Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[C:7]([O:9][C:10]2[C:19]3[C:14](=[CH:15][C:16]([O:22][CH3:23])=[C:17]([O:20][CH3:21])[CH:18]=3)[N:13]=[CH:12][N:11]=2)[CH:6]=[CH:5][C:3]=1[NH2:4].[C:24]1([CH3:30])[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.C(N(CC)CC)C.Cl[C:39](Cl)([O:41][C:42](=[O:48])OC(Cl)(Cl)Cl)Cl.CC1C=CC(CO)=CC=1>C(Cl)Cl>[Cl:1][C:2]1[CH:8]=[C:7]([O:9][C:10]2[C:19]3[C:14](=[CH:15][C:16]([O:22][CH3:23])=[C:17]([O:20][CH3:21])[CH:18]=3)[N:13]=[CH:12][N:11]=2)[CH:6]=[CH:5][C:3]=1[NH:4][C:42](=[O:48])[O:41][CH2:39][C:27]1[CH:28]=[CH:29][C:24]([CH3:30])=[CH:25][CH:26]=1
Reactant: COc1cc2ncnc(Oc3ccc(N)c(Cl)c3)c2cc1OC
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: Cc1ccccc1
Agent: Cc1ccc(CO)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1cc2ncnc(Oc3ccc(NC(=O)OCc4ccc(C)cc4)c(Cl)c3)c2cc1OC
Temperature: 25 °C
Yield: 28 %

Procedure:
2-Chloro-4-[(6,7-dimethoxy-4-quinazolinyl)oxy]aniline (109 mg) was added to toluene/triethylamine=10/1 (10 ml), and the mixture was heated under reflux to prepare a solution. A solution of triphosgene (146 mg) in methylene chloride was then added to the solution, and the mixture was heated under reflux for 15 min. Subsequently, 4-methylbenzyl alcohol (61 mg) was added thereto, and the mixture was further stirred with heating under reflux for 2 hr. After the completion of the reaction, the reaction solution was allowed to cool to room temperature before distilled water was added thereto. The mixture was subjected to separatory extraction with chloroform, followed by washing with a 1 N aqueous hydrochloric acid solution and saturated brine. The washed solution was dried over sodium sulfate and was concentrated. The residue was purified on a column using chloroform/methanol to give the title compound (48 mg, yield 28%).
Reaction SMILES: Cl[S:2]([C:5]1[CH:14]=[CH:13][C:12]2[NH:11][C:10](=[O:15])[C:9]3[NH:16][CH:17]=[C:18]([C:19]([OH:21])=[O:20])[C:8]=3[C:7]=2[CH:6]=1)(=[O:4])=[O:3].[OH:22][C:23]1[CH:24]=[C:25]([CH:27]=[CH:28][CH:29]=1)[NH2:26]>>[OH:22][C:23]1[CH:24]=[C:25]([NH:26][S:2]([C:5]2[CH:14]=[CH:13][C:12]3[NH:11][C:10](=[O:15])[C:9]4[NH:16][CH:17]=[CH:18][C:8]=4[C:7]=3[CH:6]=2)(=[O:3])=[O:4])[CH:27]=[CH:28][CH:29]=1.[CH2:18]([C:19]([O-:21])=[O:20])[CH3:17]
Reactant: O=C(O)c1c[nH]c2c(=O)[nH]c3ccc(S(=O)(=O)Cl)cc3c12
Reactant: Nc1cccc(O)c1
Product: CCC(=O)[O-]
Product: O=c1[nH]c2ccc(S(=O)(=O)Nc3cccc(O)c3)cc2c2cc[nH]c12
Yield: 22.3 %

Procedure:
This compound is prepared according to synthesis 25, from 150 mg (0.46 mmol) of 8-chlorosulfonyl-4-oxo-4,5-dihydro-3H-pyrrolo[2,3-c]quinoline-1-carboxylic acid (synthesis 2) and 60 mg (0.55 mmol) of 3-hydroxy-aniline. After purification by chromatography on silica (eluent dichloromethane/methanol 95/5) then trituration in diethyl ether, 22 mg (12%) of 8-(3-hydroxy-phenylsulfamoyl)-4-oxo-4,5-dihydro-3H-pyrrolo[2,3-c]quinoline-1-ethyl carboxylate is obtained in the form of a yellow solid.
Reaction SMILES: C1(C)C=CC(S(O[CH2:11][CH2:12][CH:13]2[CH2:22][C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[O:15][CH2:14]2)(=O)=O)=CC=1.[ClH:24].[CH3:25][O:26][C:27]([CH2:29][CH2:30][NH2:31])=[O:28].C(N(C(C)C)C(C)C)C>CN(C)C=O>[ClH:24].[O:15]1[C:16]2[C:21](=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH2:22][CH:13]([CH2:12][CH2:11][NH:31][CH2:30][CH2:29][C:27]([O:26][CH3:25])=[O:28])[CH2:14]1
Reactant: Cc1ccc(S(=O)(=O)OCCC2COc3ccccc3C2)cc1
Reactant: COC(=O)CCN
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COC(=O)CCNCCC1COc2ccccc2C1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
33.2 g (0.1 mol) of 3-[2-(p-toluenesulphonyloxy)ethyl]chroman, 14.0 g of N-(2-methoxycarbonylethyl)-amine hydrochloride and 39 g of N-ethyl-N,N-diisopropylamine are dissolved under nitrogen in 750 ml of dimethylformamide and the solution is stirred for 16 hours at room temperature. The reaction mixture is subsequently concentrated to approximately 200 ml under reduced pressure, 500 ml of water are then added and the whole is extracted by shaking three times with 150 ml of dichloromethane each time. The combined organic phases are dried over sodium sulphate and concentrated to dryness by evaporation. By adding ethanolic hydrochloric acid and cooling, N-[2-(chroman-3-yl)ethyl]-N-(2-methoxycarbonylethyl)-amine hydrochloride having a melting point of 190°-192° is obtained.
Reaction SMILES: CS(O[CH:6]([CH2:26][CH2:27][CH2:28][CH2:29][CH3:30])[CH2:7][CH2:8][C@@H:9]1[C@@H:13]([CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21])[C:12](=[O:25])[CH2:11][CH2:10]1)(=O)=O.CN(C)C=O.[Cl-:36].[Li+]>O>[Cl:36][CH:6]([CH2:26][CH2:27][CH2:28][CH2:29][CH3:30])[CH2:7][CH2:8][C@@H:9]1[C@@H:13]([CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21])[C:12](=[O:25])[CH2:11][CH2:10]1
Reactant: CCCCCC(CC[C@H]1CCC(=O)[C@@H]1CCCCCCC(=O)OCC)OS(C)(=O)=O
Reactant: [Cl-]
Agent: [Li+]
Solvent: O
Solvent: CN(C)C=O
Product: CCCCCC(Cl)CC[C@H]1CCC(=O)[C@@H]1CCCCCCC(=O)OCC

Procedure:
A solution of 1.35 g. of ethyl 15-methanesulfonyloxy 9-oxo-prostanoate (Example 90) in 40 ml. of N,N-dimethylformamide containing 650 mg. of lithium chloride is heated on the steam bath for 18 hours. The cooled solution is diluted with water and the resulting mixture is extracted with ether. The ether extract is washed with saline, dried with saline, dried with anhydrous magnesium sulfate and evaporated to dryness to give an oil. Chromatography on silica gel affords an oil; λ max. 5.78 μ (carbonyl groups).
Reaction SMILES: N(C1C=C(C=CC=1C)C(O)=O)=[N+]=[N-].C(C1C=NC=CC=1)#C.Cl[C:23]1[N:28]=[CH:27][C:26]([C:29]2[N:30]=[N:31][N:32]([C:34]3[CH:35]=[C:36]([CH:40]=[CH:41][C:42]=3[CH3:43])[C:37]([OH:39])=[O:38])[CH:33]=2)=[CH:25][CH:24]=1>>[CH3:43][C:42]1[CH:41]=[CH:40][C:36]([C:37]([OH:39])=[O:38])=[CH:35][C:34]=1[N:32]1[CH:33]=[C:29]([C:26]2[CH:27]=[N:28][CH:23]=[CH:24][CH:25]=2)[N:30]=[N:31]1
Reactant: Cc1ccc(C(=O)O)cc1-n1cc(-c2ccc(Cl)nc2)nn1
Agent: C#Cc1cccnc1
Agent: Cc1ccc(C(=O)O)cc1N=[N+]=[N-]
Product: Cc1ccc(C(=O)O)cc1-n1cc(-c2cccnc2)nn1

Procedure:
4-Methyl-3-(4-pyridin-3-yl-[1,2,3]triazol-1-yl)-benzoic acid was prepared from 3-azido-4-methyl benzoic acid and 3-ethynyl pyridine (Aldrich) in the same manner as 3-[4-(6-chloro-pyridin-3-yl)-1,2,3-triazol-1-yl]-4-methyl-benzoic acid (Example 1).
Reaction SMILES: [CH:1]([CH:3]1[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:4]1)=O.[C:15](=O)([O-])[O-].[K+].[K+]>CO>[C:1]([CH:3]1[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:4]1)#[CH:15]
Reactant: O=C([O-])[O-]
Reactant: CC(C)(C)OC(=O)N1CCC(C=O)C1
Agent: [K+]
Solvent: CO
Product: C#CC1CCN(C(=O)OC(C)(C)C)C1
Reaction time: 16 h

Procedure:
Dimethyl-1-diazo-2-oxypropylphosphonate (11.5 g, 60 mmol) was added to a solution of tert-butyl 3-formylpyrrolidine-1-carboxylate (10 g, 50 mmol) and potassium carbonate (13.8 g, 100 mmol) in dry methanol (150 mL). After 16 hours, the reaction mixture was filtered and washed with methanol. The filtrate was extracted with diethyl ether, and the organic layer was washed with 5% aqueous sodium bicarbonate, dried over sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by column chromatography on silica gel to afford tert-butyl 3-ethynylpyrrolidine-1-carboxylate.
Reaction SMILES: [CH3:1][C:2]1([OH:12])[CH:9]2[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:11][CH:3]1[CH2:4]3)[CH2:8]2.C(OC(C)C)(C)C.[C:20]([O:25][CH2:26][CH2:27][N:28]=[C:29]=[O:30])(=[O:24])[C:21]([CH3:23])=[CH2:22].CS(O)(=O)=O.C([O-])(O)=O.[Na+]>CCCCCC>[C:20]([O:25][CH2:26][CH2:27][NH:28][C:29](=[O:30])[O:12][C:2]1([CH3:1])[CH:3]2[CH2:11][CH:7]3[CH2:6][CH:5]([CH2:10][CH:9]1[CH2:8]3)[CH2:4]2)(=[O:24])[C:21]([CH3:23])=[CH2:22]
Reactant: C=C(C)C(=O)OCCN=C=O
Reactant: CC1(O)C2CC3CC(C2)CC1C3
Agent: CS(=O)(=O)O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(C)OC(C)C
Solvent: CCCCCC
Product: C=C(C)C(=O)OCCNC(=O)OC1(C)C2CC3CC(C2)CC1C3
Temperature: 5.5 °C
Reaction time: 15 h
Yield: 39.5 %

Procedure:
In a three-necked flask having an inner volume of 50 mL equipped with a thermometer and a stirring apparatus were charged 1.66 g (9.98 mmol) of 2-methyl-2-adamantanol, 2.0 mg of 4-acetamido-2,2,6,6-tetramethylpiperidine-N-oxyl, 6.7 g of isopropyl ether, and 1.66 g (10.5 mmol) of 2-methacryloyloxyethyl isocyanate. After the mixture was cooled by ice water to an inner temperature of 5° C., 290 mg (3.0 mmol) of methanesulfonic acid was added dropwise. After stirring the reaction mixture for 15 hours with the reaction temperature maintained at 5 to 6° C., 10 g of a saturated aqueous NaHCO3 solution was added dropwise with the inner temperature maintained at 10° C. or less and, after completion of the dropwise addition, the mixture was allowed to stand still for 30 minutes. The organic layer (upper layer) formed was separated and the aqueous layer (lower layer) was extracted twice with 10 g of isopropyl ether. All the separated organic layers were combined, washed with 10 g of distilled water, and the organic layer concentrated under reduced pressure to obtain 2.82 g of a concentrate. The concentrate was dissolved in 15 g of hexane at 30° C. and the solution was cooled to −10° C. at a rate of 10° C./hour. The crystals which precipitated were separated by filtration and the crystals obtained were dried under vacuum (26.7 Pa) at 30° C. for 2 hours to obtain 1.29 g (purity 98.2%, 3.94 mmol, yield: 39.5%) of 2-methyladamantan-2-yl (2-methacryloyloxyethyl)carbamate.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][C:11]([C:13]([F:16])([F:15])[F:14])=[C:10]([C:17](Cl)=[O:18])[CH:9]=2)=[CH:4][CH:3]=1.[F:20][C:21]([F:34])([F:33])[C:22]1[CH:23]=[C:24]([NH2:32])[CH:25]=[C:26]([C:28]([F:31])([F:30])[F:29])[CH:27]=1.C(N(CC)C(C)C)(C)C.Cl.C([O-])(O)=O.[Na+]>ClCCl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][C:11]([C:13]([F:16])([F:15])[F:14])=[C:10]([C:17]([NH:32][C:24]3[CH:25]=[C:26]([C:28]([F:29])([F:30])[F:31])[CH:27]=[C:22]([C:21]([F:20])([F:33])[F:34])[CH:23]=3)=[O:18])[CH:9]=2)=[CH:4][CH:3]=1
Reactant: Nc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reactant: O=C(Cl)c1cc(-c2ccc(Cl)cc2)oc1C(F)(F)F
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: O=C(Nc1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1cc(-c2ccc(Cl)cc2)oc1C(F)(F)F
Temperature: 25 °C
Reaction time: 24 h
Yield: 63.1 %

Procedure:
5-(4-Chloro-phenyl)-2-trifluoromethyl-furan-3-carbonyl chloride (0.050 g) was added to a solution of 3,5-bis-trifluoromethyl-phenylamine (0.034 g) and N,N-diisopropylethylamine (0.026 mL) in dichloromethane (5 mL). After stirring at room temperature for 1 day, the reaction underwent an aqueous acidic (dilute HCl, 2×5 mL) and basic (dilute NaHCO3, 2×5 mL) workup followed by washing with brine (saturated NaCl, 2×5 mL), drying over MgSO4, and concentration. The crude compound was purified by column chromatography eluting with ethyl acetate/hexanes (4:1) to afford the title compound (0.047 g, 58% yield). 1H NMR (CDCl3) δ 8.12 (s, 2H), 7.83 (bs, 1H), 7.70 (s, 1H), 7.68 (d, 2H, J=0.017 Hz), 7.47 (d, 2H, J=0.017 Hz), 7.03 (s, 1H). ES-MS negative Q1 (m/z) 501.
Reaction SMILES: [C:1]([O:9][CH2:10][CH3:11])(=[O:8])[CH2:2][C:3]([O:5][CH2:6][CH3:7])=[O:4].Cl[CH2:13][CH2:14]Cl.C(=O)([O-])[O-].[K+].[K+].C(=O)=O>O.CN(C)C=O>[C:2]1([C:3]([O:5][CH2:6][CH3:7])=[O:4])([C:1]([O:9][CH2:10][CH3:11])=[O:8])[CH2:14][CH2:13]1
Reactant: ClCCCl
Reactant: CCOC(=O)CC(=O)OCC
Agent: O=C([O-])[O-]
Agent: O=C=O
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)C1(C(=O)OCC)CC1
Reaction time: 3 h

Procedure:
The apparatus described in Example 1 was successively charged with 320 g diethyl malonate (2.0 mols), 1000 ml dimethylformamide, 1308 g of 1,2-dichloroethane (13.2 mols) and 664 g (4.8 mols) of finely comminuted potassium carbonate. While thoroughly stirring, the mixture was heated to 115° C., whereupon release of carbon dioxide and separation of water commenced. Over a period of 3 hours, another 320 g of diethyl malonate (2.0 mols) were metered into the reaction vessel through a dropping funnel. After 6 hours, when no more water separated out, the reaction was complete.
Reaction SMILES: CI.[C:3]([O-])([O-])=O.[K+].[K+].[I:9][C:10]1[CH:11]=[CH:12][C:13]([O:19][CH3:20])=[C:14]([CH:18]=1)[C:15]([O-:17])=[O:16].C(OCC)(=O)C>CN(C=O)C>[CH3:3][O:16][C:15](=[O:17])[C:14]1[CH:18]=[C:10]([I:9])[CH:11]=[CH:12][C:13]=1[O:19][CH3:20]
Reactant: COc1ccc(I)cc1C(=O)[O-]
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: CI
Product: COC(=O)c1cc(I)ccc1OC
Temperature: 25 °C
Reaction time: 24 h
Yield: 87.7 %

Procedure:
Methyl iodide (2.40 mL, 38.48 mmol) and K2CO3 (10.60 g, 76.96 mmol) were added to a solution of 5-iodo-2-methoxybenzoate (5.37 g, 19.24 mmol) in DMF (20 mL) and stirred at rt under Ar for 24 h. Upon completion, ethyl acetate was added and the reaction was washed with 1% HCl (2×20 mL), brine (1×), dried over MgSO4 and concentrated in vacuo. The residue was purified by flash chromatography (3:1 hexane:ethyl acetate) to afford methyl-5-iodo-2-methoxybenzoate (4.93 g, 88%) as a white solid. See, for example, Corey, E. J.; Myers, A. G. J. Am. Chem. Soc. 1985, 107, 5574-5576, which is incorporated by reference in its entirety. 1H NMR (DMSO-d6, 400 MHz) δ 7.90 (d, 1H, J=2.4 Hz), 7.80 (dd, 1H, J=8.8, 2.4 Hz), 6.96 (d, 1H, J=9.0 Hz), 3.81 (s, 3H), 3.79 (s, 3H). 13C NMR (DMSO-d6, 100 MHz) δ 164.7, 158.0, 141.6, 138.5, 122.2, 115.2, 82.1, 55.9, 52.0. HREIMS calculated for C9H9IO3 (M+) 291.9608, found 291.9596.
Reaction SMILES: [O:1]=[C:2]1[N:7]2[CH:8]=[C:9]([C:12]([O:14]CC)=[O:13])[CH:10]=[CH:11][C:6]2=[N:5][C:4]2[CH2:17][S:18][CH2:19][C:3]1=2>Cl>[O:1]=[C:2]1[N:7]2[CH:8]=[C:9]([C:12]([OH:14])=[O:13])[CH:10]=[CH:11][C:6]2=[N:5][C:4]2[CH2:17][S:18][CH2:19][C:3]1=2
Reactant: CCOC(=O)c1ccc2nc3c(c(=O)n2c1)CSC3
Agent: Cl
Product: O=C(O)c1ccc2nc3c(c(=O)n2c1)CSC3

Procedure:
A suspension of ethyl 3,10-dihydro-10-oxo-1H-pyrido[1,2-a]thieno[3,4-d]pyrimidine-7-carboxylate (0.25 g., 0.001 mol) in 2 N hydrochloric acid is refluxed for 2.5 hours. The reaction mixture is cooled in an ice-bath. The product is filtered off and recrystallized from dimethylformamide to give yellow crystals (0.14 g.), mp 311°-312° C.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[CH:4][C:5]([F:16])=[C:6]2[C:10]=1[NH:9][CH:8]=[C:7]2[C:11](=[O:15])[C:12]([O-:14])=O.[K+].[C:18]([N:26]1[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]1)(=[O:25])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.CCOP(ON1N=NC2C=CC=CC=2C1=O)(OCC)=O>>[C:18]([N:26]1[CH2:31][CH2:30][N:29]([C:12](=[O:14])[C:11]([C:7]2[C:6]3[C:10](=[C:2]([Cl:1])[N:3]=[CH:4][C:5]=3[F:16])[NH:9][CH:8]=2)=[O:15])[CH2:28][CH2:27]1)(=[O:25])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: O=C(c1ccccc1)N1CCNCC1
Reactant: O=C([O-])C(=O)c1c[nH]c2c(Cl)ncc(F)c12
Agent: CCOP(=O)(OCC)On1nnc2ccccc2c1=O
Agent: [K+]
Product: O=C(C(=O)N1CCN(C(=O)c2ccccc2)CC1)c1c[nH]c2c(Cl)ncc(F)c12

Procedure:
Addition of precursor 2d to a solution of aluminum trichloride in dichloromethane stirring at ambient temperature followed 30 minutes later with chloromethyl or chloroethyl oxalate (according to the method described for precursor 3a) provides either the methyl or ethyl ester, respectively. Hydrolysis with KOH (as in the standard hydrolysis procedure described for precursor 4a) provided potassium (7-chloro-4-fluoro-6-azaindol-3-yl)oxoacetate. Potassium (7-chloro-4-fluoro-6-azaindol-3-yl)oxoacetate was then reacted with 1-benzoyl piperazine in the presence of DEPBT under the standard conditions (as described for precursor 5a) to provide 1-benzoyl-4-[(4-fluoro-7-chloro-6-azaindol-3-yl)-oxoacetyl]piperazine, precursor 5i. 1H NMR (500 MHz, CD3OD) δ 8.40 (s, 1H), 8.04 (s, 1H), 7.46 (bs, 5H), 3.80-3.50 (m, 8H); LC/MS (ES+) m/z (M+H)+ 415 observed; retention time 1.247 minutes; LC/MS method: YMC ODS-A C18 S7 3.0×50 mm column; Start % B=0, Final % B=100, Gradient time=2 minutes; Flow rate=5 mL/min; detector wavelength=220 nm.
Reaction SMILES: CC1C(CN2C=C(C(N=[N+]=[N-])=O)C=N2)=C(C)ON=1.[N:19]([C:22]1[CH:23]=[N:24][N:25]([CH2:27][C:28]2[C:29]([CH3:34])=[N:30][O:31][C:32]=2[CH3:33])[CH:26]=1)=[C:20]=[O:21].Cl.[NH2:36][C:37]([CH3:44])([CH3:43])[C:38](OCC)=[O:39]>C1(C)C=CC=CC=1>[CH3:34][C:29]1[C:28]([CH2:27][N:25]2[CH:26]=[C:22]([N:19]3[C:38](=[O:39])[C:37]([CH3:44])([CH3:43])[NH:36][C:20]3=[O:21])[CH:23]=[N:24]2)=[C:32]([CH3:33])[O:31][N:30]=1
Reactant: CCOC(=O)C(C)(C)N
Reactant: Cc1noc(C)c1Cn1cc(N=C=O)cn1
Agent: Cc1noc(C)c1Cn1cc(C(=O)N=[N+]=[N-])cn1
Agent: Cl
Solvent: Cc1ccccc1
Product: Cc1noc(C)c1Cn1cc(N2C(=O)NC(C)(C)C2=O)cn1
Temperature: 50 °C
Reaction time: 3 h
Yield: 65 %

Procedure:
1-((3,5-dimethylisoxazol-4-yl)methyl)-1H-pyrazole-4-carbonyl azide (Example 10-1a) (10 g, 41.0 mmol) is stirred under nitrogen in dry toluene (150 mL) along with molecular sieves at reflux until no emission of nitrogen was observed, which indicates complete conversion of 1-((3,5-dimethylisoxazol-4-yl)methyl)-1H-pyrazole-4-carbonyl azide into 4-((4-isocyanato-1H-pyrazol-1-yl)methyl)-3,5-dimethylisoxazole. The solution was cooled down to 50° C. and ethyl 2-amino-2-methylpropanoate hydrochloride (5.30 g, 41.0 mmol) was added in one portion. Stirring continued for 3 hours at 50° C. followed by reflux for 12 hours. The mixture was filtered over a pad of celite. The filtrate was concentrated on the rotovap and the residue was purified over silica gel using 25% ethyl acetate in hexanes. Yield 65% (8.00 g), white solid. 1H NMR (DMSO-d6, 400 MHz): s, 6H), 2.15 (s, 3H), 2.41 (s, 3H), 5.18 (s, 2H), 7.78 (d, J=0.4 Hz, 1H), 8.16 (d, J=0.4 Hz, 1H), 8.59 (br s, 1H). MS 304 (MH+). This compound was shown to inhibit hT2R08 bitter receptor and had an IC50 of 2.27 μM.
Reaction SMILES: [Cl:1][C:2]1[N:11]=[CH:10][C:9]2[C:4](=[C:5]([O:12]C)[CH:6]=[CH:7][CH:8]=2)[N:3]=1.B(Br)(Br)Br>C(Cl)Cl>[Cl:1][C:2]1[N:11]=[CH:10][C:9]2[C:4](=[C:5]([OH:12])[CH:6]=[CH:7][CH:8]=2)[N:3]=1
Reactant: COc1cccc2cnc(Cl)nc12
Agent: BrB(Br)Br
Solvent: ClCCl
Product: Oc1cccc2cnc(Cl)nc12
Temperature: 25 °C
Reaction time: 22 h
Yield: 79 %

Procedure:
To a 0.55M solution of 2-chloro-8-methoxyquinazoline in DCM was added boron tribromide (2.2 eq. of a 1.0 M solution in DCM) over 5 minutes at 0° C. The reaction mixture was stirred at ambient temperature for 22 hours, and then cooled to −5° C. for 30 minutes. The precipitate was collected by vacuum filtration and then stirred in ice water for 30 minutes. The solid was collected by vacuum filtration and rinsed with 2-propanol. The off-white solid was dried in a desiccator to give the desired product in 79% yield. ES/MS m/z 181 (MH+).
Reaction SMILES: Br[C:2]1[N:7]=[CH:6][C:5]([CH2:8][OH:9])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[Cs+].[Cs+].[N:16]1[CH:21]=[C:20](B2OC(C)(C)C(C)(C)O2)[CH:19]=[CH:18][C:17]=1[CH3:31]>C1COCC1.ClCCl>[CH3:31][C:17]1[N:16]=[CH:21][C:20]([C:2]2[CH:3]=[CH:4][C:5]([CH2:8][OH:9])=[CH:6][N:7]=2)=[CH:19][CH:18]=1
Reactant: OCc1ccc(Br)nc1
Reactant: Cc1ccc(B2OC(C)(C)C(C)(C)O2)cn1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: ClCCl
Solvent: C1CCOC1
Product: Cc1ccc(-c2ccc(CO)cn2)cn1
Temperature: 85 °C

Procedure:
To a solution of (6-bromo-pyridin-3-yl)-methanol (0.614 g, 3.27 mmol) in 10 mL of THF under an atmosphere of nitrogen was added cesium carbonate (3.27 mL, 2 N aqueous, 6.53 mmol), 2-picoline-5-boronic acid pinacol ester (0.477 g, 2.18 mmol), and [1,1′-bis(diphenylphosphino)-ferrocene]dichloro-palladium(II), 1:1 complex with dichloromethane (0.178 g, 0.218 mmol). The reaction was heated at 85° C. for 1 h, cooled to rt, and diluted with dichloromethane. The organic solution was washed with water, dried over sodium sulfate, filtered, and concentrated in vacuo. The aqueous fraction was concentrated in vacuo, triturated 3× with 20% methanol in dichloromethane, and collected via filtration. The combined solids were purified via silica gel chromatography, eluting with 100% ethyl acetate to provide (6′-methyl-2,3′-bipyridin-5-yl)methanol that gave a proton NMR spectra consistent with theory and a mass ion (ES+) of 201.1 for [M+H]+.
Reaction SMILES: [CH2:1]([C:3]1[C:8]2[C:9]3[CH:15]=[CH:14][CH:13]=[N:12][C:10]=3[NH:11][C:7]=2[CH:6]=[N:5][C:4]=1[C:16]#[N:17])[CH3:2].C1C(=O)N([Br:25])C(=O)C1>CN(C=O)C.C(OCC)(=O)C>[Br:25][C:14]1[CH:13]=[N:12][C:10]2[NH:11][C:7]3[CH:6]=[N:5][C:4]([C:16]#[N:17])=[C:3]([CH2:1][CH3:2])[C:8]=3[C:9]=2[CH:15]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: CCc1c(C#N)ncc2[nH]c3ncccc3c12
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCc1c(C#N)ncc2[nH]c3ncc(Br)cc3c12
Temperature: 25 °C
Reaction time: 18 h
Yield: 79.1 %

Procedure:
To a solution of 5-ethyl-9H-dipyrido[2,3-b;4′,3′-d]pyrrole-6-carbonitrile (48 mg, 0.21 mmol) in DMF (1 mL) was added NBS (54 mg, 0.30 mmol) then the reaction mixture was stirred for 18 h at ambient temperature. The reaction mixture was then diluted with ethyl acetate (20 mL) and washed with saturated aqueous sodium carbonate (10 mL). The aqueous phase was washed with DCM (2×10 mL), the combined organic phase was washed with saturated brine (2×10 mL) and concentrated in vacuo to afford the title compound as a yellow solid (50 mg, 79%). LCMS (Method B): RT=3.34 min, M+H+=301/303.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH2:20])=[CH:18][CH:17]=1.Cl[C:24](Cl)([O:26][C:27](=[O:33])OC(Cl)(Cl)Cl)Cl.[CH2:35](O)[CH2:36][CH2:37][CH:38]=C.C(=O)(O)[O-].[Na+]>C(Cl)Cl.C(N(CC)CC)C.C1(C)C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH:20][C:27](=[O:33])[O:26][CH2:24][CH2:38][CH2:37][CH:36]=[CH2:35])=[CH:18][CH:17]=1
Reactant: COc1cc2nccc(Oc3ccc(N)cc3)c2cc1OC
Reactant: C=CCCCO
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: C=CCCCOC(=O)Nc1ccc(Oc2ccnc3cc(OC)c(OC)cc23)cc1
Yield: 111.7 %

Procedure:
4-[(6,7-Dimethoxy-4-quinolyl)oxy]aniline (50 mg) was added to toluene (5 ml), and triethylamine (0.5 ml), and the mixture was heated under reflux to prepare a solution. A solution of triphosgene (77 mg) in methylene chloride was then added thereto, and the mixture was heated under reflux for 10 min. Next, 4-penten-1-ol (22 mg) was added thereto, and the mixture was further stirred with heating under reflux for 3 hr. A saturated aqueous sodium bicarbonate solution was added to stop the reaction, and the reaction solution was then extracted with chloroform, followed by washing with a 1 N aqueous hydrochloric acid solution, water, and saturated brine in that order. The extract was dried over sodium sulfate and was then concentrated. The residue was purified on a column using chloroform/methanol to give the title compound (77 mg, yield 100%).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([CH2:7][CH2:8][C:9]([O:11][CH3:12])=[O:10])[CH2:3][CH2:2]1.[C:13](OC(=O)C)(=[O:15])[CH3:14]>CO>[C:13]([N:1]1[CH2:6][CH2:5][CH:4]([CH2:7][CH2:8][C:9]([O:11][CH3:12])=[O:10])[CH2:3][CH2:2]1)(=[O:15])[CH3:14]
Reactant: COC(=O)CCC1CCNCC1
Reactant: CC(=O)OC(C)=O
Solvent: CO
Product: COC(=O)CCC1CCN(C(C)=O)CC1

Procedure:
Methyl 3-[piperid-4-yl]propionate (11 g) and acetic anhydride (35 ml) were heated together on a steam bath for 1 hour. The mixture was cooled and methanol (50 ml) was added to destroy excess anhydride. The solution was evaporated to dryness in vacuo and the residue was partitioned between chloroform (200 ml) and 2 N hydrochloric acid (100 ml) dried (Na2CO3) and evaporated to give methyl 3-[1-acetyl-piperid-4-yl]propionate (13 g) as an oil.