Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C1(C(=CC(=C(C=1)C)C)C)C.[C:11]([C:19]#[N:20])(=[O:18])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C(O)(=O)C1C=CC=CC=1.[Cl:30]C1C=CC=CC=1>>[C:11]([Cl:30])(=[O:18])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.[C:11]([C:19]#[N:20])(=[O:18])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: Clc1ccccc1
Agent: Cc1cc(C)c(C)cc1C
Agent: N#CC(=O)c1ccccc1
Agent: O=C(O)c1ccccc1
Product: O=C(Cl)c1ccccc1
Temperature: 7.5 °C

Procedure:
A mixture of benzoyl chloride (1.85 g, 13 millimoles, Aldrich, 99%) and Aliquat 336 (0.043 g, 0.1 millimoles) was added to a cooled one neck 250 mL flask containing an aqueous solution consisting of sodium cyanide (0.49 g, 10 millimoles, Aldrich, 95+%), sodium hydroxide (0.135 g, 3 millimoles, Merck; the purpose of adding sodium hydroxide is to prevent acidification of the system as a result of benzoyl chloride hydrolysis), and water (50.17 g). The organic phase:aqueous phase weight ratio was 1:26. The reaction mixture was stirred magnetically at 7-8° C. After 5 minutes an aliquot of the mixture (0.50 g) was taken and mixed with 0.25 g of 5% w/w solution of durene in chlorobenzene. The organic phase was injected into the GC instrument. Benzoyl cyanide is the only product (no “dimer” could be detected). The yield is 95%. No benzoyl cyanide was present in the reaction mixture after 5 minutes when the similar reaction was performed without the phase transfer catalyst. Another blank experiment showed that rather insignificant amounts of benzoic acid (less than 10% after 40 minutes at room temperature) were formed from benzoyl chloride within time limits of the benzoyl cyanide formation.
Reaction SMILES: [CH2:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH:2]1[NH:10][S:11]([CH:14]([CH3:16])[CH3:15])(=[O:13])=[O:12].S(=O)(=O)(O)O.[I:22](O)(=O)(=O)=O.II>C(O)(=O)C.O>[I:22][C:6]1[CH:5]=[C:4]2[C:9](=[CH:8][CH:7]=1)[CH2:1][CH:2]([NH:10][S:11]([CH:14]([CH3:16])[CH3:15])(=[O:13])=[O:12])[CH2:3]2
Reactant: [O-][I+3]([O-])([O-])O
Reactant: CC(C)S(=O)(=O)NC1Cc2ccccc2C1
Agent: II
Agent: O=S(=O)(O)O
Solvent: CC(=O)O
Solvent: O
Product: CC(C)S(=O)(=O)NC1Cc2ccc(I)cc2C1
Yield: 483.7 %

Procedure:
Intermediate 1 (1.75 g, 7.32 mmol) was dissolved in glacial acetic acid (30 ml) and then treated with concentrated sulfuric acid (0.8 ml) followed by water (2.8 ml) with stirring. This mixture was then treated with periodic acid (0.23 eq., 0.38 g, 1.67 mmol) then iodine (0.43 eq., 800 mg, 3.15 mmol), and the whole mix was stirred at 60° C. for 3-4 h. The reaction mixture was allowed to cool and then partitioned between ethyl acetate and 10% aqueous sodium metabisulfite. The organic layer was separated and dried over sodium sulphate and evaporated in vacuo to give the title compound as a yellow oil (2.95 g).
Reaction SMILES: [CH2:1]([S:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[C:10]1[NH:11][C:12](=O)[C:13]2[N:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][C:14]=2[N:15]=1)[CH3:2].P(Cl)(Cl)([Cl:27])=O.C(N(CC)C(C)C)(C)C>C1(C)C=CC=CC=1>[Cl:27][C:12]1[C:13]2[N:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][C:14]=2[N:15]=[C:10]([C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[S:3][CH2:1][CH3:2])[N:11]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: CCSc1ccccc1-c1nc2cc(C(F)(F)F)cnc2c(=O)[nH]1
Solvent: Cc1ccccc1
Solvent: CCN(C(C)C)C(C)C
Product: CCSc1ccccc1-c1nc(Cl)c2ncc(C(F)(F)F)cc2n1
Temperature: 100 °C
Reaction time: 0.5 h

Procedure:
A mixture of 400 mg of 2-(2-ethylsulfanylphenyl)-7-trifluoromethyl-3H-pyrido[3,2-d]pyrimidin-4-one, 0.16 ml of phosphorus oxychloride, 221 mg of N,N-diisopropylethylamine and 6 ml of toluene was stirred at 100° C. for 30 minutes. The reaction mixture was cooled, and the precipitated solid was filtered. The resulting solid was sequentially washed with a saturated aqueous sodium bicarbonate solution, water and toluene, and then dried to obtain 320 mg of 4-chloro-2-(2-ethylsulfanylphenyl)-7-trifluoromethylpyrido[3,2-d]pyrimidine (Compound of Present Invention 17).
Reaction SMILES: [N:1]1([CH:6]2[CH2:11][CH2:10][NH:9][CH2:8][CH2:7]2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[S:12](N)([NH2:15])(=[O:14])=[O:13]>O1CCOCC1>[N:1]1([CH:6]2[CH2:11][CH2:10][N:9]([S:12]([NH2:15])(=[O:14])=[O:13])[CH2:8][CH2:7]2)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: C1CCN(C2CCNCC2)C1
Reactant: NS(N)(=O)=O
Solvent: C1COCCO1
Product: NS(=O)(=O)N1CCC(N2CCCC2)CC1

Procedure:
A mixture of 4-pyrrolidin-1-ylpiperidine (0.67 g) and sulfamide (0.46 g) were heated at 115° C. in dry 1,4-dioxane (30 ml) for 16 h. The solvents were evaporated in vacuo and the residue partitioned between EtOAc (containing a little methanol) and H2O. The organic phase was collected and the aqueous layer further extracted with EtOAc(×2). The combined organic phases collected, dried (MgSO4) and the solvent evaporated. The residue was triturated with Et2O and filtered to give the subtitle product as a beige solid. Yield: 0.43 g
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])O[C:6]([C:13]([OH:15])=[O:14])=[C:5]2[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.[NH2:22][CH2:23][C:24]1[CH:32]=[CH:31][C:27]2[O:28][CH2:29][CH2:30][C:26]=2[CH:25]=1.C(N(CC)CC)C>CO>[O:28]1[C:27]2[CH:31]=[CH:32][C:24]([CH2:23][N:22]3[C:6]([C:13]([OH:15])=[O:14])=[C:5]([C:16]4[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=4)[C:4]4[C:9](=[CH:10][CH:11]=[C:2]([F:1])[CH:3]=4)[C:8]3=[O:12])=[CH:25][C:26]=2[CH2:30][CH2:29]1
Reactant: O=C(O)c1oc(=O)c2ccc(F)cc2c1-c1ccccc1
Reactant: NCc1ccc2c(c1)CCO2
Solvent: CCN(CC)CC
Solvent: CO
Product: O=C(O)c1c(-c2ccccc2)c2cc(F)ccc2c(=O)n1Cc1ccc2c(c1)CCO2
Temperature: 50 °C
Reaction time: 36 h
Yield: 82.1 %

Procedure:
A mixture of 6-fluoro-1-oxo-4-phenyl-1H-isochromen-3-carboxylic acid (1 g), 5-aminomethyl-2,3-dihydrobenzo[b]furan (1.1 g), triethylamine (1 ml) and methanol (10 ml) was stirred at 50° C. for 36 hrs. The reaction mixture was concentrated, 1N-hydrochloric acid was added and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. To the residue was added 4N-hydrochloric acid-ethyl acetate solution (5 ml) at room temperature and the mixture was stirred for 12 hrs. The reaction mixture was concentrated under reduced pressure and the residue was purified by recrystallization (ethyl acetate-hexane) to give the title compound (1.2 g).
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:4]=[C:5]([CH2:11][OH:12])[CH:6]=[CH:7][C:8]=1[CH2:9][OH:10].[CH:13](=O)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.O.[O-2].[O-2].[O-2].O=[Si]=O.O=[Si]=O.O=[Si]=O.O=[Si]=O.[Al+3].[Al+3]>C1(C)C=CC=CC=1>[C:14]1([CH:13]2[O:1][CH2:2][C:3]3[CH:4]=[C:5]([CH2:11][OH:12])[CH:6]=[CH:7][C:8]=3[CH2:9][O:10]2)[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: OCc1ccc(CO)c(CO)c1
Reactant: O=Cc1ccccc1
Agent: O=[Si]=O
Agent: [Al+3]
Agent: [O-2]
Solvent: Cc1ccccc1
Solvent: O
Product: OCc1ccc2c(c1)COC(c1ccccc1)OC2

Procedure:
4 g of (3,4-bis-hydroxymethylphenyl)methanol (23.8 mmol), 40 ml of toluene, 3.06 g of benzaldehyde (28.5 mmol) and 0.24 g of Montmorillonite KSF (10 mg/mmol) are introduced into a flask equipped with a Dean-Stark. The medium is heated under reflux for 3 hours. After filtration, the toluene is evaporated under vacuum at 30° C. The residue is chromatographed on silica gel (heptane/ethyl acetate=7/3) to give 1.8 g of (7-phenyl)-(5H,9H)-6,8-dioxabenzocyclohepten-2-yl)methanol in the form of a white powder.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[CH:5]=[CH:4][C:3]=1[O:10][CH3:11].C1N2CN3CN(C2)CN1C3.[C:22]([O-])(O)=[O:23].[Na+]>C(O)(C(F)(F)F)=O>[Cl:1][C:2]1[C:3]([O:10][CH3:11])=[CH:4][C:5]([CH:22]=[O:23])=[C:6]([O:8][CH3:9])[CH:7]=1
Reactant: O=C([O-])O
Reactant: COc1ccc(OC)c(Cl)c1
Agent: C1N2CN3CN1CN(C2)C3
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Product: COc1cc(C=O)c(OC)cc1Cl
Temperature: 95 °C
Reaction time: 5 h
Yield: 99.7 %

Procedure:
(Wright et al., J. Am. Chem. Soc. 2008, 130, 16786-16790; Bloomer et al., J. Org. Chem. 1993, 58, 7906-7912.) To a stirred solution of 2-chloro-1,4-dimethoxybenzene (25.0 g, 0.145 mol, 1 equiv) and hexamethylene tetramine (20.5 g, 0.145 mol, 1 equiv) at room temperature was carefully added TFA (250 mL). The resulting yellow suspension was heated to 95° C. and allowed to stir for 5 h. After 5 h, the hot brown solution was poured into a 2 L Erlenmeyer flask containing approximately 250 g of crushed ice. To the vigorously stirred mixture was added solid NaHCO3 (243 g, 2.90 mol, 20 equiv) cautiously in 5-10 g portions over two hours. The resulting yellow precipitate was filtered through Celite, washed with water, and dissolved in Et2O. The organic layer was washed with water, brine, dried (MgSO4), filtered, and concentrated under reduced pressure to yield 29.0 g (100% yield) of the desired product as an off-white solid: Mp 109-109° C.; Rf 0.70 (EtOAc/hexanes, 3:7); IR (neat) 2941, 2874, 1664, 1601, 1575, 1497, 1478, 1461, 1389, 1269, 1213, 1023, 977 cm−1; 1H NMR (400 MHz, CDCl3) δ 10.35 (s, 1 H), 7.33 (s, 1 H), 3.87 (s, 6 H); 13C NMR (100 MHz, CDCl3) δ 188.4, 156.1, 149.4, 130.4, 123.4, 114.5, 109.9, 56.5, 56.3; HRMS (EI+) m/z calcd for C9H9O3Cl 200.0240, found 200.02377. Characterization matches that reported by Bloomer et al. (J. Org. Chem. 1993, 58, 7906-7912.)
Reaction SMILES: [NH2:1][C@@H:2]1[C:7]2[CH:8]=[C:9]([C:12]#[N:13])[CH:10]=[CH:11][C:6]=2[O:5][C:4]([CH3:15])([CH3:14])[C@H:3]1[OH:16].[CH3:17][C:18]1[N:22]=[C:21]([C:23]2[CH:24]=[C:25]([NH:29][C:30](=O)[O:31]C3C=CC([N+]([O-])=O)=CC=3)[CH:26]=[CH:27][CH:28]=2)[O:20][N:19]=1.CN(C)C=O>C(#N)C>[C:12]([C:9]1[CH:10]=[CH:11][C:6]2[O:5][C:4]([CH3:14])([CH3:15])[C@@H:3]([OH:16])[C@H:2]([NH:1][C:30]([NH:29][C:25]3[CH:26]=[CH:27][CH:28]=[C:23]([C:21]4[O:20][N:19]=[C:18]([CH3:17])[N:22]=4)[CH:24]=3)=[O:31])[C:7]=2[CH:8]=1)#[N:13]
Reactant: CC1(C)Oc2ccc(C#N)cc2[C@@H](N)[C@@H]1O
Reactant: Cc1noc(-c2cccc(NC(=O)Oc3ccc([N+](=O)[O-])cc3)c2)n1
Solvent: CC#N
Solvent: CN(C)C=O
Product: Cc1noc(-c2cccc(NC(=O)N[C@@H]3c4cc(C#N)ccc4OC(C)(C)[C@H]3O)c2)n1

Procedure:
A mixture of (3S-trans)-4-amino-3,4-dihydro-3-hydroxy-2,2-dimethyl-2H-1-benzopyran-6-carbonitrile (0.65 g, 3.0 mmol, from Example 1, part B) and [3-[3-methyl(1,2,4-oxadiazol-5-yl)]phenyl]carbamic acid, 4-nitrophenyl ester (1.12 g, 3.3 mmol, title A compound) in acetonitrile (20 mL) and dimethyl-formamide (40 mL) was stirred at 80° C. for two hours. The reaction mixture was concentrated in vacuo and the residue, diluted with ethyl acetate, was washed with 10% citric acid and water. The organic layer was dried over MgSO4 and concentrated in vacuo. The product was purified by flash chromatography (Sorbisol C 60 flash silica gel, 400 mL) and eluted with Hexane/EtOAc (1:1). The solvent was removed in vacuo, to give a solid that was triturated in hexane and dried in vacuo to yield 1.10 g of the title compound, m.p. 157°-161 ° C. TLC, silica gel, EtOAc/Hexane(2:1), Rf =0.41. 1H-NMR (DMSO-d6) δ9.1 (s, 1H), 8.4 (s, 1H), 7.5 (m, 5H), 6.9 (d, J=9.4 Hz, 1H), 6.8 (d, J=8.2 Hz, 1H), 5.7 (d, J=5.9 Hz, 1H), 4.7 (t, J=8.8 Hz, 1H), 3.7 (dd, J =5.9 & 4.1Hz, 1H), 2.4 (s, 3H), 1.4 (s, 3H), 1.2 (s, 3H); 13C-NMR (DMSO-d6) δ174.9, 167.6, 156.3, 155.6, 141.4, 132.6, 132.5, 130.0, 125.9, 123.8, 122.1, 120.4, 119.1, 117.9. 116.6, 102.76, 80.4, 71.2, 49.5, 26.5, 18.9, 11.3; IR (KBr) 2980, 2228, 1670, 1574, 1553, 1489 cm-1. M.S. (M+H)+ at 420, M.W. 419; [α]D =-43.6° (c=0.77 DMSO).
Reaction SMILES: [Si]([O:18][CH2:19][C:20]1[CH:25]=[CH:24][C:23]([C:26]#[C:27][Si:28]([CH3:31])([CH3:30])[CH3:29])=[CH:22][CH:21]=1)(C(C)(C)C)(C1C=CC=CC=1)C1C=CC=CC=1.Br[C:33]1[CH:38]=[C:37]([C:39]([CH3:42])([CH3:41])[CH3:40])[CH:36]=[C:35]([C:43]([CH3:46])([CH3:45])[CH3:44])[CH:34]=1>>[C:43]([C:35]1[CH:34]=[C:33](/[C:27](/[Si:28]([CH3:29])([CH3:30])[CH3:31])=[CH:26]/[C:23]2[CH:22]=[CH:21][C:20]([CH2:19][OH:18])=[CH:25][CH:24]=2)[CH:38]=[C:37]([C:39]([CH3:42])([CH3:41])[CH3:40])[CH:36]=1)([CH3:46])([CH3:45])[CH3:44]
Reactant: CC(C)(C)[Si](OCc1ccc(C#C[Si](C)(C)C)cc1)(c1ccccc1)c1ccccc1
Reactant: CC(C)(C)c1cc(Br)cc(C(C)(C)C)c1
Product: CC(C)(C)c1cc(/C(=C/c2ccc(CO)cc2)[Si](C)(C)C)cc(C(C)(C)C)c1

Procedure:
Following General Procedure A, 4-[(trimethylsilyl)ethynyl]benzyl tert-butyldiphenylsilyl ether and 1-bromo-3,5-Di-tert-butylbenzene (which can be prepared by the procedure described in Komen and Bickel Synth. Commun, 1996, 26, 1693-1698) were coupled to give the title compound (Compound 32). PNMR (300 MHz, CDCl3) δ7.40 (s, 4H), 7.33 (s, 2H), 7.08 (s, 1H), 7.07(s, 1H), 4.78 (d, J=5.9 Hz, 1H), 1.41 (s, 18H), 0.00 (s, 9H).
Reaction SMILES: [H-].[Na+].[CH3:3][C:4]1[C:9]([CH3:10])=[CH:8][C:7]([CH3:11])=[CH:6][C:5]=1[OH:12].[Cl:13][C:14]1[N:19]=[C:18](Cl)[C:17]([CH:21]([CH3:23])[CH3:22])=[C:16]([Cl:24])[N:15]=1.C(OCC)(=O)C>CN(C=O)C>[Cl:13][C:14]1[N:15]=[C:16]([Cl:24])[C:17]([CH:21]([CH3:23])[CH3:22])=[C:18]([O:12][C:5]2[CH:6]=[C:7]([CH3:11])[CH:8]=[C:9]([CH3:10])[C:4]=2[CH3:3])[N:19]=1
Reactant: Cc1cc(C)c(C)c(O)c1
Reactant: CC(C)c1c(Cl)nc(Cl)nc1Cl
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Cc1cc(C)c(C)c(Oc2nc(Cl)nc(Cl)c2C(C)C)c1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 93.9 %

Procedure:
Sodium hydride (60%, 59 mg, 1.44 mmol. 1.1 eq.) was added to 2,3,5-trimethyl-phenol (179 mg, 1.31 mmol) in DMF (2 mL). The mixture was stirred at room temperature for 15 minutes and then added to 2,4,6-trichloro-5-isopropyl-pyrimidine (296 mg, 1.31 mmol) in 1 mL DMF. The reaction was stirred at room temperature for 4 hours. Ethyl acetate was added and washed with brine. The organic layer was concentrated down and purified (silica gel, 0-50% EtOAC/hexane) to give white solid (400 mg, 94%). LC-MS shows 325.2 (M+1). 1H NMR (300 MHz, CDCl3): δ 6.94 (s, 1H), 6.63 (s, 1H), 3.61 (m, 1H), 2.32 (s, 6H), 2.02 (s, 3H), 1.42 (d, 6H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:10]=[C:9]([CH2:11][CH:12]=[O:13])[CH:8]=[CH:7][C:4]=1[C:5]#[N:6].[CH3:14][Mg]Br>ClCCl.C1COCC1>[OH:13][CH:12]([CH3:14])[CH2:11][C:9]1[CH:8]=[CH:7][C:4]([C:5]#[N:6])=[C:3]([O:2][CH3:1])[CH:10]=1
Reactant: C[Mg]Br
Reactant: COc1cc(CC=O)ccc1C#N
Solvent: C1CCOC1
Solvent: ClCCl
Product: COc1cc(CC(C)O)ccc1C#N
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a stirred solution of 2-methoxy-4-(2-oxoethyl)benzonitrile (1.5 g, 8.5 mmol) in dichloromethane (30 mL) at 0° C. was added 2.8 mL (8.5 mmol) of a 3.0 M solution of methylmagnesium bromide in THF. The reaction mixture was allowed to warm up to rt and stirred for 12 h. The reaction was then quenched by the addition of 10 mL of 1 N hydrochloric acid and extracted with dichloromethane (2×30 mL). The combined organic extracts were dried with magnesium sulfate, filtered, and concentrated in vacuo. The crude residue was purified on silica (30% EtOAc/hexanes as eluent) to afford 4-(2-hydroxypropyl)-2-methoxybenzonitrile.
Reaction SMILES: [CH2:1]([O:3][C:4]([C@@H:6]1[C@@H:11]2[C@H:7]1[CH2:8][C:9](=[O:25])[C@@:10]2([N:22]=[N+]=[N-])[C:12]([O:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[O:13])=[O:5])[CH3:2].[C:26]([OH:29])(=S)[CH3:27]>>[CH2:1]([O:3][C:4]([C@@H:6]1[C@@H:11]2[C@H:7]1[CH2:8][C:9](=[O:25])[C@@:10]2([NH:22][C:26](=[O:29])[CH3:27])[C:12]([O:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[O:13])=[O:5])[CH3:2]
Reactant: CC(O)=S
Reactant: CCOC(=O)[C@H]1[C@@H]2CC(=O)[C@@](N=[N+]=[N-])(C(=O)OCc3ccccc3)[C@@H]21
Product: CCOC(=O)[C@H]1[C@@H]2CC(=O)[C@@](NC(C)=O)(C(=O)OCc3ccccc3)[C@@H]21
Yield: 71 %

Procedure:
A solution of (1S,2R,5R,6S)-2-Azido-3-oxo-bicyclo[3.1.0]hexane-2,6-dicarboxylic acid 2-benzyl ester 6-ethyl ester (IX) (974 mg, 2.84 mmol) in thioacetic acid (6.5 mL) was stirred at 70° C. for 2 d. The reaction mixture was concentrated in vacuum and subjected to silica gel column chromatography with hexane/ethyl acetate 3:2->1:1 to yield (1S,2R,5R,6S)-2-acetylamino-3-oxo-bicyclo [3.1.0]hexane-2,6-dicarboxylic acid 2-benzyl ester 6-ethyl ester (XVI) (726 mg, 71%) as a pink oil. 1H-NMR (250 MHz, CDCl3) □1.25 (3H, t, 1=7.1 Hz), 1.63 (1H, t, J=3.5 Hz), 2.05 (3H, s), 2.32 (1H, ddd,J=7, 6,3.5 Hz), 2.54 (1H, d,J=19 Hz), 2.90 (1H, dd,J=19, 6 Hz), 3.06 (1H, dd, J=7, 3.5 Hz), 4.12 (2H, m), 5.16 (1H, d, J=12 Hz), 5.25 (1H, d, J=12 Hz), 7.24-7.35 (5H, m); MS[ISP] 360 (M+H+); □D20 +44.33° (c=0.97, CHCl3).
Reaction SMILES: [NH:1]1[CH2:4][CH:3]([CH2:5][C:6]2[N:7]([CH3:31])[C:8]3[C:13]([N:14]=2)=[C:12]([N:15]2[CH2:20][CH2:19][O:18][CH2:17][CH2:16]2)[N:11]=[C:10]([N:21]2[C:25]4[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=4[N:23]=[C:22]2[CH3:30])[N:9]=3)[CH2:2]1.Cl[C:33]([C:35]([O:38][C:39](=[O:41])[CH3:40])([CH3:37])[CH3:36])=[O:34].CCN(CC)CC>C1COCC1>[CH3:36][C:35]([O:38][C:39](=[O:41])[CH3:40])([CH3:37])[C:33]([N:1]1[CH2:2][CH:3]([CH2:5][C:6]2[N:7]([CH3:31])[C:8]3[C:13]([N:14]=2)=[C:12]([N:15]2[CH2:20][CH2:19][O:18][CH2:17][CH2:16]2)[N:11]=[C:10]([N:21]2[C:25]4[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=4[N:23]=[C:22]2[CH3:30])[N:9]=3)[CH2:4]1)=[O:34]
Reactant: Cc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(CC3CNC3)n(C)c2n1
Reactant: CC(=O)OC(C)(C)C(=O)Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(=O)OC(C)(C)C(=O)N1CC(Cc2nc3c(N4CCOCC4)nc(-n4c(C)nc5ccccc54)nc3n2C)C1
Temperature: 25 °C
Reaction time: 16 h
Yield: 73.8 %

Procedure:
A mixture of 8-azetidin-3-ylmethyl-2-(2-methylbenzoimidazol-1-yl)-9-methyl-6-morpholin-4-yl-9H-purine (131 mg, 0.31 mmol), acetic acid 1-chlorocarbonyl-1-methylethyl ester (45 μL, 0.31 mmol) and NEt3 (40 μL, 0.31 mmol) in THF (3 mL) was allowed to stir at r.t. for 16 h then concentrated in vacuo. The resulting residue was partitioned between DCM and H2O, the organic phase dried (Na2SO4) and concentrated in vacuo. The residue was purified by column chromatography (Si—PCC, MeOH:EtOAc, 0-10%) affording the title compound as a white solid (125 mg, 73%). LCMS (method H): RT 2.50 min [M+H]+ 547.5
Reaction SMILES: [Br:1][C:2]1[CH:7]=[N:6][C:5]([Cl:8])=[C:4]2[NH:9][CH:10]=[C:11]([CH2:12]N(C)C)[C:3]=12.[C-:16]#[N:17].[K+]>CN(C=O)C.O>[Br:1][C:2]1[CH:7]=[N:6][C:5]([Cl:8])=[C:4]2[NH:9][CH:10]=[C:11]([CH2:12][C:16]#[N:17])[C:3]=12
Reactant: CN(C)Cc1c[nH]c2c(Cl)ncc(Br)c12
Reactant: [C-]#N
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: N#CCc1c[nH]c2c(Cl)ncc(Br)c12

Procedure:
A solution of [(4-bromo-7-chloro-1H-pyrrolo[2,3-c]pyridin-3-yl)methyl]dimethylamine from Step A (195 mg, 0.676 mmol) and potassium cyanide (440 mg, 6.76 mmol) in DMF (0.5 mL) and H2O (0.5 mL) was heated at 100° C. for 2 h. The reaction mixture was partitioned between EtOAc (20 mL) and H2O (10 mL). The layers were separated and the organic layer was dried over Na2SO4, filtered, and concentrated in vacuo to give the title compound. MS: m/z=272 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[C:19]3[C:14](=[CH:15][N:16]=[C:17](F)[CH:18]=3)[N:13]=[CH:12][C:11]=2[C:21]#[N:22])[CH:5]=[CH:6][C:7]=1[F:8].[CH2:23]1[CH2:27][O:26][CH2:25][CH2:24]1>>[Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[C:19]3[C:14](=[CH:15][N:16]=[C:17]([NH:9][C@H:4]([CH3:3])[C@@H:25]([OH:26])[C:24]4[CH:23]=[CH:27][CH:7]=[CH:6][CH:5]=4)[CH:18]=3)[N:13]=[CH:12][C:11]=2[C:21]#[N:22])[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: C1CCOC1
Reactant: N#Cc1cnc2cnc(F)cc2c1Nc1ccc(F)c(Cl)c1
Product: C[C@@H](Nc1cc2c(Nc3ccc(F)c(Cl)c3)c(C#N)cnc2cn1)[C@@H](O)c1ccccc1
Temperature: 140 °C
Yield: 18.7 %

Procedure:
Following the procedure described above in Example 51, 4-(3-Chloro-4-fluoro-phenylamino)-6-fluoro-[1,7]naphthyridine-3-carbonitrile (0.10 g, 0.32 mmol) was reacted with (1S, 2R)-(+) norephdrine (0.96 g, 6.32 mmol) in 2 mL of THF. The reaction mixture was heated in a sealed vial in a microwave reactor at 140° C. for 50 min, then heated to 160° C. for 30 min. The crude product was purified by preparative HPLC and lyophilized to give a fluffy, yellow solid (26.4 mg, 18.7% yield): 1H NMR (400 MHz, DMSO-D6) δ ppm 1.03 (d, J=6.32 Hz, 3 H) 3.87-4.02 (m, 1 H) 4.67 (t, J=4.67 Hz, 1 H) 5.46 (d, J=4.29 Hz, 1 H) 6.43 (d, J=9.35 Hz, 1 H) 6.93 (s, 1 H) 7.12 (t, J=7.33 Hz, 1 H) 7.18-7.46 (m, 6 H) 7.48-7.55 (m, 1 H) 8.19 (s, 1 H) 8.75 (s, 1 H) 9.54 (s, 1 H); HRMS (ESI+) calcd for C24H19ClFN5O 448.13349, found (MH+), 448.1334.
Reaction SMILES: [C:1]([C:3]([C:12]#[N:13])=[C:4]([NH:6][C:7](=[O:11])[N:8]([CH3:10])[CH3:9])[SH:5])#[N:2].[OH:14]O>O>[C:1]([C:3]1[C:12]([OH:14])=[N:13][S:5][C:4]=1[NH:6][C:7](=[O:11])[N:8]([CH3:10])[CH3:9])#[N:2]
Reactant: OO
Reactant: CN(C)C(=O)NC(S)=C(C#N)C#N
Solvent: O
Product: CN(C)C(=O)Nc1snc(O)c1C#N
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of 3-(2,2-Dicyano-1-mercapto-vinyl)-1,1-dimethyl-urea (sodium salt) (30 g, 137 mmol) in water (300 mL) was treated at ambient temperature with hydrogen peroxide (14 mL of a 10 M solution). The reaction warmed and thickened with solid formation and so was treated with additional water (100 mL). The mixture was heated to reflux for 15 minutes, effecting complete dissolution and then cooled to ambient temperature. After 1 hour at ambient temperature, the mixture was concentrated to a constant weight (35 g, >100% due to water content) and was used immediately in the next step.
Reaction SMILES: C1(S([N:10]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[C:12]([C:19]3[CH:28]=[C:27]([C:29]([OH:31])=[O:30])[C:26]4[C:21](=[CH:22][C:23]([O:34][CH3:35])=[C:24]([O:32][CH3:33])[CH:25]=4)[N:20]=3)=[CH:11]2)(=O)=O)C=CC=CC=1.CO>O>[NH:10]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[C:12]([C:19]2[CH:28]=[C:27]([C:29]([OH:31])=[O:30])[C:26]3[C:21](=[CH:22][C:23]([O:34][CH3:35])=[C:24]([O:32][CH3:33])[CH:25]=3)[N:20]=2)=[CH:11]1
Reactant: COc1cc2nc(-c3cn(S(=O)(=O)c4ccccc4)c4ccccc34)cc(C(=O)O)c2cc1OC
Solvent: O
Solvent: CO
Product: COc1cc2nc(-c3c[nH]c4ccccc34)cc(C(=O)O)c2cc1OC

Procedure:
A stirred solution of (0.547 g) of 2-(N-phenylsulfonylindol-3-yl)-4-carboxy-6,7-dimethoxyquinoline, K2 CO3 (0.380 g), MeOH (40 ml) and H2O (10 ml) are heated to reflux. The MeOH is evaporated in vacuo, and the aqueous residue diluted with more H2O, and acidified with 0.1N HCl to pH between 6-7 while contained in an ice-bath. An orange solid precipitates. This is collected, washed with ether then dried under vacuum (0.1 mm at 22° C.) for a few hours to obtain 2-(indol-3-yl)-4-carboxy-6,7-dimethoxyquinoline m.p. 286° C. dec).
Reaction SMILES: [CH3:1][C:2]1[C:6]([CH2:7][N:8]2[CH:12]=[C:11]([N:13]3[C:17](=[O:18])[CH2:16][NH:15][C:14]3=[O:19])[CH:10]=[N:9]2)=[C:5]([CH3:20])[O:4][N:3]=1.[CH3:21][O:22][C:23]1[CH:24]=[C:25]([CH:29]=[CH:30][CH:31]=1)[CH2:26][CH2:27]Br>>[CH3:1][C:2]1[C:6]([CH2:7][N:8]2[CH:12]=[C:11]([N:13]3[C:17](=[O:18])[CH2:16][N:15]([CH2:27][CH2:26][C:25]4[CH:29]=[CH:30][CH:31]=[C:23]([O:22][CH3:21])[CH:24]=4)[C:14]3=[O:19])[CH:10]=[N:9]2)=[C:5]([CH3:20])[O:4][N:3]=1
Reactant: COc1cccc(CCBr)c1
Reactant: Cc1noc(C)c1Cn1cc(N2C(=O)CNC2=O)cn1
Product: COc1cccc(CCN2CC(=O)N(c3cnn(Cc4c(C)noc4C)c3)C2=O)c1
Yield: 34 %

Procedure:
Prepared as in example 10-52 from 3-(1-((3,5-dimethylisoxazol-4-yl)methyl)-1H-pyrazol-4-yl)imidazolidine-2,4-dione (example 10-1) and 3-methoxyphenethyl bromide. Yield: 34%. MS M+H calculated 410.18; found 410.1. The title compound was shown to inhibit hT2R08 bitter receptor and had an IC50 of 0.16 μM.
Reaction SMILES: [C:1](Cl)(Cl)=[O:2].[CH:5]1([C:12]2[S:16][C:15]([NH2:17])=[N:14][N:13]=2)[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6]1>C(OCC)(=O)C>[CH:5]1([C:12]2[S:16][C:15]([N:17]=[C:1]=[O:2])=[N:14][N:13]=2)[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11]1
Reactant: Nc1nnc(C2CCCCCC2)s1
Reactant: O=C(Cl)Cl
Solvent: CCOC(C)=O
Product: O=C=Nc1nnc(C2CCCCCC2)s1
Reaction time: 16 h

Procedure:
A saturated solution of phosgene in ethyl acetate (100 ml) is charged into a glass reaction vessel equipped with a mechanical stirrer. A slurry of 5-cycloheptyl-2-amino-1,3,4-thiadiazole (50 grams) in ethyl acetate (300 ml) is added to the reaction vessel and the resulting mixture is stirred for a period of about 16 hours, resulting in the formation of a precipitate. The reaction mixture is then purged with nitrogen gas to remove unreacted phosgene. The purged mixture is then filtered to recover the precipitate. The precipitate is then recrystallized to yield the desired product 5-cycloheptyl-1,3,4-thiadiazol-2-yl isocyanate dimer.