Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([CH2:3][NH2:4])[OH:2].C(O)=O.[CH:8]([C:10](=[N+:16]=[N-:17])[C:11]([O:13][CH2:14][CH3:15])=[O:12])=O>CO>[OH:2][CH2:1][CH2:3][N:4]1[CH:8]=[C:10]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[N:16]=[N:17]1
Reactant: NCCO
Reactant: CCOC(=O)C(C=O)=[N+]=[N-]
Solvent: O=CO
Solvent: CO
Product: CCOC(=O)c1cn(CCO)nn1
Temperature: 25 °C
Reaction time: 48 h
Yield: 74.9 %

Procedure:
A solution of ethanolamine (60 ml, 1 mole) in methanol (320 ml) at 5° was treated with formic acid until a pH of 5 was obtained. A solution of ethyl α-formyldiazoacetate (crude, approximately 0.3 mole) in methanol (320 ml) was then added and the mixture stirred at room temperature for two days. The mixture was then evaporated, chloroform (1 liter), then water (200 ml) was added and the mixture was treated with sodium bicarbonate until a pH of 7 was reached. The phases were separated and the aqueous phase saturated with sodium chloride and extracted with chloroform (6×300 ml). The combined organic phases were dried (MgSO4), filtered and evaporated. The residue was then dissolved in toluene (approximately 100 ml). The resulting crystalline solid was filtered, washed with ether and dried to provide the title compound (41.6 g) as a solid; υmax (nujol) 3320, 3140, 1725 cm-1 ; δ (CDCl3), 1.38 (3H, t, J 7.5 Hz), 4.00-4.80 (7H, m, becomes 6H, m on D2O exch), 8.40 (1H, s). This material was pure enough for further synthetic progression.
Reaction SMILES: [CH3:1][CH:2]1[CH:7]=[C:6]([C:8]([O:10]CC(Cl)(Cl)Cl)=[O:9])[N:5]2[C:16](=[O:31])[CH:17]([NH:18][C:19](=[O:30])[C:20](=[N:27][O:28][CH3:29])[C:21]3[N:22]=[C:23]([NH2:26])[S:24][CH:25]=3)[C@H:4]2[S:3]1.C(O)(=O)C>O1CCCC1.[Zn]>[CH3:1][CH:2]1[CH:7]=[C:6]([C:8]([OH:10])=[O:9])[N:5]2[C:16](=[O:31])[CH:17]([NH:18][C:19](=[O:30])[C:20](=[N:27][O:28][CH3:29])[C:21]3[N:22]=[C:23]([NH2:26])[S:24][CH:25]=3)[C@H:4]2[S:3]1
Reactant: CON=C(C(=O)NC1C(=O)N2C(C(=O)OCC(Cl)(Cl)Cl)=CC(C)S[C@H]12)c1csc(N)n1
Agent: CON=C(C(=O)NC1C(=O)N2C(C(=O)OCC(Cl)(Cl)Cl)=CC(C)S[C@H]12)c1csc(=N)[nH]1
Agent: [Zn]
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: CON=C(C(=O)NC1C(=O)N2C(C(=O)O)=CC(C)S[C@H]12)c1csc(N)n1

Procedure:
To a solution of 2,2,2-trichloroethyl 2-methyl-7-[2-methoxyimino-2-(2-aminothiazol-4-yl)acetamido]-3-cephem-4-carboxylate (syn isomer), which can be represented as 2,2,2-trichloroethyl 2-methyl-7-[2-methoxyimino-2-(2-imino-2,3-dihydrothiazol-4-yl)acetamido]-3-cephem-4-carboxylate (syn isomer), (0.1 g.) in tetrahydrofuran (2 ml.) and glacial acetic acid (0.25 ml.) was added zinc powder (0.1 g.) all at once with stirring at keeping the temperature below 25° C. in an ice-bath and then the mixture was stirred for 1 hour at room temperatures. To the reaction mixture was further added zinc powder (0.1 g.) and the mixture was stirred for 1 hour at the same temperature. The reaction mixture was filtered, and the insoluble material was washed with a small amount of tetrahydrofuran. After the filtrate and the washing were combined together, the solvents were distilled off. To the residue were added 5% aqueous sodium bicarbonate solution and ethyl acetate so that the aqueous layer became pH 7 to 8, and the mixture was filtered, and then the aqueous layer was separated. The aqueous layer was adjusted to pH 2 to 3 with 2 N hydrochloric acid and then concentrated slightly. Thus obtained aqueous layer was subjected to column chromatography (non-ionic adsorption resin, Diaion HP 20 prepared by Mitsubishi Chemical Industries) and the column was washed with water and then eluted with 20% methanol and 40% methanol in turn. The eluates containing the object compound were collected and then lyophilized to give white powder of 2-methyl-7-[2-methoxyimino-2-(2-aminothiazol-4-yl)acetamido]-3-cephem-4-carboxylic acid (syn isomer), which can be represented as 2-methyl-7-[2-methoxyimino-2-(2-imino-2,3-dihydrothiazol-4-yl)acetamido]-3-cephem-4-carboxylic acid (syn isomer), (0.015 g.), mp 230° to 235° C. (dec.).
Reaction SMILES: CC[O-].[Na+].[CH3:5][C:6]1[CH:7]=[C:8]([CH:11]=O)[S:9][CH:10]=1.[C:13]([O:22]CC)(=[O:21])[CH2:14][CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17]>C(O)C>[CH2:19]([O:18][C:16]([C:15](=[CH:11][C:8]1[S:9][CH:10]=[C:6]([CH3:5])[CH:7]=1)[CH2:14][C:13]([OH:22])=[O:21])=[O:17])[CH3:20]
Reactant: CCOC(=O)CCC(=O)OCC
Reactant: Cc1csc(C=O)c1
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Product: CCOC(=O)C(=Cc1cc(C)cs1)CC(=O)O
Yield: 42.9 %

Procedure:
Sodium ethylate (71 g, 1.05 mol) was added under vigorous stirring to a solution of 4-methylthiopene-2-carbaldehyde (88 g, 80% purity, 0.56 mol) and diethyl succinate (183 g, 1.05 mol) in ethanol (1 L). The reaction mixture was refluxed for 3 h and evaporated in vacuum (˜20 mmHg) at 50° C. until the solvent distillation ceased. The obtained residue was diluted with 500 mL of 10% HCl and 500 mL of ethyl acetate. The mixture was shaken. The organic layer was separated, diluted with 1 L of a saturated aqueous solution of NaHCO3, and shaken. The aqueous layer was separated, neutralized by 10% HCl to pH 2, and subjected to extraction by 1 L of ethyl acetate. The organic layer was evaporated in vacuum (˜20 mmHg) at 60° C. and chromatographed on a layer of silica gel (300×150 mm) with hexane/ethyl acetate mixture, 1:1 as eluent. Fractions with the target product were collected and evaporated in vacuum to give the desired product 61 g (0.24 mol, 43%) as yellow crystals.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[CH3:7][N:8]([CH3:20])[CH:9]1[C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=2[NH:13][CH2:12][CH2:11][CH2:10]1.[Cl:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[CH2:28][C:29]([NH:31][C:32]1[CH:40]=[CH:39][C:35]([C:36](Cl)=[O:37])=[CH:34][CH:33]=1)=[O:30]>CC(C)=O.O>[CH3:7][N:8]([CH3:20])[CH:9]1[C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=2[N:13]([C:36](=[O:37])[C:35]2[CH:39]=[CH:40][C:32]([NH:31][C:29](=[O:30])[CH2:28][C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=3[Cl:21])=[CH:33][CH:34]=2)[CH2:12][CH2:11][CH2:10]1
Reactant: O=C(Cc1ccccc1Cl)Nc1ccc(C(=O)Cl)cc1
Reactant: CN(C)C1CCCNc2ccccc21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC(C)=O
Product: CN(C)C1CCCN(C(=O)c2ccc(NC(=O)Cc3ccccc3Cl)cc2)c2ccccc21
Yield: 99.6 %

Procedure:
38.8 g of potassium carbonate was added to a solution of 50 g of 5-dimethylamino-2,3,4,5-tetrahydro-1H-benzoazepine dissolved in 400 ml of acetone and 200 ml of water. To the mixture was added 66.5 g of 4-[2-(2-chloro-phenyl)acetylamino]benzoyl chloride with ice-cooling and stirring. The mixture was stirred overnight at room temperature. The reaction mixture was mixed with water, followed by extraction with dichloromethane. The dichloromethane layer was dried over magnesium sulfate and then subjected to vacuum distillation to remove the solvent. The residue was purified by silica gel column chromatography and then recrystallized from methanol to obtain 99.3 g of 5-dimethylamino-1-{4-[2-(2-chlorophenyl)acetylamino]benzoyl}-2,3,4,5-tetrahydro-1H-benzoazepine.
Reaction SMILES: [CH2:1]([N:3]1[C:7]2=[N:8][C:9]([CH2:61][CH3:62])=[C:10]([CH2:19][NH:20][C:21]([C:23]3[CH:24]=[C:25]([C:29]([NH:31][CH2:32][C:33]4[C:34]([F:60])=[C:35]([C:39]5[CH:44]=[CH:43][CH:42]=[C:41]([CH2:45][N:46]6[CH2:51][CH2:50][N:49](C(OC(C)(C)C)=O)[C@@H:48]([CH3:59])[CH2:47]6)[CH:40]=5)[CH:36]=[CH:37][CH:38]=4)=[O:30])[CH:26]=[CH:27][CH:28]=3)=[O:22])[C:11]([NH:12][CH:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)=[C:6]2[CH:5]=[N:4]1)[CH3:2].C(O)(C(F)(F)F)=O>C1COCC1>[CH2:1]([N:3]1[C:7]2=[N:8][C:9]([CH2:61][CH3:62])=[C:10]([CH2:19][NH:20][C:21]([C:23]3[CH:28]=[CH:27][CH:26]=[C:25]([C:29]([NH:31][CH2:32][C:33]4[C:34]([F:60])=[C:35]([C:39]5[CH:44]=[CH:43][CH:42]=[C:41]([CH2:45][N:46]6[CH2:51][CH2:50][NH:49][C@@H:48]([CH3:59])[CH2:47]6)[CH:40]=5)[CH:36]=[CH:37][CH:38]=4)=[O:30])[CH:24]=3)=[O:22])[C:11]([NH:12][CH:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)=[C:6]2[CH:5]=[N:4]1)[CH3:2]
Reactant: CCc1nc2c(cnn2CC)c(NC2CCOCC2)c1CNC(=O)c1cccc(C(=O)NCc2cccc(-c3cccc(CN4CCN(C(=O)OC(C)(C)C)[C@@H](C)C4)c3)c2F)c1
Solvent: C1CCOC1
Solvent: O=C(O)C(F)(F)F
Product: CCc1nc2c(cnn2CC)c(NC2CCOCC2)c1CNC(=O)c1cccc(C(=O)NCc2cccc(-c3cccc(CN4CCN[C@@H](C)C4)c3)c2F)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
283(b) The partially purified 1,1-dimethylethyl (2S)-4-[(3′-{[({3-[({[1,6-diethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridin-5-yl]methyl}amino)carbonyl]-phenyl}carbonyl)amino]methyl}-2′-fluoro-3-biphenylyl)methyl]-2-methyl-1-piperazinecarboxylate was mixed with THF (1 mL) and TFA (0.2 mL). The mixture was stirred at room temperature for 1 h. Purification was done with a Gilson HPLC using TFA conditions. The desired fraction was collected, concentrated and re-dissolved in MeOH. Filtration though an amine cartridge and solvent concentration then afforded the above named product (10 mg). LC-MS m/z 747 (M+H)+.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][NH:4][C:5](=[O:11])[O:6][C:7]([CH3:10])([CH3:9])[CH3:8].C(N(CC)CC)C.[C:19]([C:21]1[CH:22]=[C:23]([S:27](Cl)(=[O:29])=[O:28])[CH:24]=[CH:25][CH:26]=1)#[N:20]>O1CCOCC1>[C:19]([C:21]1[CH:22]=[C:23]([S:27]([NH:1][CH2:2][CH2:3][NH:4][C:5](=[O:11])[O:6][C:7]([CH3:8])([CH3:10])[CH3:9])(=[O:29])=[O:28])[CH:24]=[CH:25][CH:26]=1)#[N:20]
Reactant: N#Cc1cccc(S(=O)(=O)Cl)c1
Reactant: CC(C)(C)OC(=O)NCCN
Solvent: C1COCCO1
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)NCCNS(=O)(=O)c1cccc(C#N)c1
Reaction time: 8 h
Yield: 100 %

Procedure:
To a stirring mixture consisting of tert-butyl 2-aminoethylcarbamate (Sigma-Aldrich, 832 mg), triethylamine (1.44 mL), and 1,4-dioxane (25 mL) was added 3-cyanobenzene-1-sulfonyl chloride (Compound 14, Sigma-Aldrich, 942 mg) and the mixture was stirred overnight. The solvent was removed under reduced pressure and the residue was partitioned between ethyl acetate and 5% aqueous potassium hydrogen sulfate. The organic phase was washed with brine, dried over magnesium sulfate, filtered, and concentrated under reduced pressure to afford the title intermediate (1.52 g), which was carried on without further purification.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH2:8][NH:9][C:10](=[O:15])[C:11]([F:14])([F:13])[F:12])[CH:5]=[CH:6][CH:7]=1.Cl[C:17]1[N:22]=[C:21]([C:23]2[C:24]([C:32]3[CH:33]=[C:34]([NH:38][C:39](=[O:46])[CH2:40][C:41]4[CH:45]=[CH:44][S:43][CH:42]=4)[CH:35]=[CH:36][CH:37]=3)=[N:25][N:26]3[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=23)[CH:20]=[CH:19][N:18]=1>CC(O)C.Cl.C(Cl)Cl>[F:14][C:11]([F:12])([F:13])[C:10]([NH:9][CH2:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([NH:1][C:17]2[N:22]=[C:21]([C:23]3[C:24]([C:32]4[CH:37]=[CH:36][CH:35]=[C:34]([NH:38][C:39](=[O:46])[CH2:40][C:41]5[CH:45]=[CH:44][S:43][CH:42]=5)[CH:33]=4)=[N:25][N:26]4[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=34)[CH:20]=[CH:19][N:18]=2)[CH:3]=1)=[O:15]
Reactant: Nc1cccc(CNC(=O)C(F)(F)F)c1
Reactant: O=C(Cc1ccsc1)Nc1cccc(-c2nn3ccccc3c2-c2ccnc(Cl)n2)c1
Agent: Cl
Solvent: ClCCl
Solvent: CC(C)O
Product: O=C(Cc1ccsc1)Nc1cccc(-c2nn3ccccc3c2-c2ccnc(Nc3cccc(CNC(=O)C(F)(F)F)c3)n2)c1
Temperature: 80 °C
Reaction time: 8 h
Yield: 53 %

Procedure:
A suspension of N-[(3-aminophenyl)methyl]-2,2,2-trifluoroacetamide (73 mg, 0.34 mmol) and N-{3-[3-(2-chloro-4-pyrimidinyl)pyrazolo[1,5-a]pyridin-2-yl]phenyl}-2-(3-thienyl)acetamide (120 mg, 0.27 mmol) in i-PrOH (4 mL) was acidified with 3 drops of 12 N HCl and stirred at 80° C. overnight. After 16 h, the reaction mixture was diluted with DCM, washed with saturated aqueous NaHCO3, dried over Na2SO4, and adsorbed onto silica gel. The crude product was purified by column chromatography to generate the title compound in 53% yield. 1H NMR (400 MHz, d6-DMSO) δ 10.28 (s, 1H), 9.98 (t, 1H), 9.63 (s, 1H), 8.83 (d, J=6.9 Hz, 1H), 8.52 (d, J=9.0 Hz, 1H), 8.24 (d, J=5.1 Hz, 1H), 7.90 (s, 1H), 7.63 (s, 1H), 7.75 (d, J=9.0 Hz, 1H), 7.71 (s, 1H), 7.67 (d, J=8.2 Hz, 1H), 7.47-7.49 (m, 2H), 7.42 (t, J=7.9 Hz, 1H), 7.32 (d, J=2.2 Hz, 1H), 7.26 (d, J=9.1 Hz, 1H), 7.22 (d, J=7.9 Hz, 1H), 7.08-7.13 (m, 2H), 6.85 (d, J=7.7 Hz, 1H), 6.51 (d, J=5.1 Hz, 1H), 4.35 (d, J=5.9 Hz, 2H), 3.66 (s, 2H). ES-LC/MS m/z=628 [M+H]+.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][N:5]=[C:4]([NH:8][C:9]2[N:10]=[CH:11][C:12]([C:15]#[N:16])=[N:13][CH:14]=2)[CH:3]=1.[NH2:17][CH2:18][CH:19]1[CH2:24][CH2:23][O:22][CH2:21][CH2:20]1.C(N(CC)CC)C>CC#N>[O:22]1[CH2:23][CH2:24][CH:19]([CH2:18][NH:17][C:2]2[N:7]=[CH:6][N:5]=[C:4]([NH:8][C:9]3[N:10]=[CH:11][C:12]([C:15]#[N:16])=[N:13][CH:14]=3)[CH:3]=2)[CH2:20][CH2:21]1
Reactant: N#Cc1cnc(Nc2cc(Cl)ncn2)cn1
Reactant: NCC1CCOCC1
Solvent: CCN(CC)CC
Solvent: CC#N
Product: N#Cc1cnc(Nc2cc(NCC3CCOCC3)ncn2)cn1
Yield: 41.1 %

Procedure:
A solution of 5-(6-chloropyrimidin-4-ylamino)pyrazine-2-carbonitrile (20 mg, 0.086 mmol), 4-(aminomethyl)tetrahydropyran (18 mg, 0.17 mmol), and triethylamine (0.02 mL, 0.13 mmol) in MeCN (0.2 mL) was heated to 145° C. for 30 minutes by microwave irradiation. The mixture was cooled and solvent was removed by evaporation. The crude material was redissolved in a mixture of dichloromethane (89%), MeOH (10%), 0.88 s.g. NH3 (1%) and adsorbed onto a solvent-conditioned Trikonex silica chromatography column. Elution with the same solvent mixture gave 5-(6-((tetrahydro-2H-pyran-4-yl)methylamino)pyrimidin-4-ylamino)pyrazine-2-carbonitrile as a yellow powder (11 mg, 41%).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([NH:8][C:9](=[O:28])[CH2:10][C:11]2[CH:16]=[CH:15][C:14]([O:17][C:18]3[CH:23]=[CH:22][C:21]([N+:24]([O-:26])=[O:25])=[C:20]([OH:27])[CH:19]=3)=[CH:13][CH:12]=2)=[N:6][CH:7]=1.[CH3:29][O:30][C:31]1[CH:36]=[CH:35][C:34](B(O)O)=[CH:33][CH:32]=1>>[CH3:29][O:30][C:31]1[CH:36]=[CH:35][C:34]([C:2]2[CH:3]=[CH:4][C:5]([NH:8][C:9](=[O:28])[CH2:10][C:11]3[CH:16]=[CH:15][C:14]([O:17][C:18]4[CH:23]=[CH:22][C:21]([N+:24]([O-:26])=[O:25])=[C:20]([OH:27])[CH:19]=4)=[CH:13][CH:12]=3)=[N:6][CH:7]=2)=[CH:33][CH:32]=1
Reactant: O=C(Cc1ccc(Oc2ccc([N+](=O)[O-])c(O)c2)cc1)Nc1ccc(Br)cn1
Reactant: COc1ccc(B(O)O)cc1
Product: COc1ccc(-c2ccc(NC(=O)Cc3ccc(Oc4ccc([N+](=O)[O-])c(O)c4)cc3)nc2)cc1
Yield: 45 %

Procedure:
The resin-bound N-(5-bromo-pyridin-2-yl)-2-[4-(3-hydroxy-4-nitro-phenoxy)-phenyl]-acetamide (120 mg, 0.1 mmol) was reacted with 4-methoxy-phenyl boronic acid (45 mg, 0.3 mmol) as described in example 208 to afford 21.2 mg (45%) of the title compound.
Reaction SMILES: [CH2:1]1[C:3]2([CH2:8][CH2:7][CH2:6][C:5](=[O:9])[CH2:4]2)[CH2:2]1.[Li+].[CH3:11][Si]([N-][Si](C)(C)C)(C)C.IC>C1COCC1>[CH3:11][CH:6]1[CH2:7][CH2:8][C:3]2([CH2:2][CH2:1]2)[CH2:4][C:5]1=[O:9]
Reactant: C[Si](C)(C)[N-][Si](C)(C)C
Reactant: O=C1CCCC2(CC2)C1
Agent: [Li+]
Solvent: CI
Solvent: C1CCOC1
Product: CC1CCC2(CC2)CC1=O
Temperature: -75 °C
Reaction time: 1 h
Yield: 35 %

Procedure:
Spiro[2.5]octan-5-one (2.4 g, 19.32 mmol) was dissolved in THF (100 mL) and cooled to −75° C. At that temperature LHMDS 1M in THF (24 mL, 24 mmol) was added dropwise over 15 minutes. The resulting pale yellow solution was stirred 1 hour at −75° C. Iodomethane (1.3 mL, 21.26 mmol) was added and stirring was continued at −75° C. for another hour before letting the mixture warm up to RT. The reaction was quenched by addition of saturated aqueous NH4Cl. The layers were separated and the aqueous layer was extracted with Et2O. The combined organic layers were washed with brine, dried (Na2SO4), filtered and evaporated. The remaining yellow oil was purified by SiO2 chromatography (330 g SiO2, hexanes/EtOAc 0 to 3% EtOAc) to give 0.93 g of racemic 6-methyl-spiro[2.5]octan-5-one as a colorless liquid (35% yield).
Reaction SMILES: [CH3:1][N:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([NH:14][C:15]([C:17]3[S:21][C:20]4[CH2:22][CH2:23][CH2:24][CH2:25][C:19]=4[CH:18]=3)=[O:16])[C:9]=2[CH3:26])[N:5]=[C:4]([O-])[C:3]1=[O:28].[Na+].P(Br)(Br)([Br:32])=O.CN(C)C=O.C(=O)([O-])[O-].[K+].[K+]>C(Cl)Cl>[Br:32][C:4]1[C:3](=[O:28])[N:2]([CH3:1])[CH:7]=[C:6]([C:8]2[C:9]([CH3:26])=[C:10]([NH:14][C:15]([C:17]3[S:21][C:20]4[CH2:22][CH2:23][CH2:24][CH2:25][C:19]=4[CH:18]=3)=[O:16])[CH:11]=[CH:12][CH:13]=2)[N:5]=1
Reactant: Cc1c(NC(=O)c2cc3c(s2)CCCC3)cccc1-c1cn(C)c(=O)c([O-])n1
Reactant: O=P(Br)(Br)Br
Agent: O=C([O-])[O-]
Agent: [K+]
Agent: [Na+]
Solvent: ClCCl
Solvent: CN(C)C=O
Product: Cc1c(NC(=O)c2cc3c(s2)CCCC3)cccc1-c1cn(C)c(=O)c(Br)n1
Yield: 49.9 %

Procedure:
A 250-mL single-neck round-bottomed flask equipped with a magnetic stirrer and reflux condenser was purged with nitrogen and charged with 10 (6.55 g, 15.7 mmol) and anhydrous methylene chloride (60 mL). To the resulting suspension phosphorous oxybromide (9.95 g, 34.3 mmol) and N,N-dimethylformamide (190 mg, 2.60 mmol) were added and the reaction was then heated at reflux for 4 h. After this time the reaction mixture was poured into a 10% aqueous potassium carbonate solution (100 mL) and methylene chloride (75 mL) was added. The resulting suspension was filtered through. Celite 521 and the layers separated. The aqueous layer was extracted with methylene chloride (2×100 mL) and the combined organic layers were dried over sodium sulfate, filtered and concentrated under reduced pressure. The resulting residue was triturated with a 2:1 solution of ethyl acetate/hexanes (10 mL) and filtered. The filter cake was washed with the 2:1 ethyl acetate/hexanes solution (20 mL) and dried to a constant weight under vacuum to afford a 50% yield (3.59 g) of 11 as a light yellow solid: mp 240-241° C., 1H NMR (500 MHz, DMSO-d6) δ 9.86 (s, 1H), 7.98 (s, 1H), 7.67 (s, 1H), 7.28 (m, 3H), 3.57 (s, 3H), 2.76 (t, 2H, J=5.5 Hz), 2.61 (t, 2H, J=5.5 Hz), 2.18 (s, 3H), 1.76 (m, 4H); MS (ESI+) m/z 458 (M+H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C@H:9]2[N:14](C(OC(C)(C)C)=O)[C:13](=[O:22])[C:12]([CH2:25][CH3:26])([CH2:23][CH3:24])[CH2:11][CH2:10]2)[CH:5]=[C:6]([F:8])[CH:7]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[F:1][C:2]1[CH:3]=[C:4]([C@H:9]2[NH:14][C:13](=[O:22])[C:12]([CH2:25][CH3:26])([CH2:23][CH3:24])[CH2:11][CH2:10]2)[CH:5]=[C:6]([F:8])[CH:7]=1
Reactant: CCC1(CC)CC[C@@H](c2cc(F)cc(F)c2)N(C(=O)OC(C)(C)C)C1=O
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCC1(CC)CC[C@@H](c2cc(F)cc(F)c2)NC1=O
Reaction time: 1.5 h

Procedure:
To a solution of tert-butyl (6S)-6-(3,5-difluorophenyl)-3,3-diethylpiperidin-2-one-1-carboxylate from Step D (1.22 g, 3.32 mmol) in CH2Cl2 (7 mL) at ambient temperature was added TFA (3 mL). After stirring for 1.5 h, the reaction mixture was concentrated in vacuo. The residue was partitioned between CH2Cl2 (30 mL) and saturated NaHCO3 (30 mL). The layers were separated and the aqueous layer was further extracted with CH2Cl2 (2×30 mL). The combined organics were dried over sodium sulfate, filtered and then concentrated in vacuo to provide the title compound, which could be used without further purification. MS: m/z=268 (M+1).
Reaction SMILES: Cl.[N:2]1([CH:7]2[CH2:12][CH2:11][N:10]([CH2:13][C:14]([OH:16])=O)[CH2:9][CH2:8]2)[CH2:6][CH2:5][CH2:4][CH2:3]1.[NH2:17][C@@H:18]([CH2:36][O:37][CH2:38][C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1)[C:19]([NH:21][C:22]1[CH:27]=[CH:26][C:25]([O:28][C:29]2[CH:34]=[CH:33][C:32]([F:35])=[CH:31][CH:30]=2)=[CH:24][CH:23]=1)=[O:20]>>[CH2:38]([O:37][CH2:36][C@H:18]([NH:17][C:14](=[O:16])[CH2:13][N:10]1[CH2:9][CH2:8][CH:7]([N:2]2[CH2:3][CH2:4][CH2:5][CH2:6]2)[CH2:12][CH2:11]1)[C:19]([NH:21][C:22]1[CH:27]=[CH:26][C:25]([O:28][C:29]2[CH:34]=[CH:33][C:32]([F:35])=[CH:31][CH:30]=2)=[CH:24][CH:23]=1)=[O:20])[C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1
Reactant: O=C(O)CN1CCC(N2CCCC2)CC1
Reactant: N[C@@H](COCc1ccccc1)C(=O)Nc1ccc(Oc2ccc(F)cc2)cc1
Agent: Cl
Product: O=C(CN1CCC(N2CCCC2)CC1)N[C@@H](COCc1ccccc1)C(=O)Nc1ccc(Oc2ccc(F)cc2)cc1
Yield: 48.1 %

Procedure:
Proceeding as in Example 1, but substituting 2-(4-(pyrrolidin-1-yl)piperidin-1-yl)acetic acid hydrochloride and (S)-2-amino-3-(benzyloxy)-N-(4-(4-fluorophenoxy)phenyl)propanamide, gave Compound 43, (S)-3-(benzyloxy)-N-(4-(4-fluorophenoxy)phenyl)-2-(2-(4-(pyrrolidin-1-yl)piperidin-1-yl)acetamido)propanamide (22.1 mg, 48.1%). 1H-NMR (400 MHz, DMSO-D6): σ 10.22 (s, 1H), 7.96 (d, 1H), 7.59 (d, 2H), 7.30 (m, 5H), 7.21 (m, 2H), 7.01 (m, 4H), 4.68 (m, 1H), 4.52 (s, 2H), 3.75 (m, 2H), 3.25 (m, 2H), 2.95 (s, 2H), 2.83 (m, 2H), 2.09 (t, 2H), 2.00 (m, 1H), 1.79 (m, 2H), 1.68 (m, 5H), 1.44 (m, 2H). MS (EI) for C33H39FN4O4: 575.8 (MH+).
Reaction SMILES: [CH:1]([C@@H:3]1[C@@H:7]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH2:6][N:5]([C@H:14]([CH2:27][CH:28]2[CH2:31][CH2:30][CH2:29]2)[C:15]([O:17][CH2:18][C:19]2[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=2)=[O:16])[CH2:4]1)=O.[F:32][C:33]1[CH:34]=[C:35]([CH2:40][CH2:41][CH2:42][CH:43]2[CH2:48][CH2:47][NH:46][CH2:45][CH2:44]2)[CH:36]=[C:37]([F:39])[CH:38]=1.Cl>>[F:32][C:33]1[CH:34]=[C:35]([CH2:40][CH2:41][CH2:42][CH:43]2[CH2:44][CH2:45][N:46]([CH2:1][C@@H:3]3[C@@H:7]([C:8]4[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=4)[CH2:6][N:5]([C@H:14]([CH2:27][CH:28]4[CH2:29][CH2:30][CH2:31]4)[C:15]([O:17][CH2:18][C:19]4[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=4)=[O:16])[CH2:4]3)[CH2:47][CH2:48]2)[CH:36]=[C:37]([F:39])[CH:38]=1
Reactant: Fc1cc(F)cc(CCCC2CCNCC2)c1
Reactant: COc1ccc(COC(=O)[C@@H](CC2CCC2)N2C[C@H](c3ccccc3)[C@@H](C=O)C2)cc1
Agent: Cl
Product: COc1ccc(COC(=O)[C@@H](CC2CCC2)N2C[C@H](CN3CCC(CCCc4cc(F)cc(F)c4)CC3)[C@@H](c3ccccc3)C2)cc1
Yield: 59.7 %

Procedure:
The title compound was prepared from 19 mg (0.04 mmol) of 2-(R)-(3-(R)-formyl-4-(S)-phenylpyrrolidin-1-yl)-3-(cyclobutyl)propanoic acid, (4-methoxy)benzyl ester (from EXAMPLE 19, Step F) and 12.5 mg (0.04 mmol) of 4-(3-(3,5-difluorophenyl)propyl)piperidine.HCl (from EXAMPLE 95, Step E) using a procedure analogous to that described in EXAMPLE 1, Step J to provide 15.4 mg (53%) of the title compound: RF: 0.40 (1:1 v/v hexanes/EtOAc); 1H NMR (300 MHz) δ 1.04-3.27 (m, 33H), 3.80 (s, 3H), 5.04-5.13 (m, 2H), 6.57-6.69 (m, 21), 6.87 (d, J 8.8, 2H), 7.14-7.33 (m, 8H).
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][CH2:3][C:2]1=[O:6].I[C:8]1[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[CH:10][CH:9]=1.C(=O)([O-])[O-].[K+].[K+]>[Cu]>[CH3:15][O:14][C:11]1[CH:12]=[CH:13][C:8]([N:1]2[CH2:5][CH2:4][CH2:3][C:2]2=[O:6])=[CH:9][CH:10]=1
Reactant: COc1ccc(I)cc1
Reactant: O=C1CCCN1
Agent: [Cu]
Agent: O=C([O-])[O-]
Agent: [K+]
Product: COc1ccc(N2CCCC2=O)cc1

Procedure:
In step a of the overall synthesis, 2-pyrrolidinone and 4-iodoanisole are heated in the presence of copper powder and potassium carbonate to give the N-(4-methoxyphenyl)pyrrolidin-2-one, which in step b is treated with ethylmagnesium bromide Grignard reagent to give an aliphatic ketone after ring opening of the pyrrolidinone. This ketone is isolated and then undergoes ring closure to form the 3-hydroxy-1,2,5,6-tetrahydropyridin-2-one intermediate in steps c and d using ethyl oxalyl chloride and sodium hydroxide in step c and sodium ethoxide and ethanol in step d. The corresponding 3-methoxy intermediate is obtained in step e by treatment with 3-methyl-p-tolyltriazine, after which in step f the 4,5,6,7-tetrahydro-7-oxo-1H-pyrazolo[3,4-c]pyridine intermediate is obtained by ring closure using cyclopentyl hydrazine hydrochloride. The 4-methoxyphenyl N-protecting group is removed in step g by treatment with cerium (IV) ammonium nitrate to give the lactam intermediate, after which in step h the lactam intermediate is converted to the corresponding thiolactam intermediate by treatment with phosphorus pentasulfide. The tricyclic final product is prepared in steps i′, j and k by treatment with anhydrous hydrazine in step i, followed by treatment with 2-thiophene carbonyl chloride in step j and refluxing in step k.