Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([S:12]([N:15]([CH2:21][C:22]3[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][C:23]=3[O:30][CH3:31])[C:16]3[S:17][CH:18]=[CH:19][N:20]=3)(=[O:14])=[O:13])=[CH:9][CH:10]=2)[C:5]([OH:32])=[CH:4][N:3]=1.[F:33][C:34]1[CH:39]=[CH:38][C:37](B(O)O)=[C:36]([O:43][CH3:44])[CH:35]=1.C(=O)([O-])[O-].[K+].[K+].O1CCOCC1>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.O>[CH3:31][O:30][C:23]1[CH:24]=[C:25]([O:28][CH3:29])[CH:26]=[CH:27][C:22]=1[CH2:21][N:15]([C:16]1[S:17][CH:18]=[CH:19][N:20]=1)[S:12]([C:8]1[CH:7]=[C:6]2[C:11](=[CH:10][CH:9]=1)[C:2]([C:37]1[CH:38]=[CH:39][C:34]([F:33])=[CH:35][C:36]=1[O:43][CH3:44])=[N:3][CH:4]=[C:5]2[OH:32])(=[O:14])=[O:13]
Reactant: COc1ccc(CN(c2nccs2)S(=O)(=O)c2ccc3c(Cl)ncc(O)c3c2)c(OC)c1
Reactant: COc1cc(F)ccc1B(O)O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: COc1ccc(CN(c2nccs2)S(=O)(=O)c2ccc3c(-c4ccc(F)cc4OC)ncc(O)c3c2)c(OC)c1

Procedure:
A microwave vial was charged with 1-chloro-N-(2,4-dimethoxybenzyl)-4-hydroxy-N-(thiazol-2-yl)isoquinoline-6-sulfonamide (INTERMEDIATE WWW) (0.263 g, 0.535 mmol), (4-fluoro-2-methoxyphenyl)boronic acid (0.136 g, 0.802 mmol), tetrakis(triphenylphosphine)palladium(0) (0.062 g, 0.053 mmol), and potassium carbonate (0.369 g, 2.67 mmol). Dioxane (2.67 ml) and Water (0.891 ml) were added, the vial was flushed with argon and sealed, and microwaved at 100° C. for 30 minutes. The reaction was diluted with ethyl acetate and washed with water. The aqueous layer was extracted with ethyl acetate, and the combined organic layers were dried with sodium sulfate, filtered, and concentrated. The material was purified via column chromatography (RediSep Gold 12 g, gradient elution 0-100% EtOAc:Heptane) to afford N-(2,4-dimethoxybenzyl)-1-(4-fluoro-2-methoxyphenyl)-4-hydroxy-N-(thiazol-2-yl)isoquinoline-6-sulfonamide. (ESI) 582.2 (M+H)+.
Reaction SMILES: C([N:8]1[CH2:12][CH2:11][CH2:10][C@@H:9]1[C:13]#[CH:14])(OC(C)(C)C)=O.[CH3:15][OH:16].[ClH:17].O>C(O)C>[ClH:17].[CH3:13][C:9]1[N:8]=[C:12]2[CH:14]=[C:13]([C@H:9]3[CH2:10][CH2:11][CH2:12][NH:8]3)[O:16][C:15]2=[CH:11][CH:10]=1
Reactant: CO
Reactant: C#C[C@H]1CCCN1C(=O)OC(C)(C)C
Agent: Cl
Solvent: CCO
Solvent: O
Product: Cc1ccc2oc([C@H]3CCCN3)cc2n1

Procedure:
The title compound was prepared from 1-Boc-2(R)-ethynylpyrrolidine according to the procedures of Example 5 above: [α]D≤ +16.5° (c 1.0, MeOH); Anal. Calcd for C12H14N2O.2.0 HCl.0.2 H2O.0.2 ethanol: C, 51.39; H, 6.19; N, 9.67. Found: C, 51.63; H, 6.49; N, 9.33.
Reaction SMILES: C[O:2][C:3](=[O:39])[CH2:4][C:5]1[CH:10]=[CH:9][C:8]([CH2:11][N:12]([C:14]2[CH:19]=[CH:18][C:17]([O:20][CH2:21][C:22]3[N:23]([C:30]4[C:35]([Cl:36])=[CH:34][CH:33]=[CH:32][C:31]=4[Cl:37])[N:24]=[CH:25][C:26]=3[CH:27]([CH3:29])[CH3:28])=[CH:16][C:15]=2[CH3:38])[CH3:13])=[CH:7][CH:6]=1.[OH-].[Li+]>O1CCOCC1>[Cl:37][C:31]1[CH:32]=[CH:33][CH:34]=[C:35]([Cl:36])[C:30]=1[N:23]1[C:22]([CH2:21][O:20][C:17]2[CH:18]=[CH:19][C:14]([N:12]([CH2:11][C:8]3[CH:7]=[CH:6][C:5]([CH2:4][C:3]([OH:39])=[O:2])=[CH:10][CH:9]=3)[CH3:13])=[C:15]([CH3:38])[CH:16]=2)=[C:26]([CH:27]([CH3:29])[CH3:28])[CH:25]=[N:24]1
Reactant: COC(=O)Cc1ccc(CN(C)c2ccc(OCc3c(C(C)C)cnn3-c3c(Cl)cccc3Cl)cc2C)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: C1COCCO1
Product: Cc1cc(OCc2c(C(C)C)cnn2-c2c(Cl)cccc2Cl)ccc1N(C)Cc1ccc(CC(=O)O)cc1
Temperature: 50 °C
Yield: 94.9 %

Procedure:
To an ambient temperature solution of {4-[({4-[2-(2,6-Dichloro-phenyl)-4-isopropyl-2H-pyrazol-3-ylmethoxy]-2-methyl-phenyl}-methyl-amino)-methyl]-phenyl}-acetic acid methyl ester (81 mg, 0.143 mmol) in dioxane (2 mL) is added a solution of lithium hydroxide (215 μL, 0.429 mmol, 2.0N in water). The reaction mixture is heated to 50° C. The reaction is concentrated and the residue is partitioned between Et2O and water. The aqueous layer pH is adjusted to approximately 7 and the aqueous layer is extracted with a second portion of Et2O. The combined organic layers are washed with water, dried (MgSO4), filtered, and concentrated to yield the title compound (75 mg, 95%). ES/MS m/e (35Cl) 552.0 (M+1).
Reaction SMILES: Br[C:2]1[S:11][C:5]2[N:6]=[CH:7][N:8]=[C:9]([Cl:10])[C:4]=2[CH:3]=1.[F:12][C:13]1[CH:18]=[CH:17][C:16](B(O)O)=[CH:15][CH:14]=1.C([O-])([O-])=O.[K+].[K+].Cl>O1CCOCC1.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Cl:10][C:9]1[C:4]2[CH:3]=[C:2]([C:16]3[CH:17]=[CH:18][C:13]([F:12])=[CH:14][CH:15]=3)[S:11][C:5]=2[N:6]=[CH:7][N:8]=1
Reactant: Clc1ncnc2sc(Br)cc12
Reactant: OB(O)c1ccc(F)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: O
Solvent: C1COCCO1
Product: Fc1ccc(-c2cc3c(Cl)ncnc3s2)cc1
Temperature: 25 °C
Yield: 47.2 %

Procedure:
A solution of 6-bromo-4-chlorothieno[2,3-d]pyrimidine (0.12 g, 0.48 mmol), 4-fluorophenylboronic acid (67 mg, 0.48 mmol), K2CO3 (0.266 g, 1.92 mmol) and Pd(PPh3)4 in dioxane/H2O (3:1, 3 ml) was refluxed under N2 for 2 hours. After cooling to room temperature, 1N HCl was added slowly to neutralize the mixture to pH=7-8. The mixture was extracted with CH2Cl2, washed with water and brine and dried over Na2SO4. After removing the solvents under reduced pressure, the crude residue was purified by silica gel chromatography (hexane/EtOAc 30:1) to yield the title compound as a pale yellow solid (60 mg, 47%).
Reaction SMILES: [OH:1][N:2]=[C:3](Cl)[C:4]1[CH:9]=[CH:8][C:7]([O:10][C:11]([F:14])([F:13])[F:12])=[CH:6][CH:5]=1.[C:16]([O:20][CH3:21])(=[O:19])[C:17]#[CH:18].CCN(CC)CC>C1(C)C=CC=CC=1.CCOC(C)=O>[F:12][C:11]([F:14])([F:13])[O:10][C:7]1[CH:8]=[CH:9][C:4]([C:3]2[CH:18]=[C:17]([C:16]([O:20][CH3:21])=[O:19])[O:1][N:2]=2)=[CH:5][CH:6]=1
Reactant: ON=C(Cl)c1ccc(OC(F)(F)F)cc1
Reactant: C#CC(=O)OC
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: COC(=O)c1cc(-c2ccc(OC(F)(F)F)cc2)no1
Temperature: 80 °C
Yield: 76.6 %

Procedure:
To a mixture of N-hydroxy-4-(trifluoromethoxy)benzimidoyl chloride (1.2 g, 5 mmol) and methyl propiolate (0.9 mL, 10 mmol) in toluene (12 mL) was added Et3N (0.73 mL, 5.3 mmol) dropwise over 10 minutes. The resulting reaction mixture was heated at 80° C. for 2.5 h and then diluted with EtOAc (20 mL). The organic layer was washed with 0.1 M aq. HCl, H2O, and brine. The organic layer was dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was crystallized from CHCl3 and petroleum ether to afford the title compound (1.1 g, 77%). MS (ES+) C12H8F3NO4 requires: 287. found: 288 [M+H]+. 1H NMR (500 MHz, CDCl3) δ 7.88 (d, J=6.8 Hz, 2H), 7.33 (d, J=6.8 Hz, 2H), 7.25 (s, 1H).
Reaction SMILES: [C:1]([CH2:3][C:4]1([N:20]2[CH:24]=[C:23]([C:25]3[C:26]4[CH:33]=[CH:32][N:31](COCC[Si](C)(C)C)[C:27]=4[N:28]=[CH:29][N:30]=3)[CH:22]=[N:21]2)[CH2:7][N:6]([C:8]2[CH:19]=[CH:18][C:11]([C:12]([NH:14][CH:15]([CH3:17])[CH3:16])=[O:13])=[CH:10][CH:9]=2)[CH2:5]1)#[N:2].FC(F)(F)C(O)=O>C(Cl)Cl>[C:1]([CH2:3][C:4]1([N:20]2[CH:24]=[C:23]([C:25]3[C:26]4[CH:33]=[CH:32][NH:31][C:27]=4[N:28]=[CH:29][N:30]=3)[CH:22]=[N:21]2)[CH2:5][N:6]([C:8]2[CH:9]=[CH:10][C:11]([C:12]([NH:14][CH:15]([CH3:17])[CH3:16])=[O:13])=[CH:18][CH:19]=2)[CH2:7]1)#[N:2]
Reactant: CC(C)NC(=O)c1ccc(N2CC(CC#N)(n3cc(-c4ncnc5c4ccn5COCC[Si](C)(C)C)cn3)C2)cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(C)NC(=O)c1ccc(N2CC(CC#N)(n3cc(-c4ncnc5[nH]ccc45)cn3)C2)cc1

Procedure:
4-{3-(Cyanomethyl)-3-[4-(7-{[2-(trimethylsilyl)ethoxy]methyl}-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-1-yl}-N-isopropylbenzamide (1.74 g, 3.05 mmol) was dissolved in methylene chloride (5.0 mL) and trifluoroacetic acid (5.0 mL, 26 mmol) and stirred at room temperature After 4 hours, LC/MS data indicated that the reaction was complete and the desired product was formed (LCMS (M+H)+: m/z=471.3). The volatiles were removed in vacuo and the residue was azeotropically washed with acetonitrile several times (4×10 mL) to remove the excess TFA. The residue was dissolved in methanol (15 mL) and to this was added 14.8 M ammonium hydroxide in H2O (3.0 mL, 44 mmol) and ethylenediamine (0.10 mL, 1.5 mmol) and the resulting solution was stirred at room temperature for 3 hours to afford the desired product. The product was further precipitated out as a white solid by the addition of H2O (15 mL) and the heterogeneous solution was stirred for 30 minutes prior to pouring into water (60 mL). The precipitate was filtered off, washed with water (2×10 mL), and dried under high vacuum to afford the desired product (1.05 g, 78% yield). LCMS (M+H)+: m/z=441.1. 1H NMR (400 MHz, CD3OD): δ 8.78 (s, 1H), 8.66 (s, 1H), 8.42 (s, 1H), 7.99 (d, J=8.0 Hz, 1H), 7.75 (d, J=8.5 Hz, 2H), 7.50 (d, J=4.0 Hz, 1H), 7.00 (d, =4.0 Hz, 1H), 6.64 (t, J=8.5 Hz, 2H), 4.55 (d, J=8.0 Hz, 2H), 4.40 (d, J=8.0 Hz, 2H), 4.19 (m, 1H), 3.62 (s, 2H), 1.22 (d, J=7.0 Hz, 6H).
Reaction SMILES: [NH2:1][C:2]1[C:3]2[N:4]([C:8]([C@@H:27]3[CH2:31][CH2:30][CH2:29][NH:28]3)=[N:9][C:10]=2[C:11]2[CH:25]=[CH:24][C:14]([C:15]([NH:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=3)=[O:16])=[C:13]([F:26])[CH:12]=2)[CH:5]=[CH:6][N:7]=1.[C:32](Cl)(=[O:35])[CH:33]=[CH2:34]>>[C:32]([N:28]1[CH2:29][CH2:30][CH2:31][C@H:27]1[C:8]1[N:4]2[CH:5]=[CH:6][N:7]=[C:2]([NH2:1])[C:3]2=[C:10]([C:11]2[CH:25]=[CH:24][C:14]([C:15]([NH:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=3)=[O:16])=[C:13]([F:26])[CH:12]=2)[N:9]=1)(=[O:35])[CH:33]=[CH2:34]
Reactant: C=CC(=O)Cl
Reactant: Nc1nccn2c([C@@H]3CCCN3)nc(-c3ccc(C(=O)Nc4ccccn4)c(F)c3)c12
Product: C=CC(=O)N1CCC[C@H]1c1nc(-c2ccc(C(=O)Nc3ccccn3)c(F)c2)c2c(N)nccn12
Yield: 38.4 %

Procedure:
This compound was prepared, in an analogous manner as described in Example 1, from (S)-4-(8-amino-3-(pyrrolidin-2-yl)imidazo[1,5-a]pyrazin-1-yl)-2-fluoro-N-(pyridin-2-yl)benzamide (intermediate 17) and acryloylchloride, to afford the title compound (13 mg, 38.4%). Data: UPLC (C) Rt: 1.67 min; m/z 472.3 (M+H)+.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.[H-].[Na+].[CH:12](I)([CH3:14])[CH3:13].O>CN(C=O)C>[CH:12]([N:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1)([CH3:14])[CH3:13]
Reactant: CC(C)I
Reactant: c1ccc2[nH]ccc2c1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)n1ccc2ccccc21
Temperature: 25 °C
Reaction time: 14 h
Yield: 42.4 %

Procedure:
The title compound was prepared according to general procedure A described in Scheme 1. A solution of indole (5 g, 43 mmol) in DMF (60 mL) at to 0° C. was treated with NaH (60% in mineral oil, 3.4 g, 86 mmol) in 4 portions providing a slurry that was gradually warmed to RT over a 30 min period. Isopropyl iodide (1.1 g, 64 mmol) was added to the reaction mixture at RT and the mixture was stirred for 14 h. The reaction mixture was then treated with H2O (50 mL) and extracted with EtOAc (3×50 mL). The combined organic extracts were washed with sat. NaHCO3 (1×50 mL), H2O (1×50 mL) and dried over anhydrous Na2SO4. The solvent was removed under reduced pressure and the crude material was purified on silica gel (Biotage, 0-10% EtOAc/Hexanes, 30 min.) to provide N-isopropylindole as a colorless oil (2.9 g, 43% yield).
Reaction SMILES: F[C:2]1[CH:9]=[CH:8][C:7]([F:10])=[CH:6][C:3]=1[C:4]#[N:5].[NH:11]1[CH:15]=[N:14][CH:13]=[N:12]1.C([O-])([O-])=O.[Cs+].[Cs+]>CN(C=O)C>[F:10][C:7]1[CH:8]=[CH:9][C:2]([N:11]2[CH:15]=[N:14][CH:13]=[N:12]2)=[C:3]([CH:6]=1)[C:4]#[N:5]
Reactant: N#Cc1cc(F)ccc1F
Reactant: c1nc[nH]n1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: N#Cc1cc(F)ccc1-n1cncn1
Temperature: 80 °C

Procedure:
A mixture of 2,5-difluorobenzonitrile (500 mg, 3.6 mmol), 1,2,4-triazole (273 mg, 3.9 mmol) and Cs2CO3 (1.27 g, 3.9 mmol) in DMF (10 mL) was heated at 80° C. for 2 days. The solvent was removed under reduced pressure. The residue was partitioned between H2O and EtOAc. The layers were separated and the aqueous layer extracted with EtOAc (×3). The combined organic extracts were washed with brine, dried over MgSO4, filtered and concentrated to give the title compound as an off white solid (596 mg) along with a minor bis-alkylated byproduct. 1H NMR (400 MHz, CDCl3): δ 8.71 (s, 1H), 8.19 (s, 1H), 7.75–7.98 (m, 1H), 7.48–7.57 (m, 2H).
Reaction SMILES: [NH:1]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[C@H:2]([C:5]([OH:7])=[O:6])[CH2:3][NH2:4].C([O-])([O-])=O.[K+].[K+].[OH-].[K+].[CH:23]1[CH:28]=[CH:27][C:26]([CH2:29][O:30][C:31](Cl)=[O:32])=[CH:25][CH:24]=1>O.C1COCC1>[NH:1]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[C@H:2]([C:5]([OH:7])=[O:6])[CH2:3][NH:4][C:31]([O:30][CH2:29][C:26]1[CH:27]=[CH:28][CH:23]=[CH:24][CH:25]=1)=[O:32]
Reactant: CC(C)(C)OC(=O)N[C@@H](CN)C(=O)O
Reactant: O=C(Cl)OCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N[C@@H](CNC(=O)OCc1ccccc1)C(=O)O
Temperature: -5 °C
Reaction time: 8 h
Yield: 93.9 %

Procedure:
A stirring mixture of the N-Boc-Dap-OH 1 (10.00 g, 49.02 mmol), THF (90 mL), water (30 mL), K2CO3 (13.53 g, 98.04 mmol) and KOH (2.75 g, 49.02 mmol) was cooled to −5° C. Cbz-Cl solution (50 wt % in toluene, 25 mL, 73.53 mmol) was then added dropwise over a period of an hour. The mixture was allowed to stir for 8 h before being concentrated under reduced pressure to remove the THF. The aqueous residue was extracted with diethyl ether (50 mL), acidified to pH 4 by solid citric acid and the resulting precipitate was extracted by CH2Cl2 (2 50 mL). Combined organic layers were dried (Na2SO4) and evaporated to furnish the free acid 2 (15.57 g, 94% yield) as a gummy white solid which was used without further purification. 1H NMR (300 MHz, CDCl3) δ10.76 (1H), 7.25 (5H), 6.24, 5.67 (2H), 5.85 (1H), 5.08, 5.02 (2H), 4.36-4.23 (1H), 3.63-3.35 (2H), 1.38 (9H); 13C NMR (75 MHz, CDCl3)δ 173.5, 157.5, 156.2, 136.4, 128.6, 128.2, 80.6, 67.3, 54.4, 42.9, 28.6.
Reaction SMILES: [CH3:1][C:2]1[CH:6]=[C:5]([C:7]2[CH:12]=[C:11]([O:13][C:14]3[CH:15]=[CH:16][C:17]([NH:20]C(=O)OC(C)(C)C)=[N:18][CH:19]=3)[CH:10]=[CH:9][N:8]=2)[O:4][N:3]=1.Cl>C1COCC1>[CH3:1][C:2]1[CH:6]=[C:5]([C:7]2[CH:12]=[C:11]([O:13][C:14]3[CH:15]=[CH:16][C:17]([NH2:20])=[N:18][CH:19]=3)[CH:10]=[CH:9][N:8]=2)[O:4][N:3]=1
Reactant: Cc1cc(-c2cc(Oc3ccc(NC(=O)OC(C)(C)C)nc3)ccn2)on1
Agent: Cl
Solvent: C1CCOC1
Product: Cc1cc(-c2cc(Oc3ccc(N)nc3)ccn2)on1
Temperature: 55 °C
Yield: 106.5 %

Procedure:
A solution of tert-butyl (5-((2-(3-methylisoxazol-5-yl)pyridin-4-yl)oxy)pyridin-2-yl)carbamate (0.30 g, 0.84 mmol) in THF (5 mL) was treated with HCl (3 M, 2.8 mL, 8.4 mmol), heated at 55° C. for 4 h, then cooled to RT and concentrated to dryness. The residue was treated with NaHCO3, EtOAc and water, the layers separated and the aqueous layer extracted with EtOAc (2×). The combined organics were washed with brine, dried over Na2SO4 and concentrated to dryness to afford 5-((2-(3-methylisoxazol-5-yl)pyridin-4-yl)oxy)pyridin-2-amine (0.24 g, 106%). 1H NMR (400 MHz, DMSO-d6): δ 8.52 (d, J=5.6 Hz, 1 H), 7.84 (br s, 1 H), 7.32 (m, 2 H), 6.95 (m, 2 H), 6.53 (d, J=9.2 Hz, 1 H), 6.07 (br s, 2 H), 2.28 (s, 3 H); MS (ESI) m/z: 269.1 (M+H+).
Reaction SMILES: [OH:1][NH:2][C:3](=[NH:6])[CH2:4][CH3:5].[O-]CC.[Na+].Cl.[NH:12]1[CH2:17][CH2:16][CH:15]([CH2:18][CH2:19][O:20][C:21]2[CH:31]=[CH:30][C:24]([C:25](OCC)=O)=[CH:23][CH:22]=2)[CH2:14][CH2:13]1>C(O)C>[CH2:4]([C:3]1[N:6]=[C:25]([C:24]2[CH:23]=[CH:22][C:21]([O:20][CH2:19][CH2:18][CH:15]3[CH2:16][CH2:17][NH:12][CH2:13][CH2:14]3)=[CH:31][CH:30]=2)[O:1][N:2]=1)[CH3:5]
Reactant: CCOC(=O)c1ccc(OCCC2CCNCC2)cc1
Reactant: CCC(=N)NO
Agent: CC[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: CCc1noc(-c2ccc(OCCC3CCNCC3)cc2)n1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 89.9 %

Procedure:
A mixture of 4.0 parts of N-hydroxypropanimidamide, 2.9 parts of sodiumethoxide, 94.8 parts of ethanol and 25.3 parts of molecular sieve was stirred for 15 min. at room temperature. There were added 7.5 parts of ethyl 4-[2-(4-piperidinyl)ethoxy]benzoate monohydrochloride and stirring was continued for 12 hours at reflux temperature. The cooled reaction mixture was filtered and the filtrate was evaporated. The residue was partitioned between water and dichloromethane. The organic layer was separated, dried, filtered and evaporated, yielding 6.5 parts (89.9%) of 4-[2-[4-(3-ethyl-1,2,4-oxadiazol-5-yl)phenoxy]ethyl]piperidine (interm. 7).
Reaction SMILES: S(=O)(=O)(O)O.[N+:6]([O-:9])(O)=[O:7].[CH3:10][C:11]1[NH:12][C:13]([CH3:18])=[CH:14][C:15](=[O:17])[CH:16]=1.[OH-].[Na+].N>C(O)=O>[CH3:10][C:11]1[NH:12][C:13]([CH3:18])=[CH:14][C:15](=[O:17])[C:16]=1[N+:6]([O-:9])=[O:7]
Reactant: Cc1cc(=O)cc(C)[nH]1
Reactant: O=[N+]([O-])O
Agent: N
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: O=CO
Product: Cc1cc(=O)c([N+](=O)[O-])c(C)[nH]1
Temperature: 25 °C
Reaction time: 72 h
Yield: 15.8 %

Procedure:
To a cooled (0° C.) solution of sulfuric acid (4.0 mL, 16.24 mmol) was added fuming nitric acid (4.0 mL, 16.24 mmol) via pipette over 5 min. The reaction was maintained at 0° C. for 30 min, at which time 2,6-dimethylpyridin-4(1H)-one (2.0 g, 16.24 mmol) was added as a solid over 5 min. The mixture was allowed to warm to ambient temperature and was stirred for 3 days. The reaction mixture was then heated at 100° C. for 2 h, at which time it was allowed to cool to ambient temperature. The red fumes were blown into a base trap with nitrogen and the reaction mixture was poured over ˜33 g of ice. The mixture was cooled in an ice bath and was stirred (some precipitate formed). The reaction was treated with 8 M NaOH and the pH was further adjusted to ˜5.3 with formic acid and ammonia. The mixture was stirred for 5 min and cooled in a freezer for 15 min. The solids were filtered, washed with water, air dried for 5 min, and further dried in a vacuum oven at 37° C. overnight to give 2,6-dimethyl-3-nitropyridin-4(1H)-one (440 mg, 2.56 mmol, 15.79% yield). 1H NMR (400 MHz, DMSO-d6) δ 2.22 (s, 3H) 2.28 (s, 3H) 6.18 (s, 1H) 11.84 (br. s., 1H). MS(ES) [M+H]+ 168.9.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:9]2[CH:16]=[CH:15][CH:14]=[CH:13][C:10]=2[C:11]#[N:12])[CH:5]=[CH:6][C:7]=1[NH2:8].O.[F:18][C:19]([F:24])([F:23])[C:20](O)=O>>[C:11]([C:10]1[CH:13]=[CH:14][CH:15]=[CH:16][C:9]=1[C:4]1[CH:5]=[CH:6][C:7]2[NH:8][C:20]([C:19]([F:24])([F:23])[F:18])=[N:1][C:2]=2[CH:3]=1)#[N:12]
Reactant: N#Cc1ccccc1-c1ccc(N)c(N)c1
Reactant: O=C(O)C(F)(F)F
Solvent: O
Product: N#Cc1ccccc1-c1ccc2[nH]c(C(F)(F)F)nc2c1
Temperature: 85 °C

Procedure:
2-(3,4-Diaminophenyl)benzonitrile (0.01 moles, 2.09 g) was dissolved in 10 ml trifluoroacetic acid and heated at 85° C. for 16 hours. The solution was poured into water and extracted with ethyl acetate. The pH was adjusted to 3.0 using 5N NaOH. The ethyl acetate was washed with brine, dried over sodium sulfate, and concentrated. The residue was chromatographed on silica gel eluted with 25% ethyl acetate in hexane. The reaction yielded 2.05 g of 5-(2-cyanophenyl)-2-trifluoromethyl-1H-benzimidazole. (MS)
Reaction SMILES: [NH2:1][C:2]([NH2:4])=[O:3].Cl.C(O)=O.[NH2:9][NH:10][C:11]([NH2:13])=[O:12]>>[NH2:9][NH:10][C:11]([NH2:13])=[O:12].[N:4]1[C:2](=[O:3])[N:1]=[CH:11][N:10]=1
Reactant: NC(N)=O
Agent: Cl
Agent: NNC(N)=O
Solvent: O=CO
Product: O=C1N=CN=N1
Temperature: 10 °C
Yield: 47.4 %

Procedure:
Aqueous semicarbazide free base feedstock (523.8 grams) was prepared from 64 percent N2H4 (4.18 moles) and urea (4.17 moles) by the method of Example 1. Thirty-seven percent hydrochloric acid (205.6 grams, 2.08 moles) and 90 percent formic acid (533.3 grams, 10.44 moles) were successively added to the aqueous semicarbazide free base. The mixture was heated to 107°-110° C. for four hours; a formic acid-H2O azeotrope distilled (610.5 grams), followed by H2O addition (160 ml) and resumption of stripping (107 grams). After cooling to 10° C., the mother liquor was siphoned (307 grams). The crude 1,2,4-triazol-5-one was recrystallized from H2O (760 ml). After cooling to 10° C., the supernatant liquid was siphoned (807 grams) and the product was slurried with an additional 210 ml H2O (10° C.), filtered, and vacuum-dried to give 168.5 grams of 1,2,4-triazol-5-one (1.98 moles, 47.4 percent yield based on N2H4 charged), m.p. 236.5°-8° C. (Cl-, 0.22 percent).
Reaction SMILES: N1(S(N)(=O)=O)C2C(=CC=CC=2)CC1.[Br:14][C:15]1[CH:16]=[CH:17][CH:18]=[C:19]2[C:23]=1[NH:22][CH:21]=[CH:20]2.[BH3-]C#N.[Na+]>CC(O)=O>[Br:14][C:15]1[CH:16]=[CH:17][CH:18]=[C:19]2[C:23]=1[NH:22][CH2:21][CH2:20]2
Reactant: Brc1cccc2cc[nH]c12
Agent: NS(=O)(=O)N1CCc2ccccc21
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Product: Brc1cccc2c1NCC2

Procedure:
Similarly, the route shown in Scheme 2 below exemplifies synthesis of certain 7-aryl(heteroaryl)-indoline(indole)-1-sulfonamide compounds of the present invention. To synthesize indole-1-sulfonamide compound (9), 1-bromo-2-nitrobenzene (6) is reduced to afford 7-bromo-1H-indole (7), which reacts with 4-methoxyphenylsulfonyl chloride to provide 7-bromo-1-(4-methoxyphenylsulfonyl)-1H-indole (8). The sulfonamide (8), is then treated with an aryl or heteroaryl boronic acid, Pd(PPh3)4, and K2CO3 in toluene/EtOH to afford final compound (9). To synthesize indoline-1-sulfonamide compound (12), 7-bromo-1H-indole (7) is further reduced (with NaCNBH3 and CH3COOH, at room temperature) to afford 7-bromoindoline (10), which reacts with a substituted phenylsulfonyl chloride to provide bromo-indoline-sulfonamide (11). The bromo-indoline-sulfonamide (11) is then treated with an aryl or heteroaryl boronic acid, Pd(PPh3)4, and K2CO3 in toluene/EtOH to afford final compound (12), which can be further modified to obtain compound (13).
Reaction SMILES: [CH:1]([C@H:4]1[C:9](=[S:10])[N:8]([CH2:11][C:12]([O:14][C@@H](C)C(OC)=O)=[O:13])[C:7]2[CH:21]=[CH:22][CH:23]=[C:24]([CH:25]([CH3:27])[CH3:26])[C:6]=2[O:5]1)([CH3:3])[CH3:2]>CO>[CH:1]([C@H:4]1[C:9](=[S:10])[N:8]([CH2:11][C:12]([OH:14])=[O:13])[C:7]2[CH:21]=[CH:22][CH:23]=[C:24]([CH:25]([CH3:27])[CH3:26])[C:6]=2[O:5]1)([CH3:3])[CH3:2]
Reactant: COC(=O)[C@H](C)OC(=O)CN1C(=S)[C@H](C(C)C)Oc2c(C(C)C)cccc21
Solvent: CO
Product: CC(C)c1cccc2c1O[C@@H](C(C)C)C(=S)N2CC(=O)O
Yield: 61.7 %

Procedure:
(S)-Methyl 2-[(S)-3,4-dihydro-2,8-diisopropyl-3-thioxo-2H-1,4-benzoxazin-4-yl]acetoxypropionate (1.1 g) was hydrolyzed and worked up in the manner same as that used in Example 22 to yield (S)-(-)-3,4-dihydro-2,8-diisopropyl-3-thioxo-2H-1,4-benzoxazine-4-acetic acid (0.53 g), mp 109°-110° C. [α]D23 -105° MeOH).
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[C:5](B(O)O)[CH:6]=[C:7]([CH3:9])[CH:8]=1)=[O:2].[F-].[Cs+].[CH2:15](Br)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.COCCOC>[CH2:15]([C:5]1[CH:4]=[C:3]([CH:8]=[C:7]([CH3:9])[CH:6]=1)[CH:1]=[O:2])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: Cc1cc(C=O)cc(B(O)O)c1
Reactant: BrCc1ccccc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cs+]
Agent: [F-]
Solvent: COCCOC
Product: Cc1cc(C=O)cc(Cc2ccccc2)c1
Temperature: 25 °C

Procedure:
To a DME solution (0.1 M) of (3-formyl-5-methylphenyl)boronic acid (1 eq.) was added cesium fluoride (3 eq.), tetrakis(triphenylphosphine)palladium (0.1 eq.) and benzyl bromide (1.2 eq.). The mixture was refluxed for 3 h, cooled down to RT and quenched with saturated aqueous sodium bicarbonate. The mixture was extracted with ethyl acetate. The combined organic extracts were then washed with brine, dried over Na2SO4, filtered and the filtrate concentrated in vacuo. Purification of the crude product by way of flash chromatography (SiO2, Hex→7:3 (v/v) Hex:EtOAc) afforded the title compound.