Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3](=[O:19])[CH2:4][N:5]([CH2:11][C:12]1[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=1)[CH:6]1[CH2:10][CH2:9][NH:8][CH2:7]1.N1C(C)=CC=CC=1C.[I-].[K+].Br[CH2:31][CH2:32][CH:33]=[C:34]1[C:40]2[CH:41]=[CH:42][CH:43]=[N:44][C:39]=2[CH2:38][O:37][C:36]2[CH:45]=[CH:46][C:47]([C:49]([OH:52])([CH3:51])[CH3:50])=[CH:48][C:35]1=2>C(O)(C)C>[CH3:1][O:2][C:3](=[O:19])[CH2:4][N:5]([CH2:11][C:12]1[CH:13]=[CH:14][C:15]([Cl:18])=[CH:16][CH:17]=1)[CH:6]1[CH2:10][CH2:9][N:8]([CH2:31][CH2:32][CH:33]=[C:34]2[C:40]3[CH:41]=[CH:42][CH:43]=[N:44][C:39]=3[CH2:38][O:37][C:36]3[CH:45]=[CH:46][C:47]([C:49]([OH:52])([CH3:51])[CH3:50])=[CH:48][C:35]2=3)[CH2:7]1
Reactant: COC(=O)CN(Cc1ccc(Cl)cc1)C1CCNC1
Reactant: CC(C)(O)c1ccc2c(c1)C(=CCCBr)c1cccnc1CO2
Agent: [I-]
Agent: [K+]
Solvent: CC(C)O
Solvent: Cc1cccc(C)n1
Product: COC(=O)CN(Cc1ccc(Cl)cc1)C1CCN(CCC=C2c3cc(C(C)(C)O)ccc3OCc3ncccc32)C1

Procedure:
To a solution of [(4-Chloro-benzyl)-pyrrolidin-3-yl-amino]-acetic acid methyl ester (188 mg, 0.67 mmol) in isopropanol (5 mL) was added 2,6-lutidine (186 uL, 1.6 mmol), and a catalytic amount of potassium iodide. The resultant solution was heated at 80° C. and to it was added 2-[5-(3-Bromo-propylidene)-5,1 1-dihydro-10-oxa-1-aza-dibenzo[a,d]cyclohepten-7-yl]-propan-2-ol (149 mg, 0.4 mmol) portionwise over 0.5 h. The reaction solution was heated overnight then partitioned between water and ethyl acetate. The product was purified on SiO2 (ethyl acetate:methanol:triethylamine 95:4.5:0.4) and isolated as a film. LCMS (retention time=1.84, ES+; 576); 1H NMR (CD3OD): δ 8.46 (1H, d), 7.76 (1H, d), 7.45 (2H, m), 7.23 (5H, m), 6.74 (1H, d), 6.15 (1H, m), 3.72 (2H, m), 3.60 (4H, s), 3.30 (6H, m), 2.78 (4H, m), 2.42 (2H, m), 2.05 (1H, m), 1.82 (1H, m), 1.50 (6H, s)
Reaction SMILES: C[O:2][C:3](=[O:26])[CH2:4][C:5](=[O:25])[CH2:6][C:7]([CH:20]1[CH2:24][CH2:23][CH2:22][CH2:21]1)(O)[CH2:8][CH2:9][C:10]#[C:11][C:12]1[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=1.COC(=O)CC(=O)CC(C1CCCC1)(O)CCC#CC1C=C(C)C(O)=CC=1C>>[CH:20]1([C:7]2([CH2:8][CH2:9][C:10]#[C:11][C:12]3[CH:13]=[CH:14][C:15]([F:18])=[CH:16][CH:17]=3)[O:26][C:3](=[O:2])[CH2:4][C:5](=[O:25])[CH2:6]2)[CH2:21][CH2:22][CH2:23][CH2:24]1
Reactant: COC(=O)CC(=O)CC(O)(CCC#Cc1ccc(F)cc1)C1CCCC1
Agent: COC(=O)CC(=O)CC(O)(CCC#Cc1cc(C)c(O)cc1C)C1CCCC1
Product: O=C1CC(=O)OC(CCC#Cc2ccc(F)cc2)(C2CCCC2)C1

Procedure:
The desired product was prepared analogously to example F(1), substituting 5-cyclopentyl-9-(4-fluoro-phenyl)-5-hydroxy-3-oxo-non-8-ynoic acid methyl ester (400 mg, 1.1 mmol) from Step 2 below in place of 5-cyclopentyl-5-hydroxy-9-(4-hydroxy-2,5-dimethyl-phenyl)-3-oxo-non-8-ynoic acid methyl ester. Yield: 190 mg, 53%. MS (ESI): 327 (M−H).
Reaction SMILES: F[C:2]1C=C2C(=C[CH:11]=1)NC(=O)[C@H](C)N2.[C:14](=[O:40])([O-:39])[O:15][C:16]1[CH:21]=[CH:20][C:19]([S:22]([N:25]2[C:34]3[C:29](=[CH:30][CH:31]=[C:32]([F:35])[CH:33]=3)[NH:28][C:27](=[O:36])[C@@H:26]2[CH2:37]C)(=[O:24])=[O:23])=[CH:18][CH:17]=1>>[C:14](=[O:40])([O:15][C:16]1[CH:21]=[CH:20][C:19]([S:22]([N:25]2[C:34]3[C:29](=[CH:30][CH:31]=[C:32]([F:35])[CH:33]=3)[NH:28][C:27](=[O:36])[C@@H:26]2[CH3:37])(=[O:24])=[O:23])=[CH:18][CH:17]=1)[O:39][CH2:2][CH3:11]
Reactant: C[C@@H]1Nc2cc(F)ccc2NC1=O
Reactant: CC[C@H]1C(=O)Nc2ccc(F)cc2N1S(=O)(=O)c1ccc(OC(=O)[O-])cc1
Product: CCOC(=O)Oc1ccc(S(=O)(=O)N2c3cc(F)ccc3NC(=O)[C@@H]2C)cc1

Procedure:
(3S)-6-Fluoro-3-methyl-3,4-dihydroquinoxalin-2(1H)-one was treated according to the procedure for the preparation of 4-{[(2S)-2-ethyl-7-fluoro-3-oxo-3,4-dihydroquinoxalin-1(2H)-yl]sulfonyl}phenyl carbonate (see Example 20) to yield ethyl 4-{[(2S)-7-fluoro-2-methyl-3-oxo-3,4-dihydroquinoxalin-1(2H)-yl]sulfonyl}phenyl carbonate. MS (ESI) m/z 409 ([M+H]+); MS (ESI) m/z 407 ([M−H]−);
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([OH:8])[C:5]([OH:9])=[C:4]([N+:10]([O-:12])=[O:11])[CH:3]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:20][CH2:21]Br.O>CN(C=O)C>[F:1][C:2]1[CH:3]=[C:4]([N+:10]([O-:12])=[O:11])[C:5]2[O:9][CH2:21][CH2:20][O:8][C:6]=2[CH:7]=1
Reactant: BrCCBr
Reactant: O=[N+]([O-])c1cc(F)cc(O)c1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1cc(F)cc2c1OCCO2
Temperature: 80 °C
Yield: 93 %

Procedure:
A mixture of 5-fluoro-3-nitro-1,2-benzenediol (6.55 g, 37.9 mmol), anhydrous potassium carbonate (21 g, 151.6 mmol) and 1,2-dibromoethane (8.2 mL) in DMF (70 ml) was heated at 80° C. under argon for 5 h. The reaction was cooled to rt, water (200 ml) added and the aqueous phase extracted with ethyl acetate (3×200 ml). The organics were washed with brine, dried, filtered and evaporated to afford the desired compound (6.96 g, 93%).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([Cl:18])=[C:6]([C@:8]2([CH3:17])[C:13]([F:15])([F:14])[CH2:12][O:11][C:10]([NH2:16])=[N:9]2)[CH:7]=1.[C:19]([C:21]1[CH:22]=[CH:23][C:24]([C:27](O)=[O:28])=[N:25][CH:26]=1)#[N:20]>>[NH2:16][C:10]1[O:11][CH2:12][C:13]([F:14])([F:15])[C@:8]([C:6]2[CH:7]=[C:2]([NH:1][C:27]([C:24]3[CH:23]=[CH:22][C:21]([C:19]#[N:20])=[CH:26][N:25]=3)=[O:28])[CH:3]=[CH:4][C:5]=2[Cl:18])([CH3:17])[N:9]=1
Reactant: N#Cc1ccc(C(=O)O)nc1
Reactant: C[C@]1(c2cc(N)ccc2Cl)N=C(N)OCC1(F)F
Product: C[C@]1(c2cc(NC(=O)c3ccc(C#N)cn3)ccc2Cl)N=C(N)OCC1(F)F

Procedure:
The condensation of (R)-4-(5-amino-2-chloro-phenyl)-5,5-difluoro-4-methyl-5,6-dihydro-4H-[1,3]oxazin-2-ylamine (intermediate XI-3) and 5-cyano-pyridine-2-carboxylic acid following procedure I yielded the title compound as an off-white solid. MS (ISP): m/z=406.3 [M+H]+.
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]([CH2:8][N:9]2[CH2:14][CH2:13][N:12](C(OC(C)(C)C)=O)[CH2:11][CH2:10]2)[CH:5]=[CH:4][C:3]=1[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[CH3:28].FC(F)(F)C(O)=O>ClCCl>[CH3:1][C:2]1[N:7]=[C:6]([CH2:8][N:9]2[CH2:10][CH2:11][NH:12][CH2:13][CH2:14]2)[CH:5]=[CH:4][C:3]=1[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[CH3:28]
Reactant: Cc1ccccc1-c1ccc(CN2CCN(C(=O)OC(C)(C)C)CC2)nc1C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1ccccc1-c1ccc(CN2CCNCC2)nc1C
Temperature: 25 °C
Reaction time: 8 h
Yield: 108.5 %

Procedure:
A 100 mL round-bottom flask was charged with tert-butyl 4-[[6-methyl-5-(2-methylphenyl)pyridin-2-yl]methyl]piperazine-1-carboxylate (1.00 g, 2.62 mmol, 1.00 equiv), dichloromethane (20 mL). Trifluoroacetic acid (2.5 mL) was added dropwise at 0° C. The resulting solution was stirred overnight at room temperature and concentrated under reduced pressure to yield 0.800 g (crude) of 1-[[6-methyl-5-(2-methylphenyl)pyridin-2-yl]methyl]piperazine as a yellow solid. LCMS (ESI, m/z): 282 [M+H]+.
Reaction SMILES: [C:1]([O:5][C:6](=[O:27])[NH:7][C:8]1[CH2:9][O:10][CH2:11][C:12]([C:17]2[CH:22]=[C:21]([N:23]=[N+]=[N-])[CH:20]=[CH:19][C:18]=2[F:26])([CH:14]([F:16])[F:15])[N:13]=1)([CH3:4])([CH3:3])[CH3:2]>CCO.C1COCC1.[Pd]>[C:1]([O:5][C:6](=[O:27])[NH:7][C:8]1[CH2:9][O:10][CH2:11][C:12]([C:17]2[CH:22]=[C:21]([NH2:23])[CH:20]=[CH:19][C:18]=2[F:26])([CH:14]([F:16])[F:15])[N:13]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)NC1=NC(c2cc(N=[N+]=[N-])ccc2F)(C(F)F)COC1
Agent: [Pd]
Solvent: CCO
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)NC1=NC(c2cc(N)ccc2F)(C(F)F)COC1

Procedure:
A solution of 4.89 g (12.69 mmol) [5-(5-azido-2-fluoro-phenyl)-5-difluoromethyl-5,6-dihydro-2H-[1,4]oxazin-3-yl]-carbamic acid tert-butyl ester in 64 ml EtOH and 17 ml THF was treated with 1.1 g 10% Pd—C and stirred under an atmosphere of hydrogen until the starting material had been consumed. The mixture was diluted with DCM and filtered over celite. The product was purified by chromatography on silica gel (hexane/25-50% EtOAc) to give the desired product as colorless foam.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH2:17][C:16](=[O:18])[C:15]2[C:10](=[CH:11][CH:12]=[C:13]([O:21][CH3:22])[C:14]=2[O:19]C)[N:9]=1.B(Cl)(Cl)Cl>C(Cl)Cl>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH2:17][C:16](=[O:18])[C:15]2[C:10](=[CH:11][CH:12]=[C:13]([O:21][CH3:22])[C:14]=2[OH:19])[N:9]=1
Reactant: COc1ccc2c(c1OC)C(=O)CC(c1ccccc1F)=N2
Agent: ClB(Cl)Cl
Solvent: ClCCl
Product: COc1ccc2c(c1O)C(=O)CC(c1ccccc1F)=N2
Temperature: 25 °C
Reaction time: 2 h
Yield: 24.1 %

Procedure:
To a solution of 16 (0.2 g, 0.67 mmol) in CH2Cl2 (3 mL) was added 5 mL of BCl3 solution (1 M in CH2Cl2) dropwise at 0°±1° C. The mixture was stirred at 25±1° C. for 2 h and then poured into crushed ice, extracted with EtOAc. The organic layer was washed with H2O, dried over MgSO4 and evaporated. The crude was purified by column chromatography (SiO2, CHCl3: MeOH=15:1) and recrystallized from MeOH to give 37. Yellow solid; yield: 24.1%; mp 268-270° C.; MS (EI, 70 eV): m/z 285 (M+); IR (KBr): 1604.77 (C═O) cm−1; 1H-NMR (DMSO-d6. 200 MHz): δ 3.78 (s, 3H), 6.11 (s, 1H), 7.01 (d, J=7.4 Hz, 1H), 7.36-7.48 (m, 3H), 7.54-7.72 (m, 2H), 12.25 (s, 1H), 14.54 (s, 1H); 13C-NMR (DMSO-d6, 50 MHz): δ 55.80, 106.22, 106.43, 112.88, 116.36 (d, J=23 Hz), 120.81, 121.96 (d, J=13.5 Hz), 125.04, 130.85, 132.67 (d, J=8.6 Hz), 135.09, 141.02, 146.27, 149.29, 158.92 (d, J=247.7 Hz), 181.97; Anal. calcd for C16H12FNO3: C, 67.36; H, 4.24; N, 4.91. Found: C, 67.32; H, 4.26; N, 4.89.
Reaction SMILES: S([O-])([O-])=O.[Na+:5].[Na+].C(=O)(O)[O-].[Na+].O.[Cl:13][C:14]1[CH:19]=[CH:18][C:17]([N+:20]([O-:22])=[O:21])=[CH:16][C:15]=1[S:23](Cl)(=[O:25])=[O:24]>C1(C)C=CC=CC=1>[Cl:13][C:14]1[CH:19]=[CH:18][C:17]([N+:20]([O-:22])=[O:21])=[CH:16][C:15]=1[S:23]([O-:25])=[O:24].[Na+:5]
Reactant: O=[N+]([O-])c1ccc(Cl)c(S(=O)(=O)Cl)c1
Agent: O=C([O-])O
Agent: O=S([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: Cc1ccccc1
Product: O=[N+]([O-])c1ccc(Cl)c(S(=O)[O-])c1
Reaction time: 2 h

Procedure:
321 ml. (4.7 moles) of chlorosulfonic acid and 79 g. (0.5 moles) of 4-chloro-nitrobenzene are stirred at 130° C. for 6 hours. The reaction mixture is then cooled to a temperature below 10° C. and is poured onto 750 ml. of icy water. The mixture is filtered at room temperature and the substance collected on the filter is washed solid-free with about 2 litres of water. The crude 2-chloro-5-nitrobenzene sulfonyl chloride obtained is subjected to the subsequent reaction steps without purification. 118 g. (0.935 moles) of anhydrous sodium sulfite and 20 g. of sodium bicarbonate are dissolved in 250 ml. of water, and to the solution obtained a mixture of the crude 2-chloro-5-nitrobenzene sulfonyl chloride and 20 g. of sodium bicarbonate is added at a temperature of 23° to 25° C., in one hour. The reaction mixture is stirred for two hours at a temperature of 23° to 25° C., and, after the addition of 200 ml. of toluene, for further 15 minutes. The mixture is stirred at 25° C. and the substance filtered off is washed with 100 ml. of toluene. The sodium 2-chloro-5-nitrobenzene sulfinate obtained is dissolved in 400 ml. of water at 40° C., and the solution is admixed with 200 ml. of toluene. The insoluble part is filtered off and the toluene phase is separated from the filtrate. The aqueous phase is cooled to 10° C., acidified with 100 ml. of concentrated aqueous hydrochloric acid solution and the precipitated crystals are stirred, filtered off at 10° C. and dried. 61 g. of 2-chloro-5-nitrobenzene sulfinic acid are obtained. Yield: 55% of theoretical related to 4-chloro-nitrobenzene.
Reaction SMILES: C[O:2][C:3](=[O:12])[C:4]1[CH:9]=[C:8]([Br:10])[C:7](Cl)=[N:6][CH:5]=1.[CH3:13][O:14][CH2:15][CH2:16][NH:17][CH3:18].[OH-].[Na+].Cl.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>N12CCCN=C1CCCCC2>[Br:10][C:8]1[C:7]([N:17]([CH2:16][CH2:15][O:14][CH3:13])[CH3:18])=[N:6][CH:5]=[C:4]([CH:9]=1)[C:3]([OH:2])=[O:12]
Reactant: CNCCOC
Reactant: COC(=O)c1cnc(Cl)c(Br)c1
Agent: Cl
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [Na+]
Solvent: C1CCC2=NCCCN2CC1
Product: COCCN(C)c1ncc(C(=O)O)cc1Br
Temperature: 90 °C
Reaction time: 1 h
Yield: 91.8 %

Procedure:
A suspension of 5-bromo-6-chloro-nicotinic acid methyl ester (1 g) and N-(2-methoxyethyl)methylamine (0.89 g) in 1,8-diazabicyclo[5.4.0]undec-7-ene (1.519 g) was stirred at 60° C. for 3 h and at 90° C. for 1 h. 2 M NaOH (3.99 ml) was added and the mixture was stirred at 90° C. for 15 min. After cooling to room temperature 2 M HCl (3.99 ml) was added. The mixture was acidified using concentrated citric acid solution. The mixture was extracted with ethyl acetate. The org. phase was washed with brine, dried, filtered and concentrated. The product was purified by flash chromatography (SiO2, CH2Cl2=>CH2Cl2/MeOH 4:1) to give 5-bromo-6-[(2-methoxy-ethyl)-methyl-amino]-nicotinic acid (1.06 g) as a white solid.
Reaction SMILES: [Li].[Cl:2][C:3]1[CH:4]=[C:5]([C:10]([O-])=[CH:11][C:12](=O)[C:13]([O:15]CC)=[O:14])[CH:6]=[C:7]([F:9])[CH:8]=1.Cl.[N:21]1[CH:26]=[CH:25][CH:24]=[C:23]([NH:27][NH2:28])[CH:22]=1.ClC1C=C(N2C(C3C=C(OC(F)(F)F)C=C(F)C=3)=CC(C(O)=O)=N2)C=CC=1F>>[Cl:2][C:3]1[CH:4]=[C:5]([C:10]2[N:27]([C:23]3[CH:22]=[N:21][CH:26]=[CH:25][CH:24]=3)[N:28]=[C:12]([C:13]([OH:15])=[O:14])[CH:11]=2)[CH:6]=[C:7]([F:9])[CH:8]=1
Reactant: NNc1cccnc1
Reactant: CCOC(=O)C(=O)C=C([O-])c1cc(F)cc(Cl)c1
Agent: Cl
Agent: O=C(O)c1cc(-c2cc(F)cc(OC(F)(F)F)c2)n(-c2ccc(F)c(Cl)c2)n1
Agent: [Li]
Product: O=C(O)c1cc(-c2cc(F)cc(Cl)c2)n(-c2cccnc2)n1

Procedure:
807 mg (2.90 mmol) of the compound from example 7A is reacted with 464 mg (3.19 mmol) 3-pyridylhydrazine hydrochloride in a manner analogous to the synthesis of the compound from example 8A. Following hydrolysis, 353 mg (38% of theoretical yield) of the title compound is produced.
Reaction SMILES: O[CH2:2][C:3]1[CH:12]=[N:11][C:10]2[N:9]3[CH2:13][CH2:14][CH2:15][C@H:8]3[C:7](=[O:16])[NH:6][C:5]=2[CH:4]=1.[F:17][C:18]1[CH:23]=[C:22]([F:24])[CH:21]=[CH:20][C:19]=1[N:25]1[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]1.[I-].C(C[P+](C)(C)C)#N.C(N(CC)C(C)C)(C)C>C(#N)CC.CS(C)=O>[F:17][C:18]1[CH:23]=[C:22]([F:24])[CH:21]=[CH:20][C:19]=1[N:25]1[CH2:26][CH2:27][N:28]([CH2:2][C:3]2[CH:12]=[N:11][C:10]3[N:9]4[CH2:13][CH2:14][CH2:15][C@H:8]4[C:7](=[O:16])[NH:6][C:5]=3[CH:4]=2)[CH2:29][CH2:30]1
Reactant: O=C1Nc2cc(CO)cnc2N2CCC[C@@H]12
Reactant: Fc1ccc(N2CCNCC2)c(F)c1
Agent: C[P+](C)(C)CC#N
Agent: [I-]
Solvent: CS(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CCC#N
Product: O=C1Nc2cc(CN3CCN(c4ccc(F)cc4F)CC3)cnc2N2CCC[C@@H]12
Temperature: 90 °C
Yield: 23.1 %

Procedure:
(S)-3-(hydroxymethyl)-6a,7,8,9-tetrahydropyrido[3,2-e]pyrrolo[1,2-a]pyrazin-6(5H)-one (150 mg, 0.684 mmol), 1-(2,4-difluorophenyl)piperazine (136 mg, 0.684 mmol), (cyanomethyl)trimethylphosphonium iodide (249 mg, 1.026 mmol) and N,N-diisopropylethylamine (0.597 ml, 3.42 mmol) were suspended in propionitrile (2 ml) and heated in a closed vial at 90° C. for 2 h. The reaction mixture became a clear dark brown solution. It was cooled to room temperature, diluted with DMSO (2 mL) and purified using preparative HPLC (25-95% acetonitrile in water, NH4HCO3 buffered). The fractions containing product were concentrated in vacuo and crystallized from water (3 mL). The precipitate was filtered and dried in vacuum to afford (S)-3-((4-(2,4-difluorophenyl)piperazin-1-yl)methyl)-6a,7,8,9-tetrahydropyrido[3,2-e]pyrrolo[1,2-a]pyrazin-6(5H)-one (63.2 mg, 0.158 mmol, 23.13% yield) as a light brown solid. 1H NMR (400 MHz, DMSO-d6) δ (ppm): 1.84-2.03 (m, 3 H) 2.09-2.26 (m, 1 H) 2.41-2.49 (m, 4 H) 2.88-2.99 (m, 4 H) 3.34-3.43 (m, 3 H) 3.54-3.63 (m, 1 H) 3.94-4.02 (m, 1 H) 6.93-7.09 (m, 3 H) 7.18 (ddd, J=12.44, 9.16, 2.91 Hz, 1 H) 7.61 (d, J=1.77 Hz, 1 H) 10.44 (s, 1 H); [M+H] calc'd for C21H23F2N5O, 400; found, 400.
Reaction SMILES: C(OC([N:8]([S:24]([N:27]1[CH2:32][CH2:31][N:30]([C:33]2[CH:38]=[CH:37][C:36]([Cl:39])=[CH:35][CH:34]=2)[CH2:29][CH2:28]1)(=[O:26])=[O:25])[C@H:9]([CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[C:10]([O:12]C(C)(C)C)=[O:11])=O)(C)(C)C.Cl>C(Cl)Cl>[Cl:39][C:36]1[CH:35]=[CH:34][C:33]([N:30]2[CH2:29][CH2:28][N:27]([S:24]([NH:8][C@H:9]([CH2:17][C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=3)[C:10]([OH:12])=[O:11])(=[O:26])=[O:25])[CH2:32][CH2:31]2)=[CH:38][CH:37]=1
Reactant: CC(C)(C)OC(=O)[C@@H](Cc1ccccc1)N(C(=O)OC(C)(C)C)S(=O)(=O)N1CCN(c2ccc(Cl)cc2)CC1
Agent: Cl
Solvent: ClCCl
Product: O=C(O)[C@@H](Cc1ccccc1)NS(=O)(=O)N1CCN(c2ccc(Cl)cc2)CC1
Temperature: 25 °C
Reaction time: 72 h
Yield: 74 %

Procedure:
A solution of tert-butyl 2-(R)-{tert-butoxycarbonyl-[4-(4-chlorophenyl)piperazine-1-sulfonyl]amino}-3-phenylpropionate (579 mg, 1.15 mmol), [prepared as described in Step 2 above], in methylene chloride (20 ml) was saturated with dry hydrogen chloride gas at 0° C. The reaction vessel was sealed and the reaction mixture was stirred at RT. After 72 h, the reaction mixture was vented with nitrogen and then concentrated in vacuo. The residue was treated with methylene chloride and the product was filtered to give 2-(R)-{[4-(4-chlorophenyl)piperazine-1-sulfonyl]amino}-3-phenylpropionic acid as a white solid (74%), mp 176.0-178.0° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:16]3[C:11](=[CH:12][CH:13]=[C:14]([OH:17])[CH:15]=3)[N:10]([CH3:18])[C:9]=2[CH3:19])=[CH:4][CH:3]=1.Br[C:21]([CH3:26])([CH3:25])[C:22]([OH:24])=[O:23]>C(Cl)(Cl)Cl.CO>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:16]3[C:11](=[CH:12][CH:13]=[C:14]([O:17][C:21]([CH3:26])([CH3:25])[C:22]([OH:24])=[O:23])[CH:15]=3)[N:10]([CH3:18])[C:9]=2[CH3:19])=[CH:4][CH:3]=1
Reactant: Cc1c(-c2ccc(Cl)cc2)c2cc(O)ccc2n1C
Reactant: CC(C)(Br)C(=O)O
Solvent: ClC(Cl)Cl
Solvent: CO
Product: Cc1c(-c2ccc(Cl)cc2)c2cc(OC(C)(C)C(=O)O)ccc2n1C

Procedure:
A mixture of 5.4 g (0.02 mole) of 3-(4-chlorophenyl)-1,2-dimethyl-1H-indole-5-ol, and 5.1 g (0.03 mole) of 2-bromo-2-methyl-propanoic acid was heated for two hours to 90°-130° C. Subsequently the mixture was taken up in chloroform/methanol (8:2) and chromatographed on silicagel. The evaporation residue of the eluate was stirred with cyclohexane and suction filtered.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:28]([F:31])([F:30])[F:29])=[C:6]([CH:27]=1)[CH2:7][N:8]1[CH2:13][CH2:12][NH:11][C:10]2[N:14]=[CH:15][C:16]([C:18]3[CH:26]=[CH:25][C:21]([C:22](O)=[O:23])=[CH:20][CH:19]=3)=[CH:17][C:9]1=2.[NH:32]1[CH2:37][CH2:36][CH:35]([N:38]2[C:42]3[CH:43]=[CH:44][CH:45]=[CH:46][C:41]=3[NH:40][C:39]2=[O:47])[CH2:34][CH2:33]1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:28]([F:31])([F:29])[F:30])=[C:6]([CH:27]=1)[CH2:7][N:8]1[CH2:13][CH2:12][NH:11][C:10]2[N:14]=[CH:15][C:16]([C:18]3[CH:19]=[CH:20][C:21]([C:22]([N:32]4[CH2:33][CH2:34][CH:35]([N:38]5[C:42]6[CH:43]=[CH:44][CH:45]=[CH:46][C:41]=6[NH:40][C:39]5=[O:47])[CH2:36][CH2:37]4)=[O:23])=[CH:25][CH:26]=3)=[CH:17][C:9]1=2
Reactant: O=C(O)c1ccc(-c2cnc3c(c2)N(Cc2cc(Cl)ccc2C(F)(F)F)CCN3)cc1
Reactant: O=c1[nH]c2ccccc2n1C1CCNCC1
Product: O=C(c1ccc(-c2cnc3c(c2)N(Cc2cc(Cl)ccc2C(F)(F)F)CCN3)cc1)N1CCC(n2c(=O)[nH]c3ccccc32)CC1

Procedure:
4-{1-[5-chloro-2-(trifluoromethyl)benzyl]-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl}benzoic acid was reacted with 1,3-dihydro-1-(4-piperidinyl)benzoimidazol-2-one as in General Procedure 10 to give the title compound. LCMS: m/z=647.03 (M+H+); retention time=0.81 minutes.
Reaction SMILES: [CH3:1][C:2]1([CH3:10])[C:5](=[O:6])[C:4]([CH3:8])([CH3:7])[C:3]1=[O:9].[H][H]>>[CH3:7][C:4]1([CH3:8])[CH:5]([OH:6])[C:2]([CH3:10])([CH3:1])[CH:3]1[OH:9]
Reactant: CC1(C)C(=O)C(C)(C)C1=O
Reactant: [H][H]
Product: CC1(C)C(O)C(C)(C)C1O

Procedure:
In one embodiment, the present invention provides processes for producing 2,2,4,4-tetramethylcyclobutane-1,3-diol, comprising contacting 2,2,4,4-tetramethylcyclobutane-1,3-dione, a promoted copper-based catalyst, a non-protic solvent, and hydrogen in a hydrogenation zone under conditions of temperature and pressure sufficient to form 2,2,4,4-tetramethylcyclobutane-1,3-diol. In one such embodiment, the 2,2,4,4-tetramethylcyclobutane-1,3-dione and hydrogen are continuously fed into the hydrogenation zone. In one such embodiment, the hydrogenation zone has a temperature ranging from 75° C. to 250° C. In one such embodiment, the pressure ranges from 689 kPa (100 psi) to 41,368 kPa (6000 psi). In one embodiment, the present invention provides processes for producing 2,2,4,4-tetramethylcyclobutane-1,3-diol, comprising contacting 2,2,4,4-tetramethylcyclobutane-1,3-dione, a promoted copper-based catalyst, a non-protic solvent, and hydrogen in a hydrogenation zone under conditions of temperature and pressure sufficient to form 2,2,4,4-tetramethylcyclobutane-1,3-diol, and further comprising continuously recovering an effluent comprising the 2,2,4,4-tetramethylcyclobutane-1,3-diol and the solvent from the hydrogenation zone. In one such embodiment, the process further comprises continuously recycling a portion of the effluent to the hydrogenation zone. In one such embodiment, the process further comprises continuously recovering the effluent from the hydrogenation zone and recovering at least a portion of the 2,2,4,4-tetramethylcyclobutane-1,3-diol from the effluent to form a depleted 2,2,4,4-tetramethylcyclobutane-1,3-diol stream. In one such embodiment, at least a portion of the depleted 2,2,4,4-tetramethylcyclobutane-1,3-diol stream is recycled to the hydrogenation zone. The term “depleted 2,2,4,4-tetramethylcyclobutane-1,3-diol stream” means that the depleted stream has less 2,2,4,4-tetramethylcyclobutane-1,3-diol in it than the effluent from which the depleted stream is derived. In one such embodiment, the hydrogenation zone comprises a tubular, fixed bed, or trickle bed reactor. In one such embodiment, the hydrogenation zone comprises a stirred tank, a continuous stirred tank, or a slurry reactor. In one such embodiment, the 2,2,4,4-tetramethylcyclobutane-1,3-diol has a cis/trans molar ratio of 1.3 or less. In one such embodiment, the 2,2,4,4-tetramethylcyclobutane-1,3-diol has a cis/trans molar ratio of 0.3 or more.
Reaction SMILES: [O:1]=[CH:2][C@@H:3]([C@H:5]([C@@H:7]([C@@H:9]([CH2:11][OH:12])[OH:10])[OH:8])[OH:6])O.C(=O)(O)[O-].[NH4+].[NH2:18]C1C=C(C(O)=O)C(O)=CC=1.C(Cl)(Cl)Cl>N1C=CC=CC=1.CO>[C@@H:11]1([NH2:18])[O:12][C@H:3]([CH2:2][OH:1])[C@@H:5]([OH:6])[C@H:7]([OH:8])[C@H:9]1[OH:10]
Reactant: Nc1ccc(O)c(C(=O)O)c1
Reactant: O=C[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO
Agent: O=C([O-])O
Agent: [NH4+]
Solvent: c1ccncc1
Solvent: CO
Solvent: ClC(Cl)Cl
Product: N[C@@H]1O[C@H](CO)[C@@H](O)[C@H](O)[C@H]1O

Procedure:
Beta-D-glucosylamine is prepared by the reaction of D-(+)-glucose with ammonium bicarbonate as described by Likhosherstov, L. M. et al. (Carbohydr. Res. 146: C1, 1986). A reaction mixture containing the glycosylamine and a 1- to 2-fold excess by weight of 5-aminosalicylic acid is allowed to react overnight in pyridine at 50° C. The reaction is monitored by thin-layer chromatography (TLC) (silica gel; eluent: CHCl3:MeOH, 1:1, by volume). The solvent is removed, and the reaction mixture is purified by chromatography on silica gel or BIOGEL-F2™ (BioRad, Richmond, Calif.), using absorbance at 254 nm as detection. The products are characterized by TLC on silica gel, electrospray mass spectrometry, and 1H- and 13C-NMR analysis. The transamination reaction is indicated by a downfield shift of resonance of the anomeric proton (observed at δ=4.1 ppm by analysis of the unsubstituted glycosyl-1-amine) to δ=4.3–4.7 ppm in the 1H-NMR spectrum of the β-anomer of the synthetic glycoconjugate product. (This anomer is the major product of the transamination reaction.)
Reaction SMILES: [CH2:1]([N:3]1[CH2:8][CH2:7][C:6](=[N:9]O)[C:5]([F:12])([F:11])[CH2:4]1)[CH3:2].[AlH4-].[Li+]>O1CCCC1>[CH2:1]([N:3]1[CH2:8][CH2:7][CH:6]([NH2:9])[C:5]([F:12])([F:11])[CH2:4]1)[CH3:2]
Reactant: CCN1CCC(=NO)C(F)(F)C1
Agent: [AlH4-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CCN1CCC(N)C(F)(F)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 82.6 %

Procedure:
A solution of 1-ethyl-3,3-difluoro-piperidin-4-one oxime (6.186 g, 34.72 mmol) in tetrahydrofuran (300 ml) was cooled to 0° C. over an ice bath and charged with 1M lithium tetrahydroaluminate in tetrahydrofuran (69.4 ml, 69.4 mmol) and left to stand overnight gradually warming to room temperature. The reaction was quenched with the addition of 1 N aqueous solution of sodium potassium tartrate (70 ml) and left to stir for an additional night. The white slurry was extracted twice with ethyl acetate (50 ml) and twice with dichloromethane (50 ml) and dried over sodium sulfate and concentrated under vacuum to yield 4.71 g 1-ethyl-3,3-difluoro-piperidin-4-ylamine (83%) LCMS (Method F): RT=0.14 min, m+H=179.0 1H NMR (400 MHz, D2O) δ 4.07-3.82 (m, 2H), 3.53 (s, 2H), 3.38 (q, J=7.3 Hz, 2H), 3.13 (s, 2H), 1.38 (t, J=7.3 Hz, 3H).