Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[N:10]=[CH:9][N:8]([C:11]3[CH:16]=[CH:15][CH:14]=[C:13]([C:17]4[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=4)[CH:12]=3)[C:5]2=[N:6][CH:7]=1.[C:23]1(B(O)O)[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>C(O)C>[C:23]1([C:2]2[CH:3]=[C:4]3[N:10]=[CH:9][N:8]([C:11]4[CH:16]=[CH:15][CH:14]=[C:13]([C:17]5[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=5)[CH:12]=4)[C:5]3=[N:6][CH:7]=2)[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: OB(O)c1ccccc1
Reactant: Brc1cnc2c(c1)ncn2-c1cccc(-c2cccnc2)c1
Solvent: CCO
Product: c1ccc(-c2cnc3c(c2)ncn3-c2cccc(-c3cccnc3)c2)cc1

Procedure:
The title compound was prepared from 6-bromo-3-[3-(pyridin-3-yl)phenyl]-3H-imidazo[4,5-b]pyridine and phenylboronic acid as described in Example 1. Free base, white powder, m.p. 179-180° C. (from ethanol); δH (400 MHz, CDCl3) 7.41-7.44 (1H, m), 7.52 (2H, t, J 7), 7.65-7.74 (4H, m), 7.83 (1H, d, J 8), 7.97 (1H, d, J 8), 8.07 (1H, s), 8.35 (1H, d, J 2), 8.44 (1H, s), 8.49 (1H, s), 8.65 (1H, d, J 5), 8.72 (1H, s), 8.95 (1H, s); m/z (ES+) 349 (M++H).
Reaction SMILES: [F-].C([N+](CCCC)(CCCC)CCCC)CCC.[Si]([O:36][CH2:37][CH2:38][O:39][CH2:40][C@H:41]([O:52][C:53]1[N:58]=[CH:57][N:56]=[C:55]2[N:59]([C:62]3[CH:67]=[CH:66][CH:65]=[C:64]([C:68]#[N:69])[C:63]=3[CH3:70])[N:60]=[CH:61][C:54]=12)[C:42]([NH:44][C:45]1[CH:50]=[CH:49][C:48]([Cl:51])=[CH:47][N:46]=1)=[O:43])(C(C)(C)C)(C1C=CC=CC=1)C1C=CC=CC=1>C1COCC1>[Cl:51][C:48]1[CH:49]=[CH:50][C:45]([NH:44][C:42](=[O:43])[C@@H:41]([O:52][C:53]2[N:58]=[CH:57][N:56]=[C:55]3[N:59]([C:62]4[CH:67]=[CH:66][CH:65]=[C:64]([C:68]#[N:69])[C:63]=4[CH3:70])[N:60]=[CH:61][C:54]=23)[CH2:40][O:39][CH2:38][CH2:37][OH:36])=[N:46][CH:47]=1
Reactant: Cc1c(C#N)cccc1-n1ncc2c(O[C@@H](COCCO[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)C(=O)Nc3ccc(Cl)cn3)ncnc21
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: Cc1c(C#N)cccc1-n1ncc2c(O[C@@H](COCCO)C(=O)Nc3ccc(Cl)cn3)ncnc21
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Tetrabutylammonium fluoride (1M in THF) (1.174 mL, 1.17 mmol) was added to (2S)-3-(2-(tert-butyldiphenylsilyloxy)ethoxy)-N-(5-chloropyridin-2-yl)-2-(1-(3-cyano-2-methylphenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yloxy)propanamide (Intermediate AT7) (860 mg, 1.17 mmol) in THF (2 mL) under nitrogen. The resulting mixture was stirred at ambient temperature for 2 hours. The reaction mixture was quenched with saturated NH4Cl (1 mL), diluted with DCM (10 mL) and poured onto a phase separator. The organic layer was evaporated to a gum. The crude product was purified by flash silica chromatography, elution gradient 0 to 100% EtOAc in isohexane to afford the product (284 mg, 49.0%, 91% ee). 1H NMR (300 MHz, CDCl3) δ 2.40 (3H, s), 2.55-2.65 (1H, m), 3.70-3.86 (4H, m), 4.14-4.27 (2H, m), 6.08 (1H, t), 7.49 (1H, t), 7.63-7.73 (2H, m), 7.76-7.82 (1H, m), 8.15-8.25 (2H, m), 8.44 (1H, s), 8.59 (1H, s), 9.03 (1H, s); m/z (ES+) (M+H)+=494.45; HPLC tR=2.13 min.
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.[C:21](=O)([O-])[O-].[Cs+].[Cs+].IC.O>CN(C=O)C>[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]([CH3:21])[C:14]3=[O:19])[CH:10]=[N:9]2)=[C:5]([CH3:20])[O:4][N:3]=1
Reactant: O=C([O-])[O-]
Reactant: Cc1noc(C)c1Cn1cc(N2C(=O)CNC2=O)cn1
Agent: [Cs+]
Solvent: CI
Solvent: O
Solvent: CN(C)C=O
Product: Cc1noc(C)c1Cn1cc(N2C(=O)CN(C)C2=O)cn1
Reaction time: 2 h
Yield: 79.8 %

Procedure:
3-(1-((3,5-dimethylisoxazol-4-yl)methyl)-1H-pyrazol-4-yl)imidazolidine-2,4-dione (example 10-1) (50 mg, 0.182 mmol) and cesium carbonate (60 mg, 0.185 mmol) were mixed in DMF (1 mL) for 15 minutes under a nitrogen atmosphere at room temperature. Then, iodomethane (14 mg, 0.185 mmol) was added and the reaction continued to stir for an addition 2 hours. H2O (2 mL) was added and the product was extracted with ethyl acetate (1 mL, 2×). The organic phase was collected and washed with saturated sodium bicarbonate solution (2 ml, 2×), dried, and filtered. Solvent was removed under a stream of nitrogen and then further dried under high vacuum to afford 3-(1-((3,5-dimethylisoxazol-4-yl)methyl)-1H-pyrazol-4-yl)-1-methylimidazolidine-2,4-dione as a white solid (42 mg, 80%). Yield: 80%. 1H NMR (CDCl3, 400 MHz): δ 2.18 (s, 3H), 2.41 (s, 3H), 3.06 (s, 3H), 3.95 (s, 2H), 5.05 (s, 2H), 7.89 (s, 1H), 8.05 (s, 1H). The title compound was shown to inhibit hT2R08 bitter receptor and had an IC50 of 0.58 μM.
Reaction SMILES: F[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[N+:12]([O-:14])=[O:13])[NH:8][C:7](=[O:15])[N:6]([NH:16][S:17]([CH3:20])(=[O:19])=[O:18])[C:5]2=[O:21].[CH2:22]([NH2:29])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>>[CH2:22]([NH:29][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[N+:12]([O-:14])=[O:13])[NH:8][C:7](=[O:15])[N:6]([NH:16][S:17]([CH3:20])(=[O:19])=[O:18])[C:5]2=[O:21])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: NCc1ccccc1
Reactant: CS(=O)(=O)Nn1c(=O)[nH]c2cc([N+](=O)[O-])c(F)cc2c1=O
Product: CS(=O)(=O)Nn1c(=O)[nH]c2cc([N+](=O)[O-])c(NCc3ccccc3)cc2c1=O
Yield: 31 %

Procedure:
N-(6-Fluoro-7-nitro-2,4-dioxo-1,4-dihydro-2H-quinazolin-3-yl)-methanesulfonamide (20 mg, 0.0628 mmol) is reacted with benzylamine according to the GPA affording 8 mg (31%) of a red powder. Rt=3.45 min.
Reaction SMILES: [F:1][C:2]1[CH:24]=[CH:23][C:5]([CH2:6][O:7][C:8]2[N:13]=[CH:12][C:11]([N:14]3[C:18](=[O:19])[CH2:17][CH:16]([C:20]([OH:22])=O)[CH2:15]3)=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.Cl.CN.[CH2:28]([N:30](CC)CC)C>CN(C)C=O>[CH3:28][NH:30][C:20]([CH:16]1[CH2:17][C:18](=[O:19])[N:14]([C:11]2[CH:12]=[N:13][C:8]([O:7][CH2:6][C:5]3[CH:4]=[CH:3][C:2]([F:1])=[CH:24][CH:23]=3)=[CH:9][CH:10]=2)[CH2:15]1)=[O:22]
Reactant: O=C(O)C1CC(=O)N(c2ccc(OCc3ccc(F)cc3)nc2)C1
Reactant: CCN(CC)CC
Agent: CN
Agent: Cl
Solvent: CN(C)C=O
Product: CNC(=O)C1CC(=O)N(c2ccc(OCc3ccc(F)cc3)nc2)C1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 14.6 %

Procedure:
A solution of 105 mg (0.3 mmol) of (RS)-1-[6-(4-fluoro-benzyloxy)-pyridin-3-yl]-5-oxo-pyrrolidine-3-carboxylic acid in 5 ml N,N-dimethylformamide is treated with 58 mg (0.35 mmol) of N,N-carbonyl-diimidazole, and the mixture is stirred at RT for 15 min. Thereafter, 26 mg (0.38 mmol) of methylamine hydrochloride and 50 μl (0.35 mmol) of triethylamine are added. After 30 min, the solvent is evaporated under reduced pressure and the residue is chromatographed on silica gel using a 98:2-mixture of dichloromethane and methanol as the eluent. There are obtained 15 mg (15% of theory) of (RS)-1-[6-(4-fluoro-benzyloxy)-pyridin-3-yl]-5-oxo-pyrrolidine-3-carboxylic acid methylamide as a green oil which solidifies on standing. MS: m/e=344 (M+H)+.
Reaction SMILES: O=S(Cl)Cl.[CH3:5][O:6][C:7]1[CH:22]=[C:21]([O:23][CH3:24])[CH:20]=[CH:19][C:8]=1[CH2:9][N:10]1[C:14](=[O:15])[CH2:13][CH:12]([C:16]([OH:18])=[O:17])[CH2:11]1.[CH3:25]O>>[CH3:5][O:6][C:7]1[CH:22]=[C:21]([O:23][CH3:24])[CH:20]=[CH:19][C:8]=1[CH2:9][N:10]1[C:14](=[O:15])[CH2:13][CH:12]([C:16]([O:18][CH3:25])=[O:17])[CH2:11]1
Reactant: CO
Reactant: COc1ccc(CN2CC(C(=O)O)CC2=O)c(OC)c1
Solvent: O=S(Cl)Cl
Product: COC(=O)C1CC(=O)N(Cc2ccc(OC)cc2OC)C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 81 %

Procedure:
SOCl2 (6.4 g, 54 mmol) was added dropwise to methanol (40 mL) followed by addition of 1-(2,4-dimethoxybenzyl)-5-oxopyrrolidine-3-carboxylic acid (5.0 g, 18 mmol) at 0° C. The reaction mixture was stirred at ambient temperature for 1 h and then heated under reflux for 7 h. The mixture was cooled to ambient temperature and concentrated. The residue was purified by flash column chromatography on silica gel (petroleum ether/EtOAc=6:1 to 2:1) to afford methyl 1-(2,4-dimethoxybenzyl)-5-oxopyrrolidine-3-carboxylate (a mixture of two enantiomers, 4.3 g, 81% yield) as a colorless oil. The two enantiomers were separated by chiral prep-HPLC.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:9][CH2:10][CH2:11][O:12]S(C)(=O)=O)[CH:6]=[CH:7][CH:8]=1.[CH2:17]([O:19][C:20]([C:22]1[S:26][C:25](=O)[NH:24][C:23]=1[CH3:28])=[O:21])[CH3:18].C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C>[CH2:17]([O:19][C:20]([C:22]1[S:26][C:25]([O:12][CH2:11][CH2:10][CH2:9][C:5]2[CH:6]=[CH:7][CH:8]=[C:3]([O:2][CH3:1])[CH:4]=2)=[N:24][C:23]=1[CH3:28])=[O:21])[CH3:18]
Reactant: COc1cccc(CCCOS(C)(=O)=O)c1
Reactant: CCOC(=O)c1sc(=O)[nH]c1C
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1sc(OCCCc2cccc(OC)c2)nc1C
Temperature: 75 °C
Yield: 51 %

Procedure:
A mixture of methanesulfonic acid 3-(3-methoxy-phenyl)-propyl ester (1.20 g, 4.912 mmol), 4-Methyl-2-oxo-2,3-dihydro-thiazole-5-carboxylic acid ethyl ester (0.960 g, 5.128 mmol) and cesium carbonate (3.2 hm, 9.82 mmol) in anhydrous DMF was heated to oil bath at 75° C. for 2.5 h. The reaction mixture was cooled, concentrated and diluted with water (50 mL) and extracted with EtOAc (3×50 mL). The organic layers were washed with 2N HCl (30 mL), water ((30 mL), brine (30 mL), dried over magnesium sulphate, filtered and concentrated to give a brown oil. The crude product is purified by flash column chromatography (10%-30% EtOAc in hexane) to give 2-[3-(3-Methoxy-phenyl)-propoxy]-4-methyl-thiazole-5-carboxylic acid ethyl ester (0.84 g, 51%) as a yellow oil. MS m/e 336.4 (M+H+).
Reaction SMILES: [OH:1][NH:2][C:3](=[NH:14])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([S:10](=[O:13])(=[O:12])[NH2:11])[CH:5]=1.[F:15][C:16]([F:37])([F:36])[C:17]1[CH:22]=[CH:21][C:20]([C:23]2[CH:28]=[C:27]([C:29]([F:32])([F:31])[F:30])[N:26]=[C:25]([C:33](O)=O)[N:24]=2)=[CH:19][CH:18]=1>>[F:32][C:29]([F:30])([F:31])[C:27]1[CH:28]=[C:23]([C:20]2[CH:21]=[CH:22][C:17]([C:16]([F:37])([F:36])[F:15])=[CH:18][CH:19]=2)[N:24]=[C:25]([C:33]2[O:1][N:2]=[C:3]([C:4]3[CH:5]=[C:6]([S:10]([NH2:11])(=[O:12])=[O:13])[CH:7]=[CH:8][CH:9]=3)[N:14]=2)[N:26]=1
Reactant: O=C(O)c1nc(-c2ccc(C(F)(F)F)cc2)cc(C(F)(F)F)n1
Reactant: N=C(NO)c1cccc(S(N)(=O)=O)c1
Product: NS(=O)(=O)c1cccc(-c2noc(-c3nc(-c4ccc(C(F)(F)F)cc4)cc(C(F)(F)F)n3)n2)c1

Procedure:
The title compound was prepared from N-hydroxy-3-sulfamoyl-benzamidine [CAS-No. 9000-88-7] (0.16 g, 0.75 mmol) and 4-(4-trifluoromethyl-phenyl)-6-trifluoromethyl-pyrimidine-2-carboxylic acid (example D.2) (0.17 g, 0.5 mmol) according to the general procedure V. Obtained as a white solid (0.099 g, 38%). MS (ISN) 514.1 [(M−H)−]; mp 204° C.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]([F:14])([F:13])[C:9]([F:12])([F:11])[F:10])[C:5]([C:15]([O:17][CH3:18])=[O:16])=[CH:4][N:3]=1.ClC1N=C(C(F)(F)C(F)(F)F)C(C(Cl)=O)=CN=1.[NH2:36][NH2:37]>CO>[NH:36]([C:2]1[N:7]=[C:6]([C:8]([F:14])([F:13])[C:9]([F:12])([F:11])[F:10])[C:5]([C:15]([O:17][CH3:18])=[O:16])=[CH:4][N:3]=1)[NH2:37]
Reactant: NN
Reactant: COC(=O)c1cnc(Cl)nc1C(F)(F)C(F)(F)F
Agent: O=C(Cl)c1cnc(Cl)nc1C(F)(F)C(F)(F)F
Solvent: CO
Product: COC(=O)c1cnc(NN)nc1C(F)(F)C(F)(F)F
Yield: 99 %

Procedure:
The title compound was prepared according to the procedure of Example 47 but employing a solution of methyl 2-chloro-4-pentafluoroethylpyrimidine-5-carboxylate (0.55 g, 1.9 mmol; itself prepared by a reaction of methanol with 2-chloro-4-pentafluoroethylpyrimidine-5-carbonyl chloride (see Example 17)) and hydrazine (0.3 g, 9.4 mmol), resulting in a yield of 99% (0.54 g); 1HNMR (CDCl3) δ 8.87 (s, 1H), 7.09 (s, 1H), 3.92 (s, 3H), 1.7 (s, 2H).
Reaction SMILES: S([C:11]1[C:24]2[C:23](=[O:25])[C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[C:16](=[O:26])[C:15]=2[C:14]([S:27]([C:30]2[CH:36]=[CH:35][C:33]([CH3:34])=[CH:32][CH:31]=2)(=[O:29])=[O:28])=[CH:13][CH:12]=1)(C1C=CC(C)=CC=1)(=O)=O.[CH2:37]([NH2:40])[CH2:38][CH3:39]>>[CH2:37]([NH:40][C:11]1[C:24]2[C:23](=[O:25])[C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[C:16](=[O:26])[C:15]=2[C:14]([S:27]([C:30]2[CH:31]=[CH:32][C:33]([CH3:34])=[CH:35][CH:36]=2)(=[O:29])=[O:28])=[CH:13][CH:12]=1)[CH2:38][CH3:39]
Reactant: Cc1ccc(S(=O)(=O)c2ccc(S(=O)(=O)c3ccc(C)cc3)c3c2C(=O)c2ccccc2C3=O)cc1
Reactant: CCCN
Product: CCCNc1ccc(S(=O)(=O)c2ccc(C)cc2)c2c1C(=O)c1ccccc1C2=O
Yield: 73 %

Procedure:
1-(n-propylamino)-4-tosylanthraquinone was prepared by reaction of 1,4-ditosylanthraquinone with n-propyl amine. The isolated and purified reaction product has the structure illustrated below (where "Ts" is ##STR10## The yield was 73% and the m.p. 163°-164° C. Mass spec m/e 435 (M+), 406 (M-C2H5), 280 (M-C7H7SO2), 252 (280-CO), 155 (C7H7SO2), 91 (C7H7); 1H-NMR (CD2Cl2)δ10.01 (br s, 1H), 8.21-7.87 (m, 2H), 7.81-7.65 (m, 4H), 7.35-6.96 (m, 4H), 3.41-3.20 (m, 2H), 2.31 (s, 3H), 1.91-1.67 (m,2H), 1.16-1.00 (t, 3H); IR (Nujol) 1368 cm-1 (asymmetrical stretch), 1170 cm-1 (symmetric stretch), 932, 898, 865, 830, 785 cm-1 (S--O--C stretch); UV/VIS max (Xylenes) 501 nm (ε6380).
Reaction SMILES: [OH:1][CH:2]1[CH2:11][CH:10]([CH3:12])[N:9]2[C:4]3[C:5](=[CH:17][CH:18]=[CH:19][C:3]1=3)[C:6](=[O:16])[C:7]([C:13]([OH:15])=[O:14])=[CH:8]2.S(=O)(=O)(O)O.[N+:25]([O-])([OH:27])=[O:26].[OH-].[NH4+]>>[OH:1][CH:2]1[CH2:11][CH:10]([CH3:12])[N:9]2[C:4]3[C:5](=[C:17]([N+:25]([O-:27])=[O:26])[CH:18]=[CH:19][C:3]1=3)[C:6](=[O:16])[C:7]([C:13]([OH:15])=[O:14])=[CH:8]2
Reactant: CC1CC(O)c2cccc3c(=O)c(C(=O)O)cn1c23
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Agent: [NH4+]
Agent: [OH-]
Product: CC1CC(O)c2ccc([N+](=O)[O-])c3c(=O)c(C(=O)O)cn1c23
Reaction time: 24 h

Procedure:
A solution of 0.1 mole of 6,7-dihydro-7-hydroxy-5-methyl-1-oxo-1H,5H-benzo[ij]quinolizine-2-carboxylic acid in 150 ml. of concentrated sulfuric acid is treated with a mixture of 150 ml. of concentrated sulfuric acid and 10 ml. of nitric acid while keeping the temperature below 30° C. The solution is stirred for about 24 hours, poured over ice and partially neutralized to a pH of 2 with ammonium hydroxide. The product, 6,7-dihydro-7-hydroxy-5-methyl-10-nitro-1-oxo-1H,5H-benzo[ij]quinolizine-2-carboxylic acid is isolated by filtration.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=1.[CH2:11]([O:13][C:14]([CH:16]1[CH2:20][CH:19]([OH:21])[CH2:18][NH:17]1)=[O:15])[CH3:12].C(=O)(O)[O-].[Na+].O>CN(C=O)C.C(OCC)(=O)C>[CH2:11]([O:13][C:14]([CH:16]1[CH2:20][CH:19]([OH:21])[CH2:18][N:17]1[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=1)=[O:15])[CH3:12]
Reactant: CCOC(=O)C1CC(O)CN1
Reactant: O=[N+]([O-])c1ccc(F)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: O
Product: CCOC(=O)C1CC(O)CN1c1ccc([N+](=O)[O-])cc1
Temperature: 80 °C
Reaction time: 24 h
Yield: 35 %

Procedure:
4-Fluoronitrobenzene (0.28 mL, 2.65 mmol), 4-hydroxy-pyrrolidine-2-carboxylic acid ethyl ester (419 mg, 2.65 mmol), and sodium bicarbonate (222 mg, 2.65 mmol) were dissolved in 5 mL dry DMF and heated to 80° C. After 24 h at this temperature, the reaction was cooled and water and ethyl acetate were added. The organic phase washed with brine, dried (MgSO4), and concentrated. Flash chromatography (65-75% ethyl acetate/hexanes) gave 260 mg (35% yield) of the desired product. 1H NMR (CDCl3, 500 MHz) 8.15 (d, J=9.3 Hz, 2H), 6.54 (d, J=9.3 Hz, 2H), 4.60 (m, 1H), 4.41 (d, J=9.2 Hz, 1H), 4.31 (dq, J=10.8, 7.1 Hz, 1H), 4.29 (dq, J=10.8, 7.1 Hz, 1H), 3.73 (dt, J=11.0, 1.2 Hz, 1H), 3.70 (dd, J=11.0, 4.2 Hz, 1H), 2.51 (ddd, J=14.2, 9.2, 4.2 Hz, 1H), 2.35 (dd, J=14.2, 1.2 Hz, 1H), 1.34 (t, J=7.1 Hz, 3H).
Reaction SMILES: [C:1]([C:5]1[O:9][C:8]([C@@H:10]2[C@H:14]3[O:15][C:16]([CH3:19])([CH3:18])[O:17][C@H:13]3[C@H:12]([N:20]3[CH:28]=[N:27][C:26]4[C:21]3=[N:22][CH:23]=[N:24][C:25]=4Cl)[O:11]2)=[N:7][N:6]=1)([CH3:4])([CH3:3])[CH3:2].C([O-])([O-])=O.[Ca+2].C(O)(=O)C.[Cl:39][C:40]1[CH:46]=[CH:45][C:43]([NH2:44])=[C:42]([F:47])[CH:41]=1>C1(C)C=CC=CC=1>[C:1]([C:5]1[O:9][C:8]([C@@H:10]2[C@H:14]3[O:15][C:16]([CH3:18])([CH3:19])[O:17][C@H:13]3[CH:12]([N:20]3[CH:28]=[N:27][C:26]4[C:21]3=[N:22][CH:23]=[N:24][C:25]=4[NH:44][C:43]3[CH:45]=[CH:46][C:40]([Cl:39])=[CH:41][C:42]=3[F:47])[O:11]2)=[N:7][N:6]=1)([CH3:3])([CH3:2])[CH3:4]
Reactant: CC1(C)O[C@@H]2[C@H](O1)[C@@H](c1nnc(C(C)(C)C)o1)O[C@H]2n1cnc2c(Cl)ncnc21
Reactant: Nc1ccc(Cl)cc1F
Agent: O=C([O-])[O-]
Agent: [Ca+2]
Solvent: Cc1ccccc1
Solvent: CC(=O)O
Product: CC1(C)O[C@@H]2[C@@H](c3nnc(C(C)(C)C)o3)OC(n3cnc4c(Nc5ccc(Cl)cc5F)ncnc43)[C@@H]2O1
Temperature: 76 °C

Procedure:
To a mixture of 40.0 g (95.1 mmol) of 9-[(3aR,4R,6S,6aS)-6-(5-tert-butyl-1,3,4-oxadiazol-2-yl)-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl]-6-chloro-9H-purine and 9.52 g (95.1 mmol) of CaCO3 powder was successively added 200 mL of glacial acetic acid and 21.1 mL (190 mmol) of 4-chloro-2-fluoroaniline at ambient temperature under nitrogen. The light brown mixture was heated at 76° C. for 1.5 to 2.0 h. The mixture was cooled to below 30° C. and diluted with 200 mL of toluene. The mixture was concentrated to about 120 mL by distillation at 35-45° C. under vacuum below 50 torr. This azeotropic process was repeated with a second charge of 240 mL of toluene and distilled to about 200 mL. The above mixture was filtered by suction and the filtrate was concentrated to about 80 mL at 35-45° C. under vacuum to provide a toluene solution of crude product of N-{9-[(3aR,6S,6aS)-6-(5-tert-butyl-1,3,4-oxadiazol-2-yl)-2,2-dimethyltetrahydrofuro [3,4-d][1,3]dioxol-4-yl]-9H-purin-6-yl}N-(4-chloro-2-fluorophenyl)amine.
Reaction SMILES: [CH:1]1([NH:5][C:6]([C:8]2[CH:17]=[CH:16][C:15]3[CH2:14][N:13]([CH2:18][C:19]([O:21]C(C)(C)C)=[O:20])[CH2:12][CH2:11][C:10]=3[N:9]=2)=[O:7])[CH2:4][CH2:3][CH2:2]1.[ClH:26]>O1CCOCC1>[ClH:26].[CH:1]1([NH:5][C:6]([C:8]2[CH:17]=[CH:16][C:15]3[CH2:14][N:13]([CH2:18][C:19]([OH:21])=[O:20])[CH2:12][CH2:11][C:10]=3[N:9]=2)=[O:7])[CH2:2][CH2:3][CH2:4]1
Reactant: CC(C)(C)OC(=O)CN1CCc2nc(C(=O)NC3CCC3)ccc2C1
Agent: Cl
Solvent: C1COCCO1
Product: O=C(O)CN1CCc2nc(C(=O)NC3CCC3)ccc2C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
The oil obtained from step 2 is dissolved in dioxane (5 mL). 4 N HCl in dioxane (5 ml, 20 mmol) is added. The mixture is stirred at rt overnight. The solvent is removed and the residue is washed with ether to give the title compound as a white solid. MS (M+1): 290.1.
Reaction SMILES: [SH:1][C:2]1[N:6]([CH2:7][C:8]2[CH:13]=[CH:12][C:11]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=3[C:20]3[NH:24][N:23]=[N:22][N:21]=3)=[CH:10][CH:9]=2)[C:5]2[C:25]([C:29]([O:31][CH2:32][CH3:33])=[O:30])=[CH:26][CH:27]=[CH:28][C:4]=2[N:3]=1.[OH-].[Na+].[CH2:36](I)[CH3:37].Cl>C(O)C>[CH2:36]([S:1][C:2]1[N:6]([CH2:7][C:8]2[CH:9]=[CH:10][C:11]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=3[C:20]3[NH:24][N:23]=[N:22][N:21]=3)=[CH:12][CH:13]=2)[C:5]2[C:25]([C:29]([O:31][CH2:32][CH3:33])=[O:30])=[CH:26][CH:27]=[CH:28][C:4]=2[N:3]=1)[CH3:37]
Reactant: CCI
Reactant: CCOC(=O)c1cccc2nc(S)n(Cc3ccc(-c4ccccc4-c4nnn[nH]4)cc3)c12
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CCOC(=O)c1cccc2nc(SCC)n(Cc3ccc(-c4ccccc4-c4nnn[nH]4)cc3)c12
Temperature: 25 °C
Reaction time: 4 h
Yield: 56.9 %

Procedure:
To a solution of ethyl 2-mercapto-1-[[2'-(1H-tetrazol-5-yl)biphenyl-4-yl]methyl]benzimidazole-7-carboxylate (0.91 g) in ethanol (13 ml) containing 1N-NaOH (4 ml) was added ethyl iodide (0.34 g), and the mixture was stirred at room temperature for 4 hours. The reaction mixture was adjusted to pH 4 with dilute hydrochloric acid to give crystals. The crystals were collected by filtration and purified by column chromatography on silica gel. Recrystallization from ethyl acetate gave colorless prisms (0.55 g, 57%), m.p. 153°-154° C. (decomp.).
Reaction SMILES: C(N(CC)CC)C.Cl[CH2:9][CH2:10][S:11](Cl)(=[O:13])=[O:12].[F:15][C:16]1[CH:21]=[CH:20][C:19]([F:22])=[CH:18][C:17]=1[C:23]1[CH2:27][NH:26][CH:25]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH:24]=1>ClCCl>[F:15][C:16]1[CH:21]=[CH:20][C:19]([F:22])=[CH:18][C:17]=1[C:23]1[CH2:27][N:26]([S:11]([CH:10]=[CH2:9])(=[O:13])=[O:12])[CH:25]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH:24]=1
Reactant: Fc1ccc(F)c(C2=CC(c3ccccc3)NC2)c1
Reactant: O=S(=O)(Cl)CCCl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C=CS(=O)(=O)N1CC(c2cc(F)ccc2F)=CC1c1ccccc1
Reaction time: 1 h

Procedure:
Triethylamine (122 μL, 0.874 mmol, 5.00 equiv) and 2-chloroethanesulfonyl chloride (29 mg, 0.175 mmol, 1.00 equiv) were added sequentially to a solution of 4-(2,5-difluorophenyl)-2-phenyl-2,5-dihydro-1H-pyrrole (2-4, 45 mg, 0.175 mmol, 1 equiv) in dichloromethane (10 mL) at 23° C., and the resulting mixture was stirred for 1 hour. The reaction mixture was partitioned between saturated aqueous sodium bicarbonate solution (50 mL) and ethyl acetate (2×50 mL). The combined organic layers were dried over sodium sulfate and were concentrated to provide 4-(2,5-difluorophenyl)-2-phenyl-1-(vinylsulfonyl)-2,5-dihydro-1H-pyrrole (8-1) as a brown oil. LRMS m/z (M+H) 348.0 found, 348.1 required.
Reaction SMILES: O.[SH-].[Na+].[CH3:4][C:5]1([CH3:15])[O:9][N:8]=[C:7]([S:10]([CH2:13][CH3:14])(=O)=O)[CH2:6]1.C(=O)([O-])[O-].[K+].[K+].C(S([O-])=O)O.[Na+].BrCC1[C:31]([C:37]([F:40])([F:39])[F:38])=[N:32][N:33]([CH3:36])[C:34]=1[Cl:35]>CN(C)C=O.O>[Cl:35][C:34]1[N:33]([CH3:36])[N:32]=[C:31]([C:37]([F:40])([F:39])[F:38])[C:14]=1[CH2:13][S:10][C:7]1[CH2:6][C:5]([CH3:15])([CH3:4])[O:9][N:8]=1
Reactant: Cn1nc(C(F)(F)F)c(CBr)c1Cl
Reactant: CCS(=O)(=O)C1=NOC(C)(C)C1
Agent: O=C([O-])[O-]
Agent: O=S([O-])CO
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: Cn1nc(C(F)(F)F)c(CSC2=NOC(C)(C)C2)c1Cl
Reaction time: 1 h
Yield: 80.3 %

Procedure:
5.59 g of sodium hydrosulfide hydrate (purity: 70%, 69.8 mmoles) was added, at room temperature, to a solution of 6.84 g (35.8 mmoles) of 5,5-dimethyl-3-ethanesulfonyl-2-isoxazoline dissolved in 200 ml of N,N-dimethylformamide. The mixture was stirred for 1 hour. To the reaction mixture, were added 4.94 g (35.8 mmoles) of anhydrous potassium carbonate, 5.51 g (35.8 mmoles) of Rongalit and further 9.46 g (34.1 mmoles) of 4-bromomethyl-5-chloro-1-methyl-3-trifluoromethyl-1H-pyrazole. The resulting mixture was stirred at room temperature over one night to give rise to a reaction. After confirmation of the completion of the reaction, the reaction mixture was poured into water, followed by extraction with ethyl acetate. The resulting organic layer was washed with water and an aqueous sodium chloride solution in this order and then dried over anhydrous magnesium sulfate. The resulting solution was subjected to vacuum distillation to remove the solvent contained therein. The residue was purified by silica gel column chromatography to obtain 8.97 g (yield: 80.3%) of 3-(5-chloro-1-methyl-3-trifluoromethylpyrazol-4-ylmethylthio)-5,5-dimethyl-2-isoxazoline.
Reaction SMILES: [CH3:1][C:2]1([CH3:20])[C:15]2=[CH:16][CH:17]=[N:18][CH:19]=[C:14]2[C:5]2[C:6]([OH:13])=[CH:7][C:8]([CH:10]([CH3:12])[CH3:11])=[CH:9][C:4]=2[O:3]1.[C:21](OC(=O)C)(=[O:23])[CH3:22]>N1C=CC=CC=1>[C:21]([O:13][C:6]1[C:5]2[C:14]3[C:15]([C:2]([CH3:1])([CH3:20])[O:3][C:4]=2[CH:9]=[C:8]([CH:10]([CH3:12])[CH3:11])[CH:7]=1)=[CH:16][CH:17]=[N:18][CH:19]=3)(=[O:23])[CH3:22]
Reactant: CC(=O)OC(C)=O
Reactant: CC(C)c1cc(O)c2c(c1)OC(C)(C)c1ccncc1-2
Solvent: c1ccncc1
Product: CC(=O)Oc1cc(C(C)C)cc2c1-c1cnccc1C(C)(C)O2

Procedure:
10-Acetoxy-5,5-dimethyl-8-iso-propyl-5H-[1]benzopyrano[3,4-d]pyridine is prepared by reacting 5,5-dimethyl-10-hydroxy-8-iso-propyl-5H-[1]benzopyrano[3,4-d]pyridine and acetic anhydride in the presence of pyridine according to the method of Example 12.