Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC(OCC)[N:5]1[CH:9]=[CH:8][N:7]=[CH:6]1)C.C([Li])CCC.[CH3:18][C:19]1[CH:39]=[CH:38][CH:37]=[CH:36][C:20]=1[O:21][CH2:22][C:23]1[CH:35]=[CH:34][CH:33]=[CH:32][C:24]=1[C:25](N1CCCC1)=[O:26].[Cl-].[NH4+]>O1CCCC1.CO>[CH3:18][C:19]1[CH:39]=[CH:38][CH:37]=[CH:36][C:20]=1[O:21][CH2:22][C:23]1[CH:35]=[CH:34][CH:33]=[CH:32][C:24]=1[C:25]([C:6]1[NH:5][CH:9]=[CH:8][N:7]=1)=[O:26]
Reactant: Cc1ccccc1OCc1ccccc1C(=O)N1CCCC1
Reactant: CCOC(OCC)n1ccnc1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CO
Product: Cc1ccccc1OCc1ccccc1C(=O)c1ncc[nH]1
Temperature: -60 °C
Reaction time: 1 h
Yield: 63.9 %

Procedure:
At −40° C., 6.9 g (0.0405 mol) of N-diethoxymethylimidazole (J. Org. Chem. Vol. 45, No. 20, 1980, page 4040) in 40 ml of tetrahydrofuran are mixed with 11.3 g (0.0405 mol) of 23% pure n-butyllithium, and the mixture is stirred at −60° C. for one hour. At −40° C., 6 g (0.0203 mol) of N-[2-(2-methylphenoxymethyl)-benzoyl]-pyrrolidine are added, and the mixture is stirred for 30 minutes without any further cooling, on which the reaction mixture warms to 20° C. 5 g of ammonium chloride and 50 ml of methanol are added, and the mixture is heated at reflux for 15 minutes. The volatile components are distilled off under reduced pressure and the residue is admixed with water and extracted with ethyl acetate. The organic phase is dried and concentrated under reduced pressure. The residue is recrystallized from ethyl acetate. 3.79 g (63.8% of theory) of 2[2-(2-methylphenoxymethyl)-benzoyl]-imidazole are obtained.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][C:3]=1[CH3:10].[CH3:11][C:12]1[O:16][C:15]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[N:14][C:13]=1[CH2:23][CH2:24]OS(C)(=O)=O.[OH-].[K+]>C([N+](CCCC)(CCCC)CCCC)CCC.S([O-])(O)(=O)=O.C1(C)C=CC=CC=1>[CH3:10][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][C:2]=1[O:1][CH2:24][CH2:23][C:13]1[N:14]=[C:15]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[O:16][C:12]=1[CH3:11])[CH:6]=[O:7]
Reactant: Cc1cc(C=O)ccc1O
Reactant: Cc1oc(-c2ccccc2)nc1CCOS(C)(=O)=O
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=S(=O)([O-])O
Agent: [K+]
Solvent: Cc1ccccc1
Product: Cc1cc(C=O)ccc1OCCc1nc(-c2ccccc2)oc1C
Temperature: 0 °C
Yield: 70.6 %

Procedure:
4-Hydroxy-3-methylbenzaldehyde (9 g, 66.10 mmol), methanesulfonic acid 2-(5-methyl-2-phenyl-oxazol-4-yl)-ethyl ester [PCT Int. Appl. (2000) WO0008002] (22.5 g, 80 mmol), KOH (80 mmol, 4.48 g) and tetrabutylammonium-hydrogensulfate (2 g) in 400 ml toluene/100 ml water were heated at 80° C. during 17 hours. The reaction mixture was then cooled to 0° C., washed with water/ice and brine, the aqueous layer extracted with tBuOMe, the combined organic layers dried over Na2SO4 and evaporated. The crude product was purified by chromatography (SiO2; AcOEt/heptane) and the product was crystallized from CH2Cl2/heptane to yield 15 g (72%) of the title compound as a white solid.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[CH3:7][C:8]1([C:11](=[O:15])[CH2:12][CH:13]=[CH2:14])[CH2:10][CH2:9]1>O1CCCC1>[CH3:7][C:8]1([CH:11]([OH:15])[CH2:12][CH:13]=[CH2:14])[CH2:10][CH2:9]1
Reactant: C=CCC(=O)C1(C)CC1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: C=CCC(O)C1(C)CC1
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
To a suspension of lithium aluminum hydride (7.17 g, 189 mmol) in tetrahydrofuran (200 mL) at −78° C. was added drop-wise a solution of 1-(1-methylcyclopropyl)but-3-en-1-one (C51) (15.6 g, 126 mmol) in tetrahydrofuran (100 mL). After the addition, the mixture was stirred at −78° C. for 0.5 hours. The reaction mixture was quenched with water (7 mL) at −78° C., then dichloromethane (100 mL) was added and the mixture was stirred at room temperature for 0.5 hours. The mixture was filtered, the filter cake was washed with dichloromethane (2×150 mL), and the combined filtrates were dried and concentrated in vacuo to give crude product; purification via silica gel chromatography (Gradient: 4% to 10% ethyl acetate in petroleum ether) afforded the product as a yellow oil. Yield: 12 g, 95 mmol, 76% over 2 steps. 1H NMR (400 MHz, CDCl3) δ 5.68-5.90 (m, 1H), 5.07-5.17 (m, 2H), 2.92 (dd, J=13.2, 4.4 Hz, 1H), 2.25-2.40 (m, 2H), 1.06 (s, 3H), 0.38-0.45 (m, 2H), 0.30-0.36 (m, 2H).
Reaction SMILES: [CH3:1][C:2]1[NH:3][CH:4]=[CH:5][N:6]=1.Cl[C:8]1[N:9]=[C:10]([NH:20][CH2:21][C:22]2[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[C:24]([Cl:30])[CH:23]=2)[C:11]2[CH:16]=[C:15]([N+:17]([O-:19])=[O:18])[S:14][C:12]=2[N:13]=1>>[CH3:1][C:2]1[N:3]([C:8]2[N:9]=[C:10]([NH:20][CH2:21][C:22]3[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[C:24]([Cl:30])[CH:23]=3)[C:11]3[CH:16]=[C:15]([N+:17]([O-:19])=[O:18])[S:14][C:12]=3[N:13]=2)[CH:4]=[CH:5][N:6]=1
Reactant: Cc1ncc[nH]1
Reactant: COc1ccc(CNc2nc(Cl)nc3sc([N+](=O)[O-])cc23)cc1Cl
Product: COc1ccc(CNc2nc(-n3ccnc3C)nc3sc([N+](=O)[O-])cc23)cc1Cl

Procedure:
Following the procedure of Example 97, the reaction of 2-methylimidazole with 2-chloro-6-nitro-4-(3-chloro-4-methoxybenzylamino)-thieno-[2,3-d]-pyrimidine gives 2-(2-methylimidazol-1-yl)-6-nitro-4-(3-chloro-4-methoxybenzylamino)-thieno-[2,3-d]-pyrimidine.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[N:6][C:7]([N:10]2[CH2:15][CH2:14][CH:13]([C:16]3[CH:17]=[CH:18][C:19]([CH2:22][O:23][C:24]4[CH:29]=[CH:28][C:27]([S:30]([CH3:33])(=[O:32])=[O:31])=[CH:26][CH:25]=4)=[N:20][CH:21]=3)[CH2:12][CH2:11]2)=[N:8][CH:9]=1)([CH3:3])=[CH2:2]>CO.[C].[Pd]>[CH:1]([C:4]1[CH:5]=[N:6][C:7]([N:10]2[CH2:15][CH2:14][CH:13]([C:16]3[CH:17]=[CH:18][C:19]([CH2:22][O:23][C:24]4[CH:25]=[CH:26][C:27]([S:30]([CH3:33])(=[O:31])=[O:32])=[CH:28][CH:29]=4)=[N:20][CH:21]=3)[CH2:12][CH2:11]2)=[N:8][CH:9]=1)([CH3:3])[CH3:2]
Reactant: C=C(C)c1cnc(N2CCC(c3ccc(COc4ccc(S(C)(=O)=O)cc4)nc3)CC2)nc1
Agent: [Pd]
Solvent: CO
Product: CC(C)c1cnc(N2CCC(c3ccc(COc4ccc(S(C)(=O)=O)cc4)nc3)CC2)nc1
Reaction time: 1 h
Yield: 71.4 %

Procedure:
To a solution of 5-isopropenyl-2-[4-[2-(4-methanesulfonylphenoxymethyl)pyridin-5-yl]piperidin-1-yl]pyrimidine (Example 58) (21 mg, 0.045 mmol) in methanol (0.45 mL) was added 10% palladium-carbon (10 mg). The mixture was hydrogenated at room temperature for 1 hour and filtered through Celite pad. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate=1/2) to give the title compound as a white crystal (15 mg, yield 71%).
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][C:6]([C@@H:9]([O:13][C:14]2[CH:15]=[C:16]3[C:20](=[CH:21][CH:22]=2)[N:19]([C:23]2[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=2)[N:18]=[CH:17]3)[C@@H:10]([NH2:12])[CH3:11])=[CH:5][CH:4]=1)[CH3:2].[CH3:30][C:31]([CH3:36])([CH3:35])[C:32](Cl)=[O:33]>>[CH2:1]([C:3]1[CH:4]=[CH:5][C:6]([C@@H:9]([O:13][C:14]2[CH:15]=[C:16]3[C:20](=[CH:21][CH:22]=2)[N:19]([C:23]2[CH:24]=[CH:25][C:26]([F:29])=[CH:27][CH:28]=2)[N:18]=[CH:17]3)[C@@H:10]([NH:12][C:32](=[O:33])[C:31]([CH3:36])([CH3:35])[CH3:30])[CH3:11])=[CH:7][CH:8]=1)[CH3:2]
Reactant: CC(C)(C)C(=O)Cl
Reactant: CCc1ccc([C@@H](Oc2ccc3c(cnn3-c3ccc(F)cc3)c2)[C@H](C)N)cc1
Product: CCc1ccc([C@@H](Oc2ccc3c(cnn3-c3ccc(F)cc3)c2)[C@H](C)NC(=O)C(C)(C)C)cc1

Procedure:
Prepared as described in Example 1 using (1R,2S)-1-(4-ethylphenyl)-1-{[1-(4-fluorophenyl)-1H-indazol-5-yl]oxy}propan-2-amine (7a, 20 mg, 50 μmol) and 2,2-dimethylpropanoyl chloride (18 mg, 150 μmol). Yield 17 mg (71%)
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][CH3:10])[CH:6]=[CH:5][C:4]=1[C:11]1[C:20]2[C:15](=[CH:16][C:17]([O:21][CH3:22])=[CH:18][CH:19]=2)[C:14](=O)[NH:13][N:12]=1.P(Cl)(Cl)([Cl:26])=O>>[Cl:26][C:14]1[C:15]2[C:20](=[CH:19][CH:18]=[C:17]([O:21][CH3:22])[CH:16]=2)[C:11]([C:4]2[CH:5]=[CH:6][C:7]([O:9][CH3:10])=[CH:8][C:3]=2[O:2][CH3:1])=[N:12][N:13]=1
Reactant: COc1ccc(-c2n[nH]c(=O)c3cc(OC)ccc23)c(OC)c1
Reactant: O=P(Cl)(Cl)Cl
Product: COc1ccc(-c2nnc(Cl)c3cc(OC)ccc23)c(OC)c1

Procedure:
This compound is obtained according to the procedure described in 1.3. by reacting 4-(2,4-dimethoxyphenyl)-7-methoxy-2H-phthalazin-1-one with phosphoryl chloride.
Reaction SMILES: [N:1]1([C:7]2[N:12]=[CH:11][N:10]=[C:9]([NH:13][C:14]3[CH:15]=[C:16]([CH2:20][S:21]([NH2:24])(=[O:23])=[O:22])[CH:17]=[CH:18][CH:19]=3)[N:8]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.ClC1N=CN=C(NC2C=C(CS(N)(=O)=O)C=CC=2)N=1.[CH3:44][O:45]C[C@H]1CCCN1>>[CH3:44][O:45][CH2:6][C@H:5]1[CH2:4][CH2:3][CH2:2][N:1]1[C:7]1[N:12]=[CH:11][N:10]=[C:9]([NH:13][C:14]2[CH:15]=[C:16]([CH2:20][S:21]([NH2:24])(=[O:23])=[O:22])[CH:17]=[CH:18][CH:19]=2)[N:8]=1
Reactant: NS(=O)(=O)Cc1cccc(Nc2ncnc(N3CCCCC3)n2)c1
Reactant: COC[C@H]1CCCN1
Agent: NS(=O)(=O)Cc1cccc(Nc2ncnc(Cl)n2)c1
Product: COC[C@H]1CCCN1c1ncnc(Nc2cccc(CS(N)(=O)=O)c2)n1

Procedure:
B17 was prepared following the procedure reported for B1 using A1 and (R)-2-(methoxymethyl)pyrrolidine. 1H NMR (400 MHz, DMSO, 300K) δ 1.85-2.01 (m, 4H), 3.25 (s, 3H), 3.31-3.63 (m, 4H), 4.18-4.29 (m, 3H), 6.81 (s, 2H), 6.98 (t, J=8.4 Hz, 1H), 7.25 (dt, J=4.7 Hz, J=7.8 Hz, 1H), 7.65-7.87 (m, 2H), 8.20 (s, 1H), 9.63 (s, 1H). MS (ES) C16H22N6O3S requires: 378. found: 379 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[C:6]([C:7]([C:9]2[O:10][CH:11]=[CH:12][CH:13]=2)=[O:8])=[CH:5][NH:4][N:3]=1.[CH2:14](O)[CH3:15]>B(F)(F)F.CCOCC>[O:10]1[CH:11]=[CH:12][CH:13]=[C:9]1[C:7]([C:6]1[CH:5]=[N:4][N:3]2[C:13]([C:15]3[CH:14]=[CH:9][CH:7]=[CH:6][CH:5]=3)=[CH:12][CH:11]=[N:1][C:2]=12)=[O:8]
Reactant: CCO
Reactant: Nc1n[nH]cc1C(=O)c1ccco1
Agent: FB(F)F
Solvent: CCOCC
Product: O=C(c1ccco1)c1cnn2c(-c3ccccc3)ccnc12

Procedure:
A mixture of 0.86 g of (3-amino-1H-pyrazol-4-yl)-2-furanylmethanone and 0.63 g of 1-phenyl-1-propynone in 35 ml of ethanol with several drops of boron trifluoride etherate was refluxed for 18 hours. The solvent was removed and the residue chromatographed on silica gel with ethyl acetate:hexane (1:20) as eluent and a gradual change to ethyl acetate:hexane (2:5). Elution with ethyl acetate gave a solid which was recrystallized from dichloromethanehexane, giving the desired product, mp 185°-187° C.
Reaction SMILES: Br[C:2]1[C:11]2[C:6](=[CH:7][C:8]([C:12]3[O:13][C:14]4[CH:25]=[CH:24][CH:23]=[CH:22][C:15]=4[C:16]=3[CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])=[CH:9][CH:10]=2)[CH:5]=[CH:4][C:3]=1[O:26][CH2:27][C:28]#[N:29].[N-:30]=[N+:31]=[N-:32].[Na+].[Cl-].[NH4+]>CN(C=O)C>[CH2:17]([C:16]1[C:15]2[CH:22]=[CH:23][CH:24]=[CH:25][C:14]=2[O:13][C:12]=1[C:8]1[CH:7]=[C:6]2[C:11](=[CH:10][CH:9]=1)[CH:2]=[C:3]([O:26][CH2:27][C:28]1[NH:29][N:32]=[N:31][N:30]=1)[CH:4]=[CH:5]2)[CH2:18][CH2:19][CH2:20][CH3:21]
Reactant: CCCCCc1c(-c2ccc3c(Br)c(OCC#N)ccc3c2)oc2ccccc12
Reactant: [N-]=[N+]=[N-]
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCCCCc1c(-c2ccc3cc(OCc4nnn[nH]4)ccc3c2)oc2ccccc12
Yield: 66.1 %

Procedure:
Following the procedure described in Step 6, of Example 1, the title compound was prepared from [1-bromo-6-(3-pentyl-benzofuran-2-yl)-naphthalen-2-yloxy]-acetonitrile (1.23 g, 2.75 mmol), sodium azide (1.8 g, 27.5 mmol) and ammonium chloride (1.45 g, 27.5 mmol) in DMF (30 mL). Crystallization from methanol afforded the title compound as an off-white solid (0.75 g), mp 192-194° C. Mass spectrum (+APCl, [M+H]+) m/z 491. 1HNMR (400 MHz, DMSO-d6): δ8.36 (d, 1H, J=1.5 Hz), 8.23-8.17 (m, 2H), 8.05 (dd, 1H, J=9.0, 1.7 Hz), 7.72-7.68 (m, 2H), 7.61 (m, 1H, J=8.1 Hz), 7.37-7.27 (m, 2H), 5.75 (s, 2H), 3.00 (t, 2H, J=7.8 Hz), 1.74-1.767 (m, 2H), 1.42-1.26 (m, 4H), and 0.84-0.80 ppm (m, 3H). Elemental Analysis for C25H24N4O2.0.75H2O: Calculated: C, 59.47; H, 4.89; N, 11.09. Found: C, 59.51; H, 4.6; N, 11.09.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:9]2[CH2:13][CH:12]([CH2:14]OS(C)(=O)=O)[O:11][N:10]=2)[CH:5]=[CH:6][C:7]=1[I:8].[H-].[Na+].C([N:25]1[CH:29]([NH:30][C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[CH:28]=[CH:27][O:26]1)C=C>CN(C)C=O>[F:1][C:2]1[CH:3]=[C:4]([C:9]2[CH2:13][CH:12]([CH2:14][N:30]([C:29]3[CH:28]=[CH:27][O:26][N:25]=3)[C:31]([O:33][C:34]([CH3:37])([CH3:35])[CH3:36])=[O:32])[O:11][N:10]=2)[CH:5]=[CH:6][C:7]=1[I:8]
Reactant: CS(=O)(=O)OCC1CC(c2ccc(I)c(F)c2)=NO1
Reactant: C=CCN1OC=CC1NC(=O)OC(C)(C)C
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N(CC1CC(c2ccc(I)c(F)c2)=NO1)c1ccon1
Reaction time: 0.08 h
Yield: 86.9 %

Procedure:
A solution of (5RS)-3-(3-Fluoro-4-iodophenyl)-5-methanesulfonyloxymethyl-4,5-dihydroisoxazole (1.7 g, 4.26 mM) in dry N,N-dimethylformamide (40 ml) under nitrogen, was treated with sodium hydride (60% in oil, 0.205 g, 5.13 mM), and stirred for 5 minutes. N-Allyl-3-(t-Butoxycarbonylamino)isoxazole (0.86 g, 4.69 mM) was added, and the mixture heated at 60° for 18 hours. After cooling and dilution with water (200 ml), the mixture was extracted with ethyl acetate (3×100 ml), the extracts were washed with water (2×100 ml), brine (100 ml), dried (magnesium sulfate). The residue after evaporation was purified by chromatography on a 50 g silica Mega Bond Elut® column, eluting with a mixture of 25% ethyl acetate in isohexane. Relevant fractions were combined to give the desired product (1.61 g). MS (ESP): 488 (MH+) for C18H19FIN3O4
Reaction SMILES: [CH3:1][S:2][C:3]1[C:4](=[O:27])[C:5](=[CH:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][C:23]([O:25][CH3:26])=[O:24])[C:6]([OH:16])([CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH3:15])[CH:7]=1.ClC1C=CC=C(C(OO)=[O:36])C=1.C(=O)([O-])O.[Na+]>ClCCl>[CH3:1][S:2]([C:3]1[C:4](=[O:27])[C:5](=[CH:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][C:23]([O:25][CH3:26])=[O:24])[C:6]([OH:16])([CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH3:15])[CH:7]=1)=[O:36]
Reactant: CCCCCCCCC1(O)C=C(SC)C(=O)C1=CCCCCCC(=O)OC
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CCCCCCCCC1(O)C=C(S(C)=O)C(=O)C1=CCCCCCC(=O)OC
Temperature: 0 °C
Reaction time: 1 h
Yield: 61 %

Procedure:
To a solution of 12 mg of 2-methylthio-4-hydroxy-5-(6-methoxycarbonylhexylidene)-4-octyl-2-cyclopentenone obtained in Example 101 dissolved in 2 ml of dichloromethane was added 6.5 mg of 3-chloroperbenzoic acid. After the mixture was stirred at 0° C. for 1 hour, saturated aqueous sodium hydrogencarbonate was added, and the mixture was extracted with ethyl acetate. After washing with saturated aqueous sodium chloride, the product was subjected to silica gel chromatography to obtain 7.3 mg (yield 61%).
Reaction SMILES: [CH2:1]([O:8][CH:9]1[CH2:13][CH:12]([OH:14])[CH:11]([CH2:15][C:16]([NH2:18])=[O:17])[CH:10]1[CH2:19][O:20][CH:21]1[CH2:26][CH2:25][CH2:24][CH2:23][O:22]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.OS(O)(=O)=O.O.C(O)(C)C>CC(C)=O.C(N(CC)CC)C>[O:22]1[CH2:23][CH2:24][CH2:25][CH2:26][CH:21]1[O:20][CH2:19][CH:10]1[CH:9]([O:8][CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[CH2:13][C:12](=[O:14])[CH:11]1[CH2:15][C:16]([NH2:18])=[O:17]
Reactant: NC(=O)CC1C(O)CC(OCc2ccccc2)C1COC1CCCCO1
Agent: O=S(=O)(O)O
Solvent: O
Solvent: CCN(CC)CC
Solvent: CC(C)O
Product: NC(=O)CC1C(=O)CC(OCc2ccccc2)C1COC1CCCCO1
Temperature: -20 °C
Reaction time: 2 h

Procedure:
70 ml of Jones solution containing 19.32 g (0.193 mole) of CrO3 are added dropwise at -20° to -25° C. to a solution of 49.3 g (0.136 mole) of the alcohol of Example 2 in 350 ml of acetone. (Jones solution comprises 26.7 g of CrO3, 23 ml of concentrated H2SO4, and 21 ml of H2O made up to 100 ml.) The solution is stirred for a further 2 hours at -20° C., and an excess of i-propanol is then added at this temperature. The solution is neutralized with triethylamine, allowed to warm up to room temperature and filtered over Celite. The residue is washed thoroughly with acetone, the filtrate is concentrated almost to dryness and ethyl acetate is added to the residue. The organic phase is washed several times with half-saturated NaCl solution, and the combined aqueous phases are saturated with NaCl and extracted several times with ethyl acetate. The combined extracts are dried over MgSO4, concentrated and filtered over a short column (5 times the quantity of silica gel, developing solvent: ethyl acetate).
Reaction SMILES: [C:1]([C:4]1[CH:8]=[C:7]([Cl:9])[S:6][C:5]=1[S:10]([NH:13][C:14]1C=CC(CCO)=CC=1)(=[O:12])=[O:11])(=[O:3])C.B(Cl)([C@@H]1[C@@H](C)C2C(C)(C)C(C2)C1)[C@@H]1[C@@H](C)C2C(C)(C)C(C2)C1.[OH-].[Na+]>CC(OC)(C)C>[Cl:9][C:7]1[S:6][C:5]2[S:10](=[O:11])(=[O:12])[NH:13][CH2:14][C@@H:1]([OH:3])[C:4]=2[CH:8]=1
Reactant: CC(=O)c1cc(Cl)sc1S(=O)(=O)Nc1ccc(CCO)cc1
Agent: C[C@H]1C2CC(C[C@@H]1B(Cl)[C@H]1CC3CC([C@@H]1C)C3(C)C)C2(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: COC(C)(C)C
Product: O=S1(=O)NC[C@@H](O)c2cc(Cl)sc21
Temperature: -40 °C
Reaction time: 2 h

Procedure:
A 50-L, 5-necked flask equipped with a mechanical stirrer and a thermometer was flushed with nitrogen overnight. Working under nitrogen, the flask was charged with the product from Step B (855 g, 2.68 mol) and t-butyl methyl ether (MTBE, 12.5 L). The stirred suspension was cooled to -40° C. using a dry-ice/2-propanol bath and (+)-β-chlorodiisopino-campheylborane (4.5 L of a 1.2M solution in MTBE, 5.4 mol) was added via a cannula over 30 minutes, causing the temperature to rise to -32° C. The reaction mixture was maintained between -25° to -20° C. for 3.5 hours. The mixture was warmed to 0° C. and 1M sodium hydroxide (11 L) was added from an addition funnel over 10 minutes, causing the temperature to rise to 22° C. The biphasic mixture was stirred vigorously at ambient temperature for 2 hours, after which TLC analysis indicated complete cyclization. The phases were split, and the dark aqueous layer was extracted with t-butyl methyl ether (3 L), acidified to pH 1 using concentrated hydrochloric acid, and extracted with ethyl acetate (2×4 L). The combined ethyl acetate extracts were washed with saturated aqueous sodium chloride (3 L), dried over sodium sulfate (1 kg), filtered, and concentrated to a volume of about 1 liter by rotary evaporation, at which point toluene (2 L) was added. As the remainder of the ethyl acetate was removed, the product crystallized from toluene. It was collected by filtration, washed with toluene (2 L) and methylene chloride (2 L, and dried in air at ambient temperature (498 grams, 77%): mp 126°-127° C.; [α]25D -5.9° (c=1, CH3OH). Analysis. Calculated for C6H6ClNO3S2 : C, 30.06; H, 2.52; N, 5.84. Found: C, 30.14; H, 2.56; N, 5.80.
Reaction SMILES: I[C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[CH2:5]2.C(N(CC)CC)C.[CH2:19]([O:21][CH:22]([O:25][CH2:26][CH3:27])[C:23]#[CH:24])[CH3:20].O>C1COCC1.[Cu]I.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CCOC(C)=O>[CH2:19]([O:21][CH:22]([O:25][CH2:26][CH3:27])[C:23]#[C:24][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[CH2:5]2)[CH3:20]
Reactant: O=C1Cc2cc(I)ccc2N1
Reactant: C#CC(OCC)OCC
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCOC(C#Cc1ccc2c(c1)CC(=O)N2)OCC
Temperature: 50 °C
Reaction time: 4 h
Yield: 59.3 %

Procedure:
To a solution of 5-iodo-2-oxoindoline (497 mg, 1.9 mmol) in THF (20 ml) were added triethylamine (0.80 ml, 5.7 mmol), 3,3-diethoxyprop-1-yne (738 mg, 5.7 mmol), CuI (73 mg, 0.38 mmol) and Pd(PPh3)4 (222 mg, 0.19 mmol). The reaction mixture was stirred for 4 h at 50° C. The mixture was poured into H2O and EtOAc. The mixture was separated into an aqueous layer and an organic layer. The aqueous layer was extracted with ethyl acetate 3 times. The combined organic layer was washed with sat. NaHCO3 solution, and brine, and then dried over Na2SO4. The solvent was evaporated and the residue purified by column chromatography (EtOAc then CHCl3/MeOH) to give 5-(3,3-diethoxyprop-1-ynyl)indolin-2-one as a brown solid (292 mg, 59%).
Reaction SMILES: C[O:2][C:3](=[O:35])[CH2:4][O:5][C:6]1[C:15]([CH3:16])=[CH:14][C:13]([S:17][CH2:18][C:19]2[CH:24]=[CH:23][C:22]([C:25]3[CH:30]=[CH:29][C:28]([C:31]([F:34])([F:33])[F:32])=[CH:27][N:26]=3)=[CH:21][CH:20]=2)=[C:12]2[C:7]=1[CH2:8][CH2:9][CH2:10][O:11]2.[K+].[Br-]>>[CH3:16][C:15]1[C:6]([O:5][CH2:4][C:3]([OH:35])=[O:2])=[C:7]2[C:12](=[C:13]([S:17][CH2:18][C:19]3[CH:20]=[CH:21][C:22]([C:25]4[CH:30]=[CH:29][C:28]([C:31]([F:34])([F:32])[F:33])=[CH:27][N:26]=4)=[CH:23][CH:24]=3)[CH:14]=1)[O:11][CH2:10][CH2:9][CH2:8]2
Reactant: COC(=O)COc1c(C)cc(SCc2ccc(-c3ccc(C(F)(F)F)cn3)cc2)c2c1CCCO2
Agent: [Br-]
Agent: [K+]
Product: Cc1cc(SCc2ccc(-c3ccc(C(F)(F)F)cn3)cc2)c2c(c1OCC(=O)O)CCCO2

Procedure:
The title compound was prepared in the manner analogous to Example 1 using 36A. mp 156-157° C.; IR (KBr) cm−1: 2928, 1731, 1710, 1603, 1329, 1113, 1082; 400 MHz 1H NMR (DMSO-d6): δ 12.84 (br(s), 1H), 8.97 (s, 1H), 8.22 (dd, 1H, J=8.4, 2.0 Hz), 8.12 (d, 1H, J=8.4 Hz), 8.04 (d, 2H, J=8.2 Hz), 7.42 (d, 2H, J=8.2 Hz), 6.88 (s, 1H), 4.29 (s, 2H), 4.05-4.14 (m, 4H), 2.64 (t, 2H, J=6.3 Hz), 2.04 (s, 3H), 1.81 (pentet, 2H); MS m/z 490 (M+1). Anal. Calc'd for C25H22F3NO4S: C, 61.34; H, 4.53; N, 2.86. found: C, 60.96; H, 4.48; N, 2.79.
Reaction SMILES: [NH2:1][NH2:2].C([O:5][C:6]([CH:8]([CH:13]1[CH2:18][CH2:17][N:16]([C:19]([O:21][CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[O:20])[CH2:15][CH2:14]1)[CH2:9][C:10](=O)[CH3:11])=O)C>C(O)(=O)C>[CH3:11][C:10]1[CH2:9][CH:8]([CH:13]2[CH2:18][CH2:17][N:16]([C:19]([O:21][CH2:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)=[O:20])[CH2:15][CH2:14]2)[C:6](=[O:5])[NH:1][N:2]=1
Reactant: NN
Reactant: CCOC(=O)C(CC(C)=O)C1CCN(C(=O)OCc2ccccc2)CC1
Solvent: CC(=O)O
Product: CC1=NNC(=O)C(C2CCN(C(=O)OCc3ccccc3)CC2)C1
Temperature: 50 °C
Reaction time: 1 h

Procedure:
Hydrazine (4.72 mL, 148.7 mmol) was added to a solution of benzyl 4-[1-(ethoxycarbonyl)-3-oxobutyl]piperidine-1-carboxylate (2.69 g, 7.44 mmol) in acetic acid (110 mL). The reaction mixture was heated at 50° C. After 1 h, the reaction mixture was concentrated. The residue was diluted with dichloromethane, neutralized by saturated aqueous sodium bicarbonate. The mixture was extracted with dichloromethane (3×), and the combined organic extracts were dried over magnesium sulfate and concentrated to give the title compound. MS 330.2 (M+1).
Reaction SMILES: [CH:1]1[C:16]2[C:17]3[C:4]([C:5](=O)[O:6][C:7](=[O:18])[C:8]=3[CH:9]=[C:10]3[C:15]=2[CH2:14][O:13][CH2:12][O:11]3)=[CH:3][CH:2]=1.Cl.[NH2:21][OH:22]>N1C=CC=CC=1>[OH:22][N:21]1[C:5](=[O:6])[C:4]2=[CH:3][CH:2]=[CH:1][C:16]3[C:17]2=[C:8]([CH:9]=[C:10]2[C:15]=3[CH2:14][O:13][CH2:12][O:11]2)[C:7]1=[O:18]
Reactant: O=C1OC(=O)c2cc3c(c4cccc1c24)COCO3
Reactant: NO
Agent: Cl
Solvent: c1ccncc1
Product: O=C1c2cccc3c4c(cc(c23)C(=O)N1O)OCOC4
Yield: 110.6 %

Procedure:
11H-5,8,10-Trioxabenzo[de]anthracene-4,6-dione (0.14 g, 0.5 mmol, from Example K1) and hydroxylamine hydrochloride (0.06 g, 0.9 mmol) were reacted in pyridine (4.0 mL) following the procedure of Example 1 to give 0.15 g of the title compound, mp >350° C.;
Reaction SMILES: [Si:1]([O:8][C:9]1[CH:18]=[CH:17][C:12]([C:13](OC)=[O:14])=[CH:11][C:10]=1[CH2:19][CH:20]=[CH2:21])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[H-].[Al+3].[Li+].[H-].[H-].[H-]>C1COCC1>[Si:1]([O:8][C:9]1[CH:18]=[CH:17][C:12]([CH2:13][OH:14])=[CH:11][C:10]=1[CH2:19][CH:20]=[CH2:21])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:2])[CH3:3]
Reactant: C=CCc1cc(C(=O)OC)ccc1O[Si](C)(C)C(C)(C)C
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: C=CCc1cc(CO)ccc1O[Si](C)(C)C(C)(C)C
Reaction time: 2 h
Yield: 93.1 %

Procedure:
To a magnetically stirred solution of 8.523 g (28.0 mmol) of the product from Step C in 35 mL of anhydrous THF was added 15.0 mL of a 1.0M solution of lithium aluminum hydride in THF, and the reaction mixture was stirred under a nitrogen atmosphere for 2 hours. At this point, the reaction was quenched by cautious addition of 10 mL water, the resulting precipitate was dissolved by addition of 1.0N hydrochloric acid and the product was extracted into ethyl acetate. The organic layer was separated, dried (MgSO4), filtered and evaporated in vacuo to afford 7.258 g (93%) of the title compound.