Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:6]=[N:7][C:8]([C:11](=[O:18])[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[N:9][CH:10]=1)=[O:4].[Li+].[OH-]>C1COCC1.O>[C:11]([C:8]1[N:9]=[CH:10][C:5]([C:3]([OH:4])=[O:2])=[CH:6][N:7]=1)(=[O:18])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: COC(=O)c1cnc(C(=O)c2ccccc2)nc1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)c1cnc(C(=O)c2ccccc2)nc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 65.9 %

Procedure:
2-Benzoyl-pyrimidine-5-carboxylic acid methyl ester (420 mg, 1.73 mmol) is dissolved in THF (5 mL), and a solution of LiOH (46 mg, 1.91 mmol) in water (5 mL) is added in one portion at 0° C. The mixture is stirred at 0° C. for 60 min. THF is evaporated in vacuo, and the residue is diluted with water (5 mL) and washed with ether (10 mL). The aqueous layer is acidified with 2 N aqueous HCl to pH ˜3. The resulting precipitate is collected by filtration, washed with water three times, and dried in vacuum oven overnight to afford 2-benzoyl-pyrimidine-5-carboxylic acid (260 mg, 66%). MS: 229 (M+H); 1H NMR (300 MHz, DMSO): δ 7.60 (m, 3H), 7.73 (m, 1H), 7.85 (m, 2H), 9.4 (s, 1H).
Reaction SMILES: Br[CH2:2][C:3]1[C:8]([CH3:9])=[N:7][C:6]([CH3:10])=[C:5]([CH3:11])[N:4]=1.[CH2:12]([O:14][C:15](=[O:25])[C:16]1[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[C:18]([OH:24])[CH:17]=1)[CH3:13].C(=O)([O-])[O-].[K+].[K+].CN(C=O)C>O>[CH2:12]([O:14][C:15](=[O:25])[C:16]1[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[C:18]([O:24][CH2:2][C:3]2[C:8]([CH3:9])=[N:7][C:6]([CH3:10])=[C:5]([CH3:11])[N:4]=2)[CH:17]=1)[CH3:13]
Reactant: CCOC(=O)c1ccc(OC)c(O)c1
Reactant: Cc1nc(C)c(CBr)nc1C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)c1ccc(OC)c(OCc2nc(C)c(C)nc2C)c1
Temperature: 90 °C
Yield: 71.6 %

Procedure:
Adding 2-bromomethyl-3,5,6-trimethylpyrazine (0.768 g, 0.003 mol), 3-hydroxy-4-methoxybenzoic acid ethyl ester (0.954 g, 0.005 mol), anhydrous potassium carbonate (1.1 g, 0.008 mol), and DMF (60 mL) into a 100 mL three-necked bottle in turn, wherein the solution appears orange, heating to 90° C. with oil bath, stirring to react for 12 hours, TLC [V(petroleum ether):V(ethyl acetate)=3:1 as developing agent] detecting shows that reaction is complete, (Rf of raw material=0.6, Rf of product=0.4), and the reaction solution appears orange, filtering to obtain orange filtrate, adding 30 mL water, extracting with chloroform (3×30 mL), incorporating the chloroform layer and wishing with water (2×20 mL), drying with anhydrous sodium sulfate, recycling chloroform under reduced pressure to obtain a light yellow oily matter, separating with a silica column, wherein eluant is V(petroleum ether):V(ethyl acetate)=3:1, collecting product, recycling the solution under reduced pressure to obtain light yellow solid, recrystallizing with anhydrous alcohol to obtain 0.71 g 3-((3,5,6-trimethylpyrazine-2-yl)methoxyl)-4-methoxybenzoic acid ethyl ester, a yield is 60.7%, m.p. 129.8-130.4° C.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:8]2[N:7]([CH3:11])[C:6]3[C:12](=[O:19])[CH:13]=[C:14]([C:16](O)=[O:17])[O:15][C:5]=3[C:4]=2[CH:3]=1.C(OC(N1C2C(=CC=CC=2)C=CC1OCC)=O)C.O.[NH2:39][C:40]1[NH:44][N:43]=[N:42][N:41]=1>C1C=CC=CC=1>[Cl:1][C:2]1[CH:10]=[CH:9][C:8]2[N:7]([CH3:11])[C:6]3[C:12](=[O:19])[CH:13]=[C:14]([C:16]([NH:39][C:40]4[NH:44][N:43]=[N:42][N:41]=4)=[O:17])[O:15][C:5]=3[C:4]=2[CH:3]=1
Reactant: Cn1c2ccc(Cl)cc2c2oc(C(=O)O)cc(=O)c21
Reactant: Nc1nnn[nH]1
Agent: CCOC(=O)N1c2ccccc2C=CC1OCC
Solvent: c1ccccc1
Solvent: O
Product: Cn1c2ccc(Cl)cc2c2oc(C(=O)Nc3nnn[nH]3)cc(=O)c21
Reaction time: 0.75 h

Procedure:
A mixture of 2.5 g (9.1 mmole) 8-chloro-4, 5-dihydro-5-methyl-4-oxopyrano[3,2-b]indole-2-carboxylic acid and 4.8 g (19.7 mmole) N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline (EEDQ) in 300 ml benzene was stirred for 45 min under nitrogen. To the reaction mixture was added 1.1 g (10.7 mmole) of 5-aminotetrazole monohydrate, and stirring was continued for a total of 88 hrs. The precipitate that had formed was filtered, stirred overnight in 50 ml of methanol, and refiltered. Two recrystallizations from DMF yielded a yellow solid of mp 300° C. dec.
Reaction SMILES: [Na].[C:2]([C:4]1[C:9](=[S:10])[NH:8][C:7]([C:11]2[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=2)=[C:6]([C:19]([O:21][CH2:22][CH3:23])=[O:20])[C:5]=1[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[N+:30]([O-:32])=[O:31])#[N:3].[CH3:33]I>CO>[C:2]([C:4]1[C:9]([S:10][CH3:33])=[N:8][C:7]([C:11]2[CH:12]=[CH:13][C:14]([O:17][CH3:18])=[CH:15][CH:16]=2)=[C:6]([C:5]=1[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[N+:30]([O-:32])=[O:31])[C:19]([O:21][CH2:22][CH3:23])=[O:20])#[N:3]
Reactant: CCOC(=O)c1c(-c2ccc(OC)cc2)[nH]c(=S)c(C#N)c1-c1ccccc1[N+](=O)[O-]
Reactant: CI
Agent: [Na]
Solvent: CO
Product: CCOC(=O)c1c(-c2ccc(OC)cc2)nc(SC)c(C#N)c1-c1ccccc1[N+](=O)[O-]
Reaction time: 0.08 h
Yield: 59 %

Procedure:
69 mg (3 mmol) of sodium is added at room temperature in small portions to 0.4 ml of methanol. After the sodium disappears, 870 mg (2 mmol) of ethyl 5-cyano-2-(4-methoxyphenyl)-4-(2-nitrophenyl)-6-thioxo-1,6-dihydropyridine-3-carboxylate is added. The reaction mixture is stirred for 5 minutes, and then 0.18 ml (3 mmol) of methyl iodide is added and stirring is continued for 3 hours. The solvent is concentrated and the precipitate formed is filtered, rinsed with water and then diethyl ether and then dried under vacuum to yield 0.53 g (59%) of ethyl 5-cyano-2-(4-methoxyphenyl)-6-(methylthio)-4-(2-nitrophenyl)nicotinate in the form of a yellow powder.
Reaction SMILES: [CH2:1]([NH:3][C:4]([N:6]1[C:14]2[C:9](=[CH:10][C:11]([O:15][C:16]3[CH:21]=[CH:20][N:19]=[C:18]([NH:22][C:23](=[O:31])OC4C=CC=CC=4)[CH:17]=3)=[CH:12][CH:13]=2)[CH:8]=[CH:7]1)=[O:5])[CH3:2].[CH2:32]([O:34][CH2:35][CH2:36][NH2:37])[CH3:33]>CN(C)C=O>[CH2:1]([NH:3][C:4]([N:6]1[C:14]2[C:13](=[CH:12][C:11]([O:15][C:16]3[CH:21]=[CH:20][N:19]=[C:18]([NH:22][C:23]([NH:37][CH2:36][CH2:35][O:34][CH2:32][CH3:33])=[O:31])[CH:17]=3)=[CH:10][CH:9]=2)[CH:8]=[CH:7]1)=[O:5])[CH3:2]
Reactant: CCNC(=O)n1ccc2cc(Oc3ccnc(NC(=O)Oc4ccccc4)c3)ccc21
Reactant: CCOCCN
Solvent: CN(C)C=O
Product: CCNC(=O)n1ccc2cc(Oc3ccnc(NC(=O)NCCOCC)c3)ccc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 100 %

Procedure:
Phenyl N-(4-(1-(ethylamino)carbonyl-1H-5-indolyl)oxy-2-pyridyl)carbamate (100 mg, 0.24 mmol) was dissolved in N,N-dimethylformamide (1.0 ml), and 2-ethoxyethylamine (0.063 ml, 0.6 mmol) was added while stirred at room temperature. After 1 hour, the reaction mixture was partitioned between ethyl acetate and water. The organic layer was washed with water and brine, and dried over anhydrous sodium sulfate. After the solvent was distilled off, the crystals were precipitated from ethyl acetate-hexane (1:5), filtered off, and dried under aeration to yield the title compound (100 mg, 0.24 mmol, quantitative) as white crystals.
Reaction SMILES: C(OC([NH:8][CH:9]1[CH2:14][CH2:13][N:12]([C:15]([O:17][CH2:18][C:19]2[CH:24]=[C:23]([C:25]([F:28])([F:27])[F:26])[CH:22]=[C:21]([CH3:29])[CH:20]=2)=[O:16])[CH2:11][CH2:10]1)=O)(C)(C)C.Cl.O1CCOCC1>C(Cl)Cl>[NH2:8][CH:9]1[CH2:10][CH2:11][N:12]([C:15]([O:17][CH2:18][C:19]2[CH:24]=[C:23]([C:25]([F:28])([F:26])[F:27])[CH:22]=[C:21]([CH3:29])[CH:20]=2)=[O:16])[CH2:13][CH2:14]1
Reactant: Cc1cc(COC(=O)N2CCC(NC(=O)OC(C)(C)C)CC2)cc(C(F)(F)F)c1
Agent: Cl
Solvent: ClCCl
Solvent: C1COCCO1
Product: Cc1cc(COC(=O)N2CCC(N)CC2)cc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a stirred solution of 3-methyl-5-(trifluoromethyl)benzyl 4-((tert-butoxycarbonyl)amino)piperidine-1-carboxylate (237 mg, 0.569 mmol) in DCM (5 ml) at RT under nitrogen was added 4M HCl in Dioxane (1.423 ml, 5.69 mmol) and the reaction mixture stirred at RT for 3 hours. The reaction mixture was concentrated under reduced pressure to afford the title product as the hydrochloride salt;
Reaction SMILES: [CH3:1][C@H:2]1[CH2:7][N:6]([C:8]2[C:13]([N+:14]([O-:16])=[O:15])=[CH:12][N:11]=[C:10]3[CH2:17][CH2:18][CH2:19][C:9]=23)[CH2:5][C@@H:4]([NH:20][C:21](=[O:27])[O:22][C:23]([CH3:26])([CH3:25])[CH3:24])[CH2:3]1.C1C=C(Cl)C=C(C(OO)=[O:36])C=1.[O-]S([O-])(=S)=O.[Na+].[Na+].[OH-].[Na+]>C(Cl)Cl>[CH3:1][C@H:2]1[CH2:7][N:6]([C:8]2[C:13]([N+:14]([O-:16])=[O:15])=[CH:12][N+:11]([O-:36])=[C:10]3[CH2:17][CH2:18][CH2:19][C:9]=23)[CH2:5][C@@H:4]([NH:20][C:21](=[O:27])[O:22][C:23]([CH3:26])([CH3:25])[CH3:24])[CH2:3]1
Reactant: C[C@@H]1C[C@H](NC(=O)OC(C)(C)C)CN(c2c([N+](=O)[O-])cnc3c2CCC3)C1
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Product: C[C@@H]1C[C@H](NC(=O)OC(C)(C)C)CN(c2c([N+](=O)[O-])c[n+]([O-])c3c2CCC3)C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 59.3 %

Procedure:
To a solution of tert-butyl [(3S,5R)-5-methyl-1-(3-nitro-6,7-dihydro-5H-cyclopenta[b]pyridin-4-yl)piperidin-3-yl]carbamate (32.3 mg, 0.086 mmol) in DCM (0.50 mL) at 0° C. was added mCPBA (25.0 mg, 0.112 mmol). The reaction mixture was stirred at room temperature for 1 h. The mixture was treated with Na2S2O3 solution, followed by 1N NaOH, and stirred for 30 min. at room temperature. The organic layer was separated, dried, filtered and concentrated under vacuum to give the crude N-oxide product. The crude product was purified by preparative LC-MS (XBridge™ preparative C18 5 μm OBD™ column, 30×10 mm, 60 mL/min., eluting with a gradient of MeCN and water with 0.1% NH4OH) to afford the sub-title compound (20 mg, 40%). LCMS calc. for C19H29N4O5 (M+H)+: m/z=393.2. Found: 393.1.
Reaction SMILES: Cl.[C:2]([C:6]1[CH:11]=[CH:10][C:9]([C@@H:12]([NH2:14])[CH3:13])=[CH:8][CH:7]=1)([CH3:5])([CH3:4])[CH3:3].[Cl:15][C:16]1[CH:36]=[CH:35][C:19]([CH2:20][N:21]2[C:29]3[C:24](=[CH:25][C:26]([C:30](O)=[O:31])=[CH:27][CH:28]=3)[C:23]([CH3:33])=[C:22]2[CH3:34])=[CH:18][C:17]=1[O:37][C@@H:38]([CH3:43])[C:39]([O:41][CH3:42])=[O:40]>>[C:2]([C:6]1[CH:7]=[CH:8][C:9]([C@@H:12]([NH:14][C:30]([C:26]2[CH:25]=[C:24]3[C:29](=[CH:28][CH:27]=2)[N:21]([CH2:20][C:19]2[CH:35]=[CH:36][C:16]([Cl:15])=[C:17]([CH:18]=2)[O:37][C@@H:38]([CH3:43])[C:39]([O:41][CH3:42])=[O:40])[C:22]([CH3:34])=[C:23]3[CH3:33])=[O:31])[CH3:13])=[CH:10][CH:11]=1)([CH3:5])([CH3:3])[CH3:4]
Reactant: COC(=O)[C@H](C)Oc1cc(Cn2c(C)c(C)c3cc(C(=O)O)ccc32)ccc1Cl
Reactant: C[C@H](N)c1ccc(C(C)(C)C)cc1
Agent: Cl
Product: COC(=O)[C@H](C)Oc1cc(Cn2c(C)c(C)c3cc(C(=O)N[C@@H](C)c4ccc(C(C)(C)C)cc4)ccc32)ccc1Cl

Procedure:
The title compound was prepared following the same protocol as described in Step 5, Example 36, using the (S)-1-(4-(tert-butyl)phenyl)ethanamine hydrochloride instead of the (S)-1-(3-cyclopropylphenyl)ethanamine hydrochloride the (S)-1-(4-chloro-3-((1-methoxy-1-oxopropan-2-yl)oxy)benzyl)-2,3-dimethyl-1H-indole-5-carboxylic acid instead of the 1-(4-(2-methoxy-2-oxoethoxy)benzyl)-2,3-dimethyl-1H-indole-5-carboxylic acid.
Reaction SMILES: C([O:3][C:4](=[O:22])[CH2:5][CH:6]([C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:19]=[CH:18][C:17]([F:20])=[CH:16][C:15]=2[F:21])=[CH:10][CH:9]=1)[CH3:7])C>O>[F:21][C:15]1[CH:16]=[C:17]([F:20])[CH:18]=[CH:19][C:14]=1[C:11]1[CH:12]=[CH:13][C:8]([CH:6]([CH3:7])[CH2:5][C:4]([OH:22])=[O:3])=[CH:9][CH:10]=1
Reactant: CCOC(=O)CC(C)c1ccc(-c2ccc(F)cc2F)cc1
Solvent: O
Product: CC(CC(=O)O)c1ccc(-c2ccc(F)cc2F)cc1

Procedure:
A mixture of 1 g. of 3-(2',4'-difluoro-4-biphenylyl)butyric acid ethyl ester and 100 ml. of water is heated to 180° in an autoclave for 24 hours. It is cooled and worked up in the customary manner to give 3-(2',4'-difluoro-4-biphenylyl)butyric acid, m.p. 109°-110°.
Reaction SMILES: [O:1]=[C:2]([CH3:12])[CH2:3][CH2:4][CH2:5][C:6]#[C:7][CH2:8][CH2:9][CH2:10][OH:11].CC(C)=[O:15].OS(O)(=O)=O.O=[Cr](=O)=O>CC(C)=O>[O:1]=[C:2]([CH3:12])[CH2:3][CH2:4][CH2:5][C:6]#[C:7][CH2:8][CH2:9][C:10]([OH:15])=[O:11]
Reactant: CC(C)=O
Reactant: CC(=O)CCCC#CCCCO
Agent: O=[Cr](=O)=O
Agent: O=S(=O)(O)O
Product: CC(=O)CCCC#CCCC(=O)O

Procedure:
20 Parts of 9-oxodec-4-yn-1-ol of Example 4 is dissolved in 200 parts by volume of acetone and cooled to 0 C. The cold solution is stirred and treated dropwise with 90 parts by volume of 2.67 molar Jones reagent (chromic acid and sulfuric acid and water). The acetone solution is decanted from the solid chromium salts, which are then rinsed with fresh acetone. The acetone solutions are combined and poured into a mixture of ether and water. The ether layer is separated from the water, washed once with water, and then extracted three times with 5% potassium carbonate solution. The alkaline extracts are combined, acidified with concentrated hydrochloric acid and extracted twice with ether and once with ethyl acetate. The extracts are combined, dried over sodium sulfate, and stripped of solvent to give the pure product, 9-oxodec-4-ynoic acid.
Reaction SMILES: [C:1]([O:4][C:5]1[CH:13]=[CH:12][C:8]([C:9](O)=[O:10])=[CH:7][CH:6]=1)(=[O:3])[CH3:2].S(Cl)([Cl:16])=O>CN(C)C=O.C1C=CC=CC=1>[C:1]([O:4][C:5]1[CH:13]=[CH:12][C:8]([C:9]([Cl:16])=[O:10])=[CH:7][CH:6]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)Oc1ccc(C(=O)O)cc1
Reactant: O=S(Cl)Cl
Solvent: CN(C)C=O
Solvent: c1ccccc1
Product: CC(=O)Oc1ccc(C(=O)Cl)cc1

Procedure:
In a 20 ml-round-bottomed flask, 2.90 g (16.1 mM) of 4-acetoxybenzoic acid and 3.7 ml of thionyl chloride were placed. To the mixture, two drops of N,N-dimethylformamide was added at room temperature under stirring, followed by heat-refluxing for 20 minutes under stirring. After the reaction, dry benzene was added to the reaction mixture, followed by distilling-off of excessive thionyl chloride together with benzene. The above operation was repeated two times to obtain 4-acetoxybenzoic acid chloride. Then, in a 100 ml-round-bottomed flask, the above-prepared 4-acetoxybenzoic acid chloride, 3.10 g (15.1 mM) of 2-amino-4-octylphenol and 40 ml of dioxane were placed and heated. To the mixture, 5.5 ml of pyridine was added dropwise at 80°-84° C. under stirring, followed by further stirring for 20 minutes at 85°-88.5° C. After the reaction, the reaction mixture was cooled on an ice bath and poured into about 200 ml of ice water to precipitate a crystal. The crystal was recovered by filtration and washed with water, followed by recrystallization from methanol to obtain 4.10 g of 2-(4-acetoxybenzoylamino)-4-octylphenol (Yield: 70.8%).
Reaction SMILES: [CH3:1][C:2]1([CH3:10])[C:7](=[O:8])[CH2:6][C:5](=O)[CH2:4][O:3]1.S(=O)(=O)(O)O.[NH3:16]>C(O)C>[NH2:16][C:5]1[CH2:4][O:3][C:2]([CH3:10])([CH3:1])[C:7](=[O:8])[CH:6]=1
Reactant: CC1(C)OCC(=O)CC1=O
Reactant: N
Agent: O=S(=O)(O)O
Solvent: CCO
Product: CC1(C)OCC(N)=CC1=O
Temperature: 25 °C
Reaction time: 16 h

Procedure:
The product from Example 66C (1.5 g, 11 mmol) in ethanol (40 mL) was treated with concentrated sulfuric acid (0.4 mL), refluxed for 4 hours, cooled to ambient temperature, treated with 2M ammonia in ethanol (50 mL), stirred at ambient temperature for 16 hours and concentrated. The residue was purified by chromatography on silica gel eluting with 10% methanol in dichloromethane to provide the title compound (1.0 g).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([S:11]([CH2:14][C:15]([O:17][CH3:18])=[O:16])(=[O:13])=[O:12])[CH:5]=[CH:6][C:7]=1[N+:8]([O-])=O>[Ni].CO>[NH2:1][C:2]1[CH:3]=[C:4]([S:11]([CH2:14][C:15]([O:17][CH3:18])=[O:16])(=[O:13])=[O:12])[CH:5]=[CH:6][C:7]=1[NH2:8]
Reactant: COC(=O)CS(=O)(=O)c1ccc([N+](=O)[O-])c(N)c1
Agent: [Ni]
Solvent: CO
Product: COC(=O)CS(=O)(=O)c1ccc(N)c(N)c1

Procedure:
14.3 500 mg of Raney nickel are added to a solution of 2.40 g (8.76 mmol) of methyl (3-amino-4-nitrobenzenesulfonyl)acetate in 50 ml of methanol, and the mixture is hydrogenated at room temperature and atmospheric pressure. The catalyst is filtered off, and the filtrate is evaporated, giving methyl (3,4-diaminobenzenesulfonyl)acetate as a yellow solid; ESI 245.
Reaction SMILES: [Si:1]([O:8][CH:9]([C:22]1[O:23][C:24]([Sn](CCCC)(CCCC)CCCC)=[CH:25][N:26]=1)[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].I[C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][C:42]=1[O:47][CH3:48]>>[Si:1]([O:8][CH:9]([C:22]1[O:23][C:24]([C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][C:42]=2[O:47][CH3:48])=[CH:25][N:26]=1)[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)([C:4]([CH3:7])([CH3:5])[CH3:6])([CH3:2])[CH3:3]
Reactant: COc1ccccc1I
Reactant: CCCC[Sn](CCCC)(CCCC)c1cnc(C(CCCCCCc2ccccc2)O[Si](C)(C)C(C)(C)C)o1
Product: COc1ccccc1-c1cnc(C(CCCCCCc2ccccc2)O[Si](C)(C)C(C)(C)C)o1
Yield: 77 %

Procedure:
The title compound was prepared from 2-(1-(tert-butyldimethylsilyloxy)-7-phenylheptyl)-5-(tributylstannyl)oxazole (140 mg, 0.211 mmol) and 1-iodo-2-methoxybenzene following General Procedure A. Flash chromatography (2% EtOAc/hexanes) yielded the title compound as a white solid (78 mg, 77%): 1H NMR (CDCl3, 400 MHz) δ 7.81 (dd, 1H, J=9.2, 6.0 Hz), 7.49 (s, 1H), 7.30-7.27 (m, 3H), 7.19-7.16 (m, 3H), 7.07-7.05 (m, 1H), 6.99 (d, 1H, J=8.4 Hz), 4.85 (t, 1H, J=6.8 Hz), 3.98 (s, 3H), 2.58 (t, 2H, J=8.0 Hz), 1.95-1.91 (m, 2H), 1.63-1.60 (m, 2H), 1.38-1.34 (m, 6H), 0.91 (s, 9H), 0.11 (s, 3H), 0.00 (s, 3H); 13C NMR (CDCl3, 100 MHz) δ 168.8, 160.7, 152.7, 148.0, 134.0, 133.5, 133.3, 131.0, 130.9, 130.7, 125.9, 122.4, 115.9, 73.8, 60.5, 41.6, 41.1, 36.6, 34.3, 34.3, 30.9, 30.3, 23.3, 0.2, 0.0.
Reaction SMILES: [K].[C:2]([C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=1)#[N:3].[Br:11][CH2:12][CH2:13][CH2:14][CH2:15]Br>>[C:2]([C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:15][CH2:14][CH2:13][CH2:12][Br:11])=[CH:6][CH:5]=1)#[N:3]
Reactant: N#Cc1ccc(O)cc1
Reactant: BrCCCCBr
Agent: [K]
Product: N#Cc1ccc(OCCCCBr)cc1

Procedure:
The intermediate 4-(4-cyanophenoxy)butyl bromide was prepared from the potassium salt of 4-cyanophenol and 1,4-dibromobutane.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[C:9]1[S:10][C:11]2[C:12]([NH2:18])=[N:13][CH:14]=[CH:15][C:16]=2[N:17]=1.[CH:19]12[CH2:24][CH:23]1[C:22](=[O:25])[O:21][C:20]2=O>O1CCOCC1>[Cl:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[C:3]=1[C:9]1[S:10][C:11]2[C:12]([N:18]3[C:20](=[O:21])[CH:19]4[CH:23]([CH2:24]4)[C:22]3=[O:25])=[N:13][CH:14]=[CH:15][C:16]=2[N:17]=1
Reactant: Nc1nccc2nc(-c3c(Cl)cccc3Cl)sc12
Reactant: O=C1OC(=O)C2CC12
Solvent: C1COCCO1
Product: O=C1C2CC2C(=O)N1c1nccc2nc(-c3c(Cl)cccc3Cl)sc12
Temperature: 25 °C
Yield: 78.8 %

Procedure:
A solution of 2-(2,6-dichlorophenyl)thiazolo[5,4-c]pyridin-4-amine (550 mg, 1.86 mmol) and 3-oxabicyclo[3.1.0]hexane-2,4-dione (835 mg, 7.46 mmol) in 1,4-dioxane (10 mL) was heated at 90° C. for 2 hours. The reaction mixture was then cooled to room temperature and concentrated. The residue was purified by column chromatography eluting with ethyl acetate/petroleum ether (1:10 to 1:2) to give the desired product as a solid. (570 mg, 78.8% yield). LCMS (ESI) m/z: 390.0 [M+H+].
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([F:11])=[C:6]2[C:10]=1[NH:9][CH:8]=[CH:7]2.C([Li])CCC.[C:17](=[O:19])=[O:18].O>C1COCC1.CCCCCC>[F:11][C:5]1[CH:4]=[CH:3][C:2]([C:17]([OH:19])=[O:18])=[C:10]2[C:6]=1[CH:7]=[CH:8][NH:9]2
Reactant: Fc1ccc(Br)c2[nH]ccc12
Reactant: O=C=O
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: O
Solvent: CCCCCC
Product: O=C(O)c1ccc(F)c2cc[nH]c12
Temperature: -78 °C
Yield: 80 %

Procedure:
492 mg (2.30 mmol) of 7-bromo-4-fluoro-1H-indole were dissolved in 14 ml THF. The reaction mixture was cooled to −78° C. and 4.31 ml of a 1.6 M butyl lithium solution in hexane were added under nitrogen in such a way, that the temperature did not exceed a maximum of −70° C. The yellow solution was stirred at 0 to 5° C. after complete addition for 30 min. The reaction mixture was cooled to −78° C. and dry ice was added. The reaction mixture was warmed to rt, stirred for 15 min and poured onto 100 ml water. The aqueous layer was washed twice with diethyl ether, acidified with 1N aqueous HCl solution and extracted twice with DCM. The combined organic layers were washed with saturated aqueous sodium chloride solution, dried over sodium sulfate, filtered and the solvent was evaporated. The crude residue was stirred with hexane for 15 min, filtered and dried to yield 328 mg (80%) of 4-fluoro-1H-indole-7-carboxylic acid as an off-white solid. MS (ISP) 177.9 (M−H)−.
Reaction SMILES: [NH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]=[CH:3][C:2]1=O.O=P(Cl)(Cl)[Cl:14]>O>[Cl:14][C:2]1[CH:3]=[N:4][C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[N:1]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: O=c1cnc2ccccc2[nH]1
Solvent: O
Product: Clc1cnc2ccccc2n1

Procedure:
Quinoxalin-2-one (14.62 g, 100 mmol) was added to POCl3 (100 g, 0.65 mmol) and the mixture heated at reflux for 1.5 hours under N2. Upon cooling, the mixture was poured slowly, portionwise onto 700 ml of H2O. The black solution was extracted with CH2Cl2 (2×250 ml). The combined CH2Cl2 portions were washed with H2O, dried over Na2SO4, filtered, and evaporated to give a brown, solid 2-chloroquinoxaline. A portion of said product (4.00 g, 24.3 mmol) was combined with 5 ml of 1 N HCl, and NaN3 (1.89 g, 29.1 mmol) in 220 ml of abs EtOH and heated at reflux for 7 hours. The mixture was allowed to cool overnight, which led to precipitation of yellow-brown needles of tetrazolo[1,5-a]quinoxaline (19).
Reaction SMILES: [CH:1]([NH:3][NH:4][C:5]1[CH:10]=[CH:9][C:8]([NH2:11])=[CH:7][CH:6]=1)=[O:2].C(N(CC)CC)C.[CH3:19][N:20]([CH3:24])[C:21](Cl)=[S:22]>C(#N)C>[CH:1]([NH:3][NH:4][C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:21]([N:20]([CH3:24])[CH3:19])=[S:22])=[CH:7][CH:6]=1)=[O:2]
Reactant: Nc1ccc(NNC=O)cc1
Reactant: CN(C)C(=S)Cl
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CN(C)C(=S)Nc1ccc(NNC=O)cc1
Temperature: 60 °C

Procedure:
1-Formyl-2-(4-aminophenyl)hydrazine (1.51 g, 0.01 mole) and triethylamine (1.0 g, 0.01 mole) were mixed with dry acetonitrile (30 ml). The mixture was kept under a nitrogen atmosphere and a solution of dimethylthiocarbamoyl chloride (1.24 g, 0.01 mole) in acetonitrile (10 ml) was added dropwise at room temperature. After the addition was complete, the reaction mixture was chilled in ice, then filtered. The solid was washed with ethanol and allowed to dry. The material was stirred in water (40 ml) and heated to 60° C. to remove any hydrochloride salts. The aqueous mixture was filtered; the solid was washed with ether and dried. This gave 0.60 g (25 percent) of product as a pale tan powder, m.p. 187°-189° C.
Reaction SMILES: [C:1]([O:4][C@@H:5]1[C@@H:9]([CH2:10][O:11][C:12](=[O:14])[CH3:13])[O:8][C@@H:7]([N:15]2[C:19]([N:20]3[C:24](=[O:25])[C:23]4=[CH:26][CH:27]=[CH:28][CH:29]=[C:22]4[C:21]3=[O:30])=[C:18]([C:31]([O:33]C(C)(C)C)=[O:32])[N:17]=[CH:16]2)[C@@H:6]1[Cl:38])(=[O:3])[CH3:2]>FC(F)(F)C(O)=O.ClCCl>[C:1]([O:4][C@@H:5]1[C@@H:9]([CH2:10][O:11][C:12](=[O:14])[CH3:13])[O:8][C@@H:7]([N:15]2[C:19]([N:20]3[C:21](=[O:30])[C:22]4=[CH:29][CH:28]=[CH:27][CH:26]=[C:23]4[C:24]3=[O:25])=[C:18]([C:31]([OH:33])=[O:32])[N:17]=[CH:16]2)[C@@H:6]1[Cl:38])(=[O:3])[CH3:2]
Reactant: CC(=O)OC[C@H]1O[C@@H](n2cnc(C(=O)OC(C)(C)C)c2N2C(=O)c3ccccc3C2=O)[C@H](Cl)[C@@H]1OC(C)=O
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(=O)OC[C@H]1O[C@@H](n2cnc(C(=O)O)c2N2C(=O)c3ccccc3C2=O)[C@H](Cl)[C@@H]1OC(C)=O
Reaction time: 8 h
Yield: 97 %

Procedure:
Compound (34) obtained in step (2) above (1.50 g) was dissolved in a mixture of trifluoroacetic acid-dichloromethane (1:4) (25 ml), and the solution so obtained was allowed to stand at room temperature overnight so that there occurred de-esterification of compound (34). The resulting reaction solution was concentrated to leave a solid. This solid was then washed with diethyl ether to yield the titled compound (35) (1.31 g) which was insoluble in diethyl ether (1.31 g). Yield: 97%.