Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C@:2]12[C@@:19]3([CH3:20])[C@@H:10]([C@:11]4([CH3:32])[C@@H:16]([CH2:17][CH2:18]3)[C:15]([CH3:22])([CH3:21])[C:14]([C:23]3[CH:31]=[CH:30][C:26]([C:27]([OH:29])=[O:28])=[CH:25][CH:24]=3)=[CH:13][CH2:12]4)[CH2:9][CH2:8][C@@H:7]1[C@H:6]1[C@H:33]([C:36]([CH3:38])=[CH2:37])[CH2:34][CH2:35][C@:5]1([NH:39][CH2:40][CH2:41][N:42]1[CH2:47][C@@H:46]3[CH2:48][C@H:43]1[CH2:44][N:45]3[S:49]([CH3:52])(=[O:51])=[O:50])[CH2:4][CH2:3]2.[C:53]([OH:59])([C:55]([F:58])([F:57])[F:56])=[O:54]>C1COCC1.CO.[OH-].[OH-].[Pd+2]>[CH:36]([C@H:33]1[C@@H:6]2[C@@H:7]3[C@@:2]([CH3:1])([CH2:3][CH2:4][C@@:5]2([NH:39][CH2:40][CH2:41][N:42]2[CH2:47][C@@H:46]4[CH2:48][C@H:43]2[CH2:44][N:45]4[S:49]([CH3:52])(=[O:50])=[O:51])[CH2:35][CH2:34]1)[C@@:19]1([CH3:20])[C@@H:10]([C@:11]2([CH3:32])[C@@H:16]([CH2:17][CH2:18]1)[C:15]([CH3:21])([CH3:22])[C:14]([C:23]1[CH:24]=[CH:25][C:26]([C:27]([OH:29])=[O:28])=[CH:30][CH:31]=1)=[CH:13][CH2:12]2)[CH2:9][CH2:8]3)([CH3:38])[CH3:37].[C:53]([OH:59])([C:55]([F:58])([F:57])[F:56])=[O:54]
Reactant: C=C(C)[C@@H]1CC[C@]2(NCCN3C[C@@H]4C[C@H]3CN4S(C)(=O)=O)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(c6ccc(C(=O)O)cc6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Agent: [Pd+2]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Solvent: O=C(O)C(F)(F)F
Product: CC(C)[C@@H]1CC[C@]2(NCCN3C[C@@H]4C[C@H]3CN4S(C)(=O)=O)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(c6ccc(C(=O)O)cc6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Reaction time: 16 h

Procedure:
To a solution of 4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-5a,5b,8,8,11a-pentamethyl-3a-((2-((1S,4S)-5-(methylsulfonyl)-2,5-diazabicyclo[2.2.1]heptan-2-yl)ethyl)amino)-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoic acid, 2 TFA (10 mg, 10.42 μmol) in a mixture of THF (1.5 mL) and MeOH (0.5 mL) was added palladium hydroxide on carbon (14.63 mg, 0.021 mmol). The resulting slurry was purged with H2 (g) and stirred under a H2 (g) atmosphere for 16 h. The mixture was treated with celite (15 mg), filtered, washed with THF and concentrated. A grey residue was dissolved in THF (1 mL) and MeOH (0.5 mL), purified by reverse phase prep-HPLC using HPLC methods 6 and dried under vacuum to give 4-((1S,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-1-isopropyl-5a,5b,8,8,11a-pentamethyl-3a-((2-((1S,4S)-5-(methylsulfonyl)-2,5-diazabicyclo[2.2.1]heptan-2-yl)ethyl)amino)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoic acid, 2 TFA (6.2 mg, 60.6% yield) as white solid. LC/MS: m/e 734.6 (M+H)+, 2.25 min (method 3). 1H NMR (400 MHz, 1:1 CDCl3:METHANOL-d4) δ 7.91 (d, J=8.3 Hz, 2H), 7.19 (d, J=8.3 Hz, 2H), 5.29 (d, J=4.6 Hz, 1H), 4.35 (s, 1H), 3.82 (s, 1H), 3.61 (d, J=10.3 Hz, 1H), 3.28 (d, J=1.7 Hz, 1H), 3.15 (d, J=11.7 Hz, 1H), 3.10-3.00 (m, 3H), 2.92 (s, 3H), 2.82 (d, J=10.0 Hz, 1H), 2.14 (dd, J=17.1, 6.4 Hz, 1H), 2.09-2.03 (m, 1H), 2.02-1.86 (m, 5H), 1.85-1.64 (m, 7H), 1.57 (dd, J=17.4, 11.7 Hz, 5H), 1.51-1.40 (m, 4H), 1.39-1.21 (m, 4H), 1.15 (s, 3H), 1.07 (s, 3H), 1.02 (s, 3H), 0.94 (s, 3H), 0.93 (s, 3H), 0.90 (d, J=6.8 Hz, 3H), 0.81 (d, J=6.6 Hz, 3H).
Reaction SMILES: [C:1]([N:3]1[C@H:12]2[C@@H:7]([CH2:8][C:9](=[O:13])[CH2:10][CH2:11]2)[CH2:6][CH2:5][CH2:4]1)#[N:2].[CH3:14][N:15]([CH:17](N(C)C)N(C)C)[CH3:16]>C1(C)C=CC=CC=1>[C:1]([N:3]1[C@H:12]2[C@@H:7]([CH2:8][C:9](=[O:13])[C:10](=[CH:14][N:15]([CH3:17])[CH3:16])[CH2:11]2)[CH2:6][CH2:5][CH2:4]1)#[N:2]
Reactant: CN(C)C(N(C)C)N(C)C
Reactant: N#CN1CCC[C@@H]2CC(=O)CC[C@H]21
Solvent: Cc1ccccc1
Product: CN(C)C=C1C[C@@H]2[C@H](CCCN2C#N)CC1=O

Procedure:
A reaction mixture was prepared from 4.18 g. of trans-(±)-1-cyano-6-oxodecahydroquinoline, 5.0 g. of tris-dimethylaminomethane and 50 ml. of toluene. The reaction mixture was refluxed under nitrogen temperature for five hours and then was concentrated in vacuo. Five and seventy-six hundredths grams of a crude yellow solid comprising trans-(±)-1-cyano-6-oxo-7-dimethylaminomethylenedecahydroquinoline were obtained. This crude product was mixed with 2.25 g. of guanidine carbonate in 100 ml. of anhydrous methanol. This reaction mixture was heated to reflux under nitrogen overnight, and was then concentrated in vacuo. The resulting solid residue was triturated with hot methanol and filtered. The filter cake was washed twice with methanol and once with ether. A yield of 4.11 g. (78%) of trans-(±)-2-amino-6-cyano-5,5a,6,7,8,9,9a,10-octahydropyrimido[4,5-g]quinoline were obtained having the following physical characteristics. Mass spectrum, molecular ion at 229; infrared spectrum peaks at 3307.18, 3157.70, 2202.87, 1660.83, 1599.10, 1564.38, 1486.26.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][C:4](=[O:7])[CH2:3][CH2:2]1.Cl[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][O:15][CH3:16]>>[CH3:16][O:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][N:1]1[CH2:6][CH2:5][C:4](=[O:7])[CH2:3][CH2:2]1
Reactant: COCCCCCCCl
Reactant: O=C1CCNCC1
Product: COCCCCCCN1CCC(=O)CC1

Procedure:
1-(6-Methoxyhexyl)-4-piperidone is prepared from 4-piperidone and 1-chloro-6-methoxyhexane essentially as described above in Example 38, Scheme C, step a.
Reaction SMILES: [O:1]=[C:2]1[NH:5][CH:4]([CH2:6][CH:7]=[CH:8][C:9]([O:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[O:10])[CH2:3]1.C([O:23]O)(C)(C)C>C(O)(=O)C.[Na+].[Na+].Cl[Pd+2](Cl)(Cl)Cl>[O:23]=[C:7]([CH2:6][CH:4]1[CH2:3][C:2](=[O:1])[NH:5]1)[CH2:8][C:9]([O:11][CH2:12][C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1)=[O:10]
Reactant: CC(C)(C)OO
Reactant: O=C1CC(CC=CC(=O)OCc2ccccc2)N1
Agent: Cl[Pd]Cl
Agent: [Na+]
Solvent: CC(=O)O
Product: O=C(CC(=O)OCc1ccccc1)CC1CC(=O)N1
Temperature: 50 °C
Reaction time: 72 h

Procedure:
A mixture of benzyl 4-[(2RS)-4-oxoazetidin-2-yl]but-2-enoate (167 mg), tert-butylhydroperoxide (0.3 ml), and sodium tetrachloropalladate (80 mg) in 67% aqueous acetic acid (2.7 ml) was heated at 50° C. for 8.5 hours. Additional tert-butylhydroperoxide (0.5 ml) and sodium tetrachloropalladate (40 mg) were added. The reaction mixture was stirred at room temperature for three days and heated at 50° C. for 14 hours. After evaporation of the solvent in vacuo, the residue was taken up into ethyl acetate (20 ml) and washed with dilute aqueous sodium chloride. Drying over magnesium sulfate and evaporation left an oil (200 mg), which was chromatographed on silica gel plate (developing solvent: 20% acetone in dichloromethane) afforded benzyl 3-oxo-4-[(2RS)-4-oxoazetidin-2-yl]butanoate (66 mg).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:19]=[CH:18][C:12]2[CH2:13][CH2:14][NH:15][CH2:16][CH2:17][C:11]=2[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:20]1(=O)[CH2:23][CH2:22][CH2:21]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)([O-])[O-].[Na+].[Na+]>C(O)(=O)C.ClCCl>[CH2:1]([O:8][C:9]1[CH:19]=[CH:18][C:12]2[CH2:13][CH2:14][N:15]([CH:20]3[CH2:23][CH2:22][CH2:21]3)[CH2:16][CH2:17][C:11]=2[CH:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: c1ccc(COc2ccc3c(c2)CCNCC3)cc1
Reactant: O=C1CCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(=O)O
Product: c1ccc(COc2ccc3c(c2)CCN(C2CCC2)CC3)cc1
Reaction time: 0.5 h

Procedure:
7-Benzyloxy-1,2,4,5-tetrahydro-benzo[d]azepine (D2) (25.3 g, 100 mmol) was dissolved in 2.5% acetic acid in dichloromethane (400 ml) at 0° C. and treated dropwise with cyclobutanone (11.2 ml, 150 mmol). The mixture was stirred for 30 minutes and then sodium triacetoxyborohydride (31.8 g, 150 mmol) was added portion wise. The reaction mixture was stirred at room temperature for 4 hours, basified with saturated sodium carbonate solution and extracted with dichloromethane. The combined extracts were washed with water, brine, dried over anhydrous sodium sulfate and concentrated in vacuo. The crude residue was triturated with hexane and filtered to afford the title product (E1). MS (ES+) m/e 308 [M+H]+.
Reaction SMILES: O[CH2:2][CH2:3][CH2:4][CH2:5][C:6]1[CH:11]=[C:10]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=2)[N:9]=[C:8]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=2)[CH:7]=1.C([O-])([O-])=O.[Na+].[Na+].[BrH:30]>>[Br:30][CH2:2][CH2:3][CH2:4][CH2:5][C:6]1[CH:11]=[C:10]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=2)[N:9]=[C:8]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=2)[CH:7]=1
Reactant: OCCCCc1cc(-c2ccccn2)nc(-c2ccccn2)c1
Reactant: Br
Agent: O=C([O-])[O-]
Agent: [Na+]
Product: BrCCCCc1cc(-c2ccccn2)nc(-c2ccccn2)c1
Temperature: 25 °C
Yield: 78 %

Procedure:
the alcohol (20) (0.200 gm., 0.65 mmol) was dissolved in 5 mL HBr (45%) and refluxed for 6 hours. After cooling to room temperature the mixture was poured over 20 gm. of crushed ice, basified with saturated aqueous solution of Na2CO3 and extracted with CH2Cl2. The extracts were dried over (MgSO4) and evaporated to dryness to yield the bromo derivative (21) (0.186 gm., 0.51 mmol, 78%).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([N:9]([CH3:14])[CH2:10]C(O)=O)=[CH:5][CH:4]=1)#[N:2].[N:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[N:21]([CH2:33][CH2:34][C:35]([O:37][CH2:38][CH3:39])=[O:36])[C:22](=[O:32])[C:23]1[CH:28]=[CH:27][C:26]([NH:29][CH3:30])=[C:25]([NH2:31])[CH:24]=1.Cl[CH2:41]Cl.CO>>[N:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[N:21]([CH2:33][CH2:34][C:35]([O:37][CH2:38][CH3:39])=[O:36])[C:22]([C:23]1[CH:28]=[CH:27][C:26]2[N:29]([CH3:41])[C:30]([CH2:14][N:9]([C:6]3[CH:7]=[CH:8][C:3]([C:1]#[N:2])=[CH:4][CH:5]=3)[CH3:10])=[N:31][C:25]=2[CH:24]=1)=[O:32]
Reactant: CCOC(=O)CCN(C(=O)c1ccc(NC)c(N)c1)c1ccccn1
Reactant: CN(CC(=O)O)c1ccc(C#N)cc1
Reactant: ClCCl
Solvent: CO
Product: CCOC(=O)CCN(C(=O)c1ccc2c(c1)nc(CN(C)c1ccc(C#N)cc1)n2C)c1ccccn1
Yield: 71 %

Procedure:
Prepared analogously to Example 25c from N-(4-cyanophenyl)-N-methylglycine and 3-amino-4-methylamino-benzoic acid-N-(2-pyridyl)-N-(2-ethoxycarbonylethyl)-amide. Yield: 71% of theory, Rf value: 0.66 (silica gel; dichloromethane/methanol=19:1)
Reaction SMILES: [Cl:1][C:2]1[C:3]([N:8]2[C:12]([C:13]([O:15][CH3:16])=[O:14])=[CH:11][C:10]([CH:17]=[O:18])=[N:9]2)=[N:4][CH:5]=[CH:6][CH:7]=1.[I-].[CH3:20][S+](C)C.CC([O-])(C)C.[K+].O>CS(C)=O>[Cl:1][C:2]1[C:3]([N:8]2[C:12]([C:13]([O:15][CH3:16])=[O:14])=[CH:11][C:10]([CH:17]3[CH2:20][O:18]3)=[N:9]2)=[N:4][CH:5]=[CH:6][CH:7]=1
Reactant: C[S+](C)C
Reactant: COC(=O)c1cc(C=O)nn1-c1ncccc1Cl
Agent: CC(C)(C)[O-]
Agent: [I-]
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: COC(=O)c1cc(C2CO2)nn1-c1ncccc1Cl
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 20.9 %

Procedure:
5.00 g (18.8 mmol) of methyl 1-(3-chloropyridin-2-yl)-3-formyl-1H-pyrazole-5-carboxylate (known from WO 2006/000336) and 5.76 g (28.2 mmol) of trimethylsulphonium iodide were initially charged in 12.5 ml of dimethyl sulphoxide, and 2.64 g (23.5 mmol) of t-BuOK in 12.5 ml of dimethyl sulphoxide were added dropwise at room temperature. After 1.5 hours of stirring at room temperature, 60 ml of water were carefully added dropwise with ice cooling, whereupon the reaction mixture was extracted repeatedly with ethyl acetate. The combined organic phases were washed three times with water and then dried over magnesium sulphate. The solvent was distilled off under reduced pressure and the residue was chromatographed on silica gel, which gave 1.10 g (21% of theory) of methyl 1-(3-chloropyridin-2-yl)-3-(oxiran-2-yl)-1H-pyrazole-5-carboxylate. (logP: 1.67; MH+: 280.0; 1H-NMR (400 MHz, CD3CN, δ, ppm): 3.10 (m, 2H), 3.71 (s, 3H), 3.98 (s, 1H), 6.92 (s, 1H), 7.56 (m, 1H), 8.07 (m, 1H), 8.51 (m, 1H).)
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH2:14])[C:6](=[C:10]([O:12][CH3:13])[CH:11]=1)[C:7]([OH:9])=[O:8].[CH2:15](N(CC)CC)[CH3:16].C(OC(=O)C)(=O)C.O>C(Cl)Cl>[CH3:13][O:12][C:10]1[C:6]2[C:7](=[O:9])[O:8][C:15]([CH3:16])=[N:14][C:5]=2[CH:4]=[C:3]([O:2][CH3:1])[CH:11]=1
Reactant: COc1cc(N)c(C(=O)O)c(OC)c1
Reactant: CCN(CC)CC
Solvent: CC(=O)OC(C)=O
Solvent: ClCCl
Solvent: O
Product: COc1cc(OC)c2c(=O)oc(C)nc2c1
Temperature: 40 °C
Yield: 51 %

Procedure:
The anthranilic acid (388 mg, 1.97 mmol) prepared in Example 2 was taken up in anhydrous methylene chloride (10 mL). Triethylamine (2.36 mmol) was added followed by addition of acetic anhydride (2.36 mmol). The reaction mixture was heated at 40° C. for 18 hours. Subsequently, the reaction mixture was poured into water and extracted with methylene chloride. The organic layer was washed with saturated aqueous sodium bicarbonate, brine, dried over magnesium sulfate, filtered, and concentrated in vacuo to afford 5,7-dimethoxy-2-methyl-3,1-benzoxazine-4-one (51% yield).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:15]=[C:16]([F:18])[CH:17]=1)[CH2:5][C:6]1[CH:7]=[CH:8][C:9](F)=[C:10]([CH:13]=1)[C:11]#[N:12].O.[NH2:20][NH2:21]>C(O)CCC.O.C(OCC)(=O)C>[F:1][C:2]1[CH:3]=[C:4]([CH:15]=[C:16]([F:18])[CH:17]=1)[CH2:5][C:6]1[CH:13]=[C:10]2[C:9](=[CH:8][CH:7]=1)[NH:21][N:20]=[C:11]2[NH2:12]
Reactant: NN
Reactant: N#Cc1cc(Cc2cc(F)cc(F)c2)ccc1F
Solvent: CCOC(C)=O
Solvent: CCCCO
Solvent: O
Product: Nc1n[nH]c2ccc(Cc3cc(F)cc(F)c3)cc12
Temperature: 120 °C
Yield: 62 %

Procedure:
A mixture of 5-(3,5-difluoro-benzyl)-2-fluoro-benzonitrile (20 g, 80.9 mmol) and hydrazine hydrate (19.6 mL, 404 mmol) in n-butanol (200 mL) was heated at 120° C. overnight. The reaction mixture was diluted with water/ethyl acetate and the organic phase washed twice with brine, dried and evaporated. Crude was triturated with diethyl ether and filtered to afford 13 gr of final product. Purification of the resulting organic phase by chromatography over silica gel (DCM/EtOH 95:5) afforded further 6.3 g of the title compound (total amount 19.2 g, 92% yield).
Reaction SMILES: [CH:1]1([Mg]Br)[CH2:3][CH2:2]1.[Cl:6][C:7]1[CH:8]=[CH:9][C:10]([C:30](OC)=[O:31])=[C:11]2[C:15]=1[N:14]=[C:13]1[N:16]([C:20]3[C:21]([CH3:29])=[N:22][C:23]([O:27][CH3:28])=[N:24][C:25]=3[CH3:26])[CH2:17][CH2:18][CH2:19][N:12]21.O1[CH2:38][CH2:37][CH2:36]C1>>[Cl:6][C:7]1[C:15]2[N:14]=[C:13]3[N:16]([C:20]4[C:25]([CH3:26])=[N:24][C:23]([O:27][CH3:28])=[N:22][C:21]=4[CH3:29])[CH2:17][CH2:18][CH2:19][N:12]3[C:11]=2[C:10]([C:30]([CH:36]2[CH2:37][CH2:38]2)([CH:1]2[CH2:3][CH2:2]2)[OH:31])=[CH:9][CH:8]=1
Reactant: C1CCOC1
Reactant: Br[Mg]C1CC1
Reactant: COC(=O)c1ccc(Cl)c2nc3n(c12)CCCN3c1c(C)nc(OC)nc1C
Product: COc1nc(C)c(N2CCCn3c2nc2c(Cl)ccc(C(O)(C4CC4)C4CC4)c23)c(C)n1
Temperature: 60 °C
Reaction time: 3 h
Yield: 38 %

Procedure:
Cyclopropylmagnesium bromide (1.0 M solution in tetrahydrofuran, 1.84 mL, 1.84 mmol) was added to a stirred solution of methyl 9-chloro-1-(2-methoxy-4,6-dimethylpyrimidin-5-yl)-1,2,3,4-tetrahydropyrimido[1,2-a]benzimidazole-6-carboxylate (185 mg, 0.460 mmol) in tetrahydrofuran (2.3 mL), and the mixture was stirred at 60° C. for 3 hr. The reaction was quenched by aqueous saturated ammonium chloride, and the mixture was extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous magnesium sulfate, filtered, and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel eluting with a 70-100% ethyl acetate/n-hexane gradient mixture. The filtrate was concentrated in vacuo to give the solid, which was recrystallized from ethyl acetate to give the title compound as a colorless crystal (78.7 mg, 0.173 mmol, 38%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([S:9]([C:12]([CH2:24][C:25]#[C:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31])([CH2:16][C:17]#[C:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])[C:13](O)=[O:14])(=[O:11])=[O:10])=[CH:5][CH:4]=1.Cl.[NH2:33][OH:34].[K+].[Br-]>>[OH:34][NH:33][C:13](=[O:14])[C:12]([S:9]([C:6]1[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=1)(=[O:11])=[O:10])([CH2:24][C:25]#[C:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31])[CH2:16][C:17]#[C:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23]
Reactant: NO
Reactant: CCCCCC#CCC(CC#CCCCCC)(C(=O)O)S(=O)(=O)c1ccc(OC)cc1
Agent: Cl
Agent: [Br-]
Agent: [K+]
Product: CCCCCC#CCC(CC#CCCCCC)(C(=O)NO)S(=O)(=O)c1ccc(OC)cc1
Yield: 62 %

Procedure:
2-(4- Methoxy-benzenesulfonyl)-2-oct-2-ynyl-dec-4-ynoic acid hydroxyamide was prepared according to the method as outlined in example 1. Starting from 2-(4-methoxy-benzenesulfonyl)-2-oct-2-ynyl-dec-4-ynoic acid (0.36 g, 0.81 mmol) and hydroxylamine hydrochloride (0.70 g, 10 mmol), 0.25 g of the product isolated. Yield 62%; white solid; mp 83-84° C.; 462.0 (M+H)+; 1H NMR (300 MHz, DMSO-d6) δ0.82-0.90 (m, 6H), 1.15-1.45 (m, 12H), 1.90-2.05 (m, 4H), 2.86 (brd, J=17.0 Hz, 2H), 3.00 (brd, J=17.0 Hz, 2H), 3.87 (s, 3H), 7.15 (d, J=10.0 Hz, 1H), 7.71 (d, J=10.0 Hz, 1H), 9.20 (brs, 1H), 10.90 (brs, 1H); IR (KBr, cm−1): 3344s, 3208m, 2930m, 2870m, 1677s, 1592s; Anal. Calc'd for C25H35NO5S: C, 65.05; H, 7.64; N, 3.03. Found: C, 65.26; H, 7.68; N, 2.90.
Reaction SMILES: [CH3:1][N:2]([CH3:18])[CH:3]1[C:12]2[CH2:11][O:10][C:9]([CH:13]=[CH2:14])=[CH:8][C:7]3=[CH:15][NH:16][CH:17]=[C:5]([C:6]=23)[CH2:4]1>CO.[H][H].[Pd]>[CH2:13]([C:9]1[O:10][CH2:11][C:12]2[CH:3]([N:2]([CH3:1])[CH3:18])[CH2:4][C:5]3=[CH:17][NH:16][CH:15]=[C:7]([C:6]=23)[CH:8]=1)[CH3:14]
Reactant: C=CC1=CC2=CNC=C3CC(N(C)C)C(=C23)CO1
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: CCC1=CC2=CNC=C3CC(N(C)C)C(=C23)CO1
Yield: 99 %

Procedure:
Compound (40) 242 mg was dissolved in methanol 4 ml and 5% palladium/C 60 mg was added. A mixture was stirred in hydrogen atmosphere at room temperature for 3 h. The catalyst was filtered off and the filtrate was concentrated under reduced pressure. The residue obtained was chromatographed on aluminum oxide in ethyl acetate:hexane (1:2) to give the titled compound as colorless crystals 241.6 mg. Yield 99%. This was recrystallized from acetone-hexane to give the titled compound as colorless crystals, m.p. 91-92° C.
Reaction SMILES: [C:1]([N:4]1[CH2:12][CH2:11][CH:7]([C:8](Cl)=[O:9])[CH2:6][CH2:5]1)(=[O:3])[CH3:2].[C:13]1([O:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.[Cl-].[Al+3].[Cl-].[Cl-]>C(Cl)CCl>[C:1]([N:4]1[CH2:12][CH2:11][CH:7]([C:8](=[O:9])[C:23]2[CH:24]=[CH:25][C:20]([O:19][C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)=[CH:21][CH:22]=2)[CH2:6][CH2:5]1)(=[O:3])[CH3:2]
Reactant: c1ccc(Oc2ccccc2)cc1
Reactant: CC(=O)N1CCC(C(=O)Cl)CC1
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCCl
Product: CC(=O)N1CCC(C(=O)c2ccc(Oc3ccccc3)cc2)CC1

Procedure:
By following the manipulative procedure described above in Example 4(a), 32.0 g of 1-acetylisonipecotoyl chloride, [Example 1(b)] are added to a stirring solution of 30.6 g of diphenylether and 45.3 g of aluminum chloride in 100 ml of ethylene dichloride to produce a yellow oil of 1-acetyl-4-(4-phenoxybenzoyl)piperidine.
Reaction SMILES: Cl.[NH2:2][C:3]1[CH:8]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:6]=[CH:5][C:4]=1[NH:13][C:14]1[CH:19]=[C:18]([C:20]([F:23])([F:22])[F:21])[CH:17]=[CH:16][C:15]=1[O:24][CH3:25].C(N(CC)CC)C.[C:33](Cl)(Cl)=[S:34].O>C(Cl)Cl>[CH3:25][O:24][C:15]1[CH:16]=[CH:17][C:18]([C:20]([F:21])([F:22])[F:23])=[CH:19][C:14]=1[N:13]1[C:4]2[CH:5]=[CH:6][C:7]([C:9]([F:12])([F:11])[F:10])=[CH:8][C:3]=2[NH:2][C:33]1=[S:34]
Reactant: COc1ccc(C(F)(F)F)cc1Nc1ccc(C(F)(F)F)cc1N
Reactant: S=C(Cl)Cl
Agent: Cl
Solvent: ClCCl
Solvent: O
Solvent: CCN(CC)CC
Product: COc1ccc(C(F)(F)F)cc1-n1c(=S)[nH]c2cc(C(F)(F)F)ccc21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To an ice cooled suspension of N-(2-amino-4-trifluoromethylphenyl)-2-methoxy-5-trifluoromethylaniline, hydrochloride (3 mmol, 1.2 g) in dry methylenechloride (20 ml) is added triethylamine (9 mmol, 0.73 ml) and thiophosgene (3 mmol, 0.23 ml). The reaction mixture is stirred at room temperature overnight and poured into water. The mixture is extracted with methylenechloride and the organic phases are dried and concentrated in vacuo. The crude product is subjected to column chromatography using petroleum ether+ethylacetate (4+1) as eluent. The fractions containing the product are concentrated in vacuo yielding a yellow oil which solidifies upon treatment with petroleum ether, yielding the title compound as off white crystals, which were used without further purification.
Reaction SMILES: [CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[S:11][C:10]([NH2:12])=[N:9][C:8]=2[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[N:3]=1.[CH3:19][C:20]([CH3:26])([CH3:25])[CH2:21][C:22](Cl)=[O:23]>>[CH3:19][C:20]([CH3:26])([CH3:25])[CH2:21][C:22]([NH:12][C:10]1[S:11][C:7]([C:4]2[N:3]=[C:2]([CH3:1])[O:6][N:5]=2)=[C:8]([C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)[N:9]=1)=[O:23]
Reactant: Cc1nc(-c2sc(N)nc2-c2ccccc2)no1
Reactant: CC(C)(C)CC(=O)Cl
Product: Cc1nc(-c2sc(NC(=O)CC(C)(C)C)nc2-c2ccccc2)no1

Procedure:
Prepared from 5-(5-methyl-[1,2,4]oxadiazol-3-yl)-4-phenyl-thiazol-2-ylamine and 3,3-dimethyl-butyryl chloride.
Reaction SMILES: C([N:4]1[C:12]2[C:7](=[CH:8][C:9]([C:13](Cl)=[O:14])=[CH:10][CH:11]=2)[C:6]([C:16]2[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=2)=[N:5]1)(=O)C.[OH-].[NH4+:24].O>C(Cl)Cl>[F:22][C:19]1[CH:20]=[CH:21][C:16]([C:6]2[C:7]3[C:12](=[CH:11][CH:10]=[C:9]([C:13]([NH2:24])=[O:14])[CH:8]=3)[NH:4][N:5]=2)=[CH:17][CH:18]=1
Reactant: [NH4+]
Reactant: CC(=O)n1nc(-c2ccc(F)cc2)c2cc(C(=O)Cl)ccc21
Agent: [OH-]
Solvent: ClCCl
Solvent: O
Product: NC(=O)c1ccc2[nH]nc(-c3ccc(F)cc3)c2c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 72 %

Procedure:
To a solution of 1-acetyl-3-(4-fluorophenyl)-1H-indazole-5-carbonyl chloride (200 mg, 0.63 mmol) in methylene chloride (20 mL) was added saturated ammonium hydroxide (NH4OH). The solution was stirred overnight at room temperature when it was added to water (100 mL) and extracted with ethyl acetate (3×40 mL). The combined organic layers were dried (Na2SO4) and concentrated under vacuo to an oil. The resulting oil was chromatographed on silica gel, eluting with 10% methanol in methylene chloride to give the title compound (115 mg, 72%). 1H NMR (DMSO-d6) δ 13.4 (s, 1H), 8.60 (s, 1H), 0.09 (m, 2H), 7.94 (d, 1H), 7.61 (d, 1H), 7.38 (t, 2H); ES-MS (m/z) 256 [M+1]+.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:10])=[C:6]([CH:9]=1)[C:7]#[N:8].[Br:11]N1C(=O)CCC1=O>C(Cl)(Cl)(Cl)Cl>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:10][Br:11])=[C:6]([CH:9]=1)[C:7]#[N:8]
Reactant: Cc1ccc(Br)cc1C#N
Reactant: O=C1CCC(=O)N1Br
Solvent: ClC(Cl)(Cl)Cl
Product: N#Cc1cc(Br)ccc1CBr
Temperature: 25 °C
Yield: 38.4 %

Procedure:
A mixture of 5-bromo-2-methylbenzonitrile (5.0 g, 25.5 mmol), N-bromosuccinimide (4.54 g, 25.5 mmol), 2′,2′-azobis(2-methylpropionitrile) (0.05 g) and carbon tetrachloride (25 mL) is heated at reflux for 75 min. After cooling to room temperature, the solids are removed by filtration. The filtrate is concentrated and the residue purified by chromatography eluting with cyclohexane-20% ethyl acetate. Product containing fractions are combined and concentrated to afford 5-bromo-2-bromomethylbenzonitrile (2.69 g, 38%). LC/MS: MS showed no parent molecular ion peak; RT 3.52 min.
Reaction SMILES: N[C:2]1[CH:23]=[CH:22][C:5]([O:6][CH2:7][C:8]2([CH3:21])[CH2:17][C:16](=[O:18])[C:15]3[C:10](=[CH:11][C:12]([CH3:20])=[CH:13][C:14]=3[CH3:19])[O:9]2)=[CH:4][CH:3]=1.[ClH:24].N([O-])=O.[Na+].[C:29]([O:33][CH2:34][CH3:35])(=[O:32])[CH:30]=[CH2:31]>O.CC(C)=O>[Cl:24][CH:30]([CH2:31][C:2]1[CH:23]=[CH:22][C:5]([O:6][CH2:7][C:8]2([CH3:21])[CH2:17][C:16](=[O:18])[C:15]3[C:10](=[CH:11][C:12]([CH3:20])=[CH:13][C:14]=3[CH3:19])[O:9]2)=[CH:4][CH:3]=1)[C:29]([O:33][CH2:34][CH3:35])=[O:32]
Reactant: Cl
Reactant: C=CC(=O)OCC
Reactant: Cc1cc(C)c2c(c1)OC(C)(COc1ccc(N)cc1)CC2=O
Agent: O=N[O-]
Agent: [Na+]
Solvent: CC(C)=O
Solvent: O
Product: CCOC(=O)C(Cl)Cc1ccc(OCC2(C)CC(=O)c3c(C)cc(C)cc3O2)cc1

Procedure:
A procedure similar to that described in Preparation 5 was repeated, except that 1.8 g of 2-(4-aminophenoxymethyl)-2,5,7-trimethyl-4-oxochroman (prepared as described in Preparation 28), 2 ml of concentrated aqueous hydrochloric acid, 520 mg of sodium nitrite, 6 ml of ethyl acrylate, 83 mg of cuprous oxide, 20 ml of acetone and 1 ml of water were reacted, to afford 1.52 g of the title compound as a pale yellow oil.