Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:19]=[CH:18][C:12]([O:13][CH2:14][CH:15]2[O:17][CH2:16]2)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.Cl.[CH3:22][O:23][C:24]1[CH:29]=[C:28]([O:30][CH3:31])[CH:27]=[CH:26][C:25]=1[N:32]1[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]1.C(N(CC)CC)C>O1CCOCC1>[CH2:1]([O:8][C:9]1[CH:19]=[CH:18][C:12]([O:13][CH2:14][CH:15]([OH:17])[CH2:16][N:35]2[CH2:34][CH2:33][N:32]([C:25]3[CH:26]=[CH:27][C:28]([O:30][CH3:31])=[CH:29][C:24]=3[O:23][CH3:22])[CH2:37][CH2:36]2)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COc1ccc(N2CCNCC2)c(OC)c1
Reactant: c1ccc(COc2ccc(OCC3CO3)cc2)cc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: C1COCCO1
Product: COc1ccc(N2CCN(CC(O)COc3ccc(OCc4ccccc4)cc3)CC2)c(OC)c1
Yield: 67.3 %

Procedure:
Using 1.56 g of 1-(4-benzyloxyphenoxy)-2,3-epoxypropane, 1.80 g of 1-(2,4-dimethoxyphenyl)piperazine dihydrochloride, 1.9 ml of triethylamine and 50 ml of dioxane, reaction and workup were carried out as in Example 1-A. Purification by column chromatography (silica gel, elution with ethyl acetate:hexane =1:0.5) gave 1.96 g of pale red crystals, m.p. 110-112° C.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([N:15]2[CH:19]=[C:18]([C:20]([O:22]CC)=[O:21])[CH:17]=[N:16]2)[CH:6]=[CH:7][C:8]=1[O:9][CH2:10][CH2:11][CH:12]([CH3:14])[CH3:13])#[N:2].[OH-].[Na+].O.C(O)(=O)C>C(O)C>[C:1]([C:3]1[CH:4]=[C:5]([N:15]2[CH:19]=[C:18]([C:20]([OH:22])=[O:21])[CH:17]=[N:16]2)[CH:6]=[CH:7][C:8]=1[O:9][CH2:10][CH2:11][CH:12]([CH3:14])[CH3:13])#[N:2]
Reactant: CCOC(=O)c1cnn(-c2ccc(OCCC(C)C)c(C#N)c2)c1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Solvent: CC(=O)O
Product: CC(C)CCOc1ccc(-n2cc(C(=O)O)cn2)cc1C#N
Temperature: 80 °C
Yield: 66.3 %

Procedure:
To a solution (15 ml) of ethyl 1-(3-cyano-4-(3-methylbutoxy)phenyl)pyrazole-4-carboxylate (1.6 g) in ethanol was added 1.5 N aqueous sodium hydroxide solution (4 ml) with stirring, and the mixture was heated at 80° C. for 30 minutes. After the completion of the reaction, the reaction mixture was poured into water and neutralized with acetic acid. The precipitated crystals were recrystallized from ethyl acetate to give 0.97 g of 1-(3-cyano-4-(3-methylbutoxy)phenyl)pyrazole-4-carboxylic acid, melting point 210-211° C.
Reaction SMILES: O=[C:2]1[CH2:11][N:10]2[C@H:12]3[CH2:17][CH2:16][N:15](C(OCC)=O)[CH2:14][C@H:13]3[C:8]3[C:9]2=[C:4]([CH:5]=[CH:6][CH:7]=3)[NH:3]1.[CH2:23](I)[CH2:24][CH3:25]>>[CH2:23]([N:3]1[C:4]2[CH:5]=[CH:6][CH:7]=[C:8]3[C@@H:13]4[CH2:14][NH:15][CH2:16][CH2:17][C@@H:12]4[N:10]([C:9]=23)[CH2:11][CH2:2]1)[CH2:24][CH3:25]
Reactant: CCCI
Reactant: CCOC(=O)N1CC[C@H]2[C@@H](C1)c1cccc3c1N2CC(=O)N3
Product: CCCN1CCN2c3c(cccc31)[C@@H]1CNCC[C@@H]12

Procedure:
Utilizing the material from Example 255 Step A, the title compound was prepared in analogous fashion using propyl iodide as the alkyl halide and following the procedure of Step B-D of Example 255, as an amorphous tan solid. 1H NMR (CDCl3, 300 MHz) δ 0.94 (t, 2H), 1.40–2.01 (m, 6H), 2.65–2.70 (t, J=9.6 Hz, 2H), 2.70–2.95 (m, 2H), 2.95–3.45 (m, 7H)), 3.3.60–3.95 (m, 1H), 6.37 (d, J=7.7 Hz, 1H), 6.46 (d, J=7.0 Hz, 1H), 6.64 (t, J=7.6 Hz) ppm. MS (CI): 258 (M+H+).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][NH:4][CH2:3][C:2]1=[O:7].C[O:9][C:10]([C:12]1[C:16]([NH:17][C:18]([C:20]2[C:25]([NH:26][C:27]3[CH:28]=[N:29][CH:30]=[N:31][CH:32]=3)=[CH:24][CH:23]=[C:22]([CH:33]3[CH2:35][CH2:34]3)[N:21]=2)=[O:19])=[CH:15][N:14]([CH3:36])[N:13]=1)=O>>[CH3:36][N:14]1[CH:15]=[C:16]([NH:17][C:18]([C:20]2[C:25]([NH:26][C:27]3[CH:32]=[N:31][CH:30]=[N:29][CH:28]=3)=[CH:24][CH:23]=[C:22]([CH:33]3[CH2:34][CH2:35]3)[N:21]=2)=[O:19])[C:12]([C:10]([N:4]2[CH2:5][CH2:6][NH:1][C:2](=[O:7])[CH2:3]2)=[O:9])=[N:13]1
Reactant: O=C1CNCCN1
Reactant: COC(=O)c1nn(C)cc1NC(=O)c1nc(C2CC2)ccc1Nc1cncnc1
Product: Cn1cc(NC(=O)c2nc(C3CC3)ccc2Nc2cncnc2)c(C(=O)N2CCNC(=O)C2)n1
Yield: 12 %

Procedure:
According to the general method described in step 5 of example 27, reaction of piperazine-2-one with 4-{[6-cyclopropyl-3-(pyrimidin-5-ylamino)-pyridine-2-carbonyl]-amino}-1-methyl-1H-pyrazole-3-carboxylic acid methyl ester provided the title compound (12%) as pale yellow solid.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]2[S:9][CH:10]=[C:11]([NH:13][C:14]([NH:16][C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([CH2:23][N:24]4[CH2:29][CH2:28][O:27][CH2:26][CH2:25]4)[N:18]=3)=[O:15])[N:12]=2)[CH:5]=[CH:4][N:3]=1.[CH3:30][CH2:31][OH:32].CC[O-].[Na+].CCO>CN(C=O)C>[CH2:31]([O:32][C:2]1[CH:7]=[C:6]([C:8]2[S:9][CH:10]=[C:11]([NH:13][C:14]([NH:16][C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([CH2:23][N:24]4[CH2:29][CH2:28][O:27][CH2:26][CH2:25]4)[N:18]=3)=[O:15])[N:12]=2)[CH:5]=[CH:4][N:3]=1)[CH3:30]
Reactant: CCO
Reactant: O=C(Nc1cccc(CN2CCOCC2)n1)Nc1csc(-c2ccnc(Cl)c2)n1
Agent: CC[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOc1cc(-c2nc(NC(=O)Nc3cccc(CN4CCOCC4)n3)cs2)ccn1
Reaction time: 2.5 h

Procedure:
To a mixture of 1-[2-(2-chloropyridin-4-yl)thiazol-4-yl]-3-(6-morpholin-4-ylmethyl-pyridin-2-yl)urea (100 mg, 0.23 mmol, Example 90) and EtOH (50 mL) was added a 21 wt % NaOEt/EtOH solution (0.4 mL, 1.2 mmol) and DMF (2 mL). The mixture was heated to reflux for 15 h then additional 21 wt % NaOEt/EtOH solution (10 mL) were added. After 2.5 h, the reaction was complete as judged by LC/MS. The reaction mixture was concentrated in vacuo then diluted with EtOAc and the solid was filtered off. The filtrate was concentrated in vacuo to afford an orange slushy oil which was purified by silica flash chromatography (5-10% MeOH/CH2Cl2) to afford the title compound as a yellow solid. MS m/z: 441.1 (M+H). Calc'd for C21H24N6O3S: 440.16.
Reaction SMILES: [BrH:1].S[C:3]1[NH:4][C:5]2[CH:11]=[CH:10][CH:9]=[CH:8][C:6]=2[N:7]=1.BrBr>CO>[Br:1][C:3]1[NH:4][C:5]2[CH:11]=[CH:10][CH:9]=[CH:8][C:6]=2[N:7]=1
Reactant: Br
Reactant: Sc1nc2ccccc2[nH]1
Agent: BrBr
Solvent: CO
Product: Brc1nc2ccccc2[nH]1
Reaction time: 16 h

Procedure:
To a flask were added 24 ml 48% hydrobromic acid and 120 ml methanol. The mixture was cooled to 5 C and 10 g 2-mercaptobenzimidazole was added. Maintaining a temperature of less than 10 C, 41.5 g of bromine were added in small portions. The mixture was allowed to warm to 22 C, and stirred for 16 hours under nitrogen. After cooling to 5 C, the solid was filtered and then added to 50 ml methanol containing 20 ml aqueous ammounium hydroxide. The pH was adjusted to 6.5 with acetic acid, and the mixture was cooled to 5 C. The product was filtered and washed with water, and dried. A second crop was obtained by cooling the filtrates which was filtered, washed with water and dried. The combined crops resulted in 9.05 g of a solid.
Reaction SMILES: CCN([CH:7]([CH3:9])[CH3:8])C(C)C.[CH3:10][C:11]1[CH:16]=[CH:15][C:14]([S:17]([NH:20][C@H:21]([C@@H:28]([NH2:35])[C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)(=[O:19])=[O:18])=[CH:13][CH:12]=1>C1(C)C=CC=CC=1>[CH3:10][C:11]1[CH:16]=[CH:15][C:14]([S:17]([NH:20][C@@H:21]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[C@@H:28]([NH:35][CH2:31][CH2:30][CH2:29][CH2:28][C:21]2[CH2:9][C:7]([CH3:8])=[CH:24][CH2:23][CH:22]=2)[C:29]2[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=2)(=[O:19])=[O:18])=[CH:13][CH:12]=1
Reactant: Cc1ccc(S(=O)(=O)N[C@@H](c2ccccc2)[C@@H](N)c2ccccc2)cc1
Reactant: CCN(C(C)C)C(C)C
Solvent: Cc1ccccc1
Product: CC1=CCC=C(CCCCN[C@@H](c2ccccc2)[C@@H](NS(=O)(=O)c2ccc(C)cc2)c2ccccc2)C1
Temperature: 135 °C
Reaction time: 14 h
Yield: 110.9 %

Procedure:
The tosylates (10.45 g, 32.61 mmol, isomer ratio: 1,4 type/1,5 type=77/23) obtained in Example 2 were dissolved in 40 ml of toluene, and DIPEA (4.79 g, 32.61 mmol) and (S,S)-TsDPEN (11.95 g, 32.61 mmol) were added thereto, followed by stirring at 135° C. for 14 hours. After that, the solvent was evaporated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (hexane/ethyl acetate=2/1). Thus, 9.31 g of the title compounds were obtained as a yellow oily substance. Yield: 55.5% (isomer ratio: 1,4 type/1,5 type=77/23). Note that the following NMR spectrum data are those of the isomer mixture.
Reaction SMILES: [CH2:1]1[C@@H:3]([NH3+:4])[C@H:2]1[C:5]1[CH:10]=[CH:9][C:8]([F:11])=[C:7]([F:12])[CH:6]=1.C1C=CC(C(O)C([O-])=O)=CC=1.C(=O)([O-])[O-].[K+].[K+].Cl[C:31]1[C:32]2[N:43]=[N:42][N:41]([C@H:44]3[C@@H:48]4[O:49][C:50]([CH3:53])([CH3:52])[O:51][C@@H:47]4[C@@H:46]([O:54][CH2:55][CH2:56][OH:57])[CH2:45]3)[C:33]=2[N:34]=[C:35]([S:37][CH2:38][CH2:39][CH3:40])[N:36]=1>O>[F:12][C:7]1[CH:6]=[C:5]([C@@H:2]2[CH2:1][C@H:3]2[NH:4][C:31]2[C:32]3[N:43]=[N:42][N:41]([C@H:44]4[C@@H:48]5[O:49][C:50]([CH3:52])([CH3:53])[O:51][C@@H:47]5[C@@H:46]([O:54][CH2:55][CH2:56][OH:57])[CH2:45]4)[C:33]=3[N:34]=[C:35]([S:37][CH2:38][CH2:39][CH3:40])[N:36]=2)[CH:10]=[CH:9][C:8]=1[F:11]
Reactant: [NH3+][C@@H]1C[C@@H]1c1ccc(F)c(F)c1
Reactant: CCCSc1nc(Cl)c2nnn([C@@H]3C[C@H](OCCO)[C@H]4OC(C)(C)O[C@H]43)c2n1
Agent: O=C([O-])C(O)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: CCCSc1nc(N[C@@H]2C[C@H]2c2ccc(F)c(F)c2)c2nnn([C@@H]3C[C@H](OCCO)[C@H]4OC(C)(C)O[C@H]43)c2n1

Procedure:
trans-(1R,2S)-2-(3,4-Difluorophenyl)cyclopropanaminium (2R)-2-hydroxy-2-phenylethanoate (146 kg, prepared as described in WO2008/018822, WO2008/018823, WO01/92200) and potassium carbonate (156 kg) were dissolved in water (576 kg) and charged to the 2-({(3aR,4S,6R,6aS)-6-[7-Chloro-5-(propylthio)-3H-[1,2,3]triazolo[4,5-d]pyrimidin-3-yl]-2,2-dimethyltetrahydro-3 aH-cyclopenta[d][1,3]dioxol-4-yl}oxy)ethanol solution with a rate that kept the temperature of the reaction ≦30° C. After the conversion criterion was reached (>99%) the water layer was separated off. The organic layer was washed twice with acetic acid (18 kg) and sodium chloride (13 kg) in water (560 kg) and then twice with sodium chloride (54 kg) in water (438 kg), whereafter the organic layer was used in the next step.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]([N:10]2[CH2:15][CH2:14][N:13]([C:16]3[C:21]([CH3:22])=[CH:20][C:19]([CH3:23])=[CH:18][N:17]=3)[CH2:12][CH2:11]2)=[O:9])=[C:4]([F:24])[CH:3]=1.[CH3:25][O:26][C:27]1[CH:40]=[CH:39][C:30]([CH2:31][N:32]2[CH2:36][CH:35]([CH3:37])[NH:34][C:33]2=[O:38])=[CH:29][CH:28]=1>>[CH3:22][C:21]1[C:16]([N:13]2[CH2:14][CH2:15][N:10]([C:8]([C:5]3[CH:6]=[CH:7][C:2]([N:34]4[CH:35]([CH3:37])[CH2:36][N:32]([CH2:31][C:30]5[CH:39]=[CH:40][C:27]([O:26][CH3:25])=[CH:28][CH:29]=5)[C:33]4=[O:38])=[CH:3][C:4]=3[F:24])=[O:9])[CH2:11][CH2:12]2)=[N:17][CH:18]=[C:19]([CH3:23])[CH:20]=1
Reactant: COc1ccc(CN2CC(C)NC2=O)cc1
Reactant: Cc1cnc(N2CCN(C(=O)c3ccc(Br)cc3F)CC2)c(C)c1
Product: COc1ccc(CN2CC(C)N(c3ccc(C(=O)N4CCN(c5ncc(C)cc5C)CC4)c(F)c3)C2=O)cc1

Procedure:
Using (4-bromo-2-fluorophenyl)[4-(3,5-dimethylpyridin-2-yl)piperazin-1-yl]methanone (157 mg) described in Preparation Example 114 and 1-(4-methoxybenzyl)-4-methylimidazolidin-2-one (132 mg) described in Preparation Example 52 and by the reaction and treatment in the same manner as in Example 1, 3-{4-[4-(3,5-dimethylpyridin-2-yl)piperazine-1-carbonyl]-3-fluorophenyl}-1-(4-methoxybenzyl)-4-methylimidazolidin-2-one was obtained. Using the obtained 3-{4-[4-(3,5-dimethylpyridin-2-yl)piperazine-1-carbonyl]-3-fluorophenyl}-1-(4-methoxybenzyl)-4-methylimidazolidin-2-one and by the reaction and treatment in the same manner as in Example 421, the title compound (89 mg) was obtained.
Reaction SMILES: [Br:1][CH2:2][C:3]([O:5][CH2:6][CH3:7])=[O:4].[CH3:8][N:9]([CH3:18])[CH:10]=[N:11][C:12]1[S:13][C:14]([CH3:17])=[CH:15][N:16]=1>>[Br-:1].[CH3:18][N:9]([CH:10]=[N:11][C:12]1[S:13][C:14]([CH3:17])=[CH:15][N+:16]=1[CH2:2][C:3]([O:5][CH2:6][CH3:7])=[O:4])[CH3:8]
Reactant: Cc1cnc(N=CN(C)C)s1
Reactant: CCOC(=O)CBr
Product: CCOC(=O)C[n+]1cc(C)sc1N=CN(C)C
Product: [Br-]

Procedure:
prepared by reaction of ethyl bromoacetate with N,N-dimethyl-N′-(5-methyl-thiazol-2-yl)-formamidine. LC-MS: tR=0.63 min; [M+H]+=256.2.
Reaction SMILES: C1C=C[NH+]=CC=1.[Br:7][Br-]Br.[CH3:10][O:11][C:12]1[CH:13]=[C:14]2[C:19](=[CH:20][CH:21]=1)[C:18]([C:22]1[CH:35]=[CH:34][C:25]([O:26][CH2:27][CH2:28][N:29]3[CH2:33][CH2:32][CH2:31][CH2:30]3)=[CH:24][CH:23]=1)=[CH:17][CH2:16][CH2:15]2>C1COCC1>[Br:7][C:17]1[CH2:16][CH2:15][C:14]2[C:19](=[CH:20][CH:21]=[C:12]([O:11][CH3:10])[CH:13]=2)[C:18]=1[C:22]1[CH:35]=[CH:34][C:25]([O:26][CH2:27][CH2:28][N:29]2[CH2:33][CH2:32][CH2:31][CH2:30]2)=[CH:24][CH:23]=1
Reactant: COc1ccc2c(c1)CCC=C2c1ccc(OCCN2CCCC2)cc1
Agent: c1cc[nH+]cc1
Solvent: C1CCOC1
Product: COc1ccc2c(c1)CCC(Br)=C2c1ccc(OCCN2CCCC2)cc1
Reaction time: 60 h
Yield: 82.9 %

Procedure:
Pyridinium bromide perbromide (21.22 g, 60.55 mmol) was added portionwise to a solution of 1-{2-[4(6-methoxy-3,4-dihydronaphthalen-1-yl)phenoxy]ethyl}pyrrolidine (23 g, 72 mmol) in THF (700 mL). The reaction was stirred for 60 h. The precipitate was filtered through a Celite pad with the aid of THF. The off-white solid was dissolved in CH2Cl2 and MeOH and was filtered away from the Celite. The organic solution was washed with 0.5 N aq HCl followed by satd NaHCO3 (aq). The organic solution was dried (MgSO4), filtered, and concentrated to provide a brown solid (21.5 g, 83%). 1H NMR (250 MHz, CDCl3): δ7.14 (d, J=8.7 Hz, 2 H), 6.97 (d, J=8.8 Hz, 2 H), 6.71 (d, J=2.2 Hz, 1 H), 6.55 (m, 2 H), 4.17 (t, J=6.0 Hz, 2 H), 3.77 (s, 3 H), 2.96 (m, 4 H), 2.66 (m, 4 H), 1.85 (m, 4 H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:8]=[C:9](OC)[C:10]=1[O:11][CH3:12])[CH:6]=[O:7].B(Br)(Br)Br.[OH2:19]>C(Cl)Cl>[OH:19][C:8]1[CH:9]=[C:10]([O:11][CH3:12])[C:3]([O:2][CH3:1])=[CH:4][C:5]=1[CH:6]=[O:7]
Reactant: COc1cc(C=O)cc(OC)c1OC
Reactant: O
Agent: BrB(Br)Br
Solvent: ClCCl
Product: COc1cc(O)c(C=O)cc1OC
Temperature: 25 °C
Reaction time: 9 h
Yield: 87 %

Procedure:
To a solution of 3,4,5-trimethoxybenzaldehyde (5 g, 25.510 mmol) in CH2Cl2 (125 ml) at 0° C., BBr3 (6.39 g, 25.510 mmol) was added. The resulting dark mixture was stirred at rt for 9 h. Water (100 mL) was charged and the mixture was stirred for 10 min, the aqueous phase was extracted by CH2Cl2. Organic phase was dried over Na2SO4, and evaporated under reduced pressure. The resulting residue was purified by silica gel column chromatography using plain dichloromethane as eluent, afforded the 2-hydroxy-4,5-dimethoxybenzaldehyde 13 (4.3 g, 87%) isolated as yellow solid. Mp 105-107° C.; 1H NMR (CDCl3, 400 MHz): δ 11.40 (br. s, 1H), 9.70 (s, 1H), 6.91 (s, 1H), 6.48 (s, 1H), 3.94 (s, 3H), 3.88 (s, 3H) ppm. 13C NMR (CDCl3. 125 MHz): 194.0, 159.3, 157.3, 142.9, 113.3, 112.9, 100.1, 56.4, 56.3. HRMS (ESI) m/z: [M+H]+ calcd for C9H10O4+H+ 183.0657. Found 183.0653.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7][O:8][C:9]1[CH:14]=[CH:13][NH:12][C:11](=[O:15])[CH:10]=1.Br[C:17]1[CH:18]=[CH:19][C:20]2[C:21]3[CH2:30][N:29]([C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[CH2:28][CH2:27][C:22]=3[N:23]([CH3:26])[C:24]=2[CH:25]=1>>[CH3:26][N:23]1[C:24]2[CH:25]=[C:17]([N:12]3[CH:13]=[CH:14][C:9]([O:8][CH2:7][C:2]4[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=4)=[CH:10][C:11]3=[O:15])[CH:18]=[CH:19][C:20]=2[C:21]2[CH2:30][N:29]([C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[CH2:28][CH2:27][C:22]1=2
Reactant: Cn1c2c(c3ccc(Br)cc31)CN(C(=O)OC(C)(C)C)CC2
Reactant: O=c1cc(OCc2ccccn2)cc[nH]1
Product: Cn1c2c(c3ccc(-n4ccc(OCc5ccccn5)cc4=O)cc31)CN(C(=O)OC(C)(C)C)CC2
Yield: 43 %

Procedure:
4-(Pyridin-2-ylmethoxy)pyridin-2(1H)-one (110 mg, 0.54 mmol) and tert-butyl 7-bromo-5-methyl-3,4-dihydro-1H-pyrido[4,3-b]indole-2(5H)-carboxylate (200 mg, 0.54 mmol) were reacted following the procedure of Example 30 (step g) to provide the title compound (113 mg, 43%) as a yellow oil: 1H NMR (300 MHz, CDCl3) δ 8.63 (ddd, J=4.9, 1.6, 0.9 Hz, 1H), 7.75 (overlapping ddd, J=7.6, 1.8 Hz, 1H), 7.49 (t, J=7.3 Hz, 2H), 7.33 (d, J=7.5 Hz, 1H), 7.29 (d, J=1.4 Hz, 1H), 7.26 (m overlapping with solvent, 1H), 7.01 (d, J=7.9 Hz, 1H), 6.12-6.07 (m, 2H), 5.19 (s, 2H), 4.64 (s, 2H), 3.84 (t, J=5.4 Hz, 2H), 3.62 (s, 3H), 2.82 (t, J=5.4 Hz, 2H), 1.52 (s, 9H).
Reaction SMILES: [C:1]([O:5][C:6](=[O:48])[CH2:7][O:8][CH2:9][CH2:10][O:11][CH2:12][CH2:13][O:14][CH2:15][CH2:16][O:17][CH2:18][CH2:19][O:20][CH2:21][CH2:22][O:23][C:24]1[CH:29]=[CH:28][C:27]([O:30][CH2:31][CH2:32][O:33][CH2:34][CH2:35][O:36][CH2:37][CH2:38][O:39][CH2:40][CH2:41][O:42][CH2:43][CH2:44][N:45]=[N+]=[N-])=[CH:26][CH:25]=1)([CH3:4])([CH3:3])[CH3:2].[H][H]>CO.[OH-].[Pd+2].[OH-]>[C:1]([O:5][C:6](=[O:48])[CH2:7][O:8][CH2:9][CH2:10][O:11][CH2:12][CH2:13][O:14][CH2:15][CH2:16][O:17][CH2:18][CH2:19][O:20][CH2:21][CH2:22][O:23][C:24]1[CH:25]=[CH:26][C:27]([O:30][CH2:31][CH2:32][O:33][CH2:34][CH2:35][O:36][CH2:37][CH2:38][O:39][CH2:40][CH2:41][O:42][CH2:43][CH2:44][NH2:45])=[CH:28][CH:29]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)COCCOCCOCCOCCOCCOc1ccc(OCCOCCOCCOCCOCCN=[N+]=[N-])cc1
Reactant: [H][H]
Agent: [Pd+2]
Agent: [OH-]
Solvent: CO
Product: CC(C)(C)OC(=O)COCCOCCOCCOCCOCCOc1ccc(OCCOCCOCCOCCOCCN)cc1
Reaction time: 1 h

Procedure:
In a nitrogen atmosphere, to a suspension of palladium hydroxide (20% by weight; 18 mg) in methanol (1 ml), a solution of Compound 27 (190 mg, 0.323 mmol) in methanol (1.5 ml) was added; after the nitrogen atmosphere was replaced with a hydrogen atmosphere, stirring was conducted at room temperature for 1 hour. After a nitrogen atmosphere was restored, insoluble matter was separated by filtration on Celite and washed with methanol. Concentration under reduced pressure was conducted to yield a crude product of Compound 28.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[C:7]1([NH:13][C:14]2([CH2:20][NH:21][CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24])[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]2)[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.Cl[CH2:29][C:30](Cl)=[O:31].O>CN(C)C=O>[O:31]=[C:30]1[N:21]([CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24])[CH2:20][C:14]2([CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]2)[N:13]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[CH2:29]1
Reactant: O=C(Cl)CCl
Reactant: CCOC(=O)CNCC1(Nc2ccccc2)CCCCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)CN1CC2(CCCCC2)N(c2ccccc2)CC1=O
Yield: 96.5 %

Procedure:
95 mg (0.69 mmol) of potassium carbonate are added to a solution of 200 mg (0.69 mmol) of ethyl [(1-phenylaminocyclohexylmethyl)amino]-acetate and 55 μl (0.69 mmol) of chloroacetyl chloride in 15 ml of dimethylformamide. The reaction medium is stirred at reflux for 6 h and poured into water and extracted with ethyl acetate. The organic phases are collected and washed with water. They are dried over sodium sulfate. The solvents are evaporated. 220 mg of ethyl (3-oxo-1-phenyl-1,4-diazaspiro[5.5]undec-4-yl)acetate are obtained in the form of an orange oil. Yield=97%.
Reaction SMILES: [C:1]([O:5][C:6](=[O:21])[CH2:7]/[C:8](=[CH:12]\[CH2:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)/[C:9]([OH:11])=[O:10])([CH3:4])([CH3:3])[CH3:2]>CO>[C:1]([O:5][C:6](=[O:21])[CH2:7][C@@H:8]([CH2:12][CH2:13][CH2:14][C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1)[C:9]([OH:11])=[O:10])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)C/C(=C\CCc1ccccc1)C(=O)O
Solvent: CO
Product: CC(C)(C)OC(=O)C[C@@H](CCCc1ccccc1)C(=O)O
Yield: 99.2 %

Procedure:
A solution of (E)-2-[2-(tert-butoxy)-2-oxoethyl]-5-phenyl-2-pentenoic acid (5.8g, 20 mmol) and 1,1′-bis[(2S,4S)-2,4-diethylphosphetano]ferrocene-(1,5-cyclooctadiene)-rhodium (I) tetrafluoroborate (7.4 mg, 10 μmol) in methanol (10 ml) was stirred at 20-25° C. for 24 hours, under hydrogen (4 atmospheres, 60 p.s.i.). The mixture was then concentrated in vacuo to leave the title compound as a yellow oil (5.8 g, 98% conversion, enantiomeric excess=97%, 95% pure by NMR).
Reaction SMILES: Cl[CH2:2][C:3]1[CH:21]=[CH:20][C:6]([O:7][CH2:8][C:9]2[N:10]=[C:11]([C:15]3[O:16][CH:17]=[CH:18][CH:19]=3)[O:12][C:13]=2[CH3:14])=[C:5]([O:22][CH3:23])[CH:4]=1.[C:24]1([N:30]2[C:34]([CH2:35][CH2:36][C:37]3[CH:42]=[CH:41][CH:40]=[CH:39][N:38]=3)=[CH:33][C:32]([OH:43])=[N:31]2)[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.CN(C)C=O.[H-].[Na+]>O>[O:16]1[CH:17]=[CH:18][CH:19]=[C:15]1[C:11]1[O:12][C:13]([CH3:14])=[C:9]([CH2:8][O:7][C:6]2[CH:20]=[CH:21][C:3]([CH2:2][O:43][C:32]3[CH:33]=[C:34]([CH2:35][CH2:36][C:37]4[CH:42]=[CH:41][CH:40]=[CH:39][N:38]=4)[N:30]([C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)[N:31]=3)=[CH:4][C:5]=2[O:22][CH3:23])[N:10]=1
Reactant: Oc1cc(CCc2ccccn2)n(-c2ccccc2)n1
Reactant: COc1cc(CCl)ccc1OCc1nc(-c2ccco2)oc1C
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1cc(COc2cc(CCc3ccccn3)n(-c3ccccc3)n2)ccc1OCc1nc(-c2ccco2)oc1C
Reaction time: 15 h
Yield: 92.9 %

Procedure:
To a mixture of 4-[(4-chloromethyl-2-methoxyphenoxy)methyl]-2-(2-furyl)-5-methyl-1,3-oxazole (0.30 g), 1-phenyl-5-[2-(pyridin-2-yl)ethyl]-1H-pyrazol-3-ol (0.43 g) and N,N-dimethylformamide (20 mL) was added sodium hydride (60% in oil, 0.050 g) at room temperature, and the mixture was stirred at the same temperature for 15 hrs. Water was poured into the reaction mixture, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated. The residue was subjected to silica gel column chromatography to give 2-(2-{3-[(4-{[2-(2-furyl)-5-methyl-1,3-oxazol-4-yl]methoxy}-3-methoxybenzyl)oxy]-1-phenyl-1H-pyrazol-5-yl}ethyl)pyridine as a colorless oil (0.47 g, yield 76%) from a fraction eluted with ethyl acetate-hexane (1:1, v/v). Recrystallization from ethyl acetate-hexane gave colorless prism crystals. melting point: 104-105° C.
Reaction SMILES: [C:1]1([NH2:8])[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[NH2:7].[C:9](O)(=O)[C:10]1[C:11](=[CH:15][CH:16]=[CH:17][CH:18]=1)[C:12](O)=O.[OH-].[NH4+:22]>O>[C:11]1([C:12]2[NH:7][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][C:1]=3[N:22]=2)[CH:15]=[CH:16][CH:17]=[CH:18][C:10]=1[C:9]1[NH:8][C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=2[N:7]=1
Reactant: [NH4+]
Reactant: O=C(O)c1ccccc1C(=O)O
Reactant: Nc1ccccc1N
Agent: [OH-]
Solvent: O
Product: c1ccc(-c2nc3ccccc3[nH]2)c(-c2nc3ccccc3[nH]2)c1

Procedure:
To a flask were added 50 g polyphosphoric acid. After heating to 90 C under nitrogen, a mixture of 2.7 g 1,2-phenylenediamine and 2.1 g phthalic acid were added. The reaction mixture was heated to 180 C for 4 hours, then cooled to 130 C and poured into 150 ml water. The mixture was basified with aqueous ammonium hydroxide. After cooling to 5 C, the product was filtered and washed with water. After drying, 3.3 g of a gray solid remained.
Reaction SMILES: [CH:1](Br)([CH3:3])[CH3:2].C([O-])([O-])=O.[K+].[K+].[O:11]=[CH:12][C:13]1[CH:21]=[CH:20][C:17]([O:18][CH3:19])=[C:15]([OH:16])[CH:14]=1>CN(C=O)C.CCOCC>[CH:1]([O:16][C:15]1[CH:14]=[C:13]([CH:21]=[CH:20][C:17]=1[O:18][CH3:19])[CH:12]=[O:11])([CH3:3])[CH3:2]
Reactant: COc1ccc(C=O)cc1O
Reactant: CC(C)Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOCC
Product: COc1ccc(C=O)cc1OC(C)C
Temperature: 80 °C

Procedure:
Isopropyl bromide (19.0 mL, 200 mmol) was added to a suspension of K2CO3 (42.0 g, 302 mmol) and isovanillin (23 g, 151.3 mmol) in DMF (100 gmL) and the stirring slurry heated to 80° C. for 13 h. The reaction mixture was then cooled to room temperature, diluted with ether (200 mL) and washed with H2O (4×200 mL), dried (MgSO4) and concentrated under reduced pressure giving the title compound as a slightly tan oil (29.3 g, 100%) which required no further purification. The spectra of this material are identical with those previously reported (H. Ishii, I. -S. Chen and T. Ishikawa J. Chem. Soc., Perkin Trans. 1, 1987, 671.).