Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:13]=[C:12]([C:14]3[CH:19]=[CH:18][CH:17]=[C:16]([OH:20])[CH:15]=3)[C:11]([O:21][CH3:22])=[CH:10][N:9]=2)=[CH:4][CH:3]=1.[CH3:23][S:24](Cl)(=[O:26])=[O:25]>N1C=CC=CC=1>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:13]=[C:12]([C:14]3[CH:19]=[CH:18][CH:17]=[C:16]([O:20][S:24]([CH3:23])(=[O:26])=[O:25])[CH:15]=3)[C:11]([O:21][CH3:22])=[CH:10][N:9]=2)=[CH:6][CH:7]=1
Reactant: CS(=O)(=O)Cl
Reactant: COc1cnc(-c2ccc(F)cc2)nc1-c1cccc(O)c1
Solvent: c1ccncc1
Product: COc1cnc(-c2ccc(F)cc2)nc1-c1cccc(OS(C)(=O)=O)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 66 %

Procedure:
1.2 g of 2-(4-fluorophenyl)-4-(3-hydroxyphenyl)-5-methoxypyrimidine and 0.57 g of methanesulfonyl chloride were added to 10 ml of pyridine, and the resulting mixture was stirred for 3 hours at room temperature. After completion of the reaction, ice-cold water was added to the mixture. Subsequently, the mixture was extracted with ethyl acetate. The solvent was evaporated off, and the residue was purified by column chromatography on silica gel, thereby obtaining 1.0 g 2-(4-fluorophenyl)-4-(3-methanesulfonyloxyphenyl)-5-methoxypyrimidine (Compound 54).
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([C:10]2[CH:15]=[CH:14][C:13]([C:16]([OH:19])([CH3:18])[CH3:17])=[CH:12][C:11]=2[F:20])=[CH:5][C:6]=1[C:7]([NH2:9])=[O:8].Br[C:22]1[N:27]=[C:26]([CH2:28][NH:29][CH2:30][C:31]2[O:35][N:34]=[C:33]([CH:36]([CH3:38])[CH3:37])[N:32]=2)[CH:25]=[CH:24][CH:23]=1>>[F:20][C:11]1[CH:12]=[C:13]([C:16]([OH:19])([CH3:17])[CH3:18])[CH:14]=[CH:15][C:10]=1[C:4]1[S:3][C:2]([NH:1][C:22]2[CH:23]=[CH:24][CH:25]=[C:26]([CH2:28][NH:29][CH2:30][C:31]3[O:35][N:34]=[C:33]([CH:36]([CH3:38])[CH3:37])[N:32]=3)[N:27]=2)=[C:6]([C:7]([NH2:9])=[O:8])[CH:5]=1
Reactant: CC(C)c1noc(CNCc2cccc(Br)n2)n1
Reactant: CC(C)(O)c1ccc(-c2cc(C(N)=O)c(N)s2)c(F)c1
Product: CC(C)c1noc(CNCc2cccc(Nc3sc(-c4ccc(C(C)(C)O)cc4F)cc3C(N)=O)n2)n1

Procedure:
The title compound was prepared according to the general procedure in Example 1 using 2-amino-5-[2-fluoro-4-(1-hydroxy-1-methylethyl)phenyl]thiophene-3-carboxamide (116 mg, 0.393 mmol) and 1-(6-bromopyridin-2-yl)-N-[(3-isopropyl-1,2,4-oxadiazol-5-yl)methyl]methanamine (120 mg, 0.39 mmol) as the starting materials.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][C:4]1([CH3:18])[O:9][C:8]2[C:10]([CH3:17])=[C:11]([CH3:16])[C:12]([OH:15])=[C:13]([CH3:14])[C:7]=2[CH2:6][CH2:5]1.[ClH:19].[NH:20]([C:24]1[CH:32]=[CH:31][C:27]([C:28](O)=[O:29])=[CH:26][CH:25]=1)[C:21]([NH2:23])=[NH:22].C1(N=C=NC2CCCCC2)CCCCC1>N1C=CC=CC=1.CN(C)C=O>[ClH:19].[OH:15][C:12]1[C:11]([CH3:16])=[C:10]([CH3:17])[C:8]2[O:9][C:4]([CH2:3][CH2:2][NH:1][C:28](=[O:29])[C:27]3[CH:26]=[CH:25][C:24]([NH:20][C:21]([NH2:23])=[NH:22])=[CH:32][CH:31]=3)([CH3:18])[CH2:5][CH2:6][C:7]=2[C:13]=1[CH3:14]
Reactant: Cc1c(C)c2c(c(C)c1O)CCC(C)(CCN)O2
Reactant: N=C(N)Nc1ccc(C(=O)O)cc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cl
Solvent: c1ccncc1
Solvent: CN(C)C=O
Product: Cc1c(C)c2c(c(C)c1O)CCC(C)(CCNC(=O)c1ccc(NC(=N)N)cc1)O2
Reaction time: 60 h
Yield: 15.3 %

Procedure:
The amine (prepared in reference example 3, 1.0 g) and 4-guanidinobenzoic acid hydrochloride (0.95 g) were dissolved in the mixture of pyridine (5 ml) and dimethylformamide (5 ml). Dicyclohexylcarbodiimide (0.91 g) was added to the solution. The mixture was stirred for 2.5 days. The reaction solution was fitered. The filtrate was evaporated. The residue was dissolved in methanol (10 ml), and 1N hydrochloric acid (6 ml) was added to the solution. The solution was evaporated. The residue was purified by column chromatography on silica gel (methylene chloride:methanol=10:1) to give the title compound (275 mg) having the following physical data.
Reaction SMILES: [Li+].CC([N-]C(C)C)C.[CH2:9]([O:11][C:12](=[O:16])[CH:13]([CH3:15])[CH3:14])[CH3:10].[O:17]1[CH2:22][CH2:21][C:20](=[O:23])[CH2:19][CH2:18]1.[NH4+].[Cl-]>O1CCCC1.CCCCCC>[CH2:9]([O:11][C:12](=[O:16])[C:13]([C:20]1([OH:23])[CH2:21][CH2:22][O:17][CH2:18][CH2:19]1)([CH3:15])[CH3:14])[CH3:10]
Reactant: CCOC(=O)C(C)C
Reactant: O=C1CCOCC1
Agent: CC(C)[N-]C(C)C
Agent: [Cl-]
Agent: [Li+]
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CCOC(=O)C(C)(C)C1(O)CCOCC1
Temperature: -50 °C
Reaction time: 1 h
Yield: 92 %

Procedure:
Step A To a hexane solution (Aldrich, 2 M) of LDA (78 mL, 160 mmol) in tetrahydrofuran (100 mL) at −50° C. was added a solution of isobutyric acid ethyl ester (Alfa) (17 mL, 127 mmol) in tetrahydrofuran (20 mL) dropwise. The reaction mixture was stirred −50° C. for 1 h, then a tetrahydrofuran solution (10 mL) of tetrahydro-pyran-4-one (Aldrich) (9.8 g, 98 mmol) was added dropwise. The reaction mixture was warmed up to room temperature and stirred for 18 h. Aqueous saturated NH4Cl was added to quench the reaction. The mixture was extracted with ethyl ether. The organic layer was separated, and the aqueous layer was extracted with ethyl ether. The organic layers were combined, washed with brine, water, dried over MgSO4, and concentrated to give 2-(4-hydroxy-tetrahydro-pyran-4-yl)-2-methyl-propionic acid ethyl ester as a yellow oil (19.5 g, 92%).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]2[CH2:13][N:12]([C@@H:14]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[CH3:15])[C:11](=O)[CH2:10][O:9]2)=[CH:4][CH:3]=1.B.O1CCCC1.CO.BrC1C=CC([C@H](O)CN[C@@H](C2C=CC=CC=2)C)=CC=1>O1CCCC1>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C@@H:8]2[O:9][CH2:10][CH2:11][N:12]([C@@H:14]([C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=3)[CH3:15])[CH2:13]2)=[CH:6][CH:7]=1
Reactant: C[C@H](c1ccccc1)N1C[C@H](c2ccc(Br)cc2)OCC1=O
Agent: B
Agent: C[C@@H](NC[C@@H](O)c1ccc(Br)cc1)c1ccccc1
Solvent: C1CCOC1
Solvent: CO
Product: C[C@H](c1ccccc1)N1CCO[C@@H](c2ccc(Br)cc2)C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 76.9 %

Procedure:
To a ice-cooled solution of (6S)-6-(4-bromophenyl)-4-((1R)-1-phenylethyl) morpholin-3-one (intermediate 12, 92 g) obtained in step 1-10 in tetrahydrofuran (400 ml) was added dropwise over 30 minutes a borane-tetrahydrofuran complex (1.0 M solution in tetrahydrofuran, 600 ml, 600 mmol). After being warmed to room temperature and stirred for 2 hours, the mixture was ice-cooled again and added dropwise with methanol (70 ml). The solvent was evaporated under reduced pressure. The residue was added with methanol (750 ml) and 1 M aqueous sodium hydroxide (280 ml). The mixture was stirred at 80° C. for one hour, during which period 1 M aqueous sodium hydroxide (70 ml) was added 3 times in every 15 minutes. After the mixture was cooled to room temperature, methanol was evaporated under reduced pressure and the resulting solution was extracted with ethyl acetate. The organic layers was washed with water and brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure to give (25)-2-(4-bromophenyl)-4-((1R)-1-phenylethyl)morpholine (intermediate 13, 68 g, yield 88% from intermediate 11) as white crystals.
Reaction SMILES: [H-].[Na+].[CH2:3]([OH:13])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].[C:14](#[N:17])[CH:15]=[CH2:16]>C(OCC)C>[CH2:3]([O:13][CH2:16][CH2:15][C:14]#[N:17])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12]
Reactant: C=CC#N
Reactant: CCCCCCCCCCO
Agent: [H-]
Agent: [Na+]
Solvent: CCOCC
Product: CCCCCCCCCCOCCC#N
Temperature: 60 °C
Yield: 41.3 %

Procedure:
Sodium hydride (200 mg, 5 mmol; washed three times with hexane) was treated with 1-decanol (12 mL, 63 mmol) for 1 hour at room temperature. Acrylonitrile (10 mL, 152 mmol) was added dropwise and the resulting paste warmed to 60 ° C. for 2 hours. After cooling to room temperature, the paste was dissolved in diethyl ether and washed with copious water, one portion of brine, dried over magnesium sulfate, filtered and concentrated. Chromatography of the crude residue on silica gel using 25-75 ethyl acetate-hexane as eluant gave the title compound (5.5 g) as a water-white liquid. The structure was supported by NMR, infrared spectroscopy, elemental analysis and mass spectroscopy.
Reaction SMILES: [Cl:1][C:2]1[C:15]2[C:6](=[C:7]([C:16]([OH:18])=[O:17])[C:8]3[C:13]([CH:14]=2)=[CH:12][CH:11]=[CH:10][CH:9]=3)[C:5]([C:19](O)=[O:20])=[CH:4][CH:3]=1.C(OC(=O)C)(=O)C>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[C:19](=[O:20])[O:18][C:16](=[O:17])[C:7]3=[C:8]4[C:13](=[CH:14][C:15]=1[C:6]=23)[CH:12]=[CH:11][CH:10]=[CH:9]4
Reactant: O=C(O)c1ccc(Cl)c2cc3ccccc3c(C(=O)O)c12
Solvent: CC(=O)OC(C)=O
Product: O=C1OC(=O)c2c3ccccc3cc3c(Cl)ccc1c23
Temperature: 170 °C
Reaction time: 8 h
Yield: 93 %

Procedure:
4-chloro-anthracene-1,9-dicarboxylic acid (1.6 g, 5.35 mmol) was placed in a 50 ml flask and mixed with 25 ml of acetic anhydride. The mixture was refluxed under argon at 170° C. for six hours and left at room temperature overnight to crystallize. An orange precipitate was collected by filtration, washed five times with dry diethyl ether (15 ml), and dried under vacuum overnight. The yield was 93%.
Reaction SMILES: [H-].C([Al+]CC(C)C)C(C)C.[C:11]([O:15][C:16]([NH:18][C@@H:19]1[CH2:25][CH2:24][C@@H:23]([C:26]2[CH:31]=[CH:30][CH:29]=[C:28]([F:32])[C:27]=2[F:33])[CH2:22][N:21]2[C:34]([CH2:37][C:38](OC)=[O:39])=[CH:35][N:36]=[C:20]12)=[O:17])([CH3:14])([CH3:13])[CH3:12].C(C(C(C([O-])=O)O)O)([O-])=O.[Na+].[K+]>ClCCl>[F:33][C:27]1[C:28]([F:32])=[CH:29][CH:30]=[CH:31][C:26]=1[C@H:23]1[CH2:22][N:21]2[C:34]([CH2:37][CH2:38][OH:39])=[CH:35][N:36]=[C:20]2[C@H:19]([NH:18][C:16](=[O:17])[O:15][C:11]([CH3:13])([CH3:12])[CH3:14])[CH2:25][CH2:24]1
Reactant: COC(=O)Cc1cnc2n1C[C@H](c1cccc(F)c1F)CC[C@H]2NC(=O)OC(C)(C)C
Agent: CC(C)C[Al+]CC(C)C
Agent: O=C([O-])C(O)C(O)C(=O)[O-]
Agent: [H-]
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N[C@@H]1CC[C@@H](c2cccc(F)c2F)Cn2c(CCO)cnc21
Reaction time: 1 h
Yield: 71.3 %

Procedure:
Diisobutylaluminum hydride (1.0 M in hexanes; 3.77 mL, 3.77 mmol) was added to a solution of methyl [(6S,9R)-9-[(tert-butoxycarbonyl)amino]-6-(2,3-difluorophenyl)-6,7,8,9-tetrahydro-5H-imidazo[1,2-a]azepin-3-yl]acetate (328 mg, 0.75 mmol) in dichloromethane (12 mL) at 0° C. After 1 h, saturated aqueous potassium sodium tartrate was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with brine, dried over magnesium sulfate, filtered and concentrated. Purification by silica gel chromatography (100% dichloromethane→94% dichloromethane/methanol) gave the title compound (218 mg). MS 408.1 (M+1).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([NH2:10])[C:5]([NH:8][CH3:9])=[CH:6][CH:7]=1.[C:11](Cl)(Cl)=[O:12].C(N(CC)CC)C.Cl>C(Cl)Cl.C1(C)C=CC=CC=1>[Br:1][C:2]1[CH:7]=[CH:6][C:5]2[N:8]([CH3:9])[C:11](=[O:12])[NH:10][C:4]=2[CH:3]=1
Reactant: O=C(Cl)Cl
Reactant: CNc1ccc(Br)cc1N
Agent: Cl
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cn1c(=O)[nH]c2cc(Br)ccc21
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
A solution of 4-bromo-N1-methylbenzene-1,2-diamine (581 mg, 2.89 mmol) in methylene chloride (50 mL) was cooled to 0° C. in an ice/water bath and treated dropwise with a solution of 20% phosgene in toluene (1.52 mL). When the addition was complete, triethylamine (585 mg, 5.78 mmol) was added and the reaction stirred at 0° C. for 30 min. After this time, the reaction was poured into 1 M hydrochloric acid (80 mL) and extracted with methylene chloride. The combined organic layers were washed with water and dried over sodium sulfate. The drying agent was removed by filtration and the filtrate concentrated under reduced pressure. The resulting residue was purified by trituration with ethyl acetate to afford 5-bromo-1-methyl-1H-benzo[d]imidazol-2(3H)-one. 1H NMR (400 MHz, DMSO-d6) δ 10.98 (bs, 1H), 7.17 (dd, J=8.4, 1.6 Hz, 1H), 7.10 (d, J=1.6 Hz, 1H), 7.05 (d, J=8.4 Hz, 1H), 3.26 (s, 3H).
Reaction SMILES: [N:1]1([C:7]2[CH:12]=[C:11]([NH2:13])[CH:10]=[CH:9][N:8]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[CH3:14][O:15][C:16](=[O:30])[C:17]([C:19]1[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[C:22](Br)=[CH:21][CH:20]=1)=[O:18].C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1>C1(C)C=CC=CC=1.O1CCOCC1.CC([O-])=O.CC([O-])=O.[Pd+2]>[CH3:14][O:15][C:16](=[O:30])[C:17]([C:19]1[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[C:22]([NH:13][C:11]2[CH:10]=[CH:9][N:8]=[C:7]([N:1]3[CH2:2][CH2:3][O:4][CH2:5][CH2:6]3)[CH:12]=2)=[CH:21][CH:20]=1)=[O:18]
Reactant: Nc1ccnc(N2CCOCC2)c1
Reactant: COC(=O)C(=O)c1ccc(Br)c2ccccc12
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: c1ccc(P(c2ccccc2)c2ccc3ccccc3c2-c2c(P(c3ccccc3)c3ccccc3)ccc3ccccc23)cc1
Solvent: C1COCCO1
Solvent: Cc1ccccc1
Product: COC(=O)C(=O)c1ccc(Nc2ccnc(N3CCOCC3)c2)c2ccccc12
Reaction time: 18 h
Yield: 40.6 %

Procedure:
2-Morpholin-4-yl-pyridin-4-ylamine (159 mg, 0.88 mmol) and (4-Bromo-naphthalen-1-yl)-oxo-acetic acid methyl ester (18) (260 mg, 0.89 mmol) were suspended in 6 mL toluene/Dioxane 1/1 and Pd(OAc)2 (6 mg, 3 mol %), BINAP (27 mg, 5 mol %) and CS2CO3 (858 mg, 2.64 mmol) were added. The reaction mixture was stirred from 80° C. to 80° C. over 18 hrs. The cooled mixture was purified by column chromatography (0-100% EtOAc/Hex) to yield 140 mg of product. This product was subjected to the methods described previously to obtain the final compounds of interest.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([O:15][CH3:16])=[C:6]([CH:14]=1)CC1SC(N)=NC=1.ClC(CC1C=C(F)C=CC=1OC)C=O.[NH2:31]C(N)=S>C(O)C>[F:1][C:2]1[CH:3]=[CH:4][C:5]([O:15][CH3:16])=[C:6]([NH2:31])[CH:14]=1
Reactant: COc1ccc(F)cc1Cc1cnc(N)s1
Reactant: NC(N)=S
Agent: COc1ccc(F)cc1CC(Cl)C=O
Solvent: CCO
Product: COc1ccc(F)cc1N

Procedure:
5-(5-Fluoro-2-methoxy-benzyl)-thiazol-2-ylamine A mixture of 2-chloro-3-(5-fluoro-2-methoxy-phenyl)-propionaldehyde (crude from above) and thiourea (29.2 g, 0.384 mol) in ethanol (400 mL) was heated to reflux for 15 hours. The solvent was removed and the residue was diluted with dichloromethane (300 mL), sodium hydroxide (10% aqueous solution, 150 mL) and water (200 mL). The aqueous phase was extracted twice with dichloromethane (150 mL). The combined organic layer was washed with water, a saturated aqueous solution of sodium chloride, dried over sodium sulfate, and evaporated to dryness. The crude product was recrystallized from a mixture of ethyl acetate and hexanes to give the pure product (6.5 g, 0.027 mol, 6.2% from 5-fluoro-2-methoxy-phenylamine). ESI-MS m/z calc. 238.1, found 239.2 (M+1)+ 1H NMR(CDCl3): δ 6.90-6.81 (m, 2 H), 6.79-6.76 (m, 2 H), 4.75 (br, 2 H), 3.91 (s, 2 H), 3.82 (s, 3 H).
Reaction SMILES: [NH:1]1[C:5]2=[N:6][CH:7]=[CH:8][C:9]([NH:10][C:11](=[O:31])[C:12]3[CH:17]=[CH:16][C:15]([C@H:18]([NH:20]C(OCC4C=CC=CC=4)=O)[CH3:19])=[CH:14][CH:13]=3)=[C:4]2[CH:3]=[CH:2]1.[ClH:32].CO>[C+4].[OH-].[Pd+2].[OH-].[OH-].[OH-].[OH-].[OH-].CO>[ClH:32].[ClH:32].[NH:1]1[C:5]2=[N:6][CH:7]=[CH:8][C:9]([NH:10][C:11](=[O:31])[C:12]3[CH:17]=[CH:16][C:15]([C@H:18]([NH2:20])[CH3:19])=[CH:14][CH:13]=3)=[C:4]2[CH:3]=[CH:2]1
Reactant: C[C@@H](NC(=O)OCc1ccccc1)c1ccc(C(=O)Nc2ccnc3[nH]ccc23)cc1
Agent: [Pd+2]
Agent: Cl
Agent: [C+4]
Solvent: CO
Product: C[C@@H](N)c1ccc(C(=O)Nc2ccnc3[nH]ccc23)cc1
Temperature: 40 °C
Reaction time: 1 h

Procedure:
To a mixture of (R)-N-(1H-pyrrolo[2,3-b]pyridin-4-yl)-4-(1-benzyloxycarbonylaminoethyl)benzamide (200 mg), 15% hydrochloric acid-methanol (1 mL) and methanol (6 mL) was added 10% palladium hydroxide carbon (80 mg), and the mixture was stirred under a hydrogen stream at 40° C. for 1 hr. After the reaction, the catalyst was filtered off and the residue was concentrated under reduced pressure. The obtained crystals were recrystallized from methanol-ether to give (R)-(+)-N-(1H-pyrrolo[2,3-b]pyridin-4-yl)-4-(1-aminoethyl)benzamide dihydrochloride 3/2 hydrate (120 mg), melting point: 286° C. (decomposition).
Reaction SMILES: [C:1]([C:9]1[NH:10][CH:11]=[CH:12][CH:13]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[CH:15]([C:21]([O:23][CH2:24][CH3:25])=[O:22])[C:16]([O:18][CH2:19][CH3:20])=[O:17].C(B(CC)CC)C.O>C1C=CC=CC=1>[C:1]([C:9]1[NH:10][C:11]([CH:15]([C:16]([O:18][CH2:19][CH3:20])=[O:17])[C:21]([O:23][CH2:24][CH3:25])=[O:22])=[CH:12][CH:13]=1)(=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)C(Br)C(=O)OCC
Reactant: O=C(c1ccccc1)c1ccc[nH]1
Agent: CCB(CC)CC
Solvent: c1ccccc1
Solvent: O
Product: CCOC(=O)C(C(=O)OCC)c1ccc(C(=O)c2ccccc2)[nH]1
Reaction time: 1 h
Yield: 86.2 %

Procedure:
To a solution of 2-benzoylpyrrole (171mg, 1 mmol) and diethyl bromomalonate (1185 mg, 5 mmol) in benzene (20 mL) was added triethylborane (1.0 M in hexane, 5 mL, 5 mmol). The reaction mixture was stirred for 1 hour in an open vessel. Additional triethylborane (1 mL, 1 mmol) was added and the reaction was stirred for an additional hour. The mixture was poured into water and extracted with diethyl ether. The ethereal extract was washed with saturated aqueous sodium chloride, dried (Na2SO4), and concentrated. The residue was purified by column chromatography on silica eluting with hexane/ethyl acetate (87:13) to provide 284 mg (86%) of diethyl (5-benzoylpyrrol-2-yl)methane-dicarboxylate.
Reaction SMILES: [CH2:1]([C:5]1[N:9]([CH2:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]3[C:18]([C:23]([O:25]C(C)(C)C)=[O:24])=[CH:19][CH:20]=[CH:21][CH:22]=3)=[CH:13][CH:12]=2)[C:8]2[CH:30]=[C:31]([N:34]([C:43]([NH:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH3:51])=[O:44])[CH2:35][CH2:36][C:37]3[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=3)[CH:32]=[CH:33][C:7]=2[N:6]=1)[CH2:2][CH2:3][CH3:4].FC(F)(F)C(O)=O>>[CH2:1]([C:5]1[N:9]([CH2:10][C:11]2[CH:12]=[CH:13][C:14]([C:17]3[C:18]([C:23]([OH:25])=[O:24])=[CH:19][CH:20]=[CH:21][CH:22]=3)=[CH:15][CH:16]=2)[C:8]2[CH:30]=[C:31]([N:34]([C:43]([NH:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH3:51])=[O:44])[CH2:35][CH2:36][C:37]3[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=3)[CH:32]=[CH:33][C:7]=2[N:6]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCCCNC(=O)N(CCc1ccccc1)c1ccc2nc(CCCC)n(Cc3ccc(-c4ccccc4C(=O)OC(C)(C)C)cc3)c2c1
Solvent: O=C(O)C(F)(F)F
Product: CCCCCCNC(=O)N(CCc1ccccc1)c1ccc2nc(CCCC)n(Cc3ccc(-c4ccccc4C(=O)O)cc3)c2c1

Procedure:
Prepared in analogous manner to Example 9 from tert.butyl 4'-[(2-n-butyl-6-(N-(n-hexylaminocarbonyl)-N-(2-phenylethyl)-amino)-benzimidazol-1-yl)-methyl]biphenyl-2-carboxylate and trifluoroacetic acid.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]([NH:11][C:12]([C:14]2[CH:22]=[C:21]3[C:17]([CH2:18][CH2:19][N:20]3[S:23]([C:26]3[CH:31]=[CH:30][C:29]([Cl:32])=[C:28]([Cl:33])[CH:27]=3)(=[O:25])=[O:24])=[CH:16][CH:15]=2)=[O:13])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].Cl[C:35]1C=C(S(Cl)(=O)=O)C=CC=1Cl>>[CH3:35][O:5][C:4](=[O:6])[C:3]1[CH:7]=[CH:8][C:9]([NH:11][C:12]([C:14]2[CH:22]=[C:21]3[C:17]([CH2:18][CH2:19][N:20]3[S:23]([C:26]3[CH:31]=[CH:30][C:29]([Cl:32])=[C:28]([Cl:33])[CH:27]=3)(=[O:25])=[O:24])=[CH:16][CH:15]=2)=[O:13])=[CH:10][C:2]=1[Cl:1]
Reactant: O=C(Nc1ccc(C(=O)O)c(Cl)c1)c1ccc2c(c1)N(S(=O)(=O)c1ccc(Cl)c(Cl)c1)CC2
Reactant: O=S(=O)(Cl)c1ccc(Cl)c(Cl)c1
Product: COC(=O)c1ccc(NC(=O)c2ccc3c(c2)N(S(=O)(=O)c2ccc(Cl)c(Cl)c2)CC3)cc1Cl

Procedure:
2-Chloro-4-{[1-(3,4-dichloro-benzenesulfonyl)-2,3-dihydro-1H-indole-6-carbonyl]-amino}-benzoic acid, m/z (ES+): 525.18 (M+H+.), was prepared in analogy to example 1, steps 1 to 5. Step 4 was performed using 3,4-dichloro-benzenesulfonyl chloride and yielded 2-chloro-4-{[1-(3,4-dichloro-benzenesulfonyl)-2,3-dihydro-1H-indole-6-carbonyl]-amino}-benzoic acid methyl ester, which was hydrolyzed in step 5.
Reaction SMILES: [O:1]=[C:2]([N:9]1[CH2:14][CH2:13][O:12][CH2:11][CH2:10]1)[CH2:3][CH2:4][CH2:5][C:6]([OH:8])=O.[CH3:15][O:16][C:17]1[CH:32]=[CH:31][C:20]([C:21]([NH:23][C:24]2[C:25]([NH2:30])=[CH:26][CH:27]=[CH:28][CH:29]=2)=[O:22])=[CH:19][CH:18]=1>C(Cl)Cl>[CH3:15][O:16][C:17]1[CH:18]=[CH:19][C:20]([C:21]([NH:23][C:24]2[C:25]([NH:30][C:6](=[O:8])[CH2:5][CH2:4][CH2:3][C:2](=[O:1])[N:9]3[CH2:14][CH2:13][O:12][CH2:11][CH2:10]3)=[CH:26][CH:27]=[CH:28][CH:29]=2)=[O:22])=[CH:31][CH:32]=1
Reactant: O=C(O)CCCC(=O)N1CCOCC1
Reactant: COc1ccc(C(=O)Nc2ccccc2N)cc1
Solvent: ClCCl
Product: COc1ccc(C(=O)Nc2ccccc2NC(=O)CCCC(=O)N2CCOCC2)cc1
Yield: 85 %

Procedure:
Using the procedure described in Example 161, 5-oxo-5-morpholinopentanoic acid (166 mg, 0.826 mmol) was reacted with N1-(4-methoxybenzoyl)-1,2-benzenediamine. The reaction mixture was diluted with additional methylene chloride and washed with 1 N aqueous sodium hydroxide. The organic phase was washed with 1 N aqueous hydrochloric acid, dried (sodium sulfate), filtered, and concentrated in vacuo to provide 300 mg (85%) of the title compound as an amorphous white solid.
Reaction SMILES: [Cl:1][C:2]1[C:10]([F:11])=[C:9]2[C:5]([C:6]([S:20][C:21]3[CH:22]=[C:23]([CH:29]=[CH:30][CH:31]=3)[C:24]([O:26][CH2:27][CH3:28])=[O:25])=[CH:7][N:8]2[C:12]2[CH:13]=[N:14][N:15]([CH2:17][CH2:18][CH3:19])[CH:16]=2)=[CH:4][CH:3]=1.C1C(=O)N([Cl:39])C(=O)C1>C(Cl)Cl.O>[Cl:39][C:7]1[N:8]([C:12]2[CH:13]=[N:14][N:15]([CH2:17][CH2:18][CH3:19])[CH:16]=2)[C:9]2[C:5]([C:6]=1[S:20][C:21]1[CH:22]=[C:23]([CH:29]=[CH:30][CH:31]=1)[C:24]([O:26][CH2:27][CH3:28])=[O:25])=[CH:4][CH:3]=[C:2]([Cl:1])[C:10]=2[F:11]
Reactant: CCCn1cc(-n2cc(Sc3cccc(C(=O)OCC)c3)c3ccc(Cl)c(F)c32)cn1
Reactant: O=C1CCC(=O)N1Cl
Solvent: O
Solvent: ClCCl
Product: CCCn1cc(-n2c(Cl)c(Sc3cccc(C(=O)OCC)c3)c3ccc(Cl)c(F)c32)cn1
Reaction time: 16 h
Yield: 63.5 %

Procedure:
To a stirred solution of compound 4 (150 mg, 0.32 mmol) in CH2Cl2 (3 mL) under inert atmosphere was added NCS (87 mg, 0.65 mmol) at RT. After 16 h stirring, NCS (87 mg, 0.65 mmol) was added again at RT and stirred for additional 24 h. The reaction was monitored by TLC; after completion of the reaction, the reaction mixture was diluted with water (15 mL) and extracted with CH2Cl2 (2×20 mL). The combined organic extracts were washed with water (15 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to obtain the crude. This was purified by silica gel column chromatography using 7% EtOAc/n-Hexane to afford compound 5 (100 mg, 62%) as a brown solid. 1H NMR (500 MHz, CDCl3): δ 7.89 (s, 1H), 7.80-7.79 (m, 1H), 7.67 (s, 1H), 7.65 (s, 1H), 7.28-7.26 (m, 3H), 7.17-7.14 (m, 1H), 4.33 (q, J=7.5 Hz, 2H), 4.18 (t, J=7.5 Hz, 2H), 2.00-1.95 (m, 2H), 1.36 (t, J=7.5 Hz, 3H), 0.98 (t, J=7.5 Hz, 3H); LC-MS (ESI): 97.6%; m/z 492.4 (M+H+); (column: X Select CSH C-18, 50×3.0 mm, 3.5 μm); RT 5.07 min; 5 mM NH4OAc: ACN; 0.8 mL/min).
Reaction SMILES: C(OC([N:8]1[CH2:12][CH2:11][CH2:10][C@@H:9]1[CH2:13][O:14][C:15]1[CH:20]=[CH:19][C:18]([O:21][C:22]2[CH:27]=[CH:26][C:25]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)=[CH:24][CH:23]=2)=[CH:17][CH:16]=1)=O)(C)(C)C.[ClH:34]>O1CCOCC1>[ClH:34].[C:25]1([C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=2)[CH:24]=[CH:23][C:22]([O:21][C:18]2[CH:19]=[CH:20][C:15]([O:14][CH2:13][C@H:9]3[CH2:10][CH2:11][CH2:12][NH:8]3)=[CH:16][CH:17]=2)=[CH:27][CH:26]=1
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H]1COc1ccc(Oc2ccc(-c3ccccc3)cc2)cc1
Agent: Cl
Solvent: C1COCCO1
Product: c1ccc(-c2ccc(Oc3ccc(OC[C@H]4CCCN4)cc3)cc2)cc1
Yield: 62 %

Procedure:
Following the general procedure for Example 11 (step 4), the product from step 3 (0.2 g, 0.45 mmol) was treated with 4M HCl in dioxane (5 mL) to afford the title product (0.11 g, 62%) as a white solid; 1H NMR (400 MHz, DMSO-d6) 1.75 (m, 1H), 1.88-2.02 (m, 2H), 2.12 (m 1H), 3.23 (m, 2H), 3.91 (m, 1H), 4.14 (m 1H), 4.26 (dd, J1=3.8 Hz, J2=10.4 Hz, 1H), 7.00 (d, J=8.8 Hz, 2H), 7.04-7.11 (m, 4H), 7.34 (m, 1H), 7.45 (m, 2H), 7.61-7.66 (m, 4H); MS (m/z) 346.7 (M+1); LC (98.9%); Elemental Analysis (Calc): C, 72.34; H, 6.33; N, 3.67. (Found): C, 71.72; H, 6.29; N, 3.66.