Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([C:15]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[CH3:23])=[O:16])=[C:11]([Cl:24])[CH:10]=2)=[C:4]([CH2:25][O:26][CH2:27][CH2:28]O)[CH:3]=1.[C:30]1([NH:37][C:35](=[O:36])[NH:34][C:32]1=[O:33])=[O:31]>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([C:15]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[CH3:23])=[O:16])=[C:11]([Cl:24])[CH:10]=2)=[C:4]([CH:3]=1)[CH2:25][O:26][CH2:27][CH2:28][N:34]1[C:32](=[O:33])[C:30](=[O:31])[NH:37][C:35]1=[O:36]
Reactant: O=C1NC(=O)C(=O)N1
Reactant: Cc1ccccc1C(=O)c1ccc(Nc2ccc(Br)cc2COCCO)cc1Cl
Product: Cc1ccccc1C(=O)c1ccc(Nc2ccc(Br)cc2COCCN2C(=O)NC(=O)C2=O)cc1Cl

Procedure:
Compound 158 (47 mg, 0.1 mmol) and parabanic acid (16 mg, 0.14 mmol) were treated as described in the preparation of compound 219. Purification was done by flash chromatography (CH2Cl2/ethyl acetate 4:1) to provide the title compound, which was impure. The product was further purified by preparative TLC (CH2Cl2/ethyl acetate 20:1) to furnish the title compound as yellow oil.
Reaction SMILES: [F:1][CH2:2][CH2:3][C:4]1([CH2:10][CH2:11][C:12]2[CH:17]=[CH:16][C:15]([O:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])=[C:14]([C:26]([F:29])([F:28])[F:27])[CH:13]=2)[CH2:8][O:7]C(C)=[N:5]1.[ClH:30]>C(O)C>[ClH:30].[NH2:5][C:4]([CH2:10][CH2:11][C:12]1[CH:17]=[CH:16][C:15]([O:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])=[C:14]([C:26]([F:27])([F:28])[F:29])[CH:13]=1)([CH2:3][CH2:2][F:1])[CH2:8][OH:7]
Reactant: CCCCCCCOc1ccc(CCC2(CCF)COC(C)=N2)cc1C(F)(F)F
Agent: Cl
Solvent: CCO
Product: CCCCCCCOc1ccc(CCC(N)(CO)CCF)cc1C(F)(F)F
Temperature: 70 °C
Reaction time: 4.5 h

Procedure:
Compound 22-1 (400 mg) was dissolved in ethanol (10 ml), concentrated hydrochloric acid (2 ml) was added, and the mixture was stirred at 70° C. for 4.5 hr. The reaction mixture was concentrated, and the residue was washed with diisopropyl ether to give the object product (360 mg) as a white powder.
Reaction SMILES: [NH:1]1[CH2:4][CH:3]([NH:5][C:6](=[O:22])[CH2:7][NH:8][C:9]2[C:17]3[C:12](=[CH:13][CH:14]=[C:15]([C:18]([F:21])([F:20])[F:19])[CH:16]=3)[NH:11][N:10]=2)[CH2:2]1.[OH:23][C:24]1([C:31]2[CH:32]=[N:33][C:34]([CH3:37])=[CH:35][CH:36]=2)[CH2:29][CH2:28][C:27](=O)[CH2:26][CH2:25]1>>[OH:23][C:24]1([C:31]2[CH:32]=[N:33][C:34]([CH3:37])=[CH:35][CH:36]=2)[CH2:25][CH2:26][CH:27]([N:1]2[CH2:2][CH:3]([NH:5][C:6](=[O:22])[CH2:7][NH:8][C:9]3[C:17]4[C:12](=[CH:13][CH:14]=[C:15]([C:18]([F:20])([F:19])[F:21])[CH:16]=4)[NH:11][N:10]=3)[CH2:4]2)[CH2:28][CH2:29]1
Reactant: O=C(CNc1n[nH]c2ccc(C(F)(F)F)cc12)NC1CNC1
Reactant: Cc1ccc(C2(O)CCC(=O)CC2)cn1
Product: Cc1ccc(C2(O)CCC(N3CC(NC(=O)CNc4n[nH]c5ccc(C(F)(F)F)cc45)C3)CC2)cn1

Procedure:
The title compound was prepared as a white solid from reaction of N-azetidin-3-yl-2-(5-trifluoromethyl-1H-indazol-3-ylamino)-acetamide (as prepared in Example 41, Step A) and 4-hydroxy-4-(6-methyl-pyridin-3-yl)-cyclohexanone using the procedure described in Step E of Example 1.
Reaction SMILES: [CH3:1][O:2][CH:3]([O:12][CH3:13])[CH2:4][NH:5][CH2:6][C:7]1[S:8][CH:9]=[CH:10][CH:11]=1.N1C=CC=CC=1.[C:20]1([CH3:30])[CH:25]=[CH:24][C:23]([S:26](Cl)(=[O:28])=[O:27])=[CH:22][CH:21]=1>ClCCl>[CH3:1][O:2][CH:3]([O:12][CH3:13])[CH2:4][N:5]([CH2:6][C:7]1[S:8][CH:9]=[CH:10][CH:11]=1)[S:26]([C:23]1[CH:24]=[CH:25][C:20]([CH3:30])=[CH:21][CH:22]=1)(=[O:28])=[O:27]
Reactant: COC(CNCc1cccs1)OC
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: c1ccncc1
Solvent: ClCCl
Product: COC(CN(Cc1cccs1)S(=O)(=O)c1ccc(C)cc1)OC
Temperature: 0 °C
Reaction time: 4 h
Yield: 86.7 %

Procedure:
2,2-Dimethoxy-N-(thiophen-2-ylmethyl)ethanamine (5 g, 24 mmol) was dissolved in anhydrous dichloromethane and pyridine (5.82 mL, 72 mmol) was added to the reaction. The mixture was cooled down to 0° C. and was treated with para-toluenesulfonyl chloride (5.6 g, 29 mmol) added portionwise. The reaction was allowed to stir at 0° C. for 4 h and was then washed 3 times with 1 N HCl, water and a saturated solution of sodium bicarbonate. The organic layer was dried with sodium sulfate. Purification by flash chromatography using a gradient of 5-30% ethyl acetate in hexanes yielded a white crystalline solid (7.4 g) MS (M+H)+ 356.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[NH:20])[NH:9][C:10]2[CH:15]=[CH:14][C:13]([S:16]([CH3:19])(=[O:18])=[O:17])=[CH:12][CH:11]=2)=[CH:4][CH:3]=1.C(=O)(O)[O-].[Na+].[F:26][C:27]([F:40])([F:39])[O:28][C:29]1[CH:38]=[CH:37][C:32]([C:33](=O)[CH2:34]Br)=[CH:31][CH:30]=1>C(O)(C)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:9]([C:10]3[CH:15]=[CH:14][C:13]([S:16]([CH3:19])(=[O:17])=[O:18])=[CH:12][CH:11]=3)[CH:34]=[C:33]([C:32]3[CH:31]=[CH:30][C:29]([O:28][C:27]([F:26])([F:39])[F:40])=[CH:38][CH:37]=3)[N:20]=2)=[CH:6][CH:7]=1
Reactant: CS(=O)(=O)c1ccc(NC(=N)c2ccc(Cl)cc2)cc1
Reactant: O=C(CBr)c1ccc(OC(F)(F)F)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(C)O
Product: CS(=O)(=O)c1ccc(-n2cc(-c3ccc(OC(F)(F)F)cc3)nc2-c2ccc(Cl)cc2)cc1
Temperature: 82.5 °C
Yield: 42.3 %

Procedure:
To a mixture of 4-chloro-N-[4-(methylsulfonyl)phenyl]benzenecarboximidamide (Example 1, Step 1) (700 mg, 2.24 mmol) and sodium bicarbonate (376 mg, 4.48 mmol) in isopropanol (25 mL), 4-(trifluoromethoxy)phenacyl bromide (950 mg, 3.36 mmol) was added. After heating the reaction mixture at 80-85° C. for 22 hours, the solvent was removed. The residue was redissolved in methylene chloride and washed with aqueous sodium bicarbonate and water. The organic fractions were combined, dried over sodium sulfate, filtered and concentrated in vacuo. The crude product was purified by chromatography (silica gel, hexane/ethyl acetate, 6/4) to give 2-(4-chlorophenyl)-1-[4-(methylsulfonyl)phenyl]-4-[4-(trifluoromethoxy)phenyl]-1H-imidazole (467 mg, 42%) as a pale yellow solid: mp 95-97° C. Anal. Calc'd. for C23H16N2SO3F3Cl: C, 56.05, H, 3.27, N, 5.68, S, 6.51. Found: C, 55.90, H, 3.04, N, 5.62, S, 6.74.
Reaction SMILES: [CH:1]1([N:6]2[CH2:12][C:11]3([CH2:14][CH2:13]3)[C:10](=[O:15])[N:9]([CH3:16])[C:8]3[CH:17]=[N:18][C:19]([NH:21][C:22]4[CH:30]=[CH:29][C:25]([C:26](O)=[O:27])=[CH:24][C:23]=4[O:31][CH3:32])=[N:20][C:7]2=3)[CH2:5][CH2:4][CH2:3][CH2:2]1.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.[CH2:64]([N:71]1[CH2:77][CH2:76][CH2:75][N:74]([CH:78]2[CH2:83][CH2:82][CH:81]([NH2:84])[CH2:80][CH2:79]2)[CH2:73][CH2:72]1)[C:65]1[CH:70]=[CH:69][CH:68]=[CH:67][CH:66]=1>CN(C=O)C>[CH2:64]([N:71]1[CH2:77][CH2:76][CH2:75][N:74]([CH:78]2[CH2:83][CH2:82][CH:81]([NH:84][C:26](=[O:27])[C:25]3[CH:29]=[CH:30][C:22]([NH:21][C:19]4[N:18]=[CH:17][C:8]5[N:9]([CH3:16])[C:10](=[O:15])[C:11]6([CH2:13][CH2:14]6)[CH2:12][N:6]([CH:1]6[CH2:2][CH2:3][CH2:4][CH2:5]6)[C:7]=5[N:20]=4)=[C:23]([O:31][CH3:32])[CH:24]=3)[CH2:80][CH2:79]2)[CH2:73][CH2:72]1)[C:65]1[CH:66]=[CH:67][CH:68]=[CH:69][CH:70]=1
Reactant: COc1cc(C(=O)O)ccc1Nc1ncc2c(n1)N(C1CCCC1)CC1(CC1)C(=O)N2C
Reactant: NC1CCC(N2CCCN(Cc3ccccc3)CC2)CC1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COc1cc(C(=O)NC2CCC(N3CCCN(Cc4ccccc4)CC3)CC2)ccc1Nc1ncc2c(n1)N(C1CCCC1)CC1(CC1)C(=O)N2C
Temperature: 25 °C
Reaction time: 2 h

Procedure:
4-(9′-Cyclopentyl-5′-methyl-6′-oxo-5′,6′,8′,9′-tetrahydrospiro[cyclopropane-1,7′-pyrimido[4,5-b][1,4]diazepine]-2′-ylamino)-3-methoxybenzoic acid (Intermediate 5) (66 mg, 0.15 mmol, 1 eq), DIPEA (52 μl, 0.3 mmol, 2 eq) and TBTU (54 mg, 0.17 mmol, 1.1 eq) were added to 1 mL DMF and the resulting solution was stirred at rt for 20 min before the addition of 4-(4-benzyl-1,4-diazepan-1-yl)cyclohexanamine (Intermediate 16) (54 mg, 0.19 mmol, 1.27 eq) dissolved in DMF (0.5 mL). The RM was then stirred at rt for 2 hours before purifying by preparative RP-HPLC-MS (Preparative—5) to provide N-(4-(4-benzyl-1,4-diazepan-1-yl)cyclohexyl)-4-(9′-cyclopentyl-5′-methyl-6′-oxo-5′,6′,8′,9′-tetrahydrospiro[cyclopropane-1,7′-pyrimido[4,5-b][1,4]diazepine]-2′-ylamino)-3-methoxybenzamide as a mixture cis and trans isomers (off-white solid, 33 mg, 31%).
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8](/[C:11](/[C:16]2[CH:21]=[CH:20][C:19]([Cl:22])=[C:18]([O:23][CH3:24])[N:17]=2)=[CH:12]\[CH2:13][C:14]#[N:15])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[NH2:25][OH:26].[CH:27]([OH:30])(C)C>>[C:1]([C:5]1[CH:10]=[CH:9][C:8](/[C:11](/[C:16]2[CH:21]=[CH:20][C:19]([Cl:22])=[C:18]([O:23][CH3:24])[N:17]=2)=[CH:12]\[CH2:13][C:14]2[NH:25][O:26][C:27](=[O:30])[N:15]=2)=[CH:7][CH:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)O
Reactant: COc1nc(/C(=C/CC#N)c2ccc(C(C)(C)C)cc2)ccc1Cl
Reactant: NO
Product: COc1nc(/C(=C/Cc2nc(=O)o[nH]2)c2ccc(C(C)(C)C)cc2)ccc1Cl
Reaction time: 2 h
Yield: 62 %

Procedure:
A solution of (3E)-4-(4-tert-butylphenyl)-4-(5-chloro-6-methoxypyridin-2-yl)but-3-enenitrile obtained in Reference Example 4-13 (101 mg) in isopropanol (3 mL) was stirred at 105° C., during which a 50% hydroxylamine solution (0.1 mL) was added dropwise thereto. The mixture was stirred at the same temperature for two hours. The reaction solution was left to cool and then the solvent was evaporated under reduced pressure. Carbonyldiimidazole (72 mg) was added to a solution of the residue in 1,4-dioxane (3 mL), and the mixture was stirred at 120° C. for 30 minutes. Carbonyldiimidazole (55 mg) was further added and the mixture was stirred at 140° C. for 30 minutes. The reaction solution was left to cool and then water was added, followed by extraction with ethyl acetate. The organic layer was washed with brine, dried over sodium sulfate and filtered, after which the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform:methanol=10:0→9:1) to give 3-[(2E)-3-(4-tert-butylphenyl)-3-(5-chloro-6-methoxypyridin-2-yl)prop-2-en-1-yl]-1,2,4-oxadiazol-5(2H)-one as an orange oil (73 mg, 62%).
Reaction SMILES: [CH:1]([O:14][C:15]([C:17]1([O:20]/[N:21]=[C:22](/[C:26]2[N:27]=[C:28]([NH:31][C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[S:29][CH:30]=2)\[C:23](O)=[O:24])[CH2:19][CH2:18]1)=[O:16])([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.[NH2:39][C@@H:40]1[C:43](=[O:44])[NH:42][C@@H:41]1[CH2:45][N:46]1[N:50]=[C:49]([CH2:51][NH:52][C:53](=[O:59])[O:54][C:55]([CH3:58])([CH3:57])[CH3:56])[C:48]([CH3:60])=[N:47]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.CCOC(C)=O>[C:55]([O:54][C:53]([NH:52][CH2:51][C:49]1[C:48]([CH3:60])=[N:47][N:46]([CH2:45][C@@H:41]2[C@H:40]([NH:39][C:23](=[O:24])/[C:22](=[N:21]\[O:20][C:17]3([C:15]([O:14][CH:1]([C:2]4[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=4)[C:8]4[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=4)=[O:16])[CH2:18][CH2:19]3)/[C:26]3[N:27]=[C:28]([NH:31][C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[S:29][CH:30]=3)[C:43](=[O:44])[NH:42]2)[N:50]=1)=[O:59])([CH3:58])([CH3:56])[CH3:57]
Reactant: Cc1nn(C[C@H]2NC(=O)[C@H]2N)nc1CNC(=O)OC(C)(C)C
Reactant: CC(C)(C)OC(=O)Nc1nc(/C(=N/OC2(C(=O)OC(c3ccccc3)c3ccccc3)CC2)C(=O)O)cs1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: Cc1nn(C[C@H]2NC(=O)[C@H]2NC(=O)/C(=N\OC2(C(=O)OC(c3ccccc3)c3ccccc3)CC2)c2csc(NC(=O)OC(C)(C)C)n2)nc1CNC(=O)OC(C)(C)C
Reaction time: 16 h
Yield: 82.6 %

Procedure:
To a solution of (Z)-2-((1-((benzhydryloxy)carbonyl)cyclopropoxy)imino)-2-(2-((tert-butoxycarbonyl)amino)thiazol-4-yl)acetic acid (120 mg, 0.213 mmol), tert-butyl ((2-(((2R,3S)-3-amino-4-oxoazetidin-2-yl)methyl)-5-methyl-2H-1,2,3-triazol-4-yl)methyl)carbamate (65.2 mg, 0.210 mmol) and HATU (86 mg, 0.22 mmol) in DMF (2.1 mL) at 0° C., was added DIPEA (0.073 mL, 0.420 mmol). After stirring for 16 h, the reaction mixture was diluted with EtOAc and washed with LiCl solution (5% aq). The aqueous layer was extracted with EtOAc (3×) and the combined organic layers were washed with LiCl solution (5% aq), saturated NaHCO3 (aq), brine, dried over Na2SO4 and concentrated in vacuo. Purification of the crude residue via silica gel chromatography (EtOAc-Heptane, 0-90%) afforded the title compound (144 mg, 82%). LCMS: Rt=1.12 min, m/z=830.5 (M+1) Method 2m_acidic.
Reaction SMILES: COC([N:5]1[C:13]2[C:8](=[C:9]([NH:14][C:15]([NH:17][CH:18]3[C:27]4[C:22](=[CH:23][C:24]([C:28]([CH3:31])([CH3:30])[CH3:29])=[CH:25][CH:26]=4)[O:21][CH2:20][CH2:19]3)=[O:16])[CH:10]=[CH:11][CH:12]=2)[CH:7]=[N:6]1)=O.[OH-].[Na+]>CO.O1CCCC1.O>[C:28]([C:24]1[CH:23]=[C:22]2[C:27]([CH:18]([NH:17][C:15]([NH:14][C:9]3[CH:10]=[CH:11][CH:12]=[C:13]4[C:8]=3[CH:7]=[N:6][NH:5]4)=[O:16])[CH2:19][CH2:20][O:21]2)=[CH:26][CH:25]=1)([CH3:31])([CH3:29])[CH3:30]
Reactant: COC(=O)n1ncc2c(NC(=O)NC3CCOc4cc(C(C)(C)C)ccc43)cccc21
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: CC(C)(C)c1ccc2c(c1)OCCC2NC(=O)Nc1cccc2[nH]ncc12
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 86.8 %

Procedure:
A solution of the product of Example 1D (1.00 g, 2.37 mmol) in a mixture of 5 mL methanol and 5 mL tetrahydrofuran was treated with 5M sodium hydroxide (2 mL ) in methanol, and stirred at ambient temperature for 90 minutes. The reaction mixture was diluted with water, and the resulting precipitate was collected by filtration to give 0.75 g of the title compound (86% yield). 1H NMR (300 MHz, DMSO-d6) δ 13.00 (broad s, 1H), 8.59 (s, 1H), 8.03 (s, 1H), 7.66 (d, J=7.5 Hz, 1H), 7.20 (m, 2H), 7.10-6.90 (m, 4H), 4.91 (m, 1H), 4.30-4.12 (m, 2H), 2.20-2.00 (m, 2H), 1.22 (s, 9H). MS (ESI) m/e 365 (M+H)+. Calc'd. For C17H16N4O2.1.0 H2O: C, 65.95; H, 6.85; N, 14.65. Found: C, 65.93; H, 6.69; N, 14.41.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8]C)=[O:7])=[CH:4][CH:3]=1.[F:12][C@@H:13]([CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])[CH2:14]O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>O1CCCC1>[F:12][C@@H:13]([CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])[CH2:14][O:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([OH:8])=[O:7])=[CH:4][CH:3]=1
Reactant: COC(=O)c1ccc(O)cc1
Reactant: CCCCCC[C@H](F)CO
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CCCCCC[C@H](F)COc1ccc(C(=O)O)cc1
Temperature: 25 °C

Procedure:
0.1 mol of methyl 4-hydroxybenzoate, 0.1 mol of (S)-2-fluoro-1-octanol and 0.12 mol of triphenylphosphine are dissolved in 250 ml of tetrahydrofuran, and 0.12 mol of diethyl azodicarboxylate is added dropwise with stirring and ice cooling. The mixture is allowed to warm to room temperature, and is then stirred for a further 8 hours. The solvent is then distilled, and the methyl 4-(2-fluorooctyloxy)benzoate is purified by column chromatography. Saponification using aqueous/alcoholic potassium hydroxide solution gives (S)-4-(2-fluorooctyloxy)benzoic acid.
Reaction SMILES: C(OCC)C.O[CH:7]([CH2:15][C:16]([CH2:19][Si](C)(C)C)=[C:17]=[CH2:18])[CH2:8][CH:9]1[CH2:13][CH2:12][CH2:11][C:10]1=[O:14].[Si](OS(C(F)(F)F)(=O)=O)(C)(C)C.O>CCOC(C)=O>[CH2:19]=[C:16]1[C:17](=[CH2:18])[C:10]23[O:14][CH:7]([CH2:8][CH:9]2[CH2:13][CH2:12][CH2:11]3)[CH2:15]1
Reactant: C=C=C(CC(O)CC1CCCC1=O)C[Si](C)(C)C
Agent: C[Si](C)(C)OS(=O)(=O)C(F)(F)F
Solvent: O
Solvent: CCOC(C)=O
Solvent: CCOCC
Product: C=C1CC2CC3CCCC3(O2)C1=C
Temperature: -78 °C
Yield: 78.6 %

Procedure:
1.1 mL of diethyl ether was added to 2-(2-hydroxy-4-trimethylsilanylmethyl-hexa-4,5-dienyl)-cyclopentanone (70 mg, 0.26 mmol) under nitrogen atmosphere. While stirring at −78° C., TMSOTf (48 μL, 0.26 mmol) was added. While stirring the reaction mixture, the reaction temperature was slowly increased to room temperature for 3 hours. The reaction mixture was stirred at room temperature for 30 minutes. After the reaction was completed, H2O was added. After stirring for about 5 minutes, the reaction mixture was diluted with EtOAc and washed with water and saturated brine. The organic layer was separated from the reaction mixture and dried with anhydrous MgSO4. The solvent was removed under reduced pressure and the remaining material was purified with column chromatography (EtOAc/n-hexane=1/15) to obtain 36 mg of the product (77%).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([OH:7])[CH2:3][CH2:2]1.C(N(CC)CC)C.[C:15](Cl)(=[O:20])[C:16]([CH3:19])([CH3:18])[CH3:17].[NH4+]>ClCCl>[OH:7][CH:4]1[CH2:5][CH2:6][N:1]([C:15](=[O:20])[C:16]([CH3:19])([CH3:18])[CH3:17])[CH2:2][CH2:3]1
Reactant: CC(C)(C)C(=O)Cl
Reactant: OC1CCNCC1
Agent: [NH4+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)C(=O)N1CCC(O)CC1
Temperature: 2.5 °C
Reaction time: 0.5 h
Yield: 106.3 %

Procedure:
4-piperidinol (2 g, 19.8 mmol) was added to dichloromethane (20 mL), and cooled to an internal temperature of 0-5° C. Then, triethylamine (3.31 mL, 23.7 mmol) was added thereto and stirred for 30 min. Pivaloyl chloride (2.62 g, 21.8 mmol) was dropwise added thereto and heated to room temperature. The reaction mixture was stirred at room temperature for 5 hours. After completion of the reaction, the reaction mixture was mixed with a saturated aqueous solution of ammonium (50 mL) and extracted twice with dichloromethane (50 mL). The organic layer thus obtained was dried over anhydrous magnesium sulfate, and filtered and distilled under reduced pressure to obtain the title compound (3.9 g).
Reaction SMILES: C(N(CC)CC)C.Cl[C:9](=[N:16][OH:17])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.[CH2:18]([OH:21])[C:19]#[CH:20].O>O1CCCC1>[C:10]1([C:9]2[CH:20]=[C:19]([CH2:18][OH:21])[O:17][N:16]=2)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: C#CCO
Reactant: ON=C(Cl)c1ccccc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Solvent: O
Product: OCc1cc(-c2ccccc2)no1
Temperature: 25 °C
Reaction time: 96 h
Yield: 75 %

Procedure:
Triethylamine (7.28 ml) was added to a solution of α-chlorobenzaldehyde oxime (4.04 g) and 2-propyn-1-ol (1.66 ml) in tetrahydrofuran (130 ml) and stirred at room temperature for 4 days. Water was added to the reaction mixture and extracted with ethyl acetate. The ethyl acetate layer was washed with an aqueous saturated solution of sodium chloride, dried (MgSO4) and concentrated. The remaining crystals were recrystallized from ethyl acetate-hexane to obtain (3-phenyl-5-isoxazolyl)methanol (3.42 g, yield 75%) as colorless crystals. m.p. 48-49° C.
Reaction SMILES: [CH3:1][C:2]1[N:3]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:4]2[C:9]([C:10]=1[CH3:11])=[CH:8][CH:7]=[CH:6][CH:5]=2.[NH:18]1[CH2:22][CH2:21][CH2:20][CH2:19]1.O.[CH2:24]=O>C(O)(=O)C>[CH3:11][C:10]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:2]=1[CH2:1][CH2:24][N:18]1[CH2:22][CH2:21][CH2:20][CH2:19]1
Reactant: Cc1c(C)n(-c2ccccc2)c2ccccc12
Reactant: C=O
Reactant: C1CCNC1
Solvent: O
Solvent: CC(=O)O
Product: Cc1c(CCN2CCCC2)n(-c2ccccc2)c2ccccc12
Reaction time: 0.25 h

Procedure:
To a solution of 310 g of 2,3-dimethyl-1-phenylindole in 170 ml 40% formaldehyde and 1.6 liters acetic acid there is added dropwise 175 ml pyrrolidine at such a rate that the mixture temperature is 55° to 60°. When the addition is complete the mixture is stirred for 15 minutes and treated at 55° to 60° for 2 hours. 1.6 liters of water are added. The mixture is extracted with toluene (five times 1.6 liters), and the extracts are carefully washed with two 1.6 liter portions of 2 N NaOH. The solution is dried with 100 g of magnesium sulphate and the solvent removed to give 3-methyl-1-phenyl-2-[2-(1-pyrrolidinyl)ethyl]indole as a brown oil which is treated with 7.5 liters of petroleum ether (B.pt. 90°-120°) and then filtered. The petroleum ether solution of 3-methyl-1-phenyl-2-[2(1-pyrrolidinyl)ethyl]indole is treated with hydrogen chloride gas to yield the hydrochloride salt. M.pt. 213°-216°. The free base is set free from the hydrochloride in toluene using 2 N NaOH and obtained as an oil.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][C:5]([C:7]1[CH:12]=[CH:11][C:10]([F:13])=[CH:9][CH:8]=1)=[O:6].ClCCCC(C1C=CC=CC=1)=O.Cl.[NH:27]1[CH2:32][CH2:31][CH:30]([C:33]([C:35]2[C:44]3[C:39](=[CH:40][CH:41]=[CH:42][CH:43]=3)[CH:38]=[CH:37][CH:36]=2)=[O:34])[CH2:29][CH2:28]1.Cl.N1CCC(C(C2C=CC3C(=CC=CC=3)C=2)=O)CC1>>[ClH:1].[C:35]1([C:33]([CH:30]2[CH2:31][CH2:32][N:27]([CH2:2][CH2:3][CH2:4][C:5]([C:7]3[CH:12]=[CH:11][C:10]([F:13])=[CH:9][CH:8]=3)=[O:6])[CH2:28][CH2:29]2)=[O:34])[C:44]2[C:39](=[CH:40][CH:41]=[CH:42][CH:43]=2)[CH:38]=[CH:37][CH:36]=1
Reactant: O=C(CCCCl)c1ccc(F)cc1
Reactant: O=C(c1cccc2ccccc12)C1CCNCC1
Agent: Cl
Agent: O=C(CCCCl)c1ccccc1
Agent: O=C(c1ccc2ccccc2c1)C1CCNCC1
Product: O=C(CCCN1CCC(C(=O)c2cccc3ccccc23)CC1)c1ccc(F)cc1

Procedure:
When in the procedure of Example 19, 4-chloro-1-(4-fluorophenyl)-1-butanone is substituted for 4-chloro-1-phenyl-1-butanone and 1-naphthyl 4-piperidyl ketone hydrochloride is substituted for 2-naphthyl 4-piperidyl ketone hydrochloride, 4-[4-(1-naphthoyl)-1-piperidyl]-1-(4-fluorophenyl)-1-butanone hydrochloride is produced. M.P. 239°-41°.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][CH2:9][CH2:10][CH2:11][CH2:12][CH:13]2[CH2:18][C:17]([CH3:20])([CH3:19])[N:16]([O:21][CH:22]3[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]3)[C:15]([CH3:29])([CH3:28])[CH2:14]2)[N:5]=[C:4]([NH:30][CH2:31][CH2:32][CH2:33][CH2:34][CH:35]2[CH2:40][C:39]([CH3:42])([CH3:41])[N:38]([O:43][CH:44]3[CH2:49][CH2:48][CH2:47][CH2:46][CH2:45]3)[C:37]([CH3:51])([CH3:50])[CH2:36]2)[N:3]=1.[NH2:52][CH2:53][CH2:54][CH2:55][CH2:56][CH2:57][C:58]([O-:60])=[O:59].[Na+]>COCCOCCOC>[CH:44]1([O:43][N:38]2[C:37]([CH3:51])([CH3:50])[CH2:36][CH:35]([CH2:34][CH2:33][CH2:32][CH2:31][NH:30][C:4]3[N:5]=[C:6]([NH:8][CH2:9][CH2:10][CH2:11][CH2:12][CH:13]4[CH2:14][C:15]([CH3:28])([CH3:29])[N:16]([O:21][CH:22]5[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]5)[C:17]([CH3:19])([CH3:20])[CH2:18]4)[N:7]=[C:2]([NH:52][CH2:53][CH2:54][CH2:55][CH2:56][CH2:57][C:58]([OH:60])=[O:59])[N:3]=3)[CH2:40][C:39]2([CH3:42])[CH3:41])[CH2:49][CH2:48][CH2:47][CH2:46][CH2:45]1
Reactant: NCCCCCC(=O)[O-]
Reactant: CC1(C)CC(CCCCNc2nc(Cl)nc(NCCCCC3CC(C)(C)N(OC4CCCCC4)C(C)(C)C3)n2)CC(C)(C)N1OC1CCCCC1
Agent: [Na+]
Solvent: COCCOCCOC
Product: CC1(C)CC(CCCCNc2nc(NCCCCCC(=O)O)nc(NCCCCC3CC(C)(C)N(OC4CCCCC4)C(C)(C)C3)n2)CC(C)(C)N1OC1CCCCC1
Temperature: 140 °C
Yield: 69.5 %

Procedure:
A mixture of 20.0 g (27.3 mmol) of 2-chloro-4,6-bis[N-(1-cyclohexyloxy-2,2,6,6-tetramethylpiperidin-4-yl)butylamino]-1,3,5-triazine, 25.1 g (0.164 mol) of sodium 6-aminohexanoate, and 200 ml of diglyme is heated at 140° C. for seven hours. The reaction mixture is partitioned between 1N HCl (500 ml) and ether (400 ml), and the aqueous phase is extracted with ether (200 ml). The combined organic layers are washed with water (2×200 ml) and saturated aqueous sodium chloride solution (200 ml), and then dried over anhydrous magnesium sulfate, and finally concentrated to obtain a glass. Purification by flash chromatography on silica gel (2:1 heptane:ethyl acetate) affords 15.7 g (69% yield) of the title compound as a white powdery glass.