Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1](C(OCC1C=CC=CC=1)=O)[C@H:2]([C:12]([NH:14][C@H:15]([C:24]([NH:26][C@H:27]([C:37]([NH:39][C@H:40]([C:47]([O:49][C:50]([CH3:53])([CH3:52])[CH3:51])=[O:48])[CH2:41][O:42][C:43]([CH3:46])([CH3:45])[CH3:44])=[O:38])[CH2:28][CH2:29][C:30](=[O:36])[O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:25])[CH2:16][C:17](=[O:23])[O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:13])[CH2:3][CH2:4][C:5](=[O:11])[O:6][C:7]([CH3:10])([CH3:9])[CH3:8]>[Pd].CO>[NH2:1][C@H:2]([C:12]([NH:14][C@H:15]([C:24]([NH:26][C@H:27]([C:37]([NH:39][C@H:40]([C:47]([O:49][C:50]([CH3:53])([CH3:52])[CH3:51])=[O:48])[CH2:41][O:42][C:43]([CH3:46])([CH3:45])[CH3:44])=[O:38])[CH2:28][CH2:29][C:30](=[O:36])[O:31][C:32]([CH3:34])([CH3:35])[CH3:33])=[O:25])[CH2:16][C:17](=[O:23])[O:18][C:19]([CH3:20])([CH3:21])[CH3:22])=[O:13])[CH2:3][CH2:4][C:5](=[O:11])[O:6][C:7]([CH3:10])([CH3:9])[CH3:8]
Reactant: CC(C)(C)OC[C@H](NC(=O)[C@H](CCC(=O)OC(C)(C)C)NC(=O)[C@H](CC(=O)OC(C)(C)C)NC(=O)[C@H](CCC(=O)OC(C)(C)C)NC(=O)OCc1ccccc1)C(=O)OC(C)(C)C
Agent: [Pd]
Solvent: CO
Product: CC(C)(C)OC[C@H](NC(=O)[C@H](CCC(=O)OC(C)(C)C)NC(=O)[C@H](CC(=O)OC(C)(C)C)NC(=O)[C@@H](N)CCC(=O)OC(C)(C)C)C(=O)OC(C)(C)C
Yield: 95 %

Procedure:
A solution of 12.5 g. (14 mmoles) of Z-28-31-OtBu in 250 ml. of methanol is hydrogenated for 0.5 hours in the presence of 1.8 g. of palladium-on-carbon. The catalyst is removed by filtration, and the filtrate is evaporated to dryness. The solid residue is triturated with n-hexane, and the mixture is filtered. 10.09 g. (95 %) of H-28-31-OtBu are obtained. M.p.: 130°-140° C, Rf11 = 0.25.
Reaction SMILES: [C:1]1([C:43]2[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=2)[CH:6]=[CH:5][C:4]([O:7][CH2:8][C:9]2[CH:14]=[C:13]([C:15]3[O:16][CH:17]=[CH:18][N:19]=3)[CH:12]=[CH:11][C:10]=2[C:20]2[C:21]([S:26]([N:29]([C:36]3[O:40][N:39]=[C:38]([CH3:41])[C:37]=3[CH3:42])COCCOC)(=[O:28])=[O:27])=[CH:22][CH:23]=[CH:24][CH:25]=2)=[CH:3][CH:2]=1>CCO.Cl>[C:1]1([C:43]2[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=2)[CH:2]=[CH:3][C:4]([O:7][CH2:8][C:9]2[CH:14]=[C:13]([C:15]3[O:16][CH:17]=[CH:18][N:19]=3)[CH:12]=[CH:11][C:10]=2[C:20]2[C:21]([S:26]([NH:29][C:36]3[O:40][N:39]=[C:38]([CH3:41])[C:37]=3[CH3:42])(=[O:28])=[O:27])=[CH:22][CH:23]=[CH:24][CH:25]=2)=[CH:5][CH:6]=1
Reactant: COCCOCN(c1onc(C)c1C)S(=O)(=O)c1ccccc1-c1ccc(-c2ncco2)cc1COc1ccc(-c2ccccc2)cc1
Agent: Cl
Solvent: CCO
Product: Cc1noc(NS(=O)(=O)c2ccccc2-c2ccc(-c3ncco3)cc2COc2ccc(-c3ccccc3)cc2)c1C

Procedure:
To a solution of the title compound of Step (A) in 3 ml of 95% EtOH, 3 ml 6N HCl was added. The reaction was refluxed for 1 h and 10 min and concentrated. The residue was neutralized to pH>8 with NaHCO3, and was then acidified to pH 5 with aq. NaHSO4, and extracted with 3×20 ml EtOAc. The organic extracts were washed with brine, dried and concentrated. The residue was chromatographed on silica gel using 70:30:0.25 hexane/EtOAc/AcOH to furnish the title compound of this Example (45 mg, 75% for two steps) as a light yellow solid, m.p. 95°-105° C. (amorphous).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]([N:10]2[CH2:15][CH2:14][C@:13]([CH2:22][CH2:23][CH2:24][NH:25][S:26]([CH3:29])(=[O:28])=[O:27])([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[O:12][C:11]2=[O:30])[CH3:9])=[CH:4][CH:3]=1.[CH3:31][O:32][C:33]1[N:38]=[CH:37][C:36](B(O)O)=[CH:35][CH:34]=1>>[CH3:31][O:32][C:33]1[N:38]=[CH:37][C:36]([C:2]2[CH:7]=[CH:6][C:5]([C@@H:8]([N:10]3[CH2:15][CH2:14][C@:13]([CH2:22][CH2:23][CH2:24][NH:25][S:26]([CH3:29])(=[O:28])=[O:27])([C:16]4[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=4)[O:12][C:11]3=[O:30])[CH3:9])=[CH:4][CH:3]=2)=[CH:35][CH:34]=1
Reactant: C[C@@H](c1ccc(Br)cc1)N1CC[C@](CCCNS(C)(=O)=O)(c2ccccc2)OC1=O
Reactant: COc1ccc(B(O)O)cn1
Product: COc1ccc(-c2ccc([C@H](C)N3CC[C@](CCCNS(C)(=O)=O)(c4ccccc4)OC3=O)cc2)cn1

Procedure:
The title compound was prepared from N-(3-((R)-3-((S)-1-(4-bromophenyl)ethyl)-2-oxo-6-phenyl-1,3-oxazinan-6-yl)propyl)methanesulfonamide and 6-methoxypyridine-3-boronic acid following procedures analogous to those described in Example 1 Step 2. LC-MS Method 2 tR=1.316 min, m/z=524.1; 1H NMR (CDCl3) 1.28-1.38 (m, 1H), 1.48 (d, 3H), 1.67 (m, 1H), 1.81-1.98 (m, 2H), 2.13 (m, 1H), 2.24 (m, 2H), 2.83 (m, 4H), 3.01 (m, 2H), 3.91 (s, 3H), 4.15 (m, 1H), 5.62 (m, 1H), 6.73 (d, 1H), 6.91 (d, 2H), 7.18-7.32 (m, 7H), 7.62 (dd, 1H), 8.21 (s, 1H).
Reaction SMILES: [CH3:1][C:2]([CH3:21])([CH3:20])[C:3]([N:5]1[CH2:9][CH2:8][C@H:7]([C:10]2[CH:15]=[CH:14][C:13]([OH:16])=[CH:12][CH:11]=2)[C@H:6]1[C:17](O)=[O:18])=[O:4].Cl.[CH3:23][C:24]([O:27][C:28]([C@@H:30]1[CH2:46][S:45][S:44][CH2:43][C@H:42]([NH2:47])[C:41](=[O:48])[NH:40][CH2:39][CH2:38][C:33]2([CH2:37][CH2:36][CH2:35][CH2:34]2)[C:32](=[O:49])[NH:31]1)=[O:29])([CH3:26])[CH3:25].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.O>[CH3:26][C:24]([O:27][C:28]([C@@H:30]1[CH2:46][S:45][S:44][CH2:43][C@H:42]([NH:47][C:17]([C@@H:6]2[C@@H:7]([C:10]3[CH:15]=[CH:14][C:13]([OH:16])=[CH:12][CH:11]=3)[CH2:8][CH2:9][N:5]2[C:3](=[O:4])[C:2]([CH3:20])([CH3:1])[CH3:21])=[O:18])[C:41](=[O:48])[NH:40][CH2:39][CH2:38][C:33]2([CH2:34][CH2:35][CH2:36][CH2:37]2)[C:32](=[O:49])[NH:31]1)=[O:29])([CH3:23])[CH3:25]
Reactant: CC(C)(C)OC(=O)[C@@H]1CSSC[C@H](N)C(=O)NCCC2(CCCC2)C(=O)N1
Reactant: CC(C)(C)C(=O)N1CC[C@H](c2ccc(O)cc2)[C@H]1C(=O)O
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)[C@@H]1CSSC[C@H](NC(=O)[C@@H]2[C@@H](c3ccc(O)cc3)CCN2C(=O)C(C)(C)C)C(=O)NCCC2(CCCC2)C(=O)N1
Temperature: 25 °C
Reaction time: 3 h
Yield: 94.6 %

Procedure:
To a mixture of (2S,3R)-1-(2,2-dimethyl-1-oxopropyl)-3-(4-hydroxyphenyl)pyrolidine-2-carboxylic acid (45 mg, 0.15 mmol) and (8R,13R)-13-amino-6,14-dioxo-10,11-dithia-7,15-diazaspiro[4.12]heptadecane-8-carboxylic acid 1,1-dimethylethyl ester hydrochloride 70 mg, 0.15 mmol), prepared in Example 6, in 0.5 mL of DMF was added DIPEA (58 mg, 0.45 mmol) and HBTU (59 mg, 0.15 mmol). The solution was stirred at room temperature for 3 hours and was diluted with water to 3 mL. The resulting white precipitate was collected and was dried over night at reduced pressure to give 98 mg of (8R,13R)-13-[[[1-(2,2-dimethyl-1-oxopropyl)-3-(R)-(4-hydroxyphenyl)-2-(S)-pyrrolidinyl]carbonyl]amino]-6,14-dioxo-10,11-dithia-7,15-diazaspiro[4.12]heptadecane-8-carboxylic acid 1,1-dimethylethyl ester as a white solid. This dried solid was the dissolved in 1 mL of dichloromethane and the solution was treated with 4 N HCl in dioxane (2 mL). The solution was stirred overnight and was concentrated. The residue was purified by reversed phase HPLC (5-95% of acetonitrile containing 0.75% of TFA in water over 40 min linear gradient) to give (8R,13R)-13-[[[1-(2,2-dimethyl-1-oxopropyl)-3(R)-(4-hydroxyphenyl)-2(S)-pyrrolidinyl]carbonyl]amino]-6,14-dioxo-10,11-dithia-7,15-diazaspiro[4.12]heptadecane-8-carboxylic acid as white solid (9 mg). HRMS (M+H): Obs. 635.2543, Calcd. 635.2573.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[N:3][C:2]=1[NH:7][CH:8]1[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10][CH2:9]1.C[Si](C)(C)[N-][Si](C)(C)C.[Na+].[CH2:31](Br)[CH:32]=[CH2:33].[Cl-].[NH4+]>C1COCC1.C(Cl)Cl>[N:1]1[CH:6]=[CH:5][CH:4]=[N:3][C:2]=1[N:7]([CH:8]1[CH2:9][CH2:10][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:12][CH2:13]1)[CH2:33][CH:32]=[CH2:31]
Reactant: CC(C)(C)OC(=O)N1CCC(Nc2ncccn2)CC1
Reactant: C=CCBr
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: ClCCl
Product: C=CCN(c1ncccn1)C1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 60.7 %

Procedure:
A solution of 4-(N-(pyrimidin-2-yl)amino)-1-t-butoxycarbonylpiperidine from Step B (528 mg, 1.9 mmol) in dry THF (5 mL) was cooled to −78° C. and a solution of sodium hexamethyldisilazide (2.8 mL, 1.0 M in THF, 2.8 mmol) was added via syringe. The mixture was stirred cold for 20 min then allyl bromide (0.23 mL, 2.7 mmol) was added. The mixture was then warmed to rt and stirred for 1.5 h at which time TLC showed very little starting material. The solution was poured into sat'd ammonium chloride and methylene chloride. The layers were separated and the organic phase was dried over sodium sulfate and concentrated. FC (25 g silica, 4/1 hexanes/ethyl acetate) afforded the title compound (367 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:20]=[CH:19][C:5]([O:6][CH:7]([N:14]2[CH:18]=[CH:17][N:16]=[CH:15]2)[CH:8]([OH:13])[C:9]([CH3:12])([CH3:11])[CH3:10])=[CH:4][CH:3]=1.[C:21]([O-])(=[O:23])[CH3:22].[Na+]>C(OC(=O)C)(=O)C>[C:21]([O:13][CH:8]([C:9]([CH3:11])([CH3:12])[CH3:10])[CH:7]([O:6][C:5]1[CH:4]=[CH:3][C:2]([Cl:1])=[CH:20][CH:19]=1)[N:14]1[CH:18]=[CH:17][N:16]=[CH:15]1)(=[O:23])[CH3:22]
Reactant: CC(=O)[O-]
Reactant: CC(C)(C)C(O)C(Oc1ccc(Cl)cc1)n1ccnc1
Agent: [Na+]
Solvent: CC(=O)OC(C)=O
Product: CC(=O)OC(C(Oc1ccc(Cl)cc1)n1ccnc1)C(C)(C)C
Temperature: 0 °C
Reaction time: 8 h
Yield: 730.7 %

Procedure:
8.0 g (0.027 mol) of 1-(4-chlorophenoxy)-1-imidazol-1-yl-3,3-dimethyl-butan-2-ol are heated in 40 ml of acetic anhydride with 0.15 g of sodium acetate for 10 hours at 100° C. The solution is then cooled and stirred into 400 ml of ice water, the temperature being kept at 20°-25° C. The mixture is left to stand overnight. A smeary crystalline mass precipitates out and is taken up in chloroform. The chloroform solution is washed several times with water and sodium bicarbonate solution, dried over sodium sulphate and concentrated in vacuo by distilling off the solvent. The crystalline residue is boiled up in petroleum ether and the product is filtered off cold and dried. 4.5 g (49% of theory) of 2-acetoxy-1-(4-chlorophenoxy)-1-imidazol-1-yl-3,3-dimethylbutane are obtained as a mixture of isomers with a melting point of 81°-91° C.
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[CH:11]=[CH:10][C:9]([CH3:12])=[CH:8][C:7]=2[C:13]2[C:14]3[N:21]([CH2:22][O:23][CH2:24][CH2:25][Si:26]([CH3:29])([CH3:28])[CH3:27])[C:20]([CH3:30])=[C:19]([C:31]([OH:33])=O)[C:15]=3[N:16]=[CH:17][N:18]=2)[CH2:3][CH2:2]1.[NH2:34][C@H:35]1[CH2:40][CH2:39][C@H:38]([NH:41][C:42](=[O:48])[O:43][C:44]([CH3:47])([CH3:46])[CH3:45])[CH2:37][CH2:36]1>>[CH:1]1([CH2:4][O:5][C:6]2[CH:11]=[CH:10][C:9]([CH3:12])=[CH:8][C:7]=2[C:13]2[C:14]3[N:21]([CH2:22][O:23][CH2:24][CH2:25][Si:26]([CH3:29])([CH3:27])[CH3:28])[C:20]([CH3:30])=[C:19]([C:31]([NH:34][C@H:35]4[CH2:40][CH2:39][C@H:38]([NH:41][C:42](=[O:48])[O:43][C:44]([CH3:46])([CH3:45])[CH3:47])[CH2:37][CH2:36]4)=[O:33])[C:15]=3[N:16]=[CH:17][N:18]=2)[CH2:3][CH2:2]1
Reactant: CC(C)(C)OC(=O)N[C@H]1CC[C@H](N)CC1
Reactant: Cc1ccc(OCC2CC2)c(-c2ncnc3c(C(=O)O)c(C)n(COCC[Si](C)(C)C)c23)c1
Product: Cc1ccc(OCC2CC2)c(-c2ncnc3c(C(=O)N[C@H]4CC[C@H](NC(=O)OC(C)(C)C)CC4)c(C)n(COCC[Si](C)(C)C)c23)c1

Procedure:
Starting from 4-[2-(cyclopropylmethoxy)-5-methylphenyl]-6-methyl-5-{[2-(trimethylsilyl)ethoxy]methyl}-5H-pyrrolo[3,2-d]pyrimidine-7-carboxylic acid (example D.c7) and commercially available tert-butyl trans-(4-amino-cyclohexyl)-carbamate the title compound is obtained as colorless solid.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([N+:9]([O-:11])=[O:10])=[CH:4][C:3]=1[CH3:12].CC1(C)C(C)(C)OB([C:21]2[CH2:30][CH2:29][C:24]3([O:28][CH2:27][CH2:26][O:25]3)[CH2:23][CH:22]=2)O1.[F-].[Cs+]>CC(O)C(O)C.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:12][C:3]1[CH:4]=[C:5]([N+:9]([O-:11])=[O:10])[C:6]([CH3:8])=[CH:7][C:2]=1[C:21]1[CH2:30][CH2:29][C:24]2([O:28][CH2:27][CH2:26][O:25]2)[CH2:23][CH:22]=1
Reactant: Cc1cc([N+](=O)[O-])c(C)cc1Br
Reactant: CC1(C)OB(C2=CCC3(CC2)OCCO3)OC1(C)C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: CC(O)C(C)O
Agent: [Cs+]
Solvent: O
Product: Cc1cc([N+](=O)[O-])c(C)cc1C1=CCC2(CC1)OCCO2
Temperature: 130 °C

Procedure:
A mixture of 1-bromo-2,5-dimethyl-4-nitrobenzene (100 mg, 0.43 mmol), 4,4,5,5-tetramethyl-2-(1,4-dioxaspiro[4.5]dec-7-en-8-yl)-1,3,2-dioxaborolane (112 mg, 0.43 mmol), Pd(PPh3)4 (49 mg, 0.043 mmol) and CsF (196 mg, 1.29 mmol) in a mixture of dimethyl ethylene glycol and water (2:1, 1.5 mL) was degassed and heated under N2 at 130° C. in microwave reactor for 15 min. After cooling down to room temperature, the reaction mixture was treated with saturated NH4Cl aqueous solution (5 mL) and extracted with EtOAc (3×4 mL). The combined organic layers were concentrated and purified by flash column chromatography (silica gel, 0%-30% EtOAc in hexanes gradient) to provide 8-(2,5-dimethyl-4-nitrophenyl)-1,4-dioxaspiro[4.5]dec-7-ene as a white solid; ESMS m/z 290.1 (M+H+).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[NH:7][C:6](=[O:13])/[C:5]/2=[CH:14]/OC.[CH3:17][N:18]([CH:26]1[CH2:30][CH2:29][N:28]([CH3:31])[CH2:27]1)[C:19]1[CH:24]=[CH:23][C:22]([NH2:25])=[CH:21][CH:20]=1.C(N(CC)CC)C>CN(C)C=O>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[NH:7][C:6](=[O:13])/[C:5]/2=[CH:14]\[NH:25][C:22]1[CH:21]=[CH:20][C:19]([N:18]([CH3:17])[CH:26]2[CH2:30][CH2:29][N:28]([CH3:31])[CH2:27]2)=[CH:24][CH:23]=1
Reactant: CN1CCC(N(C)c2ccc(N)cc2)C1
Reactant: CO/C=C1/C(=O)NC(=O)c2ccc(Br)cc21
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CN1CCC(N(C)c2ccc(N/C=C3\C(=O)NC(=O)c4ccc(Br)cc43)cc2)C1
Yield: 43.2 %

Procedure:
(4E)-6-Bromo-4-(methoxymethylene)isoquinoline-1,3(2H,4H)-dione (0.17 g, 0.61 mmol) and N-methyl-N-(1-methyl-pyrrolidin-3-yl)-benzene-1,4-diamine (0.12 g, 0.61 mmol) were stirred in N,N-dimethylformamide (3 mL) and triethylamine (0.16 mL) at 60-70° C. The reaction mixture is quenched by the addition of water. The solid material is then collected, washed with diethyl ether, water, and methanol, and then dried under vacuum to give (4Z)-6-bromo-4-[({4-[methyl(1-methylpyrrolidin-3-yl)amino]phenyl}amino)methylene]isoquinoline-1,3(2H,4H)-dione (0.12 g, 44%) as a rust colored powder.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].S(=O)(=O)(O)O.[Cl:12][C:13]1[CH:33]=[CH:32][C:16]2[O:17][CH2:18][O:19][C:20]3[CH:31]=[CH:30][CH:29]=[CH:28][C:21]=3[N:22]([C:23](=O)[CH2:24][CH2:25][Cl:26])[C:15]=2[CH:14]=1>O1CCCC1>[Cl:12][C:13]1[CH:33]=[CH:32][C:16]2[O:17][CH2:18][O:19][C:20]3[CH:31]=[CH:30][CH:29]=[CH:28][C:21]=3[N:22]([CH2:23][CH2:24][CH2:25][Cl:26])[C:15]=2[CH:14]=1
Reactant: O=C(CCCl)N1c2ccccc2OCOc2ccc(Cl)cc21
Agent: O=S(=O)(O)O
Agent: [Al+3]
Agent: [H-]
Solvent: C1CCOC1
Product: ClCCCN1c2ccccc2OCOc2ccc(Cl)cc21
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To a cooled suspension of lithium aluminium hydride (3.0 g, 79 mmol) in dry tetrahydrofuran (80 ml), concentrated sulfuric acid (3.87 g, 39.5 mmol) was added dropwise at a rate to maintain a temperature <12° C. The mixture was stirred at room temperature for 1.5 h. A solution of the above amide (12.8 g, 37.8 mmol) in dry tetrahydrofuran (80 ml) was added dropwise and stirring was continued for 2 h. The reaction was quenched by careful addition of ethyl acetate (100 ml) followed by water (5.7 ml). Filtration of the mixture and evaporation of the filtrate in vacuo afforded 2-chloro-12-(3-chloropropyl)-12H-dibenzo[d,g][1,3,6]dioxazocine as a foam.
Reaction SMILES: [Cl:1][C:2]1[S:6][N:5]=[C:4]([OH:7])[CH:3]=1.[CH:8]#[C:9][C:10](=[O:12])[CH3:11].C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[O:12]=[C:10]([CH:9]=[CH:8][N:5]1[C:4](=[O:7])[CH:3]=[C:2]([Cl:1])[S:6]1)[CH3:11]
Reactant: Oc1cc(Cl)sn1
Reactant: C#CC(C)=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: CC(=O)C=Cn1sc(Cl)cc1=O

Procedure:
A stirred solution of 5-chloro-3-hydroxyisothiazole (1.5 g, 0.011 mole), 1-butyn-3-one (3.5 g, 0.05 mole) and p-toluenesulfonic acid (0.02 g) in 25 ml of toluene was heated at 80° C. for 24 hours. Upon cooling, the dark brown reaction mixture was concentrated and the residual oil was column chromatographed on silica gel, using diethyl ether/hexane as eluant. Compound 11 was obtained as a yellowish solid; 1.8 g; mp 137°-139° C.; IR (KBr) 1675, 1620 cm-1 ; NMR (CDCl3) δ8.2 (d, 1H, J=13.9 Hz); 6.35 (s, 1H); 5.85 (d, 1H, J=13.9 Hz); 2.35 (s, 3H).
Reaction SMILES: [C:1]1([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH:6]=[CH:5][C:4]([CH2:7][C@H:8]([NH:12][CH2:13][P:14]([O:18]C)([O:16]C)=[O:15])[C:9]([OH:11])=[O:10])=[CH:3][CH:2]=1.CCOCC>Br.C(O)(=O)C>[C:1]1([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH:2]=[CH:3][C:4]([CH2:7][C@H:8]([NH:12][CH2:13][P:14]([OH:18])([OH:16])=[O:15])[C:9]([OH:11])=[O:10])=[CH:5][CH:6]=1
Reactant: COP(=O)(CN[C@@H](Cc1ccc(-c2ccccc2)cc1)C(=O)O)OC
Agent: Br
Solvent: CC(=O)O
Solvent: CCOCC
Product: O=C(O)[C@H](Cc1ccc(-c2ccccc2)cc1)NCP(=O)(O)O
Reaction time: 2 h

Procedure:
(S)-3-(Biphenyl-4-yl)-2-(dimethylphosphonomethyl-amino)-propionic acid (278 mg, 0.76 mmol) is dissolved in a 30% solution of hydrobromic acid in acetic acid (10 mL) under nitrogen. After 2 hours, ether (50 mL) is added and the product precipitates. The mixture is kept at 0° for 18 hours and then filtered. The solid is dissolved in 0.1N sodium hydroxide (25 mL) and the insoluble material is filtered. The filtrate is acidified with 2N hydrochloric acid (5 mL). The gelatinous solid is filtered, washed with water and dried under high vacuum at 75° to give the (S)-3-(biphenyl-4-yl)-2-(phosphonomethylamino)-propionic acid as a white powder; m.p.: 241° (dec.); [α]D =+33.16 (c 0.95, 0.1N NaOH). ##STR30##
Reaction SMILES: [OH-].[Na+].[CH3:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[C:19]3[C:18]([O:20][CH:21]([CH3:26])[CH2:22][CH:23]([OH:25])[CH3:24])=[N:17][CH:16]=[N:15][C:14]=3[O:13][C:12]=2[C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)=[CH:7][CH:6]=1.Br[CH2:34][C:35]([O:37]C(C)(C)C)=[O:36].Cl>C1(C)C=CC=CC=1.S([O-])(O)(=O)=O.C([N+](CCCC)(CCCC)CCCC)CCC>[CH3:3][O:4][C:5]1[CH:6]=[CH:7][C:8]([C:11]2[C:19]3[C:18]([O:20][CH:21]([CH3:26])[CH2:22][CH:23]([CH3:24])[O:25][CH2:34][C:35]([OH:37])=[O:36])=[N:17][CH:16]=[N:15][C:14]=3[O:13][C:12]=2[C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)=[CH:9][CH:10]=1
Reactant: CC(C)(C)OC(=O)CBr
Reactant: COc1ccc(-c2c(-c3ccccc3)oc3ncnc(OC(C)CC(C)O)c23)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: Cl
Agent: O=S(=O)([O-])O
Solvent: Cc1ccccc1
Product: COc1ccc(-c2c(-c3ccccc3)oc3ncnc(OC(C)CC(C)OCC(=O)O)c23)cc1
Temperature: 70 °C
Reaction time: 15 h

Procedure:
Add 4.8 ml of 11.25 N sodium hydroxide solution to a solution of 2.19 g (5.41 mmol) 4-{[5-(4-methoxyphenyl)-6-phenylfuro[2,3-d]pyrimidin-4-yl]oxy}pentan-2-ol in 20 ml toluene. After adding 184 mg (0.54 mmol) tetra-n-butylammonium hydrogensulphate and 2.11 g (10.83 mmol) tert.-butyl bromoacetate, stir the reaction mixture for 15 h at 70° C. After cooling to room temperature, adjust to pH 7 with concentrated hydrochloric acid and extract three times with 50 ml dichloromethane each time. Wash the combined organic extracts with satd. aqueous sodium chloride solution, dry over sodium sulphate, and filter. Concentrate the filtrate by vacuum evaporation. Take up the residue in ethyl acetate and purify by flash chromatography on silica gel (solvent: first ethyl acetate, then ethyl acetate/methanol 5:1). Purify the product obtained once more by preparative RP-HPLC (gradient: water/acetonitrile). 0.29 g (11% of theor.) of the desired product is obtained as a racemic mixture of diastereomers.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[CH:14]=[CH:13][C:12]([C@@H:15]([OH:21])[CH2:16][CH2:17][CH2:18][CH:19]=[CH2:20])=[CH:11][CH:10]=1.B(F)(F)F.CC[O:28]CC.[OH-].[Na+].OO.C([O-])([O-])=O.[K+].[K+]>[BH4-].[Na+].COCCOCCOC.O>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[CH:14]=[CH:13][C:12]([C@@H:15]([OH:21])[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][OH:28])=[CH:11][CH:10]=1
Reactant: C=CCCC[C@H](O)c1ccc(-c2ccc(Cl)cc2Cl)cc1
Reactant: CCOCC
Agent: FB(F)F
Agent: O=C([O-])[O-]
Agent: OO
Solvent: O
Solvent: COCCOCCOC
Product: OCCCCC[C@H](O)c1ccc(-c2ccc(Cl)cc2Cl)cc1
Reaction time: 1 h

Procedure:
Impure (S)-1-(2′,4′-dichloro-biphenyl-4-yl)hex-5-en-1-ol (1 g) was dissolved in 0.5 M NaBH4 in diglyme (9 mL) and chilled in an ice bath. BF3.OEt2 (1 mL) in diglyme (4 mL) was added with vigorous stirring. Stirring was continued for 1 hour and water (1 mL) was added. 3 M NaOH (2 mL) was added followed by 30% H2O2 (3 mL). Anhydrous K2CO3 (5 g) was added and the solvent was decanted. The K2CO3 was washed with ethyl acetate and the combined organics were dried (Na2SO4) and evaporated. Distillation under vacuum removed most of the remaining diglyme. The residue was purified by column chromatography (light petroleum:diethyl ether 2:1) to give the title compound as a clear oil. 13C NMR (CDCl3): δ 25.6, 25.6, 32.6, 39.0, 62.8, 74.2, 125.7, 127.2, 129.5, 129.7, 132.1, 133.2, 133.7, 137.5, 138.7 and 144.6.
Reaction SMILES: C[Si]([N-][Si](C)(C)C)(C)C.[Na+].[CH2:11]1COCC1.[CH3:16][O:17][C:18](=[O:27])[CH2:19][CH2:20][C:21]1[C:22](=[O:26])[NH:23][CH2:24][CH:25]=1.S(OC)(OC)(=O)=O>[NH4+].[Cl-]>[CH3:16][O:17][C:18](=[O:27])[CH2:19][CH2:20][C:21]1[C:22](=[O:26])[N:23]([CH3:11])[CH2:24][CH:25]=1
Reactant: C1CCOC1
Reactant: COC(=O)CCC1=CCNC1=O
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Cl-]
Agent: [NH4+]
Solvent: COS(=O)(=O)OC
Product: COC(=O)CCC1=CCN(C)C1=O
Reaction time: 0.5 h
Yield: 33 %

Procedure:
0.33 ml of NaHMDS solution (1.0 M in THF, 0.33 mM) was added to 0.6 ml of THF solution containing 50 mg of 3-(2-oxo-2,5-dihydro-1H-pyrrol-3-yl)-propionic acid methyl ester (20 (0.295 mM) prepared by the Step 1 in a dropwise manner at −79° C. and stirred for 30 mins. After 0.3 ml of dimethyl sulfate 0.359 mM) was added thereto, the reaction mixture was stirred for 4 hrs at 0° C. Then the resulting mixture was dissolved in 2 ml of saturated NH4Cl solution and extracted with 7 ml of ethyl acetate to separate into an organic layer and water layer. The organic layer was washed with 2 ml of saturated NaHCO3 solution and 2 ml of saturated NaCl solution, dried over anhydrous MgSO4, filtered and concentrated in vacuo. The resultant was purified by Silica gel column chromatography with EtOAc as an eluant to give 18 mg of 3-(1-methyl-2-oxo-2,5-dihydro-1H-pyrrol-3-yl)-propionic acid methyl ester (2g) (yield: 33%).
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[C:9](=[O:13])[N:8]([CH:14]1[CH2:19][CH2:18][C:17](=[O:20])[NH:16][C:15]1=[O:21])[C:7]2=[O:22].[F:23][C:24]([F:36])([F:35])[S:25][C:26]1[CH:34]=[CH:33][C:29]([C:30](Cl)=[O:31])=[CH:28][CH:27]=1>C(#N)C.O.C(OCC)(=O)C>[O:21]=[C:15]1[CH:14]([N:8]2[C:7](=[O:22])[C:6]3[C:10](=[CH:11][CH:12]=[C:4]([CH2:3][NH:2][C:30](=[O:31])[C:29]4[CH:33]=[CH:34][C:26]([S:25][C:24]([F:36])([F:23])[F:35])=[CH:27][CH:28]=4)[CH:5]=3)[C:9]2=[O:13])[CH2:19][CH2:18][C:17](=[O:20])[NH:16]1
Reactant: NCc1ccc2c(c1)C(=O)N(C1CCC(=O)NC1=O)C2=O
Reactant: O=C(Cl)c1ccc(SC(F)(F)F)cc1
Agent: Cl
Solvent: O
Solvent: CC#N
Solvent: CCOC(C)=O
Product: O=C1CCC(N2C(=O)c3ccc(CNC(=O)c4ccc(SC(F)(F)F)cc4)cc3C2=O)C(=O)N1
Temperature: 25 °C
Reaction time: 1 h
Yield: 76 %

Procedure:
TEA was added to a stirred mixture of 5-aminomethyl-2-(2,6-dioxo-piperidin-3-yl)-isoindole-1,3-dione hydrochloride (1.0 g, 3.1 mmol) and 4-(trifluoromethylthio)benzoyl chloride (0.75 g, 3.1 mmol) in acetonitrile (30 mL), and the resulting mixture was stirred at room temperature for 1 hour. The mixture was diluted with water (100 mL) and ethyl acetate (100 mL). The organic phase was separated and concentrated in vacuo. The residue was chromatographed on silica gel using a hexanes-ethyl acetate gradient, eluting 1.2 g of the product at 60-70% ethyl acetate, in 76% yield as a white solid; mp 171-173° C.; HPLC, Waters Symmetry C-18, 3.9×150 mm, 5 μm, 1 mL/min, 240 nm, 50/50 CH3CN/0.1% H3PO4, 4.72 (97.94%); 1H NMR (DMSO-d6) δ 2.02-2.10 (m, 1H), 2.46-2.63 (m, 2H), 2.83-2.95 (m, 1H), 4.66 (d, J=5.8 Hz, 2H), 5.15 (dd, J=12.8 Hz, J=5.3 Hz, 1H), 7.81-7.92 (m, 5H), 8.00-8.03 (m, 2H), 9.41 (t, J=5.8 Hz, 1H), 11.13 (s, 1H); 13C NMR (DMSO-d6) δ 22.0, 30.9, 42.7, 49.0, 122.0, 123.6, 126.4, 128.7, 129.5 (q, J=306 Hz), 129.9, 131.6, 133.5, 135.9, 136.5, 147.2, 165.5, 167.0, 167.1, 169.8, 172.7; Anal. Calcd for C22H16N3O5F3S: C, 53.77; H, 3.28; N, 8.55. Found: C, 53.55; H, 3.14; N, 8.37.