Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(N(CC)CC)C.[S:8](Cl)([CH3:11])(=[O:10])=[O:9].[F:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]2[CH:21]=[CH:22][C:23]([N:26]3[CH2:35][CH2:34][C:29]4([CH2:32][CH:31]([OH:33])[CH2:30]4)[CH2:28][CH2:27]3)=[N:24][CH:25]=2)=[CH:16][CH:15]=1>ClCCl>[CH3:11][S:8]([O:33][CH:31]1[CH2:30][C:29]2([CH2:34][CH2:35][N:26]([C:23]3[CH:22]=[CH:21][C:20]([C:17]4[CH:16]=[CH:15][C:14]([F:13])=[CH:19][CH:18]=4)=[CH:25][N:24]=3)[CH2:27][CH2:28]2)[CH2:32]1)(=[O:10])=[O:9]
Reactant: CS(=O)(=O)Cl
Reactant: OC1CC2(CCN(c3ccc(-c4ccc(F)cc4)cn3)CC2)C1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CS(=O)(=O)OC1CC2(CCN(c3ccc(-c4ccc(F)cc4)cn3)CC2)C1
Yield: 99.7 %

Procedure:
The process is performed according to the procedure described in Example 6 (step 6.2.). 3.25 mL (23.34 mmol) of triethylamine and then 0.91 mL (11.67 mmol) of mesyl chloride are added to a solution of 2.43 g (7.78 mmol) of 7-[5-(4-fluorophenyl)pyridin-2-yl]-7-azaspiro[3.5]nonan-2-ol, obtained in step 10.2., in 25 mL of dichloromethane. 3.03 g of product are obtained in the form of a yellow oil, which is used without further purification in the following step.
Reaction SMILES: C([Si](C)(C)[O:6][C@@H:7]1[C@@:11]([CH:31]([NH:40][CH2:41][C:42]2[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=2)[NH:32][CH2:33][C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)([CH2:12][O:13][Si](C(C)(C)C)(C2C=CC=CC=2)C2C=CC=CC=2)[O:10][C@@H:9]([N:48]2[CH:56]=[C:54]([CH3:55])[C:52](=[O:53])[NH:51][C:49]2=[O:50])[CH2:8]1)(C)(C)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC.CO>O1CCCC1>[C:34]1([CH2:33][NH:32][CH:31]([C@:11]2([CH2:12][OH:13])[O:10][C@@H:9]([N:48]3[CH:56]=[C:54]([CH3:55])[C:52](=[O:53])[NH:51][C:49]3=[O:50])[CH2:8][C@@H:7]2[OH:6])[NH:40][CH2:41][C:42]2[CH:43]=[CH:44][CH:45]=[CH:46][CH:47]=2)[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1
Reactant: Cc1cn([C@H]2C[C@H](O[Si](C)(C)C(C)(C)C)[C@](CO[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)(C(NCc3ccccc3)NCc3ccccc3)O2)c(=O)[nH]c1=O
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: CO
Solvent: C1CCOC1
Product: Cc1cn([C@H]2C[C@H](O)[C@](CO)(C(NCc3ccccc3)NCc3ccccc3)O2)c(=O)[nH]c1=O
Temperature: 25 °C
Reaction time: 3 h
Yield: 92.9 %

Procedure:
3′-O-[(tertbutyl)dimethylsilyl]-5′-O-[(tertbutyl)diphenylsilyl]-4′-C-(1,1′-diphenylmethylaminomethyl)thymidine (2) (1.2 g, 1.5 mmol) was dissolved in tetrahydrofuran (50 mL) at ambient temperature. A solution of tetrabutylammonium fluoride in tetrahydrofuran (4.5 mL) was then added to the solution. The resulting mixture was stirred for 3 hours at ambient temperature. Methanol (5 mL) was then added and the reaction mixture concentrated under vacuum. The residue was purified by flash column chromatography (95:5 dichloromethane:methanol) to give the title compound (3) as an amorphous white solid (0.65 g, 100%) on removal of solvent from the appropriate fractions. δH(300 MHz, d6-DMSO) 11.23(1H, s, br, N3—H), 7.75(1H, s, H-6), 7.41–7.15(10H, m, Ph2CHNH), 6.21(1H, dd, H-1′), 5.57(1H, d, br, 3′-OH), 5.21(1H, t, 5′-OH), 4.78(1H, s, Ph2CHNH), 4.35(1H, m, H-3′), 3.61(2H, 2d, H-5′), 2.54(2H, 2d, 4′-C—CH2), 2.18(2H, m, H-2′), 1.75(3H, s, 5-CH3); δC(75.45 MHz, d6-DMSO) 150.46, 144.53, 144.28, 136.28, 128.36, 126.99, 126.74, 109.17, 88.39, 83.18, 66.79, 64.10, 54.91, 12.27.
Reaction SMILES: C#CC(N1CCCC1C)C.[CH2:11]([N:15]1[CH2:19][CH2:18][CH2:17][C@H:16]1[CH3:20])[CH2:12][C:13]#[CH:14].[Br:21][C:22]1[CH:27]=[CH:26][C:25]([NH2:28])=[C:24](I)[CH:23]=1.C(NC(C)C)(C)C>[Cu]I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[Br:21][C:22]1[CH:27]=[CH:26][C:25]([NH2:28])=[C:24]([C:14]#[C:13][CH2:12][CH2:11][N:15]2[CH2:19][CH2:18][CH2:17][C@H:16]2[CH3:20])[CH:23]=1
Reactant: Nc1ccc(Br)cc1I
Reactant: C#CCCN1CCC[C@H]1C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Agent: C#CC(C)N1CCCC1C
Solvent: CC(C)NC(C)C
Product: C[C@@H]1CCCN1CCC#Cc1cc(Br)ccc1N
Temperature: 25 °C
Reaction time: 2 h
Yield: 97.3 %

Procedure:
To a solution of 1-butyn-3-yl-2-methyl-pyrrolidine in CH3CN (prepared in Example 65A assuming 100% conversion, 89 mmol) was added 4-bromo-2-iodo-phenylamine (12.0 g, 40 mmol) under nitrogen followed by addition of CuI (0.38 g, 2.0 mmol), PdCl2(PPh3)2 (0.70 mg, 1.0 mmol) and diisopropylamine (33.6 mL, 240 mmol). The resulting solution was stirred at room temperature for 2 hours, at which time analytical HPLC analysis indicated that all 4-bromo-2-iodo-phenylamine was consumed. The solvent CH3CN was removed under vacuo and the residue was extracted with IPAC (500 mL) and 5% NaHCO3 (2×300 mL). The organic layer was washed with brine, dried over Na2SO4 and concentrated under reduced pressure to give the title compound as a thick oil (11.96 g), which was used in the next step without further purification.
Reaction SMILES: [F:1][C:2]1([F:22])[CH2:6][CH2:5][N:4]([C:7]2[C:20]([F:21])=[CH:19][CH:18]=[CH:17][C:8]=2[CH:9]=[N:10][CH2:11][CH2:12][C:13]([CH3:16])([CH3:15])[CH3:14])[CH2:3]1.[SH:23][C@@H:24]([CH2:28][C:29]([OH:31])=[O:30])[C:25](O)=[O:26]>C1(C)C=CC=CC=1>[F:21][C:20]1[C:7]([N:4]2[CH2:5][CH2:6][C:2]([F:1])([F:22])[CH2:3]2)=[C:8]([CH:9]2[N:10]([CH2:11][CH2:12][C:13]([CH3:16])([CH3:15])[CH3:14])[C:25](=[O:26])[C@H:24]([CH2:28][C:29]([OH:31])=[O:30])[S:23]2)[CH:17]=[CH:18][CH:19]=1
Reactant: CC(C)(C)CCN=Cc1cccc(F)c1N1CCC(F)(F)C1
Reactant: O=C(O)C[C@H](S)C(=O)O
Solvent: Cc1ccccc1
Product: CC(C)(C)CCN1C(=O)[C@H](CC(=O)O)SC1c1cccc(F)c1N1CCC(F)(F)C1

Procedure:
N-(2-(3,3-Difluoropyrrolidin-1-yl)-3-fluorobenzylidene)-3,3-dimethylbutan-1-amine (400.2 mg, 1.281 mmol) was taken in toluene and (S)-2-mercaptosuccinic acid (192.3 mg, 1.281 mmol) was added. The reaction mixture was refluxed overnight with a Dean Stark trap to remove the water. Then the reaction mixture was concentrated, triturated with ether and dried overnight to give 2-((5S)-2-(3-fluoro-2-(3,3-difluoropyrrolidin-1-yl)phenyl)-3-(3,3-dimethylbutyl)-4-oxothiazolidin-5-yl)acetic acid which was used directly in the next step. The product was identified by LC/MS. LC/MS: m/z=445.5M+1.
Reaction SMILES: C(O[C:4]([CH:6]([C:28]([O:30]CC)=O)[C:7]1[C:16]2[C:11](=[C:12]([NH:17][C:18](=[O:27])[C:19]3[C:24]([Cl:25])=[CH:23][CH:22]=[CH:21][C:20]=3[Cl:26])[CH:13]=[CH:14][CH:15]=2)[N:10]=[CH:9][CH:8]=1)=[O:5])C.O.[NH2:34][NH2:35]>C(O)C>[Cl:26][C:20]1[CH:21]=[CH:22][CH:23]=[C:24]([Cl:25])[C:19]=1[C:18]([NH:17][C:12]1[CH:13]=[CH:14][CH:15]=[C:16]2[C:11]=1[N:10]=[CH:9][CH:8]=[C:7]2[C:6]1[C:28]([OH:30])=[N:34][NH:35][C:4]=1[OH:5])=[O:27]
Reactant: CCOC(=O)C(C(=O)OCC)c1ccnc2c(NC(=O)c3c(Cl)cccc3Cl)cccc12
Reactant: NN
Solvent: CCO
Solvent: O
Product: O=C(Nc1cccc2c(-c3c(O)n[nH]c3O)ccnc12)c1c(Cl)cccc1Cl

Procedure:
A mixture or 4-[bis(ethoxycarbonyl)methyl]-8-(2,6-dichlorobenzoylamino)quinoline (200 mg) and hydrazine monohydrate (211 mg) in ethanol (2 ml) was refluxed overnight. After cooling, the resulting precipitates were collected by the filtration, and the residue was washed with ethanol to give 8-(2,6-dichlorobenzoylamino)-4-(3,5-dihydroxypyrazol-4-yl)quinoline as a solid. The obtained solid was treated with ethanol solution of hydrogen chloride, and the precipitates were collected and recrystallized from isopropyl alcohol to give 8-(2,6-dichlorobenzoylamino)-4-(3,5-dihydroxypyrazol-4-yl)quinoline hydrochloride (95 mg).
Reaction SMILES: [OH:1][CH2:2][CH:3]([NH:5][C:6](=[O:15])[O:7][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[CH3:4].C(N(CC)CC)C.[CH3:23][S:24](Cl)(=[O:26])=[O:25]>O1CCCC1>[CH3:23][S:24]([O:1][CH2:2][CH:3]([NH:5][C:6]([O:7][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)=[O:15])[CH3:4])(=[O:26])=[O:25]
Reactant: CC(CO)NC(=O)OCc1ccccc1
Reactant: CS(=O)(=O)Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(COS(C)(=O)=O)NC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 5 h
Yield: 77.6 %

Procedure:
In tetrahydrofuran (400 ml) were dissolved 46.5 g (222 mmol) of benzyl (2-hydroxy-1-methylethyl)carbamate and 26.96 g (266 mmol) of triethylamine, and a solution of 27.96 g (244 mmol) of methanesulfonyl chloride in tetrahydrofuran was slowly dropped thereinto at 0° C. After the resulting mixture was stirred at room temperature for 5 hours, the triethylamine hydrochloride precipitated was filtered under reduced pressure and washed with ethyl acetate. The filtrate was concentrated under reduced pressure and water was added thereto, followed by three runs of extraction with ethyl acetate. The extract solution was washed with saturated aqueous sodium hydrogencarbonate solution and then saturated aqueous sodium chloride solution, and dried over anhydrous sodium sulfate. The solvent was distilled off and the crude crystals thus obtained were washed twice with a solvent (hexane:ethyl acetate=4:1) to obtain 49.5 g (yield 78%) of 2-(benzyloxycarbonylamino)propyl methanesulfonate.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[C@H:9]1[C@H:14]([O:15][CH3:16])[CH2:13][CH2:12][NH:11][CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl[C:25]1[CH:30]=[CH:29][N:28]=[CH:27][C:26]=1[N+:31]([O-:33])=[O:32].CCN(C(C)C)C(C)C>CCOC(C)=O>[C:6]([N:8]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[C@H:9]1[C@H:14]([O:15][CH3:16])[CH2:13][CH2:12][N:11]([C:25]2[CH:30]=[CH:29][N:28]=[CH:27][C:26]=2[N+:31]([O-:33])=[O:32])[CH2:10]1)([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7]
Reactant: O=[N+]([O-])c1cnccc1Cl
Reactant: CO[C@@H]1CCNC[C@H]1N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Product: CO[C@@H]1CCN(c2ccncc2[N+](=O)[O-])C[C@H]1N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C
Yield: 59 %

Procedure:
Method 1 was followed using trans (+/−)-3-(bis(tert-butoxycarbonyl)amino)-4-methoxypiperidine (1.0 equiv.), 4-chloro-3-nitropyridine (1.2 equiv.), and DIEA (4.0 equiv.) to give trans (+/−)-N,N-di-BOC-4-methoxy-1-(3-nitropyridin-4-yl)-piperidin-3-amine after column chromatography (EtOAc and hexanes, 50%) in 59% yield for two steps. LCMS (m/z): 453.2 (MH+), LC Rt=3.24 min.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([S:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][O:18][C:19]2[CH:20]=[CH:21][C:22]3[NH:27][C:26](=[O:28])[O:25][C:24]([CH3:30])([CH3:29])[C:23]=3[CH:31]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].[OH:32]O>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([S:11]([CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][O:18][C:19]2[CH:20]=[CH:21][C:22]3[NH:27][C:26](=[O:28])[O:25][C:24]([CH3:29])([CH3:30])[C:23]=3[CH:31]=2)=[O:32])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: COc1ccc(SCCCCCCOc2ccc3c(c2)C(C)(C)OC(=O)N3)cc1OC
Reactant: OO
Product: COc1ccc(S(=O)CCCCCCOc2ccc3c(c2)C(C)(C)OC(=O)N3)cc1OC

Procedure:
Prepared analogously to Example 2 from 6-[6-(3,4-dimethoxy-phenylmercapto)-hexyloxy]-4,4-dimethyl-4H-3,1-benzoxazin-2-one and hydrogen peroxide.
Reaction SMILES: [CH3:1][C:2]1[C:10]([CH3:12])([CH3:11])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.Br[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25].[OH-].[K+]>C(Cl)(Cl)Cl>[CH3:11][C:10]1([CH3:12])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]([CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH3:14])[C:2]1=[CH2:1]
Reactant: CC1=Nc2ccccc2C1(C)C
Reactant: CCCCCCCCCCCCBr
Agent: [K+]
Agent: [OH-]
Solvent: ClC(Cl)Cl
Product: C=C1N(CCCCCCCCCCCC)c2ccccc2C1(C)C
Temperature: 80 °C
Yield: 82 %

Procedure:
To a solution of 1.6 g of 2,3,3-trimethylindolenine in 10 ml of chloroform was added 2.8 g of 1-bromododecane and the mixture was heated in an autoclave at 80° C. for 20 hours. The resulting precipitate was recovered by filtration to give 3.7 g of 1-dodecyl-2,3,3-trimethylindolenium as white crystals. To the crystals thus obtained was added 40 ml of 10N aqueous potassium hydroxide solution in a nitrogen atmosphere and the mixture was heated at 50° C. for 3 hours. The reaction mixture was then extracted with ether and the extract was dried over magnesium sulfate and concentrated under reduced pressure to give 2.7 g of 3,3-dimethyl-1-dodecyl-2-methyleneindoline (Yield 82%).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([CH2:32][C:33]1[CH:42]=[CH:41][C:36]([C:37]([O:39]C)=[O:38])=[CH:35][CH:34]=1)[S:9]([C:12]1[CH:17]=[C:16]([C:18](=[O:30])[NH:19][N:20]2[C:28]3[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=3)[CH2:22][CH:21]2[CH3:29])[CH:15]=[CH:14][C:13]=1[Cl:31])(=[O:11])=[O:10])=[O:7])([CH3:4])([CH3:3])[CH3:2].[OH-].[Li+]>C(#N)C.O>[C:1]([O:5][C:6]([N:8]([CH2:32][C:33]1[CH:34]=[CH:35][C:36]([C:37]([OH:39])=[O:38])=[CH:41][CH:42]=1)[S:9]([C:12]1[CH:17]=[C:16]([C:18](=[O:30])[NH:19][N:20]2[C:28]3[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=3)[CH2:22][CH:21]2[CH3:29])[CH:15]=[CH:14][C:13]=1[Cl:31])(=[O:11])=[O:10])=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: COC(=O)c1ccc(CN(C(=O)OC(C)(C)C)S(=O)(=O)c2cc(C(=O)NN3c4ccccc4CC3C)ccc2Cl)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CC#N
Product: CC1Cc2ccccc2N1NC(=O)c1ccc(Cl)c(S(=O)(=O)N(Cc2ccc(C(=O)O)cc2)C(=O)OC(C)(C)C)c1

Procedure:
Dissolve the compound obtained in Step A (1.30×10−3 mol) in a mixture of acetonitrile (45 ml) and water (9 ml). Add lithium hydroxide (1.30×10−2 mol) and heat at 50° C. with stirring. After heating for 5 hours, the dark-brown reaction mixture is poured into water (100 ml). Extract 3 times with ethyl acetate (50 ml). The organic phase is then washed with water and then with brine, dried over magnesium sulphate, filtered and evaporated to dryness under reduced pressure.
Reaction SMILES: [C:1]([OH:11])(=[O:10])[C@H:2]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)[OH:3].C(#N)C.[C:15]1([C:21]2([C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)[CH:29]3[CH:25]([CH2:26][NH:27][CH2:28]3)[S:24](=[O:30])[CH2:23][CH2:22]2)[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>O>[C:1]([OH:11])(=[O:10])[C@H:2]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)[OH:3].[C:31]1([C:21]2([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[C@H:29]3[C@H:25]([CH2:26][NH:27][CH2:28]3)[S@:24](=[O:30])[CH2:23][CH2:22]2)[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=1
Reactant: O=S1CCC(c2ccccc2)(c2ccccc2)C2CNCC21
Agent: O=C(O)[C@@H](O)c1ccccc1
Solvent: CC#N
Solvent: O
Product: O=[S@@]1CCC(c2ccccc2)(c2ccccc2)[C@@H]2CNC[C@@H]21
Reaction time: 48 h
Yield: 14.1 %

Procedure:
3.5 g of (S)-mandelic acid and 90 cm3 of a mixture of acetonitrile and water (99/1 by volume) are added to 7.15 g of (1RS,4aRS,7aRS)-4,4-diphenylperhydrothiopyrano[2,3-c]pyrrole 1-oxide. After stirring, the resulting solution is allowed to stand for 48 hours at room temperature. The crystals obtained are drained, washed with the acetonitrile-water mixture and then dried. The crystals are taken up in 200 cm3 of a boiling acetonitrile-water mixture and after filtering while still hot, the solution obtained is allowed to stand for 5 hours at room temperature. The crystals are drained, washed twice with 10 cm3 of acetonitrile and then dried. 1.5 g of (1R*,4aR*,7aR*)4,4-diphenylperhydrothiopyrano[2,3-c]pyrrole 1-oxide (S)-mandelate are obtained; [α]D 20 =-228°, (c =0 44; acetic acid). The filtrate is allowed to stand for 20 hours at room temperature, the crystals obtained are drained, washed twice with 5 cm3 of acetonitrile and then dried. 0.62 g of (1R*,4aR*,7aR*)-4,4-diphenylperhydrothiopyrano[2,3-c]pyrrole 1-oxide (S)-mandelate is obtained; [α]D 20 =-230°, (c =0.45; acetic acid).
Reaction SMILES: [C:1]([NH:4][C:5]1[C:10]([C:11]([F:14])([F:13])[F:12])=[CH:9][C:8]([N+:15]([O-])=O)=[CH:7][C:6]=1[C:18]([F:21])([F:20])[F:19])(=[O:3])[CH3:2].[H][H]>[Pd].C(O)C>[C:1]([NH:4][C:5]1[C:6]([C:18]([F:20])([F:21])[F:19])=[CH:7][C:8]([NH2:15])=[CH:9][C:10]=1[C:11]([F:12])([F:13])[F:14])(=[O:3])[CH3:2]
Reactant: [H][H]
Reactant: CC(=O)Nc1c(C(F)(F)F)cc([N+](=O)[O-])cc1C(F)(F)F
Agent: [Pd]
Solvent: CCO
Product: CC(=O)Nc1c(C(F)(F)F)cc(N)cc1C(F)(F)F

Procedure:
A solution of 7.9 g. of 4-acetylamino-3,5-bis-trifluoromethylnitrobenzene in 200 ml. of ethanol is hydrogenated under 40 lbs. of hydrogen pressure with 1 g. of 5% palladium on charcoal catalyst. When the calculated amount of hydrogen is consumed, the solution is filtered and concentrated in vacuo to give 4-acetylamino-3,5-bis-trifluoromethylaniline.
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[F:13][C:14]1[CH:15]=[N:16][CH:17]=[CH:18][CH:19]=1.[Br:20][C:21]1[CH:22]=[C:23]([C:27]([C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][C:36]=2[C:41]#[N:42])=[N:28]S(C(C)(C)C)=O)[CH:24]=[CH:25][CH:26]=1.Cl>O1CCCC1.O>[Br:20][C:21]1[CH:22]=[C:23]([C:27]2([C:19]3[CH:18]=[CH:17][N:16]=[CH:15][C:14]=3[F:13])[C:35]3[C:36](=[CH:37][CH:38]=[CH:39][CH:40]=3)[C:41]([NH2:42])=[N:28]2)[CH:24]=[CH:25][CH:26]=1
Reactant: CC(C)(C)S(=O)N=C(c1cccc(Br)c1)c1ccccc1C#N
Reactant: Fc1cccnc1
Agent: Cl
Agent: [Li]CCCC
Solvent: O
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: NC1=NC(c2cccc(Br)c2)(c2ccncc2F)c2ccccc21
Reaction time: 0.5 h
Yield: 63.8 %

Procedure:
To a −78° C. solution of diisopropylamine (0.77 mL, 5.50 mmol) in tetrahydrofuran (10 mL) was n-butyllithium (2.5 M in hexane, 2.20 mL, 5.50 mmol) added, the mixture was stirred 0.5 h and then a solution of 3-fluoropyridine (0.47 mL, 5.50 mmol) in tetrahydrofuran (2 mL) was added and after another 0.5 h N-[(3-bromophenyl)(2-cyanophenyl)methylene]-2-methylpropane-2-sulfinamide (Scheme #5, N) (1.95 g, 5.0 mmol) in tetrahydrofuran (5 mL) was added. After 1.5 h at −78° C. water was added, the mixture was extracted with ethyl acetate, the organic phase was dried over magnesium sulfate and concentrated. The residue was dissolved in methanol (40 mL) and treated with hydrochloric acid (2 M in diethylether, 5 mL, 10.0 mmol) over night. After evaporation, the residue was partitioned between aqueous saturated sodium bicarbonate and chloroform, the organic phase was dried over magnesium sulfate and evaporated. Purification of the residue by column chromatography using a stepwise gradient of methanol in chloroform (0-10%) as the eluent gave the title compound (1.22 g, 64%). 1H NMR (CDCl3) δ 8.43 (d, J=2.78 Hz, 1 H), 8.35 (d, J=5.05 Hz, 1 H), 7.76 (d, J=8.08 Hz, 1 H), 7.60-7.50 (m, 3 H), 7.45-7.37 (m, 2 H), 7.37-7.33 (m, 1 H), 7.20-7.13 (m, 2 H), 5.37 (br s, 2 H); MS (AP) m/z 382, 384 [M+1]+.
Reaction SMILES: [Br:1]N1C(=O)CCC1=O.[Cl:9][C:10]1[CH:30]=[CH:29][C:13]([CH2:14][NH:15][C:16]([C:18]2[C:19](=[O:28])[C:20]3[CH:27]=[CH:26][O:25][C:21]=3[N:22]([CH3:24])[CH:23]=2)=[O:17])=[CH:12][CH:11]=1>C(Cl)(Cl)Cl>[Br:1][C:26]1[O:25][C:21]2[N:22]([CH3:24])[CH:23]=[C:18]([C:16]([NH:15][CH2:14][C:13]3[CH:12]=[CH:11][C:10]([Cl:9])=[CH:30][CH:29]=3)=[O:17])[C:19](=[O:28])[C:20]=2[CH:27]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: Cn1cc(C(=O)NCc2ccc(Cl)cc2)c(=O)c2ccoc21
Solvent: ClC(Cl)Cl
Product: Cn1cc(C(=O)NCc2ccc(Cl)cc2)c(=O)c2cc(Br)oc21
Temperature: 50 °C
Yield: 60.9 %

Procedure:
N-Bromosuccinimide (2.77 g) was added to a solution of N-(4-chlorobenzyl)-7-methyl-4-oxo-4,7-dihydrofuro[2,3-b]pyridine-5-carboxamide (Example 78, 2.46 g) in CHCl3 (100 mL). The reaction mixture was heated to 50° C. for 18 h. The mixture was allowed to cool to room temperature and was washed with water (100 mL) and brine (100 mL). The organic layer was dried (MgSO4), filtered, and concentrated in vacuo. The resulting solid was purified by column chromatography (CH2Cl2/methanol, 99/1) followed by recrystallization from ethyl acetate to yield 1.87 g (61%) of the title compound as a white solid. Physical characteristics. M.p. 232-233° C.; 1H NMR (400 MHz, DMSO-d6) δ 10.50, 8.57, 7.41-7.32, 7.23, 4.55, 3.92; MS (EI) m/z 394 (M+), 396 (M++2).
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([C:7]2[CH:15]=[C:14]3[C:10]([C:11](=[O:25])[C:12](=[O:24])[N:13]3[CH2:16][C:17]([O:19]C(C)(C)C)=[O:18])=[CH:9][CH:8]=2)[CH2:3][CH2:2]1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[O:1]1[CH2:6][CH2:5][N:4]([C:7]2[CH:15]=[C:14]3[C:10]([C:11](=[O:25])[C:12](=[O:24])[N:13]3[CH2:16][C:17]([OH:19])=[O:18])=[CH:9][CH:8]=2)[CH2:3][CH2:2]1
Reactant: CC(C)(C)OC(=O)CN1C(=O)C(=O)c2ccc(N3CCOCC3)cc21
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(O)CN1C(=O)C(=O)c2ccc(N3CCOCC3)cc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 98.4 %

Procedure:
To a solution of tert-butyl 2-(6-morpholino-2,3-dioxoindolin-1-yl)acetate (0.400 g, 1.155 mmol) in DCM (10 ml), TFA (1.716 ml, 23.10 mmol) was added drop wise. The resulting red solution was stirred at room temperature overnight. The volatiles were evaporated under vacuum to afford 2-(6-morpholino-2,3-dioxoindolin-1-yl)acetic acid (0.330 g, 1.137 mmol, 98% yield). MS/ESI+ 291.1 [MH]+.
Reaction SMILES: [OH:1][C@@H:2]1[CH2:6][O:5][C@H:4]([C:7]2[CH:8]=[N:9][CH:10]=[CH:11][CH:12]=2)[C@H:3]1[CH2:13][CH2:14]/[CH:15]=[CH:16]\[CH2:17][CH2:18][C:19]([O:21][CH3:22])=[O:20].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(O)=O.N(C(OCC)=O)=NC(OCC)=O>O1CCCC1>[OH:1][C@H:2]1[CH2:6][O:5][C@H:4]([C:7]2[CH:8]=[N:9][CH:10]=[CH:11][CH:12]=2)[C@H:3]1[CH2:13][CH2:14]/[CH:15]=[CH:16]\[CH2:17][CH2:18][C:19]([O:21][CH3:22])=[O:20]
Reactant: COC(=O)CC/C=C\CC[C@H]1[C@H](O)CO[C@@H]1c1cccnc1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O=CO
Solvent: C1CCOC1
Product: COC(=O)CC/C=C\CC[C@@H]1[C@@H](c2cccnc2)OC[C@@H]1O
Temperature: 10 °C
Reaction time: 8 h
Yield: 97.7 %

Procedure:
To a solution of 12.97 g (0.0425 mol) of methyl (Z)-(2S,3S,4S)-7-[4-hydroxy-2-(3-pyridyl)-tetrahydrofuran-3-yl]-4-heptenoate, 26.57 g (0.101 mol) of triphenylphosphine and 3.32 g (2.72 mL, 0.069 mol) of 95% formic acid in 130 ml of tetrahydrofurane is added dropwise with stirring under argon at 10° C. 17.63 g (15.94 ml, 0.101 mol) of diethyl azodicarboxylate over a period of 10 min. The mixture is stirred at room temperature for one h and evaporated. The residue is triturated with ether and the mixture is allowed to stand at 0° C. overnight. The precipitated triphenylphosphine oxide is filtered and washed with ether. The combined filtrates and washings axe evaporated to dryness. The residue is dissolved in 130 ml of methanol and hydrogen chloride gas is bubbled through the solution for 3 to 5 min. The mixture is stirred for 30 min and evaporated to dryness. The residue is dissolved in 56 ml of water and the solution is extracted with ethyl acetate (3×). The aqueous layer is mixed with 100 ml of methylene chloride and neutralized with solid sodium bicarbonate with vigorous stirring. The layers are separated and the aqueous layer is extracted with methylene chloride (3×). The combined methylene chloride extracts are washed with brine, dried (MgSO4) and evaporated to give 12.68 g of methyl (Z)-(2S,3S,4R)-7-[4-hydroxy-2-(3-pyridyl)-tetrahydrofuran-3-yl]-4-heptenoate as oil with elemental analysis: C,66.1; H,7.36; N,4.89 (theory: C,66.86; H,7.59; N,4.59) and mass spectrum m/z 306 (M+1) (Calcd. MW=305.38).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[Mg]Br.[CH2:10]([N:12]([CH2:34][CH3:35])[C@H:13]1[CH2:16][C@H:15]([CH2:17][N:18]2[C:26]3[C:21](=[C:22]([C:28]([F:31])([F:30])[F:29])[CH:23]=[C:24]([I:27])[CH:25]=3)[C:20](=[O:32])[C:19]2=[O:33])[CH2:14]1)[CH3:11]>>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:20]1([OH:32])[C:21]2[C:26](=[CH:25][C:24]([I:27])=[CH:23][C:22]=2[C:28]([F:30])([F:31])[F:29])[N:18]([CH2:17][C@H:15]2[CH2:14][C@H:13]([N:12]([CH2:10][CH3:11])[CH2:34][CH3:35])[CH2:16]2)[C:19]1=[O:33]
Reactant: Clc1ccccc1[Mg]Br
Reactant: CCN(CC)[C@H]1C[C@H](CN2C(=O)C(=O)c3c2cc(I)cc3C(F)(F)F)C1
Product: CCN(CC)[C@H]1C[C@H](CN2C(=O)C(O)(c3ccccc3Cl)c3c2cc(I)cc3C(F)(F)F)C1

Procedure:
2-chlorophenylmagnesium bromide (0.35 mmol) and the compound of Example 1-1 were reacted in a similar manner to Example 1-2 to give the titled compound (50.4 mg, 74%).