Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].[CH3:3][C:4]1([CH3:20])[O:9][C:8]2[CH:10]=[CH:11][C:12]([C@H:14]3[O:18][C:17](=[O:19])[NH:16][CH2:15]3)=[CH:13][C:7]=2[CH2:6][O:5]1.[I:21][C:22]1[CH:23]=[C:24]([CH2:28][CH2:29][CH2:30][CH2:31][O:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38]Br)[CH:25]=[CH:26][CH:27]=1.[Cl-].[NH4+]>CN(C=O)C>[CH3:3][C:4]1([CH3:20])[O:9][C:8]2[CH:10]=[CH:11][C:12]([C@H:14]3[O:18][C:17](=[O:19])[N:16]([CH2:38][CH2:37][CH2:36][CH2:35][CH2:34][CH2:33][O:32][CH2:31][CH2:30][CH2:29][CH2:28][C:24]4[CH:25]=[CH:26][CH:27]=[C:22]([I:21])[CH:23]=4)[CH2:15]3)=[CH:13][C:7]=2[CH2:6][O:5]1
Reactant: CC1(C)OCc2cc([C@@H]3CNC(=O)O3)ccc2O1
Reactant: BrCCCCCCOCCCCc1cccc(I)c1
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: CN(C)C=O
Product: CC1(C)OCc2cc([C@@H]3CN(CCCCCCOCCCCc4cccc(I)c4)C(=O)O3)ccc2O1
Temperature: 50 °C
Reaction time: 0.25 h
Yield: 73.5 %

Procedure:
Sodium hydride (60% dispersion in oil 1.26 g) was added to a stirred, cooled (ice-bath) solution of (5R)-5-(2,2-dimethyl-4H-1,3-benzodioxin-6-yl)-2-oxazolidinone (5.47 g) in dry DMF (50 ml) under nitrogen and the mixture was stirred for 15 min at 50° C. A solution of 6-bromohexyl 4-(3-iodophenyl)butyl ether (10.7 g) in DMF (30 ml) was then added dropwise over 10 min. The mixture was stirred for 2 h at ambient temperature, then poured into aqueous solution of ammonium chloride and extracted into ethyl acetate. The combined extracts were washed with water, dried (Na2SO4) and evaporated. The residue was purified on biotage (90 g cartridge) eluting with ether-hexane (3:2) to give the title compound (9.8 g). LCMS RT=4.20 min.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([O:22][CH2:23][C:24]([CH3:26])=[CH2:25])=[C:6]([CH:21]=1)[CH2:7][N:8]([C:11]1[N:16]=[N:15][C:14]([C:17]([NH:19][NH2:20])=[O:18])=[CH:13][CH:12]=1)[CH2:9][CH3:10].C(N(CC)CC)C.[C:34](Cl)(Cl)=[S:35]>C1COCC1>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([O:22][CH2:23][C:24]([CH3:26])=[CH2:25])=[C:6]([CH:21]=1)[CH2:7][N:8]([C:11]1[N:16]=[N:15][C:14]([C:17]2[O:18][C:34](=[S:35])[NH:20][N:19]=2)=[CH:13][CH:12]=1)[CH2:9][CH3:10]
Reactant: C=C(C)COc1ccc(Br)cc1CN(CC)c1ccc(C(=O)NN)nn1
Reactant: S=C(Cl)Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: C=C(C)COc1ccc(Br)cc1CN(CC)c1ccc(-c2n[nH]c(=S)o2)nn1
Temperature: 25 °C
Reaction time: 3 h
Yield: 206.6 %

Procedure:
6-[N-(5-Bromo-2-(2-methylprop-2-en-1-yloxy)benzyl)-N-ethylamino]pyridazine-3-carbohydrazide (reference example 26) (750 mg, 1.78 mmol) was dissolved in THF (25 ml) and triethylamine (0.57 ml, 3.91 mmol) added followed by thiophosgene (0.1 ml, 1.96 mmol). The solution was stirred at ambient temperature under argon for 3 hours, then the THF removed in vacuo, water (75 ml) added, and then acetic acid was added dropwise till the mixture was at pH 5. The mixture was extracted with ethyl acetate(3×200 ml) and the combined organic phases washed with water and saturated brine (100 ml of each), dried (MgSO4) and concentrated in vacuo to give the title compound as a gum (1.7 g) which was purified by MPLC (98:2 dichloromethane:methanol), to give a solid foam (230 mg 28%).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[C:9]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:10].C(Cl)(Cl)Cl.C(N(CC)CC)C.CN(C=O)C.C[CH2:34][O:35][C:36](C)=[O:37]>CO>[C:9]([C:3]1[CH:4]=[C:5]([F:8])[CH:6]=[CH:7][C:2]=1[C:36]([O:35][CH3:34])=[O:37])(=[O:10])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: O=C(c1ccccc1)c1cc(F)ccc1Br
Reactant: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: CO
Product: COC(=O)c1ccc(F)cc1C(=O)c1ccccc1

Procedure:
A mixture of the product of example 35B (0.516 g, 1.85 mmol), PdCl2dppf.CHCl3 (75 mg, 0.091 mmol), and triethylamine (0.39 mL, 2.8 mmol) was stirred in 1:1 DMF:MeOH (6 mL, pre-saturated with CO) under CO (1 atm) at 80° C. for 4 hours, diluted with EtOAc, washed with water and brine, dried (Na2SO4), and filtered. The residue was chromatographed on SiO2 (3-12% Et2O/hexanes) to give 112.0 mg of the title compound as a clear gum. 1H NMR (300 MHz, DMSO) δ 8.09 (dd, 1H), 7.62-7.69 (m, 3H), 7.49-7.57 (m, 3H), 7.45 (dd, 1H), 3.57 (s, 3H).
Reaction SMILES: [CH3:1][C:2]1[CH:9]=[C:8]([N+:10]([O-:12])=[O:11])[CH:7]=[CH:6][C:3]=1[C:4]#[N:5].[Br:13]N1C(=O)CCC1=O.N(C(C)(C)C#N)=NC(C)(C)C#N>C(Cl)(Cl)(Cl)Cl>[Br:13][CH2:1][C:2]1[CH:9]=[C:8]([N+:10]([O-:12])=[O:11])[CH:7]=[CH:6][C:3]=1[C:4]#[N:5]
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1cc([N+](=O)[O-])ccc1C#N
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Product: N#Cc1ccc([N+](=O)[O-])cc1CBr

Procedure:
A degassed solution of 2-methyl-4-nitrobenzonitrile (10 g, 61.7 mmol), N-bromosuccinimide (13.2 g (74.17 mmol, 1.2 eq.) and azobisisobutyronitrile (AlBN) (2.0 g, 12.18 mmol, 0.2 eq) in 300 ml CCl4 was heated at reflux for 3 days. After solvent was evaporated the residue was taken in ethyl acetate and washed 2× with aq. NaHCO3, aq. Na2S2O3, brine, dried over MgSO4, filtered, concentrated and purified chromatography using 15% ethyl acetate in hexane to provide 11.7 g of 2-bromomethyl-4-nitrobenzonitrile.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][C:3]=1[O:10][CH3:11].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O[C@H:32]1[CH2:36][CH2:35][N:34](C(OC(C)(C)C)=O)[CH2:33]1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>O1CCCC1>[CH3:11][O:10][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][C:2]=1[O:1][C@@H:32]1[CH2:36][CH2:35][NH:34][CH2:33]1)[C:6]#[N:7]
Reactant: COc1cc(C#N)ccc1O
Reactant: CC(C)(C)OC(=O)N1CC[C@H](O)C1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COc1cc(C#N)ccc1O[C@@H]1CCNC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 67 %

Procedure:
4-Hydroxy-3-methoxybenzonitrile (12 g, 80.2 mmol) and triphenylphosphine (21 g, 80.2 mmol) were added portionwise to an ice-cold solution of tert-butyl (3S)-3-hydroxypyrrolidine-1-carboxylate (15 g, 80.2 mmol) in tetrahydrofuran (225 mL). A solution of diisopropyl azodicarboxylate (16.2 g, 80.2 mmol) in tetrahydrofuran (100 mL) was then added dropwise and the mixture was stirred at room temperature for 18 hours. The reaction mixture was then concentrated in vacuo and the residue was treated with hydrochloric acid (4M in dioxane, 250 mL). The mixture was concentrated in vacuo and the residue was partitioned between ethyl acetate and water. The organic layer was separated and washed with water (100 mL), and the combined aqueous solution was washed with ethyl acetate (2×150 mL), basified to pH10 with solid potassium carbonate and extracted with ethyl acetate (2×250 mL). The combined organic solution was washed with brine (100 mL), dried over magnesium sulfate and concentrated in vacuo to afford the title compound as a cream solid in 67% yield, 11.8 g. LRMS ESI m/z 219 [M+H]+
Reaction SMILES: Cl.[OH:2][N:3]1[C:7]2[CH:8]=[CH:9][C:10]([C:12]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)=[O:13])=[CH:11][C:6]=2[N:5]=[C:4]1[CH3:20].[Na].[CH3:22]O>>[CH3:22][O:2][N:3]1[C:7]2[CH:8]=[CH:9][C:10]([C:12]([C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=3)=[O:13])=[CH:11][C:6]=2[N:5]=[C:4]1[CH3:20]
Reactant: CO
Reactant: Cc1nc2cc(C(=O)c3ccccc3)ccc2n1O
Agent: Cl
Agent: [Na]
Product: COn1c(C)nc2cc(C(=O)c3ccccc3)ccc21
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 60 %

Procedure:
(a-3) 11.55 Parts of (1-hydroxy-2-methyl-1H-benzimidazol-5-yl) phenyl methanone monohydrochloride were added to a stirred solution of 1.84 parts of sodium in 80 parts of methanol. After stirring for 15 minutes at room temperature, the solvent was evaporated and the residue was taken up in methylbenzene. After evaporation, the residue was dissolved in 54 parts of N,N-dimethylformamide and 6.24 parts of iodomethane were added. The reaction mixture was stirred for 2 hours at room temperature. The N,N-dimethylformamide layer was evaporated in vacuo. The residue was taken up in water and the product was extracted with methylbenzene. The extract was dried, filtered and evaporated. The residue was washed with 2,2'-oxybispropane, yielding 6.4 parts (60.0%) of (1-methoxy-2-methyl-1H-benzimidazol-5-yl) phenylmethanone; mp. 67.7° C. (int. 50).
Reaction SMILES: Cl.[N:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]([CH2:32][CH2:33][C:34]([O:36][CH2:37][CH3:38])=[O:35])[C:9]([C:11]1[CH:31]=[CH:30][C:14]2[N:15]([CH3:29])[C:16]([CH2:18][CH2:19][C:20]3[CH:25]=[CH:24][C:23]([C:26](=[NH:28])[NH2:27])=[CH:22][CH:21]=3)=[N:17][C:13]=2[CH:12]=1)=[O:10].[C:39](Cl)(=[O:46])[C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1>ClCCl.CO>[N:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]([CH2:32][CH2:33][C:34]([O:36][CH2:37][CH3:38])=[O:35])[C:9]([C:11]1[CH:31]=[CH:30][C:14]2[N:15]([CH3:29])[C:16]([CH2:18][CH2:19][C:20]3[CH:25]=[CH:24][C:23]([C:26](=[NH:27])[NH:28][C:39](=[O:46])[C:40]4[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=4)=[CH:22][CH:21]=3)=[N:17][C:13]=2[CH:12]=1)=[O:10]
Reactant: O=C(Cl)c1ccccc1
Reactant: CCOC(=O)CCN(C(=O)c1ccc2c(c1)nc(CCc1ccc(C(=N)N)cc1)n2C)c1ccccn1
Agent: Cl
Solvent: ClCCl
Solvent: CO
Product: CCOC(=O)CCN(C(=O)c1ccc2c(c1)nc(CCc1ccc(C(=N)NC(=O)c3ccccc3)cc1)n2C)c1ccccn1
Yield: 79 %

Procedure:
Prepared analogously to Example 90 from 1-methyl-2-[2-(4-amidinophenyl)ethyl]benzimidazol-5-yl-carboxylic acid-N-(2-pyridyl)-N-(2-ethoxycarbonylethyl)amide hydrochloride and benzoyl chloride. Yield: 79% of theory, C35H34N6O4 (602.7); Rf value: 0.52 (silica gel; dichloromethane/methanol=9:1); EKA mass spectrum: (M+H)+=603; (M+Na)+=625.
Reaction SMILES: [CH2:1]([O:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][Br:12])[C:2]#[CH:3].Br[C:14]1[CH:15]=[C:16]([S:20]([NH2:23])(=[O:22])=[O:21])[CH:17]=[CH:18][CH:19]=1.CCN(CC)CC>C1COCC1.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Br:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][O:4][CH2:1][C:2]#[C:3][C:14]1[CH:15]=[C:16]([S:20]([NH2:23])(=[O:22])=[O:21])[CH:17]=[CH:18][CH:19]=1
Reactant: C#CCOCCCCCCCBr
Reactant: NS(=O)(=O)c1cccc(Br)c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: NS(=O)(=O)c1cccc(C#CCOCCCCCCCBr)c1
Yield: 46.1 %

Procedure:
7-Bromoheptyl prop-2-ynyl ether (55.1 g) in THF (250 ml) was added dropwise over ca 8 h to a stirred mixture of 3-bromobenzenesulfonamide (43.5 g), PdCl2(PPh3)2 (6.48 g), PPh3 (1.45 g), CuI (1.4 g) and Et3N (52 ml) in THF (250 ml) at 55±5° C. under nitrogen then the mixture heated for a further ca 15 hrs. The reaction was cooled, filtered through Celite and the solids washed with THF. The solution was concentrated and the product purified by chromatography on flash silica gel (600 g) eluting with petroleum ether:ethyl acetate (ratios ranging successively from 19:1 to 7:3) to give the title compound (33 g)—LC RT=5.85 min.
Reaction SMILES: [F:1][C:2]([F:35])([F:34])[C@@:3]([C:6]1[CH:11]=[CH:10][C:9]([N:12]2[CH2:17][CH2:16][N:15]([S:18]([C:21]3[S:22][CH:23]=[CH:24][CH:25]=3)(=[O:20])=[O:19])[CH2:14][C@@H:13]2[CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=2[F:33])=[CH:8][CH:7]=1)([OH:5])[CH3:4].FC(F)(F)[C@](C1C=CC(N2CCN(S(C3SC=CC=3)(=O)=O)C[C@H]2CC2C=CC=CC=2F)=CC=1)(O)C.FC(F)(F)[C@](C1C=CC(N2CCN(S(C3SC=CC=3)(=O)=O)C[C@@H]2CC2C=CC=CC=2F)=CC=1)(O)C.C1N=C(N)C2N=CN([C@@H]3O[C@H](COP(OP(OC[C@H]4O[C@@H](N5C=C(C(N)=O)CC=C5)[C@H](O)[C@@H]4O)(O)=O)(O)=O)[C@@H](O)[C@H]3OP(O)(O)=O)C=2N=1>>[F:35][C:2]([F:1])([F:34])[C@@:3]([C:6]1[CH:11]=[CH:10][C:9]([N:12]2[CH2:17][CH2:16][N:15]([S:18]([C:21]3[S:22][CH:23]=[CH:24][CH:25]=3)(=[O:20])=[O:19])[CH2:14][C@H:13]2[CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=2[F:33])=[CH:8][CH:7]=1)([OH:5])[CH3:4]
Reactant: C[C@@](O)(c1ccc(N2CCN(S(=O)(=O)c3cccs3)C[C@@H]2Cc2ccccc2F)cc1)C(F)(F)F
Agent: C[C@](O)(c1ccc(N2CCN(S(=O)(=O)c3cccs3)C[C@@H]2Cc2ccccc2F)cc1)C(F)(F)F
Agent: C[C@](O)(c1ccc(N2CCN(S(=O)(=O)c3cccs3)C[C@H]2Cc2ccccc2F)cc1)C(F)(F)F
Agent: NC(=O)C1=CN([C@@H]2O[C@H](COP(=O)(O)OP(=O)(O)OC[C@H]3O[C@@H](n4cnc5c(N)ncnc54)[C@H](OP(=O)(O)O)[C@@H]3O)[C@@H](O)[C@H]2O)C=CC1
Product: C[C@@](O)(c1ccc(N2CCN(S(=O)(=O)c3cccs3)C[C@H]2Cc2ccccc2F)cc1)C(F)(F)F

Procedure:
(2R)-1,1,1-trifluoro-2-(4-((2S)-2-(2-fluorobenzyl)-4-(2-thiophenylsulfonyl)-1-piperazinyl)phenyl)-2-propanol; (2S)-1,1,1-trifluoro-2-(4-((2R)-2-(2-fluorobenzyl)-4-(2-thiophenylsulfonyl)-1-piperazinyl)phenyl)-2-propanol; (2S)-1,1,1-trifluoro-2-(4-((2S)-2-(2-fluorobenzyl)-4-(2-thiophenylsulfonyl)-1-piperazinyl)phenyl)-2-propanol. 1H NMR (400 MHz, CD3OD) δ 7.86 (d, J=4.9 Hz, 1H), 7.64-7.54 (m, 1H), 7.45 (d, J=8.8 Hz, 2H), 7.32 (t, J=7.6 Hz, 1H), 7.26-7.16 (m, 2H), 7.14-6.93 (m, 4H), 4.29-4.18 (m, 1H), 3.87-3.76 (m, 1H), 3.61-3.48 (m, 2H), 3.41 (dt, J=3.5, 12.0 Hz, 1H), 3.13-3.01 (m, 1H), 2.85 (dd, J=3.8, 13.2 Hz, 1H), 2.62-2.49 (m, 2H), 1.69 (s, 3H). m/z (ESI, +ve ion) 529.0 (M+H)+. GK-GKRP EC50 (NADPH-coupled)=0.515 μM; GK-GKRP EC50 (LC MS/MS)=0.850 μM.
Reaction SMILES: [Cl:1][CH2:2][C@@H:3]([OH:12])[C@@H:4]([OH:11])[C@@H:5]([OH:10])[C@@H:6]([OH:9])[CH:7]=[O:8]>CO>[Cl:1][CH2:2][C@@H:3]([OH:12])[C@@H:4]([OH:11])[C@@H:5]([OH:10])[C@@H:6]([OH:9])[CH2:7][OH:8]
Reactant: O=C[C@H](O)[C@H](O)[C@H](O)[C@H](O)CCl
Solvent: CO
Product: OC[C@H](O)[C@H](O)[C@H](O)[C@H](O)CCl

Procedure:
6-Chloro-6-deoxy-D-allose was reduced by the method described in Example 1 to give 6-chloro-6-deoxy-D-allitol as a colourless syrup, [α]D20 +5.3° (c=1.0, methanol); Rf 0.72 (t.l.c. silica gel; n-butanol:ethanol:water, 5:3:2).
Reaction SMILES: [CH3:1][N:2]([CH3:24])[S:3]([N:6]1[C:10]2[CH:11]=[C:12]([C:15](=[O:22])[C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[CH:13]=[CH:14][C:9]=2[N:8]=[C:7]1[NH2:23])(=[O:5])=[O:4].[CH:25]([Mg]Cl)([CH3:27])[CH3:26]>O1CCCC1>[CH3:1][N:2]([CH3:24])[S:3]([N:6]1[C:10]2[CH:11]=[C:12]([C:15]([CH:25]([CH3:27])[CH3:26])([OH:22])[C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[CH:13]=[CH:14][C:9]=2[N:8]=[C:7]1[NH2:23])(=[O:4])=[O:5]
Reactant: CC(C)[Mg]Cl
Reactant: CN(C)S(=O)(=O)n1c(N)nc2ccc(C(=O)c3ccccc3)cc21
Solvent: C1CCOC1
Product: CC(C)C(O)(c1ccccc1)c1ccc2nc(N)n(S(=O)(=O)N(C)C)c2c1
Yield: 65 %

Procedure:
When the procedure of Example 71 was repeated using 4.1 g. (12 mmole) of 1-dimethylaminosulfonyl-2-amino-6-benzoylbenzimidazole in 180 ml. of tetrahydrofuran, 100 ml. tetrahydrofuran, and 28.6 ml. (60 mmole) of isopropyl magnesium chloride in 100 ml. of tetrahydrofuran, there was obtained 1-dimethylaminosulfonyl-2-amino-6-(α-isopropyl-α-hydroxybenzyl)benzimidazole, yield 65%.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C:16]2[C:11](=[CH:12][C:13]([C:17]3[CH:18]=[N:19][CH:20]=[C:21]([O:23][CH:24]([C:34](C)(C)[O:35][SiH2]C(C)(C)C)[CH2:25][NH:26][C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH:22]=3)=[CH:14][CH:15]=2)[C:10]([CH3:43])=[N:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CCCC[N+](CCCC)(CCCC)CCCC.[F-]>C1COCC1>[C:1]([O:5][C:6]([N:8]1[C:16]2[C:11](=[CH:12][C:13]([C:17]3[CH:18]=[N:19][CH:20]=[C:21]([O:23][CH:24]([CH2:34][OH:35])[CH2:25][NH:26][C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH:22]=3)=[CH:14][CH:15]=2)[C:10]([CH3:43])=[N:9]1)=[O:7])([CH3:2])([CH3:4])[CH3:3]
Reactant: Cc1nn(C(=O)OC(C)(C)C)c2ccc(-c3cncc(OC(CNC(=O)OC(C)(C)C)C(C)(C)O[SiH2]C(C)(C)C)c3)cc12
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: Cc1nn(C(=O)OC(C)(C)C)c2ccc(-c3cncc(OC(CO)CNC(=O)OC(C)(C)C)c3)cc12
Temperature: 25 °C
Reaction time: 1 h
Yield: 89.9 %

Procedure:
To a solution of Example 393C (1.122 g, 1.83 mmol) in THF (20 mL) was added TBAF (1.92 mL) at rt. The solution was stirred at rt for 1 h and was concentrated. The residual oil was separated by flash chromatography (0-15% CH3OH in 2:1 EtOAc/hexane) to give the title compound (0.82 g, 90%). MS (DCI) m/z 499 (M+1)+.
Reaction SMILES: C1(C2C=CC=CC=2)C=CC=CC=1C([N:9]1[CH2:15][CH:14]2[CH:11]([CH2:12][NH:13]2)[CH2:10]1)=O.[CH3:22][C:23]1[CH:24]=[CH:25][C:26]([N:32]2[N:36]=[CH:35][CH:34]=[N:33]2)=[C:27]([CH:31]=1)[C:28]([OH:30])=O.C1(C2C=CC=CC=2)C(C(O)=O)=CC=CC=1>>[CH:11]12[CH2:12][NH:13][CH:14]1[CH2:15][N:9]([C:28]([C:27]1[CH:31]=[C:23]([CH3:22])[CH:24]=[CH:25][C:26]=1[N:32]1[N:36]=[CH:35][CH:34]=[N:33]1)=[O:30])[CH2:10]2
Reactant: Cc1ccc(-n2nccn2)c(C(=O)O)c1
Reactant: O=C(c1ccccc1-c1ccccc1)N1CC2CNC2C1
Agent: O=C(O)c1ccccc1-c1ccccc1
Product: Cc1ccc(-n2nccn2)c(C(=O)N2CC3CNC3C2)c1

Procedure:
The title compound was prepared in a manner analogous to Intermediate 19, substituting 5-methyl-2-[1,2,3]triazol-2-yl-benzoic acid (Intermediate 59) for biphenyl-2-carboxylic acid. MS (ESI) mass calcd. for C15H17N5O, 283.33; m/z found, 284.2 [M+H]+.
Reaction SMILES: [OH:1][C:2]1[C:3]([O:30][CH3:31])=[CH:4][C:5]2[O:10][C:9](=[O:11])[C:8]([CH2:12][CH2:13][N:14]3[CH2:19][CH2:18][N:17]([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=4[O:26][CH3:27])[CH2:16][CH2:15]3)=[C:7]([CH3:28])[C:6]=2[CH:29]=1.[OH-].[Na+].[CH2:34]([S:36](O)(=[O:38])=[O:37])[CH3:35]>O.C(O)C.C(Cl)(Cl)Cl>[CH2:34]([S:36]([O:1][C:2]1[C:3]([O:30][CH3:31])=[CH:4][C:5]2[O:10][C:9](=[O:11])[C:8]([CH2:12][CH2:13][N:14]3[CH2:19][CH2:18][N:17]([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=4[O:26][CH3:27])[CH2:16][CH2:15]3)=[C:7]([CH3:28])[C:6]=2[CH:29]=1)(=[O:38])=[O:37])[CH3:35]
Reactant: CCS(=O)(=O)O
Reactant: COc1cc2oc(=O)c(CCN3CCN(c4ccccc4OC)CC3)c(C)c2cc1O
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: ClC(Cl)Cl
Solvent: O
Product: CCS(=O)(=O)Oc1cc2c(C)c(CCN3CCN(c4ccccc4OC)CC3)c(=O)oc2cc1OC
Temperature: 25 °C
Reaction time: 60 h
Yield: 59 %

Procedure:
Alternative process: 1.3 g (3.1 mmol) of 6-hydroxy-7-methoxy-3-{2-[4-(2-methoxyphenyl)-1-piperazinyl]ethyl}-4-methyl-2H-1-benzopyran-2-one (Example 2), two equivalents of sodium hydroxide and 2.5 equivalents of ethanesulphonic acid are dissolved in water/ethanol and stirred for 60 hours at room temperature. The reaction product is taken up in chloroform, washed with dilute sodium hydroxide and with water, dried over sodium sulphate, and the solvent is removed under reduced pressure. 0.94 g (59%) of pale yellow crystals with a melting point of 148°-150° C. (from ethanol/TBME) are obtained by column chromatography over silica gel (solvent: acetone/petroleum ether 1/1).
Reaction SMILES: [C:1]1([C:7]2[CH2:8][CH2:9][N:10]([CH2:13][CH2:14][CH2:15]CSC3C=CN=CC=3)[CH2:11][CH:12]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl.Cl.[N:26]1[CH:31]=[CH:30][C:29]([S:32]CCCCN2CC=C(C3SC=CC=3)CC2)=[CH:28][CH:27]=1>>[C:1]1([C:7]2[CH2:8][CH2:9][N:10]([CH2:13][CH2:14][CH2:15][S:32][C:29]3[CH:30]=[CH:31][N:26]=[CH:27][CH:28]=3)[CH2:11][CH:12]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: C1=C(c2cccs2)CCN(CCCCSc2ccncc2)C1
Reactant: C1=C(c2ccccc2)CCN(CCCCSc2ccncc2)C1
Agent: Cl
Product: C1=C(c2ccccc2)CCN(CCCSc2ccncc2)C1

Procedure:
1,2,3,6-Tetrahydro-4-phenyl-1-[4-(4-pyridinyl-thio)butyl]pyridine and 1,2,3,6 tetrahydro-1-[4-(4-pyridinylthio)butyl]-4-(2 thienyl)pyridine, dihydrochloride; or a pharmaceutically acceptable acid addition salt thereof.
Reaction SMILES: [C:1]([CH:11]([CH:27]1[NH:32][CH2:31][CH2:30][NH:29][CH2:28]1)[N:12]([NH:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[CH3:26])[C:13]([CH:15]1[CH2:18][CH2:17][CH2:16]1)=[O:14])(OCC1C=CC=CC=1)=O.C(Br)[CH2:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1.C([O-])([O-])=O.[K+].[K+]>CO.CC#N.[Pd]>[CH2:1]([CH:11]([CH:27]1[NH:32][CH2:31][CH2:30][NH:29][CH2:28]1)[N:12]([NH:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[CH3:26])[C:13]([CH:15]1[CH2:18][CH2:17][CH2:16]1)=[O:14])[CH2:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1
Reactant: BrCCc1ccccc1
Reactant: Cc1ccccc1NN(C(=O)C1CCC1)C(C(=O)OCc1ccccc1)C1CNCCN1
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: CC#N
Product: Cc1ccccc1NN(C(=O)C1CCC1)C(CCc1ccccc1)C1CNCCN1
Reaction time: 12 h
Yield: 41.5 %

Procedure:
A solution of 213 (0.302 mmol, 127 mg) in CH3OH (1 mL) at 25° C. was treated with 30% Pd-C (25 mg) and then placed under a hydrogen atmosphere. The reaction mixture stirred for 12 h and then was filtered through a pad of celite. The solvents were removed in vacuo and the resulting oil was then treated with phenethyl bromide (1.5 equiv, 0.453 mmol, 62 μL) and K2CO3 (2.0 equiv, 0.604 mmol, 83 mg) in CH3CN (1.0 mL). The reaction mixture stirred for 12 h at 65° C. The reaction mixture was then purified directly by chromatography (PTLC, SiO2, 20 cm×20 cm, 1 mm, EtOAc-10% CH3OH) which provided 214 (51 mg, 118 mg theoretical, 43%) as colorless oil: Rf 0.45 (SiO2, EtOAc-10% CH3OH); LRMS m/z 390 (M+, C26H34N2O, requires 390).
Reaction SMILES: [CH2:1]([O:3][C:4]([CH2:6][CH2:7][N:8]1[CH2:17][CH2:16][C:15]2[C:10](=[CH:11][C:12]([N+:18]([O-:20])=[O:19])=[CH:13][CH:14]=2)[CH2:9]1)=[O:5])[CH3:2].[OH-].[Na+].[CH2:23](O)C>>[CH:1]([O:3][C:4]([CH2:6][CH2:7][N:8]1[CH2:17][CH2:16][C:15]2[C:10](=[CH:11][C:12]([N+:18]([O-:20])=[O:19])=[CH:13][CH:14]=2)[CH2:9]1)=[O:5])([CH3:23])[CH3:2]
Reactant: CCOC(=O)CCN1CCc2ccc([N+](=O)[O-])cc2C1
Reactant: CCO
Agent: [Na+]
Agent: [OH-]
Product: CC(C)OC(=O)CCN1CCc2ccc([N+](=O)[O-])cc2C1
Temperature: 25 °C
Reaction time: 14 h
Yield: 74 %

Procedure:
To the solution (60 ml) in ethanol of 2.04 g of 2-(2-(ethoxycarbonyl)ethyl)-7-nitro-1,2,3,4-tetrahydroisoquinoline obtained in Example 2 was added 3.75 ml of 2N aqueous solution of sodium hydroxide, and the solution was stirred at room temperature for 14 hours. The solution was concentrated under reduced pressure, and to the residue were added 300 ml of isopropylalcohol and 0.60 ml of sulfuric acid. The solution was heated under reflux for 20 hours, and concentrated under reduced pressure. After adding saturated aqueous solution of sodium bicarbonate to the residue, the solution was extracted with ethyl acetate, washed with water, dried with anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to obtain 1.58 g of 2-(2-(isopropyloxycarbonyl)ethyl)-7-nitro-1,2,3,4-tetrahydroisoquinoline (yield: 74%).
Reaction SMILES: [Br:1][C:2]1[C:7]([CH:8]=[O:9])=[C:6]([OH:10])[C:5]([O:11]C)=[CH:4][CH:3]=1.B(Br)(Br)Br>C(Cl)Cl>[Br:1][C:2]1[C:7]([CH:8]=[O:9])=[C:6]([OH:10])[C:5]([OH:11])=[CH:4][CH:3]=1
Reactant: COc1ccc(Br)c(C=O)c1O
Agent: BrB(Br)Br
Solvent: ClCCl
Product: O=Cc1c(Br)ccc(O)c1O
Temperature: 0 °C
Reaction time: 1 h
Yield: 97 %

Procedure:
6-Bromo-2-hydroxy-3-methoxybenzaldehyde (2.00 g, 8.65 mmol) was dissolved in methylene chloride (10 mL) and cooled to 0° C. Boron tribromide (17.0 mL of a 1.0 M solution, 17.00 mmol) was added by syringe and the solution was stirred at 0° C. for 1 h before allowing the reaction to warm up to ambient temperature and stir for 15 h at which time TLC analysis indicated the reaction complete. The reaction mixture was poured onto ice and extracted with ethyl acetate. The organic layers were dried with magnesium sulfate and concentrated by rotary evaporation to afford 1.82 g of 6-bromo-2,3-dihydroxybenzaldehyde (8.39 mmol, 97% yield) as a yellow solid.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[C:6]3[N:15]([CH:16]4[CH2:20][CH2:19][CH2:18][CH2:17]4)[N:14]=[CH:13][C:7]=3[C:8](=[O:12])[NH:9][C:10]=2[CH:11]=1.C1(P(C2C=CC=CC=2)CCCP(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(N(CC)CC)C.[C]=O.[C:59]([O:62][CH2:63]C)(=[O:61])C>CS(C)=O.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.O.CO>[CH:16]1([N:15]2[C:6]3[C:5]4[CH:4]=[CH:3][C:2]([C:59]([O:62][CH3:63])=[O:61])=[CH:11][C:10]=4[NH:9][C:8](=[O:12])[C:7]=3[CH:13]=[N:14]2)[CH2:20][CH2:19][CH2:18][CH2:17]1
Reactant: CCOC(C)=O
Reactant: O=c1[nH]c2cc(Br)ccc2c2c1cnn2C1CCCC1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: [C]=O
Solvent: CCN(CC)CC
Solvent: O
Solvent: CO
Product: COC(=O)c1ccc2c(c1)[nH]c(=O)c1cnn(C3CCCC3)c12
Temperature: 70 °C
Reaction time: 7 h

Procedure:
To a solution of 735 mg of 7-bromo-1-cyclopentyl-1,5-dihydro-4H-pyrazolo[4,3-c]quinolin-4-one in 6 mL of dimethylsulfoxide were sequentially added 49 mg of palladium acetate, 91 mg of 1,3-bis(diphenylphosphino)propane, 0.62 mL of triethylamine, and 3 mL of methanol, and the atmosphere in the reaction container was replaced with carbon monoxide. The mixture was stirred at 70° C. for 7 hours, cooled to room temperature, and then poured into a mixture of water and ethyl acetate. The aqueous layer was separated, the organic layer was washed with diluted hydrochloric acid and saturated brine, and then dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (chloroform/methanol) to obtain 551 mg of methyl 1-cyclopentyl-4-oxo-4,5-dihydro-1H-pyrazolo[4,3-c]quinoline-7-carboxylate.