Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([NH:5][C:6]2[N:7]=[N:8][C:9]([C:12]#[CH:13])=[CH:10][CH:11]=2)[CH2:4][CH2:3][CH2:2]1.I[C:15]1[CH:16]=[C:17]([C:22]2[NH:26][C:25]3[CH:27]=[C:28]([CH2:31][N:32]4[CH2:37][CH2:36][N:35]([CH3:38])[CH2:34][CH2:33]4)[CH:29]=[CH:30][C:24]=3[N:23]=2)[CH:18]=[CH:19][C:20]=1[CH3:21].CCN(C(C)C)C(C)C.CN(C=O)C>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.[Cu]I.O>[CH:1]1([NH:5][C:6]2[N:7]=[N:8][C:9]([C:12]#[C:13][C:15]3[CH:16]=[C:17]([C:22]4[NH:26][C:25]5[CH:27]=[C:28]([CH2:31][N:32]6[CH2:33][CH2:34][N:35]([CH3:38])[CH2:36][CH2:37]6)[CH:29]=[CH:30][C:24]=5[N:23]=4)[CH:18]=[CH:19][C:20]=3[CH3:21])=[CH:10][CH:11]=2)[CH2:4][CH2:3][CH2:2]1
Reactant: C#Cc1ccc(NC2CCC2)nn1
Reactant: Cc1ccc(-c2nc3ccc(CN4CCN(C)CC4)cc3[nH]2)cc1I
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: Cc1ccc(-c2nc3ccc(CN4CCN(C)CC4)cc3[nH]2)cc1C#Cc1ccc(NC2CCC2)nn1
Temperature: 25 °C
Reaction time: 20 h
Yield: 59 %

Procedure:
N-Cyclobutyl-6-ethynylpyridazin-3-amine (62 mg, 0.36 mmol), 2-(3-iodo-4-methylphenyl)-6-((4-methylpiperazin-1-yl)methyl)-1H-benzo[d]imidazole (134 mg, 0.3 mmol), Pd(PPh3)4 (18 mg, 0.015 mmol) and CuI (4.3 mg, 0.023 mmol) were placed in a two neck flask with a rubber plug. The mixture underwent 3 cycles of vacuum and filling with Are, a solution of DIPEA (58 mg, 0.45 mmol) and DMF (2 mL) was injected to the flask. The mixture was stirred at rt for 20 hrs, and then was poured into 25 mL water, extracted with CH2Cl2 (20 mL×3), organic layer was washed with brine, dried with Na2SO4, filtered, and the filtrate was evaporated in vacuo. The residue was purified by chromatography on silica gel (CH2Cl2/CH3OH 97:3 to 97:6) to give 0.12 g crude product, continue to purify via preparation TLC(CH2Cl2/CH3OH 120:8) to give 87 mg product as a pale yellow solid. Mp: 148-150° C.; 1H NMR (300 MHz, CDCl3) δ: 8.07-8.10 (1H, d, J=9.0 Hz), 7.90 (1H, s), 7.63-7.66 (1H, d, J=9.0 Hz), 7.63 (1H, s), 7.26-7.24 (1H, d, J=6.0 Hz), 7.20 (1H, m), 7.15 (1H, m), 6.60-6.63 (1H, d, J=9.0 Hz), 5.63 (1H, s), 4.26-4.33 (1H, m), 3.62 (2H, s), 2.58 (8H, brs), 2.35 (3H, s), 2.31 (3H, s), 1.94-2.03 (2H, m), 1.82-1.85 (2H, m). HRMS (ESI-TOF+): m/z [M+H]+ calcd for C30H34N7: 492.2870. found: 492.2856.
Reaction SMILES: Cl[C:2]1[CH:11]=[C:10]2[C:5]([C:6]([OH:15])=[C:7]([C:12]([OH:14])=[O:13])[CH:8]=[N:9]2)=[CH:4][CH:3]=1.[CH3:16][O:17][C:18]1[CH:25]=[CH:24][C:21]([CH2:22]Cl)=[CH:20][CH:19]=1.Cl.Cl.[NH:28]1[CH2:33][CH2:32][CH:31]([CH:34]2[CH2:39][CH2:38][NH:37][CH2:36][CH2:35]2)[CH2:30][CH2:29]1>>[CH3:16][O:17][C:18]1[CH:25]=[CH:24][C:21]([CH2:22][N:9]2[C:10]3[C:5](=[CH:4][CH:3]=[C:2]([N:28]4[CH2:33][CH2:32][CH:31]([CH:34]5[CH2:39][CH2:38][NH:37][CH2:36][CH2:35]5)[CH2:30][CH2:29]4)[CH:11]=3)[C:6](=[O:15])[C:7]([C:12]([OH:14])=[O:13])=[CH:8]2)=[CH:20][CH:19]=1
Reactant: O=C(O)c1cnc2cc(Cl)ccc2c1O
Reactant: C1CC(C2CCNCC2)CCN1
Reactant: COc1ccc(CCl)cc1
Agent: Cl
Product: COc1ccc(Cn2cc(C(=O)O)c(=O)c3ccc(N4CCC(C5CCNCC5)CC4)cc32)cc1

Procedure:
Using 7-chloro-4-hydroxyquinoline-3-carboxylic acid, 4-methoxybenzyl chloride and 4,4'-bipiperidine dihydrochloride, the same procedure as in Reference Example 5 and Production Example 1 was followed to yield the title compound as a colorless crystal.
Reaction SMILES: C([O-])(=O)C.[C:5]([O:8][C@H:9]1[CH2:33][CH2:32][C@@:31]2([CH3:34])[C:11](=[CH:12][C@@H:13](Br)[C@@H:14]3[C@@H:30]2[CH2:29][CH2:28][C@@:27]2([CH3:35])[C@H:15]3[CH2:16][CH2:17][C@@H:18]2[C@H:19]([CH3:26])[CH2:20][CH2:21][CH2:22][CH:23]([CH3:25])[CH3:24])[CH2:10]1)(=[O:7])[CH3:6].[F-].C([N+](CCCC)(CCCC)CCCC)CCC.O>O1CCCC1>[CH3:26][C@@H:19]([C@@H:18]1[C@@:27]2([CH3:35])[CH2:28][CH2:29][C@@H:30]3[C@@:31]4([CH3:34])[CH2:32][CH2:33][C@H:9]([O:8][C:5]([CH3:6])=[O:7])[CH2:10][C:11]4=[CH:12][CH:13]=[C:14]3[C@@H:15]2[CH2:16][CH2:17]1)[CH2:20][CH2:21][CH2:22][CH:23]([CH3:24])[CH3:25]
Reactant: CC(=O)O[C@H]1CC[C@@]2(C)C(=C[C@@H](Br)[C@H]3[C@@H]4CC[C@H]([C@H](C)CCCC(C)C)[C@@]4(C)CC[C@@H]32)C1
Agent: CC(=O)[O-]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: O
Solvent: C1CCOC1
Product: CC(=O)O[C@H]1CC[C@@]2(C)C(=CC=C3[C@@H]4CC[C@H]([C@H](C)CCCC(C)C)[C@@]4(C)CC[C@@H]32)C1
Reaction time: 1 h

Procedure:
507.6 mg of the pure 7α-bromocholester acetate obtained sub (a) were dissolved in 5 ml of anhydrous tetrahydrofuran. To this solution was added at 25° C. a solution of 1.0 g of tetrabutyl ammonium fluoride which contained per mol 1 mol of crystal water, in 5 ml of anhydrous tetrahydrofuran, and then, after stirring at 20°-25° C. for 60 minutes, 10 ml of petroleum ether (40°-60° C.). The 1 mole crystal water-containing tetrabutyl ammonium fluoride was obtained by freeze-drying a 10% solution in water. After washing the reaction mixture three times with 10 ml of water, the organic layer was evaporated to dryness. 426 mg (100%) of dry substance were obtained with a content of 7-dehydrocholesterol acetate of 100% (UV). The final product could be recrystallized from ethanol in which 400 mg of white crystalline material were obtained with a melting-point of 128°-129° C. The crystalline final product was 100% pure Δ5,7-cholestadienol acetate both according to the UV-absorption spectrum and according to the NMR spectrum.
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[C:13]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])(=[O:15])[CH3:14].[Br:21][CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([CH2:29]Br)[CH:24]=1>O1CCCC1.CN(C)P(N(C)C)(N(C)C)=O>[Br:21][CH2:22][C:23]1[CH:24]=[C:25]([CH2:29][CH2:14][C:13]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH:26]=[CH:27][CH:28]=1
Reactant: CC(=O)OC(C)(C)C
Reactant: BrCc1cccc(CBr)c1
Agent: [Li]CCCC
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)CCc1cccc(CBr)c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solution of di-isopropylamine (4.04 g) and butyl-lithium (25 ml, 160 M in hexane) in dry tetrahydrofuran (40.0 ml), stirred at -78° under dry nitrogen, was treated over 5 minutes with t-butyl acetate (4.64 g). To this solution was added, over 5 minutes, a solution of α,α'-dibromo-m-xylene (11.60 g) and dry hexamethyl phosphoramide (1.42 g) in dry tetrahydrofuran (8.0 ml). The resulting yellow solution was stirred at -78° for 1/2 hour, then allowed to warm to room temperature over 3 hours. Excess ice-water was added, and the mixture extracted with ether, and the extract washed with 1N hydrochloric acid (60 ml) then water. The dried extract was concentrated in vacuo, to give a yellow oil which was purified by column chromatography on silica, eluting with 1:1 ether:hexane, giving t-butyl 3-(3-bromomethylphenyl)propionate as a colourless oil. Using the method described in the last foregoing paragraph this was converted to the desired diethylester which was used in each of Examples 22 to 25.
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[C:5]([C:9]2[CH:14]=[CH:13][C:12]([C:15]#[N:16])=[CH:11][C:10]=2[O:17][CH2:18][O:19][CH3:20])[CH:6]=[CH:7][CH:8]=1)=O.[CH3:21][NH:22][CH3:23].C([BH-](C(=O)C)C(=O)C)(=O)C>C(Cl)Cl>[CH3:21][N:22]([CH2:1][C:3]1[CH:4]=[C:5]([C:9]2[CH:14]=[CH:13][C:12]([C:15]#[N:16])=[CH:11][C:10]=2[O:17][CH2:18][O:19][CH3:20])[CH:6]=[CH:7][CH:8]=1)[CH3:23]
Reactant: CNC
Reactant: COCOc1cc(C#N)ccc1-c1cccc(C=O)c1
Agent: CC(=O)[BH-](C(C)=O)C(C)=O
Solvent: ClCCl
Product: COCOc1cc(C#N)ccc1-c1cccc(CN(C)C)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
3′-Formyl-2-methoxymethoxy-biphenyl-4-carbonitrile (128 mg, 0.48 mmol) is dissolved in CH2Cl2 (5 mL), and to which dimethylamine (2 mL, 2 M solution in THF, 4 mmol) is added. Triacetylborohydride (300 mg, 1.59 mmol) is added and the mixture is stirred at room temperature for 1 hour before it is quenched with ice water. The organic layer is washed with NH4OH and dried over Na2SO4. After concentration, the residue is directly used in the next step. MS (ESI): 297 (M+1)+1.
Reaction SMILES: Cl.[C:2](=[NH:9])([NH2:8])[CH2:3][CH2:4][CH2:5][CH:6]=[CH2:7].[C:10]1([C:16]#[C:17][CH:18]=O)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.C(=O)([O-])[O-].[Na+].[Na+]>C(#N)C>[CH2:3]([C:2]1[N:8]=[C:16]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:17]=[CH:18][N:9]=1)[CH2:4][CH2:5][CH:6]=[CH2:7]
Reactant: O=CC#Cc1ccccc1
Reactant: C=CCCCC(=N)N
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC#N
Product: C=CCCCc1nccc(-c2ccccc2)n1
Yield: 20.7 %

Procedure:
A mixture of 5-hexenimidamide hydrochloride (P4, 500 mg), 3-phenyl-2-propynal (398 mg), and sodium carbonate (786 mg) in acetonitrile (15 mL) was irradiated in a microwave synthesizer at 120° C. for 40 min and then allowed to cool. The solution was filtered and evaporated in vacuo. The residue was dissolved in dichloromethane and the organic layer was washed with H2O, dried over Na2SO4, filtered and evaporated in vacuo. The crude was purified by column chromatography (eluting with ciclohexane/ethyl acetate 9/1) to give 142 mg of the title compound.
Reaction SMILES: [C:1]1(=[O:11])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH2:2]1.Cl[CH2:13][C:14]1[CH:23]=[CH:22][C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[N:15]=1.[C:24](=[O:27])([O-])[O-].[K+].[K+].O>CN(C)C=O>[CH2:10]([C:7]1([CH2:6][CH2:4][CH2:5][CH3:6])[CH2:8][CH2:9][C:10]2[C:5](=[CH:4][CH:3]=[CH:2][C:1]=2[O:11][CH2:13][C:14]2[CH:23]=[CH:22][C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[N:15]=2)[C:24]1=[O:27])[CH2:1][CH2:2][CH3:3]
Reactant: O=C1CC=Cc2ccccc21
Reactant: ClCc1ccc2ccccc2n1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCCCC1(CCCC)CCc2c(OCc3ccc4ccccc4n3)cccc2C1=O
Temperature: 80 °C
Reaction time: 4 h
Yield: 81.1 %

Procedure:
A mixture of 2,2-dibutyl-3,4-dihydro-5-hydroxy-(1(2H)-naphthalenone (2.643 g), 2-chloromethylquinoline (1.7 g), and potassium carbonate (1.67 g) in N,N-dimethylformamide (16 ml) was stirred at 80° C. for 4 hours. The cooled mixture was poured into water. The separated oil was extracted with ethyl acetate. The ethyl acetate layer was washed with water, dried, and concentrated in vacuo. The crude product was chromatographed on silica gel using 25% ethyl acetate in n-hexane as eluent to yield 2,2-dibutyl-3,4-dihydro-5-(2-quinolylmethoxy)-1(2H)-naphthalenone (3.09 g) as a pale yellow syrup.
Reaction SMILES: [O:1]=[C:2]1[C:7]2[C:8]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)=[C:9](C=O)[NH:10][C:6]=2[CH2:5][CH2:4][NH:3]1.[Br:19][C:20]1[CH:21]=[C:22]2[C:26](=[CH:27][CH:28]=1)[NH:25][C:24](=[O:29])[CH2:23]2.N1CCCC[CH2:31]1.CN(C)C=O>C(O)C>[Br:19][C:20]1[CH:21]=[C:22]2[C:26](=[CH:27][CH:28]=1)[NH:25][C:24](=[O:29])[C:23]2=[CH:31][N:10]1[C:6]2[CH2:5][CH2:4][NH:3][C:2](=[O:1])[C:7]=2[C:8]([C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)=[CH:9]1
Reactant: O=Cc1[nH]c2c(c1-c1ccccc1)C(=O)NCC2
Reactant: C1CCNCC1
Reactant: O=C1Cc2cc(Br)ccc2N1
Solvent: CN(C)C=O
Solvent: CCO
Product: O=C1Nc2ccc(Br)cc2C1=Cn1cc(-c2ccccc2)c2c1CCNC2=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 88 %

Procedure:
A stirred solution of 4-oxo-3-phenyl-4,5,6,7-tetrahydro-1H-pyrrolo[3,2-c]pyridine-2-carbaldehyde (36 mg, 0.15 mmol), 5-bromo-1,3-dihydro-indol-2-one (33 mg, 0.146 mmol), piperidine (0.05 ml), N,N-dimethylformamide (0.05 ml) in anhydrous ethanol (0.75 ml) was heated to reflux for 2 hours and stirred at room temperature overnight. The resulting mixture was filtered to give (5-bromo-2-oxo-1,2-dihydro-indol-3-ylidenemethyl)-3-phenyl-1,5,6,7-tetrahydro-pyrrolo[3,2-c]pyridin-4-one (61 mg, 88%) as a yellow solid.
Reaction SMILES: C1C=CC(C2C=CC=CC=2)=CC=1.C1C=CC(OC2C=CC=CC=2)=CC=1.[CH3:26][O:27][C:28](=[O:43])[C:29]([NH:35][C:36]1[CH:41]=[CH:40][C:39]([F:42])=[CH:38][CH:37]=1)=[CH:30][C:31]([O:33]C)=O>CO>[F:42][C:39]1[CH:38]=[C:37]2[C:36](=[CH:41][CH:40]=1)[NH:35][C:29]([C:28]([O:27][CH3:26])=[O:43])=[CH:30][C:31]2=[O:33]
Reactant: COC(=O)C=C(Nc1ccc(F)cc1)C(=O)OC
Solvent: CO
Solvent: c1ccc(Oc2ccccc2)cc1
Solvent: c1ccc(-c2ccccc2)cc1
Product: COC(=O)c1cc(=O)c2cc(F)ccc2[nH]1
Temperature: 235 °C

Procedure:
250 ml de Dowtherm-A are brought to reflux (about 235° C.) under a nitrogen atmosphere. 41 g (0.16 M) of 2-(4-fluorophenylamino)but-2-enedioic acid dimethyl ester are then introduced dropwise. The methanol formed is separated out. Refluxing is maintained for 10 minutes after the end of introduction. The reaction mixture is then cooled to about 50° C., followed by addition of 250 ml of petroleum ether: a solid precipitates out. It is filtered off by suction, washed three times with petroleum ether and then dried under reduced pressure.
Reaction SMILES: [O:1]=[O+][O-].[Br:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([CH:11]([CH2:15][CH:16]=C)[CH2:12]C=C)[CH:6]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH3:37][OH:38]>C(Cl)Cl>[Br:4][C:5]1[CH:6]=[C:7]([CH:11]([CH2:15][CH:16]=[O:1])[CH2:12][CH:37]=[O:38])[CH:8]=[CH:9][CH:10]=1
Reactant: CO
Reactant: O=[O+][O-]
Reactant: C=CCC(CC=C)c1cccc(Br)c1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: O=CCC(CC=O)c1cccc(Br)c1
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
Ozone was bubbled through a solution of 1-bromo-3-(hepta-1,6-dien-4-yl)benzene (6.14 g, 24.4 mmol) in CH3OH (10 ml) and CH2Cl2 (90 ml) at −78° C. for 30 min at which time the solution was pale blue. Nitrogen was then bubbled through the solution for 5 min and the solution became clear. Polymer support triphenylphosphine (20 g, 60.0 mmol) was added and the solution stirred at −78° C. for 30 min. The dry ice/acetone bath was removed and the heterogeneous mixture was stirred for 1 h. The heterogeneous mixture was filtered through Celite and the filtrate was concentrated to afford compound 87.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[N:4][C:5]2[CH2:11][CH2:10][N:9]([CH2:12][CH3:13])[CH2:8][CH2:7][C:6]=2[N:14]=1.[Cl:15]Cl.[OH-].[Na+]>C(O)(=O)C>[ClH:15].[NH2:1][C:2]1[C:3]([Cl:15])=[N:4][C:5]2[CH2:11][CH2:10][N:9]([CH2:12][CH3:13])[CH2:8][CH2:7][C:6]=2[N:14]=1
Reactant: CCN1CCc2ncc(N)nc2CC1
Reactant: ClCl
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Product: CCN1CCc2nc(N)c(Cl)nc2CC1
Product: Cl

Procedure:
6 gm (31.3 mmols) of 2-amino-7-ethyl-6,7,8,9-tetrahydro-5H-pyrazino[2,3-d]azepine were dissolved in 100 ml of glacial acetic acid and, while cooling the solution with ice, chlorine was introduced until the thin-layer chromatogram showed that no more starting material was present. Thereafter, the reaction mixture was made alkaline with 2N sodium hydroxide and was then extracted with chloroform. The chloroform extract solution was evaporated, and the residue was column-chromatographically purified on silicagel with ethyl acetate/methanol/ethanolic ammonia (4:1:0.5) as the mobile phase. The hydrochloride was precipitated from ethanol with ethanolic hydrochloric acid.
Reaction SMILES: N[CH2:2][CH2:3][CH2:4][CH2:5][NH:6][C:7](=[O:13])[O:8][C:9]([CH3:12])([CH3:11])[CH3:10].[Cl:14][C:15]1[C:20]([N+:21]([O-:23])=[O:22])=[C:19](Cl)[C:18]([CH3:25])=[C:17]([CH3:26])[N:16]=1.CN(C)C=O.C(N(CC)CC)C>C(OCC)(=O)C>[Cl:14][C:15]1[C:20]([N+:21]([O-:23])=[O:22])=[C:19]([CH2:2][CH2:3][CH2:4][CH2:5][NH:6][C:7](=[O:13])[O:8][C:9]([CH3:12])([CH3:11])[CH3:10])[C:18]([CH3:25])=[C:17]([CH3:26])[N:16]=1
Reactant: CC(C)(C)OC(=O)NCCCCN
Reactant: Cc1nc(Cl)c([N+](=O)[O-])c(Cl)c1C
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: Cc1nc(Cl)c([N+](=O)[O-])c(CCCCNC(=O)OC(C)(C)C)c1C
Reaction time: 8 h
Yield: 79.8 %

Procedure:
Tert-butyl 4-aminobutylcarbamate (60 g, 339 mmol) was slowly added to a mixture of 2,4-dichloro-5,6-dimethyl-3-nitropyridine (50 g, 226 mmol), anhydrous N,N-dimethylformamide (500 mL) and triethylamine (50 mL, 339 mmol). The reaction mixture was allowed to stir overnight and then it was concentrated under reduced pressure to provide an oil. The oil was dissolved in ethyl acetate and then washed with water. The organic layer was dried over magnesium sulfate and then concentrated under reduced pressure to provide a dark oil. This material was purified by column chromatography (silica gel eluting with 40/60 ethyl acetate/hexanes) to provide 64.5 g of tert-butyl 4-(2-chloro-5,6-dimethyl-3-nitropyridin-4-yl)butylcarbamate as a bright orange oil which solidified on standing.
Reaction SMILES: [OH:1][C:2]1[CH:12]=[CH:11][C:10]([N:13]=[CH:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[CH:9][C:3]=1[C:4]([O:6][CH2:7][CH3:8])=[O:5].[C:21](OC(=O)C)(=[O:23])[CH3:22]>N1C=CC=CC=1>[C:21]([O:1][C:2]1[CH:12]=[CH:11][C:10]([N:13]=[CH:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[CH:9][C:3]=1[C:4]([O:6][CH2:7][CH3:8])=[O:5])(=[O:23])[CH3:22]
Reactant: CC(=O)OC(C)=O
Reactant: CCOC(=O)c1cc(N=Cc2ccccc2)ccc1O
Solvent: c1ccncc1
Product: CCOC(=O)c1cc(N=Cc2ccccc2)ccc1OC(C)=O
Reaction time: 48 h
Yield: 73 %

Procedure:
Ethyl 2-hydroxy-5-benzylideneaminobenzoate (21 g, 78 mmole) was dissolved in pyridine (60 ml) and acetic anhydride (8.9 ml) was added after which the reaction mixture was kept at room temperature for 48 hours, evaporated to dryness in vacuo, and the residue recrystallized from hexane to give the title compound (17.8 g, 73%), m.p. 79°-80° C. Found (Calc. for C18H17NO4) C 69.33 (69.45), H 5.51 (5.47), N 4.57 (4.50).
Reaction SMILES: [CH3:1][N:2]([CH2:16][C@H:17]1[CH2:22][CH2:21][C@H:20]([CH2:23]OS(C)(=O)=O)[CH2:19][CH2:18]1)[S:3]([C:6]1[CH:11]=[CH:10][C:9]([C:12]([F:15])([F:14])[F:13])=[CH:8][CH:7]=1)(=[O:5])=[O:4].[NH:29]1[CH:33]=[CH:32][N:31]=[CH:30]1.[H-].[Na+]>CN(C)C=O>[N:29]1([CH2:23][C@H:20]2[CH2:21][CH2:22][C@H:17]([CH2:16][N:2]([CH3:1])[S:3]([C:6]3[CH:11]=[CH:10][C:9]([C:12]([F:15])([F:14])[F:13])=[CH:8][CH:7]=3)(=[O:5])=[O:4])[CH2:18][CH2:19]2)[CH:33]=[CH:32][N:31]=[CH:30]1
Reactant: CN(C[C@H]1CC[C@H](COS(C)(=O)=O)CC1)S(=O)(=O)c1ccc(C(F)(F)F)cc1
Reactant: c1c[nH]cn1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CN(C[C@H]1CC[C@H](Cn2ccnc2)CC1)S(=O)(=O)c1ccc(C(F)(F)F)cc1

Procedure:
In analogy to the procedure described in example 25.1, trans-methanesulfonic acid 4-{[methyl-(4-trifluoromethyl-benzenesulfonyl)-amino]-methyl}-cyclohexylmethyl ester (example 5.2) was reacted with imidazole in N,N-dimethylformamide in the presence of sodium hydride to yield trans-N-(4-imidazol-1-ylmethyl-cyclohexylmethyl)-N-methyl-4-trifluoromethyl-benzenesulfonamide as colorless solid, MS: 416 (MH+).
Reaction SMILES: C([O:3][C:4](=[O:32])[CH2:5][CH2:6][CH2:7][CH:8]1[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][CH:16]=[C:17]2[C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=3[CH2:21][CH2:20][C:19]3[CH:28]=[CH:29][CH:30]=[CH:31][C:18]2=3)[CH2:10][CH2:9]1)C.[OH-:33].[Na+].C([OH:37])C>>[C:4]([OH:3])(=[O:32])[C:5]([OH:37])=[O:33].[CH:27]1[C:22]2[CH2:21][CH2:20][C:19]3[CH:28]=[CH:29][CH:30]=[CH:31][C:18]=3[C:17](=[CH:16][CH2:15][CH2:14][N:11]3[CH2:10][CH2:9][CH:8]([CH2:7][CH2:6][CH2:5][C:4]([OH:32])=[O:3])[CH2:13][CH2:12]3)[C:23]=2[CH:24]=[CH:25][CH:26]=1
Reactant: CCO
Reactant: CCOC(=O)CCCC1CCN(CCC=C2c3ccccc3CCc3ccccc32)CC1
Reactant: [OH-]
Agent: [Na+]
Product: O=C(O)C(=O)O
Product: O=C(O)CCCC1CCN(CCC=C2c3ccccc3CCc3ccccc32)CC1
Reaction time: 72 h
Yield: 77 %

Procedure:
The above ester (6.7 g, 15.9 mmol) was dissolved in ethanol (30 ml) and 20% sodium hydroxide (10 ml) was added. After stirring for 3 days, ethanol was evaporated in vacuo, water (50 ml) and diethyl ether (50 ml) were added and the phases were separated. The water phase was treated with acetic acid and extracted with dichloromethane. The organic phase was dried (MgSO4) and the solvent was evaporated in vacuo. The residue (7.0 g) was dissolved in acetone (30 ml) and treated with a solution of oxalic acid dihydrate (2.0 g) in acetone (10 ml). The precipitate was filtered off and dried, affording 6.1 g (77%) of the title compound.
Reaction SMILES: CC(C)CC[N+]([O-])=O.N(OCCC(C)C)=O.[Br:17]Br.N[C:20]1[S:24][N:23]=[C:22]([C:25]([F:28])([F:27])[F:26])[C:21]=1[C:29]#[N:30]>C(Cl)Cl>[Br:17][C:20]1[S:24][N:23]=[C:22]([C:25]([F:28])([F:27])[F:26])[C:21]=1[C:29]#[N:30]
Reactant: N#Cc1c(C(F)(F)F)nsc1N
Reactant: BrBr
Agent: CC(C)CCON=O
Agent: CC(C)CC[N+](=O)[O-]
Solvent: ClCCl
Product: N#Cc1c(C(F)(F)F)nsc1Br
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
Into a 100-mL round-bottom flask, was placed 3-methyl-1-nitrobutane (14.4 g, 122.92 mmol, 6.00 equiv), isopentyl nitrite (30 mL), Br2 (32.4 g, 202.74 mmol, 10.00 equiv). This was followed by the addition of 5-amino-3-(trifluoromethyl)-1,2-thiazole-4-carbonitrile (4.0 g, 20.71 mmol, 1.00 equiv), in portions at 0° C. The resulting solution was stirred for 30 min at 0° C. in a water/ice bath. The reaction progress was monitored by TLC (ethyl acetate/petroleum ether=1:4). The resulting solution was diluted with 30 mL of DCM. The resulting mixture was washed with 2×50 mL of Na2SO3/H2O. The resulting mixture was concentrated under vacuum. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (1:10). This resulted in 4.5 g (85%) of 5-bromo-3-(trifluoromethyl)-1,2-thiazole-4-carbonitrile as yellow crude oil.
Reaction SMILES: [O:1]=[C:2]1[O:7][CH:6]([CH2:8][CH2:9][CH2:10][C:11]2([CH3:18])[O:15][CH:14]([CH3:16])[CH:13]([CH3:17])[O:12]2)[CH2:5][CH2:4][CH2:3]1.[CH:19]([Mg]Cl)=[CH2:20].CO.[Cl-].[NH4+].O1CC[CH2:29][CH2:28]1>CCOCC>[OH:7][CH:6]([CH2:8][CH2:9][CH:10]([C:11]1([CH3:18])[O:15][CH:14]([CH3:16])[CH:13]([CH3:17])[O:12]1)[CH2:19][CH3:20])[CH2:5][CH2:4][CH2:3][C:2](=[O:1])[CH:28]=[CH2:29]
Reactant: C=C[Mg]Cl
Reactant: CC1OC(C)(CCCC2CCCC(=O)O2)OC1C
Reactant: C1CCOC1
Agent: [Cl-]
Agent: [NH4+]
Solvent: CO
Solvent: CCOCC
Product: C=CC(=O)CCCC(O)CCC(CC)C1(C)OC(C)C(C)O1
Reaction time: 0.58 h

Procedure:
A solution containing (±)-2-[3-(6-oxo-2-tetrahydropyranyl)propyl] -2,4,5-trimethyl-1,3-dioxolane (40 g.) in 200 ml. of tetrahydrofuran was cooled to -45° under nitrogen. A 2.12 molar solution of vinyl magnesium chloride in tetrahydrofuran was added dropwise at -45° to -50° over 10 minutes, stirring being continued at -55° to -60° for an additional 35 minutes. Then 10 ml. of methanol was added dropwise and the reaction mixture was poured onto a slurry of ice, ammonium chloride and ether. The ether layer was separated and the aqueous layer re-extracted twice with more ether. The ether layers were washed three times with brine, combined and dried over sodium sulfate. A small sample of the ether solution upon evaporation yielded 2-(7-hydroxy-3-oxo-dodec-1-en-10-yl)-2,4,5-trimethyl-1,3-dioxolane as an oil, UV absolute maximum (in ethanol) at 208 mμ,ε = 9,100.
Reaction SMILES: [Br:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][O:10][CH:11]1[CH2:16][CH2:15][CH2:14][CH2:13][O:12]1.[C:17]1([P:23]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>C(#N)C>[Br-:1].[O:12]1[CH2:13][CH2:14][CH2:15][CH2:16][CH:11]1[O:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][P+:23]([C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1)([C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)[C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: BrCCCCCCCCOC1CCCCO1
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CC#N
Product: [Br-]
Product: c1ccc([P+](CCCCCCCCOC2CCCCO2)(c2ccccc2)c2ccccc2)cc1

Procedure:
A solution of 1-bromo-8-tetrahydropyranyloxyoctane (9.8 g) and triphenyl phosphine (8.8 g) in acetonitrile (50 ml) was heated under reflux for 8 hours. The solution was evaporated and the residue washed with ether to give the title compound as a hygroscopic white solid which was dried by addition of benzene and re-evaporation.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[O:9][C:10]1[CH:15]=[CH:14][C:13]([N+:16]([O-])=O)=[CH:12][N:11]=1.O.NN>C(O)C.[Pd]>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[O:9][C:10]1[N:11]=[CH:12][C:13]([NH2:16])=[CH:14][CH:15]=1
Reactant: Cc1ccc(C)c(Oc2ccc([N+](=O)[O-])cn2)c1
Agent: [Pd]
Agent: NN
Solvent: O
Solvent: CCO
Product: Cc1ccc(C)c(Oc2ccc(N)cn2)c1
Yield: 88.2 %

Procedure:
2-[(2,5-dimethylphenyl)oxy]-5-nitropyridine (Intermediate 33, 140 mg, 0.450 mmol) was dissolved in ethanol (3 mL). Hydrazine hydrate (83 μL, 0.884 mmol) and palladium on carbon (47 mg, 0.044 mmol) were added. The reaction mixture was heated at reflux under argon. After overnight heating, the reaction was cooled down. The reaction mixture was filtered. The organic phase was evaporated under vacuum. The residue was purified by SCX (wash with MeOH, desorbed with 2N methanolic ammonia). Evaporation afforded the title compound (85 mg).