Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH2:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[N:3]=1.[ClH:15]>[Pt]=O>[ClH:15].[CH:9]1([CH2:8][CH:4]2[NH:3][C:2](=[NH:1])[CH2:7][CH2:6][CH2:5]2)[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]1
Reactant: Nc1cccc(Cc2ccccc2)n1
Agent: O=[Pt]
Agent: Cl
Product: N=C1CCCC(CC2CCCCC2)N1

Procedure:
The 2-amino-6-benzylpyridine was reduced as in Example 94, except platinum oxide was used as the catalyst. The product was obtained as an oil which was dissolved in 1 N HCl and lyophilized to give a white solid. The solid was recrystallized from EtOAc to give the desired title compound as white crystals. The analysis of the product was found to be consistent with the proposed structure.
Reaction SMILES: C([O-])([O-])=O.[Na+].[Na+].Br[C:8]1[CH:13]=[CH:12][N:11]([CH2:14][C:15]([CH3:19])([CH3:18])[CH2:16][OH:17])[C:10](=[O:20])[CH:9]=1.[OH:21][C:22]([CH3:55])([CH3:54])[CH2:23][C@@:24]1([C:48]2[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=2)[O:29][C:28](=[O:30])[N:27]([C@H:31]([C:33]2[CH:38]=[CH:37][C:36](B3OC(C)(C)C(C)(C)O3)=[CH:35][CH:34]=2)[CH3:32])[CH2:26][CH2:25]1>CN(C)C=O>[OH:17][CH2:16][C:15]([CH3:19])([CH3:18])[CH2:14][N:11]1[CH:12]=[CH:13][C:8]([C:36]2[CH:35]=[CH:34][C:33]([C@@H:31]([N:27]3[CH2:26][CH2:25][C@:24]([CH2:23][C:22]([OH:21])([CH3:54])[CH3:55])([C:48]4[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=4)[O:29][C:28]3=[O:30])[CH3:32])=[CH:38][CH:37]=2)=[CH:9][C:10]1=[O:20]
Reactant: CC(C)(CO)Cn1ccc(Br)cc1=O
Reactant: C[C@@H](c1ccc(B2OC(C)(C)C(C)(C)O2)cc1)N1CC[C@](CC(C)(C)O)(c2ccccc2)OC1=O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: C[C@@H](c1ccc(-c2ccn(CC(C)(C)CO)c(=O)c2)cc1)N1CC[C@](CC(C)(C)O)(c2ccccc2)OC1=O
Temperature: 100 °C
Reaction time: 4 h

Procedure:
2 M aqueous Na2CO3 solution (0.32 mL) was added to a mixture of 4-bromo-1-(3-hydroxy-2,2-dimethyl-propyl)-1H-pyridin-2-one (0.13 g) and (S)-6-(2-hydroxy-2-methylpropyl) -6-phenyl-3-[(S)-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)ethyl]-1,3-oxazinan-2-one (0.15 g) in N,N-dimethylformamide (3 mL). The resulting mixture was sparged with argon for 5 min, before [1,1′-bis(diphenylphosphino)-ferrocene]dichloro-palladium(II) dichloromethane complex (26 mg) was added. The mixture was heated to 100° C. and stirred at this temperature for 4 h. After cooling to ambient temperature, water was added and the resulting mixture was extracted with ethyl acetate. The combined organic extracts were washed with water and brine and dried (MgSO4). The solvent was evaporated and the residue was purified by HPLC on reversed phase (methanol/water/NH4OH) to afford the title compound as a beige solid. Yield: 0.10 g (60% of theory); Mass spectrum (ESI+): m/z=533 [M+H]+.
Reaction SMILES: [F:1][C:2]([F:21])([F:20])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:13]([C:14]3[CH:19]=[CH:18][N:17]=[CH:16][CH:15]=3)=[CH:12][NH:11][N:10]=2)=[CH:5][CH:4]=1.[CH2:22]([CH:24]1[O:26][CH2:25]1)Cl.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C.CCOC(C)=O>[O:26]1[CH2:25][CH:24]1[CH2:22][N:11]1[CH:12]=[C:13]([C:14]2[CH:19]=[CH:18][N:17]=[CH:16][CH:15]=2)[C:9]([C:6]2[CH:5]=[CH:4][C:3]([C:2]([F:1])([F:20])[F:21])=[CH:8][CH:7]=2)=[N:10]1
Reactant: FC(F)(F)c1ccc(-c2n[nH]cc2-c2ccncc2)cc1
Reactant: ClCC1CO1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: FC(F)(F)c1ccc(-c2nn(CC3CO3)cc2-c2ccncc2)cc1
Reaction time: 24 h
Yield: 33.1 %

Procedure:
To a solution of 4-[3-(4-trifluoromethyl-phenyl)-1H-pyrazol-4-yl]-pyridine (0.5 g, 1.73 mmol) and epichlorohydrin (1.35 mL, 17.3 mmol) in DMF (2 mL) was added cesium carbonate (0.676 g, 2.07 mmol). The reaction mixture was allowed to stir for 24 h, diluted with EtOAc and washed successively with saturated NaHCO3, water, and brine. The organic layer was dried over Na2SO4, concentrated and partially purified by running through a plug of silica gel (5% acetone/CH2Cl2) to afford 4-[1-oxiranylmethyl-3-(4-trifluoromethyl-phenyl)-1H-pyrazol-4-yl]-pyridine (0.198 g, 33%) as an unstable oil. TLC (silica, 20% acetone/CH2Cl2): Rf=0.39. MS (electrospray): exact mass calculated for C18H14F3N3O, 346.1 [M+H]+, m/z found, 346.1.
Reaction SMILES: [CH3:1][O:2]/[N:3]=[C:4](/[C:25]1[N:26]=[CH:27][S:28][CH:29]=1)\[C:5]([NH:7][CH:8]1[C:23](=[O:24])[N:10]2[C:11]([C:20]([O-:22])=[O:21])=[C:12]([CH2:15][O:16][C:17](=[O:19])[NH2:18])[CH2:13][S:14][C@H:9]12)=[O:6].[Na+].Br[CH:32]1[C:41]2[C:36](=[CH:37][CH:38]=[CH:39][CH:40]=2)[C:34](=[O:35])[O:33]1.Cl.C(OCC)(=O)C>CN(C)C=O>[CH3:1][O:2]/[N:3]=[C:4](/[C:25]1[N:26]=[CH:27][S:28][CH:29]=1)\[C:5]([NH:7][CH:8]1[C:23](=[O:24])[N:10]2[C:11]([C:20]([O:22][CH:32]3[C:41]4[C:36](=[CH:37][CH:38]=[CH:39][CH:40]=4)[C:34](=[O:35])[O:33]3)=[O:21])=[C:12]([CH2:15][O:16][C:17](=[O:19])[NH2:18])[CH2:13][S:14][C@H:9]12)=[O:6]
Reactant: CO/N=C(\C(=O)NC1C(=O)N2C(C(=O)[O-])=C(COC(N)=O)CS[C@H]12)c1cscn1
Reactant: O=C1OC(Br)c2ccccc21
Agent: Cl
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CO/N=C(\C(=O)NC1C(=O)N2C(C(=O)OC3OC(=O)c4ccccc43)=C(COC(N)=O)CS[C@H]12)c1cscn1
Temperature: 25 °C
Reaction time: 1 h
Yield: 36.4 %

Procedure:
Sodium 7-[(Z)-2-methoxyimino-2-(thiazol-4-yl)-acetamido]-3-carbamoyloxymethyl-3-cephem-4-carboxylate (100 mg) was dissolved in dimethylformamide (1 ml). 3-Bromophthalide (69 mg) was added to the solution. After stirring for one hour at room temperature, the reaction mixture was added to a mixture of dil. HCl (10 ml) and ethyl acetate (20 ml). The resulting ethyl acetate layer was separated, washed successively with dil. HCl (10 ml) and saturated aqueous NaCl (10 ml×2), dried over anhydrous magnesium sulfate, and concentrated to dryness under reduced pressure. The residue was dissolved in ethyl acetate (2 ml) and the solution was added dropwise to a petroleum ether-diethyl ether mixture (100 ml) with stirring. Resulting crystals well filtered, and dried under reduced pressure to give the title compound (45 mg).
Reaction SMILES: COC1C=C(OC)C=CC=1C[O:6][N:7]1[C:12](=[O:13])[C:11]2[S:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[C:10]=2[NH:9][C:8]1=[O:21].[CH3:28]I>>[OH:6][N:7]1[C:12](=[O:13])[C:11]2[S:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[C:10]=2[N:9]([CH3:28])[C:8]1=[O:21]
Reactant: COc1ccc(COn2c(=O)[nH]c3c(sc4ccccc43)c2=O)c(OC)c1
Reactant: CI
Product: Cn1c(=O)n(O)c(=O)c2sc3ccccc3c21

Procedure:
3-(2,4-Dimethoxy-benzyloxy)-1H-benzo[4,5]thieno[3,2-d]pyrimidine-2,4-dione was alkylated with methyl iodide according to procedure B2. The crude intermediate was deprotected via general procedure D1 to give the title compound which was purified by mass-triggered preparative HPLC. 1H NMR (d6-DMSO, 300 MHz) δ 3.76 (s, 3H); 7.33 (dd, J=7 Hz, 1H); 7.42 (dd, J=7 Hz, 1H); 7.93 (d, J=8 Hz, 1H); 8.27 (d, J=8 Hz, 1H); Retention time=1.81 min., m/z=249.0.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].N1C=CC=CC=1.[C:18]([C:22]1[CH:30]=[CH:29][C:25]([C:26](Cl)=[O:27])=[CH:24][CH:23]=1)([CH3:21])([CH3:20])[CH3:19]>ClCCl.CN(C)C1C=CN=CC=1>[C:18]([C:22]1[CH:23]=[CH:24][C:25]([C:26]([NH:1][C:2]2[CH:11]=[CH:10][CH:9]=[CH:8][C:3]=2[C:4]([O:6][CH3:7])=[O:5])=[O:27])=[CH:29][CH:30]=1)([CH3:21])([CH3:19])[CH3:20]
Reactant: CC(C)(C)c1ccc(C(=O)Cl)cc1
Reactant: COC(=O)c1ccccc1N
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: c1ccncc1
Product: COC(=O)c1ccccc1NC(=O)c1ccc(C(C)(C)C)cc1
Temperature: 0 °C
Reaction time: 8 h

Procedure:
To a stirring solution of methyl 2-aminobenzoate (5 g, 33.1 mmol) and pyridine (5.3 g, 66 mmol) in dichloromethane (100 mL) was added 4-dimethylaminopyridine (0.2 g, 1.6 mmol). The mixture was cooled to 0° C. and treated with 4-tert-butylbenzoyl chloride (6.5 g, 33.1 mmol). After stirring overnight, the reaction mixture was diluted with dichloromethane (100 mL)and washed twice with 1 M aqueous citric acid (100 mL). The organic layer was then washed sequentially with water (100 mL) and 5 N aqueous HCl. It was dried over MgSO4, filtered and concentrated in vacuo to give 10.68 g (quantitative) of a colorless oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([CH3:13])=[N+:5]([O-:12])[CH:6]=[CH:7][C:8]=1[N+]([O-])=O.[CH3:14][O-:15].[Na+].S(=O)(=O)(O)O>CO>[CH3:1][O:2][C:3]1[C:4]([CH3:13])=[N+:5]([O-:12])[CH:6]=[CH:7][C:8]=1[O:15][CH3:14]
Reactant: COc1c([N+](=O)[O-])cc[n+]([O-])c1C
Reactant: C[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: CO
Product: COc1cc[n+]([O-])c(C)c1OC
Temperature: 40 °C
Reaction time: 16 h
Yield: 88 %

Procedure:
4.5 g (25 mmol) of 3-methoxy-2-methyl-4-nitropyridine 1-oxide are stirred at 40° C. in 75 ml of dry methanol, after addition of 4.7 ml of 30% strength sodium methylate solution, for 16 hours. The mixture is then cooled, brought to pH 7 with concentrated sulfuric acid, filtered and concentrated completely in vacuo, the oily, reddish residue is taken up in 50 ml of toluene, the mixture is filtered again to remove insoluble constituents and the filtrate is concentrated to dryness. The yellow oily residue crystallizes on an ice-bath and is finally extracted by stirring with 30 ml of petroleum ether (50/70) at 40° C. filtration and drying in a desiccator gives 5.2 g (88% of theory) of 3,4-dimethoxy-2-methyl-pyridine 1-oxide in the form of pale yellow crystals of m.p. 111°-113° C.
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3]1.[CH2:11]([O:18][C:19]([N:21]1[C@H:23]([CH3:24])[C@@H:22]1[C:25]([O:27][CH3:28])=[O:26])=[O:20])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.B(F)(F)F.CCOCC>C(Cl)Cl>[CH3:28][O:27][C:25](=[O:26])[C@@H:22]([C@H:23]([CH3:24])[C:4]1[C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[N:2]([CH3:1])[CH:3]=1)[NH:21][C:19]([O:18][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[O:20]
Reactant: COC(=O)[C@H]1[C@@H](C)N1C(=O)OCc1ccccc1
Reactant: Cn1ccc2ccccc21
Agent: FB(F)F
Solvent: ClCCl
Solvent: CCOCC
Product: COC(=O)[C@H](NC(=O)OCc1ccccc1)[C@H](C)c1cn(C)c2ccccc12
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 39.3 %

Procedure:
To a mixture of 1-methylindole (4.26 g) and methyl (2R,3R)-N-benzyloxycarbonyl-3-methyl-2-aziridinecarboxylate (2.70 g) in dry methylene chloride (50 ml) was added boron trifluoride etherate (1.33 ml) under ice-bath cooling. The mixture was stirred for five minutes at ambient temperature and the solvent was evaporated off. The residue was chromatographed on silica gel (chloroform and a 1:1 mixture of hexane and ether as eluent) to give (αR,βR)-N-benzyloxycarbonyl-1,β-dimethyltryptophane methyl ester (1.62 g) as an oil.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:18][C:11]3[N:12]=[C:13]([CH3:17])[NH:14][C:15](=O)[C:10]=3[CH:9]=2)=[CH:4][CH:3]=1.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.C1CCN2C(=NCCC2)CC1.[Cl:57][C:58]1[CH:73]=[CH:72][C:61]([O:62][CH2:63][C:64]([N:66]2[CH2:71][CH2:70][NH:69][CH2:68][CH2:67]2)=[O:65])=[CH:60][CH:59]=1>CC#N>[Cl:57][C:58]1[CH:59]=[CH:60][C:61]([O:62][CH2:63][C:64]([N:66]2[CH2:71][CH2:70][N:69]([C:15]3[C:10]4[CH:9]=[C:8]([C:5]5[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=5)[S:18][C:11]=4[N:12]=[C:13]([CH3:17])[N:14]=3)[CH2:68][CH2:67]2)=[O:65])=[CH:72][CH:73]=1
Reactant: Cc1nc2sc(-c3ccc(F)cc3)cc2c(=O)[nH]1
Reactant: O=C(COc1ccc(Cl)cc1)N1CCNCC1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: C1CCC2=NCCCN2CC1
Solvent: CC#N
Product: Cc1nc(N2CCN(C(=O)COc3ccc(Cl)cc3)CC2)c2cc(-c3ccc(F)cc3)sc2n1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 88.5 %

Procedure:
To a solution of 6-(4-fluorophenyl)-2-methylthieno[2,3-d]pyrimidin-4(3H)-one (40 mg, 0.15 mmol) and BOP (88 mg, 0.20 mmol) in CH3CN (1 ml) was added DBU (34 μl, 0.23 mmol). After stirring for 10 minutes at room temperature, 2-(4-chlorophenoxy)-1-(piperazin-1-yl)ethanone (59 mg, 0.23 mmol) was added. The reaction was stirred at room temperature overnight and then heated at 60° C. for 4 hours. The solvents were removed under reduced pressure, and the crude residue was purified by flash chromatography on silica gel (CH2Cl2/MeOH 100:1) to yield the title compound as a white solid (66 mg, 86%).
Reaction SMILES: [CH2:1]([C:5]1[CH:6]=[C:7]([OH:32])[CH:8]=[CH:9][C:10]=1[O:11][CH2:12][CH2:13][C:14]1[N:15]=[C:16]([C:20]2[CH:21]=[C:22]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[CH:23]=[CH:24][CH:25]=2)[O:17][C:18]=1[CH3:19])[CH2:2][CH2:3][CH3:4].Br[C:34]([CH3:41])([CH3:40])[C:35]([O:37][CH2:38][CH3:39])=[O:36].C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C>[CH2:38]([O:37][C:35](=[O:36])[C:34]([O:32][C:7]1[CH:8]=[CH:9][C:10]([O:11][CH2:12][CH2:13][C:14]2[N:15]=[C:16]([C:20]3[CH:21]=[C:22]([C:26]4[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=4)[CH:23]=[CH:24][CH:25]=3)[O:17][C:18]=2[CH3:19])=[C:5]([CH2:1][CH2:2][CH2:3][CH3:4])[CH:6]=1)([CH3:41])[CH3:40])[CH3:39]
Reactant: CCOC(=O)C(C)(C)Br
Reactant: CCCCc1cc(O)ccc1OCCc1nc(-c2cccc(-c3ccccc3)c2)oc1C
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CCCCc1cc(OC(C)(C)C(=O)OCC)ccc1OCCc1nc(-c2cccc(-c3ccccc3)c2)oc1C
Temperature: 55 °C

Procedure:
A mixture of 3-butyl-4-[2-(5-methyl-2-biphenyl-3-yl-oxazole-4-yl)ethoxy]phenol (0.90 mmol), ethyl 2-bromo-2-methylpropanoate (2.25 mmol) and cesium carbonate (0.45 g, 1.38 mmol) in anhydrous DMF (4 mL) was heated for 24 h at 55° C. The mixture was concentrated in vacuo, and the residue was partitioned between ethyl acetate (50 mL) and water (40 mL), washed with brine, dried (Na2SO4), and removed in vacuo to give a crude oil which was purified using radial chromatography eluting with 2% ethyl acetate/dichloromethane to give 2-{4-[2-(2-biphenyl-3-yl-5-methyloxazol-4-yl)ethoxy]-3-butylphenoxy}-2-methylpropionic acid ethyl ester. 1H NMR (400 MHz, CDCl3) δ8.22 (d, J=1.5 Hz, 1H), 7.95 (dd, J=7.8, 1.5 Hz, 1H), 7.67-7.62 (m, 3H), 7.51-7.44 (m, 3H), 7.37 (t, J=6.8 Hz, 1H), 6.72-6.69 (m, 2H), 6.64 (dd, J=8.8, 2.9 Hz, 1H), 4.25-4.19 (m, 4H), 2.97 (t,J=6.6 Hz, 2H), 2.50 (t, J=7.6 Hz, 2H), 2.38 (s, 3H), 1.52 (s, 6H), 1.51-1.43 (m, 2H), 1.33-1.23 (m, 5H), 0.85 (t, J=7 Hz, 3H); Rf=0.24 (2% ethyl acetate/dichloromethane).
Reaction SMILES: [CH:1]1([CH2:7][C@@H:8]([NH:24][CH3:25])[CH2:9][N:10]2[CH2:15][CH2:14][N:13]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[O:22][CH3:23])[CH2:12][CH2:11]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(N(CC)CC)C.[CH3:33][C:34]1([C:40](Cl)=[O:41])[CH2:39][CH2:38][CH2:37][CH2:36][CH2:35]1>ClCCl>[CH:1]1([CH2:7][C@@H:8]([N:24]([CH3:25])[C:40]([C:34]2([CH3:33])[CH2:39][CH2:38][CH2:37][CH2:36][CH2:35]2)=[O:41])[CH2:9][N:10]2[CH2:15][CH2:14][N:13]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[O:22][CH3:23])[CH2:12][CH2:11]2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: CN[C@H](CC1CCCCC1)CN1CCN(c2ccccc2OC)CC1
Reactant: CC1(C(=O)Cl)CCCCC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1ccccc1N1CCN(C[C@@H](CC2CCCCC2)N(C)C(=O)C2(C)CCCCC2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 100.3 %

Procedure:
To a solution of 0.30 g (0.87 mmol) of {(1R)-1-cyclohexylmethyl-2-[4-(2-methoxyphenyl)-piperazin-1-yl]-ethyl}-methyl-amine and 0.25 mL (1.74 mmol) of triethylamine in 10 mL of dichloromethane at 0° C. was added dropwise 0.21 g (1.31 mmol) of 1-methyl-cyclohexanecarboxylic acid chloride in 4 mL of dichloromethane. The reaction mixture was allowed to stir under nitrogen overnight at ambient temperature, and was then concentrated on a rotary evaporator, diluted with ethyl acetate and washed with aqueous NaHCO3 and brine. The organic phase was dried over anhydrous sodium sulfate, filtered and concentrated on a rotary evaporator to yield the crude product, which was purified by flash chromatography on silica gel (dichloromethane/methanol) and then converted to the dihydrochloride salt of the title compound with ethanolic HCl to yield 0.41 g (86%) of white solid; mp=208-210° C.; MS (+) ESI m/z=470 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([C@@H:8]([NH:18][C:19](=[O:25])[O:20]C(C)(C)C)[C@@H:9]([C:11]2[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=2)O)[C:5]([F:26])=[CH:4][N:3]=1.FC(F)(F)C(O)=O.C(N1C=CN=C1)(N1C=CN=C1)=O>ClCCl>[Br:1][C:2]1[CH:7]=[C:6]([C@@H:8]2[C@@H:9]([C:11]3[CH:12]=[CH:13][C:14]([F:17])=[CH:15][CH:16]=3)[O:20][C:19](=[O:25])[NH:18]2)[C:5]([F:26])=[CH:4][N:3]=1
Reactant: CC(C)(C)OC(=O)N[C@H](c1cc(Br)ncc1F)[C@H](O)c1ccc(F)cc1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C1N[C@H](c2cc(Br)ncc2F)[C@@H](c2ccc(F)cc2)O1
Temperature: 25 °C
Yield: 17.1 %

Procedure:
To a 25 mL round bottom flask was added tert-butyl (1R,2R)-1-(2-bromo-5-fluoropyridin-4-yl)-2-(4-fluorophenyl)-2-hydroxyethylcarbamate (141 mg, 0.328 mmol) in dichloromethane (4 mL). To this solution was added trifluoroacetic acid (0.253 mL, 3.28 mmol) and the reaction was allowed to stir over night at room temperature. The next day the reaction was checked by LC/MS and was complete. The reaction solvent was evaporated in vacuo and the crude oil was diluted with diethylether and washed with saturated sodium bicarbonate. The organic layer was separated, dried over sodium sulfate and the solvent was then evaporated in vacuo and the crude residue was diluted with dry tetrahydrofuran. The solution was cooled to 0° C. and carbonyldiimidazole (53.3 mg, 0.328 mmol) was added and the reaction was allowed to stir overnight. The reaction was complete by LC/MS. The reaction solvent was then evaporated in vacuo and the crude solid was purified by silica gel chromatography 15% EtOAc/85% Hexanes to 50% EtOAc/50% Hexanes affording (4R,5R)-4-(2-bromo-5-fluoropyridin-4-yl)-5-(4-fluorophenyl)oxazolidin-2-one (20 mg, 0.056 mmol, 42.9% yield) and its regioisomer as an inseparable mixture. LC/Mass spec. (Analytical HPLC method 2): RT=1.79 min. Mass=354.89 (MH)+.
Reaction SMILES: [N:1]([C:4]1[CH:13]=[CH:12][CH:11]=[CH:10][C:5]=1[C:6]([O:8]C)=O)=[C:2]=[S:3].[NH2:14][CH2:15][CH:16]([N:18]1[CH2:23][CH2:22][CH:21]([C:24]([C:26]2[CH:31]=[CH:30][C:29]([F:32])=[CH:28][CH:27]=2)=[O:25])[CH2:20][CH2:19]1)[CH3:17]>O1CCCC1>[F:32][C:29]1[CH:28]=[CH:27][C:26]([C:24]([CH:21]2[CH2:20][CH2:19][N:18]([CH:16]([CH3:17])[CH2:15][N:14]3[C:6](=[O:8])[C:5]4[C:4](=[CH:13][CH:12]=[CH:11][CH:10]=4)[NH:1][C:2]3=[S:3])[CH2:23][CH2:22]2)=[O:25])=[CH:31][CH:30]=1
Reactant: CC(CN)N1CCC(C(=O)c2ccc(F)cc2)CC1
Reactant: COC(=O)c1ccccc1N=C=S
Solvent: C1CCOC1
Product: CC(Cn1c(=S)[nH]c2ccccc2c1=O)N1CCC(C(=O)c2ccc(F)cc2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 13 %

Procedure:
A mixture of 6.7 parts of methyl 2-isothiocyanatobenzoate, 8 parts of [1-(2-amino-1-methylethyl)-4-piperidinyl](4-fluorophenyl)methanone and 108 parts of tetrahydrofuran is stirred overnight at room temperature. The reaction mixture is evaporated. The residue is purified twice by column-chromatography over silica gel using first a mixture of trichloromethane and methanol (90:10 by volume) and then a mixture of trichloromethane and methanol (95:5 by volume) as eluent. The pure fractions are collected and the eluent is evaporated. The residue is crystallized twice from 2-propanol, yielding 1.6 parts (13%) of 3-[2-[4-(4-fluorobenzoyl)-1-piperidinyl]propyl]-2,3-dihydro-2-thioxo-4(1H)-quinazolinone; mp. 160.6° C.
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:10](=O)[CH2:11][C:12](=O)[C:13]([F:16])([F:15])[F:14].Cl.[S:20]([C:24]1[CH:29]=[CH:28][C:27]([NH:30][NH2:31])=[CH:26][CH:25]=1)(=[O:23])(=[O:22])[NH2:21]>>[S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:10]1[N:30]([C:27]2[CH:26]=[CH:25][C:24]([S:20]([NH2:21])(=[O:23])=[O:22])=[CH:29][CH:28]=2)[N:31]=[C:12]([C:13]([F:16])([F:15])[F:14])[CH:11]=1
Reactant: O=C(CC(=O)C(F)(F)F)c1nc2ccccc2s1
Reactant: NNc1ccc(S(N)(=O)=O)cc1
Agent: Cl
Product: NS(=O)(=O)c1ccc(-n2nc(C(F)(F)F)cc2-c2nc3ccccc3s2)cc1
Yield: 44 %

Procedure:
The product obtained in Example 7.1), 1-(benzothiazol-2-yl)-4,4,4-trifluorobutane-1,3-dione, was treated with 4-sulfamoylphenylhydrazine hydrochloride in the same manner as in Example 9 to give 4-[5-(benzothiazol-2-yl)-3-trifluoromethyl-1H-pyrazol-1-yl]benzenesulfonamide (yield, 44%).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([C@@H:24]3[CH2:27][C@H:26]([OH:28])[CH2:25]3)[N:9]=[C:10]([C:11]3[CH:16]=[CH:15][C:14]([O:17][C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)=[CH:13][CH:12]=3)[C:3]=12.[N+:29]([C:32]1[CH:40]=[CH:39][C:35]([C:36](O)=[O:37])=[CH:34][CH:33]=1)([O-:31])=[O:30].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>O1CCCC1>[N+:29]([C:32]1[CH:33]=[CH:34][C:35]([C:36]([O:28][C@H:26]2[CH2:25][C@H:24]([N:8]3[C:4]4=[N:5][CH:6]=[N:7][C:2]([NH2:1])=[C:3]4[C:10]([C:11]4[CH:12]=[CH:13][C:14]([O:17][C:18]5[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=5)=[CH:15][CH:16]=4)=[N:9]3)[CH2:27]2)=[O:37])=[CH:39][CH:40]=1)([O-:31])=[O:30]
Reactant: O=C(O)c1ccc([N+](=O)[O-])cc1
Reactant: Nc1ncnc2c1c(-c1ccc(Oc3ccccc3)cc1)nn2[C@H]1C[C@@H](O)C1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: Nc1ncnc2c1c(-c1ccc(Oc3ccccc3)cc1)nn2[C@H]1C[C@H](OC(=O)c2ccc([N+](=O)[O-])cc2)C1

Procedure:
A solution of cis 3-[4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl]-1-cyclobutanol (0.113 g, 0.000302 mol), 4-nitrobenzoic acid (0.101 g, 0.000605 mol) and triphenylphosphine (0.159 g, 0.000605 mol) in tetrahydrofuran (5 mL) was cooled to 0° C. Diethyl azodicarboxylate (0.096 mL, 0.159 g, 0.000605 mol) was added dropwise, keeping the temperature below 10° C. The mixture was allowed to come to room temperature over eighteen hours. The solvent was removed in vacuo and the residue was purified by flash column chromatography on silica using heptane/ethyl acetate (3:1). The solvent was removed in vacuo to give trans 3-[4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl]cyclobutyl 4-nitrobenzoate (0.081 g, 0.000164 mmol) as a tan solid.
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([CH:18]3[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]3)=[CH:7][N:8]2[CH2:11][CH2:12][C:13]2[CH:17]=[CH:16][S:15][CH:14]=2)=[CH:4][CH:3]=1.C([O:26][C:27](=[O:38])[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=1[O:34][CH2:35][CH2:36]Cl)C>>[F:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([CH:18]3[CH2:19][CH2:20][N:21]([CH2:36][CH2:35][O:34][C:29]4[CH:30]=[CH:31][CH:32]=[CH:33][C:28]=4[C:27]([OH:38])=[O:26])[CH2:22][CH2:23]3)=[CH:7][N:8]2[CH2:11][CH2:12][C:13]2[CH:17]=[CH:16][S:15][CH:14]=2)=[CH:4][CH:3]=1
Reactant: Fc1ccc2c(C3CCNCC3)cn(CCc3ccsc3)c2c1
Reactant: CCOC(=O)c1ccccc1OCCCl
Product: O=C(O)c1ccccc1OCCN1CCC(c2cn(CCc3ccsc3)c3cc(F)ccc23)CC1
Yield: 6.5 %

Procedure:
This compound was prepared following the procedure described in example 13 (part D) starting with 0.1 g (0.31 mmol) of 6-fluoro-3-piperidin-4-yl-1-(2-thiophen-3-yl-ethyl)-1H-indole (example 78, part B) and 0.09 g (0.42 mmol) of 2-(2-chloro-ethoxy)-benzoic acid ethyl ester. After purification by HPLC-MS using a C-18 column, 0.01 g (99% of purity) of 2-(2-{4-[6-fluoro-1-(2-thiophen-3-yl-ethyl)-1H-indol-3-yl]-piperidin-1-yl}-ethoxy)-benzoic acid were obtained.
Reaction SMILES: C([C@@H]1COC(=O)N1[C:14]([C@H:16]1[C@H:20]([C:21]2[CH:26]=[CH:25][C:24]([Cl:27])=[C:23]([Cl:28])[CH:22]=2)[CH2:19][N:18]([C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[CH2:17]1)=[O:15])C1C=CC=CC=1.[OH-].[Li+].C(O)(=O)CC(CC(O)=O)(C(O)=O)[OH:41]>C1COCC1>[C:32]([O:31][C:29]([N:18]1[CH2:19][C@@H:20]([C:21]2[CH:26]=[CH:25][C:24]([Cl:27])=[C:23]([Cl:28])[CH:22]=2)[C@H:16]([C:14]([OH:41])=[O:15])[CH2:17]1)=[O:30])([CH3:33])([CH3:34])[CH3:35]
Reactant: CC(C)(C)OC(=O)N1C[C@@H](C(=O)N2C(=O)OC[C@H]2Cc2ccccc2)[C@H](c2ccc(Cl)c(Cl)c2)C1
Reactant: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1C[C@@H](C(=O)O)[C@H](c2ccc(Cl)c(Cl)c2)C1
Reaction time: 60 h
Yield: 81 %

Procedure:
To a solution of the compound (2.5 g) obtained in step 3 in THF (27 mL) was added 4N aqueous lithium hydroxide solution (3.6 mL) at room temperature, and the mixture was stirred for 60 hr. The reaction mixture was made slightly acidic with aqueous citric acid solution, and the resultant product was extracted with ethyl acetate. The organic layer was washed with water and dried, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (solvent; 0→70% ethyl acetate/hexane) to give (3S,4R)-1-(tert-butoxycarbonyl)-4-(3,4-dichlorophenyl)pyrrolidine-3-carboxylic acid (1.41 g, 81%) as a white powder.