Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1](=[C:8]1[C:16]2[C:11](=[N:12][CH:13]=[C:14]([C:17]3[CH:22]=[C:21]([O:23][CH3:24])[C:20]([O:25][CH3:26])=[C:19]([O:27][CH3:28])[CH:18]=3)[CH:15]=2)[NH:10][C:9]1=[O:29])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1COCC1.O.[BH4-].[Na+]>CO>[CH2:1]([CH:8]1[C:16]2[C:11](=[N:12][CH:13]=[C:14]([C:17]3[CH:18]=[C:19]([O:27][CH3:28])[C:20]([O:25][CH3:26])=[C:21]([O:23][CH3:24])[CH:22]=3)[CH:15]=2)[NH:10][C:9]1=[O:29])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COc1cc(-c2cnc3c(c2)C(=Cc2ccccc2)C(=O)N3)cc(OC)c1OC
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: COc1cc(-c2cnc3c(c2)C(Cc2ccccc2)C(=O)N3)cc(OC)c1OC
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 12.6 %

Procedure:
To a solution of 3-benzylidene-5-(3,4,5-trimethoxy-phenyl)-1,3-dihydro-pyrrolo[2,3-b]pyridin-2-one (41 mg, 0.106 mmol) in a mixture of MeOH (2 ml), THF (1 ml) and water (0.3 ml) was added sodium borohydride (40 mg, 1.06 mmol). The reaction was stirred at room temperature for 10 min after which it was quenched by the addition of 1 N HCl and partitioned between water and DCM. The residue was purified by preparatory HPLC to yield the title compound (5.2 mg, 13%).
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[C:7]3[O:13][CH2:12][CH2:11][O:10][C:8]3=[CH:9][C:4]=2[N:3]=[C:2]1[SH:14].[OH-].[Na+].Cl.Cl[CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=1>O>[N:21]1[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=1[CH2:19][S:14][C:2]1[NH:3][C:4]2[CH:9]=[C:8]3[O:10][CH2:11][CH2:12][O:13][C:7]3=[CH:6][C:5]=2[N:1]=1
Reactant: ClCc1ccccn1
Reactant: Sc1nc2cc3c(cc2[nH]1)OCCO3
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: c1ccc(CSc2nc3cc4c(cc3[nH]2)OCCO4)nc1
Reaction time: 0.5 h
Yield: 52.9 %

Procedure:
To 4.6 g of 6,7-dihydro-1H-p-dioxino(2,3-f)benzimidazole-2-thiol, suspended in 50 ml of alcohol, were added dropwise while stirring 1.8 g of sodium hydroxide in 25 ml of water and, after 30 minutes, there were added 3.7 g of 2-chloromethyl-pyridine hydrochloride. The mixture was left to boil at reflux overnight, it was then evaporated, and the residue was taken up in methylene chloride. This mixture was washed first with 3N sodium hydroxide, then neutral with water, dried over sodium sulfate and evaporated in vacuo. The crude product was recrystallized from ethyl acetate/petroleum ether. 3.5 g (53% of theory) of 6,7-dihydro-2-[(2-pyridylmethyl)thio]-1H-p-dioxino(2,3-f)benzimidazole of melting point 155°-156° C. were prepared.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[S:12][C:11]2[CH:10]=[N:9][N:8](C(=O)C)[C:7]=2[CH:6]=1)=[O:4].C[O-].[Na+].[I:19]I>CO.CN(C)C=O>[CH3:1][O:2][C:3]([C:5]1[S:12][C:11]2[C:10]([I:19])=[N:9][NH:8][C:7]=2[CH:6]=1)=[O:4]
Reactant: II
Reactant: COC(=O)c1cc2c(cnn2C(C)=O)s1
Agent: C[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CO
Product: COC(=O)c1cc2[nH]nc(I)c2s1
Temperature: 60 °C
Reaction time: 0.33 h
Yield: 88.6 %

Procedure:
To a suspension of 1-acetyl-1H-thieno[3,2-c]pyrazole-5-carboxylic acid methyl ester [1.3 g, 5.79 mmol, Intermediate (25)] in methanol (30 mL) is added sodium methoxide (25 wt % in methanol). The resulting solution mixture is stirred at 60° C. oil bath for 20 minutes. The oil bath is removed and stirred for 5 minutes. To this is added a solution of iodine (1.76 g, 6.93 mmol) in dimethyl formamide (2 mL). The reaction mixture then heated to 60° C. for 1 hour. The solvent is removed in vacuo. The crude is partitioned between ethyl acetate (100 mL) and water (100 mL) and aqueous layer is further extracted with twice ethyl acetate (25 mL). The combined ethyl acetate phases are washed with brine, dried over sodium sulfate and filtered. The solvent is removed in vacuo to give 3-iodo-1H-thieno[3,2-c]pyrazole-5-carboxylic acid methyl ester [1.58 g, 89%, Intermediate (26)] as light yellow solid; 1H NMR [(CD3)2SO)]: δ 13.80 (1H, brs, NH), 7.947 (1H, s), 3.870 (3H, s).
Reaction SMILES: C([O:8][C@H:9]([C@@H:11]([N:14]1[C:18](=[O:19])[N:17]([C:20]2[CH:25]=[CH:24][C:23]([N:26]3[CH2:31][CH2:30][N:29]([C:32]4[CH:37]=[CH:36][C:35](O)=[CH:34][CH:33]=4)[CH2:28][CH2:27]3)=[CH:22][CH:21]=2)[CH:16]=[N:15]1)[CH2:12][CH3:13])[CH3:10])C1C=CC=CC=1.CS(C)=O.[OH-].[Na+].[N:45]1([CH2:50][C@@:51]2([C:68]3[CH:73]=[CH:72][C:71]([F:74])=[CH:70][C:69]=3[F:75])[O:55][CH2:54][C@@H:53]([CH2:56][O:57]S(C3C=CC(C)=CC=3)(=O)=O)[CH2:52]2)[CH:49]=[N:48][CH:47]=[N:46]1>C(O)(C)C.O>[CH3:13][CH2:12][C@H:11]([N:14]1[N:15]=[CH:16][N:17]([C:20]2[CH:25]=[CH:24][C:23]([N:26]3[CH2:27][CH2:28][N:29]([C:32]4[CH:33]=[CH:34][C:35]([O:57][CH2:56][C@@H:53]5[CH2:54][O:55][C@:51]([C:68]6[CH:73]=[CH:72][C:71]([F:74])=[CH:70][C:69]=6[F:75])([CH2:50][N:45]6[N:46]=[CH:47][N:48]=[CH:49]6)[CH2:52]5)=[CH:36][CH:37]=4)[CH2:30][CH2:31]3)=[CH:22][CH:21]=2)[C:18]1=[O:19])[C@@H:9]([OH:8])[CH3:10]
Reactant: Cc1ccc(S(=O)(=O)OC[C@@H]2CO[C@@](Cn3cncn3)(c3ccc(F)cc3F)C2)cc1
Reactant: CC[C@@H]([C@H](C)OCc1ccccc1)n1ncn(-c2ccc(N3CCN(c4ccc(O)cc4)CC3)cc2)c1=O
Agent: [Na+]
Agent: [OH-]
Solvent: CS(C)=O
Solvent: O
Solvent: CC(C)O
Product: CC[C@@H]([C@H](C)O)n1ncn(-c2ccc(N3CCN(c4ccc(OC[C@@H]5CO[C@@](Cn6cncn6)(c6ccc(F)cc6F)C5)cc4)CC3)cc2)c1=O
Temperature: 45 °C
Reaction time: 5 h
Yield: 98 %

Procedure:
Added 1-((2S,3S)-2-(benzyloxy)pentan-3-yl)-4-(4-(4-(4-hydroxyphenyl) piperazin-1-yl)phenyl)-1H-1,2,4-triazol-5(4H)-one compound of formula-20 (35 g) to a mixture of dimethylsulfoxide (350 ml) and sodium hydroxide (3.4 g) and water (7 ml) at 25-30° C. and stirred for 45 minutes at 25-30° C. ((3S,5R)-5-((1H-1,2,4-triazol-1-yl)methyl)-5-(2,4-difluorophenyl)tetrahydrofuran-3-yl)methyl-4-methylbenzenesulfonate compound of formula-10 (31.5 g) was added to the above reaction mixture at 25-30° C. and heated the reaction mixture to 45° C. and stirred for 5 hours at the same temperature. After completion of the reaction, cooled the reaction mixture to room temperature and water was added to the reaction mixture. The reaction mixture was extracted twice with ethyl acetate. Adjusted the pH of the reaction mixture with aqueous hydrochloric acid solution. The organic layers were washed with sodium chloride solution. Distilled off the solvent under reduced pressure to get the compound as residue. Dissolved the obtained residue in isopropanol (320 ml) at 45-50° C. Filtered the solid, washed with isopropanol and dried aerially to get the title compound. Yield: 98%; Purity by HPLC: 99.5%; M.R: 117° C.-119° C.
Reaction SMILES: [ClH:1].[NH2:2][C:3]1[NH:8][C:7]2[NH:9][CH:10]=[C:11]([CH2:12][CH2:13][C:14]3[CH:31]=[CH:30][C:17]([C:18]([NH:20][C@H:21]([C:27]([OH:29])=[O:28])[CH2:22][CH2:23][C:24]([OH:26])=[O:25])=[O:19])=[CH:16][CH:15]=3)[C:6]=2[C:5](=[O:32])[N:4]=1.[OH-].[Na+:34].[CH2:35]([OH:46])[C@H:36]([C@H:38]([C@@H:40]([C@@H:42]([CH2:44][OH:45])[OH:43])[OH:41])[OH:39])[OH:37]>O>[Na+:34].[Na+:34].[NH2:2][C:3]1[NH:8][C:7]2[NH:9][CH:10]=[C:11]([CH2:12][CH2:13][C:14]3[CH:15]=[CH:16][C:17]([C:18]([NH:20][C@H:21]([C:27]([O-:29])=[O:28])[CH2:22][CH2:23][C:24]([O-:26])=[O:25])=[O:19])=[CH:30][CH:31]=3)[C:6]=2[C:5](=[O:32])[N:4]=1.[CH2:44]([OH:45])[C@H:42]([C@H:40]([C@@H:38]([C@@H:36]([CH2:35][OH:46])[OH:37])[OH:39])[OH:41])[OH:43].[Cl-:1].[Na+:34]
Reactant: Nc1nc(=O)c2c(CCc3ccc(C(=O)N[C@@H](CCC(=O)O)C(=O)O)cc3)c[nH]c2[nH]1
Reactant: Cl
Agent: OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: Nc1nc(=O)c2c(CCc3ccc(C(=O)N[C@@H](CCC(=O)[O-])C(=O)[O-])cc3)c[nH]c2[nH]1
Product: [Cl-]

Procedure:
5 grams of N-[4-[2-(2-amino-4,7-dihydro-4-oxo-1H-pyrrolo[2,3-d]pyrimidin-5-yl)ethyl]benzoyl]-L-glutamic acid hydrochloride (purity 99.4% by HPLC) is dissolved in 1 L of distilled water and 16.168 ml of a 2.0 M solution of sodium hydroxide is added to the solution. Mannitol (10 g) was then added to the solution and dissolved. The solution is then filtered through a bacterial filter and dried in a freeze-drier to afford the title compound as a white solid in mixture with mannitol and sodium chloride (15.6 g, HPLC purity 99.4% area by HPLC).
Reaction SMILES: F[P-](F)(F)(F)(F)F.C([N+]1C=CN(C)C=1)CCC.[C:18]([N:21]1[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]1)(=[O:20])[CH3:19].F[C:28]1[CH:33]=[CH:32][C:31]([N+:34]([O-:36])=[O:35])=[CH:30][C:29]=1[CH3:37]>CC#N>[C:18]([N:21]1[CH2:26][CH2:25][N:24]([C:28]2[CH:33]=[CH:32][C:31]([N+:34]([O-:36])=[O:35])=[CH:30][C:29]=2[CH3:37])[CH2:23][CH2:22]1)(=[O:20])[CH3:19]
Reactant: Cc1cc([N+](=O)[O-])ccc1F
Reactant: CC(=O)N1CCNCC1
Agent: CCCC[n+]1ccn(C)c1
Agent: F[P-](F)(F)(F)(F)F
Solvent: CC#N
Product: CC(=O)N1CCN(c2ccc([N+](=O)[O-])cc2C)CC1
Temperature: 85 °C

Procedure:
1-Butyl-3-methylimidazolium hexafluorophosphate (1.75 g, 7.7 mmol) and acetyl piperazine (39.7 g, 309.4 mmol) was added to a stirred solution of 2-fluoro-5-nitrotoluene (12 g, 77.4 mmol) in MeCN (3 mL) and heated to 85° C. for 2 h. The reaction was cooled and concentrated in vacuo. Water (100 mL) was added to the resulting residue and the reaction extracted with EtOAc (3×100 mL). The solvent was dried (MgSO4), filtered, and concentrated in vacuo to yield the product as a yellow solid which was triturated with isohexane and dried in vacuo at 60° C.; 1H NMR δ 8.05 (2H, m), 7.14 (1H, d), 3.64-3.58 (4H, m), 3.05-2.94 (4H, m), 2.37 (3H, s), 2.37 (3H, s); MS m/e MH+ 264.
Reaction SMILES: [CH3:1][C:2]([CH3:9])([CH2:7][OH:8])[C@@H:3]([OH:6])[CH2:4][OH:5].CO[CH:12](OC)[C:13]1[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=1.C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1>C(Cl)Cl>[CH3:20][O:19][C:16]1[CH:17]=[CH:18][C:13]([C@H:12]2[O:6][C@@H:3]([CH2:4][OH:5])[C:2]([CH3:9])([CH3:1])[CH2:7][O:8]2)=[CH:14][CH:15]=1
Reactant: COc1ccc(C(OC)OC)cc1
Reactant: CC(C)(CO)[C@@H](O)CO
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Product: COc1ccc([C@@H]2OCC(C)(C)[C@H](CO)O2)cc1
Temperature: 25 °C

Procedure:
To a stirred solution of compound obtained in Step A (5.6 g, 41.76 mmol) in dry CH2Cl2 (115 mL) was added p-methoxybenzaldehyde dimethyl acetal (11.42 g, 62.64 mmol) and pyridinium p-toluenesulfonate (2.1 g, 8.35 mmol). The mixture was heated at reflux for 18 h, then was cooled to room temperature and the reaction was quenched with saturated aqueous NaHCO3 solution (50 mL). The separated aqueous layer was extracted with Et2O (3×75 mL) and the combined extracts were washed with saturated aqueous NaCl solution (100 mL) and dried (MgSO4). Filtration and concentration of the filtrate in vacuo left a residue which was purified by flash chromatography (silica gel, gradient elution from 20% Et2O in hexanes to 40% Et2O in hexanes) to give the title compound as a colorless oil.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][N:7]=1.[CH3:12][N:13]=[C:14]=[S:15]>C(O)C>[CH3:12][NH:13][C:14]([NH:1][CH2:2][CH2:3][CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][N:7]=1)=[S:15]
Reactant: NCCCCc1ccccn1
Reactant: CN=C=S
Solvent: CCO
Product: CNC(=S)NCCCCc1ccccn1
Yield: 67.3 %

Procedure:
The reaction of 2-(4-aminobutyl)pyridine (3.0 g) and methyl isothiocyanate (1.6g) in ethanol (25 ml) for 0.5 hours followed by chromatography of the product on silica and elution with ethyl acetate affords N-methyl-N'-(4-(2-pyridyl)butyl)thiourea (3.0 g) as a colourless oil.
Reaction SMILES: C(OC(=O)[NH:7][CH2:8][CH:9]1[CH2:14][CH2:13][N:12]([C:15]2[CH:16]=[CH:17][CH:18]=[C:19]3[C:24]=2[N:23]=[C:22]([C:25]2[N:29]4[CH:30]=[CH:31][C:32]([CH:34]([OH:37])[CH2:35][OH:36])=[CH:33][C:28]4=[N:27][N:26]=2)[CH:21]=[CH:20]3)[CH2:11][CH2:10]1)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH2:7][CH2:8][CH:9]1[CH2:10][CH2:11][N:12]([C:15]2[CH:16]=[CH:17][CH:18]=[C:19]3[C:24]=2[N:23]=[C:22]([C:25]2[N:29]4[CH:30]=[CH:31][C:32]([CH:34]([OH:37])[CH2:35][OH:36])=[CH:33][C:28]4=[N:27][N:26]=2)[CH:21]=[CH:20]3)[CH2:13][CH2:14]1
Reactant: CC(C)(C)OC(=O)NCC1CCN(c2cccc3ccc(-c4nnc5cc(C(O)CO)ccn45)nc23)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: NCC1CCN(c2cccc3ccc(-c4nnc5cc(C(O)CO)ccn45)nc23)CC1
Reaction time: 1 h
Yield: 119.5 %

Procedure:
To tert-butyl(1-(2-(7-(1,2-dihydroxyethyl)-[1,2,4]triazolo[4,3-a]pyridin-3-yl)quinolin-8-yl)piperidin-4-yl)methylcarbamate (2 mg, 0.004 mmol) in DCM (1 mL) was added TFA (0.5 mL). The reaction was then stirred for 1 hour, then concentrated and purified by flash column chromatography (DCM/MeOH/NH4OH 20:1:0.1), affording the final product as a white solid (0.002 g; quantitative yield). MS ESI (+) m/z 419 (M+1) detected.
Reaction SMILES: Cl.[I:2][C:3]1[C:11]2[C:6](=[N:7][CH:8]=[N:9][C:10]=2[NH2:12])[N:5]([CH:13]2[CH2:17][CH2:16][NH:15][CH2:14]2)[N:4]=1.[CH3:18][N:19]([CH3:24])[CH2:20][C:21](O)=[O:22].ON1C2N=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC.C(N(C(C)C)CC)(C)C>ClCCl.O>[NH2:12][C:10]1[N:9]=[CH:8][N:7]=[C:6]2[N:5]([CH:13]3[CH2:17][CH2:16][N:15]([C:21](=[O:22])[CH2:20][N:19]([CH3:24])[CH3:18])[CH2:14]3)[N:4]=[C:3]([I:2])[C:11]=12
Reactant: CN(C)CC(=O)O
Reactant: Nc1ncnc2c1c(I)nn2C1CCNC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2cccnc21
Solvent: O
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CN(C)CC(=O)N1CCC(n2nc(I)c3c(N)ncnc32)C1
Temperature: 25 °C
Reaction time: 18 h
Yield: 67 %

Procedure:
To a solution of rac-3-iodo-1-tetrahydro-1H-3-pyrrolyl-1H-pyrazolo[3,4-d]pyrimidin-4-amine monohydrochloride (0.367 g, 1.00 mmol) in dichloromethane (10 mL) was added 2-(dimethylamino)acetic acid (0.134 g, 1.30 mmol), 1-hydroxy-7-azabenzotriazole (0.150 g, 1.10 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.249 g, 1.30 mmol), and diisopropylethyl amine (0.65 g, 0.87 mL, 5.0 mmol). The reaction mixture stirred at room temperature for 18 h and was then poured into water (10 mL). The organic phase was separated and washed with brine (10 mL), dried over anhydrous magnesium sulfate, filtered, and concentrated to afford rac-1-[3-(4-amino-3-iodo-1H-pyrazolo[3,4-d]pyrimidin-1-yl)tetrahydro-1H-1-pyrrolyl]-2-(dimethylamino)-1-ethanone as a yellow-orange solid (0.278 g, 67%) which was used in subsequent reactions without further purification.
Reaction SMILES: [H-].[Na+].O1CCC[CH2:4]1.C[C:9](P(OC)(O)=O)([C:11]([O-:13])=[O:12])[CH3:10].[CH3:19][O:20][C:21]1[CH:22]=[C:23]([CH:29]2C[CH2:33][CH2:32][CH2:31][C:30]2=O)[CH:24]=[C:25]([O:27][CH3:28])[CH:26]=1>O.C(O)(=O)C>[CH3:28][O:27][C:25]1[CH:24]=[C:23]([CH:29]2[CH2:30][CH2:31][CH2:32][CH2:33][C:10]2=[CH:9][C:11]([O:13][CH3:4])=[O:12])[CH:22]=[C:21]([O:20][CH3:19])[CH:26]=1
Reactant: COc1cc(OC)cc(C2CCCCC2=O)c1
Reactant: C1CCOC1
Reactant: COP(=O)(O)C(C)(C)C(=O)[O-]
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: COC(=O)C=C1CCCCC1c1cc(OC)cc(OC)c1
Temperature: 70 °C

Procedure:
To a suspension of 3.9 g. (0.081 mole) 50% sodium hydride in 500 ml. anhydrous tetrahydrofuran (THF) was added dropwise at room temperature a solution of 16.2 g. (0.089 mole) trimethylphosphonoacetate in 50 ml. THF and the mixture stirred for 15 minutes. A solution of 17.4 g. (0.074 mole) 2-(3,5-dimethoxyphenyl)cyclohexanone in 100 ml. THF was added in portions after which the mixture was heated at 70° C. for three hours and cooled to 0° C. Glacial acetic acid, 5.4 g., was added and the resulting mixture diluted with water and extracted with ethyl acetate. The extracts were dried (Na2SO4) and evaporated to give 2 g. of crude product which was crystallized from isopropyl ether; 20.4 g., M.P. 80°-81° C. 1H--NMR (CDCl3) ppm (delta): 3.60 (s, 3H, COOCH3), 3.80 (s, 6H, OCH3), 5.20 (s, 1H, olefin), 6.34 (s, 3H, aromatic). Mass spectrum, exact mass for C17H24O4 : 292.3783. Found: 292.1658.
Reaction SMILES: [N:1]([CH2:4][C:5]1[C:13]2[N:12]=[CH:11][N:10]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[C:9]=2[CH:8]=[CH:7][CH:6]=1)=[N+]=[N-].[Cl:21][C:22]1[CH:23]=[C:24]([CH:35]=[CH:36][C:37]=1[C:38]([O:40][CH3:41])=[O:39])[C:25](ON1C(=O)CCC1=O)=[O:26]>[Pd].CO.C1C=CC=CC=1>[Cl:21][C:22]1[CH:23]=[C:24]([C:25]([NH:1][CH2:4][C:5]2[C:13]3[N:12]=[CH:11][N:10]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[C:9]=3[CH:8]=[CH:7][CH:6]=2)=[O:26])[CH:35]=[CH:36][C:37]=1[C:38]([O:40][CH3:41])=[O:39]
Reactant: COC(=O)c1ccc(C(=O)ON2C(=O)CCC2=O)cc1Cl
Reactant: CC(C)(C)OC(=O)n1cnc2c(CN=[N+]=[N-])cccc21
Agent: [Pd]
Solvent: CO
Solvent: c1ccccc1
Product: COC(=O)c1ccc(C(=O)NCc2cccc3c2ncn3C(=O)OC(C)(C)C)cc1Cl
Reaction time: 1.75 h
Yield: 66.3 %

Procedure:
A mixture of 4-(azidomethyl)benzimidazole-1-carboxylic acid, 1,1-dimethylethyl ester (Example 13; 1.40, 5.1 mmol), 1-[[3-chloro-4-(methoxycarbonyl)benzoyl]oxy]-2,5-pyrrolidinedione (Example 5; 1.62 g, 5.2 mmol), and 10% palladium on charcoal (210 mg) in methanol (40 mL) and benzene (2 mL) was hydrogenated at atmospheric pressure for 105 min and then filtered through Celite. Tlc indicated that the reaction was not complete so more 10% palladium on charcoal (210 mg) was added and the mixture was hydrogenated at atmospheric pressure for 3 h and then shaken at 50 psi of hydrogen for 3 h. The reaction mixture was allowed to stand under hydrogen for 12 h, then filtered through Celite, evaporated, and chromatographed (20-100% ethyl acetate/hexanes) to give 2-chloro-4-[[[[1-[(1,1-dimethylethoxy)carbonyl]benzimidazol-4-yl]methyl]amino]carbonyl]benzoic acid, methyl ester (1.50 g, 66%). A solution of the ester (1.45 g, 3.3 mmol) in methanol (15 mL) and 3 M lithium hydroxide solution (5.5 mL) was stirred at room temperature overnight. A white solid was filtered off and discarded. The filtrate was evaporated to dryness. Water and 1 M HCl (16.6 mL) were added, and the mixture was filtered and washed with water to give 2-chloro-4-[[[(benzimidazol-4-yl)methyl]amino]carbonyl]-benzoic acid (925 mg, 86%).
Reaction SMILES: [CH2:1]=[C:2]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[N:6]([C:13](=[O:30])[C:14]2[CH:19]=[CH:18][C:17]([NH:20][C:21](=[O:29])[C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=3[CH3:28])=[CH:16][CH:15]=2)[CH2:5][CH2:4][CH2:3]1.[H][H].[OH-:33].[Na+].OO>O1CCCC1.O>[OH:33][CH2:1][CH:2]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[N:6]([C:13](=[O:30])[C:14]2[CH:19]=[CH:18][C:17]([NH:20][C:21](=[O:29])[C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=3[CH3:28])=[CH:16][CH:15]=2)[CH2:5][CH2:4][CH2:3]1
Reactant: C=C1CCCN(C(=O)c2ccc(NC(=O)c3ccccc3C)cc2)c2ccccc21
Reactant: [OH-]
Reactant: [H][H]
Agent: OO
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: Cc1ccccc1C(=O)Nc1ccc(C(=O)N2CCCC(CO)c3ccccc32)cc1
Temperature: 25 °C
Reaction time: 6 h

Procedure:
5-Methylidene-1-[4-(2-methylbenzoylamino)benzoyl]-2,3,4,5-tetrahydro-1H-benzazepine (2.84 g) is suspended in tetrahydrofuran (50 ml) and thereto is added 1M solution of boran-tetrahydrofuran complex in tetrahydrofuran (43 ml). The mixture is stirred at room temperature for 6 hours. After completion of the reaction, the reaction solution is cooled with ice, and thereto is added water (70 ml). After termination of the evolution of hydrogen gas, to the reaction solution are added 25% aqueous sodium hydroxide solution (7.0 ml), and subsequently 31% aqueous hydrogen peroxide solution (4.7 ml), and the mixture is heated with stirring at 50° C. for 1 hour. After cooling, to the reaction solution is added saturated saline solution and the tetrahydrofuran layer is collected, washed with saturated saline solution and dried over magnesium sulfate. The solvent is distilled off and the resulting residue is recrystallized from ethyl acetate/n-hexane to give 5-hydroxymethyl-1-[4-(2-methylbenzoylamino)benzoyl]-2,3,4,5-tetrahydro-1H-benzazepine (1.96 g) as white powder, m.p. 202°-206° C.
Reaction SMILES: [Cl:1][C:2]1[C:7]([F:8])=[CH:6][C:5]([OH:9])=[C:4]([N+:10]([O-:12])=[O:11])[CH:3]=1.[C:13]([O-])([O-])=O.[K+].[K+].IC.O>CN(C=O)C>[CH3:13][O:9][C:5]1[CH:6]=[C:7]([F:8])[C:2]([Cl:1])=[CH:3][C:4]=1[N+:10]([O-:12])=[O:11]
Reactant: O=[N+]([O-])c1cc(Cl)c(F)cc1O
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CI
Product: COc1cc(F)c(Cl)cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 8 h

Procedure:
4-Chloro-5-fluoro-2-nitrophenol (2.29 g, 12.0 mmol) was dissolved in DMF (25 mL). K2CO3 (2.5 g, 18 mmol) and iodomethane (0.893 mL, 14.3 mmol) were added and the mixture was stirred at rt overnight. The mixture was then poured into H2O and extracted with EtOAc (2×) and then the combined organics were extracted with H2O (5×). The organic layer was dried with MgSO4, filtered, and concentrated in vacuo to give the title compound of step B without further purification (2.19 g, 89%). 1H NMR (400 MHz, DMSO-d6) δ ppm 8.22 (dd, J=7.8, 1.0 Hz, 1H), 7.54 (d, J=11.4 Hz, 1H), 3.90 (d, J=1.1 Hz, 3H).
Reaction SMILES: Cl[C:2]1[N:7]=[N:6][C:5]([C:8]2[CH:49]=[CH:48][C:11]([CH2:12][C:13]3[N:14]([C:26]4[CH:31]=[CH:30][C:29]([N:32]5[S:36](=[O:38])(=[O:37])[N:35]([CH2:39][O:40][CH2:41][CH2:42][Si:43]([CH3:46])([CH3:45])[CH3:44])[C:34](=[O:47])[CH2:33]5)=[CH:28][CH:27]=4)[CH:15]=[C:16]([C:18]4[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][C:19]=4[Cl:25])[N:17]=3)=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.[CH:50]1([CH2:56][CH2:57][OH:58])[CH2:55][CH2:54][CH2:53][CH2:52][CH2:51]1>>[CH:50]1([CH2:56][CH2:57][O:58][C:2]2[N:7]=[N:6][C:5]([C:8]3[CH:9]=[CH:10][C:11]([CH2:12][C:13]4[N:14]([C:26]5[CH:31]=[CH:30][C:29]([N:32]6[S:36](=[O:38])(=[O:37])[N:35]([CH2:39][O:40][CH2:41][CH2:42][Si:43]([CH3:44])([CH3:46])[CH3:45])[C:34](=[O:47])[CH2:33]6)=[CH:28][CH:27]=5)[CH:15]=[C:16]([C:18]5[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][C:19]=5[Cl:25])[N:17]=4)=[CH:48][CH:49]=3)=[CH:4][CH:3]=2)[CH2:55][CH2:54][CH2:53][CH2:52][CH2:51]1
Reactant: OCCC1CCCCC1
Reactant: C[Si](C)(C)CCOCN1C(=O)CN(c2ccc(-n3cc(-c4ccc(Cl)cc4Cl)nc3Cc3ccc(-c4ccc(Cl)nn4)cc3)cc2)S1(=O)=O
Product: C[Si](C)(C)CCOCN1C(=O)CN(c2ccc(-n3cc(-c4ccc(Cl)cc4Cl)nc3Cc3ccc(-c4ccc(OCCC5CCCCC5)nn4)cc3)cc2)S1(=O)=O

Procedure:
5-{4-[2-[4-(6-Chloro-pyridazin-3-yl)-benzyl]-4-(2,4-dichloro-phenyl)-imidazol-1-yl]-phenyl}-1,1-dioxo-2-(2-trimethylsilanyl-ethoxymethyl)-[1,2,5]thiadiazolidin-3-one (38 mg, 0.05 mmol) was treated as described in general procedure L using 2-cyclohexyl ethanol (35 μL, 0.25 mmol) to give 5-{-4-[2-{-4-[6-(2-cyclohexyl-ethoxy)-pyridazin-3-yl]-benzyl}-4-(2,4-dichloro-phenyl)-imidazol-1-yl]-phenyl}-1,1-dioxo-2-(2-trimethylsilanyl-ethoxymethyl)-[1,2,5]thiadiazolidin-3-one.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([NH:11][C:12]2[CH:17]=[CH:16][C:15]([OH:18])=[C:14]([C:19]3[N:20]([CH3:24])[N:21]=[CH:22][CH:23]=3)[CH:13]=2)=[O:10])=[CH:4][CH:3]=1.[Cl:25]N1C(=O)CCC1=O.[O-]S([O-])(=S)=O.[Na+].[Na+].C([O-])(O)=O.[Na+]>CN(C=O)C.O>[Cl:25][C:23]1[CH:22]=[N:21][N:20]([CH3:24])[C:19]=1[C:14]1[CH:13]=[C:12]([NH:11][C:9]([NH:8][C:5]2[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=2)=[O:10])[CH:17]=[CH:16][C:15]=1[OH:18]
Reactant: O=C1CCC(=O)N1Cl
Reactant: Cn1nccc1-c1cc(NC(=O)Nc2ccc(Cl)cc2)ccc1O
Agent: O=C([O-])O
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Cn1ncc(Cl)c1-c1cc(NC(=O)Nc2ccc(Cl)cc2)ccc1O
Yield: 58.9 %

Procedure:
To a stirred and cooled solution of Compound 119 (0.22 g, 0.63 mmol), in DMF (2.0 mL) was added N-chlorosuccinimide (0.168, 1.26 mmol). The reaction was stirred until the LCMS showed no starting material (2.5 hrs). The reaction mixture was poured into ice cooled water containing Na2S2O3 and NaHCO3 and the resulting solid was filtered, washed with ice-cooled water and dried in vacuo to afford a off-white solid 1-[3-(4-Chloro-2-methyl-2H-pyrazol-3-yl)-4-hydroxy-phenyl]-3-(4-chloro-phenyl)-urea (0.14 g, 58%). LCMS m/z (%)=377 (M+H, 35Cl, 35Cl, 100), 379 (M+H, 35Cl, 37Cl, 59.4), 381 (M+H, 37Cl, 37Cl, 10.0). 1H NMR (400 MHz, DMSO-d6) δ: 9.76 (bs, 1H), 8.73 (bs, 1H), 8.56 (bs, 1H), 7.58 (s, 1H), 7.44-7.46 (dd, J=8.6, 2.03 Hz, 2H), 7.34-7.37 (dd, J=8.79, 2.7 Hz, 1H), 7.29 (dd, J=8.85, 2.07 Hz, 3H), 6.92-6.94 (d, J=6.78 Hz, 1H), 3.64 (s, 3H).