Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[N:6]([C:7]2[C:12]([F:13])=[C:11]([F:14])[C:10]([C:15]([F:18])([F:17])[F:16])=[C:9]([F:19])[C:8]=2[F:20])[N:5]=[CH:4][CH:3]=1.[C:21](OC(=O)C)(=[O:23])[CH3:22]>C(O)(=O)C>[F:20][C:8]1[C:9]([F:19])=[C:10]([C:15]([F:18])([F:17])[F:16])[C:11]([F:14])=[C:12]([F:13])[C:7]=1[N:6]1[C:2]([NH:1][C:21]([CH3:22])=[O:23])=[CH:3][CH:4]=[N:5]1
Reactant: Nc1ccnn1-c1c(F)c(F)c(C(F)(F)F)c(F)c1F
Reactant: CC(=O)OC(C)=O
Solvent: CC(=O)O
Product: CC(=O)Nc1ccnn1-c1c(F)c(F)c(C(F)(F)F)c(F)c1F
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A mixture of 7.48 grams (0.0250 mole) of 5-amino-1-(2,3,5,6-tetrafluoro-4-trifluoromethylphenyl)pyrazole, 21.0 mL of glacial acetic acid, and 3.1 mL of acetic anhydride was stirred at room temperature for approximately 18 hours. The reaction mixture was poured into 100 mL of ice-water, forming a white precipitate. This solid was collected by filtration and washed in succession with dilute acetic acid and water. The washed solid was dried to yield 8.1 grams of 1-(2,3,5,6-tetrafluoro-4-trifluoromethylphenyl)-5-methylcarbonylaminopyrazole, m.p. 103-105° C. The nmr spectrum was consistent with the proposed structure.
Reaction SMILES: [C:1]([NH2:9])(=[NH:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N+:10]([C:13]1[CH:24]=[CH:23][C:16]([CH:17]=[CH:18][S:19](Cl)(=[O:21])=[O:20])=[CH:15][CH:14]=1)([O-:12])=[O:11]>>[N+:10]([C:13]1[CH:14]=[CH:15][C:16]([CH:17]=[CH:18][S:19]([NH:8][C:1](=[NH:9])[C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)(=[O:21])=[O:20])=[CH:23][CH:24]=1)([O-:12])=[O:11]
Reactant: O=[N+]([O-])c1ccc(C=CS(=O)(=O)Cl)cc1
Reactant: N=C(N)c1ccccc1
Product: N=C(NS(=O)(=O)C=Cc1ccc([N+](=O)[O-])cc1)c1ccccc1

Procedure:
Reaction of benzamidine with 4-nitrostyrylsulfonyl chloride according to the above procedure affords N-(4-NITROSTYRYLSULFONYL)BENZAMIDINE m.p. 173°-175° C., by triturating with methanol.
Reaction SMILES: [CH3:1][C:2]1([CH3:14])[C@@H:4](/[CH:5]=[CH:6]/[C:7]([O:9][CH3:10])=[O:8])[C@H:3]1[C:11](Cl)=[O:12].[C:15]([OH:19])([CH3:18])([CH3:17])[CH3:16]>C1C=CC=CC=1.C(Cl)(Cl)Cl>[CH3:1][C:2]1([CH3:14])[C@@H:4](/[CH:5]=[CH:6]/[C:7]([O:9][CH3:10])=[O:8])[C@H:3]1[C:11]([O:19][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:12]
Reactant: CC(C)(C)O
Reactant: COC(=O)/C=C/[C@H]1[C@@H](C(=O)Cl)C1(C)C
Solvent: ClC(Cl)Cl
Solvent: c1ccccc1
Product: COC(=O)/C=C/[C@H]1[C@@H](C(=O)OC(C)(C)C)C1(C)C

Procedure:
Using the procedure of Example 3, 1.51 g of (1R,cis) 2,2-dimethyl-3-[(E)-3-methoxy-3-oxo-1-propenyl]-cyclopropane-1-carboxylic acid chloride in benzene and 0.754 ml of tert.-butanol were reacted to obtain 0.235 g of tert.-butyl (1R,cis) 2,2-dimethyl-3-[(E)-3-methoxy-3-oxo-1-propenyl]-cyclo-propane-1-carboxylate with a specific rotation of [α]D20 =-23°±1.5°(c=0.9% in chloroform).
Reaction SMILES: [Si:1]([O:18][CH2:19][C:20]1[N:25]=[C:24]2[C:26]([C:29]([O:31]CC)=O)=[N:27][O:28][C:23]2=[C:22]([Cl:34])[C:21]=1[N:35]1[CH2:40][C@H:39]([CH3:41])[O:38][C@H:37]([CH3:42])[CH2:36]1)([C:14]([CH3:17])([CH3:16])[CH3:15])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:43]([NH2:47])([CH3:46])([CH3:45])[CH3:44]>>[C:43]([NH:47][C:29]([C:26]1[C:24]2=[N:25][C:20]([CH2:19][O:18][Si:1]([C:14]([CH3:16])([CH3:17])[CH3:15])([C:8]3[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=3)[C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)=[C:21]([N:35]3[CH2:36][C@H:37]([CH3:42])[O:38][C@H:39]([CH3:41])[CH2:40]3)[C:22]([Cl:34])=[C:23]2[O:28][N:27]=1)=[O:31])([CH3:46])([CH3:45])[CH3:44]
Reactant: CCOC(=O)c1noc2c(Cl)c(N3C[C@@H](C)O[C@@H](C)C3)c(CO[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)nc12
Reactant: CC(C)(C)N
Product: C[C@@H]1CN(c2c(CO[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)nc3c(C(=O)NC(C)(C)C)noc3c2Cl)C[C@H](C)O1

Procedure:
Starting material: ethyl 5-((tert-butyldiphenylsilyloxy)methyl)-7-chloro-6-((2R,6S)-2,6-dimethylmorpholino)isoxazolo[4,5-b]pyridine-3-carboxylate (Intermediate 211) and t-butylamine.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]([CH2:17][C@H:18]([N:20]([CH2:28][CH2:29][O:30][C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=2[O:37][CH2:38][CH3:39])C(=O)OC(C)(C)C)[CH3:19])[CH:7]=[C:8]2[C:12]=1[N:11]([CH2:13][CH2:14][CH2:15][OH:16])[CH:10]=[CH:9]2)(=[O:3])[NH2:2].Cl.C(=O)(O)[O-].[Na+]>C(O)(C)C>[CH2:38]([O:37][C:32]1[CH:33]=[CH:34][CH:35]=[CH:36][C:31]=1[O:30][CH2:29][CH2:28][NH:20][C@H:18]([CH3:19])[CH2:17][C:6]1[CH:7]=[C:8]2[C:12](=[C:4]([C:1]([NH2:2])=[O:3])[CH:5]=1)[N:11]([CH2:13][CH2:14][CH2:15][OH:16])[CH:10]=[CH:9]2)[CH3:39]
Reactant: CCOc1ccccc1OCCN(C(=O)OC(C)(C)C)[C@H](C)Cc1cc(C(N)=O)c2c(ccn2CCCO)c1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(C)O
Product: CCOc1ccccc1OCCN[C@H](C)Cc1cc(C(N)=O)c2c(ccn2CCCO)c1
Yield: 35 %

Procedure:
tert-Butyl (R)-N-[2-[7-carbamoyl-1-(3-hydroxy-propyl)-1H-indol-5-yl]-1-methylethyl]-N-[2-(2-ethoxyphenoxy)ethyl]carbamate (4.45 g) was dissolved in isopropanol (50 ml), and concentrated hydrochloric acid (25 ml) was added portionwise to the solution under ice-cooling with stirring. After the mixture was stirred for 3 hours at room temperature, a saturated aqueous sodium bicarbonate solution was added to the reaction mixture under ice-cooling and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with brine, and dried over anhydrous sodium sulfate. The solvent was removed in vacuo, and the residue was purified by column chromatography on aminopropyl silica gel (eluent: methylene chloride/methanol=20/1) to give white amorphous (R)-5-[2-[[2-(2-ethoxyphenoxy)ethyl]amino]-propyl]-1-(3-hydroxypropyl)-1H-indole-7-carboxamide (1.27 g). Unpurified mixture was further purified by column chromatography on aminopropyl silica gel (eluent:ethyl acetate/ethanol=7/1) and the purified product was combined with the previously purified product to give white amorphous (R)-5-[2-[[2-(2-ethoxyphenoxy)ethyl]amino]propyl]-1-(3-hydroxypropyl)-1H-indole-7-carboxamide (2.39 g).
Reaction SMILES: [Cl:1][C:2]1[CH:16]=[CH:15][C:5]([CH2:6][N:7]2[CH:12]=[C:11](Br)[CH:10]=[CH:9][C:8]2=[O:14])=[C:4]([F:17])[CH:3]=1.[CH3:18][O:19][C:20]1[N:25]=[CH:24][C:23](B(O)O)=[CH:22][CH:21]=1>O1CCOCC1.[O-]P([O-])([O-])=O.[K+].[K+].[K+].CCOC(C)=O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Cl:1][C:2]1[CH:16]=[CH:15][C:5]([CH2:6][N:7]2[CH:12]=[C:11]([C:23]3[CH:24]=[N:25][C:20]([O:19][CH3:18])=[CH:21][CH:22]=3)[CH:10]=[CH:9][C:8]2=[O:14])=[C:4]([F:17])[CH:3]=1
Reactant: COc1ccc(B(O)O)cn1
Reactant: O=c1ccc(Br)cn1Cc1ccc(Cl)cc1F
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: COc1ccc(-c2ccc(=O)n(Cc3ccc(Cl)cc3F)c2)cn1
Temperature: 80 °C
Yield: 91 %

Procedure:
According to Scheme 3 Method A: To a mixture of 1-(4-chloro-2-fluorobenzyl)-5-bromopyridin-2(1H)-one (1 eq, 1.00 mmol, 0.40 g) in dioxane/K3PO4 (2M, 10 mL), were added Pd(PPh3)4 (0.3 eq, 0.4 mmol, 0.4 g) and 6-methoxypyridin-3-ylboronic acid (1.5 eq, 2.00 mmol, 0.30 g) then the reaction mixture was heated at 80° C. for 17 hours. The mixture was diluted with AcOEt. The organic fraction washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure. The crude product was purified by silica gel chromatography (AIT Flashsmart prepacked column 25 g SiO2, CH2Cl2/AcOEt 70/30) and by crystallization in pentane/Et2O to afford 1-(4-chloro-2-fluorobenzyl)-5-(6-methoxypyridin-3-yl)pyridin-2(1H)-one (0.91 mmol, 0.40 g, 91%) as a white solid.
Reaction SMILES: [OH:1][C:2]1[C:11]2[C:10](=[O:12])[CH2:9][CH2:8][CH2:7][C:6]=2[N:5]=[CH:4][C:3]=1[C:13]([O:15][CH2:16][CH3:17])=[O:14].C(=O)([O-])[O-].[K+].[K+].[CH2:24](I)[CH3:25]>CN(C)C=O>[CH2:24]([N:5]1[C:6]2[CH2:7][CH2:8][CH2:9][C:10](=[O:12])[C:11]=2[C:2](=[O:1])[C:3]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[CH:4]1)[CH3:25]
Reactant: CCI
Reactant: CCOC(=O)c1cnc2c(c1O)C(=O)CCC2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1cn(CC)c2c(c1=O)C(=O)CCC2
Temperature: 60 °C
Reaction time: 0.5 h
Yield: 92.3 %

Procedure:
By the method described in Japanese Patent Application No. 24956/1978, diethyl N-(3-oxo-1-cyclohexen-1-yl)-aminomethylenemalonate was prepared from 3-amino-2-cyclohexenone and diethyl ethoxymethylenemalonate. The product was cyclized under heat to form ethyl 4-hydroxy-5-oxo-5,6,7,8-tetrahydroquinonine-3-carboxylate, followed by hydrolysis. The resulting ethyl 4-hydroxy-5-oxo-5,6,7,8-tetrahydroquinoline-3-carboxylate (2.35 g) was suspended in 80 ml of dimethylformamide. The suspension was heated to 60° C., and 1.52 g of potassium carbonate and 1.54 g of ethyl iodide were added, and the mixture was stirred at 70° C. for 30 minutes. Further, 3.46 g of ethyl iodide was added, and the mixture was stirred for 1 hour. The insoluble matter was removed by filtration, and the mother liquor was concentrated to dryness. The product was extracted with chloroform, and the chloroform was distilled off. Methylene chloride was added to the residue, and the insoluble matter was collected by filtration. There was obtained 2.4 g of the captioned product as a light yellow powder. The nuclear magnetic resonance spectrum (DMSO-d6, 60 MC, TMS) had signals at δ1.2-1.5 (6H, m), 1.8-3.3 (6H, m), 4.0-4.5 (4H, m), and 8.4 (1H, s).
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][NH2:7])=[CH:4][CH:3]=1.[CH3:10][O:11][C:12](=[O:15])[CH2:13]Br.C([O-])([O-])=O.[K+].[K+]>CC#N>[CH3:10][O:11][C:12](=[O:15])[CH2:13][NH:7][CH2:6][C:5]1[CH:8]=[CH:9][C:2]([Cl:1])=[CH:3][CH:4]=1
Reactant: COC(=O)CBr
Reactant: NCc1ccc(Cl)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: COC(=O)CNCc1ccc(Cl)cc1
Temperature: 20 °C
Reaction time: 15 h

Procedure:
To a solution of 4-chloro-benzylamine (1 eq.) in MeCN was added bromo-acetic acid methyl ester (1 eq.), K2CO3 (1.5 eq.) and KI (0.1 eq.). The reaction was stirred for 15 h at 20° C. The crude was concentrated under reduced pressure then partitioned between water and EtOAc. The organic layer was dried over MgSO4, filtered and concentrated under reduced pressure. The crude was purified by chromatography on silica gel (elution with heptane/EtOAc: 1/0 to 8/2) to afford (4-chloro-benzylamino)-acetic acid methyl ester.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][C:9](=[O:30])[C:10]2[CH:15]=[C:14]([Cl:16])[CH:13]=[C:12]([O:17][CH3:18])[C:11]=2[NH:19][C:20]([C:22]2[S:23][CH:24]=[C:25]([CH2:28]Cl)[C:26]=2[Cl:27])=[O:21])=[N:6][CH:7]=1.[F:31][C:32]([F:36])([F:35])[CH2:33][NH2:34]>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][C:9](=[O:30])[C:10]2[CH:15]=[C:14]([Cl:16])[CH:13]=[C:12]([O:17][CH3:18])[C:11]=2[NH:19][C:20]([C:22]2[S:23][CH:24]=[C:25]([CH2:28][NH:34][CH2:33][C:32]([F:36])([F:35])[F:31])[C:26]=2[Cl:27])=[O:21])=[N:6][CH:7]=1
Reactant: NCC(F)(F)F
Reactant: COc1cc(Cl)cc(C(=O)Nc2ccc(Cl)cn2)c1NC(=O)c1scc(CCl)c1Cl
Solvent: CN(C)C=O
Product: COc1cc(Cl)cc(C(=O)Nc2ccc(Cl)cn2)c1NC(=O)c1scc(CNCC(F)(F)F)c1Cl
Temperature: 75 °C
Yield: 94.5 %

Procedure:
To a solution of N-(5-chloropyridin-2-yl)-2-[((4-(chloromethyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide (2.1 g, 4.1 mmol) in DMF (20 mL) was added a 2,2,2-trifluoroethylamine (3.2 mL, 41 mmol). The mixture was heated at 75° C. for 18 hours, then cooled to ambient temperature and concentrated in vacuo to remove excess 2,2,2-trifluoroethylamine. Water was added and the mixture was extracted with methylene chloride. The organic layer was dried over Na2SO4 and concentrated in vacuo. Purification by flash chromatography on silica gel afforded 2.2 g (95% yield) of N-(5-chloropyridin-2-yl)-2-[((4-(((2,2,2-trifluoroethyl)amino)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide; NMR (DMSO-dr/TFA) 10.8 (s, 1) 9.4 (s, 1), 8.2 (d, 1), 8.1 (d, 1), 8.0 (s, 1), 7.8 (dd, 1), 7.2 (d, 2), 4.2 (s, 2), 4.1 (q, 2), 3.8 (s, 3) ppm.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7]([OH:22])=[C:8]2[C:14]([C:15]3[CH:20]=[CH:19][CH:18]=[C:17]([Cl:21])[CH:16]=3)=[N:13][O:12][C:9]2=[CH:10][N:11]=1)=[O:5])[CH3:2].CC1C=C(C)N=C(C)C=1.CC1C([IH+:39])=C(C)N=C(C)C=1.F[P-](F)(F)(F)(F)F>ClCCl>[CH2:1]([O:3][C:4]([C:6]1[C:7]([OH:22])=[C:8]2[C:14]([C:15]3[CH:20]=[CH:19][CH:18]=[C:17]([Cl:21])[CH:16]=3)=[N:13][O:12][C:9]2=[C:10]([I:39])[N:11]=1)=[O:5])[CH3:2]
Reactant: Cc1cc(C)c([IH+])c(C)n1
Reactant: CCOC(=O)c1ncc2onc(-c3cccc(Cl)c3)c2c1O
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: Cc1cc(C)nc(C)c1
Product: CCOC(=O)c1nc(I)c2onc(-c3cccc(Cl)c3)c2c1O
Temperature: 25 °C
Reaction time: 20 h
Yield: 83.9 %

Procedure:
A mixture of 3-(3-chloro-phenyl)-4-hydroxy-isoxazolo[5,4-c]pyridine-5-carboxylic acid ethyl ester (377 mg, 1.18 mmole), bis(2,4,6-trimethylpyridine)iodine(I) hexafluorophosphate (1.22 g, 2.36 mmole), and dichloromethane (12 ml) was stirred at room temperature for 20 h before it was concentrated and purified by flash column chromatography on silica gel with a gradient of dichloromethane and hexanes to give the title compound as a white solid (440 mg); MS: (+) m/z 445.02 (M+H+).
Reaction SMILES: [CH2:1]([S:5]([C:8]1[N:12]=[CH:11][NH:10][N:9]=1)(=[O:7])=[O:6])[CH2:2][CH2:3][CH3:4].[CH2:13]([N:16]([CH2:20][CH2:21][CH3:22])[C:17](Cl)=[O:18])[CH2:14][CH3:15].O1CCCC1>C(N(CC)CC)C>[CH2:13]([N:16]([CH2:20][CH2:21][CH3:22])[C:17]([N:10]1[CH:11]=[N:12][C:8]([S:5]([CH2:1][CH2:2][CH2:3][CH3:4])(=[O:6])=[O:7])=[N:9]1)=[O:18])[CH2:14][CH3:15]
Reactant: CCCCS(=O)(=O)c1nc[nH]n1
Reactant: CCCN(CCC)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCCCS(=O)(=O)c1ncn(C(=O)N(CCC)CCC)n1

Procedure:
A mixture of 5.7 g. 3-n-butylsulphonyl-1,2,4-triazole, 5.4 g. dipropylcarbamoyl chloride, 25 ml. dry tetrahydrofuran and 6 ml. dry triethylamine was refluxed under anhydrous conditions for 1.5 hours. The reaction mixture was worked up as described in Example 1 to produce a solid product which was recrystallized from petroleum ether (60° - 80°C.) to give 1-dipropylcarbamoyl-3-n-butylsulphonyl-1,2,4-triazole, m.p. 46° - 47°C. Elemental analysis satisfactory.
Reaction SMILES: [Li+].C[Si]([N-][Si](C)(C)C)(C)C.Cl[C:12]1[CH:21]=[CH:20][C:19]2[C:14](=[C:15]([C:22]3[O:23][C:24]4[CH:29]=[CH:28][NH:27][C:26](=[O:30])[C:25]=4[N:31]=3)[CH:16]=[CH:17][CH:18]=2)[N:13]=1.[NH2:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1>O1CCOCC1.CCOC(C)=O>[C:33]1([NH:32][C:12]2[CH:21]=[CH:20][C:19]3[C:14](=[C:15]([C:22]4[O:23][C:24]5[CH:29]=[CH:28][NH:27][C:26](=[O:30])[C:25]=5[N:31]=4)[CH:16]=[CH:17][CH:18]=3)[N:13]=2)[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1
Reactant: Nc1ccccc1
Reactant: O=c1[nH]ccc2oc(-c3cccc4ccc(Cl)nc34)nc12
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: O=c1[nH]ccc2oc(-c3cccc4ccc(Nc5ccccc5)nc34)nc12
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 14 %

Procedure:
LHMDS (1.0M in THF; 2015 μl, 2.015 mmol) was added to a solution of 2-(2-chloroquinolin-8-yl)oxazolo[4,5-c]pyridin-4(5H)-one (Example 181; 120 mg, 0.403 mmol) and aniline (184 μl, 2.015 mmol) in dioxane (4031 μl) at RT; and the resulting mixture was stirred at RT for 30 min. The mixture was diluted with EtOAc (150 ml), added to a separatory funnel, and washed with saturated aq. NH4Cl (2×100 ml) before the organic layer was separated, dried over Na2SO4, and concentrated. Purification by silica gel (100% DCM to 5% MeOH/DCM) provided 2-(2-(phenylamino)quinolin-8-yl)oxazolo[4,5-c]pyridin-4(5H)-one (14% yield) as a dark orange solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 6.87-6.94 (m, 2H) 7.16 (d, J=9.00 Hz, 1H) 7.27 (t, J=7.82 Hz, 2H) 7.45 (t, J=7.63 Hz, 1H) 7.55 (t, J=6.55 Hz, 1H) 7.98 (d, J=6.85 Hz, 1H) 8.10 (d, J=7.83 Hz, 2H) 8.15-8.20 (m, 2H) 9.69 (s, 1H) 11.87 (br. s., 1H). MS (ESI, pos. ion) m/z: 355.1 (M+1).
Reaction SMILES: C(O[C:6]([NH:8][CH2:9][C@@H:10]1[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][NH:21][C:22]([C:24]2[C:32]3[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=3)[N:26]([CH3:33])[CH:25]=2)=[O:23])[CH2:11]1)=[O:7])(C)(C)C.[NH2:34][C:35]1[C:43]([Cl:44])=[CH:42][C:38](C(O)=O)=[C:37]([O:45][CH3:46])[CH:36]=1>>[NH2:34][C:35]1[C:43]([Cl:44])=[CH:42][C:38]([C:6]([NH:8][CH2:9][C@@H:10]2[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][NH:21][C:22]([C:24]3[C:32]4[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=4)[N:26]([CH3:33])[CH:25]=3)=[O:23])[CH2:11]2)=[O:7])=[C:37]([O:45][CH3:46])[CH:36]=1
Reactant: COc1cc(N)c(Cl)cc1C(=O)O
Reactant: Cn1cc(C(=O)NCCCCCCN2CC[C@@H](CNC(=O)OC(C)(C)C)C2)c2ccccc21
Product: COc1cc(N)c(Cl)cc1C(=O)NC[C@@H]1CCN(CCCCCCNC(=O)c2cn(C)c3ccccc23)C1

Procedure:
N-(6-((3S)-3-tert-Butoxycarbonylaminomethylpyrrolidin-1-yl)-hexyl)-1-methyl-1 H-indole-3-carboxamide (1.00 g) as starting compound was reacted and treated in the same manner as in Example 67 using 4-amino-5-chloro-2-methoxybenzoic acid (0.50 g) to give N-(6-((3S)-3-(4-amino-5-chloro-2-methoxybenzoylaminomethyl)pyrrolidin-1-yl)hexyl)-1-methyl-1 H-indole-3-carboxamide.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[O:7][CH:8]=[C:9]([CH2:11][OH:12])[N:10]=1.Cl[C:14]1[CH:19]=[CH:18][C:17]([CH2:20][CH2:21][CH2:22][N:23]2[CH:27]=[CH:26][N:25]=[CH:24]2)=[CH:16][N:15]=1>>[N:23]1([CH2:22][CH2:21][CH2:20][C:17]2[CH:18]=[CH:19][C:14]([O:12][CH2:11][C:9]3[N:10]=[C:6]([C:2]4[S:1][CH:5]=[CH:4][CH:3]=4)[O:7][CH:8]=3)=[N:15][CH:16]=2)[CH:27]=[CH:26][N:25]=[CH:24]1
Reactant: OCc1coc(-c2cccs2)n1
Reactant: Clc1ccc(CCCn2ccnc2)cn1
Product: c1csc(-c2nc(COc3ccc(CCCn4ccnc4)cn3)co2)c1
Yield: 67 %

Procedure:
In substantially the same manner as in Working Example 125, 2-(2-thienyl)-4-oxazolylmethanol was allowed to react with 2-chloro-5-[3-(1-imidazolyl)propyl]pyridine to give 5-[3-(1-imidazolyl)propyl]-2-[2-(2-thienyl)-4-oxazolylmethoxy]pyridine. The yield was 67%. Recrystallization from ethyl acetate-hexane gave brown prisms, mp 86-87° C.
Reaction SMILES: [C:1]([C:5]1[N:9]([CH2:10][CH:11]2[CH2:16][CH2:15][O:14][CH2:13][CH2:12]2)[C:8]2[CH:17]=[CH:18][C:19]([S:21](Cl)(=[O:23])=[O:22])=[CH:20][C:7]=2[N:6]=1)([CH3:4])([CH3:3])[CH3:2].[NH:25]1[CH:29]=[CH:28][C:27]([NH:30]C(=O)OC(C)(C)C)=[N:26]1>CN(C1C=CN=CC=1)C.CC#N>[C:1]([C:5]1[N:9]([CH2:10][CH:11]2[CH2:16][CH2:15][O:14][CH2:13][CH2:12]2)[C:8]2[CH:17]=[CH:18][C:19]([S:21]([N:25]3[CH:29]=[CH:28][C:27]([NH2:30])=[N:26]3)(=[O:23])=[O:22])=[CH:20][C:7]=2[N:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)c1nc2cc(S(=O)(=O)Cl)ccc2n1CC1CCOCC1
Reactant: CC(C)(C)OC(=O)Nc1cc[nH]n1
Agent: CN(C)c1ccncc1
Solvent: CC#N
Product: CC(C)(C)c1nc2cc(S(=O)(=O)n3ccc(N)n3)ccc2n1CC1CCOCC1
Yield: 18.9 %

Procedure:
Following the same procedure in Example 1, Step A, using 2-tert-butyl-1-(tetrahydro-2H-pyran-4-ylmethyl)-1H-benzimidazole-5-sulfonyl chloride (1.46 g, 3.93 mmol), tert-butyl 1H-pyrazol-3-ylcarbamate (0.80 g, 4.33 mmol) (see following step B for preparation), and DMAP (1.47 g, 12.0 mmol) in MeCN (40 mL). The crude product was purified by MPLC using EtOAc on silica gel to give 0.31 g (19%) of a white solid as the title compound. 1H NMR (400 MHz, DMSO-D6) δ 1.25-1.44 (m, 4 H), 1.46 (s, 9 H), 2.05-2.24 (m, 1 H), 3.15 (m, 2 H), 3.77 (m, 2 H), 4.28 (d, J=7.03 Hz, 2 H), 5.38 (s, 2 H), 5.78 (d, J=2.93 Hz, 1 H), 7.63 (dd, J=8.79, 1.76 Hz, 1 H), 7.82 (d, J=8.59 Hz, 1 H), 7.97 (d, J=1.76 Hz, 1 H), 8.00 (d, J=2.93 Hz, 1 H); MS (ESI) (M+H)+=417.8; Anal. Calcd for C20H27N5O3S+1.30 TFA+0.10 EtOAc (575.78): C, 48.19; H, 5.09; N, 12.16. Found: C, 48.12; H, 5.02; N, 12.29.
Reaction SMILES: [C:1]([N:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[Br:14][C:15]1[C:23]2[O:22][CH:21]=[C:20]([CH:24]=O)[C:19]=2[CH:18]=[CH:17][CH:16]=1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>CCOC(C)=O>[Br:14][C:15]1[C:23]2[O:22][CH:21]=[C:20]([CH2:24][N:11]3[CH2:10][CH2:9][N:8]([C:1]([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2])[CH2:13][CH2:12]3)[C:19]=2[CH:18]=[CH:17][CH:16]=1
Reactant: O=Cc1coc2c(Br)cccc12
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CCN(Cc2coc3c(Br)cccc23)CC1
Reaction time: 12 h

Procedure:
To a flask charged with Boc-piperazine (130 mg, 0.70 mmol) and 7-bromo-1-benzofuran-3-carbaldehyde (141 mg, 0.63 mmol) was added NaBH(OAc)3 (761 mg, 2.80 mmol). The mixture was stirred at room temperture for 12 hours. Then the reaction was diluted with EtOAc (50 mL), washed with brine (15 mL), dried over Na2SO4 and concentrated. The residue was purified with prep-TLC to obtain the pure product tert-butyl 4-[(7-bromo-1-benzofuran-3-yl)methyl]piperazine-1-carboxylate.
Reaction SMILES: C([Sn](CCCC)(CCCC)[C:6]1[N:7]=[CH:8][N:9]([C:11]2[CH:16]=[C:15]([C:17]([F:20])([F:19])[F:18])[CH:14]=[C:13]([C:21]3[CH:26]=[CH:25][C:24]([C:27]([F:30])([F:29])[F:28])=[CH:23][CH:22]=3)[N:12]=2)[CH:10]=1)CCC.[C:39]([NH:43][S:44]([C:47]1[S:51][C:50](Cl)=[N:49][C:48]=1[CH3:53])(=[O:46])=[O:45])([CH3:42])([CH3:41])[CH3:40].CCCCCCC>C1(C)C=CC=CC=1>[C:39]([NH:43][S:44]([C:47]1[S:51][C:50]([C:6]2[N:7]=[CH:8][N:9]([C:11]3[CH:16]=[C:15]([C:17]([F:20])([F:19])[F:18])[CH:14]=[C:13]([C:21]4[CH:22]=[CH:23][C:24]([C:27]([F:29])([F:30])[F:28])=[CH:25][CH:26]=4)[N:12]=3)[CH:10]=2)=[N:49][C:48]=1[CH3:53])(=[O:46])=[O:45])([CH3:42])([CH3:41])[CH3:40]
Reactant: Cc1nc(Cl)sc1S(=O)(=O)NC(C)(C)C
Reactant: CCCC[Sn](CCCC)(CCCC)c1cn(-c2cc(C(F)(F)F)cc(-c3ccc(C(F)(F)F)cc3)n2)cn1
Solvent: Cc1ccccc1
Solvent: CCCCCCC
Product: Cc1nc(-c2cn(-c3cc(C(F)(F)F)cc(-c4ccc(C(F)(F)F)cc4)n3)cn2)sc1S(=O)(=O)NC(C)(C)C
Temperature: 25 °C
Yield: 65.1 %

Procedure:
A stirred mixture of 2-(4-tributylstannanyl-imidazol-1-yl)-4-trifluoromethyl-6-(4-trifluoromethyl-phenyl)-pyridine (Example G.11) (0.718 g, 1.0 mmol), 2-chloro-4-methyl-thiazole-5-sulfonic acid tert-butylamide (Example H.5) (0.295 g, 1.1 mmol), tetrakis(triphenyl-phosphine)palladium (0.058 g, 0.044 mmol) in toluene (5 mL) was heated under reflux conditions for 18 h. Cooled to rt, some precipitate occurred, diluted with toluene (˜5 mL), added heptane, filtered the precipitate off, washed with toluene/heptane, dried in HV to give the title compound as a white solid (384 mg, 59%). MS (ISP) 590.4 [(M+H)+]; mp>250° C.
Reaction SMILES: [OH:1][CH2:2][CH2:3][O:4][C:5]1([C:17]2[S:18][CH:19]=[CH:20][N:21]=2)[CH2:9][CH2:8][N:7]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:6]1.C(N(CC)CC)C.[C:29]1([CH3:39])[CH:34]=[CH:33][C:32]([S:35](Cl)(=[O:37])=[O:36])=[CH:31][CH:30]=1>ClCCl.CN(C)C1C=CN=CC=1>[S:18]1[CH:19]=[CH:20][N:21]=[C:17]1[C:5]1([O:4][CH2:3][CH2:2][O:1][S:35]([C:32]2[CH:33]=[CH:34][C:29]([CH3:39])=[CH:30][CH:31]=2)(=[O:37])=[O:36])[CH2:9][CH2:8][N:7]([C:10]([O:12][C:13]([CH3:16])([CH3:14])[CH3:15])=[O:11])[CH2:6]1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: CC(C)(C)OC(=O)N1CCC(OCCO)(c2nccs2)C1
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)OCCOC2(c3nccs3)CCN(C(=O)OC(C)(C)C)C2)cc1
Reaction time: 16 h

Procedure:
To an ambient solution of tert-butyl 3-(2-hydroxyethoxy)-3-(thiazol-2-yl)pyrrolidine-1-carboxylate (1.92 g, 6.11 mmol) in dichloromethane (20 mL) was added triethylamine (1.70 mL, 12.21 mmol), 4-dimethylaminopyridine (0.075 g, 0.611 mmol), and para-toluenesulfonyl chloride (1.28 g, 6.72 mmol). The reaction was stirred for 16 hours and was quenched by the addition of saturated ammonium chloride solution. The layers were separated, and the aqueous layer was extracted with additional dichloromethane. The combined organics were dried with anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give the product, which was used without further purification. MS ESI(+) m/z 468.8 [M+H]+.