Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O-].[Na+].[NH:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH:6]=[CH:5]1.[NH:13]1[CH2:18][CH2:17][C:16](=O)[CH2:15][CH2:14]1.O.Cl>CO>[NH:13]1[CH2:14][CH:15]=[C:16]([C:6]2[C:7]3[C:12](=[CH:11][CH:10]=[CH:9][CH:8]=3)[NH:4][CH:5]=2)[CH2:17][CH2:18]1
Reactant: O=C1CCNCC1
Reactant: c1ccc2[nH]ccc2c1
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Solvent: O
Product: C1=C(c2c[nH]c3ccccc23)CCNC1

Procedure:
To a solution of sodium methoxide (450 ml, 30% in methanol, 2.5 mol) in 1000 ml of methanol was added indole (50 g, 0.427 mol) and 4-piperidone.H2O.HCl (162 g, 1.05 mol). The mixture was heated under reflux for 18 h forming a yellow precipitate. The mixture was concentrated and water (1000 ml) was added. The precipitate was collected, washed with water and petroleum ether and then dried in a vacuum oven at 50° C. Yield 77 g (91%) of a pale yellow solid.
Reaction SMILES: [C:1]([S:4][CH2:5][CH:6]([CH:10]([C:12]1[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=1)[CH3:11])[C:7]([OH:9])=O)(=[O:3])[CH3:2].[NH2:19][C@H:20]([C:22]([OH:24])=[O:23])[CH3:21]>>[CH2:10]([O:23][C:22](=[O:24])[C@H:20]([CH3:21])[NH:19][C:7](=[O:9])[CH:6]([CH2:5][S:4][C:1](=[O:3])[CH3:2])[CH:10]([C:12]1[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=1)[CH3:11])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: C[C@H](N)C(=O)O
Reactant: CC(=O)SCC(C(=O)O)C(C)c1ccc(F)cc1
Product: CC(=O)SCC(C(=O)N[C@@H](C)C(=O)OCc1ccccc1)C(C)c1ccc(F)cc1
Yield: 73 %

Procedure:
Working as in Example 60, but starting with 2-acetylthiomethyl-3-(4-fluorophenyl)butanoic acid and benzyl esters of alanine, the title compound is obtained in a yield of 73% as an oil having the characteristics:
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[CH:14]=[CH:13][C:12]([CH2:15][N:16]2[C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=3[CH2:20][CH2:19][C@@H:18]([NH:27][C:28](=[O:41])[CH2:29][C:30]([NH:33][C:34](=[O:40])[O:35][C:36]([CH3:39])([CH3:38])[CH3:37])([CH3:32])[CH3:31])[C:17]2=[O:42])=[CH:11][CH:10]=1)#[N:2].C(N(CC)CC)C.[SH2:50].[OH-].[Na+]>N1C=CC=CC=1.O>[C:36]([O:35][C:34]([NH:33][C:30]([CH3:32])([CH3:31])[CH2:29][C:28]([NH:27][C@@H:18]1[CH2:19][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=2[N:16]([CH2:15][C:12]2[CH:11]=[CH:10][C:9]([C:4]3[C:3]([C:1](=[S:50])[NH2:2])=[CH:8][CH:7]=[CH:6][CH:5]=3)=[CH:14][CH:13]=2)[C:17]1=[O:42])=[O:41])=[O:40])([CH3:37])([CH3:39])[CH3:38]
Reactant: CC(C)(CC(=O)N[C@@H]1CCc2ccccc2N(Cc2ccc(-c3ccccc3C#N)cc2)C1=O)NC(=O)OC(C)(C)C
Reactant: S
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCN(CC)CC
Solvent: c1ccncc1
Product: CC(C)(CC(=O)N[C@@H]1CCc2ccccc2N(Cc2ccc(-c3ccccc3C(N)=S)cc2)C1=O)NC(=O)OC(C)(C)C
Temperature: 90 °C
Yield: 82 %

Procedure:
A solution of 380 mg (0.67 mmol) of 3-[[1-[[2'-cyano-[1,1'-biphenyl]-4-yl]methyl]-2,3,4,5-tetrahydro-2-oxo-1H-benzazepin-3(R)-yl]amino]-1,1-dimethyl-3-oxopropylcarbamic acid, 1,1-dimethylethyl ester (Example 69, Step D), in 5 mL of pyridine was placed in a bomb and treated with 5 mL of triethylamine and excess hydrogen sulfide was introduced under pressure. The bomb was sealed and heated for 12 hours at 90° C. The bomb was vented into 5 M sodium hydroxide and the contents poured into 40 mL of water, then extracted with ether (3×). The combined extracts were washed with water (3×), dried over magnesium sulfate, filtered and evaporated under vacuum to afford 330 mg (0.53 mmol, 82%) of product. 1H NMR (200 MHz,CDCl3): 1.38 (s,6H), 1.45 (s,9H), 1.90 (m,1H), 2.4-2.7 (m,4H), 2.92 (m,1H), 4.55 (m,1H), 4.94 (d,15 Hz,1H), 5.22 (d,15 Hz,1H), 5.31 (br s,1H), 6.50 (br s,1H), 6.70 (m,1H), 7.1-7.5 (m,12H), 7.82 (m,1H). FAB-MS (Li+ spike): calculated for C34H40N4O4S 600; found 607 (M+Li,65%).
Reaction SMILES: [CH2:1]([N:8]1[C:17]([C:18]([OH:20])=[O:19])=[C:16]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:15]2[C:10](=[CH:11][CH:12]=[C:13]([O:27][CH2:28][C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[CH:14]=2)[C:9]1=[O:35])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CI.[C:38](=O)([O-])[O-].[K+].[K+].O>CN(C=O)C>[CH3:38][O:19][C:18]([C:17]1[N:8]([CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[C:9](=[O:35])[C:10]2[C:15]([C:16]=1[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)=[CH:14][C:13]([O:27][CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)=[CH:12][CH:11]=2)=[O:20]
Reactant: O=C([O-])[O-]
Reactant: O=C(O)c1c(-c2ccccc2)c2cc(OCc3ccccc3)ccc2c(=O)n1Cc1ccccc1
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CI
Solvent: O
Product: COC(=O)c1c(-c2ccccc2)c2cc(OCc3ccccc3)ccc2c(=O)n1Cc1ccccc1
Reaction time: 12 h
Yield: 90.6 %

Procedure:
2-Benzyl-6-benzyloxy-1-oxo-4-phenyl-1,2-dihydroisoquinoline-3-carboxylic acid (150 mg) was dissolved in DMF (3 ml) and methyl iodide (0.04 ml) and potassium carbonate (90 mg) were added at room temperature. The mixture was stirred for 12 hrs. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine. The solvent was dried over anhydrous sodium sulfate and evaporated under reduced pressure, and the obtained residue was crystallized from hexane to give the title compound (140 mg).
Reaction SMILES: Cl.[C:2]([O:6][C:7](=[O:10])[CH2:8][NH2:9])([CH3:5])([CH3:4])[CH3:3].C([O-])(O)=O.[Na+].[C:16]([O:20][C:21](=[O:33])[NH:22][C:23]1[CH:28]=[CH:27][C:26](F)=[C:25]([N+:30]([O-:32])=[O:31])[CH:24]=1)([CH3:19])([CH3:18])[CH3:17]>CS(C)=O>[C:2]([O:6][C:7](=[O:10])[CH2:8][NH:9][C:26]1[CH:27]=[CH:28][C:23]([NH:22][C:21]([O:20][C:16]([CH3:18])([CH3:19])[CH3:17])=[O:33])=[CH:24][C:25]=1[N+:30]([O-:32])=[O:31])([CH3:5])([CH3:4])[CH3:3]
Reactant: CC(C)(C)OC(=O)Nc1ccc(F)c([N+](=O)[O-])c1
Reactant: CC(C)(C)OC(=O)CN
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CS(C)=O
Product: CC(C)(C)OC(=O)CNc1ccc(NC(=O)OC(C)(C)C)cc1[N+](=O)[O-]
Temperature: 65 °C

Procedure:
Glycine tert-butyl ester hydrochloride (4.1 g, 29.4 mmol) and NaHCO3 (5.1 g, 61.0 mmol) were added to a solution of (4-fluoro-3-nitro-phenyl)-carbamic acid tert-butyl ester (5.2 g, 20.3 mmol) in DMSO (16 mL). The reaction was heated to 65° C. for 5 hours, cooled to room temperature, and partitioned between H2O and EtOAc. The organic layer was washed several times with H2O and concentrated to afford the sub-title compound. MS calculated for C17H25N3O6+H: 368, observed: 368.
Reaction SMILES: C([O:3][C:4](=[O:17])[CH:5]([C:7]1[CH:16]=[CH:15][C:10]2[NH:11][C:12](=[S:14])[O:13][C:9]=2[CH:8]=1)[CH3:6])C.[OH-].[Na+].C(O)(=O)C>CCO.O>[S:14]=[C:12]1[NH:11][C:10]2[CH:15]=[CH:16][C:7]([CH:5]([CH3:6])[C:4]([OH:17])=[O:3])=[CH:8][C:9]=2[O:13]1
Reactant: CCOC(=O)C(C)c1ccc2[nH]c(=S)oc2c1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Solvent: CC(=O)O
Product: CC(C(=O)O)c1ccc2[nH]c(=S)oc2c1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a stirred solution of 2-(2-Thioxo-2,3-dihydro-benzooxazol-6-yl)-propionic acid ethyl ester (76 mg) in 90% aq. EtOH was added NaOH (48 mg) at room temperature. After stirred for 16 h at room temperature, the reaction mixture was cooled to room temperature, diluted with water. The resulting aqueous layer was acidified with acetic acid and then extracted with dichloromethane. The combined organic layer was dried over magnesium sulfate, filtered and concentrated in vacuo. (58 mg, 86.0%, brown solid)
Reaction SMILES: C1(S)C=CC=CC=1.[H-].[Na+].[CH3:10][NH:11][C:12](=[O:55])[C:13]1[CH:18]=[C:17]([Br:19])[C:16]([CH2:20][N:21]([CH2:34][C:35]([C:37]2[CH:42]=[C:41]([C:43]([CH3:46])([CH3:45])[CH3:44])[C:40]([OH:47])=[C:39]([C:48]([CH3:51])([CH3:50])[CH3:49])[CH:38]=2)=[O:36])S(C2C=CC([N+]([O-])=O)=CC=2)(=O)=O)=[CH:15][C:14]=1[O:52][CH2:53][CH3:54]>CN(C)C=O.C(OCC)(=O)C>[CH3:10][NH:11][C:12](=[O:55])[C:13]1[CH:18]=[C:17]([Br:19])[C:16]([CH2:20][NH:21][CH2:34][C:35]([C:37]2[CH:38]=[C:39]([C:48]([CH3:51])([CH3:50])[CH3:49])[C:40]([OH:47])=[C:41]([C:43]([CH3:46])([CH3:45])[CH3:44])[CH:42]=2)=[O:36])=[CH:15][C:14]=1[O:52][CH2:53][CH3:54]
Reactant: CCOc1cc(CN(CC(=O)c2cc(C(C)(C)C)c(O)c(C(C)(C)C)c2)S(=O)(=O)c2ccc([N+](=O)[O-])cc2)c(Br)cc1C(=O)NC
Agent: Sc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCOc1cc(CNCC(=O)c2cc(C(C)(C)C)c(O)c(C(C)(C)C)c2)c(Br)cc1C(=O)NC
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 79.9 %

Procedure:
After dissolving thiophenol (1.27 ml) in dimethylformamide (20 ml), sodium hydride (480 mg) was added. The mixture was stirred at room temperature for 30 minutes and then the N1-methyl-5-bromo-4-({{2-[3,5-di(tert-butyl)-4-hydroxyphenyl]-2-oxoethyl}[(4-nitrophenyl)sulfonyl]amino}methyl)-2-ethoxybenzamide (2.95 g) was added. After stirring at room temperature for 1 hour, the mixture was diluted with ethyl acetate and washed with water and brine, and then the organic layer was dried over anhydrous magnesium sulfate, filtered and concentrated and the residue was purified by silica gel column chromatography (solvent: n-hexane-ethyl acetate) to yield the title compound (1.75 g) as a light orange oil. (78% yield)
Reaction SMILES: CON(C)[C:4]([C:6]1[C:10]([CH3:11])=[C:9]([CH3:12])[S:8][CH:7]=1)=[O:5].[Cl:14][C:15]1[CH:20]=[CH:19][C:18]([Mg]Br)=[CH:17][CH:16]=1.Cl>C1COCC1.C(OCC)C>[Cl:14][C:15]1[CH:20]=[CH:19][C:18]([C:4]([C:6]2[C:10]([CH3:11])=[C:9]([CH3:12])[S:8][CH:7]=2)=[O:5])=[CH:17][CH:16]=1
Reactant: Clc1ccc([Mg]Br)cc1
Reactant: CON(C)C(=O)c1csc(C)c1C
Agent: Cl
Solvent: C1CCOC1
Solvent: CCOCC
Product: Cc1scc(C(=O)c2ccc(Cl)cc2)c1C
Temperature: 25 °C
Yield: 89.6 %

Procedure:
To a cooled (−40° C.) solution of N-methoxy-N,4,5-trimethylthiophene-3-carboxamide (1.77 g, 8.88 mmol) in THF (10 mL) was slowly added (over 10 min) a solution of 4-chlorophenylmagnesium bromide (17 mL, 17.00 mmol, 1 M) in diethyl ether. The reaction mixture was allowed to gradually warm to room temperature and age for several hours. To the mixture was added 1 N HCl and the aqueous layer was extracted with EtOAc (2×). The combined organic layer was washed with saturated NaHCO3, water, dried over Na2SO4, and concentrated to give an oil. The resultant oil was purified on Biotage system (gradient elution 1% EtOAc:99% Hexanes to 4% EtOAc:96% Hexanes) to give the titled compound as white solids (2.00 g, 7.96 mmol, 90% yield). LC/MS m/z 251 [M+H]+.
Reaction SMILES: [F:1][C:2]1[C:3]([O:9][CH3:10])=[C:4]([CH:6]=[CH:7][CH:8]=1)[NH2:5].[C:11]1(C)[CH:16]=CC(S(O)(=O)=O)=C[CH:12]=1.C(C=C)=O>ClC1C=CC=CC=1Cl>[F:1][C:2]1[C:3]([O:9][CH3:10])=[C:4]2[C:6]([CH:12]=[CH:11][CH:16]=[N:5]2)=[CH:7][CH:8]=1
Reactant: COc1c(N)cccc1F
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Agent: C=CC=O
Solvent: Clc1ccccc1Cl
Product: COc1c(F)ccc2cccnc12
Temperature: 170 °C
Reaction time: 1 h
Yield: 361 %

Procedure:
A solution of 3-fluoro 2-methoxyaniline (5.0 g) in 1,2-dichlorobenzene (50 ml) was heated to 170° C. and treated with p-toluenesulphonic acid (0.7 g). A solution of acrolein (4.0 g) in 1,2-dichlorobenzeue (20 ml) was added dropwise over 20 minutes. The reaction was stirred for 1 hour at 170° C. before being allowed to cool. The mixture was extracted with 2N hydrochloric acid (3×200 ml) and the combined extracts washed with dichloromethane (20 ml), basified with 25% aqueous sodium hydroxide, and extracted with ethyl acetate (3×200 ml). The combined extracts were dried over magnesium sulphate, filtered and the filtrate evaporated in vacuo. The residue was purified by column chromatography on silica gel eluting with 50% ethyl acetate in hexane to yield the desired product (2.6 g) as a clear oil.
Reaction SMILES: [CH:1]1([NH2:8])[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C1(S([N:18]2[C:22]3=[N:23][CH:24]=[CH:25][CH:26]=[C:21]3[C:20]([C:27]3[CH:32]=[CH:31][N:30]=[C:29](Cl)[N:28]=3)=[CH:19]2)(=O)=O)C=CC=CC=1>>[CH:1]1([NH:8][C:29]2[N:28]=[C:27]([C:20]3[C:21]4[C:22](=[N:23][CH:24]=[CH:25][CH:26]=4)[NH:18][CH:19]=3)[CH:32]=[CH:31][N:30]=2)[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: NC1CCCCCC1
Reactant: O=S(=O)(c1ccccc1)n1cc(-c2ccnc(Cl)n2)c2cccnc21
Product: c1cnc2[nH]cc(-c3ccnc(NC4CCCCCC4)n3)c2c1
Yield: 41 %

Procedure:
Using the procedure of example 1, cycloheptylamine (92 mg) was reacted with compound 1f (100 mg) to provide compound 15 (34 mg, 41%). 1H NMR (400 MHz, CD3OD) δ 8.95 (d, J=8.0 Hz, 1H), 8.28 (d, J=4.8 Hz, 1H), 8.19 (s, 1H), 8.12 (d, J=5.6 Hz, 1H), 7.25 (dd, J=8.0 Hz, 4.8 Hz, 1H), 7.01 (d, J=5.6 Hz, 1H), 4.12 (m, 1H), 2.13 (m, 2H), 1.79-1.63 (m, 10H). MS (ESI) m/z: 308 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:27]=[CH:26][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12]([CH:16]=[C:17]4[S:21][C:20](SCC)=[N:19][C:18]4=[O:25])=[CH:13][CH:14]=3)[CH:9]=[N:8]2)=[C:4]([C:28]([F:31])([F:30])[F:29])[CH:3]=1.[C:32]([O:36][C:37](=[O:45])[NH:38][C@@H:39]1[CH2:44][CH2:43][CH2:42][NH:41][CH2:40]1)([CH3:35])([CH3:34])[CH3:33]>>[C:32]([O:36][C:37](=[O:45])[NH:38][CH:39]1[CH2:44][CH2:43][CH2:42][N:41]([C:20]2[S:21][C:17](=[CH:16][C:12]3[CH:11]=[C:10]4[C:15](=[CH:14][CH:13]=3)[N:7]([CH2:6][C:5]3[CH:26]=[CH:27][C:2]([Cl:1])=[CH:3][C:4]=3[C:28]([F:30])([F:31])[F:29])[N:8]=[CH:9]4)[C:18](=[O:25])[N:19]=2)[CH2:40]1)([CH3:35])([CH3:33])[CH3:34].[NH2:38][C@@H:39]1[CH2:44][CH2:43][CH2:42][N:41]([C:20]2[S:21][C:17](=[CH:16][C:12]3[CH:11]=[C:10]4[C:15](=[CH:14][CH:13]=3)[N:7]([CH2:6][C:5]3[CH:26]=[CH:27][C:2]([Cl:1])=[CH:3][C:4]=3[C:28]([F:29])([F:31])[F:30])[N:8]=[CH:9]4)[C:18](=[O:25])[N:19]=2)[CH2:40]1
Reactant: CC(C)(C)OC(=O)N[C@@H]1CCCNC1
Reactant: CCSC1=NC(=O)C(=Cc2ccc3c(cnn3Cc3ccc(Cl)cc3C(F)(F)F)c2)S1
Product: CC(C)(C)OC(=O)NC1CCCN(C2=NC(=O)C(=Cc3ccc4c(cnn4Cc4ccc(Cl)cc4C(F)(F)F)c3)S2)C1
Product: N[C@@H]1CCCN(C2=NC(=O)C(=Cc3ccc4c(cnn4Cc4ccc(Cl)cc4C(F)(F)F)c3)S2)C1

Procedure:
(1-{5-[1-(4-Chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-4-oxo-4,5-dihydro-thiazol-2-yl}-piperidin-3-yl)-carbamic acid tert-butyl ester was prepared from 5-[1-(4-chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-ethylsulfanyl-thiazol-4-one and piperidin-3-(R)-yl-carbamic acid tert-butyl ester following General Procedure C. The compound was used directly following General Procedure H to provide 2-(3-(R)-Amino-piperidin-1-yl)-5-[1-(4-chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-thiazol-4-one.
Reaction SMILES: [Cl:1][C:2]1[C:10]2[CH:9]([CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])[O:8][B:7]([OH:17])[C:6]=2[CH:5]=[C:4]([OH:18])[CH:3]=1.IC.[C:21]([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[Cl:1][C:2]1[C:10]2[CH:9]([CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])[O:8][B:7]([OH:17])[C:6]=2[CH:5]=[C:4]([O:18][CH3:21])[CH:3]=1
Reactant: CCOC(=O)CC1OB(O)c2cc(O)cc(Cl)c21
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: CN(C)C=O
Product: CCOC(=O)CC1OB(O)c2cc(OC)cc(Cl)c21
Reaction time: 10 h
Yield: 31.4 %

Procedure:
To a mixture of ethyl 2-(4-chloro-1,6-dihydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-3-yl)acetate (150 mg, 0.55 mmol) and iodomethane (254 mg, 2.22 mL) in anhydrous DMF (2 mL) was added anhydrous K2CO3 (380 mg, 2.75 mmol). The reaction mixture was stirred for 10 h and concentrated under reduced pressure. The residue was purified by prep HPLC to give the title compound as a yellow oil (49.1 mg. Yield: 31%). 1H NMR (400 MHz, DMSO-d6) δ 9.45 (s, 1H), 7.22-7.23 (d, J=4.0 Hz, 1H), 7.14-7.15 (d, J=4.0 Hz, 1H), 5.45-5.48 (m, 1H), 4.03-4.09 (m, 2H), 3.81 (s, 3H), 3.21-3.25 (m, 1H), 2.39-2.45 (m, 1H), 1.14-1.17 (m, 3H).
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[C:3]([C:11]([NH:13][C:14]2[NH:15][C:16]3[C:22]([C:23]([OH:25])=O)=[CH:21][CH:20]=[CH:19][C:17]=3[N:18]=2)=[O:12])[N:2]=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[NH:59]1[C:63]2[CH2:64][CH2:65][CH2:66][CH2:67][C:62]=2[N:61]=[C:60]1[NH2:68]>CN(C=O)C>[NH:59]1[C:63]2[CH2:64][CH2:65][CH2:66][CH2:67][C:62]=2[N:61]=[C:60]1[NH:68][C:23]([C:22]1[C:16]2[N:15]=[C:14]([NH:13][C:11]([C:3]3[N:2]=[CH:1][C:10]4[C:5]([CH:4]=3)=[CH:6][CH:7]=[CH:8][CH:9]=4)=[O:12])[NH:18][C:17]=2[CH:19]=[CH:20][CH:21]=1)=[O:25]
Reactant: Nc1nc2c([nH]1)CCCC2
Reactant: O=C(Nc1nc2cccc(C(=O)O)c2[nH]1)c1cc2ccccc2cn1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=C(Nc1nc2c(C(=O)Nc3nc4c([nH]3)CCCC4)cccc2[nH]1)c1cc2ccccc2cn1
Temperature: 80 °C
Reaction time: 0.08 h
Yield: 13 %

Procedure:
To a solution of 70 mg (0.2 mmol) of 2-[(isoquinoline-3-carbonyl)-amino]-3H-benzoimidazole-4-carboxylic acid in DMF (2 mL) was added 100 mg (0.26 mmol) of HBTU and DIEA (0.3 mL). The mixture was stirred for 5 min, then 100 mg (0.7 mmol) of (4,5,6,7-tetrahydro-1H-benzoimidazol-2-ylamine was added. The resulting reaction mixture was heated at 80° C. for 1.5 h. After usual workup, the residue was purified by column chromatography eluting with DCM/EtOAc (v/v=11:1) to afford 12 mg (13%) of isoquinoline-3-carboxylic acid [4-(4,5,6,7-tetrahydro-1H-benzoimidazol-2-ylcarbamoyl)-1H-benzoimidazol-2-yl]-amide. LCMS: 452 (M+1)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[C:22]([CH3:23])=[CH:21][C:19]([NH2:20])=[C:18]([CH3:24])[CH:17]=1.Cl[C:26](Cl)([O:28][C:29](=[O:35])OC(Cl)(Cl)Cl)Cl.[CH2:37](O)[CH2:38][CH2:39][CH2:40][CH2:41]C.C(=O)(O)[O-].[Na+]>C(Cl)Cl.C(N(CC)CC)C.C1(C)C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[C:22]([CH3:23])=[CH:21][C:19]([NH:20][C:29](=[O:35])[O:28][CH2:26][CH2:37][CH2:38][CH2:39][CH2:40][CH3:41])=[C:18]([CH3:24])[CH:17]=1
Reactant: CCCCCCO
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: COc1cc2nccc(Oc3cc(C)c(N)cc3C)c2cc1OC
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: CCCCCCOC(=O)Nc1cc(C)c(Oc2ccnc3cc(OC)c(OC)cc23)cc1C
Yield: 110.4 %

Procedure:
4-[(6,7-Dimethoxy-4-quinolyl)oxy]-2,5-dimethylaniline (100 mg) was added to toluene (10 ml) and triethylamine (1 ml), and the mixture was heated under reflux to prepare a solution. A solution of triphosgene (140 mg) in methylene chloride was then added thereto, and the mixture was heated under reflux for 10 min. Next, 1-hexanol (48 mg) was added thereto, and the mixture was further stirred with heating under reflux for 3 hr. A saturated aqueous sodium bicarbonate solution was added to stop the reaction, and the reaction solution was then extracted with chloroform, followed by washing with a 1 N aqueous hydrochloric acid solution, water, and saturated brine in that order. The extract was dried over sodium sulfate and was then concentrated. The residue was purified on a column using chloroform/methanol to give the title compound (154 mg, yield 100%).
Reaction SMILES: Br[C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=[O:5].C(=O)([O-])[O-].[Na+].[Na+].[S:16]1[CH:20]=[CH:19][CH:18]=[C:17]1B(O)O>COCCOC>[S:16]1[CH:20]=[CH:19][CH:18]=[C:17]1[C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=[O:5]
Reactant: O=Cc1ccccc1Br
Reactant: OB(O)c1cccs1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Product: O=Cc1ccccc1-c1cccs1

Procedure:
To a mixture of 2-bromobenzaldehyde (1.17 mL, 10.0 mmol) and 2.0 M aqueous sodium carbonate (75 mL) in DME (225 mL) were added thiophene-2-boronic acid (1.53 g, 12.0 mmol) and tetrakis(triphenylphosphine)palladium[0] (578 mg, 0.5 mmol). The mixture was heated to reflux under nitrogen for 16 hr. The resulting solution was cooled, and the crude product was extracted from aqueous solution with ethyl acetate. The organic layer was dried over MgSO4, and the solvents were removed under vacuum. The crude product was purified on flash column with 25% DCM in hexane to yield 2-(2-thienyl)benzaldehyde.
Reaction SMILES: [C:1]1([CH:8]=[CH:7][CH:6]=[C:4]([OH:5])[CH:3]=1)[OH:2].[CH2:9](Cl)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.C([O-])([O-])=O.[K+].[K+]>O>[C:10]1([CH2:9][O:2][C:1]2[CH:3]=[C:4]([OH:5])[CH:6]=[CH:7][CH:8]=2)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: ClCc1ccccc1
Reactant: Oc1cccc(O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: Oc1cccc(OCc2ccccc2)c1
Yield: 27.1 %

Procedure:
36.6 g (332.40 mmol) of resorcinol and 42 g (331.78 mmol) of benzyl chloride are refluxed overnight in 250 ml of dry Me2CO in the presence of 46.6 g of K2CO3, with stirring. The mixture is cooled, filtered and evaporated. The residue obtained is diluted in 500 ml of water and extracted with ethanol. The organic layer is washed with 10% aqueous NaOH and extracted with ethanol. The red oil obtained is distilled with the aid of a bulb tube distillation apparatus to give 18 g of m-PhCH2OC6H4OH, b.p.15 240-245° C. (lit. b.p.11 202-210° C.). A solution of 3.3 g (16.5 mmol) of m-PhCH2OC6H4OH in 50 ml of DMF is treated with 0.8 g (16.5 mmol) of sodium hydride and the mixture is stirred for 15 minutes. After the addition of 13.75 ml (16.5 mmol) of epichlorohydrin, the mixture is stirred at 60° C. for one hour until alkylation is complete. The excess reagent and the solvent are evaporated off under reduced pressure and the residue is partitioned between the following two phases: ethyl acetate and water. The organic phase yields the epoxide, which is used without further purification.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:21]=[CH:22][C:23]=1[O:24][CH3:25])[CH2:6][CH:7]1[C:16]2[C:11](=[CH:12][C:13]([O:19][CH3:20])=[C:14]([O:17][CH3:18])[CH:15]=2)[CH2:10][CH2:9][NH:8]1.Br[CH2:27][C:28](Br)=[O:29].[CH3:31][O:32][C:33]1[CH:40]=[C:39]([O:41][CH3:42])[CH:38]=[CH:37][C:34]=1[CH2:35][NH2:36]>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:21]=[CH:22][C:23]=1[O:24][CH3:25])[CH2:6][CH:7]1[C:16]2[C:11](=[CH:12][C:13]([O:19][CH3:20])=[C:14]([O:17][CH3:18])[CH:15]=2)[CH2:10][CH2:9][N:8]1[CH2:27][C:28]([NH:36][CH2:35][C:34]1[CH:37]=[CH:38][C:39]([O:41][CH3:42])=[CH:40][C:33]=1[O:32][CH3:31])=[O:29]
Reactant: O=C(Br)CBr
Reactant: COc1ccc(CC2NCCc3cc(OC)c(OC)cc32)cc1OC
Reactant: COc1ccc(CN)c(OC)c1
Product: COc1ccc(CNC(=O)CN2CCc3cc(OC)c(OC)cc3C2Cc2ccc(OC)c(OC)c2)c(OC)c1

Procedure:
prepared by reaction of 1-(3,4-Dimethoxy-benzyl)-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline and 2-bromoacetyl bromide with 2,4-dimethoxybenzylamine
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][C:3]=1[F:9].C(=O)([O-])[O-].[K+].[K+].Cl[C:17]([F:27])([F:26])C(C1C=CC=CC=1)=O>C(#N)C.O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH:17]([F:27])[F:26])=[CH:4][C:3]=1[F:9]
Reactant: O=C(c1ccccc1)C(F)(F)Cl
Reactant: Oc1ccc(Br)c(F)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: O
Product: Fc1cc(OC(F)F)ccc1Br
Temperature: 80 °C
Yield: 78.3 %

Procedure:
To a solution of 4-bromo-3-fluoro-phenol (962 mg, 5.037 mmol) in acetonitrile (25 mL) was added a solution of potassium carbonate (28.3 g, 181 mmol) dissolved in water (25 mL) all under nitrogen. To the reaction mixture was added 2-chloro-2,2-difluoroacetophenone (5 g, 25 mmol) and the reaction was heated to 80° C. for 4 hours. The reaction was cooled to room temperature and extracted with ethyl acetate (3×50 mL). The organic layer was dried with sodium sulfate, filtered and concentrated onto silica gel. Silica gel chromotography (5% ethyl acetate 95% heptane to 100% ethyl acetate over 55 minutes) furnished a clear oil (950 mg, 78%). LCMS m/z 531.7 (M−1)1H NMR (400 MHz, METHANOL-d4) δ ppm 6.85 (s, 1H) 6.92 (dd, J=8.88, 2.63 Hz, 1H) 7.05 (t, 1H) 7.38 (t, 1H)