Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC(=O)[NH:7][CH2:8][CH2:9][N:10]([C:21](=[O:24])[CH2:22]Br)[CH2:11][CH2:12][C:13]1[CH:18]=[CH:17][C:16]([F:19])=[C:15]([F:20])[CH:14]=1)(C)(C)C.FC(F)(F)C(O)=O.C(Cl)Cl.C([O-])([O-])=O.[K+].[K+]>CCO>[F:20][C:15]1[CH:14]=[C:13]([CH2:12][CH2:11][N:10]2[CH2:9][CH2:8][NH:7][CH2:22][C:21]2=[O:24])[CH:18]=[CH:17][C:16]=1[F:19]
Reactant: CC(C)(C)OC(=O)NCCN(CCc1ccc(F)c(F)c1)C(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Solvent: CCO
Product: O=C1CNCCN1CCc1ccc(F)c(F)c1
Yield: 91.6 %

Procedure:
In the same way as that described in Example 2, Step 3 using 2-[(bromoacetyl)(2-(3,4-difluorophenyl)ethyl)amino]ethyl carbamic acid tert-butyl ester (549 mg, 1.3 mmol), trifluoroacetic acid (2.5 mL) and CH2Cl2 (25 mL), followed by K2CO3 (0.36 g, 2.6 mmol) and EtOH (50 mL). The piperazinone (286 mg, 91%) was isolated as a yellow oil. 1H NMR (250 MHz, CDCl3) δ 2.85 (2H, t, J=7.3Hz), 2.99-3.03 (2H, m), 3.17-3.21 (2H, m), 3.52 (2H, s), 3.56 (2H, t, J=7.3Hz), 6.90-7.16 (3H, m). MS (ES+) (241, M+1).
Reaction SMILES: Cl.[O:2]1[C:6]2[CH:7]=[CH:8][C:9]([C:11]3[N:12]=[C:13]([C:22]4[CH:30]=[CH:29][C:25]([C:26](Cl)=[O:27])=[CH:24][CH:23]=4)[NH:14][C:15]=3[C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=3)=[CH:10][C:5]=2[O:4][CH2:3]1.[NH3:31]>O1CCCC1>[O:2]1[C:6]2[CH:7]=[CH:8][C:9]([C:11]3[N:12]=[C:13]([C:22]4[CH:30]=[CH:29][C:25]([C:26]([NH2:31])=[O:27])=[CH:24][CH:23]=4)[NH:14][C:15]=3[C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=3)=[CH:10][C:5]=2[O:4][CH2:3]1
Reactant: N
Reactant: O=C(Cl)c1ccc(-c2nc(-c3ccc4c(c3)OCO4)c(-c3ccccn3)[nH]2)cc1
Agent: Cl
Solvent: C1CCOC1
Product: NC(=O)c1ccc(-c2nc(-c3ccc4c(c3)OCO4)c(-c3ccccn3)[nH]2)cc1
Temperature: 25 °C
Yield: 48 %

Procedure:
4-(4-Benzo[1,3]dioxol-5-yl-5-pyridin-2-yl-1H-imidazol-2-yl)benzoyl chloride hydrochloride (100 mg; 0.23 mmol) was suspended in tetrahydrofuran (5 ml) and treated with 0.88 aq. ammonia solution (1 ml) and the resulting mixture stirred at ambient temperature. The title compound (42 mg; 48%) was obtained as a brown powder and collected by filtration, washed with water and dried at 40° C. under reduced pressure. 1H NMR (250 MHz, CDCl3) δ: 5.50-6.40 (2H, br, exchangeable), 6.03 (2H, s), 6.90 (1H, d, J=8 Hz), 7.15 (3H, m), 7.55 (2H, brm), 7.89 (2H, d, J=8 Hz), 8.06 (2H, d, J=8 Hz), 8.54 (1H, brd); (ESMS) (M+H)+=385.4.
Reaction SMILES: [H-].[Na+].[NH2:3][C:4]1[S:5][C:6]([S:9][CH2:10][CH2:11][CH2:12][N:13]2[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]2)=[N:7][N:8]=1.[CH2:19]([O:29][C:30]1[CH:38]=[CH:37][C:33]([C:34](O)=[O:35])=[CH:32][CH:31]=1)/[CH:20]=[C:21](/[CH2:23][CH2:24][CH:25]=[C:26]([CH3:28])[CH3:27])\[CH3:22].C(N1C=CN=C1)(N1C=CN=C1)=O>O1CCCC1>[CH2:19]([O:29][C:30]1[CH:31]=[CH:32][C:33]([C:34]([NH:3][C:4]2[S:5][C:6]([S:9][CH2:10][CH2:11][CH2:12][N:13]3[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]3)=[N:7][N:8]=2)=[O:35])=[CH:37][CH:38]=1)/[CH:20]=[C:21](/[CH2:23][CH2:24][CH:25]=[C:26]([CH3:28])[CH3:27])\[CH3:22]
Reactant: Nc1nnc(SCCCN2CCCCC2)s1
Reactant: CC(C)=CCC/C(C)=C/COc1ccc(C(=O)O)cc1
Agent: O=C(n1ccnc1)n1ccnc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)=CCC/C(C)=C/COc1ccc(C(=O)Nc2nnc(SCCCN3CCCCC3)s2)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 70 %

Procedure:
Sodium hydride (0.4 g) and 2-amino-5-piperidinopropylthio-1,3,4-thiadiazole (1.6 g) were stirred in tetrahydrofuran (30 ml) for 30 minutes while being cooled with ice. 4-Geranyloxybenzoic acid (1.6 g) and carbonyldiimidazole (1.1 g) were stirred in tetrahydrofuran (30 ml) for 30 minutes at room temperature and the mixture was added to the former reaction mixture. The mixture was stirred for 4 hours at room temperature, and then concentrated under a vacuum. The residue, with water added thereto, was extracted with ethyl acetate. The extract was dried over sodium sulfate anhydride, and then concentrated under a vacuum. The residue was purified by silica gel column chromatography (chloroform:methanol=10:1). The resulting solid was recrystallized from n-hexane/ethanol, hereby yielding 2.1 g of the aimed compound.
Reaction SMILES: [Cl:1][C:2]1[N:6]([C:7]2[CH:12]=[CH:11][C:10]([C:13]#[N:14])=[CH:9][CH:8]=2)[C:5]([CH3:15])=[N:4][C:3]=1[CH:16]=[O:17].O.C1(C)C=CC(S(O)(=O)=O)=CC=1.[CH2:30](O)[CH2:31][OH:32]>ClCCl>[Cl:1][C:2]1[N:6]([C:7]2[CH:8]=[CH:9][C:10]([C:13]#[N:14])=[CH:11][CH:12]=2)[C:5]([CH3:15])=[N:4][C:3]=1[CH:16]1[O:32][CH2:31][CH2:30][O:17]1
Reactant: OCCO
Reactant: Cc1nc(C=O)c(Cl)n1-c1ccc(C#N)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: ClCCl
Solvent: O
Product: Cc1nc(C2OCCO2)c(Cl)n1-c1ccc(C#N)cc1
Reaction time: 70 h

Procedure:
A stirred solution of the aldehyde from (c) (0.24 g, lmmol) and 4-toluenesulphonic acid hydrate (0.21 g, 1.1 mmol) and ethane-1,2-diol (0.5 ml, 8 mmol) in dichloromethane (8 ml) was heated at reflux through a Dean-Stark trap containing 4A molecular sieves for 6 hours. After standing at 25° C. for 70 hours the mixture was washed with aqueous sodium bicarbonate and evaporated to a yellow solid.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH2:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]([CH3:21])([CH3:20])[CH3:19])=[CH:14][CH:13]=1)[CH:6]=[CH:5]2.[Cl:22][C:23]1[CH:28]=[CH:27][C:26](B(O)O)=[CH:25][CH:24]=1>>[C:18]([C:15]1[CH:14]=[CH:13][C:12]([CH2:11][N:7]2[C:8]3[C:4](=[CH:3][C:2]([C:26]4[CH:27]=[CH:28][C:23]([Cl:22])=[CH:24][CH:25]=4)=[CH:10][CH:9]=3)[CH:5]=[CH:6]2)=[CH:17][CH:16]=1)([CH3:21])([CH3:20])[CH3:19]
Reactant: OB(O)c1ccc(Cl)cc1
Reactant: CC(C)(C)c1ccc(Cn2ccc3cc(Br)ccc32)cc1
Product: CC(C)(C)c1ccc(Cn2ccc3cc(-c4ccc(Cl)cc4)ccc32)cc1

Procedure:
The title compound was prepared from 5-bromo-1-[4-(tert-butyl)benzyl]-1H-indole (Step 1 of Example 34) and 4-chlorophenylboronic acid in substantially the same manner, as described in Step 2 of Example 25. The product was obtained as an oil. Mass spectrum (ESI, [M+H]+) m/z 374. 1HNMR (400 MHz, DMSO-d6): δ 7.82 (d, 1H, J=1.52 Hz), 7.66 (d, 2H, J=8.55 Hz), 7.55-7.53 (m, 2H), 7.46 (d, 2H, J=8.55 Hz), 7.39 (d, 1H, J=8.56 Hz), 7.31 (d, 2H, J=8.40 Hz), 7.13 (d, 2H, J=8.24 Hz), 6.53 (d, 1H, J=3.05 Hz), 5.39 (s, 2H), and 1.21 ppm (s, 9H).
Reaction SMILES: [Si]([O:8][C@@H:9]1[C@@H:13]([CH2:14][O:15][S:16](=[O:28])(=[O:27])[NH:17][C:18](=[O:26])[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=2[OH:25])[O:12][C@@H:11]([N:29]2[C:38]3[N:37]=[CH:36][N:35]=[C:33]([NH2:34])[C:32]=3[N:31]=[CH:30]2)[CH2:10]1)(C(C)(C)C)(C)C.CC[CH2:41][CH2:42][N+:43](CCCC)([CH2:48][CH2:49]CC)[CH2:44][CH2:45]CC.[F-]>C1COCC1>[CH2:42]([NH+:43]([CH2:48][CH3:49])[CH2:44][CH3:45])[CH3:41].[OH:25][C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=1[C:18]([NH:17][S:16]([O:15][CH2:14][C@H:13]1[O:12][C@@H:11]([N:29]2[C:38]3[N:37]=[CH:36][N:35]=[C:33]([NH2:34])[C:32]=3[N:31]=[CH:30]2)[CH2:10][C@@H:9]1[OH:8])(=[O:27])=[O:28])=[O:26]
Reactant: CC(C)(C)[Si](C)(C)O[C@H]1C[C@H](n2cnc3c(N)ncnc32)O[C@@H]1COS(=O)(=O)NC(=O)c1ccccc1O
Reactant: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: CC[NH+](CC)CC
Product: Nc1ncnc2c1ncn2[C@H]1C[C@H](O)[C@@H](COS(=O)(=O)NC(=O)c2ccccc2O)O1
Temperature: 25 °C
Reaction time: 3 h
Yield: 50 %

Procedure:
To a solution of 3′-O-tert-butyldimethylsilyl-2′-deoxy-5′-O—[N-(2-hydroxybenzoyl)sulfamoyl]-adenosine (10.5 mg, 0.018 mmol, 1.0 equiv) in THF (2.0 mL) was added TBAF (1.0 M solution in THF, 0.1 mL, 6.0 equiv) and the solution stirred 3 hours at room temperature. The reaction mixture was concentrated and purification of the residue by flash chromatography (65:35:1 EtOAc/MeOH/Et3N) afforded the title compound (5.1 mg, 50%): Rf 0.15 (3:1 EtOAc/MeOH); [α]20D −99 (c 0.25, CH3OH) 1H NMR (600 MHz, CD3OD) δ 1.29 (t, J=7.2 Hz, 9H), 2.44 (ddd, J=13.8, 5.4, 2.4 Hz, 1H), 2.70-2.90 (m, 1H), 3.18 (q, J=7.2 Hz, 6H), 4.24 (s, 1H), 4.32 (dd, J=11.4, 3.6 Hz, 1H), 4.35 (dd, J=10.8, 3.6 Hz, 1H), 4.62-4.70 (m, 1H), 6.50 (t, J=6.6 Hz, 1H), 6.75-6.84 (m, 2H), 7.29 (t, J=7.8 Hz, 1H), 7.93 (d, J=7.8 Hz, 1H), 8.16 (s, 1H), 8.50 (s, 1H); 13C NMR (150 MHz, CD3OD) δ 9.4, 41.6, 48.1, 70.0, 73.5, 85.9, 87.0, 118.0, 119.4, 120.3, 120.8, 131.5, 134.5, 141.3, 150.6, 153.9, 157.4, 162.2, 175.1; HRMS (ESI+) calcd for C17H19N6O7S [M+H]+ 451.1030, found 451.1014 (error 3.5 ppm).
Reaction SMILES: Br.[NH2:2][C:3]1[S:4][C:5]([C:9](=O)[CH2:10]Br)=[C:6]([CH3:8])[N:7]=1.[NH2:13][C:14]1[N:19]=[CH:18][CH:17]=[CH:16][N:15]=1.C(N(CC)CC)C>C(O)C>[NH2:2][C:3]1[S:4][C:5]([C:9]2[N:13]=[C:14]3[N:19]=[CH:18][CH:17]=[CH:16][N:15]3[CH:10]=2)=[C:6]([CH3:8])[N:7]=1
Reactant: Nc1ncccn1
Reactant: Cc1nc(N)sc1C(=O)CBr
Agent: Br
Solvent: CCN(CC)CC
Solvent: CCO
Product: Cc1nc(N)sc1-c1cn2cccnc2n1
Yield: 15.2 %

Procedure:
A solution of 2-amino-4-methyl-5-(2-bromoacetyl)thiazole hydrobromide (7.2 g), 2-aminopyrimidine (3.8 g) and triethylamine (11 ml) in ethanol (200 ml) was refluxed for 8 hours and the reaction mixture was evaporated in vacuo. To the residue was added water and the resulting mixture was acidified to pH 1.0 with 10% hydrochloric acid. The acidified solution was treated with charcoal and filtered. The filtrate was adjusted to pH 7.0 with 20% aqueous potassium carbonate. The resulting precipitate was collected by filtration, washed successively with water and ethyl acetate, and recrystallized from aqueous ethanol to give 2-(2-amino-4-methyl-5-thiazolyl)imidazo[1,2-a]pyrimidine (0.8 g). mp 285°-286° C. (dec.).
Reaction SMILES: P(Cl)(Cl)(Cl)=O.[Br:6][C:7]1[N:8]([C:17]2[C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[C:20]([CH:27]3[CH2:29][CH2:28]3)=[CH:19][CH:18]=2)[C:9]([S:12][CH2:13][C:14]([OH:16])=[O:15])=[N:10][N:11]=1.[OH:30][CH:31]1[O:37][C@H:36]([C@@H:38]([CH2:40]O)[OH:39])[C@H:34]([OH:35])[C@H:32]1[OH:33]>N1C=CC=CC=1>[Br:6][C:7]1[N:8]([C:17]2[C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[C:20]([CH:27]3[CH2:29][CH2:28]3)=[CH:19][CH:18]=2)[C:9]([S:12][CH2:13][C:14]([O:16][CH2:40][CH:38]([OH:39])[CH:36]2[CH:34]([OH:35])[CH:32]([OH:33])[CH:31]([OH:30])[O:37]2)=[O:15])=[N:10][N:11]=1
Reactant: O=C(O)CSc1nnc(Br)n1-c1ccc(C2CC2)c2ccccc12
Reactant: OC[C@@H](O)[C@H]1OC(O)[C@H](O)[C@H]1O
Solvent: O=P(Cl)(Cl)Cl
Solvent: c1ccncc1
Product: O=C(CSc1nnc(Br)n1-c1ccc(C2CC2)c2ccccc12)OCC(O)C1OC(O)C(O)C1O
Temperature: 0 °C
Reaction time: 1 h

Procedure:
Phosphorus oxychloride (2.4 mmol) is added dropwise over 5 mins to a solution of 2-(5-bromo-4-(1-cyclopropylnaphthalen-4-yl)-4H-1,2,4-triazol-3-ylthio)acetic acid (810 mg, 2.0 mmol) in pyridine (20 mL) at 0° C. The mixture is stirred at 0° C. for a further 1 hour and then 1,2-O-isopropilydene-□-D-glucofuranose (440 mg, 2.0 mmol) dissolved in pyridine (5 mL) is added dropwise over 5 mins. The mixture is stirred at 0° C. for a further 3 hours and 1 hour at 20° C. and then quenched by addition of water (1 mL). Volatile solvents are removed in vacuo and DCM (200 mL) added. The organic phase is washed with water (1×50 mL), saturated sodium carbonate solution (1×50 mL) and brine (1×50 mL), dried over Na2SO4 and concentrated to dryness. Ethanol and water are added to produce a solid which is collected by filtration. Additional product is recovered by extraction of the filtrate with DCM. Combined product is concentrated, dried and purified by column chromatography (acetone/DCM eluent). The combined solids are dissolved in acetic acid (25 mL) and water (5 mL) mixture, heated at 60° C. for 3 hours. Volatile solvents are removed in vacuo. Ethanol and water are added to produce a solid which is collected by filtration.
Reaction SMILES: [OH:1][CH:2]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[N:6]2[CH2:13][CH2:14][NH:15][CH2:16][CH:5]2[C:4]2[CH:17]=[CH:18][CH:19]=[CH:20][C:3]1=2.[CH2:21]([OH:23])C.[CH3:24]C(C)=O>>[OH:1][CH:2]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[N:6]2[CH2:13][CH2:14][N:15]([CH3:24])[CH2:16][CH:5]2[C:4]2[C:17]([O:23][CH3:21])=[CH:18][CH:19]=[CH:20][C:3]1=2
Reactant: CCO
Reactant: OC1c2ccccc2C2CNCCN2c2ccccc21
Reactant: CC(C)=O
Product: COc1cccc2c1C1CN(C)CCN1c1ccccc1C2O

Procedure:
10-hydroxy-1,2,3,4,10,14b-hexahydrodibenzo[c,f]pyrazino[1,2-a]azepine, (cis configuration), Rf in ethanol:acetone (9:1)=0.43 on SiO2, m.p. 217° C.
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[C:8]([O:10][CH3:11])[CH:7]=[CH:6][C:5]=1[OH:12])([CH3:3])[CH3:2].[C:13]1([CH3:23])[CH:18]=[CH:17][C:16]([S:19](Cl)(=[O:21])=[O:20])=[CH:15][CH:14]=1.C(N(CC)CC)C>C1(C)C=CC=CC=1>[CH:1]([C:4]1[CH:9]=[C:8]([O:10][CH3:11])[CH:7]=[CH:6][C:5]=1[O:12][S:19]([C:16]1[CH:17]=[CH:18][C:13]([CH3:23])=[CH:14][CH:15]=1)(=[O:21])=[O:20])([CH3:3])[CH3:2]
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: COc1ccc(O)c(C(C)C)c1
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: COc1ccc(OS(=O)(=O)c2ccc(C)cc2)c(C(C)C)c1
Temperature: 10 °C
Reaction time: 3 h
Yield: 95.6 %

Procedure:
To a solution of 180 g of 2-Isopropyl-4-methoxy-phenol (1.084 moles) in 2.5 L toluene was added 206.7 g p-toluene sulfonylchloride (1.084 moles), and the reaction mixture was stirred vigorously The resultant mixture was cooled to 10° C., and triethylamine (3 mol) was gradually added, keeping the temperature below 50 degrees C. The reaction mixture was aged for 3 hours at approximately 50° C. and then allowed to cool to RT. An HPLC sample obtained at this point showed completion of the reaction. The resultant suspension was filtered and the filter-cake was washed with 300 mL toluene. The collected filtrate was distilled under vacuum until the pot-temperature reached 65° C., and 1 L of methanol was added to the mixture. The methanolic solution was stirred for 30 minutes at reflux; then the mixture was permitted to cool overnight. The white crystalline solid which separated was collected by filtration and dried at 50° C. under vacuum to yield a total of 332 grams of toluene-4-sulfonic acid 2-isopropyl-4-methoxy-phenyl ester, representing an yield of 95.7%:m.p. 85.1 degrees C.
Reaction SMILES: C([O:8][CH2:9][CH2:10][CH2:11][O:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]2[CH:20]=[C:21]([C:32]3[CH:37]=[CH:36][C:35]([O:38][CH2:39][CH2:40][O:41][CH2:42][O:43][CH2:44][CH3:45])=[CH:34][CH:33]=3)[CH:22]=[C:23]([O:25][CH2:26][O:27][CH2:28][CH2:29][O:30][CH3:31])[CH:24]=2)=[CH:15][C:14]=1[F:46])C1C=CC=CC=1.C1C[O:50][CH2:49]C1>[Pd]>[F:46][C:14]1[CH:15]=[C:16]([C:19]2[CH:20]=[C:21]([C:32]3[CH:33]=[CH:34][C:35]([O:38][CH2:39][CH2:40][O:41][CH2:42][O:43][CH2:44][CH2:45][O:50][CH3:49])=[CH:36][CH:37]=3)[CH:22]=[C:23]([O:25][CH2:26][O:27][CH2:28][CH2:29][O:30][CH3:31])[CH:24]=2)[CH:17]=[CH:18][C:13]=1[O:12][CH2:11][CH2:10][CH2:9][OH:8]
Reactant: CCOCOCCOc1ccc(-c2cc(OCOCCOC)cc(-c3ccc(OCCCOCc4ccccc4)c(F)c3)c2)cc1
Reactant: C1CCOC1
Agent: [Pd]
Product: COCCOCOCCOc1ccc(-c2cc(OCOCCOC)cc(-c3ccc(OCCCO)c(F)c3)c2)cc1

Procedure:
2.60 g (4.20 mmol) 4″-(3-benzyloxy-propoxy)-3″-fluoro-5′-(2-methoxy-ethoxymethoxy)-4-(2-ethoxymethoxy-ethoxy)-[1,1′;3′,1″]terphenyl are hydrogenated in 50 ml THF on 1.0 g Pd/activated charcoal until the reaction is completed. The catalyst is filtered off and the solvent is removed in vacuo. 3-{3″-fluoro-5′-(2-methoxy-ethoxymethoxy)-4-[2-(2-methoxy-ethoxymethoxy)-ethoxy]-[1 1′;3′,1″]terphenyl-4″-yloxy}-propane-1-ol is obtained as colourless oil, which is used for the next step without further purification.
Reaction SMILES: COC1C=CC(C2CCC3C(=CC=C(OC)C=3)C2)=C(N2CC3C(=CC=C(O)C=3)C2)C=1.Cl.ClCCN1CCCCCC1.[N:42]1([CH2:49][CH2:50][O:51][C:52]2[CH:53]=[C:54]3[C:58](=[CH:59][CH:60]=2)[CH2:57][N:56]([C:61]2[CH:66]=[C:65]([O:67]C)[CH:64]=[CH:63][C:62]=2[CH:69]2[CH2:78][CH2:77][C:76]4[C:71](=[CH:72][CH:73]=[C:74]([O:79]C)[CH:75]=4)[CH2:70]2)[CH2:55]3)[CH2:48][CH2:47][CH2:46][CH2:45][CH2:44][CH2:43]1>>[N:42]1([CH2:49][CH2:50][O:51][C:52]2[CH:53]=[C:54]3[C:58](=[CH:59][CH:60]=2)[CH2:57][N:56]([C:61]2[CH:66]=[C:65]([OH:67])[CH:64]=[CH:63][C:62]=2[CH:69]2[CH2:78][CH2:77][C:76]4[CH:75]=[C:74]([OH:79])[CH:73]=[CH:72][C:71]=4[CH2:70]2)[CH2:55]3)[CH2:48][CH2:47][CH2:46][CH2:45][CH2:44][CH2:43]1
Reactant: COc1ccc2c(c1)CCC(c1ccc(OC)cc1N1Cc3ccc(OCCN4CCCCCC4)cc3C1)C2
Agent: COc1ccc2c(c1)CCC(c1ccc(OC)cc1N1Cc3ccc(O)cc3C1)C2
Agent: Cl
Agent: ClCCN1CCCCCC1
Product: Oc1ccc2c(c1)CCC(c1ccc(O)cc1N1Cc3ccc(OCCN4CCCCCC4)cc3C1)C2
Yield: 70.6 %

Procedure:
Synthesized from 2-[5-methoxy-2-(6-methoxy-1,2,3,4-tetrahydronaphthalen-2-yl)phenyl]-2,3-dihydro-1H-isoindol-5-ol and 1-(2-chloroethyl)azepane hydrochloride according to an analogous synthetic method to Preparation Example 40, 5-(2-azepan-1-ylethoxy)-2-[5-methoxy-2-(6-methoxy-1,2,3,4-tetrahydronaphthalen-2-yl)phenyl]-2,3-dihydro-1H-isoindole (223 mg) was used according to an analogous synthetic method to Example 111 to provide the title compound (149 mg).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:13][CH2:14][CH2:15]O)[CH:6]=[C:7]([O:11][CH3:12])[C:8]=1[O:9][CH3:10].P(Br)(Br)[Br:18].O>O1CCCC1.C(OCC)(=O)C>[Br:18][CH2:15][CH2:14][CH2:13][C:5]1[CH:6]=[C:7]([O:11][CH3:12])[C:8]([O:9][CH3:10])=[C:3]([O:2][CH3:1])[CH:4]=1
Reactant: COc1cc(CCCO)cc(OC)c1OC
Reactant: BrP(Br)Br
Solvent: C1CCOC1
Solvent: O
Solvent: CCOC(C)=O
Product: COc1cc(CCCBr)cc(OC)c1OC
Temperature: 25 °C
Reaction time: 12 h
Yield: 84 %

Procedure:
To a solution of 3-(3,4,5-trimethoxyphenyl)-propan-1-ol (9.50 g, 0.042 mol) in 50 ml of tetrahydrofuran, 5.0 ml (0.053 mol) of phosphorus tribromide were added dropwise at 0° C., followed by stirring at room temperature for 12 hours. The reaction mixture was added with water under ice cooling. The resulting solution was dissolved in 200 ml of ethyl acetate. The orqanic layer was washed successively with water, saturated NaHCO3 and saturated NaCl and then dried over anhydrous magnesium sulfate. The solvent was thereafter distilled off under reduced pressure. The oil thus obtained was purified by column chromatography (silica gel: "MERCK #9385", eluent: ether), whereby 10.2 g of the title compound were obtained as colorless oil (yield: 84%).
Reaction SMILES: [H-].[Na+].[C:3](=[N:13][OH:14])([NH2:12])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11].[C:15]1([C:21]([C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[N:22]2[CH2:27][CH:26]([C:28](OC)=O)[CH2:25][N:24]=[CH:23]2)[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>C1COCC1>[C:38]1([C:21]([C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)([C:32]2[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=2)[N:22]2[CH2:27][CH:26]([C:28]3[O:14][N:13]=[C:3]([CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11])[N:12]=3)[CH2:25][N:24]=[CH:23]2)[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1
Reactant: COC(=O)C1CN=CN(C(c2ccccc2)(c2ccccc2)c2ccccc2)C1
Reactant: CCCCCCCCC(N)=NO
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCCCCCCCc1noc(C2CN=CN(C(c3ccccc3)(c3ccccc3)c3ccccc3)C2)n1
Temperature: 0 °C
Reaction time: 18 h
Yield: 59.2 %

Procedure:
Prepared by a procedure similar to Example 9, where sodium hydride (60% dispersion in mineral oil 104 mg, 2.6 mmol) and n-nonanamidoxime (448 mg, 2.6 mmol) were suspended in dry THF in an oven dried round bottom flask with stirring under nitrogen at 0° C. After 15 minutes stirring the ice bath was removed and the grey suspension refluxed 45 minutes to give a white suspension. 1-Triphenylmethyl-1,4,5,6-tetrahydro-5-methoxycarbonylpyrimidine (1.0 g, 2.6 mmol) was added dissolved in dry THF and reflux continued 18 hours. The solvents were evaporated in vacuo and the residue was chromatographed (silica, chloroform/methanol, 9:1) to yield 1-triphenylmethyl-1,4,5,6-tetrahydro-5-(3-octyl-1,2,4-oxadiazol-5-yl)pyrimidine 780 mg (60%). This product was dissolved in triflouroacetic acid (2 ml), with stirring at room temperature for 24 hours. The yellow solution was then evaporated in vacuo, and the residue recrystallized from methanol/ether to yield 182 mg (30%) white crystals, mp 97°-99° C. identified by 300 MHz nmr.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][O:7][C:8]([NH:10][C:11]1([C:17]([OH:19])=O)[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1)=[O:9].[NH2:20][C@H:21]([CH2:25][OH:26])[CH:22]([CH3:24])[CH3:23]>>[O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][O:7][C:8]([NH:10][C:11]1([C:17]([NH:20][C@H:21]([CH2:25][OH:26])[CH:22]([CH3:24])[CH3:23])=[O:19])[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16]1)=[O:9]
Reactant: O=C(NC1(C(=O)O)CCCCC1)OCc1ccco1
Reactant: CC(C)[C@H](N)CO
Product: CC(C)[C@@H](CO)NC(=O)C1(NC(=O)OCc2ccco2)CCCCC1

Procedure:
2.00 g (7.48 mmol) of 1-[[(2-furanylmethoxy)carbonyl]amino]cyclohexanecarboxylic acid was used instead of 2-benzothiophenecarboxylic acid, and 772 mg (7.48 mmol) of L-valinol was used instead of 1-aminocyclohexanecarboxylic acid phenylmethyl ester in the process according to Reference Example 197 to obtain 2.67 g (quantitative) of the title compound.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH3:11])[CH:6]=[C:5]2[C:12]([OH:14])=O.C(Cl)(=O)C(Cl)=O.[NH2:21][C:22]1[C:27]([Cl:28])=[CH:26][C:25]([CH2:29][C:30]([O:32][CH2:33][CH3:34])=[O:31])=[C:24]([F:35])[CH:23]=1.C(N(CC)CC)C>C(Cl)Cl.Cl>[Cl:28][C:27]1[C:22]([NH:21][C:12]([C:5]2[C:4]3[C:8](=[CH:9][CH:10]=[C:2]([F:1])[CH:3]=3)[N:7]([CH3:11])[CH:6]=2)=[O:14])=[CH:23][C:24]([F:35])=[C:25]([CH2:29][C:30]([O:32][CH2:33][CH3:34])=[O:31])[CH:26]=1
Reactant: Cn1cc(C(=O)O)c2cc(F)ccc21
Reactant: CCOC(=O)Cc1cc(Cl)c(N)cc1F
Agent: Cl
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOC(=O)Cc1cc(Cl)c(NC(=O)c2cn(C)c3ccc(F)cc23)cc1F
Temperature: 0 °C
Yield: 46.6 %

Procedure:
In methylene chloride (30 ml) was dissolved 5-fluoro-1-methylindole-3-carboxylic acid (885 mg, 4.58 mmol). To the resulting solution was added oxalyl chloride (600 μl, 6.87 mmol) under stirring at 0° C., and the resulting mixture was stirred at room temperature for 1 hour. From the reaction mixture, the solvent was distilled off under reduced pressure. The residue was dissolved in methylene chloride (50 ml). The resulting solution was added dropwise to a solution of ethyl (4-amino-5-chloro-2-fluorophenyl)acetate (1.06 g, 4.58 mmol) in methylene chloride (20 ml), followed by heating under reflux for 15 minutes. The reaction mixture was cooled and triethylamine (3.19 ml, 22.9 mmol) was added thereto. The resulting mixture was heated under reflux for 18 hours. The reaction mixture was cooled and poured in 1N HCl, followed by extraction with ethyl acetate. The extract was dried over anhydrous sodium sulfate, and distilled under reduced pressure to remove the solvent. The residue was purified by chromatography on a silica gel column, whereby from hexane/ethyl acetate (2/1) eluate fractions, ethyl (5-chloro-2-fluoro-4-(((5-fluoro-1-methyl-3-indolyl)carbonyl)amino)phenyl)acetate (868 mg, 47%) was obtained as a white solid.
Reaction SMILES: [OH:1][CH2:2][CH2:3][C:4]1[N:5]=[C:6]([C:9]2[CH:14]=[C:13]([O:15][CH3:16])[C:12]([O:17][CH3:18])=[C:11]([O:19][CH3:20])[CH:10]=2)[S:7][CH:8]=1.[CH3:21][S:22](Cl)(=[O:24])=[O:23]>N1C=CC=CC=1.C(OCC)(=O)C>[CH3:21][S:22]([O:1][CH2:2][CH2:3][C:4]1[N:5]=[C:6]([C:9]2[CH:10]=[C:11]([O:19][CH3:20])[C:12]([O:17][CH3:18])=[C:13]([O:15][CH3:16])[CH:14]=2)[S:7][CH:8]=1)(=[O:24])=[O:23]
Reactant: COc1cc(-c2nc(CCO)cs2)cc(OC)c1OC
Reactant: CS(=O)(=O)Cl
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Product: COc1cc(-c2nc(CCOS(C)(=O)=O)cs2)cc(OC)c1OC
Reaction time: 1.5 h

Procedure:
4-(2-Hydroxyethyl)-2-(3,4,5-trimethoxyphenyl)-thiazole (1.60 g) was dissolved in pyridine (15 mL), and to the solution methanesulfonyl chloride (807 mg) was added at 0° C., and the mixture was stirred for 1.5 hours. The reaction mixture was diluted with ethyl acetate, washed with 2 M hydrochloric acid, water and saturated brine and dried over anhydrous sodium sulfate. After concentrating the reaction mixture under reduced pressure, the residue was purified by column chromatography on silica gel (ethyl acetate) to obtain the title compound.