Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1](OC(=O)C)(=[O:3])[CH3:2].[NH2:8][C:9]1[C:14]([Cl:15])=[CH:13][C:12]([CH:16]([CH2:18][NH:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][O:26][CH2:27][CH2:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][N:30]=2)[OH:17])=[CH:11][C:10]=1[Cl:35].O.[CH3:37][CH2:38][O:39]CC>N1C=CC=CC=1>[C:1]([O:17][CH:16]([CH2:18][N:19]([C:38](=[O:39])[CH3:37])[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][O:26][CH2:27][CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][N:30]=1)[C:12]1[CH:13]=[C:14]([Cl:15])[C:9]([NH2:8])=[C:10]([Cl:35])[CH:11]=1)(=[O:3])[CH3:2]
Reactant: Nc1c(Cl)cc(C(O)CNCCCCCCOCCc2ccccn2)cc1Cl
Reactant: CCOCC
Reactant: CC(=O)OC(C)=O
Solvent: c1ccncc1
Solvent: O
Product: CC(=O)OC(CN(CCCCCCOCCc1ccccn1)C(C)=O)c1cc(Cl)c(N)c(Cl)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Acetic anhydride (132 mg) in pyridine (2 ml) was added dropwise to a solution of 4-amino-3,5-dichloro-α-[[[6-[2-(2-pyridinyl)ethoxy]hexyl]amino]methyl]benzenemethanol (250 mg) in pyridine (2 ml). The solution was stirred under nitrogen at room temperature overnight and more acetic anhydride (66 mg) in pyridine was added. After stirring for a further 12 h, the solution was evaporated in vacuo to give an oil which was partioned between water (5 ml) and ether (5 ml). The aqueous layer was re-extracted with ether (5 ml) and the combined organic layers were dried and concentrated to give the title compound as a clear oil (190 mg), t.l.c. (System A 80:20:1) Rf 0.5.
Reaction SMILES: Br[CH2:2][C:3]([NH:5][C:6]1[CH:14]=[CH:13][CH:12]=[CH:11][C:7]=1[C:8]([OH:10])=[O:9])=[O:4].[CH3:15][O:16][C:17]1[CH:23]=[CH:22][C:20]([NH2:21])=[CH:19][CH:18]=1.CN(C=O)C.[OH-].[K+]>O>[CH3:15][O:16][C:17]1[CH:23]=[CH:22][C:20]([NH:21][CH2:2][C:3]([NH:5][C:6]2[CH:14]=[CH:13][CH:12]=[CH:11][C:7]=2[C:8]([OH:10])=[O:9])=[O:4])=[CH:19][CH:18]=1
Reactant: O=C(CBr)Nc1ccccc1C(=O)O
Reactant: COc1ccc(N)cc1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccc(NCC(=O)Nc2ccccc2C(=O)O)cc1
Yield: 81.9 %

Procedure:
A solution of 2-(N-bromoacetylamino)benzoic acid from Example 79 (8.00 g, 31.0 mmol) , para-methoxyaniline (9.55 g, 77.5 mmol) and DMF (80 mL) was heated to 80° C. for 8 h. The mixture was cooled, poured over H2O (1 L) and 5% KOH (300 mL) and washed with CH2Cl2 (3×300 mL). The aqueous layer was acidified to pH 2 with 2N HCl, cooled below room temperature, and filtered. The filter cake was rinsed with cold water (100 mL) and dried under high vacuum at 45° C. to yield 7.62 g (85%) of the title compound as a white solid; 1H NMR (DMSO-d6) δ 13.5 (broad s, 1H), 12.04 (s, 1H), 8.73 (dd, J=8.4, J=1.0, 1H), 7.93 (dd, J=7.8, J=1.8, 1H), 7.59 (td, J=8.0, J=1.8, 1H), 7.13 (td, J=7.6, J=1.2, 1H), 6.73 (dt, J=8.8, J=2.2, 2H), 6.54 (dt, J=9.2, J=2.4, 2H), 6.2 (broad s, 1H), 3.77 (s, 2H), 3.62 (s, 3H); 13C NMR (DMSO-d6) δ 171.18, 168.95, 151.53, 142.2, 140.58, 134.12, 131.12, 122.62, 119.42, 116.03, 114.57, 113.42, 55.20, 49.76; MS (EI, m/z) 300 (M+).
Reaction SMILES: Cl[CH2:2][C:3](=O)[C:4](=[N:10][OH:11])[C:5]([O:7][CH2:8][CH3:9])=[O:6].[C:13]([NH2:21])(=[S:20])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>C1C=CC=CC=1>[N:10](=[C:4]([C:3]1[N:21]=[C:13]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[S:20][CH:2]=1)[C:5]([O:7][CH2:8][CH3:9])=[O:6])[OH:11]
Reactant: CCOC(=O)C(=NO)C(=O)CCl
Reactant: NC(=S)c1ccccc1
Solvent: c1ccccc1
Product: CCOC(=O)C(=NO)c1csc(-c2ccccc2)n1
Reaction time: 4 h
Yield: 107.9 %

Procedure:
A solution of ethyl γ-chloro-α-oximinoacetoacetate (2.10 g, 10.8 mmol) and thiobenzamide (1.49 g, 10.8 mmol) in dry benzene (15 mL) was heated to reflux. After 4 hours, the reaction mixture was poured onto NaHCO3 (sat., aq., 50 mL); The resulting mixture was extracted with ethyl acetate (2×50 mL); and the combined extracts dried over MgSO4 and evaporated under reduced pressure. Flash chromatography (ethyl acetate:hexane 1:4, Rf 0.30) then afforded impure ethyl α-oximino-2-phenylthiazole-4-acetate (3.22 g). The crude oxime was then dissolved in methanol (15 mL) and formic acid (50% aq., 15 mL) was added. The mixture was cooled to 0° C. and zinc dust (2.00 g, 30.6 mmol) was added portionwise over 30 minutes. The reaction mixture was allowed to warm to room temperature, and stirred for 6 hours. The solution was then filtered, basified to pH 9 with solid NaHCO3, and extracted with ethyl acetate (3×80 mL). The combined extracts were then dried and evaporated to afford D/L-2-phenylthiazol-4-ylglycine ethyl ester (1.43 g, 5.45 mmol, 50% from the chloro-oxime). The ester (194 mg, 0.74 mmol) was then dissolved in tetrahydrofuran (5 mL). Triethylamine (120 μL, 87 mg, 0.86 mmol) was added, followed by di-t-butyl dicarbonate (180 mg, 0.82 mmol). After stirring at room temperature for 4 days, water (20 mL) was added and the solution extracted with dichloromethane (2×20 mL). The combined extracts were evaporated and purified by flash column chromatography (ethyl acetate:hexane 1:4, Rf 0.45) to afford N-t-butyloxycarbonyl-D/L-2-phenylthiazol-4-ylglycine ethyl ester (158 mg, 0.44 mmol, 59%) as a clear oil. The oil was dissolved in tetrahydrofuran (2 mL) and LiOH.H2O (80 mg as a solution in 2 mL water) was added. After stirring at room temperature for 2 hours, water (10 mL) was added, and the solution extracted with ethyl acetate (5 mL). The aqueous layer was then acidified to pH 4 with 2N HCl, and extracted with ethyl acetate (2×20 mL); The latter extracts were combined and evaporated to afford N-BOC-D/L-2-phenylthiazol-4-ylglycine (116 mg, 0.35 mmol, 75%) as a white powder.
Reaction SMILES: [N-:1]=[N+:2]=[N-:3].[Na+].[CH:5](OCC)(OCC)OCC.Cl.[CH2:16]([O:18][C:19](=[O:25])[CH2:20][CH2:21][CH2:22][CH2:23][NH2:24])[CH3:17]>C(O)(=O)C>[CH2:16]([O:18][C:19](=[O:25])[CH2:20][CH2:21][CH2:22][CH2:23][N:24]1[CH:5]=[N:3][N:2]=[N:1]1)[CH3:17]
Reactant: CCOC(=O)CCCCN
Reactant: CCOC(OCC)OCC
Reactant: [N-]=[N+]=[N-]
Agent: Cl
Agent: [Na+]
Solvent: CC(=O)O
Product: CCOC(=O)CCCCn1cnnn1
Reaction time: 6 h

Procedure:
13 g of sodium azide and 59 ml of triethyl orthoformate are added to a solution of 13.4 g of 5-amino-valeric acid ethyl ester hydrochloride in 89 ml of acetic acid and the whole is stirred for 6 hours at 100°. The reaction mixture is cooled and partitioned betwen ethyl acetate and water. The organic phase is washed several times with saturated sodium bicarbonate solution and once with brine and, after drying over sodium sulphate, is concentrated. After purification by chromatography over silica gel (eluant: toluene/ethyl acetate 4:1 to 7:3), the pure title compound is obtained. Rf (toluene/ethyl acetate 1:1); 0.32.
Reaction SMILES: Br[C:2]1[N:3]=[C:4]2[CH2:10][C:9]3[CH:11]=[C:12]4[O:17][CH2:16][O:15][C:13]4=[CH:14][C:8]=3[C:7]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[N:6][N:5]2[C:24]=1[CH3:25].C([Li])CCC.CN(C)[CH:33]=[O:34].O>O1CCCC1>[CH:33]([C:2]1[N:3]=[C:4]2[CH2:10][C:9]3[CH:11]=[C:12]4[O:17][CH2:16][O:15][C:13]4=[CH:14][C:8]=3[C:7]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[N:6][N:5]2[C:24]=1[CH3:25])=[O:34]
Reactant: CN(C)C=O
Reactant: Cc1c(Br)nc2n1N=C(c1ccccc1)c1cc3c(cc1C2)OCO3
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: O
Product: Cc1c(C=O)nc2n1N=C(c1ccccc1)c1cc3c(cc1C2)OCO3
Reaction time: 0.25 h

Procedure:
120 mg of 9-bromo-8-methyl-5-phenyl-11H-1,3-dioxolo[4,5-h]imidazo[1,2-c][2,3]benzodiazepine is mixed in 15 ml of tetrahydrofuran at −78° C. with 0.36 ml of butyllithium (hexane, 1 mol) and stirred for 15 minutes. It is then mixed at this temperature with 0.6 ml of dimethylformamide and stirred for 15 minutes. After stirring to room temperature, it is mixed with water, the tetrahydrofuran is distilled off and extracted with ethyl acetate. After the solvent is distilled off, it is chromatographed on silica gel with dichloromethane:ethanol=95:5 as an eluant. 46 mg of 9-formyl-8-methyl-5-phenyl-11H-1,3-dioxolo[4,5-h]imidazo[1,2-c][2,3]benzodiazepine is obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[N:13]=[C:12]3[CH2:14][CH2:15][CH2:16][C:11]3=[C:10]([NH:17][C:18]3[N:23]=[CH:22][C:21]([CH2:24][C:25](OCC)=[O:26])=[CH:20][CH:19]=3)[CH:9]=2)[CH:5]=[CH:6][CH:7]=1.[NH3:30]>CO>[ClH:1].[Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[N:13]=[C:12]3[CH2:14][CH2:15][CH2:16][C:11]3=[C:10]([NH:17][C:18]3[N:23]=[CH:22][C:21]([CH2:24][C:25]([NH2:30])=[O:26])=[CH:20][CH:19]=3)[CH:9]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)Cc1ccc(Nc2cc(-c3cccc(Cl)c3)nc3c2CCC3)nc1
Reactant: N
Solvent: CO
Product: Cl
Product: NC(=O)Cc1ccc(Nc2cc(-c3cccc(Cl)c3)nc3c2CCC3)nc1
Yield: 75 %

Procedure:
Following general procedure C, ethyl 2-(6-((2-(3-chlorophenyl)-6,7-dihydro-5H-cyclopenta[b]pyridin-4-yl)amino)pyridin-3-yl)acetate (0.100 g, 0.24 mmol) was reacted with ammonia in methanol (7.0 M, 3 mL), followed by formation of the hydrochloride salt to afford the title compound (0.100 g, 75%) as a white solid. MW=415.32. 1H NMR (DMSO-d6, 500 MHz) δ 14.36 (s, 1H), 9.86 (s, 1H), 8.80-8.76 (m, 1H), 8.31-8.27 (m, 1H), 7.98-7.95 (m, 1H), 7.82-7.78 (m, 1H), 7.77-7.74 (m, 1H), 7.72-7.63 (m, 2H), 7.58-7.53 (m, 1H), 7.38 (d, J=8.5 Hz, 1H), 6.97 (s, 1H), 3.42 (s, 2H), 3.19 (t, J=7.5 Hz, 2H), 3.05 (t, J=7.5 Hz, 2H), 2.26 (t, J=7.5 Hz, 2H); APCI MS m/z 379 [M+H]+.
Reaction SMILES: C(=O)(O)[O-].[Na+].[C:6]1([SH:12])[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.[CH3:13][C:14]1[CH:19]=[CH:18][C:17]([S:20]([OH:23])(=[O:22])=O)=[CH:16][CH:15]=1.[OH-].[Na+].O[CH2:27][CH:28]1[CH2:33][CH2:32][CH2:31][NH:30][CH2:29]1>CN(C)C=O>[CH3:13][C:14]1[CH:15]=[CH:16][C:17]([S:20]([N:30]2[CH2:31][CH2:32][CH2:33][CH:28]([CH2:27][S:12][C:6]3[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=3)[CH2:29]2)(=[O:22])=[O:23])=[CH:18][CH:19]=1
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: OCC1CCCNC1
Reactant: Sc1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Product: Cc1ccc(S(=O)(=O)N2CCCC(CSc3ccccc3)C2)cc1
Temperature: 80 °C
Reaction time: 12 h

Procedure:
To a mixture of 130 g (1.23 mole) of sodium bicarbonate and 145 g (1.32 mole) of thiophenol in 1.5 liters of dimethylformamide (which had stirred at room temperature for about 1 hr) was added 1-[(4-methylphenyl)sulfonyl]-3-piperidinemethanol ester with 4-methylbenzenesulfonic acid (the oil produced in Preparation 23) in 500 ml of dimethylformamide. The mixture was stirred at 80° C. for 12 hours and then at room temperature for 48 hr. One liter of dilute sodium hydroxide was added and the mixture was stirred for 2 hr. A viscous gum formed. The gum was separated and dissolved in methylene chloride. The resulting solution was extracted with several portions of dilute aqueous sodium hydroxide. The methylene chloride phase was dried over magnesium sulfate and the solvent was removed in vacuo. The residue was recrystallized from diethyl ether-methylene chloride to give 221.4 g (72% based on starting 3-(hydroxymethyl)piperidine in Preparation 23) of white crystalline solid, m.p. 72°-75° C.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=2)=[CH:4][C:3]=1[N+:15]([O-])=O.Cl.C(=O)(O)[O-].[K+]>>[NH2:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=2)=[CH:4][C:3]=1[NH2:15]
Reactant: Nc1ccc(Sc2ccccn2)cc1[N+](=O)[O-]
Agent: Cl
Agent: O=C([O-])O
Agent: [K+]
Product: Nc1ccc(Sc2ccccn2)cc1N

Procedure:
2.3 G. of 1-amino-2-nitro-4-(pyrid-2-ylthio)benzene in 12 ml. concentrated hydrochloric acid is treated with 12 g. of stannous chloride on the steam bath for 15 minutes. The cooled solution is treated with an excess of potassium bicarbonate and extracted with chloroform and filtered. The chloroform layer is separated, dried and evaporated to yield 1,2-diamino-4-(pyrid-2-ylthio)benzene.
Reaction SMILES: [CH3:1][CH:2]1[CH2:11][C:10]2[C:9]([CH3:13])([CH3:12])[CH:8]([CH3:14])[CH2:7][C:6]([CH3:16])([CH3:15])[C:5]=2[C:4](=O)[CH2:3]1.[C:18](O)(=O)C.[CH:22]([NH2:24])=[NH:23]>C(O)CCC>[CH3:1][CH:2]1[CH2:11][C:10]2[C:9]([CH3:13])([CH3:12])[CH:8]([CH3:14])[CH2:7][C:6]([CH3:16])([CH3:15])[C:5]=2[C:4]2[N:24]=[CH:22][N:23]=[CH:18][C:3]1=2
Reactant: N=CN
Reactant: CC(=O)O
Reactant: CC1CC(=O)C2=C(C1)C(C)(C)C(C)CC2(C)C
Solvent: CCCCO
Product: CC1CC2=C(c3ncncc31)C(C)(C)CC(C)C2(C)C
Temperature: 130 °C
Reaction time: 24 h

Procedure:
A 100 mL reaction flask is charged with 3,5,5,6,8,8-hexamethyl-3,4,5,6,7,8-hexahydro-2H-naphthalen-1-one (prepared as described in U.S. Pat. No. 3,927,083) (10 g, 0.042 mol), formamidine acetate (21 g, 0.2 mol), and butanol (50 mL). The reaction mixture is heated to 130° C. and stirred for 24 hours. The crude mass is washed once with aqueous sulfuric acid (10%, 100 mL) followed by twice with brine (30 mL). Butanol is recovered by roto-evaporation. The crude product is further purified with liquid chromatography (Biotage® system) and then crystallized. Product 5,7,7,8,10,10-hexamethyl-5,6,7,8,9,10-hexahydro-benzo[h]quinazoline (˜5 g) is obtained.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[CH:5]=[CH:4][C:3]=1[C:10](=O)[CH3:11].[CH3:13][O:14][C:15]1[N:20]=[CH:19][C:18]([CH2:21][C:22](O)=[O:23])=[CH:17][CH:16]=1>>[CH3:9][O:8][C:6]1[CH:7]=[C:2]2[C:3]([C:10]([CH3:11])=[C:21]([C:18]3[CH:19]=[N:20][C:15]([O:14][CH3:13])=[CH:16][CH:17]=3)[C:22](=[O:23])[O:1]2)=[CH:4][CH:5]=1
Reactant: COc1ccc(C(C)=O)c(O)c1
Reactant: COc1ccc(CC(=O)O)cn1
Product: COc1ccc2c(C)c(-c3ccc(OC)nc3)c(=O)oc2c1

Procedure:
The title product was prepared as a white solid according to the procedure described in Example 9 using 1-(2-hydroxy-4-methoxy-phenyl)-ethanone and (6-methoxy-pyridin-3-yl)-acetic acid as the starting material.
Reaction SMILES: [NH:1]([C:8]([N:10]1[C:18]2[C:13](=[CH:14][C:15]([O:19][C:20]3[CH:25]=[CH:24][N:23]=[C:22]([NH:26][C:27]([CH:29]4[CH2:34][CH2:33][N:32](C(OC(C)(C)C)=O)[CH2:31][CH2:30]4)=[O:28])[CH:21]=3)=[CH:16][CH:17]=2)[C:12]([Cl:42])=[CH:11]1)=[O:9])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O.C(=O)(O)O.[OH-].[Na+]>FC(F)(F)C(O)=O>[C:2]1([NH:1][C:8]([N:10]2[C:18]3[C:13](=[CH:14][C:15]([O:19][C:20]4[CH:25]=[CH:24][N:23]=[C:22]([NH:26][C:27]([CH:29]5[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]5)=[O:28])[CH:21]=4)=[CH:16][CH:17]=3)[C:12]([Cl:42])=[CH:11]2)=[O:9])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)N1CCC(C(=O)Nc2cc(Oc3ccc4c(c3)c(Cl)cn4C(=O)Nc3ccccc3)ccn2)CC1
Agent: O=C(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: O=C(O)C(F)(F)F
Solvent: O
Product: O=C(Nc1cc(Oc2ccc3c(c2)c(Cl)cn3C(=O)Nc2ccccc2)ccn1)C1CCNCC1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 92.6 %

Procedure:
After dissolving 260 mg of tert-butyl 4-{[(4-{[1-(anilinocarbonyl)-3-chloro-1H-5-indolyl]oxy}-2-pyridyl)amino]carbonyl}-1-piperidinecarboxylate in 5 ml of trifluoroacetic acid, the solution was stirred at room temperature for 5 minutes. Bicarbonate water and 5N aqueous sodium hydroxide were added, and the mixture was extracted with ethyl acetate and dried over magnesium sulfate. The drying agent was filtered off and the solvent was distilled off under reduced pressure to obtain 200 mg of N1-phenyl-3-chloro-5-[(2-{[(4-piperidyl)carbonyl]amino}-4-pyridyl)oxy]-1H-1-indolecarboxamide as a faint yellow solid. After adding 0.5 ml of formaldehyde (37% in water), 170 mg of sodium triacetoxyborohydride, 50 mg of acetic acid and 5 ml of tetrahydrofuran to the solid, the mixture was stirred at room temperature for 10 minutes. Bicarbonate water and 5N aqueous sodium hydroxide were added, extraction was performed with ethyl acetate, and the extract was washed once with saline. The obtained ethyl acetate solution was passed through a glass filter coated with NH type silica gel. The silica gel was washed with ethyl acetate, and the solvent was distilled off under reduced pressure to obtain 210 mg of a faint yellow oil. The oil was solidified from a hexane and ethyl acetate mixed solvent to obtain 90 mg of a powder.
Reaction SMILES: [CH:1]1([S:4]([C:7]2[CH:12]=[CH:11][C:10]([CH:13]([CH2:31][CH:32]3[CH2:37][CH2:36][O:35][CH2:34][CH2:33]3)[C:14](=O)[CH2:15][CH2:16][C:17]([C:19]3[S:20][C:21]([CH:24]([OH:29])[C:25]([F:28])([F:27])[F:26])=[CH:22][N:23]=3)=O)=[CH:9][CH:8]=2)(=[O:6])=[O:5])[CH2:3][CH2:2]1.C([O-])(=O)C.[NH4+:42].[OH-].[Na+]>C(O)(=O)C>[CH:1]1([S:4]([C:7]2[CH:12]=[CH:11][C:10]([CH:13]([C:14]3[NH:42][C:17]([C:19]4[S:20][C:21]([CH:24]([OH:29])[C:25]([F:28])([F:26])[F:27])=[CH:22][N:23]=4)=[CH:16][CH:15]=3)[CH2:31][CH:32]3[CH2:33][CH2:34][O:35][CH2:36][CH2:37]3)=[CH:9][CH:8]=2)(=[O:6])=[O:5])[CH2:3][CH2:2]1
Reactant: [NH4+]
Reactant: O=C(CCC(=O)C(CC1CCOCC1)c1ccc(S(=O)(=O)C2CC2)cc1)c1ncc(C(O)C(F)(F)F)s1
Agent: CC(=O)[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Product: O=S(=O)(c1ccc(C(CC2CCOCC2)c2ccc(-c3ncc(C(O)C(F)(F)F)s3)[nH]2)cc1)C1CC1
Temperature: 80 °C
Reaction time: 3 h
Yield: 65 %

Procedure:
A mixture of 5-[4-(cyclopropylsulfonyl)phenyl]-6-(tetrahydro-2H-pyran-4-yl)-1-[5-(2,2,2-trifluoro-1-hydroxyethyl)-1,3-thiazol-2-yl]hexane-1,4-dione (0.45 g), ammonium acetate (0.31 g) and acetic acid (6 mL) was stirred at 80° C. for 3 hr. The reaction mixture was neutralized with 8M sodium hydroxide, and extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried (MgSO4) and concentrated. The residue was subjected to basic silica gel column chromatography, and the title compound (0.28, yield 65%) was obtained as a yellow amorphous solid from a fraction eluted with ethyl acetate-hexane (9:1, volume ratio). MS: 541 (MH+).
Reaction SMILES: [Cl:1][C:2]1[C:3]([N:18]2[CH2:23][CH2:22][CH2:21][C@@H:20]([NH:24]C(=O)OC(C)(C)C)[CH2:19]2)=[C:4]2[C:10]([NH:11][C:12](=[O:17])[C:13]([OH:16])([CH3:15])[CH3:14])=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1>FC(F)(F)C(O)=O>[ClH:1].[NH2:24][C@@H:20]1[CH2:21][CH2:22][CH2:23][N:18]([C:3]2[C:2]([Cl:1])=[CH:7][N:6]=[C:5]3[NH:8][CH:9]=[C:10]([NH:11][C:12](=[O:17])[C:13]([OH:16])([CH3:14])[CH3:15])[C:4]=23)[CH2:19]1
Reactant: CC(C)(C)OC(=O)N[C@@H]1CCCN(c2c(Cl)cnc3[nH]cc(NC(=O)C(C)(C)O)c23)C1
Solvent: O=C(O)C(F)(F)F
Product: CC(C)(O)C(=O)Nc1c[nH]c2ncc(Cl)c(N3CCC[C@@H](N)C3)c12
Product: Cl
Yield: 108.5 %

Procedure:
(R)-tert-Butyl 1-(5-chloro-3-(2-hydroxy-2-methylpropanamido)-1H-pyrrolo[2,3-b]pyridin-4-yl)piperidin-3-ylcarbamate (221 mg, 0.489 mmol) was stirred in trifluoroacetic acid (3 mL) at room temperature for 1.5 hours. The solvent was evaporated in vacuo, and the residue was purified by reverse phase chromatography (Biotage SP4, C-18 25M+, 2-55% CH3CN/water, 25CV). The isolated product was taken up in a minimal volume of methanol and added to a stirred solution of 2N HCl-Et2O. The salt formed was collected by filtration, washed with acetonitrile and dried under vacuum to give (R)—N-(4-(3-aminopiperidin-1-yl)-5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-2-hydroxy-2-methylpropanamide hydrochloride (103 mg, 50% yield) as a solid. 1H NMR (400 MHz, D2O) δ 8.05 (s, 1H), 7.53 (s, 1H), 3.64-3.48 (m, 2H), 3.53-3.22 (m, 1H), 3.24-3.16 (m, 1H), 3.12-3.04 (m, 1H), 2.12-2.04 (m, 1H), 1.80-1.66 (m, 2H), 1.56-1.44 (m, 1H), 1.38 (s, 3H), 1.35 (s, 3H). LCMS (APCI+) m/z 352.1, 354.1 (M+H)+, Retention time=2.02 minutes.
Reaction SMILES: [CH3:1][C:2]1[C:6]2[CH:7]=[C:8]3[C:13]4([C:21]5[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=5)[NH:15][C:14]4=[O:22])[CH2:12][O:11][C:9]3=[CH:10][C:5]=2[O:4][N:3]=1.[H-].[Na+].Br[CH2:26][C:27]1[CH:32]=[CH:31][C:30]([C:33]2[O:37][N:36]=[CH:35][CH:34]=2)=[CH:29][CH:28]=1.O>CN(C)C=O>[CH3:1][C:2]1[C:6]2[CH:7]=[C:8]3[C:13]4([C:21]5[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=5)[N:15]([CH2:26][C:27]5[CH:28]=[CH:29][C:30]([C:33](=[O:37])[CH2:34][C:35]#[N:36])=[CH:31][CH:32]=5)[C:14]4=[O:22])[CH2:12][O:11][C:9]3=[CH:10][C:5]=2[O:4][N:3]=1
Reactant: Cc1noc2cc3c(cc12)C1(CO3)C(=O)Nc2ccccc21
Reactant: BrCc1ccc(-c2ccno2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1noc2cc3c(cc12)C1(CO3)C(=O)N(Cc2ccc(C(=O)CC#N)cc2)c2ccccc21
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 73.4 %

Procedure:
To a solution of 3-methylspiro[furo[3,2-f][1,2]benzisoxazole-5,3′-indol]-2′(1′H)-one (0.35 g, 1.20 mmol) in anhydrous N,N-dimethylformamide (20 mL) at 0° C. was added slowly sodium hydride (60% w/w dispersion in mineral oil, 0.072 g, 1.50 mmol). The solution was stirred at ambient temperature for 30 min, 5-(4-(bromomethyl)phenyl)isoxazole (Sasaki et al., Biorg. Med. Chem. Lett. (1998) 8:2241-2246) (0.24 g, 1.00 mmol) was added and the mixture was stirred for 16 h at ambient temperature. The reaction mixture was poured into water (200 mL) and extracted with ethyl acetate (3×200 mL). The combined organic extracts were washed with brine (3×100 mL), dried over magnesium sulfate, filtered and concentrated in vacuo. The residue was purified by column chromatography and eluted with a 15% to 50% gradient of ethyl acetate in hexanes to afford 3-{4-[(3-methyl-2′-oxospiro[furo[3,2-f][1,2]benzisoxazole-5,3′-indol]-1′(2′H)-yl)methyl]phenyl}-3-oxopropanenitrile (0.33 g, 61%) as a colorless solid: 1H NMR (300 MHz, CDCl3) δ 7.96-7.92 (m, 2H), 7.63-7.60 (m, 2H), 7.50-7.46 (m, 1H), 7.23-7.13 (m, 2H), 7.04 6.97 (m, 2H), 6.71-6.67 (m, 1H), 5.43-4.76 (m, 4H), 4.06 (s, 2H), 2.46 (s, 3H).
Reaction SMILES: [H-].[Na+].[NH:3]1[CH2:8][CH2:7][O:6][CH2:5][CH:4]1CCCO.Cl[C:14]1[CH:19]=[CH:18][C:17]([N+:20]([O-:22])=[O:21])=[CH:16][N:15]=1.[O:23]1C[CH2:26][CH2:25][CH2:24]1>>[N:3]1([CH2:26][CH2:25][CH2:24][O:23][C:14]2[CH:19]=[CH:18][C:17]([N+:20]([O-:22])=[O:21])=[CH:16][N:15]=2)[CH2:4][CH2:5][O:6][CH2:7][CH2:8]1
Reactant: OCCCC1COCCN1
Reactant: O=[N+]([O-])c1ccc(Cl)nc1
Reactant: C1CCOC1
Agent: [H-]
Agent: [Na+]
Product: O=[N+]([O-])c1ccc(OCCCN2CCOCC2)nc1
Reaction time: 1 h

Procedure:
To a cooled (0° C., ice bath) suspension of NaH (0.96 g, 20 mmol) in anhydrous tetrahydrofuran (100 ml) was added 3-morpholin-propanol (2.9 g, 20 mmol) under argon. This solution was stirred for an additional 1 hr. A solution of 2-chloro-5-nitropyridine (3.2 g, 20 mmol) in tetrahydrofuran (20 ml) was added all at once, and the resulting mixture was heated at reflux for 5 hrs under argon. After cooling, the solvent was removed by rotary evaporation, and the residue was dissolved in ethyl acetate. The ethyl acetate layer was washed (brine), dried (Na2SO4) and concentrated to dryness. The residue was chromatographed (flash column, silica gel, 10% ether in CH2Cl2) to give the title compound. mass spectrum (electrospray, m/e): 267.9 (M+H); IR cm-1: 2955, 1603, 1579, 1515; H-NMR δ (CDCl3): 1.95-2.05 (2H, m), 2.46-2.54 (6H, m), 3.71-3.74 (4H, m), 4.489 (2H, t), 6.812 (1H, d, C3-H), 8.49 (1H, dd, C4-H), 9.065 (1H, d, C5-H).
Reaction SMILES: [CH2:1]([C:3]1[CH:16]=[CH:15][C:14]2[C:13](=O)[C:12]3[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=3)[C:6](=O)[C:5]=2[CH:4]=1)[CH3:2].[NH4+].[OH-]>[Zn]>[CH2:1]([C:3]1[CH:16]=[CH:15][C:14]2[C:5](=[CH:6][C:7]3[C:12]([CH:13]=2)=[CH:11][CH:10]=[CH:9][CH:8]=3)[CH:4]=1)[CH3:2]
Reactant: CCc1ccc2c(c1)C(=O)c1ccccc1C2=O
Agent: [NH4+]
Agent: [OH-]
Agent: [Zn]
Product: CCc1ccc2cc3ccccc3cc2c1
Yield: 38021.4 %

Procedure:
To a 5 L 3-neck flask fitted with condenser, thermometer, and overhead stirrer was added 2-ethylanthraquinone (Aldrich, 120 g, 0.51 mmol), Zn dust (Mallinckrodt, 300 g, 4.59 mol), CuSO4.5H2O (Mallinckrodt, 3.0 g) and 28% NH4OH (Mallinckrodt, 2.8 mL). The temperature was increased until the initial dark red color had faded (about 6 h). The reaction mixture was then filtered. The filtrate was extracted with EtOAc (5×1 L), and the filter cake washed with EtOAc (2×1 L). The EtOAc solutions were combined and the solvent removed. The residue was refluxed with a mixture of conc. HCl (10 mL) in i-PrOH (1.2 L) for 2 h. Upon cooling, a solid precipitated which was filtered, washed with abs. EtOH (100 mL) and dried to give 40 g (38%) of 2-ethylanthracene mp 140°-142°, (lit. mp 148°-150°, L. H. Klemm et al., J. Org. Chem. 28, 625 (1983), (C, H).