Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[N:6]=[C:5]([CH2:7][C:8](=[O:10])[CH3:9])[O:4][N:3]=1.C(O[CH:16](N(C)C)[N:17]([CH3:19])[CH3:18])(C)(C)C>>[CH3:16][N:17]([CH3:19])[CH:18]=[C:7]([C:5]1[O:4][N:3]=[C:2]([CH3:1])[N:6]=1)[C:8](=[O:10])[CH3:9]
Reactant: CN(C)C(OC(C)(C)C)N(C)C
Reactant: CC(=O)Cc1nc(C)no1
Product: CC(=O)C(=CN(C)C)c1nc(C)no1

Procedure:
1-(3-Methyl-[1,2,4]oxadiazol-5-yl)-propan-2-one (224 mg, 1.6 mmol) was reacted with tert.-butoxy-bis-(dimethylamino)-methane using in analogous manner the procedure described in example 28a) to give crude title compound (313 mg) as a yellow oil which was used directly in the next step.
Reaction SMILES: C([Li])(CC)C.[F:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[CH:18]=[CH:17][C:16](Br)=[CH:15][CH:14]=2)=[CH:9][CH:8]=1.CN(C)[CH:22]=[O:23].[Cl-].[NH4+]>C1CCCCC1.O1CCCC1>[F:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[CH:18]=[CH:17][C:16]([CH:22]=[O:23])=[CH:15][CH:14]=2)=[CH:9][CH:8]=1
Reactant: Fc1ccc(-c2ccc(Br)cc2)cc1
Reactant: CN(C)C=O
Agent: [Cl-]
Agent: [Li]C(C)CC
Agent: [NH4+]
Solvent: C1CCCCC1
Solvent: C1CCOC1
Product: O=Cc1ccc(-c2ccc(F)cc2)cc1
Temperature: -75 °C
Reaction time: 0.25 h
Yield: 33 %

Procedure:
A 1.3M solution of sec-butyl lithium in cyclohexane (6.6 ml) was added to a stirred solution of 4'-fluoro-4-bromobiphenyl (1.76 g) in tetrahydrofuran (35 ml) at a temperature below -75° C. and under an atmosphere of argon. The reaction mixture was stirred at -75° C. for 15 minutes. A solution of dry dimethylformamide (1.74 ml) in dry tetrahydrofuran (3.5 ml) was added to the reaction mixture whilst maintaining the temperature below -75° C. and the reaction mixture was then stirred at -75° C. for a further 30 minutes. The mixture was then allowed to warm to ambient temperature over a period of 2 hours and was then poured into saturated ammonium chloride solution (35 ml). The mixture was extracted with diethyl ether (3×35 ml), the diethyl ether extracts combined, washed with saturated brine (50 ml), dried (MgSO4) and evaporated. The residue was purified by medium pressure chromatography on silica gel using a mixture of 5% ethyl acetate/hexane as eluant to give 4'-fluoro 4-biphenylcarboxaldehyde as a colourless oil (33% yield), microanalysis, found: C, 75.1; H, 4.4%; C13H9FO. 0.5H2O requires: C, 75.0; H, 4.8%; NMR (CDCl3): 7.2 (2H, m), 7.6 (6H, m), 7.9 (2H, d) and 10.0 (1H, s), m/z 201 (M+H).
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[C:8]([N:10]1[C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=2[O:13][CH2:12][CH2:11]1)=[O:9].[Cl:20][C:21]1[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][C:22]=1[OH:28].C(=O)([O-])[O-].[Cs+].[Cs+]>C1(C)C=CC=CC=1.CC#N.CC#N.CC#N.CC#N.F[P-](F)(F)(F)(F)F.[Cu+]>[Cl:20][C:21]1[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][C:22]=1[O:28][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[C:8]([N:10]1[C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=2[O:13][CH2:12][CH2:11]1)=[O:9]
Reactant: O=C(c1ccncc1Br)N1CCOc2ccccc21
Reactant: Oc1cc(Cl)ccc1Cl
Agent: [Cu+]
Agent: F[P-](F)(F)(F)(F)F
Agent: O=C([O-])[O-]
Solvent: Cc1ccccc1
Solvent: CC#N
Product: O=C(c1ccncc1Oc1cc(Cl)ccc1Cl)N1CCOc2ccccc21
Temperature: 160 °C
Yield: 16.9 %

Procedure:
To a solution of (3-bromo-pyridin-4-yl)-(2,3-dihydro-benzo[1,4]oxazin-4-yl)-methanone (80 mg, 0.25 mmol, 1.0 equiv) and 2,5-dichloro-phenol (49 mg, 0.30 mmol, 1.2 equiv; [CAS RN 583-78-8]) in anhydrous toluene (1.5 mL) was added caesium carbonate (204 mg, 0.63 mmol, 2.5 equiv; [CAS RN 534-17-8]) and tetrakis(acetonitrile)copper(I) hexafluorophosphate (18.7 mg, 0.050 mmol, 0.2 equiv; [CAS RN 64443-05-6]). The reaction mixture was heated by microwave irradiation to 160° C. for 2 h. Purification by preparative HPLC on reversed phase (Xterra® PrepMSC 18, 5 μm, 19×50 mm column equipped with a Gilson Liquid Handler 215 autosampler, two Rainin Dynamax® SD-300 pumps, a Sedex ELSD 75 lightscatter and a Dionex UVD 340S UV detector) eluting with a gradient of acetonitrile/water provided 17 mg (17%) of the title compound as a light brown solid. MS (ISP): 400.9 [M+H]+.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:8]2[N:13]=[C:12]([S:14][CH3:15])[N:11]3[N:16]=[CH:17][CH:18]=[C:10]3[CH:9]=2)[CH:5]=[CH:6][CH:7]=1.[CH3:19][O:20][C:21]1[CH:26]=[CH:25][C:24](B(O)O)=[CH:23][CH:22]=1.C(=O)([O-])[O-].[Na+].[Na+]>C(COC)OC.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>[CH3:19][O:20][C:21]1[CH:26]=[CH:25][C:24]([C:2]2[CH:7]=[CH:6][CH:5]=[C:4]([C:8]3[N:13]=[C:12]([S:14][CH3:15])[N:11]4[N:16]=[CH:17][CH:18]=[C:10]4[CH:9]=3)[CH:3]=2)=[CH:23][CH:22]=1
Reactant: CSc1nc(-c2cccc(Br)c2)cc2ccnn12
Reactant: COc1ccc(B(O)O)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: COCCOC
Product: COc1ccc(-c2cccc(-c3cc4ccnn4c(SC)n3)c2)cc1
Yield: 151.1 %

Procedure:
Under an inert gas atmosphere is dissolved 5-(3bromophenyl)-7-methylsulfanyl-pyrazolo-[1,5-c]pyrimidine (compound D3)(0.25 g) and 4-methoxyphenyl boronic acid (0.45 g) in dimethoxyethane. To this solution are added bis-(triphenylphosphine)palladium(II) chloride (0.13 mmol) and an aqueous sodium carbonate solution (2M, 8 ml). The reaction mixture is heated to reflux for 18 h The mixture is diluted with ethyl acetate and filtered over silica gel. The product is partitioned between ethyl acetate and an aqueous solution of sodium bicarbonate (5%), the organic phase is dned over sodium sulfate and the crude product is purified by silica gel flash chromatography. A nearly colorless solid (0.41 g) in 60% yield is obtained,
Reaction SMILES: CO[C:3]([CH2:5][NH:6][CH:7]([CH3:33])[CH:8]([C:24]1[CH:29]=[CH:28][C:27]2[O:30][CH2:31][O:32][C:26]=2[CH:25]=1)[CH2:9][C:10]1[O:11][C:12]([C:15](=[O:23])[NH:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[CH:13][CH:14]=1)=[O:4].[OH-].[Na+].Cl>O1CCCC1>[C:17]1([NH:16][C:3]([CH2:5][NH:6][CH:7]([CH3:33])[CH:8]([C:24]2[CH:25]=[CH:26][C:27]3[O:30][CH2:31][O:32][C:28]=3[CH:29]=2)[CH2:9][C:10]2[O:11][C:12]([C:15](=[O:23])[NH:16][C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=3)=[CH:13][CH:14]=2)=[O:4])[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: COC(=O)CNC(C)C(Cc1ccc(C(=O)Nc2ccccc2)o1)c1ccc2c(c1)OCO2
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CC(NCC(=O)Nc1ccccc1)C(Cc1ccc(C(=O)Nc2ccccc2)o1)c1ccc2c(c1)OCO2
Temperature: 25 °C
Reaction time: 17 h
Yield: 113 %

Procedure:
159 mg of N-(methoxycarbonylmethyl)-[(1RS,2RS)-1-methyl-2-(3,4-methylenedioxyphenyl)-3-{5-(phenylcarbamoyl)-2-furyl}propyl]amine in 5 ml of tetrahydrofuran was stirred together with 0.3 ml of 4N aqueous sodium hydroxide at room temperature for 1.5 hours. The reaction solution was acidified with 1N hydrochloric acid and then extracted with ethyl acetate, and the extract was dried over anhydrous magnesium sulfate. The desiccant was filtered off, and the solvent was distilled off under reduced pressure. The residue was dissolved in 3 ml of dimethylformamide and stirred together with 161 mg of aniline and 98 mg of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride at room temperature for 17 hours. After addition of water, the reaction solution was extracted with ethyl acetate, and the extract was washed with 1N aqueous sodium hydroxide and saturated aqueous sodium chloride and dried over anhydrous magnesium sulfate. The desiccant was filtered off, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel thin layer chromatography [Kieselgel™60F254, Art™5717; hexane/ethyl acetate=1/1] to give 102 mg of the title compound as a colorless foamy substance.
Reaction SMILES: [CH3:1][N:2]1[C:10]([CH2:11][CH2:12][CH2:13][C:14]([OH:16])=[O:15])=[N:9][C:8]2[CH:7]=[C:6]([N:17]([CH2:21][CH2:22][Cl:23])[CH2:18][CH2:19][Cl:20])[CH:5]=[CH:4][C:3]1=2.Cl.[CH:25]1(O)[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]1.C1(N=C=NC2CCCCC2)CCCCC1>CN(C1C=CN=CC=1)C>[CH:25]1([O:15][C:14](=[O:16])[CH2:13][CH2:12][CH2:11][C:10]2[N:2]([CH3:1])[C:3]3[CH:4]=[CH:5][C:6]([N:17]([CH2:18][CH2:19][Cl:20])[CH2:21][CH2:22][Cl:23])=[CH:7][C:8]=3[N:9]=2)[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]1
Reactant: OC1CCCCC1
Reactant: Cn1c(CCCC(=O)O)nc2cc(N(CCCl)CCCl)ccc21
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Agent: Cl
Product: Cn1c(CCCC(=O)OC2CCCCC2)nc2cc(N(CCCl)CCCl)ccc21
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A 250 mL three neck round bottom flask was equipped with an overhead stirrer, thermocouple, temperature controller and nitrogen sweep then charged with 10 g (25.34 mmol) of bendamustine hydrochloride, 2.56 g (2.7 mL, 25.6 mmol, 1.01 eq) of cyclohexanol, 5.3 g (25.6 mmol, 1.01 eq) of dicyclohexylcarbodiimide (DCC), 100 mL of MDC and 0.31 g (2.54 mmol, 0.1 eq) of DMAP. The reaction slurry was stirred at RT for 18 h until an in process analysis indicated the reaction was complete. Two new major product peaks were observed. Solids were removed by vacuum filtration and washed with 5 mL of MDC. The filtrate was washed with 4% aqueous sodium bicarbonate solution (2×100 mL) before drying over sodium sulfate, filtering and concentrating to dryness in vacuo to yield a yellow oil with some solids present. 1H NMR analysis indicated residual DMAP and cyclohexanol was along with DCC by-products were present in addition to the desired product. The residue was slurried with 50 mL of MDC to remove residual cyclohexanol then concentrated in vacuo and chromatographed. The chromatography was carried out using 50 g of silica gel 60, 230-400 mesh, eluting with 1:1 heptane/EtOAc collecting 100 mL fractions. Product containing fractions were combined and concentrated to dryness in vacuo to yield 3.11 g (7.06 mmol, 27.9%) of the product as an off-white solid with an HPLC purity of 97.8 A %. 1H NMR (400 MHz, DMSO-d6) δ 7.31 (d, J=8.76 Hz, 1H), 6.93 (d, J=2.28 Hz, 1H), 6.77 (dd, J=2.40, 8.80 Hz, 1H), 4.65 (m, 1H), 3.7 (s, 8H), 3.65 (s, 3H), 2.83 (t, J=7.4 Hz, 2H), 2.44 (t, J=7.36 Hz, 2H), 2.00 (m, 2H), 1.76 (m, 4H), 1.65 (m, 2H), 1.33 (m, b, 6H).
Reaction SMILES: [OH:1][C:2]1[CH:19]=[CH:18][C:5]([C:6]([C:8]2[CH:9]=[C:10]([CH2:14][C:15]([OH:17])=[O:16])[CH:11]=[CH:12][CH:13]=2)=[O:7])=[CH:4][CH:3]=1.O.[C:21]1(C)C=CC(S(O)(=O)=O)=CC=1>CO>[CH3:21][O:16][C:15](=[O:17])[CH2:14][C:10]1[CH:11]=[CH:12][CH:13]=[C:8]([C:6](=[O:7])[C:5]2[CH:4]=[CH:3][C:2]([OH:1])=[CH:19][CH:18]=2)[CH:9]=1
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: O=C(O)Cc1cccc(C(=O)c2ccc(O)cc2)c1
Solvent: O
Solvent: CO
Product: COC(=O)Cc1cccc(C(=O)c2ccc(O)cc2)c1
Yield: 573.5 %

Procedure:
A mixture of the acid (8.56 g, 33.4 mmole) of Step E and p-toluenesulfonic acid monohydrate (1.05 g, 5.6 mmole) in methanol (70 mL) is refluxed for 2.5 hours (TLC, methanol-toluene 1:9). The methanol is evaporated and the residue is dissolved in ethyl acetate and washed with brine. After drying (MgSO4) the solvent is removed to yield a tan solid (8.68 g, 96.2%, m.p. 111°-113° C.). The crude product is used as such in the next step.
Reaction SMILES: [OH:1]O.[C:3]([C:7]1[CH:12]=[CH:11][C:10]([CH:13]=[C:14]([CH3:22])[CH2:15][N:16]2[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]2)=[CH:9][CH:8]=1)([CH3:6])([CH3:5])[CH3:4]>C(O)(C)C.[Pt]>[C:3]([C:7]1[CH:12]=[CH:11][C:10]([CH:13]=[C:14]([CH3:22])[CH2:15][N+:16]2([O-:1])[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21]2)=[CH:9][CH:8]=1)([CH3:6])([CH3:4])[CH3:5]
Reactant: CC(=Cc1ccc(C(C)(C)C)cc1)CN1CCCCC1
Reactant: OO
Agent: [Pt]
Solvent: CC(C)O
Product: CC(=Cc1ccc(C(C)(C)C)cc1)C[N+]1([O-])CCCCC1
Temperature: 40 °C
Reaction time: 24 h

Procedure:
5.4 g of 30% hydrogen peroxide are added dropwise at 40° C. to a solution of 5.4 g of 1-[3-(p-tert.butyl-phenyl)-2-methyl-2-propenyl]-piperidine in 40 ml of isopropanol, this addition being repeated after 24 hours. After stirring at 40° C. for 60 hours, the mixture is cooled and the excess hydrogen peroxide is decomposed by the addition of platinum sponge. The solution is filtered, the filtrate is evaporated, the residue is taken up in 50 ml of water and extracted with hexane. The aqueous solution is subsequently evaporated and the residue is crystallised from pentane. There is obtained pure 1-[3-(p-tert.butyl-phenyl)-2-methyl-2-propenyl]-piperidine-1-oxide of melting point 82°-88° C. (hydrate).
Reaction SMILES: [CH2:1](Br)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:9]1([S:15]([C:18]2[CH:19]=[CH:20][C:21]([OH:27])=[C:22]([C:24](=[O:26])[CH3:25])[CH:23]=2)(=[O:17])=[O:16])[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C.C(OCC)(=O)C>[C:9]1([S:15]([C:18]2[CH:19]=[CH:20][C:21]([O:27][CH2:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)=[C:22]([C:24](=[O:26])[CH3:25])[CH:23]=2)(=[O:17])=[O:16])[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1
Reactant: CC(=O)c1cc(S(=O)(=O)c2ccccc2)ccc1O
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: CCOC(C)=O
Product: CC(=O)c1cc(S(=O)(=O)c2ccccc2)ccc1OCc1ccccc1
Temperature: 25 °C

Procedure:
Benzyl bromide (1.443 g; 0.0087 mol) was added to a suspension of 1-(5-benzenesulfonyl-2-hydroxy-phenyl)-ethanone (2.01 g; 0.0073 mol) and potassium carbonate (2.01 g; 0.015 mol) in acetonitrile (5.0 mL). The mixture was heated under reflux for 18 hours. After cooling to ambient temperature, the mixture was diluted with ethyl acetate, filtered, washed with water and saturated sodium bicarbonate, dried (Na2SO4) and concentrated in vacuo. The crude material was purified by flash chromatography on silica gel (hexane-ethyl acetate; 7:3) to give 1-(5-benzenesulfonyl-2-benzyloxy-phenyl)-ethanone as a white solid (2.17 g; 81%). A sample was recrystallized from diethyl ether-hexane: M. p. 80.5-82.4° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([NH:14]S(C2C=CC=CC=2)(=O)=O)=[C:6]([CH:13]=1)/[CH:7]=[CH:8]/[C:9]([O:11][CH3:12])=[O:10].Br.Br[CH2:26][C:27]([C:29]1[S:33][N:32]=[N:31][C:30]=1[CH3:34])=[O:28]>>[CH3:12][O:11][C:9](=[O:10])[CH2:8][C:7]1[C:6]2[C:5](=[CH:4][CH:3]=[C:2]([Cl:1])[CH:13]=2)[NH:14][C:26]=1[C:27]([C:29]1[S:33][N:32]=[N:31][C:30]=1[CH3:34])=[O:28]
Reactant: Cc1nnsc1C(=O)CBr
Reactant: COC(=O)/C=C/c1cc(Cl)ccc1NS(=O)(=O)c1ccccc1
Agent: Br
Product: COC(=O)Cc1c(C(=O)c2snnc2C)[nH]c2ccc(Cl)cc12

Procedure:
The title compound was prepared according to the procedure described in Example 57 from methyl trans-5-chloro-2-(phenylsulfonylamino)cinnamate (Example 36, step 3) and 5-bromoacetyl-4-methyl-1,2,3-thiadiazole hydrobromide*.
Reaction SMILES: [C:1]([CH:4]([CH2:10][CH2:11][CH:12]=[CH:13][CH2:14][CH2:15][C:16]1[CH:21]=[CH:20][C:19]2[O:22][CH2:23][O:24][C:18]=2[CH:17]=1)C(OCC)=O)(=[O:3])[CH3:2].[OH-].[K+]>CO>[CH2:23]1[O:22][C:19]2[CH:20]=[CH:21][C:16]([CH2:15][CH2:14][CH:13]=[CH:12][CH2:11][CH2:10][CH2:4][C:1](=[O:3])[CH3:2])=[CH:17][C:18]=2[O:24]1
Reactant: CCOC(=O)C(CCC=CCCc1ccc2c(c1)OCO2)C(C)=O
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: CC(=O)CCCC=CCCc1ccc2c(c1)OCO2

Procedure:
9-(3,4-Methylenedioxyphenyl)-6-nonen-2-one [XI; R" is CH3, Ar is 3,4-methylenedioxyphenyl, Y is CH=CHCH2CH2 ] was prepared from 27 g. of ethyl 2-acetyl-8-(3,4-methylenedioxyphenyl)-5-octenoate and potassium hydroxide in aqueous methanol according to the procedure described above in Example 2, part (b). The neutral fraction of the product was chromatographed on 390 g. of activated magnesium silicate and the column was eluted with pentane containing increasing amounts of benzene. The later fractions brought out the desired product, 12.3 g. of 9-(3,4-methylenedioxyphenyl)-6-nonen-2-one.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11](=[O:14])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl[Si:16]([CH3:19])([CH3:18])[CH3:17].C(N(CC)CC)C>CN(C=O)C>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH:10]=[C:11]([O:14][Si:16]([CH3:19])([CH3:18])[CH3:17])[CH2:12][CH2:13]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Reactant: C[Si](C)(C)Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CC=C(O[Si](C)(C)C)CC1
Yield: 85.9 %

Procedure:
To a stirred solution of 1-tert-butoxycarbonyl-4-piperidone (10.13 g, 50.8 mmol) in anhydrous DMF (20 mL) under argon was added chlorotrimethylsilane (7.74 mL, 61.0 mmol), then anhydrous triethylamine (17.0 mL, 122 mmol) and the mixture was stirred at 80° C. for 16 h under argon. The mixture was partitioned between hexane (60 mL) and cold saturated NaHCO3 solution (50 mL). The organic layer was washed with more cold saturated NaHCO3 solution (2×30 mL), dried (Na2SO4) and evaporated in vacuo. The residue was purified by flash chromatography (silica gel, 10% EtOAc/petroleum ether) to give 11.84 g (86%) of the title compound as a colourless oil. δH (250 MHz, CDCl3) 0.20 (9H, s), 1.47 (9H, s), 2.11 (2H, m), 3.52 (2H, t, J=5.8 Hz), 3.87 (2H, m), 4.80 (1H, m).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:21])[CH2:4][N:5]1[C:9](=[O:10])[N:8]([CH2:11][CH:12]=C)[C:7]([C:14]2[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=2)=[N:6]1.O.I([O-])(=O)(=O)=[O:24].[Na+]>O1CCOCC1.[Os](=O)(=O)(=O)=O>[CH3:1][O:2][C:3](=[O:21])[CH2:4][N:5]1[C:9](=[O:10])[N:8]([CH2:11][CH:12]=[O:24])[C:7]([C:14]2[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=2)=[N:6]1
Reactant: C=CCn1c(-c2ccc(Cl)cc2)nn(CC(=O)OC)c1=O
Reactant: [O-][I+3]([O-])([O-])[O-]
Agent: O=[Os](=O)(=O)=O
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: COC(=O)Cn1nc(-c2ccc(Cl)cc2)n(CC=O)c1=O
Reaction time: 60 h

Procedure:
1.00 g (3.25 mmol) of the compound from Example 214A and 217 mg of OsEnCat 40 (micro-encapsulated osmium tetroxide, 0.3 mmol/g, 65 μmol) are placed in 20 ml dioxan and 9 ml water and slowly treated with 2.09 g (9.8 mmol) of sodium periodate at RT. This is allowed to react with vigorous stirring (1-4 days) until HPLC testing of the mixture shows adequate conversion. For the workup, the osmium catalyst is removed by filtration, then washed with dioxan and the total filtrate freed from the organic solvents on the rotary evaporator. The aqueous residue is diluted with more water and extracted three times with dichloromethane. The combined organic phases are dried over sodium sulphate and the solvent removed on the rotary evaporator. The oily residue is dried under high vacuum. 948 mg (purity ca. 84%, 79% of theory) of the title compound are obtained.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:11]2[O:10][C:9]([CH3:13])([CH3:12])[CH2:8][C:7]=2[CH:6]=[C:5]([C:14](=O)[C:15]([CH3:21])([CH3:20])[C:16](OC)=[O:17])[CH:4]=1.Cl.Cl.[NH:25]1[CH2:30][CH2:29][CH:28]([NH:31][NH2:32])[CH2:27][CH2:26]1>>[CH3:1][O:2][C:3]1[C:11]2[O:10][C:9]([CH3:12])([CH3:13])[CH2:8][C:7]=2[CH:6]=[C:5]([C:14]2[C:15]([CH3:21])([CH3:20])[C:16](=[O:17])[N:31]([CH:28]3[CH2:29][CH2:30][NH:25][CH2:26][CH2:27]3)[N:32]=2)[CH:4]=1
Reactant: NNC1CCNCC1
Reactant: COC(=O)C(C)(C)C(=O)c1cc2c(c(OC)c1)OC(C)(C)C2
Agent: Cl
Product: COc1cc(C2=NN(C3CCNCC3)C(=O)C2(C)C)cc2c1OC(C)(C)C2

Procedure:
Prepared analogous as described for the example B1 (Alternative 2) using methyl 3-(7-methoxy-2,2-dimethyl-2,3-dihydro-1-benzofuran-5-yl)-2,2-dimethyl-3-oxopropanoate (compound D12) and piperidin-4-yl-hydrazine dihydrochloride as starting compounds resulting in the title compound. (compound B12)
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][C:5]2[C:10]([CH:11]=1)=[CH:9][CH:8]=[C:7]([Cl:12])[CH:6]=2.[C:13]([Cu])#[N:14].CN(C=O)C>C(Cl)Cl>[Cl:12][C:7]1[CH:6]=[C:5]2[C:10]([CH:11]=[C:2]([C:13]#[N:14])[CH:3]=[N:4]2)=[CH:9][CH:8]=1
Reactant: Clc1ccc2cc(Br)cnc2c1
Reactant: N#C[Cu]
Solvent: ClCCl
Solvent: CN(C)C=O
Product: N#Cc1cnc2cc(Cl)ccc2c1
Temperature: 150 °C

Procedure:
To a flask containing a stir bar was added 3-bromo-7-chloroquinoline (1.0 g, 4.1 mmol), CuCN (0.55 g, 6.2 mmol) followed by addition of DMF (25 mL). The resulting mixture was then heated to 150° C. overnight. When the reaction was complete as evidenced by LC analyisis, the reaction flask was taken out of the oil bath and cooled to RT. To the reaction mixture was then poured DCM (20 mL) and a precipitate formed immediately, which was filtered. The filtrated was washed with aq. NH4Cl, dried over sodium sulfate, and purified by flash chromatography. LC-MS (IE, m/z): 189 [M+1]+.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([F:10])[C:3]=1[C:4]#[N:5].C(N(CC)CC)C.O.[S-2:19].[Na+].[Na+].Cl>N1C=CC=CC=1>[Cl:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([F:10])[C:3]=1[C:4](=[S:19])[NH2:5]
Reactant: [S-2]
Reactant: N#Cc1c(F)cccc1Cl
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CCN(CC)CC
Solvent: c1ccncc1
Product: NC(=S)c1c(F)cccc1Cl
Temperature: 25 °C

Procedure:
Into a 250-mL three necked round bottom flask equipped with a mechanical stirrer, dry ice condenser, dropping funnel, and outlet to a trap filled with bleach was added pyridine (45 mL), 2-chloro-6-fluorobenzonitrile (15.5 g, 0.1 mol), triethylamine (13.4 g, 18.6 mL, 0.133 mol), and sodium sulfide hydrate (36.0 g, 0.15 mol). The temperature of the resulting solution was lowered to approximately 5° C. using an ice bath. To the stirred slurry was added dropwise concentrated hydrochloric acid (25.8 g, 0.266 mol). The rate of addition of the hydrochloric acid was such that the temperature of the reaction mixture did not exceed 25° C. with an addition time of 20 min. The cooling bath was removed and the slurry was allowed to warm to RT and to stir over night. An additional 40 grams of sodium sulfide and 50 mL of hydrochloric acid was added to the mixture and allowed to stir over night. An additional 40 grams of sodium sulfide and 50 mL of hydrochloric acid was added and the mixture allowed to stir over the weekend. The mixture was poured into water (2 L) and was extracted with ether. The ether layer was washed with dilute sulfuric acid, water, brine, dried (MgSO4), and the solvent removed in vacuo to give 16.1 g of crude product which was recrystallized from ethyl acetate to give 2-chloro-6-fluoro-benzthioamide as light yellow crystals: mp 156-158° C.
Reaction SMILES: [Br-].[F:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]([C:24]2[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=2)[CH2:10][CH2:11][CH2:12][N+:13]2[CH:22]=[CH:21][C:20]3[C:15](=[CH:16][CH:17]=[CH:18][C:19]=3[OH:23])[CH:14]=2)=[CH:5][CH:4]=1.[BH4-].[Na+]>CO>[F:2][C:3]1[CH:4]=[CH:5][C:6]([CH:9]([C:24]2[CH:25]=[CH:26][C:27]([F:30])=[CH:28][CH:29]=2)[CH2:10][CH2:11][CH2:12][N:13]2[CH2:22][CH2:21][C:20]3[C:19]([OH:23])=[CH:18][CH:17]=[CH:16][C:15]=3[CH2:14]2)=[CH:7][CH:8]=1
Reactant: Oc1cccc2c[n+](CCCC(c3ccc(F)cc3)c3ccc(F)cc3)ccc12
Agent: [BH4-]
Agent: [Br-]
Agent: [Na+]
Solvent: CO
Product: Oc1cccc2c1CCN(CCCC(c1ccc(F)cc1)c1ccc(F)cc1)C2
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 60.8 %

Procedure:
To a solution of 2-[4,4-bis-(4-fluorophenyl)butyl]-5-hydroxyisoquinolinium bromide (4.99 g, 10.61 mmol) in 165 mL of methanol at 0° C. was added sodium borohydride (1.54 g, 40.71 mmol). The reaction mixture was stirred at 0° C. for 15 minutes, then at room temperature for 15 minutes. The mixture was concentrated on a rotavap. The residue was dissolved in ethyl acetate (200 mL) and washed with saturated ammonium chloride solution (150 mL). The organic layer was collected, and the aqueous layer was extracted with ethyl acetate (1×100 mL). The combined organic layers was dried with magnesium sulphate, filtered, and concentrated to give 1.9 g of crude product as a brown oil. The oil was chromatographed on silica gel eluted with 50% ethyl acetate in hexanes to give 2.54 g of product.
Reaction SMILES: [OH:1][C@H:2]1[C@H:6]([NH:7][CH3:8])[CH2:5][N:4](C(OC(C)(C)C)=O)[CH2:3]1.[C:16](OC(=O)C)(=[O:18])[CH3:17]>N1C=CC=CC=1>[OH:1][C@@H:2]1[CH2:3][NH:4][CH2:5][C@H:6]1[N:7]([CH3:8])[C:16](=[O:18])[CH3:17]
Reactant: CN[C@@H]1CN(C(=O)OC(C)(C)C)C[C@H]1O
Reactant: CC(=O)OC(C)=O
Solvent: c1ccncc1
Product: CC(=O)N(C)[C@@H]1CNC[C@H]1O
Reaction time: 3 h

Procedure:
tert-Butyl trans-3-hydroxy-4-methylaminopyrrolidin-1-carboxylate (1.0 g, tetrahedron: Asymmetry 2001, 12, 2989) was mixed with pyridine (1.5 g) and acetic anhydride (0.567 g). After 3 hours, volatile fractions were removed under high vacuum. The residue was treated by method G. This resulted in the product with the molecular weight of 158.20 (C7H14N2O2); MS (ESI): 159 (M+H+).