Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: FC(F)(F)C(O)=O.C(OC([N:15]1[CH2:20][CH2:19][CH:18]([N:21]2[CH:25]=[C:24]([C:26]3[CH:27]=[N:28][C:29]([NH2:41])=[C:30]([C:32]4[S:33][C:34]5[CH:40]=[CH:39][CH:38]=[CH:37][C:35]=5[N:36]=4)[CH:31]=3)[CH:23]=[N:22]2)[CH2:17][CH2:16]1)=O)(C)(C)C>ClCCl>[S:33]1[C:34]2[CH:40]=[CH:39][CH:38]=[CH:37][C:35]=2[N:36]=[C:32]1[C:30]1[C:29]([NH2:41])=[N:28][CH:27]=[C:26]([C:24]2[CH:23]=[N:22][N:21]([CH:18]3[CH2:17][CH2:16][NH:15][CH2:20][CH2:19]3)[CH:25]=2)[CH:31]=1
Reactant: CC(C)(C)OC(=O)N1CCC(n2cc(-c3cnc(N)c(-c4nc5ccccc5s4)c3)cn2)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Nc1ncc(-c2cnn(C3CCNCC3)c2)cc1-c1nc2ccccc2s1
Reaction time: 1 h

Procedure:
Trifluoroacetic acid (3 ml) was added to a stirred solution of tert-butyl-4-[4-[6-amino-5-(1,3-benzothiazol-2-yl)-3-pyridyl]pyrazol-1-yl]piperidine-1-carboxylate (0.300 g) in dichloromethane (4 ml). The mixture was stirred for 1 hour, then concentrated under reduced pressure. The residue was dissolved in DCM (60 ml) and the solution was washed with a 0.5M solution of aqueous sodium hydroxide (30 ml). The organic phases were washed with water (15 ml) and brine (15 ml). The aqueous phase was extracted with DCM (3×30 ml), and then the organic layers were combined and concentrated under reduced pressure. The residue was stirred in acetonitrile (10 ml) for 18 hours. The solid was filtered and dried under vacuum. There was thus obtained 3-(1,3-benzothiazol-2-yl)-5-[1-(4-piperidyl)pyrazol-4-yl]pyridin-2-amine (0.109 g); Mass Spectrum: M+H+ 377; NMR Spectrum: (DMSOd6 and CF3CO2D) 8.73 (d, 1H), 8.56 (d, 1H), 8.53 (s, 1H), 8.26 (d, 1H), 8.21 (d, 1H), 8.16 (s, 1H), 7.66 (dd, 1H), 7.59 (dd, 1H), 4.52-4.62 (m, 1H), 3.41-3.52 (m, 2H), 3.09-3.21 (m, 2H), 2.24-2.33 (m, 2H), 2.10-2.23 (m, 2H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[CH2:12][CH2:11][C:10](=[O:13])[CH2:9][CH2:8][C:7]=2[CH:14]=1.FC(F)(F)C(OC(=O)C(F)(F)F)=O.[N+:28]([O-])([O-:30])=[O:29].[K+]>C(#N)C>[CH3:1][O:2][C:3]1[C:4]([N+:28]([O-:30])=[O:29])=[CH:5][C:6]2[CH2:12][CH2:11][C:10](=[O:13])[CH2:9][CH2:8][C:7]=2[CH:14]=1
Reactant: COc1ccc2c(c1)CCC(=O)CC2
Reactant: O=[N+]([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Product: COc1cc2c(cc1[N+](=O)[O-])CCC(=O)CC2
Temperature: 25 °C

Procedure:
2-Methoxy-5,6,8,9-tetrahydro-benzocyclohepten-7-one (6.00 g, 0.0315 mol) was dissolved in Acetonitrile (280 mL, 5.4 mol) and was added to a mixture of Trifluoroacetic anhydride (13.4 mL, 0.0946 mol) in Acetonitrile at 0° C. Potassium nitrate (3.19 g, 0.0315 mol) was then added and the reaction was allowed to warm to room temperature. When HPLC showed consumption of starting material, the mixture was poured over saturated sodium bicarbonate, and organics were extracted with ethyl acetate/dichloromethane. Combined organics were dried over sodium sulfate, filtered and reduced en vacuo. The crude mixture was purified by Isco flash column chromatography (Hexane/Ethyl Acetate). The gradient run was 0% EA-50% EA. Combined fractions were reduced en vacuo to afford 3.62 (49%) of 2-Methoxy-3-nitro-5,6,8,9-tetrahydro-benzocyclohepten-7-one and 1.80 grams (25%).
Reaction SMILES: C(O[C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:15]=[C:16]3[C:20](=[CH:21][CH:22]=2)[NH:19][CH:18]=[CH:17]3)[CH:10]([CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH2:9]1)=O)(C)(C)C.[H-].[H-].[H-].[H-].[Li+].[Al+3]>C1COCC1>[CH2:23]([CH:10]1[CH2:9][N:8]([CH3:6])[CH2:13][CH2:12][N:11]1[C:14]1[CH:15]=[C:16]2[C:20](=[CH:21][CH:22]=1)[NH:19][CH:18]=[CH:17]2)[C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc3[nH]ccc3c2)C(Cc2ccccc2)C1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CN1CCN(c2ccc3[nH]ccc3c2)C(Cc2ccccc2)C1
Temperature: 25 °C
Yield: 68.8 %

Procedure:
To a solution of 3-benzyl-4-(1H-indol-5-yl)-piperazine-1-carboxylic acid tert-butyl ester (0.39 g, 1.0 mmol) in 30 mL THF was added LiAlH4 (2.5 mL, 1.0 M in THF). The solution was warmed to reflux for 2 hours, then cooled to room temperature and quenched by the slow addition of 50 mL saturated Rochelle's salt. The mixture was extracted with EtOA, and the combined organic layers were washed with brine, dried over MgSO4, filtered and concentrated under reduced pressure to give an oil. Purification via flash chromatography (94:5:1 DCM/MeOH/NH4OH) afforded 5-(2-benzyl-4-methyl-piperazin-1-yl)-1H-indole (0.21 g, 76%); 1H NMR (300, MHz, CDCl3) δ 8.14 (bs, 1H), 7.37 (J=8.7 Hz, 1H), 7.31 (d, J=2.2 Hz, 1H), 7.26-7.05 (m, 1H), 6.52-6.49 (m, 1H), 3.64-3.71 (m, 1H), 3.31-3.21 (m, 1H), 3.20-3.11 (m, 1H), 2.82-2.70 (m, overlapping, 2H), 2.64 (dd, J=13.2, 7.7, 1H), 2.53-2.36 (m, 3H), 2.30 (s, 3H), MS (+H)=306).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[CH:18](O)[C:10]3[N:11]=[C:12]([CH3:17])[N:13]([CH2:14][CH2:15][OH:16])[C:9]=3[CH:8]=[CH:7][C:6]=2[CH:20]=1.[CH3:21][N:22]1[CH:29]=[CH:28][C:26](=[O:27])[NH:25][C:23]1=[O:24]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[CH:18]([C:28]3[C:26](=[O:27])[NH:25][C:23](=[O:24])[N:22]([CH3:21])[CH:29]=3)[C:10]3[N:11]=[C:12]([CH3:17])[N:13]([CH2:14][CH2:15][OH:16])[C:9]=3[CH:8]=[CH:7][C:6]=2[CH:20]=1
Reactant: Cc1nc2c(n1CCO)C=Cc1cc(Cl)ccc1C2O
Reactant: Cn1ccc(=O)[nH]c1=O
Product: Cc1nc2c(n1CCO)C=Cc1cc(Cl)ccc1C2c1cn(C)c(=O)[nH]c1=O

Procedure:
The subtitle compound was prepared from the product from step (ii) (1.85 g) and 1-methyluracil (0.4 g) according to the method of example 42 step (iv). Purification was by biotage chromatography on silica eluting with 5% methanol in dichloromethane with 1% 0.880 ammonia present.
Reaction SMILES: [CH2:1]([NH:4][S:5]([NH:8][C:9]1[C:14]([C:15]([O:17]C)=O)=[CH:13][CH:12]=[CH:11][N:10]=1)(=[O:7])=[O:6])[CH2:2][CH3:3].[OH-].[Na+]>O>[CH2:1]([N:4]1[S:5](=[O:7])(=[O:6])[NH:8][C:9]2[N:10]=[CH:11][CH:12]=[CH:13][C:14]=2[C:15]1=[O:17])[CH2:2][CH3:3]
Reactant: CCCNS(=O)(=O)Nc1ncccc1C(=O)OC
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CCCN1C(=O)c2cccnc2NS1(=O)=O
Reaction time: 4 h

Procedure:
Methyl 2-(((n-propylamino)sulfonyl)amino)-3-pyridinecarboxylate (15.7 grams; 0.057 mole), 95 ml of water and 10.5 ml of 50 percent aqueous sodium hydroxide were mixed and the resulting reaction mixture stirred for about 11/4 hours at ambient temperatures. The reaction mixture was extracted with two -- 50 ml portions of methylene chloride and one -- 50 ml portion of ether to remove impurities. The aqueous layer was separated from the organic layer and acidified to a pH of about 4.5 with concentrated hydrochloric acid. The solution was filtered and the filtrate acidified to a pH of about 1. The resulting product precipitate was recovered by filtration, dissolved in acetone and the solution filtered and dried with magnesium sulfate. The mixture was again filtered and the filtrate reduced in vacuo to obtain the title compound as a yellow powder having a melting point of 208° C.-210° C.
Reaction SMILES: [Cl-].[CH2:2]([O:4][C:5]([C:7]1[N:8]=[C:9]([CH:12]2[CH2:17][CH2:16][NH2+:15][CH2:14][CH2:13]2)[S:10][CH:11]=1)=[O:6])[CH3:3].[CH3:18][C:19]1[CH:23]=[C:22]([CH3:24])[N:21]([C:25]([CH3:30])([CH3:29])[C:26](O)=[O:27])[N:20]=1>>[CH3:18][C:19]1[CH:23]=[C:22]([CH3:24])[N:21]([C:25]([CH3:30])([CH3:29])[C:26]([N:15]2[CH2:16][CH2:17][CH:12]([C:9]3[S:10][CH:11]=[C:7]([C:5]([O:4][CH2:2][CH3:3])=[O:6])[N:8]=3)[CH2:13][CH2:14]2)=[O:27])[N:20]=1
Reactant: Cc1cc(C)n(C(C)(C)C(=O)O)n1
Reactant: CCOC(=O)c1csc(C2CC[NH2+]CC2)n1
Agent: [Cl-]
Product: CCOC(=O)c1csc(C2CCN(C(=O)C(C)(C)n3nc(C)cc3C)CC2)n1

Procedure:
4-[4-(Ethoxycarbonyl)-1,3-thiazol-2-yl]piperidinium chloride (VI-1, 8.23 g) is reacted analogously to Example IV-1 with 2-(3,5-dimethyl-1H-pyrazol-1-yl)-2-methylpropanoic acid (5.42 g). This gives, after chromatographic purification, ethyl 2-{1-[2-(3,5-dimethyl-1H-pyrazol-1-yl)-2-methylpropanoyl]piperidin-4-yl}-1,3-thiazole-4-carboxylate (9.64 g, 80%)
Reaction SMILES: [O:1]([C:8]1[CH:9]=[C:10]([CH2:14][N:15]2[C:27]3[CH:26]=[CH:25][CH:24]=[C:23]([OH:28])[C:22]=3[C:21]3[C:16]2=[CH:17][CH:18]=[CH:19][C:20]=3[C:29]([O:31]C)=O)[CH:11]=[CH:12][CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[OH-].[NH4+:35]>C1COCC1.C(OCC)(=O)C>[O:1]([C:8]1[CH:9]=[C:10]([CH2:14][N:15]2[C:27]3[CH:26]=[CH:25][CH:24]=[C:23]([OH:28])[C:22]=3[C:21]3[C:16]2=[CH:17][CH:18]=[CH:19][C:20]=3[C:29](=[O:31])[NH2:35])[CH:11]=[CH:12][CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COC(=O)c1cccc2c1c1c(O)cccc1n2Cc1cccc(Oc2ccccc2)c1
Reactant: [NH4+]
Agent: Cl
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: NC(=O)c1cccc2c1c1c(O)cccc1n2Cc1cccc(Oc2ccccc2)c1
Yield: 43 %

Procedure:
A solution of the 9-[(3-phenoxyphenyl)methyl]-4-hydroxy-5-carbomethoxy carbazole (100.0 mg, 0.24 mM) in 5 mL THF and 20 mL concentrated aqueous ammonium hydroxide was sonicated for 24 hours at 40-50° C. The mixture was diluted with ethyl acetate and acidified to pH 1 with 5 N HCl. The aqueous layer was extracted twice with ethyl acetate. The combined organic extracts were washed with saturated brine, dried over magnesium sulfate, filtered, and concentrated. The residue was purified by column chromatography on silica gel (elution with gradient methylene chloride/ethyl acetate) to afford 41.0 mg (43%) of the 9-[(3-phenoxyphenyl)methyl]-4-hydroxy-5-carbamoyl carbazole as a white solid. 1H NMR (DMSO-d6) δ10.5 (s, 1H), 8.8 (br s, 1H), 8.4 (br s, 1H), 7.8 (dd, 1H, J=1 and 8 Hz), 7.5-6.7 (m, 13H), 6.6 (d, 1H, J=8 Hz), and 5.7 (s, 2H). MS (ES) m/e 407, 409.
Reaction SMILES: [H-].[Na+].[CH3:3][O:4][C:5]1[CH:6]=[C:7]([C:13]2[CH:18]=[CH:17][N:16]=[C:15]3[NH:19][CH:20]=[CH:21][C:14]=23)[CH:8]=[CH:9][C:10]=1[O:11][CH3:12].[CH2:22]([O:24][C:25]1[CH:34]=[CH:33][C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[C:26]=1[C:35](Cl)=[O:36])[CH3:23]>CCCCCC.O1CCCC1>[CH3:3][O:4][C:5]1[CH:6]=[C:7]([C:13]2[CH:18]=[CH:17][N:16]=[C:15]3[N:19]([C:35]([C:26]4[C:27]5[C:32](=[CH:31][CH:30]=[CH:29][CH:28]=5)[CH:33]=[CH:34][C:25]=4[O:24][CH2:22][CH3:23])=[O:36])[CH:20]=[CH:21][C:14]=23)[CH:8]=[CH:9][C:10]=1[O:11][CH3:12]
Reactant: COc1ccc(-c2ccnc3[nH]ccc23)cc1OC
Reactant: CCOc1ccc2ccccc2c1C(=O)Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CCOc1ccc2ccccc2c1C(=O)n1ccc2c(-c3ccc(OC)c(OC)c3)ccnc21
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
Sodium hydride (60% dispersion in mineral oil, 39.9 mg, 0.997 mmol) was washed with hexane and put under an atmosphere of nitrogen, and 1 mL of tetrahydrofuran was added. 4-(3,4-dimethoxy-phenyl)-1H-pyrrolo[2,3-b]pyridine (50, 195 mg, 0.767 mmol) in tetrahydrofuran (6.2 mL) was added, and the resulting mixture was stirred for 10 minutes at room temperature. 2-ethoxy naphthoyl chloride (202 mg, 0.844 mmol) in tetrahydrofuran was added. After two hours, the reaction was quenched with water, and the two layers were separated. The aqueous layer was extracted with ethyl acetate. The combined organic layers were washed with brine and dried over anhydrous sodium sulfate. Concentration under reduced pressure afforded the crude material, which was purified by column chromatography (35-60% ethyl acetate in hexane) to yield the desired product in light yellow solid (48, 262 mg, 0.579 mmol). MS(ESI) [M+H+]+=453.2.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([N+:9]([O-:11])=[O:10])=[CH:4][C:3]=1[N+:12]([O-:14])=[O:13].[CH3:15][O:16][C:17]1[CH:23]=[CH:22][C:20]([NH2:21])=[CH:19][CH:18]=1.C([O-])([O-])=O.[K+].[K+]>CS(C)=O>[Cl:8][C:6]1[C:5]([N+:9]([O-:11])=[O:10])=[CH:4][C:3]([N+:12]([O-:14])=[O:13])=[C:2]([CH:7]=1)[NH:21][C:20]1[CH:22]=[CH:23][C:17]([O:16][CH3:15])=[CH:18][CH:19]=1
Reactant: O=[N+]([O-])c1cc([N+](=O)[O-])c(Cl)cc1Cl
Reactant: COc1ccc(N)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: COc1ccc(Nc2cc(Cl)c([N+](=O)[O-])cc2[N+](=O)[O-])cc1
Temperature: 0 °C

Procedure:
2,4-Dichloro-1,5-dinitrobenzene (II-1, 0.5 g, 2.11 mmol) and p-methoxyaniline (III-2, 0.2 g, 2.11 mmol) were dissolved in 5 mL DMSO. To the solution were added K2CO3 (0.58 g, 4.22 mmol) and metal Cu in catalytic amount. The mixture was allowed to react at 115° C. for 2 hours with stirring in an atmosphere of nitrogen. The resultant was poured into ice water, stirred to precipitate a solid. The solid was filtered, washed with water several times, dried, and separated on silica gel column (petroleum ether/ethyl acetate) to obtain a bronzing solid (IV-2, 0.68 g, 67%). 1H NMR (CDCl3) δ ppm 3.88 (3H, s, OCH3), 7.02 (1H, s, ArH-6), 7.03 (2H, d, J=8.96 Hz, ArH-3′, 5′), 7.21 (2H, d, J=8.96 Hz, ArH-2′, 6′), 9.07 (1H, s, ArH-3), 9.73 (1H, s, NH).
Reaction SMILES: [N:1]([CH2:4][CH2:5][C:6]1[C:14]2[C:9](=[N:10][CH:11]=[C:12]([Cl:15])[CH:13]=2)[NH:8][C:7]=1[Si:16]([CH2:21][CH3:22])([CH2:19][CH3:20])[CH2:17][CH3:18])=[N+]=[N-].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>CO>[Cl:15][C:12]1[CH:13]=[C:14]2[C:6]([CH2:5][CH2:4][NH2:1])=[C:7]([Si:16]([CH2:19][CH3:20])([CH2:17][CH3:18])[CH2:21][CH3:22])[NH:8][C:9]2=[N:10][CH:11]=1
Reactant: CC[Si](CC)(CC)c1[nH]c2ncc(Cl)cc2c1CCN=[N+]=[N-]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CO
Product: CC[Si](CC)(CC)c1[nH]c2ncc(Cl)cc2c1CCN
Yield: 62 %

Procedure:
A mixture of 3-(2-azidoethyl)-5-chloro-2-(triethylsilyl)-1H-pyrrolo[2,3-b]pyridine (0.900 g; 2.68 mmol) and triphenylphosphine 1.05 g; 4.02 mmol) in methanol (25 ml) was stirred at 80° C. for 1 hour and was concentrated under reduced pressure. The residue was dissolved in toluene (15 mL). Hydrochloric acid (2 mL) and water 15 mL were added. After separation of the two layers, the aqueous solution was extracted with 3×15 mL of toluene and was made alkaline by addition of a solution of sodium hydroxide 2N. The formed precipitate for filtered off. The filtrate was extracted with dichloromethane (5×15 mL). Combined dichloromethane extracts were dried over magnesium sulphate and was concentrated under reduced pressure to give 0.515 g (62%) of 2-(5-chloro-2-(triethylsilyl)-1H-pyrrolo[2,3-b]pyridin-3-yl)ethanamine as an oily residue.
Reaction SMILES: [CH:1]1([NH:4][C:5](=O)[O:6]C2C=CC=CC=2)[CH2:3][CH2:2]1.[OH:14][CH:15]1[CH2:20][CH2:19][N:18]([CH2:21][CH2:22][CH2:23][C:24]([NH:26][C:27]2[CH:32]=[C:31]([O:33][C:34]3[CH:35]=[C:36]4[C:40](=[CH:41][CH:42]=3)[NH:39][CH:38]=[CH:37]4)[CH:30]=[CH:29][N:28]=2)=[O:25])[CH2:17][CH2:16]1.[H-].[Na+].CN(C)C=O>O>[CH:1]1([NH:4][C:5]([N:39]2[C:40]3[C:36](=[CH:35][C:34]([O:33][C:31]4[CH:30]=[CH:29][N:28]=[C:27]([NH:26][C:24](=[O:25])[CH2:23][CH2:22][CH2:21][N:18]5[CH2:17][CH2:16][CH:15]([OH:14])[CH2:20][CH2:19]5)[CH:32]=4)=[CH:42][CH:41]=3)[CH:37]=[CH:38]2)=[O:6])[CH2:3][CH2:2]1
Reactant: O=C(NC1CC1)Oc1ccccc1
Reactant: O=C(CCCN1CCC(O)CC1)Nc1cc(Oc2ccc3[nH]ccc3c2)ccn1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: O=C(CCCN1CCC(O)CC1)Nc1cc(Oc2ccc3c(ccn3C(=O)NC3CC3)c2)ccn1
Temperature: 25 °C

Procedure:
Phenyl N-cyclopropylcarbamate (120 mg) was added to a solution of 260 mg of 5-[(2-{[4-(4-hydroxypiperidino)butanoyl]amino}-4-pyridyl)oxy]indole, 53 mg of sodium hydride (60% in oil) and 5 ml of dimethylformamide while stirring at room temperature. After stirring for 10 minutes, water was added and extraction was performed with ethyl acetate. NH type silica gel was added to the ethyl acetate layer, the solvent was distilled off under reduced pressure and the reaction product was adsorbed onto the silica gel. The silica gel was charged into a dry column packed with NH type silica gel, and purification was performed by column chromatography (chloroform:methanol=30:1). The solvent was distilled off under reduced pressure, and the residue was dissolved in ethyl acetate and washed twice with 1N aqueous sodium hydroxide. After drying over sodium sulfate, the solvent was distilled off under reduced pressure to obtain 20 mg of the target substance as a white powder.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[CH2:5]2.[Li+].C[Si]([N-][Si](C)(C)C)(C)C.[Br:22][C:23]1[C:27]([CH3:29])([CH3:28])[O:26][C:25](=O)[CH:24]=1.Cl>C1COCC1.O>[Br:22][C:23]1[C:27]([CH3:29])([CH3:28])[O:26]/[C:25](=[C:5]2/[C:6](=[O:11])[NH:7][C:8]3[C:4]/2=[CH:3][C:2]([F:1])=[CH:10][CH:9]=3)/[CH:24]=1
Reactant: O=C1Cc2cc(F)ccc2N1
Reactant: CC1(C)OC(=O)C=C1Br
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: Cl
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: CC1(C)O/C(=C2/C(=O)Nc3ccc(F)cc32)C=C1Br
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 81.3 %

Procedure:
To a solution of 5-fluorooxindole (7.5 g, 49 mmol) in THF (80 mL) at 0° C., was added 1M LHMDS in THF (100 mL, 100 mmol). The reaction mixture was stirred at 0° C. for 20 minutes. A solution of 4-bromo-5,5-dimethyl-5H-furan-2-one (6.4 g, 33 mmol) in THF (20 mL) was added to the reaction mixture. The reaction was stirred at 0° C. for 30 minutes and then allowed to warm to room temperature over 5 hours. To the reaction mixture was added aqueous 2 M HCl (100 mL). The resulting mixture was stirred at 60-65° C. for 1 hour, cooled to room temperature, poured into water (3000 mL) and stirred at room temperature for 2 hours. The precipitates separated and were collected, washed with water, and dried in vacuo to provide 3-[4-bromo-5,5-dimethyl-5H-furan-(2E)-ylidene]-5-fluoro-1,3-dihydro-indol-2-one as a yellow solid (8.7 g, yield 80%), which was used for the next reaction without further purification.
Reaction SMILES: [C:1]([C:9]1[CH:13]=[CH:12][NH:11][CH:10]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[K+].[NH2:16]OS(O)(=O)=O>CN(C)C=O.O>[NH2:16][N:11]1[CH:12]=[CH:13][C:9]([C:1]([C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)=[O:8])=[CH:10]1
Reactant: O=C(c1ccccc1)c1cc[nH]c1
Reactant: NOS(=O)(=O)O
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CN(C)C=O
Product: Nn1ccc(C(=O)c2ccccc2)c1
Temperature: 25 °C

Procedure:
To a solution of 3-benzoylpyrrole (4.92 g) in 50 ml of dry dimethylformamide was added milled potassium hydroxide (8.06 g). Hydroxylamine-O-sulfonic acid (4.23 g) was added to the suspension in 4 portions over a period of 1 hour with stirring at room temperature. After the addition was completed the reaction mixture was stirred for 30 minutes at room temperature, and subsequently diluted with 50 ml of water and extracted with DCM. The combined organic layers were washed with water, dried over magnesium sulfate and evaporated in vacuo. The residue was purified by flash column chromatography (silica gel, DCM/ethyl acetate, 5:1), affording starting material (1.44 g) and the desired product as the second fraction. Recrystallization from ethyl ether/hexane gave the product as crystals (1.80 g), which was combined with material obtained from a 36.9 mmol scale reaction and recrystallized from DCM/hexane affording 3.20 g of crystals, m.p. 82°-83° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:28]([F:31])([F:30])[F:29])=[C:6]([CH:27]=1)[CH2:7][N:8]1[CH2:13][CH2:12][NH:11][C:10]2[N:14]=[CH:15][C:16]([C:18]3[CH:26]=[CH:25][C:21]([C:22](O)=[O:23])=[CH:20][CH:19]=3)=[CH:17][C:9]1=2.[S:32]([C:36]1[CH:41]=[CH:40][C:39]([CH2:42][CH2:43][NH2:44])=[CH:38][CH:37]=1)(=[O:35])(=[O:34])[NH2:33]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:28]([F:31])([F:30])[F:29])=[C:6]([CH:27]=1)[CH2:7][N:8]1[CH2:13][CH2:12][NH:11][C:10]2[N:14]=[CH:15][C:16]([C:18]3[CH:19]=[CH:20][C:21]([C:22]([NH:44][CH2:43][CH2:42][C:39]4[CH:38]=[CH:37][C:36]([S:32](=[O:35])(=[O:34])[NH2:33])=[CH:41][CH:40]=4)=[O:23])=[CH:25][CH:26]=3)=[CH:17][C:9]1=2
Reactant: NCCc1ccc(S(N)(=O)=O)cc1
Reactant: O=C(O)c1ccc(-c2cnc3c(c2)N(Cc2cc(Cl)ccc2C(F)(F)F)CCN3)cc1
Product: NS(=O)(=O)c1ccc(CCNC(=O)c2ccc(-c3cnc4c(c3)N(Cc3cc(Cl)ccc3C(F)(F)F)CCN4)cc2)cc1

Procedure:
4-{1-[5-chloro-2-(trifluoromethyl)benzyl]-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl}benzoic acid was reacted with 2-(4-sulfamoylphenyl)ethylamine as in General Procedure 10 to give the title compound. LCMS: m/z=629.94 (M+H+); retention time=0.75 minutes.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:23]=[C:22]([O:24][CH3:25])[CH:21]=[CH:20][C:17]=1[CH:18]=[O:19].[CH2:26]([Mg]Br)[CH3:27].O>O1CCCC1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:23]=[C:22]([O:24][CH3:25])[CH:21]=[CH:20][C:17]=1[CH:18]([OH:19])[CH2:26][CH3:27]
Reactant: COc1ccc(C=O)c(Oc2ccnc3cc(OC)c(OC)cc23)c1
Reactant: CC[Mg]Br
Solvent: C1CCOC1
Solvent: O
Product: CCC(O)c1ccc(OC)cc1Oc1ccnc2cc(OC)c(OC)cc12
Temperature: 0 °C
Reaction time: 1 h

Procedure:
2-[(6,7-Dimethoxy-4-quinolyl)oxy]-4-methoxybenzaldehyde was dissolved in anhydrous tetrahydrofuran (1 ml), and a 1 M tetrahydrofuran solution of ethylmagnesium bromide (0.5 ml) was added to the solution at 0° C., and the mixture was stirred at 0° C. for one hr. Water (1 ml) was added dropwise to the reaction solution to stop the reaction. The mixture was extracted with ethyl acetate, and the ethyl acetate layer was then washed with water and saturated brine and was dried over anhydrous sodium sulfate. The solvent was removed by distillation under the reduced pressure to give 1-{2-[(6,7-dimethoxy-4-quinolyl)oxy]-4-methoxyphenyl}-1-propanol.
Reaction SMILES: [C:1]([O:14][C@H:15]([CH2:71][O:72][C:73](=[O:85])[CH2:74][CH2:75][CH2:76][CH2:77][CH2:78][CH2:79][CH2:80][CH2:81][CH2:82][CH2:83][CH3:84])[CH2:16][S:17][CH2:18][C@H:19]([NH:53]C(OCC1C2C=CC=CC=2C2C1=CC=CC=2)=O)[C:20](=[O:52])[NH:21][CH2:22][CH2:23][CH2:24]OCCCCOCCCNC(=O)OCC1C2C=CC=CC=2C2C1=CC=CC=2)(=[O:13])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].[NH:86]1CCC[CH2:88][CH2:87]1>C(#N)C>[C:73]([O:72][CH2:71][C@@H:15]([O:14][C:1](=[O:13])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12])[CH2:16][S:17][CH2:18][C@H:19]([NH2:53])[C:20]([NH:21][CH2:22][CH2:23][CH2:24][CH2:88][CH2:87][NH2:86])=[O:52])(=[O:85])[CH2:74][CH2:75][CH2:76][CH2:77][CH2:78][CH2:79][CH2:80][CH2:81][CH2:82][CH2:83][CH3:84]
Reactant: C1CCNCC1
Reactant: CCCCCCCCCCCC(=O)OC[C@H](CSC[C@H](NC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)NCCCOCCCCOCCCNC(=O)OCC1c2ccccc2-c2ccccc21)OC(=O)CCCCCCCCCCC
Solvent: CC#N
Product: CCCCCCCCCCCC(=O)OC[C@H](CSC[C@H](N)C(=O)NCCCCCN)OC(=O)CCCCCCCCCCC
Reaction time: 0.5 h

Procedure:
A solution of (19R,23R)-19-(((9H-fluoren-9-yl)methoxy)carbonylamino)-1-(9H-fluoren-9-yl)-3,18-dioxo-2,8,13-trioxa-21-thia-4,17-diazatetracosane-23,24-diyl didodecanoate in acetonitrile (0.1M) was stirred at room temperature. Piperidine (final conc. 20%) was then added and the reaction stirred for 30 minutes. After concentration, the product was purified by mass triggered HPLC using a 50-100% MeCN in H2O (0.1% TFA) gradient to give (R)-3-((R)-2-amino-3-(5-aminopentylamino)-3-oxopropylthio)propane-1,2-diyl didodecanoate). 1H NMR (DMSO d-6): δ 8.49 (t, 1H), 5.12 (m, 1H), 4.26-4.32 (dd, 1H), 4.08-4.12 (m, 1H), 3.85 (t, 1H), 3.32-3.41 (m, 7H), 3.20 (m, 2H), 3.11 (m, 1H), 2.91 (dd, 1H), 2.82 (m, 4H), 2.73 (m, 1H), 2.52 (m, 2H), 2.29-2.34 (q, 4H), 1.71-1.79 (m, 2H), 1.62-1.68 (m, 2H), 1.49-1.52 (m, 8H), 1.21-1.34 (m, 32H), 1.18-1.21 (t, 2H), 0.88 (t, 6H). LRMS [M+H]=747.1.