Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:6]([NH:14][C:15]([O:17][CH:18]([CH3:20])[CH3:19])=[O:16])=[C:7]2[C:11](=[CH:12][CH:13]=1)[CH2:10][CH2:9][CH2:8]2)=[O:4].[H-].[Na+].Br[CH2:24][CH2:25][CH2:26][C:27]([O:29][CH2:30][CH3:31])=[O:28]>CN(C=O)C.C(OCC)(=O)C>[CH3:1][O:2][C:3]([C:5]1[C:6]([N:14]([CH2:24][CH2:25][CH2:26][C:27]([O:29][CH2:30][CH3:31])=[O:28])[C:15]([O:17][CH:18]([CH3:20])[CH3:19])=[O:16])=[C:7]2[C:11](=[CH:12][CH:13]=1)[CH2:10][CH2:9][CH2:8]2)=[O:4]
Reactant: CCOC(=O)CCCBr
Reactant: COC(=O)c1ccc2c(c1NC(=O)OC(C)C)CCC2
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCOC(=O)CCCN(C(=O)OC(C)C)c1c(C(=O)OC)ccc2c1CCC2
Temperature: 65 °C
Reaction time: 1 h
Yield: 79.2 %

Procedure:
Add a solution of 4-Isopropoxycarbonylamino-indan-5-carboxylic acid methyl ester (570 mg, 2.1 mmol) in DMF (8.2 mL) to a suspension of sodium hydride 60% dispersion mineral oil (82 mg, 2.1 mmol) in DMF (8.2 mL) at 0° C. under an atmosphere of nitrogen and allow to reach room temperature over 1 h. Add ethyl 4-bromobutyrate (0.44 mL, 3.09 mmol) and stir at room temperature for 14 h, then heat at 65° C. for 2 h. Cool the mixture to room temperature, dilute with ethyl acetate, wash with 1M HCl, water and brine. Dry the organic layer over anhydrous sodium sulfate, filter and remove the solvent under reduced pressure. Purify the residue by flash chromatography, eluting with hexanes/ethyl acetate, to provide the title compound (651 mg, 81%): 1H NMR (MeOD, 300 MHz) δ 1.03-1.34 (m, 9H), 1.85 (m, 2H), 2.10 (m, 2H), 2.30 (m, 2H), 2.82-3.01 (m, 4H), 3.32 (m, 1H), 3.68 (m, 1H), 3.86 (s, 3H), 4.08 (m, 2H), 4.91 (m, 1H), 7.19 (d, J=7.7 Hz, 1H), 7.77 (d, J=7.7 Hz, 1H). MS (ES+): 392 (M+H).
Reaction SMILES: Cl[CH2:2][C:3]1[CH:12]=[CH:11][C:10]2[C:5](=[CH:6][CH:7]=[C:8]([O:13][CH3:14])[CH:9]=2)[N:4]=1.[CH3:15][NH2:16]>>[CH3:14][O:13][C:8]1[CH:9]=[C:10]2[C:5](=[CH:6][CH:7]=1)[N:4]=[C:3]([CH2:2][NH:16][CH3:15])[CH:12]=[CH:11]2
Reactant: CN
Reactant: COc1ccc2nc(CCl)ccc2c1
Product: CNCc1ccc2cc(OC)ccc2n1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 76 %

Procedure:
2-(Chloromethyl)-6-methoxyquinoline (0.40 g, 2.05 mmol) was dissolved in ethanolic methylamine (15 mL, 33 wt % in EtOH) at 0° C. under a nitrogen atmosphere. After 10 minutes the reaction mixture was warmed to room temperature and stirring was continued for 1.5 hours. The reaction mixture was concentrated, partitioned between 10% K2CO3 /ethyl acetate, dried over MgSO4 and evaporated under reduced pressure to afford 0.30 g (76%) of a pale yellow oil which was used directly in the next step.
Reaction SMILES: C(N(CC)CC)C.[NH2:8][C@@H:9]([CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[CH2:10][OH:11].Cl[C:20](=[O:26])[C:21]([O:23]CC)=[O:22].[OH-].[Na+].Cl>ClCCl.O>[OH:11][CH2:10][C@@H:9]([NH:8][C:20](=[O:26])[C:21]([OH:23])=[O:22])[CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: CCOC(=O)C(=O)Cl
Reactant: N[C@H](CO)Cc1ccccc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(O)C(=O)N[C@H](CO)Cc1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 92.8 %

Procedure:
Triethylamine (0.703 mL; 5.01 mmol) was added to the mixture of (S)-2-amino-3-phenylpropan-1-ol (0.515 g; 3.34 mmol) and ethyl 2-chloro-2-oxoacetate (0.400 mL; 3.50 mmol) in dichloromethane (15 mL) at 0° C. After addition, the mixture was stirred at room temperature for 30 minutes, diluted with 40 mL of dichloromethane, and washed successively with an aqueous solution of sodium carbonate, and water. The organic layer was dried over magnesium sulfate and concentrated under reduced pressure. Water (5 mL) and a 2M solution of sodium hydroxide (5 mL; 10 mmol) were added to the resulting residue and the mixture was stirred at room temperature for 10 minutes. Water (10 mL) was added and the pH of the solution was adjusted to 1 by addition of a 6N hydrochloric acid. The formed solid was filtered off, and the filtrate was extracted with ethyl acetate (5×20 mL). The combined organic layers were dried over magnesium sulfate and evaporated to dryness to give 0.692 g (94%) of (S)-2-(1-hydroxy-3-phenylpropan-2-ylamino)-2-oxoacetic acid as a white solid.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:8](Cl)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[NH:12]1[CH2:17][CH2:16][O:15][CH2:14][CH2:13]1>ClCCl>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: O=S(=O)(Cl)c1ccc(Br)cc1
Reactant: C1COCCN1
Solvent: ClCCl
Product: O=S(=O)(c1ccc(Br)cc1)N1CCOCC1
Yield: 27.2 %

Procedure:
According to general procedure C, 4-Bromobenzene sulfonyl chloride (0.40 g, 1.56 mmol) and morpholine (0.34 mL, 3.90 mmol) were stirred together in dry dichloromethane (5 mL) for 16 hours. 4-[(4-bromophenyl)sulfonyl]morpholine (0.13 g, 28%) was provided after purification. MS (ESI) m/z 306. HPLC purity 100.0% at 210-370 nm, 8.2 min.; the Xterra® RP18 column, 3.5μ, 150×4.6 mm column, 1.2 mL/min., 85/15-5/95 (ammonium formate buffer pH=3.5/ACN+MeOH) for 10 min., hold 4 min.
Reaction SMILES: Cl.[CH3:2][N:3]1[CH2:8][CH2:7][N:6]([C:9]([Cl:11])=[O:10])[CH2:5][CH2:4]1.Cl.[OH2:13].[NH:14]1[CH2:19][CH2:18][CH2:17][CH2:16][C:15]1=O.C(N(CC)CC)C>ClCCl>[ClH:11].[CH3:2][N:3]1[CH2:8][CH2:7][N:6]([C:9]([N:14]2[CH2:19][CH2:18][C:17](=[O:13])[CH2:16][CH2:15]2)=[O:10])[CH2:5][CH2:4]1
Reactant: O
Reactant: O=C1CCCCN1
Reactant: CN1CCN(C(=O)Cl)CC1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CN1CCN(C(=O)N2CCC(=O)CC2)CC1
Reaction time: 2 h
Yield: 49.7 %

Procedure:
To a suspension of 4-methylpiperazine-1-carbonyl chloride hydrochloride (19.9 g 0.1 mol) and piperidone monohydrate hydrochloride (15.3 g 0.1 mol), in 200 mL of dichloromethane, dry triethylamine (45 mL, 0.33 mol) was added dropwise. The mixture was stirred for 2 hours. The organic phase was washed with brine (2×20 mL) and dried over sodium sulfate. After filtration, the solvent was evaporated in vacuo and the crude product was dissolved in EtOH (50 mL) and diethylether (100 mL) and treated with HCl 4N in dioxane (25 mL). After 1 hour, the precipitate was filtered and dried in oven to give 13 g (yield 50%) of the title compound.
Reaction SMILES: [CH3:1][O:2][C:3]1C2C(=O)[CH2:10][C:11]3([O:17][C:7]=2[CH:6]=[C:5]([O:19][CH2:20][C:21]([O:23][CH2:24][CH3:25])=[O:22])[CH:4]=1)[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]3.[CH:26]([SH:29])([SH:28])[CH3:27].[CH:30]1C=CC=C[CH:31]=1>C1(C)C=CC(S(O)(=O)=O)=CC=1>[CH3:1][O:2][C:3]1[C:27]2[C:26]3([CH2:10][C:11]4([O:17][C:7]=2[CH:6]=[C:5]([O:19][CH2:20][C:21]([O:23][CH2:24][CH3:25])=[O:22])[CH:4]=1)[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]4)[S:29][CH2:31][CH2:30][S:28]3
Reactant: CCOC(=O)COc1cc(OC)c2c(c1)OC1(CCCCC1)CC2=O
Reactant: c1ccccc1
Reactant: CC(S)S
Agent: Cc1ccc(S(=O)(=O)O)cc1
Product: CCOC(=O)COc1cc(OC)c2c(c1)OC1(CCCCC1)CC21SCCS1
Yield: 82.1 %

Procedure:
A mixture of ethyl {(5-methoxy-3,4-dihydro-4-oxospiro[2H-1-benzopyran-2,1'-cyclohexan]-7-yl)oxy}acetate (prepared in Preparation 49) (0.5 g, 1.44 mmol), ethanedithiol (0.149 g, 1.59 mmol), dry benzene (10 ml), and p-toluenesulfonic acid (0.013 g, 0.076 mmol) is heated to reflux for 12 hours under conditions for azeotropic dehydration. The solvent is removed under reduced pressure. The residue is applied to a silica gel column and eluted with a mixture of ethyl acetate and dichloromethane (1:9). The eluate is applied to a Lober column and eluted with a mixture of ethyl acetate and hexane (1:2) to obtain ethyl {(5-methoxy-3,4-dihydrodispiro[2H-1-benzopyran-2,1'-cyclohexan-4,2"-[1,3]dithiolan]-7-yl)oxy}acetate as an oil (0.50 g, 82.1%). A mixture of the ester (0.49 g, 1.16 mmol), 1N sodium hydroxide (1.27 ml, 1.27 mmol), and ethanol (5 ml) is stirred at room temperature for 0.5 hours. The reaction mixture is made acid with 1N HCl and distilled under reduced pressure at room temperature to remove ethanol. The residue is extracted with diethyl ether. The extract is washed with saturated brine, dried, and the solvent is removed under reduced pressure. The residue is treated with a mixture of diethyl ether and hexane to obtain the title compound as a crystalline soild (0.43 g, 93.7%). Recrystallization from ethyl acetate gives a product having a melting point of 189°-190° C.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:8]=[O:9].OO>[O-][W]([O-])(=O)=O.[Na+].[Na+].O>[CH:8]([NH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)=[O:9]
Reactant: Nc1ccccc1
Reactant: C=O
Agent: O=[W](=O)([O-])[O-]
Agent: OO
Agent: [Na+]
Solvent: O
Product: O=CNc1ccccc1

Procedure:
18.6 g (0.2 mol) of aniline are introduced into 30 ml of water, followed by the dropwise addition with stirring of 20 g (0.2 mol) of a 30 % by weight aqueous formaldehyde solution. 0.2 g of sodium tungstate are then added, followed by the dropwise addition with continued stirring of 25 g of a 30 % by weight aqueous hydrogen peroxide solution. The temperature rises to about 60° to 70°C. The dark oil precipitated is taken up in about 30 ml of methylene chloride and the organic phase is separated off. The aqueous phase is repeatedly extracted with methylene chloride. The combined organic phases are dried over sodium sulphate and subsequently subjected to fractional distillation in vacuo, giving 12.2 g (51 % of the theoretical yield) of formanilide boiling at 160° to 172°C/ 15 Torr.
Reaction SMILES: CN(C1CCCCC1)C1CCCCC1.Br[C:16]1[C:17]([N:22]([CH2:42][O:43][CH2:44][CH2:45][Si:46]([CH3:49])([CH3:48])[CH3:47])[C:23](=[O:41])[CH2:24][C:25]2[CH2:26][CH2:27][N:28]([C:31]([O:33][CH2:34][C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=3)=[O:32])[CH2:29][CH:30]=2)=[N:18][CH:19]=[CH:20][CH:21]=1>O1CCOCC1.O.[Pd].C(P(C(C)(C)C)C(C)(C)C)(C)(C)C.C(P(C(C)(C)C)C(C)(C)C)(C)(C)C>[O:41]=[C:23]1[CH2:24][C:25]2([CH:26]=[CH:27][N:28]([C:31]([O:33][CH2:34][C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=3)=[O:32])[CH2:29][CH2:30]2)[C:16]2[C:17](=[N:18][CH:19]=[CH:20][CH:21]=2)[N:22]1[CH2:42][O:43][CH2:44][CH2:45][Si:46]([CH3:49])([CH3:48])[CH3:47]
Reactant: C[Si](C)(C)CCOCN(C(=O)CC1=CCN(C(=O)OCc2ccccc2)CC1)c1ncccc1Br
Agent: [Pd]
Agent: CC(C)(C)P(C(C)(C)C)C(C)(C)C
Agent: CN(C1CCCCC1)C1CCCCC1
Solvent: C1COCCO1
Solvent: O
Product: C[Si](C)(C)CCOCN1C(=O)CC2(C=CN(C(=O)OCc3ccccc3)CC2)c2cccnc21
Temperature: 50 °C
Reaction time: 0.08 h
Yield: 79.6 %

Procedure:
To a mixture of N-methyldicyclohexylamine (0.042 mg, 0.20 mmol) and benzyl 4-[2-((3-bromopyridin-2-yl){[2-(trimethylsilyl)ethoxy]methyl}amino)-2-oxoethyl]-3,6-dihydropyridine-1(2H)-carboxylate (100 mg, 0.178 mmol) in dioxane (2 mL) was added bis(tri-tert-butylphosphine) palladium(0) (9 mg, 0.018 mmol). After 5 min, the reaction was heated to 50° C. After 90 min, bis(tri-tert-butylphosphine) palladium(0) (9 mg) was added. After an additional 30 min at 50° C., the reaction mixture was diluted with water and extracted with ether (3×). The combined organic layers were dried over MgSO4, filtered, and concentrated. The crude product was purified by silica gel chromatography, eluting with a gradient of 5 to 60% ethyl acetate:hexanes to give the title compound (68 mg). MS: m/z=480.2 (M+1).
Reaction SMILES: [C:1]([OH:9])(=[O:8])[C:2]([CH2:4][C:5]([OH:7])=[O:6])=[CH2:3].C1CC(NC2[C:25]3[C:20](=[CH:21][C:22](Cl)=[C:23](Cl)[CH:24]=3)[C:19]([C:28]3C=CN=CC=3)=NN=2)CC1.S(OOS([O-])(=O)=O)([O-])(=O)=O.[Na+].[Na+]>O>[CH2:1]=[CH:2][CH:4]=[CH2:5].[CH2:28]=[CH:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.[C:1]([OH:9])(=[O:8])[C:2]([CH2:4][C:5]([OH:7])=[O:6])=[CH2:3]
Reactant: Clc1cc2c(NC3CCCC3)nnc(-c3ccncc3)c2cc1Cl
Agent: C=C(CC(=O)O)C(=O)O
Agent: O=S(=O)([O-])OOS(=O)(=O)[O-]
Agent: [Na+]
Solvent: O
Product: C=CC=C
Product: C=Cc1ccccc1
Temperature: 65.55555555555556 °C

Procedure:
A styrene-butadiene-itaconic acid copolymer was prepared by adding to a pressure reactor with constant stirring 29.1 parts water, 1.0 parts itaconic acid, 0.5 parts of a 10 percent solution of Aerosol A-196 surfactant (sodium dicyclohexyl sulfosuccinate, available from American Cyanamid Co., Wayne, N.J.), and 0.5 parts of a polystyrene seed, 25 nm particle size. The mixture was heated to 150° F. and 0.2 parts sodium persulfate in 2.7 parts water was added to initiate the reaction.
Reaction SMILES: [CH2:1]([O:4][N:5]=[C:6]1[CH2:10][N:9]([C:11]([O:13]C(C)(C)C)=O)[C@H:8]([C:18]([OH:20])=O)[CH2:7]1)[CH:2]=[CH2:3].[O:21]=[C:22]1[C:27](C(Cl)=O)=[CH:26][CH:25]=[C:24]([CH2:31][CH2:32][CH2:33][CH2:34][CH3:35])[O:23]1.[CH2:36]([N:38]1[C:50]2[CH:49]=[CH:48][C:47]([NH2:51])=[CH:46][C:45]=2[C:44]2[C:39]1=[CH:40][CH:41]=[CH:42][CH:43]=2)[CH3:37]>>[CH2:1]([O:4][N:5]=[C:6]1[CH2:10][N:9]([C:11]([C:27]2[C:22](=[O:21])[O:23][C:24]([CH2:31][CH2:32][CH2:33][CH2:34][CH3:35])=[CH:25][CH:26]=2)=[O:13])[C@H:8]([C:18]([NH:51][C:47]2[CH:48]=[CH:49][C:50]3[N:38]([CH2:36][CH3:37])[C:39]4[C:44]([C:45]=3[CH:46]=2)=[CH:43][CH:42]=[CH:41][CH:40]=4)=[O:20])[CH2:7]1)[CH:2]=[CH2:3]
Reactant: C=CCON=C1C[C@@H](C(=O)O)N(C(=O)OC(C)(C)C)C1
Reactant: CCn1c2ccccc2c2cc(N)ccc21
Reactant: CCCCCc1ccc(C(=O)Cl)c(=O)o1
Product: C=CCON=C1C[C@@H](C(=O)Nc2ccc3c(c2)c2ccccc2n3CC)N(C(=O)c2ccc(CCCCC)oc2=O)C1

Procedure:
Following the general method as outlined in Example 22, starting from (2S,4EZ)-4-[(allyloxy)-imino]-1-(tert-butoxycarbonyl)-2-pyrrolidinecarboxylic acid, 2-oxo-6-pentyl-2H-pyran-3-carbonyl chloride, and 9-ethyl-9H-carbazol-3-amine the title compound was obtained in 48% purity by LC/MS. MS(ESI+): m/z=569.4.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:9]=[C:10]2[C:14]3=[C:15]([CH2:17][CH2:18][N:13]3[C@@H:12]3[CH2:19][CH2:20][N:21](C(OC(C)(C)C)=O)[CH2:22][C@H:11]23)[CH:16]=1.[OH-].[Na+]>C(O)(C(F)(F)F)=O.C(Cl)Cl>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:9]=[C:10]2[C:14]3=[C:15]([CH2:17][CH2:18][N:13]3[C@@H:12]3[CH2:19][CH2:20][NH:21][CH2:22][C@H:11]23)[CH:16]=1
Reactant: CC(C)(C)OC(=O)N1CC[C@@H]2[C@H](C1)c1cc(-c3ccccc3Cl)cc3c1N2CC3
Agent: [Na+]
Agent: [OH-]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Clc1ccccc1-c1cc2c3c(c1)[C@H]1CNCC[C@H]1N3CC2
Temperature: 25 °C
Reaction time: 2 h
Yield: 85.7 %

Procedure:
Tert-butyl (±)-cis-2-(2-chlorophenyl)-4,5,7,8,10,10a-hexahydropyrido[4,3-b]pyrrolo[3,2,1-hi]indole-9(6aH)-carboxylate (45.1 mg, 0.11 mmol) was dissolved in 20% TFA in methylene chloride (4 mL) and was stirred at RT for 2 h. The reaction was solution was cooled to 0° C. and basified with 1M NaOH until pH>14. The layers were separated. The aqueous phase was extracted the methylene chloride (2×10 ml). The organic layers were washed with brine and dried. Concentration afforded the title compound (29.3 mg, 86%) as a pale yellow amorphous solid. 1H NMR (CDCl3, 300 MHz) δ7.42 (dd, 1H, J=1.4, 7.3 Hz), 7.16-7.33 (m, 3H), 7.02 (s, 1H), 6.96 (s, 1H), 3.69 (dt, 1H, J=1.4, 8.1 Hz), 3.15-3.50 (m, 5H), 3.06 (dt, 1H, J=3.2, 12.3 Hz), 2.82-2.97 (m, 3H), 1.78-1.93 (m, 2H) ppm. MS (CI, NH3): 311 (base, M+H).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([CH2:12][N:13]([CH3:15])[CH3:14])=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH:7]=[CH:6]2.CN(C=O)C.[CH3:21][O:22][C:23]1[CH:28]=[C:27]([CH3:29])[CH:26]=[CH:25][C:24]=1[S:30](Cl)(=[O:32])=[O:31]>>[CH3:1][O:2][C:3]1[C:4]([CH2:12][N:13]([CH3:14])[CH3:15])=[C:5]2[C:9](=[CH:10][CH:11]=1)[N:8]([S:30]([C:24]1[CH:25]=[CH:26][C:27]([CH3:29])=[CH:28][C:23]=1[O:22][CH3:21])(=[O:32])=[O:31])[CH:7]=[CH:6]2
Reactant: COc1ccc2[nH]ccc2c1CN(C)C
Reactant: COc1cc(C)ccc1S(=O)(=O)Cl
Solvent: CN(C)C=O
Product: COc1cc(C)ccc1S(=O)(=O)n1ccc2c(CN(C)C)c(OC)ccc21
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 18.4 %

Procedure:
To a solution of 1-(5-methoxy-1H-indol-4-yl)-N,N-dimethylmethanamine (15 mg, 0.07 mmol; Intermediate 97) in DMF (1 mL) NaH (4 mg, 0.15 mmol) was added at rt. The reaction mixture was stirred at rt for 15 min and 2-methoxy-4-methylbenzenesulfonyl chloride (24 mg, 0.11 mmol) was added. The reaction mixture was allowed to stir at rt over night. The reaction was quenched by addition of water. Purification by preparative HPLC/UV (System B) afforded the title product (5 mg, 17%) as a white solid. MS (ESI+) for C20H24N2O4S m/z 389 (M+H)+.
Reaction SMILES: [CH3:1][N:2]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[C:6]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[F:19])=[N:5][CH2:4][CH:3]1[CH2:20][NH2:21].[NH:22]1[C:30]2[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=2)[C:24]([CH2:31][C:32]([OH:34])=[O:33])=[CH:23]1.Cl.C(N=C=NCCCN(C)C)C>C(Cl)Cl>[OH2:33].[CH3:1][N:2]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[C:6]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[F:19])=[N:5][CH2:4][CH:3]1[CH2:20][NH:21][C:32]([CH2:31][C:24]1[C:25]2[C:30](=[CH:29][CH:28]=[CH:27][CH:26]=2)[NH:22][CH:23]=1)=[O:34]
Reactant: CN1c2ccccc2C(c2ccccc2F)=NCC1CN
Reactant: O=C(O)Cc1c[nH]c2ccccc12
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Product: CN1c2ccccc2C(c2ccccc2F)=NCC1CNC(=O)Cc1c[nH]c2ccccc12
Product: O
Reaction time: 8 h
Yield: 71.9 %

Procedure:
According to the method of Example 1, 1-methyl-2-aminomethyl-5-(2'-fluorophenyl)-2,3-dihydro-1H-1,4-benzodiazepine (250 mg, 0.88 mmole) and indole-3-acetic acid (154 mg, 0.88 mmole) were combined with 4 ml of dry methylene chloride, and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (169 mg, 0.88 mmole) was added to this mixture. After pH-adjustment, overnight stirring, dilution and washing, rotoevaporation of the dried extracts of the reaction afforded 290 mg of an oil which was purified by silica gel chromatography (ethyl acetate elution) to give material which was 70% pure by HPLC. Rechromatography (chloroform-ethanol elution, 95:5 v/v) afforded the analytical sample, 93% pure, as a yellow solid.
Reaction SMILES: [P:1]([NH2:4])([O-:3])[O-:2].CO[C:7](OC)([O:19][C:20]([C:33]1[CH:38]=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[CH:8]1[CH2:13]CC(CP(=O)([O-])O)CC1.C([NH+:43](CC)CC)C>C(Cl)(Cl)(Cl)Cl>[CH2:13]([NH2:43])[C:8]#[CH:7].[P:1]([NH2:4])(=[O:2])([O-:3])[O:19][CH2:20][C:33]#[CH:38]
Reactant: COC(OC)(OC(c1ccccc1)(c1ccccc1)c1ccccc1)C1CCC(CP(=O)([O-])O)CC1
Reactant: NP([O-])[O-]
Reactant: CC[NH+](CC)CC
Solvent: ClC(Cl)(Cl)Cl
Product: C#CCN
Product: C#CCOP(N)(=O)[O-]

Procedure:
We first prepared a cyanoethyl-protected dodecathymidine (T12*) on solid support using well established phosphoramidite chemistry (Beaucage, S. L.; Caruthers, M. H. Tetrahedron Lett. 1981, 22, 1859-1862). Then three H-phosphonate diester linkages were introduced using H-phosphonate monoester 1 to yield the modified supported oligonucleotide 2 (FIG. 8). An amidative oxidation with CCl4 in the presence of propargylamine afforded the alkyne-functionalized oligonucleotide 3 with three propargyl phosphoramidate linkages. An aliquot was treated with aqueous ammonia and analyzed by HPLC/MS to determine the efficiency of these synthetic steps (i.e. three H-phosphonate couplings and amidative oxidation). The first H-phosphonate coupling was not complete (86-94%) while the two subsequent couplings were higher yielding. The resulting mixture was composed of 3 (˜75%), unreacted T12 (˜14%) and intermediates with one (˜3%) and two propargyl groups (˜4%) as determined by MALDI-TOF MS analyses.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1[S:11]([OH:14])(=O)=[O:12].P(Cl)(Cl)(Cl)=O.[OH-].[NH4+:21]>S1(CCCC1)(=O)=O>[NH2:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1[S:11]([NH2:21])(=[O:14])=[O:12]
Reactant: Nc1ccc([N+](=O)[O-])cc1S(=O)(=O)O
Reactant: [NH4+]
Agent: [OH-]
Solvent: O=S1(=O)CCCC1
Solvent: O=P(Cl)(Cl)Cl
Product: Nc1ccc([N+](=O)[O-])cc1S(N)(=O)=O
Temperature: 120 °C
Yield: 63 %

Procedure:
To a suspension of 2-amino-5-nitro-benzenesulfonic acid (3.00 g, 13.75 mmol) in sulfolane (10 mL) was slowly added phosphorous oxychloride (3.43 mL, 37.47 mmol) at 25° C. The mixture was heated at 120° C. for 3.5 h, allowed to cool to 25° C. and slowly poured into aqueous ammonium hydroxide solution (30 mL) at 25° C. The pH of the solution was adjusted to ca. 6-7 upon which a solid precipitated. The solid was collected by vacuum filtration and the precipitate was washed water (100 mL) and dried in vacuo for 16 h at 60° C. to afford the desired product, 2-amino-5-nitrobenzenesulfonamide (1.87 g, 8.62 mmol, 63% yield) as a yellow-brown solid.
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:9]2[N:8]=[CH:7][C:6]3[N:12]([CH3:23])[C:13](=[O:22])[N:14]([C:15]4[C:16]([Cl:21])=[N:17][N:18]([CH3:20])[CH:19]=4)[C:5]=3[C:4]=2[CH:3]=1.[CH3:24][O:25][C:26]1[C:31]([C:32]([O:34][CH3:35])=[O:33])=[CH:30][C:29](B2OC(C)(C)C(C)(C)O2)=[CH:28][N:27]=1>>[CH3:35][O:34][C:32](=[O:33])[C:31]1[CH:30]=[C:29]([C:2]2[CH:11]=[CH:10][C:9]3[N:8]=[CH:7][C:6]4[N:12]([CH3:23])[C:13](=[O:22])[N:14]([C:15]5[C:16]([Cl:21])=[N:17][N:18]([CH3:20])[CH:19]=5)[C:5]=4[C:4]=3[CH:3]=2)[CH:28]=[N:27][C:26]=1[O:25][CH3:24]
Reactant: Cn1cc(-n2c(=O)n(C)c3cnc4ccc(Br)cc4c32)c(Cl)n1
Reactant: COC(=O)c1cc(B2OC(C)(C)C(C)(C)O2)cnc1OC
Product: COC(=O)c1cc(-c2ccc3ncc4c(c3c2)n(-c2cn(C)nc2Cl)c(=O)n4C)cnc1OC

Procedure:
The title compound was synthesized in a similar manner as described for Example 1 using 8-bromo-1-(3-chloro-1-methyl-1H-pyrazol-4-yl)-3-methyl-1,3-dihydro-imidazo[4,5-c]quinolin-2-one (Intermediate K) and 2-methoxy-3-(carbomethoxy)pyridine-5-boronic acid pinacol ester (Combi-Blocks, San Diego, USA) to give the title compound as a white solid. (HPLC: tR 2.75 min (Method A); M+H=479 MS-ES).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:10]=[N:11][N:12]([C:15]3[CH:23]=[CH:22][C:18]([C:19](O)=[O:20])=[CH:17][N:16]=3)[C:13]=2[OH:14])=[C:5]([CH3:24])[CH:4]=1)#[N:2].[CH2:25]([NH2:27])[CH3:26]>>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:10]=[N:11][N:12]([C:15]3[CH:23]=[CH:22][C:18]([C:19]([NH:27][CH2:25][CH3:26])=[O:20])=[CH:17][N:16]=3)[C:13]=2[OH:14])=[C:5]([CH3:24])[CH:4]=1)#[N:2]
Reactant: CCN
Reactant: Cc1cc(C#N)ccc1-c1cnn(-c2ccc(C(=O)O)cn2)c1O
Product: CCNC(=O)c1ccc(-n2ncc(-c3ccc(C#N)cc3C)c2O)nc1

Procedure:
The title compound was prepared in a manner similar to Example 74 using 6-(4-(4-cyano-2-methylphenyl)-5-hydroxy-1H-pyrazol-1-yl)nicotinic acid and ethanamine 1H NMR (400 MHz, DMSO-d6) δ ppm 1.09 (t, J=7.33 Hz, 3 H) 2.36 (s, 3 H) 3.16-3.37 (m, 2 H) 7.59 (d, J=8.08 Hz, 1 H) 7.66 (s, 1 H) 7.71 (br. s., 1 H) 7.99-8.22 (m, 1 H) 8.34 (d, J=7.58 Hz, 2H) 8.65 (t, J=5.05 Hz, 1 H) 8.78-8.90 (m, 1 H) 12.84-13.41 (m, 1 H). MS m/z [M+H]+ 348.1.
Reaction SMILES: [NH2:1][C:2]1[CH:16]=[CH:15][C:14]([CH2:17][CH3:18])=[CH:13][C:3]=1[CH2:4][N:5]1[CH:9]=[CH:8][CH:7]=[C:6]1[C:10](O)=O.[OH:19][CH2:20][CH2:21][N:22]1[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]1>>[CH2:17]([C:14]1[CH:15]=[CH:16][C:2]2[N:1]=[C:10]([N:25]3[CH2:26][CH2:27][N:22]([CH2:21][CH2:20][OH:19])[CH2:23][CH2:24]3)[C:6]3=[CH:7][CH:8]=[CH:9][N:5]3[CH2:4][C:3]=2[CH:13]=1)[CH3:18]
Reactant: OCCN1CCNCC1
Reactant: CCc1ccc(N)c(Cn2cccc2C(=O)O)c1
Product: CCc1ccc2c(c1)Cn1cccc1C(N1CCN(CCO)CC1)=N2

Procedure:
In the manner described in Example 5, reaction of 1-(2-amino-5-ethylbenzyl)-2-pyrrolecarboxylic acid with N-(β-hydroxyethyl)piperazine provides the title compound after cyclization.