Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: I[C:2]1[NH:6][C:5]([C@@H:7]2[CH2:11][CH2:10][CH2:9][N:8]2[C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])=[N:4][CH:3]=1.C(N(CC)CC)C.[C:26]([Si:28]([CH3:31])([CH3:30])[CH3:29])#[CH:27]>[Cu]I.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.CN(C=O)C>[CH3:29][Si:28]([C:26]#[C:27][C:2]1[NH:6][C:5]([C@@H:7]2[CH2:11][CH2:10][CH2:9][N:8]2[C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])=[N:4][CH:3]=1)([CH3:31])[CH3:30]
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1c1ncc(I)[nH]1
Reactant: C#C[Si](C)(C)C
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC[C@H]1c1ncc(C#C[Si](C)(C)C)[nH]1
Temperature: 50 °C
Yield: 79.2 %

Procedure:
(S)-tert-Butyl 2-(5-iodo-1H-imidazol-2-yl)pyrrolidine-1-carboxylate (750 mg, 2.07 mmol) and copper(I) iodide (79 mg, 0.41 mmol) were dissolved into DMF (20 mL) and triethylamine (1.439 mL, 10.33 mmol). The reaction solution was vacuum flushed for 10 minutes (aspirator vacuum, flushed with nitrogen) and then ethynyltrimethylsilane (1.2 mL, 8.3 mmol) and finally Pd(PPh3)4 (119 mg, 0.103 mmol) were added. The flask was flushed with nitrogen, seal and heated at 50° C. overnight. The reaction was concentrated to a crude black tar, dissolved into DCM and purified via BIOTAGE® Horizon (80 g SiO2, 20-40% EtOAc/hexanes) to yield (S)-tert-butyl 2-(5-((trimethylsilyl)ethynyl)-1H-imidazol-2-yl)pyrrolidine-1-carboxylate (546 mg, 1.64 mmol, 79% yield) as a yellow solid. This material was used without further purification. LC-MS retention time 1.393 min; m/z 332.33 (MH−). LC data was recorded on a Shimadzu LC-10AS liquid chromatograph equipped with a PHENOMENEX® Luna 10u C18 3.0×50 mm column using a SPD-10AV UV-Vis detector at a detector wave length of 220 nM. The elution conditions employed a flow rate of 5 mL/min, a gradient of 100% Solvent A/0% Solvent B to 0% Solvent A/100% Solvent B, a gradient time of 2 min, a hold time of 1 min, and an analysis time of 3 min where Solvent A was 5% acetonitrile/95% H2O/10 mM ammonium acetate and Solvent B was 5% H2O/95% acetonitrile/10 mM ammonium acetate. MS data was determined using a MICROMASS® Platform for LC in electrospray mode. 1H NMR (400 MHz, CDCl3) δ ppm 7.19-7.13 (m, 1H), 4.92-4.85 (m, 1H), 3.43-3.31 (m, 2H), 3.04-2.83 (m, 1H), 2.20-1.88 (m, 3H), 1.51 (s, 3H), 1.49 (s, 6H), 0.25 (s, 3H), 0.23 (s, 6H).
Reaction SMILES: [NH2:1][C:2]1[N:3]=[C:4](O)[C:5]2[CH:10]=[CH:9][NH:8][C:6]=2[N:7]=1.P(Cl)(Cl)([Cl:14])=O>>[Cl:14][C:4]1[C:5]2[CH:10]=[CH:9][NH:8][C:6]=2[N:7]=[C:2]([NH2:1])[N:3]=1
Reactant: Nc1nc(O)c2cc[nH]c2n1
Reactant: O=P(Cl)(Cl)Cl
Product: Nc1nc(Cl)c2cc[nH]c2n1
Temperature: 110 °C

Procedure:
A mixture of 2-amino-7H-pyrrolo[2,3-d]pyrimidin-4-ol (Sigma, 150 mg, 1.0 mmol) in phosphorus oxychloride (1.5 mL) was heated at about 110° C. for about 30 minutes. Phosphorus oxychloride was carefully removed under reduced pressure and the reaction mixture was quenched by slow addition of ice water (10 mL). The resulting mixture was neutralized with saturated aqueous sodium carbonate (about 5 mL) to pH 7. The crude product was extracted into dichloromethane (20 mL) and washed with water (15 mL). The organic layer was separated and the aqueous phase was further extracted with dichloromethane (3×30 mL). The combined organic extracts were dried over anhydrous sodium sulfate and concentrated to give 4-chloro-7H-pyrrolo[2,3-d]pyrimidin-2-ylamine (0.036 g, 0.21 mmol) as a light yellow solid; LC/MS (Table 1, Method a) Rt 1.17 min; MS m/z: (M+H)+ 169.
Reaction SMILES: [C:1]([O:5][C:6]([CH3:9])([CH3:8])[CH3:7])(=[O:4])[CH:2]=[CH2:3].[CH3:10][O:11][CH2:12][CH2:13][NH2:14]>CO>[CH3:10][O:11][CH2:12][CH2:13][NH:14][CH2:3][CH2:2][C:1]([O:5][C:6]([CH3:9])([CH3:8])[CH3:7])=[O:4]
Reactant: COCCN
Reactant: C=CC(=O)OC(C)(C)C
Solvent: CO
Product: COCCNCCC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 3 h

Procedure:
tert-Butyl acrylate (4.4 ml) is dissolved in methanol (5 ml), and thereto is added 2-methoxyethylamine (3.1 ml). The mixture is stirred at room temperature for 3 hours. The reaction solution is concentrated under reduced pressure. The resulting residue is purified by distillation under reduced pressure to give tert-butyl 3-(2-methoxyethylamino)-propionate (4.61 g). Boiling point 98.0-102.0° C. (5.8 mmHg), MS (m/z): 204 [M+H]+.
Reaction SMILES: Cl[C:2]1[C:3]([N+:19]([O-:21])=[O:20])=[CH:4][C:5]([CH3:18])=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([C:14]([NH:16][CH3:17])=[O:15])=[CH:10][CH:9]=2)[CH:7]=1.[CH2:22](OB(C=C)OCCCC)[CH2:23]CC.C(=O)([O-])[O-].[Na+].[Na+]>C1COCC1.O>[CH3:17][NH:16][C:14]([C:11]1[CH:12]=[CH:13][C:8]([C:6]2[CH:7]=[C:2]([CH:22]=[CH2:23])[C:3]([N+:19]([O-:21])=[O:20])=[CH:4][C:5]=2[CH3:18])=[CH:9][CH:10]=1)=[O:15]
Reactant: CNC(=O)c1ccc(-c2cc(Cl)c([N+](=O)[O-])cc2C)cc1
Reactant: C=CB(OCCCC)OCCCC
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: C=Cc1cc(-c2ccc(C(=O)NC)cc2)c(C)cc1[N+](=O)[O-]
Temperature: 90 °C

Procedure:
To a mixture of 5′-chloro-N,2′-dimethyl-4′-nitrobiphenyl-4-carboxamide (Step 2, 100 mg, 0.33 mmol), vinylboronic acid dibutyl ester (90 mg, 0.5 mmol) and sodium carbonate (245 mg, 2.31 mmol) in THF/H2O (8/2 mL) is added dichlorobis(triphenylphospine) palladium (II) (12 mg, 5% mmol). The reaction tube is sealed, the mixture is purged with N2 for 3 min and then heated at 90° C. under N2 for overnight. The reaction is cooled to room temperature and poured into saturated aqueous ammonia chloride solution. The crude reaction mixture is extracted with ethyl acetate (3×15 mL). The organic extracts are combined, washed with brine and concentrated. The crude product is purified with silica gel column chromatography (30% ethyl acetate in DCM) to afford N,2′-dimethyl-4′-nitro-5′-vinylbiphenyl-4-carboxamide as a yellow solid. The obtained solid is dissolved in methanol (20 mL). To this solution is added Pd/C (10%). The reaction mixture is degassed and purged with H2 for several times and stirred under atmospheric hydrogen overnight. The mixture is filtered and concentrated to afford 4′-amino-5′-ethyl-N,2′-dimethylbiphenyl-4-carboxamide as a yellow solid. ESMS m/z 269.2 (M+H+).
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]2[O:8][C:7]([C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=3)=[N:6][C:5]2=[C:15]([C:17]([OH:19])=O)[CH:16]=1.Cl.C(N=C=NCCCN(C)C)C.ON1C2C=CC=CC=2N=N1.Cl.Cl.[NH2:44][CH:45]1[CH2:52][CH:51]2[N:53]([CH3:54])[CH:47]([CH2:48][CH2:49][CH2:50]2)[CH2:46]1.C(N(CC)CC)C>CN(C=O)C.C(OCC)C>[CH3:54][N:53]1[CH:47]2[CH2:48][CH2:49][CH2:50][CH:51]1[CH2:52][CH:45]([NH:44][C:17]([C:15]1[CH:16]=[C:2]([I:1])[CH:3]=[C:4]3[O:8][C:7]([C:9]4[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=4)=[N:6][C:5]=13)=[O:19])[CH2:46]2
Reactant: CN1C2CCCC1CC(N)C2
Reactant: O=C(O)c1cc(I)cc2oc(-c3ccccc3)nc12
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCOCC
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CN1C2CCCC1CC(NC(=O)c1cc(I)cc3oc(-c4ccccc4)nc13)C2
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 60.8 %

Procedure:
A mixture of 6-iodo-2-phenylbenzoxazole-4-carboxylic acid (75 mg, 0.21 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (78 mg, 0.41 mmol), 1-hydroxybenzotriazole (55 mg, 0.41 mmol) and 3-amino-9-methyl-9-azabicyclo[3.3.1]nonane dihydrochloride (69 mg, 0.25 mmol) in DMF (5 mL) was stirred 10 min at room temperature, then triethylamine (0.10 mL, 0.82 mmol) was added. The resulting reaction mixture was stirred at room temperature overnight. The mixture was diluted with diethyl ether (50 mL) and then washed with a saturated solution of sodium bicarbonate. The aqueous layer was further extracted with ethyl acetate (2×50 mL). The combined organics were dried (Na2SO4), filtered and concentrated under reduced pressure. The crude material was purified by column chromatography (silica gel, 90:9:1 methylene chloride/methanol/concentrated ammonium hydroxide) followed by recrystallization from acetonitrile to afford N-(9-methyl-9-azabicyclo[3.3.1]non-3-yl)-6-iodo-2-phenylbenzoxazole-4-carboxamide (64 mg, 63%) as a light yellow solid: 1H NMR (500 MHz, CDCl3) δ 8.91 (br s, 1H), 8.52 (d, J=1.6 Hz, 1H), 8.25-8.20 (m, 2H), 8.06 (d, J=1.5 Hz, 1H), 7.65-7.55 (m, 3H), 4.65-4.52 (m, 1H), 3.32-3.10 (m, 2H), 2.70-2.50 (m, 5H), 2.20-1.20 (m, 2H), 1.65-1.45 (m, 4H), 1.25-1.10 (m, 2H); MS (ESI+) m/z 502 (M+H); HPLC>99% (AUC), tR=13.83 min.
Reaction SMILES: [Cl:1][C:2]1[C:9]([OH:10])=[CH:8][CH:7]=[C:6]([Cl:11])[C:3]=1[CH:4]=[O:5].[CH2:12](Br)[CH:13]=[CH2:14].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[CH2:14]([O:10][C:9]1[C:2]([Cl:1])=[C:3]([C:6]([Cl:11])=[CH:7][CH:8]=1)[CH:4]=[O:5])[CH:13]=[CH2:12]
Reactant: C=CCBr
Reactant: O=Cc1c(Cl)ccc(O)c1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: C=CCOc1ccc(Cl)c(C=O)c1Cl
Temperature: 25 °C
Reaction time: 18 h

Procedure:
2,6-dichloro-3-hydroxybenzaldehyde (960 mg, 5.03 mmol) (Synthesis, 2004, 12, 2062), allyl bromide (431 μL, 5.03 mmol) and potassium carbonate (563 mg, 10.06 mmol) were combined in DMF (5 mL) and stirred at room temperature for 18 hours. The DMF was removed in vacuo and the residue partitioned between diethyl ether (50 mL) and water (30 mL). The layers were separated and the aqueous extracted with diethyl ether (2×30 mL). The combined organic solution was dried over magnesium sulphate and concentrated in vacuo to afford the title compound as a yellow solid which was used without further purification in preparation 75.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:34]=[CH:33][C:6]([CH2:7][N:8]2[C:12]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[C:11]([C:18](=[O:32])[C:19]3[CH:24]=[CH:23][C:22]([NH:25][C:26](=[O:28])[CH3:27])=[CH:21][C:20]=3[N+:29]([O-])=O)[N:10]=[N:9]2)=[CH:5][CH:4]=1.COC1C=CC(CN2C(C(=O)C3C=CC(NC(=O)C)=CC=3[N+]([O-])=O)=C(C(OCC)=O)N=N2)=CC=1>C(OCC)(=O)C.[Pd]>[NH2:29][C:20]1[CH:21]=[C:22]([NH:25][C:26](=[O:28])[CH3:27])[CH:23]=[CH:24][C:19]=1[C:18]([C:11]1[N:10]=[N:9][N:8]([CH2:7][C:6]2[CH:33]=[CH:34][C:3]([O:2][CH3:1])=[CH:4][CH:5]=2)[C:12]=1[C:13]([O:15][CH2:16][CH3:17])=[O:14])=[O:32]
Reactant: CCOC(=O)c1c(C(=O)c2ccc(NC(C)=O)cc2[N+](=O)[O-])nnn1Cc1ccc(OC)cc1
Agent: [Pd]
Agent: CCOC(=O)c1nnn(Cc2ccc(OC)cc2)c1C(=O)c1ccc(NC(C)=O)cc1[N+](=O)[O-]
Solvent: CCOC(C)=O
Product: CCOC(=O)c1c(C(=O)c2ccc(NC(C)=O)cc2N)nnn1Cc1ccc(OC)cc1
Temperature: 25 °C
Reaction time: 96 h
Yield: 93 %

Procedure:
The 3:1 mixture (650 mg, 1.39 mmol) of ethyl 1-(4-methoxybenzyl)-4-(4-acetylamino-2-nitrobenzoyl)-1,2,3-triazole-5-carboxylate (b-1) and ethyl 1-(4-methoxybenzyl)-5-(4-acetylamino-2-nitrobenzoyl)-1,2,3-triazole-4-carboxylate (b-2) prepared in the above step (b) was dissolved in ethyl acetate (29 ml), 10% palladium on carbon (65 mg) was added to the solution, and the mixture was stirred under a hydrogen atmosphere at room temperature for four days. The reaction mixture was filtered through Celite, the filtrate was concentrated under reduced pressure, and the resultant precipitate was collected by filtration to give a 3:1 mixture (565.5 mg, 93%) of ethyl 4-(2-amino-4-acetylaminobenzoyl)-1-(4-methoxybenzyl)-1,2,3-triazole-5-carboxylate (c-1) and ethyl 5-(2-amino-4-acetylaminobenzoyl)-1-(4-methoxybenzyl)-1,2,3-triazole-5-carboxylate (c-2).
Reaction SMILES: COC[N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][C:11]=2[N:13]([S:15]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[O:24][CH3:25])(=[O:17])=[O:16])[CH3:14])[CH:6]=[C:5]1[C:26]([O:28]CC)=[O:27].Cl.O1CCCC1>CO>[CH3:25][O:24][C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=1[S:15]([N:13]([CH3:14])[C:11]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:12]=1[NH:4][C:5]([C:26]([OH:28])=[O:27])=[CH:6]2)(=[O:17])=[O:16]
Reactant: CCOC(=O)c1cc2cccc(N(C)S(=O)(=O)c3ccccc3OC)c2n1COC
Agent: Cl
Solvent: CO
Solvent: C1CCOC1
Product: COc1ccccc1S(=O)(=O)N(C)c1cccc2cc(C(=O)O)[nH]c12
Temperature: 90 °C
Reaction time: 24 h
Yield: 71.2 %

Procedure:
A mixture of ethyl 1-(methoxymethyl)-7-[[(2-methoxyphenyl)sulfonyl](methyl)amino]-1H-indole-2-carboxylate (10.9 g), 6N-hydrochloric acid (50 mL), tetrahydrofuran (50 mL) and methanol (50 mL) was stirred at 90° C. for 24 hr. The organic solvent of the reaction solution was evaporated under reduced pressure, and the residue was diluted with ethyl acetate. The solution was washed with water and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained residue was dissolved in a mixed solvent of tetrahydrofuran (50 mL)-methanol (50 mL), aqueous potassium hydroxide solution (prepared by dissolving potassium hydroxide (4.2 g) in water (30 mL)) was added to this solution, and the mixture was stirred at room temperature for 15 hr. The reaction solution was acidified with aqueous citric acid solution, and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained pale-brown crystals were filtered off, and washed with ethyl acetate-hexane. The filtrate was concentrated under reduced pressure, and the obtained crystals were washed with ethyl acetate-hexane to give the title compound (6.47 g, crude yield: 71%) as pale-yellow crystals. MS: 361 (MH+).
Reaction SMILES: C[O:2][CH:3](OC)[C:4]1[NH:5][CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[N:8]=1.[OH-].[Na+]>S(=O)(=O)(O)O>[F:12][C:9]([F:10])([F:11])[C:7]1[N:8]=[C:4]([CH:3]=[O:2])[NH:5][CH:6]=1
Reactant: COC(OC)c1nc(C(F)(F)F)c[nH]1
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Product: O=Cc1nc(C(F)(F)F)c[nH]1
Temperature: 90 °C
Reaction time: 1 h
Yield: 66.8 %

Procedure:
2 N sulfuric acid (20 ml) was added to 2-(dimethoxymethyl)-4-(trifluoromethyl)-1H-imidazole obtained in Example (33a) (720 mg, 3.43 mmol), and the mixture was stirred at 90° C. for one hour. The reaction solution was neutralized with a 1 N aqueous sodium hydroxide solution, followed by extraction with ethyl acetate. Then, the organic layer was washed with brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure, to obtain 0.376 g of the title compound as a white solid (67%).
Reaction SMILES: F[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[CH:4][N:3]=1.[O:11]1[CH2:16][CH2:15][CH:14]([OH:17])[CH2:13][CH2:12]1>>[N+:8]([C:7]1[C:2]([O:17][CH:14]2[CH2:15][CH2:16][O:11][CH2:12][CH2:13]2)=[N:3][CH:4]=[CH:5][CH:6]=1)([O-:10])=[O:9]
Reactant: O=[N+]([O-])c1cccnc1F
Reactant: OC1CCOCC1
Product: O=[N+]([O-])c1cccnc1OC1CCOCC1

Procedure:
Prepared analogously to I.1 from 2-fluor-3-nitropyridine and tetrahydro-pyran-4-ol.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([CH2:20][CH2:21][C:22]([N:24]3[CH2:29][CH2:28][CH:27]([CH2:30][OH:31])[CH2:26][CH2:25]3)=[O:23])[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:10]3=[N:17][CH:18]=[CH:19][N:9]23)=[CH:4][CH:3]=1>C(Cl)Cl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([CH2:20][CH2:21][C:22]([N:24]3[CH2:25][CH2:26][CH:27]([CH:30]=[O:31])[CH2:28][CH2:29]3)=[O:23])[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:10]3=[N:17][CH:18]=[CH:19][N:9]23)=[CH:4][CH:3]=1
Reactant: O=C(CCC1(c2ccc(Cl)cc2)c2ccccc2-c2nccn21)N1CCC(CO)CC1
Solvent: ClCCl
Product: O=CC1CCN(C(=O)CCC2(c3ccc(Cl)cc3)c3ccccc3-c3nccn32)CC1

Procedure:
To a solution of (1-{3-[5-(4-chlorophenyl)-5H-imidazo[2,1-a]isoindol-5-yl]propanoyl}piperidin-4-yl)methanol (36 mg) in CH2Cl2 was added resin (polystyrene) bound IBX (2 equivalent) and allowed to react overnight. The reaction mixture was then filtered through a fitted funnel and the resin was washed thoroughly with THF. Combined filtrate and washings were concentrated to give the title compound as a colorless glass. Mass. found (M+H)+, 480.0.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[C:5]#[N:6].[N:10]([Si](C)(C)C)=[N+:11]=[N-:12].C([Sn](=O)CCCC)CCC>C1(C)C=CC=CC=1.CCOC(C)=O>[Br:1][C:2]1[CH:3]=[C:4]([C:5]2[N:10]=[N:11][NH:12][N:6]=2)[CH:7]=[CH:8][CH:9]=1
Reactant: C[Si](C)(C)N=[N+]=[N-]
Reactant: N#Cc1cccc(Br)c1
Agent: CCCC[Sn](=O)CCCC
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: Brc1cccc(-c2nn[nH]n2)c1
Temperature: 110 °C
Reaction time: 3 h

Procedure:
3-Bromobenzonitrile (2.49 g, 13.7 mmol) and azidotrimethylsilane (3.14 g, 27.3 mmol) were stirred in anhydrous toluene (100 mL) under argon at ambient temperature. To this was added dibutyltin oxide (341 mg, 1.37 mmol) and the resulting reaction was fitted with a reflux condenser and heated with stirring at 110° C. for 3 h. Upon cooling, the reaction mixture was concentrated in vacuo, and then concentrated to dryness twice following the addition of MeOH (ca. 25 mL each). The crude reaction mixture was dissolved in EtOAc (300 mL) and washed with H2O (2×100 mL). The organic phase was washed with 1N aqueous NaOH (4×75 mL), the combined basic aqueous portions were treated with 4N HCl to obtain an endpoint of pH=4 and the acidic aqueous phase was extracted with EtOAc (4×100 mL washes). The combined EtOAc layers were dried (MgSO4), filtered, and concentrated in vacuo to obtain 5-(3-bromophenyl)-2H-tetrazole as a white solid.
Reaction SMILES: C([O:3][C:4](=[O:19])[C@@H:5]1[CH2:9][C@H:8]([C:10]#[N:11])[CH2:7][N:6]1[C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])C.[OH-].[Na+].C(O)(=O)C.O.[K+].[Br-]>CO>[C:15]([O:14][C:12]([N:6]1[CH2:7][C@@H:8]([C:10]#[N:11])[CH2:9][C@H:5]1[C:4]([OH:19])=[O:3])=[O:13])([CH3:18])([CH3:16])[CH3:17]
Reactant: CCOC(=O)[C@@H]1C[C@H](C#N)CN1C(=O)OC(C)(C)C
Agent: [Br-]
Agent: [K+]
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Solvent: O
Product: CC(C)(C)OC(=O)N1C[C@@H](C#N)C[C@H]1C(=O)O
Temperature: 22 °C
Reaction time: 16 h
Yield: 76 %

Procedure:
The cyano ethyl ester (11a) from the previous experiment (2.9 g, 12.1 mmol) was dissolved in 100 mL methanol and 15 mL of 1M NaOH was added over five minutes with good stirring. This was allowed to stir for 16 h at 22° C. and was then treated with 1 mL of 80% acetic acid/water. This solution was then concentrated and worked-up according to method A. The residue crystallized on standing at 5° C., and was recrystallized from EtOAc/hexane to give 2.2 g (76% yield), m.p.=138°-139° C. (decomposition). IR (KBr) 2253 cm-1 (nitrile). 1H NMR δ 1.40/1.46 (2s, 9H), 2.44 (m, 1H), 2.70 (m, 1H), 3.12 (m, 1H), 3.65 (m, 1H), 3.92 (m, 1H), 4.36 (m, 1H). Anal. (C11H16N2O4), C, H, N. The X-ray crystal structure of this compound unambiguously confirmed the expected cis orientation of the nitrile with respect to the carboxylic acid.
Reaction SMILES: [CH2:1]([C:8]1[C:9]([O:37][CH3:38])=[N:10][C:11]2[C:16]([C:17]=1[Cl:18])=[CH:15][C:14]([C:19]([C:31]1[N:35]([CH3:36])[CH:34]=[N:33][CH:32]=1)([C:21]1[CH:22]=[N:23][C:24]([C:27]([F:30])([F:29])[F:28])=[CH:25][CH:26]=1)O)=[CH:13][CH:12]=2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:39]([OH:45])([C:41]([F:44])([F:43])[F:42])=[O:40].[H-].[Na+].C(OC(=O)C)(=O)C.[NH3:55]>CN(C=O)C>[CH2:1]([C:8]1[C:9]([O:37][CH3:38])=[N:10][C:11]2[C:16]([C:17]=1[Cl:18])=[CH:15][C:14]([C:19]([C:31]1[N:35]([CH3:36])[CH:34]=[N:33][CH:32]=1)([C:21]1[CH:22]=[N:23][C:24]([C:27]([F:28])([F:29])[F:30])=[CH:25][CH:26]=1)[NH2:55])=[CH:13][CH:12]=2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:39]([OH:45])([C:41]([F:44])([F:43])[F:42])=[O:40].[C:39]([OH:45])([C:41]([F:44])([F:43])[F:42])=[O:40]
Reactant: COc1nc2ccc(C(O)(c3ccc(C(F)(F)F)nc3)c3cncn3C)cc2c(Cl)c1Cc1ccccc1
Reactant: N
Agent: [H-]
Agent: [Na+]
Solvent: CC(=O)OC(C)=O
Solvent: O=C(O)C(F)(F)F
Solvent: CN(C)C=O
Product: COc1nc2ccc(C(N)(c3ccc(C(F)(F)F)nc3)c3cncn3C)cc2c(Cl)c1Cc1ccccc1
Reaction time: 0.25 h

Procedure:
To a solution of (3-benzyl-4-chloro-2-methoxyquinolin-6-yl)(1-methyl-1H-imidazol-5-yl)(6-(trifluoromethyl)pyridin-3-yl)methanol (446 mg, 0.830 mmol, Example 110) and DMF (15 mL) was added NaH (60% in mineral oil, 90 mg, 2.3 mmol) at room temperature. After stirring for 15 minutes, acetic anhydride (0.16 mL, 1.7 mmol) was added. After stirring for 1 hour, NH3 (7.0 M in MeOH, 1.0 mL, 7.0 mmol) was added. The mixture was stirred overnight and concentrated in vacuo. The residue was partitioned between EtOAc and water. The organic layers were washed with water, and the aqueous layer was back extracted with EtOAc. The extracts were dried (Na2SO4), filtered, and concentrated. The residue was purified by reverse phase HPLC (water/acetonitrile/0.1% TFA) to afford the title compound as a TFA salt. 1H NMR (400 MHz, MeOH-d4) δ 8.97 (s, 1H), 8.77 (d, J=2.02 Hz, 1H), 8.11 (d, J=2.02 Hz, 1H), 8.00 (dd, J=2.27, 8.34 Hz, 1H), 7.94 (d, J=9.09 Hz, 1H), 7.88 (d, J=8.08 Hz, 1H), 7.62 (dd, J=2.27, 8.84 Hz, 1H), 7.20-7.24 (m, 4H), 7.12-7.18 (m, 1H), 6.94 (d, J=1.52 Hz, 1H), 4.30 (s, 2H), 4.08 (s, 3H), 3.72 (s, 3H); MS m/e 538.2 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[C:10](Br)=[CH:9][C:8]([CH3:12])=[CH:7][C:3]=1[C:4]([NH2:6])=[O:5].CC1(C)C(C)(C)OB([C:21]2[CH:22]=[C:23]3[C:28](=[CH:29][CH:30]=2)[CH:27]=[C:26]([NH:31][C:32]([C:34]2[CH:38]=[CH:37][S:36][CH:35]=2)=[O:33])[CH:25]=[CH:24]3)O1.C([O-])([O-])=O.[K+].[K+].O1CCOCC1>[Pd].O>[NH2:1][C:2]1[C:3]([C:4](=[O:5])[NH2:6])=[CH:7][C:8]([CH3:12])=[CH:9][C:10]=1[C:21]1[CH:22]=[C:23]2[C:28](=[CH:29][CH:30]=1)[CH:27]=[C:26]([NH:31][C:32]([C:34]1[CH:38]=[CH:37][S:36][CH:35]=1)=[O:33])[CH:25]=[CH:24]2
Reactant: CC1(C)OB(c2ccc3cc(NC(=O)c4ccsc4)ccc3c2)OC1(C)C
Reactant: Cc1cc(Br)c(N)c(C(N)=O)c1
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: Cc1cc(C(N)=O)c(N)c(-c2ccc3cc(NC(=O)c4ccsc4)ccc3c2)c1
Temperature: 25 °C
Yield: 10 %

Procedure:
2-amino-3-bromo-5-methylbenzamide (31.8 mg, 0.139 mmol), N-(6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)naphthalen-2-yl)thiophene-3-carboxamide (122 mg, 0.370 mmol), Fibercat palladium catalyst (Johnson-Matthey, 68.2 mg), and K2CO3 (2 M in water, 0.51 ml, 1.0 mmol) were combined in a microwave reaction vessel and 1,4-dioxane (1.5 ml) was added. The reaction tube was sealed and heated in the microwave (CEM microwave) at 60 Watts and 80 C for 20 minutes. The reaction was then cooled to room temperature, diluted with water (5 ml), and extracted with EtOAc (4×10 ml). The organic extracts were combined, dried over sodium sulfate, filtered, concentrated, and purified via silica gel (Biotage instrument, 13%->50%->100% EtOAc/hexanes) to afford title compound (5.6 mg, 10%). MS (ESI pos. ion) m/z: 402 (M+H). Calc'd Exact Mass for C23H19N3O2S: 401.
Reaction SMILES: [NH2:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[CH:4][C:3]=1[OH:11].C(=O)([O-])[O-].[K+].[K+].[CH3:18][O:19][C:20]1[CH:27]=[CH:26][C:23]([CH2:24]Cl)=[CH:22][CH:21]=1.O>CN(C)C=O>[CH3:18][O:19][C:20]1[CH:27]=[CH:26][C:23]([CH2:24][O:11][C:3]2[CH:4]=[CH:5][CH:6]=[C:7]([N+:8]([O-:10])=[O:9])[C:2]=2[NH2:1])=[CH:22][CH:21]=1
Reactant: Nc1c(O)cccc1[N+](=O)[O-]
Reactant: COc1ccc(CCl)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccc(COc2cccc([N+](=O)[O-])c2N)cc1
Reaction time: 0.5 h
Yield: 0.1 %

Procedure:
To a solution of 2-amino-3-nitrophenol (10 g) in dimethylformamide (100 ml) was added potassium carbonate (17.9 g) under ice-cooling, and the mixture was stirred for 30 minutes at the same temperature. To the mixture was added 4-methoxybenzyl chloride (10.7 g) at ambient temperature, and the mixture was stirred for 30 minutes under ice-cooling and then overnight at ambient temperature. To the reaction mixture was added water, and the mixture was extracted with dichloromethane, and purified by silica gel column chromatography (ethyl acetate-n-hexane). The residue was crystallized with ethanol to give 2-(4-methoxybenzyloxy)-6-nitroaniline (13.6 mg) as yellow needles.