Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:3]=1[CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH2:13][CH2:14][O:15][CH3:16])=[CH:8][CH:7]=1.[B:22](OC(C)C)([O:27]C(C)C)[O:23]C(C)C.[Li]CCCC>C1COCC1>[CH3:16][O:15][CH2:14][CH2:13][O:12][C:9]1[CH:10]=[CH:11][C:6]([O:5][CH2:4][C:3]2[CH:17]=[C:18]([Cl:21])[CH:19]=[CH:20][C:2]=2[B:22]([OH:27])[OH:23])=[CH:7][CH:8]=1
Reactant: CC(C)OB(OC(C)C)OC(C)C
Reactant: COCCOc1ccc(OCc2cc(Cl)ccc2Br)cc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: COCCOc1ccc(OCc2cc(Cl)ccc2B(O)O)cc1
Temperature: -78 °C
Reaction time: 1 h
Yield: 69.3 %

Procedure:
In a flask, 1.8 g (4.8 mmol) of the compound obtained in Step 2 was dissolved in 10 ml of anhydrous THF, and 1.34 ml (5.8 mmol) of triisopropyl borate was added thereto. The flask was cooled to −78° C. over a dry ice-acetone bath, 2.3 ml (5.8 mmol) of 2.5 M n-BuLi (in hexane) was added dropwise to the mixture over 15 min. After the reaction mixture was kept for 1 hour, the dry ice-acetone bath was removed, and 5 ml of 2 N HCl was added to the mixture. After stirring the mixture for 1 hour, the water layer was separated and extracted twice with 10 ml portions of ethyl acetate. The organic layers were combined, washed with a brine solution, dried over anhydrous MgSO4, and filtered under a reduced pressure to remove the solvent. The residue was recrystallized from ethyl acetate/hexane to obtain 1.12 g (yield 69%) of 2-((4-(2-methoxyethoxy)phenoxy)methyl)-4-chlorophenylboronic acid.
Reaction SMILES: [OH-].[Na+].[OH:3][C:4]1[C:9](=[O:10])[CH:8]=[CH:7][O:6][C:5]=1[CH3:11].[CH2:12](Cl)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>CO.O>[CH2:12]([O:3][C:4]1[C:9](=[O:10])[CH:8]=[CH:7][O:6][C:5]=1[CH3:11])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: Cc1occc(=O)c1O
Reactant: ClCc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: Cc1occc(=O)c1OCc1ccccc1
Yield: 76.8 %

Procedure:
A solution of sodium hydroxide (126 g, 1.1 mol) in 1000 ml of methanol in water (9:1 v/v) was added to 3-hydroxy-2-methyl-4-pyrone (126.12 g, 1 mol). Benzyl chloride (126.59 ml, 1.1 mol) was then added slowly and the mixture was refluxed for 10 hours with rapid stirring. The resultant solution was cooled, the methanol removed by rotary evaporation and the aqueous solution was extracted with dichloromethane (3×250 ml). The combined dichloromethane extracts were washed with 5% sodium hydroxide and then with water, dried over anhydrous sodium sulphate, filtered and evaporated to dryness. The resultant solid was recrystallised from diethylether to yield the title compound in 76.8% yield as colourless needles, m.p. 53°-55° C.
Reaction SMILES: [NH3:1].Cl[C:3]1[C:8]([C:9]#[N:10])=[CH:7][C:6]([C:11]2[CH:16]=[CH:15][N:14]=[CH:13][CH:12]=2)=[C:5]([C:17]2[O:18][CH:19]=[CH:20][CH:21]=2)[N:4]=1>C(O)C>[NH2:1][C:3]1[C:8]([C:9]#[N:10])=[CH:7][C:6]([C:11]2[CH:16]=[CH:15][N:14]=[CH:13][CH:12]=2)=[C:5]([C:17]2[O:18][CH:19]=[CH:20][CH:21]=2)[N:4]=1
Reactant: N
Reactant: N#Cc1cc(-c2ccncc2)c(-c2ccco2)nc1Cl
Solvent: CCO
Product: N#Cc1cc(-c2ccncc2)c(-c2ccco2)nc1N
Temperature: 100 °C
Reaction time: 24 h
Yield: 27 %

Procedure:
A solution of ammonia in ethanol, 30 ml, (ethanol saturated at 0° C. with an ammonia gas) was added to 2-chloro-6-(2-furyl)-5-(4-pyridyl)-3-pyridinecarbonitrile (200 mg, 0.710 mmol). Then, it was sealed in a stainless steel autoclave, and heated under stirring at 100° C. After 24 hours, the reaction solution was cooled as it was and concentrated. The residue was subjected to silica gel column chromatography (elution solvent; hexane, hexane:ethyl acetate=2:1, 1:1, 1:2), and then suspended in diethyl ether. The resulting precipitates were collected by filtration and washed with diethyl ether, to give the title compound (50 mg, 27%) as a pale orange solid.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:15])[CH2:9][N:10]2[CH:14]=[N:13][CH:12]=[N:11]2)=[CH:4][CH:3]=1.[SH:16][CH2:17][CH2:18]O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1.C(O)CCC>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([CH2:9][N:10]3[CH:14]=[N:13][CH:12]=[N:11]3)[S:16][CH2:17][CH2:18][O:15]2)=[CH:4][CH:3]=1
Reactant: OCCS
Reactant: O=C(Cn1cncn1)c1ccc(Br)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: CCCCO
Product: Brc1ccc(C2(Cn3cncn3)OCCS2)cc1
Yield: 15.3 %

Procedure:
To a slurry of 27.8 g 1-(4-bromophenyl)-2-(1H-1,2,4-triazol-1-yl) ethanone in 350 ml dry toluene and 175 ml 1-butanol were added 15.6 g 2-mercaptoethanol and 24.7 g p-toluenesulfonic acid. The mixture was refluxed under a Dean-Stark trap for 50 hours. After cooling, a white solid was removed by filtration and the filtrate evaporated. The residue was taken up in chloroform and washed twice with 10% aqueous sodium hydroxide and once with water. The organic layer was dried, filtered and evaporated to leave a liquid residue. The 1-butanol in the residue was removed azeotropically three times with cyclohexane leaving a slurry. The solid was isolated by filtration to give 5.2 g of product.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([N:7]2[CH:16]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[NH:9][C:8]2=[O:23])[CH2:3][CH2:2]1.[CH2:24](Br)[CH2:25][OH:26]>>[OH:26][CH2:25][CH2:24][N:1]1[CH2:2][CH2:3][CH:4]([N:7]2[CH:16]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[NH:9][C:8]2=[O:23])[CH2:5][CH2:6]1
Reactant: OCCBr
Reactant: O=C1Nc2ccccc2C(c2ccccc2)N1C1CCNCC1
Product: O=C1Nc2ccccc2C(c2ccccc2)N1C1CCN(CCO)CC1

Procedure:
In similar way as in Preparation Example 31, the title compound was synthesized from 3-(piperidin-4-yl)-4-phenyl-3,4-dihydro-2(1H)-quinazolinone and ethylene bromohydrin.
Reaction SMILES: [OH:1][CH2:2][CH:3]1[CH2:8][CH2:7][CH2:6][NH:5][C:4]1=[O:9].N1C=CN=C1.[Si:15](Cl)([C:28]([CH3:31])([CH3:30])[CH3:29])([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.O>CN(C)C=O>[Si:15]([O:1][CH2:2][CH:3]1[CH2:8][CH2:7][CH2:6][NH:5][C:4]1=[O:9])([C:28]([CH3:31])([CH3:30])[CH3:29])([C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: O=C1NCCCC1CO
Reactant: CC(C)(C)[Si](Cl)(c1ccccc1)c1ccccc1
Agent: c1c[nH]cn1
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](OCC1CCCNC1=O)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A solution of 5.00 g (38.7 mmol) of 3-hydroxymethylpiperidin-2-one in 40 ml of N,N-dimethylformamide is admixed successively with 3.16 g (46.5 mmol) of imidazole, and dropwise with 11 ml (42.6 mmol) of tert-butyl(diphenyl)silyl chloride. After stirring at RT for 3 hours, the mixture is admixed with approx. 400 ml of water and extracted three times with ethyl acetate. The combined organic extracts are washed successively with saturated ammonium chloride solution, water and saturated sodium chloride solution. After drying over anhydrous magnesium sulfate, the mixture is filtered and the filtrate is freed of the solvent under reduced pressure. The resulting residue is purified by suction filtration through silica gel with 20:1→1:1 cyclohexane/ethyl acetate as the eluent. This affords 9.43 g (66% of theory) of the title compound.
Reaction SMILES: [Br:1][C:2]1[CH:6]=[N:5][N:4]([CH3:7])[C:3]=1[C:8]1[CH:9]=[C:10]([NH2:16])[CH:11]=[CH:12][C:13]=1[O:14][CH3:15].[C:17]([N:25]=[C:26]=[O:27])(=[O:24])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>C(Cl)Cl>[C:17]([NH:25][C:26]([NH:16][C:10]1[CH:11]=[CH:12][C:13]([O:14][CH3:15])=[C:8]([C:3]2[N:4]([CH3:7])[N:5]=[CH:6][C:2]=2[Br:1])[CH:9]=1)=[O:27])(=[O:24])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: COc1ccc(N)cc1-c1c(Br)cnn1C
Reactant: O=C=NC(=O)c1ccccc1
Solvent: ClCCl
Product: COc1ccc(NC(=O)NC(=O)c2ccccc2)cc1-c1c(Br)cnn1C
Yield: 66.7 %

Procedure:
3-(4-Bromo-2-methyl-2H-pyrazol-3-yl)-4-methoxy-phenylamine (0.033 g, 0.12 mmol) was treated with benzoyl isocyanate (0.020 g, 0.12 mmol, 1.05 equiv.) in CH2Cl2 (1 mL), in a similar manner as described in Example 1.2 to afford Compound 73 (0.036 g, 0.08 mmol, 72%) as a white solid. LCMS m/z (%)=429 (M+H79Br, 99), 431 (M+H81Br, 100). 1H NMR (400 MHz, acetone-d6) δ: 10.92 (s, 1H), 9.85 (s, 1H), 8.12 (d, J=7.4 Hz, 2H), 7.76 (dd, J=2.6, 9.0 Hz, 1H), 7.68 (t, J=7.3 Hz, 1H), 7.62 (d, J=2.6 Hz, 1H), 7.57 (t, J=7.8 Hz, 2H), 7.51 (s, 1H), 7.21 (d, J=9.0 Hz, 1H), 3.86 (s, 3H), 3.71 (s, 3H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([CH:11]=1)[C:7](Cl)=[N:8][OH:9].[C:12]([C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([F:20])[CH:15]=1)#[CH:13].N>>[F:20][C:16]1[CH:15]=[C:14]([C:12]2[O:9][N:8]=[C:7]([C:6]3[CH:5]=[N:4][CH:3]=[C:2]([F:1])[CH:11]=3)[CH:13]=2)[CH:19]=[CH:18][CH:17]=1
Reactant: ON=C(Cl)c1cncc(F)c1
Reactant: C#Cc1cccc(F)c1
Agent: N
Product: Fc1cncc(-c2cc(-c3cccc(F)c3)on2)c1

Procedure:
The titled compound was prepared according to Method CB using the product of Example 28B (88 mg, 0.5 mmol) and 1-ethynyl-3-fluorobenzene (Aldrich, 60 mg, 0.5 mmol). 1H NMR (300 MHz, MeOH-d4) δ 7.20-7.35 (m, 1H), 7.46 (s, 1 H), 7.58 (td, J=8.0, 5.8 Hz, 1H), 7.68 (ddd, J=9.7, 2.5, 1.7 Hz, 1H), 7.76 (dt, J=8.0, 1.1 Hz, 1H), 8.17 (ddd, J=9.4, 2.8, 1.7 Hz, 1H), 8.61 (d, J=2.7 Hz, 1H), 8.97 (t, J=1.5 Hz, 1H) ppm; MS (DCI/NH3) m/z 259 (M+H)+.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([F:8])[C:5]([Br:9])=[CH:4][C:3]=1[F:10].C([Li])CCC.C([O:18][C:19]1[CH2:23][CH2:22][C:21](=O)[CH:20]=1)C.Cl>CCOCC>[Br:9][C:5]1[C:6]([F:8])=[CH:7][C:2]([C:21]2[CH2:22][CH2:23][C:19](=[O:18])[CH:20]=2)=[C:3]([F:10])[CH:4]=1
Reactant: Fc1cc(Br)c(F)cc1Br
Reactant: CCOC1=CC(=O)CC1
Agent: Cl
Agent: [Li]CCCC
Solvent: CCOCC
Product: O=C1C=C(c2cc(F)c(Br)cc2F)CC1
Temperature: -78 °C
Reaction time: 0.25 h
Yield: 52 %

Procedure:
A solution of 27.2 g (0.1 mole) of 1,4-dibromo-2,5-difluorobenzene in 200 ml of ether was blanketed with argon and cooled to -78° C. To this mixture was added 42 ml of n-butyl lithium (2.4 M; 0.10 mole) dropwise via an addition funnel. The solution was stirred at -78° C. for 15 minutes, then allowed to warm to -45° C. To the anion was added 13 ml of 3-ethoxy-2-cyclopentenone (0.10 mole); the solution was kept at -45° for 30 minutes and was then warmed slowly to room temperature. The mixture was poured into 250 ml of 1 N hydrochloric acid, stirred for 30 minutes, and extracted with ethyl acetate; the organic phases were combined, washed with water, dried over magnesium sulfate, and concentrated. The crude product was purified via silica gel chromatography using an 80:20 chloroform ethyl acetate mixture to give 14.2 g of the desired product; mp 129°-131° C.
Reaction SMILES: [CH3:1][N:2]([CH3:17])[C:3]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:4]=1[CH:5]=[CH:6][CH:7]=[C:8]2[S:13](Cl)(=[O:15])=[O:14].[NH2:18][C:19]1[C:24]([O:25][CH3:26])=[N:23][C:22]([Br:27])=[CH:21][N:20]=1>N1C=CC=CC=1>[CH3:1][N:2]([CH3:17])[C:3]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:4]=1[CH:5]=[CH:6][CH:7]=[C:8]2[S:13]([NH:18][C:19]1[C:24]([O:25][CH3:26])=[N:23][C:22]([Br:27])=[CH:21][N:20]=1)(=[O:15])=[O:14]
Reactant: CN(C)c1cccc2c(S(=O)(=O)Cl)cccc12
Reactant: COc1nc(Br)cnc1N
Solvent: c1ccncc1
Product: COc1nc(Br)cnc1NS(=O)(=O)c1cccc2c(N(C)C)cccc12
Temperature: 80 °C
Reaction time: 1 h
Yield: 23.1 %

Procedure:
5-Dimethylamino-1-naphthalenesulphonyl chloride (15.2 g) and 2-amino-5-bromo-3-methoxypyrazine (obtained as described in Gazz. Chim. Ital. 1960, 90, 1807) (9.5 g) were mixed intimately in a mortar and pestle and added to pyridine (150 ml) at 0° C. The solution was kept at 0° C. for 1 hour and then heated at 80° C. for 18 hours. Volatile material was removed by evaporation and dichloromethane (250 ml) was added to the residue. Insoluble material was removed by filtration and the filtrate was washed with water (100 ml) and saturated sodium chloride solution (100 ml). The solution was treated with charcoal and dried (MgSO4). The solvent was removed by evaporation and the residue was purified by flash chromatography, eluting with ethyl acetate/hexane (1:4 v/v). The resulting solid was triturated with ether and recrystallised from ethanol to give 5-dimethylamino-N-(5-bromo-3-methoxy-2-pyrazinyl)-1-naphthalenesulphonamide (4.7 g), m.p. 166-167° C.; 1H NMR (d6 -DMSO): 2.8 (s,6H), 3.9 (s,3H), 7.2 (d,1H), 7.55-7.7 (d,2H), 7.8 (s,1H), 8.3 (d,1H), 8.4-8.5 (m,2H), 11.5 (s,1H); mass spectrum (+ve CI): 437 (M+H)+.
Reaction SMILES: [CH:1]([C@@H:3]1[C@@H:7]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH2:6][N:5]([C@H:14]([CH:27]2[CH2:31][CH2:30][CH2:29][CH2:28]2)[C:15]([O:17][CH2:18][C:19]2[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=2)=[O:16])[CH2:4]1)=O.[C:32]1([CH2:38][CH2:39][CH2:40][CH:41]2[CH2:46][CH2:45][NH:44][CH2:43][CH2:42]2)[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1.Cl>>[C:32]1([CH2:38][CH2:39][CH2:40][CH:41]2[CH2:42][CH2:43][N:44]([CH2:1][C@@H:3]3[C@@H:7]([C:8]4[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=4)[CH2:6][N:5]([C@H:14]([CH:27]4[CH2:31][CH2:30][CH2:29][CH2:28]4)[C:15]([O:17][CH2:18][C:19]4[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=4)=[O:16])[CH2:4]3)[CH2:45][CH2:46]2)[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1
Reactant: c1ccc(CCCC2CCNCC2)cc1
Reactant: COc1ccc(COC(=O)[C@@H](C2CCCC2)N2C[C@H](c3ccccc3)[C@@H](C=O)C2)cc1
Agent: Cl
Product: COc1ccc(COC(=O)[C@@H](C2CCCC2)N2C[C@H](CN3CCC(CCCc4ccccc4)CC3)[C@@H](c3ccccc3)C2)cc1
Yield: 82.1 %

Procedure:
The title compound was prepared from 22 mg (0.053 mmol) of 2-(R)-(3-(R)-formyl-4-(S)-phenylpyrrolidin-1-yl)-2-(cyclopentyl)acetic acid, 4-(methoxy)benzyl ester (from EXAMPLE 15, Step E) and 13 mg (0.054 mmol) of 4-(3-phenylpropyl)piperidine.HCl using a procedure analogous to that described in EXAMPLE 1, Step J to provide 26.5 mg (81%) of the title compound: RF: 0.25 (4:1 v/v hexanes/EtOAc); 1H NMR (300 MHz) δ 1.18-1.95 (m, 18H), 2.21-2.89 (m, 11H), 3.14-3.29 (m, 4H), 3.80 (s, 3H), 5.09 (ABq, J=11.9, 2H), 6.87 (d, J=8.7, 2H), 7.14-7.35 (m, 12H).
Reaction SMILES: C(N(C(C)C)C(C)C)C.[C:10]([OH:16])(=O)[C:11]([CH3:14])([CH3:13])[CH3:12].[NH2:17][C:18]1[C:19]([C:24]([NH:26][NH2:27])=O)=[N:20][CH:21]=[CH:22][N:23]=1.CC1C=CC(S(Cl)(=O)=O)=CC=1>C(#N)C>[C:11]([C:10]1[O:16][C:24]([C:19]2[C:18]([NH2:17])=[N:23][CH:22]=[CH:21][N:20]=2)=[N:26][N:27]=1)([CH3:14])([CH3:13])[CH3:12]
Reactant: CC(C)(C)C(=O)O
Reactant: NNC(=O)c1nccnc1N
Agent: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: CC(C)(C)c1nnc(-c2nccnc2N)o1
Temperature: 80 °C
Reaction time: 0.33 h
Yield: 70.2 %

Procedure:
2-(1H-benzo[d][1,2,3]triazol-1-yl)-1,1,3,3-tetramethylisouronium tetrafluoroborate (47.7 g, 148.69 mmol) was added portionwise over 15 minutes to a stirred suspension of N-ethyl-N-isopropylpropan-2-amine (70.6 mL, 405.51 mmol), pivalic acid (17.08 mL, 148.69 mmol) and 3-aminopyrazine-2-carbohydrazide (20.7 g, 135.17 mmol) in acetonitrile (350 mL) and the reaction mixture was stirred at 80° C. for 20 minutes (a solution was obtained). The reaction mixture was cooled to 0° C. and N-ethyl-N-isopropylpropan-2-amine (70.6 mL, 405.51 mmol), followed by 4-methylbenzene-1-sulfonyl chloride (77 g, 405.51 mmol) were added over a period of 15 minutes. The reaction mixture (yellow suspension) was brought to reflux (solubilisation) and then allowed to stir at room temperature for 14 hours affording a dark orange solution. The solution was concentrated. The residue was diluted with dichloromethane, washed with water, brine, dried over magnesium sulfate and concentrated. The crude product was purified by flash chromatography on silica gel eluting with 0 to 40% ethyl acetate in dichloromethane. The solvent was evaporated to dryness. The resulting mixture was triturated with ether (100 mL), filtered, washed with the minimum of ether and dried to afford 3-(5-tert-butyl-1,3,4-oxadiazol-2-yl)pyrazin-2-amine (20.8 g, 70.2%) as a pale yellow soild: 1H NMR Spectrum; (CDCl3) 1.53 (9H, s), 1.58-1.68 (2H, m), 6.67 (2H, s), 8.13 (2H, dt); Mass Spectrum [M+H]+=220.
Reaction SMILES: [Li+].[OH-].C([O:5][C:6]([C:8]1[N:9]=[C:10]([C:20]2[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][C:21]=2[Cl:27])[N:11]([C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=2)[CH:12]=1)=[O:7])C>CO>[Cl:19][C:16]1[CH:15]=[CH:14][C:13]([N:11]2[CH:12]=[C:8]([C:6]([OH:7])=[O:5])[N:9]=[C:10]2[C:20]2[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][C:21]=2[Cl:27])=[CH:18][CH:17]=1
Reactant: CCOC(=O)c1cn(-c2ccc(Cl)cc2)c(-c2ccc(Cl)cc2Cl)n1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)c1cn(-c2ccc(Cl)cc2)c(-c2ccc(Cl)cc2Cl)n1
Temperature: 25 °C
Yield: 94.4 %

Procedure:
A solution of LiOH (6.36 g, 152 mmol) was added to a suspension of 1-(4-chloro-phenyl)-2-(2,4-dichloro-phenyl)-1H-imidazole-4-carboxylic acid ethyl ester I-7c (30 g, 75.8 mmol) in methanol (380 ml). The reaction mixture was heated to reflux for 1 h and then cooled to room temperature. Most of the solvent was removed in vacuo, and the residue was diluted with water and acidified with 3N HCl. The red-brown precipitate was collected by filtration and triturated with 100 ml ethyl acetate/hexanes (20:80) to afford 1-(4-chloro-phenyl)-2-(2,4-dichloro-phenyl)-1H-imidazole-4-carboxylic acid I-7d (26.3 g, 94%) as a pale yellow solid.
Reaction SMILES: [OH:1][C:2]1[C:7]2[C:8]([CH3:18])=[C:9]([CH2:14][CH2:15][CH2:16][OH:17])[C:10]([CH3:13])([CH3:12])[O:11][C:6]=2[CH:5]=[C:4]([CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])[CH:3]=1.[H-].[Na+].[CH3:26][O:27][CH2:28]Cl>CN(C=O)C>[CH3:26][O:27][CH2:28][O:1][C:2]1[C:7]2[C:8]([CH3:18])=[C:9]([CH2:14][CH2:15][CH2:16][OH:17])[C:10]([CH3:12])([CH3:13])[O:11][C:6]=2[CH:5]=[C:4]([CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])[CH:3]=1
Reactant: CCCCCc1cc(O)c2c(c1)OC(C)(C)C(CCCO)=C2C
Reactant: COCCl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCCCCc1cc(OCOC)c2c(c1)OC(C)(C)C(CCCO)=C2C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 94 %

Procedure:
To a solution of 1.96 g (6.16 mmol) of 5-Hydroxy-2,2,4-trimethyl-7-pentyl-2H-1-benzopyran-3-propanol in 10 mL of anhy. DMF (Aldrich) under argon at RT was added 260 mg (~1.05 eq.) of a 60% dispersion of sodium hydride (Aldrich) and the mixture stirred at RT under argon until effervescence had ceased and the solution had become a clear, darker colored solution. To the stirred solution was added 0.55 mL (~1 eq.) of methoxymethyl chloride (Aldrich, 85% purity technical grade) by syringe directly into the solution with the needle tip below the surface of the solution. The color of the reaction mixture discharged and a precipitate formed within 1 min. Stirring was continued for 0.5 hr. Half of the solution was then withdrawn by syringe for use in another reaction. The remaining half was poured into a mixture of 50 mL of sat. aq. NaHCO3 and 100 mL EtOAc, the mixture shaken well and sufficient water added to dissolve solids that formed to give two clear phases. The phases were separated and the organic phase washed with half-sat. aq. NaCl (2×50 mL), sat. aq. NaCl (1×50 mL), dried (Na2SO4), evaporated under reduced pressure and the residue dried under high vacuum to give 1.05 g (~94%) of the desired product 5-(Methoxymethoxy)-2,2,4-trimethyl-7-pentyl-2H-1-benzopyran-3-propanol as an oil, shown by 1H-NMR to be of good purity.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5](B(O)O)[CH:6]=[CH:7][CH:8]=1.[Cl:12][C:13]1[CH:18]=[CH:17][CH:16]=[C:15](Cl)[N:14]=1.C(=O)([O-])[O-].[K+].[K+].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>O.C(COC)OC>[Cl:12][C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([C:5]2[CH:6]=[CH:7][CH:8]=[C:3]([O:2][CH3:1])[CH:4]=2)[N:14]=1
Reactant: Clc1cccc(Cl)n1
Reactant: COc1cccc(B(O)O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: COCCOC
Solvent: O
Product: COc1cccc(-c2cccc(Cl)n2)c1
Temperature: 25 °C

Procedure:
A mixture of m-methoxy-phenylboronic acid (10 g, 65.8 mmol), 2,6-dichloropyridine (9.7 g, 65.8 mmol), potassium carbonate (27.3 g, 197.4 mmol), triphenylphosphine (2.07 g, 7.9 mmol), dimethoxyethane 250 mL and water 80 mL was prepared. Nitrogen was bubbled directly in the mixture for 20 minutes. Then palladium acetate was added (0.44 g, 2.0 mmol). Nitrogen was bubbled again in the mixture for another 10 minutes. The mixture was heated to reflux under nitrogen overnight. The reaction mixture was cooled to room temperature. The organic layer was separated and the aqueous layer was extracted with dichloromethane. The combined organic layers were dried over magnesium sulfate, filtered and evaporated. The mixture was purified by silica column with up to 10% ethyl acetate in hexanes to gain 6.5 g colorless oil (45%).
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]2)=[CH:6][CH:5]=1)(=[O:3])[CH3:2].[CH2:16]1[CH2:22][S:19](=[O:21])(=[O:20])[O:18][CH2:17]1>CC(C)=O>[S:19]([CH2:22][CH2:16][CH2:17][N:13]1[CH2:12][CH2:11][N:10]([C:7]2[CH:6]=[CH:5][C:4]([C:1](=[O:3])[CH3:2])=[CH:9][CH:8]=2)[CH2:15][CH2:14]1)([OH:21])(=[O:20])=[O:18]
Reactant: O=S1(=O)CCCO1
Reactant: CC(=O)c1ccc(N2CCNCC2)cc1
Solvent: CC(C)=O
Product: CC(=O)c1ccc(N2CCN(CCCS(=O)(=O)O)CC2)cc1
Temperature: 25 °C

Procedure:
A 4.1 g quantity (20 mmols) of 1-(p-acetylphenyl)piperazine is dissolved in 40 ml of acetone, and a solution of 2.44 g (20 mmols) of 1,3-propanesultone in 10 ml of acetone is added dropwise thereto at room temperature with stirring. After reaction at room temperature with stirring overnight, the yellow crystals precipitated are collected by filtration and then recrystallized from water-acetone.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH2:15][CH2:16][CH2:17][N:18]3[CH2:22][CH2:21][CH2:20][CH2:19]3)=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[N:4][CH:3]=1.[OH:23][C:24]1[CH:25]=[C:26]2[C:30](=[CH:31][CH:32]=1)[NH:29][CH:28]=[CH:27]2.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[NH:29]1[C:30]2[C:26](=[CH:25][C:24]([O:23][C:2]3[C:11]4[C:6](=[CH:7][C:8]([O:14][CH2:15][CH2:16][CH2:17][N:18]5[CH2:22][CH2:21][CH2:20][CH2:19]5)=[C:9]([O:12][CH3:13])[CH:10]=4)[N:5]=[N:4][CH:3]=3)=[CH:32][CH:31]=2)[CH:27]=[CH:28]1
Reactant: Oc1ccc2[nH]ccc2c1
Reactant: COc1cc2c(Cl)cnnc2cc1OCCCN1CCCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1cc2c(Oc3ccc4[nH]ccc4c3)cnnc2cc1OCCCN1CCCC1
Temperature: 100 °C
Reaction time: 6 h
Yield: 15.4 %

Procedure:
A suspension of 4-chloro-6-methoxy-7-(3-(pyrrolidin-1-yl)propoxy)cinnoline (200 mg, 0.62 mmol), (prepared as described for the starting material in Example 1), 5-hydroxyindole (100 mg, 0.75 mmol) and potassium carbonate (129 mg, 0.93 mmol) in DMF (3 ml) was stirred at 100° C. for 6 hours. After cooling, the volatiles were removed under vacuum and the residue was purified by column chromatography eluting with methylene chloride/methanol saturated with ammonia (98/2 to 90/10). The fractions containing the expected product were combined and evaporated to give 4-(indol-5-yloxy)-6-methoxy-7-(3-(pyrrolidin-1-yl)propoxy)cinnoline (40 mg, 15%).
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][N:5]1[C:9]2[CH:10]=[CH:11][CH:12]=[C:13]3[CH:14]=[CH:15][CH:16]=[C:7]([C:8]=23)[S:6]1(=[O:18])=[O:17].C(N(CC)CC)C.Br.Br.[OH:28][C:29]1[CH:30]=[C:31]([N:35]2[CH2:40][CH2:39][NH:38][CH2:37][CH2:36]2)[CH:32]=[CH:33][CH:34]=1>CN(C)C=O>[OH:28][C:29]1[CH:30]=[C:31]([N:35]2[CH2:40][CH2:39][N:38]([CH2:2][CH2:3][CH2:4][N:5]3[C:9]4[CH:10]=[CH:11][CH:12]=[C:13]5[CH:14]=[CH:15][CH:16]=[C:7]([C:8]=45)[S:6]3(=[O:18])=[O:17])[CH2:37][CH2:36]2)[CH:32]=[CH:33][CH:34]=1
Reactant: O=S1(=O)c2cccc3cccc(c23)N1CCCCl
Reactant: Oc1cccc(N2CCNCC2)c1
Agent: Br
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: O=S1(=O)c2cccc3cccc(c23)N1CCCN1CCN(c2cccc(O)c2)CC1
Temperature: 20 °C
Yield: 27.3 %

Procedure:
The experiment is carried out as in Example 1, starting with 2-(3-chloropropyl)naphtho[1,8-cd]isothiazole 1,1-dioxide (11.2 g), triethylamine (16.8 cc) and 4- (3-hydroxyphenyl)piperazine dihydrobromide (13.6 g) in dimethylformamide (250 cc). The mixture is heated for 6 hours at boiling point, then cooled to a temperature of about 20° C. Stirring is maintained for 6 hours at this temperature. After purification by crystallization from isopropyl oxide (30 cc), then recrystallization from boiling acetonitrile (125 cc), 2-{3-[4-(3-hydroxyphenyl)-1-piperazinyl]propyl}naphtho[1,8-cd]isothiazole 1,1-dioxide (4.6 g) is obtained, m.p. 175° C.