Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[CH:2]([CH2:15][CH2:16][CH2:17][CH3:18])[C:3]([O:5][C@H:6]([CH3:14])[C:7](=[O:13])[N:8]1[CH2:12][CH2:11][CH2:10][CH2:9]1)=[O:4].[Na+].[I-].C(N(CC)CC)C.[CH3:28][O:29][C:30]1[CH:36]=[CH:35][C:33]([NH2:34])=[CH:32][CH:31]=1.S([O-])([O-])=O.[Na+].[Na+]>C(OCC)(=O)C.O1CCCC1>[CH3:28][O:29][C:30]1[CH:36]=[CH:35][C:33]([NH:34][CH:2]([CH2:15][CH2:16][CH2:17][CH3:18])[C:3]([O:5][C@@H:6]([CH3:14])[C:7](=[O:13])[N:8]2[CH2:12][CH2:11][CH2:10][CH2:9]2)=[O:4])=[CH:32][CH:31]=1
Reactant: CCCCC(Br)C(=O)O[C@H](C)C(=O)N1CCCC1
Reactant: COc1ccc(N)cc1
Agent: O=S([O-])[O-]
Agent: [I-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: CCCCC(Nc1ccc(OC)cc1)C(=O)O[C@@H](C)C(=O)N1CCCC1
Temperature: 37 °C
Reaction time: 1 h
Yield: 150.8 %

Procedure:
To (1R)-1-methyl-2-oxo-2-tetrahydro-1-H-1-pyrrolylethyl 2-bromohexanoate (4.8 g, 15 mmol), NaI (2.3 g, 15 mmol), triethylamine (2.4 g, 24 mmol) and tetrahydrofuran (5 mL) were added. To the solution, p-methoxyaniline (2.4 g, 20 mmol) and tetrahydrofuran (5 mL) were added. The mixture was stirred at 37° C. for 1 hour and then at 20° C. for 5 hours. To the mixture, a saturated sodium sulfite aqueous solution and ethyl acetate were added for extraction. The obtained extract was dried with anhydrous magnesium sulfate, and then the solvent was removed away in reduced pressure in order to obtain 8.2 g of oil. The conversion ratio to the obtained compound was 1000, and the diastereo ratio calculated by NMR analysis was 94.5:5.5.
Reaction SMILES: CC(OC([N:8]1[CH2:18][CH2:17][C:11]2([CH2:15][O:14][CH2:13][CH:12]2[OH:16])[CH2:10][CH2:9]1)=O)(C)C.[ClH:19]>>[ClH:19].[CH2:15]1[C:11]2([CH2:17][CH2:18][NH:8][CH2:9][CH2:10]2)[CH:12]([OH:16])[CH2:13][O:14]1
Reactant: CC(C)(C)OC(=O)N1CCC2(CC1)COCC2O
Agent: Cl
Product: OC1COCC12CCNCC2
Yield: 77 %

Procedure:
4-Hydroxy-2-oxa-8-aza-spiro[4.5]decane-8-carboxylic acid 1,1-dimethylethyl ester (Description 7; 0.86 g, 3.3 mmol) was stirred overnight in 2M ethereal hydrogen chloride. The mixture was filtered and the solid dried to give the title compound (0.5 g, 77%).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[N:6][C:5]([NH2:8])=[C:4]([CH3:9])[CH:3]=1.[C:10](Cl)(Cl)=[S:11].O.C([O-])(=O)C>C(=O)(O)[O-].[Na+].O1CCCC1>[Cl:1][C:2]1[N:7]=[N:6][C:5]([N:8]=[C:10]=[S:11])=[C:4]([CH3:9])[CH:3]=1
Reactant: Cc1cc(Cl)nnc1N
Reactant: S=C(Cl)Cl
Agent: CC(=O)[O-]
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: Cc1cc(Cl)nnc1N=C=S
Reaction time: 1 h
Yield: 8.2 %

Procedure:
To a solution of 6-chloro-4-methylpyridazin-3-amine (2.86 g, 20.0 mmol) in aqueous sodium bicarbonate (10 mL) and tetrahydrofuran (40 mL) was added thiophosgene (1.69 mL, 22.0 mmol) dropwise at 0° C. After stirring for 1 hr, water and ethyl, acetate were added to the mixture and the insoluble materials were filtered off. The filtrate was washed with brine, dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was purified by flash chromatography on silica gel eluting with a 10-50% ethyl acetate/n-hexane gradient mixture. The filtrate was concentrated in vacuo to give the title compound (304 mg, 1.64 mmol, 8%) as a pale yellow solid.
Reaction SMILES: CO[C:3]([CH2:5][CH2:6][C@H:7]([NH2:11])[C:8]([OH:10])=[O:9])=[O:4].C1(C(O)CC(O)C)C=CC=CC=1.[CH2:24]([N:26](CC)CC)[CH3:25].C(N)C>CO>[NH2:11][C@H:7]([C:8]([OH:10])=[O:9])[CH2:6][CH2:5][C:3]([NH:26][CH2:24][CH3:25])=[O:4]
Reactant: COC(=O)CC[C@H](N)C(=O)O
Reactant: CCN(CC)CC
Agent: CC(O)CC(O)c1ccccc1
Agent: CCN
Solvent: CO
Product: CCNC(=O)CC[C@H](N)C(=O)O
Temperature: 60 °C
Yield: 87 %

Procedure:
First, 5.0 g (31 mmol) of L-glutamic acid-γ-methyl ester was suspended in 15 mL of methanol. To this, 5.6 g (34 mmol) of 1-phenyl-1,3-butanediol and 3.1 g (31 mmol) of triethylamine were added. The mixture was heated at 60° C. for 2 hours. Subsequently, 20 g (310 mmol) of 70% ethylamine was added to the mixture and the same procedure as in Example 1 was performed to obtain 4.7 g of theanine (yield: 87%). The obtained theanine had the same purity as high as in Example 1.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([F:13])=[CH:9][C:10]=2[F:12])[N:5]=[C:4]([C:14]2[CH:19]=[C:18]([F:20])[CH:17]=[CH:16][C:15]=2[S:21]([CH3:24])(=[O:23])=[O:22])[C:3]=1[CH3:25].[O:26]1[CH2:31][CH2:30][N:29]([C:32]2[CH:33]=[C:34]([NH2:38])[CH:35]=[N:36][CH:37]=2)[CH2:28][CH2:27]1>C1(C)C=CC=CC=1>[F:12][C:10]1[CH:9]=[C:8]([F:13])[CH:7]=[C:6]2[C:11]=1[C:2]([NH:38][C:34]1[CH:35]=[N:36][CH:37]=[C:32]([N:29]3[CH2:30][CH2:31][O:26][CH2:27][CH2:28]3)[CH:33]=1)=[C:3]([CH3:25])[C:4]([C:14]1[CH:19]=[C:18]([F:20])[CH:17]=[CH:16][C:15]=1[S:21]([CH3:24])(=[O:23])=[O:22])=[N:5]2
Reactant: Nc1cncc(N2CCOCC2)c1
Reactant: Cc1c(-c2cc(F)ccc2S(C)(=O)=O)nc2cc(F)cc(F)c2c1Cl
Solvent: Cc1ccccc1
Product: Cc1c(-c2cc(F)ccc2S(C)(=O)=O)nc2cc(F)cc(F)c2c1Nc1cncc(N2CCOCC2)c1

Procedure:
Essentially prepared according to Procedure H using 4-chloro-5,7-difluoro-2-(5-fluoro-2-(methylsulfonyl)phenyl)-3-methylquinoline (120.0 mg, 0.32 mmol) and 5-morpholinopyridin-3-amine in toluene to give 5,7-difluoro-2-(5-fluoro-2-(methylsulfonyl)phenyl)-3-methyl-N-(5-morpholinopyridin-3-yl)quinolin-4-amine. 1H NMR (CDCl3) δ ppm 8.21 (1H, dd, J=8.8, 5.3 Hz), 7.93 (1H, d, J=2.3 Hz), 7.84 (1H, d, J=2.3 Hz), 7.49 (1H, ddd, J=9.2, 2.5, 1.4 Hz), 7.28-7.41 (2H, m), 7.14 (1H, dd, J=8.2, 2.5 Hz), 7.04-7.12 (1H, m), 6.55 (1H, t, J=2.4 Hz), 3.78 (4H, t, J=4.9 Hz), 3.11-3.24 (4H, m), 3.10 (3H, s), 1.91 (3H, s). Mass Spectrum (ESI) m/e=529.2 (M+1).
Reaction SMILES: [Br:1][C:2]1[C:3](O)=[N:4][CH:5]=[C:6]([N+:8]([O-:10])=[O:9])[CH:7]=1.P(Br)(Br)([Br:14])=O.P(Br)(Br)Br>O>[Br:14][C:3]1[C:2]([Br:1])=[CH:7][C:6]([N+:8]([O-:10])=[O:9])=[CH:5][N:4]=1
Reactant: O=P(Br)(Br)Br
Reactant: O=[N+]([O-])c1cnc(O)c(Br)c1
Agent: BrP(Br)Br
Solvent: O
Product: O=[N+]([O-])c1cnc(Br)c(Br)c1
Temperature: 120 °C
Yield: 73 %

Procedure:
A mixture of 3-bromo-5-nitropyridin-2-ol, POBr3 and PBr3 was heated at 120° C. for 3.5 h. The crude mixture was poured into a mixture of ice and water and extracted with DCM. The crude mixture was purified by flash chromatography over SiO2 eluting with hexane/ethyl acetate mixtures affording 2.63 g (yield 73%) of the expected product.
Reaction SMILES: [CH2:1]([NH:9][C:10]1[C:11]([NH2:16])=[CH:12][CH:13]=[CH:14][CH:15]=1)[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[Cl:17][CH2:18][C:19](O)=O>>[Cl:17][CH2:18][C:19]1[N:9]([CH2:1][CH2:2][C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[N:16]=1
Reactant: Nc1ccccc1NCCc1ccccc1
Reactant: O=C(O)CCl
Product: ClCc1nc2ccccc2n1CCc1ccccc1
Yield: 61.6 %

Procedure:
The title compound was prepared in accordance with the general method of Example 191(C), from N1-phenethylbenzene-1,2-diamine (2.57 g, 12.11 mmol) and 2-chloroacetic acid (1.70 g, 18 mmol). The crude residue was purified over silicagel chromatography (prepacked 70 g silicagel column, Cyclohexane/AcOEt: from 80/20 to 70/30 as eluent) to afford 2.02 g of 2-(chloromethyl)-1-phenethyl-1H-benzo[d]imidazole (Yield: 61%) as a white crystalline solid.
Reaction SMILES: [OH:1][C@H:2]1[CH2:7][CH2:6][CH2:5][CH2:4][C@@H:3]1[N:8]1[C:17](=[O:18])[C:16]2[C:11](=[C:12]3[CH:30]=[CH:29][CH:28]=[CH:27][C:13]3=[C:14]([CH2:19][C:20]3[CH:21]=[N:22][C:23]([CH3:26])=[CH:24][CH:25]=3)[CH:15]=2)[N:10]([CH2:31][CH:32]=[CH2:33])[CH2:9]1>C(OCC)(=O)C.[Pd]>[OH:1][C@H:2]1[CH2:7][CH2:6][CH2:5][CH2:4][C@@H:3]1[N:8]1[C:17](=[O:18])[C:16]2[C:11](=[C:12]3[CH:30]=[CH:29][CH:28]=[CH:27][C:13]3=[C:14]([CH2:19][C:20]3[CH:21]=[N:22][C:23]([CH3:26])=[CH:24][CH:25]=3)[CH:15]=2)[N:10]([CH2:31][CH2:32][CH3:33])[CH2:9]1
Reactant: C=CCN1CN([C@H]2CCCC[C@@H]2O)C(=O)c2cc(Cc3ccc(C)nc3)c3ccccc3c21
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CCCN1CN([C@H]2CCCC[C@@H]2O)C(=O)c2cc(Cc3ccc(C)nc3)c3ccccc3c21
Reaction time: 4 h

Procedure:
To a solution of 3-[(1S,2S)-2-hydroxycyclohexyl]-6-[(6-methylpyridin-3-yl)methyl]-1-(prop-2-en-1-yl)-2,3-dihydrobenzo[h]quinazolin-4(1H)-one (0.030 g, 0.068 mmol) in 3 mL of ethyl acetate was added palladium on carbon (30 mg, 2.8 mmol). The mixture was placed under an atmosphere of hydrogen (1 atm) for 4 h and was then filtered through a pad of Celite, followed by filtration through a silica gel plug, eluting with 5% methanol in ethyl acetate. The filtrate was concentrated in vacuo to provide the title compound that gave a proton NMR spectra consistent with theory and a mass ion (ES+) of 444.3 for [M+H]+: 1H NMR (400 MHz, CDCl3 δ 8.46 (s, 1H), 8.24-8.21 (m, 1H), 7.93-7.90 (in 2H), 7.54-7.51 (m, 2H), 7.30-7.27 (m, 2H), 6.97 (d, J=8.0 Hz, 1H), 4.71-4.61 (m, 2H), 4.37-4.34 (m, 1H), 4.34 (s, 2H), 3.60 (br s, 1H), 3.10-3.04 (m, 2H), 2.48 (s, 3H), 2.22-2.19 (m, 2H), 1.91-1.69 (m, 4H), 1.59-1.30 (m, 4H), 1.06 (t, J=7.4 Hz, 3H).
Reaction SMILES: [Si]([O:8][CH2:9][C:10]1([CH3:36])[S:16][CH2:15][CH2:14][N:13]2[C:17]([C:20]3([C:23]4[CH:28]=[CH:27][C:26]([C:29]5[C:34]([Cl:35])=[CH:33][CH:32]=[CH:31][N:30]=5)=[CH:25][CH:24]=4)[CH2:22][CH2:21]3)=[N:18][N:19]=[C:12]2[CH2:11]1)(C(C)(C)C)(C)C.Cl>CO>[Cl:35][C:34]1[C:29]([C:26]2[CH:25]=[CH:24][C:23]([C:20]3([C:17]4[N:13]5[CH2:14][CH2:15][S:16][C:10]([CH2:9][OH:8])([CH3:36])[CH2:11][C:12]5=[N:19][N:18]=4)[CH2:22][CH2:21]3)=[CH:28][CH:27]=2)=[N:30][CH:31]=[CH:32][CH:33]=1
Reactant: CC1(CO[Si](C)(C)C(C)(C)C)Cc2nnc(C3(c4ccc(-c5ncccc5Cl)cc4)CC3)n2CCS1
Agent: Cl
Solvent: CO
Product: CC1(CO)Cc2nnc(C3(c4ccc(-c5ncccc5Cl)cc4)CC3)n2CCS1
Yield: 78.1 %

Procedure:
A solution of the compound (193 mg, 0.36 mmol) obtained in Example 27-1) and 4 M hydrochloric acid (1,4-dioxane solution, 1 mL) in methanol (2 mL) was stirred at room temperature for 5 h. The reaction mixture was concentrated under reduced pressure, saturated aqueous sodium hydrogencarbonate was added to the residue, the mixture was extracted with dichloromethane, and the organic layer was washed with saturated sodium chloride solution and dried with anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel chromatography (Isco Combiflash, 12 g, methanol:ethyl acetate=0:100 to 40:60, gradient) to obtain the title compound (120 mg, 79%) as a colorless solid.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:16]=[CH:15][C:12]([C:13]#[N:14])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N-:17]=[N+:18]=[N-:19].[Na+].[Cl-].[NH4+].[OH-].[Na+]>CN(C)C=O>[CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([C:13]2[N:17]=[N:18][NH:19][N:14]=2)=[CH:15][CH:16]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: [N-]=[N+]=[N-]
Reactant: N#Cc1ccc(OCc2ccccc2)cc1
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CN(C)C=O
Product: c1ccc(COc2ccc(-c3nn[nH]n3)cc2)cc1
Temperature: 110 °C
Reaction time: 8 h
Yield: 95 %

Procedure:
To a solution of 4-benzyloxybenzonitrile (2.0 g) in dimethylformamide (15 mL) were added sodium azide (932 mg) and ammonium chloride (767 mg). The mixture was stirred at 110° C. overnight under heating and then allowed to stand for cooling to room temperature. 1N aqueous sodium hydroxide was added thereto to adjust the pH to about 10, followed by washing with diethyl ether. To the aqueous layer was added 1N hydrochloric acid, and the resulting precipitated solid was filtered to give the title compound (2.29 g).
Reaction SMILES: [OH-].[K+].[CH3:3]C1C=CC(S(N(N=O)C)(=O)=O)=CC=1.C(O)CO.CCOCC.[NH:26]1[C:30]2[CH:31]=[C:32]([N:35]3[CH:39]([CH:40]4[CH2:45][CH2:44][N:43]([C:46]5[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=5)[CH2:42][CH2:41]4)[C:38]([CH3:52])=[C:37]([OH:53])[C:36]3=[O:54])[CH:33]=[CH:34][C:29]=2[N:28]=[CH:27]1>CO>[NH:26]1[C:30]2[CH:31]=[C:32]([N:35]3[CH:39]([CH:40]4[CH2:45][CH2:44][N:43]([C:46]5[CH:47]=[CH:48][CH:49]=[CH:50][CH:51]=5)[CH2:42][CH2:41]4)[C:38]([CH3:52])=[C:37]([O:53][CH3:3])[C:36]3=[O:54])[CH:33]=[CH:34][C:29]=2[N:28]=[CH:27]1
Reactant: CC1=C(O)C(=O)N(c2ccc3nc[nH]c3c2)C1C1CCN(c2ccccc2)CC1
Reactant: Cc1ccc(S(=O)(=O)N(C)N=O)cc1
Agent: [K+]
Agent: [OH-]
Solvent: CCOCC
Solvent: OCCO
Solvent: CO
Product: COC1=C(C)C(C2CCN(c3ccccc3)CC2)N(c2ccc3nc[nH]c3c2)C1=O

Procedure:
The compound was synthesized starting from KOH (15 eq in water), diazald (9 eq), ethylene glycol/Et2O (1/5 v/v, 18 ml), 1-(1H-Benzo[d]imidazol-6-yl)-3-hydroxy-4-methyl-5-(1-phenylpiperidin-4-yl)-1H-pyrrol-2(5H)-one (0.280 g, 0.72 mmol, 1 eq) and MeOH (15 ml), the product was further purified by prep TLC; yield: 0.021 g (5.2%); MS m/z: 403.1 [M+H]+; 1H-NMR: (400 MHz, CDCl3) δ: 7.95 (s, 1H), 7.65-7.60 (m, 1H), 7.17 (m, 3H), 6.80 (d, 1H), 4.52 (s, 1H), 4.03 (s, 3H), 3.69-3.66 (m, 3H), 2.54-2.41 (m, 3H), 2.05 (s, 4H), 1.88 (m, 5H), 1.41-1.25 (m, 2H); HPLC (METHOD [A]): rt 6.05 min (88.89%)
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][CH2:7][OH:8].[CH2:9]=O.[Br-].[Mg+2].[Br-]>C(#N)C>[S:1]1[C:2]2[CH2:6][CH2:7][O:8][CH2:9][C:3]=2[CH:4]=[CH:5]1
Reactant: OCCc1cccs1
Reactant: C=O
Agent: [Br-]
Agent: [Mg+2]
Solvent: CC#N
Product: c1cc2c(s1)CCOC2
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 43 %

Procedure:
10.0 g of 2-thiopheneethanol, 5.9 g of paraformaldehyde, and 28.7 g of magnesium bromide were added to 780 mL of acetonitrile, and the resulting mixture was refluxed for 24 hours. The reaction product solution was cooled to room temperature and concentrated by evaporation under reduced pressure. To the residue, 100 mL of water and 150 mL of n-hexane were added, and the resulting mixture was stirred for 5 minutes. The organic layer was separated and dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. The residue was distilled under reduced pressure to obtain 4.7 g (yield of 43%) of the title compound, of which analysis data were the same as obtained in Example 14.
Reaction SMILES: [NH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH:3]([NH:11]C(=O)OC(C)(C)C)[CH2:2]1.[ClH:19]>C(OCC)(=O)C.O1CCOCC1>[ClH:19].[ClH:19].[NH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH:3]([NH2:11])[CH2:2]1
Reactant: CC(C)(C)OC(=O)NC1CNc2ccccc2C1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: NC1CNc2ccccc2C1

Procedure:
To a stirred room temperature solution of tert-butyl 1,2,3,4-tetrahydroquinolin-3-ylcarbamate (1.0 g) in ethyl acetate (20 mL) was added 4 M HCl in dioxane (10 mL). After 6 hours the mixture was evaporated to dryness to obtain 1,2,3,4-tetrahydroquinolin-3-amine bis HCl salt as a cream colored solid (925 mg).
Reaction SMILES: [CH3:1][C:2]1([CH3:25])[CH2:11][CH2:10][C:9]([CH3:13])([CH3:12])[C:8]2[CH:7]=[C:6]([C:14]3[O:18][C:17]([CH:19]4[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]4)=[N:16][N:15]=3)[CH:5]=[CH:4][C:3]1=2.C([O:29][CH2:30][CH2:31][CH2:32][CH2:33]Br)(=O)C.[OH-].[Na+]>CO>[CH3:1][C:2]1([CH3:25])[CH2:11][CH2:10][C:9]([CH3:12])([CH3:13])[C:8]2[CH:7]=[C:6]([C:14]3[O:18][C:17]([CH:19]4[CH2:24][CH2:23][N:22]([CH2:33][CH2:32][CH2:31][CH2:30][OH:29])[CH2:21][CH2:20]4)=[N:16][N:15]=3)[CH:5]=[CH:4][C:3]1=2
Reactant: CC(=O)OCCCCBr
Reactant: CC1(C)CCC(C)(C)c2cc(-c3nnc(C4CCNCC4)o3)ccc21
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CC1(C)CCC(C)(C)c2cc(-c3nnc(C4CCN(CCCCO)CC4)o3)ccc21

Procedure:
The preparation was carried out as already described starting from 75 mg (0.15 mmol) of 4-[5-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl)-1,3,4-oxadiazol-2-yl]piperidine and 33 μl (0.23 mmol) of 4-bromobutyl acetate. The protecting group was cleaved off by means of a 1N NaOH solution in methanol. The product was purified by means of preparative HPLC. The product is in the form of the TFA salt.
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=3)=[C:9]([C:11]3[CH:16]=[CH:15][C:14]([CH2:17][N:18]4[CH2:23][CH2:22][CH:21]([C:24]5[N:28]=[C:27]([C:29]6[CH:34]=[CH:33][CH:32]=[CH:31][N:30]=6)[NH:26][N:25]=5)[CH2:20][CH2:19]4)=[CH:13][CH:12]=3)[N:10]=2)[N:7]=1.[O:41]([CH3:43])[Na]>CO>[CH3:43][O:41][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=3)=[C:9]([C:11]3[CH:16]=[CH:15][C:14]([CH2:17][N:18]4[CH2:23][CH2:22][CH:21]([C:24]5[N:28]=[C:27]([C:29]6[CH:34]=[CH:33][CH:32]=[CH:31][N:30]=6)[NH:26][N:25]=5)[CH2:20][CH2:19]4)=[CH:13][CH:12]=3)[N:10]=2)[N:7]=1
Reactant: CO[Na]
Reactant: Clc1ccc2nc(-c3ccc(CN4CCC(c5n[nH]c(-c6ccccn6)n5)CC4)cc3)c(-c3ccccc3)n2n1
Solvent: CO
Product: COc1ccc2nc(-c3ccc(CN4CCC(c5n[nH]c(-c6ccccn6)n5)CC4)cc3)c(-c3ccccc3)n2n1

Procedure:
To a suspension of example 31 (0.2 g, 0.366 mM) in 15 mL of methanol is added NaOCH3 (10 eq.) and the reaction mixture is refluxed for 6 h. The reaction mixture is concentrated and quenched with water. The resulting solid is filtered and dried to obtain the desired compound.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][C:3]=1[SH:10].[N+:11]([C:14]1[CH:22]=[CH:21][C:17]([C:18](Cl)=O)=[CH:16][CH:15]=1)([O-:13])=[O:12].C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[N+:11]([C:14]1[CH:22]=[CH:21][C:17]([C:18]2[S:10][C:3]3[CH:4]=[C:5]([O:8][CH3:9])[CH:6]=[CH:7][C:2]=3[N:1]=2)=[CH:16][CH:15]=1)([O-:13])=[O:12]
Reactant: O=C(Cl)c1ccc([N+](=O)[O-])cc1
Reactant: COc1ccc(N)c(S)c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: COc1ccc2nc(-c3ccc([N+](=O)[O-])cc3)sc2c1
Temperature: 25 °C
Yield: 75.9 %

Procedure:
A mixture of 2-amino-5-methoxybenzenethiol (5.0 g, 32.2 mmol) and 4-nitrobenzoyl chloride (6.0 g, 32.2 mmol) in toluene (250 ml) was heated under reflux with a catalytic amount of 4-toluenesulphonic acid in a Dean-Stark trap for 6 h. On cooling to room temperature the precipitate was collected by filtration, washed with toluene and recrystallised from AcOH to give the title compound (7.0 g, 76%) as a pale yellow solid.
Reaction SMILES: [CH3:1][C@H:2]1[CH2:6][CH2:5][CH2:4][N:3]1[CH:7]1[CH2:11][CH2:10][C@H:9]([C:12]2[CH:17]=[CH:16][C:15]([NH2:18])=[CH:14][CH:13]=2)[CH2:8]1.[F:19][C:20]([F:32])([F:31])[O:21][C:22]1[CH:30]=[CH:29][C:25]([C:26](Cl)=[O:27])=[CH:24][CH:23]=1>>[CH3:1][C@H:2]1[CH2:6][CH2:5][CH2:4][N:3]1[CH:7]1[CH2:11][CH2:10][C@H:9]([C:12]2[CH:17]=[CH:16][C:15]([NH:18][C:26](=[O:27])[C:25]3[CH:29]=[CH:30][C:22]([O:21][C:20]([F:19])([F:31])[F:32])=[CH:23][CH:24]=3)=[CH:14][CH:13]=2)[CH2:8]1
Reactant: O=C(Cl)c1ccc(OC(F)(F)F)cc1
Reactant: C[C@H]1CCCN1C1CC[C@H](c2ccc(N)cc2)C1
Product: C[C@H]1CCCN1C1CC[C@H](c2ccc(NC(=O)c3ccc(OC(F)(F)F)cc3)cc2)C1

Procedure:
The title compound was synthesized essentially in the same manner as Example 28 by employing 4-[(S)-3-((S)-2-methyl-pyrrolidin-1-yl)-cyclopentyl]-phenylamine (Intermediate 14) and 4-trifluoromethoxybenzoyl chloride.
Reaction SMILES: C([O:8][C:9]1[C:10]([CH3:30])=[C:11]([C:23](=[O:29])[CH:24](OCC)O)[CH:12]=[CH:13][C:14]=1[O:15]CC1C=CC=CC=1)C1C=CC=CC=1.[CH3:31][C:32]([NH2:44])([CH3:43])[CH2:33][C:34]1[C:39]([CH3:40])=[CH:38][C:37]([CH3:41])=[CH:36][C:35]=1[CH3:42].[BH4-].[Na+].C(OCC)(=O)C>C(O)C>[CH3:43][C:32]([NH:44][CH2:24][CH:23]([C:11]1[C:10]([CH3:30])=[C:9]([OH:8])[C:14]([OH:15])=[CH:13][CH:12]=1)[OH:29])([CH3:31])[CH2:33][C:34]1[C:39]([CH3:40])=[CH:38][C:37]([CH3:41])=[CH:36][C:35]=1[CH3:42]
Reactant: Cc1cc(C)c(CC(C)(C)N)c(C)c1
Reactant: CCOC(O)C(=O)c1ccc(OCc2ccccc2)c(OCc2ccccc2)c1C
Agent: [BH4-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CCO
Product: Cc1cc(C)c(CC(C)(C)NCC(O)c2ccc(O)c(O)c2C)c(C)c1
Temperature: 80 °C
Reaction time: 1 h

Procedure:
350 mg (0.86 mmol) of 1-(3,4-bis-benzyloxy-2-methylphenyl)-2-ethoxy-2-hydroxyethanone and 198 mg (1.03 mmol) of 1,1-dimethyl-2-(2,4,6-trimethylphenyl)ethylamine were dissolved in 3 mL of ethanol and heated to 80° C. for 30 minutes in the presence of some molecular sieve. After cooling to ambient temperature, 33 mg (0.86 mmol) sodium borohydride was added and the mixture was stirred for 1 hour. The reaction mixture was combined with ethyl acetate and washed with sodium hydrogen carbonate solution. Then the organic phase was freed from solvent and chromatographed. In order to cleave the benzyl protecting groups, the ethanolamine-thus-obtained (364 mg) was dissolved in methanol, combined with 150 mg of Pearlman's catalyst, and hydrogenated at ambient temperature and under normal pressure. The reaction mixture was filtered through CELITE® filter agent and evaporated down. Chromatographic purification of the residue with dichloromethane and methanol as eluent yielded the target compound as a beige solid. Yield: 179 mg (29%); mass spectrometry: [M+H]+=391.
Reaction SMILES: CN(C)C=[CH:4][C:5]1[CH:14]=[CH:13][C:8]([C:9]([O:11][CH3:12])=[O:10])=[CH:7][C:6]=1[N+:15]([O-:17])=[O:16].I([O-])(=O)(=O)=[O:20].[Na+]>O1CCCC1.O.O.C(Cl)Cl>[CH:4]([C:5]1[CH:14]=[CH:13][C:8]([C:9]([O:11][CH3:12])=[O:10])=[CH:7][C:6]=1[N+:15]([O-:17])=[O:16])=[O:20]
Reactant: COC(=O)c1ccc(C=CN(C)C)c([N+](=O)[O-])c1
Reactant: [O-][I+3]([O-])([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Solvent: C1CCOC1
Product: COC(=O)c1ccc(C=O)c([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
1.2 g (4.8 mmol) of methyl 4-(2-dimethylaminovinyl)-3-nitrobenzoate were dissolved in 120 mL of tetrahydrofuran/water (1:1) and after the addition of 3.0 g (14.3 mmol) of sodium metaperiodate the mixture was stirred for 20 hours at ambient temperature. The suspension was then diluted with water and methylene chloride and extracted with methylene chloride. The combined organic extracts were washed with sodium hydrogen carbonate solution, dried, and evaporated down. The residue was chromatographed on silica gel and eluted with ethyl acetate/cyclohexane (1:3). Yield: 0.6 g (63% of theory); Rf value: 0.63 (silica gel, ethyl acetate/cyclohexane=1:1).
Reaction SMILES: [NH2:1][C:2]1[C:3]2[C:4](=[N:12][N:13]([CH2:15][C:16]3[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=3)[CH:14]=2)[N:5]=[C:6]([Cl:11])[C:7]=1[C:8]([OH:10])=[O:9].[F:24][C:25]1[C:30](O)=[C:29]([F:32])[C:28]([F:33])=[C:27]([F:34])[C:26]=1[F:35].C1CCC(N=C=NC2CCCCC2)CC1>CN(C=O)C.CCOC(C)=O>[F:24][C:25]1[C:30]([O:9][C:8]([C:7]2[C:6]([Cl:11])=[N:5][C:4]3=[N:12][N:13]([CH2:15][C:16]4[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=4)[CH:14]=[C:3]3[C:2]=2[NH2:1])=[O:10])=[C:29]([F:32])[C:28]([F:33])=[C:27]([F:34])[C:26]=1[F:35]
Reactant: Oc1c(F)c(F)c(F)c(F)c1F
Reactant: COc1ccc(Cn2cc3c(N)c(C(=O)O)c(Cl)nc3n2)cc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COc1ccc(Cn2cc3c(N)c(C(=O)Oc4c(F)c(F)c(F)c(F)c4F)c(Cl)nc3n2)cc1
Yield: 89 %

Procedure:
To a cold (0° C.) solution of 4-amino-6-chloro-2-(4-methoxyphenyl)methyl-2H-pyrazolo[3,4-b]pyridine-5-carboxylic acid (952 mg, 2.86 mmol) and pentafluorophenol (830 mg) in DMF was added a solution of DCC (620 mg, 3 mmol) in EtOAc (9 mL). After work up the crude product was purified by flash column (silica gel, EtOAc/hexane, 1:1) to give the desired product (1.27 g) as a white solid. LC: 4.64 (Gradient 1), MH+: 499.
Reaction SMILES: [NH2:1][C:2]1[O:6][N:5]=[C:4]([CH3:7])[C:3]=1[Br:8].[H-].[Na+].[CH3:11][O:12][C:13]1[CH:32]=[CH:31][CH:30]=[CH:29][C:14]=1[CH2:15][C:16]1[S:20][C:19]2[CH:21]=[CH:22][CH:23]=[CH:24][C:18]=2[C:17]=1[S:25](Cl)(=[O:27])=[O:26]>C1COCC1>[Br:8][C:3]1[C:4]([CH3:7])=[N:5][O:6][C:2]=1[NH:1][S:25]([C:17]1[C:18]2[CH:24]=[CH:23][CH:22]=[CH:21][C:19]=2[S:20][C:16]=1[CH2:15][C:14]1[CH:29]=[CH:30][CH:31]=[CH:32][C:13]=1[O:12][CH3:11])(=[O:26])=[O:27]
Reactant: Cc1noc(N)c1Br
Reactant: COc1ccccc1Cc1sc2ccccc2c1S(=O)(=O)Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COc1ccccc1Cc1sc2ccccc2c1S(=O)(=O)Nc1onc(C)c1Br

Procedure:
N-(4-bromo-3-methyl-5-isoxazolyl)-2-(2-methoxybenzyl)benzo[b]thiophene-3-sulfonamide was prepared by the method of Example 41 with 5-amino-4-bromo-3-methylisoxazole (1.0 mmoles, 0.18 g), NaH (2.5 mmoles, 100 mg), 2-(2-methoxybenzyl)-benzo[b]thiophene-3-sulfonyl chloride (1.4 mmoles, 0.49 g) and THF (7ml). Flash chromatography (50% ethyl acetate/hexanes) followed by recrystallization from chloroform and hexanes provided 0.30 g (61%) of a brown solid, m.p. 80°-84° C.