Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:20][CH2:19][C:18]2[C:13](=[CH:14][CH:15]=[C:16]([F:22])[C:17]=2[Br:21])[CH:12]1[C:23]1[CH:28]=[C:27]([Cl:29])[CH:26]=[CH:25][C:24]=1[OH:30])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+].[CH2:37](Br)[CH:38]=[CH2:39]>CC(C)=O.O>[CH2:1]([O:8][C:9]([N:11]1[CH2:20][CH2:19][C:18]2[C:13](=[CH:14][CH:15]=[C:16]([F:22])[C:17]=2[Br:21])[CH:12]1[C:23]1[CH:28]=[C:27]([Cl:29])[CH:26]=[CH:25][C:24]=1[O:30][CH2:39][CH:38]=[CH2:37])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(OCc1ccccc1)N1CCc2c(ccc(F)c2Br)C1c1cc(Cl)ccc1O
Reactant: C=CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: O
Product: C=CCOc1ccc(Cl)cc1C1c2ccc(F)c(Br)c2CCN1C(=O)OCc1ccccc1
Temperature: 60 °C

Procedure:
To a mixture of (±)-5-bromo-1-(5-chloro-2-hydroxy-phenyl)-6-fluoro-3,4-dihydro-1H-isoquinoline-2-carboxylic acid benzyl ester (150 mg, 0.28 mmol, 1.00 eq.) and K2CO3 (43 mg, 0.31 mmol, 1.10 eq.) in acetone (0.7 mL), allyl bromide (26 μL, 0.29 mmol, 1.05 eq.) was added. The mixture was heated to 60° C. in a sealed vial for 18 hours. The reaction mixture was allowed to cool to r.t. and poured in water (4 mL). The mixture was extracted with DCM (2×5 mL). The comb. org. phases were dried over MgSO4, filtered, and concentrated in vacuo. The residue was partially purified by flash master (column: 10 g, flow: 15 mL/min, Heptane to Heptane+10% AcOEt) to yield (±)-1-(2-allyloxy-5-chloro-phenyl)-5-bromo-6-fluoro-3,4-dihydro-1H-isoquinoline-2-carboxylic acid benzyl ester as a colorless oil.
Reaction SMILES: [C:1]([NH2:5])([CH3:4])([CH3:3])[CH3:2].CN1CCOCC1.[Cl:13][CH2:14][S:15](Cl)(=[O:17])=[O:16]>C(OCC)C.C(OCC)(=O)C>[C:1]([NH:5][S:15]([CH2:14][Cl:13])(=[O:17])=[O:16])([CH3:4])([CH3:3])[CH3:2]
Reactant: O=S(=O)(Cl)CCl
Reactant: CC(C)(C)N
Solvent: CCOC(C)=O
Solvent: CN1CCOCC1
Solvent: CCOCC
Product: CC(C)(C)NS(=O)(=O)CCl
Reaction time: 5 h
Yield: 64.3 %

Procedure:
At 0° C., to a mixture of tert-butylamine (10.3 g, 141 mmol) and N-methylmorpholine (14.9 g, 147 mmol) in diethyl ether (200 mL) was added dropwise a solution of chloromethanesulfonyl chloride (20 g, 134 mmol) in diethyl ether (400 mL). After stirred for 5 h, the solution was diluted with ethyl acetate (200 mL). The organic phase was washed with HCl solution (1 N), water and brine, dried over anhydrous Na2SO4 and concentrated to give the title compound as a colorless oil (16 g).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[S:12][C:11]([C:13]([CH3:16])([CH3:15])[CH3:14])=[N:10][C:9]=2[C:17]2[CH:18]=[C:19]([NH:23][S:24]([C:27]3[CH:32]=[C:31]([F:33])[CH:30]=[CH:29][C:28]=3[F:34])(=[O:26])=[O:25])[CH:20]=[CH:21][CH:22]=2)[CH:5]=[CH:4][N:3]=1.[NH3:35].C(O)(C)C>>[NH2:35][C:2]1[N:7]=[C:6]([C:8]2[S:12][C:11]([C:13]([CH3:16])([CH3:15])[CH3:14])=[N:10][C:9]=2[C:17]2[CH:18]=[C:19]([NH:23][S:24]([C:27]3[CH:32]=[C:31]([F:33])[CH:30]=[CH:29][C:28]=3[F:34])(=[O:26])=[O:25])[CH:20]=[CH:21][CH:22]=2)[CH:5]=[CH:4][N:3]=1
Reactant: N
Reactant: CC(C)(C)c1nc(-c2cccc(NS(=O)(=O)c3cc(F)ccc3F)c2)c(-c2ccnc(Cl)n2)s1
Solvent: CC(C)O
Product: CC(C)(C)c1nc(-c2cccc(NS(=O)(=O)c3cc(F)ccc3F)c2)c(-c2ccnc(N)n2)s1
Temperature: 100 °C

Procedure:
A suspension of N-{3-[5-(2-chloro-4-pyrimidinyl)-2-(1,1-dimethylethyl)-1,3-thiazol-4-yl]phenyl}-2,5-difluorobenzenesulfonamide (150 mg, 0.288 mmol) and 2M ammonia in isopropanol (8.0 mL, 16.0 mmol) was heated in a sealed tube at 100° C. overnight. The reaction mixture was evaporated onto silica gel and chromatographed (10-100% 1:9 MeOH:EtOAc in DCM). The title compound was recovered as a beige solid (38 mg, 25% yield). 1H NMR (400 MHz, DMSO-d6) δ ppm 10.89 (s, 1H), 7.95 (d, J=5.1 Hz, 1H), 7.41-7.68 (m, 3H), 7.31 (t, J=7.9 Hz, 1H), 7.23 (s, 1H), 7.17 (d, J=7.9 Hz, 2H), 6.74 (s, 2H), 6.01 (d, J=5.1 Hz, 1H), 1.38 (s, 9H). MS (ESI): 502.1 [M+H]+.
Reaction SMILES: [Na].[CH2:2]([OH:5])[CH2:3][OH:4].[C:6]([O-:10])(=[O:9])[CH2:7][OH:8].[Na+:11].[Br:12][C:13]1[C:14](=[O:22])[CH:15]2[CH2:21][CH:18]([C:19]=1Br)[CH:17]=[CH:16]2.P([O-])(O)(O)=O.[Na+]>O1CCCC1.CCCCCC.C(OCC)(=O)C>[C:6]([O-:10])(=[O:9])[CH2:7][OH:8].[Na+:11].[Br:12][CH:13]1[C:19]2([O:5][CH2:2][CH2:3][O:4]2)[CH:18]2[CH2:21][CH:15]([CH:16]=[CH:17]2)[C:14]1=[O:22]
Reactant: O=C1C(Br)=C(Br)C2C=CC1C2
Reactant: OCCO
Agent: O=C([O-])CO
Agent: O=P([O-])(O)O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CCCCCC
Solvent: C1CCOC1
Product: O=C1C2C=CC(C2)C2(OCCO2)C1Br
Yield: 100 %

Procedure:
A sodium glycolate solution is prepared by stirring 124 mg (5.4 mmol) of metallic sodium into 2.7 ml (42.42 mmol) of anhydrous ethylene glycol at ambient temperature and, when the sodium has completely dissolved, 1.5 ml of tetrahydrofuran are added. To the resulting monosodium glycolate solution there is then added dropwise a solution of 1 g (3.6 mmol) of 3,4-dibromo-bicyclo[3.2.1]octa-3,6-dien-2-one (prepared according to Organic Lett. 4(12), 1997 (2002)) dissolved in 5 ml of tetrahydrofuran. The reaction mixture is then stirred at ambient temperature for 90 minutes with TLC monitoring (mobile phase hexane/ethyl acetate 4:1). The reaction mixture is then treated with 8 ml of 10% sodium dihydrogen phosphate solution and extracted with ethyl acetate (3×). The organic phase is washed with water to remove ethylene glycol, then dried and concentrated by evaporation. 930 mg (˜100%) of 3-bromo-4,4-ethylenedioxy-bicyclo[3.2.1]oct-6-en-2-one are obtained in the form of a white solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:12]2[C:7](=[C:8]([CH3:13])[CH:9]=[CH:10][CH:11]=2)[C:6]([C:14]([OH:16])=O)=[CH:5][CH:4]=1.[NH:17]1[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1>>[CH3:1][O:2][C:3]1[C:12]2[C:7](=[C:8]([CH3:13])[CH:9]=[CH:10][CH:11]=2)[C:6]([C:14]([N:17]2[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]2)=[O:16])=[CH:5][CH:4]=1
Reactant: C1CCNCC1
Reactant: COc1ccc(C(=O)O)c2c(C)cccc12
Product: COc1ccc(C(=O)N2CCCCC2)c2c(C)cccc12

Procedure:
4-Methoxy-8-methyl-1-naphthoic acid (Step-5 of Intermediate-22) was reacted with piperidine by following the similar procedure as described in Step-6 of Intermediate-22.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([C:21](O)=[O:22])=[CH:5][C:6]2[C:11]([CH:12]=1)=[CH:10][CH:9]=[C:8]([C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([O:19][CH3:20])[CH:14]=1)[CH:7]=2.CCN=C=NCCCN(C)C.O[C:36]1[C:44]2[N:43]=NN[C:40]=2[CH:39]=[CH:38][CH:37]=1.NC1C=CC=CC=1.C(N(CC)CC)C.Cl>ClCCl>[CH3:1][O:2][C:3]1[C:4]([C:21]([NH:43][C:44]2[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=2)=[O:22])=[CH:5][C:6]2[C:11]([CH:12]=1)=[CH:10][CH:9]=[C:8]([C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([O:19][CH3:20])[CH:14]=1)[CH:7]=2
Reactant: COc1cccc(-c2ccc3cc(OC)c(C(=O)O)cc3c2)c1
Reactant: Oc1cccc2[nH]nnc12
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: Nc1ccccc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1cccc(-c2ccc3cc(OC)c(C(=O)Nc4ccccc4)cc3c2)c1
Temperature: 0 °C
Yield: 70 %

Procedure:
3-Methoxy-7-(3-methoxyphenyl)-2-naphthoic acid (323 mg, 1.05 mmol, 1 eq), EDCI (1 eq) and hydroxybenzotriazole (1 eq) are dissolved in 50 ml of dry dichloromethane. To this solution, cooled at 0° C., are added dropwise aniline (1 eq) and triethylamine (1 eq) in 40 ml of dry dichloromethane. The reaction mixture is boiled under reflux for 1.5 h, and after cooling, the reaction is stopped by adding 20 ml of 0.1 M HCl. The organic phase is separated, washed with saturated sodium carbonate and chloride solutions, dried over magnesium sulfate, filtered and concentrated in vacuum on a rotary evaporator. Purification by column chromatography with hexane/ethyl acetate 8/2 and 6/4 as the eluent yielded the desired product in a yield of 70%, 282 mg.
Reaction SMILES: Br[C:2]1[S:6][C:5]2[C:7](=[O:17])[CH2:8][CH:9]([C:10]3[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][CH:11]=3)[C:4]=2[CH:3]=1.[N:18]1[CH:23]=[CH:22][C:21](B(O)O)=[CH:20][CH:19]=1.O1CCOCC1.O.C(=O)([O-])[O-].[Cs+].[Cs+]>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[Cl:16][C:13]1[CH:14]=[CH:15][C:10]([CH:9]2[C:4]3[CH:3]=[C:2]([C:21]4[CH:22]=[CH:23][N:18]=[CH:19][CH:20]=4)[S:6][C:5]=3[C:7](=[O:17])[CH2:8]2)=[CH:11][CH:12]=1
Reactant: O=C1CC(c2ccc(Cl)cc2)c2cc(Br)sc21
Reactant: OB(O)c1ccncc1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: O
Solvent: C1COCCO1
Product: O=C1CC(c2ccc(Cl)cc2)c2cc(-c3ccncc3)sc21
Temperature: 90 °C
Reaction time: 18 h
Yield: 88.5 %

Procedure:
To a 40 mL vial was added a solution of 2-bromo-4-(4-chlorophenyl)-4,5-dihydro-6H-cyclopenta[b]thiophen-6-one (0.150 g, 0.458 mmol) and pyridine-4-boronic acid (0.105 g, 0.855 mmol) in a solution of 1,4-dioxane (8.000 mL, 102.5 mmol) and water (0.800 mL, 44.4 mmol). Cesium carbonate (0.448 g, 1.374 mmol) was added followed by [1,1′-bis(diphenylphosphino)ferrocene]palladium(II)dichloride (0.045 g, 0.055 mmol). The reaction mixture was heated to 90° C. and allowed to stir for 18 h. The reaction was cooled to ambient temperature and quenched by the addition of a saturated aqueous solution of sodium bicarbonate (10.0 mL) and extracted with EtOAc (10.0 mL×3). The combined organic layers were dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The crude material was dry loaded onto silica gel and then purified using ISCO (12 g cartridge, gradient hexanes to 100% EtOAc over 30 min) to afford the title compound (0.132 g, 84%) as a white solid. LC/MS (AA) ES+ 326, 328. 1H NMR (dmso-d6, 400 MHz): δ 8.65-8.63 (m, 2H), 7.79 (s, 1H). 7.77-7.76 (m, 2H), 7.42-7.40 (m, 2H), 7.30-7.28 (m, 2H), 4.72 (dd, 1H), 3.49 (dd, 1H), 2.81 (dd, 1H).
Reaction SMILES: [CH3:1][C:2]1[C:14]2[N:13]([CH3:15])[C:12]3[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=3)[C:6]=2[CH:5]=[C:4]([CH:16]=O)[CH:3]=1.[CH3:18][CH:19]([CH3:35])[C:20]([NH:22][C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([CH:29]2[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]2)[CH:24]=1)=[O:21]>CC(O)=O>[CH3:1][C:2]1[C:14]2[N:13]([CH3:15])[C:12]3[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=3)[C:6]=2[CH:5]=[C:4]([CH2:16][N:32]2[CH2:33][CH2:34][CH:29]([C:25]3[CH:24]=[C:23]([NH:22][C:20](=[O:21])[CH:19]([CH3:35])[CH3:18])[CH:28]=[CH:27][CH:26]=3)[CH2:30][CH2:31]2)[CH:3]=1
Reactant: CC(C)C(=O)Nc1cccc(C2CCNCC2)c1
Reactant: Cc1cc(C=O)cc2c3ccccc3n(C)c12
Solvent: CC(=O)O
Product: Cc1cc(CN2CCC(c3cccc(NC(=O)C(C)C)c3)CC2)cc2c3ccccc3n(C)c12

Procedure:
Prepared by Procedure F and Scheme R, without HOAc, using 1,9-dimethyl-9H-carbazole-3-carbaldehyde and 2-methyl-N-[3-(4-piperidinyl)phenyl]propanamide: 1H NMR (400 MHz, CDCl3) δ 8.05–6.77 (m, 10H) 5.20–5.12 (m, 1H), 4.04 (s, 3H) 3.93 (s, 2H), 3.34–3.24 (m, 2H), 2.79 (s, 3H), 2.56–2.38 (m, 2H), 2.38–2.26 (m, 2H), 2.08–1.88 (m, 2H), 1.82–1.70 (m, 2H), 1.16 (d, 6H, J=6.8 Hz); ESMS m/e: 454.2 (M+H)+.
Reaction SMILES: [F:1][C:2]([F:14])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:3]([O:5]CC)=[O:4].[OH-].[Na+].Cl>>[C:8]1([C:2]([C:3]([OH:5])=[O:4])([F:14])[F:1])[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: CCOC(=O)C(F)(F)c1ccccc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: O=C(O)C(F)(F)c1ccccc1
Temperature: 25 °C
Reaction time: 36 h
Yield: 74.6 %

Procedure:
A suspension of ethyl 2,2-difluoro-2-phenylacetate (6.0 g, 30 mmol), as prepared in the preceding step, in 1 N NaOH (36 mL, 36 mmol) was stirred at ambient temperature. After 36 hours, the reaction became almost homogeneous. The mixture was acidified with 1N HCl (36 mL), and extracted with DCM twice. The extracts were combined, washed with H2O, dried over Na2SO4, and concentrated to give the title compound (3.85 g, 81% yield) as a pale yellow solid, that was used without further purification.
Reaction SMILES: Cl.[NH2:2][CH2:3][CH2:4][C:5]([O:7][CH2:8][CH3:9])=[O:6].[CH3:10][O:11][C:12]1[CH:13]=[C:14]([CH:20]=[CH:21][CH:22]=1)[O:15][CH2:16][CH:17]1[O:19][CH2:18]1.[OH-].[Na+]>>[CH3:10][O:11][C:12]1[CH:13]=[C:14]([CH:20]=[CH:21][CH:22]=1)[O:15][CH2:16][CH:17]([OH:19])[CH2:18][NH:2][CH2:3][CH2:4][C:5]([O:7][CH2:8][CH3:9])=[O:6]
Reactant: CCOC(=O)CCN
Reactant: COc1cccc(OCC2CO2)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: CCOC(=O)CCNCC(O)COc1cccc(OC)c1

Procedure:
This compound was prepared in accordance with Example 1 using 7.6 g of the hydrochloride of ethyl 3-aminopropanoate, 4.5 g of 3-(3-methoxyphenoxy)-1,2-epoxypropane, and 2.0 g of NaOH. The crude product was washed with 150 ml of water and dissolved in 100 ml of water and 10 ml of 2-n HCl. This solution was extracted with ethyl acetate, treated with NaHCO3, and extracted with CH2Cl2. The organic layer was separated, dried over MgSO4, filtered and evaporated. Ethyl N-[3-(2-cyano-4-methoxyphenoxy)-2-hydroxypropyl]-3-aminopropanoate crystallized. Yield 1.2 g. Melting point 72° C. (base). The structure was determined by NMR.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9]([NH:10][C@@H:11]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[F:19])[CH3:12])=[C:8]([C:20]([NH2:22])=[O:21])[CH:7]=[N:6][N:5]2[CH:23]=1.[C:24]1(B(O)O)[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.[O-]P([O-])([O-])=O.[K+].[K+].[K+].N#N>O1CCOCC1>[F:19][C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=1[C@H:11]([NH:10][C:9]1[C:4]2[N:5]([CH:23]=[C:2]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[CH:3]=2)[N:6]=[CH:7][C:8]=1[C:20]([NH2:22])=[O:21])[CH3:12]
Reactant: C[C@@H](Nc1c(C(N)=O)cnn2cc(Br)cc12)c1ccccc1F
Reactant: OB(O)c1ccccc1
Agent: N#N
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Product: C[C@@H](Nc1c(C(N)=O)cnn2cc(-c3ccccc3)cc12)c1ccccc1F
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
(R)-6-bromo-4-(1-(2-fluorophenyl)ethylamino)pyrrolo[1,2-b]pyridazine-3-carboxamide (Intermediate 7, 1 equiv), phenylboronic acid (1 equiv), PdCl2(dppf)-CH2Cl2 complex (0.05 equiv) and 2M K3PO4 (3.4 equiv) in dioxane (0.5 mL) was purged with N2 then at 140° C. for 0.5 h. Following cooling to rt, the product was isolated via reverse-phase preparative HPLC (condition F) of the crude reaction mixture to afford the title compound (3.8 mg) as a brown solid. HPLC (conditions B): retention time=4.28 min; LCMS: 375.14 (M+H)+; 1H NMR (CD3OD, 400 MHz) δ 8.17 (s, 1H), 7.88 (d, J=1.7 Hz, 1H), 7.52 (d, J=7.0 Hz, 2H), 7.14-7.44 (m, 7H), 7.03 (d, J=1.8 Hz, 1H), 5.80 (q, J=6.6 Hz, 1H), 1.70 (d, J=6.6 Hz, 3H).
Reaction SMILES: [OH-:1].[Na+].[O:3]1[CH2:7][CH2:6][CH2:5][CH2:4]1.O>>[CH:5]12[CH2:4][CH:4]([CH2:7][CH2:6]1)[CH2:5][CH:6]2[C:7]([OH:3])=[O:1]
Reactant: C1CCOC1
Reactant: [OH-]
Agent: [Na+]
Solvent: O
Product: O=C(O)C1CC2CCC1C2
Temperature: 25 °C
Reaction time: 24 h

Procedure:
5.00 g (20.0 mmol) of the Diels-Alder adduct obtained by the step 2 of Example 1 was dissolved in 45 ml of a mixture solvent of tetrahydrofuran-water (5:4), 1.85 g (43.0 mmol) of sodium hydroxide (93%) was added on ice cooling, and the mixture was stirred at room temperature for 24 hours. After tetrahydrofuran was distilled off, the reaction mixture was neutralized with concentrated hydrochloric acid. Then, 280 mg of 5% palladium-carbon powder was added and the mixture was stirred for 30 hours under an atmosphere of hydrogen. The catalyst was filtered off, the filtrate was acidified with concentrated hydrochloric acid and extracted with a mixture solvent of hexane-methylene chloride (98:2) (50 ml×4). The extract was dried over anhydrous magnesium sulfate and filtered, the solvent was distilled off, and 2.66 g of crude 2-norbornanecarboxylic acid was obtained. Crude yield: 95%.
Reaction SMILES: [CH:1]1[C:6](N=C=S)=[CH:5][C:4]2[C:10]([O:12][C:13]3([C:23]4[CH:24]=[CH:25][C:26]([OH:28])=[CH:27][C:22]=4[O:21][C:15]4[CH:16]=[C:17]([OH:20])[CH:18]=[CH:19][C:14]3=4)[C:3]=2[CH:2]=1)=[O:11].O>CN(C=O)C.B([O-])([O-])[O-]>[CH:1]1[CH:6]=[CH:5][C:4]([C:10]([OH:12])=[O:11])=[C:3]([C:13]2[C:14]3[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][C:15]=3[O:21][C:22]3[C:23]=2[CH:24]=[CH:25][C:26]([CH:27]=3)=[O:28])[CH:2]=1
Reactant: O=C1OC2(c3ccc(O)cc3Oc3cc(O)ccc32)c2ccc(N=C=S)cc21
Agent: [O-]B([O-])[O-]
Solvent: CN(C)C=O
Solvent: O
Product: O=C(O)c1ccccc1-c1c2ccc(=O)cc-2oc2cc(O)ccc12
Reaction time: 8 h

Procedure:
A solution of fluorescein isothiocyanate (Aldrich) 10 μl of 10% solution in DMF) was added to the aminooligonucleotide (0.25 A260 units) in 0.2 M borate buffer, pH 8.6, 100 μl). The mixture was shaken in the dark overnight; then water (400 μl) was added and the mixture was desalted by gel filtration on a NAP-5 column (Pharmacia). The filtrate (1 ml) was collected, concentrated, and repurified by gel filtration. Reversed phase HPLC showed that the oligomers were converted essentially completely to the fluorescein conjugated derivatives: for the derivative of 3'-amino-oligomer 18, elution time 21.5 min (compared to 19.0 min for the starting amino-oligomer); for the derivative of 5'3'-diamino-oligomer 19, elution time 23.6 min (compared to 18.5 min for the starting diaminooligomer). The UV spectra show the presence of both the thymidine and fluorescein moieties: for derivative of 18, λmax 266, 456, 480 nm, λmin 240, 332, 468 nm; for derivative of 19, λmax 266, 460, 482, μmin 250, 332, 470 nm.
Reaction SMILES: [C:1]([NH:3][C:4](=[N:12][C:13]1[CH:18]=[CH:17][C:16]([O:19][CH:20]([F:22])[F:21])=[C:15]([O:23][CH:24]([CH3:26])[CH3:25])[CH:14]=1)OC1C=CC=CC=1)#[N:2].[NH:27]([C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][N:30]=1)[NH2:28]>CC(N(C)C)=O>[F:22][CH:20]([F:21])[O:19][C:16]1[CH:17]=[CH:18][C:13]([NH:12][C:4]2[N:3]=[C:1]([NH2:2])[N:27]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][N:30]=3)[N:28]=2)=[CH:14][C:15]=1[O:23][CH:24]([CH3:25])[CH3:26]
Reactant: CC(C)Oc1cc(N=C(NC#N)Oc2ccccc2)ccc1OC(F)F
Reactant: NNc1ccccn1
Solvent: CC(=O)N(C)C
Product: CC(C)Oc1cc(Nc2nc(N)n(-c3ccccn3)n2)ccc1OC(F)F
Temperature: 220 °C
Reaction time: 0.5 h
Yield: 94.9 %

Procedure:
A mixture of N-cyano-N′-(4-difluoromethoxy-3-iso-propyloxyphenyl)-O-phenylisourea (0.10 g, 0.28 mmol) and 2-hydrazino-pyridine (0.06 g, 0.56 mmol) in dimethylacetamide (3 mL) was heated in the microwave apparatus at 220° C. for 15 min. The reaction was cooled, poured into ice-water and stirred for 0.5 h. The precipitate was filtered off, washed with cold water and dried to provide the title compound (0.10 g, 97% yield) as a pale pink solid.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][C:9](=[O:20])[C:10]2[CH:15]=[CH:14][C:13](Cl)=[C:12]([N+:17]([O-:19])=[O:18])[CH:11]=2)=[N:6][CH:7]=1.[NH2:21][C:22]1[CH:27]=[CH:26][C:25]([SH:28])=[CH:24][CH:23]=1.O.O.O.C([O-])(=O)C.[Na+].O>C(O)C>[NH2:21][C:22]1[CH:27]=[CH:26][C:25]([S:28][C:13]2[CH:14]=[CH:15][C:10]([C:9]([NH:8][C:5]3[CH:4]=[CH:3][C:2]([Br:1])=[CH:7][N:6]=3)=[O:20])=[CH:11][C:12]=2[N+:17]([O-:19])=[O:18])=[CH:24][CH:23]=1
Reactant: O=C(Nc1ccc(Br)cn1)c1ccc(Cl)c([N+](=O)[O-])c1
Reactant: Nc1ccc(S)cc1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: Nc1ccc(Sc2ccc(C(=O)Nc3ccc(Br)cn3)cc2[N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 98.7 %

Procedure:
A mixture of the product of Example 364A (24.2 g, 0.0678 mol), 4-amino-benzenethiol (12.7 g, 0.102 mol, 1.5 equiv.), and sodium acetate trihydrate (46.1 g, 0.339 mol, 5.0 equiv.) in 500 mL of ethanol was heated under reflux under nitrogen with stirring for 2 hours. The reaction mixture was then allowed to cool to room temperature and 200 mL of water added. The mixture was stirred for 30 minutes, filtered, and dried in vacuo to give the title compound (29.8 g, 99%).
Reaction SMILES: C(OC([NH:8][CH2:9][CH2:10][NH:11][C:12]1[N:17]=[C:16]([NH:18]C(=O)OC(C)(C)C)[C:15]([C:26](=[O:31])[C:27]([F:30])([F:29])[F:28])=[CH:14][CH:13]=1)=O)(C)(C)C.[ClH:32]>O1CCOCC1>[ClH:32].[NH2:18][C:16]1[C:15]([C:26](=[O:31])[C:27]([F:28])([F:30])[F:29])=[CH:14][CH:13]=[C:12]([NH:11][CH2:10][CH2:9][NH2:8])[N:17]=1
Reactant: CC(C)(C)OC(=O)NCCNc1ccc(C(=O)C(F)(F)F)c(NC(=O)OC(C)(C)C)n1
Agent: Cl
Solvent: C1COCCO1
Product: NCCNc1ccc(C(=O)C(F)(F)F)c(N)n1
Reaction time: 20 h

Procedure:
2.5 g (5.57 mmol) of tert-butyl [6-({2-[(tert-butoxycarbonyl)amino]ethyl}amino)-3-(trifluoro-acetyl)pyridin-2-yl]carbamate (Example 114A) dissolved in 15 ml of 4N hydrogen chloride in dioxane and stirred for 20 h. The reaction mixture is concentrated to one half, and an equal portion of diethyl ether is added. The reaction mixture is stirred for 20 min, and the product is filtered off and washed with diethyl ether. 1.4 g (89% of theory) of the product are obtained as a solid.
Reaction SMILES: [Cl:1][C:2]1[CH:37]=[CH:36][C:5]2[N:6](CC3C=CC(OC)=CC=3)[C:7](=[O:26])[CH:8]([CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[CH3:25])[N:9]=[C:10]([C:11]3[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=3)[C:4]=2[CH:3]=1.C1(OC)C=CC=CC=1.[Al+3].[Cl-].[Cl-].[Cl-]>ClC(Cl)C.C(OCC)(=O)C>[Cl:1][C:2]1[CH:37]=[CH:36][C:5]2[NH:6][C:7](=[O:26])[CH:8]([CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[CH3:25])[N:9]=[C:10]([C:11]3[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=3)[C:4]=2[CH:3]=1
Reactant: COc1ccc(CN2C(=O)C(Cc3ccccc3C)N=C(c3ccc(F)cc3)c3cc(Cl)ccc32)cc1
Agent: [Al+3]
Agent: [Cl-]
Solvent: CCOC(C)=O
Solvent: CC(Cl)Cl
Solvent: COc1ccccc1
Product: Cc1ccccc1CC1N=C(c2ccc(F)cc2)c2cc(Cl)ccc2NC1=O
Temperature: 85 °C
Reaction time: 0.33 h
Yield: 79.9 %

Procedure:
7-Chloro-5-(4-fluorophenyl)-1-(4-methoxybenzyl)-3-(2-methylbenzyl)-1H-benzo[e][1,4]diazepin-2(3H)-one (44 mg, 0.086 mmol) was dissolved in dichloroethane (1 mL) under nitrogen and 200 μL of anisole was added followed by AlCl3 (69 mg, 0.515 mmol). This mixture was heated to 85° C. for 2.5 h then allowed to cool and diluted with ethyl acetate and ice. This biphasic mixture was stirred vigorously for 20 min, then partitioned, and the organic layer was washed with water twice, then brine once. The aqueous layers were back-extracted once with ethyl acetate, and the combined organic extracts dried over MgSO4. Chromatography on silica gel (5%-30%-40%-50% ethyl acetate in hexanes) provided the title compound (27 mg, 80%) as a yellow solid. APCI MS m/z 415.1 [M+Na+], 393.1 [M+H+]; 1H NMR (300 MHz, CDCl3) δ 9.28 (s, 1H), 7.61-7.16 (m, 11H), 3.91 (t, J=7 Hz, 1H), 3.72-3.69 (m, 2H), 2.50 (s, 3H).
Reaction SMILES: C([O:3][C:4]([CH2:6][O:7][C:8]1[CH:35]=[CH:34][CH:33]=[CH:32][C:9]=1[C:10]([NH:12][C:13]1[CH:31]=[CH:30][C:16]([C:17]([N:19]2[C:25]3[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=3[CH2:23][CH2:22][CH2:21][CH2:20]2)=[O:18])=[CH:15][CH:14]=1)=[O:11])=O)C.[NH3:36].[Cl-].[NH4+]>CO>[C:4]([CH2:6][O:7][C:8]1[CH:35]=[CH:34][CH:33]=[CH:32][C:9]=1[C:10]([NH:12][C:13]1[CH:14]=[CH:15][C:16]([C:17]([N:19]2[C:25]3[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=3[CH2:23][CH2:22][CH2:21][CH2:20]2)=[O:18])=[CH:30][CH:31]=1)=[O:11])(=[O:3])[NH2:36]
Reactant: N
Reactant: CCOC(=O)COc1ccccc1C(=O)Nc1ccc(C(=O)N2CCCCc3ccccc32)cc1
Agent: [Cl-]
Agent: [NH4+]
Solvent: CO
Product: NC(=O)COc1ccccc1C(=O)Nc1ccc(C(=O)N2CCCCc3ccccc32)cc1
Temperature: 100 °C

Procedure:
A mixture of 1-[4-(2-ethoxycarbonylmethoxybenzoylamino)benzoyl]-2,3,4,5-tetrahydro-1H-benzazepine (1.00 g), aqueous ammonia (100 ml), ammonium chloride (0.3 g) and methanol (150 ml) is heated at 100° C. for 4 hours in a sealed tube. The solvent is distilled off and the resulting residue is extracted with chloroform, washed successively with water and saturated saline solution, and dried over magnesium sulfate. The solvent is concentrated and the resulting residue is purified by silica gel column chromatography (eluent; chloroform:methanol=50:1), and recrystallized from methanol/diethyl ether to give 1-[4-(2-carbamoylmethoxybenzoylamino)benzoyl]-2,3,4,5-tetrahydro-1H-benzazepine (0.43 g) as white powder, m.p. 198°-199° C.