Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([CH:3]=[CH:4][C:5]1[CH:6]=[C:7]([CH:11]2OCC[O:12]2)[CH:8]=[CH:9][CH:10]=1)#[N:2].Cl>O1CCCC1>[C:1](/[CH:3]=[CH:4]/[C:5]1[CH:6]=[C:7]([CH:8]=[CH:9][CH:10]=1)[CH:11]=[O:12])#[N:2]
Reactant: N#CC=Cc1cccc(C2OCCO2)c1
Agent: Cl
Solvent: C1CCOC1
Product: N#C/C=C/c1cccc(C=O)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
11.91 g of the cis-trans isomer mixture of 2-[3-(2-cyanoethenyl)phenyl]-[1,3]dioxolane was dissolved in 180 ml of tetrahydrofuran, and thereto 40 ml of 6 N hydrochloric acid was added dropwise under ice-cooling. After stirred at room temperature overnight, the reaction solution was concentrated under reduced pressure, and extracted with t-butyl methyl ether and then ethyl acetate. The organic layers were combined, and washed successively with an aqueous saturated sodium bicarbonate solution and then an aqueous saturated sodium chloride solution. After dried over anhydrous magnesium sulfate, crystals obtained by concentration under reduced pressured were filtered to obtain 4.90 g of trans-3-(2-cyanoethenyl)benzaldehyde [Compound No. (e)] as a white solid.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[C:20]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)=[C:19]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=[CH:18]3)[C:12]=2C(OC)=O)=[CH:7][CH:6]=1)(=[O:4])=[O:3].P(=O)(O)(O)O>>[CH3:1][S:2]([C:5]1[CH:6]=[CH:7][C:8]([C:11]2[CH:12]=[C:13]3[C:19](=[CH:18][CH:17]=[CH:16][CH:15]=[CH:14]3)[C:20]=2[C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[CH:9][CH:10]=1)(=[O:3])=[O:4]
Reactant: COC(=O)c1c2cccccc-2c(-c2ccccc2)c1-c1ccc(S(C)(=O)=O)cc1
Agent: O=P(O)(O)O
Product: CS(=O)(=O)c1ccc(-c2cc3cccccc-3c2-c2ccccc2)cc1
Temperature: 120 °C
Reaction time: 0.17 h
Yield: 89.4 %

Procedure:
Methyl 2-(4-methylsulfonylphenyl)-3-phenylazulene-1-carboxylate(0.13 g) was treated with 100% phosphoric acid (5.0 ml). After stirring for 10 min at 120° C., the reaction mixture was poured into ice-water, followed by extracted with EtOAc. The combined EtOAc extracts were washed with water and brine, dried over Na2SO4 and concentrated. The crude product was purified by SiO2 column chromatography (benzenee/Et2O, 50: 1) to give the title compound (0.10 g) as violet crystals; mp 139°-140° C.
Reaction SMILES: [BH4-].[Li+].C[Si](C)(C)Cl.[CH3:8][O:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[CH2:16][C:17]([NH:19][C:20]1[N:25]2[N:26]=[C:27]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[N:28]=[C:24]2[CH:23]=[C:22]([C:35]2[CH:40]=[CH:39][N:38]=[CH:37][CH:36]=2)[CH:21]=1)=O.CO>O1CCCC1>[CH3:8][O:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[CH2:16][CH2:17][NH:19][C:20]1[N:25]2[N:26]=[C:27]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[N:28]=[C:24]2[CH:23]=[C:22]([C:35]2[CH:36]=[CH:37][N:38]=[CH:39][CH:40]=2)[CH:21]=1
Reactant: COc1ccccc1CC(=O)Nc1cc(-c2ccncc2)cc2nc(-c3ccccc3)nn12
Agent: C[Si](C)(C)Cl
Agent: [BH4-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CO
Product: COc1ccccc1CCNc1cc(-c2ccncc2)cc2nc(-c3ccccc3)nn12
Temperature: 25 °C
Reaction time: 1 h
Yield: 0.1 %

Procedure:
To 10 ml of a 1 molar solution of lithiumborohydride in tetrahydrofuran were added 2.17 g (0.02 mol) trimethylchlorosilane. After stirring for one hour at room temperature the suspension was added dropwise to a suspension of 0.11 g (0.25 mol) 2-(2-methoxy-phenyl)-N-(2-phenyl-7-pyridin-4-yl-[1,2,4]triazolo[1,5-a]pyridin-5-yl)-acetamide and the mixture heated for 18 hours at 50° C. Then 5 ml methanol were slowly added, the solvents were distilled off and the residue taken up in ethylacetate. The solution was washed with aqueous sodiumhydroxide and with water, dried with sodiumsulfate and evaporated. Recrystallisation from ethanol yielded 0.10 g (94%) [2-(2-methoxy-phenyl)-ethyl]-(2-phenyl-7-pyridin-4-yl-[1,2,4]triazolo[1,5-a]pyridin-5-yl)-amine as beige crystals. MS m/e(%):422 (M+H+, 100).
Reaction SMILES: Br[C:2]1[CH:12]=[CH:11][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:4][CH:3]=1.[NH:13]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[NH2:14].C(=O)([O-])[O-].[Cs+].[Cs+]>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C1(P(C2C=CC=CC=2)[C-]2C=CC=C2)C=CC=CC=1.[C-]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C1.[Fe+2].C1(C)C=CC=CC=1>[CH2:9]([O:8][C:6]([C:5]1[CH:11]=[CH:12][C:2]([N:13]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[NH2:14])=[CH:3][CH:4]=1)=[O:7])[CH3:10]
Reactant: CC(C)(C)OC(=O)NN
Reactant: CCOC(=O)c1ccc(Br)cc1
Agent: [Fe+2]
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: Cc1ccccc1
Product: CCOC(=O)c1ccc(N(N)C(=O)OC(C)(C)C)cc1
Temperature: 100 °C
Reaction time: 18 h
Yield: 97.7 %

Procedure:
Ethyl 4-bromobenzoate (25.0 g), tert-butyl hydrazinecarboxylate (28.8 g), tris(dibenzylideneacetone)dipalladium(0) (1.00 g), 1,1′-bis(diphenylphosphino)ferrocene (1.82 g) and cesium carbonate (35.6 g) were added to toluene (220 ml) under an argon atmosphere, and the mixture was stirred at 100° C. for 18 hr. The reaction mixture was filtered through celite, and the residue was washed with dichloromethane. The filtrate was concentrated under reduced pressure and the residue was purified by silica gel column chromatography (hexane:ethyl acetate=4:1, volume ratio) to give the title compound (29.9 g). A part of the compound was recrystallized from ethyl acetate-diisopropyl ether to give a colorless crystal.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:16])[C@@H:4]1[CH2:8][CH2:7][CH2:6][N:5]1[C:9]([O:11]C(C)(C)C)=[O:10].N1C(C)=CC=CC=1C.[Si:25](OS(C(F)(F)F)(=O)=O)([C:28]([CH3:31])([CH3:30])[CH3:29])([CH3:27])[CH3:26].[Cl-].[NH4+]>C(Cl)Cl>[CH3:1][O:2][C:3](=[O:16])[C@@H:4]1[CH2:8][CH2:7][CH2:6][N:5]1[C:9]([O:11][Si:25]([C:28]([CH3:31])([CH3:30])[CH3:29])([CH3:27])[CH3:26])=[O:10]
Reactant: COC(=O)[C@@H]1CCCN1C(=O)OC(C)(C)C
Reactant: CC(C)(C)[Si](C)(C)OS(=O)(=O)C(F)(F)F
Agent: [Cl-]
Agent: [NH4+]
Solvent: ClCCl
Solvent: Cc1cccc(C)n1
Product: COC(=O)[C@@H]1CCCN1C(=O)O[Si](C)(C)C(C)(C)C
Reaction time: 0.25 h

Procedure:
To a methylene chloride solution (1 ml) of N-t-butoxycarbonyl-L-proline methyl ester (114.5 mg, 0.5 mmol) and 2,6-lutidine (0.116 ml, 1.0 mmol), t-butyldimethylsilyltrifluoromethane sulfonate (TBDMSOTf) (0.172 ml, 0.75 mmol) was added dropwise at room temperature in a nitrogen atmosphere. After the mixture was stirred for 15 minutes, a saturated aqueous solution of ammonium chloride (2 ml) was added to quench the reaction and extraction with ether was conducted. The organic layer was dried over anhydrous magnesium sulfate and filtered. By distilling off the solvent under vacuum, the titled compound was obtained in an amount of 153 mg.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[N:25]=[C:24]([O:26][C@H:27]3[C@H:31]4[O:32][CH2:33][C@@H:34]([OH:35])[C@H:30]4[O:29][CH2:28]3)[N:23]([CH2:36][O:37][CH2:38][CH2:39][Si:40]([CH3:43])([CH3:42])[CH3:41])[C:5]2=[N:6][C:7]=1[C:8]1[CH:13]=[CH:12][C:11](B2OC(C)(C)C(C)(C)O2)=[CH:10][CH:9]=1.Br[C:45]1[CH:50]=[CH:49][C:48]([CH2:51][N:52]=[S:53]([CH3:60])(=[O:59])[N:54]2[CH2:58][CH2:57][CH2:56][CH2:55]2)=[CH:47][CH:46]=1>O1CCOCC1>[Cl:1][C:2]1[CH:3]=[C:4]2[N:25]=[C:24]([O:26][C@H:27]3[C@H:31]4[O:32][CH2:33][C@@H:34]([OH:35])[C@H:30]4[O:29][CH2:28]3)[N:23]([CH2:36][O:37][CH2:38][CH2:39][Si:40]([CH3:43])([CH3:42])[CH3:41])[C:5]2=[N:6][C:7]=1[C:8]1[CH:9]=[CH:10][C:11]([C:45]2[CH:50]=[CH:49][C:48]([CH2:51][N:52]=[S:53]([CH3:60])(=[O:59])[N:54]3[CH2:58][CH2:57][CH2:56][CH2:55]3)=[CH:47][CH:46]=2)=[CH:12][CH:13]=1
Reactant: CC1(C)OB(c2ccc(-c3nc4c(cc3Cl)nc(O[C@@H]3CO[C@H]5[C@@H]3OC[C@H]5O)n4COCC[Si](C)(C)C)cc2)OC1(C)C
Reactant: CS(=O)(=NCc1ccc(Br)cc1)N1CCCC1
Solvent: C1COCCO1
Product: C[Si](C)(C)CCOCn1c(O[C@@H]2CO[C@H]3[C@@H]2OC[C@H]3O)nc2cc(Cl)c(-c3ccc(-c4ccc(CN=S(C)(=O)N5CCCC5)cc4)cc3)nc21

Procedure:
The title compound is prepared from (3R,3aR,6R,6aR)-6-(6-chloro-5-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-3-(2-trimethylsilanyl-ethoxymethyl)-3H-imidazo[4,5-b]pyridin-2-yloxy)hexahydrofuro[3,2-b]furan-3-ol and [(4-bromophenyl)-methyl][methyl(oxo)pyrrolidin-1-yl-λ6-sulfanylidene]amine following a procedure analogous to that described for Intermediate 3 (Step 3) using 1,4-dioxane as a solvent. LC (method 1): tR=1.05 min; Mass spectrum (ESI+): m/z=740 [M+H]+.
Reaction SMILES: [CH3:1][N:2]=[C:3]=[O:4].[ClH:5].Cl.[Cl:7][C:8]1[CH:24]=[CH:23][C:11]([CH2:12][N:13]2[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][CH2:21][SH:22])[CH2:15][CH2:14]2)=[CH:10][CH:9]=1.C(N(CC)CC)C>C(Cl)Cl>[ClH:7].[ClH:5].[CH3:1][NH:2][C:3](=[SH:22][CH2:21][CH2:20][CH2:19][N:16]1[CH2:17][CH2:18][N:13]([CH2:12][C:11]2[CH:10]=[CH:9][C:8]([Cl:7])=[CH:24][CH:23]=2)[CH2:14][CH2:15]1)[OH:4]
Reactant: CN=C=O
Reactant: SCCCN1CCN(Cc2ccc(Cl)cc2)CC1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CNC(O)=[SH]CCCN1CCN(Cc2ccc(Cl)cc2)CC1
Yield: 64.4 %

Procedure:
The procedure described in Example 2 was followed, using 0.4 g of methyl isocyanate, 2.0 g of 3-[4-(4-chlorobenzyl)piperazin-1-yl]propanethiol dihydrochloride, 0.7 g of triethylamine and 50 ml of methylene chloride, to give 0.75 g (32% of theory) of N-methyl-S-{3-[4-(4-chlorobenzyl)piperazin-1-yl]propyl}thiocarbamate dihydrochloride as a white crystalline solid, M.p. 240°-243° C.
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][C:3]=1[F:12].[CH:13]([Sn](CCCC)(CCCC)CCCC)=[CH2:14]>CN(C=O)C.C(OCC)(=O)C.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>[F:12][C:3]1[CH:4]=[C:5]([CH:10]=[CH:11][C:2]=1[CH:13]=[CH2:14])[C:6]([O:8][CH3:9])=[O:7]
Reactant: COC(=O)c1ccc(Br)c(F)c1
Reactant: C=C[Sn](CCCC)(CCCC)CCCC
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: C=Cc1ccc(C(=O)OC)cc1F
Temperature: 80 °C
Reaction time: 0.5 h
Yield: 63 %

Procedure:
N-(4-chlorophenyl)-N-[(2S,4R)-1-(4-ethyl-3-fluorobenzoyl)-2-methyl-1,2,3,4-tetrahydroquinolin-4-yl]acetamide was prepared following general procedure B, substituting 4-ethyl-3-fluorobenzoyl chloride for 6-trifluoromethyl nicotinyl chloride. (4-ethyl-3-fluorobenzoyl chloride was prepared in five steps from commercially available 4-bromo-3-fluorobenzoic acid. 4-Bromo-3-fluorobenzoic acid (0.828 g, 3.8 mmol) was dissolved in 20 mL of benzene/methanol (5:1) mixture. To the above mixture was added trimethylsilyldiazomethane until the reaction showed a light yellow color. Let stir for 30 minutes and concentrate down to yield methyl 4-bromo-3-fluorobenzoate. Methyl 4-bromo-3-fluorobenzoate was dissolved in 2 mL of DMF and vinyl tributyl tin (0.431 mL, 1.5 mmol), and degassed for 5 min with nitrogen gas. To the above mixture was added Pd(PPh3)2Cl2 (0.086 g, 0.12 mmol) and heated at 80° C. with a condenser for 16 h. Cool to room temperature and dilute with ethyl acetate and wash with a 10% solution of KF in water. The mixture was allowed to stir for ˜30 min at room temperature, then filter and extract the aqueous with ethyl acetate (3×). Dry over MgSO4, filter and concentrate down. The residue was concentrated down and purified with 100% hexane to 10% ethyl acetate/90% hexane to yield 0.140 g, 63% of methyl 3-fluoro-4-vinylbenzoate. Methyl 3-fluoro-4-vinylbenzoate (0.750 g, 4.1 mmol) was reduced in the presence of Pd on carbon (10%) in ethanol to provide methyl 4-ethyl-3-fluorobenzoate (0.450 g, 59%). Methyl 4-ethyl-3-fluorobenzoate was hydrolyzed to the acid by dissolving in tetrahydrofuran and methanol and sodium hydroxide (1N) was added. The mixture was stirred at room temperature overnight. The mixture was cooled to rt, acidified to pH=5 with 1N HCl to form a white precipitate (0.270 g, 65%). The solid was filtered to give 4-ethyl-3-fluorobenzoic acid. The acid was converted to the acid chloride as described in general procedure B).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:10]=[CH:9][C:6]([CH2:7][NH2:8])=[CH:5][CH:4]=1.[CH3:11][OH:12]>>[CH3:11][O:12][C:3](=[O:2])[CH2:4][CH2:5][NH:8][CH2:7][C:6]1[CH:9]=[CH:10][C:3]([O:2][CH3:1])=[CH:4][CH:5]=1
Reactant: CO
Reactant: COc1ccc(CN)cc1
Product: COC(=O)CCNCc1ccc(OC)cc1

Procedure:
A solution of p-methoxybenzyl amine (690 mg, 722 μL, 8.01 mmol) in dry methanol (5 ml), under nitrogen was cooled to 0° and treated dropwise with a solution of metacrylate (951 μL, 1.0 g, 7.28 mmol) in MeOH (1.0 ml) added over 2 min. After 15.5 h the clear solution was distilled at atmospheric pressure to remove MeOH. The high boiling residue (>170) formed 3-(4-Methoxy-benzylamino)-propionic acid methyl ester (1.88 g, Quantitative) 1H (300 MHz, CDCl3) 1.78 (bs, 1H), 2.45 and 2.53 (t, J=3.0 Hz, 2H), 2.77 and 2.87 (t, J=3.0 Hz, 2H), 3.46 and 3.67 (s, 3H), 3.64 and 3.73 (s, 3H), 3.88 (m, 2H), 6.78 and 6.85 (m, 2H), 7.17 and 7.23 (m, 2H).
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9](=[S:35])[NH:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]2[CH:25]=[C:24]3[C:20]([CH2:21][N:22]([C@@H:27]([CH:32]([CH3:34])[CH3:33])[C:28]([O:30][CH3:31])=[O:29])[C:23]3=[O:26])=[CH:19][CH:18]=2)=[CH:13][CH:12]=1.NC1C=CC(C2C=C3C(CN([C@@H](C(C)C)C(OC)=O)[C:49]3=[O:52])=CC=2)=CC=1.COC1C=C(N=C=S)C=CC=1>>[CH3:49][O:52][C:7]1[CH:2]=[C:3]([NH:8][C:9](=[S:35])[NH:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]3[CH:25]=[C:24]4[C:20]([CH2:21][N:22]([C@@H:27]([CH:32]([CH3:34])[CH3:33])[C:28]([O:30][CH3:31])=[O:29])[C:23]4=[O:26])=[CH:19][CH:18]=3)=[CH:13][CH:12]=2)[CH:4]=[CH:5][CH:6]=1
Reactant: COC(=O)[C@H](C(C)C)N1Cc2ccc(-c3ccc(N)cc3)cc2C1=O
Reactant: COC(=O)[C@H](C(C)C)N1Cc2ccc(-c3ccc(NC(=S)Nc4ccccc4F)cc3)cc2C1=O
Agent: COc1cccc(N=C=S)c1
Product: COC(=O)[C@H](C(C)C)N1Cc2ccc(-c3ccc(NC(=S)Nc4cccc(OC)c4)cc3)cc2C1=O

Procedure:
The compound of example 59 was prepared analogous to compound of example 51 by reaction of compound of example 6 with 3-methoxyphenyl isothiocyanate. The compound of example 59 was used directly without isolation for the preparation of compound of example 60.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[C:11]1[CH2:12][CH2:13][N:14]([CH3:17])[CH2:15][CH:16]=1.[C:18](Cl)(=[O:25])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>>[C:18]([NH:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[C:11]1[CH2:12][CH2:13][N:14]([CH3:17])[CH2:15][CH:16]=1)(=[O:25])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: CN1CC=C(c2c[nH]c3ccc(N)cc23)CC1
Product: CN1CC=C(c2c[nH]c3ccc(NC(=O)c4ccccc4)cc23)CC1
Yield: 28.8 %

Procedure:
Beginning with 1.13 gm (5.0 mMol) 5-amino-3-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)-1H-indole and 0.58 mL (5.0 mMol) benzoyl chloride, 0.477 gm (28.9%) of the title compound were recovered as a light green solid.
Reaction SMILES: [F:1][C:2]1[C:7]([CH3:8])=[CH:6][CH:5]=[CH:4][C:3]=1/[N:9]=[C:10](\[CH2:15][C:16]([O:18]C)=O)/[C:11]([O:13][CH3:14])=[O:12].CS(O)(=O)=O.O=P12OP3(OP(OP(O3)(O1)=O)(=O)O2)=O.C([O-])(O)=O.[Na+]>>[F:1][C:2]1[C:7]([CH3:8])=[CH:6][CH:5]=[C:4]2[C:3]=1[N:9]=[C:10]([C:11]([O:13][CH3:14])=[O:12])[CH:15]=[C:16]2[OH:18]
Reactant: COC(=O)C/C(=N\c1cccc(C)c1F)C(=O)OC
Agent: CS(=O)(=O)O
Agent: O=C([O-])O
Agent: O=P12OP3(=O)OP(=O)(O1)OP(=O)(O2)O3
Product: COC(=O)c1cc(O)c2ccc(C)c(F)c2n1
Temperature: 50 °C
Yield: 92.7 %

Procedure:
A mixture of (E)-dimethyl 2-(2-fluoro-3-methylphenylimino)succinate (7-14, 14.59 g, 54.6 mmol) and Eaton's reagent (52.0 mL, 328 mmol) was heated at 50° C. for 1 h. After cooling to room temperature, the mixture was added slowly to a cold sat. NaHCO3 solution (gas released!), followed by EtOAc extraction (twice). The combined organic fractions were washed with brine, dried (Na2SO4), filtered and the solvent was evaporated under reduced pressure to afford methyl 8-fluoro-4-hydroxy-7-methylquinoline-2-carboxylate (7-15, 11.9 g). LRMS m/z (M+H)+ 236.2 found, 236.1 required.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([SH:8])=[C:4]([CH2:9][OH:10])[CH:3]=1.F[C:12]1[CH:13]=[CH:14][C:15]([N+:20]([O-:22])=[O:21])=[C:16]([CH:19]=1)[NH:17][CH3:18].C([O-])([O-])=O.[K+].[K+].O>CN(C=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][C:12]2[CH:13]=[CH:14][C:15]([N+:20]([O-:22])=[O:21])=[C:16]([CH:19]=2)[NH:17][CH3:18])=[C:4]([CH2:9][OH:10])[CH:3]=1
Reactant: CNc1cc(F)ccc1[N+](=O)[O-]
Reactant: OCc1cc(Cl)ccc1S
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CNc1cc(Sc2ccc(Cl)cc2CO)ccc1[N+](=O)[O-]
Yield: 87.1 %

Procedure:
The solution of 4-chloro-2-(hydroxymethyl)thiophenol (1.0 g) from Example 16, 5-fluoro-N-methyl-2-nitroaniline (1.0 g) and K2CO3 (0.81 g) in DMF (20 ml) was heated at 90° C. for 15 minutes. After leaving the solution to stand at room temperature, water was added to the solution prior to extraction in ethyl acetate. The organic layer was washed with saturated sodium chloride solution, and dried over anhydrous sodium sulfate. After removal of the solvent under reduced pressure, the residue was purified by chromatography on a silica gel column (methylene chloride) to give the title compound (1.62 g; 85%).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([N:9]([CH2:16][C:17]([F:20])([F:19])[F:18])[CH2:10][CH:11]([CH3:15])[C:12]([OH:14])=O)=[CH:5][C:4]=1[C:21]([F:24])([F:23])[F:22])#[N:2].C(Cl)(=O)C(Cl)=O.C[N:32](C=O)C.[NH4+].[OH-]>C(Cl)Cl>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([N:9]([CH2:16][C:17]([F:20])([F:19])[F:18])[CH2:10][CH:11]([CH3:15])[C:12]([NH2:32])=[O:14])=[CH:5][C:4]=1[C:21]([F:23])([F:24])[F:22])#[N:2]
Reactant: CC(CN(CC(F)(F)F)c1ccc(C#N)c(C(F)(F)F)c1)C(=O)O
Reactant: CN(C)C=O
Agent: O=C(Cl)C(=O)Cl
Agent: [NH4+]
Agent: [OH-]
Solvent: ClCCl
Product: CC(CN(CC(F)(F)F)c1ccc(C#N)c(C(F)(F)F)c1)C(N)=O
Temperature: 42 °C
Reaction time: 1 h
Yield: 88 %

Procedure:
To an ice-cold solution of 3-[[4-cyano-3-(trifluoromethyl)phenyl](2,2,2-trifluoroethyl)amino]-2-methylpropanoic acid (0.050 g, 0.14 mmol) in CH2Cl2 (3 mL), under nitrogen was added oxalyl chloride (0.023 g, 0.18 mmol) and DMF (cat) and the mixture was heated at 42° C. for 30 min. Upon cooling, additional oxalyl chloride (0.014 g, 0.11 mmol) and DMF (cat.) were added and heated for 30 min. Upon cooling, NH4OH (30% aqueous solution, 5 mL) was added and the mixture stirred at rt. After 1 h, the mixture was partitioned between CH2Cl2 and water. The organic phase was washed with 0.1N HCl and brine, dried (Na2SO4) and concentrated in vacuo. The residue was purified by silica gel chromatography (1-5% MeOH—CH2Cl2 gradient) to give the title compound (0.044 g, 88% yield): 1H NMR (400 MHz, CDCl3) δ 7.58 (d, J=8.6 Hz, 1H), 7.01 (d, J=2.6 Hz, 1H), 6.89 (dd, J=8.6, 2.6 Hz, 1H), 5.70 (bs, NH), 5.54 (bs, NH), 4.22-4.08 (m, 2H), 3.85 (dd, J=15.4, 10.3 Hz, 1H), 3.54 (dd, J=15.4, 3.7 Hz, 1H), 2.80-2.70 (m, 1H), 1.23 (d, J=7.0 Hz, 3H).
Reaction SMILES: [I-].[CH3:2][S+](C)(C)=O.[CH3:7][O:8][CH2:9][O:10][C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([O:17][CH2:18][O:19][CH3:20])[C:12]=1[C:21](=[CH2:27])[C:22]([O:24][CH2:25][CH3:26])=[O:23]>CS(C)=O>[CH3:20][O:19][CH2:18][O:17][C:13]1[CH:14]=[CH:15][CH:16]=[C:11]([O:10][CH2:9][O:8][CH3:7])[C:12]=1[C:21]1([C:22]([O:24][CH2:25][CH3:26])=[O:23])[CH2:2][CH2:27]1
Reactant: C=C(C(=O)OCC)c1c(OCOC)cccc1OCOC
Reactant: C[S+](C)(C)=O
Agent: [I-]
Solvent: CS(C)=O
Product: CCOC(=O)C1(c2c(OCOC)cccc2OCOC)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 80.6 %

Procedure:
To a solution of trimethylsulfoxonium iodide (1.805 g, 8.20 mmol) in dry dimethyl sulfoxide (20 mL) sodium hydride 60% dispersion in mineral oil (0.310 g, 7.75 mmol) was added and the reaction mixture was stirred for 1 hour at room temperature. A solution of ethyl 2-(2,6-bis{[(methyloxy)methyl]oxy}phenyl)-2-propenoate (Reference Intermediate 210, 1.35 g) in dry dimethyl sulfoxide (10 mL) was slowly added and the reaction mixture was stirred for 1 hour at room temperature. The reaction was quenched with an aqueous saturated solution of ammonium chloride (10 ml), diluted with water (20 ml) and extracted with ethyl acetate (2×50 ml). The organic layer was washed with water (50 ml), dried over sodium sulphate, filtered and evaporated. The residue was purified by flash chromatography (Biotage system) on silica gel using a 50 g SNAP column and cyclohexane to cyclohexane/ethyl acetate 8:2 as eluents affording the title as a colourless oil (1.14 g).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][N:3]=1.ClC1C=CC=C(C(OO)=[O:17])C=1>C(Cl)(Cl)Cl>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][N+:3]=1[O-:17]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: Cc1ccc(Br)nc1
Solvent: ClC(Cl)Cl
Product: Cc1ccc(Br)[n+]([O-])c1
Temperature: 50 °C
Reaction time: 3 h
Yield: 91.7 %

Procedure:
A mixture of 2-bromo-5-methylpyridine (2.0 g, 11.6 mmol) and 3-chloroperbenzoic acid (3.0 g, 14.8 mmol) in chloroform (7 mL) was stirred at 50° C. for 3 hours, cooled down to room temperature and filtered. The filtrate was concentrated under reduced pressure to give a residue that was purified by flash chromatography (Si—PPC, MeOH:EtOAc, gradient 0:100 to 10:90) to give 2-Bromo-5-methylpyridine 1-oxide as a white solid (2.0 g, 91%). 1H NMR (400 MHz, CHCl3-d): δ 8.24 (s, 1 H); 7.52 (d, J=8.3 Hz, 1 H); 6.93 (d, J=8.33 Hz, 1 H); 2.29 (s, 3 H).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([CH3:10])=[O:9])=[CH:4][CH:3]=1>O>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]([OH:9])[CH3:10])=[CH:4][CH:3]=1
Reactant: CC(=O)c1ccc(C)cc1
Solvent: O
Product: Cc1ccc([C@H](C)O)cc1
Reaction time: 24 h

Procedure:
Washed phaseolus aureus L (green grams) 50 g. were taken into a conical flask and allowed to soak in deionised water (400 ml) for a period of 24 hr. 4-methylacetophenone (0.500 g; 0.0037 moles) I(c) was added to the soaked phaseolus aureus L (green grams) in the above water, covered and allowed to shake for 24 hr at 15–20° C. Then the green grams were filtered off and washed with deionised water (3×100 ml). The combined filtrate was extracted with chloroform (3×500 ml). The chloroform layer was dried and the crude product obtained (340 mg). Pure 1-(4-methylphenyl-(1S)-ethan-1-ol II(c) was obtained after column chromatography with silica gel using chloroform as eluent;
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:14]([CH:15]=[N:16][OH:17])=[CH:13][N:12]=[C:11]([S:18][CH3:19])[N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.ClN1C(=O)CCC1=O.[CH2:28]([N:32]1[C:36](=[O:37])[C:35]2=[CH:38][CH:39]=[CH:40][CH:41]=[C:34]2[C:33]1=[O:42])[CH2:29][C:30]#[CH:31].C(N(CC)CC)C>CN(C)C=O.N1C=CC=CC=1.O1CCCC1.O.C(OCC)(=O)C>[CH2:1]([O:8][C:9]1[C:14]([C:15]2[CH:31]=[C:30]([CH2:29][CH2:28][N:32]3[C:36](=[O:37])[C:35]4[C:34](=[CH:41][CH:40]=[CH:39][CH:38]=4)[C:33]3=[O:42])[O:17][N:16]=2)=[CH:13][N:12]=[C:11]([S:18][CH3:19])[N:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CSc1ncc(C=NO)c(OCc2ccccc2)n1
Reactant: C#CCCN1C(=O)c2ccccc2C1=O
Agent: O=C1CCC(=O)N1Cl
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CSc1ncc(-c2cc(CCN3C(=O)c4ccccc4C3=O)on2)c(OCc2ccccc2)n1
Temperature: 50 °C
Reaction time: 1 h
Yield: 36.3 %

Procedure:
To a solution of 4-(benzyloxy)-2-(methylthio)pyrimidine-5-carbaldehyde oxime (S21, 705 mg) in N,N-dimethylformamide (6.0 mL), pyridine (20.6 μL) and N-chlorosuccinimide (471 mg) were added under ice cooling, and the mixture was stirred at 50° C. for 1 hour. The reaction mixture was cooled to room temperature, then a solution of N-(3-butynyl)phthalimide (765 mg) and triethylamine (603 μL) in tetrahydrofuran (8.5 mL) was added to the reaction mixture, and the mixture was stirred at 50° C. for 2 hours. The reaction mixture was cooled to room temperature, and then ethyl acetate and water were added to the reaction mixture. The organic layer was separated, washed successively with water and saturated aqueous sodium chloride, and then dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography to obtain 2-(2-(3-(4-(benzyloxy)-2-(methylthio)pyrimidin-5-yl)isoxazol-5-yl)ethyl)isoindoline-1,3-dione (S22, 439 mg).