Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: N1C=CC=CC=1.[Cl:7][C:8]1[CH:14]=[CH:13][CH:12]=[CH:11][C:9]=1[NH2:10].[CH3:15][C:16]1[N:20]=[C:19]([CH2:21][C:22](O)=[O:23])[O:18][N:17]=1>O1CCOCC1.C1(C)C=CC=CC=1>[Cl:7][C:8]1[CH:14]=[CH:13][CH:12]=[CH:11][C:9]=1[NH:10][C:22](=[O:23])[CH2:21][C:19]1[O:18][N:17]=[C:16]([CH3:15])[N:20]=1
Reactant: Nc1ccccc1Cl
Reactant: Cc1noc(CC(=O)O)n1
Solvent: C1COCCO1
Solvent: c1ccncc1
Solvent: Cc1ccccc1
Product: Cc1noc(CC(=O)Nc2ccccc2Cl)n1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 77 %

Procedure:
Using the procedure of Example 20, 1.65 ml of dry pyridine and 1.33 ml of 2-chloro-aniline were added successively to a solution of 2.0 g of 3-methyl-1,2,4-oxadiazol-5-yl-acetic acid in a mixture of 13 ml of dioxane and 13 ml of toluene and the precipitation of a viscous oil was observed. The reaction mixture was stirred for 90 minutes at room temperature and then was evaporated to dryness. The residue was thoroughly stirred with 10 ml of iced water, whereupon dichloromethane was added. The pH of the resulting, clear two-layer system was 0.8 and the pH was raised to 3.0 and the layers separated. The water layer was extracted 4 times with 25 ml volumes of dichloromethane and the 5 extracts were combined, washed once with a small volume of iced water, dried over anhydrous magnesium sulfate, filtered and evaporated. The residue was crystallized from carbon tetrachloride to obtain 2.7 g (77% yield) of pure N-(2-chloro-phenyl)-3-methyl-1,2,4-oxadiazol-5-yl-acetamide with a m.p. of 118.5°-119.5° C.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:25])[CH:5]=[CH:6][C:7]1[CH:12]=[CH:11][C:10]([Cl:13])=[CH:9][C:8]=1[NH:14]S(C1C=CC(C)=CC=1)(=O)=O)[CH3:2].C(=O)([O-])[O-].[K+].[K+].Br[CH2:33][C:34]([C:36]1[CH:41]=[CH:40][C:39]([Cl:42])=[CH:38][CH:37]=1)=[O:35].N12CCCN=C1CCCCC2.Cl>CN(C)C(=O)C.C(OC)(C)(C)C>[CH2:1]([O:3][C:4](=[O:25])[CH2:5][C:6]1[C:7]2[C:8](=[CH:9][C:10]([Cl:13])=[CH:11][CH:12]=2)[NH:14][C:33]=1[C:34](=[O:35])[C:36]1[CH:41]=[CH:40][C:39]([Cl:42])=[CH:38][CH:37]=1)[CH3:2]
Reactant: O=C(CBr)c1ccc(Cl)cc1
Reactant: CCOC(=O)C=Cc1ccc(Cl)cc1NS(=O)(=O)c1ccc(C)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: COC(C)(C)C
Solvent: C1CCC2=NCCCN2CC1
Solvent: CC(=O)N(C)C
Product: CCOC(=O)Cc1c(C(=O)c2ccc(Cl)cc2)[nH]c2cc(Cl)ccc12
Reaction time: 0.5 h
Yield: 81.4 %

Procedure:
To a solution of 3-[4-chloro-2-(toluene-4-sulfonylamino)-phenyl]-acrylic acid ethyl ester (3.00 g, 7.90 mmol) in N,N-dimethylacetamide (15.0 ml) was added potassium carbonate (2.18 g, 15.8 mmol) and 2-bromo-4′-chloroacetophenone (2.03 g, 8.69 mmol). The reaction was stirred 30 minutes and 1,8-diazabicyclo[5.4.0]undec-7-ene (3.54 ml, 23.7 mmol) was added. The reaction mixture was stirred one hour, poured into 1N hydrochloric acid (30 ml) and extracted with methyl t-butyl ether (2×30 ml). The organic extracts were dried with magnesium sulfate, filtered, and concentrated to provide a solid which was slurried in a mixture of methyl t-butyl ether and hexanes to afford [6-chloro-2-(4-chloro-benzoyl)-1H-indol-3-yl]-acetic acid ethyl ester (2.42 g, 81%). mp=186-188° C. 1H NMR (300 MHz, CDCl3) d 1.27 (t, 2, J=7.1), 3.80 (s, 2), 4.11 (q, 2, J=7.1), 7.15 (ddd, 1, J=8.5, 1.7, 0.5), 7.28-7.30 (m, 1), 7.48 (d, J=8.3), 7.54-7.57 (m, 1), 7.77 (d, 2, J=8.3), 9.16 (bs, 1). 13C NMR (75 MHz, CDCl3) d 15.42, 32.29, 62.45, 113.27, 117.60, 122.99, 123.23, 127.85, 130.12, 131.77, 133.61, 137.86, 138.13, 140.10, 172.45, 188.25. IR 3305, 1732, 1618, 1323 cm−1. Analysis calculated for C19H15Cl2NO3: C, 60.65; H, 4.02; N, 3.72. Found: C, 60.70; H, 3.97; N, 3.71.
Reaction SMILES: [OH:1][C@H:2]1[CH2:19][CH2:18][C@@:17]2([CH3:20])[C@H:4]([CH2:5][CH2:6][C@@H:7]3[C@@H:16]2[CH2:15][CH2:14][C@@:12]2([CH3:13])[C@:8]3([OH:22])[CH2:9][CH2:10][C:11]2=O)[CH2:3]1.Br.[NH:24]([C:26]1[NH:27][CH2:28][CH2:29][N:30]=1)[NH2:25].C(N(CC)CC)C.[OH-].[Na+]>C(O)C.O>[NH:30]1[CH2:29][CH2:28][N:27]=[C:26]1[NH:24]/[N:25]=[C:11]1/[C@:12]2([CH2:14][CH2:15][C@H:16]3[C@@H:7]([CH2:6][CH2:5][C@H:4]4[C@:17]3([CH3:20])[CH2:18][CH2:19][C@H:2]([OH:1])[CH2:3]4)[C@@:8]2([OH:22])[CH2:9][CH2:10]/1)[CH3:13]
Reactant: C[C@]12CC[C@H](O)C[C@H]1CC[C@@H]1[C@@H]2CC[C@]2(C)C(=O)CC[C@]12O
Reactant: NNC1=NCCN1
Agent: Br
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Solvent: CCN(CC)CC
Product: C[C@]12CC[C@H](O)C[C@H]1CC[C@@H]1[C@@H]2CC[C@]2(C)/C(=N/NC3=NCCN3)CC[C@]12O
Yield: 56.5 %

Procedure:
A mixture of 0.60 g of 3β,14β-dihydroxy-5β-androstane-17-one (Lindig C., J. Prakt. Chem., 1983, 325, 587), 1.00 g of 2-hydrazino-2-imidazoline hydrobromide and 1.50 ml of triethylamine in 50 ml of ethanol and 50 mI of water was stirred at reflux for 2 days. After cooling the mixture was added with 1N sodium hydroxide until pH 12.5 was reached. The mixture was evaporated under reduced pressure and the residue was purified by flash-chromatography (SiO2) using chloroform/methanol/28% ammonium hydroxide 88/20/2 as eluant; the fractions containing the title compound were collected and evaporated to dryness. The residue was ground with ethanol/diethyl ether to give 0.43 g of the title compound (I-bo) as a white solid.
Reaction SMILES: CN(C)CCNC.[CH2:8]([Li])[CH2:9][CH2:10]C.[Si:13]([O:20][C:21]1[CH:28]=[CH:27][C:24]([CH:25]=[O:26])=[CH:23][CH:22]=1)([C:16]([CH3:19])([CH3:18])[CH3:17])([CH3:15])[CH3:14]>C1COCC1>[Si:13]([O:20][C:21]1[CH:28]=[CH:27][C:24]([CH:25]=[O:26])=[C:23]([CH2:8][CH2:9][CH3:10])[CH:22]=1)([C:16]([CH3:19])([CH3:18])[CH3:17])([CH3:15])[CH3:14]
Reactant: [Li]CCCC
Reactant: CC(C)(C)[Si](C)(C)Oc1ccc(C=O)cc1
Agent: CNCCN(C)C
Solvent: C1CCOC1
Product: CCCc1cc(O[Si](C)(C)C(C)(C)C)ccc1C=O
Temperature: -20 °C
Reaction time: 0.29 h
Yield: 13 %

Procedure:
To a solution of 1.226 g (0.012 mol) of N,N,N'-trimethylethylenediamine in 25 mL of anhydrous THF was added 4.40 mL of a 2.5M solution of n-butyllithium in THF at -20° C. under a nitrogen atmosphere. After 15-20 minutes, 2.501 g (0.010 mol) of the product of Step C dissolved in 5.0 mL of THF was added and the reaction mixture was stirred at -20° C. for an additional 15-20 minutes. Next, 12.0 mL of a 2.5M solution of n-butyllithium in THF was added to the reaction, the cooling bath was removed and the mixture was stirred at room temperature for 3.5 hours. At the end of this period, the reaction mixture was cooled to -40° C. and 5.85 mL of 1-iodopropane was added via syringe. The reaction mixture was then allowed to slowly warm to room temperature and was stirred for 16 hours. The mixture was then partitioned between diethylether and 10% aqueous NaHSO4 and extracted. The organic layer was separated, dried (MgSO4), filtered, and evaporated. The residue was partially purified on a silica gel flash chromatography column eluted with 5% EtOAc-hexane. The semi-purified fractions were combined and evaporated, then rechromatographed on a silica gel flash chromatography column eluted with 50% CHCl3 -hexane. Evaporation of the purified fractions and solvent removal in vacuo afforded 0.386 g (13%) of the title compound.
Reaction SMILES: [C:1]([C:5]1[NH:9][CH:8]=[N:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].[CH3:12][Si:13]([CH2:16][CH2:17][O:18][CH2:19]Cl)([CH3:15])[CH3:14]>>[C:1]([C:5]1[N:9]([CH2:19][O:18][CH2:17][CH2:16][Si:13]([CH3:15])([CH3:14])[CH3:12])[CH:8]=[N:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: C[Si](C)(C)CCOCCl
Reactant: CC(C)(C)c1cnc[nH]1
Agent: [H-]
Agent: [Na+]
Product: CC(C)(C)c1cncn1COCC[Si](C)(C)C
Yield: 57.6 %

Procedure:
Reaction of 5-tert-butyl-1H-imidazole (423 mg, 3.41 mmol), NaH (60%, 132 mg, 3.31 mmol), and SEMCl (639 uL, 3.61 mmol) followed by column chromatography on silica gel (hexane/EtOAC 3:2) gave the title compound (500 mg, 57%) as a yellow oil. 1H NMR (300 MHz, CDCl3) δ major isomer: 0.00 (s, 9H), 0.89 (t, 2H, J=7.5 Hz), 1.29 (s, 9H), 3.47 (t, 2H, J=7.5 Hz), 5.19 (s, 2H), 6.73 (s, 1H), 7.50 (s, 1).
Reaction SMILES: [CH2:1]([O:3][CH:4]([C:9]1[CH:10]=[N:11][C:12]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][C:20]([C:23]([F:26])([F:25])[F:24])=[CH:19][CH:18]=2)=[CH:13][CH:14]=1)[CH2:5][C:6]([OH:8])=[O:7])[CH3:2].C(O)(C)C.CCCCCC.C(O)(C)C.FC(F)(F)C(O)=O>CCCCCC>[CH2:1]([O:3][C@H:4]([C:9]1[CH:10]=[N:11][C:12]([O:15][CH2:16][C:17]2[CH:18]=[CH:19][C:20]([C:23]([F:26])([F:24])[F:25])=[CH:21][CH:22]=2)=[CH:13][CH:14]=1)[CH2:5][C:6]([OH:8])=[O:7])[CH3:2]
Reactant: CCOC(CC(=O)O)c1ccc(OCc2ccc(C(F)(F)F)cc2)nc1
Solvent: CCCCCC
Solvent: O=C(O)C(F)(F)F
Solvent: CC(C)O
Product: CCO[C@@H](CC(=O)O)c1ccc(OCc2ccc(C(F)(F)F)cc2)nc1
Yield: 23 %

Procedure:
3-Ethoxy-3-(6-{[4-(trifluoromethyl)benzyl]oxy}pyridin-3-yl)propionic acid (200 mg) produced in Example 17 (17D) was dissolved in hexane (6 mL) and isopropanol (3 mL) and the resulting solution was subjected to optical resolution by high-performance liquid chromatography using a Chiralpak AD semi-preparative column (2.0 cm×25.0 cm, manufactured by Daicel Chemical Industries, Ltd.) (conditions: flow rate: 20 mL/min, solvent: hexane/isopropanol/trifluoroacetic acid=90/10/0.1 (v/v), detection wavelength: 220 nm). The solvent in the solution having been subjected to optical resolution was distilled off under reduced pressure, and a compound with a retention time of 7 minutes was obtained as (3S)-3-ethoxy-3-(6-{[4-(trifluoromethyl)benzyl]oxy}pyridin-3-yl)propionic acid (a white solid, 45 mg, yield: 23%), and a compound with a retention time of 10 minutes was obtained as (3R)-3-ethoxy-3-(6-{[4-(trifluoromethyl)benzyl]oxy}pyridin-3-yl)propionic acid (a white solid, 47 mg, yield: 24%).
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[N:10]1[CH:14]=[CH:13][N:12]=[CH:11]1)[CH3:2].[Br:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22]>C(OCC)C>[Br-:15].[CH2:1]([O:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[N+:10]1[CH:14]=[CH:13][N:12]([CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])[CH:11]=1)[CH3:2]
Reactant: CCCCCCCBr
Reactant: CCOc1ccccc1-n1ccnc1
Solvent: CCOCC
Product: CCCCCCCn1cc[n+](-c2ccccc2OCC)c1
Product: [Br-]

Procedure:
According to the general synthesis procedure, 1.62 mmol (0.305 g) 1-(2-ethoxyphenyl)imidazole and 11.00 mmol (0.319 g, 0.280 ml) 1-bromoheptane are dissolved in 3 ml diethylether and heated for 4 h to 100° C.
Reaction SMILES: [CH3:1][CH:2]([S:5][C:6]1[CH:13]=[C:12]([C:14]([F:17])([F:16])[F:15])[CH:11]=[CH:10]C=1C#N)[CH2:3][CH3:4].[OH-:18].[Na+].[CH2:20]([OH:22])[CH3:21]>O>[CH3:1][CH:2]([S:5][C:6]1[CH:13]=[C:12]([C:14]([F:17])([F:16])[F:15])[CH:11]=[CH:10][C:21]=1[C:20]([OH:18])=[O:22])[CH2:3][CH3:4]
Reactant: CCO
Reactant: CCC(C)Sc1cc(C(F)(F)F)ccc1C#N
Reactant: [OH-]
Agent: [Na+]
Solvent: O
Product: CCC(C)Sc1cc(C(F)(F)F)ccc1C(=O)O

Procedure:
A solution of 2-(1-methylpropylsulphenyl)-4-trifluoromethylbenzonitrile (8.6 g) in ethanol was added to a solution of sodium hydroxide (47.3 g) in water and the resultant mixture was heated at reflux for 24 hours. It was poured into water and acidified to pH 1. The mixture was extracted with ethyl acetate, washed with water, dried (MgSO4) and filtered. The filtrate was evaporated to dryness to give 2-(1-methylpropylsulphenyl)-4-trifluoromethylbenzoic acid (8.1 g) as a white solid, m.p. 99.8°-101° C.
Reaction SMILES: [C:1]([O:5][C:6](=[O:10])[CH2:7][NH:8][CH3:9])([CH3:4])([CH3:3])[CH3:2].Cl.C(N(CC)CC)C.F[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[N+:26]([O-:28])=[O:27]>C(#N)C>[C:1]([O:5][C:6](=[O:10])[CH2:7][N:8]([CH3:9])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[N+:26]([O-:28])=[O:27])([CH3:4])([CH3:3])[CH3:2]
Reactant: O=[N+]([O-])c1ccccc1F
Reactant: CNCC(=O)OC(C)(C)C
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CN(CC(=O)OC(C)(C)C)c1ccccc1[N+](=O)[O-]
Temperature: 50 °C
Reaction time: 8 h

Procedure:
In acetonitrile (80 mL) was stirred sarcosine t-butyl ester•hydrochloride (10.1 g, 55.5 mmol) and triethylamine (6.57 g, 65 mmol). To this was added 2-fluoronitrobenzene (5.66 g, 40 mmol) and the mixture was stirred overnight at 50° C. The solution was evaporated at a reduced pressure until free of acetonitrile. The residue was partitioned between ether (100 m]L) and water (100 mL). The ether layer was washed with brine and dried over magnesium sulfate. The solvent was evaporated at reduced pressure to give an oil which was dried at 60° C. in vacuo to remove all traces of fluoronitrobenzene. MS: M++1=267.1 Da.
Reaction SMILES: [BH4-].[Na+].[CH3:3][C:4]1([CH3:14])[O:9][C:8]2[CH:10]=[CH:11][S:12][C:7]=2[C:6](=[O:13])[CH2:5]1.O>C(O)C>[OH:13][CH:6]1[CH2:5][C:4]([CH3:14])([CH3:3])[O:9][C:8]2[CH:10]=[CH:11][S:12][C:7]1=2
Reactant: CC1(C)CC(=O)c2sccc2O1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: CC1(C)CC(O)c2sccc2O1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Sodium borohydride (0.97 g, 25.5 mmol) was added to a solution of 5,6-dihydro-5,5-dimethyl-7H-thieno [3,2-b]pyran-7-one (3.1 g, 17.0 mmol) in ethanol (50 mL) and stirred at rt for 2 h. An additional 0.97 g of sodium borohydride was added and the mixture was stirred 16 h. The mixture was poured into water and extracted with dichloromethane. The dichloromethane solution was washed with water (5×) and dried over magnesium sulfate. The solvent was evaporated in vacuo to give the product, 2.96 g (95%), as a brown oil: IR (neat): 3373, 2976, 1561 and 1400 cm-1 ; MS: m/z 185 (MH+ ; 1H NMR (CDCl3): δ1.34(s, 3H), 1.45(s, 3H), 1.87(m, 1H), 1.94(d, J=7.0 Hz, 1H, exchanges with D2O), 2.16(m, 1H), 4.88(m, 1H), 6.57(d, J=5.4 Hz, 1H), 7.13(d, J=5.4 Hz, 1H). This oil was used without further purification in the next step.
Reaction SMILES: Cl.[CH2:2]([O:4][C:5](=[O:8])[CH2:6][NH2:7])[CH3:3].N12CCCN=C1CCCCC2.[S:20]1[CH:24]=[CH:23][CH:22]=[C:21]1[CH2:25][C:26](Cl)=[O:27]>ClCCl>[S:20]1[CH:24]=[CH:23][CH:22]=[C:21]1[CH2:25][C:26]([NH:7][CH2:6][C:5]([O:4][CH2:2][CH3:3])=[O:8])=[O:27]
Reactant: CCOC(=O)CN
Reactant: O=C(Cl)Cc1cccs1
Agent: Cl
Solvent: ClCCl
Solvent: C1CCC2=NCCCN2CC1
Product: CCOC(=O)CNC(=O)Cc1cccs1
Temperature: 25 °C
Reaction time: 1 h
Yield: 89 %

Procedure:
To a suspension of glycine ethyl ester hydrochloride (21.77 g, 156 mmol) in anhydrous dichloromethane (260 mL), 1,8-diazabicyclo[5.4.0]undec-7-ene (55 mL, 368 mmol) was added under nitrogen, which addition turned the suspension clear. Then 2-thiopheneacetyl chloride (19.2 mL, 156 mmol) was added dropwise. After completion of the addition, the flask was warmed to room temperature and the mixture was stirred for 1 hour. Then it was washed with water (260 mL×3), dried and concentrated. A dark brown oil was obtained (31.77 g, yield 89%), which turned into a dark brown solid upon standing. 1H NMR (CDCl3, 500 MHz), δ=7.26 (dd, J=5.0, 1.0 Hz, 1H), 7.01-6.97 (m, 2H), 6.19 (s, 1H), 4.18 (q, J=7.0 Hz, 2H), 4.00 (d, J=5.0 Hz, 2H), 3.83 (s, 2H), 1.26 (t, J=7.0 Hz, 3H).
Reaction SMILES: [O:1]=[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4](=[O:11])[N:3]1[CH2:12][CH2:13][CH2:14][CH2:15][N:16]1[C:24]2[C:19](=[CH:20][CH:21]=[C:22]([C:25]([C:27]3[S:28][C:29]([C:38]4[CH:43]=[CH:42][CH:41]=[C:40]([OH:44])[CH:39]=4)=[C:30]([CH2:32][C:33]([O:35][CH2:36][CH3:37])=[O:34])[CH:31]=3)=[O:26])[CH:23]=2)[CH:18]=[C:17]1[C:45]1[CH:60]=[CH:59][C:48]([C:49]([O:51]CC2C=CC=CC=2)=[O:50])=[CH:47][CH:46]=1>CO.CCOC(C)=O.[Pd]>[O:1]=[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4](=[O:11])[N:3]1[CH2:12][CH2:13][CH2:14][CH2:15][N:16]1[C:24]2[C:19](=[CH:20][CH:21]=[C:22]([C:25]([C:27]3[S:28][C:29]([C:38]4[CH:43]=[CH:42][CH:41]=[C:40]([OH:44])[CH:39]=4)=[C:30]([CH2:32][C:33]([O:35][CH2:36][CH3:37])=[O:34])[CH:31]=3)=[O:26])[CH:23]=2)[CH:18]=[C:17]1[C:45]1[CH:46]=[CH:47][C:48]([C:49]([OH:51])=[O:50])=[CH:59][CH:60]=1
Reactant: CCOC(=O)Cc1cc(C(=O)c2ccc3cc(-c4ccc(C(=O)OCc5ccccc5)cc4)n(CCCCN4C(=O)c5ccccc5C4=O)c3c2)sc1-c1cccc(O)c1
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CO
Product: CCOC(=O)Cc1cc(C(=O)c2ccc3cc(-c4ccc(C(=O)O)cc4)n(CCCCN4C(=O)c5ccccc5C4=O)c3c2)sc1-c1cccc(O)c1
Yield: 88 %

Procedure:
A mixture of 6 (50 mg, 0.061 mmol) and 10% Pd—C (20 mg) in MeOH (8 mL) and EtOAc (3 mL) was stirred under 1 atm H2 atmosphere until no 6 was detected by TLC. The resulting solution was filtered and concentrated in vacuo to give 7 as a yellow amorphous solid (39 mg, 88%). 1H NMR (400 MHz, CDCl3) δ 8.16 (d, J=8.4 Hz, 2H), 8.06 (s, 1H), 7.77-7.65 (m, 7H), 7.59 (d, J=8.0 Hz, 2H), 7.29 (t, J=8.0 Hz, 2H), 7.11 (s, 1H), 7.03 (d, J=7.6 Hz, 1H), 6.93 (d, J=8.0 Hz, 1H), 6.66 (s, 1H), 4.34 (brt, 2H), 4.15 (q, J=7.2 Hz, 2H), 3.72 (s, 2H), 3.52 (brt, 2H), 1.72-1.65 (m, 2H), 1.51-1.47 (m, 2H), and 1.24 (t, J=7.2 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 188.63, 171.67, 170.53, 168.73, 157.13, 149.52, 143.65, 141.52, 137.98, 137.73, 137.34, 134.34, 134.25, 131.97, 131.89, 131.84, 130.82, 130.56, 130.40, 129.55, 129.37, 123.54, 121.93, 121.17, 120.89, 116.52, 116.44, 112.83, 104.34, 61.59, 43.97, 37.38, 34.90, 27.46, 25.84, and 14.40.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[N:7]1[C:11](B2OC(C)(C)C(C)(C)O2)=[CH:10][CH:9]=[N:8]1.Br[C:22]1[CH:23]=[C:24]([NH2:30])[C:25]([O:28][CH3:29])=[N:26][CH:27]=1.COCCOC>O>[CH3:29][O:28][C:25]1[C:24]([NH2:30])=[CH:23][C:22]([C:11]2[N:7]([CH:2]3[CH2:3][CH2:4][CH2:5][CH2:6][O:1]3)[N:8]=[CH:9][CH:10]=2)=[CH:27][N:26]=1
Reactant: CC1(C)OB(c2ccnn2C2CCCCO2)OC1(C)C
Reactant: COc1ncc(Br)cc1N
Solvent: COCCOC
Solvent: O
Product: COc1ncc(-c2ccnn2C2CCCCO2)cc1N
Temperature: 92 °C

Procedure:
To a 100 ml flask was added 1-(tetrahydro-2H-pyran-2-yl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole 14.1.B (6.0 g, 22 mmol), 5-bromo-2-methoxypyridin-3-amine (4 g, 20 mmol), 100 ml of DME, and 30 ml of water. Argon was then bubbled through the solution for 8 minutes at which time Pd(Ph3)4 (460 mg, 0.39 mmole) was added and argon was then bubbled through the solution for an additional 2 minutes. The reaction was then heated to 92° C. for 12 hours at which time the crude was quenched with brine and extracted with EtAc. The solvent was removed and the crude purifed on silica gel (eluting with 0-70% EtAc in Hexanes) to 2-methoxy-5-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl)pyridin-3-amine 14.1.C (5.3 g, 97. % yield).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][CH:3]([C:7]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[NH:9][CH:8]=2)[CH2:2]1.[C:16]([O-:19])([O-])=[O:17].[K+].[K+]>CC(C)=O.O>[C:3]([O:19][C:16]([N:1]1[CH2:6][CH2:5][CH2:4][CH:3]([C:7]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[NH:9][CH:8]=2)[CH2:2]1)=[O:17])([CH3:7])([CH3:4])[CH3:2]
Reactant: O=C([O-])[O-]
Reactant: c1ccc2c(C3CCCNC3)c[nH]c2c1
Agent: [K+]
Solvent: CC(C)=O
Solvent: O
Product: CC(C)(C)OC(=O)N1CCCC(c2c[nH]c3ccccc23)C1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of the 3-piperidin-3-yl-1H-indole obtained in Example 29 in acetone/water (1:1) at 0° C. is treated with di-tert-dicarbonate (4.1 g, 18.7 mmol) and K2CO3 (11.75 g, 85 mmol), stirred for 2 hours while warming to room temperature, and concentrated in vacuo. The resultant aqueous mixture is extracted with ethyl acetate. The extracts are combined, dried over Na2SO4 and concentrated in vacuo. The resultant residue is purified by column chromatography (silica gel, 1% NH4OH in MeOH:CHCl3, 0:100 to 10:90 as eluent) to afford the title product, 1.25 g, identified by HPLC and mass spectral analyses.
Reaction SMILES: [Sn].[Cl:2][C:3]1[CH:16]=[CH:15][C:14]2[C:13](=[O:17])[C:12]3[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=3)[C:6](=[O:18])[C:5]=2[CH:4]=1.Cl>C(O)(=O)C>[Cl:2][C:3]1[CH:16]=[CH:15][C:14]2[CH2:13][C:12]3[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=3)[C:6](=[O:18])[C:5]=2[CH:4]=1.[Cl:2][C:3]1[CH:16]=[CH:15][C:14]2[C:13](=[O:17])[C:12]3[C:7]([CH2:6][C:5]=2[CH:4]=1)=[CH:8][CH:9]=[CH:10][CH:11]=3
Reactant: O=C1c2ccccc2C(=O)c2cc(Cl)ccc21
Agent: Cl
Agent: [Sn]
Solvent: CC(=O)O
Product: O=C1c2ccccc2Cc2cc(Cl)ccc21
Product: O=C1c2ccccc2Cc2ccc(Cl)cc21

Procedure:
Tin powder (100 g) and 2-chloroanthraquinone (70 g) were refluxed in acetic acid (500 ml) while concentrated hydrochloric acid (130 ml) was added over a period of 3 hours. The solution was cooled and the product was separated by filtration, and then chromatographed on silica gel, eluting with benzene:ether, so as to afford 2-chloroanthrone and 3-chloroanthrone.
Reaction SMILES: [CH2:1]([N:8]1[C:12](=[O:13])[CH2:11][CH2:10][C@H:9]1[C:14]([OH:16])=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O=S(Cl)Cl.[Cl-].[Al+3].[Cl-].[Cl-]>CN(C)C=O>[CH2:10]1[CH:9]2[N:8]([CH2:1][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][C:7]=3[C:14]2=[O:16])[C:12](=[O:13])[CH2:11]1
Reactant: O=C(O)[C@@H]1CCC(=O)N1Cc1ccccc1
Agent: [Al+3]
Agent: [Cl-]
Solvent: CN(C)C=O
Solvent: O=S(Cl)Cl
Product: O=C1c2ccccc2CN2C(=O)CCC12
Reaction time: 8 h
Yield: 69.5 %

Procedure:
To a solution prepared from 11.68 g of (+)-N-benzylpyroglutamic acid (See E. Campaigne and D. P. Matthews, J. Het. Chem., 12, 391 (1975)), 100 ml of CH2CL2 and a drop of dimethylformamide (DMF), 7.57 g of SOCl2 was added dropwise. The mixture was refluxed for five hours and allowed to stand overnight at ambient temperature. The reaction mixture was cooled in an ice-salt bath. Aluminum chloride (22.6 g) was added in portions with exclusion of moisture and vigorous stirring. The temperature did not exceed 10° C. during the addition. The mixture was stirred 1.5 hours and then ice was added gradually. The mixture was partitioned between water and CH2Cl2. The CH2Cl2 phase was washed with water, dried (Na2SO4), filtered and evaporated to give 10 g of a crude product. Recrystallization from toluene gave 7.45 g of crystals, m.p. 103°-105° C.
Reaction SMILES: C([O:3][C:4]([C@@H:6]1[CH2:11][CH2:10][CH2:9][N:8]([CH2:12][CH2:13][CH2:14][CH2:15][O:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH2:7]1)=[O:5])C.[OH-].[Na+].CC(C)=O.[ClH:29]>C(O)C.O>[ClH:29].[O:16]([CH2:15][CH2:14][CH2:13][CH2:12][N:8]1[CH2:9][CH2:10][CH2:11][C@@H:6]([C:4]([OH:5])=[O:3])[CH2:7]1)[C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: CCOC(=O)[C@@H]1CCCN(CCCCOc2ccccc2)C1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: CC(C)=O
Solvent: O
Product: O=C(O)[C@@H]1CCCN(CCCCOc2ccccc2)C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
The above ester (3.5 g, 11.5 mmol) was dissolved in ethanol (35 ml) and 4N sodium hydroxide (5.7 ml) was added. The mixture was stirred at ambient temperature overnight. The reaction mixture was diluted with water and 4M hydrochloric acid (11.5 ml) was added. The mixture was concentrated in vacuo and dichloromethane (50 ml) and acetone were added to the residue. The mixture was concentrated in vacuo to give a residue which was heated at reflux with acetone (700 ml). The mixture was filtered while still hot and the filtrate was left for crystallisation. The solid which formed was isolated by filtration and dried to give 1.9 g of the title compound as a solid.
Reaction SMILES: Cl[C:2]1[C:7]([O:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[O:15][CH3:16])=[C:6]([Cl:17])[N:5]=[C:4]([CH3:18])[N:3]=1.[K+].[CH:20]([C:23]1[CH:24]=[CH:25][C:26]([S:29]([NH-:32])(=[O:31])=[O:30])=[N:27][CH:28]=1)([CH3:22])[CH3:21]>CS(C)=O.O>[CH:20]([C:23]1[CH:24]=[CH:25][C:26]([S:29]([NH:32][C:2]2[C:7]([O:8][C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=3[O:15][CH3:16])=[C:6]([Cl:17])[N:5]=[C:4]([CH3:18])[N:3]=2)(=[O:31])=[O:30])=[N:27][CH:28]=1)([CH3:22])[CH3:21]
Reactant: COc1ccccc1Oc1c(Cl)nc(C)nc1Cl
Reactant: CC(C)c1ccc(S([NH-])(=O)=O)nc1
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: COc1ccccc1Oc1c(Cl)nc(C)nc1NS(=O)(=O)c1ccc(C(C)C)cn1
Temperature: 25 °C
Reaction time: 72 h
Yield: 93.1 %

Procedure:
To a solution of 2.15 g of 4,6-dichloro-5-(o-methoxyphenoxy)-2-methyl-pyrimidine in 40 ml of DMSO was added 3.59 g of 5-isopropyl-2-pyridine sulfonamide potassium salt. The mixture was stirred for 72 h at room temperature. The solution was diluted with 350 ml of water and extracted twice with 200 ml of diehtyl ether. The organic layers were extracted twice with water. The combined aqueous layers were acidified to pH 4 with 5 ml of acetic acid and extracted twice with DCM. The organic layers were washed with water, and dried over Na2SO4. The solution was treated with activated charcoal, filtered over Celite and evaporated. The residue was suspended in 30 ml of diethyl ether, filtered off and dried to give 3.15 g of 5-isopropyl-N-[6-chloro-5-(o-methoxyphenoxy)-2-methyl-4-pyrimidinyl]-2-pyridine sulfonamide as a pale beige powder. LC-MS: tR=5.18 min, [M+1]+=449.25, [M−1]−=447.31.