Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+](C1C=CC(O[C:11](=[O:21])[C:12]2[CH:17]=[CH:16][C:15]([C:18](=[O:20])[CH3:19])=[CH:14][CH:13]=2)=CC=1)([O-])=O.[NH2:22][C:23]1[S:24][CH:25]=[C:26]([C:28]([NH:30][CH2:31][CH2:32][N:33]([CH:37]([CH3:39])[CH3:38])[CH:34]([CH3:36])[CH3:35])=[O:29])[N:27]=1>>[C:18]([C:15]1[CH:14]=[CH:13][C:12]([C:11]([NH:22][C:23]2[S:24][CH:25]=[C:26]([C:28]([NH:30][CH2:31][CH2:32][N:33]([CH:37]([CH3:39])[CH3:38])[CH:34]([CH3:35])[CH3:36])=[O:29])[N:27]=2)=[O:21])=[CH:17][CH:16]=1)(=[O:20])[CH3:19]
Reactant: CC(C)N(CCNC(=O)c1csc(N)n1)C(C)C
Reactant: CC(=O)c1ccc(C(=O)Oc2ccc([N+](=O)[O-])cc2)cc1
Product: CC(=O)c1ccc(C(=O)Nc2nc(C(=O)NCCN(C(C)C)C(C)C)cs2)cc1
Temperature: 130 °C
Reaction time: 8 h
Yield: 57.1 %

Procedure:
To 831 mg of 4-acetylbenzoic acid p-nitrophenyl ester, 788 mg of 2-amino-4-[(2-diisopropylaminoethyl)aminocarbonyl]-1,3-thiazole were added. The resulting mixture was stirred at 130° C. for 8 hours. The reaction mixture was purified by column chromatography on NH silica gel (chloroform), whereby 693 mg of 2-[N-(4-acetylbenzoyl)amino]-4-[(2-diisopropylaminoethyl)aminocarbonyl]-1,3-thiazole were obtained. After 2 ml of a 4N hydrochloric acid--dioxane solution were added to the resulting compound, the solvent was distilled off under reduced pressure. The residue was recrystallized from a mixed solvent of isopropyl ether and ethanol, whereby 395 mg of the title compound were obtained as yellow powder.
Reaction SMILES: [N:1]([CH2:4][C:5]1[CH:18]=[CH:17][C:16]2[C:15](=[O:19])[C:14]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[C:8](=[O:20])[C:7]=2[CH:6]=1)=[N+]=[N-].[H][H]>CN(C=O)C.[Pt]>[NH2:1][CH2:4][C:5]1[CH:18]=[CH:17][C:16]2[C:15](=[O:19])[C:14]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[C:8](=[O:20])[C:7]=2[CH:6]=1
Reactant: [H][H]
Reactant: [N-]=[N+]=NCc1ccc2c(c1)C(=O)c1ccccc1C2=O
Agent: [Pt]
Solvent: CN(C)C=O
Product: NCc1ccc2c(c1)C(=O)c1ccccc1C2=O
Yield: 75.9 %

Procedure:
9.5 g of 2-azidomethylanthraquinone are dissolved in 100 ml of DMF, 1.0 g of platinum-on-charcoal catalyst (5% by weight of Pt) is added and hydrogenation is carried out with hydrogen for 15 minutes. The catalyst is filtered off, 200 ml of water are added to the filtrate and the mixture is filtered. The red crystals which have precipitated are recrystallised from dioxane. 6.5 g (70.01% of theory) of 2-aminomethylanthraquinone are obtained; melting point: 170°-78° C.
Reaction SMILES: [Cr](O[Cr]([O-])(=O)=O)([O-])(=O)=O.[NH+]1C=CC=CC=1.[NH+]1C=CC=CC=1.[CH2:22]([O:29][C:30]([NH:32][C@H:33]([C:37]([NH:39][C@@H:40]([CH2:57][C:58]1[CH:63]=[CH:62][CH:61]=[CH:60][CH:59]=1)[C@H:41]([OH:56])[CH2:42][C@@H:43]1[CH2:48][CH2:47][CH2:46][CH2:45][C@H:44]1[C:49]([NH:51][C:52]([CH3:55])([CH3:54])[CH3:53])=[O:50])=[O:38])[CH:34]([CH3:36])[CH3:35])=[O:31])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.O>CN(C)C=O>[CH2:22]([O:29][C:30]([NH:32][C@H:33]([C:37]([NH:39][C@@H:40]([CH2:57][C:58]1[CH:59]=[CH:60][CH:61]=[CH:62][CH:63]=1)[C:41](=[O:56])[CH2:42][C@@H:43]1[CH2:48][CH2:47][CH2:46][CH2:45][C@H:44]1[C:49]([NH:51][C:52]([CH3:54])([CH3:55])[CH3:53])=[O:50])=[O:38])[CH:34]([CH3:36])[CH3:35])=[O:31])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: CC(C)[C@H](NC(=O)OCc1ccccc1)C(=O)N[C@@H](Cc1ccccc1)[C@H](O)C[C@@H]1CCCC[C@H]1C(=O)NC(C)(C)C
Agent: O=[Cr](=O)([O-])O[Cr](=O)(=O)[O-]
Agent: c1cc[nH+]cc1
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)[C@H](NC(=O)OCc1ccccc1)C(=O)N[C@@H](Cc1ccccc1)C(=O)C[C@@H]1CCCC[C@H]1C(=O)NC(C)(C)C
Temperature: 25 °C
Reaction time: 18 h
Yield: 67.1 %

Procedure:
220 mg (0.59 mmol) of pyridinium dichromate were added to a solution of 48 mg (0.08 mmol) of 2(S)-[3(S)-[[N-(benzyloxycarbonyl)-L-valyl]amino]-2(R)-hydroxy-4-phenylbutyl]-N-tert.butyl-1(R)-cyclohexanecarboxamide in 1 ml of dimethylformamide and the mixture was stirred at room temperature for 18 hours. 10 ml of water were added and the mixture was extracted with two 10 ml portions of ethyl acetate. The combined extracts were washed with two 10 ml portions of water, dried over anhydrous magnesium sulphate and evaporated; The crude product was chromatographed on a column of silica gel using 4% methanol in dichloromethane for the elution to give 31 mg of 2(S)-[3(S)-[[N-(benzyloxycarbonyl)-L-valyl]amino]-2-oxo-4-phenylbutyl]-N-tert.butyl-1(R)-cyclohexanecarboxamide as a white solid of melting point 186°-188° C.; MS m/e 578 [M+H]+.
Reaction SMILES: [CH2:1]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[CH:16](O)[CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH3:9].O.C1(C)C=CC(S(O)(=O)=O)=CC=1.C1(C)C=CC=CC=1>O>[CH2:1]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1/[CH:16]=[CH:17]/[CH2:18][CH2:19][CH2:20][CH3:21])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH3:9]
Reactant: CCCCCCCCCc1ccccc1C(O)CCCCC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: Cc1ccccc1
Product: CCCC/C=C/c1ccccc1CCCCCCCCC

Procedure:
A mixture of 14.4 g of 1-(2-nonylphenyl)-1-hexanol, 2 g of toluene-4-sulphonic acid monohydrate and 250 ml of toluene is heated under reflux for 3 hours using a water separator. After cooling, the reaction mixture is washed twice with 10% strength (w/v) sodium bicarbonate solution and twice with water. The organic phase is dried over sodium sulphate and concentrated by evaporation in vacuo, and the residue is purified by chromatography on silica gel using hexene as eluant. The desired 1-(2-nonylphenyl)-trans-hexene is obtained in the form of a pale yellow oil.
Reaction SMILES: C([O:5][C:6](=[O:59])[CH2:7][N:8]([CH2:51][C:52](=[O:58])[O:53]C(C)(C)C)[CH:9]([CH2:39][CH2:40][CH2:41][C:42]1[CH:47]=[CH:46][C:45]([N+:48]([O-:50])=[O:49])=[CH:44][CH:43]=1)[CH2:10][N:11]1[CH2:22][CH2:21][N:20]([CH2:23][C:24]([O:26]C(C)(C)C)=[O:25])[CH2:19][CH2:18][N:17]([CH2:31][C:32]([O-:34])=[O:33])[CH2:16][CH2:15][N:14]([CH2:35][C:36]([O-:38])=[O:37])[CH2:13][CH2:12]1)(C)(C)C.Cl.CCOCC>O1CCOCC1>[C:52]([CH2:51][N:8]([CH2:7][C:6]([OH:59])=[O:5])[CH:9]([CH2:39][CH2:40][CH2:41][C:42]1[CH:47]=[CH:46][C:45]([N+:48]([O-:50])=[O:49])=[CH:44][CH:43]=1)[CH2:10][N:11]1[CH2:12][CH2:13][N:14]([CH2:35][C:36]([OH:38])=[O:37])[CH2:15][CH2:16][N:17]([CH2:31][C:32]([OH:34])=[O:33])[CH2:18][CH2:19][N:20]([CH2:23][C:24]([OH:26])=[O:25])[CH2:21][CH2:22]1)([OH:58])=[O:53]
Reactant: CC(C)(C)OC(=O)CN1CCN(CC(=O)[O-])CCN(CC(=O)[O-])CCN(CC(CCCc2ccc([N+](=O)[O-])cc2)N(CC(=O)OC(C)(C)C)CC(=O)OC(C)(C)C)CC1
Agent: Cl
Solvent: CCOCC
Solvent: C1COCCO1
Product: O=C(O)CN1CCN(CC(=O)O)CCN(CC(CCCc2ccc([N+](=O)[O-])cc2)N(CC(=O)O)CC(=O)O)CCN(CC(=O)O)CC1
Temperature: 25 °C
Reaction time: 22 h

Procedure:
Compound 10 (77.0 mg, 0.081 mmol) at 0-5° C. was treated dropwise with 4M HCl(g) in 1,4-dioxane (15 mL) over 20 min. The resulting mixture was allowed to warm to room temperature. After 22 h, ether (˜20 mL) was added and continued to stir for 10 min. The resulting mixture was capped and placed in the freezer for 1 h. The solid formed was filtered, washed with ether, and quickly dissolved in DI water. Evaporation of the aqueous solution gave an off-white solid 3p-2C-DEPA (68.0 mg, 97%). 1H NMR (D2O, 300 MHz) δ 1.26-1.40 (m, 1H), 1.48-1.70 (m, 3H), 2.52-2.78 (m, 2H), 2.90-3.70 (m, 27H), 3.75-3.98 (m, 2H), 7.35 (d, J=8.3 Hz, 2H), 8.06 (d, J=8.2 Hz, 2H); 13C NMR (D2O, 300 MHz) δ 27.08 (t), 27.12 (t), 34.64 (t), 48.45 (t), 48.82 (t), 50.22 (t), 51.09 (t), 52.40 (t), 53.58 (t), 54.28 (t), 55.46 (t), 59.43 (d), 123.55 (d), 129.40 (d), 145.71 (s), 150.54 (s), 169.54 (s), 172.97 (s), 173.93 (s); HRMS (Positive ion FAB) Calcd for C29H45N6O12 [M+H]+ m/z 669.3095. Found: [M+]+ m/z 669.3086.
Reaction SMILES: [CH:1]([N:14]1[CH2:19][C@@H:18]2[CH2:20][C@H:15]1[CH2:16][N:17]2C(OC(C)(C)C)=O)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[ClH:28]>O1CCOCC1>[ClH:28].[ClH:28].[CH:1]([N:14]1[CH2:19][C@@H:18]2[CH2:20][C@H:15]1[CH2:16][NH:17]2)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)N1C[C@@H]2C[C@H]1CN2C(c1ccccc1)c1ccccc1
Agent: Cl
Solvent: C1COCCO1
Product: c1ccc(C(c2ccccc2)N2C[C@@H]3C[C@H]2CN3)cc1
Yield: 59 %

Procedure:
A solution of compound 200 (0.5 g, 1.37 mmol) in 4N HCl in dioxane (5 mL) was stirred for 1 h at room temperature and then concentrated. The residue was purified by trituration with Et2O and filtered to afford 201 (0.24 g, 59%) as a beige solid. LRMS (ESI): (calc) 264.2 (found) 265.3 (MH)+.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][N:3]=[CH:2]1.[CH2:6]([N:10]1[C:18]2[C:13](=[C:14](I)[CH:15]=[C:16]([C:19]([O:21]C)=[O:20])[CH:17]=2)[CH:12]=[CH:11]1)[CH2:7][CH2:8][CH3:9]>C1COCC1.[Cl-].[Zn+2].[Cl-]>[CH2:6]([N:10]1[C:18]2[C:13](=[C:14]([C:2]3[O:1][CH:5]=[CH:4][N:3]=3)[CH:15]=[C:16]([C:19]([OH:21])=[O:20])[CH:17]=2)[CH:12]=[CH:11]1)[CH2:7][CH2:8][CH3:9]
Reactant: c1cocn1
Reactant: CCCCn1ccc2c(I)cc(C(=O)OC)cc21
Agent: [Cl-]
Agent: [Zn+2]
Solvent: C1CCOC1
Product: CCCCn1ccc2c(-c3ncco3)cc(C(=O)O)cc21
Temperature: 85 °C
Yield: 70.4 %

Procedure:
To a −72° C. solution of oxazole (0.069 g) in dry THF (20 mL) was added dropwise 1.6 M N-butyl lithium (0.68 mL). The mixture was stirred at −72° C. for 30 minutes at which time 1.0 M zinc chloride (3.3 mL) was added. The mixture was allowed to warm to 0° C. at which time methyl 1-butyl-4-iodo-1H-indole-6-carboxylate (0.37 g) and tetrakis triphenylphosphine palladium(0) (0.07 g) were added and the mixture heated to 85° C. The mixture was heated at 85° C. for 20 h then cooled to room temperature and partitioned between water and ethyl acetate. The layers were separated and the organic layer washed with water, dried over anhydrous sodium sulfate and concentrated under reduced pressure. Column chromatography was performed on silica gel (100 mL) using 20% ethyl acetate in hexanes as eluent. The residue was dissolved in methanol (10 mL) and 1N NaOH (3 mL) and heated at 60° C. for 2 h. The mixture was acidified to pH 4 with 1N HCl and extracted with ethyl acetate. The ethyl acetate extracts were dried over anhydrous sodium sulfate and concentrated to dryness under reduced pressure to give 0.2 g of the title compound: MS (ESI+) for C16H16N2O3 m/a 283.16 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[CH2:9][CH2:10][CH2:11][O:12][C:13]1[C:14]2[N:15]([CH:19]=[C:20]([CH3:22])[N:21]=2)[CH:16]=[CH:17][CH:18]=1.Cl.[CH3:24][NH:25][CH3:26].C=O>CO>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[CH2:9][CH2:10][CH2:11][O:12][C:13]1[C:14]2[N:15]([C:19]([CH2:24][NH:25][CH3:26])=[C:20]([CH3:22])[N:21]=2)[CH:16]=[CH:17][CH:18]=1
Reactant: Cc1cn2cccc(OCCCc3ccc(Cl)cc3Cl)c2n1
Reactant: CNC
Agent: C=O
Agent: Cl
Solvent: CO
Product: CNCc1c(C)nc2c(OCCCc3ccc(Cl)cc3Cl)cccn12
Yield: 53.7 %

Procedure:
A mixture of 8-[3-(2,4-dichlorophenyl)propoxy]-2-methylimidazo[1,2-α]pyridine (703 mg, 2 mmol, see example 1), dimethylamine hydrochloride (700 mg, 8.48 mmol) and paraformaldehyde (256 mg, 8.48 mmol) in methanol (5 mL) was refluxed for 40 h. The reaction mixture was concentrated in vacuo and the residue was partitioned between dichloromethane (15 mL) and saturated aq sodium bicarbonate solution (5 mL) and water (5 mL). The layers were separated and the aqueous layer was extracted with dichloromethane (2×10 mL). The organic extracts were combined, dried over anhydrous sodium sulfate and concentrated in vacuo. Purification by dry column (60 mL funnel, silica gel 10–40μl, Sigma cat. S-6628) eluted with increasingly polar mixtures of ethyl acetate-hexanes (v/v: 1:1.4, 1.2:1, 2:1, 2.9:1, 5:1, containing 0.5% v/v isopropylamine) yielded 406 mg (52% yield) of 8-[3-(2,4-dichlorophenyl)propoxy]-3-[(methylamino)methyl]-2-methylimidazo[1,2-α]pyridine in the first fraction (Rf=0.20 in ethyl acetate-hexanes, 2:1 v/v, containing 0.5% v/v isopropylamine) and 221 mg (27% yield) of 8-[3-(2,4-dichlorophenyl)propoxy]-3-[(dimethylamino)methyl]-2-methylimidazo[1,2-α]pyridine in the second fraction (Rf=0.07 in ethyl acetate-hexanes, 2:1 v/v, containing 0.5% v/v isopropylamine).
Reaction SMILES: [NH3:1].Cl[C:3]1[C:4]2[N:5]([C:9]([CH:25]3[CH2:27][CH2:26]3)=[N:10][C:11]=2[C:12]2[CH:17]=[CH:16][C:15]([O:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)=[CH:14][CH:13]=2)[CH:6]=[CH:7][N:8]=1>O.CC(O)CC>[CH:25]1([C:9]2[N:5]3[CH:6]=[CH:7][N:8]=[C:3]([NH2:1])[C:4]3=[C:11]([C:12]3[CH:17]=[CH:16][C:15]([O:18][C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)=[CH:14][CH:13]=3)[N:10]=2)[CH2:27][CH2:26]1
Reactant: N
Reactant: Clc1nccn2c(C3CC3)nc(-c3ccc(Oc4ccccc4)cc3)c12
Solvent: CCC(C)O
Solvent: O
Product: Nc1nccn2c(C3CC3)nc(-c3ccc(Oc4ccccc4)cc3)c12
Reaction time: 8 h

Procedure:
A solution of NH3 in H2O (20 M, 2 mL) was added to a suspension of 8-chloro-3-cyclopropyl-1-(4-phenoxyphenyl)-imidazo[1,5-a]pyrazine (33 mg, 0.091 mmol) in 2-butanol (0.4 mL). The mixture was heated in an oil bath set at 105° C. overnight. Reaction mixture was concentrated in vacuo and purification by prep TLC (4% MeOH in DCM as eluent) afforded the title compound as a solid. 1H NMR (400 MHz, CDCl3): δ 0.95-1.22 (m, 4H), 1.93-2.09 (m, 1H), 5.10 (br. s., 2H), 7.02-7.18 (m, 6H), 7.32-7.44 (m, 3H), 7.55-7.62 (m, 2H). MS (ES+): m/z 343.15 (100)[MH+]. HPLC: tR=2.52 min (Open Lynx polar—5 min).
Reaction SMILES: [F:1][CH:2]([F:24])[C:3]1[N:8]2[N:9]=[CH:10][C:11]([C:12]#[CH:13])=[C:7]2[N:6]=[C:5]([C:14]2[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][CH:15]=2)[CH:4]=1.Br[C:26]1[CH:31]=[CH:30][C:29]([S:32]([NH:35][CH2:36][CH2:37][OH:38])(=[O:34])=[O:33])=[CH:28][CH:27]=1>>[F:24][CH:2]([F:1])[C:3]1[N:8]2[N:9]=[CH:10][C:11]([C:12]#[C:13][C:26]3[CH:31]=[CH:30][C:29]([S:32]([NH:35][CH2:36][CH2:37][OH:38])(=[O:34])=[O:33])=[CH:28][CH:27]=3)=[C:7]2[N:6]=[C:5]([C:14]2[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][CH:15]=2)[CH:4]=1
Reactant: C#Cc1cnn2c(C(F)F)cc(-c3ccc(C(F)(F)F)cc3)nc12
Reactant: O=S(=O)(NCCO)c1ccc(Br)cc1
Product: O=S(=O)(NCCO)c1ccc(C#Cc2cnn3c(C(F)F)cc(-c4ccc(C(F)(F)F)cc4)nc23)cc1

Procedure:
The title compound was prepared from 7-difluoromethyl-3-ethynyl-5-(4-trifluoromethyl-phenyl)-pyrazolo[1,5-a]pyrimidine (example C.2) (340 mg, 1.0 mmol) and 4-bromo-N-(2-hydroxy-ethyl)-benzenesulfonamide (example B.29) (276 mg, 1.0 mmol) according to general procedure II. Obtained as a yellow solid (360 mg, 66%). MS (ISP) 537.3 [(M+H)+]; mp 191–194° C.
Reaction SMILES: [Br-].[CH3:2][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[NH2-].[Na+].[CH3:24][C:25]1([CH3:41])[C:33]2[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=2)[CH:27]([N:34]2[C:38]([CH:39]=O)=[CH:37][N:36]=[CH:35]2)[CH2:26]1>C1COCC1>[CH3:24][C:25]1([CH3:41])[C:33]2[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=2)[CH:27]([N:34]2[C:38]([CH:39]=[CH2:2])=[CH:37][N:36]=[CH:35]2)[CH2:26]1
Reactant: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: CC1(C)CC(n2cncc2C=O)c2ccccc21
Agent: [Br-]
Agent: [NH2-]
Agent: [Na+]
Solvent: C1CCOC1
Product: C=Cc1cncn1C1CC(C)(C)c2ccccc21
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of methyltriphenylphosphonium bromide/sodium amide [2.4 mmol/gram of salt (0.86 g, 2.06 mmol)] in THF (3.0 mL) is added a solution of 3-(3,3-dimethyl-indan-1-yl)-3H-imidazole-4-carbaldehyde (165 mg, 0.69 mmol) in THF (2 mL). The reaction is permitted to stir at room temperature for 30 minutes and is then quenched with saturated aqueous NH4Cl. The reaction is diluted with ethyl acetate and the layers are separated. The aqueous layer is extracted with ethyl acetate and the organic layers are combined, dried with Na2SO4, filtered, and concentrated. The resulting residue is purified by silica gel flash chromatography (ethyl acetate-dichloromethane, 0:1 to 1:4) to furnish semi-pure 1-(3,3-dimethyl-indan-1-yl)-5-vinyl-1H-imidazole. Further purification via semi-preparative reverse phase HPLC (5 to 100% acetonitrile/water w/0.1% NH4OH), affords 1-(3,3-dimethyl-indan-1-yl)-5-vinyl-1H-imidazole; MS: (ESI) m/z 239 (M+H)+; 1H NMR (400 MHz, CDCl3) δ ppm 1.29 (s, 3 H), 1.39 (s, 3 H), 2.11 (dd, J=13.0, 7.7 Hz, 1 H), 2.54 (dd, J=12.9, 7.8 Hz, 1 H), 5.20 (dd, J=11.4, 1.3 Hz, 1 H), 5.62 (dd, J=17.4, 1.3 Hz, 1 H), 5.72 (t, J=7.7 Hz, 1 H), 6.42 (dd, J=17.4, 11.1 Hz, 1 H), 7.09 (dd, J=7.6, 0.8 Hz, 1 H), 7.23-7.30 (m, 3 H), 7.32 (s, 1 H), 7.37 (t, J=7.5 Hz, 1 H). The HCl salt of the title compound can be prepared by dissolution in diethyl ether, followed by treatment with an excess of 1N HCl in diethyl ether. The resulting heterogeneous solution is concentrated to furnish the HCl salt of 1-(3,3-dimethyl-indan-1-yl)-5-vinyl-1H-imidazole.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16](=N)[C:15]3([OH:18])[CH:10]([CH2:11][CH2:12][CH2:13][CH2:14]3)[C:9]2=[S:19])=[C:4]([F:20])[CH:3]=1.Cl.[OH2:22]>C(O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16](=[O:22])[C:15]3([OH:18])[CH:10]([CH2:11][CH2:12][CH2:13][CH2:14]3)[C:9]2=[S:19])=[C:4]([F:20])[CH:3]=1
Reactant: O
Reactant: N=C1N(c2ccc(Cl)cc2F)C(=S)C2CCCCC12O
Agent: Cl
Solvent: CCO
Product: O=C1N(c2ccc(Cl)cc2F)C(=S)C2CCCCC12O
Yield: 83 %

Procedure:
In 220 ml of ethanol was suspended 25.0 g of 2-(4-chloro-2-fluorophenyl)-3a-hydroxy-3-imino-octahydroisoindol-1-thione and 20 ml of concentrated hydrochloric acid was added to the suspension, followed by stirring at 50° to 60° C. for several minutes. After cooling, 200 ml of water was added to the mixture, and the resulting crystals were collected by filtration, washed with 50% ethanol and dried, thereby producing 20.8 g (yield of 83%) of the subject compound. Recrystallization from ethanol yielded slightly yellow crystals, m.p. 156°-157° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][CH:11]([C:14]([OH:16])=O)[CH2:10][CH2:9]2)=[CH:4][C:3]=1[NH:17][C@@H:18]([C:20]1[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][C:21]=1[Cl:27])[CH3:19].C[N:29]1[CH2:34][CH2:33][O:32][CH2:31][CH2:30]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][CH:11]([C:14]([N:29]3[CH2:34][CH2:33][O:32][CH2:31][CH2:30]3)=[O:16])[CH2:10][CH2:9]2)=[CH:4][C:3]=1[NH:17][C@@H:18]([C:20]1[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][C:21]=1[Cl:27])[CH3:19]
Reactant: C[C@@H](Nc1cc(N2CCC(C(=O)O)CC2)ccc1Cl)c1ccc(Cl)cc1Cl
Reactant: CN1CCOCC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: C[C@@H](Nc1cc(N2CCC(C(=O)N3CCOCC3)CC2)ccc1Cl)c1ccc(Cl)cc1Cl
Temperature: 25 °C
Reaction time: 2 h
Yield: 41.7 %

Procedure:
To a stirred solution of the (R)-1-(4-chloro-3-(1-(2,4-dichlorophenyl)ethylamino)phenyl)piperidine-4-carboxylic acid (0.0.05 g, 0.12 mmol) and N-methylmorpholine (0.01 g, 0.12 mmol) in DMF (1.5 mL) was added HATU (0.049 g, 0.13 mmol) and iPr2NEt (0.75 g, 5.8 mmol). The reaction mixture was stirred at room temperature for 2 h, and quenched with deionzied water. The aqueous layer was extracted with diethyl ether (2×10 mL). The organic layer was dried (Na2SO4), filtered, and concentrated in vacuo. The crude product purified by reverse phase HPLC (C18 column, acetonitrile-H2O with 0.1% TFA as eluent) to give a white solid (0.025 g, 0.050 mmol, 43%). 1H NMR (400 MHz, CDCl3) δ 7.36-7.33 (m, 1H), 7.17 (dd, J=1.6, 8.4 Hz, 1H), 7.06 (d, J=8.8 Hz, 1H), 6.18 (dd, J=2.8, 8.4 Hz, 1H), 5.78 (d, J=2.4 Hz, 1H), 4.90 (ddd, J=6.4, 6.4, 12.4 Hz, 1H), 4.65 (d, J=5.2 Hz, 1H), 3.68-3.63 (m, 5H), 3.50-3.47 (m, 3H), 2.64-2.48 (m, 3H), 1.92-1.80 (m, 5H), 1.71-1.67 (m, 2H), 1.53 (d, J=6.4 Hz, 3H); MS: (ES) m/z calculated for C24H29Cl3N3O2 [M+H]+496.1. found 496.3.
Reaction SMILES: O.[O:2]=[C:3]1[CH2:8][CH2:7][CH2:6][C:5](=O)[CH:4]1[CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12].S(Cl)([Cl:18])=O>C(Cl)Cl>[Cl:18][C:5]1[CH2:6][CH2:7][CH2:8][C:3](=[O:2])[C:4]=1[CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12]
Reactant: CCOC(=O)CC1C(=O)CCCC1=O
Reactant: O=S(Cl)Cl
Solvent: O
Solvent: ClCCl
Product: CCOC(=O)CC1=C(Cl)CCCC1=O

Procedure:
A slurry of ethyl α-(2,6-dioxocyclohexyl)acetate hydrate (1.53 kg) in methylene chloride (7.7L) is brought to reflux and then thionyl chloride (1.80 kg) is added dropwise over a period of 1.75 hours. The solution is refluxed for 3 hours and then evaporated in vacuo to yield an oil which is distilled to give ethyl α-(2-chloro-6-oxocyclohex-1-enyl)acetate as a yellow oil, bp 115°-125°/0.2 mm.
Reaction SMILES: [OH:1][C:2]1[CH:12]=[CH:11][C:5]2[C:6](=[O:10])[CH2:7][CH2:8][O:9][C:4]=2[C:3]=1[CH2:13][CH2:14][CH3:15].C[O:17][C:18](=[O:49])[CH2:19][CH2:20][C:21]1[C:26]([CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32]OS(C)(=O)=O)=[CH:25][CH:24]=[CH:23][C:22]=1[O:38][CH2:39][CH2:40][CH2:41][C:42]([CH3:48])([CH3:47])[C:43]([O:45]C)=[O:44]>>[C:43]([C:42]([CH3:47])([CH3:48])[CH2:41][CH2:40][CH2:39][O:38][C:22]1[CH:23]=[CH:24][CH:25]=[C:26]([CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][O:1][C:2]2[CH:12]=[CH:11][C:5]3[C:6](=[O:10])[CH2:7][CH2:8][O:9][C:4]=3[C:3]=2[CH2:13][CH2:14][CH3:15])[C:21]=1[CH2:20][CH2:19][C:18]([OH:49])=[O:17])([OH:45])=[O:44]
Reactant: CCCc1c(O)ccc2c1OCCC2=O
Reactant: COC(=O)CCc1c(CCCCCCOS(C)(=O)=O)cccc1OCCCC(C)(C)C(=O)OC
Product: CCCc1c(OCCCCCCc2cccc(OCCCC(C)(C)C(=O)O)c2CCC(=O)O)ccc2c1OCCC2=O

Procedure:
Using the procedure of example 126, 2,3-dihydro-7-hydroxy-8-propyl-4H-1-benzopyran-4-one was converted into the title compound by alkylation with 2-[(5-methoxy-4,4-dimethyl-5-oxopentyl)oxy]-6-[6-[(methylsulfonyl)oxy]hexyl]benzenepropanoic acid methyl ester from the preceding example, followed by saponification, in 33.9% overall yield. The product was a colorless solid, mp 85°-87° C., recrystallized from hexane-ethyl acetate.
Reaction SMILES: CCN=C=NCCCN(C)C.CS(C)=O.[CH3:16][O:17][C:18](=[O:34])[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][N:25]1[C:30](=[O:31])[CH2:29][CH2:28][CH2:27][CH:26]1[CH2:32][OH:33].FC(F)(F)C([O-])=O.[NH+]1C=CC=CC=1>C1C=CC=CC=1>[CH3:16][O:17][C:18](=[O:34])[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][N:25]1[C:30](=[O:31])[CH2:29][CH2:28][CH2:27][CH:26]1[CH:32]=[O:33]
Reactant: COC(=O)CCCCCCN1C(=O)CCCC1CO
Agent: CCN=C=NCCCN(C)C
Agent: O=C([O-])C(F)(F)F
Agent: c1cc[nH+]cc1
Solvent: c1ccccc1
Solvent: CS(C)=O
Product: COC(=O)CCCCCCN1C(=O)CCCC1C=O
Temperature: 0 °C
Reaction time: 3.5 h

Procedure:
EDCI (212 mg, 1.10 mmol) and DMSO (0.10 mL, 1.48 mmol) were added sequentially to a solution of 7-(2-hydroxymethyl-6-oxo-piperidin-1-yl)-heptanoic acid methyl ester (100 mg, 0.37 mmol) in benzene (4.0 mL) at rt. The mixture was cooled to 0° C. and pyridinium trifluoroacetate (79 mg, 0.41 mmol) was added. The reaction was allowed to warm to rt and then was stirred at rt for 3.5 h. The solution was decanted from the oily residue and the residue was washed with benzene (3×3 mL). The combined benzene phases were concentrated in vacuo to afford crude 7-(2-formyl-6-oxo-piperidin-1-yl)-heptanoic acid methyl ester that was used without further purification.
Reaction SMILES: [C:1]([NH2:5])(=[O:4])[CH:2]=[CH2:3].[F:6][C:7]([F:20])([C:16]([F:19])([F:18])[F:17])[C:8](=O)[CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11].C1(C)C=CC(S(O)(=O)=O)=CC=1>ClC1C=CC=CC=1>[O:4]=[C:1]1[NH:5][C:8]([C:7]([F:6])([F:20])[C:16]([F:18])([F:17])[F:19])=[C:9]([C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH2:3][CH2:2]1
Reactant: CCOC(=O)CC(=O)C(F)(F)C(F)(F)F
Reactant: C=CC(N)=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Clc1ccccc1
Product: CCOC(=O)C1=C(C(F)(F)C(F)(F)F)NC(=O)CC1
Temperature: 120 °C
Yield: 4.2 %

Procedure:
A suspension of acrylamide (4.11 g), ethyl 4,4,5,5,5-pentafluoro-3-oxopentanoate (16.5 g) and p-toluenesulphonic acid (0.120 g) in chlorobenzene (40 mL) was sonicated for 30 minutes then heated by microwave irradiation (150 W, 120° C.) for 3 h. The reaction mixture was concentrated in vacuo and subjected to flash column chromatography (eluent 1:3 ethyl acetate/isohexane) to yield a colourless solid (0.697 g).