Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1([CH2:5][C:6]([O:8][CH3:9])=[O:7])[CH2:4][O:3]1.[C-:10]#[N:11].[Na+]>>[CH3:1][C@:2]1([CH2:5][C:6]([O:8][CH3:9])=[O:7])[CH2:4][O:3]1.[C:10]([CH2:4][C@@:2]([OH:3])([CH3:1])[CH2:5][C:6]([O:8][CH3:9])=[O:7])#[N:11]
Reactant: COC(=O)CC1(C)CO1
Reactant: [C-]#N
Agent: [Na+]
Product: COC(=O)C[C@@](C)(O)CC#N
Product: COC(=O)C[C@@]1(C)CO1
Temperature: 22 °C
Reaction time: 2 h
Yield: 37 %
Yield: 35 %

Procedure:
200 mg (1.53 mmol) of racemic methyl 2-methyloxiraneacetate was dissolved in 30 mL Tris-SO4 buffer (200 mM, pH 7.5), followed by addition of purified enzyme (15 mg of halohydrin dehalogenase HheC in 450 ρL buffer) and 38 mg (0.77 mmol) NaCN. The reaction mixture was stirred at room temperature (22° C.) and monitored by gas chromatography (GC). The reaction was stopped after 2 h and extracted 3×25 mL ethylacetate. The organic phase was dried over Na2SO4 and evaporated. The crude product was chromatographed on a silica gel 60 H column using pentane/CH2Cl2 (4:6) as eluent. This yielded pure (S)-methyl 2-methyloxiraneacetate (75 mg, 37% yield, e.e. 81%) and (S)-methyl 4-cyano-3-hydroxy-3-methylbutanoate (84 mg, 35% yield, e.e.>99%). The optical purities were determined by GC using a Chiraldex G-TA column (30 m×0.25 mm×0.25 μm). The NMR data were identical with those of synthesized racemic reference compounds.
Reaction SMILES: [CH2:1]([NH:8][C:9]1[C:10]2[S:18][CH:17]=[C:16]([C:19]#[CH:20])[C:11]=2[N:12]=[C:13](Cl)[N:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:21][CH2:22][C@@H:23]([OH:25])[CH3:24].C(OCC)(=O)C>O1CCOCC1>[CH2:1]([NH:8][C:9]1[C:10]2[S:18][CH:17]=[C:16]([C:19]#[CH:20])[C:11]=2[N:12]=[C:13]([NH:21][CH2:22][C@@H:23]([OH:25])[CH3:24])[N:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C[C@H](O)CN
Reactant: C#Cc1csc2c(NCc3ccccc3)nc(Cl)nc12
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: C#Cc1csc2c(NCc3ccccc3)nc(NC[C@H](C)O)nc12
Temperature: 120 °C
Reaction time: 24 h
Yield: 52.3 %

Procedure:
N-Benzyl-2-chloro-7-ethynylthieno[3,2-d]pyrimidin-4-amine (30 mg, 0.096 mmol) was dissolved in anhydrous dioxane (0.5 mL) and (S)-1-aminopropan-2-ol (23 μL, 0.288 mmol) was added. The reaction mixture was stirred at 120° C. for 24 hours. After adding ethyl acetate (3 mL), the reaction mixture was washed with brine. After drying with MgSO4 and concentrating by filtration, purification by silica gel chromatography (ethyl acetate/hexane:1/3→1/1) yielded the target compound of Example 44 (17 mg, 50% yield).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([N:8](C)[C:9]2[CH:27]=[CH:26][C:12]3[N:13]([CH3:25])[C:14]([NH:16][CH2:17][CH2:18][C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)=[N:15][C:11]=3[CH:10]=2)[CH:5]=[CH:4][N:3]=1.[NH2:29][C:30]1[CH:31]=[C:32]([S:36]([NH2:39])(=[O:38])=[O:37])[CH:33]=[CH:34][CH:35]=1>>[ClH:1].[CH3:25][N:13]1[C:12]2[CH:26]=[CH:27][C:9]([NH:8][C:6]3[CH:5]=[CH:4][N:3]=[C:2]([NH:29][C:30]4[CH:31]=[C:32]([S:36]([NH2:39])(=[O:37])=[O:38])[CH:33]=[CH:34][CH:35]=4)[N:7]=3)=[CH:10][C:11]=2[N:15]=[C:14]1[NH:16][CH2:17][CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: Nc1cccc(S(N)(=O)=O)c1
Reactant: CN(c1ccc2c(c1)nc(NCCc1ccccc1)n2C)c1ccnc(Cl)n1
Product: Cl
Product: Cn1c(NCCc2ccccc2)nc2cc(Nc3ccnc(Nc4cccc(S(N)(=O)=O)c4)n3)ccc21

Procedure:
The title compound was prepared following the procedure of example 1 with N5-(2-Chloro-pyrimidin-4-yl)-1,N5-dimethyl-N2-phenethyl-1H-benzoimidazole-2,5-diamine (98 mg, 0.25 mmol) and 3-amino-benzenesulfonamide (43 mg, 0.25 mmol) as a white solid (95 mg, 67%). 1H NMR (400 MHz, d6-DMSO) δ 9.83 (br s, 1H), 9.04 (br s, 1H), 8.49 (s, 1H), 7.87 (d, J=6.0 Hz, 1H), 7.72-7.74 (m, 1H), 7.56 (d, J=8.4 Hz, 1H), 7.18-7.40 (m, 11H), 5.72 (d, J=5.6 Hz, 1H), 3.65-3.71 (m, 2H), 3.64 (s, 3H), 3.46 (s, 3H), 2.96 (m, 2H) ppm. MS (ESI) m/z=529 [M+H]+.
Reaction SMILES: [CH3:1][C:2](=[O:8])[CH2:3][C:4](=[O:7])[CH2:5][CH3:6].[H-].[Na+].Br[CH2:12][C:13]1[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=1>CN(C)C=O.Cl>[Cl:19][C:16]1[CH:17]=[CH:18][C:13]([CH2:12][CH:3]([C:4](=[O:7])[CH2:5][CH3:6])[C:2](=[O:8])[CH3:1])=[CH:14][CH:15]=1
Reactant: CCC(=O)CC(C)=O
Reactant: Clc1ccc(CBr)cc1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCC(=O)C(Cc1ccc(Cl)cc1)C(C)=O
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solution of hexane-2,4-dione (5.7 g) in N,N-dimethylformamide (20 mL) was added dropwise over a period of 15 minutes to a stirred suspension of sodium hydride (60% in oil, 2.2 g) in N,N-dimethylformamide (60 mL) at −5° C. The mixture was stirred a room temperature for 30 minutes and then a solution of 1-bromomethyl-4-chlorobenzene (11 g) in N,N-dimethylformamide (20 mL) was added dropwise over a period of 20 minutes. The resulting mixture Was stirred at room temperature for 17 hours and then diluted with 1.0 M aqueous hydrochloric acid (100 mL). The mixture was extracted with diethyl ether and the combined extracts, washed with 1.0 M aqueous hydrochloric acid and saturated aqueous sodium chloride solution and then dried over magnesium sulfate. The solvent was removed under reduced pressure and purification of the residue by column chromatography on silica gel, eluting with a mixture of pentane and toluene (1:1 to 1:2 to 0:1 by volume) gave title compound (55:45 mixture of keto-enol tautomers) as a white solid, 2.6 g.
Reaction SMILES: C(N1C=CN=C1)(N1C=CN=C1)=[O:2].C(S(N)(=O)=O)(CC)C.[CH2:21]1[CH2:31][CH2:30][N:29]2[C:24](=N[CH2:26][CH2:27][CH2:28]2)C[CH2:22]1>C1COCC1.C(Cl)Cl>[C@@:30]12([OH:2])[N:29]([CH3:24])[C@@H:28]([CH2:27][CH2:26]1)[CH2:22][CH2:21][CH2:31]2
Reactant: C1CCC2=NCCCN2CC1
Reactant: O=C(n1ccnc1)n1ccnc1
Agent: CCC(C)S(N)(=O)=O
Solvent: ClCCl
Solvent: C1CCOC1
Product: CN1[C@@H]2CCC[C@@]1(O)CC2
Temperature: 25 °C
Reaction time: 1 h
Yield: 195.7 %

Procedure:
In a 100 mL round-bottomed flask (RBF) was added carboxylic acid 1 (575 mg, 1.291 mmol) and 1,1′-carbonyldiimidazole (460 mg, 2.84 mmol) in THF (15 mL) to give a yellow solution. The mixture was stirred at room temperature under nitrogen for 1 hour then heated to 70° C., in an oil bath, for 90 minutes. The mixture was cooled and sec-butyl sulfonamide (921 mg, 6.71 mmol) in 4 mL of THF was added along with neat DBU (0.389 mL, 2.58 mmol). The RBF was returned to the oil bath and heated overnight at 70° C. The reaction mixture was transferred to a separatory funnel, diluted with 100 mL of DCM, washed ×3 with 100 mL of 0.5 M HCl, then with 100 mL of H2O, and finally saturated NaCl. The organic mixture was dried over MgSO4, filtered and concentrated to give 713 mgs of the desired acylsulfonamide 2 as a yellow solid (96% yield) which was placed under vacuum overnight. LC data was recorded on a Shimadzu LC-10AS liquid chromatograph equipped with a Phenomenex-Luna 10μ, C18, 4.6×30 mm column, using a SPD-10AV UV-Vis detector at a detector wave length of 220 nM. The elution conditions employed a flow rate of 5 ml/min., a gradient of 100% solvent A/0% solvent B to 0% solvent A/100% solvent B, a gradient time of 2 min., a hold time of 1 min., and an analysis time of 3 min. where solvent A was 10% MeOH/90% H2O/0.1% trifluoroacetic acid and solvent B was 10% H2O/90% MeOH/0.1% trifluoroacetic acid. MS data was determined using a Micromass Platform for LC in electrospray mode. 1H NMR (500 MHz, CD3OD): δ ppm 0.84-0.92 (m, 3 H), 1.03 (t, J=7.32 Hz, 3 H), 1.23 (m, 1 H), 1.28-1.44 (m, 7 H), 1.58 (m, 1 H), 1.72 (m, 2 H), 1.85 (m, 1 H), 1.95-2.07 (m, 3 H), 2.17 (m, 1 H), 2.78 (m, 1 H), 3.69 (m, 2 H), 3.83-3.91 (m, 3 H), 7.02 (s, 1 H), 7.11 (m, 1 H), 7.47 (d, J=7.63 Hz, 1 H), 7.74 (m, 3 H), 8.25 (s, 1 H). LC/MS: m/z 565.22, Rf 2.192 min., 97.5% purity.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][C:5]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[NH:7][CH:6]=1.C(=O)([O-])[O-].[K+].[K+].[Cl:20][C:21]1[C:26]([Cl:27])=[CH:25][CH:24]=[CH:23][C:22]=1[N:28]1[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]1>C(#N)C>[ClH:20].[Cl:20][C:21]1[C:26]([Cl:27])=[CH:25][CH:24]=[CH:23][C:22]=1[N:28]1[CH2:33][CH2:32][N:31]([CH2:2][CH2:3][CH2:4][C:5]2[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[NH:7][CH:6]=2)[CH2:30][CH2:29]1
Reactant: Clc1cccc(N2CCNCC2)c1Cl
Reactant: BrCCCc1c[nH]c2ccccc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: Cl
Product: Clc1cccc(N2CCN(CCCc3c[nH]c4ccccc34)CC2)c1Cl
Temperature: 25 °C

Procedure:
A mixture of 3-(3-bromopropyl)-1H-indole (1.19 g), potassium carbonate (1.4 g) and 1-(2,3-dichlorophenyl)piperazine (1.27 g) in anhydrous acetonitrile (10 mL) was boiled under reflux for 5 h and cooled to room temperature. The mixture was added silicagel (7 g), and the solvent was evaporated in vacuo. The compound was purified by flash chromatography on silicagel (eluent: ethylacetate/heptane/triethylamine 49:49:2). Fractions containing the compound were combined and evaporated in vacuo. Recrystallisation from acetonitrile gave the title compound as a white crystalline material. The compound was precipitated as the hydrochloride salt (1 g). Mp 241–242° C. 1H NMR (DMSO-d6): 2.10–2.25 (m, 2H); 2.75 (t, 2H); 3.10–3.30 (m, 6H); 3.40 (t, 2H); 3.60 (d, 2H); 7.00 (t, 1H); 7.05 (t, 1H); 7.15 (d, 1H); 7.25 (s, 1H); 7.30–7.40 (m, 3H); 7.55 (d, 1H); 10.90 (b s, 1H); 11.40 (b s, 1H). Ms m/z: 388 (MH+).
Reaction SMILES: I[C:2]1[C:11]([NH:12][C:13](=[O:15])[CH3:14])=[C:10]([Cl:16])[CH:9]=[C:4]([C:5]([O:7][CH3:8])=[O:6])[C:3]=1[OH:17].[CH3:18][Si:19]([C:22]#[CH:23])([CH3:21])[CH3:20]>CCN(CC)CC.O1CCOCC1.[Cu]I>[CH3:18][Si:19]([C:22]#[C:23][C:2]1[C:11]([NH:12][C:13](=[O:15])[CH3:14])=[C:10]([Cl:16])[CH:9]=[C:4]([C:5]([O:7][CH3:8])=[O:6])[C:3]=1[OH:17])([CH3:21])[CH3:20]
Reactant: COC(=O)c1cc(Cl)c(NC(C)=O)c(I)c1O
Reactant: C#C[Si](C)(C)C
Agent: [Cu]I
Solvent: CCN(CC)CC
Solvent: C1COCCO1
Product: COC(=O)c1cc(Cl)c(NC(C)=O)c(C#C[Si](C)(C)C)c1O
Temperature: 40 °C
Reaction time: 1.5 h

Procedure:
To a solution of methyl 3-iodo-4-acetamido-5-chlorosalicylate (2 g) in distilled Et3N (60 ml) and dioxane (40 ml), trimethylsilylacetylene (1 ml), CuI (23 mg), and PdCl2 (PPh3)2 (152 mg) were added. The reaction mixture was stirred at 40° C. for 1.5 hours, after which time the solvents were removed in vacuo. A sample of the residue was purified by column chromatography for analytical purposes eluting with diethyl ether/hexane mixtures to yield the intermediate methyl 3-trimethylsilylethynyl-4-acetamido-5-chloro-salic ylate.
Reaction SMILES: C[C:2]1[CH:7]=[C:6](N)[C:5]([CH3:9])=[CH:4][C:3]=1N.N[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>>[CH:13]1[C:14]2[CH2:15][C:6]3[C:5](=[CH:4][CH:3]=[CH:2][CH:7]=3)[C:9]=2[CH:16]=[CH:17][CH:12]=1
Reactant: Cc1cc(N)c(C)cc1N
Reactant: Nc1ccccc1
Product: c1ccc2c(c1)Cc1ccccc1-2

Procedure:
In the following Examples, 9,9-bis(3-methyl-4-aminophenyl)fluorene (OTBAF) was prepared as described in U.S. Pat. No. 4,684,678, Example 2. It was recrystallized from anhydrous dichloroethane prior to use. p-Phenylenediamine (PDA) was obtained in a sublimed, zone-refined form from Aldrich Chemical Company. 2,5-Dimethyl(p-phenylenediamine) (DMPDA) was obtained from Aldrich and recrystallized from absolute ethanol prior to use. 4,4′-(1,4-Phenylenebis(1-methylethylidene))bisbenzamine (EHPT) was obtained from Shell Chemical Company and was recrystallized from anhydrous dichloroethane prior to use. 9,9-Bis((3,5-dimethyl-4-amino)phenyl)fluorene (DM-OTBAF), 9,9-Bis[(3-ethyl-5-methyl-4-amino)phenyl)]fluorene (DE-OTBAF), and 9,9-bis[(2,5-diethyl-4-amino)phenyl]fluorene (DEAF) were prepared analogously, but using a different aniline derivative, as OTBAF, and were recrystallized prior to use. 3,3′-4,4′-Benzophenone tetracarboxylic acid dianhydride (BTDA) was purchased from Aldrich in a sublimed form. 4,4′-Oxydi(phthalic anhydride) (ODPA) was obtained from Occidental Chemical Company and purified via recrystallization from anisole. Pyromellitic dianhydride (PMDA), 2,2′-bis-((3,4-dicarboxyphenyl)-hexafluoropropane dianhydride (6FDA), 3,3′-4,4′-biphenyltetracarboxylic dianhydride (s-BPDA), and DSDA (3,3′-4,4′-diphenyl sulfone tetracarboxylic acid dianhydride) were purchased and used as received from Chriskev Company of Leawood, Kans.
Reaction SMILES: [C:1]([C:6]1[C:7](=[O:25])[CH2:8][CH:9]([C:13]2[CH:22]=[C:21]([CH3:23])[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[C:14]=2[CH3:24])[CH2:10][C:11]=1[OH:12])(=O)[CH2:2][CH2:3][CH3:4].Cl.[CH2:27]([O:29][NH2:30])[CH3:28].O.O.O.C([O-])(=O)C.[Na+]>C(O)C>[CH3:24][C:14]1[C:15]2[C:20](=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:21]([CH3:23])=[CH:22][C:13]=1[CH:9]1[CH2:10][C:11](=[O:12])[C:6]([C:1](=[N:30][O:29][CH2:27][CH3:28])[CH2:2][CH2:3][CH3:4])=[C:7]([OH:25])[CH2:8]1
Reactant: CCON
Reactant: CCCC(=O)C1=C(O)CC(c2cc(C)c3ccccc3c2C)CC1=O
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: CCCC(=NOCC)C1=C(O)CC(c2cc(C)c3ccccc3c2C)CC1=O

Procedure:
A mixture of 2-butyryl-5-(1,4-dimethylnaphth-2-yl)-3-hydroxycyclohex-2-en-1-one (0.25 g), ethoxyamine hydrochloride (1.3 equiv) and sodium acetate trihydrate (1.3 equiv) were stirred in ethanol (30 ml) at room temperature for 4 hr. The mixture was then immediately extracted with ether. The dried (MgSO4) organic extract was evaporated to give 5-(1,4-dimethylnaphth-2-yl)-2-[1-(ethoxyimino)butyl]-3-hydroxycyclohex-2-en-1-one as a pale yellow oil. The product was characterized by proton nuclear magnetic resonance spectroscopy and the spectroscopic data is recorded in Table 4, Example 10.
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][N:5]2[C:10]([C:11]3[CH:12]=[N:13][CH:14]=[CH:15][CH:16]=3)=[CH:9][CH:8]=[N:7][C:6]=12.[CH3:17][N:18](C)C=O>>[N:13]1[CH:14]=[CH:15][CH:16]=[C:11]([C:10]2[N:5]3[N:4]=[CH:3][C:2]([C:17]#[N:18])=[C:6]3[N:7]=[CH:8][CH:9]=2)[CH:12]=1
Reactant: Brc1cnn2c(-c3cccnc3)ccnc12
Reactant: CN(C)C=O
Product: N#Cc1cnn2c(-c3cccnc3)ccnc12

Procedure:
A mixture of 1.0 g. of 3-bromo-7-(3-pyridyl)pyrazolo[1,5-a]pyrimidine and 0.50 g. of cuprous cyanide in 25 ml. of N,N-dimethylformamide is heated at reflux temperature for 16 hours. The solvent is removed in vacuo and the residue is triturated with dichloromethane. The dichloromethane solution is passed through a column of hydrous magnesium silicate. The eluent is concentrated and hexane added to give the product of the example as tan crystals, m.p. 258°-260° C.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([C:8]([F:11])([F:10])[F:9])[N:3]=1.[NH:12]1[CH2:17][CH2:16][CH:15]([C:18]([N:20]2[CH2:24][CH2:23][C@H:22]([NH:25][C:26](=[O:32])[O:27][C:28]([CH3:31])([CH3:30])[CH3:29])[CH2:21]2)=[O:19])[CH2:14][CH2:13]1.C(N(CC)CC)C.C(OCC)(=O)C>CN(C=O)C>[F:9][C:8]([F:11])([F:10])[C:4]1[N:3]=[C:2]([N:12]2[CH2:13][CH2:14][CH:15]([C:18]([N:20]3[CH2:24][CH2:23][C@H:22]([NH:25][C:26](=[O:32])[O:27][C:28]([CH3:30])([CH3:29])[CH3:31])[CH2:21]3)=[O:19])[CH2:16][CH2:17]2)[CH:7]=[CH:6][CH:5]=1
Reactant: CC(C)(C)OC(=O)N[C@H]1CCN(C(=O)C2CCNCC2)C1
Reactant: FC(F)(F)c1cccc(Cl)n1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N[C@H]1CCN(C(=O)C2CCN(c3cccc(C(F)(F)F)n3)CC2)C1
Yield: 29.7 %

Procedure:
A solution of 2-chloro-6-(trifluoromethyl)pyridine (1.8 g, 9.9 mmol), tert-butyl [(3S)-1-(piperidin-4-ylcarbonyl)pyrrolidin-3-yl]carbamate (2.97 g, 10.0 mmol) and triethylamine (4.1 mL, 30 mmol) in DMF (50 mL) was heated at 100° C. for 4 hrs. After cooling down, ethyl acetate was added. The resulting solution was washed with brine several times, dried over Na2SO4 and concentrated. The residue was chromatographed on silica gel to give the title compound (1.3 g) as a yellow solid. MS (M+H) 443.2.
Reaction SMILES: C([C@H:3]([S:7]([C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)(=[N:9][C:10]([C:12]1[CH:13]=[N:14][CH:15]=[C:16]([C:18]#[C:19][C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([NH:26][C:27]([C:29]3[O:30][CH:31]=[CH:32][C:33]=3[CH3:34])=[O:28])[CH:21]=2)[CH:17]=1)=[O:11])=[O:8])[C:4]([O-])=[O:5])C.[NH:41]1[CH2:45][CH2:44][CH2:43][CH2:42]1>>[CH3:34][C:33]1[CH:32]=[CH:31][O:30][C:29]=1[C:27]([NH:26][C:22]1[CH:21]=[C:20]([C:19]#[C:18][C:16]2[CH:15]=[N:14][CH:13]=[C:12]([CH:17]=2)[C:10]([N:9]=[S@:7](=[O:8])([CH2:3][C:4](=[O:5])[N:41]2[CH2:45][CH2:44][CH2:43][CH2:42]2)[C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)=[O:11])[CH:25]=[CH:24][CH:23]=1)=[O:28]
Reactant: C1CCNC1
Reactant: CC[C@@H](C(=O)[O-])S(=O)(=NC(=O)c1cncc(C#Cc2cccc(NC(=O)c3occc3C)c2)c1)c1ccccc1
Product: Cc1ccoc1C(=O)Nc1cccc(C#Cc2cncc(C(=O)N=[S@](=O)(CC(=O)N3CCCC3)c3ccccc3)c2)c1

Procedure:
In a manner similar to that described in Example 534, (S)-Ethyl(N-{[5-({3-[(3-methyl-2-furoyl)amino]phenyl}ethynyl)pyridin-3-yl]carbonyl}-S-phenylsulfonimidoyl)acetate and pyrrolidine were reacted to give the title compound.
Reaction SMILES: [S:1]1[C:9]2[CH2:8][CH2:7][NH:6][CH2:5][C:4]=2[CH:3]=[CH:2]1.C(=O)(O)[O-].[Na+].[Cl:15][C:16]1[CH:23]=[CH:22][CH:21]=[CH:20][C:17]=1[CH2:18]Cl>C(O)C>[ClH:15].[Cl:15][C:16]1[CH:23]=[CH:22][CH:21]=[CH:20][C:17]=1[CH2:18][N:6]1[CH2:7][CH2:8][C:9]2[S:1][CH:2]=[CH:3][C:4]=2[CH2:5]1
Reactant: ClCc1ccccc1Cl
Reactant: c1cc2c(s1)CCNC2
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Product: Cl
Product: Clc1ccccc1CN1CCc2sccc2C1

Procedure:
26.1 g of 4,5,6,7-tetrahydrothieno[3,2-c]pyridine, 80 ml of ethanol and 19 g of sodium bicarbonate are charged into a 250-ml three-necked round bottom flask fitted with a thermometer, a condenser and a mechanical stirrer. 30.2 g of o-chlorobenzyl chloride are then added and the mixture is heated to about 75°-80° C. during 1 hour. The reaction mixture is evaporated down and the residue is taken up with 200 ml of isopropyl ether. The 5-(2-chlorobenzyl)-4,5,6,7-tetrahydrothieno[3,2-c]pyridine obtained is then added to 100 ml of ethanol. After adding 20 ml of concentrated hydrochloric acid to the ethanolic solution, heating to reflux and cooling the mixture, 46.6 g of 5-(2-chlorobenzyl)-4,5,6,7-tetrahydrothieno[3,2-c]pyridine hydrochloride, which crystallises, are obtained.
Reaction SMILES: [C:1]([N:5]1[C:9]([C:10]2[S:11][CH:12]=[CH:13][CH:14]=2)=[CH:8][C:7]([CH2:15][CH2:16][CH:17]=O)=[N:6]1)([CH3:4])([CH3:3])[CH3:2].[C:19]1([N:25]2[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]2)[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.CCN(C(C)C)C(C)C.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>>[C:1]([N:5]1[C:9]([C:10]2[S:11][CH:12]=[CH:13][CH:14]=2)=[CH:8][C:7]([CH2:15][CH2:16][CH2:17][N:28]2[CH2:29][CH2:30][N:25]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[CH2:26][CH2:27]2)=[N:6]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)n1nc(CCC=O)cc1-c1cccs1
Reactant: c1ccc(N2CCNCC2)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)n1nc(CCCN2CCN(c3ccccc3)CC2)cc1-c1cccs1

Procedure:
81 mg (95%) of target compound was obtained by using a method same as in Example 1 by using 3-(1-tert-butyl-5-(thiophene-2-yl)-1H-pyrazol-3-yl)propanal (50 mg, 0.191 mmol), 1-phenylpiperazine (0.029 mL, 0.191 mmol), DIPEA (0.050 mL, 0.287 mmol) and NaBH(OAc)3 (121 mg, 0.573 mmol).
Reaction SMILES: Cl[C:2]1[C:3]2[N:4]([C:13]([O:16]C)=[N:14][N:15]=2)[C:5]2[C:10]([N:11]=1)=[CH:9][CH:8]=[C:7]([F:12])[CH:6]=2.[CH2:18]([NH2:25])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>CN(C=O)C.CCOC(C)=O.Br.CC(O)=O>[CH2:18]([NH:25][C:2]1[C:3]2[N:4]([C:13](=[O:16])[NH:14][N:15]=2)[C:5]2[C:10]([N:11]=1)=[CH:9][CH:8]=[C:7]([F:12])[CH:6]=2)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: COc1nnc2c(Cl)nc3ccc(F)cc3n12
Reactant: NCc1ccccc1
Agent: Br
Solvent: CN(C)C=O
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: O=c1[nH]nc2c(NCc3ccccc3)nc3ccc(F)cc3n12
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of 500 mg of 4-chloro-8-fluoro-1-methoxy-[1,2,4]triazolo[4,3-a]quinoxaline in DMF (6.0 mL) was added 637 mg of benzylamine. This solution was stirred at room temperature for 18 hrs. and then diluted with EtOAc and washed with water and saturated lithium chloride. The extracts were dried over sodium sulfate, filtered, and concentrated and the residue was separated by silica gel chromatography to give a yellow solid. This material was dissolved in a 1:1.5 mixture of 48% HBr/AcOH, and refluxed for 12 hrs. The reaction mixture was concentrated and the residue was recrystallized from MeOH to afford the title compound as a yellow solid. MS (M+H)+=310.0.
Reaction SMILES: C([O:3][C:4](=[O:38])[CH2:5][N:6]1[CH2:11][CH2:10][CH:9]([CH:12]([N:14]2[C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[C:16]([C:23](=[O:36])[NH:24][CH2:25][C:26]3[C:27](=[O:35])[NH:28][C:29]([CH3:34])=[CH:30][C:31]=3[O:32][CH3:33])=[C:15]2[CH3:37])[CH3:13])[CH2:8][CH2:7]1)C.C1COCC1.CO.O.[OH-].[Li+]>O>[CH3:33][O:32][C:31]1[CH:30]=[C:29]([CH3:34])[NH:28][C:27](=[O:35])[C:26]=1[CH2:25][NH:24][C:23]([C:16]1[C:17]2[C:22](=[CH:21][CH:20]=[CH:19][CH:18]=2)[N:14]([CH:12]([CH:9]2[CH2:8][CH2:7][N:6]([CH2:5][C:4]([OH:38])=[O:3])[CH2:11][CH2:10]2)[CH3:13])[C:15]=1[CH3:37])=[O:36]
Reactant: CCOC(=O)CN1CCC(C(C)n2c(C)c(C(=O)NCc3c(OC)cc(C)[nH]c3=O)c3ccccc32)CC1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: COc1cc(C)[nH]c(=O)c1CNC(=O)c1c(C)n(C(C)C2CCN(CC(=O)O)CC2)c2ccccc12
Temperature: 25 °C
Yield: 81.8 %

Procedure:
To a round bottomed flask was charged with a magnetic stir bar was added (R or S)-ethyl-2-(4-(1-(3-((4-methoxy-6-methyl-2-oxo-1,2-dihydropyridin-3-yl)methylcarbamoyl)-2-methyl-1H-indol-1-yl)ethyl)piperidin-1-yl)acetate (Compound 363) (69 mg, 0.132 mmol), THF (1.5 mL), MeOH (1.5 mL), and water (0.75 mL). To this solution was added lithium hydroxide monohydrate (5.54 mg, 0.132 mmol) and the reaction stirred at room temperature for 1H. The organics were removed under reduced pressure and the resulting aqueous solution purified via reverse phase-HPLC (water/MeCN) 0→95% to afford the title compound (66 mg, 0.108 mmol, 82% yield). LCMS 514 (M+1) 1H NMR (400 MHz, DMSO-d6) δ=11.67 (s, 1H), 9.65 (s, 1H), 7.84-7.68 (m, 2H), 7.63 (d, J=7.4 Hz, 1H), 7.14-7.03 (m, 2H), 6.18 (s, 1H), 4.33 (d, J=3.6 Hz, 2H), 4.27-4.15 (m, 1H), 4.04 (br. s., 2H), 3.85 (s, 3H), 3.57 (s, 1H), 3.35-3.23 (m, 1H), 3.14-2.99 (m, 1H), 2.86-2.74 (m, 1H), 2.62 (s, 3H), 2.21 (s, 3H), 2.18-2.08 (m, 1H), 1.75 (s, 1H), 1.60-1.49 (m, 4H), 1.46-1.33 (m, 1H), 0.92-0.81 (m, 1H).
Reaction SMILES: Cl.CS([NH:6][NH:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)(=O)=O.[CH3:14][NH:15][S:16]([C:19]1[CH:20]=[C:21]2[C:25](=[CH:26][CH:27]=1)[NH:24][C:23](=[O:28])[C:22]2=[O:29])(=[O:18])=[O:17]>>[CH3:14][NH:15][S:16]([C:19]1[CH:20]=[C:21]2[C:25](=[CH:26][CH:27]=1)[NH:24][C:23](=[O:28])[C:22]2=[O:29])(=[O:18])=[O:17].[CH3:14][NH:15][S:16]([C:19]1[CH:20]=[C:21]2[C:25](=[CH:26][CH:27]=1)[NH:24][C:23](=[O:28])[C:22]2=[N:6][NH:7][C:8]1[CH:9]=[CH:10][C:11]([S:16](=[O:18])(=[O:17])[NH:15][CH3:14])=[CH:12][CH:13]=1)(=[O:18])=[O:17]
Reactant: CS(=O)(=O)NNc1ccccc1
Agent: CNS(=O)(=O)c1ccc2c(c1)C(=O)C(=O)N2
Agent: Cl
Product: CNS(=O)(=O)c1ccc(NN=C2C(=O)Nc3ccc(S(=O)(=O)NC)cc32)cc1

Procedure:
1H-indole-2,3-dione-5-sulfonic acid methylamide was prepared from N-methylsulfonamidoaniline hydrochloride according to Procedure A: 1H NMR (DMSO-d6): δ 2.37 (d, J=4.7 Hz, 3H), 7.04 (d, J=8.4 Hz, 1H), 7.45 (q, J=5.0 Hz, 1H), 7.73 (s, 1H), 7.91 (d, J=8.4 Hz, 1H), 11.38 (s, 1H); APCI-MS m/z 239 (M−H)−. The title compound was prepared from 1H-indole-2,3-dione-5-sulfonic acid methylamide and 4-(N-methylsulfonamido)-phenylhydrazine according to Procedure G: mp>250° C.; 1H NMR (DMSO-d6): δ 2.38 (d, J=4.9 Hz, 6H), 7.08 (d, J=8.2 Hz, 1H), 7.33 (q, J=5.2 Hz, 1H), 7.35 (q, J=4.9 Hz, 1H), 7.65 (d, J=8.7 Hz, 2H), 7.66 (dd, J=8.1, 1.8 Hz, 1H), 7.73 (d, J=8.8 Hz, 2H), 7.91 (d, J=1.5 Hz, 1H), 11.48 (s, 1H), 12.77 (s, 1H); APCI-MS m/z 422 (M−H)−. Anal. Calcd for C16H17N5O5S2: C, 45.38; H, 4.05; N, 16.54. Found: C, 45.46; H, 4.04; N, 16.45.