Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Li]CCCC.Br[C:7]1[CH:12]=[CH:11][N:10]=[C:9]([N:13]([CH3:15])[CH3:14])[CH:8]=1.[CH2:16]([N:23]([CH3:31])[CH:24]1[CH2:29][CH2:28][C:27](=[O:30])[CH2:26][CH2:25]1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>C(OCC)C>[CH2:16]([N:23]([CH3:31])[CH:24]1[CH2:29][CH2:28][C:27]([C:7]2[CH:12]=[CH:11][N:10]=[C:9]([N:13]([CH3:15])[CH3:14])[CH:8]=2)([OH:30])[CH2:26][CH2:25]1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: CN(Cc1ccccc1)C1CCC(=O)CC1
Reactant: CN(C)c1cc(Br)ccn1
Agent: [Li]CCCC
Solvent: CCOCC
Product: CN(C)c1cc(C2(O)CCC(N(C)Cc3ccccc3)CC2)ccn1
Reaction time: 0.75 h
Yield: 71 %

Procedure:
n-BuLi (3 ml, 5.98 mmol, 1.2 eq., 2 M solution in hexane) was added at −78° C. to a solution of 4-bromo-N,N-dimethylpyridin-2-amine (978 mg, 5.23 mmol, 1.05 eq.) in diethyl ether (15 ml) and the mixture was stirred for 45 minutes. A solution of 4-(benzyl(methyl)amino)cyclo-hexanone (stage 3, AMN-50) (1.08 g, 4.9, 8 mmol 1.0 eq.) in diethyl ether (10 ml) was added dropwise thereto at the same temperature. The reaction mixture was stirred for 16 hours at RT and was then hydrolyzed with sat. ammonium chloride solution (30 ml) and extracted with ethyl acetate (3×60 ml). The combined org. phases were washed with sat. NaCl solution (100 ml), dried over sodium sulfate, concentrated and purified by column chromatography (silica gel, 2,5% MeOH in DCM). Yield: 71% (1.20 g, 3.54 mmol)
Reaction SMILES: [CH3:1][CH2:2][C@H:3]1[O:18][C:16](=[O:17])[C@H:15]([CH3:19])[C@@H:14]([O:20][C@@H:21]2[O:26][C@@H:25]([CH3:27])[C@H:24]([OH:28])[C@@:23]([O:30][CH3:31])([CH3:29])[CH2:22]2)[C@H:13]([CH3:32])[C@@H:12]([O:33][C@@H:34]2[O:39][C@H:38]([CH3:40])[CH2:37][C@H:36]([N:41]([CH3:43])[CH3:42])[C@H:35]2[OH:44])[C@@:11](O)([CH3:45])[CH2:10][C@@H:9]([CH3:47])[C:7](=[O:8])[C@H:6]([CH3:48])[C@@H:5]([OH:49])[C@@:4]1([OH:51])[CH3:50]>C(O)(=O)C>[CH3:1][CH2:2][C@H:3]1[O:18][C:16](=[O:17])[C@H:15]([CH3:19])[C@@H:14]([O:20][C@@H:21]2[O:26][C@@H:25]([CH3:27])[C@H:24]([OH:28])[C@@:23]([O:30][CH3:31])([CH3:29])[CH2:22]2)[C@H:13]([CH3:32])[C@@H:12]([O:33][C@@H:34]2[O:39][C@H:38]([CH3:40])[CH2:37][C@H:36]([N:41]([CH3:42])[CH3:43])[C@H:35]2[OH:44])[C@:11]2([CH3:45])[O:8][C:7](=[C:9]([CH3:47])[CH2:10]2)[C@H:6]([CH3:48])[C@@H:5]([OH:49])[C@@:4]1([OH:51])[CH3:50]
Reactant: CC[C@H]1OC(=O)[C@H](C)[C@@H](O[C@H]2C[C@@](C)(OC)[C@@H](O)[C@H](C)O2)[C@H](C)[C@@H](O[C@@H]2O[C@H](C)C[C@H](N(C)C)[C@H]2O)[C@](C)(O)C[C@@H](C)C(=O)[C@H](C)[C@@H](O)[C@]1(C)O
Solvent: CC(=O)O
Product: CC[C@H]1OC(=O)[C@H](C)[C@@H](O[C@H]2C[C@@](C)(OC)[C@@H](O)[C@H](C)O2)[C@H](C)[C@@H](O[C@@H]2O[C@H](C)C[C@H](N(C)C)[C@H]2O)[C@@]2(C)CC(C)=C(O2)[C@H](C)[C@@H](O)[C@]1(C)O

Procedure:
That is, according to references (a) I. O. Kibwage, R. Busson, G. Janssen, J. Hoogmartens, H. Vanderhaeghe, Translactonization of Erythromycins, J. Org. Chem., 52, 990-996, 1987, (b) H. A. Kirst, J. A. Wind, J. W. Paschal, Synthesis of Ring-Constracted Derivatives of Erythromycin, J. Org. Chem. 52, 4359-4362, 1987, erythromycin A was treated with glacial acetic acid to give 8,9-anhydroerythromycin A 6,9-hemiketal (EM201). Successively, the compound was heated under reflux in the presence of potassium carbonate in methanol to give 8,9-anhydro-pseudoerythromycin A 6,9-hemiketal (EM701).
Reaction SMILES: C[O-].[Na+:3].[OH:4][C@H:5]([CH2:10][C@H:11]([OH:33])[CH2:12][CH2:13][C@@H:14]1[C@@H:23]2[C:18](=[CH:19][C@@H:20]([OH:31])[CH2:21][C@@H:22]2[O:24]C(=O)[C@@H](C)CC)[CH:17]=[CH:16][C@@H:15]1[CH3:32])[CH2:6][C:7]([O-:9])=[O:8].CC[C@@H](C(O[C@@H]1[C@@H]2[C@@H](CC[C@@H](O)C[C@@H](O)CC(O)=O)[C@@H](C)C=CC2=C[C@@H](O)C1)=O)C>CO>[OH:4][C@H:5]([CH2:10][C@H:11]([OH:33])[CH2:12][CH2:13][C@@H:14]1[C@@H:23]2[C:18](=[CH:19][C@@H:20]([OH:31])[CH2:21][C@@H:22]2[OH:24])[CH:17]=[CH:16][C@@H:15]1[CH3:32])[CH2:6][C:7]([O-:9])=[O:8].[Na+:3]
Reactant: CC[C@H](C)C(=O)O[C@H]1C[C@H](O)C=C2C=C[C@H](C)[C@H](CC[C@@H](O)C[C@@H](O)CC(=O)[O-])[C@H]21
Agent: CC[C@H](C)C(=O)O[C@H]1C[C@H](O)C=C2C=C[C@H](C)[C@H](CC[C@@H](O)C[C@@H](O)CC(=O)O)[C@H]21
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: C[C@H]1C=CC2=C[C@@H](O)C[C@H](O)[C@@H]2[C@H]1CC[C@@H](O)C[C@@H](O)CC(=O)[O-]
Temperature: 25 °C

Procedure:
50 ml (0.24 mol) of a 28% w/v solution of sodium methoxide in methanol were added to a solution of 100 g (0.31 mol) of (3R,5R)-3,5-dihydroxy-7-[(1S,2S,6S,8S,8aR)-6-hydroxy-2-methyl-8-[(S)-2-methyl-butyryloxy]-1,2,6,7,8,8a-hexahydro-1-naphthyl]heptanoate (pravastatin: prepared as described in U.S. Pat. No. 4,346,227) in 900 ml of methanol, and the resulting mixture was heated under reflux for 60 hours. At the end of this time, the mixture was cooled to room temperature, and the methanol was then removed from the reaction mixture by distillation under reduced pressure. The resulting residue was washed with 200 ml of hexane and then dried in vacuo to give 120 g of the title compound.
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[OH:13][C@H:14]([CH2:20][CH2:21][CH3:22])[CH2:15][C:16]([O:18][CH3:19])=[O:17].[CH2:23](Br)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>C1COCC1.C1COCC1.CN(P(N(C)C)(N(C)C)=O)C>[CH2:23]([C@H:15]([C@H:14]([OH:13])[CH2:20][CH2:21][CH3:22])[C:16]([O:18][CH3:19])=[O:17])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: CCC[C@@H](O)CC(=O)OC
Reactant: BrCc1ccccc1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Solvent: CC(C)NC(C)C
Product: CCC[C@@H](O)[C@@H](Cc1ccccc1)C(=O)OC
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 46.8 %

Procedure:
Diisopropylamine (8.61 mL, 65.7 mmol) is dissolved in 40 mL of anhydrous THF and chilled to 0° C. n-Butyllithium (30.1 mL of a 2.0M solution in hexanes, 60.2 mmol) is added dropwise over 10 min and the resulting pale yellow solution cooled to −78° C. A 15-mL THF solution of methyl (3R)-3-hydroxyhexanoate (4.00 g, 27.4 mmol) is added over 10 min and stirred for 30 min. Benzyl bromide (3.60 mL, 30.1 mmol) is dissolved in 12 mL of a 1:1 THF/HMPA solution and added at −78° C. dropwise. The resulting solution is allowed to warm slowly to 0° C. over 3 h. Aqueous 5% citric acid solution (250 mL) is added and the organics are extracted with two 250-mL portions of ether. The combined organics are washed with saturated aqueous sodium chloride. Drying over sodium sulfate and concentration is followed by which is chromatography on silica gel (elution with 25% EtOAc-hexanes) giving methyl (2R,3R)-2-benzyl-3-hydroxyhexanoate as an oil (3.03 g, 64% yield).
Reaction SMILES: [CH3:1][C:2]1[S:3][C:4]([C:8]([OH:10])=O)=[C:5]([CH3:7])[N:6]=1.[NH2:11][C:12]1[CH:13]=[C:14]([CH:31]=[CH:32][CH:33]=1)[O:15][C:16]1[CH:17]=[CH:18][C:19]2[N:20]([CH:22]=[C:23]([NH:25][C:26]([CH:28]3[CH2:30][CH2:29]3)=[O:27])[N:24]=2)[N:21]=1.ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C.C(N(CC)CC)C>CN(C)C=O>[CH:28]1([C:26]([NH:25][C:23]2[N:24]=[C:19]3[CH:18]=[CH:17][C:16]([O:15][C:14]4[CH:13]=[C:12]([NH:11][C:8]([C:4]5[S:3][C:2]([CH3:1])=[N:6][C:5]=5[CH3:7])=[O:10])[CH:33]=[CH:32][CH:31]=4)=[N:21][N:20]3[CH:22]=2)=[O:27])[CH2:29][CH2:30]1
Reactant: Nc1cccc(Oc2ccc3nc(NC(=O)C4CC4)cn3n2)c1
Reactant: Cc1nc(C)c(C(=O)O)s1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: Cc1nc(C)c(C(=O)Nc2cccc(Oc3ccc4nc(NC(=O)C5CC5)cn4n3)c2)s1
Yield: 71.1 %

Procedure:
Using 2,4-dimethyl-1,3-thiazole-5-carboxylic acid (78.8 mg, 0.50 mmol), N-[6-(3-aminophenoxy)imidazo[1,2-b]pyridazin-2-yl]cyclopropanecarboxamide (129 mg, 0.417 mmol), 1-hydroxybenzotriazole (68 mg, 0.50 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (96 mg, 0.50 mmol), triethylamine (50 mg, 0.50 mmol) and N,N-dimethylformamide (5.0 mL) as starting materials and in the same manner as in Example 106, the title compound (133 mg, 71%) was obtained as a white powder. melting point 249° C.
Reaction SMILES: [NH:1]1[CH2:8][CH2:7][CH2:6][C@H:2]1[C:3]([OH:5])=O.[CH3:9][N:10]1C(=O)O[C:13](=[O:14])[C:12]2=[CH:18][CH:19]=[CH:20][CH:21]=[C:11]12.CS(C)=O>O>[CH3:9][N:10]1[C:11]2[CH:21]=[CH:20][CH:19]=[CH:18][C:12]=2[C:13](=[O:14])[N:1]2[CH2:8][CH2:7][CH2:6][CH:2]2[C:3]1=[O:5]
Reactant: O=C(O)[C@@H]1CCCN1
Reactant: Cn1c(=O)oc(=O)c2ccccc21
Solvent: O
Solvent: CS(C)=O
Product: CN1C(=O)C2CCCN2C(=O)c2ccccc21

Procedure:
A mixture of 12.3 g. of L-proline, 17.7 g. of N-methyl isatoic anhydride and 100 ml. of dimethyl sulfoxide is heated on a steam bath for 6 hours, cooled and then dilted with 250 ml. of water. The reaction mixture is extracted three times with benzene. The combined benzene layers are washed with water and concentrated to remove the solvent. The residue is recrystallized from ethyl acetate yielding the pure dextrorotatory isomer.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][O:8][CH2:9][CH2:10][O:11][CH2:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=1.[CH2:20]([NH2:27])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>>[N:15]1[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=1[CH2:13][CH2:12][O:11][CH2:10][CH2:9][O:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][NH:27][CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: NCc1ccccc1
Reactant: BrCCCCCCOCCOCCc1ccccn1
Product: c1ccc(CNCCCCCCOCCOCCc2ccccn2)cc1
Yield: 82.5 %

Procedure:
A solution of 2-[2-[2-[(6-bromohexyl)oxy]ethoxy]ethyl]pyridine (1.55 g) in benzylamine (3.1 g) was heated at 125° under nitrogen for 3 h. The solution was allowed to cool and then partitioned between 8% sodium bicarbonate (100 ml) and diethyl ether (2×100 ml). The solvent was evaporated in vacuo and the residual oil distilled (Kugelrohr) to remove excess benzylamine. Purification by FCC eluting with System G 92:8:1) gave the title compound (1.38 g) as a colourless oil. T.l.c. (System G 95:5:1) Rf 0.14
Reaction SMILES: [CH2:1]([C:3]1[C:8](=[O:9])[NH:7][C:6]([CH3:10])=[C:5]([C:11]2[CH:16]=[C:15]([C:17]([OH:19])=O)[CH:14]=[CH:13][N:12]=2)[CH:4]=1)[CH3:2].[CH:20]1([NH2:25])[CH2:24][CH2:23][CH2:22][CH2:21]1>>[CH:20]1([NH:25][C:17]([C:15]2[CH:14]=[CH:13][N:12]=[C:11]([C:5]3[CH:4]=[C:3]([CH2:1][CH3:2])[C:8](=[O:9])[NH:7][C:6]=3[CH3:10])[CH:16]=2)=[O:19])[CH2:24][CH2:23][CH2:22][CH2:21]1
Reactant: CCc1cc(-c2cc(C(=O)O)ccn2)c(C)[nH]c1=O
Reactant: NC1CCCC1
Product: CCc1cc(-c2cc(C(=O)NC3CCCC3)ccn2)c(C)[nH]c1=O

Procedure:
Method 1, Example 205 is substantially repeated except for utilizing 5′-ethyl-2′-methyl-6′-oxo-1′,6′-dihydro-[2,3′]bipyridinyl-4-carboxylic acid and cyclopentyl amine to afford the title compound. MS: m/e=326 (M+H).
Reaction SMILES: [OH-:1].[Na+].[C:3]1(=[O:10])[NH:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]1>>[NH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][C:3]([OH:10])=[O:1]
Reactant: [OH-]
Reactant: O=C1CCCCCN1
Agent: [Na+]
Product: NCCCCCC(=O)O

Procedure:
The removal of water takes place in the presence of a total of less than 20 mmol of sodium hydroxide, in aqueous solution, per kg of caprolactam. The aqueous sodium hydroxide solution for this is added to the caprolactam prior to the evaporators. The aqueous sodium hydroxide solution is to react with caprolactam to give the Na-salt of 6-aminocaproic acid. This salt, according to DD-A-202870, has the same purification effect as sodium hydroxide, but, in contrast to sodium hydroxide, does not cause any caprolactam oligomerization.
Reaction SMILES: [CH2:1]([C:3]1([OH:13])[CH:10]2[CH2:11][CH:6]3[CH2:7][CH:8]([CH2:12][CH:4]1[CH2:5]3)[CH2:9]2)[CH3:2].C(N(CC)CC)C.[C:21](Cl)(=[O:25])[C:22]([CH3:24])=[CH2:23]>CC(CC(C)C)=O>[C:21]([O:13][C:3]1([CH2:1][CH3:2])[CH:4]2[CH2:12][CH:8]3[CH2:7][CH:6]([CH2:11][CH:10]1[CH2:9]3)[CH2:5]2)(=[O:25])[C:22]([CH3:24])=[CH2:23]
Reactant: CCC1(O)C2CC3CC(C2)CC1C3
Reactant: C=C(C)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: CC(=O)CC(C)C
Product: C=C(C)C(=O)OC1(CC)C2CC3CC(C2)CC1C3
Temperature: 90 °C
Yield: 60 %

Procedure:
180 g of 2-Ethyl-2-adamantanol, 303 g of triethylamine and 500 g of methylisobutyl ketone were mixed by stirring at 90° C. While stirring, 157 g of methacrylic acid chloride was added dropwise to the mixture. After completion of the dropwise addition, the mixture was further stirred for 72 hours. Then, extraction and distillation were conducted to obtain 2-ethyl-2-adamantyl methacrylate at the yield of 60%.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([CH2:8][CH3:9])[N:5]=[C:4]([CH:10]2[CH2:14][CH2:13][CH2:12][CH2:11]2)[N:3]=1.[NH2:15][C:16]1[CH:21]=[CH:20][C:19]([CH2:22][C:23]([NH2:25])=[O:24])=[CH:18][CH:17]=1>>[CH:10]1([C:4]2[N:3]=[C:2]([NH:15][C:16]3[CH:17]=[CH:18][C:19]([CH2:22][C:23]([NH2:25])=[O:24])=[CH:20][CH:21]=3)[CH:7]=[C:6]([CH2:8][CH3:9])[N:5]=2)[CH2:14][CH2:13][CH2:12][CH2:11]1
Reactant: CCc1cc(Cl)nc(C2CCCC2)n1
Reactant: NC(=O)Cc1ccc(N)cc1
Product: CCc1cc(Nc2ccc(CC(N)=O)cc2)nc(C2CCCC2)n1
Yield: 63.6 %

Procedure:
Following General Procedure A2, 4-chloro-2-cyclopentyl-6-ethylpyrimidine (0.100 g, 0.47 mmol) was reacted with 2-(4-aminophenyl)acetamide (0.086 g, 0.57 mmol) to afford the title compound (0.097 g, 97%) as a tan solid. MW=324.42. 1H NMR (DMSO-d6, 500 MHz) δ 14.18 (s, 1H), 11.23 (s, 1H), 7.64 (s, 1H), 7.49 (s, 1H), 7.36-7.25 (m, 2H), 6.88 (s, 1H), 6.76 (s, 1H), 3.37 (d, J=7.5 Hz, 3H), 2.82-2.66 (m, 2H), 2.13-1.98 (m, 2H), 1.94-1.73 (m, 4H), 1.72-1.59 (m, 2H), 1.25 (s, 3H); APCI MS m/z 325 [M+H]+.
Reaction SMILES: [CH2:1]([N:8]([CH2:21][C:22]1[CH:40]=[CH:39][C:25]([O:26][C:27]2[CH:32]=[CH:31][C:30]([CH2:33][CH2:34][CH2:35][C:36](O)=[O:37])=[CH:29][CH:28]=2)=[CH:24][CH:23]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([NH:15][S:16]([CH3:19])(=[O:18])=[O:17])[C:10]=1[CH3:20])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.C[O:43][C:44](=[O:50])[C@H:45]([CH:47]([CH3:49])[CH3:48])[NH2:46]>>[CH2:1]([N:8]([CH2:21][C:22]1[CH:23]=[CH:24][C:25]([O:26][C:27]2[CH:28]=[CH:29][C:30]([CH2:33][CH2:34][CH2:35][C:36]([NH:46][C@H:45]([C:44]([OH:43])=[O:50])[CH:47]([CH3:49])[CH3:48])=[O:37])=[CH:31][CH:32]=2)=[CH:39][CH:40]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([NH:15][S:16]([CH3:19])(=[O:17])=[O:18])[C:10]=1[CH3:20])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)[C@@H](N)C(C)C
Reactant: Cc1c(NS(C)(=O)=O)cccc1N(Cc1ccccc1)Cc1ccc(Oc2ccc(CCCC(=O)O)cc2)cc1
Agent: Cl
Product: Cc1c(NS(C)(=O)=O)cccc1N(Cc1ccccc1)Cc1ccc(Oc2ccc(CCCC(=O)N[C@H](C(=O)O)C(C)C)cc2)cc1

Procedure:
The product from Example 100 (56 mg, 0.1 mmole) and L-Valine methyl ester hydrochloride (34 mg, 0.2 mmole) were processed as in Examples 213A and 224B to provide the title compound. 1H NMR (500 MHz, DMSO-d6) δ12.28-12.62 (br.s, 1 H), 8.94 (s, 1 H), 7.92 (d, 1 H), 7.26 (m, 6 H), 7.18 (m, 3 H), 7.04 (m, 1 H), 6.96 (m, 2 H), 6.88 (m, 4 H), 4.15 (dd, 1 H), 4.05 (s, 2 H), 4.01 (s, 2 H), 2.91 (s, 3 H), 2.54 (t, 2 H), 2.39 (s, 3 H), 2.19 (td, 2 H), 2.02 (m, 1 H), 1.78 (m, 2 H), 0.88 (s, 3 H), 0.87 (s, 3 H); MS (APCI+) m/z 658 (M+H)+.
Reaction SMILES: [CH:1]1[C:11]2[CH2:10][CH2:9][C:8]3[CH:12]=[CH:13][CH:14]=[CH:15][C:7]=3[CH:6]([CH2:16][N:17]3[CH2:22][CH2:21][C:20](=[O:23])[CH2:19][CH2:18]3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.[C:24]([Li])([CH3:27])([CH3:26])[CH3:25]>C1C=CC=CC=1>[C:24]([C:20]1([OH:23])[CH2:21][CH2:22][N:17]([CH2:16][CH:6]2[C:5]3[CH:4]=[CH:3][CH:2]=[CH:1][C:11]=3[CH2:10][CH2:9][C:8]3[CH:12]=[CH:13][CH:14]=[CH:15][C:7]2=3)[CH2:18][CH2:19]1)([CH3:27])([CH3:26])[CH3:25]
Reactant: [Li]C(C)(C)C
Reactant: O=C1CCN(CC2c3ccccc3CCc3ccccc32)CC1
Solvent: c1ccccc1
Product: CC(C)(C)C1(O)CCN(CC2c3ccccc3CCc3ccccc32)CC1
Reaction time: 2 h

Procedure:
Solution of 5 parts of 1-[(10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5-yl)methyl]-4-piperidinone in 150 parts by volume of benzene is added dropwise over a period of 50 minutes to a stirred, cooled solution of tert-butyllithium (33.8 parts by volume of 1.9 M ethyl ether solution) in 150 parts by volume of benzene under a nitrogen atmosphere. The resultant solution is stirred at ambient temperature for about 1 hour and quenched with the addition of 100 parts by volume of 10% ammonium chloride. The solution is stirred for additional 2 hours, the organic layer separated, washed with brine, dried with magnesium sulfate and concentrated in vacuo to give clear yellow oil. This oil is chromatographed on silica gel using 1% ethanol/methylene chloride as eluent to afford 4-tert-butyl-1-[(10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5-yl)-methyl]-4-piperidinol melting at about 96°-98.5° C. This compound is represented by the following general formula ##STR27##
Reaction SMILES: [C:1]12([CH2:11][CH2:12][C:13]([OH:15])=O)[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.S(Cl)([Cl:18])=O>>[C:1]12([CH2:11][CH2:12][C:13]([Cl:18])=[O:15])[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2
Reactant: O=S(Cl)Cl
Reactant: O=C(O)CCC12CC3CC(CC(C3)C1)C2
Product: O=C(Cl)CCC12CC3CC(CC(C3)C1)C2

Procedure:
3-(1-Adamantyl)propanic acid was reacted with thionyl chloride as describe in Example 10A to provide the title compound as colorless oil.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7](=[O:12])[C:6]([C:13]1[S:14][CH:15]=[CH:16][CH:17]=1)=[C:5]2[O:18][CH2:19][CH:20]1[CH2:25][CH2:24][O:23][CH2:22][CH2:21]1.[CH3:26][C:27]([OH:31])([C:29]#[CH:30])[CH3:28].C(N(C(C)C)CC)(C)C>[Cu]I.[Pd].C(P(C(C)(C)C)C(C)(C)C)(C)(C)C.C(P(C(C)(C)C)C(C)(C)C)(C)(C)C>[O:23]1[CH2:24][CH2:25][CH:20]([CH2:19][O:18][C:5]2[C:4]3[C:9](=[CH:10][CH:11]=[C:2]([C:30]#[C:29][C:27]([OH:31])([CH3:28])[CH3:26])[CH:3]=3)[NH:8][C:7](=[O:12])[C:6]=2[C:13]2[S:14][CH:15]=[CH:16][CH:17]=2)[CH2:21][CH2:22]1
Reactant: C#CC(C)(C)O
Reactant: O=c1[nH]c2ccc(Br)cc2c(OCC2CCOCC2)c1-c1cccs1
Agent: [Cu]I
Agent: [Pd]
Agent: CC(C)(C)P(C(C)(C)C)C(C)(C)C
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(O)C#Cc1ccc2[nH]c(=O)c(-c3cccs3)c(OCC3CCOCC3)c2c1
Temperature: 100 °C

Procedure:
A 5 mL microwave vial was charged with a magnetic stir bar, 6-bromo-4-(tetrahydro-2H-pyran-4-ylmethoxy)-3-(thiophen-2-yl)quinolin-2(1H)-one (22 mg, 52 mop, copper(I) iodide (1.0 mg, 5.0 mop, and bis(tri-t-butylphosphine) palladium(0) (1.0 mg, 3.0 μmol). The vessel was sealed. The contents of the vessel were dried under high vacuum, and flushed with nitrogen. Acetonitrile (500 μL) was added under nitrogen followed by addition of 2-methyl-3-butyn-2-ol (18 mg, 210 μmol), and diisopropylethyl amine (46 μL, 260 μmol). The reaction was heated to 100° C. in an oil bath for 3 h. The crude product was purified by reverse-phase chromatography to yield 4-(tetrahydro-2H-pyran-4-ylmethoxy)-6-(3-hydroxy-3-methylbut-1-yn-1-yl)-3-(thiophen-2-yl)quinolin-2(1H)-one as off white solid. LCMS (M+H)=423.9. 1H NMR (400 MHz, CDCl3) 11.0 (s, 1H), 7.90 (s, 1H), 7.84 (d, 1H), 7.52 (m, 2H), 7.24 (1H), 7.18 (t, 1H), 4.00 (dd, 2H) 3.65 (d, 2H), 3.45 (t, 2H), 2.15 (m, 1H), 1.75 (d, 2H), 1.65 (s, 6H), 1.50-1.40 (m, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]3[C:12]([CH3:15])=[N:13][N:14]=[C:10]3[CH2:9][N:8]=[C:7]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[Cl:22])[C:6]=2[CH:23]=1.[CH2:24]=[O:25]>C1(C)C(C)=CC=CC=1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]3[C:12]([CH2:15][CH2:24][OH:25])=[N:13][N:14]=[C:10]3[CH2:9][N:8]=[C:7]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[Cl:22])[C:6]=2[CH:23]=1
Reactant: Cc1nnc2n1-c1ccc(Cl)cc1C(c1ccccc1Cl)=NC2
Reactant: C=O
Solvent: Cc1ccccc1C
Product: OCCc1nnc2n1-c1ccc(Cl)cc1C(c1ccccc1Cl)=NC2

Procedure:
In the manner given in Example 1, 8-chloro-6-(o-chlorophenyl)-1-methyl-4H-s-triazolo[4,3-a][1,4]benzodiazepine in xylene is heated in an oil bath at 122°-124° C. with repeated addition of portions of paraformaldehyde to give 8-chloro-1-(2-hydroxyethyl)-6-(o-chlorophenyl)-4H-s-triazolo[4,3-a][1,4]benzodiazepine.
Reaction SMILES: [CH3:1][C:2]1([CH3:15])[NH:7][CH:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:5]([NH2:14])[CH2:4][CH2:3]1.[CH3:16][O:17][C:18]1[CH:19]=[C:20]2[C:25](=[CH:26][C:27]=1[CH:28]=O)[N:24]([CH3:30])[C:23](=[O:31])[CH2:22][CH2:21]2>>[CH3:1][C:2]1([CH3:15])[NH:7][CH:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:5]([NH:14][CH2:28][C:27]2[CH:26]=[C:25]3[C:20]([CH2:21][CH2:22][C:23](=[O:31])[N:24]3[CH3:30])=[CH:19][C:18]=2[O:17][CH3:16])[CH2:4][CH2:3]1
Reactant: COc1cc2c(cc1C=O)N(C)C(=O)CC2
Reactant: CC1(C)CCC(N)C(c2ccccc2)N1
Product: COc1cc2c(cc1CNC1CCC(C)(C)NC1c1ccccc1)N(C)C(=O)CC2

Procedure:
By a procedure similar to the previous examples 9 and 9A: prepared through the reaction of 6,6-dimethyl-2-phenyl-piperidin-3-ylamine with 6-Methoxy-1-methyl-2-oxo-1,2,3,4-tetrahydro-quinoline-7-carbaldehyde. Mass spectrum calcd for C25H34N3O2 (M+1) 408; found 408.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[NH2:9].[CH:10](=O)/[CH:11]=[CH:12]/[CH3:13].O.[NH4+].[OH-]>Cl.[Cl-].[Cl-].[Zn+2]>[Br:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[C:4]2[C:3]=1[N:9]=[C:12]([CH3:13])[CH:11]=[CH:10]2
Reactant: Nc1ccc(F)cc1Br
Reactant: C/C=C/C=O
Agent: Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Product: Cc1ccc2cc(F)cc(Br)c2n1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 84.7 %

Procedure:
2-Bromo-4-fluorobenzenamine (10 g, 52.6 mmol) was weighed into a round bottom flask, and dissolved in 40 mL of 6N HCl. The reaction mixture was then heated to reflux, followed by drop-wise addition of (E)-but-2-enal (4.578 mL, 55.3 mmol) mixed with 1.0 mL deionized water over 25 minutes. Following complete addition the reaction was heated at 100° C. for an additional 35 minutes, until all the 2-bromo-4-fluorobenzenamine had been consumed. The reaction was cooled to ambient temperature, followed by addition of 50 mL of Et2O. The reaction was stirred for 5 minutes followed by removal of Et2O by partitioning. The aqueous layer was replaced into the original reaction flask and ZnCl2 (3.586 g, 26.3 mmol) was then added in two portions followed by cooling to 0° C. over 30 minutes. The pH of the crude reaction mixture was then adjusted to pH=8.0 using concentrated NH4OH. The crude mixture was then extracted with Et2O, followed by ethyl acetate. The combined organics were then dried over Na2SO4, and then concentrated in vacuo, affording the desired product as a brown solid (10.7 g, 85% yield). MS APCI (+) m/z 240.2 and 242.2 (M+1 of each Br isotope) detected.
Reaction SMILES: C([O:9][CH2:10][C:11]1[S:12][CH:13]=[C:14](/[CH:16]=[CH:17]/[C:18]2[C:19]([O:29][CH2:30][C:31]3[CH:36]=[CH:35][C:34]([O:37][CH2:38][C:39]4[N:40]=[C:41]([C:45]5[CH:50]=[CH:49][C:48]([CH2:51][C:52]([O:54]CC)=[O:53])=[CH:47][CH:46]=5)[O:42][C:43]=4[CH3:44])=[C:33]([O:57][CH3:58])[CH:32]=3)=[N:20][N:21]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[CH:22]=2)[N:15]=1)(=O)C1C=CC=CC=1.O1CCCC1.[OH-].[Na+].Cl>O.C(O)C>[OH:9][CH2:10][C:11]1[S:12][CH:13]=[C:14](/[CH:16]=[CH:17]/[C:18]2[C:19]([O:29][CH2:30][C:31]3[CH:36]=[CH:35][C:34]([O:37][CH2:38][C:39]4[N:40]=[C:41]([C:45]5[CH:46]=[CH:47][C:48]([CH2:51][C:52]([OH:54])=[O:53])=[CH:49][CH:50]=5)[O:42][C:43]=4[CH3:44])=[C:33]([O:57][CH3:58])[CH:32]=3)=[N:20][N:21]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[CH:22]=2)[N:15]=1
Reactant: CCOC(=O)Cc1ccc(-c2nc(COc3ccc(COc4nn(-c5ccccc5)cc4/C=C/c4csc(COC(=O)c5ccccc5)n4)cc3OC)c(C)o2)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Solvent: C1CCOC1
Product: COc1cc(COc2nn(-c3ccccc3)cc2/C=C/c2csc(CO)n2)ccc1OCc1nc(-c2ccc(CC(=O)O)cc2)oc1C
Temperature: 50 °C
Reaction time: 20 h
Yield: 95.9 %

Procedure:
To a mixture of {4-[(E)-2-(3-{[4-({2-[4-(2-ethoxy-2-oxoethyl)phenyl]-5-methyl-1,3-oxazol-4-yl}methoxy)-3-methoxybenzyl]oxy}-1-phenyl-1H-pyrazol-4-yl)ethenyl]-1,3-thiazol-2-yl}methyl benzoate (0.5 g), tetrahydrofuran (6 mL) and ethanol (3 mL) was added 1N aqueous sodium hydroxide solution (3 mL), and the mixture was stirred at 50° C. for 20 hrs. To the reaction mixture were added 1N hydrochloric acid (3 mL) and water, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated to give (4-{4-[(4-{[(4-{(E)-2-[2-(hydroxymethyl)-1,3-thiazol-4-yl]ethenyl}-1-phenyl-1H-pyrazol-3-yl)oxy]methyl}-2-methoxyphenoxy)methyl]-5-methyl-1,3-oxazol-2-yl}phenyl)acetic acid as crystals (0.4 g, yield 90%). Recrystallization twice from tetrahydrofuran-hexane gave colorless prism crystals. melting point: 204-205° C.