.2 (C), 132.2 (C), 130.5 (CH), 128.5 (CH), 128.1 (CH), 127.4 (CH), 127.2 (CH), 124.4 (CH), 119.9 (CH), 118.9 (CH), 102.4 (CH), 60.9 (CH3), 35.8 (C), 30.8 (CH3). 19F NMR (564 MHz, CDCl3) δ ppm −81.61 (2F), −86.42 (3F), −88.11 (2F), −112.90 (2F). LC-MS m/z 715.0 [M+H]+.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9](=[S:35])[NH:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]2[CH:25]=[C:24]3[C:20]([CH2:21][N:22]([C@@H:27]([CH:32]([CH3:34])[CH3:33])[C:28]([O:30][CH3:31])=[O:29])[C:23]3=[O:26])=[CH:19][CH:18]=2)=[CH:13][CH:12]=1.NC1C=CC(C2C=C3C(CN([C@@H](C(C)C)C(OC)=O)[C:49]3=[O:52])=CC=2)=CC=1.COC1C=CC=CC=1N=C=S>>[CH3:49][O:52][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9](=[S:35])[NH:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]2[CH:25]=[C:24]3[C:20]([CH2:21][N:22]([C@@H:27]([CH:32]([CH3:34])[CH3:33])[C:28]([O:30][CH3:31])=[O:29])[C:23]3=[O:26])=[CH:19][CH:18]=2)=[CH:13][CH:12]=1
Reactant: COC(=O)[C@H](C(C)C)N1Cc2ccc(-c3ccc(NC(=S)Nc4ccccc4F)cc3)cc2C1=O
Reactant: COC(=O)[C@H](C(C)C)N1Cc2ccc(-c3ccc(N)cc3)cc2C1=O
Agent: COc1ccccc1N=C=S
Product: COC(=O)[C@H](C(C)C)N1Cc2ccc(-c3ccc(NC(=S)Nc4ccccc4OC)cc3)cc2C1=O

Procedure:
The compound of example 73 was prepared analogous to compound of example 51 by reaction of compound of example 6 with 2-methoxyphenyl isothiocyanate. The compound of example 73 was used directly without isolation for the preparation of compound of example 74.
Reaction SMILES: [CH3:1][NH:2][CH2:3][C:4]1[CH:9]=[C:8]([C:10]2[O:11][CH:12]=[CH:13][N:14]=2)[CH:7]=[CH:6][C:5]=1[C:15]1[C:16]([S:21]([NH:24][C:25]2[O:29][N:28]=[C:27]([CH3:30])[C:26]=2[CH3:31])(=[O:23])=[O:22])=[CH:17][CH:18]=[CH:19][CH:20]=1.[Cl:32][C:33]1[CH:41]=[CH:40][CH:39]=[CH:38][C:34]=1[C:35](Cl)=[O:36].C(N(CC)CC)C>C(Cl)Cl>[Cl:32][C:33]1[CH:41]=[CH:40][CH:39]=[CH:38][C:34]=1[C:35]([N:2]([CH2:3][C:4]1[CH:9]=[C:8]([C:10]2[O:11][CH:12]=[CH:13][N:14]=2)[CH:7]=[CH:6][C:5]=1[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[S:21]([NH:24][C:25]1[O:29][N:28]=[C:27]([CH3:30])[C:26]=1[CH3:31])(=[O:22])=[O:23])[CH3:1])=[O:36]
Reactant: CNCc1cc(-c2ncco2)ccc1-c1ccccc1S(=O)(=O)Nc1onc(C)c1C
Reactant: O=C(Cl)c1ccccc1Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1noc(NS(=O)(=O)c2ccccc2-c2ccc(-c3ncco3)cc2CN(C)C(=O)c2ccccc2Cl)c1C
Temperature: 25 °C
Reaction time: 12 h
Yield: 25.7 %

Procedure:
To a solution of 0.12 g (0.29 mmol) of 2'-[(methylamino)methyl]-N-(3,4-dimethyl-5-isoxazolyl)-4'-(2-oxazolyl)[1,1'-biphenyl]-2-sulfonamide (prepared as described in Step (A) of Example 28) in 5 mL of CH2Cl2, 0.061 g (0.348 mmol) of 2-chlorobenzoyl chloride and 0.065 g (0.638 mmol) of triethylamine were added. The mixture was then stirred at room temperature for 12 hr and evaporated. The residue was purified by reverse phase preparative HPLC on a 30×500 mm ODS S10 column using 72% solvent B (90% MeOH, 10% H2O, 0.1% TFA) and 28% solvent A (10% MeOH, 90% H2O, 0.1% TFA). The appropriate fractions were collected and neutralized with aqueous sodium bicarbonate to pH 7 and concentrated to 10 mL. The solution was then acidified to pH 4 using aqueous sodium bisulfate and the white solid was filtered and dried to provide 0.043 g (26%) of the title compound of this Example as a white solid.
Reaction SMILES: [OH-:1].[K+].[CH2:3]([N:10]1[CH2:33][CH2:32][C:13]2([N:17]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[C:16](=[O:24])[NH:15][C:14]2=NC2CCCCC2)[CH2:12][CH2:11]1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1>C(O)CO>[CH2:3]([N:10]1[CH2:11][CH2:12][C:13]2([N:17]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[C:16](=[O:24])[NH:15][C:14]2=[O:1])[CH2:32][CH2:33]1)[C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: [OH-]
Reactant: O=C1NC(=NC2CCCCC2)C2(CCN(Cc3ccccc3)CC2)N1c1ccccc1
Agent: [K+]
Solvent: OCCO
Product: O=C1NC(=O)C2(CCN(Cc3ccccc3)CC2)N1c1ccccc1
Temperature: 50 °C
Yield: 69.9 %

Procedure:
Potassium hydroxide (50.4 g, 0.9 mol) was added to 300 mL of ethylene glycol followed by 8-benzyl-4-cyclohexylimino-1-phenyl-1,3,8-triazaspiro[4,5]decane-2-one (37.7 g, 0.11 mol) from Step A. The reaction mixture was heated slowly to a gentle reflux and 100 mL of solvent was removed by distillation over a 4.5 hour period. The reaction mixture was then cooled in ice to 50° C. and poured into water (500 mL). The aqueous solution was adjusted to approximately pH 8-9 by adding concentrated hydrochloric acid while cooling in ice. The precipitate was filtered and washed with water to give 25.8 g of solid. The solid was crystallized from boiling chloroform to give 19.45 g of the title compound, m.p. 159°-160° C.
Reaction SMILES: [CH3:1][C:2]1([CH3:10])[CH2:8][CH2:7][C:6](=[O:9])[O:5][C:3]1=[O:4].[OH:11][CH2:12][C:13]1[CH:20]=[CH:19][C:16]([O:17][CH3:18])=[CH:15][CH:14]=1.C(N(CC)CC)C>O1CCOCC1>[C:3]([C:2]([CH3:10])([CH3:1])[CH2:8][CH2:7][C:6]([O:11][CH2:12][C:13]1[CH:20]=[CH:19][C:16]([O:17][CH3:18])=[CH:15][CH:14]=1)=[O:9])([OH:5])=[O:4]
Reactant: CC1(C)CCC(=O)OC1=O
Reactant: COc1ccc(CO)cc1
Solvent: C1COCCO1
Solvent: CCN(CC)CC
Product: COc1ccc(COC(=O)CCC(C)(C)C(=O)O)cc1
Temperature: 80 °C
Reaction time: 3.5 h

Procedure:
A mixture of 2,2-dimethylglutaric anhydride (19.34 g), anise alcohol (22.08 g) and triethylamine (19.39 g) in dry dioxane (360 ml) was stirred at 80° C. for 3.5 hours. The reaction mixture was evaporated and the residue was diluted with water and adjusted to pH 9 with potassium carbonate. The aqueous layer was washed with benzene, acidified with dilute hydrochloric acid and extracted with benzene. The extract was washed with water, dried over anhydrous sodium sulfate and evaporated to give p-methoxybenzyl 4-carboxy-4-methylvalerate.
Reaction SMILES: [Cl:1][C:2]([Cl:20])([Cl:19])[CH2:3][C:4]([C:12]1[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=1)([OH:11])[CH2:5][N:6]1[CH:10]=[N:9][CH:8]=[N:7]1.[C:21](OC(=O)C)(=[O:23])[CH3:22]>C1C=CC=CC=1.CN(C)C1C=CN=CC=1>[C:21]([O:11][C:4]([C:12]1[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=1)([CH2:5][N:6]1[CH:10]=[N:9][CH:8]=[N:7]1)[CH2:3][C:2]([Cl:19])([Cl:1])[Cl:20])(=[O:23])[CH3:22]
Reactant: OC(Cn1cncn1)(CC(Cl)(Cl)Cl)c1ccc(Cl)cc1
Reactant: CC(=O)OC(C)=O
Agent: CN(C)c1ccncc1
Solvent: c1ccccc1
Product: CC(=O)OC(Cn1cncn1)(CC(Cl)(Cl)Cl)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 30 h

Procedure:
Five (5) g (0.0141 mol) of 4,4,4-trichloro-2-(4-chlorophenyl)-2-hydroxy-(1,2,4-(1H)-triazolyl)butane (prepared as in Example I) was slurried in 75 mls of benzene, 4.31 g (0.0422 mol) of acetic anhydride and 2.6 g (0.0211 mol) of 4-dimethylaminopyridine. This mixture was stirred at room temperature for 30 hours and then diluted with 75 mls of benzene. The mixture was washed thrice with 100 mL portions of water. Evaporation of the solvent under reduced pressure and purification of the residue by preparative high pressure liquid chromatography (HPLC) in a 1:1 mixture of ethyl acetate and hexane gave the desired product as a white solid in a yield of 2.2 g (39 percent of theoretical) melting at 112°-114° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:10]=[CH:11][CH:12]=1)/[CH:5]=[CH:6]/[C:7](O)=[O:8].S(Cl)([Cl:15])=O>C1C=CC=CC=1>[Br:1][C:2]1[CH:3]=[C:4]([CH:10]=[CH:11][CH:12]=1)/[CH:5]=[CH:6]/[C:7]([Cl:15])=[O:8]
Reactant: O=S(Cl)Cl
Reactant: O=C(O)/C=C/c1cccc(Br)c1
Solvent: c1ccccc1
Product: O=C(Cl)/C=C/c1cccc(Br)c1
Yield: 99.8 %

Procedure:
Trans m-bromocinnamic acid (11.4 g) in dry benzene (75 ml) was heated to reflux and then a mixture of thionyl chloride (12 g) in dry benzene (50 ml) was added at such a rate as to maintain constant reflux. The reaction mixture was heated at reflux for an additional 2 hr after the addition of thionyl chloride. The solvent and excess thionyl chloride were then removed under reduced pressure to give trans 3-bromocinnamoyl chloride (ca. 12.3 g). A solution of the 3-bromocinnamoyl chloride in toluene (150 ml) was added dropwise with stirring to a solution of isopropylamine (10 g) in ether (200 ml). The reaction mixture was stirred at room temperature for one hour and then heated at reflux for one hour. The solvent and excess amine were removed under reduced pressure. The crude residue was triturated with water, filtered, and recrystallized from ethanol-water to give white, crystalline trans 3-bromo-N-isopropylcinnamamide, m.p. 85°-86° C. Elemental analysis, NMR and IR spectra all confirmed the identity of the product.