Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:23])([F:22])[O:3][C:4]1[CH:21]=[CH:20][C:7]([O:8][C:9]2[CH:15]=[CH:14][C:12]([NH2:13])=[CH:11][C:10]=2[C:16]([F:19])([F:18])[F:17])=[CH:6][CH:5]=1.[CH3:24][CH:25]([C:31]([CH3:33])=O)[C:26](OCC)=[O:27].C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C(C)=CC=CC=1>[CH3:33][C:31]1[C:25]([CH3:24])=[C:26]([OH:27])[C:14]2[C:12](=[CH:11][C:10]([C:16]([F:17])([F:18])[F:19])=[C:9]([O:8][C:7]3[CH:20]=[CH:21][C:4]([O:3][C:2]([F:22])([F:23])[F:1])=[CH:5][CH:6]=3)[CH:15]=2)[N:13]=1
Reactant: Nc1ccc(Oc2ccc(OC(F)(F)F)cc2)c(C(F)(F)F)c1
Reactant: CCOC(=O)C(C)C(C)=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1C
Product: Cc1nc2cc(C(F)(F)F)c(Oc3ccc(OC(F)(F)F)cc3)cc2c(O)c1C
Yield: 41.1 %

Procedure:
A solution of 3.4 g of 4-(4-trifluoromethoxyphenoxy)-3-trifluoromethyl-aniline, 2.4 g of ethyl 2-methylacetoacetate, and 0.3 g of p-toluenesulfonic acid dissolved in 100 mL of xylene was heated under reflux for 36 hr. This reaction solution was cooled, and the precipitated crystals were collected by filtration to give 1.73 g of 2,3-dimethyl-4-hydroxy-6-(4-trifluoromethoxyphenoxy)-7-trifluoromethyl-quinoline. The filtrate was concentrated under the reduced pressure to give 2,3-dimethyl-4-hydroxy-6-(4-trifluoromethoxyphenoxy)-5-trifluoromethyl-quinoline. Acetic anhydride (40 mL) was added to 2,3-dimethyl-4-hydroxy-6-(4-trifluoromethoxyphenoxy)-5-trifluoromethyl-quinoline obtained from the filtrate, and the mixture was heated at 120 to 125° C. for one hr. This reaction solution was concentrated under the reduced pressure, ethyl acetate was then added to the concentrate, and the mixture was washed with brine. Thereafter, the solvent was removed under the reduced pressure, and the crude product was purified by column chromatography on silica gel (BW300, manufactured by Fuji Sylysia Chemical Ltd., solvent: n-hexane/ethyl acetate) to give 0.35 g of 4-acetoxy-2,3-dimethyl-6-(4-trifluoromethoxyphenoxy)-5-trifluoromethyl-quinoline.
Reaction SMILES: C(Cl)(=O)C([Cl:4])=O.[CH2:7]([O:9][C:10]([C:12]1[C:17](=[O:18])[N:16]([CH2:19][C:20]2[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=2)[C:15]2[CH:28]=[CH:29][S:30][C:14]=2[C:13]=1O)=[O:11])[CH3:8].CN(C=O)C>C(Cl)Cl>[CH2:7]([O:9][C:10]([C:12]1[C:17](=[O:18])[N:16]([CH2:19][C:20]2[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=2)[C:15]2[CH:28]=[CH:29][S:30][C:14]=2[C:13]=1[Cl:4])=[O:11])[CH3:8]
Reactant: CCOC(=O)c1c(O)c2sccc2n(Cc2ccc(OC)cc2)c1=O
Reactant: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CCOC(=O)c1c(Cl)c2sccc2n(Cc2ccc(OC)cc2)c1=O
Temperature: 25 °C
Reaction time: 24 h
Yield: 85 %

Procedure:
Oxalyl chloride (4.8 mL, 55 mmol) was added to a solution of 7-hydroxy-4-(4-methoxybenzyl)-5-oxo-4,5-dihydro-thieno[3,2-b]pyridine-6-carboxylic acid ethyl ester (54) (9.87 g, 27 mmol) in dry CH2Cl2 at 0° C. After adding anhydrous DMF (0.5 mL), the solution was allowed to come at room temperature and was further stirred at room temperature for 24 h. Excess solvent was evaporated to yield 7-chloro-4-(4-methoxybenzyl)-5-oxo-4,5-dihydro-thieno[3,2-b]pyridine-6-carboxylic acid ethyl ester as off white solids. Yield 85%; 1H NMR (400 MHz, DMSO-d6) δ 1.30 (t, J=7.2 Hz, 3H), 3.70 (s, 3H), 5.36 (s, 2H), 6.88 (d, J=8.4 Hz, 2H), 7.24 (d, J=8.4 Hz, 2H), 7.53 (d, J=5.6 Hz, 1H), 8.20 (d, J=5.6 Hz, 1H ppm; MS m/z=378 amu (M++H).
Reaction SMILES: [CH2:1]([C:12]1[NH:13][C:14]2[C:19]([CH:20]=1)=[CH:18][CH:17]=[C:16]([C:21]([OH:23])=[O:22])[CH:15]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11].Cl>C(O)CCC>[CH2:1]([C:12]1[NH:13][C:14]2[C:19]([CH:20]=1)=[CH:18][CH:17]=[C:16]([C:21]([O:23][CH2:12][CH2:1][CH2:2][CH3:3])=[O:22])[CH:15]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11]
Reactant: CCCCCCCCCCCc1cc2ccc(C(=O)O)cc2[nH]1
Agent: Cl
Solvent: CCCCO
Product: CCCCCCCCCCCc1cc2ccc(C(=O)OCCCC)cc2[nH]1
Yield: 127.9 %

Procedure:
A solution of 2-(n-undecyl)indole-6-carboxylic acid (15.0 g) in n-butanol (100 ml) containing aqueous hydrochloric acid (10 ml, of strength 36.5% w/v) was heated on a steam bath for 16 hours. The solution was concentrated in vacuo to approximately half of its volume and the solid which crystallised on cooling was collected and washed with light petroleum ether (b.p. 40°-60° C.) to give n-butyl 2-(n-undecyl)-indole-6-carboxylate (11.3 g), in the form of white crystals, m.p. 73°-76° C.
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][C:7]([CH2:10][CH:11]=O)=[CH:6][C:3]=1[C:4]#[N:5].[C:13]([O:17][C:18](=[O:23])[NH:19][CH2:20][CH2:21][NH2:22])([CH3:16])([CH3:15])[CH3:14].[BH3-]C#N.[Na+].C(O)(=O)C>CO>[C:4]([C:3]1[CH:6]=[C:7]([CH2:10][CH2:11][NH:22][CH2:21][CH2:20][NH:19][C:18](=[O:23])[O:17][C:13]([CH3:15])([CH3:14])[CH3:16])[CH:8]=[CH:9][C:2]=1[F:1])#[N:5]
Reactant: CC(C)(C)OC(=O)NCCN
Reactant: N#Cc1cc(CC=O)ccc1F
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: CC(C)(C)OC(=O)NCCNCCc1ccc(F)c(C#N)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 2-fluoro-5-(2-oxoethyl)benzonitrile (1.5 g, 9.2 mmol), tert-butyl(2-aminoethyl)carbamate (1.5 g, 9.2 mmol), NaCNBH3 (1.2 g, 18.4 mmol) and acetic acid (1.6 g, 27.6 mmol) in methanol (20 mL) was stirred at ambient temperature overnight. The solvents were evaporated, and the residue was basified with saturated NaHCO3 to pH=7-8, and extracted with EtOAc. The organic layer was separated, dried over anhydrous sodium sulfate and evaporated. The residue was purified with silica gel column chromatography to give tert-Butyl (2-{[2-(3-cyano-4-fluorophenyl)ethyl]amino}ethyl)carbamate.
Reaction SMILES: [CH3:1][C:2]1[CH:8]=[C:7]([CH3:9])[CH:6]=[C:5]([N+:10]([O-:12])=[O:11])[C:3]=1N.N([O-])=O.[Na+].[BrH:17]>O>[Br:17][C:3]1[C:5]([N+:10]([O-:12])=[O:11])=[CH:6][C:7]([CH3:9])=[CH:8][C:2]=1[CH3:1]
Reactant: Cc1cc(C)c(N)c([N+](=O)[O-])c1
Reactant: Br
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Product: Cc1cc(C)c(Br)c([N+](=O)[O-])c1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 26 %

Procedure:
To a suspension of 2,4-dimethyl-6-nitroaniline (5 g, 30.12 mmol) in water (38 mL) was added HBr (15 mL, 40%). The mixture was heated to reflux for 10 minutes and then cooled to 0° C. A solution of NaNO2 (2.07 g) in water (12 mL) was added dropwise with cooling. The mixture was stirred for 30 minutes and then added slowly to a stirred mixture of CuBr (4.33 g) in HBr (12 mL) and water (23 mL) at RT. The reaction mixture was stirred at RT for 30 minutes, heated to reflux for 3 hours, and then steam distilled. The distillate was extracted with DCM (3×30 mL), washed with aqueous saturated NaHCO3 and saturated NaCl, and concentrated to give the title compound as a solid (1.8 g, 26%). 1H NMR (400 MHz, CDCl3) δ ppm 7.26 (1H, s), 7.17 (1H, s), 2.39 (3H, s), 2.27 (3H, s).
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:8]=[CH:7][N:6]=[C:5]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([Cl:15])[CH:10]=2)[CH:4]=1.[NH2:16][C:17]1[CH:22]=[CH:21][C:20]([CH2:23][C:24]([NH2:26])=[O:25])=[CH:19][CH:18]=1>>[ClH:2].[Cl:15][C:11]1[CH:10]=[C:9]([C:5]2[CH:4]=[C:3]([NH:16][C:17]3[CH:18]=[CH:19][C:20]([CH2:23][C:24]([NH2:26])=[O:25])=[CH:21][CH:22]=3)[CH:8]=[CH:7][N:6]=2)[CH:14]=[CH:13][CH:12]=1
Reactant: Clc1cccc(-c2cc(Cl)ccn2)c1
Reactant: NC(=O)Cc1ccc(N)cc1
Agent: Cl
Product: NC(=O)Cc1ccc(Nc2ccnc(-c3cccc(Cl)c3)c2)cc1
Yield: 40.1 %

Procedure:
Following general procedure A2, 4-chloro-2-(3-chlorophenyl)pyridine hydrochloride (0.115 g, 0.44 mmol) was reacted with 2-(4-aminophenyl)acetamide (0.080 g, 0.53 mmol), followed by formation of the hydrochloride salt to afford the title compound (0.066 g, 40%) as a light yellow solid. MW=374.26. 1H NMR (DMSO-d6, 500 MHz) δ 14.01 (s, 1H), 10.64 (s, 1H), 8.29 (d, J=7.0 Hz, 1H), 7.97-7.95 (m, 1H), 7.81-7.77 (m, 1H), 7.73-7.69 (m, 1H), 7.65 (t, J=8.0 Hz, 1H), 7.51 (s, 1H), 7.41-7.29 (m, 5H), 7.13-7.09 (m, 1H), 6.91 (s, 1H), 3.42 (s, 2H); APCI MS m/z 338 [M+H]+.
Reaction SMILES: [CH2:1]([C:5]1[N:6]([CH2:18][CH2:19][CH2:20][NH2:21])[C:7]2[C:16]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[N:10]=[CH:9][C:8]=2[N:17]=1)[CH2:2][CH2:3][CH3:4].[C:22]1([S:28](Cl)(=[O:30])=[O:29])[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>>[CH2:1]([C:5]1[N:6]([CH2:18][CH2:19][CH2:20][NH:21][S:28]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)(=[O:30])=[O:29])[C:7]2[C:16]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[N:10]=[CH:9][C:8]=2[N:17]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1nc2cnc3ccccc3c2n1CCCN
Reactant: O=S(=O)(Cl)c1ccccc1
Product: CCCCc1nc2cnc3ccccc3c2n1CCCNS(=O)(=O)c1ccccc1
Yield: 94.6 %

Procedure:
Using the general method of Example 239 Part B, 3-(2-butyl-1H-imidazo[4,5-c]quinolin-1-yl)propylamine (2.00 g, 7.08 mmol) was reacted with benzenesulfonyl chloride (1.38 g, 7.79 mmol) to provide 2.83 g of N-[3-(2-butyl-1H-imidazo[4,5-c]quinolin-1-yl)propyl]benzenesulfonamide as a light red foam.
Reaction SMILES: Cl[CH2:2][C:3]1[N:7]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[C:6]2[CH:14]=[CH:15][CH:16]=[CH:17][C:5]=2[N:4]=1.[NH:18]1[CH:22]=[CH:21][N:20]=[CH:19]1>C(O)C.O>[N:18]1([CH2:2][C:3]2[N:7]([C:8]3[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=3)[C:6]3[CH:14]=[CH:15][CH:16]=[CH:17][C:5]=3[N:4]=2)[CH:22]=[CH:21][N:20]=[CH:19]1
Reactant: ClCc1nc2ccccc2n1-c1ccccc1
Reactant: c1c[nH]cn1
Solvent: CCO
Solvent: O
Product: c1ccc(-n2c(Cn3ccnc3)nc3ccccc32)cc1
Yield: 69 %

Procedure:
A solution of 2-chloromethyl-1-phenyl-1H-benzimidazole (3.4 g) and imidazole (4.8 g) in ethanol (25 ml) was stirred at 60° C for 7 hours. The reaction mixture was concentrated under reduced pressure to give an oil, which was diluted with water and extracted three times with dichloromethane. The combined extract was washed twice with water and once with brine, dried over anhydrous magnesium sulfate and evaporated under reduced pressure. The residue was purified by column chromatography on silica gel (100 g) with a mixture of methanol and dichloromethane (3:97) as an eluent to afford an oil, which was crystallized from a mixture of ethyl acetate and hexane to give 2-(imidazol-1-yl)methyl-1-phenyl-1H-benzimidazole (2.65 g).
Reaction SMILES: Cl.[NH2:2][C@H:3]1[CH2:8][CH2:7][C@H:6]([NH:9][C:10]([C:12]2[C:16]3[N:17]=[CH:18][N:19]=[C:20]([C:21]4[CH:26]=[C:25]([CH:27]([CH3:29])[CH3:28])[CH:24]=[CH:23][C:22]=4[O:30][CH2:31][CH:32]4[CH2:34][CH2:33]4)[C:15]=3[NH:14][C:13]=2[CH3:35])=[O:11])[CH2:5][CH2:4]1.[C:36](Cl)(=[O:38])[CH3:37]>>[C:36]([NH:2][C@H:3]1[CH2:8][CH2:7][C@H:6]([NH:9][C:10]([C:12]2[C:16]3[N:17]=[CH:18][N:19]=[C:20]([C:21]4[CH:26]=[C:25]([CH:27]([CH3:29])[CH3:28])[CH:24]=[CH:23][C:22]=4[O:30][CH2:31][CH:32]4[CH2:33][CH2:34]4)[C:15]=3[NH:14][C:13]=2[CH3:35])=[O:11])[CH2:5][CH2:4]1)(=[O:38])[CH3:37]
Reactant: CC(=O)Cl
Reactant: Cc1[nH]c2c(-c3cc(C(C)C)ccc3OCC3CC3)ncnc2c1C(=O)N[C@H]1CC[C@H](N)CC1
Agent: Cl
Product: CC(=O)N[C@H]1CC[C@H](NC(=O)c2c(C)[nH]c3c(-c4cc(C(C)C)ccc4OCC4CC4)ncnc23)CC1

Procedure:
Starting from N-(trans-4-aminocyclohexyl)-4-[2-(cyclopropylmethoxy)-5-(propan-2-yl)phenyl]-6-methyl-5H-pyrrolo[3,2-d]pyrimidine-7-carboxamide hydrochloride (example D.f53) and commercially available acetyl chloride the title compound is obtained as colorless solid.
Reaction SMILES: [C:1]1([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH:6]=[CH:5][C:4]([CH2:7][N:8]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[C:11](=S)[C:10]([C:19]([O:21]CC)=O)=[CH:9]2)=[CH:3][CH:2]=1.[C:30]1([NH:36][NH2:37])[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1.C(OC(OC(OC(C)(C)C)=O)=O)(C)(C)C>C(O)C>[C:1]1([C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=2)[CH:2]=[CH:3][C:4]([CH2:7][N:8]2[C:17]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[C:11]3=[N:37][N:36]([C:30]4[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=4)[C:19](=[O:21])[C:10]3=[CH:9]2)=[CH:5][CH:6]=1
Reactant: CCOC(=O)c1cn(Cc2ccc(-c3ccccc3)cc2)c2ccccc2c1=S
Reactant: NNc1ccccc1
Agent: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Solvent: CCO
Product: O=c1c2cn(Cc3ccc(-c4ccccc4)cc3)c3ccccc3c-2nn1-c1ccccc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
Ethyl 1-(biphenyl-4-ylmethyl)-4-thioxo-1,4-dihydroquinoline-3-carboxylate [(Example 8, Step 2), 72 mg, 0.18 mmol] and phenylhydrazine (0.19 g, 1.8 mmol, 10 equiv) were combined in absolute ethanol (5 mL) and placed into a preheated oil bath at 75° C. for 18 hours. The mixture was cooled to ambient temperature and concentrated in vacuo. The residue was dissolved in dichloromethane (10 mL) and treated with di-tert-butyldicarbonate (0.30 g, 1.4 mmol, 7.8 equiv). After stirring for 5 hours at ambient temperature, the mixture was concentrated in vacuo and the residue was purified by silica gel gradient chromatography (100:0 to 95:5; dichloromethane:methanol), providing the titled compound: 1H-NMR (500 MHz, d6-DMSO) δ 9.17 (1H, s), 8.31 (1H, dd, J=7.8, 1.4 Hz), 8.22 (2H, d, J=7.6 Hz), 7.81 (1H, d, J=8.8 Hz), 7.67-7.62 (5H, m), 7.57 (1H, t, J=7.8 Hz), 7.48-7.40 (6H, m), 7.35 (1H, t, J=7.4 Hz), 7.20 (1H, t, J=7.4 Hz), 5.80 (2H, s) ppm; high resolution mass spectrometry (ES+) m/z 428.1757 [(M+H)+; calculated for C29H22N3O: 428.1758].
Reaction SMILES: [CH2:1]([N:3]([CH2:12][CH3:13])[C:4]1[CH:11]=[CH:10][C:7]([CH:8]=O)=[CH:6][CH:5]=1)[CH3:2].[N+:14]([C:17]1[CH:22]=[CH:21][C:20]([CH2:23]C(O)=O)=[CH:19][CH:18]=1)([O-:16])=[O:15].N1CCCCC1>O>[CH2:1]([N:3]([CH2:12][CH3:13])[C:4]1[CH:11]=[CH:10][C:7]([CH:8]=[CH:23][C:20]2[CH:21]=[CH:22][C:17]([N+:14]([O-:16])=[O:15])=[CH:18][CH:19]=2)=[CH:6][CH:5]=1)[CH3:2]
Reactant: O=C(O)Cc1ccc([N+](=O)[O-])cc1
Reactant: CCN(CC)c1ccc(C=O)cc1
Solvent: C1CCNCC1
Solvent: O
Product: CCN(CC)c1ccc(C=Cc2ccc([N+](=O)[O-])cc2)cc1
Temperature: 0 °C

Procedure:
A mixture of 5.00 g (28 mmol) of 4-diethylaminobenzaldehyde, 5.62 g (31 mmol) of 4-nitrophenylacetic acid, 2.40 g (28 mmol) of piperidine, and 100 mL of xylenes was heated with stirring at reflux for 20 hours with continuous removal of water using a Dean-Stark apparatus. The mixture turned dark red. Approximately half the xylenes was distilled, and the residue was cooled to 3 0° C. Red crystals separated which were collected and then recrystallized from isopropanol/pyridine. Yield: 4.05 g (48%), mp 179-181 (lit2 182°-182.5° C.).
Reaction SMILES: [OH:1][C@@H:2]([C@H:4]1[C:24](=[O:25])[N:6]2[C:7]([C:21]([O-:23])=[O:22])=[C:8]([S:11]/[CH:12]=[CH:13]\[C:14]3[S:18][CH:17]=[N:16][C:15]=3[CH2:19][OH:20])[C@H:9]([CH3:10])[C@H:5]12)[CH3:3].[Na+].[N:27]1([C:33]([O:35][CH2:36]I)=[O:34])[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]1>>[OH:1][C@@H:2]([C@H:4]1[C:24](=[O:25])[N:6]2[C:7]([C:21]([O:23][CH2:36][O:35][C:33]([N:27]3[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]3)=[O:34])=[O:22])=[C:8]([S:11]/[CH:12]=[CH:13]\[C:14]3[S:18][CH:17]=[N:16][C:15]=3[CH2:19][OH:20])[C@H:9]([CH3:10])[C@H:5]12)[CH3:3]
Reactant: O=C(OCI)N1CCCCC1
Reactant: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)[O-])=C(S/C=C\c3scnc3CO)[C@H](C)[C@H]12
Agent: [Na+]
Product: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)OCOC(=O)N3CCCCC3)=C(S/C=C\c3scnc3CO)[C@H](C)[C@H]12
Yield: 92.7 %

Procedure:
In the same manner as in Example 81, 192 mg of the title compound was prepared from 160 mg of sodium (1R,5S,6S)-6-((1R)-1-hydroxyethyl)-2-[[(Z)-2-(4-hydroxymethylthiazol-5-yl)ethen-1-yl]thio]-1-methyl-1-carbapen-2-em-3-carboxylate and 130 mg of (piperidin-1-yl)carbonyloxymethyl iodide.
Reaction SMILES: C(OC([NH:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][C@H:18]([NH:24][C@@H:25]1[C:31](=[O:32])[N:30]([CH2:33][C:34]([O:36]C(C)(C)C)=[O:35])[C:29]2[CH:41]=[CH:42][CH:43]=[CH:44][C:28]=2[S:27][CH2:26]1)[C:19]([O:21][CH2:22][CH3:23])=[O:20])=O)(C)(C)C.C(OCC)(=O)C.[ClH:51]>CCOCC>[ClH:51].[ClH:51].[NH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][C@H:18]([NH:24][C@@H:25]1[C:31](=[O:32])[N:30]([CH2:33][C:34]([OH:36])=[O:35])[C:29]2[CH:41]=[CH:42][CH:43]=[CH:44][C:28]=2[S:27][CH2:26]1)[C:19]([O:21][CH2:22][CH3:23])=[O:20]
Reactant: CCOC(=O)[C@H](CCCCCCCCCNC(=O)OC(C)(C)C)N[C@H]1CSc2ccccc2N(CC(=O)OC(C)(C)C)C1=O
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CCOCC
Product: CCOC(=O)[C@H](CCCCCCCCCN)N[C@H]1CSc2ccccc2N(CC(=O)O)C1=O

Procedure:
A solution of tert-butyl 3(R)-[10-tert-butoxycarbonylamino-1(S)-ethoxycarbonyldecyl]amino-4-oxo-2,3,4,5-tetrahydro-1,5-benzothiazepine-5-acetate (0.3 g) in a hydrogen chloride-ethyl acetate solution (5N, 10 ml) stands for 3 hours at room temperature, and then a mixture of ether and petroleum ether is added. After agitating thoroughly, the supernatant is removed by decantation. The deposited precipitate is dried under reduced pressure to provide 3(R)-[10-amino-1(S)-ethoxycarbonyldecyl]amino-4-oxo-2,3,4,5-tetrahydro-1,5-benzothiazepine-5-acetic acid dihydrochloride (0.23) g as a colorless powder.
Reaction SMILES: [OH:1][C@H:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][C@:3]1([CH2:20][C:21]1[CH:29]=[CH:28][C:24]([C:25](O)=[O:26])=[CH:23][CH:22]=1)[C:11]1[CH2:12][C:13]2[C:18]([CH:19]=1)=[CH:17][CH:16]=[CH:15][CH:14]=2.CC(OC(OC(OC(C)(C)C)=O)=O)(C)C.[N:45]1C=CC=CC=1.C(=O)(O)[O-].[NH4+]>CS(C)=O.O>[OH:1][C@H:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][C@:3]1([CH2:20][C:21]1[CH:29]=[CH:28][C:24]([C:25]([NH2:45])=[O:26])=[CH:23][CH:22]=1)[C:11]1[CH2:12][C:13]2[C:18]([CH:19]=1)=[CH:17][CH:16]=[CH:15][CH:14]=2
Reactant: O=C(O)c1ccc(C[C@]2(C3=Cc4ccccc4C3)Cc3ccccc3[C@@H]2O)cc1
Reactant: c1ccncc1
Agent: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Agent: O=C([O-])O
Agent: [NH4+]
Solvent: O
Solvent: CS(C)=O
Product: NC(=O)c1ccc(C[C@]2(C3=Cc4ccccc4C3)Cc3ccccc3[C@@H]2O)cc1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 59.5 %

Procedure:
To a solution of 4-(((1R,2R)-1-hydroxy-2,3-dihydro-1H,1′H-[2,2′-biinden]-2-yl)methyl)benzoic acid (100 mg, 0.26 mmol) in DMSO (5 mL) was added Boc anhydride (69 mg, 0.31 mmol) followed by pyridine (24 mg, 0.26 mmol) and stirred at room temperature for 5 min. Ammonium bicarbonate (62 mg, 0.78 mmol) was added and stirred for additional 1 h. Reaction mixture was poured into water (25 mL) and extracted with ethyl acetate (3×25 mL). The organic layer was washed with brine (25 mL), dried over anhydrous Na2SO4 and evaporated under reduced pressure. The residue was purified by CombiFlash using 20% ethyl acetate in chloroform as an eluent to yield 59 mg (59%) of the title compound as an off white solid.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([N:9]2[CH:13]=[CH:12][C:11]([NH2:14])=[N:10]2)[CH:5]=[CH:6][C:7]=1[CH3:8].N1C=CC=CC=1.[Cl:21][C:22]1[CH:23]=[CH:24][C:25]([N+:31]([O-:33])=[O:32])=[C:26]([CH:30]=1)[C:27](Cl)=[O:28]>ClCCl>[Cl:21][C:22]1[CH:23]=[CH:24][C:25]([N+:31]([O-:33])=[O:32])=[C:26]([CH:30]=1)[C:27]([NH:14][C:11]1[CH:12]=[CH:13][N:9]([C:4]2[CH:5]=[CH:6][C:7]([CH3:8])=[C:2]([CH3:1])[CH:3]=2)[N:10]=1)=[O:28]
Reactant: Cc1ccc(-n2ccc(N)n2)cc1C
Reactant: O=C(Cl)c1cc(Cl)ccc1[N+](=O)[O-]
Solvent: c1ccncc1
Solvent: ClCCl
Product: Cc1ccc(-n2ccc(NC(=O)c3cc(Cl)ccc3[N+](=O)[O-])n2)cc1C
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Into a 100-mL round bottom flask, was placed a solution of 1-(3,4-dimethylphenyl)-1H-pyrazol-3-amine (408 mg, 2.18 mmol, 1.00 equiv) in dichloromethane (10 mL), pyridine (518 mg, 6.56 mmol, 3.00 equiv), and 5-chloro-2-nitrobenzoyl chloride (575 mg, 2.61 mmol, 1.00 equiv). The resulting solution was stirred for 2 h at room temperature. The resulting mixture was concentrated under vacuum. The solution was adjusted to pH 7 with hydrochloric acid (1 mol/L). The resulting solution was extracted with 3×50 mL of ethyl acetate and the organic layers combined dried over anhydrous sodium sulfate, and concentrated under vacuum. This resulted in 600 mg (59%) of 5-chloro-N-(1-(3,4-dimethylphenyl)-1H-pyrazol-3-yl)-2-nitrobenzamide as a yellow solid.
Reaction SMILES: [CH3:1][CH:2]([OH:4])[CH3:3].[H-].[Na+].[Cl:7][C:8]1[CH:13]=[N:12][CH:11]=[C:10](Cl)[N:9]=1>C1COCC1>[Cl:7][C:8]1[CH:13]=[N:12][CH:11]=[C:10]([O:4][CH:2]([CH3:3])[CH3:1])[N:9]=1
Reactant: Clc1cncc(Cl)n1
Reactant: CC(C)O
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)Oc1cncc(Cl)n1
Reaction time: 0.25 h
Yield: 86.9 %

Procedure:
To a solution of 2-propanol (2.26 mL, 31.99 mmol) in dry THF (40 mL) was added 60% NaH (960 mg, 39.90 mmol) at 0° C. and the reaction was stirred for 15 min. To the mixture at 0° C. was added 2,6-dichloropyrazine (4 g, 26.66 mmol, Aldrich) and the reaction was stirred for 2 h at RT. The reaction was quenched with ice cold H2O (20 mL) and extracted with EtOAc. The organic layer was dried over anhydrous Na2SO4, filtered and concentrated. The residue was purified with silica gel column chromatography (eluent: 100% petroleum ether) to afford 2-chloro-6-isopropoxypyrazine (4.0 g, 86%) as an off brown liquid. MS (ESI, pos. ion) m/z: 173.0 (M+1); 1H NMR (400 MHz, CDCl3): δ 8.28 (s, 1H), 8.14 (s, 1H), 5.31-5.25 (m, 1H), 1.37-1.36 (m, 6H).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[NH:12][N:11]=[N:10][N:9]=2)=[CH:4][CH:3]=1.[CH3:13][O:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[C:21]1[C:29]2[C:24](=[N:25][CH:26]=[C:27](B3OC(C)(C)C(C)(C)O3)[CH:28]=2)[N:23](COCC[Si](C)(C)C)[N:22]=1>O1CCCC1.C(#N)C>[CH3:13][O:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[C:21]1[C:29]2[C:24](=[N:25][CH:26]=[C:27]([C:2]3[CH:7]=[CH:6][C:5]([C:8]4[NH:12][N:11]=[N:10][N:9]=4)=[CH:4][CH:3]=3)[CH:28]=2)[NH:23][N:22]=1
Reactant: Brc1ccc(-c2nnn[nH]2)cc1
Reactant: COc1ccccc1-c1nn(COCC[Si](C)(C)C)c2ncc(B3OC(C)(C)C(C)(C)O3)cc12
Solvent: C1CCOC1
Solvent: CC#N
Product: COc1ccccc1-c1n[nH]c2ncc(-c3ccc(-c4nnn[nH]4)cc3)cc12
Temperature: 25 °C
Reaction time: 16 h
Yield: 5.1 %

Procedure:
In a microwave vial 5-(4-bromo-phenyl)-1H-tetrazole (89.2 mg, 0.4 mmol), 3-(2-methoxy-phenyl)-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1-(2-trimethylsilanyl-ethoxymethyl)-1H-pyrazolo[3,4-b]pyridine (200 mg, 0.40 mmol) in tetrahydrofuran/aceto-nitrile/1 N aqueous sodium bicarbonate (4 ml) was degassed with nitrogen and 1,1′-bis-(diphenylphosphino)ferrocenepalladium(II)-dichloride dichloromethane adduct (32.4 mg, 0.04 mmol) was added and the vial sealed. This reaction mixture was irradiated to 150° C. for 30 minutes in a microwave reactor. The mixture was extracted with ethyl acetate (3×) and the combined organic layers were dried over magnesium sulfate and filtered through a silica gel plug MS: m/z 500.6 (M+H+). To this crude was added trifluoroacetic acid (1 ml) and the reaction mixture stirred for 16 hours at ambient temperature. The solvent was removed under reduced pressure and the resulting solid was purified by preparative mass-triggered reverse-phase HPLC to yield 3-(2-methoxy-phenyl)-5-[4-(1H-tetrazol-5-yl)-phenyl]-1H-pyrazolo[3,4-b]pyridine as a white solid (7.5 mg, 5%). 1H NMR (500 MHz, DMSO-d6) δ 3.87 (s, 3H); 6.56 (s, 3H); 7.11 (t, J=8 Hz 1H) 7.23 (d, J=8 Hz 1H); 7.48 (t, J=8 Hz, 1H); 7.66 (d, J=8 Hz 1H); 8.01 (t, J=9 Hz, 1H); 8.14 (d, J=9 Hz 1H); 8.44 (s, 1H); 8.94 (s, 1H); 13.84 (s, br, 1H); MS: m/z 369.3 (M+H+).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[N:7][C:6]([NH2:12])=[CH:5]2.[CH3:13][O-:14].[Na+]>CS(C)=O>[CH3:13][O:14][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[N:7][C:6]([NH2:12])=[CH:5]2
Reactant: C[O-]
Reactant: Nc1cc2cc(Br)ccc2cn1
Agent: [Na+]
Solvent: CS(C)=O
Product: COc1ccc2cnc(N)cc2c1
Temperature: 150 °C
Yield: 53.8 %

Procedure:
In a dry box, to the microwave test tube (20 ml volume) was added the 6-bromoisoquinolin-3-amine (1.0 g, 4.5 mmol) and the NaOMe (242.0 mg, 4.5 mmol) in 10 ml of DMSO. The microwave test tube was capped and moved from the dry box. The test tube was place into Microwave station to heat at 150° C. for 30 min. The crude residue was purified by a silica gel column to give 420 mg (yield 53.8%). 1H NMR (400 MHz, DMSO-d6) ppm 2.44 (s, 3H), 7.94-8.11 (m, 2H), 8.17 (d, J=8.56 Hz, 2H), 8.82 (s, 1H). MS m/z, (APCI); 175.1 ([M+H]+).
Reaction SMILES: Br[C:2]1[S:6][C:5]([CH:7]=[O:8])=[CH:4][CH:3]=1.[F:9][C:10]([F:18])([F:17])[CH2:11][CH2:12][B-](F)(F)F>>[F:9][C:10]([F:18])([F:17])[CH2:11][CH2:12][C:2]1[S:6][C:5]([CH:7]=[O:8])=[CH:4][CH:3]=1
Reactant: F[B-](F)(F)CCC(F)(F)F
Reactant: O=Cc1ccc(Br)s1
Product: O=Cc1ccc(CCC(F)(F)F)s1
Yield: 89.5 %

Procedure:
The compound was synthesized as in Example 3.1 using 5-bromothiophene-2-carbaldehyde (250 mg, 1.31 mmol) in place of 5-bromo-2-formylfuran and 3,3,3-trifluoropropyltrifluoroborate (440 mg, 2.16 mmol) in place of hexylboronic acid to give 5-(3,3,3-trifluoropropyl)thiophene-2-carbaldehyde (244 mg, 90%). Used without further characterization.