Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[C:7]([C:22]3[CH:26]=[CH:25][S:24][CH:23]=3)[N:8]2[CH2:11][C:12]2[N:17]=[C:16]([C:18]([O:20]C)=O)[CH:15]=[CH:14][CH:13]=2)=[CH:4][C:3]=1[O:27][CH3:28].[NH3:29]>O1CCCC1>[F:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[C:7]([C:22]3[CH:26]=[CH:25][S:24][CH:23]=3)[N:8]2[CH2:11][C:12]2[N:17]=[C:16]([C:18]([NH2:29])=[O:20])[CH:15]=[CH:14][CH:13]=2)=[CH:4][C:3]=1[O:27][CH3:28]
Reactant: N
Reactant: COC(=O)c1cccc(Cn2c(-c3ccsc3)cc3cc(OC)c(F)cc32)n1
Solvent: C1CCOC1
Product: COc1cc2cc(-c3ccsc3)n(Cc3cccc(C(N)=O)n3)c2cc1F
Temperature: 25 °C
Reaction time: 6 h

Procedure:
A mixture of methyl 6-[6-fluoro-5-methoxy-2-(thiophen-3-yl)indol-1-ylmethyl]pyridine-2-carboxylate (168 mg) and ammonia (about 7 mol/L methanol solution, 4.2 mL) was stirred at room temperature for 6 hours. The reaction mixture was diluted with tetrahydrofuran (4.2 mL), followed by stirring for 66 more hours. The reaction mixture was then concentrated under reduced pressure to obtain the title compound (166 mg). 1H-NMR (CDCl3) δ ppm: 3.94 (3H, s), 5.45 (2H, s), 5.51 (1H, br s), 6.61 (1H, d, J=0.4 Hz), 6.90-7.00 (2H, m). 7.15 (1H, dd, J=1.3, 5.0 Hz), 7.18 (1H, d, J=8.3 Hz), 7.24 (1H, dd, J=1.3, 2.9 Hz), 7.39 (1H, dd, J=2.9, 5.0 Hz), 7.65 (1H, br s), 7.75 (1H, t. J=7.8 Hz), 8.09 (1H, d, J=7.8 Hz).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]([NH2:19])=[N:10][NH:11][C:12]=2[C:13]2[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=2)=[CH:4][CH:3]=1.[CH3:20][N:21]=[C:22]=[O:23]>CN(C)C1C=CN=CC=1.C(Cl)Cl>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:9]([NH:19][C:22]([NH:21][CH3:20])=[O:23])=[N:10][NH:11][C:12]=2[C:13]2[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=2)=[CH:6][CH:7]=1
Reactant: Nc1n[nH]c(-c2ccncc2)c1-c1ccc(F)cc1
Reactant: CN=C=O
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: CNC(=O)Nc1n[nH]c(-c2ccncc2)c1-c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solution of 4-(4-fluorophenyl)-5-(4-pyridinyl)-1H-pyrazol-3-amine prepared as set forth in Example 2 (100 mg, 0.38 mmol), methyl isocyanate (22 mg, 0.39 mmol) and 4-dimethylaminopyridine (2.5 mg) in methylene chloride (10 ml) was stirred at room temperature for 30 minutes. The reaction was stripped in vacuo. The residue was triturated with hexane and the solid filtered to give pure N-[4-(4-fluorophenyl)-5-(4-pyridinyl)-1H-pyrazol-3-yl]-N′-methylurea, m.p. 212–213° C.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:19])[CH:5]([O:16][CH2:17][CH3:18])[CH2:6][C:7]1[CH:15]=[CH:14][CH:13]=[C:12]2[C:8]=1[CH:9]=[CH:10][NH:11]2)[CH3:2].Cl[CH2:21][C:22]1[N:23]=[C:24]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=2[F:34])[O:25][C:26]=1[CH3:27].[H-].[Na+]>CN(C)C=O>[CH2:1]([O:3][C:4](=[O:19])[CH:5]([O:16][CH2:17][CH3:18])[CH2:6][C:7]1[CH:15]=[CH:14][CH:13]=[C:12]2[C:8]=1[CH:9]=[CH:10][N:11]2[CH2:21][C:22]1[N:23]=[C:24]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=2[F:34])[O:25][C:26]=1[CH3:27])[CH3:2]
Reactant: Cc1oc(-c2ccccc2F)nc1CCl
Reactant: CCOC(=O)C(Cc1cccc2[nH]ccc12)OCC
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)C(Cc1cccc2c1ccn2Cc1nc(-c2ccccc2F)oc1C)OCC

Procedure:
In analogy to the procedures described in examples 1 a] and 1 b], rac-2-ethoxy-3-(1H-indol-4-yl)-propionic acid ethyl ester was reacted with 4-chloromethyl-2-(2-fluoro-phenyl)-5-methyl-oxazole in N,N-dimethylformamide in the presence of sodium hydride to yield rac-2-ethoxy-3-{1-[2-(2-fluoro-phenyl)-5-methyl-oxazol-4-ylmethyl]-1H-indol-4-yl}-propionic acid ethyl ester, which was subsequently saponified to yield rac-2-ethoxy-3-{1-[2-(2-fluoro-phenyl)-5-methyl-oxazol-4-ylmethyl]-1H-indol-4-yl}-propionic acid as off-white solid.
Reaction SMILES: FC(F)(F)C(O)=O.[O:8]1[C:14]2[CH:15]=[CH:16][C:17]([C:19]3[CH:20]=[C:21]4[N:27]([C:28]([O:30][CH2:31][CH:32]([CH3:34])[CH3:33])=[O:29])[CH:26]=[N:25][C:22]4=[N:23][CH:24]=3)=[CH:18][C:13]=2[CH2:12][NH:11][CH2:10][CH2:9]1.[F:35][C:36]1[CH:37]=[C:38]([CH:42]2[CH2:47][C:46](=[O:48])[CH2:45][CH2:44][N:43]2[C:49](Cl)=[O:50])[CH:39]=[CH:40][CH:41]=1.C(N(C(C)C)CC)(C)C>CN(C)C=O.C(OCC)(=O)C>[F:35][C:36]1[CH:37]=[C:38]([CH:42]2[CH2:47][C:46](=[O:48])[CH2:45][CH2:44][N:43]2[C:49]([N:11]2[CH2:12][C:13]3[CH:18]=[C:17]([C:19]4[CH:20]=[C:21]5[N:27]([C:28]([O:30][CH2:31][CH:32]([CH3:34])[CH3:33])=[O:29])[CH:26]=[N:25][C:22]5=[N:23][CH:24]=4)[CH:16]=[CH:15][C:14]=3[O:8][CH2:9][CH2:10]2)=[O:50])[CH:39]=[CH:40][CH:41]=1
Reactant: O=C1CCN(C(=O)Cl)C(c2cccc(F)c2)C1
Reactant: CC(C)COC(=O)n1cnc2ncc(-c3ccc4c(c3)CNCCO4)cc21
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(C)COC(=O)n1cnc2ncc(-c3ccc4c(c3)CN(C(=O)N3CCC(=O)CC3c3cccc(F)c3)CCO4)cc21
Yield: 63.6 %

Procedure:
A solution of 2-methylpropyl 6-(2,3,4,5-tetrahydro-1,4-benzoxazepin-7-yl)-1H-imidazo[4,5-b]pyridine-1-carboxylate trifluoroacetic acid salt (0.20 g, 0.53 mmol), 2-(3-fluorophenyl)-4-oxopiperidine-1-carbonyl chloride (reagent preparation 37) (0.13 g, 0.51 mmol) and diisopropylethylamine (3.0 g, 23 mmol) in N,N-dimethylformamide (8 mL) was heated to 65° C. for 18 hours. The resulting mixture was diluted with ethyl acetate (50 mL) and washed with water (2×25 mL) and once with brine (15 mL) then dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by silica gel column chromatography (acetone/ethyl acetate, 1:4) to give 2-methylpropyl 6-(4-{[2-(3-fluorophenyl)-4-oxopiperidin-1-yl]carbonyl}-2,3,4,5-tetrahydro-1,4-benzoxazepin-7-yl)-1H-imidazo[4,5-b]pyridine-1-carboxylate (0.19 g, 64% yield). MS (EI) for C35H35FN5O5: 586 (MH+)
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[CH2:11][CH:12]([CH3:14])[CH3:13])[C:5]([OH:7])=O.ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C.[CH2:37]([C:39]1[C:44]([C:45](=[N:47]O)[NH2:46])=[CH:43][CH:42]=[C:41]([CH2:49][O:50][Si](C(C)C)(C(C)C)C(C)C)[N:40]=1)[CH3:38].[F-].C([N+](CCCC)(CCCC)CCCC)CCC.O1CCCC1>>[Cl:1][C:2]1[CH:3]=[C:4]([C:5]2[O:7][N:47]=[C:45]([C:44]3[CH:43]=[CH:42][C:41]([CH2:49][OH:50])=[N:40][C:39]=3[CH2:37][CH3:38])[N:46]=2)[CH:8]=[CH:9][C:10]=1[CH2:11][CH:12]([CH3:14])[CH3:13]
Reactant: CC(C)Cc1ccc(C(=O)O)cc1Cl
Reactant: CCc1nc(CO[Si](C(C)C)(C(C)C)C(C)C)ccc1C(N)=NO
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: C1CCOC1
Product: CCc1nc(CO)ccc1-c1noc(-c2ccc(CC(C)C)c(Cl)c2)n1

Procedure:
The crude product of the title compound was synthesized by conducting the similar reaction to that mentioned in Example 12 (12a) using 3-chloro-4-isobutylbenzoic acid (0.10 g, 0.48 mmol) that was obtained in Example 24 (24h), 1-hydroxybenzotriazole (69 mg, 0.51 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (97 mg, 0.51 mmol), 2-ethyl-N′-hydroxy-6-{[(triisopropylsilyl)oxy]methyl}pyridine-3-carboximidamide (0.16 g, 0.46 mmol) that was obtained in Example 25 (25b), and a 1.0 M solution of tetrabutylammonium fluoride in tetrahydrofuran (0.92 ml, 0.92 mmol). Subsequently, the crude product of the title compound thus obtained was purified by chromatography on a silica gel column using a mixed solvent of ethyl acetate and hexane (1:2) as the eluent to afford the title compound (0.15 g) in a yield of 89% as a white crystalline solid.
Reaction SMILES: Cl.[F:2][C@@:3]12[C@:16]3([CH3:17])[C:11](=[CH:12][C:13](=[O:18])[CH:14]=[CH:15]3)[C@@H:10]([F:19])[CH2:9][C@H:8]1[C@@H:7]1[CH2:20][C@@H:21]3[C@:25]([C:26](=[O:32])[CH2:27][O:28][C:29](=[O:31])[CH3:30])([C@@:6]1([CH3:33])[CH2:5][C@@H:4]2[OH:34])[CH2:24][NH:23][CH2:22]3.[CH3:35][C:36]([CH3:41])([CH3:40])[CH2:37][CH:38]=O.C(O)=O>C(#N)C>[CH3:35][C:36]([CH3:41])([CH3:40])[CH2:37][CH2:38][N:23]1[CH2:24][C@:25]2([C:26](=[O:32])[CH2:27][O:28][C:29](=[O:31])[CH3:30])[C@@H:21]([CH2:20][C@H:7]3[C@H:8]4[C@@:3]([F:2])([C@:16]5([CH3:17])[C:11]([C@@H:10]([F:19])[CH2:9]4)=[CH:12][C:13](=[O:18])[CH:14]=[CH:15]5)[C@@H:4]([OH:34])[CH2:5][C@@:6]32[CH3:33])[CH2:22]1
Reactant: CC(=O)OCC(=O)[C@@]12CNC[C@@H]1C[C@H]1[C@@H]3C[C@H](F)C4=CC(=O)C=C[C@]4(C)[C@@]3(F)[C@@H](O)C[C@@]12C
Reactant: CC(C)(C)CC=O
Agent: Cl
Solvent: O=CO
Solvent: CC#N
Product: CC(=O)OCC(=O)[C@@]12CN(CCC(C)(C)C)C[C@@H]1C[C@H]1[C@@H]3C[C@H](F)C4=CC(=O)C=C[C@]4(C)[C@@]3(F)[C@@H](O)C[C@@]12C
Yield: 73.1 %

Procedure:
A solution of compound 20 (900 mg, 1.800 mmol), 3,3-dimethylbutyraldehyde (904 μl, 7.20 mmol), formic acid (552 μl, 14.40 mmol) and TEA (251 μl, 1.800 mmol) in acetonitrile (45 ml) is irradiated with microwaves (140° C., 15 minutes). The reaction is partitioned between AcOEt and NaHCO3 solution. The organic layers are then washed with brine, dried over Na2SO4 and filtered. The solvent is evaporated to give a oil which is purified by silica gel chromatography (from DCM:MeOH 100:0 to 98.5:1.5) to give the title compound (721 mg, 1.316 mmol, 73.1% yield).
Reaction SMILES: [CH2:1]([N:3]1[C:12]2[C:7](=[C:8]([OH:14])[C:9]([OH:13])=[CH:10][CH:11]=2)[C:6](=[O:15])[C:5]([C:16]([O:18][CH2:19][CH3:20])=[O:17])=[CH:4]1)[CH3:2].C(=O)([O-])[O-].[K+].[K+].[CH3:27][O:28][C:29]1[CH:36]=[CH:35][C:32]([CH2:33]Cl)=[CH:31][CH:30]=1>CC(C)=O>[CH2:1]([N:3]1[C:12]2[C:7](=[C:8]([OH:14])[C:9]([O:13][CH2:33][C:32]3[CH:35]=[CH:36][C:29]([O:28][CH3:27])=[CH:30][CH:31]=3)=[CH:10][CH:11]=2)[C:6](=[O:15])[C:5]([C:16]([O:18][CH2:19][CH3:20])=[O:17])=[CH:4]1)[CH3:2]
Reactant: COc1ccc(CCl)cc1
Reactant: CCOC(=O)c1cn(CC)c2ccc(O)c(O)c2c1=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCOC(=O)c1cn(CC)c2ccc(OCc3ccc(OC)cc3)c(O)c2c1=O
Yield: 20.9 %

Procedure:
To a suspension of ethyl 1-ethyl-5,6-dihydroxy-4-oxo-1,4-dihydroquinoline-3-carboxylate (5 g, 18.03 mmol) and potassium carbonate (8.72 g, 63.1 mmol) in Acetone (120 mL) at r.t. was added 4-methoxybenzyl chloride (7.37 mL, 54.1 mmol) and KI (0.599 g, 3.61 mmol). The mixture was heated under reflux for 2 days. After cooling, the reaction mixture was filtered and the filtrate was concentrated. The residue was partitioned between DCM and water, and the organic layer was washed with sat. NaHCO3 and brine, dried over Na2SO4 and concentrated. The crude product was purified by normal phase automatic silica column chromatography (Combiflash RF), eluting with EtOAc/hexanes (0-100%) to afford ethyl 1-ethyl-5-hydroxy-6-((4-methoxybenzyl)oxy)-4-oxo-1,4-dihydroquinoline-3-carboxylate (1.5 g, 3.77 mmol, 20.9% yield) as a light yellow solid that contained some PMB-ester. LCMS: (M+H)+: 398.3.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([C:8]2[CH:13]=[C:12]([C:14]([F:17])([F:16])[F:15])[CH:11]=[CH:10][C:9]=2[C:18]2[CH:27]=[CH:26][CH:25]=[C:24]3[C:19]=2[CH2:20][CH2:21][N:22](C(OC(C)(C)C)=O)[CH2:23]3)[CH2:4][CH2:3]1.Cl.O1CCOCC1>C1COCC1>[CH3:1][N:2]1[CH2:7][CH2:6][N:5]([C:8]2[CH:13]=[C:12]([C:14]([F:16])([F:15])[F:17])[CH:11]=[CH:10][C:9]=2[C:18]2[CH:27]=[CH:26][CH:25]=[C:24]3[C:19]=2[CH2:20][CH2:21][NH:22][CH2:23]3)[CH2:4][CH2:3]1
Reactant: CN1CCN(c2cc(C(F)(F)F)ccc2-c2cccc3c2CCN(C(=O)OC(C)(C)C)C3)CC1
Agent: Cl
Solvent: C1CCOC1
Solvent: C1COCCO1
Product: CN1CCN(c2cc(C(F)(F)F)ccc2-c2cccc3c2CCNC3)CC1
Yield: 77.9 %

Procedure:
A solution of tert-butyl 5-(2-(4-methylpiperazin-1-yl)-4-(trifluoromethyl)phenyl)-3,4-dihydroisoquinoline-2(1H)-carboxylate (1.680 g, 3.53 mmol) in 4 mL THF was treated with HCl 4N in dioxane (8.83 ml, 35.3 mmol) and was heated to reflux with a heat gun. The reaction mixture was allowed to stir for an additional hour then the reaction mixture was concentrated. Purification of the resulting residue by reverse phase column chromatography [RediSep Gold C18 150 g, 5-100% (0.1% NH4OH in MeOH)/(0.1% NH4OH in water)] gave 5-(2-(4-methylpiperazin-1-yl)-4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydroisoquinoline (1.031 g, 2.75 mmol,) as a light yellow solid.
Reaction SMILES: FC(F)(F)C(O)=O.[CH3:8][C@@:9]1([C:42]([F:45])([F:44])[F:43])[CH2:24][N:12]2[C:13](=[O:23])[CH:14]=[C:15]([N:17]3[CH2:22][CH2:21][O:20][CH2:19][CH2:18]3)[N:16]=[C:11]2[N:10]1[CH2:25][C:26]1[C:34]2[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=2)[N:28](C(OC(C)(C)C)=O)[CH:27]=1>C(Cl)Cl>[NH:28]1[C:29]2[C:34](=[CH:33][CH:32]=[CH:31][CH:30]=2)[C:26]([CH2:25][N:10]2[C:11]3=[N:16][C:15]([N:17]4[CH2:18][CH2:19][O:20][CH2:21][CH2:22]4)=[CH:14][C:13](=[O:23])[N:12]3[CH2:24][C@@:9]2([CH3:8])[C:42]([F:44])([F:45])[F:43])=[CH:27]1
Reactant: CC(C)(C)OC(=O)n1cc(CN2c3nc(N4CCOCC4)cc(=O)n3C[C@@]2(C)C(F)(F)F)c2ccccc21
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: C[C@@]1(C(F)(F)F)Cn2c(nc(N3CCOCC3)cc2=O)N1Cc1c[nH]c2ccccc12
Reaction time: 8 h
Yield: 46.2 %

Procedure:
1 ml of trifluoroacetic acid is added to a solution of 200 mg of 2-methylpropan-2-yl 3-{[(2S)-2-methyl-7-(morpholin-4-yl)-5-oxo-2-(trifluoromethyl)-2,3-dihydroimidazo[1,2-a]pyrimidin-1(5H)-yl]methyl}-1H-indole-1-carboxylate in 3 ml of methylene chloride. After an overnight period at a temperature in the region of 20° C., the reaction mixture is concentrated to dryness under reduced pressure. After purification by preparative LC MS (method D), the acetonitrile is concentrated and then the aqueous phase is extracted with ethyl acetate. The organic phase is successively washed with a saturated aqueous solution of sodium bicarbonate, twice with water and once with a saturated aqueous solution of sodium chloride. The resulting organic phase is dried over anhydrous magnesium sulphate, filtered and then concentrated to dryness under reduced pressure. The residue it taken up with water and then lyophilized. 75 mg of (2S)-1-(1H-indol-3-ylmethyl)-2-methyl-7-(morpholin-4-yl)-2-(trifluoromethyl)-2,3-dihydroimidazo[1,2-a]pyrimidin-5(1H)one are thus obtained in the form of a pinkish-coloured lyophilisate, the characteristics of which are the following:
Reaction SMILES: [C:1]([C:5]1[C:10]([OH:11])=[C:9]([C:12]([CH3:15])([CH3:14])[CH3:13])[CH:8]=[C:7]([CH3:16])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[Cl:17][P:18](Cl)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>C(N(CC)CC)C>[C:19]1([P:18]([Cl:17])[O:11][C:10]2[C:5]([C:1]([CH3:4])([CH3:3])[CH3:2])=[CH:6][C:7]([CH3:16])=[CH:8][C:9]=2[C:12]([CH3:15])([CH3:14])[CH3:13])[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: Cc1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1
Reactant: ClP(Cl)c1ccccc1
Solvent: CCN(CC)CC
Product: Cc1cc(C(C)(C)C)c(OP(Cl)c2ccccc2)c(C(C)(C)C)c1

Procedure:
To a solution of 110 grams of 2,6-di-tert-butyl-p-cresol in 252 grams of triethylamine was added at 25°-26° C. over a 15-minute period 89.5 grams of dichlorophenylphosphine. The reaction mixture was heated for 31 hours at 95°-97° C. The excess triethylamine solvent was then removed by distillation under vacuum, the resulting residue was triturated with 200 ml of dry benzene, and the white crystalline solid triethylamine hydrochloride was separated by filtration. The desired product named above was isolated from the filtrate by distillation of the benzene under vacuum and crystallization of the residue from acetonitrile. The product was obtained as white crystals melting at 103°-106° C.
Reaction SMILES: [H-].[Na+].[OH:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:15]=[CH:14][C:13]([OH:16])=[CH:12][CH:11]=2)=[CH:6][CH:5]=1.FC(F)(F)S(O[CH2:23][CH2:24][C:25]([F:37])([F:36])[C:26]([F:35])([F:34])[C:27]([F:33])([F:32])[C:28]([F:31])([F:30])[F:29])(=O)=O.Cl>C(COC)OC>[OH:3][C:4]1[CH:5]=[CH:6][C:7]([C:10]2[CH:15]=[CH:14][C:13]([O:16][CH2:23][CH2:24][C:25]([F:36])([F:37])[C:26]([F:34])([F:35])[C:27]([F:32])([F:33])[C:28]([F:31])([F:30])[F:29])=[CH:12][CH:11]=2)=[CH:8][CH:9]=1
Reactant: O=S(=O)(OCCC(F)(F)C(F)(F)C(F)(F)C(F)(F)F)C(F)(F)F
Reactant: Oc1ccc(-c2ccc(O)cc2)cc1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: COCCOC
Product: Oc1ccc(-c2ccc(OCCC(F)(F)C(F)(F)C(F)(F)C(F)(F)F)cc2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 27.2 %

Procedure:
In a Schlenk tube whose content had been replaced with Ar, 9.0 g of 60% sodium hydride and 400 ml of dry dimethoxyethane were placed. While this solution was being cooled with ice water, 29.8 g of 4,4'-dihydroxybiphenyl was added. Thereafter, the reaction solution was allowed to warm up to room temperature, and was stirred for two hours. Thereafter, the reaction solution was cooled to -60° C. After 86 g of 2-(perfluorobutyl)ethyl trifluoromethane sulfonate was added dropwise to the reaction solution, the reaction solution was allowed to warm up to room temperature, and was stirred overnight. Subsequently, the reaction solution was poured into dilute hydrochloric acid, and an organic layer was extracted with benzene. After the benzene layer was washed with water and dried over sodium sulfate anhydrous, the solvent was distilled away. The residue was purified by silica gel column chromatography (eluent: benzene), and recrystallized from toluene to give 18.8 g of 4-hydroxy-4'-[2-(perfluorobutyl)ethyloxy]biphenyl (Y: 27.1%). The purity of the compound thus obtained was 98.4% by GC.
Reaction SMILES: C1C(=O)N([Br:8])C(=O)C1.[C:9]([C:13]1[CH:35]=[CH:34][C:16]2[C:17]3[N:25]([C:26]([C:28]([CH3:31])([CH3:30])[CH3:29])=[CH:27][C:15]=2[N:14]=1)[C:24]1[C:19](=[CH:20][C:21]([CH3:33])=[C:22]([CH3:32])[CH:23]=1)[N:18]=3)([CH3:12])([CH3:11])[CH3:10]>CN(C=O)C>[Br:8][C:20]1[C:21]([CH3:33])=[C:22]([CH3:32])[CH:23]=[C:24]2[C:19]=1[N:18]=[C:17]1[N:25]2[C:26]([C:28]([CH3:29])([CH3:31])[CH3:30])=[CH:27][C:15]2[N:14]=[C:13]([C:9]([CH3:12])([CH3:10])[CH3:11])[CH:35]=[CH:34][C:16]=21
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1cc2nc3c4ccc(C(C)(C)C)nc4cc(C(C)(C)C)n3c2cc1C
Solvent: CN(C)C=O
Product: Cc1cc2c(nc3c4ccc(C(C)(C)C)nc4cc(C(C)(C)C)n23)c(Br)c1C
Reaction time: 6 h

Procedure:
19.6 g (110 mmol) of NBS are added in portions to a solution, warmed to 100° C., of 36.0 g (100 mmol) of 3,6-di-tert-butyl-8,9-dimethyl-4,6a,11-triazabenzo[a]fluorene, L111, in 300 ml of DMF, and the mixture is subsequently stirred for a further 6 h. The reaction mixture is evaporated to about 150 ml in vacuo, stirred for a further 2 h, the precipitated crystals are filtered off with suction and finally washed twice with 50 ml of methanol each time. Yield: 33.8 g (77 mmol), 77%. Purity: 97% according to 1H-NMR.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6](=[O:26])[N:7]([CH3:25])[C:8]([C:12]3[CH:24]=[CH:23][C:15]([CH2:16][P:17](=[O:22])([O-])[O:18][CH2:19][CH3:20])=[CH:14][CH:13]=3)=[N:9]2)=[CH:4][CH:3]=1.S(Cl)(Cl)=O.[CH2:31]([NH2:38])[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1.C1CCN2C(=NCCC2)CC1>ClCCl.CN(C=O)C>[Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6](=[O:26])[N:7]([CH3:25])[C:8]([C:12]3[CH:13]=[CH:14][C:15]([CH2:16][P:17]([NH:38][CH2:31][C:32]4[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=4)(=[O:22])[O:18][CH2:19][CH3:20])=[CH:23][CH:24]=3)=[N:9]2)=[CH:4][CH:3]=1
Reactant: NCc1ccccc1
Reactant: CCOP(=O)([O-])Cc1ccc(-c2nc3cc(Cl)ccc3c(=O)n2C)cc1
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: C1CCC2=NCCCN2CC1
Product: CCOP(=O)(Cc1ccc(-c2nc3cc(Cl)ccc3c(=O)n2C)cc1)NCc1ccccc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
The compound obtained in Example 61 (0.50 g), 1 ml of DMF and 0.15 g of thionyl chloride were suspended in 10 ml of dichloromethane and refluxed for 3 hours. After completion of the reaction, the reaction mixture was allowed to cool, 10 ml of dichloromethane containing 0.14 g of benzylamine and 0.58 g of DBU was added dropwise, and the mixture was stirred at room temperature for 18 hours. After the reaction, the organic layer was washed with diluted hydrochloric acid, distilled water and saturated brine in this order, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue thus obtained was purified by silica gel column chromatography (eluent: dichloromethane: methanol=30:1) and recrystallized from ethyl acetate-n-hexane to provide 0.28 g of the desired compound as colorless crystals. Table 3 shows the chemical structure and physical property (melting point) of the compound obtained.
Reaction SMILES: [OH:1][CH:2]1[CH:7]([C:8]2[CH:13]=[CH:12][C:11]([O:14][CH2:15][CH2:16][CH2:17][O:18][CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[O:26][CH3:27])=[CH:10][CH:9]=2)[CH2:6][CH2:5][N:4]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH2:3]1.[Br:35][C:36]1[CH:41]=[CH:40][C:39]([CH2:42]Br)=[CH:38][C:37]=1[O:44][CH2:45][CH2:46][CH2:47][O:48][CH3:49]>>[Br:35][C:36]1[CH:41]=[CH:40][C:39]([CH2:42][O:1][CH:2]2[CH:7]([C:8]3[CH:13]=[CH:12][C:11]([O:14][CH2:15][CH2:16][CH2:17][O:18][CH2:19][C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=4[O:26][CH3:27])=[CH:10][CH:9]=3)[CH2:6][CH2:5][N:4]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH2:3]2)=[CH:38][C:37]=1[O:44][CH2:45][CH2:46][CH2:47][O:48][CH3:49]
Reactant: COCCCOc1cc(CBr)ccc1Br
Reactant: COc1ccccc1COCCCOc1ccc(C2CCN(C(=O)OC(C)(C)C)CC2O)cc1
Product: COCCCOc1cc(COC2CN(C(=O)OC(C)(C)C)CCC2c2ccc(OCCCOCc3ccccc3OC)cc2)ccc1Br

Procedure:
Analogously to Method D, 3:35 g of tert-butyl 3-hydroxy-4-{4-[3-(2-methoxybenzyloxy)-propoxy]phenyl}piperidine-1-carboxylate and 3.17 g of 1-bromo-4-bromomethyl-2-(3-methoxypropoxy)benzene (Example 79c) are used to obtain the title compound as a slightly yellowish oil. Rf=0.35 (1:1 EtOAc-heptane); Rt=6.42.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:25]=[CH:26][C:27]=1[O:28][CH2:29][O:30][CH3:31])/[CH:6]=[CH:7]/[C:8]1[NH:16][C:15]2[C:14](=[O:17])[N:13]([CH2:18][CH2:19][CH3:20])[C:12](=[O:21])[N:11]([CH2:22][CH2:23][CH3:24])[C:10]=2[N:9]=1.[C:32](=O)([O-])[O-].[K+].[K+].CI.O>CN(C)C=O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:25]=[CH:26][C:27]=1[O:28][CH2:29][O:30][CH3:31])/[CH:6]=[CH:7]/[C:8]1[N:16]([CH3:32])[C:15]2[C:14](=[O:17])[N:13]([CH2:18][CH2:19][CH3:20])[C:12](=[O:21])[N:11]([CH2:22][CH2:23][CH3:24])[C:10]=2[N:9]=1
Reactant: CCCn1c(=O)c2[nH]c(/C=C/c3ccc(OCOC)c(OC)c3)nc2n(CCC)c1=O
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CI
Product: CCCn1c(=O)c2c(nc(/C=C/c3ccc(OCOC)c(OC)c3)n2C)n(CCC)c1=O
Temperature: 50 °C
Reaction time: 1 h
Yield: 78.8 %

Procedure:
Compound c (4.5 g, 10.5 mmol) obtained in Reference Example 3 was dissolved in 90 ml of dimethylformamide, and potassium carbonate (3.63 g, 26.26 mmol) and methyl iodide (1.31 ml, 21.04 mmol) were added thereto, followed by stirring at 50° C. for 1 hour. After cooling, water was added to the reaction mixture, and the resulting precipitate was collected by filtration. The obtained crude product was recrystallized from hexane/ethyl acetate to give 3.66 g (79% yield) of Compound d as pale yellow crystals.
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]1[C:9]([C:10]([CH3:13])([CH3:12])[CH3:11])=[CH:8][C:7]([C:14]([CH3:17])([CH3:16])[CH3:15])=[CH:6][C:5]=1[OH:18].C([O-])(O)=O.[Na+].[CH2:24](I)[CH:25]=[CH2:26]>C(Cl)Cl>[C:10]([C:9]1[C:4]([CH2:3][NH:2][CH2:26][CH:25]=[CH2:24])=[C:5]([OH:18])[CH:6]=[C:7]([C:14]([CH3:17])([CH3:16])[CH3:15])[CH:8]=1)([CH3:11])([CH3:12])[CH3:13]
Reactant: C=CCI
Reactant: CC(C)(C)c1cc(O)c(CN)c(C(C)(C)C)c1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: C=CCNCc1c(O)cc(C(C)(C)C)cc1C(C)(C)C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To 0.705 g (2.99 mmol) of the product of Example 19 in 15 mL of CH2Cl2 was added 1 g of solid NaHCO3 followed by 0.525 g (3.12 mmol) of allyl iodide. The reaction mixture was stirred overnight at room temperature, then filtered and evaporated in vacuo. The residue was purified on a silica gel flash chromatography column eluted with 0-1% MeOH in CH2Cl2. Evaporation of the purified fractions and drying in vacuo afforded the title compound.
Reaction SMILES: [F:1][C:2]1[C:3]([CH3:11])=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([OH:7])=[O:6].B(F)(F)F.[CH3:16]COCC>CO>[CH3:16][O:6][C:5](=[O:7])[C:4]1[CH:8]=[CH:9][CH:10]=[C:2]([F:1])[C:3]=1[CH3:11]
Reactant: Cc1c(F)cccc1C(=O)O
Reactant: CCOCC
Agent: FB(F)F
Solvent: CO
Product: COC(=O)c1cccc(F)c1C
Temperature: 25 °C
Yield: 87 %

Procedure:
A solution of 3-fluoro-2-methyl-benzoic acid (Aldrich, 10.2 g, 66.17 mmol) in methanol (135 mL) at room temperature was treated with boron trifluoride etherate (15 mL) and was allowed to stir at room temperature. The reaction mixture was then concentrated in vacuo to remove the methanol and then diethyl ether (˜300 mL) was added. The solution was transferred to a separatory funnel and washed with water (200 mL) and a 5% aqueous sodium bicarbonate solution to pH>7.5. The organic layer was then dried over magnesium sulfate and concentrated in vacuo to afford 3-fluoro-2-methyl-benzoic acid methyl ester (9.74 g, 87%) as a light orange colored oil which was used without purification.