Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][CH:6]=[C:5]2[O:12][CH3:13].C([Li])CCC.CN(C)[CH:21]=[O:22]>O1CCCC1.[Cl-].[NH4+].C(#N)C>[CH3:13][O:12][C:5]1[C:4]2[C:9](=[CH:10][CH:11]=[C:2]([CH:21]=[O:22])[CH:3]=2)[N:8]=[CH:7][CH:6]=1
Reactant: COc1ccnc2ccc(Br)cc12
Reactant: CN(C)C=O
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: CC#N
Solvent: C1CCOC1
Product: COc1ccnc2ccc(C=O)cc12
Temperature: -60 °C
Reaction time: 0.5 h
Yield: 63.8 %

Procedure:
To a solution of 6-bromo-4-methoxy-quinoline (8.91 g, 37.42 mmol) in THF (tetrahydrofuran) (155 mL) was added dropwise a 2.5M solution of n-butyllithium in hexanes (16.46 mL, 4.16 mmol, 1.1 equiv.) at −70° C. During the addition, the temperature of the reaction mixture was raised slightly to −60° C. and it gave a very dark brown solution. The resulting colored solution was stirred for 30 min at this temperature. Then, a solution of dimethylformamide (5.78 mL, 74.84 mmol) in THF (10 mL) was added dropwise. After addition, the mixture was allowed to warm to room temperature and stirred for 15 h. Then, the mixture was diluted with saturated ammonium chloride solution and the two layers were separated. The aqueous layer was extracted with ethyl acetate (3×150 mL). The combined organic extracts were washed with brine solution and dried over anhydrous magnesium sulfate. Filtration of the drying agent and removal of the solvent under the vacuum gave the crude brown solid. This solid was dissolved in acetonitrile (˜50 mL) at hot condition and then stored in the refrigerator overnight. The solids were collected by filtration and washed with diethyl ether. After drying in air, 4.47 g (64% yield) of 4-methoxy-quinoline-6-carbaldehyde was isolated as a white solid: EI-HRMS m/e calcd for C11H9NO2 (M+) 187.0633, found 187.0638.
Reaction SMILES: [CH:1]1([N:4]2[C:13]3[C:8](=[C:9]([CH3:16])[C:10]([F:15])=[C:11](F)[CH:12]=3)[C:7](=[O:17])[C:6]([C:18]([OH:20])=[O:19])=[CH:5]2)[CH2:3][CH2:2]1.C(OC([NH:28][CH:29]1[CH2:33][CH2:32][NH:31][CH2:30]1)=O)(C)(C)C.C(N(CC)CC)C>C(#N)C>[NH2:28][CH:29]1[CH2:33][CH2:32][N:31]([C:11]2[CH:12]=[C:13]3[C:8]([C:7](=[O:17])[C:6]([C:18]([OH:20])=[O:19])=[CH:5][N:4]3[CH:1]3[CH2:3][CH2:2]3)=[C:9]([CH3:16])[C:10]=2[F:15])[CH2:30]1
Reactant: Cc1c(F)c(F)cc2c1c(=O)c(C(=O)O)cn2C1CC1
Reactant: CC(C)(C)OC(=O)NC1CCNC1
Solvent: CCN(CC)CC
Solvent: CC#N
Product: Cc1c(F)c(N2CCC(N)C2)cc2c1c(=O)c(C(=O)O)cn2C1CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 110 %

Procedure:
A mixture of 0.70 g (2.50 mmol) of 1-cyclopropyl-6,7-difluoro-1,4-dihydro-5-methyl-4-oxo-3-quinolinecarboxylic acid, 0.56 g (3.00 mmol) of 3-(t-butoxycarbonyl)aminopyrrolidine, 0.76 g (7.52 mmol) of triethylamine, and 25 ml of acetonitrile was refluxed for 4.5 hours, then stirred at room temperature overnight. The solids were filtered and washed with acetonitrile and ether. The crude product was dissolved in 20 ml of 6N hydrochloric acid and 20 ml of acetic acid and was stirred at room temperature for three hours. The solution was concentrated to an oil which was triturated with 2:1 ether:isopropanol. The solids were filtered and washed with ether to give 0.95 g of the title compound as the hydrochloride salt, mp >300° C.
Reaction SMILES: Br[C:2]1[CH:23]=[CH:22][C:5]2[C:6]3[N:7]([CH:11]=[C:12]([C:14]4[N:18]([CH:19]([CH3:21])[CH3:20])[N:17]=[CH:16][N:15]=4)[N:13]=3)[CH2:8][CH2:9][O:10][C:4]=2[CH:3]=1.O[C@H:25]1[CH2:29][NH:28][C@H:27]([C:30]([OH:32])=[O:31])[CH2:26]1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].[CH3:41]S(C)=O>[Cu]I>[CH:19]([N:18]1[C:14]([C:12]2[N:13]=[C:6]3[N:7]([CH2:8][CH2:9][O:10][C:4]4[CH:3]=[C:2]([N:28]5[CH2:29][CH2:25][CH2:41][CH2:26][CH:27]5[C:30]([OH:32])=[O:31])[CH:23]=[CH:22][C:5]=43)[CH:11]=2)=[N:15][CH:16]=[N:17]1)([CH3:21])[CH3:20]
Reactant: CC(C)n1ncnc1-c1cn2c(n1)-c1ccc(Br)cc1OCC2
Reactant: O=C(O)[C@@H]1C[C@@H](O)CN1
Reactant: CS(C)=O
Agent: [Cu]I
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Product: CC(C)n1ncnc1-c1cn2c(n1)-c1ccc(N3CCCCC3C(=O)O)cc1OCC2
Temperature: 80 °C
Yield: 87 %

Procedure:
9-bromo-2-(1-isopropyl-1H-1,2,4-triazol-5-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine 194 (1.01 g, 2.7 mmol), methyl piccolinate (3.86 g, 27.0 mmol), copper (I) iodide (0.2 g, 1.08 mmol), trans-4-hydroxy(L)proline (0.14 g, 1.08 mmol) and potassium phosphate (1.14 g, 5.4 mmol) in DMSO (10 mL) were heated at 80° C. for 24 hours. The cooled reaction mixture was loaded onto an Isolute SCX-2 cartridge, washed with methanol and eluted with 2M ammonia in methanol. The resultant residue was triturated with diethyl ether to afford 1-[2-(2-Isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-1,3a-diaza-benzo[e]azulen-8-yl]-piperidine-2-carboxylic acid (1.04 g, 87% total). LCMS: RT=2.94 min, [M+H]+=423.
Reaction SMILES: COC1C=C(OC)C=CC=1C[N:6]1[C:14](=[O:15])[N:13]([CH2:16][C:17]([F:23])([F:22])[C:18]([F:21])([F:20])[F:19])[C:12]2[C:7]1=[N:8][C:9]([C:24]1[C:32]3[C:27](=[N:28][CH:29]=[CH:30][CH:31]=3)[N:26]([CH2:33][C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=3[F:40])[N:25]=1)=[N:10][CH:11]=2.C([SiH](CC)CC)C.O.C(=O)([O-])O.[Na+]>FC(F)(F)C(O)=O.C(OCC)(=O)C>[F:40][C:35]1[CH:36]=[CH:37][CH:38]=[CH:39][C:34]=1[CH2:33][N:26]1[C:27]2=[N:28][CH:29]=[CH:30][CH:31]=[C:32]2[C:24]([C:9]2[N:8]=[C:7]3[C:12]([N:13]([CH2:16][C:17]([F:22])([F:23])[C:18]([F:19])([F:20])[F:21])[C:14](=[O:15])[NH:6]3)=[CH:11][N:10]=2)=[N:25]1
Reactant: COc1ccc(Cn2c(=O)n(CC(F)(F)C(F)(F)F)c3cnc(-c4nn(Cc5ccccc5F)c5ncccc45)nc32)c(OC)c1
Agent: CC[SiH](CC)CC
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: O=C(O)C(F)(F)F
Product: O=c1[nH]c2nc(-c3nn(Cc4ccccc4F)c4ncccc34)ncc2n1CC(F)(F)C(F)(F)F
Yield: 85.1 %

Procedure:
471 mg (0.60 mmol) of the compound from example 85A were dissolved in 15 ml of trifluoroacetic acid, 698 mg (6.01 mmol) of triethylsilane were added and the mixture was heated to reflux for 18 h. The reaction mixture was admixed with water and ethyl acetate, and neutralized with saturated aqueous sodium hydrogencarbonate solution. The organic phase was dried over sodium sulfate and concentrated on a rotary evaporator. The residue was dried under high vacuum, and purified by means of preparative HPLC (eluent: methanol/water with 0.1% trifluoroacetic acid, gradient 30:70→90:10). 252 mg of the title compound were obtained (85% of theory).
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[C:10]([CH3:11])=[CH:9][C:8]([O:12][C:13]2[CH:18]=[N:17][C:16]([O:19][CH3:20])=[CH:15][N:14]=2)=[CH:7][C:6]=1[CH3:21])=O.[NH2:22][C:23]([NH2:25])=[S:24]>CCO>[CH3:20][O:19][C:16]1[N:17]=[CH:18][C:13]([O:12][C:8]2[CH:9]=[C:10]([CH3:11])[C:5]([C:3]3[N:22]=[C:23]([NH2:25])[S:24][CH:2]=3)=[C:6]([CH3:21])[CH:7]=2)=[N:14][CH:15]=1
Reactant: COc1cnc(Oc2cc(C)c(C(=O)CBr)c(C)c2)cn1
Reactant: NC(N)=S
Solvent: CCO
Product: COc1cnc(Oc2cc(C)c(-c3csc(N)n3)c(C)c2)cn1
Yield: 15.8 %

Procedure:
A mixture of 2-bromo-1-{4-((5-methoxypyrazin-2-yl)oxy)-2,6-dimethylphenyl}ethanone (15-2, 2.70 g, 7.69 mmol) and thiourea (0.59 g, 7.69 mmol) in 95% EtOH (11.0 mL) was heated at reflux for 60 min. The solution was concentrated and added with water and saturated aqueous Na2CO3 (1.0 mL). The resultant precipitate was purified by column chromatography on silica gel (EtOAc:hexanes=2:1 as eluant) to give 4-{4-((5-methoxypyrazin-2-yl)oxy)-2,6-dimethylphenyl}thiazol-2-amine (15-3, 0.40 g) as yellow oils in 16% yield: 1H NMR (500 MHz, CDCl3) δ 7.91 (s, 1 H), 7.87 (s, 1 H), 6.77 (s, 2 H), 6.28 (s, 1 H), 5.19 (bs, 2 H), 3.96 (s, 3 H), 2.15 (s, 6 H).
Reaction SMILES: C([O:5][C:6]([CH2:8][CH2:9][C:10]([NH:12][C@H:13]([C:22]([NH:24][C@H:25]([C:35]([NH:37][C@H:38]([C:47]([NH:49][C@H:50]([C:55]([NH:57][C@H:58]([C:63]([NH:65][CH:66]([CH:73](OC)[O:74]C)[CH2:67][C:68]1[CH:72]=[CH:71][S:70][CH:69]=1)=[O:64])[CH2:59][CH:60]([CH3:62])[CH3:61])=[O:56])[C:51]([CH3:54])([CH3:53])[CH3:52])=[O:48])[CH2:39][C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][C:41]=1[CH3:46])=[O:36])[CH2:26][CH2:27][C:28](=[O:34])[O:29]C(C)(C)C)=[O:23])[CH2:14][C:15](=[O:21])[O:16]C(C)(C)C)=[O:11])=[O:7])(C)(C)C>ClCCl.FC(F)(F)C(O)=O.O>[C:6]([CH2:8][CH2:9][C:10]([NH:12][C@H:13]([C:22]([NH:24][C@H:25]([C:35]([NH:37][C@H:38]([C:47]([NH:49][C@H:50]([C:55]([NH:57][C@H:58]([C:63]([NH:65][CH:66]([CH2:67][C:68]1[CH:72]=[CH:71][S:70][CH:69]=1)[CH:73]=[O:74])=[O:64])[CH2:59][CH:60]([CH3:61])[CH3:62])=[O:56])[C:51]([CH3:54])([CH3:52])[CH3:53])=[O:48])[CH2:39][C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][C:41]=1[CH3:46])=[O:36])[CH2:26][CH2:27][C:28](=[O:29])[OH:34])=[O:23])[CH2:14][C:15](=[O:16])[OH:21])=[O:11])([OH:7])=[O:5]
Reactant: COC(OC)C(Cc1ccsc1)NC(=O)[C@H](CC(C)C)NC(=O)[C@@H](NC(=O)[C@H](Cc1ccccc1C)NC(=O)[C@H](CCC(=O)OC(C)(C)C)NC(=O)[C@H](CC(=O)OC(C)(C)C)NC(=O)CCC(=O)OC(C)(C)C)C(C)(C)C
Solvent: O
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1ccccc1C[C@H](NC(=O)[C@H](CCC(=O)O)NC(=O)[C@H](CC(=O)O)NC(=O)CCC(=O)O)C(=O)N[C@H](C(=O)N[C@@H](CC(C)C)C(=O)NC(C=O)Cc1ccsc1)C(C)(C)C
Temperature: 25 °C
Reaction time: 3 h
Yield: 65.8 %

Procedure:
0.065 g (0.06 mmol) of N2-[N-[N-[N-[N-[3-(tert-butoxycarbonyl)propionyl]-O-tert-butyl-L-α-aspartyl]-O-tert-butyl-L-α-glutamyl]-2-methyl-L-phenylalanyl]-3-methyl-L-valyl]-N1-[1(RS)-(dimethoxymethyl)-2-(3-thienyl)ethyl]-L-leucinamide was dissolved in 10 ml of dichloromethane/trifluoroacetic acid (1:1) containing 3 drops of water. The solution was stirred for 3 hours at room temperature. After removal of the solvent by evaporation the crude product was chromatographed on silica gel using dichloromethane:methanol:acetic acid:water (120:15:3:2) as the eluent to give 0.035 g of 2(RS)-[[N-[N-[N-[N-[N-(3-carboxypropionyl)-L-α-aspartyl-L-α-glutamyl]-2-methyl-L-phenylalanyl]-3-methyl-L-valyl]-L-leucyl]amino]-3(3-thienyl)propionaldehyde as a white solid; MS: m/e 887.7 [M+H]+.
Reaction SMILES: S(Cl)([Cl:3])=O.[CH3:5][O:6][C:7]1[CH:8]=[C:9]([CH:12]=[C:13]([O:29][CH3:30])[C:14]=1[O:15][CH2:16][C:17]1[N:18]=[C:19]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[O:20][C:21]=1[CH3:22])[CH2:10]O.C1(C)C=CC=CC=1>O1CCCC1>[Cl:3][CH2:10][C:9]1[CH:8]=[C:7]([O:6][CH3:5])[C:14]([O:15][CH2:16][C:17]2[N:18]=[C:19]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[O:20][C:21]=2[CH3:22])=[C:13]([O:29][CH3:30])[CH:12]=1
Reactant: COc1cc(CO)cc(OC)c1OCc1nc(-c2ccccc2)oc1C
Reactant: O=S(Cl)Cl
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: COc1cc(CCl)cc(OC)c1OCc1nc(-c2ccccc2)oc1C
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Thionyl chloride (3.62 g) was added dropwise to a stirred suspension of 3,5-dimethoxy-4-(5-methyl-2-phenyl-4-oxazolylmethoxy)benzyl alcohol (9.00 g) in tetrahydrofuran (50 ml)-toluene (150 ml) at 0° C. After stirring at room temperature for 3 hours, the reaction mixture was concentrated. The residual crystals were dissolved in ethyl acetate and washed with aqueous sodium bicarbonate and water. The ethyl acetate layer was separated, dried (MgSO4), and concentrated to give 4-(4-chloromethyl-2,6-dimethoxyphenoxymethyl)-5-methyl-2-phenyloxazole as crystals. Recrystallization from acetone-hexane gave colorless needles (7.00 g, yield 74%). m.p. 118-119° C.
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:10]([S:12][CH3:13])=S.[O:14]1[CH:19]=CSC=[N:15]1.Cl.NO>C(N(CC)CC)C>[S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:10]1[S:12][CH2:13][CH2:19][O:14][N:15]=1
Reactant: C1=CSC=NO1
Reactant: CSC(=S)c1nc2ccccc2s1
Agent: Cl
Agent: NO
Solvent: CCN(CC)CC
Product: c1ccc2sc(C3=NOCCS3)nc2c1

Procedure:
Methyl 2-benzothiazolecarbodithioate (37 g, 0.16 mol) was converted to 1,4,2-oxathiazine using hydroxylamine hydrochloride (13.2 g) and triethylamine (33 ml) as described in Example 4. The ethyl acetate extract of the product was washed successively with diluted hydrochloric acid (2N), water, 5% sodium hydroxide and water. Evaporation of the solvent left a solid residue which was recrystallized from ethanol/ethyl acetate to 5,6-dihydro-3-(2-benzothiazolyl)-1,4,2-oxathiazine (18.0 g, mp 150°-151° C.) Found C 50.68, H 3.27, N 11.78, C10 H8N2OS2 requires C 50.85, H 3.39, N 11.80.
Reaction SMILES: [F:1][C:2]([F:28])([F:27])[C:3]1[CH:26]=[CH:25][C:6]([C:7]([CH2:23][CH3:24])([OH:22])[C:8]2[CH:13]=[CH:12][C:11]([O:14]CC3C=CC=CC=3)=[CH:10][CH:9]=2)=[CH:5][CH:4]=1.[H][H]>[Pd].C1C=CC=CC=1>[F:1][C:2]([F:27])([F:28])[C:3]1[CH:26]=[CH:25][C:6]([C:7]([CH2:23][CH3:24])([OH:22])[C:8]2[CH:9]=[CH:10][C:11]([OH:14])=[CH:12][CH:13]=2)=[CH:5][CH:4]=1
Reactant: [H][H]
Reactant: CCC(O)(c1ccc(OCc2ccccc2)cc1)c1ccc(C(F)(F)F)cc1
Agent: [Pd]
Solvent: c1ccccc1
Product: CCC(O)(c1ccc(O)cc1)c1ccc(C(F)(F)F)cc1

Procedure:
of 4-trifluoromethyl-4'-benzyloxy-α-ethyl-benzhydrol are dissolved in 270 ml. of benzene, and the solution is hydrogenated in the presence of 13.5 g. of a 10% palladium-on-charcoal catalyst. When the uptake of the calculated amount of hydrogen is complete (about 80 minutes), the catalyst is filtered off, benzene is distilled off under reduced pressure, and the residue is crystallized from a mixture of ethyl acetate and n-hexane. 19 g. of the named compound are obtained, melting at 126° to 127° C.
Reaction SMILES: [C:1]1([O:7][C:8]([N:10]2[CH:23]([C:24]#[C:25]/[CH:26]=[CH:27]\[C:28]#[C:29][Si:30]([CH3:33])([CH3:32])[CH3:31])[C:22]3[CH2:21][CH2:20][CH2:19][CH:18]([O:34][Si:35]([C:38]([CH3:41])([CH3:40])[CH3:39])([CH3:37])[CH3:36])[C:17]=3[C:16]3[CH:15]=[CH:14][C:13]([O:42][C:43](=[O:48])[C:44]([CH3:47])([CH3:46])[CH3:45])=[CH:12][C:11]2=3)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C1C=C(Cl)C=C(C(OO)=[O:57])C=1>C(Cl)Cl>[C:1]1([O:7][C:8]([N:10]2[CH:23]([C:24]#[C:25]/[CH:26]=[CH:27]\[C:28]#[C:29][Si:30]([CH3:31])([CH3:33])[CH3:32])[C:22]34[O:57][C:17]3([CH:18]([O:34][Si:35]([C:38]([CH3:41])([CH3:39])[CH3:40])([CH3:36])[CH3:37])[CH2:19][CH2:20][CH2:21]4)[C:16]3[CH:15]=[CH:14][C:13]([O:42][C:43](=[O:48])[C:44]([CH3:47])([CH3:46])[CH3:45])=[CH:12][C:11]2=3)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CC(C)(C)C(=O)Oc1ccc2c(c1)N(C(=O)Oc1ccccc1)C(C#C/C=C\C#C[Si](C)(C)C)C1=C2C(O[Si](C)(C)C(C)(C)C)CCC1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: CC(C)(C)C(=O)Oc1ccc2c(c1)N(C(=O)Oc1ccccc1)C(C#C/C=C\C#C[Si](C)(C)C)C13CCCC(O[Si](C)(C)C(C)(C)C)C21O3
Temperature: 25 °C
Reaction time: 1 h
Yield: 71.4 %

Procedure:
To a solution of Compound 209 (mixture of diastereomers, 13.0 g, 19.06 mmol) in CH2Cl2 (100 mL) cooled at zero degrees C was added mCPBA (50 percent, 7.9 g, 22.98 mmol) followed by stirring at 25° C. for one hour. The reaction mixture was diluted with CH2Cl2 ()500 mL), washed with saturated aqueous NaHCO3, dried over anahydrous Na2SO4, and concentrated in vacuo. The residue was purified by flash column chromatography (silica gel, 10 percent ethyl ether in petroleum ether) to afford Compound 210 (9.5 g, 71 percent) as a mixture of diastereomers. Major isomer: Rf =0.38 (silica, 10 percent ethyl ether in petroleum ether); IR (CHCl3) νmax 2958, 2933, 1730 (shoulder), 1721, 1382, 1307, 1118, 846 cm-1 ; 1H NMR (300 MHz, CDCl3) δ 7.28 (d, J=8.6 Hz, 1 H, H1), 7.40-7.10 (m, 6 H, H4 and aromatic), 6.95 (dd, J=8.6, 1.9 Hz, 1 H, H2), 5.84-5.62 (m, 3 H, H6 and olefinic), 4.76 (dd, J=9.6, 5.7 Hz, 1 H, H10), 2.45 (dd, J=14.5, 4.6 Hz, 1 H, H7), 1.97- 1.57 (m, 5 H, H7, H8 and H9), 1.31 (br s, 9 H, COC(CH3)3), 0.87 (s, 9 H, SiC(CH3)3), 0.19 (s, 12 H, Si(CH3)3), 0.06 (s, 3 H, SiCH3); MS (FAB+) m/e (rel intensity) 830 (M+Cs, 100), 681 (6), 624 (9), 534 (11); HRMS for C40H51NO6Si2Cs (M+Cs), calcd 830.2309, found 830.2361. Minor isomer: Rf =0.22 (silica, 10 percent ethyl ether in petroleum ether); IR (CHCl3) νmax 2958, 2933, 1747 (shoulder), 1721, 1494, 1381, 1306, 1256, 1181, 1118, 909, 844 cm-1 ; 1H NMR (300MHz, CDCl3) δ 7.58 (d, J=8.7 Hz, 1 H, H1), 7.40-7.10 (m, 6 H, H4 and aromatic), 6.95 (dd, J=8.7, 2.5 Hz, 1 H, H2), 5.80-5.60 (m, 3 H, H6 and olefinic), 4.89 (d, J=2.4 Hz, 1 H, H10), 2.66-2.50 (m, 1 H, H7), 2.18-1.63 (m, 5 H, H7, H8 and H9), 1.31 (br s, 9 H, COC(CH3)3), 0.94 and 0.79 (s, 9 H, SiC(CH3)3), 0.23, 0.21 and 0.19 (s, 9 H, Si(CH3)3), 0.14 (s, 3 H, SiCH3), 0.06 (s, 3 H, SiCH3); MS (FAB+) m/e (rel intensity) 830 (M+Cs, 100), 708 (8), 640 (13), 534 (7); HRMS for C40H51NO6Si2Cs (N+Cs), calcd 830.2309, found 830.2296.
Reaction SMILES: I[CH2:2][C@@H:3]([CH3:18])[CH2:4][N:5]1[C:10]2[CH:11]=[C:12]([O:15][CH3:16])[CH:13]=[CH:14][C:9]=2[O:8][CH2:7][C:6]1=[O:17].[CH2:19]([CH:24]1[CH2:30][CH:29]2[NH:31][CH:26]([CH2:27][CH2:28]2)[CH2:25]1)[CH2:20][CH2:21][CH2:22][CH3:23]>CCCCCCC.CCOC(C)=O>[CH3:16][O:15][C:12]1[CH:13]=[CH:14][C:9]2[O:8][CH2:7][C:6](=[O:17])[N:5]([CH2:4][C@H:3]([CH3:18])[CH2:2][N:31]3[CH:26]4[CH2:27][CH2:28][CH:29]3[CH2:30][CH:24]([CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])[CH2:25]4)[C:10]=2[CH:11]=1
Reactant: COc1ccc2c(c1)N(C[C@H](C)CI)C(=O)CO2
Reactant: CCCCCC1CC2CCC(C1)N2
Solvent: CCCCCCC
Solvent: CCOC(C)=O
Product: CCCCCC1CC2CCC(C1)N2C[C@@H](C)CN1C(=O)COc2ccc(OC)cc21
Yield: 43.5 %

Procedure:
The compound (S)-4-(3-Iodo-2-methylpropyl)-6-methoxy-4H-benzo[1,4]oxazin-3-one (111MF36) (0.226 g, 0.63 mmol) and 3-pentyl-8-azabicyclo[3.2.1]octane (0.101 g, 0.56 mmol) were mixed according to GP16. CC (SiO2; heptane/EtOAc 4:1-4) and prep HPLC gave the title compound (111MF41) (0.101 g, 39%). 1H NMR (CDCl3) δ 6.89 (d, J=8.8 Hz, 1H), 6.81 (d, J=2.8 Hz, 1H), 6.49 (dd, J=8.8 Hz, J=2.8 Hz, 1H), 4.60-4.46 (m, 2H), 4.01 (d, J=6.8 Hz, 2H), 3.77 (s, 3H), 3.15-3.02 (m, 2H), 2.32-2.26 (m, 1H), 2.20-1.79 (m; 7H), 1.68-1.51 (m, 3H), 1.42-1.16 (m, 10H), 0.89-0.85 (m, 6H); 13C NMR (CDCl3) δ 168.4, 155.6, 139.8, 129.8, 117.0, 106.9, 103.8, 68.0, 60.6, 59.1, 58.1, 56.0, 45.3, 39.4, 36.6, 36.4, 32.2, 31.5, 28.4, 28.4, 28.0, 27.3, 22.8, 16.8, 14.2; HPLC-MS (ammonium acetate) [M+H]+=415.3.
Reaction SMILES: Cl[C:2]1[NH:3][CH:4]=[C:5]([N+:7]([O-:9])=[O:8])[N:6]=1.[CH3:10][C:11]1([CH2:14][N:15]2[CH2:20][CH2:19][N:18]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:17][CH2:16]2)[CH2:13][O:12]1.C([O-])(=O)C.[Na+]>C(O)CC.C(Cl)Cl>[C:24]([O:23][C:21]([N:18]1[CH2:17][CH2:16][N:15]([CH2:14][C:11]2([CH3:13])[O:12][C:2]3=[N:6][C:5]([N+:7]([O-:9])=[O:8])=[CH:4][N:3]3[CH2:10]2)[CH2:20][CH2:19]1)=[O:22])([CH3:27])([CH3:26])[CH3:25]
Reactant: CC(C)(C)OC(=O)N1CCN(CC2(C)CO2)CC1
Reactant: O=[N+]([O-])c1c[nH]c(Cl)n1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CCCO
Product: CC(C)(C)OC(=O)N1CCN(CC2(C)Cn3cc([N+](=O)[O-])nc3O2)CC1
Yield: 23.3 %

Procedure:
2-Chloro-4-nitro-1H-imidazole (3.19 g, 21.6 mmol) and tert-butyl 4-(2-methyloxiran-2-ylmethyl)-piperazine-1-carboxylate (5.53 g, 21.6 mmol) and sodium acetate (1.95 g, 23.8 mmol) were dissolved in 1-propanol (50 ml) followed by stirring under reflux for 48 hours. The reaction mixture was diluted with methylene chloride. The solution was washed with water and a saturated saline solution, dried over sodium sulfate and then filtered. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (methylene chloride/methanol=100/1) and treated with methylene chloride-diisopropyl ether to afford 2-(4-tert-butoxycarbonylpiperazin-1-yl)methyl-2-methyl-6-nitro-2,3-dihydroimidazo[2,1-b]oxazole (1.85 g, yield 23%) as a white powder.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([O:11][CH2:12][CH:13]2[CH2:17][C:16]3[CH:18]=[CH:19][CH:20]=[C:21](Br)[C:15]=3[O:14]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[CH3:23][O:24][C:25]1[CH:30]=[CH:29][C:28](B(O)O)=[CH:27][CH:26]=1.C(=O)([O-])[O-].[K+].[K+]>CC1C=CC=CC=1[P](C1C=CC=CC=1C)([Pd](Cl)(Cl)[P](C1=C(C)C=CC=C1)(C1C=CC=CC=1C)C1C=CC=CC=1C)C1C=CC=CC=1C>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([O:11][CH2:12][CH:13]2[CH2:17][C:16]3[CH:18]=[CH:19][CH:20]=[C:21]([C:28]4[CH:29]=[CH:30][C:25]([O:24][CH3:23])=[CH:26][CH:27]=4)[C:15]=3[O:14]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: Cc1ccc(S(=O)(=O)OCC2Cc3cccc(Br)c3O2)cc1
Reactant: COc1ccc(B(O)O)cc1
Agent: Cc1ccccc1[P](c1ccccc1C)(c1ccccc1C)[Pd](Cl)(Cl)[P](c1ccccc1C)(c1ccccc1C)c1ccccc1C
Agent: O=C([O-])[O-]
Agent: [K+]
Product: COc1ccc(-c2cccc3c2OC(COS(=O)(=O)c2ccc(C)cc2)C3)cc1
Yield: 68.5 %

Procedure:
Treatment of (±)-(7-bromo-2,3-dihydro-1-benzofuran-2-yl)methyl 4-methylbenzenesulfonate (3.0 g, 7.82 mmol) with 4-methoxyphenylboronic acid (1.78 g, 11.74 mmol), dichlorobis(tri-o-tolylphosphine)-palladium(II) (0.307 g, 0.391 mmol), and potassium carbonate (2.70 g, 19.57 mmol) generally according to the procedure described for Intermediate 37 provided 2.2 g (68%) of (±)-[7-(4-methoxyphenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl 4-methylbenzenesulfonate as a yellow solid. mp 116-117° C.; Anal. calcd. for C23H22O5S: C, 67.30; H, 5.40. Found: C, 67.31; H, 5.35.
Reaction SMILES: [CH:1]1[C:6]([NH2:7])=[CH:5][CH:4]=[C:3]([S:8]([NH:11][C:12]2[S:16][CH:15]=[CH:14][N:13]=2)(=[O:10])=[O:9])[CH:2]=1.N1C=CC=CC=1.[Cl:23][CH:24]([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[C:25](Cl)=[O:26]>C(Cl)Cl>[Cl:23][CH:24]([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[C:25]([NH:7][C:6]1[CH:1]=[CH:2][C:3]([S:8](=[O:10])(=[O:9])[NH:11][C:12]2[S:16][CH:15]=[CH:14][N:13]=2)=[CH:4][CH:5]=1)=[O:26]
Reactant: Nc1ccc(S(=O)(=O)Nc2nccs2)cc1
Reactant: O=C(Cl)C(Cl)c1ccccc1
Solvent: c1ccncc1
Solvent: ClCCl
Product: O=C(Nc1ccc(S(=O)(=O)Nc2nccs2)cc1)C(Cl)c1ccccc1

Procedure:
Synthesized according to general procedure 1: N′-(2-thiazolyl)sulfanilamide (5.60 g, 22 mmol), pyridine (3.6 mL, 44 mmol), 2-chloro-2-phenyl acetylchloride (3.8 mL, 26.4 mmol, 1.2 equiv) in DCM (400 mL). Yield: 6.73 g (75%) of a white solid. 1H-NMR (DMSO-d6) δ 10.85 (s, 1H), 7.78-7.72 (m, 4H), 7.60-7.57 (m, 2H), 7.45-7.37 (m, 3H), 7.25 (d, J=4.6 Hz, 1H), 6.82 (d, J=4.6 Hz, 1H), 5.77 (s, 1H). LC/MS (10-99%) M/Z: M+1 obs=408.1; tR=2.61 min.
Reaction SMILES: [NH2:1][CH2:2][CH:3]([C:5]1[CH:10]=[C:9]([C:11]([CH3:14])([CH3:13])[CH3:12])[C:8]([OH:15])=[C:7]([C:16]([CH3:19])([CH3:18])[CH3:17])[CH:6]=1)[OH:4].O=[C:21]([CH3:35])[CH2:22][O:23][C:24]1[CH:29]=[CH:28][C:27]([CH2:30][C:31]([O:33][CH3:34])=[O:32])=[CH:26][CH:25]=1.C1C=CC=CC=1.C([BH3-])#N.[Na+]>CO>[CH3:34][O:33][C:31]([CH2:30][C:27]1[CH:26]=[CH:25][C:24]([O:23][CH2:22][CH:21]([NH:1][CH2:2][CH:3]([C:5]2[CH:10]=[C:9]([C:11]([CH3:12])([CH3:13])[CH3:14])[C:8]([OH:15])=[C:7]([C:16]([CH3:19])([CH3:18])[CH3:17])[CH:6]=2)[OH:4])[CH3:35])=[CH:29][CH:28]=1)=[O:32]
Reactant: COC(=O)Cc1ccc(OCC(C)=O)cc1
Reactant: CC(C)(C)c1cc(C(O)CN)cc(C(C)(C)C)c1O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: c1ccccc1
Product: COC(=O)Cc1ccc(OCC(C)NCC(O)c2cc(C(C)(C)C)c(O)c(C(C)(C)C)c2)cc1
Yield: 45 %

Procedure:
A procedure similar to that described in Example 6 was repeated, except that 3 g of 2-amino-1-(3,5-di-t-butyl-4-hydroxyphenyl)ethanol (prepared as described in Preparation 35), 2.2 g of methyl 4-(2-oxopropoxy)phenylacetate (prepared as described in Preparation 3), 100 ml of benzene, 60 ml of absolute methanol and 4 g of sodium cyanoborohydride were used, and that the product was purified by repeated column chromatography through silica gel, using as the eluent first ethyl acetate and then a 1:1 by volume mixture of benzene and ethyl acetate. 2.1 g of 2-[2-(4-methoxycarbonylmethylphenoxy)-1-methylethyl]amino-1-(3,5-di-t-butyl-4-hydroxyphenyl)ethanol were obtained. This product was then mixed with 246 mg of fumaric acid, and the mixture was recrystallized from ethyl acetate, to give 1.5 g of the title compound as crystals, melting at 171°-174° C.