Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]1[O:9][C:8]2[CH:7]=[CH:6][C:5]([CH:10]3[C:18]4[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=4)[CH:12]([C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)[CH:11]3[C:25]([O-:27])=[O:26])=[CH:4][C:3]=2[O:2]1.C1OC2C=CC(C3C4C(=CC=CC=4)C(C4C=CC=CC=4)=C3C(OCC)=O)=CC=2O1>CCO.[Pd]>[CH2:1]1[O:9][C:8]2[CH:7]=[CH:6][C:5]([CH:10]3[C:18]4[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=4)[CH:12]([C:19]4[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=4)[CH:11]3[C:25]([OH:27])=[O:26])=[CH:4][C:3]=2[O:2]1
Reactant: O=C([O-])C1C(c2ccccc2)c2ccccc2C1c1ccc2c(c1)OCO2
Agent: [Pd]
Agent: CCOC(=O)C1=C(c2ccccc2)c2ccccc2C1c1ccc2c(c1)OCO2
Solvent: CCO
Product: O=C(O)C1C(c2ccccc2)c2ccccc2C1c1ccc2c(c1)OCO2
Reaction time: 8 h
Yield: 65 %

Procedure:
Ethyl (1RS, 2SR, 3SR)-1-(3,4-Methylenedioxyphenyl)-3-phenylindane-2-carboxylate. To a solution of ethyl (RS)-1-(3,4-methylenedioxyphenyl)-3-phenylindene-2-carboxylate (1.00 g, 2.60 mmol) in EtOH (25 ml) was added 10% palladium on activated carbon (30 mg). The resulting suspension was stirred under an atmosphere of H2 overnight. Thin layer chromatographic analysis indicated that the reaction was incomplete, so additional 10% palladium on activated carbon (30 mg) was added, and the mixture was shaken on a Parr hydrogenator at 30 psi H2 for 2 d. At this time, thin layer chromatographic analysis again indicated that the reaction was incomplete. The reaction mixture was filtered through a pad of Celite, and 10% palladium on activated carbon (250 mg) was added. The reaction mixture was shaken on a Parr hydrogenator at 60 psi H2 overnight. Filtration and repetition of the latter hydrogenation conditions led to complete consumption of starting material. The reaction mixture was filtered through a pad of Celite, and the filtrate was concentrated under reduced pressure to afford the title compound (650 mg, 65%), which was used without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C@@H:12]([CH2:16][CH:17]2[CH2:21][CH2:20][CH2:19][CH2:18]2)[C:13]([OH:15])=O)[CH:5]=[CH:6][C:7]=1[S:8]([CH3:11])(=[O:10])=[O:9].C(Cl)(=O)C(Cl)=O.[NH2:28][C:29]1[CH:34]=[CH:33][N:32]=[CH:31][N:30]=1.N1C=CC=CC=1>C(Cl)Cl.CN(C)C=O.O1CCCC1.O>[Cl:1][C:2]1[CH:3]=[C:4]([C@@H:12]([CH2:16][CH:17]2[CH2:21][CH2:20][CH2:19][CH2:18]2)[C:13]([NH:28][C:29]2[CH:34]=[CH:33][N:32]=[CH:31][N:30]=2)=[O:15])[CH:5]=[CH:6][C:7]=1[S:8]([CH3:11])(=[O:9])=[O:10]
Reactant: Nc1ccncn1
Reactant: CS(=O)(=O)c1ccc([C@@H](CC2CCCC2)C(=O)O)cc1Cl
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: C1CCOC1
Solvent: c1ccncc1
Product: CS(=O)(=O)c1ccc([C@@H](CC2CCCC2)C(=O)Nc2ccncn2)cc1Cl
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 42.2 %

Procedure:
A solution of 2(R)-(3-chloro-4-methanesulfonyl-phenyl)-3-cyclopentyl-propionic acid (prepared as in Example 137, 200 mg, 0.61 mmol) in methylene chloride (5 mL) was treated with N,N-dimethylformamide (1 drop) and then cooled to 0° C. The reaction mixture was then treated dropwise with a 2M solution of oxalyl chloride in methylene chloride (0.45 mL, 0.91 mmol) and stirred at 0° C. for 30 min. The reaction mixture was then treated with a solution of 4-aminopyrimidine (115 mg, 1.21 mmol) and pyridine (0.245 mL, 3.03 mmol) in tetrahydrofuran (10 mL). The resulting reaction mixture was allowed to warm to 25° C. where it was stirred for 16 h. The reaction mixture was then diluted with water (10 mL) and extracted with methylene chloride (3×15 mL). The combine organic layers were dried over sodium sulfate, filtered, and concentrated in vacuo. Biotage chromatography (FLASH 40S, Silica, 20/80 hexanes/ethyl acetate) afforded 2(R)-(3-chloro-4-methanesulfonyl-phenyl)-3-cyclopentyl-N-pyrimidin-4-yl-propionamide (105 mg, 43%, 80% R-isomer) as a white foam: [α]23589=−38.0° (c=0.050, chloroform); EI-HRMS m/e calcd for C19H22ClN3O3S (M+) 407.1070, found 407.1072.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]2[CH2:12][CH2:11][C:10](=O)[CH2:9]2)=[CH:4][CH:3]=1.Cl.[F:15][C:16]1[CH:21]=[CH:20][C:19]([C@H:22]([NH2:24])[CH3:23])=[CH:18][C:17]=1[O:25][CH3:26]>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]2[CH2:12][CH2:11][C@H:10]([NH:24][C@@H:22]([C:19]3[CH:20]=[CH:21][C:16]([F:15])=[C:17]([O:25][CH3:26])[CH:18]=3)[CH3:23])[CH2:9]2)=[CH:4][CH:3]=1
Reactant: COc1cc([C@@H](C)N)ccc1F
Reactant: O=C1CC[C@@H](c2ccc(Br)cc2)C1
Agent: Cl
Product: COc1cc([C@@H](C)N[C@H]2CC[C@@H](c3ccc(Br)cc3)C2)ccc1F

Procedure:
General procedure B was followed using (3R)-3-(4-Bromo-phenyl)-cyclopentanone as the ketone and (1R)-1-(4-fluoro-3-methoxyphenyl)ethylamine hydrochloride as the amine. The product was purified by flash chromatography (gradient of 20-80% EtOAc in heptane containing 2.5% NEt3), and the faster eluting peaks were collected to afford the title compound. 1H NMR (300 MHz, CDCl3) δ 7.37 (d, J=8.4 Hz, 2H), 7.10-6.94 (m, 4H), 6.85-6.78 (m, 1H), 3.90 (s, 3H), 3.83 (q, 1H), 3.12-3.00 (m, 1H), 2.96-2.81 (m, 1H), 2.24-2.13 (m, 1H), 2.08-1.91 (m, 2H), 1.80-1.29 (m, 6H).
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH2:13][CH3:14])=[N:4][CH:5]=[CH:6][C:7]=1[NH:8][C:9](=[O:12])[O:10][CH3:11].[H-].[Na+].[F:17][C:18]([F:37])([F:36])[C:19]1[CH:20]=[CH:21][C:22]([O:25][C:26]2[CH:31]=[CH:30][C:29]([CH2:32][C:33](Cl)=[O:34])=[CH:28][CH:27]=2)=[N:23][CH:24]=1.C(=O)([O-])O.[Na+]>CN(C)C(=O)C>[Cl:1][C:2]1[C:3]([CH2:13][CH3:14])=[N:4][CH:5]=[CH:6][C:7]=1[N:8]([C:9]([O:10][CH3:11])=[O:12])[C:33](=[O:34])[CH2:32][C:29]1[CH:28]=[CH:27][C:26]([O:25][C:22]2[CH:21]=[CH:20][C:19]([C:18]([F:17])([F:37])[F:36])=[CH:24][N:23]=2)=[CH:31][CH:30]=1
Reactant: CCc1nccc(NC(=O)OC)c1Cl
Reactant: O=C(Cl)Cc1ccc(Oc2ccc(C(F)(F)F)cn2)cc1
Agent: O=C([O-])O
Agent: [H-]
Agent: [Na+]
Solvent: CC(=O)N(C)C
Product: CCc1nccc(N(C(=O)Cc2ccc(Oc3ccc(C(F)(F)F)cn3)cc2)C(=O)OC)c1Cl
Temperature: 25 °C
Yield: 26.1 %

Procedure:
2.0 g (9.3 mmol) of methyl N-(3-chloro-2-ethylpyridin-4-yl)-carbamate was dissolved in 10 ml of N,N-dimethylacetamide, and the solution was stirred at room temperature. Then, 0.27 g (11.2 mmol) of sodium hydride was gradually added thereto, and the mixture was stirred for one hour at room temperature. Then, 5.5 g (17.4 mmol) of 4-[(5-trifluoromethylpyridin-2-yl)oxy]phenylacetyl chloride was dropwise added thereto at -15° C., and the mixture was stirred for 3 hours at a temperature of from -15° to -10° C. Then, the reaction solution was poured into a sodium hydrogen carbonate solution cooled with ice and extracted with ethyl acetate. The organic layer was washed with water and then dried over anhydrous magnesium sulfate. Then, ethyl acetate was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (developing solvent: n-hexane/ethyl acetate) and further purified by a thin layer chromatography to obtain 1.2 g of the desired product as a white powder (melting point: 62° to 64° C.).
Reaction SMILES: Cl.[CH:2]1([CH2:7][CH:8]([C:19]2[NH:28][C:22]3=[N:23][CH:24]=[C:25]([NH2:27])[CH:26]=[C:21]3[CH:20]=2)[C:9]2[CH:14]=[CH:13][C:12]([S:15]([CH3:18])(=[O:17])=[O:16])=[CH:11][CH:10]=2)[CH2:6][CH2:5][CH2:4][CH2:3]1.Cl.[CH3:30][N:31]([CH3:36])[CH2:32][C:33](O)=[O:34].Cl.C(N=C=NCCCN(C)C)C.ON1C2C=CC=CC=2N=N1.C(N(CC)CC)C>CN(C)C1C=CN=CC=1.ClCCl.CN(C)C=O>[CH:2]1([CH2:7][CH:8]([C:19]2[NH:28][C:22]3=[N:23][CH:24]=[C:25]([NH:27][C:33](=[O:34])[CH2:32][N:31]([CH3:36])[CH3:30])[CH:26]=[C:21]3[CH:20]=2)[C:9]2[CH:14]=[CH:13][C:12]([S:15]([CH3:18])(=[O:17])=[O:16])=[CH:11][CH:10]=2)[CH2:6][CH2:5][CH2:4][CH2:3]1
Reactant: CN(C)CC(=O)O
Reactant: CS(=O)(=O)c1ccc(C(CC2CCCC2)c2cc3cc(N)cnc3[nH]2)cc1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CN(C)CC(=O)Nc1cnc2[nH]c(C(CC3CCCC3)c3ccc(S(C)(=O)=O)cc3)cc2c1
Temperature: 25 °C
Reaction time: 12 h
Yield: 16 %

Procedure:
A mixture of 2-[2-cyclopentyl-1-(4-methanesulfonyl-phenyl)-ethyl]-1H-pyrrolo[2,3-b]pyridin-5-ylamine hydrochloride (0.25 g, 0.6 mmol), N,N-dimethyl glycine hydrochloride (0.13 g, 0.9 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (0.23 g, 1.2 mmol), 1-hydroxybenzotriazole (0.16 g, 1.2 mmol), 4-dimethylaminopyridine (7.3 mg, 0.06 mmol), triethylamine (0.3 g, 3.0 mmol) and N,N-dimethylformamide (2 mL) in dichloromethane (5 mL) was stirred for 12 h at room temperature. The reaction was quenched with water (5 mL), extracted with ethyl acetate (2×10 mL), dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was purified using a Waters automated flash system (column: Xterra 30 mm×100 mm, sample manager 2767, pump 2525, detector: ZQ mass and UV 2487, solvent system: acetonitrile and 0.1% ammonium hydroxide in water) to afford N-{2-[2-cyclopentyl-1-(4-methanesulfonyl-phenyl)-ethyl]-1H-pyrrolo[2,3-b]pyridin-5-yl}-2-dimethylamino-acetamide (45 mg, 16%): LC/MS m/e calcd for C25H32N4O3S [M+H]+ 469.62, observed 469.1; 1H NMR (400 MHz, CDCl3) δ ppm 1.17 (m, 2H), 1.45 (m, 2H), 1.53-1.83 (m, 5H, H), 2.10 (m, 1H), 2.24 (m, 1H), 2.44 (s, 6H), 3.01 (s, 3H), 3.17 (s, 2H), 4.26 (t, J=7.8 Hz, 1H), 6.33 (s, 1H), 7.50 (d, J=8.3 Hz, 2H), 7.84 (d, J=8.3 Hz, 2H), 8.17 (d, J=2.1 Hz, 1H), 8.28 (d, J=2.1 Hz, 1H), 9.19 (s, 1H), 10.96 (s, 1H).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[CH:8]=[C:9]([CH:11]=[CH:12][CH:13]=1)[NH2:10].[Cl:14][C:15]1[CH:20]=[CH:19][C:18]([NH:21][C:22](=[O:29])[CH2:23][O:24][CH2:25][C:26](O)=[O:27])=[C:17]([C:30]([O:32]C)=[O:31])[CH:16]=1>>[Cl:14][C:15]1[CH:20]=[CH:19][C:18]([NH:21][C:22](=[O:29])[CH2:23][O:24][CH2:25][C:26](=[O:27])[NH:10][C:9]2[CH:11]=[CH:12][CH:13]=[C:7]([C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=3)[CH:8]=2)=[C:17]([CH:16]=1)[C:30]([OH:32])=[O:31]
Reactant: Nc1cccc(-c2ccccn2)c1
Reactant: COC(=O)c1cc(Cl)ccc1NC(=O)COCC(=O)O
Product: O=C(COCC(=O)Nc1ccc(Cl)cc1C(=O)O)Nc1cccc(-c2ccccn2)c1

Procedure:
Using the same method as in Example 1-(ii), 3-(pyridin-2-yl)aniline was reacted with the (2-([4-chloro-2-(methoxycarbonyl)phenyl]amino)-2-oxoethoxy)acetic acid obtained in Example 1-(i) to give 5-chloro-2-([(2-oxo-2-([3-(pyridin-2-yl)phenyl]amino)ethoxy)acetyl]amino)benzoic acid.methyl ester (yield: 79%).
Reaction SMILES: Cl.[CH2:2]([O:9][C:10]1[CH:11]=[C:12]([CH:16]([NH2:24])[C:17]2[C:22]([Cl:23])=[N:21][CH:20]=[CH:19][N:18]=2)[CH:13]=[CH:14][CH:15]=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.C1N=CN([C:30](N2C=NC=C2)=[O:31])C=1.CCN(C(C)C)C(C)C>C1COCC1>[CH2:2]([O:9][C:10]1[CH:11]=[C:12]([C:16]2[NH:24][C:30](=[O:31])[N:18]3[CH:19]=[CH:20][N:21]=[C:22]([Cl:23])[C:17]=23)[CH:13]=[CH:14][CH:15]=1)[C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1
Reactant: NC(c1cccc(OCc2ccccc2)c1)c1nccnc1Cl
Reactant: O=C(n1ccnc1)n1ccnc1
Agent: Cl
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: O=c1[nH]c(-c2cccc(OCc3ccccc3)c2)c2c(Cl)nccn12
Temperature: 80 °C

Procedure:
A solution C-(3-benzyloxy-phenyl)-C-(3-chloro-pyrazin-2-yl)-methylamine hydrochloride (5 g, 13.8 mmol) and CDI (2.46 g, 15.19 mmol) in anhydrous THF (70 mL) was charged with DIEA (2.40 mL, 13.8 mmol) and heated to 80° C. for 1 h and then concentrated in vacuo. The crude material was partitioned between EtOAc and H2O and separated. The aqueous layer was washed with EtOAc (3×) and the combined organic layers were washed with brine (1×), dried over Na2SO4, filtered and concentrated in vacuo. The crude was purified by chromatography on silica gel [eluting with 5% MeOH in DCM], to yield the desired product as a yellow solid; 1H NMR (DMSO-d6, 400 MHz) δ 5.17 (s, 2H), 6.86 (d, J=5.2 Hz, 1H), 7.10-7.16 (m, 2H), 7.22-7.23 (m, 1H), 7.34-7.48 (m, 6H), 7.50 (d, J=7.9 Hz, 1H); MS (ES+): m/z=352.15 (100) [MH+], HPLC: tR=3.19 min (MicromassZQ, polar—5 min)
Reaction SMILES: [CH3:1][CH2:2][CH2:3][CH2:4][CH2:5][N:6]([CH2:8][CH2:9][C:10]([P:16]([OH:19])([OH:18])=[O:17])([P:12]([OH:15])([OH:14])=[O:13])[OH:11])[CH3:7].CC(O)CC.[OH-].[Na+:26]>O>[CH3:1][CH2:2][CH2:3][CH2:4][CH2:5][N:6]([CH2:8][CH2:9][C:10]([P:16]([O-:19])([OH:18])=[O:17])([P:12]([OH:15])([OH:14])=[O:13])[OH:11])[CH3:7].[Na+:26]
Reactant: CCCCCN(C)CCC(O)(P(=O)(O)O)P(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCC(C)O
Product: CCCCCN(C)CCC(O)(P(=O)([O-])O)P(=O)(O)O

Procedure:
A solution of amorphous ibandronic acid (4.5 g) in water (20 ml) and 1 N aqueous sodium hydroxide (14 ml) was stirred at room temperature to obtain a pH of 3.5. The solution was added dropwise into 2-butanol (100 ml) while stirring. The obtained precipitate was stirred at room temperature for 16 hours. The precipitate was isolated by vacuum filtration, washed with 2-butanol (2×20 ml), and dried in a vacuum oven at 50° C. for 24 hours to obtain 4.4 g of ibandronate sodium crystal form Q2.
Reaction SMILES: C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C.[I:34][C:35]1[C:39]([C:40]([O:42][CH2:43][CH3:44])=[O:41])=[C:38]([C:45]([O:47][CH2:48][CH3:49])=[O:46])[NH:37][N:36]=1.O[CH2:51][CH:52]([NH:54][C:55](=[O:61])[O:56][C:57]([CH3:60])([CH3:59])[CH3:58])[CH3:53]>C1COCC1.C(OCC)(=O)C>[C:57]([O:56][C:55]([NH:54][CH:52]([CH3:53])[CH2:51][N:37]1[C:38]([C:45]([O:47][CH2:48][CH3:49])=[O:46])=[C:39]([C:40]([O:42][CH2:43][CH3:44])=[O:41])[C:35]([I:34])=[N:36]1)=[O:61])([CH3:60])([CH3:59])[CH3:58]
Reactant: CC(CO)NC(=O)OC(C)(C)C
Reactant: CCOC(=O)c1[nH]nc(I)c1C(=O)OCC
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCOC(=O)c1c(I)nn(CC(C)NC(=O)OC(C)(C)C)c1C(=O)OCC
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 59.7 %

Procedure:
To a stirred suspension of PPh3 (12.41 g, 47.3 mmol) in THF (100 mL) was added DIAD (9.20 mL, 47.3 mmol) at 10° C. and allowed to stir at 0° C. for 0.5 h. Intermediate 104C (8.0 g, 23.66 mmol) was added as a solution in THF (10 mL) at 0° C. and stirred at RT for 45 min. The reaction mixture was cooled again to 0° C. and tert-butyl (1-hydroxypropan-2-yl)carbamate (5.39 g, 30.8 mmol) was added as a solution in THF (10 mL) and the mixture was stirred at RT for 16 h. The reaction mixture was diluted with ethyl acetate (100 mL), washed with water and brine. The organic layer was dried over Na2SO4, filtered and the filtrate concentrated under reduced pressure. The crude compound was purified by silica gel chromatography (40 g REDISEP® column, eluting with 15% EtOAc in hexane). Fractions containing the product were combined and evaporated to afford the Intermediate 340A as a brown liquid (7.0 g) contaminated with impurities arising from the coupling reagents. MS(ES): m/z=496 [M+H]+. The crude intermediate was taken to the next step without further purification.
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:13]2[N:17]([CH3:18])[N:16]=[CH:15][CH:14]=2)=[CH:4][CH:5]=[C:6]2[C:11]=1[C:10](=[O:12])[NH:9][CH2:8][CH2:7]2.[CH2:19]([O:26][C:27]1[C:32]([CH2:33]Cl)=[C:31]([CH3:35])[CH:30]=[C:29]([CH3:36])[N:28]=1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.C[Si]([N-][Si](C)(C)C)(C)C.[K+].O>O1CCOCC1>[CH2:19]([O:26][C:27]1[C:32]([CH2:33][N:9]2[CH2:8][CH2:7][C:6]3[C:11](=[C:2]([Cl:1])[C:3]([C:13]4[N:17]([CH3:18])[N:16]=[CH:15][CH:14]=4)=[CH:4][CH:5]=3)[C:10]2=[O:12])=[C:31]([CH3:35])[CH:30]=[C:29]([CH3:36])[N:28]=1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: Cn1nccc1-c1ccc2c(c1Cl)C(=O)NCC2
Reactant: Cc1cc(C)c(CCl)c(OCc2ccccc2)n1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Product: Cc1cc(C)c(CN2CCc3ccc(-c4ccnn4C)c(Cl)c3C2=O)c(OCc2ccccc2)n1
Yield: 68.4 %

Procedure:
A solution of 8-chloro-7-(1-methyl-1H-pyrazol-5-yl)-3,4-dihydroisoquinolin-1(2H)-one (66b, 48.0, 0.180 mmol), 2-(benzyloxy)-3-(chloromethyl)-4,6-dimethylpyridine (Cpd Z, 71.7 mg, 0.274 mmol), and KHMDS (182 mg, 0.915 mmol) in 1,4-dioxane (5 mL) was heated at 80° C. overnight. To the reaction mixture was added H2O (10 mL), the solution was extracted with EtOAc (10 mL), the organic layer concentrated under vacuum, and the residue purified by prep chromatography to give 2-{[2-(benzyloxy)-4,6-dimethylpyridin-3-yl]methyl}-8-chloro-7-(1-methyl-1H-pyrazol-5-yl)-3,4-dihydroisoquinolin-1(2H)-one (66c, 60 mg, 67%) as a colorless oil.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([S:8][CH2:9][CH3:10])[N:5]([C:11]2[CH:16]=[CH:15][C:14]([O:17][CH2:18][C:19]([F:22])([F:21])[F:20])=[CH:13][CH:12]=2)[C:4](=[O:23])[C:3]=1Br.[SH:25][CH2:26][C:27](O)=[O:28].C(=O)([O-])O.[Na+]>C1(C)C=CC=CC=1>[CH2:9]([S:8][C:6]1[N:5]([C:11]2[CH:16]=[CH:15][C:14]([O:17][CH2:18][C:19]([F:22])([F:21])[F:20])=[CH:13][CH:12]=2)[C:4](=[O:23])[C:3]2[S:25][CH2:26][C:27](=[O:28])[NH:1][C:2]=2[N:7]=1)[CH3:10]
Reactant: O=C(O)CS
Reactant: CCSc1nc(N)c(Br)c(=O)n1-c1ccc(OCC(F)(F)F)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: Cc1ccccc1
Product: CCSc1nc2c(c(=O)n1-c1ccc(OCC(F)(F)F)cc1)SCC(=O)N2

Procedure:
A solution of 6-amino-5-bromo-2-(ethylsulfanyl)-3-[4-(2,2,2-trifluoroethoxy)phenyl]pyrimidin-4(3H)-one (0.1 g) and mercaptoacetic acid (0.168 mL) in toluene (2 mL) was stirred at 170° C. for 2 hr under microwave irradiation. To the reaction mixture was added saturated aqueous sodium hydrogen carbonate solution, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (0.04 g).
Reaction SMILES: [CH3:1][N:2]1[C:11](=[O:12])[C:10]2[C:5](=[CH:6][C:7]([C:13]([OH:15])=O)=[CH:8][CH:9]=2)[N:4]=[CH:3]1.O=S(Cl)[Cl:18]>>[CH3:1][N:2]1[C:11](=[O:12])[C:10]2[C:5](=[CH:6][C:7]([C:13]([Cl:18])=[O:15])=[CH:8][CH:9]=2)[N:4]=[CH:3]1
Reactant: O=S(Cl)Cl
Reactant: Cn1cnc2cc(C(=O)O)ccc2c1=O
Product: Cn1cnc2cc(C(=O)Cl)ccc2c1=O

Procedure:
A solution of 3-methyl-4-oxo-3,4-dihydroquinazoline-7-carboxylic acid (110 mg, 0.54 mmol) in SOCl2 (8 mL) was stirred at reflux for 5 h. The excess SOCl2 was then removed under reduced pressure. The crude 3-methyl-4-oxo-3,4-dihydroquinazoline-7-carbonyl chloride was used without further purification for the next step.
Reaction SMILES: [CH2:1]([C:3]1[CH:9]=[CH:8][CH:7]=[C:6]([CH2:10][CH3:11])[C:4]=1[NH2:5])[CH3:2].CN(C)C=O.[C:17](OC(=O)C)(=[O:19])[CH3:18]>O>[CH3:2][CH2:1][C:3]1[CH:9]=[CH:8][CH:7]=[C:6]([CH2:10][CH3:11])[C:4]=1[NH:5][C:17]([CH3:18])=[O:19]
Reactant: CC(=O)OC(C)=O
Reactant: CCc1cccc(CC)c1N
Solvent: O
Solvent: CN(C)C=O
Product: CCc1cccc(CC)c1NC(C)=O
Reaction time: 1 h

Procedure:
A solution of 74.5 parts of 2,6-diethylaniline in 200 parts of dimethylformamide is treated with 56 parts of acetic anhydride at 10°C. The mixture is stirred at 40° for one hour, poured into ice and water and stirred. The solid 2,6-diethylacetanilide is filtered, washed with water and dried.
Reaction SMILES: [CH2:1]([N:4]([CH2:14][CH:15]=[CH2:16])[CH2:5][C:6]([C:8]1[S:9][C:10]([F:13])=[CH:11][CH:12]=1)=O)[CH:2]=[CH2:3].N1C=CC=CC=1.Cl.[NH2:24][OH:25]>C(O)C>[F:13][C:10]1[S:9][C:8]([C:6](=[N:24][OH:25])[CH2:5][N:4]([CH2:14][CH:15]=[CH2:16])[CH2:1][CH:2]=[CH2:3])=[CH:12][CH:11]=1
Reactant: NO
Reactant: C=CCN(CC=C)CC(=O)c1ccc(F)s1
Agent: Cl
Solvent: CCO
Solvent: c1ccncc1
Product: C=CCN(CC=C)CC(=NO)c1ccc(F)s1
Temperature: 70 °C
Yield: 98.7 %

Procedure:
To a stirred solution of 2-(diallylamino)-1-(5-fluoro-2-thienyl)ethanone (4.051 g, 16.93 mmol) in ethanol (34 mL) under nitrogen is added pyridine (4.8 mL, 59.2 mmol) and hydroxylamine hydrochloride (2.94 g, 42.3 mmol). The mixture is heated to 70° C. for 4 hours. The mixture is allowed to cool and then concentrated under reduced pressure. The residue is diluted with ethyl acetate (100 mL) and water (50 mL). The phases are separated and the aqueous phase extracted with ethyl acetate (50 mL). The combined organic extracts are dried over sodium sulfate, filtered, and concentrated to give the title compound (4.25 g, 99%) (approximately a 1.4:1 mixture of oxime isomers by 1H-NMR (CDCl3). ES/MS (m/e): 255 (M+H).
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[C:12](F)=[C:11]([S:14]([CH3:17])(=[O:16])=[O:15])[CH:10]=[CH:9][C:5]=1[C:6]([OH:8])=[O:7].[OH:18][CH:19]1[CH2:22][O:21][CH2:20]1.O>CN(C)C=O>[Cl:3][C:4]1[C:12]([O:18][CH:19]2[CH2:22][O:21][CH2:20]2)=[C:11]([S:14]([CH3:17])(=[O:16])=[O:15])[CH:10]=[CH:9][C:5]=1[C:6]([OH:8])=[O:7]
Reactant: CS(=O)(=O)c1ccc(C(=O)O)c(Cl)c1F
Reactant: OC1COC1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CS(=O)(=O)c1ccc(C(=O)O)c(Cl)c1OC1COC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 57.5 %

Procedure:
A mixture of 0.76 g (19 mmol) of 60 percent in mineral oil sodium hydride in dry N,N-dimethylformamide was prepared in a flask under a nitrogen blanket and to it was added 2.02 g (8.0 mmol) of 2-chloro-3-fluoro-4-methylsulfonylbenzoic acid in portions with stirring at ambient temperature. The mixture was allowed to cool and then 0.71 g (9.6 mmol) of 3-hydroxyoxetane was added dropwise with stirring. There was an exotherm. After one hour, the reaction appeared to be complete and water was added cautiously. The resulting aqueous solution was extracted with ether and was then acidified with 1N aqueous hydrochloric acid. The resulting mixture was extracted three times with ethyl acetate and the three extracts were combined, washed with water, dried over magnesium sulfate, and concentrated by evaporation under reduced pressure. The residue was crystallized with a mixture of acetone and hexane to obtain 1.41 g of the title compound as white crystals melting at 180-183° C.
Reaction SMILES: [CH2:1]([OH:12])[C@H:2]([C@H:4]([C@@H:6]([C@@H:8]([CH2:10][OH:11])[OH:9])[OH:7])[OH:5])[OH:3].C(O)[C@@H]([C@H]([C@@H](CO)O)O)O>>[O:11]=[CH:10][C@@H:8]([C@H:6]([C@@H:4]([C@@H:2]([CH2:1][OH:12])[OH:3])[OH:5])[OH:7])[OH:9]
Reactant: OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO
Agent: OC[C@@H](O)[C@H](O)[C@@H](O)CO
Product: O=C[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO

Procedure:
A mixture of 7.46 g (41 mmole) of D-mannitol and 6.2 g (41 mmole) of xylitol is heated for 30 minutes to 80° C. with 67.5 g (227 mmole) of BEPDIB. After the readily volatile constituents have been distilled off in vacuo (10-3Torr), 11.6 g (96%) of bp. 108° C./10-3Torr and [α]D20 9.7 (c=6, CCl4) and 9.2 g (91%) of viscous residue are obtained.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]=[CH:3][C:2]=1[C:11](Cl)=[O:12].[CH3:14][CH:15]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[CH2:16][NH2:17]>N1C=CC=CC=1>[CH3:14][CH:15]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[CH2:16][NH:17][C:11]([C:2]1[CH:3]=[N:4][C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[N:1]=1)=[O:12]
Reactant: O=C(Cl)c1cnc2ccccc2n1
Reactant: CC(CN)c1ccccc1
Solvent: c1ccncc1
Product: CC(CNC(=O)c1cnc2ccccc2n1)c1ccccc1
Yield: 69.5 %

Procedure:
Prepared from 2-quinoxaloyl chloride (193 mg, 0.84 mmol), β-methylphenethylamine (103 mg, 0.76 mmol), and pyridine (2 mL) yielding 154 mg (69%) of (131):
Reaction SMILES: [Cl:1][C:2]1[CH:15]=[CH:14][C:13]2[CH:12]3[CH2:16][C:5]([CH:17]=O)([C:6]4[C:11]3=[CH:10][CH:9]=[CH:8][CH:7]=4)[C:4]=2[CH:3]=1.[Cl:19][C:20]1[CH:25]=[CH:24][C:23]([C:26]2([OH:32])[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]2)=[CH:22][CH:21]=1>>[Cl:1][C:2]1[CH:15]=[CH:14][C:13]2[CH:12]3[CH2:16][C:5]([CH2:17][N:29]4[CH2:28][CH2:27][C:26]([C:23]5[CH:24]=[CH:25][C:20]([Cl:19])=[CH:21][CH:22]=5)([OH:32])[CH2:31][CH2:30]4)([C:6]4[C:11]3=[CH:10][CH:9]=[CH:8][CH:7]=4)[C:4]=2[CH:3]=1
Reactant: OC1(c2ccc(Cl)cc2)CCNCC1
Reactant: O=CC12CC(c3ccccc31)c1ccc(Cl)cc12
Product: OC1(c2ccc(Cl)cc2)CCN(CC23CC(c4ccccc42)c2ccc(Cl)cc23)CC1
Yield: 29 %

Procedure:
Using a procedure similar to that described in example 21 except starting with 2-chloro-9-formyl-9,10-dihydro-9,10-methanoanthracene (described in example 1i) and 4-(4-chlorophenyl)-4-hydroxypiperidine, the title compound hydrochloride salt was obtained in 29% yield as a white powder, mp 261°-263° C. elemental