Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:18])([F:17])[C:3]([N:5]1[C:13]2[C:8](=[CH:9][CH:10]=[C:11]([N+:14]([O-])=O)[CH:12]=2)[CH2:7][CH2:6]1)=[O:4]>CO.[Pd]>[NH2:14][C:11]1[CH:12]=[C:13]2[C:8]([CH2:7][CH2:6][N:5]2[C:3](=[O:4])[C:2]([F:18])([F:1])[F:17])=[CH:9][CH:10]=1
Reactant: O=C(N1CCc2ccc([N+](=O)[O-])cc21)C(F)(F)F
Agent: [Pd]
Solvent: CO
Product: Nc1ccc2c(c1)N(C(=O)C(F)(F)F)CC2
Reaction time: 8 h
Yield: 110 %

Procedure:
To a suspension of 2,2,2-trifluoro-1-(6-nitroindolin-1-yl)ethanone (7.92 g, 30.4 mmol) in MeOH (100 mL) was added 10% Pd/C (0.648 g, 0.609 mmol) and the slurry was stirred under H2 (1 atm) overnight. The mixture was filtered through a pad of Celite and the filtrate was concentrated and dried under vacuum to yield 1-(6-aminoindolin-1-yl)-2,2,2-trifluoroethanone (7.7 g, crude yield>100%) as a yellow-brown solid. 1H-NMR (400 MHz, CDCl3): δ 7.64 (d, J=2.0 Hz, 1H), 7.01 (d, J=8.0 Hz, 1H), 6.49 (dd, J=8.4, and 2.0 Hz, 1H), 4.24 (t, J=8.0 Hz, 2H), 3.85 (brs, 2H), 3.13 (t, J=8.2 Hz, 2H); MS (ESI) m/z: 231.0 (M+H+).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=O)[CH2:9][C:10](=O)[C:11]([F:14])([F:13])[F:12])=[CH:4][C:3]=1[CH3:17].[NH2:18][C:19]1[C:23]([C:24]2[CH:29]=[CH:28][N:27]=[CH:26][CH:25]=2)=[CH:22][NH:21][N:20]=1>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10]([C:11]([F:14])([F:13])[F:12])[N:20]3[N:21]=[CH:22][C:23]([C:24]4[CH:29]=[CH:28][N:27]=[CH:26][CH:25]=4)=[C:19]3[N:18]=2)=[CH:4][C:3]=1[CH3:17]
Reactant: Cc1cc(C(=O)CC(=O)C(F)(F)F)ccc1Cl
Reactant: Nc1n[nH]cc1-c1ccncc1
Product: Cc1cc(-c2cc(C(F)(F)F)n3ncc(-c4ccncc4)c3n2)ccc1Cl
Yield: 74.6 %

Procedure:
Reaction of 1-(4-chloro-3-methyl-phenyl)-4,4,4-trifluoro-butane-1,3-dione (132 mg, 0.5 mmol), prepared from commercially available 4-chloro-3-methyl-acetophenone according to general procedure A, and 3-amino-4-(4-pyridinyl)-pyrazole [CAS No. 216661-87-9; prepared from 4-cyanomethyl-pyridine as described in Bioorg. Med. Chem. Lett. 12 (2002) 3537-3541] (80 mg, 0.5 mmol) according to general procedure B yielded the title compound as a yellow solid (145 mg, 75%). MS (ISP) 389.2 [(M+H)+]; mp 247° C.
Reaction SMILES: [N+:1]([CH:4]([N+:6]([O-:8])=[O:7])[CH3:5])([O-:3])=[O:2].[OH-].[K+].[C:11]([O:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])(=[O:14])[CH:12]=[CH2:13].CO>O>[N+:1]([C:4]([N+:6]([O-:8])=[O:7])([CH3:5])[CH2:13][CH2:12][C:11]([O:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])=[O:14])([O-:3])=[O:2]
Reactant: C=CC(=O)OCCCCCCCC
Reactant: CC([N+](=O)[O-])[N+](=O)[O-]
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CCCCCCCCOC(=O)CCC(C)([N+](=O)[O-])[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 4 h
Yield: 82.1 %

Procedure:
Dinitroethane (2.4 g, 0.02 mol) and potassium hydroxide (1.2 g, 0.22 mol) were dissolved in 50 mL of water to form a first solution. 50 mL of water was added to the first solution to dissolve a salt remaining in the first solution to form a second solution. Octyl acrylate (10.2 mL, 0.05 mol) was mixed with 50 mL of methanol, and then the mixture was slowly added to the second solution to form a third solution. The third solution was stirred at room temperature for 4 hours. The reaction product was extracted by diethyl ether, and was then distilled under reduced pressure to obtain yellow liquid octyl 4,4-dinitropentanoate (5.0 g, yield: 82%).
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[C:11]([N:18]1[CH2:24][CH2:23][CH2:22][C@H:19]1[CH2:20][OH:21])([O:13]C(C)(C)C)=[O:12].C(N(CC)CC)C>ClCCl>[CH:20]([C@@H:19]1[CH2:22][CH2:23][CH2:24][N:18]1[C:11]([OH:13])=[O:12])=[O:21]
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1CO
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: CS(C)=O
Product: O=C[C@@H]1CCCN1C(=O)O
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
A 2 L, 3-necked round bottomed flask equipped with an overhead stirrer and a N2 inlet was charged with a solution of oxalyl chloride (130 mL, 0.26 mol) in dichloromethane (250 mL). The solution was cooled to −78° C., and a solution of DMSO (20 mL, 0.28 mol) in dichloromethane (30 mL) was added dropwise. After 30 minutes, a solution of (S)—N-Boc-prolinol, Int-7a (40 g, 0.20 mol) in dichloromethane (200 mL) was added dropwise. After 30 minutes, triethylamine (140 mL, 1.00 mol) was added to the solution, and the flask was transferred to an ice/water bath and allowed to stir for another 30 minutes. The reaction mixture was diluted with dichloromethane (200 mL) and washed successively with H2O, 1M HCl, saturated NaHCO3, and brine. The organic layer was dried over Na2SO4, filtered, and concentrated in vacuo to provide crude (S)-2-formyl-pyrrolidine-1-carboxylic acid tort-butyl ester, Int-7b (40 g) as oil, which was used without further purification.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:14]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[CH:13][CH:12]=[CH:11][C:10]=1[C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([C:27]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=2[O:36][CH3:37])(O)[CH3:28])[CH:22]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1.C(OCC)(=O)C>[CH2:1]([O:8][C:9]1[C:14]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[CH:13][CH:12]=[CH:11][C:10]=1[C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([C:27]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=2[O:36][CH3:37])=[CH2:28])[CH:22]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COc1ccccc1C(C)(O)c1cccc(-c2cccc(-c3ccccc3)c2OCc2ccccc2)c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: C=C(c1cccc(-c2cccc(-c3ccccc3)c2OCc2ccccc2)c1)c1ccccc1OC
Yield: 0.1 %

Procedure:
A solution of crude 33 (3.96 mol) in toluene (150 mL) was treated with p-toluenesulfonic acid (100 mg) and refluxed under a Dean-Stark trap for 3 hr. After cooling, the reaction mixture was diluted with ethyl acetate (80 mL) and washed with saturated sodium bicarbonate (80 mL) and water (2×80 mL). The organic extract was dried over sodium sulfate and filtered. The solvent was removed in a rotary evaporator and the crude product was purified by chromatography on silica (80 g) with 2% ethyl acetate in heptane (2 L) to afford 34 (1.15 g, 62%).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]2=[CH:9][CH:10]=[C:11]3[C:20]([N:19]=[C:18]4[C:13]([CH:14]=[CH:15][CH:16]=[C:17]4[C:21](O)=[O:22])=[N:12]3)=[C:7]2[CH:6]=[CH:5][N:4]=1.[CH3:24][N:25]([CH3:30])[CH2:26][C@H:27]([NH2:29])[CH3:28]>>[CH3:24][N:25]([CH3:30])[CH2:26][C@H:27]([NH:29][C:21]([C:17]1[C:18]2[C:13](=[N:12][C:11]3[C:20]([N:19]=2)=[C:7]2[CH:6]=[CH:5][N:4]=[C:3]([O:2][CH3:1])[C:8]2=[CH:9][CH:10]=3)[CH:14]=[CH:15][CH:16]=1)=[O:22])[CH3:28]
Reactant: COc1nccc2c1ccc1nc3cccc(C(=O)O)c3nc12
Reactant: C[C@@H](N)CN(C)C
Product: COc1nccc2c1ccc1nc3cccc(C(=O)N[C@H](C)CN(C)C)c3nc12

Procedure:
4-Methoxypyrido[4,3-α]phenazine-11-carboxylic acid (2-dimethylamino-1(R)-methylethyl)-amide was prepared from 4-methoxypyrido[4,3-α]phenazine-11-carboxylic acid (II.4) and (R)-N1,N1-Dimethyl-propane-1,2-diamine
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[CH:5][C:4]([NH:7][C:8]([C:10]2[C:15](Br)=[CH:14][CH:13]=[C:12]([CH3:17])[N:11]=2)=[O:9])=[N:3]1.[NH2:18][C:19]1[S:20][CH:21]=[C:22]([CH3:24])[N:23]=1>>[CH3:1][N:2]1[CH:6]=[CH:5][C:4]([NH:7][C:8]([C:10]2[C:15]([NH:18][C:19]3[S:20][CH:21]=[C:22]([CH3:24])[N:23]=3)=[CH:14][CH:13]=[C:12]([CH3:17])[N:11]=2)=[O:9])=[N:3]1
Reactant: Cc1csc(N)n1
Reactant: Cc1ccc(Br)c(C(=O)Nc2ccn(C)n2)n1
Product: Cc1csc(Nc2ccc(C)nc2C(=O)Nc2ccn(C)n2)n1

Procedure:
The title compound, was prepared from 3-Bromo-6-methyl-pyridine-2-carboxylic acid (1-methyl-1H-pyrazol-3-yl)-amide in accordance with the general method of Example 78, step 3 using 2-Amino-4-methylthiazole instead of 3-Amino-1-methyl-pyrazole to yield the final compound as a yellow solid, MS (ISP): m/e=329.1 (M+H+).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[CH:5][C:6]([F:33])=[C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][N:16]3[CH2:21][CH2:20][N:19]([C:22]([O:24][CH2:25][C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=4)=[O:23])[C@@H:18]([CH3:32])[CH2:17]3)[CH:10]=2)[CH:8]=1)#[N:2].B>C1COCC1>[NH2:2][CH2:1][C:3]1[CH:4]=[CH:5][C:6]([F:33])=[C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][N:16]3[CH2:21][CH2:20][N:19]([C:22]([O:24][CH2:25][C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=4)=[O:23])[C@@H:18]([CH3:32])[CH2:17]3)[CH:10]=2)[CH:8]=1
Reactant: C[C@H]1CN(Cc2cccc(-c3cc(C#N)ccc3F)c2)CCN1C(=O)OCc1ccccc1
Agent: B
Solvent: C1CCOC1
Product: C[C@H]1CN(Cc2cccc(-c3cc(CN)ccc3F)c2)CCN1C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 92.2 %

Procedure:
A solution of phenylmethyl (2S)-4-[(5′-cyano-2′-fluoro-3-biphenylyl)methyl]-2-methyl-1-piperazinecarboxylate (708 mg, 1.60 mmol) in THF (10 mL) was flushed with Ar. for 15 minutes. Borane (5.6 mL of a 1M solution in THF, 5.6 mmol) was slowly added and the reaction was allowed to stir at room temperature for 12 hours. The reaction was quenched slowly with 1N HCl (1 mL) and allowed to stir for 2 hours at rt. After neutralization to pH>10 with 2N NaOH, the reaction mixture was extracted with EtOAc (2×15 mL). The combined organic layers were dried over MgSO4, filtered, and concentrated under vacuum. The crude residue was placed onto a aminopropyl SPE silica cartridge (10 g) and eluted with the following sequence: 50% hexane/50% EtOAc (3×20 mL), 10% MeOH/90% DCM (3×20 mL). The methanol fractions were combined and concentrated to give the title compound (660 mg, 92%). LC/MS: m/z, 448 (M+H), 1.63 min.
Reaction SMILES: [CH3:1][C:2]([CH2:4][CH:5]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[O:3].[CH3:18]S(C)(=O)=C>>[O:3]1[C:2]([CH3:18])([CH2:4][CH:5]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH2:1]1
Reactant: C=S(C)(C)=O
Reactant: CC(=O)CC(c1ccccc1)c1ccccc1
Product: CC1(CC(c2ccccc2)c2ccccc2)CO1

Procedure:
The 1,2-epoxy-4,4-diarylbutane starting materials can alternatively be prepared by reaction of dimethylsulfonium methylide or dimethyloxosulfonium methylide with an appropriate diarylalkyl aldehyde or a diarylalkyl ketone. For example, reaction of an aldehyde such as 3,3-diphenylpropanal with either dimethylsulfonium methylide or dimethyloxosulfonium methylide in approximately equimolar amounts provides 1,2-epoxy-4,4-diphenylbutane. Similarly, reaction of a diarylalkyl ketone such as methyl-(2,2-diphenylethyl) ketone with either dimethylsulfonium methylide or dimethyloxosulfonium methylide provides 1,2-epoxy-4,4-diphenyl-2-methylbutane. Such reactions typically are carried out in a solvent such as dimethyl sulfoxide or tetrahydrofuran, and normally at a reduced temperature of about 0° C. Dimethylsulfonium methylide is prepared by reaction of trimethylsulfonium iodide with methylsulfinylcarbanion, while dimethyloxosulfonium methylide is prepared by reaction of trimethyloxosulfonium iodide with sodium hydride. Such reactions are more fully discussed by Corey et al., J. Am. Chem. Soc., 84, 867(1962) and J. Am. Chem. Soc., 84, 3782 (1962).
Reaction SMILES: [C:1](=O)([O-])[O-].[K+].[K+].IC.[F:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[C:16]1[C:28]2[C:27]3[C:22](=[CH:23][C:24]([OH:29])=[CH:25][CH:26]=3)[NH:21][C:20]=2[C:19]([C:30]([NH2:32])=[O:31])=[CH:18][CH:17]=1>CS(C)=O.CCOC(C)=O>[F:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[C:16]1[C:28]2[C:27]3[C:22](=[CH:23][C:24]([O:29][CH3:1])=[CH:25][CH:26]=3)[NH:21][C:20]=2[C:19]([C:30]([NH2:32])=[O:31])=[CH:18][CH:17]=1
Reactant: NC(=O)c1ccc(-c2ccccc2F)c2c1[nH]c1cc(O)ccc12
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Solvent: CI
Product: COc1ccc2c(c1)[nH]c1c(C(N)=O)ccc(-c3ccccc3F)c12
Temperature: 25 °C
Reaction time: 17 h
Yield: 9.3 %

Procedure:
Potassium carbonate (25.1 mg, 0.182 mmol) and iodomethane (4.9 mL, 0.079 mmol) were added to a solution of 4-(2-fluorophenyl)-7-hydroxy-9H-carbazole-1-carboxamide (Example 40-1, 19.4 mg, 0.061 mmol) in DMSO (1 mL) and the mixture was stirred at rt. After 17 h, the mixture was diluted with EtOAc (30 mL), washed with saturated aqueous ammonium chloride (5 mL), water (2×5 mL), and brine (5 mL), dried and concentrated. The residue was purified by preparative HPLC to provide 4-(2-fluorophenyl)-7-methoxy-9H-carbazole-1-carboxamide (1.9 mg, 9%). 1H NMR (400 MHz, chloroform-d) δ 10.39 (1 H, br. s.), 7.58 (1 H, d, J=7.70 Hz), 7.44-7.55 (2 H, m), 7.28-7.39 (2 H, m), 7.07-7.22 (2 H, m), 7.00 (1 H, d, J=2.20 Hz), 6.65 (1 H, dd, J=8.80, 2.42 Hz), 6.57 (2 H, br. s.), 3.88 (3 H, s). Mass spectrum m/z 335.0 (M+H)+.
Reaction SMILES: [OH:1][CH:2]([C:8]1[CH:9]=[N:10][CH:11]=[C:12]([C:14]2[CH:15]=[C:16]3[C:22]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=4[O:29][CH3:30])=[N:21][N:20](COCC[Si](C)(C)C)[C:17]3=[N:18][CH:19]=2)[CH:13]=1)[C:3]([N:5]([CH3:7])[CH3:6])=[O:4].Cl(O)(=O)(=O)=O>C(O)(=O)C>[OH:1][CH:2]([C:8]1[CH:9]=[N:10][CH:11]=[C:12]([C:14]2[CH:15]=[C:16]3[C:22]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=4[O:29][CH3:30])=[N:21][NH:20][C:17]3=[N:18][CH:19]=2)[CH:13]=1)[C:3]([N:5]([CH3:6])[CH3:7])=[O:4]
Reactant: COc1ccccc1-c1nn(COCC[Si](C)(C)C)c2ncc(-c3cncc(C(O)C(=O)N(C)C)c3)cc12
Agent: [O-][Cl+3]([O-])([O-])O
Solvent: CC(=O)O
Product: COc1ccccc1-c1n[nH]c2ncc(-c3cncc(C(O)C(=O)N(C)C)c3)cc12
Yield: 3.6 %

Procedure:
2-Hydroxy-2-{5-[3-(2-methoxyphenyl)-1-(2-trimethylsilanylethoxymethyl)-1H-pyrazolo[3,4-b]pyridin5-yl]-pyridin-3-yl}-N,N-dimethylacetamide (374 mg, 0.702 mmol) was treated with 5% v/v of 70% perchloric acid in glacial acetic acid (5 mL) for 2 h. The solids were collected by filtration and were dissolved in ethyl acetate upon shaking with saturated sodium bicarbonate. The layers were separated and the organics were dried over sodium sulfate and concentrated in vacuo. The material was dissolved in dichloromethane (1 mL) and treated with N,N-dimethylethylenediamine (154 μL) for 2.5 h. The mixture was concentrated and the residue was dissolved in dimethylsulfoxide and purified by preparative HPLC to afford 2-hydroxy-2-{5-[3-(2-methoxyphenyl)-1H-pyrazolo[3,4-b]pyridin5-yl]-pyridin-3-yl}-N,N-dimethylacetamide (10 mg, 0.025 mmol). 1H-NMR (500 MHz, dimethylsulfoxide-d6) δ 2.79 (s, 3H), 2.92 (s, 3H), 3.79 (s, 3H), 5.52 (m, 1H), 5.78 (m, 1H), 7.03 (t, J=7.0 Hz, 1H), 7.17 (d, J=8 Hz, 1H), 7.40 (dt, J=1, J=6.5 Hz, 1H), 7.59 (dd, J=1.5, J=7.5 Hz, 1H), 8.04 (t, J=2.5 Hz, 1H), 8.33 (d, J=2.5 Hz, 1H), 8.52 (d, J=2.0 Hz, 1H), 8.81 (d, J=2.0 Hz, 1H), 8.85 (d, J=2.5 Hz, 1H). MS: m/z 404 (M+H+).
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:23])[CH2:10][C@@H:11]([C:20](O)=[O:21])[NH:12][C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CN1CCOCC1.ClC(OCC(C)C)=O.[BH4-].[Na+]>C(COC)OC.O>[C:16]([O:15][C:13]([NH:12][C@H:11]([CH2:20][OH:21])[CH2:10][C:9]([O:8][CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)=[O:23])=[O:14])([CH3:18])([CH3:19])[CH3:17]
Reactant: CC(C)(C)OC(=O)N[C@@H](CC(=O)OCc1ccccc1)C(=O)O
Agent: CC(C)COC(=O)Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: COCCOC
Solvent: CN1CCOCC1
Solvent: O
Product: CC(C)(C)OC(=O)N[C@H](CO)CC(=O)OCc1ccccc1
Temperature: -7.5 °C
Reaction time: 0.5 h

Procedure:
N-(tert-butoxycarbonyl)-L-aspartic acid 4-benzyl ester (1.23 g, 3.80 mmol) was dissolved in dimethoxyethane (3.6 mL) in a flame-dried flask. The solution was cooled to −5 to −10° C. N-methylmorpholine (0.422 mL, 3.84 mmol) was then added dropwise, followed by a slow addition of isobutyl chloroformate (0.525 mL, 3.9 mmol) while the reaction temperature was maintained below −10° C. The mixture was aged for 30 minutes. The solids were quickly filtered and washed with dimethoxyethane (3.6 mL). The filtrate was cooled to −50° C. and a solution of sodium borohydride (0.18 g, 4.76 mmol) in water (1.8 mL) was added slowly while the reaction temperature was maintained between −30° C. and −15° C. Water (20 mL) was then added such that the reaction mixture temperature was maintained below −15° C. The reaction mixture was extracted with ethyl acetate (3×5 mL), washed with cold 0.1N HCl, then saturated sodium bicarbonate solution and then brine. The organic phase was dried with magnesium sulfate. Evaporated to dryness to yield an oil that crystallizes upon standing. LC-MS m/z=332 (M+Na+).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][C:3]2[CH2:6][CH2:7][C:8](=[O:9])[C:2]1=2.Cl.[NH2:11]O.CC([O-])=O.[Na+]>CO>[S:1]1[C:2]2[C:8](=[O:9])[NH:11][CH2:7][CH2:6][C:3]=2[CH:4]=[CH:5]1
Reactant: NO
Reactant: O=C1CCc2ccsc21
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: O=C1NCCc2ccsc21
Temperature: 130 °C
Yield: 56.3 %

Procedure:
A solution of 4H-cyclopenta[b]thiophen-6(5H)-one (1.34 g, 9.7 mmol), hydroxylamine HCl (1.45 g, 20.8 mmol) and NaOAc (7.3 g, 89.0 mmol) in MeOH (150 mL) was stirred overnight at room temperature. The reaction was then concentrated under reduced pressure, taken up in EtOAc (100 mL) and filtered over a plug of silica gel, eluting with EtOAc. The filtrate was concentrated, taken up in polyphosphoric acid (100 g) and heated for 2 h at 130° C. Upon completion, the reaction was quenched by pouring over ice water (100 mL). The aqueous mixture was extracted with DCM (2×100 mL) and the combined extracts were washed with 0.1 M NaOH (100 mL), dried over Na2SO4, then filtered and concentrated. 5,6-dihydrothieno[2,3-c]pyridin-7(4H)-one (837 mg, 55% yield) was isolated as a white solid after purification by flash chromatography over silica gel (20-30% EtOAc/hexane eluent). 1H NMR (300 MHz, MeOH) δ ppm 7.69 (d, J=5.0 Hz, 1H), 7.06 (d, J=5.0 Hz, 1H), 3.57 (t, J=7.1 Hz, 2 H), 2.94 (t, J=7.1 Hz, 2H); MS (EI) m/z=154.2 [M+1]+.
Reaction SMILES: [CH2:1]([C:8]1[N:9]([CH2:20][CH2:21][CH:22]2[CH2:26][CH2:25][CH2:24][N:23]2[CH3:27])[C:10]2[C:15]([CH:16]=1)=[CH:14][CH:13]=[C:12]([N+:17]([O-])=O)[CH:11]=2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.I.CS[C:31]([C:33]1[S:34][CH:35]=[CH:36][CH:37]=1)=[NH:32]>C(O)C.[Pd]>[CH2:1]([C:8]1[N:9]([CH2:20][CH2:21][CH:22]2[CH2:26][CH2:25][CH2:24][N:23]2[CH3:27])[C:10]2[C:15]([CH:16]=1)=[CH:14][CH:13]=[C:12]([NH:17][C:31]([C:33]1[S:34][CH:35]=[CH:36][CH:37]=1)=[NH:32])[CH:11]=2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CSC(=N)c1cccs1
Reactant: CN1CCCC1CCn1c(Cc2ccccc2)cc2ccc([N+](=O)[O-])cc21
Agent: [Pd]
Agent: I
Solvent: CCO
Product: CN1CCCC1CCn1c(Cc2ccccc2)cc2ccc(NC(=N)c3cccs3)cc21
Temperature: 25 °C
Reaction time: 3 h
Yield: 78 %

Procedure:
2-benzyl-1-(2-(1-methylpyrrolidin-2-yl)ethyl)-6-nitro-1H-indole (compound 162, 40 mg, 0.110 mmol) was dissolved in anhydrous ethanol (5 mL) in a dry argon purged flask. Palladium, 10 wt % on activated carbon (11.7 mg, 0.011 mmol) is quickly added and the atmosphere from the flask evacuated by vacuum pump and replaced with hydrogen from a balloon. The atmosphere is evacuated from the flask and replaced with hydrogen twice more and the mixture stirred under a hydrogen atmosphere at room temperature. After 3 hours, thin layer chromatography in a solvent system of (5% 2M NH3 in methanol/95% dichloromethane) shows complete conversion to compound 163, 2-benzyl-1-(2-(1-methylpyrrolidin-2-yl)ethyl)-1H-indol-6-amine, which is utilized without isolation. The mixture is filtered through a pad of celite to remove insolubles, the pad washed with anhydrous ethanol (5 mL) and the ethanolic solution of the amine 163 is charged to a small, argon purged flask fitted with a magnetic stirbar. Thiophene-2-carboximidothioic acid methyl ester hydroiodide (40.8 mg, 0.143 mmol) is added to the flask and the reaction was stirred under Ar at ambient temperature for 48 hours. An additional amount of the thiophene-2-carboximidothioic acid methyl ester hydroiodide (0.3 eq) was added and stirring continued for an additional 18 hours. A further portion of thiophene-2-carboximidothioic acid methyl ester hydroiodide (0.3 eq) was added and stirring continued for an additional 18 hours, at which time the mixture was concentrated and the residue purified via chromatography on silica gel (2.5% 2M NH3 in methanol/97.5% dichloromethane to 5% 2M NH3 in methanol/95% dichloromethane) to afford yellow oil, compound 164 (38 mg, 78.0% yield); 1H-NMR (CDCl3) δ 7.72 (d, 1H, J=3.2), 7.59 (d, 1H, J=4.7), 7.38 (d, 1H, J=8.1), 7.35-7.20 (m, 5H), 7.09 (m, 1H), 6.77 (s, 1H), 6.56 (d, 1H, J=7.4), 6.36 (br s, 2H), 6.14 (s, 1H), 4.14 (s, 2H), 3.96 (t, 2H, J=7.9), 2.94-2.86 (m, 1H), 2.09 (s, 3H), 2.06-1.94 (m, 2H), 1.89-1.78 (m, 1H), 1.69-1.51 (m, 3H), 1.45-1.35 (m, 2H); MS (ESI+): 443 (M+1, 70%) 219 (100%).
Reaction SMILES: [CH3:1][NH:2][CH3:3].[N:4]([C:7]1[C:16](=[O:17])[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[O:9][CH:8]=1)=[C:5]=[O:6]>C1(C)C=CC=CC=1>[CH3:1][N:2]([CH3:3])[C:5](=[O:6])[NH:4][C:7]1[C:16](=[O:17])[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[O:9][CH:8]=1
Reactant: CNC
Reactant: O=C=Nc1coc2ccccc2c1=O
Solvent: Cc1ccccc1
Product: CN(C)C(=O)Nc1coc2ccccc2c1=O
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 33.5 %

Procedure:
A solution of anhydrous dimethylamine (7.5 g) in dry toluene (100 ml) is added rapidly to a solution of 3-isocyanatochromone (13 g) in toluene (50 ml). The temperature of the reaction mixture rapidly rises from 20° to 47° C. and crystallization then takes place. The mixture is stirred for a further 20 minutes until the temperature of the reaction medium drops to about 25° C. After filtration, recrystallization from isopropyl ether (1,000 ml) and drying, 3-(3,3-dimethylureido)-chromone (5.4 g), which melts at 148° C., is obtained.
Reaction SMILES: FC(F)(F)S([O-])(=O)=O.[C:9]1([S+:15]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[CH3:22])[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.O.[C:30]1([CH3:40])[CH:35]=[CH:34][C:33]([S:36]([OH:39])(=[O:38])=[O:37])=[CH:32][CH:31]=1>CO.C[N+](C)(C)C.[Cl-]>[C:30]1([CH3:40])[CH:31]=[CH:32][C:33]([S:36]([O-:39])(=[O:37])=[O:38])=[CH:34][CH:35]=1.[C:23]1([S+:15]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[CH3:22])[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Agent: C[N+](C)(C)C
Agent: Cc1ccccc1[S+](c1ccccc1)c1ccccc1
Agent: O=S(=O)([O-])C(F)(F)F
Solvent: CO
Solvent: O
Product: Cc1ccc(S(=O)(=O)[O-])cc1

Procedure:
In aqueous methanol solution was dissolved 18.8 g (44 mmole) of the resulting diphenyl-o-methylphenylsulfonium trifluoromethanesulfonate and passed through an activated strong base type anion exchange resin (Amberlite IRA-900; mfd. by Organo Corporation.). To the eluting solution was added 10.0 g (53 mmole) of p-toluenesulfonic acid monohydrate, followed by allowing a reaction to take place at room temperature for 1 hour with stirring. After the reaction, the solvent was removed and the residue was dissolved in 200 ml of methylene chloride, washed with water three times and concentrated under reduced pressure to give 17.2 g (Yield: 91%) of diphenyl-o-methylphenylsulfonium p-toluenesulfonate as white crystal.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:10]=[N:11][N:12]([C:15]3[CH:23]=[CH:22][C:18]([C:19](O)=[O:20])=[CH:17][N:16]=3)[C:13]=2[OH:14])=[C:5]([CH3:24])[CH:4]=1)#[N:2].[CH3:25][O:26][CH2:27][CH2:28][C@@H:29]([NH2:31])[CH3:30]>>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:10]=[N:11][N:12]([C:15]3[CH:23]=[CH:22][C:18]([C:19]([NH:31][C@H:29]([CH2:28][CH2:27][O:26][CH3:25])[CH3:30])=[O:20])=[CH:17][N:16]=3)[C:13]=2[OH:14])=[C:5]([CH3:24])[CH:4]=1)#[N:2]
Reactant: COCC[C@H](C)N
Reactant: Cc1cc(C#N)ccc1-c1cnn(-c2ccc(C(=O)O)cn2)c1O
Product: COCC[C@H](C)NC(=O)c1ccc(-n2ncc(-c3ccc(C#N)cc3C)c2O)nc1

Procedure:
The title compound was prepared in a manner similar to Example 112 using 6-(4-(4-cyano-2-methylphenyl)-5-hydroxy-1H-pyrazol-1-yl)nicotinic acid and (S)-4-methoxybutan-2-amine. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.19 (d, J=6.82 Hz, 3H) 1.67-1.77 (m, 1H) 1.77-1.88 (m, 1H) 2.44 (s, 3H) 3.23 (s, 3H) 3.39 (t, J=6.57 Hz, 2H) 4.06-4.20 (m, 1H) 7.67 (d, J=8.08 Hz, 1H) 7.73 (s, 1H) 7.78 (br. s., 1H) 8.17 (br. s., 1H) 8.43 (d, J=7.33 Hz, 3H) 8.89-8.95 (m, 1H) 13.16 (br. s., 1H); ESI-MS m/z [M+H]+ 406.2.
Reaction SMILES: [N:1]1([CH:6]([CH2:17][CH2:18][CH2:19][CH3:20])[C:7]([O:9]CC2C=CC=CC=2)=[O:8])[CH:5]=[CH:4][N:3]=[CH:2]1>C(O)(C)C.[Pd]>[N:1]1([CH:6]([CH2:17][CH2:18][CH2:19][CH3:20])[C:7]([OH:9])=[O:8])[CH:5]=[CH:4][N:3]=[CH:2]1
Reactant: CCCCC(C(=O)OCc1ccccc1)n1ccnc1
Agent: [Pd]
Solvent: CC(C)O
Product: CCCCC(C(=O)O)n1ccnc1
Yield: 82.5 %

Procedure:
A solution of 45.1 g of benzyl (1H-imidazol-1-yl)hexanoate in 200 ml of isopropanol was hydrogenated over 10% palladium on carbon. Filtration and evaporation of the solvent gave 24.9 g (80%) of (1H-imidazol-1-yl)hexanoic acid, mp 135°-137° C.