Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([CH2:12][O:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([C:21]([NH:23][CH2:24][CH2:25][C:26]#[N:27])=O)[CH:16]=1)[C:10]#[N:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O.C[Si]([N:65]=[N+:66]=[N-:67])(C)C>C(#N)C>[C:1]([O:5][C:6]([NH:8][C@H:9]([CH2:12][O:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([C:21]2[N:23]([CH2:24][CH2:25][C:26]#[N:27])[N:67]=[N:66][N:65]=2)[CH:16]=1)[C:10]#[N:11])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: C[Si](C)(C)N=[N+]=[N-]
Reactant: CC(C)(C)OC(=O)N[C@@H](C#N)COCc1cccc(C(=O)NCCC#N)c1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CC#N
Product: CC(C)(C)OC(=O)N[C@@H](C#N)COCc1cccc(-c2nnnn2CCC#N)c1
Temperature: 30 °C
Reaction time: 0.5 h

Procedure:
To a solution of (S)-2-t-butoxycarbonylamino-3-[3-(2-cyanoethylaminocarbonyl)-benzyloxy]-propionitrile (3.8 g, 10.2 mmol) and triphenylphosphine (6.7 g, 25.5 mmol) in acetonitrile (75 mL) at 0° C. is added diisopropyl azodicarboxylate (5.0 mL, 25.5 mmol) and trimethylsilyl azide (3.73 mL, 28.1 mmol) dropwise, simultaneously, via syringe. The solution is then stirred at room temp. for 0.5 h, and then heated to 30° C. overnight. After solvent evaporation, the residue is taken up in EtOAc (150 mL), and then poured onto an ice—sat'd NaHCO3 mixture (150 mL), and extracted. The organic phase is washed with brine (100 mL), dried (MgSO4), evaporated and chromatographed (silica, 65% EtOAc/hexane) to yield (S)-2-t-butoxycarbonylamino-3-{3-[1-(2-cyanoethyl)-5-tetrazolyl]-benzyloxy}-propionitrile, as a light yellow oil.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[N:7]1[C:15]2[C:10](=[CH:11][C:12]([C:16]3[N:20]=[CH:19][N:18]([C:21]([C:34]4[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=4)([C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=4)[C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)[N:17]=3)=[CH:13][CH:14]=2)[C:9]([C:40]2[CH:41]=[C:42]([CH:47]=[CH:48][CH:49]=2)[C:43]([O:45]C)=O)=[N:8]1.O.[OH-].[Li+].[CH2:53]1[C:61]2[C:56](=[CH:57][CH:58]=[CH:59][CH:60]=2)[CH2:55][NH:54]1.O.ON1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC>O1CCCC1.O1CCCC1.O>[O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[N:7]1[C:15]2[C:10](=[CH:11][C:12]([C:16]3[N:20]=[CH:19][N:18]([C:21]([C:22]4[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=4)([C:28]4[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=4)[C:34]4[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=4)[N:17]=3)=[CH:13][CH:14]=2)[C:9]([C:40]2[CH:41]=[C:42]([C:43]([N:54]3[CH2:55][C:56]4[C:61](=[CH:60][CH:59]=[CH:58][CH:57]=4)[CH2:53]3)=[O:45])[CH:47]=[CH:48][CH:49]=2)=[N:8]1
Reactant: c1ccc2c(c1)CNC2
Reactant: COC(=O)c1cccc(-c2nn(C3CCCCO3)c3ccc(-c4ncn(C(c5ccccc5)(c5ccccc5)c5ccccc5)n4)cc23)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: C1CCOC1
Product: O=C(c1cccc(-c2nn(C3CCCCO3)c3ccc(-c4ncn(C(c5ccccc5)(c5ccccc5)c5ccccc5)n4)cc23)c1)N1Cc2ccccc2C1
Temperature: 60 °C
Reaction time: 18 h
Yield: 52.9 %

Procedure:
To a stirred solution of methyl 3-{1-perhydro-2H-pyran-2-yl-5-[1-(triphenylmethyl)(1,2,4-triazol-3-yl)]-1H-indazol-3-yl}benzoate (0.400 g, 0.619 mmol) in a tetrahydrofuran/water mixture (2.50 mL/1.00 mL) was added lithium hydroxide monohydrate (0.0780 g, 1.86 mmol) and the mixture heated at 60° C. for 21 h. To this mixture was added tetrahydrofuran (2.00 mL), isoindoline (0.211 mL, 1.86 mmol), 1-hydroxybenzotriazole hydrate (0.251 g, 1.86 mmol) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.356 g, 1.86 mmol). This mixture was stirred for 18 h at ambient temperature. After the mixture was extracted with ethyl acetate (2×), the combined organic extracts were washed with aqueous saturated sodium bicarbonate, followed by brine, dried over anhydrous sodium sulfate, filtered and evaporated. Purification of the residue by flash chromatography with 30-70% ethyl acetate/hexanes gave the title compound (0.240 g, 53% yield). ES-MS (m/z) 491 [M+1(−Tr)]+
Reaction SMILES: Br[C:2]1[C:10]2[N:9]3[CH2:11][CH2:12][NH:13][C:14](=[O:15])[C:8]3=[C:7]([CH3:16])[C:6]=2[CH:5]=[C:4]([Cl:17])[CH:3]=1.[C:18]([C:20]1[CH:21]=[C:22](B(O)O)[CH:23]=[CH:24][CH:25]=1)#[N:19]>>[Cl:17][C:4]1[CH:3]=[C:2]([C:24]2[CH:25]=[C:20]([CH:21]=[CH:22][CH:23]=2)[C:18]#[N:19])[C:10]2[N:9]3[CH2:11][CH2:12][NH:13][C:14](=[O:15])[C:8]3=[C:7]([CH3:16])[C:6]=2[CH:5]=1
Reactant: Cc1c2n(c3c(Br)cc(Cl)cc13)CCNC2=O
Reactant: N#Cc1cccc(B(O)O)c1
Product: Cc1c2n(c3c(-c4cccc(C#N)c4)cc(Cl)cc13)CCNC2=O

Procedure:
The title compound, white solid (76 mg, 91%), MS (ISP) m/z=336.5 [(M+H)+], mp 199° C., was prepared in accordance with the general method of example 1 from 6-bromo-8-chloro-10-methyl-3,4-dihydro-2H-pyrazino[1,2-a]indol-1-one (intermediate 12) (78.4 mg, 0.25 mmol) and commercially available 3-cyano-phenylboronic acid (47.8 mg, 0.325 mmol).
Reaction SMILES: C([O:3][C:4]([C:6]1[NH:7][C:8]2[C:13]([CH:14]=1)=[CH:12][C:11]([C:15]1[CH:20]=[CH:19][C:18]([O:21][C:22]([F:25])([F:24])[F:23])=[CH:17][CH:16]=1)=[CH:10][CH:9]=2)=[O:5])C.Br[C:27]1[CH:32]=[CH:31][C:30]([O:33][CH3:34])=[CH:29][CH:28]=1>>[CH3:34][O:33][C:30]1[CH:31]=[CH:32][C:27]([N:7]2[C:8]3[C:13](=[CH:12][C:11]([C:15]4[CH:16]=[CH:17][C:18]([O:21][C:22]([F:23])([F:25])[F:24])=[CH:19][CH:20]=4)=[CH:10][CH:9]=3)[CH:14]=[C:6]2[C:4]([OH:3])=[O:5])=[CH:28][CH:29]=1
Reactant: CCOC(=O)c1cc2cc(-c3ccc(OC(F)(F)F)cc3)ccc2[nH]1
Reactant: COc1ccc(Br)cc1
Product: COc1ccc(-n2c(C(=O)O)cc3cc(-c4ccc(OC(F)(F)F)cc4)ccc32)cc1

Procedure:
The title compound was prepared from 5-(4-(trifluoromethoxy)-phenyl)indole-2-carboxylic acid ethyl ester (prepared in accordance with Example 1(a) from 5-bromoindole-2-carboxylic acid ethyl ester and 4-(trifluoromethoxy)phenylboronic acid) and 1-bromo-4-methoxybenzene in accordance with the procedure described in Example 9(b), followed by hydrolysis in accordance with the procedure described in Example 1(c).
Reaction SMILES: [CH2:1]([OH:9])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].[C:10](O)(=[O:14])/[CH:11]=[CH:12]/[CH3:13]>CC1C=CC(S(O)(=O)=O)=CC=1.C1(C)C=CC=CC=1>[CH2:1]([O:9][C:10](=[O:14])[CH:11]=[CH:12][CH3:13])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8]
Reactant: C/C=C/C(=O)O
Reactant: CCCCCCCCO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: CC=CC(=O)OCCCCCCCC
Temperature: 125 °C
Yield: 81.1 %

Procedure:
Octan-1-ol (221 g), crotonic acid (194 g), PTSA (6.4 g), and toluene (300 mL) were charged into a 2-L reaction flask fitted with a mechanical stirrer, a thermocouple, a Dean-Stark trap, and a condenser. The reaction mixture was heated to reflux at about 120-130° C. Water was removed azeotropically. The reaction was aged at reflux for about 7-8 hours until no more water evolved. The reaction mixture was cooled to room temperature and quenched with water (400 mL). The organic layer was separated and subsequently washed with sodium carbonate (5%, 300 mL), and further fractional distilled to provide but-2-enoic acid octyl ester (273 g) with a boiling point of 123° C. at 11 mmHg.
Reaction SMILES: [C:1]1([C:7]2[N:11]=[C:10]([N:12]3[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]3)[S:9][N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[O:18]1[C:22]2=[N:23][CH:24]=[CH:25][CH:26]=[C:21]2[C:20]([N:27](C(OCC(Cl)(Cl)Cl)=O)[C:28](OCC(Cl)(Cl)Cl)=[O:29])=[N:19]1.C(N(C(C)C)CC)(C)C.CS(C)=O>O>[O:18]1[C:22]2=[N:23][CH:24]=[CH:25][CH:26]=[C:21]2[C:20]([NH:27][C:28]([N:15]2[CH2:16][CH2:17][N:12]([C:10]3[S:9][N:8]=[C:7]([C:1]4[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=4)[N:11]=3)[CH2:13][CH2:14]2)=[O:29])=[N:19]1
Reactant: c1ccc(-c2nsc(N3CCNCC3)n2)cc1
Reactant: O=C(OCC(Cl)(Cl)Cl)N(C(=O)OCC(Cl)(Cl)Cl)c1noc2ncccc12
Solvent: O
Solvent: CS(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(Nc1noc2ncccc12)N1CCN(c2nc(-c3ccccc3)ns2)CC1
Temperature: 70 °C
Reaction time: 5 h
Yield: 58.9 %

Procedure:
A mixture of 1-(3-phenyl-1,2,4-thiadiazol-5-yl)piperazine (738 mg, 3.00 mmol), bis(2,2,2-trichloroethyl) isoxazolo[5,4-b]pyridin-3-ylimidodicarbonate (486 mg, 1.00 mmol), diisopropylethylamine (0.348 ml, 2.00 mmol) and dimethyl sulfoxide (5 ml) was stirred at 70° C. for 5 hours. The reaction mixture was poured to water and extracted with ethyl acetate. The extract was washed with water and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was recrystallized from tetrahydrofuran to yield 240 mg (59.0%) of the desired product.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-])=O)=[CH:4][N:3]=1.[CH2:11]([O:18][CH:19]1[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>>[CH2:11]([O:18][CH:19]1[CH2:24][CH2:23][N:22]([C:2]2[N:3]=[CH:4][C:5]([NH2:8])=[CH:6][CH:7]=2)[CH2:21][CH2:20]1)[C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: O=[N+]([O-])c1ccc(Cl)nc1
Reactant: c1ccc(COC2CCNCC2)cc1
Product: Nc1ccc(N2CCC(OCc3ccccc3)CC2)nc1

Procedure:
Intermediate B-23 was prepared by the general procedure for intermediate B-2, by using 2-chloro-5-nitropyridine and 4-benzyloxypiperidine as starting materials. MS (M+1): 284.
Reaction SMILES: [Br:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][C:12]([OH:14])=O.CN(C=O)C.S(Cl)([Cl:22])=O>ClCCl>[Br:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][C:12]([Cl:22])=[O:14]
Reactant: O=S(Cl)Cl
Reactant: O=C(O)CCCCCCCCCCBr
Solvent: CN(C)C=O
Solvent: ClCCl
Product: O=C(Cl)CCCCCCCCCCBr
Temperature: 39 °C
Yield: 36.9 %

Procedure:
20.0 g of 11-bromoundecanoic acid (0.0754 mol) are placed in 20 ml dichloromethane in the presence of 0.28 g DMF (0.05 eq). The reaction mixture is heated to reflux and 10.68 g of thionyl chloride (0.0905 mol) are added drop wise over a period of 1 h 40 min at 39° C. After 3 h at 39° C. the reaction mixture is cooled down to r.t. and evaporated to dryness, yielding to 7.9 g of the expected compound.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][CH3:5].NC(N)=O.S(=O)(=O)(O)O.NC(N)=O.S(=O)(=O)(O)O.[CH:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>>[CH2:2]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[CH2:3][CH2:4][CH3:5]
Reactant: c1ccccc1
Reactant: CCCCCl
Agent: NC(N)=O
Agent: O=S(=O)(O)O
Product: CCCCc1ccccc1
Reaction time: 0.17 h

Procedure:
Normal-butylbenzene is prepared by heating equal molar amounts of 1-chlorobutane and benzene in a molten urea-sulfuric acid component containing 42.6 weight percent urea and 75.4 weight percent sulfuric acid having a urea/sulfuric acid molar ratio of 1.2 at a temperature of 140° F. and a pressure of 100 psig. for a period of 10 minutes. The n-butylbenzene product is recovered by cooling the reaction mixture to solidify the urea-sulfuric acid component melt and extracting the resulting mixture with toluene. The n-butylbenzene product is removed from the toluene solvent by distilling the solvent, and the urea-sulfuric acid component is re-melted and recycled to the process.
Reaction SMILES: [I:1][C:2]1[CH:11]=[N:10][C:5]2[NH:6][CH2:7][CH2:8][NH:9][C:4]=2[CH:3]=1.[Cl:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[S:19](Cl)(=[O:21])=[O:20]>N1C=CC=CC=1>[Cl:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[S:19]([N:9]1[CH2:8][CH2:7][NH:6][C:5]2[N:10]=[CH:11][C:2]([I:1])=[CH:3][C:4]1=2)(=[O:21])=[O:20]
Reactant: O=S(=O)(Cl)c1ccccc1Cl
Reactant: Ic1cnc2c(c1)NCCN2
Solvent: c1ccncc1
Product: O=S(=O)(c1ccccc1Cl)N1CCNc2ncc(I)cc21
Temperature: 100 °C
Yield: 10 %

Procedure:
7-Iodo-1,2,3,4-tetrahydropyrido[2,3-b]pyrazine (300 mg) was dissolved in anhydrous pyridine. 2-chlorobenzene sulfonyl chloride (1.0 eq) was added and the reaction mixture was heated to 100° C. in a microwave oven for 10 minutes. Silica gel chromatography gave the title compound as a pale orange solid (10% yield). M.p. 146-147° C., LCMS: m/z=435.94 (M+H+), 1H-NMR (CDCl3, 400 MHz) δ 3.30-3.35 (m, 2H), 3.80 (t, J=5.0 Hz, 2H), 5.02 (bs, 1H), 7.42-4.57 (m, 3H), 7.81 (d, J=1.8 Hz, 1H), 8.00 (d, J=1.8 Hz, 1H), 8.10 (dd, J=8.6 Hz, 1.5 Hz, 1H).
Reaction SMILES: [I:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6](=[O:15])[C:7](C(O)=O)=[CH:8][NH:9]2)=[CH:4][C:3]=1[CH3:16].C1C=CC(C2C=CC=CC=2)=CC=1.C1C=CC(OC2C=CC=CC=2)=CC=1>CCCCCCC>[I:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6](=[O:15])[CH:7]=[CH:8][NH:9]2)=[CH:4][C:3]=1[CH3:16]
Reactant: Cc1cc2c(=O)c(C(=O)O)c[nH]c2cc1I
Solvent: c1ccc(Oc2ccccc2)cc1
Solvent: CCCCCCC
Solvent: c1ccc(-c2ccccc2)cc1
Product: Cc1cc2c(=O)cc[nH]c2cc1I
Reaction time: 1.5 h
Yield: 90.7 %

Procedure:
Under vigorous stirring, 7-iodo-6-methyl-4-oxo-1,4-dihydro-quinoline-3-carboxylic acid (6.50 g, 19.8 mmol) was added portionwise to Dowtherm® A (120 mL) at 250° C., then the mixture was stirred for another 90 min. After cooling, heptane (170 mL) was added, and the precipitate was collected by filtration. The crude material was triturated in hexane/ethyl acetate (1:1) to afford the title compound (5.12 g, 91%). Off-white solid, ISP-MS: m/e=286.1 ([M+H]+).
Reaction SMILES: Br[CH2:2][O:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.C([Mg]Cl)(C)C.[CH:15](N1CCCCC1)=[O:16]>O1CCCC1>[CH3:2][O:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[CH:15]=[O:16]
Reactant: BrCOc1ccccc1
Reactant: O=CN1CCCCC1
Agent: CC(C)[Mg]Cl
Solvent: C1CCOC1
Product: COc1ccccc1C=O

Procedure:
Alternatively, treatment of the methoxybenzene (6a) with bromine in acetic acid in the presence of iron(0) provides the 2-bromomethoxybenzene (6c). Reaction of (6c) with isopropylmagnesium chloride and 1-formylpiperidine in a solvent such as tetrahydrofuran affords the 2-methoxybenzaldehyde (2d). Removal of the methyl group is accomplished by reaction of the 2-methoxybenzaldehyde (2d) with boron tribromide in a solvent such as dichloromethane to give the 2-hydroxybenzaldehyde (2c).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]2[N:14]=[C:13]([N:15]3[CH2:20][CH2:19][NH:18][C@@H:17]([CH2:21][CH2:22][CH2:23][O:24][CH3:25])[CH2:16]3)[C:12]3[CH:11]=[C:10]([CH3:26])[S:9][C:8]=3[NH:7][C:6]=2[CH:27]=1.C=O.[C:30](O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClC(Cl)C.C(=O)(O)[O-].[Na+]>[F:1][C:2]1[CH:3]=[CH:4][C:5]2[N:14]=[C:13]([N:15]3[CH2:20][CH2:19][N:18]([CH3:30])[C@@H:17]([CH2:21][CH2:22][CH2:23][O:24][CH3:25])[CH2:16]3)[C:12]3[CH:11]=[C:10]([CH3:26])[S:9][C:8]=3[NH:7][C:6]=2[CH:27]=1
Reactant: COCCC[C@H]1CN(C2=Nc3ccc(F)cc3Nc3sc(C)cc32)CCN1
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: C=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(Cl)Cl
Product: COCCC[C@H]1CN(C2=Nc3ccc(F)cc3Nc3sc(C)cc32)CCN1C
Yield: 88.9 %

Procedure:
Combine (S)-6-fluoro-10-[3-(3-methoxy-propyl)-piperazin-1-yl]-2-methyl-4H-3-thia-4,9-diaza-benzo[f]azulene (0.105 g, 0.270 mmol), formaldehyde (31 μL, 0.378 mmol, 37%), and sodium triacetoxyborohydride (0.086 g, 0.405 mmol) in dichloroethane (6 mL) and stir at room temperature overnight. Dilute the mixture with saturated sodium bicarbonate and extract three times with methylene chloride. Combine the organic layers, dry over sodium sulfate and concentrate under reduced pressure to give the crude product. Purification by flash chromatography, eluting with a step gradient starting with dichloromethane going to 5% 2N ammonia-methanol in dichloromethane gives (S)-6-fluoro-10-[3-(3-methoxy-propyl)-4-methyl-piperazin-1-yl]-2-methyl-4H-3-thia-4,9-diaza-benzo[f]azulene (0.097 g, 0.240 mmol, 89%) as a yellow oil. Mass spectrum (APCI): m/z=403.1 (M+1). Isolate clean product as the corresponding dihydrochloride in the following manner: dissolve the yellow foam in ethanol (5 mL) and add a solution of about 5 equivalents of HCl in ethanol (5 mL). Evaporate the mixture to obtain (S)-6-fluoro-10-[3-(3-methoxy-propyl)-4-methyl-piperazin-1-yl]-2-methyl-4H-3-thia-4,9-diaza-benzo[f]azulene dihydrochloride.
Reaction SMILES: [CH:1]12[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[C:2]1=[O:11])[CH2:8]2.C([O-])([O-])=[O:13].C([O-])([O-])=O.OO.OO.OO.[Na+].[Na+].[Na+].[Na+].C([O-])(O[O-])=O.[Na+].[Na+].O>C(O)(C(F)(F)F)=O>[CH2:6]1[C@@H:5]2[CH2:10][CH:1]3[O:13][C:2](=[O:11])[CH:3]([CH2:4]2)[CH2:9][C@@H:7]1[CH2:8]3
Reactant: O=C1C2CC3CC(C2)CC1C3
Reactant: O=C([O-])[O-]
Agent: O=C([O-])O[O-]
Agent: OO
Agent: [Na+]
Solvent: O
Solvent: O=C(O)C(F)(F)F
Product: O=C1OC2C[C@@H]3CC1C[C@H](C2)C3
Temperature: 20 °C
Yield: 106.6 %

Procedure:
Commercially available 2-adamantanone (×1) (1000 g, 6.66 mol, Sigma-Aldrich) was dissolved in TFA (3 L, Sigma-Aldrich). To this mechanically stirred mixture surrounded by a cooling bath with a temperature maintained at 20° C. was added sodium percarbonate (1254.8 g, 7.99 mol, Sigma-Aldrich) (or sodium peroxocarbonate) portion-wise over 1 h; the temperature of the reaction mixture increased to 60° C. during the addition. After 2 h additional stirring, deionized water (4 L) was added followed by four extractions with DCM (2 L for each extraction). The organic portions were combined, dried (MgSO4), filtered, and evaporated under reduced pressure to provide 1180 g of (1R,3r,6s,8S)-4-oxatricyclo[4.3.1.13,8]undecan-5-one (×2) as a white crystalline solid (yield 97%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([OH:14])[C:9]([O:11][CH2:12][CH3:13])=[O:10])=[CH:4][C:3]=1[NH:15][C:16](=[O:37])[C:17]1[CH:22]=[CH:21][C:20]([O:23][CH2:24][C@@H:25]2[CH2:30][N:29]([CH3:31])[C:28]3[CH:32]=[CH:33][CH:34]=[CH:35][C:27]=3[O:26]2)=[CH:19][C:18]=1[Cl:36].C(N(C(C)C)CC)(C)C.CS(C)=O.C(OCC)(=O)C>O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:14])[C:9]([O:11][CH2:12][CH3:13])=[O:10])=[CH:4][C:3]=1[NH:15][C:16](=[O:37])[C:17]1[CH:22]=[CH:21][C:20]([O:23][CH2:24][C@@H:25]2[CH2:30][N:29]([CH3:31])[C:28]3[CH:32]=[CH:33][CH:34]=[CH:35][C:27]=3[O:26]2)=[CH:19][C:18]=1[Cl:36]
Reactant: CCOC(=O)C(O)c1ccc(Cl)c(NC(=O)c2ccc(OC[C@@H]3CN(C)c4ccccc4O3)cc2Cl)c1
Solvent: O
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: CCOC(=O)C(=O)c1ccc(Cl)c(NC(=O)c2ccc(OC[C@@H]3CN(C)c4ccccc4O3)cc2Cl)c1
Reaction time: 1 h

Procedure:
Under argon atmosphere, to a mixture of the compound (159 mg) prepared in Example 31, diisopropylethylamine (0.30 mL), dimethylsulfoxide (2 mL), and ethyl acetate (4 mL), sulfur trioxide pyridine complex (139 mg) were added at ice-cold temperature, and the mixture was stirred for 1 hour at the same temperature. Water was added to the reaction mixture, which was extracted with ethyl acetate. The organic layer was washed with water and saturated brine solution and was dried by anhydrous magnesium sulphate. The title compound (104 mg) having the following physical data was obtained by purifying the residue obtained by removing the solvent by silica gel column chromatography (n-hexane:ethyl acetate=3:1→2:1).
Reaction SMILES: [CH3:1][O:2][C@:3]1([C@@H:21]2[CH2:25][S:24][C:23](=[O:26])[N:22]2[CH2:27][C:28]2[CH:33]=[CH:32][C:31]([O:34][CH3:35])=[CH:30][CH:29]=2)[CH2:18][C@H:17]2[CH2:19][C@@H:5]([CH2:6][CH2:7][CH2:8][CH:9]=[CH:10][CH2:11][CH2:12][CH2:13][CH2:14][C:15](=[O:20])[O:16]2)[O:4]1.CO[C@]1([C@@H]2CSC(=O)N2CC2C=CC(OC)=CC=2)C[C@H]2C[C@@H](CCCC=CCCC(C)=CC(=O)O2)O1>>[CH3:1][O:2][C@:3]1([C@@H:21]2[CH2:25][S:24][C:23](=[O:26])[N:22]2[CH2:27][C:28]2[CH:29]=[CH:30][C:31]([O:34][CH3:35])=[CH:32][CH:33]=2)[CH2:18][C@H:17]2[CH2:19][C@@H:5]([CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][C:15](=[O:20])[O:16]2)[O:4]1
Reactant: COc1ccc(CN2C(=O)SC[C@H]2[C@@]2(OC)C[C@H]3C[C@@H](CCCC=CCCCCC(=O)O3)O2)cc1
Agent: COc1ccc(CN2C(=O)SC[C@H]2[C@@]2(OC)C[C@H]3C[C@@H](CCC/C=C\CCCCC(=O)O3)O2)cc1
Agent: COc1ccc(CN2C(=O)SC[C@H]2[C@@]2(OC)C[C@H]3C[C@@H](CCCC=CCC/C(C)=C\C(=O)O3)O2)cc1
Agent: COc1ccc(CN2C(=O)SC[C@H]2[C@@]2(OC)C[C@H]3C[C@@H](CCCC=CCCC(C)=CC(=O)O3)O2)cc1
Product: COc1ccc(CN2C(=O)SC[C@H]2[C@@]2(OC)C[C@H]3C[C@@H](CCCCCCCCCC(=O)O3)O2)cc1

Procedure:
Application of the method shown in Example 41, with the modification that (R)-4-((1R,13R,15R,Z)-15-methoxy-3-oxo-2,14-dioxa-bicyclo[11.3.1]heptadec-8-en-15-yl)-3-(4-methoxybenzyl)thiazolidin-2-one was substituted for (R)-4-((1R,4Z,13R,15R)-15-methoxy-5-methyl-3-oxo-2,14-dioxa-bicyclo[11.3.1]heptadeca-4,8-dien-15-yl)-3-(4-methoxybenzyl)thiazolidin-2-one, afforded the title compound.
Reaction SMILES: [C:1]1(=O)[CH2:4][CH2:3][CH2:2]1.C([O-])(=O)C.[NH4+].[CH3:11][C:12]1([CH3:20])[O:17][C:16](=[O:18])[CH2:15][C:14](=[O:19])[O:13]1.C(O)(=O)C>C1(C)C=CC=CC=1.O>[C:1]1(=[C:15]2[C:16](=[O:18])[O:17][C:12]([CH3:20])([CH3:11])[O:13][C:14]2=[O:19])[CH2:4][CH2:3][CH2:2]1
Reactant: O=C1CCC1
Reactant: CC1(C)OC(=O)CC(=O)O1
Agent: CC(=O)[O-]
Agent: [NH4+]
Solvent: O
Solvent: Cc1ccccc1
Solvent: CC(=O)O
Product: CC1(C)OC(=O)C(=C2CCC2)C(=O)O1
Temperature: 50 °C
Reaction time: 4 h
Yield: 48 %

Procedure:
Cyclobutanone (0.50 g, 7.1 mmol) (Aldrich, Cat. #C96001) was added to a mixture of ammonium acetate (1.1 g, 14 mmol) and 2,2-dimethyl-1,3-dioxane-4,6-dione (1.0 g, 7.1 mmol) (Acros Organics, Cat. #19845) in toluene (10 mL), followed by acetic acid (1.0 mL). The reaction mixture was stirred at 50° C. for 4 h. After cooled to r.t., the mixture was diluted with water, and extracted with ethyl acetate (3×20 mL). The combined organic layers were washed with brine, dried over MgSO4, filtered and concentrated under reduced pressure. The residue was purified by flash chromatography on a silica gel column with ethyl acetate in hexanes (0-30%) to afford the desired product (0.68, 48%).
Reaction SMILES: [Cl:1][CH2:2][C:3]1[CH:11]=[CH:10][C:6]([C:7](Cl)=[O:8])=[CH:5][CH:4]=1.[NH2:12][C:13]1[CH:18]=[C:17]([C:19]2[S:20][CH:21]=[CH:22][CH:23]=2)[CH:16]=[CH:15][C:14]=1[NH:24][C:25](=[O:31])[O:26][C:27]([CH3:30])([CH3:29])[CH3:28].CCN(C(C)C)C(C)C.C([O-])(O)=O.[Na+]>C1COCC1>[Cl:1][CH2:2][C:3]1[CH:11]=[CH:10][C:6]([C:7]([NH:12][C:13]2[CH:18]=[C:17]([C:19]3[S:20][CH:21]=[CH:22][CH:23]=3)[CH:16]=[CH:15][C:14]=2[NH:24][C:25](=[O:31])[O:26][C:27]([CH3:29])([CH3:28])[CH3:30])=[O:8])=[CH:5][CH:4]=1
Reactant: CC(C)(C)OC(=O)Nc1ccc(-c2cccs2)cc1N
Reactant: O=C(Cl)c1ccc(CCl)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)Nc1ccc(-c2cccs2)cc1NC(=O)c1ccc(CCl)cc1
Reaction time: 1 h

Procedure:
4-(chloromethyl)benzoyl chloride (2 g, 10.58 mmol) was dissolved in THF (20 mL) and a solution of tert-butyl [2-amino-4-(2-thienyl)phenyl]carbamate (3.38 g, 11.64 mmol) and DIPEA (2.033 mL, 11.64 mmol) in THF (50 mL) was added dropwise at room temperature. After stirring for 1 hour, saturated NaHCO3 was added and the products extracted into EtOAc (×2). The combined organic extracts were dried over MgSO4 and concentrated in vacuo. The residue was triturated in EtOAc to give tert-butyl [2-{[4-(chloromethyl)benzoyl]amino}-4-(2-thienyl)phenyl]carbamate as a beige powder.
Reaction SMILES: [C:1]([CH2:6][C:7]([O:9][CH2:10][CH3:11])=[O:8])(=[O:5])[CH:2]([CH3:4])[CH3:3].[CH:12](=O)[CH:13]([CH3:15])[CH3:14].N1CCCCC1.C(O)(=O)C>C(O)(C)C.O>[CH2:10]([O:9][C:7](/[C:6](=[CH:12]\[CH:13]([CH3:15])[CH3:14])/[C:1](=[O:5])[CH:2]([CH3:4])[CH3:3])=[O:8])[CH3:11]
Reactant: CCOC(=O)CC(=O)C(C)C
Reactant: CC(C)C=O
Solvent: C1CCNCC1
Solvent: O
Solvent: CC(C)O
Product: CCOC(=O)/C(=C\C(C)C)C(=O)C(C)C

Procedure:
158 g (1 mol) of ethyl isobutyrylacetate, 108 g (1.5 mol) of isobutyraldehyde, 8.75 ml of piperidine and 6.25 ml of acetic acid are stirred at 50° C. for 20 h in 400 ml of isopropanol. Volatile components are stripped off in a water pump vacuum and the residue is subsequently distilled in a high vacuum.
Reaction SMILES: [NH2:1][C:2]1[C:7]2[CH2:8][C:9]([CH3:12])([CH3:11])[O:10][C:6]=2[C:5]([C:13]([O:15][CH3:16])=[O:14])=[CH:4][C:3]=1[NH2:17].O.[N:19]#[C:20]Br>C(O)C>[NH2:19][C:20]1[NH:1][C:2]2[C:7]3[CH2:8][C:9]([CH3:12])([CH3:11])[O:10][C:6]=3[C:5]([C:13]([O:15][CH3:16])=[O:14])=[CH:4][C:3]=2[N:17]=1
Reactant: N#CBr
Reactant: COC(=O)c1cc(N)c(N)c2c1OC(C)(C)C2
Solvent: CCO
Solvent: O
Product: COC(=O)c1cc2nc(N)[nH]c2c2c1OC(C)(C)C2
Yield: 45.2 %

Procedure:
To a solution of methyl 4,5-diamino-2,2-dimethyl-2,3-dihydro-1-benzofuran-7-carboxylate (Intermediate-1, 2.00 g, 8.47 mmol) in ethanol:water (50:4 mL) was added cyanogen bromide (1.07 g, 10.16 mmol). The reaction mass was refluxed for 4-5 h. The reaction mass was quenched in water, neutralised with sodium bicarbonate and extracted with solution of (10%) DCM: methanol. The organic layer was dried over anhydrous sodium sulphate and concentrated to afford 1.0 g of the desired product. 1HNMR (DMSO-d6): δ 1.42 (s, 6H), 3.03 (s, 2H), 3.71 (s, 3H), 6.67 (bs, 2H), 7.33 (s, 1H), 10-11 (bs, 1H). MS [M+H]+: 237.03.