Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[N:11]3[N:12]=[C:13]([O:20][CH2:21][C:22]4[CH:23]=[CH:24][C:25]([C:28]5[CH2:29][CH2:30][N:31](C(OC(C)(C)C)=O)[CH2:32][CH:33]=5)=[N:26][CH:27]=4)[C:14]4[C:19]([C:10]3=[N:9][N:8]=2)=[CH:18][CH:17]=[CH:16][CH:15]=4)[CH:3]=1.FC(F)(F)C(O)=O>>[CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[N:11]3[N:12]=[C:13]([O:20][CH2:21][C:22]4[CH:23]=[CH:24][C:25]([C:28]5[CH2:29][CH2:30][NH:31][CH2:32][CH:33]=5)=[N:26][CH:27]=4)[C:14]4[C:19]([C:10]3=[N:9][N:8]=2)=[CH:18][CH:17]=[CH:16][CH:15]=4)[CH:3]=1
Reactant: Cc1cc(-c2nnc3c4ccccc4c(OCc4ccc(C5=CCN(C(=O)OC(C)(C)C)CC5)nc4)nn23)no1
Solvent: O=C(O)C(F)(F)F
Product: Cc1cc(-c2nnc3c4ccccc4c(OCc4ccc(C5=CCNCC5)nc4)nn23)no1
Yield: 51.3 %

Procedure:
The reaction was carried out according to Example 12 step 3 using 1,1-dimethylethyl 5-({[3-(5-methylisoxazol-3-yl)[1,2,4]triazolo[3,4-α]phthalazin-6-yl]oxy}methyl)-3′6′-dihydro-2,4′-bipyridine-1′(2′H)-carboxylate (296 mg, 0.55 mmol) and trifluoroacetic acid (5 ml). The crude residue was purified by column chromatography on silica using 7% MeOH/CH2Cl2 containing 1% NH3 to yield the desired phthalazine (124 mg, 51%). 1H NMR (360 MHz, CDCl3) δ 8.81 (1H, s), 8.68 (1H, d, J=7.6 Hz), 8.21 (1H, d, J=8.0 Hz), 8.05-7.90 (2H, m), 7.80 (1H, t, J=8.0 Hz), 7.43 (1H, t, J=8.1 Hz), 6.85 (1H, s), 6.75 (1H, broad s), 5.68 (2H, s), 3.60 (2H, q, J=2.9 Hz), 3.12 (2H, t, J=5.7 Hz), 2.67-2.55 (5H, m). m/z (ES+) 440 (M+H+).
Reaction SMILES: [CH3:1][C:2]([CH3:12])=[CH:3][CH:4]1[CH:6]([C:7]([OH:9])=[O:8])[C:5]1([CH3:11])[CH3:10].[F:13][CH:14](Br)[C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([O:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH:16]=1>>[CH3:1][C:2]([CH3:12])=[CH:3][CH:4]1[CH:6]([C:7]([O:9][CH:14]([F:13])[C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([O:21][C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=3)[CH:16]=2)=[O:8])[C:5]1([CH3:11])[CH3:10]
Reactant: FC(Br)c1cccc(Oc2ccccc2)c1
Reactant: CC(C)=CC1C(C(=O)O)C1(C)C
Product: CC(C)=CC1C(C(=O)OC(F)c2cccc(Oc3ccccc3)c2)C1(C)C

Procedure:
This compound was prepared from 3-(2-methylprop-1-enyl)-2,2-dimethylcyclopropanecarboxylic acid and α-fluoro-3-phenoxybenzylbromide following the procedure described in Example 2 Method B. The product, a colourless oil, was characterised by pmr spectroscopy. Chemical shift δppm (solvent CDCl3): 1.24 (6H, m, C(CH3)2); 1.70 (6H, s, (CH3)2C=); about 1.9 (2H, m, cyclopropyl protons); 4.93 and 5.43 (1H, 2xd, J=7 Hz, vinyl proton); 7.13 (1H, d, J=56 Hz, CHF); about 7.1 (9H, m, aromatic protons).
Reaction SMILES: [CH3:1][C:2]([C:6]1[CH:11]=[CH:10][C:9]([C:12]2[O:16][CH:15]=[N:14][C:13]=2[CH3:17])=[CH:8][CH:7]=1)([CH3:5])[C:3]#[N:4].[Li+].C[Si]([N-][Si](C)(C)C)(C)C.[Cl:28]C(Cl)(Cl)C(Cl)(Cl)Cl>C1COCC1>[Cl:28][C:15]1[O:16][C:12]([C:9]2[CH:8]=[CH:7][C:6]([C:2]([CH3:1])([CH3:5])[C:3]#[N:4])=[CH:11][CH:10]=2)=[C:13]([CH3:17])[N:14]=1
Reactant: Cc1ncoc1-c1ccc(C(C)(C)C#N)cc1
Reactant: ClC(Cl)(Cl)C(Cl)(Cl)Cl
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: Cc1nc(Cl)oc1-c1ccc(C(C)(C)C#N)cc1
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 92.9 %

Procedure:
To a solution of Example 35C (2.35 g, 10.4 mmol) in THF (50 mL) at −78° C. was added LiHMDS (1.0 M in THF, 11.4 ml, 11.4 mmol) slowly via syringe. The solution was stirred 45 min, and then solid hexachloroethane (3.69 g, 15.6 mmol) was added in one portion. The reaction was allowed to proceed for 16 hr, gradually warming to ambient temperature. The reaction was quenched with half-saturated aq NH4Cl solution, and the product was extracted with Et2O. The combined organic extract was washed with brine, dried (Na2SO4), filtered, and concentrated in vacuo. Flash chromatography (Analogix® Intelliflash 280™; 0% to 20% EtOAc/hexanes eluant; SF40-150 g column) yielded 2.52 g (93%) of the title compound as a colorless oil. 1H NMR (300 MHz, DMSO-d6) δ 7.66 (s, 4H), 2.36 (s, 3H), 1.71 (s, 6H). MS (DCI+) m/z 261 (M+H).
Reaction SMILES: Cl[C:2]1[C:3]2[CH:10]=[C:9]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[O:8][C:4]=2[N:5]=[CH:6][N:7]=1.[NH2:17][C:18]1[CH:22]=[C:21]([C:23]([CH3:26])([CH3:25])[CH3:24])[Se:20][C:19]=1[C:27]([NH2:29])=[O:28].CN(C=O)C.[OH-].[Na+]>>[C:11]1([C:9]2[O:8][C:4]3[N:5]=[CH:6][N:7]=[C:2]([NH:17][C:18]4[CH:22]=[C:21]([C:23]([CH3:26])([CH3:24])[CH3:25])[Se:20][C:19]=4[C:27]([NH2:29])=[O:28])[C:3]=3[CH:10]=2)[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: CC(C)(C)c1cc(N)c(C(N)=O)[se]1
Reactant: Clc1ncnc2oc(-c3ccccc3)cc12
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Product: CC(C)(C)c1cc(Nc2ncnc3oc(-c4ccccc4)cc23)c(C(N)=O)[se]1

Procedure:
The reaction of 4-chloro-6-phenylfuro[2,3-d]pyrimidine with 3-amino-5-tert-butylselenophene-2-carboxamide in the presence of DMF/NaOH as described in Example 1 gave title compound as a pale yellow color solid, mp 280-282° C. IR (KBr) v. 3326, 3188, 2953, 1624, 1386, 1358, 1324, 1283, 1150, 1089, 1016, 921, 822, 778, 755 cm−1; 1H NMR (400 MHz, DMSO-d6): δ 11.94 (1H, s, exchangeable with D2O), 8.53 (1H, s), 8.50 (1H, s), 7.96 (2H, d, J=7.2 Hz), 7.43-7.55 (5H, m), 7.32 (1H, s), 1.40 (9H, s); 13C NMR (100 MHz, DMSO-d6): δ 167.4, 167.1, 166.2, 153.3, 152.5, 152.3, 144.7, 129.3, 129.1, 128.6, 124.7, 121.1, 113.3, 104.4, 97.4, 36.4, 32.2; LC-MS (negative ion mode): m/z 437, 439 (M−H)−.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:8]([Cl:11])=[C:7]2[C:3]=1[C:4]1[CH2:15][CH2:14][N:13]([CH3:16])[CH2:12][C:5]=1[NH:6]2.[H-].[Na+].CC1C=CC(S(O[CH2:30][CH2:31][C:32]2[CH:33]=[N:34][C:35]([CH3:38])=[CH:36][CH:37]=2)(=O)=O)=CC=1>CN(C=O)C>[Cl:1][C:2]1[CH:10]=[CH:9][C:8]([Cl:11])=[C:7]2[C:3]=1[C:4]1[CH2:15][CH2:14][N:13]([CH3:16])[CH2:12][C:5]=1[N:6]2[CH2:30][CH2:31][C:32]1[CH:33]=[N:34][C:35]([CH3:38])=[CH:36][CH:37]=1
Reactant: Cc1ccc(S(=O)(=O)OCCc2ccc(C)nc2)cc1
Reactant: CN1CCc2c([nH]c3c(Cl)ccc(Cl)c23)C1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1ccc(CCn2c3c(c4c(Cl)ccc(Cl)c42)CCN(C)C3)cn1
Temperature: 60 °C
Reaction time: 0.5 h

Procedure:
To a solution of 5,8-dichloro-2,3,4,9-tetrahydro-2-methyl-1H-pyrido[3,4-b]indole (200 mg, 0.78 mmol) in DMF (2 mL), sodium hydride (94 mg, 2.36 mmol) was added. After stirring at 60° C. for 30 min., 2-(6-methylpyridin-3-yl)ethyl 4-methylbenzenesulfonate (572 mg, 1.96 mmol) was added to the reaction mixture and stirred at the same temperature for 40 min. The progress of reaction was monitored by TLC and LCMS. The reaction mixture was quenched with water and extracted with EtOAc. The organic layer was washed with water, dried over anhydrous sodium sulfate and concentrated to get the residue that was purified by reverse phase HPLC to obtain the 5,8-dichloro-2,3,4,9-tetrahydro-2-methyl-9-(2-(6-methylpyridin-3-yl)ethyl)-1H-pyrido[3,4-b]indole.
Reaction SMILES: [C:1]([C:3]1[C@@H:8]([C:9]2[CH:14]=[CH:13][C:12]([C:15]#[N:16])=[CH:11][C:10]=2[S:17]([CH3:20])(=[O:19])=[O:18])[N:7]([C:21](OC2C=CC([N+]([O-])=O)=CC=2)=[O:22])[C:6](=[O:33])[N:5]([C:34]2[CH:39]=[CH:38][CH:37]=[C:36]([C:40]([F:43])([F:42])[F:41])[CH:35]=2)[C:4]=1[CH3:44])#[N:2].[N:45]([CH2:50][CH2:51][OH:52])([CH2:47][CH2:48][OH:49])[NH2:46]>C(#N)C>[C:1]([C:3]1[C@@H:8]([C:9]2[CH:14]=[CH:13][C:12]([C:15]#[N:16])=[CH:11][C:10]=2[S:17]([CH3:20])(=[O:19])=[O:18])[N:7]([C:21]([NH:46][N:45]([CH2:50][CH2:51][OH:52])[CH2:47][CH2:48][OH:49])=[O:22])[C:6](=[O:33])[N:5]([C:34]2[CH:39]=[CH:38][CH:37]=[C:36]([C:40]([F:43])([F:41])[F:42])[CH:35]=2)[C:4]=1[CH3:44])#[N:2]
Reactant: CC1=C(C#N)[C@@H](c2ccc(C#N)cc2S(C)(=O)=O)N(C(=O)Oc2ccc([N+](=O)[O-])cc2)C(=O)N1c1cccc(C(F)(F)F)c1
Reactant: NN(CCO)CCO
Solvent: CC#N
Product: CC1=C(C#N)[C@@H](c2ccc(C#N)cc2S(C)(=O)=O)N(C(=O)NN(CCO)CCO)C(=O)N1c1cccc(C(F)(F)F)c1

Procedure:
According to the General Procedure 1, 4-nitrophenyl (6S)-5-cyano-6-[4-cyano-2-(methylsulfonyl)phenyl]-4-methyl-2-oxo-3-[3-(trifluoromethyl)phenyl]-3,6-dihydropyrimidine-1(2H)-carboxylate (78.0 mg, 0.125 mmol; Example 6A) was reacted with 2,2′-hydrazin-1,1-diyldiethanol (45.0 mg, 0.374 mmol) in acetonitrile (1 ml) to give the target compound (40 mg, 51% of theory).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([NH2:10])[CH:5]=[N:6][C:7]=1[O:8][CH3:9].F[C:12]1[C:17]([C:18]2[N:23]=[C:22]([CH3:24])[N:21]=[C:20]([N:25]([CH2:35][C:36]3[CH:41]=[CH:40][C:39]([O:42][CH3:43])=[CH:38][CH:37]=3)[CH2:26][C:27]3[CH:32]=[CH:31][C:30]([O:33][CH3:34])=[CH:29][CH:28]=3)[N:19]=2)=[CH:16][C:15]([CH2:44][N:45]2[CH2:50][CH2:49][N:48]([S:51]([CH3:54])(=[O:53])=[O:52])[CH2:47][C@@H:46]2[CH3:55])=[CH:14][N:13]=1.[Li+].C[Si]([N-][Si](C)(C)C)(C)C>C1COCC1>[F:1][C:2]1[CH:3]=[C:4]([NH:10][C:12]2[C:17]([C:18]3[N:23]=[C:22]([CH3:24])[N:21]=[C:20]([N:25]([CH2:26][C:27]4[CH:28]=[CH:29][C:30]([O:33][CH3:34])=[CH:31][CH:32]=4)[CH2:35][C:36]4[CH:41]=[CH:40][C:39]([O:42][CH3:43])=[CH:38][CH:37]=4)[N:19]=3)=[CH:16][C:15]([CH2:44][N:45]3[CH2:50][CH2:49][N:48]([S:51]([CH3:54])(=[O:52])=[O:53])[CH2:47][C@@H:46]3[CH3:55])=[CH:14][N:13]=2)[CH:5]=[N:6][C:7]=1[O:8][CH3:9]
Reactant: COc1ccc(CN(Cc2ccc(OC)cc2)c2nc(C)nc(-c3cc(CN4CCN(S(C)(=O)=O)C[C@@H]4C)cnc3F)n2)cc1
Reactant: COc1ncc(N)cc1F
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: COc1ccc(CN(Cc2ccc(OC)cc2)c2nc(C)nc(-c3cc(CN4CCN(S(C)(=O)=O)C[C@@H]4C)cnc3Nc3cnc(OC)c(F)c3)n2)cc1
Reaction time: 0.5 h
Yield: 59.7 %

Procedure:
A mixture of 5-fluoro-6-methoxypyridin-3-amine (3.34 g, 23.53 mmol) and (S)-4-(2-fluoro-5-((2-methyl-4-(methylsulfonyl)piperazin-1-yl)methyl)pyridin-3-yl)-N,N-bis(4-methoxybenzyl)-6-methyl-1,3,5-triazin-2-amine (13.6 g crude from previous step) in THF (150 mL) at −10° C. was treated dropwise with LiHMDS (1.0 M in THF, Aldrich; 64.2 mL, 64.2 mmol) and the mixture was stirred for 30 min. The reaction was quenched with water and saturated NH4Cl(aq) (100 mL each) and diluted with EtOAc (50 mL). The organic layer was separated, and precipitated solids were collected by filtration. The filtered organic layer was then concentrated to minimal volume, and the precipitated brownish-yellow solid was collected by filtration and washed with a minimal amount of EtOAc. All collected solids were then combined, slurried in isopropanol, collected by filtration, and dried in vacuo to give (S)-4-(2-(5-fluoro-6-methoxypyridin-3-ylamino)-5-((2-methyl-4-(methylsulfonyl)piperazin-1-yl)methyl)pyridin-3-yl)-N,N-bis(4-methoxybenzyl)-6-methyl-1,3,5-triazin-2-amine (9.678 g, 81% over 2 steps) as a yellow solid. m/z (ESI, +ve ion) 758 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][CH:3]=1.C(OO)(=[O:12])C>>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[C:4]([OH:12])[CH:3]=1
Reactant: CC(=O)OO
Reactant: COc1ccc(C)cc1
Product: COc1ccc(C)cc1O

Procedure:
The procedure of Example 18 was repeated, except Victor Wet 35B (phosphur-containing ester) was used as a reaction catalyst and 4-methyl anisole was used in place of anisole. Consequently, the conversion of peracetic acid was 96.2%, the conversion of 4-methyl anisole was 8.02% and there was formed 4.55g of 4-methyl-2-hydroxy anisole.
Reaction SMILES: [CH3:1][C:2]1[C:7]([NH2:8])=[CH:6][CH:5]=[CH:4][C:3]=1[OH:9].C(=O)([O-])[O-].[Cs+].[Cs+].Br[CH2:17][C:18]#[N:19]>CC(CC)=O>[CH3:1][C:2]1[C:7]([NH2:8])=[CH:6][CH:5]=[CH:4][C:3]=1[O:9][CH2:17][C:18]#[N:19]
Reactant: Cc1c(N)cccc1O
Reactant: N#CCBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCC(C)=O
Product: Cc1c(N)cccc1OCC#N
Temperature: 25 °C
Reaction time: 14 h
Yield: 78.7 %

Procedure:
2-methyl-3-aminophenol (20.1 g, 0.163 mol) was dissolved in methylethylketone (MEK) (150 ml). Cesium carbonate (106 g, 0.326 mmol) was added in portions followed by dropwise addition of bromoacetonitrile (29.3 g, 0.245 mol) over 30 min. The mixture was stirred 14 hr at room temperature, then filtered through a coarse fritted funnel. The solids were washed with ethylacetate (2×100 ml) and the combined washings and filtrate were concentrated at reduced pressure to give 20.8 g (79% yield) of (2-methyl-3-aminophenoxy)acetonitrile which required no further purification.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:33])[CH2:4][CH2:5][C@H:6]([C@@H:8]1[C@:25]2([CH3:26])[C@H:11]([C@H:12]3[C@H:22]([CH2:23][C@@H:24]2[OH:27])[C@:20]2([CH3:21])[C@@H:15]([CH2:16][C@@H:17]([O:28][CH2:29][CH2:30][OH:31])[CH2:18][CH2:19]2)[CH2:14][C@H:13]3[OH:32])[CH2:10][CH2:9]1)[CH3:7].[C:34]1([CH3:44])[CH:39]=[CH:38][C:37]([S:40](Cl)(=[O:42])=[O:41])=[CH:36][CH:35]=1>C(Cl)(Cl)Cl.N1C=CC=CC=1>[CH3:1][O:2][C:3](=[O:33])[CH2:4][CH2:5][C@H:6]([C@@H:8]1[C@:25]2([CH3:26])[C@H:11]([C@H:12]3[C@H:22]([CH2:23][C@@H:24]2[OH:27])[C@:20]2([CH3:21])[C@@H:15]([CH2:16][C@@H:17]([O:28][CH2:29][CH2:30][O:31][S:40]([C:37]4[CH:38]=[CH:39][C:34]([CH3:44])=[CH:35][CH:36]=4)(=[O:42])=[O:41])[CH2:18][CH2:19]2)[CH2:14][C@H:13]3[OH:32])[CH2:10][CH2:9]1)[CH3:7]
Reactant: COC(=O)CC[C@@H](C)[C@H]1CC[C@H]2[C@@H]3[C@H](O)C[C@@H]4C[C@@H](OCCO)CC[C@]4(C)[C@H]3C[C@H](O)[C@]12C
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: c1ccncc1
Solvent: ClC(Cl)Cl
Product: COC(=O)CC[C@@H](C)[C@H]1CC[C@H]2[C@@H]3[C@H](O)C[C@@H]4C[C@@H](OCCOS(=O)(=O)c5ccc(C)cc5)CC[C@]4(C)[C@H]3C[C@H](O)[C@]12C
Reaction time: 8 h

Procedure:
The compound of Example 1B (1.50 g, 3.2 mmol) was dissolved in 15 ml of chloroform and 15 ml of pyridine; p-toluenesulfonyl chloride (920 mg, 4.83 mmol) was added, and the mixture was stirred overnight. Chloroform (250 ml) was added, the resultant solution was washed with 5% HCl solution and sat. Na2SO4. After solvent removal in vacuo, the crude product was purified by column chromatography on silica gel (40%—>60% ethyl acetate/hexanes. The yield of the title compound was 1.40 g (71%).
Reaction SMILES: N1C2C(=CC=CC=2)C=CC=1.[NH2:11][C:12]1[C:25]2[C:24](=[O:26])[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[C:17](=[O:27])[C:16]=2[CH:15]=[CH:14][CH:13]=1.[N+]([C:31]1[C:44]2[C:43](=[O:45])[C:42]3[C:37](=[CH:38][CH:39]=[CH:40][CH:41]=3)[C:36](=[O:46])[C:35]=2[CH:34]=[CH:33][CH:32]=1)([O-])=O>C(O)C>[CH:20]1[CH:19]=[C:18]2[C:17]([C:16]3[CH:15]=[CH:14][CH:13]=[C:12]([NH:11][C:34]4[C:35]5[C:36]([C:37]6[C:42]([C:43](=[O:45])[C:44]=5[CH:31]=[CH:32][CH:33]=4)=[CH:41][CH:40]=[CH:39][CH:38]=6)=[O:46])[C:25]=3[C:24](=[O:26])[C:23]2=[CH:22][CH:21]=1)=[O:27]
Reactant: O=C1c2ccccc2C(=O)c2c1cccc2[N+](=O)[O-]
Reactant: Nc1cccc2c1C(=O)c1ccccc1C2=O
Solvent: c1ccc2ncccc2c1
Solvent: CCO
Product: O=C1c2ccccc2C(=O)c2c(Nc3cccc4c3C(=O)c3ccccc3C4=O)cccc21
Temperature: 120 °C
Reaction time: 5 h

Procedure:
250 ml of quinoline, 100 g of 1-aminoanthraquinone and 25 g of CaO are warmed to 200° to 210° C. in a 1 l sulphonation beaker with an anchor stirrer and shortpath distillation bridge. 120 g of 1-nitroanthraquinone are added in portions in the course of 2 hours, and the mixture is then stirred for another 5 hours at 200° to 210° C. The mixture is allowed to cool to 120° C., and is diluted slowly and under reflux with 500 ml of ethanol. The mixture is then filtered off under suction, and the residue is washed with ethanol and dried. The dry caked filter residue is heated under reflux in 1 l of water with 100 g of ammonium chloride, and is acidified slowly through the reflux condenser with concentrated hydrochloric acid. After filtering off the mixture under suction, washing the residue until the runnings are neutral, and drying, 190.4 g of 80.4% strength 1,1'-dianthraquinonylamine are obtained.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[C:10]([C:12]([O:14][CH3:15])=[O:13])[CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].Cl[C:17](Cl)([O:19]C(=O)OC(Cl)(Cl)Cl)Cl>C1(C)C=CC=CC=1>[CH3:7][O:6][C:4](=[O:5])[C:3]1[CH:8]=[CH:9][C:10]([C:12]([O:14][CH3:15])=[O:13])=[CH:11][C:2]=1[N:1]=[C:17]=[O:19]
Reactant: COC(=O)c1ccc(C(=O)OC)c(N)c1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Solvent: Cc1ccccc1
Product: COC(=O)c1ccc(C(=O)OC)c(N=C=O)c1
Reaction time: 6 h

Procedure:
Dimethyl 2-aminoterephthalate (3.0 g, 14.34 mmol) and triphosgene (5.1 g, 17.22 mmol) were dissolved in toluene. Stirring was carried out at 110° C. for 6 hours under reflux to obtain 2-isocyanato-terephthalic acid dimethyl ester. After evaporating solvent, the compound was dissolved in 1,4-dioxane and triethylamine in vacuum state. After adding cyclohexylamine (2.5 mL, 21.5 mmol), stirring was carried out at 90° C. for 60 hours under reflux. After the reaction was completed, the produced solid was filtered with ether to obtain 1.75 g (37%) of 2-(3-cyclohexyl-ureido)-terephthalic acid dimethyl ester having a urea structure.
Reaction SMILES: [F:1][C@@H:2]([CH2:19][CH2:20][CH2:21][CH3:22])[CH2:3][CH2:4][O:5][C:6]1[CH:7]=[N:8][C:9]([C:12]2[CH:17]=[CH:16][C:15]([OH:18])=[CH:14][CH:13]=2)=[N:10][CH:11]=1.C(=O)([O-])[O-].[K+].[K+].CN(C=O)C.S(C1C=CC(C)=CC=1)(O[CH2:38][C@@H:39]([O:45][CH:46]1[CH2:51][CH2:50][CH2:49][CH2:48][O:47]1)[CH2:40][CH2:41][CH2:42][CH2:43][CH3:44])(=O)=O>O>[F:1][C@@H:2]([CH2:19][CH2:20][CH2:21][CH3:22])[CH2:3][CH2:4][O:5][C:6]1[CH:11]=[N:10][C:9]([C:12]2[CH:17]=[CH:16][C:15]([O:18][CH2:38][C@@H:39]([O:45][CH:46]3[CH2:51][CH2:50][CH2:49][CH2:48][O:47]3)[CH2:40][CH2:41][CH2:42][CH2:43][CH3:44])=[CH:14][CH:13]=2)=[N:8][CH:7]=1
Reactant: CCCCC[C@@H](COS(=O)(=O)c1ccc(C)cc1)OC1CCCCO1
Reactant: CCCC[C@H](F)CCOc1cnc(-c2ccc(O)cc2)nc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCCCC[C@@H](COc1ccc(-c2ncc(OCC[C@@H](F)CCCC)cn2)cc1)OC1CCCCO1
Yield: 110.7 %

Procedure:
In a reaction flask were charged 3.5 g of 5-[3-(S)-fluoroheptyloxy]-2-(4-hydroxyphenyl)pyrimidine synthesized in the same manner as in steps 1 to 7 of Example 1, 3.17 g of potassium carbonate, 70 ml of DMF, and 6.4 g of 2-(S)-tetrahydropyranyloxyheptyl tosylate in a nitrogen stream, and the mixture was allowed to react at 80° C. for one day. After cooling, water was added thereto, the reaction mixture was extracted with toluene, and the solvent was removed from the extract to obtain 7.6 g of a crude product. Purification by silica gel column chromatography gave 6.4 g of the titled compound.
Reaction SMILES: C([O:8][C:9]1[CH:14]=[C:13]([O:15]CC2C=CC=CC=2)[C:12]([CH:23]([CH3:25])[CH3:24])=[CH:11][C:10]=1[C:26]1[N:27]([N:32]2[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]2)[C:28](=S)[NH:29][N:30]=1)C1C=CC=CC=1.C(Cl)Cl.B(Cl)(Cl)Cl.C(=O)([O-])[OH:46].[Na+]>CO>[OH:8][C:9]1[CH:14]=[C:13]([OH:15])[C:12]([CH:23]([CH3:25])[CH3:24])=[CH:11][C:10]=1[C:26]1[N:27]([N:32]2[CH2:33][CH2:34][CH2:35][CH2:36][CH2:37]2)[C:28](=[O:46])[NH:29][N:30]=1
Reactant: O=C([O-])O
Reactant: CC(C)c1cc(-c2n[nH]c(=S)n2N2CCCCC2)c(OCc2ccccc2)cc1OCc1ccccc1
Agent: ClB(Cl)Cl
Agent: [Na+]
Solvent: CO
Solvent: ClCCl
Product: CC(C)c1cc(-c2n[nH]c(=O)n2N2CCCCC2)c(O)cc1O
Temperature: 25 °C
Reaction time: 1 h
Yield: 16.6 %

Procedure:
5-(2,4-bis-benzyloxy-5-isopropyl-phenyl)-4-piperidin-1-yl-2,4-dihydro-[1,2,4]triazol-3-thione (F67-05: 92 mg, 0.18 mmol), methylene chloride (2 mL) and a methylene chloride solution of boron trichloride (1 mol/L, 1 mL) were placed in a test tube and stirred at room temperature for 1 hour. After completing the reaction, methanol and sodium hydrogencarbonate were added to the reaction mixture and solids were separated by filtration. The mother liquor thus obtained was concentrated under reduced pressure and the residue was purified by HPLC fractionation to obtain the title compound (OH-a24 trifluoroacetate, 9.5 mg, 16.6%).
Reaction SMILES: [O-2].[O-2].[O-2].[Al+3].[Al+3].[O-2].[Ca+2].[O-2].[O-2].[O-2].[Al+3].[Al+3].[C:13]1(=[O:19])[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1>>[C:13]1([C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=2[OH:19])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: O=C1CCCCC1
Agent: [Al+3]
Agent: [Ca+2]
Agent: [O-2]
Product: Oc1ccccc1-c1ccccc1

Procedure:
The same procedure as in Example 1 is repeated except that pellets of γ-alumina-calcium oxide (85:15 in weight ratio, baked product at 600° C for 3 hours) are used in place of the γ-alumina pellets. The conversion of the cyclohexanone dimer is confirmed to be always 100% during the 2,000 hours' reaction. Table 1 gives the selectivity for o-phenylphenol measured.
Reaction SMILES: COC(=O)[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([NH:10][C:11](=[O:38])[CH2:12][N:13]2[N:19]=[C:18]([CH:20]3[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]3)[C:17]3[CH:26]=[CH:27][CH:28]=[CH:29][C:16]=3[N:15]([CH2:30][C:31](=[O:36])[C:32]([CH3:35])([CH3:34])[CH3:33])[C:14]2=[O:37])[CH:5]=1.COC(=O)C([N:45]([C:53]1C=CC=[C:55](N)[CH:54]=1)[C:46]([O:48][C:49]([CH3:52])([CH3:51])[CH3:50])=[O:47])C>>[C:49]([O:48][C:46](=[O:47])[N:45]([C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([NH:10][C:11](=[O:38])[CH2:12][N:13]2[N:19]=[C:18]([CH:20]3[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]3)[C:17]3[CH:26]=[CH:27][CH:28]=[CH:29][C:16]=3[N:15]([CH2:30][C:31](=[O:36])[C:32]([CH3:35])([CH3:33])[CH3:34])[C:14]2=[O:37])[CH:5]=1)[CH2:53][CH2:54][CH3:55])([CH3:52])([CH3:51])[CH3:50]
Reactant: COC(=O)c1cccc(NC(=O)CN2N=C(C3CCCCC3)c3ccccc3N(CC(=O)C(C)(C)C)C2=O)c1
Reactant: COC(=O)C(C)N(C(=O)OC(C)(C)C)c1cccc(N)c1
Product: CCCN(C(=O)OC(C)(C)C)c1cccc(NC(=O)CN2N=C(C3CCCCC3)c3ccccc3N(CC(=O)C(C)(C)C)C2=O)c1

Procedure:
The title compound was obtained as the hydrochloride salt by the method used in the preparation of 3-{2-[5-cyclohexyl-1-(3,3-dimethyl-2-oxo-butyl)-2-oxo-1,2-dihydro-3H-1,3,4-benzotriazepin-3-yl]-acetylamino}-benzoic acid methyl ester (Example 1) except that 2-[(3-amino-phenyl)-tert-butoxycarbonyl-amino]-propionic acid methyl ester (prepared in two steps from 3-nitro-N-tert-butoxycarbonylaniline) was used instead of 3-amino-benzoic acid methyl ester in step e, followed by reaction of the product obtained, in place of (3-{2-[5-cyclohexyl-1-(3,3-dimethyl-2-oxo-butyl)-2-oxo-1,2-dihydro-3H-1,3,4-benzotriazepin-3-yl]-acetylamino}-phenyl)-propyl-carbamic acid tert-butyl ester (Example 41, step a) according to the method of Example 41, step b. 1NMR (DMSO-d6) 9.53 (1H, s), 7.50 (2H, m), 7.25 (2H, m), 6.98 (2H, m), 6.73 (1H, d), 6.30 (1H, d), 5.00 (3H, br s), 4.79 (2H, s), 4.25 (1H, m), 3.91 (2H, m), 2.86 (1H, m), 2.00-1.00 (10H, m), 1.33 (3H, d), 1.13 (9H, s). Found: C, 60.48; H, 6.77; N, 11.18%; C31H39N5O5.HCl.H2O requires: C, 60.43; H, 6.87; N, 11.37%.
Reaction SMILES: C([O:3][C:4](=[O:30])[CH:5]([CH3:29])[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][N:11]1[C:15]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[C:14]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[N:13]=[C:12]1[CH3:28])C.[OH-].[Na+]>CO>[CH3:29][CH:5]([CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][N:11]1[C:15]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[C:14]([C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)[N:13]=[C:12]1[CH3:28])[C:4]([OH:30])=[O:3]
Reactant: CCOC(=O)C(C)CCCCCn1c(C)nc(-c2ccccc2)c1-c1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: Cc1nc(-c2ccccc2)c(-c2ccccc2)n1CCCCCC(C)C(=O)O
Temperature: 25 °C
Yield: 99.6 %

Procedure:
(Scheme 3 (P)) A solution of starting material 2-Methyl-7-(2-methyl-4,5-diphenyl-imidazol-1-yl)-heptanoic acid ethyl ester (130 mg, 0.32 mmole) in Methanol (5 ml) and Sodium Hydroxide (64 mg, 1.61 mmole) was let stirred under reflux for 18 hrs. The next day, the reaction was let cooled to room temperature and concentrated in vacuo. The residue was diluted with water, and acidified with Hydrochloric Acid (3N). The aqueous layer was extracted with Dichloromethane (3×10 ml). The organic layers were combined, dried over Sodium Sulfate and filtered. The resultant filtrate was concentrated in vacuo to afford product as a white solid (120 mg, 99%). Mass Spec: 377 (MH+).