Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:3][C:4]([C@@H:6]1[C@@H:10]([C:11]2[CH:16]=[CH:15][C:14]([S:17]([CH3:20])(=[O:19])=[O:18])=[CH:13][CH:12]=2)[O:9][C:8]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[N:7]1)=O)C.[BH4-].[K+].Cl.O>CO>[CH3:20][S:17]([C:14]1[CH:13]=[CH:12][C:11]([C@H:10]2[O:9][C:8]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)=[N:7][C@@H:6]2[CH2:4][OH:3])=[CH:16][CH:15]=1)(=[O:18])=[O:19]
Reactant: CCOC(=O)[C@H]1N=C(c2ccccc2)O[C@@H]1c1ccc(S(C)(=O)=O)cc1
Agent: Cl
Agent: [BH4-]
Agent: [K+]
Solvent: O
Solvent: CO
Product: CS(=O)(=O)c1ccc([C@H]2OC(c3ccccc3)=N[C@@H]2CO)cc1
Temperature: 25 °C

Procedure:
(4S-trans)-4,5-Dihydro-5-[4-(methylsulfonyl)phenyl]-2-phenyl-4-oxazolecarboxylic acid ethyl ester (Compound IIIk) (about 5 g, 0.0134 moles) in methanol (about 50 mL) is reacted in a reaction vessel with potassium borohydride (about 1.1 g, 0.0201 moles) over about 6 hours while maintaining the temperature below about 60° C. The reaction is cooled to ambient room temperature and about 1N HCl (about 10 mL) and water (about 50 mL) are added. The resulting solids are filtered, washed with water, then dried to yield (4R,5R)-4,5-Dihydro-5-[4-(methylsulfonyl)phenyl]-2-phenyl-4-oxazolemethanol (Compound II wherein R1 is methylsulfonyl, R2 is phenyl and R3 is ethyl).
Reaction SMILES: [OH:1][C@@H:2]1[C@@H:6]([CH2:7][OH:8])[O:5][C@@H:4]([N:9]2[CH:14]=[C:13]3[CH:15]=[C:16]([C:18]4[CH:23]=[CH:22][C:21]([CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])=[CH:20][CH:19]=4)[O:17][C:12]3=[N:11][C:10]2=[O:29])[CH2:3]1.N1C=CC=CC=1.[O:36]([C:38]1[CH:59]=[CH:58][C:41]([C:42](Cl)([C:51]2[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=2)[C:43]2[CH:48]=[CH:47][C:46]([O:49][CH3:50])=[CH:45][CH:44]=2)=[CH:40][CH:39]=1)[CH3:37]>ClCCl>[CH3:50][O:49][C:46]1[CH:45]=[CH:44][C:43]([C:42]([C:41]2[CH:40]=[CH:39][C:38]([O:36][CH3:37])=[CH:59][CH:58]=2)([C:51]2[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=2)[O:8][CH2:7][C@H:6]2[O:5][C@@H:4]([N:9]3[CH:14]=[C:13]4[CH:15]=[C:16]([C:18]5[CH:19]=[CH:20][C:21]([CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])=[CH:22][CH:23]=5)[O:17][C:12]4=[N:11][C:10]3=[O:29])[CH2:3][C@@H:2]2[OH:1])=[CH:48][CH:47]=1
Reactant: CCCCCc1ccc(-c2cc3cn([C@H]4C[C@H](O)[C@@H](CO)O4)c(=O)nc3o2)cc1
Reactant: COc1ccc(C(Cl)(c2ccccc2)c2ccc(OC)cc2)cc1
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCCCCc1ccc(-c2cc3cn([C@H]4C[C@H](O)[C@@H](COC(c5ccccc5)(c5ccc(OC)cc5)c5ccc(OC)cc5)O4)c(=O)nc3o2)cc1

Procedure:
A 50 L reactor was charged with 2.8 kg (7.03 mol) of 3-((2R,4S,5R)-4-hydroxy-5-(hydroxymethyl)-tetrahydrofuran-2-yl)-6-(4-pentylphenyl)furo[2,3-d]pyrimidin-2(3H)-one, 2.8 kg (35.4 mol) of pyridine and 22.4 kg of dichloromethane. The mixture was stirred and to it was added 2.86 kg (8.44 mol) 4,4′-dimethoxyltritylchloride (DMT-Cl) in 14.9 kg dichloromethane at room temperature (rt). After addition, the mixture was stirred for 0.5 h at rt. The mixture was filtered and the filtrate was washed with brine. The filtrate contained the desired product which was used directly in the next step.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][N:7]1[C:15]2[N:14]=[C:13]([CH3:16])[N:12]([CH2:17][O:18][C:19](=[O:24])[C:20]([CH3:23])([CH3:22])[CH3:21])[C:11]=2[C:10](=[O:25])[NH:9][C:8]1=[O:26].[H-].[Na+].[C:29]([O:32][C@H:33]([CH3:39])[CH2:34][CH2:35][CH2:36][CH2:37]I)(=[O:31])[CH3:30]>CS(C)=O>[C:29]([O:32][C@H:33]([CH3:39])[CH2:34][CH2:35][CH2:36][CH2:37][N:9]1[C:10](=[O:25])[C:11]2[N:12]([CH2:17][O:18][C:19](=[O:24])[C:20]([CH3:22])([CH3:23])[CH3:21])[C:13]([CH3:16])=[N:14][C:15]=2[N:7]([CH2:6][C:2]2[O:1][CH:5]=[CH:4][CH:3]=2)[C:8]1=[O:26])(=[O:31])[CH3:30]
Reactant: CC(=O)O[C@H](C)CCCCI
Reactant: Cc1nc2c(c(=O)[nH]c(=O)n2Cc2ccco2)n1COC(=O)C(C)(C)C
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Product: CC(=O)O[C@H](C)CCCCn1c(=O)c2c(nc(C)n2COC(=O)C(C)(C)C)n(Cc2ccco2)c1=O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 45.3 %

Procedure:
To a stirring solution of 3-(2-Furylmethyl)-7-pivaloyloxymethyl-8-methylxanthine (0.65 g, 1.8 mmol) in dimethyl sulfoxide (20 ml) was added sodium hydride in one portion. After 30 minutes, (R)-5-acetoxy-1-iodohexane (0.58 g, 2.16 mmol, prepared as above) was added neat. The reaction was allowed to stir at ambient temperature for 20 hours, quenched with water (70 ml) and then extracted with ethyl acetate (3×35 ml). The extracts were washed with saturated aqueous sodium chloride solution (30 ml), dried over sodium sulfate and concentrated to give a crude yellow oil. The product was purified by flash chromatography on silica gel (ethyl acetate) to give (R)-1-(5-Acetoxyhexyl)-3-(2-furylmethyl)-7-pivaloyloxymethyl-8-methylxanthine (0.41 g) as a yellow oil. The product oil was dissolved in methanol (20 ml) and treated with a sodium methoxide solution (25 wt. % in MeOH, 0.94 ml, 4.1 mmol). The reaction was allowed to stir at ambient temperature for 48 hours. The solution was diluted with ethyl acetate (40 ml) and quenched with water (20 ml). The organic phase was collected and washed with saturated aqueous sodium chloride solution (20 ml), dried over sodium sulfate and concentrated to give a yellow solid. Column chromatography on silica gel eluting with 10% methanol-ethyl acetate gave (R)-3-(2furylmethyl)-1-(5-hydroxyhexyl)-8-methylxanthin CT2412R (21 mg) as an off-white solid.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]([NH:7][C:8]2[CH:13]=[C:12]([O:14][C:15]3[CH:16]=[C:17]([CH:22]=[CH:23][CH:24]=3)[C:18]([O:20]C)=[O:19])[CH:11]=[CH:10][N:9]=2)[S:5][CH:6]=1.[OH-].[Na+]>CO>[CH3:1][C:2]1[N:3]=[C:4]([NH:7][C:8]2[CH:13]=[C:12]([O:14][C:15]3[CH:16]=[C:17]([CH:22]=[CH:23][CH:24]=3)[C:18]([OH:20])=[O:19])[CH:11]=[CH:10][N:9]=2)[S:5][CH:6]=1
Reactant: COC(=O)c1cccc(Oc2ccnc(Nc3nc(C)cs3)c2)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: Cc1csc(Nc2cc(Oc3cccc(C(=O)O)c3)ccn2)n1
Temperature: 60 °C
Reaction time: 3 h
Yield: 78.2 %

Procedure:
A 250 mL round bottom flask was charged with methyl 3-(2-(4-methylthiazol-2-ylamino)pyridin-4-yloxy)benzoate (2.0 g, 5.859 mmol) and methanol (100 mL) was added. To this solution was added 1M NaOH (30 mL). The reaction mixture was heated at 60° C. with stirring for 3 hours. The reaction mixture was cooled and concentrated. To the residue was added 1% HCl and 0.5 mL 6N HCl. The solution was filtered and the residue was collected to give 3-(2-(4-methylthiazol-2-ylamino)pyridin-4-yloxy)benzoic acid (1.499 g, 77.38% yield) as a tan solid. 1H NMR (CDCl3) δ 8.24 (d, 1H), 7.94 (dt, 1H), 7.79 (t, 1H), 7.52 (t, 1H), 7.33 (ddd, 1H), 6.86 (bs, 1H), 6.68 (dd, 1H), 6.39 (d, 1H), 2.45 (d, 3H); Mass spectrum (apci) m/z=328 (100) (M+H).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([CH2:8][O:9][CH3:10])[N:5]=[C:4]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([CH3:17])[CH:12]=2)[N:3]=1.[Cl:18][C:19]1[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][C:20]=1[NH2:21]>>[Cl:18][C:19]1[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][C:20]=1[NH:21][C:2]1[CH:7]=[C:6]([CH2:8][O:9][CH3:10])[N:5]=[C:4]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([CH3:17])[CH:12]=2)[N:3]=1
Reactant: COc1ccc(Cl)c(N)c1
Reactant: COCc1cc(Cl)nc(-c2cccc(C)c2)n1
Product: COCc1cc(Nc2cc(OC)ccc2Cl)nc(-c2cccc(C)c2)n1

Procedure:
The title compound was prepared from a mixture of 4-chloro-6-(methoxymethyl)-2-(3-methylphenyl)pyrimidine (50 mg, 0.201 mmol) and 2-chloro-5-methoxyaniline (39 mg, 0.201 mmol) similar to Example 13 and isolated as a white solid (18 mg, 24%). 1H NMR (CDCl3): 8.27–8.25 (m, 3H), 7.40 (t, J=7.7 Hz, 1H), 7.34 (d, J=8.7 Hz, 1H), 7.33 (s, 1H), 7.19 (s, 1H), 6.83 (s, 1H), 6.66 (dd, J=3.0, 9.0 Hz, 1H), 4.59 (s, 2H), 3.93 (s, 3H), 3.58 (s, 3H), 2.47 (s, 3H).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:9]([C:11]2[CH:12]=[N:13][CH:14]=[CH:15][CH:16]=2)=[O:10])[CH:5]=[C:6]([Br:8])[CH:7]=1.C(N(C(C)C)CC)(C)C.[C:26](Cl)(=[O:29])[CH2:27][CH3:28].C(=O)(O)[O-].[Na+]>ClC(Cl)C>[Br:8][C:6]1[CH:7]=[C:2]([NH:1][C:26](=[O:29])[CH2:27][CH3:28])[CH:3]=[C:4]([C:9]([C:11]2[CH:12]=[N:13][CH:14]=[CH:15][CH:16]=2)=[O:10])[CH:5]=1
Reactant: CCC(=O)Cl
Reactant: Nc1cc(Br)cc(C(=O)c2cccnc2)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(Cl)Cl
Product: CCC(=O)Nc1cc(Br)cc(C(=O)c2cccnc2)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To 0.20 g of (3-amino-5-bromo-phenyl)-pyridin-3-yl-methanone (0.72 mmol) in 10 mL of dichloroethane was added 0.25 mL of diisopropylethylamine and 0.065 mL of propionyl chloride. The reaction was stirred 1 h at ambient temperature, then poured into saturated aqueous sodium bicarbonate. The phases were separated and the aqueous phase was washed once with methylene chloride, dried over sodium sulfate, filtered and concentrated to give 0.24 g (quantitative yield) of N-[3-bromo-5-(pyridine-3-carbonyl)-phenyl]-propionamide.
Reaction SMILES: [N:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[NH:3][C:2]=1[S:10][CH2:11][C:12]1[CH:13]=[CH:14][CH:15]=[C:16]2[C:21]=1[N:20]([CH2:22][CH3:23])[CH2:19][CH2:18][C:17]2=O.[CH3:25][NH2:26].[BH4-].[Na+]>CO>[N:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[NH:3][C:2]=1[S:10][CH2:11][C:12]1[CH:13]=[CH:14][CH:15]=[C:16]2[C:21]=1[N:20]([CH2:22][CH3:23])[CH2:19][CH2:18][CH:17]2[NH:26][CH3:25]
Reactant: CN
Reactant: CCN1CCC(=O)c2cccc(CSc3nc4ccccc4[nH]3)c21
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CCN1CCC(NC)c2cccc(CSc3nc4ccccc4[nH]3)c21
Temperature: 25 °C

Procedure:
8-(2-Benzimidazolyl)thiomethyl-1-ethyl-4-oxo-1,2,3,4-tetrahydroquinoline (1 g) and methylamine (40% methanol solution, 7.4 ml) were dissolved in methanol (15 ml) and the solution was refluxed for 14 hours. After allowing to cool, sodium borohydride (630 mg) was added by portions with stirring at room temperature, and the mixture was stirred for 1 hour at the same temperature. The solvent was distilled off and the resulting residue was extracted with dichloromethane. The extract was washed with water and dried over anhydrous magnesium sulfate, and the solvent was distilled off. The resulting residue was recrystallized from ethyl acetate to give 8-(2-benzimidazolyl)thiomethyl-1-ethyl-4-methylamino-1,2,3,4-tetrahydroquinoline (970 mg).
Reaction SMILES: [O:1]=[C:2]([C:6]1[N:14]2[C:9]([CH:10]=[CH:11][CH:12]=[CH:13]2)=[CH:8][C:7]=1[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[C:3](Cl)=[O:4].[O:21]=[S:22]1(=[O:35])[CH2:27][CH2:26][N:25]([C:28]2[CH:33]=[CH:32][C:31]([NH2:34])=[CH:30][CH:29]=2)[CH2:24][CH2:23]1.C(N(CC)CC)C>C1COCC1>[O:35]=[S:22]1(=[O:21])[CH2:23][CH2:24][N:25]([C:28]2[CH:29]=[CH:30][C:31]([NH:34][C:3](=[O:4])[C:2](=[O:1])[C:6]3[N:14]4[C:9]([CH:10]=[CH:11][CH:12]=[CH:13]4)=[CH:8][C:7]=3[C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)=[CH:32][CH:33]=2)[CH2:26][CH2:27]1
Reactant: O=C(Cl)C(=O)c1c(-c2ccccc2)cc2ccccn12
Reactant: Nc1ccc(N2CCS(=O)(=O)CC2)cc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: O=C(Nc1ccc(N2CCS(=O)(=O)CC2)cc1)C(=O)c1c(-c2ccccc2)cc2ccccn12
Temperature: 25 °C
Reaction time: 8 h
Yield: 47.7 %

Procedure:
A solution of oxo-(2-phenyl-indolizin-3-yl)-acetyl chloride (0.12 g, 0.42 mmol) in THF was added to a solution of 4-(1,1-dioxo-1λ6-thiomorpholin-4-yl)-phenylamine (70 mg, 0.31 mmol) and triethylamine (85 mg, 0.85 mmol) in THF (10 mL) at 0° C., then the mixture was stirred for 8 h at r.t. The mixture was concentrated to dryness and washed with water to give a crude product which was triturated with methanol to afford the title compound (70 mg, 48%) as a solid.
Reaction SMILES: C(O[CH:4]=[C:5]1[C:16]2[C:8](=[CH:9][CH:10]=[C:11]3[C:15]=2[S:14][CH:13]=[N:12]3)[NH:7][C:6]1=[O:17])C.[NH2:18][C:19]1[CH:24]=[CH:23][C:22]([S:25]([NH:28][C:29]2[S:30][CH:31]=[CH:32][N:33]=2)(=[O:27])=[O:26])=[CH:21][CH:20]=1>>[O:17]=[C:6]1[C:5](=[CH:4][NH:18][C:19]2[CH:24]=[CH:23][C:22]([S:25]([NH:28][C:29]3[S:30][CH:31]=[CH:32][N:33]=3)(=[O:27])=[O:26])=[CH:21][CH:20]=2)[C:16]2[C:8](=[CH:9][CH:10]=[C:11]3[C:15]=2[S:14][CH:13]=[N:12]3)[NH:7]1
Reactant: Nc1ccc(S(=O)(=O)Nc2nccs2)cc1
Reactant: CCOC=C1C(=O)Nc2ccc3ncsc3c21
Product: O=C1Nc2ccc3ncsc3c2C1=CNc1ccc(S(=O)(=O)Nc2nccs2)cc1
Yield: 33 %

Procedure:
The title compound was prepared in 33% yield from 8-ethoxymethylene-6,8-dihydro-1-thia-3,6-diaza-as-indacen-7-one and 4-amino-N-(thiazol-2-yl)-benzenesulfonamide according to Procedure J: 1H NMR (DMSO-d6): δ12.7 (s, 1H), 11.2 (d, 1H), 10.9 (s, 1H), 9.3 (s, 1H), 8.1 (d, 1H), 7.8 (t, 3H), 7.6 (d, 2H), 7.3 (d, 1H), 7.2 (d, 1H), 6.8 (d, 1H); APCI−MS m/z 456 (M+H)+ and 454 (M−H)−.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:21])[CH:4]([S:12]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)(=[O:14])=[O:13])[CH:5]1[CH2:10][CH2:9][CH2:8][C:7](=O)[CH2:6]1.Cl.[Cl:23][C:24]1[CH:29]=[CH:28][C:27]([NH:30]N)=[CH:26][CH:25]=1.C([O-])(O)=O.[Na+]>C(O)(=O)C>[CH3:1][O:2][C:3](=[O:21])[CH:4]([S:12]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)(=[O:14])=[O:13])[CH:5]1[CH2:10][CH2:9][C:8]2[C:28]3[C:27](=[CH:26][CH:25]=[C:24]([Cl:23])[CH:29]=3)[NH:30][C:7]=2[CH2:6]1
Reactant: COC(=O)C(C1CCCC(=O)C1)S(=O)(=O)c1ccccc1
Reactant: NNc1ccc(Cl)cc1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Product: COC(=O)C(C1CCc2c([nH]c3ccc(Cl)cc23)C1)S(=O)(=O)c1ccccc1
Temperature: 40 °C
Reaction time: 2 h
Yield: 64.3 %

Procedure:
To 5 g (0.016 mol) of benzenesulfonyl-(3-oxo-cyclohexyl)-acetic acid methyl ester in glacial acetic acid (30 mL), 3.17 g (0.018 mol, 1.1 eq) of 4-chlorophenylhydrazine hydrochloride were added and the reaction mixture was stirred at 40° C. for 2 hours. An aqueous solution of NaHCO3 was added until pH=7 was reached, and the mixture was extracted with EtOAc. The combined organic phases were dried over Na2SO4, filtered and evaporated. A column chromatography on silica gel followed by a trituration from Et2O yielded 4.3 g (64%) of benzenesulfonyl-(6-chloro-2,3,4,9-tetrahydro-1H-carbazol-2-yl)-acetic acid methyl ester as a racemic mixture of diastereomers, light brown crystals, MS: 418 (MH+).
Reaction SMILES: Cl[C:2]1[NH:6][C:5]2[CH:7]=[C:8]([C:11]([F:14])([F:13])[F:12])[CH:9]=[CH:10][C:4]=2[N:3]=1.[CH3:15][C@H:16]1[NH:21][CH2:20][CH2:19][N:18]([C:22]2[C:27]([C:28]([F:31])([F:30])[F:29])=[CH:26][CH:25]=[CH:24][N:23]=2)[CH2:17]1>O1CCOCC1>[CH3:15][C@@H:16]1[CH2:17][N:18]([C:22]2[C:27]([C:28]([F:31])([F:29])[F:30])=[CH:26][CH:25]=[CH:24][N:23]=2)[CH2:19][CH2:20][N:21]1[C:2]1[NH:3][C:4]2[CH:10]=[CH:9][C:8]([C:11]([F:14])([F:13])[F:12])=[CH:7][C:5]=2[N:6]=1
Reactant: FC(F)(F)c1ccc2nc(Cl)[nH]c2c1
Reactant: C[C@@H]1CN(c2ncccc2C(F)(F)F)CCN1
Solvent: C1COCCO1
Product: C[C@@H]1CN(c2ncccc2C(F)(F)F)CCN1c1nc2cc(C(F)(F)F)ccc2[nH]1

Procedure:
A mixture of 2-chloro-6-trifluoromethyl-1H-benzoimidazole (176 mg, 0.8 mmol, Example 1c) and (3R)-3-methyl-1-(3-trifluoromethyl-pyridin-2-yl)-piperazine (245 mg, 1.0 mmol, Example 79a) in dioxane (2 mL) reacted under the conditions of Example 3c to give the title compound. MS (ESI, pos. ion) m/z: 430 (M+1).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:13])[C:4]1[CH:9]=[C:8]([C:10]#[N:11])[CH:7]=[CH:6][C:5]=1[OH:12].[C:14]([O-])([O-])=O.[K+].[K+].CI>CC(C)=O>[CH3:1][O:2][C:3](=[O:13])[C:4]1[CH:9]=[C:8]([C:10]#[N:11])[CH:7]=[CH:6][C:5]=1[O:12][CH3:14]
Reactant: COC(=O)c1cc(C#N)ccc1O
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: CI
Product: COC(=O)c1cc(C#N)ccc1OC
Temperature: 65 °C
Yield: 42 %

Procedure:
To a mixture of methyl-2-hydroxy-5-cyano-benzoate (2 g, 5.6 mmol), K2CO3 (4.68 g, 16.8 mmol) in acetone (50 ml) was added methyl iodide (0.7 ml, 5.6 mmol). The reaction was then heated at 65° C. overnight resulting in formation of a solid which was filtered off whilst hot and washed with acetone to give 5-cyano-2-methoxy-benzoic acid methyl ester (0.45 g). The crude product was dissolved in THF (5 ml) and then treated with LiOH (0.108 g 0.26 mmol) in water (5 ml) and stirred at room temperature overnight. The reaction was acidified with 2M HCl and extracted EtOAc (×2). The organic portion dried (MgSO4) and reduced in vacuo to give 5-cyano-2-methoxy-benzoic acid (0.277 g). (LC/MS Acidic: Rt 2.92, [MH−H]+ 178).
Reaction SMILES: [CH:1]([C:3]1[CH:18]=[CH:17][C:6]([C:7]([NH:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][N:12]=2)=[O:8])=[C:5]([CH3:19])[CH:4]=1)=O.Cl.[OH:21][NH2:22]>C(O)C.O>[OH:21][N:22]=[CH:1][C:3]1[CH:18]=[CH:17][C:6]([C:7]([NH:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][N:12]=2)=[O:8])=[C:5]([CH3:19])[CH:4]=1
Reactant: NO
Reactant: Cc1cc(C=O)ccc1C(=O)NCc1ccccn1
Agent: Cl
Solvent: CCO
Solvent: O
Product: Cc1cc(C=NO)ccc1C(=O)NCc1ccccn1
Temperature: 25 °C
Yield: 85 %

Procedure:
In a solution of 0.50 g of 4-formyl-2-methyl-N-(2-pyridylmethyl) benzoic acid amide in 10 ml of ethanol and 5 ml of water, 0.18 g of hydroxyamine hydrochloride was added with stirring at room temperature, and stirred at the same temperature for 12 hours. After the completion of the reaction, solid was filtered off, ethanol was distilled off under reduced pressure, and 30 ml of saturated sodium hydrogen carbonate aqueous solution was added in the remaining aqueous solution. The precipitated crystal was filtered off, washed with water and dried to obtain 0.45 g of the aimed product as pale yellow crystal.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5](B(O)O)=[CH:4][CH:3]=1.Cl[C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([Cl:18])[N:13]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>C1(C)C=CC=CC=1.O.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>[Cl:18][C:14]1[CH:15]=[CH:16][CH:17]=[C:12]([C:5]2[CH:6]=[CH:7][C:2]([CH3:1])=[CH:3][CH:4]=2)[N:13]=1
Reactant: Clc1cccc(Cl)n1
Reactant: Cc1ccc(B(O)O)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: O
Product: Cc1ccc(-c2cccc(Cl)n2)cc1
Temperature: 80 °C
Reaction time: 15 h
Yield: 268.4 %

Procedure:
4-Methylphenylboronic acid (1.00 g), 2,6-dichloropyridine (3.27 g), tetrakis(triphenylphosphine)palladium(0) (0.255 g) and potassium phosphate (3.12 g) were dissolved in toluene (35 ml) and water (6.0 ml). The mixture was stirred at 80° C. for 15 hours under a nitrogen atmosphere. The organic layer was separated, washed with a saturated aqueous sodium hydrogen carbonate solution, and dried with anhydrous magnesium sulfate and the solvent was distilled off. The resultant was crudely purified through silica gel column chromatography (chloroform), thereby obtaining a mixture (4.02 g) containing the subject compound.
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.[F:21][C:22]1[CH:30]=[CH:29][C:25]([CH2:26][CH2:27]Br)=[CH:24][CH:23]=1>>[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][C:22]([F:21])=[CH:23][CH:24]=4)[C:14]3=[O:19])[CH:10]=[N:9]2)=[C:5]([CH3:20])[O:4][N:3]=1
Reactant: Fc1ccc(CCBr)cc1
Reactant: Cc1noc(C)c1Cn1cc(N2C(=O)CNC2=O)cn1
Product: Cc1noc(C)c1Cn1cc(N2C(=O)CN(CCc3ccc(F)cc3)C2=O)cn1
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 4-fluorophenethyl bromide. Yield: 34%. MS M+H calculated 398.16; found 398.1. The title compound was shown to inhibit hT2R08 bitter receptor and had an IC50 of 0.01 μM.
Reaction SMILES: Cl.[CH:2]1[C:15]2[NH:14][C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[S:7][C:6]=2[CH:5]=[CH:4][C:3]=1[C:16]1[N:17]=[C:18]([CH2:21][NH2:22])[S:19][CH:20]=1.[C:23](Cl)(=[O:27])[CH2:24][CH2:25][CH3:26].C(Cl)(=O)C>>[CH:2]1[C:15]2[NH:14][C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[S:7][C:6]=2[CH:5]=[CH:4][C:3]=1[C:16]1[N:17]=[C:18]([CH2:21][NH:22][C:23](=[O:27])[CH2:24][CH2:25][CH3:26])[S:19][CH:20]=1
Reactant: NCc1nc(-c2ccc3c(c2)Nc2ccccc2S3)cs1
Reactant: CCCC(=O)Cl
Agent: Cl
Solvent: CC(=O)Cl
Product: CCCC(=O)NCc1nc(-c2ccc3c(c2)Nc2ccccc2S3)cs1
Yield: 47.2 %

Procedure:
This compound is prepared according to a protocol identical to that described for Example 355, with the compound of Example 362 and butanoyl chloride respectively replacing intermediate 355.2 and the acetyl chloride in Stage 355.3. The expected product is obtained in the form of a yellow solid with a yield of 47.2%. Melting point: 218.0-220.0° C.
Reaction SMILES: [CH2:1]([O:3][C:4]1[C:5](I)=[CH:6][C:7]([O:10][CH3:11])=[N:8][CH:9]=1)[CH3:2].[Cl:13][C:14]1[CH:15]=[CH:16][C:17]([C:23]#[N:24])=[C:18](B(O)O)[CH:19]=1>>[Cl:13][C:14]1[CH:15]=[CH:16][C:17]([C:23]#[N:24])=[C:18]([C:5]2[C:4]([O:3][CH2:1][CH3:2])=[CH:9][N:8]=[C:7]([O:10][CH3:11])[CH:6]=2)[CH:19]=1
Reactant: CCOc1cnc(OC)cc1I
Reactant: N#Cc1ccc(Cl)cc1B(O)O
Product: CCOc1cnc(OC)cc1-c1cc(Cl)ccc1C#N

Procedure:
322 mg (purity 93%, 1.07 mmol) of 5-ethoxy-4-iodo-2-methoxypyridine and 234 mg (1.29 mmol, 1.2 eq.) of 5-chloro-2-cyanophenylboronic acid in the presence of [1,1-bis(diphenylphosphino)ferrocene]palladium(II) chloride/dichloromethane monoadduct were reacted according to General Method 2A. The crude product was purified by flash chromatography (silica gel 50, cyclohexane/ethyl acetate gradient). Yield: 135 mg (41% of theory)
Reaction SMILES: [F:1][C:2]1[C:11]([F:12])=[C:10]2[C:5]([CH:6]=[CH:7][CH:8]=[N:9]2)=[CH:4][CH:3]=1.[I:13]N1C(=O)CCC1=O>C(O)(=O)C>[F:1][C:2]1[C:11]([F:12])=[C:10]2[C:5]([CH:6]=[C:7]([I:13])[CH:8]=[N:9]2)=[CH:4][CH:3]=1
Reactant: O=C1CCC(=O)N1I
Reactant: Fc1ccc2cccnc2c1F
Solvent: CC(=O)O
Product: Fc1ccc2cc(I)cnc2c1F
Temperature: 90 °C
Reaction time: 30 h

Procedure:
185.5 g (1.12 mol) of 7,8-difluoroquinoline, 505.4 g (2.25 mol) of N-iodosuccinimide and 927 mL of acetic acid were placed in a 3 L eggplant flask containing a stirrer, followed by stirring the mixture for 30 hours at 90° C. After cooling the resultant, the precipitated crystals were filtered and dried.
Reaction SMILES: Cl[CH2:2][C:3]1[CH:4]=[CH:5][C:6]2[S:11][C:10]3[N:12]=[CH:13][CH:14]=[N:15][C:9]=3[N:8]([CH2:16][O:17][CH3:18])[C:7]=2[CH:19]=1.[CH3:20][NH2:21]>CO>[CH3:20][NH:21][CH2:2][C:3]1[CH:4]=[CH:5][C:6]2[S:11][C:10]3[N:12]=[CH:13][CH:14]=[N:15][C:9]=3[N:8]([CH2:16][O:17][CH3:18])[C:7]=2[CH:19]=1
Reactant: COCN1c2cc(CCl)ccc2Sc2nccnc21
Reactant: CN
Solvent: CO
Product: CNCc1ccc2c(c1)N(COC)c1nccnc1S2

Procedure:
8-Chloromethyl-10-methoxymethyl-10H-pyrazino[2,3-b][1,4]benzothiazine was stirred in a solution of methylamine in methanol at room temperature over day and night. Then the reaction mixture was distilled under reduced pressure and the residue was distributed into sodium hydroxide and ethyl acetate. The organic layer was extracted and dried over anhydrous sodium sulfate. After distilling off the solvent under reduced pressure, the obtained residue was purified by silica gel column chromatography (eluted with dichloromethane/methanol) to thereby give the title compound as a yellow oily substance.
Reaction SMILES: Cl.[C:2]1(=[N:10]O)[CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1.[OH2:12]>>[C:2]1(=[O:12])[CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][NH:10]1
Reactant: ON=C1CCCCCCC1
Reactant: O
Agent: Cl
Product: O=C1CCCCCCCN1
Temperature: 130 °C
Reaction time: 1 h

Procedure:
Polyphosphoric acid (31.9 g) and water (3.75 g) were placed in a 100 mL round bottom flask equipped with a stir bar and a cold water condenser. The mixture was heated to 130 degrees C., and cyclooctanone oxime hydrochloride (5.9 g, 35 mmol, 1.0 eq) was added in small portions over 10 min. The oxime dissolved readily. The reaction mixture was stirred at 130 degrees C. for 1 hour, turned dark, was cooled to 100 degrees C., and poured into 100 mL of ice water. The aqueous mixture was extracted with chloroform (3×75 mL). The combined organic layers were dried over Na2SO4 and concentrated in vacuo. The 2-azacyclononanone slowly crystallized into an off-white solid (4.69 g, 94%).