Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[C:4]([C:12]2[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][CH:13]=2)[N:3]=1.[Br:22][C:23]1[CH:24]=[N:25][NH:26][CH:27]=1>>[Br:22][C:23]1[CH:24]=[N:25][N:26]([C:2]2[N:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[C:4]([C:12]3[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][CH:13]=3)[N:3]=2)[CH:27]=1
Reactant: FC(F)(F)c1ccc(-c2cc(C(F)(F)F)nc(Cl)n2)cc1
Reactant: Brc1cn[nH]c1
Product: FC(F)(F)c1ccc(-c2cc(C(F)(F)F)nc(-n3cc(Br)cn3)n2)cc1

Procedure:
The title compound was prepared from 2-chloro-4-trifluoromethyl-6-(4-trifluoromethylphenyl)-pyrimidine (example A.2) (0.98 g, 3.0 mmol) and commercially available 4-bromopyrazole (0.66 g, 4.50 mmol) according to the general procedure IVa. Obtained as a white solid (0.83 g, 59%). MS (ISP) 437.0 [(M+H)+]; mp 175.5° C.
Reaction SMILES: [CH2:1]([CH:4]([C:8]1[CH:13]=[C:12]([C:14]([F:17])([F:16])[F:15])[CH:11]=[C:10]([C:18]([F:21])([F:20])[F:19])[CH:9]=1)[C:5](O)=[O:6])[CH:2]=[CH2:3].Cl.[O:23]=[C:24]1[CH2:29][CH2:28][C:27]([NH2:36])([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[CH2:26][CH2:25]1>>[O:23]=[C:24]1[CH2:25][CH2:26][C:27]([NH:36][C:5](=[O:6])[CH:4]([CH2:1][CH:2]=[CH2:3])[C:8]2[CH:13]=[C:12]([C:14]([F:15])([F:17])[F:16])[CH:11]=[C:10]([C:18]([F:21])([F:20])[F:19])[CH:9]=2)([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[CH2:28][CH2:29]1
Reactant: C=CCC(C(=O)O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reactant: NC1(c2ccccc2)CCC(=O)CC1
Agent: Cl
Product: C=CCC(C(=O)NC1(c2ccccc2)CCC(=O)CC1)c1cc(C(F)(F)F)cc(C(F)(F)F)c1

Procedure:
Prepared from (RS)-α-(2-propenyl)-3,5-bis(trifluoromethyl)benzeneacetic acid (Description 35) and 4-oxo-1-phenylcyclohexylamine hydrochloride (Description 18) according to the method of Example 1. 1H NMR (400 MHz, CDCl3) δ 7.80 (1H, s), 7.73 (2H, s), 7.35–7.2 (5H, m), 5.80 (1H, br s), 5.75–5.63 (1H, m), 5.13–5.05 (2H, m), 3.56 (1H, dd, J 7, 6 Hz), 2.90–2.80 (2H, m), 2.65–2.55 (1H, m), and 2.52–2.30 (7H, m).
Reaction SMILES: [H-].[Na+].[CH3:3][O:4][C:5](=[O:17])[CH2:6][C:7]1[C:15]2[C:10](=[N:11][CH:12]=[CH:13][CH:14]=2)[NH:9][C:8]=1[CH3:16].[F:18][C:19]1[CH:24]=[CH:23][C:22]([S:25](Cl)(=[O:27])=[O:26])=[CH:21][C:20]=1[O:29][CH3:30]>C1COCC1>[CH3:3][O:4][C:5](=[O:17])[CH2:6][C:7]1[C:15]2[C:10](=[N:11][CH:12]=[CH:13][CH:14]=2)[N:9]([S:25]([C:22]2[CH:23]=[CH:24][C:19]([F:18])=[C:20]([O:29][CH3:30])[CH:21]=2)(=[O:26])=[O:27])[C:8]=1[CH3:16]
Reactant: COC(=O)Cc1c(C)[nH]c2ncccc12
Reactant: COc1cc(S(=O)(=O)Cl)ccc1F
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COC(=O)Cc1c(C)n(S(=O)(=O)c2ccc(F)c(OC)c2)c2ncccc12
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a stirred, ice-cooled (0° C.). solution of sodium hydride (0.026 g of a 60% dispersion in mineral oil, 0.686 mmol) in THF (3 ml) under an inert atmosphere of Argon is added dropwise (2-methyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-acetic acid methyl ester ((0.1 g, 0.49 mmol) in dry THF (3 ml). The reaction mixture is stirred at 0° C. for 1 hour and then treated with 4-fluoro-3-methoxy-benzenesulfonyl chloride (0.154 g, 0.686 mmol) in dry THF (3 ml). Stirring continued at 0° C. for 30 minutes and then the reaction mixture is poured onto water (100 ml) and extracted with ethyl acetate (3×50 ml). The organic portions are separated and washed with water (2×50 ml), brine (50 ml), dried (MgSO4) and concentrated in vacuo. The resulting crude is purified by chromatography on silica eluting with iso-hexane/ethyl acetate (0%-20% ethyl acetate) yields the titled product. (MH+ 392).
Reaction SMILES: Cl[CH2:2][C:3]1[N:4]([CH:8]([CH3:10])[CH3:9])[CH:5]=[CH:6][N:7]=1.[CH3:11][C:12]1[N:17]=[C:16]([SH:18])[N:15]=[C:14]([OH:19])[CH:13]=1>>[CH3:11][C:12]1[N:17]=[C:16]([S:18][CH2:2][C:3]2[N:4]([CH:8]([CH3:10])[CH3:9])[CH:5]=[CH:6][N:7]=2)[N:15]=[C:14]([OH:19])[CH:13]=1
Reactant: Cc1cc(O)nc(S)n1
Reactant: CC(C)n1ccnc1CCl
Product: Cc1cc(O)nc(SCc2nccn2C(C)C)n1
Yield: 72 %

Procedure:
This example was synthesized from 2-(chloromethyl)-1-(propan-2-yl)-1H-imidazole and 6-methyl-2-sulfanylpyrimidin-4-ol following the general procedure as shown in the last step of Example 109. This provided the title compound as a pale white solid (1.0 g, 72% yield); 1H NMR (400 MHz, DMSO-d6): δ 1.33 (m, 6H), 2.18 (s, 3H), 4.52 (s, 2H), 4.54 (m, 1H), 4.54 (m, 1H), 6.00 (br, 1H), 6.83 (s, 1H), 7.26 (s, 1H); M+ 265.
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[C:6]([C:9](=[O:14])[C:10](=[CH2:13])[CH2:11][CH3:12])[CH:5]=[CH:4][C:3]=1[OH:15].C(=O)([O-])[O-].[K+].[K+].Br[CH:23]([CH3:29])[C:24]([O:26][CH2:27][CH3:28])=[O:25].O>CN(C)C=O>[Cl:1][C:2]1[C:7]([Cl:8])=[C:6]([C:9](=[O:14])[C:10](=[CH2:13])[CH2:11][CH3:12])[CH:5]=[CH:4][C:3]=1[O:15][CH:23]([CH3:29])[C:24]([O:26][CH2:27][CH3:28])=[O:25]
Reactant: CCOC(=O)C(C)Br
Reactant: C=C(CC)C(=O)c1ccc(O)c(Cl)c1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: C=C(CC)C(=O)c1ccc(OC(C)C(=O)OCC)c(Cl)c1Cl

Procedure:
To a solution of 2,3-dichloro-4-(2-methylenebutyryl)-phenol (4.90 g., 0.02 mole) in dimethylformamide (20 ml.) is added potassium carbonate (6.08 g., 0.044 mole) and ethyl 2-bromopropionate (7.97 g., 0.044 mole). The reaction mixture is heated at 55°-60° C. for one hour with stirring. The reaction mixture is cooled. Water (50 ml.) is added and the resulting oil is extracted with ether (3 × 100 ml.). The combined ether extracts are dried over anhydrous magnesium sulfate, filtered and the ether is evaporated under reduced pressure to afford ethyl 2-[2,3-dichloro-4-(2-methylenebutyryl)phenoxy]propionate. The ester is dissolved in ethanol (75 ml.) and treated with a solution of sodium bicarbonate (5.04 g., 0.06 mole) in water (150 ml.). The mixture is heated on a steam bath with stirring for 5 hours and then concentrated under reduced pressure to a volume of 50 ml. Water (50 ml.) is added and the solution is acidified to a pH of 4 with hydrochloric acid (6N). The resulting oil is extracted with ether (3 × 100 ml.) and the combined extracts are dried over anhydrous magnesium sulfate. The ether is evaporated under reduced pressure to afford 6.34 g. (100%) of a white, waxy solid. Recrystallization from cyclohexane affords 5 g. (79%) of crude product, m.p. 115°-119° C. Further purification by recrystallization from butyl chloride affords substantially pure 2-[2,3-dichloro-4-(2-methylenebutyryl)phenoxy]propionic acid, m.p., 122.5°-123.5° C.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([CH:10]=[C:11]([C:14]([CH3:17])([CH3:16])[CH3:15])[C:12]=1[OH:13])[CH2:8]Br)([CH3:4])([CH3:3])[CH3:2].[CH:18]1([P:24]([CH:27]2[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]2)([SH:26])=[S:25])[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]1>>[CH:18]1([P:24]([CH:27]2[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]2)([S:26][CH2:8][C:7]2[CH:6]=[C:5]([C:1]([CH3:4])([CH3:3])[CH3:2])[C:12]([OH:13])=[C:11]([C:14]([CH3:17])([CH3:16])[CH3:15])[CH:10]=2)=[S:25])[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23]1
Reactant: CC(C)(C)c1cc(CBr)cc(C(C)(C)C)c1O
Reactant: S=P(S)(C1CCCCC1)C1CCCCC1
Product: CC(C)(C)c1cc(CSP(=S)(C2CCCCC2)C2CCCCC2)cc(C(C)(C)C)c1O

Procedure:
3,5-di-t-butyl-4-hydroxybenzyl bromide was reacted with the ammonium salt of dicyclohexylphosphinodithioic acid to obtain 3,5-di-t-butyl-4-hydroxybenzyl dicyclohexylphosphinodithioate, m.p. 129°-131° C, which on testing lasted 475 hours* longer than the control. The total number of hours required to reach failure was 1.9 times that of the control.
Reaction SMILES: [C:1]1([CH:7]([O:14][C:15]([CH:17]2[N:22]3[C:23](=[O:26])[C@@H:24]([NH2:25])[C@H:21]3[S:20][CH2:19][CH:18]2OC(=O)C)=[O:16])[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N(CC)CC)C>ClCCl>[C:1]1([CH:7]([O:14][C:15]([C:17]2[N:22]3[C:23](=[O:26])[CH:24]([NH2:25])[C@H:21]3[S:20][CH2:19][CH:18]=2)=[O:16])[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CC(=O)OC1CS[C@@H]2[C@H](N)C(=O)N2C1C(=O)OC(c1ccccc1)c1ccccc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: NC1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=CCS[C@H]12
Temperature: 0 °C
Reaction time: 8 h
Yield: 61 %

Procedure:
To a solution of 3-acetoxy-7beta-aminocepham-4-carboxylic acid diphenylmethyl ester (4a) in dichloromethane cooling at -25° to -20° C. is added triethylamine (1 to 3 equivalents). The mixture is warmed slowly up to 0° to 5° C. and let stand overnight. To this is added ice-water (20 parts), stirred for 20 minutes, and extracted with dichloromethane. The extract is washed with hydrochloric acid, water, aqueous 7% sodium hydrogen carbonate, and aqueous 5% sodium chloride, dried, and concentrated. The residue is crystallized from ethyl acetate to give 7beta-amino-3-cephem-4-carboxylic acid diphenylmethyl ester (5). Yield 61.0% from (1). mp. 159°-160° C. (decomposition).
Reaction SMILES: [N:1]([C:4]1[CH:12]=[CH:11][C:7]2[O:8][CH2:9][O:10][C:6]=2[CH:5]=1)=[C:2]=[O:3].[NH2:13][CH:14]([CH2:22][NH:23][C:24]1[C:29]([CH2:30][CH3:31])=[C:28]([N:32]2[CH2:37][CH2:36][CH:35]([C:38]3[CH:47]=[CH:46][C:45]4[CH2:44][CH2:43][CH2:42][NH:41][C:40]=4[N:39]=3)[CH2:34][CH2:33]2)[N:27]=[CH:26][N:25]=1)[C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16]>O1CCCC1>[O:8]1[C:7]2[CH:11]=[CH:12][C:4]([NH:1][C:2](=[O:3])[NH:13][CH:14]([CH2:22][NH:23][C:24]3[C:29]([CH2:30][CH3:31])=[C:28]([N:32]4[CH2:33][CH2:34][CH:35]([C:38]5[CH:47]=[CH:46][C:45]6[CH2:44][CH2:43][CH2:42][NH:41][C:40]=6[N:39]=5)[CH2:36][CH2:37]4)[N:27]=[CH:26][N:25]=3)[C:15]([O:17][C:18]([CH3:19])([CH3:21])[CH3:20])=[O:16])=[CH:5][C:6]=2[O:10][CH2:9]1
Reactant: CCc1c(NCC(N)C(=O)OC(C)(C)C)ncnc1N1CCC(c2ccc3c(n2)NCCC3)CC1
Reactant: O=C=Nc1ccc2c(c1)OCO2
Solvent: C1CCOC1
Product: CCc1c(NCC(NC(=O)Nc2ccc3c(c2)OCO3)C(=O)OC(C)(C)C)ncnc1N1CCC(c2ccc3c(n2)NCCC3)CC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 45 %

Procedure:
34 mg (0.207 mmoles) of 5-isocyanato-benzo[1,3]dioxole in solution in 3 ml of tetrahydrofuran is added to 120 mg (0.207 mmoles) of tert-butyl 2-amino-3-{5-ethyl-6-[4-(5,6,7,8-tetrahydro-[1,8]naphthyridin-2-yl)-piperidin-1-yl]-pyrimidin-4-ylamino}-propionate in solution in 5 ml of tetrahydrofuran. The reaction mixture is stirred at ambient temperature for 3 hours and 30 minutes. Then, the solvent is evaporated off under reduced pressure (2 kPa) and the residue is chromatographed on silica gel with the following eluent: 100% ethyl acetate, ethyl acetate-dichloromethane/methanol (95/5) 50-50, ethyl acetate-dichloromethane/methanol (90-10) 50-50 and finishing with ethyl acetate/methanol (95-5). 60 mg of expected product is obtained.
Reaction SMILES: Cl[CH2:2][C:3]1[CH:22]=[CH:21][CH:20]=[CH:19][C:4]=1[O:5][CH2:6][C:7]1[N:8]=[C:9]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[O:10][C:11]=1[CH3:12].[CH2:23]([O:25][C:26]1[CH:31]=[CH:30][C:29]([OH:32])=[CH:28][C:27]=1[CH2:33][CH2:34][C:35]([O:37]CC)=[O:36])[CH3:24].C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[CH2:23]([O:25][C:26]1[CH:31]=[CH:30][C:29]([O:32][CH2:2][C:3]2[CH:22]=[CH:21][CH:20]=[CH:19][C:4]=2[O:5][CH2:6][C:7]2[N:8]=[C:9]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[O:10][C:11]=2[CH3:12])=[CH:28][C:27]=1[CH2:33][CH2:34][C:35]([OH:37])=[O:36])[CH3:24]
Reactant: Cc1oc(-c2ccccc2)nc1COc1ccccc1CCl
Reactant: CCOC(=O)CCc1cc(O)ccc1OCC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOc1ccc(OCc2ccccc2OCc2nc(-c3ccccc3)oc2C)cc1CCC(=O)O
Temperature: 80 °C
Reaction time: 5 h
Yield: 94.6 %

Procedure:
A mixture of 4-(2-chloromethylphenoxymethyl)-5-methyl-2-phenyloxazole (0.65 g), ethyl 3-(2-ethoxy-5-hydroxyphenyl)propionate (0.46 g), anhydrous potassium carbonate (0.30 g) and N,N-dimethylformamide (10 mL) was stirred at 80° C. for 5 hrs. The reaction mixture was poured into water and extracted with ethyl acetate. The organic layer was washed successively with dilute hydrochloric acid and saturated brine, dried over anhydrous magnesium sulfate and concentrated. The obtained residue was subjected to silica gel column chromatography to give an oil from a fraction eluted with ethyl acetate-hexane (1:4, v/v). To a mixture of the obtained oil, tetrahydrofuran (5 mL) and ethanol (5 mL) was added a 1N aqueous sodium hydroxide solution (5 mL) and the mixture was stirred at room temperature for 2 hrs. The reaction mixture was concentrated, and dilute hydrochloric acid was added to acidify the residue. The precipitated solid was collected by filtration and dried with air to give crystals (0.89 g, 95%) of 3-[2-ethoxy-5-[2-[(5-methyl-2-phenyl-4-oxazolyl)methoxy]benzyloxy]phenyl]propionic acid. Recrystallization from acetone-hexane gave colorless prism crystals. melting point: 146-147° C.
Reaction SMILES: [C:1]([C:3]1[CH:23]=[CH:22][C:6]2[O:7][C:8]([CH3:21])([CH3:20])[CH:9]=[C:10]([N:11]3[CH:16]=[CH:15][C:14]([CH:17]=[O:18])=[CH:13][C:12]3=[O:19])[C:5]=2[CH:4]=1)#[N:2].[Mg].Br[CH2:26][CH2:27][CH2:28][O:29][CH2:30][C:31]1[CH:36]=[CH:35][C:34]([O:37][CH3:38])=[CH:33][CH:32]=1.[Cl-].[NH4+]>O1CCCC1>[C:1]([C:3]1[CH:23]=[CH:22][C:6]2[O:7][C:8]([CH3:20])([CH3:21])[CH:9]=[C:10]([N:11]3[CH:16]=[CH:15][C:14]([CH:17]([OH:18])[CH2:26][CH2:27][CH2:28][O:29][CH2:30][C:31]4[CH:32]=[CH:33][C:34]([O:37][CH3:38])=[CH:35][CH:36]=4)=[CH:13][C:12]3=[O:19])[C:5]=2[CH:4]=1)#[N:2]
Reactant: CC1(C)C=C(n2ccc(C=O)cc2=O)c2cc(C#N)ccc2O1
Reactant: COc1ccc(COCCCBr)cc1
Agent: [Cl-]
Agent: [Mg]
Agent: [NH4+]
Solvent: C1CCOC1
Product: COc1ccc(COCCCC(O)c2ccn(C3=CC(C)(C)Oc4ccc(C#N)cc43)c(=O)c2)cc1
Reaction time: 1 h
Yield: 58.8 %

Procedure:
Forty milliliters of an anhydrous tetrahydrofuran solution containing 1.53 g of 6-cyano-2,2-dimethyl-4-(1,2-dihydro-2-oxo-4-formyl-1-pyridinyl)-2H-benzo[b]pyran, obtained in Example 25, is added at 0° C. to a Grignard reagent solution prepared from 0.19 g of magnesium and 1.94 g of 1-bromo-3-p-methoxybenzyloxy propane in 5 ml anhydrous tetrahydrofuran, and the resulting mixture is reacted first at that temperature for 10 minutes and then at room temperature for one hour. After stopping the reaction by adding a saturated aqueous solution of ammonium chloride, the reaction mixture is extracted with ethyl acetate. The organic layer is washed with saturated aqueous solution of sodium chloride and dried over anhydrous sodium sulfate. The inorganic matter is filtered off and the filtrate is concentrated under reduced pressure. The residue is purified by silica gel column chromatography using 1/1 mixture of ethyl acetate/methylene chloride as a developing solvent. Thus, 1.43 g of 6-cyano-2,2-dimethyl-4-{1,2-dihydro-2-oxo-4-(1-hydroxy-4 -p-methoxybenzyloxybutyl)-1-pyridinyl}-2H-benzo[b]pyran is obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([O:10][C:11]2[C:12](=[O:21])[NH:13][CH:14]=[CH:15][C:16]=2[C:17]([F:20])([F:19])[F:18])[CH:9]=1)[C:5]#[N:6].C(=O)([O-])[O-].[K+].[K+].[NH2:28][S:29]([C:32]1[CH:37]=[CH:36][C:35]([NH:38][C:39](=[O:42])[CH2:40]Br)=[C:34]([Cl:43])[CH:33]=1)(=[O:31])=[O:30]>CN(C)C=O.C(OCC)(=O)C>[NH2:28][S:29]([C:32]1[CH:37]=[CH:36][C:35]([NH:38][C:39](=[O:42])[CH2:40][N:13]2[CH:14]=[CH:15][C:16]([C:17]([F:18])([F:19])[F:20])=[C:11]([O:10][C:8]3[CH:7]=[C:4]([C:5]#[N:6])[CH:3]=[C:2]([Cl:1])[CH:9]=3)[C:12]2=[O:21])=[C:34]([Cl:43])[CH:33]=1)(=[O:31])=[O:30]
Reactant: NS(=O)(=O)c1ccc(NC(=O)CBr)c(Cl)c1
Reactant: N#Cc1cc(Cl)cc(Oc2c(C(F)(F)F)cc[nH]c2=O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: N#Cc1cc(Cl)cc(Oc2c(C(F)(F)F)ccn(CC(=O)Nc3ccc(S(N)(=O)=O)cc3Cl)c2=O)c1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To 3-chloro-5-{[2-oxo-4-(trifluoromethyl)-1,2-dihydropyridin-3-yl]oxy}benzonitrile (3C, 0.050 g, 0.159 mmol) and potassium carbonate (0.022 g, 0.159 mmol) suspended in dimethylformamide (1 mL) was added N-[4-(aminosulfonyl)-2-chlorophenyl]-2-bromoacetamide (0.052 g, 0.149 mmol) as a solution in dimethylformamide (1 mL). The reaction mixture was allowed to stir at room temperature. After 16 hours, the reaction mixture was diluted with ethyl acetate (20 mL), washed with water (3×10 mL), dried (MgSO4), filtered and the solvent was evaporated under reduced pressure. The resulting residue was purified by column chromatography on a pre-packed silica gel Redi Sep 12 gram column, eluting with 0-5% methanol in CH2Cl2 to yield the title compound. 1H NMR (DMSO-d6) δ 10.23 (s, 1H), 8.05-7.96 (m, 2H), 7.89 (d, J=2.1 Hz, 1H), 7.76-7.72 (m, 2H), 7.55-7.53 (m, 1H), 7.52-7.50 (m, 1H), 7.45 (s, 2H), 6.68 (d, 0.1=7.1 Hz, 1H), 5.02 (s, 2H). HRMS (M+1)=560.998.
Reaction SMILES: N12CCN(CC1)CC2.[CH2:9]([N:11]=[C:12]=[S:13])[CH3:10].[F:14][C:15]1[CH:31]=[CH:30][C:18]([O:19][C:20]2[CH:29]=[CH:28][C:23]([O:24][CH2:25][CH2:26][OH:27])=[CH:22][CH:21]=2)=[CH:17][CH:16]=1>N1C=CC=CC=1>[F:14][C:15]1[CH:31]=[CH:30][C:18]([O:19][C:20]2[CH:29]=[CH:28][C:23]([O:24][CH2:25][CH2:26][O:27][C:12](=[S:13])[NH:11][CH2:9][CH3:10])=[CH:22][CH:21]=2)=[CH:17][CH:16]=1
Reactant: CCN=C=S
Reactant: OCCOc1ccc(Oc2ccc(F)cc2)cc1
Agent: C1CN2CCN1CC2
Solvent: c1ccncc1
Product: CCNC(=S)OCCOc1ccc(Oc2ccc(F)cc2)cc1
Temperature: 80 °C
Reaction time: 16 h

Procedure:
50 mg of 1,4-diazabicyclo(2,2,2)octane and 0.9 g of ethyl isothiocyanate are added to a solution of 2.3 g of 2-[p-(p-fluorophenoxy)phenoxy]-ethanol in 10 ml of pyridine. The mixture is then allowed to stir at 80° C. for 16 hours. The cooled mixture is poured into 50 ml of ice/water and extracted three times with 80 ml of ethyl acetate each time. The extracts are washed twice with 50 ml of water each time and with 50 ml of sodium chloride solution. The extracts are dried over anhydrous sodium sulfate and evaporated. The residue is purified chromatography on silica gel with n-hexane/ethyl acetate (2:1) to yield pure [2-[p-(p-fluorophenoxy)phenoxy]-ethyl]N-ethylthiocarbamate; m.p. 73°-75° C.
Reaction SMILES: [CH2:1]([NH:8][CH2:9][P:10](=[O:17])([O:14][CH2:15][CH3:16])[O:11][CH2:12][CH3:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CCN(C(C)C)C(C)C.Br[CH2:28][C:29]([O:31][CH2:32][CH3:33])=[O:30]>C(#N)C>[CH2:1]([N:8]([CH2:9][P:10]([O:14][CH2:15][CH3:16])([O:11][CH2:12][CH3:13])=[O:17])[CH2:28][C:29]([O:31][CH2:32][CH3:33])=[O:30])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)CBr
Reactant: CCOP(=O)(CNCc1ccccc1)OCC
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)CN(Cc1ccccc1)CP(=O)(OCC)OCC
Temperature: 25 °C

Procedure:
Into a 500-mL 3-necked round-bottom flask, was placed a solution of diethyl (benzylamino)methylphosphonate (intermediate 5.2) (12 g, 46.69 mmol, 1.00 equiv) in acetonitrile (150 mL), DIEA (12 g, 2.00 equiv). This was followed by the addition of ethyl 2-bromoacetate (8.4 g, 50.30 mmol, 1.10 equiv) dropwise with stirring. The mixture was stirred for 30 min at room temperature. The resulting solution was heated to reflux for 6 hr. The resulting mixture was cooled to room temperature and concentrated under vacuum. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (1:20 to 1:5). This resulted in 8.0 g (50%) of ethyl 2-(benzyl((diethoxyphosphoryl)methyl)amino)acetate as yellow oil.
Reaction SMILES: [Cl:1][CH2:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([O:11][CH3:12])=[CH:7][CH:6]=1)=[O:4].[ClH:13].Cl.[CH2:15]([N:24]1[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]1)[C:16]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=[O:17].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[ClH:1].[ClH:13].[CH2:15]([N:24]1[CH2:29][CH2:28][N:27]([CH2:2][C:3]([C:5]2[CH:10]=[CH:9][C:8]([O:11][CH3:12])=[CH:7][CH:6]=2)=[O:4])[CH2:26][CH2:25]1)[C:16]([C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1)=[O:17]
Reactant: COc1ccc(C(=O)CCl)cc1
Reactant: O=C(CN1CCNCC1)c1ccccc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1ccc(C(=O)CN2CCN(CC(=O)c3ccccc3)CC2)cc1

Procedure:
A mixture of 2-chloro-1-(4-methoxyphenyl)ethanone (3 mmol), N-phenacyl piperazine dihydrochloride (3 mmol) and K2CO3 (10 mmol) in 30 ml of DMF was treated according to the general preparation 2 to give compound (IV-9), 0.68 g (62%), mp 226-228° C., M+ 352.
Reaction SMILES: [CH2:1]([N:5]([S:32]([C:35]1[CH:40]=[CH:39][C:38]([CH3:41])=[CH:37][CH:36]=1)(=[O:34])=[O:33])[C@H:6]([C:29]([OH:31])=[O:30])[CH2:7][CH2:8][CH2:9][CH2:10][NH:11][C:12](OCC1C2C=CC=CC=2C2C1=CC=CC=2)=[O:13])[CH:2]([CH3:4])[CH3:3].[CH3:42][C:43]1[CH:48]=[CH:47][C:46]([S:49]([NH:52][C@H:53](C(O)=O)[CH2:54][OH:55])(=[O:51])=[O:50])=[CH:45][CH:44]=1>>[CH3:42][C:43]1[CH:48]=[CH:47][C:46]([S:49]([NH:52][C@H:53]([C:12]([NH:11][CH2:10][CH2:9][CH2:8][CH2:7][C@H:6]([N:5]([S:32]([C:35]2[CH:40]=[CH:39][C:38]([CH3:41])=[CH:37][CH:36]=2)(=[O:34])=[O:33])[CH2:1][CH:2]([CH3:4])[CH3:3])[C:29]([OH:31])=[O:30])=[O:13])[CH2:54][OH:55])(=[O:51])=[O:50])=[CH:45][CH:44]=1
Reactant: Cc1ccc(S(=O)(=O)N[C@@H](CO)C(=O)O)cc1
Reactant: Cc1ccc(S(=O)(=O)N(CC(C)C)[C@@H](CCCCNC(=O)OCC2c3ccccc3-c3ccccc32)C(=O)O)cc1
Product: Cc1ccc(S(=O)(=O)N[C@@H](CO)C(=O)NCCCC[C@@H](C(=O)O)N(CC(C)C)S(=O)(=O)c2ccc(C)cc2)cc1

Procedure:
The title compound was prepared from solid phase bound Nα-isobutyl-Nα-(4-methylbenzenesulfonyl)-Nε-(9-fluorenylmethoxycarbonyl)-L-lysine as described in general procedure Bb using Nα-(4-methylbenzenesulfonyl)-L-serine (150 mg, 1.2 mmol) prepared in step A of this example. The final product was purified by preparative HPLC to yield 35 mg (46%) of the desired material.
Reaction SMILES: [F:1][C:2]1[CH:16]=[CH:15][C:5]2[C:6]([CH:9]3[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]3)=[N:7][O:8][C:4]=2[CH:3]=1>C(O)(C)C>[F:1][C:2]1[CH:16]=[CH:15][C:5]2[C:6]([CH:9]3[CH2:10][CH2:11][N:12]([CH2:5][CH:4]([OH:8])[CH2:3][CH3:2])[CH2:13][CH2:14]3)=[N:7][O:8][C:4]=2[CH:3]=1
Reactant: Fc1ccc2c(C3CCNCC3)noc2c1
Solvent: CC(C)O
Product: CCC(O)CN1CCC(c2noc3cc(F)ccc23)CC1
Temperature: 65 °C
Yield: 53.6 %

Procedure:
A stirred mixture of 4-(6-fluoro-1,2-benzisoxazol-3-yl)piperidine (5.5 g, 25 mmol) and 1,2-expoxybutane (1.89 g, 26.3 mmol) in isopropyl alcohol (100 ml) was heated at 65° C. for 2 days. This mixture was cooled and the solvent was removed to leave a brown oil which was purified by flash chromatography over a silica gel column (SiO2, 70 g; eluted with DCM, 1 l and MeOH:DCM 2% :98%) to give an off-white solid weighing 6.3 g. Recrystallization from hot ethanol yielded 1.96 g of fine crystals, m.p. 87°-88° C.
Reaction SMILES: Cl.Cl.[NH2:3][CH2:4][CH2:5][N:6]1[C:14]2[C:13]([NH:15][C:16]3[CH:21]=[CH:20][C:19]([O:22][C:23]4[CH:28]=[CH:27][CH:26]=[C:25]([C:29]([F:32])([F:31])[F:30])[CH:24]=4)=[C:18]([Cl:33])[CH:17]=3)=[N:12][CH:11]=[N:10][C:9]=2[CH:8]=[CH:7]1.C(N(CC)CC)C.[CH3:41][S:42]([CH2:45][CH2:46][O:47][C:48](ON1C(=O)CCC1=O)=[O:49])(=[O:44])=[O:43].C(=O)([O-])O.[Na+]>ClCCl>[Cl:33][C:18]1[CH:17]=[C:16]([NH:15][C:13]2[C:14]3[N:6]([CH2:5][CH2:4][NH:3][C:48](=[O:49])[O:47][CH2:46][CH2:45][S:42]([CH3:41])(=[O:44])=[O:43])[CH:7]=[CH:8][C:9]=3[N:10]=[CH:11][N:12]=2)[CH:21]=[CH:20][C:19]=1[O:22][C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([C:29]([F:32])([F:31])[F:30])[CH:24]=1
Reactant: CS(=O)(=O)CCOC(=O)ON1C(=O)CCC1=O
Reactant: NCCn1ccc2ncnc(Nc3ccc(Oc4cccc(C(F)(F)F)c4)c(Cl)c3)c21
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)CCOC(=O)NCCn1ccc2ncnc(Nc3ccc(Oc4cccc(C(F)(F)F)c4)c(Cl)c3)c21
Temperature: 25 °C
Reaction time: 2 h
Yield: 82.9 %

Procedure:
5-(2-Aminoethyl)-N-{3-chloro-4-[3-(trifluoromethyl)phenoxy]phenyl}-5H-pyrrolo[3,2-d]pyrimidin-4-amine dihydrochloride (64.1 mg) and triethylamine (1.0 mL) were dissolved in dichloromethane (5.0 mL), 1-({[2-(methylsulfonyl)ethoxy]carbonyl}oxy)pyrrolidine-2,5-dione (45.6 mg) was added, and the mixture was stirred at room temperature for 2 hrs. Saturated aqueous sodium hydrogen carbonate was added to the reaction mixture under ice-cooling, and the mixture was extracted with ethyl acetate. The extract was dried over magnesium sulfate and concentrated, and the residue was separated and purified by silica gel column chromatography (eluent, ethyl acetate:methanol=100:0→ethyl acetate:methanol=95:5). Crystallization from diethyl ether/hexane gave the title compound (61.0 mg).