Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O:2][C:3](=O)[CH2:4][C:5]1[C:6]([F:16])=[C:7]2[C:12](=[CH:13][C:14]=1[F:15])[N:11]=[CH:10][CH:9]=[CH:8]2.O.[NH2:19][NH2:20]>C(O)C>[F:16][C:6]1[C:5]([CH2:4][C:3]([NH:19][NH2:20])=[O:2])=[C:14]([F:15])[CH:13]=[C:12]2[C:7]=1[CH:8]=[CH:9][CH:10]=[N:11]2
Reactant: COC(=O)Cc1c(F)cc2ncccc2c1F
Reactant: NN
Solvent: O
Solvent: CCO
Product: NNC(=O)Cc1c(F)cc2ncccc2c1F
Temperature: 30 °C
Reaction time: 24 h

Procedure:
To a solution of (5,7-difluoro-quinolin-6-yl)-acetic acid methyl ester (1.023 g, 4.32 mmol) in ethanol (15 mL) was added hydrazine monohydrate (2 mL) and the mixture was stirred at 30° C. for 24 h. The solvent was removed in vacuo to afford 1.024 g of the title compound as white solid, which was used without further purification. 1H-NMR (400 MHz, DMSO-d6) δ ppm 9.33 (s, 1H), 8.97 (d, 1H), 8.46 (d, 1H), 7.67 (d, 1H), 7.61 (dd, 1H), 4.27 (s, 2H). LCMS (method A): [MH]+=238, tR=3.24 min. (5,7-difluoroquinolin-6-yl)-acetic acid methyl ester was synthesized using the method described in WO2008/144767 p 108 (intermediate 2), followed by the method described for Intermediate 12, step 1 WO2008/144767 p 114.
Reaction SMILES: [Si:1]([O:8][CH2:9][C:10]1[CH:15]=[C:14]([C:16]([F:19])([F:18])[F:17])[CH:13]=[CH:12][C:11]=1[CH:20]([CH:22]1[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]1)[OH:21])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[H-].[Na+].[CH3:30]I.O>C1COCC1>[CH:22]1([CH:20]([O:21][CH3:30])[C:11]2[CH:12]=[CH:13][C:14]([C:16]([F:19])([F:18])[F:17])=[CH:15][C:10]=2[CH2:9][O:8][Si:1]([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2])[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27]1
Reactant: CI
Reactant: CC(C)(C)[Si](C)(C)OCc1cc(C(F)(F)F)ccc1C(O)C1CCCCC1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: COC(c1ccc(C(F)(F)F)cc1CO[Si](C)(C)C(C)(C)C)C1CCCCC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 88 %

Procedure:
To a solution of (2-((tert-butyldimethylsilyloxy)methyl)-4-(trifluoromethyl)-phenyl)-(cyclohexyl)-methanol (1.25 g, 3.11 mmol) in THF (5 mL) at 0° C. was added sodium hydride (385 mg, 9.6 mmol). The mixture was stirred at room temperature for 1 hour, cooled to 0° C. and methyl iodide (1.0 mL, 16 mmol) was added. The mixture was stirred at room temperature overnight. Water was added and the mixture was extracted with ethyl acetate. The organic layer was washed with brine, dried over sodium sulfate and concentrated in vacuo. The residue was purified by chromatography over 25+S Biotage silica column (eluted with 0-5% ethyl acetate in heptane) to afford the title compound as a colorless oil (1.14 g, 88%). 1H NMR (400 MHz, CDCl3) δ ppm 0.12 (s, 6H) 0.94-0.96 (m, 9H) 0.98-1.29 (m, 6H) 1.54-1.59 (m, 1H) 1.61-1.67 (m, 2H) 1.71-1.79 (m, 1H) 2.00 (d, J=12.03 Hz, 1H) 3.13 (s, 3H) 4.08 (d, J=7.47 Hz, 1H) 4.71 (d, J=13.69 Hz, 1H) 4.85 (d, J=13.69 Hz, 1H) 7.44 (d, J=8.30 Hz, 1H) 7.52 (d, J=7.88 Hz, 1H) 7.76 (s, 1H).
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([O:10][CH2:11][CH3:12])=[S:9])=[CH:6][N:5]=[C:4]([CH3:13])[N:3]=1.[NH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>C(#N)C>[C:15]1([NH:14][C:2]2[C:7]([C:8]([O:10][CH2:11][CH3:12])=[S:9])=[CH:6][N:5]=[C:4]([CH3:13])[N:3]=2)[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: CCOC(=S)c1cnc(C)nc1Cl
Reactant: Nc1ccccc1
Solvent: CC#N
Product: CCOC(=S)c1cnc(C)nc1Nc1ccccc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 80.5 %

Procedure:
A mixture of ethyl 4-chloro-2-methylthiopyrimidine-5-carboxylate (15 g, 64.5 mmol) and aniline (12 mL, 132 mmol) in 200 mL of acetonitrile was stirred at room temperature for 24 hours. The mixture was then evaporated and ethyl acetate and 2M aqueous hydrochloric acid were added to the residue. The phases were separated and the organic phase was washed with aqueous hydrochloric acid, dried over sodium sulfate, filtered and evaporated. The resulting solid was purified by trituation with 1:3 ether/hexanes to give 14.2 g (64%) of ethyl 4-phenylamino-2-methylthio-pyrimidine-5-carboxylate as a white solid, mp 88.2-88.7° C.
Reaction SMILES: [NH2:1][C:2]1NO[C:5]2[CH:11]=CC=C[C:6]=2[CH:7]=1.F[C:13](F)(F)[C:14](=O)[CH2:15][C:16]([O-:18])=O.S(=O)(=O)(O)O>>[NH:1]1[C:2]2[C:13](=[CH:11][CH:5]=[CH:6][CH:7]=2)[CH:14]=[CH:15][C:16]1=[O:18]
Reactant: O=C([O-])CC(=O)C(F)(F)F
Reactant: NC1=Cc2ccccc2ON1
Agent: O=S(=O)(O)O
Product: O=c1ccc2ccccc2[nH]1

Procedure:
Quinolinones (e.g., Structure 35) are prepared from benzoxazines (e.g., Structure 34) by the synthetic route outlined in Scheme VII. Scheme VII begins with an alkylation of a haloketone onto 2-amino-5-nitrophenol (Structure 1) with, for example, 2-bromobutanone, mediated by a base, for example, potassium carbonate, followed by treatment with a reducing agent, for example, sodium cyanoborohydride, in an acid, for example acetic acid, to afford a benzoxazine compound (e.g., Structure 32). The benzoxazine is alkylated at the benzoxazine nitrogen by treatment of a benzoxazine compound (e.g., Structure 32) with an aldehyde, its corresponding hydrate or hemiacetal, with for example, trifluoroacetaldehyde hydrate in the presence of a reducing agent, for example, sodium cyanoborohydride, in an acid, for example trifluoroacetic acid. This procedure affords an alkylated benzoxazine compound (e.g., Structure 33). The nitro derivative of the alkylated benzoxazine compound (Structure 33) is reduced to the corresponding aniline by catalytic hydrogenation or with a reducing agent, for example, zinc and calcium chloride, to afford benzoxazine compound (e.g., Structure 34). Knorr cyclization of an aminobenzoxazine (e.g., Structure 34) by heating with a β-ketoester or corresponding hydrate, with for example, 4,4,4-trifluoroacetoacetate, followed by treatment with an acid, for example, sulfuric acid, affords a quinolinone product (e.g., Structure 35).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][C:9]([OH:11])=[O:10].[F:12][C:13]1[CH:19]=[CH:18][C:17]([N+:20]([O-:22])=[O:21])=[CH:16][C:14]=1[NH2:15]>>[F:12][C:13]1[CH:19]=[CH:18][C:17]([N+:20]([O-:22])=[O:21])=[CH:16][C:14]=1[NH:15][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][C:9]([OH:11])=[O:10]
Reactant: Nc1cc([N+](=O)[O-])ccc1F
Reactant: O=C(O)Cc1ccccc1Br
Product: O=C(O)Cc1ccccc1Nc1cc([N+](=O)[O-])ccc1F

Procedure:
In the manner described in example 3, 2-bromophenylacetic acid is condensed with 2-fluoro-5-nitroaniline to yield 2-[(2-fluoro-5-nitrophenyl)amino]phenylacetic acid.
Reaction SMILES: Cl.[CH3:2][O:3][C:4]1[CH:5]=[C:6]([C:12]2[C:13]([CH3:25])([CH3:24])[C:14](=[O:23])[N:15]([CH:17]3[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]3)[N:16]=2)[CH:7]=[CH:8][C:9]=1[O:10][CH3:11].[Cl:26][C:27]1[CH:32]=[CH:31][CH:30]=[C:29]([Cl:33])[C:28]=1[S:34](Cl)(=[O:36])=[O:35]>>[Cl:26][C:27]1[CH:32]=[CH:31][CH:30]=[C:29]([Cl:33])[C:28]=1[S:34]([N:20]1[CH2:21][CH2:22][CH:17]([N:15]2[C:14](=[O:23])[C:13]([CH3:25])([CH3:24])[C:12]([C:6]3[CH:7]=[CH:8][C:9]([O:10][CH3:11])=[C:4]([O:3][CH3:2])[CH:5]=3)=[N:16]2)[CH2:18][CH2:19]1)(=[O:36])=[O:35]
Reactant: O=S(=O)(Cl)c1c(Cl)cccc1Cl
Reactant: COc1ccc(C2=NN(C3CCNCC3)C(=O)C2(C)C)cc1OC
Agent: Cl
Product: COc1ccc(C2=NN(C3CCN(S(=O)(=O)c4c(Cl)cccc4Cl)CC3)C(=O)C2(C)C)cc1OC

Procedure:
The title compound is prepared analogously as described for GP1 using 5-(3,4-dimethoxyphenyl)-4,4-dimethyl-2-(piperidin-4-yl)-2,4-dihydro-3H-pyrazol-3-one (compound B1) and 2,6-dichlorobenzenesulfonyl chloride as starting compounds. The crude product is purified by crystallization from EA and diethyl ether to yield the title compound.
Reaction SMILES: [CH2:1]([C:3]1([C:9]([OH:11])=[O:10])[CH2:8][CH2:7][NH:6][CH2:5][CH2:4]1)[CH3:2].[C:12]([CH:16]1[CH2:21][CH2:20][CH:19]([O:22][C:23]2[CH:24]=[C:25]3[C:30](=[CH:31][CH:32]=2)[CH:29]=[C:28]([CH:33]=O)[CH:27]=[CH:26]3)[CH2:18][CH2:17]1)([CH3:15])([CH3:14])[CH3:13].C(O)(=O)C.CO.C([BH3-])#N.[Na+]>>[C:12]([CH:16]1[CH2:21][CH2:20][CH:19]([O:22][C:23]2[CH:24]=[C:25]3[C:30](=[CH:31][CH:32]=2)[CH:29]=[C:28]([CH2:33][N:6]2[CH2:5][CH2:4][C:3]([CH2:1][CH3:2])([C:9]([OH:11])=[O:10])[CH2:8][CH2:7]2)[CH:27]=[CH:26]3)[CH2:18][CH2:17]1)([CH3:15])([CH3:14])[CH3:13]
Reactant: CCC1(C(=O)O)CCNCC1
Reactant: CC(C)(C)C1CCC(Oc2ccc3cc(C=O)ccc3c2)CC1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: CCC1(C(=O)O)CCN(Cc2ccc3cc(OC4CCC(C(C)(C)C)CC4)ccc3c2)CC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 1.7 %

Procedure:
4-ethylpiperidine-4-carboxylic acid (0.184 g, 1.17 mmol) was combined with 6-(4-tert-Butyl-cyclohexyloxy)-naphthalene-2-carbaldehyde (0.3 g, 0.9 mmol), Acetic acid (0.19 mL, 3.4 mmol) in Methanol (1.9 mL, 48 mmol) and stirred for 30 min. The reaction was then cooled to 0° C. on an icebath and sodium cyanoborohydride (90.9 mg, 1.4 mmol) was added. The reaction was then allowed to warm to room temperature while stirring overnight. Reaction was then concentrated to about 4-5 mL then purified directly via reverse phase chromatography (5-95% CH3CN/Water (0.1% TFA), C18, 150 mm). The product was then lyophilized to dryness to give 7 mg 1-[6-(4-tert-Butyl-cyclohexyloxy)-naphthalen-2-ylmethyl]-4-ethyl-piperidine-4-carboxylic acid as a white solid (2%). ESI-MS: 452 (M+1)+. 1H NMR (DMSO-d6, 400 MHz): δ (ppm) 7.75-8.00 (m, 3H), 7.47-7.61 (m, 1H), 7.43 (s, 1H), 7.07-7.28 (m, 1H), 4.44 (m, 3H), 3.29-3.54 (m, 2H), 2.74-3.03 (m, 2H), 2.20 (s, 3H), 1.64-1.98 (m, 3H), 1.02-1.65 (m, 9H), 0.89 (s, 9H), 0.76-0.83 (m, 3H).
Reaction SMILES: C([O:3][C:4](=[O:18])[CH2:5][C@@H:6]([NH:14]C(=O)C)[C@H:7]([CH3:13])[C@H:8]([CH3:12])[CH2:9][CH2:10][CH3:11])C.[ClH:19]>>[ClH:19].[NH2:14][C@@H:6]([C@H:7]([CH3:13])[C@H:8]([CH3:12])[CH2:9][CH2:10][CH3:11])[CH2:5][C:4]([OH:18])=[O:3]
Reactant: CCC[C@@H](C)[C@@H](C)[C@@H](CC(=O)OCC)NC(C)=O
Agent: Cl
Product: CCC[C@@H](C)[C@@H](C)[C@H](N)CC(=O)O
Temperature: 25 °C
Reaction time: 16 h
Yield: 67 %

Procedure:
Under nitrogen, 167 g of crude (3R,4R,5R)-3-acetylamino-4,5-dimethyl-octanoic acid ethyl ester was diluted 1100 mL of 6N HCl, stirred at room temperature for 16 hours, and then heated to reflux for another 24 hours. The reaction mixture was concentrated and recharged with 500 mL of isopropyl alcohol (IPA), which was subsequently removed. Acetonitrile (500 mL) was added to the crude white HCl salt and the mixture stirred at 20° C. to 25° C. for 1 hour. The resulting slurry was filtered, and the solids isolated to give 97 g of the titled compound (67% yield, 89.7% chemical purity; 90.7% chiral purity with two major diastereomers, 6.8% and 1.5%): 1H NMR (CD3OD): δ 0.89t J=7.0 Hz, 3H), 0.94t, J=6.9 Hz, 6H), 1.65-1.0 (m, 4H), 2.61 (dd, J=7.6 Hz, 1H), 2.73 (dd, J=4.6 HZ, 1H), 3.27 (m, J=1.6 Hz, 2H), 3.56 (m, 1H), 4.82 (s, 3H).
Reaction SMILES: [NH2:1][C:2]1[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][C:3]=1[C:4]([C:6]1[CH:11]=[CH:10][C:9]([O:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[CH:8][C:7]=1[O:20][CH3:21])=[O:5].[BH4-].[Na+]>CO>[NH2:1][C:2]1[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][C:3]=1[CH:4]([OH:5])[C:6]1[CH:11]=[CH:10][C:9]([O:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[CH:8][C:7]=1[O:20][CH3:21]
Reactant: COc1cc(OCc2ccccc2)ccc1C(=O)c1cc(Cl)ccc1N
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: COc1cc(OCc2ccccc2)ccc1C(O)c1cc(Cl)ccc1N
Reaction time: 24 h
Yield: 94.5 %

Procedure:
To a solution of 2-amino-4'-benzyloxy-5-chloro-2'-methoxybenzophenone (10 g) in methanol (100 ml) was added sodium borohydride (1.4 g). After being stirred for 24 h, the mixture was concentrated in vacuo. The residue was diluted with water (200 ml) and extracted with ethyl acetate (300 ml). The extract was washed with water, dried over magnesium sulfate and concentrated in vacuo. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=4:1-2:1) to give 2-amino-α-(4-benzyloxy-2-methoxyphenyl)-5-chlorobenzyl alcohol (9.5 g) as colorless crystals (mp=101°-103° C.).
Reaction SMILES: [F:1][C:2]1([C:13]2[CH:18]=[CH:17][C:16]([C:19]3[CH2:23][C:22]([C:28]4[CH:33]=[C:32]([Cl:34])[C:31]([Cl:35])=[C:30]([Cl:36])[CH:29]=4)([C:24]([F:27])([F:26])[F:25])[O:21][N:20]=3)=[CH:15][CH:14]=2)[CH2:5][N:4](C(OC(C)(C)C)=O)[CH2:3]1.FC(F)(F)C(O)=O>C(Cl)Cl>[F:1][C:2]1([C:13]2[CH:18]=[CH:17][C:16]([C:19]3[CH2:23][C:22]([C:28]4[CH:33]=[C:32]([Cl:34])[C:31]([Cl:35])=[C:30]([Cl:36])[CH:29]=4)([C:24]([F:26])([F:27])[F:25])[O:21][N:20]=3)=[CH:15][CH:14]=2)[CH2:3][NH:4][CH2:5]1
Reactant: CC(C)(C)OC(=O)N1CC(F)(c2ccc(C3=NOC(c4cc(Cl)c(Cl)c(Cl)c4)(C(F)(F)F)C3)cc2)C1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: FC1(c2ccc(C3=NOC(c4cc(Cl)c(Cl)c(Cl)c4)(C(F)(F)F)C3)cc2)CNC1
Reaction time: 8 h

Procedure:
To a solution of 250 mg of tert-butyl 3-fluoro-3-(4-(5-(3,4,5-trichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)phenyl)azetidine-1-carboxylate (Preparation 8) in 2 mL CH2Cl2 was added 1 mL of trifluoroacetic acid. The reaction was stirred overnight under a positive pressure of nitrogen. The reaction was concentrated. The residue was partitioned between EtOAc and saturated aqueous NaHCO3. The aqueous layer was extracted 2× with EtOAc (20 mL). The combined organics were dried over Na2SO4 and condensed to yield 188 mg of a film. TLC shows much more polar spot. The crude product was carried on to the next reactions. MS calculated for (C19H13Cl3F4N2O), 466.00; found 467.9 M+H
Reaction SMILES: C(=O)(OC)O[CH2:3]/[CH:4]=[CH:5]/[C:6]1[CH:11]=[CH:10][C:9]([O:12][CH3:13])=[CH:8][CH:7]=1.C1([C@@H]([N:25]([C@H:49]([C:51]2[CH:56]=[CH:55]C=CC=2)C)P2OC3C=CC4C=CC=CC=4C=3C3C4C(C=CC=3O2)=CC=CC=4)C)C=CC=CC=1.C1(NC)CC1.CC1C=CC(S(O)(=O)=O)=CC=1>C1COCC1.CCO>[CH:51]1([CH2:49][NH:25][C@H:5]([C:6]2[CH:11]=[CH:10][C:9]([O:12][CH3:13])=[CH:8][CH:7]=2)[CH:4]=[CH2:3])[CH2:56][CH2:55]1
Reactant: C[C@@H](c1ccccc1)N([C@@H](C)c1ccccc1)p1oc2ccc3ccccc3c2c2c(ccc3ccccc32)o1
Reactant: COC(=O)OC/C=C/c1ccc(OC)cc1
Agent: CNC1CC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCO
Solvent: C1CCOC1
Product: C=C[C@H](NCC1CC1)c1ccc(OC)cc1
Reaction time: 2.5 h
Yield: 839.2 %

Procedure:
A mixture of (2E)-3-(4-methoxyphenyl)prop-2-en-1-yl methyl carbonate (440 mg), N,N-bis[(1S)-1-phenylethyl]dinaphtho[1,2-f:2′,1′-d][1,3,2]dioxaphosphepin-4-amine (108 mg), [Ir(COD)Cl]2 (27 mg), cyclopropyl methyl amine (374 μL) and EtOH (5 mL) was stirred under refluxing EtOH for 6H under N2. The progress of the reaction was monitered by HPLC. At the end of the reaction, addition of co-solvent (20 ml EtOH and 20 ml THF) and MP-TsOH resin (6 g) and the mixture was allowed to stirred at RT with swilling every 15 mins for 2-3 hours. Filtered the resin and washed the resin with plenty of EtOH, THF, DCM. The resin was taken up in 3.5N NH3 in MeOH (20 mL) and let it stir for overnight. Filtered the resin and washed the resin excessively with EtOH, THF and DCM. Combined the filtrate and evaporated all the solvent. The crude product was purified by flash chromatography (10% EtOAc/Hexane) to afford the title compound as a viscous oil (365 mg, 84%). 1H NMR (300 MHz, CDCl3) δ 0.27 (m, 2H), 0.47 (m, 2H), 1.10 (m, 1H), 2.40 (m, 2H), 3.75 (s, 3H), 4.51 (m, 1H), 5.25-5.39 (m, 3H), 6.89-7.06 (m, 4H) (revealed branched/linear ratio (9:1)). MS APCI, m/z=218 (M+1). LC/MS 1.1 min., Method A. 80% ee was determined by NMR in the presence of TFAE-d11.
Reaction SMILES: [CH2:1]([N:5]1[C:13]2[N:12]=[CH:11][N:10]([CH2:14][CH2:15][CH2:16][CH3:17])[C:9]=2[C:8](=[O:18])[NH:7][C:6]1=[O:19])[CH2:2][CH2:3][CH3:4].Br[CH2:21][CH2:22][CH2:23][P:24]([O:29][CH2:30][CH3:31])(=[O:28])[O:25][CH2:26][CH3:27]>>[CH2:1]([N:5]1[C:13]2[N:12]=[CH:11][N:10]([CH2:14][CH2:15][CH2:16][CH3:17])[C:9]=2[C:8](=[O:18])[N:7]([CH2:21][CH2:22][CH2:23][P:24](=[O:28])([O:29][CH2:30][CH3:31])[O:25][CH2:26][CH3:27])[C:6]1=[O:19])[CH2:2][CH2:3][CH3:4]
Reactant: CCOP(=O)(CCCBr)OCC
Reactant: CCCCn1cnc2c1c(=O)[nH]c(=O)n2CCCC
Product: CCCCn1cnc2c1c(=O)n(CCCP(=O)(OCC)OCC)c(=O)n2CCCC

Procedure:
The title substance was prepared from 0.02 mol of 3,7-dibutylxanthine and 0.022 mol of diethyl 3-bromopropanephosphonate analogously to Example 23 and chromatographed on silica gel (eluent: dichloromethane/methanol 20:1).
Reaction SMILES: [Cl:1][C:2]1[N:10]=[C:9]2[C:5]([NH:6][CH:7]=[N:8]2)=[C:4]([NH2:11])[N:3]=1.[Br:12][C:13]1[CH:14]=[C:15]([CH:18]=[CH:19][CH:20]=1)[CH2:16]Br.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.C(OCC)(=O)C>[Br:12][C:13]1[CH:14]=[C:15]([CH:18]=[CH:19][CH:20]=1)[CH2:16][N:8]1[CH:7]=[N:6][C:5]2[C:9]1=[N:10][C:2]([Cl:1])=[N:3][C:4]=2[NH2:11]
Reactant: BrCc1cccc(Br)c1
Reactant: Nc1nc(Cl)nc2nc[nH]c12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: Nc1nc(Cl)nc2c1ncn2Cc1cccc(Br)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 75.5 %

Procedure:
2-Chloroadenine (1.53 g, 9.0 mmol), 3-bromobenzyl bromide (2.48 g, 9.92 mmol), potassium carbonate (1.38 g, 10 mmol) were combined in DMF (10 mL) and stirred at ambient temperature overnight. The mixture was diluted with ethyl acetate (200 mL) and washed with water and brine. The organic layer was dried with Na2SO4 and evaporated to dryness. The residue was triturated with diethyl ether/ethyl acetate 4:1 and filtered giving 9-(3-bromobenzyl)-2-chloro-9H-purin-6-amine (Compound 53) (2.3 g) as off-white solid.
Reaction SMILES: Cl.Cl.[O:3]1[C:7]2[CH:8]=[CH:9][CH:10]=[C:11]([CH:12]3[CH2:17][CH2:16][N:15]([CH2:18][CH2:19][C@H:20]4[CH2:25][CH2:24][C@H:23]([NH2:26])[CH2:22][CH2:21]4)[CH2:14][CH2:13]3)[C:6]=2[CH2:5][CH2:4]1.[CH3:27][S:28]([C:31]1[S:35][C:34]([C:36](O)=[O:37])=[CH:33][CH:32]=1)(=[O:30])=[O:29]>>[O:3]1[C:7]2[CH:8]=[CH:9][CH:10]=[C:11]([CH:12]3[CH2:17][CH2:16][N:15]([CH2:18][CH2:19][C@H:20]4[CH2:21][CH2:22][C@H:23]([NH:26][C:36]([C:34]5[S:35][C:31]([S:28]([CH3:27])(=[O:30])=[O:29])=[CH:32][CH:33]=5)=[O:37])[CH2:24][CH2:25]4)[CH2:14][CH2:13]3)[C:6]=2[CH2:5][CH2:4]1
Reactant: N[C@H]1CC[C@H](CCN2CCC(c3cccc4c3CCO4)CC2)CC1
Reactant: CS(=O)(=O)c1ccc(C(=O)O)s1
Agent: Cl
Product: CS(=O)(=O)c1ccc(C(=O)N[C@H]2CC[C@H](CCN3CCC(c4cccc5c4CCO5)CC3)CC2)s1

Procedure:
The title compound, light yellow solid (107 mg, 83%), MS (ISP) m/z=517.2 [(M+H)+], mp 255° C., was prepared in accordance with the general method of example 1 from trans-4-{2-[4-(2,3-dihydro-benzofuran-4-yl)-piperidin-1-yl]-ethyl}-cyclohexylamine dihydrochloride (intermediate B) (100 mg, 0.25 mmol) and 5-methanesulfonyl-thiophene-2-carboxylic acid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]2[CH:18]=[C:17]3[C:12]([C:13]([OH:24])=[C:14]([C:20](OC)=[O:21])[C:15](=[O:19])[NH:16]3)=[N:11][CH:10]=2)=[C:4]([C:25]([F:28])([F:27])[F:26])[CH:3]=1.[N:29]1([CH2:35][CH2:36][NH2:37])[CH2:34][CH2:33][O:32][CH2:31][CH2:30]1>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]2[CH:18]=[C:17]3[C:12]([C:13]([OH:24])=[C:14]([C:20]([NH:37][CH2:36][CH2:35][N:29]4[CH2:34][CH2:33][O:32][CH2:31][CH2:30]4)=[O:21])[C:15](=[O:19])[NH:16]3)=[N:11][CH:10]=2)=[C:4]([C:25]([F:26])([F:28])[F:27])[CH:3]=1
Reactant: NCCN1CCOCC1
Reactant: COC(=O)c1c(O)c2ncc(Cc3ccc(F)cc3C(F)(F)F)cc2[nH]c1=O
Product: O=C(NCCN1CCOCC1)c1c(O)c2ncc(Cc3ccc(F)cc3C(F)(F)F)cc2[nH]c1=O

Procedure:
This compound was prepared from methyl 7-{[4-fluoro-2-(trifluoromethyl)phenyl]methyl}-4-hydroxy-2-oxo-1,2-dihydro-1,5-naphthyridine-3-carboxylate and [2-(4-morpholinyl)ethyl]amine employing methods similar to those those described in Example 9 and was purified by reverse phase preparative HPLC (C-18 stationary phase; 10-100% CH3CN/water/0.1% formic acid mobile phase). The product was obtained as a white solid: 1H NMR (d6-DMSO) δ 11.72 (1H, s), 10.34 (1H, br t, J=5 Hz), 8.45 (1H, d, J=1.2 Hz), 7.67 (1H, dd, J=9.3, 2.6 Hz), 7.59-7.50 (4H, m), 7.29 (1H, s), 4.29 (2H, s), 3.56 (4H, m), 3.46 (2H, q, J=6 Hz), 2.40 (4H, m); HRMS calcd for C23H22F4N4O4+H+: 495.1655. Found: 495.1659.
Reaction SMILES: ClC(Cl)(Cl)[CH2:3][O:4][C:5]([N:7]([C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)[CH2:8][C:9]([NH:11][CH:12]1[C:29](=[O:30])[N:14]2[CH:15]([C:21]([O:23][CH2:24][C:25]([Cl:28])([Cl:27])[Cl:26])=[O:22])[C:16]([CH3:20])([CH2:18]Br)[S:17][C@H:13]12)=[O:10])=[O:6].N1C=CC=CC=1.[CH:45]([Cl:48])([Cl:47])[Cl:46]>>[Cl:46][C:45]([Cl:48])([Cl:47])[CH2:3][O:4][C:5]([N:7]([C:31]1[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=1)[CH2:8][C:9]([NH:11][CH:12]1[C:29](=[O:30])[N:14]2[C:15]([C:21]([O:23][CH2:24][C:25]([Cl:28])([Cl:26])[Cl:27])=[O:22])=[C:16]([CH3:18])[CH2:20][S:17][C@H:13]12)=[O:10])=[O:6]
Reactant: ClC(Cl)Cl
Reactant: CC1(CBr)S[C@@H]2C(NC(=O)CN(C(=O)OCC(Cl)(Cl)Cl)c3ccccc3)C(=O)N2C1C(=O)OCC(Cl)(Cl)Cl
Solvent: c1ccncc1
Product: CC1=C(C(=O)OCC(Cl)(Cl)Cl)N2C(=O)C(NC(=O)CN(C(=O)OCC(Cl)(Cl)Cl)c3ccccc3)[C@H]2SC1

Procedure:
A mixture of 2,2,2-trichloroethyl 6-[N-(2,2,2-trichloroethoxycarbonyl)phenylglycyl]amino-2-methyl-2-bromomethylpenam-3-carboxylate (0.43 g.), dry pyridine (0.09 g.) and dry chloroform (10 cc) was heated under reflux for 4.5 hours. The chloroform layer was separated, washed with water, dried and then concentrated. The residue was recrystallized from ether to yield needles (0.23 g.) of 2,2,2-trichloroethyl 7-[N-(2,2,2-trichloroethoxycarbonyl)phenylglycyl]amino-3-methyl-3-cephem-4-carboxylate, m.p. 99°-100.5° C.
Reaction SMILES: [NH2:1][CH2:2][C@H:3]1[N:10]([C:11]([C:13]2[N:14]=[C:15]([CH3:25])[S:16][C:17]=2[C:18]2[CH:19]=[C:20]([CH3:24])[CH:21]=[CH:22][CH:23]=2)=[O:12])[CH2:9][C@H:8]2[C@@H:4]1[CH2:5][C:6]([F:27])([F:26])[CH2:7]2.[O:28]1[C:33]2[CH:34]=[CH:35][CH:36]=[C:37]([C:38](O)=[O:39])[C:32]=2[O:31][CH2:30][CH2:29]1>>[F:26][C:6]1([F:27])[CH2:5][C@H:4]2[C@H:8]([CH2:9][N:10]([C:11]([C:13]3[N:14]=[C:15]([CH3:25])[S:16][C:17]=3[C:18]3[CH:19]=[C:20]([CH3:24])[CH:21]=[CH:22][CH:23]=3)=[O:12])[C@@H:3]2[CH2:2][NH:1][C:38]([C:37]2[C:32]3[O:31][CH2:30][CH2:29][O:28][C:33]=3[CH:34]=[CH:35][CH:36]=2)=[O:39])[CH2:7]1
Reactant: O=C(O)c1cccc2c1OCCO2
Reactant: Cc1cccc(-c2sc(C)nc2C(=O)N2C[C@@H]3CC(F)(F)C[C@@H]3[C@H]2CN)c1
Product: Cc1cccc(-c2sc(C)nc2C(=O)N2C[C@@H]3CC(F)(F)C[C@@H]3[C@H]2CNC(=O)c2cccc3c2OCCO3)c1

Procedure:
prepared by reaction of (1S,2S,5R)-(2-aminomethyl-7,7-difluoro-3-aza-bicyclo[3.3.0]-oct-3-yl)-(2-methyl-5-m-tolyl-thiazol-4-yl)-methanone with 2,3-dihydro-benzo[1,4]dioxine-5-carboxylic acid.
Reaction SMILES: [C:1]([C:5]1[O:6][C:7]2[C:13]([S:14](Cl)(=[O:16])=[O:15])=[C:12]([Cl:18])[CH:11]=[CH:10][C:8]=2[N:9]=1)([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[CH3:26][C:27]([O:30][C:31]([NH:33][CH:34]1[CH2:39][CH2:38][NH:37][CH2:36][CH2:35]1)=[O:32])([CH3:29])[CH3:28]>C1COCC1>[C:27]([O:30][C:31](=[O:32])[NH:33][CH:34]1[CH2:39][CH2:38][N:37]([S:14]([C:13]2[C:7]3[O:6][C:5]([C:1]([CH3:4])([CH3:3])[CH3:2])=[N:9][C:8]=3[CH:10]=[CH:11][C:12]=2[Cl:18])(=[O:16])=[O:15])[CH2:36][CH2:35]1)([CH3:29])([CH3:26])[CH3:28]
Reactant: CC(C)(C)c1nc2ccc(Cl)c(S(=O)(=O)Cl)c2o1
Reactant: CC(C)(C)OC(=O)NC1CCNCC1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)NC1CCN(S(=O)(=O)c2c(Cl)ccc3nc(C(C)(C)C)oc23)CC1
Yield: 54 %

Procedure:
Following the general procedure for the synthesis of sulfonylamides outlined in example 51, 2-tert-butyl-6-chloro-benzooxazole-7-sulfonyl chloride (5.05 g, 16.4 mmol), triethylamine (4.57 mL, 32.8 mmol), and 4-N-Boc-aminopiperidine (3.288 g, 16.4 mmol) were reacted in THF (125 mL) to afford the title compound (4.18 g, 54%). 1H NMR (DMSO-d6) • 7.98 (d, 1H, J=8.48 Hz), 7.63 (d, 1H, J=8.47 Hz), 3.73 (d, 2H), 3.35 (bs, 2H), 2.92 (m, 2H), 1.75 (d, 2H), 1.35 (s, 10H).
Reaction SMILES: [Cl:1][C:2]1[CH:23]=[C:22]([OH:24])[CH:21]=[CH:20][C:3]=1[CH2:4][N:5]1[C:9]2=[N:10][C:11]([C:15]([O:17][CH3:18])=[O:16])=[CH:12][C:13]([CH3:14])=[C:8]2[N:7]=[C:6]1[CH3:19].I[CH2:26][CH2:27][CH3:28].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[Cl:1][C:2]1[CH:23]=[C:22]([O:24][CH2:26][CH2:27][CH3:28])[CH:21]=[CH:20][C:3]=1[CH2:4][N:5]1[C:9]2=[N:10][C:11]([C:15]([O:17][CH3:18])=[O:16])=[CH:12][C:13]([CH3:14])=[C:8]2[N:7]=[C:6]1[CH3:19]
Reactant: COC(=O)c1cc(C)c2nc(C)n(Cc3ccc(O)cc3Cl)c2n1
Reactant: CCCI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCCOc1ccc(Cn2c(C)nc3c(C)cc(C(=O)OC)nc32)c(Cl)c1
Temperature: 60 °C
Reaction time: 3 h
Yield: 87.4 %

Procedure:
A mixture of methyl 3-(2-chloro-4-hydroxybenzyl)-2,7-dimethylimidazo[4,5-b]pyridine-5-carboxylate (500 mg), 1-iodopropane (295 mg), potassium carbonate (300 mg) and N,N-dimethylformamide (5.0 ml) was stirred at 60° C. for 3 hr. The reaction mixture was partitioned between ethyl acetate and water, and the organic layer was washed twice with water and once with saturated brine, dried over magnesium sulfate, and concentrated to dryness under reduced pressure. The residue was powdered from diethyl ether to give methyl 3-(2-chloro-4-(1-propoxy)benzyl)-2,7-dimethylimidazo[4,5-b]pyridine-5-carboxylate (490 mg) as a pale-yellow powder.